article dict | reports listlengths 1 3.97k |
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{
"abstract": "Reinduction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (HDCT + ASCT) is second-line standard of care for transplant-eligible patients with relapsed/refractory classical Hodgkin lymphoma (r/r cHL) but has a high failure rate. Because response to reinduction is predictive of the outcome after HDCT + ASCT, we aimed to improve the standard dexamethasone, high-dose cytarabine and cisplatinum (DHAP) reinduction regimen by addition of the oral mammalian target of rapamycin inhibitor everolimus (everDHAP). Transplant-eligible patients aged 18-60 years with histologically confirmed r/r cHL were included in this experimental phase I/II trial. Everolimus (10 mg/day, determined in phase-I-part) was administered on day 0-13 of each DHAP cycle. From July 2014 to March 2018, 50 patients were recruited to the phase II everDHAP group; two were not evaluable, three discontinued due to toxicity. Randomization to a placebo group stopped in October 2015 due to poor recruitment after nine patients. The primary end-point of computed tomography (CT)-based complete remission (CR) after two cycles of everDHAP was expected to be ≥40%. With a CT-based CR rate of 27% (n = 12/45) after two cycles of everDHAP the trial did not meet the primary end-point. Adding everolimus to DHAP is thus feasible; however, the everDHAP regimen failed to show an improved efficacy.",
"affiliations": "German Hodgkin Study Group (GHSG), Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.;Department of Hematology and Stem Cell Transplantation and Cancer Center Cologne Essen - Partner Site Essen, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.;Department of Hematology and Oncology, University of Leipzig, Leipzig, Germany.;German Hodgkin Study Group (GHSG), Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.;German Hodgkin Study Group (GHSG), Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.;Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.;Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.;German Hodgkin Study Group (GHSG), Department of Nuclear Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.;German Hodgkin Study Group (GHSG), Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.;German Hodgkin Study Group (GHSG), Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.;German Hodgkin Study Group (GHSG), Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.;Institute for Medical Statistics, Informatics and Epidemiology (IMSIE), University Hospital of Cologne, University of Cologne, Cologne, Germany.;Department of Hematology and Stem Cell Transplantation and Cancer Center Cologne Essen - Partner Site Essen, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.;German Hodgkin Study Group (GHSG), Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.;German Hodgkin Study Group (GHSG), Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.;Cancer Center Cologne Essen - Partner Site Cologne, CIO Cologne, University of Cologne, Cologne, Germany.;German Hodgkin Study Group (GHSG), Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.;German Hodgkin Study Group (GHSG), Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.;German Hodgkin Study Group (GHSG), Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.;German Hodgkin Study Group (GHSG), Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.",
"authors": "Gillessen|Sarah|S|https://orcid.org/0000-0003-3114-3787;Hüttmann|Andreas|A|https://orcid.org/0000-0003-2230-3873;Vucinic|Vladan|V|;Müller|Horst|H|;Plütschow|Annette|A|;Viardot|Andreas|A|;Topp|Max S|MS|;Kobe|Carsten|C|;Böll|Boris|B|https://orcid.org/0000-0002-6432-0981;Eichenauer|Dennis A|DA|https://orcid.org/0000-0002-1927-3514;Sasse|Stephanie|S|;Haverkamp|Heinz|H|;Schmitz|Christine|C|;Borchmann|Sven|S|https://orcid.org/0000-0001-6662-6864;Bröckelmann|Paul J|PJ|;Heger|Jan-Michel|JM|;Fuchs|Michael|M|;Engert|Andreas|A|;Borchmann|Peter|P|;von Tresckow|Bastian|B|https://orcid.org/0000-0003-1410-4487",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bjh.17878",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": null,
"journal": "British journal of haematology",
"keywords": "Hodgkin lymphoma; everolimus; reinduction; relapse; salvage",
"medline_ta": "Br J Haematol",
"mesh_terms": null,
"nlm_unique_id": "0372544",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34775591",
"pubdate": "2021-11-14",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Reinduction therapy with everolimus in combination with dexamethasone, high-dose cytarabin and cisplatinum in patients with relapsed or refractory classical Hodgkin lymphoma: an experimental phase I/II multicentre trial of the German Hodgkin Study Group (GHSG HD-R3i).",
"title_normalized": "reinduction therapy with everolimus in combination with dexamethasone high dose cytarabin and cisplatinum in patients with relapsed or refractory classical hodgkin lymphoma an experimental phase i ii multicentre trial of the german hodgkin study group ghsg hd r3i"
} | [
{
"companynumb": "DE-NOVARTISPH-NVSC2021DE262860",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null... |
{
"abstract": "A 51-year-old woman presented with a 2-week history of off balance, left lower limb weakness and neglect and neck pain radiating down the right arm. Investigations revealed a metastatic, ROS1 fusion-positive, non-small cell lung cancer, and treatment with entrectinib, a recently approved multikinase inhibitor, was started. Two weeks after, she was admitted to the emergency department with new-onset pressure-like chest pain and dyspnoea. Laboratory evaluation showed elevated troponin and mild left ventricular systolic dysfunction with reduced global longitudinal strain on transthoracic echocardiogram. Cardiac magnetic resonance revealed mild oedema and non-ischaemic fibrosis. A diagnosis of drug-induced myocarditis was made. Cardioprotective medication with an angiotensin-converting enzyme inhibitor and a beta-blocker was started. Entrectinib was temporarily discontinued and restarted at a reduced dose after a multidisciplinary team meeting involving both the oncology and cardio-oncology teams. This is the second described case of entrectinib-induced myocarditis and the first one without eosinophilia.",
"affiliations": "Saint Bartholomew's Hospital Barts Heart Centre, London, UK ms.ferreira.fonseca@gmail.com.;Saint Bartholomew's Hospital Barts Heart Centre, London, UK.;Hatter Cardiovascular Institute, Hatter Institute, London, UK.;Saint Bartholomew's Hospital Barts Heart Centre, London, UK.",
"authors": "Fonseca|Marta|M|http://orcid.org/0000-0002-7656-0237;Chen|Daniel H|DH|;Walker|John Malcolm|JM|;Ghosh|Arjun K|AK|",
"chemical_list": "D001549:Benzamides; D007191:Indazoles; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C000607349:entrectinib",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-243946",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "cancer - see oncology; cardiovascular medicine; chemotherapy; lung cancer (oncology); unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001549:Benzamides; D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D006801:Humans; D007191:Indazoles; D008175:Lung Neoplasms; D008875:Middle Aged; D009205:Myocarditis; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34315748",
"pubdate": "2021-07-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Entrectinib-related myocarditis in a young female patient with metastatic non-small cell lung cancer.",
"title_normalized": "entrectinib related myocarditis in a young female patient with metastatic non small cell lung cancer"
} | [
{
"companynumb": "GB-ROCHE-2884562",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ENTRECTINIB"
},
"drugadditional": "1",
"drug... |
{
"abstract": "We present three patients with azathioprine-induced Sweet's syndrome (AISS) who attended our tertiary institution within a 12-month period. Established associations exist between Sweet's syndrome and some medications; however, to date links to azathioprine are tentative. While there are case reports of AISS, most have occurred in patients with inflammatory bowel disease (IBD), an underlying predisposition for Sweet's syndrome. Our case series adds to the evidence that the entity of AISS truly exists independent of confounding factors such as concurrent IBD.",
"affiliations": "Department of Dermatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.;SA Pathology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.;Department of Dermatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.",
"authors": "McNally|Ashling|A|;Ibbetson|Jan|J|;Sidhu|Shireen|S|",
"chemical_list": "D007166:Immunosuppressive Agents; D001379:Azathioprine",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajd.12383",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-8380",
"issue": "58(1)",
"journal": "The Australasian journal of dermatology",
"keywords": "Sweet's syndrome; acute febrile neutrophilic dermatosis; azathioprine; azathioprine hypersensitivity syndrome; drug-induced Sweet's syndrome",
"medline_ta": "Australas J Dermatol",
"mesh_terms": "D000368:Aged; D001379:Azathioprine; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D016463:Sweet Syndrome",
"nlm_unique_id": "0135232",
"other_id": null,
"pages": "53-57",
"pmc": null,
"pmid": "26299606",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Azathioprine-induced Sweet's syndrome: A case series and review of the literature.",
"title_normalized": "azathioprine induced sweet s syndrome a case series and review of the literature"
} | [
{
"companynumb": "GB-CASPER PHARMA LLC-2021CAS000186",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "... |
{
"abstract": "Finite clinical data and understanding of COVID-19 immunopathology has led to limited, opinion-based recommendations for the management of patients with immune-mediated inflammatory disease (IMID) receiving immunosuppressive (IS) therapeutics.\n\n\n\nTo determine if IS therapeutic type affects COVID-19 risk among patients with IMID.\n\n\n\nWe conducted a retrospective cohort analysis of Henry Ford Health System patients tested for COVID-19 between February 1 and April 18, 2020, treated with IS medication for IMID. Therapeutic class of IS medication, comorbidities, and demographic factors were combined into multivariate models to determine predictors of COVID-19 infection, admission, ventilation, and mortality.\n\n\n\nOf 213 patients with IMID, 36.2% tested positive for COVID-19, and they had no greater odds of being hospitalized or requiring ventilation relative to the general population. No IS therapeutic worsened the course of disease after multivariate correction, although multidrug regimens and biologics predicted an increased and decreased rate of hospitalization, respectively, with the latter driven by tumor necrosis factor α inhibitors.\n\n\n\nA single-center study somewhat limits the generalization to community-based settings. Only patients tested for COVID-19 were analyzed.\n\n\n\nIS therapies for IMIDs are not associated with a significantly greater risk of SARS-CoV-2 or severe sequelae when controlling for other factors, and tumor necrosis factor α inhibitors may decrease the odds of severe infection.",
"affiliations": "Department of Dermatology, Henry Ford Health System, Detroit, Michigan. Electronic address: jjveenst1@gmail.com.;Wayne State University School of Medicine, Detroit, Michigan.;Department of Dermatology, Henry Ford Health System, Detroit, Michigan.;Department of Dermatology, Henry Ford Health System, Detroit, Michigan.;Wayne State University School of Medicine, Detroit, Michigan.;Wayne State University School of Medicine, Detroit, Michigan.;Wayne State University School of Medicine, Detroit, Michigan.;Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan.;Department of Dermatology, Henry Ford Health System, Detroit, Michigan.;Department of Dermatology, Henry Ford Health System, Detroit, Michigan.",
"authors": "Veenstra|Jesse|J|;Buechler|Connor R|CR|;Robinson|Gabrielle|G|;Chapman|Stephanie|S|;Adelman|Madeline|M|;Tisack|Aaron|A|;Dimitrion|Peter|P|;Todter|Erika|E|;Kohen|Laurie|L|;Lim|Henry W|HW|",
"chemical_list": "D007166:Immunosuppressive Agents; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaad.2020.07.089",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-9622",
"issue": "83(6)",
"journal": "Journal of the American Academy of Dermatology",
"keywords": "COVID-19; DMARDs; SARS-CoV-2; autoimmune disease; biologics; coronavirus; immune-mediated inflammatory diseases; immunosuppression",
"medline_ta": "J Am Acad Dermatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D001327:Autoimmune Diseases; D000073640:Betacoronavirus; D000086382:COVID-19; D000086742:COVID-19 Testing; D019411:Clinical Laboratory Techniques; D018352:Coronavirus Infections; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D012189:Retrospective Studies; D018570:Risk Assessment; D000086402:SARS-CoV-2; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "7907132",
"other_id": null,
"pages": "1696-1703",
"pmc": null,
"pmid": "32735965",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": "32278362;32171074;32518921;32066541;32471903;32348641;32217650;32202064;32191143;32199889;32358580;32345594;32224277;32300516;32247631;32296135;32222883;32196933;32291112;25135860;32241793;11536154;32330632",
"title": "Antecedent immunosuppressive therapy for immune-mediated inflammatory diseases in the setting of a COVID-19 outbreak.",
"title_normalized": "antecedent immunosuppressive therapy for immune mediated inflammatory diseases in the setting of a covid 19 outbreak"
} | [
{
"companynumb": "US-AMGEN-USASP2021050229",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nInvasive fungal infections (IFI) represent a common side effect of allogeneic hematopoietic stem cell transplant (allo-SCT), resulting in increased non relapse mortality (NRM) and reduced overall survival (OS) rates. Seventy-five days of Fluconazole 400 mg/d represents the standard primary antifungal prophylaxis (PAP) after allo-SCT, especially for low-risk transplants. However, the ideal dosage of fluconazole has never been tested.\n\n\nMETHODS\nHere, we report the experience of our institution on 113 consecutive patients receiving an allo-SCT from a HLA identical sibling between 1999 and 2015, where PAP consisted of fluconazole 100 mg/d only during the pre-engraftment phase. At the time of transplant, all patients were considered at low-risk for mold infection according to ECIL-5 guidelines.\n\n\nRESULTS\nCumulative incidence of possible-probable-proven IFI was 11.7%, while proven-probable (PP-IFI) occurred in 5.5% of patients by day 100 post transplant. Of note, only 1 patient developed invasive Candidiasis due to a non-albicans strain and stool-screening tests were negative for colonization by Candida albicans species. The incidence of 1-year acute and 2-year chronic graft-versus-host-disease (GVHD) was 30% and 45%, respectively. Three-year OS and 1-year NRM were 53% and 11.3%, respectively.\n\n\nCONCLUSIONS\nIn summary, fungal prophylaxis with fluconazole 100 mg/d results in very low incidence of PP-IFI, GVHD and NRM in low-risk allo-SCT.",
"affiliations": "Bone Marrow Unit, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy.;Bone Marrow Unit, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy.;Bone Marrow Unit, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy.;Bone Marrow Unit, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy.;Bone Marrow Unit, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy.;Bone Marrow Unit, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy.;Infectious Diseases Unit, Hospital Health Direction, IRCCS Istituto Clinico Humanitas, Rozzano, Italy.;Infectious Diseases Unit, Hospital Health Direction, IRCCS Istituto Clinico Humanitas, Rozzano, Italy.;Infectious Diseases Unit, Hospital Health Direction, IRCCS Istituto Clinico Humanitas, Rozzano, Italy.;Bone Marrow Unit, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy.;Hematology Department, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy.;Hematology Department, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy.;Bone Marrow Unit, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy.",
"authors": "Sarina|Barbara|B|;Mariotti|Jacopo|J|http://orcid.org/0000-0001-6528-9296;Bramanti|Stefania|S|;Morabito|Lucio|L|;Crocchiolo|Roberto|R|;Rimondo|Andrea|A|;Tordato|Federica|F|;Pocaterra|Daria|D|;Casari|Erminia|E|;De Philippis|Chiara|C|;Carlo-Stella|Carmelo|C|;Santoro|Armando|A|;Castagna|Luca|L|",
"chemical_list": "D000935:Antifungal Agents; D006680:HLA Antigens; D015725:Fluconazole",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12906",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "20(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "allogeneic stem cell transplant; fluconazole; primary antifungal prophylaxis",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D019072:Antibiotic Prophylaxis; D000935:Antifungal Agents; D004305:Dose-Response Relationship, Drug; D005260:Female; D015725:Fluconazole; D005500:Follow-Up Studies; D006086:Graft vs Host Disease; D006680:HLA Antigens; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015994:Incidence; D000072742:Invasive Fungal Infections; D019520:Living Donors; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D035781:Siblings; D015996:Survival Rate; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e12906",
"pmc": null,
"pmid": "29668124",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A reduced dose of fluconazole as primary antifungal prophylaxis is not associated with increased risk of invasive fungal infections after allogeneic stem cell transplantation from a HLA identical sibling.",
"title_normalized": "a reduced dose of fluconazole as primary antifungal prophylaxis is not associated with increased risk of invasive fungal infections after allogeneic stem cell transplantation from a hla identical sibling"
} | [
{
"companynumb": "IT-TEVA-2018-IT-963195",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Migraine and temporomandibular disorders (TMD) are both common diseases and TMD are reported as a risk factor in migraine progression. OnabotulinumtoxinA is used in the treatment of chronic migraine (CM), and also has a potential role in TMD treatment. In this study, it is aimed to compare the efficacy of onabotulinumtoxinA treatment in CM patients with and without TMD.\n\n\n\nIn this retrospective study, 30 CM patients (age range: 18-65 years), satisfying the inclusion and follow-up criteria in their medical records were investigated. The PREEMPT injection protocol was taken as reference and onabotulinumtoxinA 155-195 U with fixed-dose has been administered into 31 specific sites within the head/neck muscles in included subjects. Two cycles of treatment were assessed in all patients at the baseline and 12 weeks later. The headache diaries, which were completed routinely one month before, and during 6 months follow-up after the treatment, were assessed. The effect of onabotulinumtoxinA treatment was compared between CM patients with and without TMD/bruxism.\n\n\n\nOf 30 female patients, 17 had concomitant TMD. In week 24, there were significant improvement in the groups with and without TMD regarding to the mean change of frequencies in the days with migraine compared to the initial findings (p<0.001). However, there was no significant difference between the two groups.\n\n\n\nOnabotulinumtoxinA is an effective and safe treatment for CM. Its efficacy appears to be similar in CM patients with and without TM, speculating that the comorbidity of TMD did not play a role for the treatment response.",
"affiliations": "Department of Neurology, Bezmialem Vakıf University, Faculty of Medicine, İstanbul, Turkey.;Department of Maxillofacial Surgery, İstanbul University, İstanbul Faculty of Dentistry, İstanbul, Turkey.;Department of Maxillofacial Surgery, İstanbul University, İstanbul Faculty of Dentistry, İstanbul, Turkey.;Department of Neurology, İstanbul University, İstanbul Medical Faculty, İstanbul, Turkey.;Department of Neurology, İstanbul Bilim University, Faculty of Medicine, İstanbul, Turkey.;Neurology, Private Office, İstanbul, Turkey.;Department of Neurology, İstanbul University, İstanbul Medical Faculty, İstanbul, Turkey.;Department of Neurology, İstanbul University, İstanbul Medical Faculty, İstanbul, Turkey.",
"authors": "Kocaman|Gülşen|G|;Kahraman|Neşe|N|;Köseoğlu|Banu Gürkan|BG|;Bilgiç|Başar|B|;Matur|Zeliha|Z|;Ertaş|Mustafa|M|;Gülşen|Yeşim|Y|;Baykan Baykal|Betül|B|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5152/npa.2017.19257",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1300-0667",
"issue": "55(4)",
"journal": "Noro psikiyatri arsivi",
"keywords": "Temporomandibular disorders; chronic migraine; headache; onabotulinumtoxinA",
"medline_ta": "Noro Psikiyatr Ars",
"mesh_terms": null,
"nlm_unique_id": "9426194",
"other_id": null,
"pages": "330-336",
"pmc": null,
"pmid": "30622389",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": "20647171;16945899;10759923;10425932;20647170;15613213;15330825;18071955;11188982;17607423;19464658;15613165;16946432;21368664;19751369;16677761;12887389;16686915;20164501;12887390;3465334;10685817;23117652;21883197;19586596;16002144;24694964;17441972;9260045;14979881;11112955;19704086;24080152;22830411;18711108;1298767;22875880;24171182;20487038;20664830;28360579;12603645;19004549;22246025;11239582;10759926;15007133",
"title": "Evaluation of OnabotulinumtoxinA Treatment in Patients with Concomitant Chronic Migraine and Temporomandibular Disorders.",
"title_normalized": "evaluation of onabotulinumtoxina treatment in patients with concomitant chronic migraine and temporomandibular disorders"
} | [
{
"companynumb": "TR-ALLERGAN-1900857US",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ONABOTULINUMTOXINA"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo investigate the acute effects of topiramate on the anterior chamber angle (ACA) and choroidal thickness in patients with migraine.\n\n\nMETHODS\nThis prospective study included 15 eyes of 15 patients with migraine who have been scheduled to start topiramate therapy. All patients underwent complete ophthalmic examination including measurement of the ACA and choroidal thickness using a spectral domain optical coherence tomography device (Optovue Inc.) and refractive status evaluation with an autorefractokeratometer (KR-8100; Topcon) at the baseline and 1 week after starting therapy. The patients were asked to report any pain or discomfort in their eyes during therapy at the follow-up visit.\n\n\nRESULTS\nNone of the patients experienced pain or discomfort in their eyes. The mean ACA significantly decreased at the first week of the therapy compared with the baseline levels (40.34±7.06° and 36.89±6.87°, respectively) (P=0.001). However, the mean choroidal thickness increased from 277.33±95.60 μm at the baseline to 323.40±84.50 μm at the first week (P=0.01). There was a nonsignificant increase in the mean refractive error (from -0.25±0.54 diopter [D] at the baseline to -0.38±0.49 D after 1 week) (P=0.06).\n\n\nCONCLUSIONS\nTopiramate can acutely decrease the ACA and increase the choroidal thickness. Because these effects may be asymptomatic, patients with migraine who start this therapy should be warned to be closely followed up by an ophthalmologist.",
"affiliations": "Department of Ophthalmology (A.K.), Baskent University, School of Medicine, Konya, Turkey; Department of Ophthalmology (B.E.K.), Selcuk University Faculty of Medicine, Konya, Turkey; and Department of Neurology (G.C.), Baskent University, School of Medicine, Konya, Turkey.",
"authors": "Karalezli|Aylin|A|;Koktekir|Bengu Ekinci|BE|;Celik|Guner|G|",
"chemical_list": "D018696:Neuroprotective Agents; D000077236:Topiramate; D005632:Fructose",
"country": "United States",
"delete": false,
"doi": "10.1097/ICL.0000000000000157",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-2321",
"issue": "42(2)",
"journal": "Eye & contact lens",
"keywords": null,
"medline_ta": "Eye Contact Lens",
"mesh_terms": "D000328:Adult; D000867:Anterior Chamber; D002829:Choroid; D005260:Female; D005632:Fructose; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders; D018696:Neuroprotective Agents; D010865:Pilot Projects; D011446:Prospective Studies; D012030:Refractive Errors; D041623:Tomography, Optical Coherence; D000077236:Topiramate; D014792:Visual Acuity",
"nlm_unique_id": "101160941",
"other_id": null,
"pages": "120-3",
"pmc": null,
"pmid": "26020486",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Topiramate-Induced Changes in Anterior Chamber Angle and Choroidal Thickness.",
"title_normalized": "topiramate induced changes in anterior chamber angle and choroidal thickness"
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"companynumb": "TR-JNJFOC-20160303538",
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"actiondrug": "5",
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"activesubstancename": "TOPIRAMATE"
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{
"abstract": "OBJECTIVE\nTo report a case of seizures in a patient with Alzheimer disease, who was receiving quetiapine for psychoses.\n\n\nMETHODS\nA 75-year-old white man with Alzheimer disease was observed to have seizures while receiving quetiapine 500 mg/d and carbamazepine 200 mg/d. He had been taking quetiapine for 18 months prior to the event. No other toxic, metabolic, or anatomic abnormalities were identified to explain the seizures. After cessation of quetiapine treatment, the patient remained seizure free. An objective causality assessment revealed that the adverse drug reaction was possible.\n\n\nCONCLUSIONS\nThe patient was taking a relatively high dose of quetiapine. An increased risk of seizures has been associated with Alzheimer disease. Using a relatively high dose of quetiapine may have resulted in seizures in our patient with Alzheimer disease.\n\n\nCONCLUSIONS\nAs with other antipsychotics, quetiapine should be used cautiously in elderly patients with conditions that can lower the seizure threshold, and special monitoring should be performed for this serious adverse effect.",
"affiliations": "Department of Neurology, Faculty of Medicine, Mersin University, Mersin, Turkey. okandogu@mersin.edu.tr",
"authors": "Dogu|Okan|O|;Sevim|Serhan|S|;Kaleagasi|Hakan S|HS|",
"chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate; D002220:Carbamazepine",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1C516",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "37(9)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000368:Aged; D000544:Alzheimer Disease; D014150:Antipsychotic Agents; D002220:Carbamazepine; D003987:Dibenzothiazepines; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D011618:Psychotic Disorders; D000069348:Quetiapine Fumarate; D012640:Seizures",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1224-7",
"pmc": null,
"pmid": "12921503",
"pubdate": "2003-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Seizures associated with quetiapine treatment.",
"title_normalized": "seizures associated with quetiapine treatment"
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"companynumb": "TR-MACLEODS PHARMACEUTICALS US LTD-MAC2022036257",
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"abstract": "A 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.",
"affiliations": "Department of Urology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.;Department of Urology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.;Department of Laboratory Medicine, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.;Department of Urology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.;Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.;Department of Urology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.;Department of Urology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.",
"authors": "Arai|Yuichi|Y|;Kitamura|Yosuke|Y|;Miyai|Kosuke|K|;Hatanaka|Mina|M|;Hashimoto|Hirofumi|H|;Horiguchi|Akio|A|;Ito|Keiichi|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2021.2233",
"fulltext": "\n==== Front\nMol Clin Oncol\nMol Clin Oncol\nMCO\nMolecular and Clinical Oncology\n2049-9450\n2049-9469\nD.A. Spandidos\n\nMCO-0-0-02233\n10.3892/mco.2021.2233\nArticles\nLong-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report\nArai Yuichi 1\nKitamura Yosuke 1\nMiyai Kosuke 2\nHatanaka Mina 1\nHashimoto Hirofumi 3\nHoriguchi Akio 1\nIto Keiichi 1\n1 Department of Urology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan\n2 Department of Laboratory Medicine, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan\n3 Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan\nCorrespondence to: Dr Keiichi Ito, Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan itok@ndmc.ac.jp\n4 2021\n12 2 2021\n12 2 2021\n14 4 7122 5 2020\n29 1 2021\nCopyright: © Arai et al.\n2020\nThis is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.\nA 46-year-old man underwent right partial nephrectomy for type 2 papillary renal cell carcinoma (PRCC) in 2011. Lung metastasis and lymph node (LN) metastases around the inferior vena cave appeared in 2012. A right radical nephrectomy and extensive LN dissection was performed and the resection of lung metastasis was performed one month after the nephrectomy. Mediastinal LN metastases occurred in 2013, and resection of the affected LNs was performed. Sunitinib and zoledronic acid was started in 2014 because mediastinal LN swelling and multiple bone metastases appeared. Sunitinib treatment was stopped soon after due to adverse events and axitinib treatment was started. Axitinib was effective and the patient had stable disease for 30 months. Adverse events were successfully controlled by dose reduction and periodic drug withdrawal schedules (for example, 5 days on, 2 days off). Axitinib was further continued for 19 months as the metastatic lesions had progressed slowly. Temsirolimus treatment was started in 2019, but it was stopped after three cycles due to interstitial pneumonia. The patient died 80 months after the initial recurrence. Using multidisciplinary treatment, durable disease control was achieved in a patient with metastatic type 2 PRCC.\n\ntype 2 papillary renal cell carcinoma\naxitinib\nmetastasectomy\nperiodic drug withdrawal schedule\nFunding: No funding was received.\n==== Body\nIntroductions\n\nRecently, the prognosis of patients with metastatic renal cell carcinoma (RCC) has been improved by molecular targeted therapies (1) and immune checkpoint inhibitors (2). However, optimal treatment strategies for metastatic non-clear cell RCC (nccRCC) has yet to be established. In previous studies, molecular targeted therapies, especially sunitinib, have shown clinical efficacy for the treatment of metastatic nccRCC (3-7). The NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is recommended at present for metastatic nccRCC. In nccRCC papillary renal cell carcinoma (PRCC) is the leading histology (8). PRCC is divided into type 1 and type 2, with type 2 PRCC showing worse prognosis compared with type 1(9). In phase 2 clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, overall survival (OS) of type1 PRCC was 17.8 months, and that of type 2 was 12.4 months (10).\n\nIn this report, we present a patient with metastatic type 2 PRCC whose metastatic lesions were controlled for a long time by multidisciplinary treatments including metastasectomies, axitinib, zoledronic acid (ZA), and radiation therapy.\n\nCase report\n\nA 46-year-old man with hematospermia was presented to a urologic clinic in April, 2011. A right renal tumor was found by ultrasound, and the patient was referred to our hospital. The tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected by contrast-enhanced computed tomography (CT) (Fig. 1A and B). A right partial nephrectomy was performed in July, 2011. Pathological diagnosis was type2 PRCC (Fig. 1C and D). A lung metastasis (S6) and paracaval lymph node (LN) metastases appeared in March, 2012 (Fig. 2A and B). After five cycles of temsirolimus, right radical nephrectomy and extensive LN dissection around the inferior vena cava (IVC) and right common iliac vein were performed in June, 2012, and the resection of the lung metastasis was performed one month after the nephrectomy. Then, radiological complete remission was achieved. LN swellings at the right tracheal bifurcation was found by CT in August, 2013 (Fig. 2C). After three cycles of temsirolimus, mediastinal LN dissection was performed in October, 2013. Mediastinal LNs (Fig. 2D) were swollen again, and multiple bone metastases [sternum, right fifth rib, thoracic spine (5-7th vertebrae), left ilium, and right pubis] appeared in 2014. The clinical course of the patient, including local treatments, medical treatments, and treatment-related adverse events are shown in Fig. 3. Sunitinib (37.5 mg/day) and ZA (4 mg/month) were started in June, 2014. Sunitinib was stopped within two weeks because of adverse events (AEs) including fever, malaise, and liver dysfunction. After the patient had recovered from the AEs, axitinib (10 mg/day) was started as a second-line treatment in July, 2014. ZA was continued after the axitinib administration. Because of diarrhea and hoarseness, the treatment schedule of axitinib was changed to a periodic drug withdrawal schedule (5 days-on, 2 days-off) in October, 2014. Next, the daily dose of axitinib was reduced to 8 mg (5 days-on, 2 days-off) to control severe diarrhea in December, 2014. Stereotactic radiation therapy (total 30 Gray, 10 fractions) was performed for bone metastasis at the left ilium in November, 2015 because only the iliac metastasis appeared to be an active lesion among all bone metastases in the bone scintigraphy. The periodic drug withdrawal schedule of axitinib (8 mg/day, 5 days-on, 2 days-off) was changed to the next schedule (8 mg/day, 4 days-on, 3 days-off) due to renal dysfunction and proteinuria in April, 2017. Mediastinal LN metastases and bone metastases was stable for 30 months after the axitinib administration (Fig. 4). Disease progression was confirmed in June, 2017 due to the appearance of multiple small lung metastases. Because the metastatic lesions progressed slowly after the disease progression, axitinib was continued for another 19 months in accordance with the patient's request. The schedule of axitinib was then changed to a third schedule (8 mg/day, 3 days-on, 3 days-off) due to symptoms of anorexia, dyspnea, and muscle pain in April, 2018. Patient was hospitalized due to severe back pain in September, 2018, and palliative radiotherapy was performed for a compression fracture due to metastasis (L1 lumber vertebrae). Axitinib was stopped in October, 2019. Temsirolimus was then administered, but interstitial pneumonia occurred after three cycles of temsirolimus. Although steroid pulse therapy was performed, respiratory and general condition became worse. The patient died in November, 2019. By multidisciplinary treatments including metastasectomy, axitinib, ZA, and radiation therapy, the patient survived for 80 months after the initial recurrence.\n\nDiscussion\n\nThis patient with metastatic type 2 PRCC could survive 80 months after the initial recurrence by multidisciplinary treatments including metastasectomies, axitinib, ZA, and radiation therapy. Patients with metastatic type 2 PRCC generally have poor prognosis. In a clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median OS in type 2 PRCC was 12.4 months (10). Metastasectomies and axitinib appeared to be especially effective in the present case.\n\nThe NCCN guidelines (2020 version) indicate that clinical trial or sunitinib is the recommended treatment for metastatic nccRCC, and cabozantinib and everolimus are options. At the beginning of targeted era, mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, was reportedly effective compared with interferon-α for metastatic nccRCC (11). A comparative study between temsirolimus and tyrosine kinase inhibitors (TKIs) in metastatic nccRCC does not exist at present. The superiority of sunitinib compared with everolimus in nccRCC treatment has been reported in two clinical trials (12,13). The ASPEN trial reported that the progression-free survival (PFS) of sunitinib was longer than that of everolimus (12). The ESPN trial reported that both PFS and OS of sunitinib were longer than those of everolimus (13). Among other TKIs, the overall response rate of pazopanib was reportedly 39% in the treatment of metastatic nccRCC (6). There are few studies evaluating the clinical efficacy of systemic therapies in metastatic PRCC. In clinical trial evaluating the efficacy of sunitinib for metastatic PRCC, the median PFS and OS were 6.6 and 17.8 months in type 1 PRCC, and 5.5 and 12.4 months in type 2, respectively (10). In a Japanese multicenter study evaluating metastatic PRCC in which most PRCC cases (91.4%) were type 2, the prognosis in the era of targeted therapy (OS=22.5 months) was improved compared with that in the cytokine era (OS=6.3 months). PRCC patients treated with TKIs in both first-line and second-line treatments (OS=31.4 months) showed better prognosis than those with mTOR inhibitors in first-line or second-line (OS=12.9 months) (14).\n\nIn our case, the second-line use of axitinib was effective and achieved a durable stable disease (SD). There have been few reports in which axitinib showed efficacies for metastatic PRCC (15,16). In our case, AEs were relieved by dose reduction and the setting of periodic drug withdrawal schedules of axitinib, and axitinib could be continued for a long time. The half-life period of axitinib was reportedly short (4.8-5.9 h) (17). Axitinib has a characteristic that AEs can be relieved in a short period because of its short half-life period. Then, axitinib can be started again after the short drug withdrawal period. The risk of regrowth should be low due to the short drug withdrawal. In our previous report of a clear cell RCC patient with metastasis at the paranasal sinus, AEs could be relieved effectively by using periodic drug withdrawal schedules of axitinib and axitinib could be used for more than 30 months (18). Takayama et al also reported a similar RCC case in which intermittent use of axitinib was effective (19).\n\nThere is a possibility that prognosis of this patient was improved by metastasectomies. LN metastases around the right common iliac vein and IVC at the time of LN dissection were pathologically confirmed. However, the relapse did not occur in the abdominal and pelvic areas after the extensive LN dissection. This appeared to indicate that LN metastases in the abdominal and the pelvic areas were completely resected by the initial LN dissection. Moreover, the three metastasectomies including the initial LN dissection around the IVC and right iliac vein, the resection of lung metastasis, and the mediastinal LN dissection could delay the timing of TKI administration for two years. Those metastasectomies might contribute to improve the patient's prognosis. In the cytokine era, an efficacy of LN dissection on radical nephrectomy was suggested in PRCC (20). Metastatectomy should be performed appropriately for patients with metastatic PRCC similar to clear cell RCC when radiological complete remission can be achieved by metastasectomy.\n\nAlthough it is difficult to evaluate the effectiveness of ZA and local radiation therapy in this case, these treatments might present some positive effects for disease control.\n\nWe were able to control metastatic lesions of type 2 PRCC for a relatively long term by multidisciplinary treatment. Axitinib was effective and periodic drug withdrawal schedules could reduce AEs and enable to continue axitinib usage.\n\nAcknowledgements\n\nNot applicable.\n\nAvailability of data and materials\n\nData sharing is not applicable to this article, as no datasets were generated or analyzed during the present study.\n\nAuthors' contributions\n\nYA contributed to the study concept, design, data collection and writing of the manuscript. YK contributed to data collection and the revision of the manuscript. MH contributed to data collection and the revision of the manuscript. HH contributed to data collection and the revision of the manuscript. KM contributed to data collection, pathological diagnosis and the revision of the manuscript. AH contributed to the study concept, design and the revision of the manuscript. KI contributed to the study concept, design, data collection, writing and the revision of the manuscript, and the supervision of the manuscript. The authenticity of all the raw data was assessed by YA, KM, AH and KI. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\n\nEthical approval was granted from the Ethics Committee of National Defense Medical College.\n\nPatient consent for publication\n\nWritten informed consent for the publication of any associated data was obtained from the patient's wife.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nFigure 1 Radiological and pathological findings of the primary tumor. (A and B) Contrast-enhanced computed tomography images. A tumor (35 mm in maximal diameter) was located in the middle of the right kidney, and RCC or fat-poor angiomyolipoma was suspected. (C and D) Microscopically, the tumor had papillary architecture. The tumor cells contained abundant eosinophilic cytoplasm with high nuclear grade (Fuhrman nuclear grade 3). The tumor was diagnosed as type 2 papillary RCC. (C) magnification, x100; scale bar, 200 µm. (D) magnification, x400; scale bar, 50 µm. RCC, renal cell carcinoma.\n\nFigure 2 CE-CT images. (A and B) CE-CT images of a (A) lung metastasis (S6) (black arrow) and (B) paracaval lymph node metastases (black arrow) that appeared in 2012. (C) CE-CT of lymph node swellings at the right tracheal bifurcation (white arrow) found in 2013. (D) CE-CT of mediastinal lymph nodes (white arrows) that were swollen again in 2014. CE-CT, Contrast-enhanced computed tomography.\n\nFigure 3 The time course of treatments for the patient with metastatic type 2 papillary renal cell carcinoma. Axi, axitinib; HT, hypertension; IVC, inferior vena cava; LND, lymph node dissection; LNM, lymph node metastasis; RNx, radical nephrectomy; SD, stable disease; SU, sunitinib; TEM, temsirolimus; ZA, zoledronic acid.\n\nFigure 4 CT images during axitinib treatment. (A) CT at axitinib administration. White arrows indicate mediastinal lymph node metastases. (B) CT 7 months after axitinib administration. Lymph node metastases shrunk by using axitinib (partial response, judged by RECIST version 1.1). (C) CT 19 months after axitinib administration. The response was maintained. (D) CT 30 months after axitinib administration. The response was still maintained. (E) Representative bone metastasis (left ilium) at axitinib administration. (F) CT 7 months after axitinib administration. (G) CT 19 months after axitinib administration. (H) CT 30 months after axitinib administration. The bone metastasis in the ilium grew slightly compared with that at axitinib administration (<10%, stable disease, judged by RECIST version 1.1).\n==== Refs\nReferences\n\n1 Wahlgren T Harmenberg U Sandström P Lundstam S Kowalski J Jakobsson M Sandin R Ljungberg B Treatment and overall survival in renal cell carcinoma: A Swedish population-based study (2000-2008) Br J Cancer 108 1541 1549 2013 10.1038/bjc.2013.119 23531701\n2 Motzer RJ Tannir NM McDermott DF Arén Frontera O Melichar B Choueiri TK Plimack ER Barthélémy P Porta C George S Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma N Engl J Med 378 1277 1290 2018 10.1056/NEJMoa1712126 29562145\n3 Tannir NM Plimack E Ng C Tamboli P Bekele NB Xiao L Smith L Lim Z Pagliaro L Araujo J A phase 2 trial of sunitinib in patients with advanced non-clear cell renal cell carcinoma Eur Urol 62 1013 1019 2012 10.1016/j.eururo.2012.06.043 22771265\n4 Lee JL Ahn JH Lim HY Park SH Lee SH Kim TM Lee DH Cho YM Song C Hong JH Multicenter phase II study of sunitinib in patients with non-clear cell renal cell carcinoma Ann Oncol 23 2108 2114 2012 10.1093/annonc/mdr586 22228449\n5 Matrana MR Baiomy A Campbell M Alamri S Shetty A Teegavarapu P Kalra S Xiao L Atkinson B Corn P Outcomes of patients with metastatic non-clear-cell renal cell carcinoma treated with pazopanib Clin Genitourin Cancer 15 e205 e208 2017 10.1016/j.clgc.2016.07.016 27568124\n6 Jung KS Lee SJ Park SH Lee JL Lee SH Lim JY Kang JH Lee S Rha SY Lee KH Pazopanib for the treatment of non-clear cell renal cell carcinoma: A single-arm, open-label, multicenter, phase II study Cancer Res Treat 50 488 494 2018 10.4143/crt.2016.584 28546525\n7 Park I Lee SH Lee JL A multicenter phase II trial of axitinib in patients with recurrent or metastatic non-clear-cell renal cell carcinoma who had failed prior treatment with temsirolimus Clin Genitourin Cancer 16 e997 e1002 2018 10.1016/j.clgc.2018.05.011 29903415\n8 Moch H Humphrey PA Ulbright TM Reuter VE WHO classification of tumours of the Urinary System and Male Genital Organs. Lyon: IARCPress, 2016.\n9 Mejean A Hopirtean V Bazin JP Larousserie F Benoit H Chrétien Y Thiounn N Dufour B Prognostic factors for the survival of patients with papillary renal cell carcinoma: Meaning of histological typing and multifocality J Urol 170 764 767 2003 10.1097/01.ju.0000081122.57148.ec 12913693\n10 Ravaud A Oudard S De Fromont M Chevreau C Gravis G Zanetta S Theodore C Jimenez M Sevin E Laguerre B First-line treatment with sunitinib for type 1 and type 2 locally advanced or metastatic papillary renal cell carcinoma: A phase II study (SUPAP) by the French Genitourinary Group (GETUG)† Ann Oncol 26 1123 1128 2015 10.1093/annonc/mdv149 25802238\n11 Dutcher JP de Souza P McDermott D Figlin RA Berkenblit A Thiele A Krygowski M Strahs A Feingold J Hudes G Effect of temsirolimus versus interferon-α on outcome of patients with advanced renal cell carcinoma of different tumor histologies Med Oncol 26 202 209 2009 10.1007/s12032-009-9177-0 19229667\n12 Armstrong AJ Halabi S Eisen T Broderick S Stadler WM Jones RJ Garcia JA Vaishampayan UN Picus J Hawkins RE Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): A multicentre, open-label, randomised phase 2 trial Lancet Oncol 17 378 388 2016 10.1016/S1470-2045(15)00515-X 26794930\n13 Tannir NM Jonasch E Albiges L Altinmakas E Ng CS Matin SF Wang X Qiao W Dubauskas Lim Z Tamboli P Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): A randomized multicenter phase 2 trial Eur Urol 69 866 874 2016 10.1016/j.eururo.2015.10.049 26626617\n14 Ito K Mikami S Tatsugami K Masumori N Shinohara N Kondo T Nakanishi S Nagashima Y Eto M Kamba T Clinical outcomes in patients with metastatic papillary renal-cell carcinoma: A multi-institutional study in Japan Clin Genitourin Cancer 16 e1201 e1214 2018 10.1016/j.clgc.2018.07.028 30224330\n15 Mori J Nakayama Y Hiragino T Matsuyama H Successful treatment of peritoneal dissemination recurrence with axitinib in papillary renal cell carcinoma: A case report Hinyokika Kiyo 64 45 48 2018 10.14989/ActaUrolJap_64_2_45 (In Japanese) 29684948\n16 Ishii G Hatano T Endo K Seki K Yamada H Kimura T Egawa S A case of papillary renal cell carcinoma type 2 resistant to sunitinib responded to second line therapy with axitinib Nihon Hinyokika Gakkai Zasshi 105 129 133 2014 10.5980/jpnjurol.105.129 (In Japanese) 25158555\n17 Mukohara T Nakajima H Mukai H Nagai S Itoh K Umeyama Y Hashimot J Minami H Effect of axitinib (AG-013736) on fatigue, thyroid-stimulating hormone, and biomarkers: A phase I study in Japanese patients Cancer Sci 101 963 968 2010 10.1111/j.1349-7006.2009.01465.x 20180805\n18 Arai Y Ito K Tachi K Koga A Shinchi Y Masunaga A Isono M Asano T Metastatic renal cell carcinoma in paranasal sinus for which periodic drug withdrawal schedule of axitinib was effective: A case report Hinyokika Kiyo 62 465 471 2016 10.14989/ActaUrolJap_62_9_465 (In Japanese) 27760971\n19 Takayama T Nagata M Kai F Sugiyama T Ozono S Axitinib controlled metastatic renal cell carcinoma for 5 years Jpn J Clin Oncol 43 747 751 2013 10.1093/jjco/hyt067 23667154\n20 Margulis V Tamboli P Matin SF Swanson DA Wood CG Analysis of clinicopathologic predictors of oncologic outcome provides insight into the natural history of surgically managed papillary renal cell carcinoma Cancer 112 1480 1488 2008 10.1002/cncr.23322 18240184\n\n",
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"issn_linking": "2049-9450",
"issue": "14(4)",
"journal": "Molecular and clinical oncology",
"keywords": "axitinib; metastasectomy; periodic drug withdrawal schedule; type 2 papillary renal cell carcinoma",
"medline_ta": "Mol Clin Oncol",
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"nlm_unique_id": "101613422",
"other_id": null,
"pages": "71",
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"pmid": "33732457",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": "29903415;26626617;28546525;30224330;27568124;18240184;25802238;20180805;22771265;12913693;23667154;25158555;22228449;26794930;27760971;29562145;19229667;29684948;23531701;26996659",
"title": "Long-term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy: A case report.",
"title_normalized": "long term disease control of metastatic type 2 papillary renal cell carcinoma using local treatment and molecular targeted therapy a case report"
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"abstract": "to describe an unusual case of necrotizing myositis in a rectus muscle, possibly related to BRAF inhibitor therapy.\nAn 18-year old man with neurodegenerative Langerhans cell histiocytosis (LCH), recently started on the BRAF inhibitor dabrafenib, presented with right eye pain. Magnetic resonance imaging (MRI) orbits revealed a rectus muscle mass concerning for LCH recurrence or malignancy. Dabrafenib was stopped, and incisional biopsy of the mass was performed. The mass was absent on post-operative MRI, so no further treatment was pursued. Histopathologic evaluation was initially concerning for sarcoma, but on further analysis, appeared more consistent with necrotizing myositis. The mass did not recur, nor did the patient develop other signs or symptoms concerning for myositis or malignancy over a 24-month follow-up period.\nNecrotizing myositis has not been previously described in a rectus muscle or with BRAF inhibitor use, though myalgias and malignancies are established side effects. Necrotizing myositis may masquerade as sarcoma and should be on the differential diagnosis for a new mass in the setting of dabrafenib therapy.",
"affiliations": "Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 2828 University Avenue, Madison, WI, 53705, USA.;Department of Pediatrics, American Family Children's Hospital University of Wisconsin-Madison, 1675 Highland Avenue, Madison, WI, 53792, USA.;Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 2828 University Avenue, Madison, WI, 53705, USA.;Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 2828 University Avenue, Madison, WI, 53705, USA.;Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.;Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 2828 University Avenue, Madison, WI, 53705, USA.",
"authors": "van Landingham|Suzanne W|SW|;Puccetti|Diane|D|;Potter|Heather|H|;Gamm|David|D|;Diamond|Eli L|EL|;Lucarelli|Mark J|MJ|",
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"doi": "10.1016/j.ajoc.2020.100868",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(20)30183-3\n10.1016/j.ajoc.2020.100868\n100868\nCase Report\nNecrotizing myositis in a rectus muscle arising in the setting of long-standing Langerhans cell histiocystosis and recent dabrafenib treatment\nvan Landingham Suzanne W. svanlandingh@wisc.edua∗ Puccetti Diane puccetti@pediatrics.wisc.edub Potter Heather hpotter@wisc.edua Gamm David dgamm@wisc.eduac Diamond Eli L. diamone1@mskcc.orgd Lucarelli Mark J. mlucarel@wisc.edua a Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 2828 University Avenue, Madison, WI, 53705, USA\nb Department of Pediatrics, American Family Children's Hospital University of Wisconsin-Madison, 1675 Highland Avenue, Madison, WI, 53792, USA\nc McPherson Eye Research Institute and Waisman Center, University of Wisconsin-Madison, 1500 Highland Avenue, Madison, WI, 53705, USA\nd Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA\n∗ Corresponding author. 2870 University Avenue, Suite 108, Madison, WI, 53705, USA. svanlandingh@wisc.edu\n13 8 2020 \n12 2020 \n13 8 2020 \n20 1008684 6 2020 7 7 2020 9 8 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nto describe an unusual case of necrotizing myositis in a rectus muscle, possibly related to BRAF inhibitor therapy.\n\nObservations\nAn 18-year old man with neurodegenerative Langerhans cell histiocytosis (LCH), recently started on the BRAF inhibitor dabrafenib, presented with right eye pain. Magnetic resonance imaging (MRI) orbits revealed a rectus muscle mass concerning for LCH recurrence or malignancy. Dabrafenib was stopped, and incisional biopsy of the mass was performed. The mass was absent on post-operative MRI, so no further treatment was pursued. Histopathologic evaluation was initially concerning for sarcoma, but on further analysis, appeared more consistent with necrotizing myositis. The mass did not recur, nor did the patient develop other signs or symptoms concerning for myositis or malignancy over a 24-month follow-up period.\n\nConclusions\nNecrotizing myositis has not been previously described in a rectus muscle or with BRAF inhibitor use, though myalgias and malignancies are established side effects. Necrotizing myositis may masquerade as sarcoma and should be on the differential diagnosis for a new mass in the setting of dabrafenib therapy.\n\nHighlights\n• A patient with a history of neurodegenerative Langerhans cell histiocytosis and dabrafenib use presented with orbital pain.\n\n• MRI revealed a rectus muscle mass. LCH recurrence or sarcoma was suspected.\n\n• Biopsy showed necrotizing myositis.\n\n• Necrotizing myositis may be related to BRAF inhibitor (Dabrafenib) use.\n\n• Rectus muscle necrotizing myositis is very uncommon.\n\n\n\nKeywords\nNecrotizing myositisNecrotizing myopathyRectus muscleOrbital myositisSarcomaMassDabrafenibbraf inhibitorB-raf inhibitorLangerhans cell histiocytosis\n==== Body\n1 Introduction\nBRAF inhibitors (Dabrafenib [TAFINLAR, Novartis Pharmaceuticals Corp], Vemurafenib [ZELBORAF, Genentech], and Encorafenib [BRAFTOVI, Array BioPharma]) are relatively new biologic agents developed for metastatic or unresectable melanoma with the BRAF V600E or V600K mutation.1 BRAF is a protein kinase active in regulating the RAS/RAF signalling pathway, which regulates cell growth, so mutations in the BRAF gene can cause cancer by allowing unregulated cell growth.2 They have been used off-label for other advanced malignancies, including BRAF V600-positive non-small cell lung cancer,3 glioma,4 anaplastic thyroid cancer,5 and hairy cell leukemia.6 In addition to its use for malignancies, Vemurafenib was approved by the FDA for treatment of V600-mutant Erdheim Chester Disease (ECD), a rare non-Langerhans-cell histiocytosis, following the demonstration of prolonged efficacy in the VE-BASKET study.7,8 Vemurafenib and other BRAF inhibitors have also been used with success in Langerhans cell histiocytosis (LCH) cases harboring the BRAF V600E mutation (50–60% of LCH cases have this mutation).9,10 Indeed, there is an ongoing phase I/IIa clinical trial of Dabrafenib for the treatment of children with BRAF V600 mutation-positive tumors that includes an LCH group (NCT01677741).\n\nWhile myalgias are a well-known side effect of Dabrafenib, we could not find a report of biopsy-proven necrotizing myositis attributed to this drug.11 Necrotizing orbital myositis has not to our knowledge been reported in the English language literature. Here, we present an unusual case of lateral rectus muscle necrotizing myositis arising in the setting of long-standing Langerhans cell histiocystosis and Dabrafenib treatment, in which the myositis masqueraded as a sarcoma.\n\n2 Case report\nAn 18-year-old man with a history of neurodegenerative Langerhans cell histiocytosis presented to the emergency department (ED) with mild right eye pain, headache, and blurred vision. He had been diagnosed with LCH at age 5 months with skin histiocytosis, and was initially treated with topical steroid and emollient. At age 19 months, his disease returned with right external ear and zygoma involvement, which was treated with local radiation and systemic prednisone. Subsequent findings of central nervous system involvement led to treatment using the LCHIII protocol of prednisone, vinblastine, and 6-mercaptopurine.12 Given continued disease progression, he received several other regimens including pentoxifylline, naturopathic care, vincristine and cytosine arabinoside, and finally rituximab, which was discontinued 2 years prior to presentation when no response was noted. As a result of the LCH, he suffered from hypopituitarism marked by central hypothyroidism, diabetes insipidus, and adrenocorticotropic hormone (ACTH) deficiency.\n\nAs an adolescent, he continued to experience gradual, ongoing neurologic decline. Molecular analysis of his skin biopsy specimen from infancy demonstrated the BRAF V600E mutation. He was started on dabrafenib in light of emerging evidence about the relationship between the BRAF V600E mutation and neurodegenerative LCH, and the therapeutic possibility of BRAF inhibition in this context.13,14 Four weeks later, he developed right eye pain as described above and presented to the ED.\n\nAt the time of presentation, his vision was 20/20 in both eyes with no afferent pupillary defect, and normal intraocular pressure. His extraocular motility exam was notable for a mild deficit of supraduction of the right eye and a long-standing left beating nystagmus in left gaze of the left eye. His confrontational visual fields and dilated fundus exams were normal.\n\nMagnetic resonance imaging (MRI) of the orbits revealed an enhancing, fusiform mass in the right lateral rectus muscle measuring 16 mm × 8 mm x 9 mm. This mass was located within his earlier radiation field and was concerning for LCH recurrence or, less likely, malignancy (Fig. 1). He was advised to stop taking Dabrafenib.Fig. 1 T2-weighted fat supressed MRI image showing a contrast-enhancing, mildly hypointense right lateral rectus mass measuring 16 × 8 × 9 mm.\n\nFig. 1\n\nIn order to establish a diagnosis, two weeks later the patient was taken to the operating room for incisional biopsy via lateral orbitotomy. The lesion appeared as a red-orange, bulbous area of the muscle. Inside, the lesion was noted to be friable and yellow within a fairly distinct capsule.\n\nInitial evaluation of the pathologic specimen was suggestive of soft tissue sarcoma: there were many spindle-shaped or pleomorphic cells infiltrating skeletal muscle, and many large anaplastic cells with marked atypia (Fig. 2). Next generation sequencing was considered but could not be accomplished due to low sample volume. The differential diagnosis initially included radiation-related sarcoma, secondary neoplasia related to dabrafenib treatment, or other soft tissue sarcoma.Fig. 2 Pathologic evaluation of orbital mass biopsy specimen. A) 20x hematoxylin and eosin (H&E) stain shows the interface of spindle to pleomorphic cells and skeletal muscle. B) 40x H&E stain highlights the enlarged, atypical, polygonal cells and background inflammation. C) 40x H&E stain shows myocytes assuming a more reactive morphology in the midst of inflammation. D) 10x desmin stain shows elongated and ragged cells, becoming more round, abnormal, and necrotic in appearance.\n\nFig. 2\n\nInitial discussion of treatment included the possible need for surgical resection, which would require orbital exenteration in order to ensure clear margins. Several weeks following biopsy, a repeat MRI orbit with contrast showed post-operative changes without clear evidence of residual tumor.\n\nIn light of the lack of recurrence of the lesion, which would be atypical for incompletely resected sarcoma, the specimen was reviewed again. The large cells were positive for desmin and negative for smooth muscle antigen (SMA), myogenin, CD1a, S100, and BRAF, and were surrounded by a mixed inflammatory infiltrate. The inflammatory cells were confirmed to be macrophages and T cells by CD68 and CD3 positivity with CD20 negativity. On review and consultation with expert colleagues, the pathology was found to be more consistent with necrotizing myositis than with sarcoma. Ragged muscle fiber margins with adherent leukocytes and vacuolization were noted. In this clinical setting, findings of increased numbers of nuclei; enlarged, atypical nuclei; and spindled and polygonal cells were determined to be reactive rather than anaplastic features.\n\nAfter discussion with the patient and his family, the decision was made to perform surveillance MRI scans every 3 months and refrain from additional surgery or chemotherapy in the absence of signs of recurrence.\n\nHe has been followed now for 24 months following his biopsy and he has shown no sign of recurrence. He is not currently receiving any treatment for his neurodegenerative LCH. His medical treatment focuses on his endocrine and neuropsychiatric needs. His eye exam is stable.\n\n3 Discussion\nThis unusual case of rectus muscle mass occurring in the setting of long-standing LCH while on Dabrafenib treatment was initially diagnosed as sarcoma based on biopsy findings. The patient had several risk factors for sarcoma, including long-standing Langerhans cell histiocytosis, which can rarely undergo malignant transformation to Langerhans cell sarcoma. Langerhans cell sarcoma is typically CD1a and S100 positive; however, the biopsy of this mass was negative for both markers.15 Secondary malignancies are a well-established risk of BRAF inhibitor therapy via a mechanism of paradoxical MAPK pathway hyperactivation, and typically occur within the first 8 weeks of treatment.16 These secondary malignancies are more commonly squamous cell carcinomas, though our patient was asked to stop BRAF inhibitor therapy due to the possible association.11 Finally, the mass was within the field of his prior radiation therapy, which is a well-established risk factor for sarcoma development (most commonly leiomyosarcomas).17\n\nDespite incomplete surgical resection, a post-operative MRI showed no definite residual mass, and the decision was made to follow the patient closely without additional treatment. This decision was made in part because clear surgical margins would have required orbital exenteration surgery, which is highly disfiguring and carries significant morbidity. The apparent involution of the lesion and its failure to recur over a two-year follow-up period prompted re-examination of the case and slides, at which point a diagnosis of necrotizing myositis was made as explained in the case description. No muscular weakness was detected, which is atypical for myositis, though this may be due to the very small focus of necrosis.\n\nNecrotizing myositis of the extraocular muscles is very rare: no reports were identified in the English-language literature. Most cases of necrotizing myositis present as proximal muscle weakness without discrete masses.18,19 They appear to be immune related, and are associated with elevated creatine kinase (CK), anti-signal recognition particle (SRP) antibodies, and anti-3hydroxy-3 methylglutarylcoenzyme A reductase (HMGCR) autoantibodies.18 Histopathological findings in necrotizing myositis are fairly heterogenous, which may in part reflect biopsies being taken at different timepoints in the disease course or may reflect different underlying biochemical processes. Previous reports have described biopsy findings of necrotic myocytes with minimal surrounding infiltration, acute lymphocytic infiltrate,20 or mixed inflammatory infiltrate, often macrophage-predominant with some T cells.21, 22, 23\n\nNecrotizing myositis is a known side effect of immune checkpoint inhibitors (ICIs), with a rate of 1% reported with anti-programmed cell death protein-1 (PD-1) antibody use.24, 25, 26 In a recent review of orbital myositis, McNab identified 17 reported ICI-associated cases.27 Most patients were using ipilimumab, a checkpoint inhibitor that targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), though none of these cases were biopsied and therefore it is unknown whether muscular necrosis occurred. Clinical findings were often similar to thyroid-associated orbitopathy. Case were typically treated empirically with anti-inflammatory medications and stopping the ICI.\n\nThe clinical findings of checkpoint inhibitor-associated necrotizing myositis can be similar to autoimmune cases, but the mechanism is unclear and there are no consistently associated antibodies. For example, steroid refractory dermatomyositis has been reported following combination Dabrafenib and Trametinib (a mitogen-activated protein kinase 1/2 [MEK1/2] inhibitor) therapy.28 The authors noted that the MAPK/ERK pathway (in which MEK1, MEK2, and BRAF play important roles) is important for T-cell receptor signalling, so suppression of this pathway may impair the development of peripheral tolerance, thereby contributing to the development of an autoimmune state.\n\nAnother series of 54 ECD patients with BRAF V600E mutations treated with BRAF or MEK inhibitors reported rhabdomyolysis in 4/15 (27%) treated with cometinib, a MEK inhibitor, though only one patient had symptoms severe enough to stop treatment, and no masses were noted.29 None of the 39 patients treated with BRAF-inhibitor monotherapy were found to have rhabdomyolysis. Our patient's presentation was quite different from these cases, though there may be a similar mechanism at play. Antibodies and CK levels were not tested at the time of the biopsy, though the patient had no symptoms suggestive of proximal muscle weakness or myalgias elsewhere in the body, and it is unlikely that such a focal area of myositis would cause a measurable elevation in CK levels. Electromyography can also be helpful in making a diagnosis of myositis but is not practical to perform on a rectus muscle.\n\nIt is unclear if the lesion at the center of this case would have involuted spontaneously as a result of cessation of dabrafenib alone, or if the incisional biopsy contributed to its resolution. Regardless, the lesion has not recurred, nor has myositis been identified elsewhere in this patient's body, without additional treatment.\n\n4 Conclusions\nIn conclusion, this is an unusual case of necrotizing myositis of the lateral rectus muscle occurring in the setting of disseminated LCH, prior radiation, and dabrafenib use, which masqueraded as sarcoma. Necrotizing myositis should be considered on the differential diagnosis of a patient with a new muscular mass in the setting of BRAF-inhibitor treatment. Biopsy is necessary for diagnosis and may contribute to involution of the mass. The authors recommend stopping BRAF-inhibitor treatment, which also may contribute to lesion resolution.\n\nPatient consent\nThe patient's legal guardian consented to publication of the case in writing.\n\nFunding\nThis work was supported in part by the unrestricted grant from 10.13039/100001818Research to Prevent Blindness, Inc. to the University of Wisconsin-Madison Department of Ophthalmology. Dr. van Landingham was supported by the 10.13039/100005242Heed Ophthalmic Foundation. Dr. Diamond was supported by the 10.13039/100000002National Institutes of Health/10.13039/100000054National Cancer Institute Core Grant [P30 CA008748], the Frame Fund, the Joy Family West Foundation and also discloses unpaid support from Third Rock Ventures, unrelated to the current work.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for authorship.\n\nCRediT authorship contribution statement\nSuzanne W. van Landingham: Conceptualization, Methodology, Investigation, Writing - original draft, Project administration. Diane Puccetti: Conceptualization, Investigation, Resources, Writing - review & editing. Heather Potter: Investigation, Resources, Writing - review & editing. David Gamm: Resources, Writing - review & editing. Eli L. Diamond: Investigation, Resources, Writing - review & editing. Mark J. Lucarelli: Investigation, Resources, Writing - review & editing, Supervision.\n\nDeclaration of competing interest\nDr. van Landingham is a paid consultant of Horizon Therapeutics, on topics unrelated to the current work. The following authors have no financial disclosures: M.L., D.P., D.G., and H.P.\n\nAcknowledgements and Disclosures\nThe authors would like to thank Dr. Cristina Antonescu for her consultation on the pathology, Dr. Victor Elner for his invaluable advice, and Dr. Spencer Cleland for his assistance with the figures.\n==== Refs\nReferences\n1 Research C for DE and. FDA Approves dabrafenib plus trametinib for adjuvant treatment of melanoma with BRAF V600E or V600K mutations. FDA Published online February 9, Accessed November 27, 2019 http://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-dabrafenib-plus-trametinib-adjuvant-treatment-melanoma-braf-v600e-or-v600k-mutations 2019 \n2 Rheault T.R. Stellwagen J.C. Adjabeng G.M. Discovery of dabrafenib: a selective inhibitor of raf kinases with antitumor activity against B-Raf-Driven tumors ACS Med Chem Lett 4 3 2013 358 362 10.1021/ml4000063 24900673 \n3 Khunger A. Khunger M. Velcheti V. Dabrafenib in combination with trametinib in the treatment of patients with BRAF V600-positive advanced or metastatic non-small cell lung cancer: clinical evidence and experience Ther Adv Respir Dis 12 2018 10.1177/1753466618767611 1753466618767611 \n4 Schreck K.C. Grossman S.A. Pratilas C.A. BRAF mutations and the utility of RAF and MEK inhibitors in primary brain tumors Cancers (Basel) 11 9 2019 10.3390/cancers11091262 \n5 Ljubas J. Ovesen T. Rusan M. A systematic review of phase II targeted therapy clinical trials in anaplastic thyroid cancer Cancers (Basel) 11 7 2019 10.3390/cancers11070943 \n6 Falini B. Tiacci E. New treatment options in hairy cell leukemia with focus on BRAF inhibitors Hematol Oncol 37 Suppl 1 2019 30 37 10.1002/hon.2594 31187521 \n7 Research C for DE and. FDA Granted approval to vemurafenib for Erdheim-Chester Disease FDA . Published online February 9, 2019. Accessed April 10, 2020 https://www.fda.gov/drugs/resources-information-approved-drugs/fda-granted-approval-vemurafenib-erdheim-chester-disease \n8 Diamond E.L. Subbiah V. Lockhart A.C. Vemurafenib for BRAF V600-mutant erdheim-chester disease and Langerhans cell histiocytosis: analysis of data from the histology-independent, phase 2, open-label VE-BASKET study JAMA Oncol 4 3 2018 384 388 10.1001/jamaoncol.2017.5029 29188284 \n9 Abla O. Weitzman S. Treatment of Langerhans cell histiocytosis: role of BRAF/MAPK inhibition Hematology Am Soc Hematol Educ Program 2015 2015 565 570 10.1182/asheducation-2015.1.565 26637773 \n10 Donadieu J. Larabi I.A. Tardieu M. Vemurafenib for refractory multisystem Langerhans cell histiocytosis in children: an international observational study J Clin Oncol 37 31 2019 2857 2865 10.1200/JCO.19.00456 31513482 \n11 Dabrafenib package insert U.S. Food and drug administration website https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202806s008lbl.pdf Revised April 2018. Accessed December 3, 2019 \n12 Gadner H. Minkov M. Grois N. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis Blood 121 25 2013 5006 5014 10.1182/blood-2012-09-455774 23589673 \n13 McClain K.L. Picarsic J. Chakraborty R. CNS Langerhans cell histiocytosis: common hematopoietic origin for LCH-associated neurodegeneration and mass lesions Cancer 124 12 2018 2607 2620 10.1002/cncr.31348 29624648 \n14 Mass E. Jacome-Galarza C.E. Blank T. A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease Nature 549 7672 2017 389 393 10.1038/nature23672 28854169 \n15 Nakamine H. Yamakawa M. Yoshino T. Fukumoto T. Enomoto Y. Matsumura I. Langerhans cell histiocytosis and Langerhans cell sarcoma: current understanding and differential diagnosis J Clin Exp Hematop 56 2 2016 109 118 10.3960/jslrt.56.109 27980300 \n16 Su F. Viros A. Milagre C. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors N Engl J Med 366 3 2012 207 215 10.1056/NEJMoa1105358 22256804 \n17 Baker M.S. McConnell L.K. Kleinberg T.T. Shriver E.M. Bilyk J.R. Allen R.C. Orbital sarcomas in retinoblastoma patients: recommendations for screening and treatment guidelines Curr Opin Ophthalmol 27 5 2016 443 448 10.1097/ICU.0000000000000295 27213925 \n18 Mohammed A.G.A. Gcelu A. Moosajee F. Botha S. Kalla A.A. Immune mediated necrotizing myopathy: where do we stand? Curr Rheumatol Rev 15 1 2019 23 26 10.2174/1573397114666180406101850 29623846 \n19 Anquetil C. Boyer O. Wesner N. Benveniste O. Allenbach Y. Myositis-specific autoantibodies, a cornerstone in immune-mediated necrotizing myopathy Autoimmun Rev 18 3 2019 223 230 10.1016/j.autrev.2018.09.008 30639649 \n20 Pinal-Fernandez I. Parks C. Werner J.L. Longitudinal course of disease in a large cohort of myositis patients with autoantibodies recognizing the signal recognition particle Arthritis Care Res (Hoboken). 69 2 2017 263 270 10.1002/acr.22920 27111848 \n21 Saleh Y. Herzallah K. Hassanein M. Chang H.T. Statin-induced necrotizing autoimmune myopathy: an uncommon complication of a commonly used medication J Saudi Heart Assoc 31 4 2019 269 272 10.1016/j.jsha.2019.08.001 31516306 \n22 Needham M. Mastaglia F.L. Immunotherapies for immune-mediated myopathies: a current perspective Neurotherapeutics 13 1 2016 132 146 10.1007/s13311-015-0394-2 26586486 \n23 Day J. Otto S. Cash K. Limaye V. Clinical and histological features of immune-mediated necrotising myopathy: a multi-centre South Australian cohort study Neuromuscul Disord 30 3 2020 186 199 10.1016/j.nmd.2020.02.003 32229165 \n24 Isami A. Uchiyama A. Shimaoka Y. Suzuki S. Kawachi I. Fujita N. [A case of anti-titin antibody positive nivolumab-related necrotizing myopathy with myasthenia gravis] Rinsho Shinkeigaku 59 7 2019 431 435 10.5692/clinicalneurol.cn-001270 31243249 \n25 Adler B.L. Christopher-Stine L. Triggers of inflammatory myopathy: insights into pathogenesis Discov Med 25 136 2018 75 83 29579414 \n26 Moreira A. Loquai C. Pföhler C. Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors Eur J Canc 106 2019 12 23 10.1016/j.ejca.2018.09.033 \n27 McNab A.A. Orbital myositis: a comprehensive review and reclassification Ophthalmic Plast Reconstr Surg 36 2 2020 109 117 10.1097/IOP.0000000000001429 31261163 \n28 Harrison S.R. Tew A. Steven N. Fisher B.A. Steroid refractory dermatomyositis following combination dabrafenib and trametinib therapy Rheumatology (Oxford) 57 8 2018 1497 1499 10.1093/rheumatology/key080 29617934 \n29 Cohen Aubart F. Emile J.-F. Carrat F. Targeted therapies in 54 patients with Erdheim-Chester disease, including follow-up after interruption (the LOVE study) Blood 130 11 2017 1377 1380 10.1182/blood-2017-03-771873 28667012\n\n",
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"issn_linking": "2451-9936",
"issue": "20()",
"journal": "American journal of ophthalmology case reports",
"keywords": "B-raf inhibitor; Dabrafenib; Langerhans cell histiocytosis; Mass; Necrotizing myopathy; Necrotizing myositis; Orbital myositis; Rectus muscle; Sarcoma; braf inhibitor",
"medline_ta": "Am J Ophthalmol Case Rep",
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"nlm_unique_id": "101679941",
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"pages": "100868",
"pmc": null,
"pmid": "32875153",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "30639649;26586486;28854169;31516306;31261163;29579414;31466300;29188284;29624648;28667012;23589673;31243249;27213925;29617934;30453170;31513482;27111848;31277524;31187521;24900673;29623846;29595366;26637773;22256804;32229165;27980300",
"title": "Necrotizing myositis in a rectus muscle arising in the setting of long-standing Langerhans cell histiocystosis and recent dabrafenib treatment.",
"title_normalized": "necrotizing myositis in a rectus muscle arising in the setting of long standing langerhans cell histiocystosis and recent dabrafenib treatment"
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"abstract": "Suboptimal platelet inhibition by clopidogrel (clopidogrel resistance) may be associated with high rates of stent thrombosis and ischemic events. Our objective was to determine if ticagrelor, a P2Y12 receptor inhibitor, can result in platelet inhibition in patients with clopidogrel resistance.\n\n\n\nA thromboelastography-platelet mapping assay was used in all patients undergoing neuroendovascular procedures requiring oral clopidogrel. In patients with suboptimal platelet inhibition (<60%) on clopidogrel, ticagrelor was imitated after an oral bolus of 180 mg followed by 90 mg twice daily and the platelet mapping assay was repeated. The primary endpoint was hemorrhagic complications classified as major (hemoglobin decrease >5 g/dL or intracranial hemorrhage with deficits), minor (hemoglobin decrease 3-5 g/dL or intracranial hemorrhage without residual deficits), or insignificant.\n\n\n\nSuboptimal platelet inhibition on clopidogrel was seen in 70 of 106 patients undergoing neuroendovascular procedures. There was a significantly higher magnitude of platelet inhibition with ticagrelor compared with clopidogrel in patients with clopidogrel resistance (mean ± SD: 85.90 ± 10.74% vs. 29.26 ± 17.71%; P < .001); 50 of 70 patients showed optimal inhibition. Two patients had major (fatal) hemorrhagic events (both received either intravenous thrombolytics and/or eptifibatide infusion). Three patients had minor hemorrhagic events, and two patients had insignificant hemorrhagic events. Four of seven hemorrhagic events occurred in patients with optimal response to clopidogrel, two occurred in patients with suboptimal response to ticagrelor, and one occurred in a patient with optimal response to ticagrelor.\n\n\n\nOral ticagrelor can augment platelet inhibition in patients who have clopidogrel resistance.",
"affiliations": "Zeenat Qureshi Stroke Institutes, Columbia, MO.;Zeenat Qureshi Stroke Institutes, Columbia, MO.;Zeenat Qureshi Stroke Institutes, Columbia, MO.;Zeenat Qureshi Stroke Institutes, Columbia, MO.;Zeenat Qureshi Stroke Institutes, Columbia, MO.;Zeenat Qureshi Stroke Institutes, Columbia, MO.;Zeenat Qureshi Stroke Institutes, Columbia, MO.;Zeenat Qureshi Stroke Institutes, Columbia, MO.;Department of Neurology, University of Missouri, Columbia, MO.;Zeenat Qureshi Stroke Institutes, Columbia, MO.;Department of Neurology, University of Missouri, Columbia, MO.;Division of Neurological Surgery, University of Missouri, Columbia, MO.;Department of Neurology, University of Missouri, Columbia, MO.",
"authors": "Qureshi|Adnan Iqbal|AI|;Jahngir|Muhammad Umair|MU|0000-0003-0510-8267;Qualls|Kathryn|K|;Akinci|Yasemin|Y|;Lobanova|Iryna|I|0000-0001-5500-6555;Liaqat|Jahanzeb|J|;Gao|Xiaoyu|X|;Akhtar|Iqra Naveed|IN|;Kraus|Jacqueline|J|;Uzun|Guven|G|;French|Brandi|B|;Siddiq|Farhan|F|;Ramiro Gomez|Camilo|C|0000-0002-8002-5157",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D000077486:Ticagrelor",
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"issue": "30(3)",
"journal": "Journal of neuroimaging : official journal of the American Society of Neuroimaging",
"keywords": "Carotid stent placement; clopidogrel; platelet mapping; thromboelastography; ticagrelor",
"medline_ta": "J Neuroimaging",
"mesh_terms": "D000368:Aged; D001792:Blood Platelets; D000077144:Clopidogrel; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D020300:Intracranial Hemorrhages; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D010979:Platelet Function Tests; D000077486:Ticagrelor; D016896:Treatment Outcome",
"nlm_unique_id": "9102705",
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"pubdate": "2020-05",
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"title": "The Effect of Ticagrelor on Platelet Reactivity in Patients with Clopidogrel Resistance Undergoing Neuroendovascular Procedures.",
"title_normalized": "the effect of ticagrelor on platelet reactivity in patients with clopidogrel resistance undergoing neuroendovascular procedures"
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"abstract": "BACKGROUND\nCryptococcus neoformans var. neoformans is an opportunistic yeast that typically infects immunocompromised patients.\n\n\nMETHODS\nA case report and review of the pertinent English-language literature are presented.\n\n\nRESULTS\nNecrotizing vasculitis associated with cryptococcal invasion was identified in 1986. Until now, only 24 cases of cryptococcal cellulitis have been reported, including one case of cryptococcal necrotizing fasciitis and one case of necrotizing vasculitis. We report an unusual case of occult disseminated cryptococcosis presenting as necrotizing cellulitis, fasciitis, and myositis.\n\n\nCONCLUSIONS\nCryptococcal soft tissue infection serves as a marker of disseminated cryptococcosis in immunocompromised hosts. Owing to its rarity as a cause of soft tissue infections, diagnosis is difficult and mortality is high.",
"affiliations": "Department of Surgery, Section of Trauma, Surgical Critical Care, and Surgical Emergencies, Yale University School of Medicine, New Haven, Connecticut, USA.",
"authors": "Gave|Asaf A|AA|;Torres|Richard|R|;Kaplan|Lewis|L|",
"chemical_list": "D000900:Anti-Bacterial Agents",
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"doi": "10.1089/sur.2004.5.309",
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"issue": "5(3)",
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"medline_ta": "Surg Infect (Larchmt)",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001707:Biopsy, Needle; D003131:Combined Modality Therapy; D003453:Cryptococcosis; D003455:Cryptococcus neoformans; D003646:Debridement; D004359:Drug Therapy, Combination; D019115:Fasciitis, Necrotizing; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007150:Immunohistochemistry; D009220:Myositis; D018570:Risk Assessment; D012720:Severity of Illness Index; D018461:Soft Tissue Infections; D014657:Vasculitis",
"nlm_unique_id": "9815642",
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"pubdate": "2004",
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"references": null,
"title": "Cryptococcal myositis and vasculitis: an unusual necrotizing soft tissue infection.",
"title_normalized": "cryptococcal myositis and vasculitis an unusual necrotizing soft tissue infection"
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"abstract": "Klebsiella oxytoca hemorrhagic colitis is a rare form of antibiotic associated hemorrhagic colitis that is Clostridium difficile negative. Klebsiella oxytoca colitis has been shown to be triggered by penicillin administration, yet other antibiotics have been implicated as well. It can mimic the appearance of ischemic colitis on endoscopy; however it will generally be found in young, otherwise healthy patients without risk factors. We present a case of a 33-year-old Caucasian female who presented to the emergency room with profuse, bloody diarrhea for 5 days, after a one-week course of ampicillin. Colonoscopy was notable for ulcerated mucosa with erythema and easy friability and the biopsy was suggestive of ischemic colitis. Stool culture was positive for many Klebsiella oxytoca. The patient was discharged home with resolution of symptoms after three days in the hospital. She was instructed to avoid penicillin antibiotics and minimize nonsteroidal anti-inflammatory drug use.",
"affiliations": "Internal Medicine Resident, Beaumont Health, Royal Oak, MI, USA.;General Internal Medicine Section Head, Beaumont Health, Royal Oak, MI, USA.",
"authors": "Fisher|Aaron|A|0000-0001-8905-2306;Halalau|Alexandra|A|0000-0002-1805-992X",
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"doi": "10.1155/2018/7264613",
"fulltext": "\n==== Front\nCase Rep Gastrointest MedCase Rep Gastrointest MedCRIGMCase Reports in Gastrointestinal Medicine2090-65282090-6536Hindawi 10.1155/2018/7264613Case ReportA Case Report and Literature Review of Clostridium difficile Negative Antibiotic Associated Hemorrhagic Colitis Caused by Klebsiella oxytoca http://orcid.org/0000-0001-8905-2306Fisher Aaron aaronsethfisher@gmail.com\n1\nhttp://orcid.org/0000-0002-1805-992XHalalau Alexandra \n2\n\n3\n\n1Internal Medicine Resident, Beaumont Health, Royal Oak, MI, USA\n2General Internal Medicine Section Head, Beaumont Health, Royal Oak, MI, USA\n3Associate Professor, Oakland University William Beaumont School of Medicine, Rochester, MI, USAAcademic Editor: Hirotada Akiho\n\n2018 24 9 2018 2018 726461315 3 2018 6 9 2018 Copyright © 2018 Aaron Fisher and Alexandra Halalau.2018This 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.\nKlebsiella oxytoca hemorrhagic colitis is a rare form of antibiotic associated hemorrhagic colitis that is Clostridium difficile negative. Klebsiella oxytoca colitis has been shown to be triggered by penicillin administration, yet other antibiotics have been implicated as well. It can mimic the appearance of ischemic colitis on endoscopy; however it will generally be found in young, otherwise healthy patients without risk factors. We present a case of a 33-year-old Caucasian female who presented to the emergency room with profuse, bloody diarrhea for 5 days, after a one-week course of ampicillin. Colonoscopy was notable for ulcerated mucosa with erythema and easy friability and the biopsy was suggestive of ischemic colitis. Stool culture was positive for many Klebsiella oxytoca. The patient was discharged home with resolution of symptoms after three days in the hospital. She was instructed to avoid penicillin antibiotics and minimize nonsteroidal anti-inflammatory drug use.\n==== Body\n1. Introduction\nColitis can originate from a wide range of etiologies including ischemic, infectious, and inflammatory bowel disease. A thorough history is imperative to determine the causative nature of the patient's presenting symptoms. Investigations range from observation and stool analysis, to endoscopy with biopsies, depending upon particular risk factors and severity of symptoms. A growing subset of colitis is antibiotic associated colitis. A majority of these cases are secondary to Clostridium difficile infection (CDI), with an estimated 453,000 cases of CDI throughout the United States in 2011 [1]. Within the most common antibiotics used, antibiotic associated diarrhea has been reported in 5-10% of patients taking ampicillin, 10 to 25% of those who are treated with amoxicillin–clavulanate, 15 to 20% of those who receive cefixime, and 2 to 5% of those who are treated with other cephalosporins, fluoroquinolones, azithromycin, clarithromycin, erythromycin, and tetracycline [2]. Yet, in cases of clostridium difficile-negative antibiotic associated hemorrhagic colitis (AAHC), Klebsiella oxytoca has been isolated at a significantly high rate [3]. In Hogenauer et al.'s study, 385 healthy patients had stool testing for Klebsiella oxytoca and in 1.6% of the patients, the pathogen was isolated [4]. Interestingly, Klebsiella oxytoca is found mainly in young healthy individuals compared to patients with CDI who are generally older and with previous hospitalizations [4]. Here we present a case of Clostridium difficile-negative AAHC caused by K. oxytoca infection after taking ampicillin for a urinary tract infection.\n\n2. Case Presentation\nA 33-year-old Caucasian female with significant family history of inflammatory bowel disease (IBD) presents with profuse, bloody diarrhea for 5 days and associated tenesmus and urgency. One day prior to admission, she completed a one-week course of ampicillin for a urinary tract infection and noted that her symptoms began three days after she had initiated treatment. On presentation, patient was hemodynamically stable, afebrile, with mild lower abdominal pain, and a positive guaiac exam. Laboratory findings showed WBC 12.4 bil/L (normal values 3.3–10.7 bil/L), neutrophils 11.0 bil/L (normal values 1.6–7.2 bil/L), Hgb 13.1 g/dL (normal values 12.1–15.0 g/dL), platelets 275 bil/L (normal values 150–400 bil/L), lactic acid 1.4 mmol/L (normal values 0.5–2.2 mmol/L), and liver function tests within normal limits. Initial stool studies that included stool culture, ova and parasite, and Clostridium difficile toxin PCR were negative. A colonoscopy was planned as the patient had an extensive family history of IBD and presented with bloody diarrhea. Klebsiella oxytoca testing was requested on the stool culture after Clostridium difficile PCR came back negative, given her previous use of penicillins. Colonoscopy was notable for ulcerated mucosa with erythema and easy friability, suggestive of moderate colitis throughout the colon with rectosigmoid sparing (Figure 1). Colonic biopsy was remarkable for mucosal congestion and ischemia suggestive of ischemic colitis (Figure 2). Subsequently, requested stool culture was positive for many Klebsiella oxytoca. The patient's hematochezia resolved prior to discharge on day 3 of hospitalization, four days after cessation of ampicillin. She was advised to avoid future use of penicillins and minimize nonsteroidal anti-inflammatory drug (NSAID) use.\n\nThe patient has continued to follow with her gastroenterologist 10 months after her colonoscopy. She has had epigastric abdominal pain relieved by daily omeprazole. She no longer has documented hematochezia and there has been no repeat colonoscopy.\n\n3. Discussion\nColitis is a well-known complication of treatment with antibiotic agents, yet the cause of antibiotic associated hemorrhagic colitis is not completely understood. Several mechanisms have been proposed including allergic reaction, mucosal ischemia, and Klebsiella oxytoca infection. Klebsiella oxytoca positive hemorrhagic colitis is a rare form of antibiotic associated hemorrhagic colitis that is Clostridium difficile negative [4]. In 1978, Toffler et al. were the first to describe AAHC [5]. It has been described that, in a majority of cases, penicillin and penicillin derivative administration typically precede AAHC; however, quinolones and cephalosporins have been described as well [6].\n\nThere appears to be a greater incidence of AAHC secondary to K. oxytoca in the Japanese population [13]. K. oxytoca has been reported in the United States as well, yet appears to be more rare. A PubMed literature review was conducted in order to consolidate all English written and adult population case reports on K. oxytoca hemorrhagic colitis. Search was conducted via the phrases “Klebsiella oxytoca AND colitis AND case report” and “colitis AND Klebsiella oxytoca.” A total of 74 articles resulted, 18 of which were case reports: 7 written in English, 8 written in French, and 3 written in Japanese. The English written cases range from the years 1999 to 2017 and total 9 cases. Five of the cases are reported from Japan and 4 from cities throughout the United States. Ages range from 37 years to 85 years with 4 males and 5 females. Eight of the 9 cases reported bloody diarrhea. The types of antibiotics reported were three penicillin derivatives (amoxicillin twice and amoxicillin-clavulanic acid once), one macrolide (clarithromycin), three fluoroquinolones (tosufloxacin, enoxacin, and levofloxacin), and one with metronidazole, and one case only reported perioperative antibiotics yet specifics were unknown. Two of the 9 cases noted prior use of a NSAID. Duration of antibiotic use ranged from 1 to 7 days. Interestingly, there was a delay of 3-4 weeks in symptomatology in patients who had taken fluoroquinolones compared to the other patients in which symptoms began closer to time of antibiotic use. Location of endoscopic findings varied throughout the 9 cases. Of the 9 cases, 2 cases were right sided only, 3 cases were from ascending to descending colon, 2 cases only involved the sigmoid colon, 1 case involved the transverse colon, and 1 patient declined colonoscopy. The duration of time for resolution of symptoms ranged from 4 days to 3 weeks. Seven of the 9 cases were treated supportively (one case was treated with prednisolone as well). Two of the 9 cases were treated with fluoroquinolones (one of the cases with metronidazole as well) with no reported recurrence of symptoms. In all cases, antibiotic course was either completed or terminated early prior to symptomatic improvement (Table 1). The diagnosis of K. oxytoca can be established by stool [6, 8–10, 12], tissue [7], or bacterial [11] culture. The priority of which culture is of highest yield is uncertain. Of the 9 cases, the most common past medical history was type 2 diabetes mellitus in 3 of the patients, hypertension in 2 of the patients, and systemic lupus erythematosus in 1 of the patients.\n\nOur case is rare given her Caucasian ethnicity; however, as evident by Table 1, K. oxytoca in Caucasians have been reported in the past. The patient's symptomatology, duration of symptoms, and time for resolution of symptoms are consistent with previous reported cases [8, 9, 14]. There have been reports of symptoms manifesting weeks after antibiotic course, yet these were reported after fluoroquinolone use [6]. Her age and lack of risk factors for hemorrhagic colitis are also consistent with previous described cases [4]. Colonic biopsy is generally misinterpreted as ischemic colitis [6–9], just as in this case. Diagnosis is made upon stool culture of K. oxytoca, which has to be specifically requested. Stool culture of K. oxytoca can result within 24 hours of testing. If suspicion is high enough, and physician is aware of such entity, diagnosis of AAHC secondary to K. oxytoca can be made and can possibly prevent unnecessary and risky diagnostic procedures. The disease course is generally self-limited with withdrawal of the offending penicillin. Avoidance of NSAIDs is recommended as well, as this can exacerbate the colitis in these patients [7, 14, 15]. It is unclear at this time if readministration of ampicillin would lead to a similar episode [16]; however, the patient has been advised to avoid all penicillins.\n\nIn conclusion, we presented a case of K. oxytoca colitis in order to raise awareness of the possible etiology of AAHC to be considered in young patients taking antibiotics in which the simple interruption of antibiotic should improve the symptomatology and potentially avoid unnecessary testing or invasive procedures like colonoscopy to be done.\n\nAcknowledgments\nThe authors would like to thank Dr. Alia Gupta for providing the histological images.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this article.\n\nFigure 1 Endoscopic view of ulcerated mucosa with erythema and easy friability, suggestive of moderate colitis.\n\nFigure 2 Colonic biopsy. Yellow arrow indicates epithelial surface erosion. Green arrow indicates extravasated red blood cells. Orange arrow indicates lymphocytes. Blue star indicates reactive intestinal glands.\n\nTable 1 Literature review of case reports of colitis secondary to Klebsiella oxytoca.\n\n\nAuthor\n\t\nYear and Location\n\t\nPatient Age and Gender\n\t\nPresenting symptoms\n\t\nAntibiotic prior to presentation\n\t\nNSAID use prior to presen- tation\n\t\nDuration of Abx prior to sx\n\t\nEndo- scopic location of disease\n\t\nTime to reso- lution of sx\n\t\nTreatment\n\t\nKoga et al. [6]\t1999 Japan\t37 y/o Female\tBloody diarrhea and abdominal pain\tTosu- floxacin tosylate 450 mg\tnone\t5 days∗\tEntire colon excluding rectum\t2 weeks\tHydration and Loperamide\t\n\n\n\t\nKoga et al. [6]\t1999 Japan\t46 y/o Male\tBloody diarrhea and abdominal pain\tEnoxacin\tnone\t7 days∗\tRight sided\t3 weeks\tSupportive\t\n\n\n\t\nKoga et al. [6]\t1999 Japan\t37 y/o Male\tBloody diarrhea\tLevo- floxacin 300 mg\tnone\t7 days∗\tTransverse to sigmoid\t3 weeks\tSupportive\t\n\n\n\t\nChen, Cachay, and Hunt [7]\t2004 San Diego, CA\t79 y/o Male\tDiarrhea, abdominal pain, hemato- chezia\tnone\tAspirin\tnone\tSigmoid colon\t2 weeks\tCipro- floxacin\t\n\n\n\t\nPhilbrick, Ernst [8]\t2007 Iowa\t63 y/o Male\tWatery diarrhea and BRBPR\tAmoxicillin 500 mg q8h\tIbuprofen 800mg q8h\t5 days\tAscending to descending colon\t1 week\tMetro- nidazole and Levo- floxacin\t\n\n\n\t\nMiyauchi, Kinoshita, Tokuda [9]\t2013 Japan\t67 y/o Female\tMucobloody diarrhea and abdominal pain\tClarithro- mycin 200 mg q12h\tnone\t5 days\tRight sided\tNot specified\tSupportive\t\n\n\n\t\nSweetser, Schroede, Pardi [10]\t2009 Rochester, MN\t67 y/o Female\tWatery diarrhea\tPeri- operative abx\tnone\t3 days\tSigmoid colon\t4 days\tSupportive\t\n\n\n\t\nKazuyuki et al. [11]\t2017 Japan\t65 y/o Female\tAbdominal pain and hemato- chezia\tAmoxicillin 1500 mg and Metro- nidazole 500 mg\tnone\t1 day\tTransverse colon\t6 days\tBowel rest and prednisolone\t\n\n\n\t\nAkanbi et al.[12]\t2017 Chicago, IL\t85 y/o Female\tAbdominal pain and muco- bloody diarrhea\tAmoxicillin - clavulanic acid\tnone\t5 days\tDeclined colon- oscopy\t5 days\tSupportive care\t\n\n∗Symptoms did not start until ~3-4 weeks after antibiotic cessation.\n\nQ8h, every 8 hours; q12h, every 12 hours; BRBPR, bright red blood per rectum; abx, antibiotics; ASA, aspirin; sx, symptoms; y/o, years old.\n==== Refs\n1 Lessa F. C. Burden of clostridium difficile infection in the united states The New England Journal of Medicine 2015 372 825 843 25714160 \n2 Bartlett J. G. Antibiotic-associated diarrhea Clinical Infectious Diseases 1992 15 4 573 581 2-s2.0-0026746192 10.1093/clind/15.4.573 1420669 \n3 Beaugerie L. Metz M. Barbut F. Klebsiella oxytoca as an agent of antibiotic-associated hemorrhagic colitis Clinical Gastroenterology and Hepatology 2003 1 5 370 376 2-s2.0-10744221916 10.1053/S1542-3565(03)00183-6 15017655 \n4 Högenauer C. Langner C. Beubler E. Klebsiella oxytoca as a causative organism of antibiotic-associated hemorrhagic colitis The New England Journal of Medicine 2006 355 23 2418 2426 10.1056/NEJMoa054765 2-s2.0-33845385703 17151365 \n5 Toffler R. Acute colitis related to penicillin and penicillin derivatives The Lancet 1978 312 8092 707 709 10.1016/S0140-6736(78)92704-6 2-s2.0-0018176194 \n6 Koga H. Can quinolones cause hemorrhagic colitis of late onset? Diseases of the Colon and Rectum 1999 42 11 1502 1504 10566543 \n7 Chen J. Cachay E. R. Hunt G. C. Klebsiella oxytoca: A rare cause of severe infectious colitis: First North American case report Gastrointestinal Endoscopy 2004 60 1 142 145 2-s2.0-3042587404 10.1016/S0016-5107(04)01537-8 15229449 \n8 Philbrick A. M. Ernst M. E. Amoxicillin-associated hemorrhagic colitis in the presence of Klebsiella oxytoca Pharmacotherapy 2007 27 11 1603 1607 2-s2.0-35848968024 10.1592/phco.27.11.1603 17963468 \n9 Miyauchi R. Kinoshita K. Tokuda Y. Clarithromycin-induced haemorrhagic colitis BMJ Case Reports 2013 2-s2.0-84885095974 \n10 Sweetser S. Schroeder K. W. Pardi D. S. Pseudomembranous colitis secondary to klebsiella oxytoca American Journal of Gastroenterology 2009 104 9 2366 2368 2-s2.0-69949169997 10.1038/ajg.2009.289 19727105 \n11 Tanaka K. Fujiya M. Sakatani A. Second-line therapy for Helicobacter pylori eradication causing antibiotic-associated hemorrhagic colitis Annals of Clinical Microbiology and Antimicrobials 2017 16 1 10.1186/s12941-017-0230-0 \n12 Akanbi O. Antibiotic-associated haemorrhagic colitis: Not always Clostridium difficile BMJ Case Reports 2017 2-s2.0-85020782773 \n13 Miller A. M. Bassett M. L. Dahlstrom J. E. Doe W. F. Case report: Antibiotic-associated haemorrhagic colitis Journal of Gastroenterology and Hepatology 1998 13 11 1115 1118 2-s2.0-0032201432 10.1111/j.1440-1746.1998.tb00586.x 9870798 \n14 Yilmaz M. Prospective observational study on antibiotic-associated bloody diarrhea European Journal of Gastroenterology and Hepatology 2012 24 6 688 694 10.1097/MEG.0b013e328352721a 22433794 \n15 Gorkiewicz G. Nosocomial and antibiotic-associated diarrhoea caused by organisms other than Clostridium difficile International Journal of Antimicrobial Agents 2009 33 1 S37 S41 2-s2.0-62249140183 10.1016/S0924-8579(09)70015-9 19303568 \n16 Moulis H. Vender R. J. Antibiotic-associated hemorrhagic colitis Journal of Clinical Gastroenterology 1994 18 3 227 231 2-s2.0-0028218835 10.1097/00004836-199404000-00012 8034921\n\n",
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"title": "A Case Report and Literature Review of Clostridium difficile Negative Antibiotic Associated Hemorrhagic Colitis Caused by Klebsiella oxytoca.",
"title_normalized": "a case report and literature review of clostridium difficile negative antibiotic associated hemorrhagic colitis caused by klebsiella oxytoca"
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"abstract": "Acanthamoeba is the most common cause of granulomatous amebic encephalitis, a typically fatal condition that is classically described as indolent and slowly progressive. We report a case of Acanthamoeba encephalitis in a kidney transplant recipient that progressed to death within 3 days of symptom onset and was diagnosed at autopsy. We also review clinical characteristics, treatments, and outcomes of all published cases of Acanthamoeba encephalitis in solid organ transplant (SOT) recipients. Ten cases were identified, and the infection was fatal in 9 of these cases. In 6 patients, Acanthamoeba presented in a fulminant manner and death occurred within 2 weeks after the onset of neurologic symptoms. These acute presentations are likely related to immunodeficiencies associated with solid organ transplantation that result in an inability to control Acanthamoeba proliferation. Skin lesions may predate neurologic involvement and provide an opportunity for early diagnosis and treatment. Acanthamoeba is an under-recognized cause of encephalitis in SOT recipients and often presents in a fulminant manner in this population. Increased awareness of this disease and its clinical manifestations is essential to attain an early diagnosis and provide the best chance of cure.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Transplantation-Oncology Infectious Diseases Program, Department of Medicine, Weill Cornell Medical College, New York, New York, USA.",
"authors": "Satlin|M J|MJ|;Graham|J K|JK|;Visvesvara|G S|GS|;Mena|H|H|;Marks|K M|KM|;Saal|S D|SD|;Soave|R|R|",
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"keywords": "Acanthamoeba; encephalitis; solid organ transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000048:Acanthamoeba; D000562:Amebiasis; D004660:Encephalitis; D017809:Fatal Outcome; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged",
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"title": "Fulminant and fatal encephalitis caused by Acanthamoeba in a kidney transplant recipient: case report and literature review.",
"title_normalized": "fulminant and fatal encephalitis caused by acanthamoeba in a kidney transplant recipient case report and literature review"
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"abstract": "A 68-year-old female was diagnosed with acute myeloid leukemia (AML-M2 without 8/21 translocation) in December 2006. Although a complete remission (CR) was obtained after induction chemotherapy, the first post-remission therapy was discontinued because of severe cardiovascular complications. She had a relapse of AML with CD33-positive myeloblasts which comprised 38.4 % of the bone marrow cells in November 2007. She received two courses of low-dose chemotherapy because of the previous complications. The amount of Wilm's tumor 1 (WT1) mRNA in the peripheral blood was 13,000 copies/μg RNA after the first course of the chemotherapy, and 4.8 % myeloblasts remained in the bone marrow after the second course. She was treated with a single course of gemtuzumab ozogamicin (GO), with a subsequent CR with 0.9 % marrow myeloblasts and fewer than 50 copies of WT-1 mRNA (normal level). Thereafter, she received five courses of GO monotherapy at each occasion of early AML relapse. Hematological remission has been sustained over a period of about 24 months with the GO monotherapy alone. This case suggests that GO monotherapy is a useful salvage therapy for early relapse of CD33-positive AML in situations in which standard chemotherapy is not indicated.",
"affiliations": "Department of Hematology, Shinko Hospital, 4-47 Wakihama-cho, 1-chome, Chuo-ku, Kobe, 651-0072, Japan.",
"authors": "Tsunemine|Hiroko|H|;Akasaka|Hiroshi|H|;Sakane|Emiko Ishikawa|EI|;Ito|Kiminari|K|;Kodaka|Taiichi|T|;Takahashi|Takayuki|T|",
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"medline_ta": "Int J Hematol",
"mesh_terms": "D000368:Aged; D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D005260:Female; D000079982:Gemtuzumab; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D012074:Remission Induction; D016879:Salvage Therapy; D055502:Secondary Prevention; D016896:Treatment Outcome",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "193-7",
"pmc": null,
"pmid": "24293280",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23709007;21172891;23110324;11432892;8321047;22851554;15541475;19752335;15920495;15147374;20849384;17768126;21258184;15187030;15168592;20230405;16562371;23591789;19360457;11792178;18443273;17051246;16079891;1317488;12801292;15223637;7596170;7808002;18410450;16116598;16447800;22482940",
"title": "Successful repeated treatment of acute myeloid leukemia in early relapse with gemtuzumab ozogamicin alone.",
"title_normalized": "successful repeated treatment of acute myeloid leukemia in early relapse with gemtuzumab ozogamicin alone"
} | [
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"companynumb": "JP-TEVA-508388ISR",
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"abstract": "OBJECTIVE\nTo compare the safety, efficacy, and immunogenicity of MSB11022 (acetate-buffered formulation), an adalimumab biosimilar, with the reference product.\n\n\nMETHODS\nAURIEL-RA study was a phase 3, multicenter, randomized, double-blind, parallel group trial (NCT03052322). Patients with moderately-to-severely active rheumatoid arthritis (RA) with an inadequate response to methotrexate were randomized 1:1 to MSB11022 or reference adalimumab. The primary endpoint was the incidence of treatment-emergent adverse events of special interest (AESIs) (predefined as hypersensitivity) up to week 52. The key secondary endpoint was ACR20 (≥ 20% improvement in American College of Rheumatology core set measurements from baseline) at week 12. Other efficacy endpoints, quality of life, immunogenicity, and pharmacokinetic parameters were evaluated up to week 52. Secondary safety endpoints were evaluated up to week 52 and at a 4-month safety follow-up.\n\n\nRESULTS\nIn total, 288 patients were randomized. The proportion of patients experiencing ≥ 1 treatment-emergent AESI up to week 52 was similar between trial arms: 6 patients (4.2%; 95% CI 1.56, 8.91) receiving MSB11022, and 8 patients (5.5%; 95% CI 2.41, 10.58) receiving reference adalimumab. No clinically meaningful differences in efficacy, quality of life, or immunogenicity were seen between treatment arms up to week 52. No notable difference in the incidence of treatment-emergent adverse events was observed between treatment arms up to the end of the follow-up period.\n\n\nCONCLUSIONS\nThese results suggest MSB11022 and reference adalimumab are similar in patients with moderately-to-severely active rheumatoid arthritis in terms of safety, immunogenicity, and efficacy. AURIEL-RA provides evidence to support the similarity of MSB11022 and adalimumab.Key Points• Incidences of hypersensitivity events were similar for MSB11022 (modified buffer) and reference adalimumab.• There was no difference in local reactions between MSB11022 (modified buffer) and reference adalimumab.• AURIEL-RA confirms the equivalence in efficacy and immunogenicity of MSB11022 (modified buffer) and reference adalimumab.",
"affiliations": "NIHR Clinical Research Facility, University of Southampton, Southampton, UK. cedwards@soton.ac.uk.;Fresenius Kabi, Eysins, Switzerland.;Fresenius Kabi, Eysins, Switzerland.;Cytel, Geneva, Switzerland.;Fresenius Kabi, Eysins, Switzerland.;Fresenius Kabi, Eysins, Switzerland.",
"authors": "Edwards|Christopher J|CJ|;Monnet|Joëlle|J|;Ullmann|Martin|M|;Vlachos|Pantelis|P|;Chyrok|Veranika|V|;Ghori|Vishal|V|",
"chemical_list": "D018501:Antirheumatic Agents; D059451:Biosimilar Pharmaceuticals; D000068879:Adalimumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-019-04679-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "38(12)",
"journal": "Clinical rheumatology",
"keywords": "Adalimumab; Biosimilar; Hypersensitivity; MSB11022; Rheumatoid arthritis; TNF inhibitor",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D059451:Biosimilar Pharmaceuticals; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "3381-3390",
"pmc": null,
"pmid": "31396834",
"pubdate": "2019-12",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "27340678;12748655;24326008;27854156;28448562;20870100;16273780;29980576;29431871;29158574;16385520;26220918;29791832;20872595;30094742;21486979;24764037;7779114;28528371;15146409;8450681;3358796;29189134;28264816;27285856;20889601;1593914",
"title": "Safety of adalimumab biosimilar MSB11022 (acetate-buffered formulation) in patients with moderately-to-severely active rheumatoid arthritis.",
"title_normalized": "safety of adalimumab biosimilar msb11022 acetate buffered formulation in patients with moderately to severely active rheumatoid arthritis"
} | [
{
"companynumb": "GB-ABBVIE-19K-167-3184727-00",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "ADALIMUMAB"
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... |
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"abstract": "BACKGROUND\nOsteosarcoma, the most common primary bone malignancy, has an extremely poor prognosis and a high rate of local recurrence and distal metastases. Because osteosarcomas of the head and neck region are rare, accounting for less than 10% of all osteosarcoma cases, limited information is available about their treatment and prognosis. Because of the high rate of distal metastases associated with extragnathic osteosarcoma, surgery combined with chemotherapy is currently considered essential in its treatment. However, the role of chemotherapy has not been well elucidated in the treatment of head and neck osteosarcoma because of the rarity of this condition.\n\n\nMETHODS\nIn this report, we present the case of a 58-year-old Japanese woman with osteosarcoma of the mandible that was treated with radical surgery combined with neoadjuvant and adjuvant chemotherapy. Because the tumor showed rapid growth during neoadjuvant chemotherapy, neoadjuvant chemotherapy was suspended and surgical resection was performed, followed by adjuvant chemotherapy. No evidence of local recurrence and distal metastasis was found 14 months after initial treatment. Local control is considered a principal prognostic factor for head and neck osteosarcoma.\n\n\nCONCLUSIONS\nWide surgical excision should be considered a primary goal even during neoadjuvant chemotherapy, especially in cases that respond poorly to neoadjuvant chemotherapy.",
"affiliations": "Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama city, Toyama, 930-0194, Japan.;Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama city, Toyama, 930-0194, Japan. tomihara@med.u-toyama.ac.jp.;Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama city, Toyama, 930-0194, Japan.;Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama city, Toyama, 930-0194, Japan.;Department of Oral and Maxillofacial Surgery, Naha City Hospital, 2-31-1 Furujima, Naha, Okinawa, 902-8511, Japan.;Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama city, Toyama, 930-0194, Japan.;Department of Orthopaedic Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama city, Toyama, 930-0194, Japan.;Department of Orthopaedic Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama city, Toyama, 930-0194, Japan.;Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama city, Toyama, 930-0194, Japan.;Division of Oral and Maxillofacial Radiology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Tobetsu, Ishikari, 061-0293, Japan.;Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama city, Toyama, 930-0194, Japan.",
"authors": "Kimura|Yutaro|Y|;Tomihara|Kei|K|;Tachinami|Hidetake|H|;Imaue|Shuichi|S|;Nakamori|Kenji|K|;Fujiwara|Kumiko|K|;Suzuki|Kayo|K|;Yasuda|Taketoshi|T|;Miwa|Shigeharu|S|;Nakayama|Eiji|E|;Noguchi|Makoto|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13256-017-1386-0",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 138610.1186/s13256-017-1386-0Case ReportConventional osteosarcoma of the mandible successfully treated with radical surgery and adjuvant chemotherapy after responding poorly to neoadjuvant chemotherapy: a case report Kimura Yutaro yukimura@med.u-toyama.ac.jp 1Tomihara Kei +81-76-434-7383tomihara@med.u-toyama.ac.jp 1Tachinami Hidetake hidetake@med.u-toyama.ac.jp 1Imaue Shuichi simaue@med.u-toyama.ac.jp 1Nakamori Kenji nakamori-hnc@umin.ac.jp 2Fujiwara Kumiko fujiwara@med.u-toyama.ac.jp 1Suzuki Kayo suzukayo@med.u-toyama.ac.jp 3Yasuda Taketoshi yasuda@med.u-toyama.ac.jp 3Miwa Shigeharu miwasige@med.u-toyama.ac.jp 4Nakayama Eiji enaka@hoku-iryo-u.ac.jp 5Noguchi Makoto mnoguchi@med.u-toyama.ac.jp 11 0000 0001 2171 836Xgrid.267346.2Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama city, Toyama 930-0194 Japan 2 0000 0004 1772 2157grid.474837.bDepartment of Oral and Maxillofacial Surgery, Naha City Hospital, 2-31-1 Furujima, Naha, Okinawa 902-8511 Japan 3 0000 0001 2171 836Xgrid.267346.2Department of Orthopaedic Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama city, Toyama 930-0194 Japan 4 0000 0001 2171 836Xgrid.267346.2Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama city, Toyama 930-0194 Japan 5 0000 0004 1769 5590grid.412021.4Division of Oral and Maxillofacial Radiology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa, Tobetsu, Ishikari, 061-0293 Japan 2 8 2017 2 8 2017 2017 11 2106 3 2017 10 7 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nOsteosarcoma, the most common primary bone malignancy, has an extremely poor prognosis and a high rate of local recurrence and distal metastases. Because osteosarcomas of the head and neck region are rare, accounting for less than 10% of all osteosarcoma cases, limited information is available about their treatment and prognosis. Because of the high rate of distal metastases associated with extragnathic osteosarcoma, surgery combined with chemotherapy is currently considered essential in its treatment. However, the role of chemotherapy has not been well elucidated in the treatment of head and neck osteosarcoma because of the rarity of this condition.\n\nCase presentation\nIn this report, we present the case of a 58-year-old Japanese woman with osteosarcoma of the mandible that was treated with radical surgery combined with neoadjuvant and adjuvant chemotherapy. Because the tumor showed rapid growth during neoadjuvant chemotherapy, neoadjuvant chemotherapy was suspended and surgical resection was performed, followed by adjuvant chemotherapy. No evidence of local recurrence and distal metastasis was found 14 months after initial treatment. Local control is considered a principal prognostic factor for head and neck osteosarcoma.\n\nConclusions\nWide surgical excision should be considered a primary goal even during neoadjuvant chemotherapy, especially in cases that respond poorly to neoadjuvant chemotherapy.\n\nKeywords\nConventional osteosarcomaMandibleHead and neckChemotherapyissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nOsteosarcoma is a high-grade primary bone malignancy with a high rate of metastasis and local recurrence [1, 2]. The most common anatomical sites affected are the long bones of the limbs, particularly in the knee region [1, 2]. In contrast, osteosarcomas of the head and neck region are rare, accounting for less than 10% of all osteosarcomas [3–5]. Although osteosarcomas of long bones commonly occur in the second decade of life during bone growth [1, 2], osteosarcomas of the head and neck generally occur later, peaking in the second, third, and fourth decades of life [3–5]. Based on the 2013 World Health Organization (WHO) classification of bone tumors [6], osteosarcomas are histologically classified into different histologic subtypes, including conventional, telangiectatic, small-cell, low-grade central, secondary, periosteal, parosteal, and high-grade surface. Moreover, conventional osteosarcoma, the most frequent type of osteosarcoma, is classified into three subtypes: osteoblastic, chondroblastic, and fibroblastic osteosarcoma [1]. The occurrence rate of distant metastases is approximately 80%, and the 5-year survival rate is 20 to 30% after surgery alone without neoadjuvant and adjuvant chemotherapy. Moreover, 20% of patients with osteosarcoma have distant metastases when the primary tumor is newly diagnosed [7]. Therefore, neoadjuvant and/or adjuvant chemotherapy is currently deemed an essential adjunct to surgical treatment, especially in the management of high-grade osteosarcoma [7, 8]. In fact, neoadjuvant and adjuvant chemotherapy in combination with surgery dramatically improves clinical outcomes in extragnathic osteosarcoma, such as an increase in the disease-free survival rate from 10 to 20% to >60% [7, 8]. Although the vast majority of head and neck osteosarcomas are high-grade conventional osteosarcomas [9–12], they are highly heterogeneous compared with extragnathic osteosarcoma. Low-grade osteosarcomas, such as parosteal and central osteosarcomas, and intermediate-grade osteosarcomas, such as periosteal osteosarcomas, sometimes overlap morphologically and clinically with benign bone diseases. This overlap occurs more frequently with head and neck osteosarcomas than with extragnathic osteosarcomas [13]. Moreover, head and neck osteosarcomas are less aggressive and have a better prognosis with surgery alone than extragnathic osteosarcoma does, in particular in low-grade osteosarcomas such as parosteal and central, which occur relatively more frequently than extragnathic osteosarcoma does [13–18]. Therefore, the management of head and neck osteosarcoma is not standardized and varies widely among institutions.\n\nIn the present case report, we describe a case of high-grade conventional osteosarcoma of the mandible that was successfully treated with a combination of surgery, and neoadjuvant and adjuvant chemotherapy.\n\nCase presentation\nA 58-year-old Japanese woman complaining of pain and numbness in her left mandible was referred to our hospital in 2014. For a couple of months prior to her visit, she had been aware of an abnormal sensation in her left mandible, which gradually progressed to mild pain and numbness. She visited a general dental practitioner, who diagnosed her condition as osteomyelitis and referred her to our department. Her medical and family histories were unremarkable. On initial assessment, no obvious systemic symptoms were evident. A panoramic radiograph showed a widening of the periodontal ligament space, periapical bone loss in tooth #37, and a diffuse radiolucent lesion involving the left body of her mandible, with an indistinct cortical margin and ill-defined cortical borders of the inferior alveolar nerve canal (Fig. 1). Moreover, the radiograph also showed that tooth #37 had previously been treated endodontically. Therefore, a diagnosis of apical periodontitis was suggested and endodontic treatment was performed; however, her symptoms were not relieved. Consequently, a neoplastic lesion was highly suspected and findings of a biopsy of the apical tissue after extraction of tooth #37 resulted in a histopathological diagnosis of tissue inflammation. However, after the biopsy, a gradual progressive swelling of the left mandible occurred (Fig. 2a). Computed tomography (CT) showed an enhanced lesion on the left mandible, and magnetic resonance image (MRI) showed abnormally high-intensity signal in the bone marrow, with surrounding soft tissue mass (Fig. 2b, c). Therefore, we performed an incisional biopsy of the swollen area, the findings of which resulted in a histopathological diagnosis of osteoblastic-type osteosarcoma of the mandible. She was then scheduled for radical surgery combined with neoadjuvant and adjuvant chemotherapy based on the regimen used in a multi-institutional clinical study of neoadjuvant chemotherapy in extragnathic osteosarcoma (NECO study) in Japan [19]. In the NECO study, neoadjuvant chemotherapy consisted of two courses of high-dose (HD) methotrexate (MTX) followed by a course of cisplatin (CDDP) and adriamycin (ADR) as phase I chemotherapy. After phase I chemotherapy was completed, the response to induction chemotherapy was evaluated. If the treatment response was assessed as complete response (CR), partial response (PR), or stable disease (SD), four courses of HD-MTX and a course of CDDP and ADR were administered. In contrast, if the treatment was assessed on the basis of the response as “not effective, with progressive disease (PD),” the chemotherapy regimen was changed to HD ifosfamide (IFO). Toxic effects during chemotherapy were graded according to the Common Terminology Criteria for Adverse Events Version 4.0. Following neoadjuvant chemotherapy, tumors were assessed using response evaluation criteria in solid tumors (RECIST) after determining their sizes using CT and MRI. In the current patient, the swelling increased rapidly during the phase I neoadjuvant chemotherapy (Fig. 3a). CT and MRI also revealed marked progression of the lesion (Fig. 3b, c), and laboratory data showed marked elevation of serum alkaline phosphatase. On the basis of these data, we assessed the response to neoadjuvant chemotherapy as not effective, with PD. Therefore, the neoadjuvant chemotherapy was suspended and radical surgery took precedence before the lesion grew to an unresectable size. She was then treated with radical surgery consisting of a hemimandibulectomy and reconstruction using a free vascularized latissimus dorsi pedicle flap and rigid titanium reconstruction plate. On histologic examination, the tumor was composed of stellate cells, which were large and atypical (Fig. 4). Highly atypical cells produced osteoid and immature bone. Moreover, chondroid matrices were also observed. Taken together, these findings indicated that the therapeutic response was poor, assessed as grade 0 (tumor necrosis area <90%). On postoperative day 25, adjuvant chemotherapy was started. Adjuvant chemotherapy was also performed in accordance with the NECO study regimen, with slight modifications. The adjuvant chemotherapy regimen included two courses of HD-IFO followed by a course of CDDP and ADR, and the same regimen was repeated for a total of three cycles. During chemotherapy, hematologic toxicities, grade 4 leukopenia, and thrombocytopenia were detected and the frequency of febrile neutropenia increased, requiring red blood cell and platelet transfusions and the use of granulocyte-colony stimulating factor. The treatment schedule and our patient’s clinical course are summarized in the Table 1. No evidence of local recurrence and distant metastasis was found at 14 months follow-up after initial treatment.Fig. 1 A panoramic radiograph showing a loss of the lamina dura and a well-defined periapical radiolucent lesion around the root apex of tooth #37, and an irregular bordered radiolucent lesion involving the left body of the mandible extending from the tooth #35 to #38 region, with an indistinct cortical margin and ill-defined cortical borders of the inferior alveolar nerve canal\n\n\nFig. 2 \na An intra-oral photograph showing a slight diffuse swelling of the mandible with normal appearance of the overlying mucosa. b A computed tomography scan acquired before neoadjuvant chemotherapy showing the lesion on the left mandible with an indistinct cortical margin and small bony spicules. c A fat-saturated T2-weighted image from magnetic resonance imaging performed before neoadjuvant chemotherapy showing a high intensity lesion on the left mandible, with peritumoral soft tissue enhancement\n\n\nFig. 3 \na An intra-oral photograph after neoadjuvant chemotherapy showing expansive diffuse swelling of the mandible with the erythematous appearance of the overlying mucosa. b A computed tomography scan acquired after neoadjuvant chemotherapy showing the lesion on the left mandible accompanied with the sunburst appearance of marked osteoid formations. c A fat-saturated T2-weighted image from magnetic resonance imaging performed after neoadjuvant chemotherapy showing a high intensity lesion on the left mandible, with prominent peritumoral soft tissue enhancement\n\n\nFig. 4 Microscopic histopathology of the hematoxylin and eosin-stained tumor specimen. Photomicrograph of the histological specimen showing conventional osteosarcoma composed of sarcomatous tumor cells that produced both osteoid and immature bone, and chondroid matrices. Insert showing a high power view of severely atypical cells of the lesion\n\n\nTable 1 Clinical course and treatment schedule\n\n\tHD-MTX\tHD-MTX\tCDDP+ADR\tSurgery\tIFO\tIFO\tCDDP+ADR\tIFO\tIFO\tCDDP+ADR\tIFO\tIFO\t\nLeukopenia\t-\t-\tG1\t\tG4\tG4\tG3\tG4\tG4\tG4\tG4\tG4\t\nNeutropenia\t-\tG2\tG2\t\tG4\tG4\tG2\tG4\tG4\tG4\tG4\tG4\t\nPlatelet\t-\t-\t-\t\t-\t-\t-\t-\t-\t-\tG3\tG4\t\nVomiting\t-\t-\t-\t\tG2\tG2\t-\tG1\tG1\t-\tG2\tG2\t\nAnemia\t-\t-\t-\t\t-\t-\t-\t-\t-\t-\t\tG4\t\n\nADR adriamycin, CDDP cisplatin, G1 Grade 1, G2 Grade 2, G3 Grade 3, G4 Grade 4, HD high-dose, IFO ifosfamide, MTX methotrexate. Regimen-related toxicity was graded according to the common terminology criteria for adverse events (CTCAE)\n\n\n\n\nDiscussion\nAlthough no consensus exists regarding the efficacy of chemotherapy in head and neck osteosarcoma, a few studies have shown that chemotherapy in neoadjuvant and adjuvant setting improves survival in patients with head and neck osteosarcoma [16, 20]. However, a more recent study failed to show a benefit of chemotherapy in head and neck osteosarcoma [10]. The principal prognostic factor in head and neck osteosarcoma is complete tumor resection with negative margins in radical surgery [10, 16, 20–23]. A distinct feature of surgery in head and neck lesions is the complexity of head and neck anatomy, which increases the potential for functional and cosmetic impairment due to ablation surgery compared with the potential at other tumor sites.\n\nAlthough the width of surgical margins remains controversial, and clear bony margins of 2 cm have been reported after effective preoperative chemotherapy [24], the safe recommended margin in osteosarcoma of the extremities is 3 cm [13]. In head and neck osteosarcomas, a clear surgical margin of at least 1 cm has been recommended because of the anatomical limitations that prevent wide resection [25]. However, this margin may still be insufficient, and probably increases the risk of local recurrence. Therefore, 2-cm bony margins and at least 5-mm soft tissue margins have been recommended, assuming that reconstructive surgery is possible [13].\n\nIn the present case, because the tumor was unresponsive and showed rapid growth during neoadjuvant chemotherapy, this therapy was suspended and radical surgery took precedence. Local control is currently the most important prognostic factor for survival in head and neck osteosarcoma. Therefore, to avoid missing the optimal time window for performing complete surgical excision with clear margins, clinicians should meticulously assess the response to neoadjuvant chemotherapy and not hesitate to suspend this treatment if the response is inadequate.\n\nThe most critical issue in the future development of novel treatment strategies for osteosarcoma in the head and neck is the circumvention of therapy-resistant osteosarcoma. To accomplish this, biomarkers predicting the response to chemotherapy urgently need to be identified, especially for the treatment of patients who respond poorly to chemotherapy. Nevertheless, limited data are available about the mechanism by which chemoresistance develops in head and neck osteosarcoma. Various processes have been implicated in the mechanism underlying the development of chemoresistance in extragnathic osteosarcoma, including altered cell cycle [26], reduced intracellular drug accumulation [27], drug inactivation [28], increased drug detoxification [29], altered deoxyribonucleic acid (DNA) repair mechanism [30], altered apoptosis signaling [31], autophagy [32], micro ribonucleic acid (RNA) dysregulation [33], and cancer stem cells [34]. A thorough understanding of these processes is important for predicting treatment response and for developing novel treatment strategies to prevent the emergence of therapy-resistance in head and neck osteosarcoma. Further studies will be necessary to elucidate the clinical impact of chemotherapy in the management of head and neck osteosarcoma, and to clarify the role of chemoresistance in disease relapse, progression, and poor prognosis for survival.\n\nConclusions\nBecause of the high rate of distal metastases, surgery combined with chemotherapy is currently recommended as an essential treatment for extragnathic osteosarcoma. Local control has been suggested to be the principal prognostic factor for head and neck osteosarcoma; therefore, the achievement of wide surgical excision should be the primary goal, even during neoadjuvant chemotherapy, especially in patients who respond poorly to neoadjuvant chemotherapy.\n\nFurther studies are necessary to clarify the clinical impact of chemotherapy on tumor control or better prognosis for survival which will contribute to the establishment of the role of chemotherapy in the management of head and neck osteosarcoma.\n\nAbbreviations\nADRAdriamycin\n\nCDDPCisplatin\n\nCRComplete response\n\nCTComputed tomography\n\nDNADeoxyribonucleic acid\n\nHDHigh-dose\n\nIFOIfosfamide\n\nMRIMagnetic resonance image\n\nMTXMethotrexate\n\nNECONeoadjuvant chemotherapy in extragnathic osteosarcoma\n\nPDProgressive disease\n\nPRPartial response\n\nRECISTResponse evaluation criteria in solid tumors\n\nRNARibonucleic acid\n\nSDStable disease\n\nWHOWorld Health Organization\n\nAcknowledgements\nThe authors would like to thank the patient for giving consent.\n\nFunding\nThe authors received no funding for the writing of this manuscript.\n\nAvailability of data and materials\nAll relevant data are within the paper.\n\nAuthors’ contributions\nKT, EN, and MN contributed to the manuscript preparation. YK, KT, HT, SI, KN, KF, KS, TY, and MN contributed to patient management. SM carried out histopathologic examination. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nBecause this report involves no experiment, ethics approval is waived.\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-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Klein MJ Siegal GP Osteosarcoma: anatomic and histologic variants Am J Clin Pathol. 2006 125 555 81 10.1309/UC6KQHLD9LV2KENN 16627266 \n2. Cotterill SJ Wright CM Pearce MS Craft AW UKCCSG/MRC Bone Tumour Working Group. Stature of young people with malignant bone tumors Pediatr Blood Cancer 2004 42 59 63 10.1002/pbc.10437 14752796 \n3. Fernandes R Nikitakis NG Pazoki A Ord RA Osteogenic sarcoma of the jaw: a 10-year experience J Oral Maxillofac Surg. 2007 65 1286 91 10.1016/j.joms.2006.10.030 17577490 \n4. Mendenhall WM Fernandes R Werning JW Vaysberg M Malyapa RS Mendenhall NP Head and neck osteosarcoma Am J Otolaryngol. 2011 32 597 600 10.1016/j.amjoto.2010.09.002 21093108 \n5. Ajura AJ Lau SH A retrospective clinicopathological study of 59 osteogenic sarcoma of jaw bone archived in a stomatology unit Malays J Pathol. 2010 32 27 34 20614723 \n6. Doyle LA Sarcoma classification: an update based on the 2013 World Health Organization classification of tumors of soft tissue and bone Cancer. 2014 120 1763 74 10.1002/cncr.28657 24648013 \n7. Thiele OC Freier K Bacon C Egerer G Hofele CM Interdisciplinary combined treatment of craniofacial osteosarcoma with neoadjuvant and adjuvant chemotherapy and excision of the tumour: a retrospective study Br J Oral Maxillofac Surg. 2008 46 533 6 10.1016/j.bjoms.2008.03.010 18436357 \n8. Meyers PA Heller G Healey J Huvos A Lane J Marcove R Applewhite A Vlamis V Rosen G Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial Sloan-Kettering experience J Clin Oncol. 1992 10 5 15 10.1200/JCO.1992.10.1.5 1370176 \n9. Huber GF Dziegielewski P Wayne Matthews T Dort JC Head and neck osteosarcoma in adults: the province of Alberta experience over 26 years J Otolaryngol Head Neck Surg. 2008 37 738 43 19128686 \n10. Guadagnolo BA Zagars GK Raymond AK Benjamin RS Sturgis EM Osteosarcoma of the jaw/craniofacial region: outcomes after multimodality treatment Cancer. 2009 115 3262 70 10.1002/cncr.24297 19382187 \n11. Ha PK Eisele DW Frassica FJ Zahurak ML McCarthy EF Osteosarcoma of the head and neck: a review of the Johns Hopkins experience Laryngoscope. 1999 109 964 9 10.1097/00005537-199906000-00023 10369291 \n12. Patel SG Meyers P Huvos AG Wolden S Singh B Shaha AR Boyle JO Pfister D Shah JP Kraus DH Improved outcomes in patients with osteogenic sarcoma of the head and neck Cancer. 2002 95 1495 503 10.1002/cncr.10849 12237918 \n13. Thariat J Julieron M Brouchet A Italiano A Schouman T Marcy PY Odin G Lacout A Dassonville O Peyrottes-Birstwisles I Miller R Thyss A Isambert N Osteosarcomas of the mandible: are they different from other tumor sites? Crit Rev Oncol Hematol. 2012 82 280 95 10.1016/j.critrevonc.2011.07.001 21868246 \n14. Forteza G Colmenero B Lopez-Barea F Osteogenic sarcoma of the maxilla and mandible Oral Surg Oral Med Oral Pathol. 1986 62 179 84 10.1016/0030-4220(86)90042-3 3462614 \n15. Unni KK Dahlin DC Osteosarcoma: pathology and classification Semin Roentgenol. 1989 24 143 52 10.1016/0037-198X(89)90010-2 2772662 \n16. Kassir RR Rassekh CH Kinsella JB Segas J Carrau RL Hokanson JA Osteosarcoma of the head and neck: meta-analysis of nonrandomized studies Laryngoscope. 1997 107 56 61 10.1097/00005537-199701000-00013 9001266 \n17. Canadian Society of Otolaryngology, Head and Neck Surgery Oncology Study Group Osteogenic sarcoma of the mandible and maxilla: a Canadian review (1980–2000) J Otolaryngol 2004 33 139 44 10.2310/7070.2004.03013 15841989 \n18. Smith RB Apostolakis LW Karnell LH Koch BB Robinson RA Zhen W Menck HR Hoffman HT National Cancer Data Base report on osteosarcoma of the head and neck Cancer 2003 98 8 1670 80 10.1002/cncr.11716 14534884 \n19. Iwamoto Y Tanaka K Isu K Kawai A Tatezaki S Ishii T Kushida K Beppu Y Usui M Tateishi A Furuse K Minamizaki T Kawaguchi N Yamawaki S Multiinstitutional phase II study of neoadjuvant chemotherapy for osteosarcoma (NECO study) in Japan: NECO-93J and NECO-95J J Orthop Sci. 2009 14 397 404 10.1007/s00776-009-1347-6 19662473 \n20. Smeele LE Snow GB van der Waal I Osteosarcoma of the head and neck: meta-analysis of the nonrandomized studies Laryngoscope. 1998 108 946 10.1097/00005537-199806000-00030 9628517 \n21. van Es RJ Keus RB van der Waal I Koole R Vermey A Osteosarcoma of the jaw bones. Long-term follow up of 48 cases Int J Oral Maxillofac Surg 1997 26 191 7 9180229 \n22. August M Magennis P Dewitt D Osteogenic sarcoma of the jaws: factors influencing prognosis Int J Oral Maxillofac Surg. 1997 26 198 204 10.1016/S0901-5027(97)80819-3 9180230 \n23. Granowski-LeCornu M Chuang SK Kaban LB August M Osteosarcoma of the jaws: factors influencing prognosis J Oral Maxillofac Surg. 2011 69 2368 75 10.1016/j.joms.2010.10.023 21288615 \n24. Li X Moretti VM Ashana AO Lackman RD Impact of close surgical margin on local recurrence and survival in osteosarcoma Int Orthop. 2012 36 131 7 10.1007/s00264-011-1230-x 21404025 \n25. Ketabchi A Kalavrezos N Newman L Sarcomas of the head and neck: a 10-year retrospective of 25 patients to evaluate treatment modalities, function and survival Br J Oral Maxillofac Surg. 2011 49 116 20 10.1016/j.bjoms.2010.02.012 20416997 \n26. Liebermann DA Hoffman B Steinman RA Molecular controls of growth arrest and apoptosis: p53-dependent and independent pathways Oncogene. 1995 11 199 210 7624128 \n27. Guo W Healey JH Meyers PA Ladanyi M Huvos AG Bertino JR Gorlick R Mechanisms of methotrexate resistance in osteosarcoma Clin Cancer Res. 1999 5 621 7 10100715 \n28. Uozaki H Horiuchi H Ishida T Iijima T Imamura T Machinami R Overexpression of resistance-related proteins (metallothioneins, glutathione-S-transferase pi, heat shock protein 27, and lung resistance-related protein) in osteosarcoma. Relationship with poor prognosis Cancer. 1997 79 2336 44 10.1002/(SICI)1097-0142(19970615)79:12<2336::AID-CNCR7>3.0.CO;2-J 9191521 \n29. Huang G Mills L Worth LL Expression of human glutathione S-transferase P1 mediates the chemosensitivity of osteosarcoma cells Mol Cancer Ther. 2007 6 1610 9 10.1158/1535-7163.MCT-06-0580 17513610 \n30. Wang D Luo M Kelley MR Human apurinic endonuclease 1 (APE1) expression and prognostic significance in osteosarcoma: enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE1 expression inhibition Mol Cancer Ther. 2004 3 679 86 10.4161/cbt.3.7.967 15210853 \n31. Posthumadeboer J van Egmond PW Helder MN de Menezes RX Cleton-Jansen AM Targeting JNK-interacting-protein-1 (JIP1) sensitises osteosarcoma to doxorubicin Oncotarget. 2012 3 1169 81 10.18632/oncotarget.600 23045411 \n32. Lambert LA Qiao N Hunt KK Lambert DH Mills GB Meijer L Keyomarsi K Autophagy: a novel mechanism of synergistic cytotoxicity between doxorubicin and roscovitine in a sarcoma model Cancer Res. 2008 68 7966 74 10.1158/0008-5472.CAN-08-1333 18829554 \n33. Gougelet A Pissaloux D Besse A Perez J Duc A Dutour A Blay JY Alberti L Micro-RNA profiles in osteosarcoma as a predictive tool for ifosfamide response Int J Cancer. 2011 129 680 90 10.1002/ijc.25715 20949564 \n34. Fujii H Honoki K Tsujiuchi T Kido A Yoshitani K Takakura Y Sphere-forming stem-like cell populations with drug resistance in human sarcoma cell lines Int J Oncol. 2009 34 1381 6 19360350\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "11(1)",
"journal": "Journal of medical case reports",
"keywords": "Chemotherapy; Conventional osteosarcoma; Head and neck; Mandible",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008339:Mandibular Neoplasms; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local; D012516:Osteosarcoma; D011379:Prognosis; D016896:Treatment Outcome",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "210",
"pmc": null,
"pmid": "28764797",
"pubdate": "2017-08-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21288615;24648013;3462614;9180230;9628517;12237918;23045411;19128686;17513610;19662473;17577490;20614723;14752796;9180229;16627266;18436357;10369291;19382187;21868246;2772662;20949564;15841989;18829554;15210853;9001266;20416997;1370176;19360350;21093108;14534884;7624128;21404025;9191521;10100715",
"title": "Conventional osteosarcoma of the mandible successfully treated with radical surgery and adjuvant chemotherapy after responding poorly to neoadjuvant chemotherapy: a case report.",
"title_normalized": "conventional osteosarcoma of the mandible successfully treated with radical surgery and adjuvant chemotherapy after responding poorly to neoadjuvant chemotherapy a case report"
} | [
{
"companynumb": "PHHY2017JP121425",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Lymphadenopathy can occur at any stage of HIV infection, with multiple aetiologies including reactive, infectious and malignant. An accurate and timely diagnosis has obvious implications for treatment. We report cryptococcal lymphadenitis as the presenting manifestation of HIV infection. The diagnosis in our patient was eventually confirmed with a lymph node biopsy. Fine needle aspiration cytology has been shown to be a rapid and cost-effective method, which has been used in the diagnosis of lymphadenopathy in HIV infection, and could have been used to make an earlier diagnosis in our patient.",
"affiliations": "Department of Internal Medicine, Yale New Haven Hospital, Saint Raphael Campus, New Haven, Connecticut, USA.",
"authors": "Dogbey|Pia|P|;Golden|Marjorie|M|;Ngo|Nhu|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D003453:Cryptococcosis; D005260:Female; D006801:Humans; D008199:Lymphadenitis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24014328",
"pubdate": "2013-09-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20608767;20306981;21534892;19610510;12627365;19776151;18097114;16321643;22882869;19843144;19008570",
"title": "Cryptococcal lymphadenitis: an unusual initial presentation of HIV infection.",
"title_normalized": "cryptococcal lymphadenitis an unusual initial presentation of hiv infection"
} | [
{
"companynumb": "US-GILEAD-2013-0088404",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo describe a case of subtherapeutic international normalized ratio (INR) associated with concomitant use of warfarin and banana flakes in a patient with diarrhea.\n\n\nCONCLUSIONS\nA man in his 30s was hospitalized for an elective procedure, but his stay was complicated by cerebral venous thrombosis requiring intravenous infusion of unfractionated heparin, ventilator-associated pneumonia, bacteremia requiring broad-spectrum antimicrobials and percutaneous endoscopic gastrostomy tube placement, and diarrhea. Eventually, the heparin was transitioned to warfarin. After several days of therapeutic INR, the INR became subtherapeutic and remained so for 3 days. The decreased INR correlated temporally with initiation of consistent administration of dried banana flakes to treat diarrhea and the subsequent decrease in the rate and extent of diarrhea. Diarrhea decreases the amount and activity of vitamin K-producing intestinal flora and dietary vitamin K absorption, resulting in increased INR. Resolution of diarrhea secondary to banana flakes administration in this patient may have contributed to the decreased INR by causing a relative increase in vitamin K-producing flora and vitamin K absorption. A probability score of 5 was obtained upon applying the Drug Interaction Probability Scale modified to address interactions between warfarin and dietary supplements, indicating a probable interaction between warfarin and banana flakes.\n\n\nCONCLUSIONS\nConcomitant use of warfarin and banana flakes supplements may result in a reduced rate and extent of diarrhea and may be associated with subtherapeutic INR and decreased warfarin efficacy. Practitioners must be aware of this potential interaction and closely monitor INR and adjust warfarin doses accordingly.",
"affiliations": "Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, Pennsylvania amber.king@jefferson.edu.;Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, Pennsylvania.",
"authors": "King|Amber E|AE|;Strnad|Kyle|K|",
"chemical_list": "D000925:Anticoagulants; D014812:Vitamin K; D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": "10.1177/0884533615591056",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0884-5336",
"issue": "31(1)",
"journal": "Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition",
"keywords": "International Normalized Ratio; prothrombin time; vitamin K; vitamin K deficiency bleeding; warfarin",
"medline_ta": "Nutr Clin Pract",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D002561:Cerebrovascular Disorders; D003967:Diarrhea; D019587:Dietary Supplements; D004347:Drug Interactions; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D028521:Musa; D020246:Venous Thrombosis; D014812:Vitamin K; D014859:Warfarin",
"nlm_unique_id": "8606733",
"other_id": null,
"pages": "125-31",
"pmc": null,
"pmid": "26137942",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Probable Interaction Between Warfarin and Banana Flakes Supplement.",
"title_normalized": "probable interaction between warfarin and banana flakes supplement"
} | [
{
"companynumb": "PHHY2016US013802",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "The outcome of SARS-CoV2 infection in patients who have received a kidney allograft and are being treated with immunosuppression is unclear. We describe 20 kidney transplant recipients (median age 59 years [inter quartile range 51-64 years], median age of transplant 13 years [9-20 years], baseline eGFR 36.5 [23-47.5]) with SARS-CoV2 induced pneumonia. At admission, all had immunosuppression withdrawn and were started on methylprednisolone 16 mg/day, all but one was commenced on antiviral therapy and hydroxychloroquine with doses adjusted for kidney function. At baseline, all patients presented fever but only one complained of difficulty in breathing. Half of patients showed chest radiographic evidence of bilateral infiltrates while the other half showed unilateral changes or no infiltrates. During a median follow-up of seven days, 87% experienced a radiological progression and among those 73% required escalation of oxygen therapy. Six patients developed acute kidney injury with one requiring hemodialysis. Six of 12 patients were treated with tocilizumab, a humanized monoclonal antibody to the IL-6 receptor. Overall, five kidney transplant recipients died after a median period of 15 days [15-19] from symptom onset. These preliminary findings describe a rapid clinical deterioration associated with chest radiographic deterioration and escalating oxygen requirement in renal transplant recipients with SARS-Cov2 pneumonia. Thus, in this limited cohort of long-term kidney transplant patients, SARS-CoV-2 induced pneumonia is characterized by high risk of progression and significant mortality.",
"affiliations": "Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy; Nephrology Unit, Spedali Civili Hospital, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy. Electronic address: federico.alberici@unibs.it.;Nephrology Unit, Spedali Civili Hospital, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy.;Nephrology Unit, Spedali Civili Hospital, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy.;Nephrology Unit, Spedali Civili Hospital, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy.;Nephrology Unit, Spedali Civili Hospital, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy.;Nephrology Unit, Spedali Civili Hospital, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy.;Nephrology Unit, Spedali Civili Hospital, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy.;Nephrology Unit, Spedali Civili Hospital, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy.;Nephrology Unit, Spedali Civili Hospital, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy.;Nephrology Unit, Spedali Civili Hospital, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy.;Nephrology Unit, Spedali Civili Hospital, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy.;Nephrology Unit, Spedali Civili Hospital, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy.;Nephrology Unit, Spedali Civili Hospital, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy.;Nephrology Unit, Spedali Civili Hospital, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy.;Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy; Nephrology Unit, Spedali Civili Hospital, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy.",
"authors": "Alberici|Federico|F|;Delbarba|Elisa|E|;Manenti|Chiara|C|;Econimo|Laura|L|;Valerio|Francesca|F|;Pola|Alessandra|A|;Maffei|Camilla|C|;Possenti|Stefano|S|;Zambetti|Nicole|N|;Moscato|Marianna|M|;Venturini|Margherita|M|;Affatato|Stefania|S|;Gaggiotti|Mario|M|;Bossini|Nicola|N|;Scolari|Francesco|F|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; C502936:tocilizumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.kint.2020.04.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0085-2538",
"issue": "97(6)",
"journal": "Kidney international",
"keywords": "acute kidney injury; inflammation; tocilizumab; transplantation",
"medline_ta": "Kidney Int",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D018450:Disease Progression; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D007558:Italy; D016030:Kidney Transplantation; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D010102:Oxygen Inhalation Therapy; D058873:Pandemics; D011024:Pneumonia, Viral; D011379:Prognosis; D000086402:SARS-CoV-2; D066027:Transplant Recipients; D016896:Treatment Outcome",
"nlm_unique_id": "0323470",
"other_id": null,
"pages": "1083-1088",
"pmc": null,
"pmid": "32354634",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "30586620;22890468;31986264;32292866;32167524;32205204",
"title": "A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia.",
"title_normalized": "a single center observational study of the clinical characteristics and short term outcome of 20 kidney transplant patients admitted for sars cov2 pneumonia"
} | [
{
"companynumb": "IT-ACCORD-181933",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "A 61-year-old man with relapsing chronic lymphocytic leukaemia, status post allogeneic stem cell transplant and multiple chemotherapy regimens presented to the emergency room after suffering a grand mal seizure. His evaluation revealed a 1.5-2 cm ring-enhancing left temporal lobe brain lesion on the CT scan. This brain lesion was resected and the histopathology revealed an invasive fungal organism resembling mucormycosis. Amplification and sequencing of the 28S ribosomal RNA gene identified the organism as Rhizomucor pusillus The patient was treated with liposomal amphotericin B 5 mg/kg every 24 hours for 4 weeks, and then was transitioned to oral posaconazole. Serial brain imaging at 1 and 3 months, while on therapy, showed significant improvement.",
"affiliations": "Department of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.;Department of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.;Department of Clinical Microbiology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Farid|Saira|S|;AbuSaleh|Omar|O|;Liesman|Rachael|R|;Sohail|Muhammad Rizwan|MR|http://orcid.org/0000-0001-6499-5543",
"chemical_list": "D000935:Antifungal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-221473",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "infection (neurology); infectious diseases",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000666:Amphotericin B; D000935:Antifungal Agents; D001922:Brain Abscess; D003937:Diagnosis, Differential; D006801:Humans; D016867:Immunocompromised Host; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D009091:Mucormycosis; D020103:Rhizomucor; D012640:Seizures; D033581:Stem Cell Transplantation; D013702:Temporal Lobe; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28978601",
"pubdate": "2017-10-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24091920;18611163;26897065;7888545;24957094;21482731;16262876;21482725;26706615;16080086;16269155;19228642",
"title": "Isolated cerebral mucormycosis caused by Rhizomucor pusillus.",
"title_normalized": "isolated cerebral mucormycosis caused by rhizomucor pusillus"
} | [
{
"companynumb": "US-TEVA-824432USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "A 72-year-old man visited our hospital because of dysphagia and weight loss. He was diagnosed by endoscopy with advanced (stage IV) basaloid squamous carcinoma of the thoracic esophagus. CT and CT-guided tumor biopsy revealed two lung metastases in the right upper and lower lobes, with diameters of 8 and 5 mm, respectively. The primary lesion disappeared after concurrent chemoradiotherapy consisting of 5-FU, cisplatin, and 60-Gy irradiation, which was administered for palliation of obstructive and hemorrhagic symptoms. Subsequently, eight cycles of chemotherapy were administered, resulting in a reduction in size of the metastases. However, multiple cycles of chemotherapy caused prolonged toxicity, and the metastases slightly enlarged during chemotherapy-free periods. Since the number of metastases did not change, stereotactic body radiotherapy was performed, which resulted in disappearance of the lung metastases. Five years following initial diagnosis, the patient has been doing well, with no signs of disease recurrence.",
"affiliations": "Department of Clinical Oncology, Hiroshima Prefectural Hospital.",
"authors": "Yamauchi|Masami|M|;Shinozaki|Katsunori|K|;Sumioka|Masaaki|M|;Nishisaka|Takashi|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.11405/nisshoshi.112.1503",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0446-6586",
"issue": "112(8)",
"journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology",
"keywords": null,
"medline_ta": "Nihon Shokakibyo Gakkai Zasshi",
"mesh_terms": "D000368:Aged; D002281:Carcinoma, Basosquamous; D059248:Chemoradiotherapy; D004938:Esophageal Neoplasms; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009367:Neoplasm Staging",
"nlm_unique_id": "2984683R",
"other_id": null,
"pages": "1503-9",
"pmc": null,
"pmid": "26250130",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Long-term survival of a patient with stage IV basaloid squamous carcinoma of the esophagus with lung metastases following combined modality therapy.",
"title_normalized": "long term survival of a patient with stage iv basaloid squamous carcinoma of the esophagus with lung metastases following combined modality therapy"
} | [
{
"companynumb": "JP-MYLANLABS-2015M1034966",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nGhan-Shyam Lohiya MD provided medico-legal opinions as a Qualified Medical Evaluator (Occupational Medicine & Toxicology) supporting a related workers' compensation death claim. Dr G. Lohiya received partial payments for his services from Gallagher Bassett Services Company (workers' compensation insurance adjuster for the patient's employer). Sonia Krishna MD, Sapna Lohiya and Sunita Lohiya MD: No actual or potential, real or perceived conflict of interest in the drugs, devices or procedures described in the enclosed manuscript.\nA patient died of renal failure related to treatment of a hand contusion with ibuprofen and valdecoxib. Her hospital records revealed several incorrect and mutually conflicting statements about seven historical items in the Initial Evaluation Reports authored by five treating physicians. There were errors of commission (relying on imperfect memory, acquiescing erroneous information), and errors of omission (failure to proofread transcribed reports, question and resolve contradictory statements in sister reports, obtain correct history, and review prior medical records). Such errors wrongly implied that patient had preexisting conditions (advanced renal failure, diabetes mellitus, hypertension, asthma and alcoholism) which caused her death, and negatively impacted her workers' compensation claim. Incorrect allergy history was also noted. Preventive measures are suggested.\nAt the 53rd Quarterly Grand Rounds in Costa Mesa, California.",
"affiliations": "Royal Medical Group. Electronic address: gslohiya@gmail.com.;Department of Oral & Maxillo-Facial Surgery, University of Washington.;Department of Psychiatry, University of California at Los Angeles.;Royal Medical Group.",
"authors": "Lohiya|Ghan-Shyam|GS|;Lohiya|Sapna|S|;Krishna|Sonia|S|;Lohiya|Sunita|S|",
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"issn_linking": "0027-9684",
"issue": "107(3)",
"journal": "Journal of the National Medical Association",
"keywords": "Errors; Hospital Records; Patient History; medico-legal cases; side-effects",
"medline_ta": "J Natl Med Assoc",
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"publication_types": "D016428:Journal Article",
"references": null,
"title": "Errors in Patient History in Hospital Records.",
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"abstract": "An 18-year-old woman developed Stevens-Johnson syndrome (SJS) with ocular involvement after taking ibuprofen. She was admitted to another hospital, received saline flushes and bacitracin ophthalmic ointment to the eyes, and became unable to open them. Upon transfer to this burn center 3 weeks after symptom onset, there was complete fusion of both eyelids with no visible cornea or sclera. She underwent bilateral operative scar release. After opening the lids, meticulous debridement of cicatricial membranes and release of symblephara were performed with subsequent placement of amniotic membrane grafts. Her vision slowly improved, though her long-term visual prognosis remains guarded. Early recognition and treatment of SJS or toxic epidermal necrolysis (TEN) with ocular involvement is imperative. Even mild cases may require intensive topical lubrication, steroids, and antibiotics, with early placement of amniotic membrane grafts in severe cases. Prompt intervention and daily evaluation are paramount in preventing lifelong visual disability.",
"affiliations": "Department of Ophthalmology, Brooke Army Medical Center, Fort Sam Houston, Texas, USA.;U.S. Army Institute of Surgical Research, Fort Sam Houston, Texas, USA.;Department of Ophthalmology, Brooke Army Medical Center, Fort Sam Houston, Texas, USA.;Department of Ophthalmology, Brooke Army Medical Center, Fort Sam Houston, Texas, USA.;Department of Ophthalmology, Brooke Army Medical Center, Fort Sam Houston, Texas, USA.;Department of Ophthalmology, Brooke Army Medical Center, Fort Sam Houston, Texas, USA.;Department of Ophthalmology, Brooke Army Medical Center, Fort Sam Houston, Texas, USA.",
"authors": "Santamaria|Joseph A|JA|;Cancio|Leopoldo C|LC|;Reed|Donovan|D|;Phillips|Hunter|H|;Chen|Sien|S|;Carlton|Darrel K|DK|;Johnson|Anthony J|AJ|",
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"issue": "42(5)",
"journal": "Journal of burn care & research : official publication of the American Burn Association",
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"pubdate": "2021-09-30",
"publication_types": "D016428:Journal Article",
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"title": "Complete Fusion of Both Eyelids in Stevens-Johnson Syndrome: Case Report.",
"title_normalized": "complete fusion of both eyelids in stevens johnson syndrome case report"
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"abstract": "BACKGROUND\nThe incidence of pregnancy in women with end-stage renal disease seems to be increasing. Improvements in dialysis, obstetrical care, and antenatal fetal monitoring over the past two decades appear to have increased fertility rates and successful pregnancies in dialysis-dependent women. A pregnancy with a successful outcome despite the long dialysis period, as in the patient described here, is very rarely reported in the literature.\n\n\nMETHODS\nI report a case of a 34-year-old white Kurdish woman who had had two uncomplicated pregnancies while on hemodialysis, with delivery of healthy babies. The first pregnancy occurred in the eighth year of her hemodialysis and ended in the 32nd week of gestation with healthy vaginal delivery of a 1900-g baby. The second pregnancy occurred in the 14th year of her hemodialysis and ended in the 30th week of gestation, with vaginal delivery of a 1400-g baby. The second baby, who had respiratory problems, was discharged after 45 days of intensive care.\n\n\nCONCLUSIONS\nAlthough pregnancy during the hemodialysis is risky, the outcomes of the pregnancies could be improved by an intensive hemodialysis regimen, appropriate anemia management, strict blood pressure follow-up, and correct evaluation of the dry weight.",
"affiliations": "Department of Nephrology, Kars State Hospital, Kars, Turkey. drayse14@hotmail.com.",
"authors": "Seker|Ayse|A|",
"chemical_list": null,
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"doi": "10.1186/s13256-016-0836-4",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 83610.1186/s13256-016-0836-4Case ReportTwo successive pregnancies in a patient during 14 years of hemodialysis: a case report Seker Ayse drayse14@hotmail.com Department of Nephrology, Kars State Hospital, Kars, Turkey 8 3 2016 8 3 2016 2016 10 5019 11 2015 14 2 2016 © Seker. 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\nThe incidence of pregnancy in women with end-stage renal disease seems to be increasing. Improvements in dialysis, obstetrical care, and antenatal fetal monitoring over the past two decades appear to have increased fertility rates and successful pregnancies in dialysis-dependent women. A pregnancy with a successful outcome despite the long dialysis period, as in the patient described here, is very rarely reported in the literature.\n\nCase presentation\nI report a case of a 34-year-old white Kurdish woman who had had two uncomplicated pregnancies while on hemodialysis, with delivery of healthy babies. The first pregnancy occurred in the eighth year of her hemodialysis and ended in the 32nd week of gestation with healthy vaginal delivery of a 1900-g baby. The second pregnancy occurred in the 14th year of her hemodialysis and ended in the 30th week of gestation, with vaginal delivery of a 1400-g baby. The second baby, who had respiratory problems, was discharged after 45 days of intensive care.\n\nConclusions\nAlthough pregnancy during the hemodialysis is risky, the outcomes of the pregnancies could be improved by an intensive hemodialysis regimen, appropriate anemia management, strict blood pressure follow-up, and correct evaluation of the dry weight.\n\nKeywords\nEnd stage renal diseaseHemodialysisTwo successful pregnanciesVaginal deliveryCase reportissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nWomen of childbearing age seldom become pregnant while on chronic dialysis, owing to disturbances in the hypothalamic-pituitary-ovarian axis and other associated psychological factors [1, 2]. The incidence of pregnancy, defined by a gestational age of 3 months or more, was reported in one study to be only 0.3 per 100 patient-years over a period of 20 years, even in women of reproductive age; the successful live birth rate was less than 60 % [3]. The risk of intrauterine growth retardation, polyhydramnios, and premature rupture of membranes in this clinical setting is increased. Most living babies are born prematurely. Although advances in dialysis technology, obstetrical monitoring, and neonatal intensive care over the last 20 years have dramatically improved fetal survival rates to roughly 80 %, fetal mortality in pregnant women on dialysis is still much higher than in the general population [4]. Our patient, despite long duration of dialysis (first pregnancy in 8th year and second in 14th year of dialysis) gave birth to two healthy babies, which is rarely reported in the literature.\n\nCase presentation\nFirst pregnancy\nA 34-year-old white Kurdish woman, gravida 4, para 3, has been on regular hemodialysis in our center for 14 years due to hypertensive nephrosclerosis. She had cerebrovascular disease at the age of 20 years and at that time was diagnosed with hypertension and end-stage renal disease. She was started on hemodialysis 4 h/day, 3 days/week. She was admitted to the author’s clinic with suspected pregnancy in the 8th year of dialysis. A pregnancy at 14 weeks of gestation was been detected on her pelvic ultrasound. She was receiving cilazapril 5 mg/day for hypertension, which was discontinued after diagnosis of pregnancy. She underwent hemodialysis 5 h/day, 6 days/week until the end of her pregnancy. Her dialysis access was via an arteriovenous fistula, and conventional hemodialysis was performed. She did not need antihypertensive medication during this pregnancy. She was given recombinant human erythropoietin, intravenous iron, calcium, and folic acid. In the 32nd week of gestation, she was admitted to the hospital with early membrane rupture. Intramuscular betamethasone was administered twice with an interval of 24 h to induce fetal lung maturation. The patient subsequently delivered a healthy, 1900-g girl. In the postpartum follow-up, neither the mother nor the baby developed a complication.\n\nSecond pregnancy\nIn the 14th year of the patient’s dialysis treatment, she presented with amenorrhea of 3 months’ duration. Her β-human chorionic gonadotropin blood test result was positive, and a pelvic ultrasound confirmed a single 12-week gestational age fetus. The patient was taking valsartan 160 mg/day and amlodipine 10 mg/day for hypertension. Valsartan was discontinued after her pregnancy diagnosis. Her dialysis regimen was intensified to a regimen consisting of 30 h/week (5-h treatment sessions on 6 days/week). During dialysis, 1.5 m2 polysulfone and a high-flux dialyzer were used and blood flow rate was kept at a level of 280 ml/minute on average. The patient was started on a 2000 kcal/day, 1.5 g/kg/day protein-rich diet. She was anticoagulated with unfractionated heparin. Her blood pressure (BP) was well controlled after intensive hemodialysis, and amlodipine was discontinued. Without any antihypertensive medication, her systolic BP remained at 110–140 mmHg and her diastolic BP was consistently 70–90 mmHg. Anemia was managed with subcutaneous recombinant human erythropoietin three times per week and intravenous iron without transfusion. The median erythropoietin dose was 12,000 international units (IU)/week (range 6,000–18,000 IU/week). Folic acid 1 mg/day and calcium 1500 mg/day were added to her medications. Dialysate bicarbonate content of 30 mEq/L was set to prevent pregnancy-induced respiratory alkalosis. The dialysate contained 1 g/L of glucose, 1.25 mEq/L of calcium, and 3 mEq/L of potassium. The estimated dry weight of the patient was increased according to her weight gain. Her dry weight was 54 kg in the beginning of pregnancy, and her weight gain was 9 kg during the pregnancy. Ultrasonography revealed polyhydramnios at 28 weeks.\n\nIn the 30th week of pregnancy, the patient’s contractions began and she had a preterm vaginal delivery of a boy weighing 1400 g. The baby, whose Apgar scores were 5 at the 1st minute and 8 at the 5th minute was taken to the intensive care unit because of his respiratory problem. Forty-five days later, the baby was discharged healthy.\n\nDiscussion\nAccording to data obtained from the European Dialysis and Transplant Association (EDTA) and national registries, the conception rate for women receiving dialysis is between 0.3 and 0.75/year/patient [3, 5]. The possibility of conception and successful conclusion of pregnancy are much higher in women who have residual renal function, and the prognosis for pregnancies is better if conception has occurred before starting dialysis. Giatras et al. [6] demonstrated that 47 % of pregnancies among women in their population were successful during the first 2 years of dialysis, whereas only 6 of the 120 pregnancies of women with 10 years of treatment had successful outcomes. In the literature, there are reports of pregnancies of women with 10 years of dialysis, but positive outcomes of these pregnancies are extremely rare [5, 7, 8]. It has been shown that the prognosis for successful conclusion of pregnancy is better for patients who begin dialysis after the onset of pregnancy as compared with patients who are already on dialysis (72.6 % vs 37.5 %, respectively) [4]. As for my patient, she conceived twice, the first time 8 years and the second time 14 years after she had started hemodialysis. The first baby was discharged without a need for intensive care, and the second was discharged healthy after 45 days of intensive care. A pregnancy with a successful outcome despite the long dialysis period as in my patient is very rarely reported in the literature. Several potential determinants of the pregnancy outcomes in such patients are residual renal function, parity, age, and maternal diseases such as hypertension. Although my patient was hypertensive during 14 years of dialysis, she was normotensive in her pregnancies. The reason for this may be 5 h/day, 6 days/week intensive hemodialysis and correct evaluation of dry weight.\n\nThe literature contains two reports of cases of three successive pregnancies while the patients were on hemodialysis [9, 10]. In a case report by Malik et al., only the first pregnancy was full-term and successful. The second pregnancy ended in premature delivery. The third pregnancy ended with antepartum hemorrhage due to placenta previa and rupture of the uterus [9]. The babies died after birth at the end of the last two pregnancies. Three successful pregnancies were also reported in a patient with chronic renal disease whose primary disease was immunoglobulin A nephropathy. In that patient, the first conception occurred in the predialysis period, hemodialysis was started at the end of the first trimester of the second pregnancy, and she conceived for the third time in the second year of dialysis [10]. At the end of the each of the three pregnancies, the babies were discharged healthy.\n\nThe past three decades have seen substantial improvements in both fertility and successful pregnancy rates in women with chronic renal failure. Since the first case report of a successful pregnancy on dialysis in 1971 [11] and the case series reported in the 1980s that suggested high rates of preterm birth, low birth weight, and refractory hypertension, the overall prognosis for these patients has improved significantly [12]. Some evidence suggests that these improvements may be due to the recognition that a more intensive dialysis regimen may be beneficial. Uremia results in increased delivery of urea to the fetus and increases fetal solute load, which may lead to fetal diuresis and resultant polyhydramnios, thereby increasing risks of preterm birth and preterm rupture of membranes. To minimize the effects of uremia on pregnancy outcomes, dialysis regimens were adjusted with the goal of attaining maximum predialysis urea levels of 100 mg/dl or less. In subsequent case reports, authors have described improved perinatal outcome with intensive dialysis. Intensive dialysis regimens are believed to reduce the fetal uremic environment, minimize large fluid shifts and placental hypoperfusion, and allow greater dietary freedom with nutritional benefits [13]. In a systematic review [14], the relationship between dialysis schedule and pregnancy outcomes in pregnancies was analyzed in chronic dialysis in the new millennium. A total of 681 pregnancies were included in that review. The most frequently reported dialysis schedule was 3.5–4 h in five to six sessions per week. The authors of that review concluded that dialysis frequency and dialysis duration expressed as the number of hours per week were significantly correlated with two major outcomes: prematurity and delivery of a small for gestational age (SGA) baby (SGA defined as birth weight less than the tenth percentile according to international standards). The facts that my patient was young (with the first pregnancy at age 28 years and the second at 34) and her hypertension was not observed during follow-up, and that with her intensive hemodialysis regimen her blood urea level could mostly be kept below 100 mg/dl, might have contributed to the successful conclusions of her pregnancies.\n\nConclusions\nThe most important factor affecting fetal and maternal prognosis is the degree of renal functional impairment at conception. A pregnancy with a successful outcome despite more than 10 years of dialysis, as in my patient, is very rarely reported in the literature. Her successful pregnancies were obtained by using an intensive hemodialysis regimen, appropriate anemia management, strict BP follow-up, and correct evaluation of her dry weight.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nBPblood pressure\n\nEDTAEuropean Dialysis and Transplant Association\n\nESRDend-stage renal disease\n\nIUinternational units\n\nSGAsmall for gestational age\n\nCompeting interests\n\nThe author declares that she has no competing interests.\n==== Refs\nReferences\n1. Espersen T Schmitz O Hansen HE Ovulation in uremic women: the reproductive cycle in women on chronic hemodialysis Int J Fertil. 1988 33 103 6 2898446 \n2. Diemont WL Vruggink PA Meuleman EJ Sexual dysfunction after renal replacement therapy Am J Kidney Dis. 2000 35 845 51 10.1016/S0272-6386(00)70254-X 10793018 \n3. Bagon JA Vernaeve H De Muylder X Pregnancy and dialysis Am J Kidney Dis. 1998 31 756 65 10.1016/S0272-6386(98)70060-5 9590184 \n4. Okundaye I Abrinko P Hou S Registry of pregnancy in dialysis patients Am J Kidney Dis. 1998 31 766 73 10.1016/S0272-6386(98)70044-7 9590185 \n5. Hou SH Frequency and outcome of pregnancy in women on dialysis Am J Kidney Dis. 1994 23 60 3 10.1016/S0272-6386(12)80813-4 8285199 \n6. Giatras I Levy DP Malone FD Carlson JA Jungers P Pregnancy during dialysis: case report and management guidelines Nephrol Dial Transplant. 1998 13 3266 72 10.1093/ndt/13.12.3266 9870513 \n7. Nakabayashi M Adachi T Itoh S Kobayashi M Mishina J Nishida H Perinatal and infant outcome of pregnant patients undergoing chronic hemodialysis Nephron. 1999 82 27 31 10.1159/000045364 10224481 \n8. Reister F Reister B Heyl W Riehl J Schroder W Mann H Dialysis and pregnancy – a case report and review of the literature Ren Fail. 1999 21 533 9 10.3109/08860229909045193 10516998 \n9. Malik GA Al-Wakeel JS Shaik JF Three successive pregnancies in a patient on haemodialysis Nephrol Dial Transplant. 1997 12 1991 3 10.1093/ndt/12.9.1991 9306358 \n10. Giofrè F Pugliese C Alati G Messina A Tramontana D Three successive pregnancies in a patient with chronic renal disease progressing from chronic renal dysfunction through to institution of dialysis during pregnancy and then on to maintenance dialysis Nephrol Dial Transplant. 2007 22 1236 40 10.1093/ndt/gfl794 17237479 \n11. Confortini P Galanti G Ancona G Giongo A Bruschi E Lorenzini E Full term pregnancy and successful delivery in a patient on chronic haemodialysis Proc Eur Dial Transplant Assoc. 1971 8 74 80 \n12. Registration Committee European Dialysis and Transplant Association Successful pregnancies in women treated by dialysis and kidney transplantation Br J Obstet Gynaecol 1980 87 839 45 10.1111/j.1471-0528.1980.tb04434.x 7000160 \n13. Smith WT Darbari S Kwan M O’Reilly-Green C Devita MV Pregnancy in peritoneal dialysis: a case report and review of adequacy and outcomes Int Urol Nephrol. 2005 37 145 51 10.1007/s11255-004-2312-0 16132778 \n14. Piccoli GB Minelli F Versino E Cabiddu G Attini R Vigotti FN Rolfo A Giuffrida D Colombi N Pani A Todros T Pregnancy in dialysis patients in the new millennium: a systematic review and meta-regression analysis correlating dialysis schedules and pregnancy outcomes Nephrol Dial Transplant 2015 0 1 20\n\n",
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"abstract": "Schizophrenia is a severe mental disorder characterised by positive and negative symptoms. Negative symptoms are difficult to treat and there is no specific treatment. In small trials, modafinil has been studied in association with antipsychotic treatment. We present three cases of its use; two have developed positive symptoms and one developed renal impairment. Further studies are needed to assess its usefulness in schizophrenia and safety in this group of patients.",
"affiliations": "Departamento de Psiquiatria e Saúde Mental, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.;Departamento de Psiquiatria e Saúde Mental, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.;Departamento de Psiquiatria e Saúde Mental, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.",
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"title": "Modafinil in schizophrenia: is the risk worth taking?",
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"abstract": "Capillary leak syndrome (CLS) is a rare disorder associated with an increased capillar permeability due to an endothelial damage, causing leakage of plasma and proteins into the interstitial compartment. CLS is characterized by rapidly developing edema, hypotension and hypoproteinemia. We observed CLS in a 54-year-old man affected by muscle-invasive bladder cancer who received neoadjuvant treatment with Cisplatin and Gemcitabine. Treatment with infusion of albumin and increasing corticosteroid doses and diuretics led to a complete regression of all signs and symptoms related to the disorder. Of note, the patient showed an objective complete response to chemotherapy and underwent radical surgery on schedule.",
"affiliations": "Department of Human Pathology \"G. Barresi\", Medical Oncology Unit, University of Messina, 98122, Messina, Italy.;Department of Human Pathology \"G. Barresi\", Medical Oncology Unit, University of Messina, 98122, Messina, Italy.;Department of Human Pathology \"G. Barresi\", Medical Oncology Unit, University of Messina, 98122, Messina, Italy.;Department of Human Pathology \"G. Barresi\", Medical Oncology Unit, University of Messina, 98122, Messina, Italy.;Department of Human Pathology \"G. Barresi\", Medical Oncology Unit, University of Messina, 98122, Messina, Italy.",
"authors": "Massafra|Marco|M|;Passalacqua|Maria Ilenia|MI|;Lupo|Giuseppe|G|;Altavilla|Giuseppe|G|;Santarpia|Mariacarmela|M|",
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"fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420\nElsevier\n\nS2214-4420(20)30350-8\n10.1016/j.eucr.2020.101461\n101461\nOncology\nCapillary leak syndrome induced by neoadjuvant cisplatin and gemcitabine in a patient with bladder cancer\nMassafra Marco marcomassafra@hotmail.it\n∗1\nPassalacqua Maria Ilenia ∗\nLupo Giuseppe\nAltavilla Giuseppe\nSantarpia Mariacarmela\nDepartment of Human Pathology “G. Barresi”, Medical Oncology Unit, University of Messina, 98122, Messina, Italy\n∗ Corresponding author. Department of Human Pathology \"G. Barresi\", Medical Oncology Unit, University of Messina, 98122 Messina, Italy. marcomassafra@hotmail.it\n1 Equally contributed.\n\n21 10 2020\n1 2021\n21 10 2020\n34 10146115 9 2020\n18 10 2020\n20 10 2020\n© 2020 The Authors\n2020\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nCapillary leak syndrome (CLS) is a rare disorder associated with an increased capillar permeability due to an endothelial damage, causing leakage of plasma and proteins into the interstitial compartment. CLS is characterized by rapidly developing edema, hypotension and hypoproteinemia. We observed CLS in a 54-year-old man affected by muscle-invasive bladder cancer who received neoadjuvant treatment with Cisplatin and Gemcitabine. Treatment with infusion of albumin and increasing corticosteroid doses and diuretics led to a complete regression of all signs and symptoms related to the disorder. Of note, the patient showed an objective complete response to chemotherapy and underwent radical surgery on schedule.\n\nKeywords\n\nCapillary leak syndrome\nBladder cancer\nGemcitabine\n==== Body\nIntroduction\n\nCapillary leak syndrome (CLS) is a rare clinical condition characterized by rapid and reversible increase in endothelial permeability, with consequent leakage of plasma proteins into the interstitial space, with peripheral edema.1 A similar phenomenon is observed during sepsis and less frequently in some manifestations of autoimmune diseases. This syndrome can be suspected in patients with hypotension, hypoalbuminemia without organ failure, partial or generalized edema, hemoconcentration and possible presence of paraproteins in the blood.\n\nIt can be idiopathic, called Clarkson's syndrome, or induced by other factors. In all cases, it can be a life-threatening condition. Among the causes that trigger this syndrome are counted some drugs, the engraftment syndrome, promyelocytic leukemia which undergoes induction treatment with either all-trans retinoic acid or arsenic trioxide, ovarian hyperstimulation syndrome, Hhemophagocytic lymphohistiocytosis, hemorrhagic fever and snakebite. Acute renal failure, hypovolemic shock and coagulopathies are often found in the conditions mentioned above. Among the drugs that have been reported to lead to CLS in the literature, there is gemcitabine. This is a chemotherapic drug used in several types of malignancies, including bladder cancer. So far, few cases, less that ten, of CLS induced by gemcitabine are found in literature. Herein we report a case of CLS developed during last cycle of neoadjuvant treatment with cisplatin and gemcitabine in a patient with muscle-invasive bladder cancer.\n\nCase\n\nA 54-year-old male, affected by locally advanced, muscle-invasive high grade papillary urothelial cancer of bladder, without any other significant comorbidities, was proposed for neoadjuvant chemotherapy with cisplatin 80 mg/mq and gemcitabine 1000 mg/mq 1,8 q21 for four cycles, as for guidelines.2 During first three cycles, the patient did not receive the gemcitabine on day 8 for grade 3 neutropenia. The fourth cycle was completed. Five days after from receiving last dose of gemcitabine, the patient developed fever and petechiae on legs and trunk and he was hospitalized. The blood count showed anemia (hemoglobin 9,6 g/dL), leukopenia (1900 mm3) and thrombocytopenia (21,000 mm3). The renal function, hepatic function and coagulation parameters were within normal ranges. Albuminemia was decreased (3.07 g/dL). He was infused with platelets concentrate and started granulocyte colony-stimulating factor (G-CSF), 30 million units/die. He also started antibiotic therapy. On day 6th, the patient showed contraction of diuresis, hypotension and edema of the trunk and arms, bilaterally. Eco-color-doppler of the arms excluded venous thrombosis. Cardiac ecocolordoppler and Angio-CT excluded thrombo-embolic events of arterial vessels. Edema progressively extended to lower limbs (Fig. 1) and the persistence of fever, neutropenia, hypotension posed the suspect of sepsis, excluded by serial hemocoltures at feverish peak, urine cultures and by normal blood procalcitonin levels. On day 8th, total protein value and level of albuminemia further decreased (4,4 g/dL and 2,45 g/dL, respectively) (Fig. 2). There was no proteinuria in the urine test and we started treatment with albumin 20% 50 ml once daily. He also received intravenous furosemide (20 mg, once daily) and prednisone 25 mg, once daily and received transfusions of platelets and red blood cells concentrates. The clinical manifestations persisted, without improvement, until day 12th, when we increased prednisone dose to 50 mg daily. On day 14th, we observed a reduction of edema of the trunk and arms, an increasing of blood cells count and normalization of diuresis and blood pressure. Renal function was within normal range. The complete normalization of clinical condition was observed on day 17th. No other cycles of chemotherapy were administered.Fig. 1 Edema of lower limbs on the day of lower level of albuminemia (2,45 g/dL on day 8th).\n\nFig. 1\n\nFig. 2 The graphic shows decreasing of total proteins and albumin levels and blood pressure until day 8th from last administration of gemcitabine and subsequent gradual normalization of this values, more evident after improving therapy with prednisone on day 12th.\n\nFig. 2\n\nInterestingly, a Chest-Abdomen CT was performed and showed an objective complete response to neoadjuvant chemotherapy (Fig. 3).Fig. 3 Comparative CT with contrast images of the bladder neoformation, before and after neoadjuvant chemotherapy treatment; A. Image before neoadjuvant treatment; C. Image after neoadjuvant treatment: we observed a total disappearance of the parietal lesion; B. Image before neoadjuvant treatment; D. Image after neoadjuvant treatment: the filling defect is no more detectable.\n\nFig. 3\n\nThe patient successfully underwent radical cystectomy and bilateral pelvic lymph node dissection, with construction of cutaneous uretero-ileostomy ad modum Bricker. At histopatological examination, there was no evidence of infiltrating tumor on bladder wall, but the presence of carcinoma in situ, mild lymphocytes infiltration and focal granulomatous inflammatory reaction with macrophages and multinucleated giant cells. Nonspecific reactive lymphadenitis in 10 lymph nodes examined was detected.\n\nDiscussion\n\nIn this clinical experience, we have witnessed a rare adverse event of gemcitabine, for the first time reported in a patient with bladder cancer receiving neoadjuvant treatment.\n\nWe cannot exclude that cisplatin, associated with gemcitabine, might also have played a role in the pathogenesis of the disorder. Nevertheless, in view of the absence of the syndrome during the first cycles in which the patient had not sustained the eighth day of treatment with gemcitabine alone, a dose-dependent effect and a particular susceptibility of the patient in metabolizing the drug may be assumed.\n\nIncreasing in corticosteroid dosage led to a rapid improvement in symptoms, demonstrating an almost total ineffectiveness of prednisone at lower doses of 0.5 mg/kg, despite simultaneous diuretic therapy.\n\nCombination of steroids and diuretics at an appropriate dosage has allowed the complete reversibility of symptoms 8–10 days after the start of treatment.\n\nSimilar experiences have already been published,3 underlying the need for prompt recognition of CLS and treatment, that need to be continued for some weeks before being able to see concrete clinical benefits.\n\nThe effectiveness of the therapy, with the complete clinical response to the chemotherapy treatment, has largely justified the risk of toxicity. The patient was subsequently operated and he returned to his previous daily routine.\n\nCases of CLS have recently been reported to be associated with the administration of immune checkpoint inhibitors (ICIs), including Nivolumab4 and during infection with SARS-CoV-2.5 These experiences suggest a probable pathogenesis due to a dysregulation of the immune response with cytokine alterations, in the absence of a cellular inflammatory response, impacting on endothelial permeability.\n\nConclusion\n\nCLS remains a clinical challenge, not just as a side effect of chemotherapy. The main goal is a prompt recognition of the symptoms, regardless of the underlying cause, because even if CLS is a rare syndrome, it needs to be treated properly to avoid serious and irreversible damages.\n\nFocusing on the pathophysiological mechanism that underlies this syndrome, a predictive role of response to chemotherapy could be assumed, for example by inducing an increased activity of the inflammatory response. This hypothesis could be investigated by other clinical experiences.\n\nDeclaration of competing interest\n\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n\n1 Siddall E. Khatri M. Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, and management Kidney Int 92 1 2017 37 46 10.1016/j.kint.2016.11.029 28318633\n2 Flaig T.W. Spiess P.E. Agarwal N. Bladder cancer, version 3.2020, NCCN clinical practice guidelines in oncology J Natl Compr Canc Netw 18 3 2020 329 354 10.6004/jnccn.2020.0011 32135513\n3 De Pas T. Curigliano G. Franceschelli L. Catania C. Spaggiari L. de Braud F. Gemcitabine-induced systemic capillary leak syndrome Ann Oncol 12 11 2001 1651 1652 10.1023/a:1013163831194 11822767\n4 Lescure C. Lescoat A. Salé A. Systemic capillary leak syndrome (Clarkson's Disease) as a Complication of Anti-Programmed Death 1 Immunotherapy J Thorac Oncol 14 6 2019 e131 e132 10.1016/j.jtho.2019.02.003 31122567\n5 Pineton de Chambrun M. Cohen-Aubart F. Donker D.W. SARS-CoV-2 Induces Acute and Refractory Relapse of Systemic Capillary Leak Syndrome (Clarkson's Disease) Am J Med S0002–9343 20 2020 30373 30379 10.1016/j.amjmed.2020.03.057 [published online ahead of print, 2020 May 13]\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "34()",
"journal": "Urology case reports",
"keywords": "Bladder cancer; Capillary leak syndrome; Gemcitabine",
"medline_ta": "Urol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101626357",
"other_id": null,
"pages": "101461",
"pmc": null,
"pmid": "33101987",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports",
"references": "28318633;32135513;32405072;11822767;31122567",
"title": "Capillary leak syndrome induced by neoadjuvant cisplatin and gemcitabine in a patient with bladder cancer.",
"title_normalized": "capillary leak syndrome induced by neoadjuvant cisplatin and gemcitabine in a patient with bladder cancer"
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"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
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"abstract": "BACKGROUND\nSpontaneous spinal and intracranial subdural hematomas are rarely reported, especially occurring simultaneously. Anticoagulation use has been associated with spontaneous hemorrhages. Prompt diagnosis is required to prevent permanent neurological sequelae. In this case report, we describe a spontaneous spinal and intracranial subdural hematoma in a woman taking warfarin and initially presenting with severe vaginal pain.\n\n\nMETHODS\nA 42-year-old woman who had a history of mechanical valve replacement and was therefore taking warfarin, came to an emergency department for relief of severe vaginal pain. Mild concurrent lumbar pain increased concern about spinal pathology, so magnetic resonance imaging of her spine was performed. It revealed a subdural hematoma extending from L1-S1 with arachnoiditis, which suggested intracranial pathology, though the patient had no complaint of a headache. Computed tomography of her brain demonstrated a large right subdural hemorrhage with midline shift. Subsequent imaging revealed no aneurysm or source of the intracranial bleeding. We concluded that the patient experienced spontaneous anticoagulation-related intracranial hemorrhage resulting in lumbar subdural hematoma and arachnoiditis with referred vaginal pain. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Pelvic, vaginal, or perineal pain may be the presenting symptom in patients with lower spinal pathology. It is important to consider causes other than gynecological ones in the differential diagnosis of these patients, as well as to be cognizant of the relationship between spinal and intracranial subdural hemorrhages. In patients with back pain or radiating lumbar pain, especially coupled with neurological effects, clinicians should consider spinal subdural hemorrhage and arachnoiditis to expedite imaging studies and treatment of these rare entities.",
"affiliations": "Department of Emergency Medicine, University of Maryland Medical Center, Baltimore, Maryland.;Department of Emergency Medicine, University of Maryland Medical Center, Baltimore, Maryland.;Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, Maryland.",
"authors": "Weiner|Lindsay A|LA|;Richardson|Adam C|AC|;Tewelde|Semhar Z|SZ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2018.12.032",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "56(4)",
"journal": "The Journal of emergency medicine",
"keywords": "back pain; intracranial hemorrhage; spinal hematoma; spontaneous hemorrhage; subdural hematoma; vaginal pain",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000328:Adult; D005260:Female; D046648:Hematoma, Subdural, Intracranial; D006801:Humans; D017116:Low Back Pain; D008161:Lumbosacral Region; D010146:Pain; D014057:Tomography, X-Ray Computed; D014621:Vagina",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "e43-e46",
"pmc": null,
"pmid": "30745198",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous Intracranial and Lumbar Subdural Hematoma Presenting as Vaginal Pain.",
"title_normalized": "spontaneous intracranial and lumbar subdural hematoma presenting as vaginal pain"
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"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-019510",
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"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
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"abstract": "Cisplatin and doxorubicin are integral components of chemotherapy regimens in the treatment of osteosarcoma. Choice of third agent high-dose methotrexate (HDMTX) or an alkylating agent such as ifosfamide is debatable. The present study compared the impact of MAP (HDMTX-doxorubicin-cisplatin) and IAP (ifosfamide-doxorubicin-cisplatin) chemotherapy regimens on toxicity and survival in children and adolescents with osteosarcoma.\n\n\n\nThis was a retrospective study including patients 18 years and younger with osteosarcoma during the study period. Clinical, demographic, chemotherapy regimen, and surgical details and treatment-related toxicity were retrieved from hospital medical records. Prognostic factors affecting overall survival (OS) and event-free survival (EFS) were analyzed.\n\n\n\nAmong 102 patients included in the study, 59 (57.8%) and 43 (42.2%) patients were treated with MAP and IAP regimens, respectively. Two groups were comparable in terms of pretreatment characteristics and surgical treatment. Overall, 95.9% patients underwent limb salvage surgery. There was a statistically increased incidence in supportive care admissions and delay in starting the next cycle of chemotherapy in the MAP group. Among the MAP cohort, the 5-year OS and EFS were 62% and 55% compared with 47% and 44%, respectively, in the IAP cohort (P=0.143 and 0.316, respectively). On univariate and multivariate analyses, statistically significant factors affecting EFS of the whole group included tumor size, stage, site of metastasis, histologic necrosis, and type of surgery.\n\n\n\nOS and EFS with both regimens were similar. However, the MAP regimen was associated with a statistically significant increase in incidence of supportive care admissions, delay in next cycle of chemotherapy, and predicted higher cost of treatment.",
"affiliations": "Departments of Pediatric Hematology and Oncology.;Departments of Pediatric Hematology and Oncology.;Departments of Pediatric Hematology and Oncology.;Research.;Departments of Pediatric Hematology and Oncology.;Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, Delhi, India.",
"authors": "Verma|Priyanka|P|;Jain|Sandeep|S|;Kapoor|Gauri|G|;Tripathi|Rupal|R|;Sharma|Payal|P|;Doval|Dinesh Chandra|DC|",
"chemical_list": "D004317:Doxorubicin; D002945:Cisplatin; D007069:Ifosfamide; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001946",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "43(4)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D002648:Child; D002945:Cisplatin; D003362:Cost-Benefit Analysis; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006801:Humans; D007069:Ifosfamide; D008297:Male; D008727:Methotrexate; D012516:Osteosarcoma; D012189:Retrospective Studies; D016879:Salvage Therapy",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e466-e471",
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"pmid": "32925402",
"pubdate": "2021-05-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "IAP Chemotherapy Regimen Is a Viable and Cost-effective Option in Children and Adolescents With Osteosarcoma: A Comparative Analysis With MAP Regimen on Toxicity and Survival.",
"title_normalized": "iap chemotherapy regimen is a viable and cost effective option in children and adolescents with osteosarcoma a comparative analysis with map regimen on toxicity and survival"
} | [
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"companynumb": "IN-HQ SPECIALTY-IN-2021INT000186",
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"actiondrug": "6",
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"activesubstancename": "CISPLATIN"
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{
"abstract": "BACKGROUND\nWe report a case of progressive Granulomatosis with Polyangiitis (Wegener's Granulomatosis) with life-threatening complications of both the underlying disease and induction immunosuppressive therapy. Here, for the first time, cyclophosphamide toxicity and severe opportunistic infections including pneumocystis jirovecii- pneumonia were found in one case in a close temporal relationship.\n\n\nMETHODS\nA 34-year-old male patient of Caucasian ethnicity presented with acute renal failure necessitating hemodialysis treatment due to Granulomatosis with Polyangiitis (Wegener's Granulomatosis). Kidney disease progressed to end-stage renal disease shortly after first diagnosis. After the 2nd bolus of cyclophosphamide shortly, induction immunosuppression (glucocorticoid/cyclophosphamide) was interrupted for repeat infections and resumed 5 years later. By that time, the lungs developed large pulmonary cavernae most likely due to smoldering granuloma indicative for the failed goal of disease remission. Therefore, induction immunosuppression was resumed. Following two monthly boli of cyclophosphamide, the patient developed pericardial effusion and, consecutively, atrioventricular blockade most likely due to cyclophosphamide. After recovery, the patient was discharged without cotrimoxacole. 10 weeks after the last cyclophosphamide bolus and 6 weeks after cessation of cotrimoxacole, the patient was readmitted to the intensive-care unit with Pneumocystis jirovecii pneumonia, and died 6 months later or 74 months after first diagnosis of Granulomatosis with Polyangiitis.\n\n\nCONCLUSIONS\nThis case illustrates both the need for adequate immunosuppressive therapy to reach disease remission and the limitations thereof in terms of complications including cardiotoxicity of cyclophosphamide and Pneumocystis jirovecii pneumonia. In line with current recommendations, the present case strongly encourages pneumocystis jirovecii- pneumonia chemoprophylaxis for at least 6 months following induction therapy in Granulomatosis with Polyangiitis.",
"affiliations": "Martin-Luther-University Halle-Wittenberg, Clinic of Internal Medicine 2, Department of Nephrology, Ernst-Grube-Str, 40, 06120 Halle (Saale), Germany. rainer.pliquett@medizin.uni-halle.de.",
"authors": "Ernst|Elena|E|;Girndt|Matthias|M|;Pliquett|Rainer U|RU|",
"chemical_list": "D007166:Immunosuppressive Agents; D003520:Cyclophosphamide",
"country": "England",
"delete": false,
"doi": "10.1186/1471-2369-15-28",
"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central 1471-2369-15-282449529710.1186/1471-2369-15-28Case ReportA case of granulomatosis with polyangiitis complicated by cyclophosphamide toxicity and opportunistic infections: choosing between Scylla and Charybdis Ernst Elena 1elena.ernst@medizin.uni-halle.deGirndt Matthias 1matthias.girndt@medizin.uni-halle.dePliquett Rainer U 1rainer.pliquett@medizin.uni-halle.de1 Martin-Luther-University Halle-Wittenberg, Clinic of Internal Medicine 2, Department of Nephrology, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany2014 4 2 2014 15 28 28 17 4 2013 2 2 2014 Copyright © 2014 Ernst et al.; licensee BioMed Central Ltd.2014Ernst et al.; licensee BioMed Central Ltd.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nWe report a case of progressive Granulomatosis with Polyangiitis (Wegener’s Granulomatosis) with life-threatening complications of both the underlying disease and induction immunosuppressive therapy. Here, for the first time, cyclophosphamide toxicity and severe opportunistic infections including pneumocystis jirovecii- pneumonia were found in one case in a close temporal relationship.\n\nCase presentation\nA 34-year-old male patient of Caucasian ethnicity presented with acute renal failure necessitating hemodialysis treatment due to Granulomatosis with Polyangiitis (Wegener’s Granulomatosis). Kidney disease progressed to end-stage renal disease shortly after first diagnosis. After the 2nd bolus of cyclophosphamide shortly, induction immunosuppression (glucocorticoid/cyclophosphamide) was interrupted for repeat infections and resumed 5 years later. By that time, the lungs developed large pulmonary cavernae most likely due to smoldering granuloma indicative for the failed goal of disease remission. Therefore, induction immunosuppression was resumed. Following two monthly boli of cyclophosphamide, the patient developed pericardial effusion and, consecutively, atrioventricular blockade most likely due to cyclophosphamide. After recovery, the patient was discharged without cotrimoxacole. 10 weeks after the last cyclophosphamide bolus and 6 weeks after cessation of cotrimoxacole, the patient was readmitted to the intensive-care unit with Pneumocystis jirovecii pneumonia, and died 6 months later or 74 months after first diagnosis of Granulomatosis with Polyangiitis.\n\nConclusions\nThis case illustrates both the need for adequate immunosuppressive therapy to reach disease remission and the limitations thereof in terms of complications including cardiotoxicity of cyclophosphamide and Pneumocystis jirovecii pneumonia. In line with current recommendations, the present case strongly encourages pneumocystis jirovecii- pneumonia chemoprophylaxis for at least 6 months following induction therapy in Granulomatosis with Polyangiitis.\n\nCyclophosphamide toxicityGranulomatosis with polyangiitisImmunosuppressionOpportunistic infections\n==== Body\nBackground\nGranulomatosis with polyangiitis (GPA), formerly called Wegener’s Granulomatosis, generally presents with pulmonary and renal failure due to vasculitis caused by antineutrophil cytoplasmic antibodies directed against cytosolic proteinase-3 (cANCA). In addition, granuloma formation of the lungs and upper airways may lead to hemoptysis and lung destruction. Less frequently, GPA-associated granuloma occur in the skin, eye, joints, gastrointestinal tract or heart [1-5]. Elevated serum cANCA, clinical clues and/or typical histological findings of kidney biopsies establish the diagnosis of GPA. Cyclophosphamide or monoclonal anti-CD20 antibody (rituximab) therapy is employed as induction immunosuppression to achieve disease remission. Nevertheless, despite optimal induction and maintenance immunosuppression, GPA relapses in about 50% of all cases within five years after first diagnosis, translating into a poorer prognosis [6].\n\nImmunosuppressive therapy renders GPA patients susceptible to life-threatening opportunistic infections such as pneumocystis jirovecii pneumonia (PCP). Current recommendations encourage the use of co-trimoxazole as PCP chemoprophylaxis following induction therapy [7,8] as well as in maintenance therapy in GPA [9,10]. Acceptance rate of this recommendation still needs to be improved [11,12]. Here, we report a case of progressive GPA complicated by cyclophosphamide cardiotoxicity and infections including PCP.\n\nCase presentation\nA 34 year-old male patient of Caucasian ethnicity was diagnosed with a 3rd degree acute kidney injury (Acute Kidney Injury Network classification [13]) in a regional German hospital. Co-morbidities included arterial hypertension, obstructive sleep apnea, obesity (body-mass index: 40.4 kg/m2), tobacco abuse, and chronic obstructive pulmonary disease (COPD). Based on an elevated serum cANCA titer, the diagnosis of GPA was established. A histological confirmation was obtained by kidney biopsy. Initially, seven sessions of plasmapheresis and induction immunosuppression (500 mg i.v. methylprednisolone for 3 days, steroid taper-off, 0.5 g cyclophosphamide i.v. twice within two months) were applied leading to a partial remission of GPA. However, a bronchoscopy-proven mycotic pneumonia (aspergillus fumigatus) occurred following the second bolus of cyclophosphamide requiring antimycotic treatment (voriconacole 200 mg bid) for several months. Immunsuppressive induction therapy was stopped immediately. Hence, due to the halted immunosuppressive therapy, kidney function progressively deteriorated. Eleven months after onset of GPA, the patient had to be hospitalized for hemodialysis-access surgery and hemodialysis initiation. During the following 4 years, hemodialysis-fistula thrombosis and repeat catheter-associated bloodstream infections, episodes of exacerbated COPD and pneumonia occurred. The patient ignored recommendations regarding fluid intake. Because of respiratory symptoms related to overhydration and infections, the patient was deemed unfit to proceed with cyclophosphamide induction. A maintenance therapy with prednisolone (10 mg) was prescribed. Four years after GPA diagnosis, CRP and cANCA serum levels rose, and the patient had to be hospitalized three times within a year due to progressive dyspnea, cough and fever. During the last hospitalization one year before index hospitalization, bronchoscopy ruled out opportunistic infections. Mycophenolate mofetil was introduced as new maintenance immunosuppression for suspected smoldering disease activity in the lungs. Five years after first diagnosis of GPA, the patient received the third and forth intravenous bolus of cyclophosphamide (0.6 g each) within two months. Voriconacole (200 mg twice daily) and co-trimoxazole (960 mg/d) were added as prophylaxis for mycotic pneumonia and PCP. Within less than 24 hours following the 4th cyclophosphamide bolus given after hemodialysis, the patient developed dyspnea at rest necessitating re-hospitalisation, endotracheal intubation and assisted mechanical ventilation. Echocardiography showed a pericardial effusion (end-diastolic: 2.5 cm), massive right-ventricular dilation and hypokinesia. New ECG changes triggered an immediate coronary angiography exam which excluded clogged coronaries. Right-ventricular catheterization showed an elevated pulmonary-artery pressure: 74/54/58 mmHg (systolic/diastolic/mean). There, pulmonary-artery embolism was excluded. Cardiac enzymes remained unrevealing. The pericardial effusion disappeared after one month. As another sign of cyclophosphamide toxicity, anemia and neutropenia occurred. Anemia had to be corrected by two packed erythrocyte concentrates. Neutropenia was complicated by sepsis with elevated procalcitonin (PCT: 13.6 ng/ml) and C-reactive protein (CRP: 259 mg/l) one week after the 4th bolus of cyclophosphamide. The patient was again on assisted mechanical ventilation for 11 days. Thoracic computed tomography showed pulmonary infiltrates within large, partly calcified pulmonary cavernae (maximum 6 cm in diameter). Under intensified antibiosis guided by microbiologic findings from bronchoalveolar lavage, the sepsis subsided. Coincidentally, either GPA disease activity or late sequelae of cyclophosphamide, the patient had to be reanimated for third-degree atrioventricular block two weeks after the 4th bolus of cyclophosphamide. The latter possibility appears to be more likely because cytoplasmic ANCA titer only was 1:20 seven days before. A permanent pacemaker was inserted, and the patient was discharged with p.o. antibiosis, p.o. prednisolone (10 mg/d), however, without voriconacole or co-trimoxazole three weeks after admission. Six weeks following discharge or 10 weeks after the fourth cyclophosphamide bolus, the patient was readmitted for suspected pneumogenic sepsis with worsening dyspnea and hypotension. At admission, the patient had to be transferred to an intensive-care unit (ICU) requiring catecholamine therapy and mechanical ventilation for five days. Blood cultures remained negative. Sputum revealed Pneumocystis jirovecii, Candida albicans, Peptostreptococcus micros, and Actinomyces israelii. Tuberculosis was ruled out using blood test and in culture of bronchoalveolar fluid following bronchoscopy. Both Cytomegalovirus (CMV) IgM and IgG were positive. However, weekly CMV PCR of serum samples remained negative. Both T-helper lymphocyte count (242/μl) and plasma immunoglobulin G level (6.4 g/l) were low indicative for a state of over-immunosuppression.\n\nIn addition, a GPA relapse was suspected based on an elevated cANCA concentration (129.9 U/ml). Thoracic computed tomography showed the known pulmonary cavernae and new pulmonary opacities consistent with PCP or GPA-associated vasculitis (Figure 1). Lung-function tests revealed an impaired vital capacity (2.08 l or 54% of reference value), ruled out obstruction (Tiffenau test: 77.7% of maximum vital capacity or 103% of reference value). Intravenous i.v. co-trimoxazole therapy (1 × 1920 mg i.v. for 2 days, 3 × 1920 mg dissolved in 500 ml saline for 12 days) was applied in addition to i.v. antibiosis (imipenem-cilastatin for 14 d) and immunosuppression (prednisolone 50 mg/d). For the suspected recurrent GPA, daily plasmapheresis was conducted over 5 days since admission with 3 liter or 70% of estimated patient’s plasma volume of 5% human-albumin solution. Under daily hemodialysis, the patient’s condition improved, cANCA concentration decreased (29.3 U/ml), serum inflammatory parameters partly normalized (Figure 2). Following discharge (38 days after admission), peroral co-trimoxazole (960 mg/d) and prednisolone (40 mg/d) were maintained. Two weeks later, the patient was readmitted for suspected pneumonia. Laboratory tests revealed an increased CRP (206 mg/l), PCT (2 ng/ml) and cANCA concentration (54.9 U/ml). Computed tomography of the chest was consistent with bronchitis, ruled out pneumonia. Bronchoscopy-guided peroral antibiosis with moxifloxacin (400 mg/d) was initiated, and maintenance immunosuppression (azathioprin 75 mg/d, prednisolone 25 mg/d) was increased for a suspected GPA relapse. However, two months later, azathioprin had to be discontinued, and prednisolone was reduced (10 mg/d) due to an aggravated respiratory infection (CRP 121 mg/l). Body weight (95 kg) was found to be decreased by 33 kg or by 25% since PCP onset. Despite antibiosis, a pneumogenic sepsis occurred. The patient was admitted to an ICU admission, received mechanical ventilation and extracorporal carbon dioxyde elimination. Intravenous antibiosis was adjusted to bronchoalveolar-lavage results. During the 5-months stay at the ICU, a non-ST segment elevation myocardial infarction occurred requiring a percutanous coronary intervention. Shortly thereafter, an intracranial bleeding under anticoagulation with epileptic convulsion, a biopsy-proven cytomegalovirus colitis and viral pneumonitis (H1N1 influenza) complicated the course of disease. Despite several switches of antimicrobial and antiviral therapy, the patient died 74 months after GPA onset.\n\nFigure 1 Representative thoracic computed tomography scan at the time of hospitalisation for Pneumocystis jirovecii pneumonia (PCP).\n\nFigure 2 Time course of C-reactive protein (CRP), procalcitonin (PCT) and anti-neutrophil cytoplasmic antibodies directed against cytosolic proteinase-3 (cANCA) during opportunistic infections (elevated CRP and PCT) and suspected relapses (elevated CRP and cANCA). The time of hospitalisation is indicated. In addition, relevant microbiologic results were provided.\n\nConclusions\nThis case of GPA illustrates the narrow path between therapeutic control of GPA activity and opportunistic infections or complications due to medical immunosuppression. The overall goal is disease remission without infectious complications or side effects. To reach this goal, various variables including age, renal and liver function need to be considered on an individual basis. Most importantly, a concomitant infection needs to be ruled out prior to medical immunosuppression. In that regard, plasma-exchange therapy may be the initial modality of choice to restore kidney function [14] given its rapid action to reduce antibody load and its moderate immunosuppressive action, especially when the exchange medium used is human plasma.\n\nHere, PCP occurred 8 weeks following cessation of PCP chemoprophylaxis or 10 weeks after the last bolus of cyclophosphamide. From this case, the role for PCP chemoprophylaxis in GPA after induction immunosuppression is emphasized. It is tempting to speculate that an ongoing PCP chemoprophylaxis would have avoided or greatly diminished the risk for PCP in this patient. Clearly, the current practice on PCP chemoprophylaxis in vasculitis such as GPA should be streamlined by guidelines [15] which has been done so far by the European League Against Rheumatism [16]. There, co-trimoxacole (800/160 mg on alternate days or 400/80 mg daily) is recommended. In analogy to kidney transplant recipients [17,18], the time of prophylaxis should cover 6 months after induction immunosuppression in GPA. In addition, PCP chemoprophylaxis may be considered, if cellular immunity is found to be greatly attenuated as indicated by a reduced total lymphocyte count [19], a reduced T-helper lymphocyte count (<400/μl) or the presence of end-stage renal disease [20]. Besides its role in PCP prophylaxis, co-trimoxazole (800/160 mg twice daily) may be considered as an adjunct to standard maintenance therapy with regard to risk reduction of GPA relapse.\n\nRegarding the underlying disease, neither the initial two cyclophosphamide boli nor the third and fourth one five years later led to complete remission of GPA. Shortly after GPA diagnosis, immunosuppressive induction therapy was withheld due to infections. Meanwhile, GPA progressed to end-stage-renal disease and caused massive pulmonary defects that, in turn, became persistent infectious foci. Clearly, disease remission is a prerequisite for an acceptable long-term outcome in GPA, even in the case when end-stage renal disease has been reached. The presence of end-stage renal disease was not shown to slow down GPA progression or prevent relapses of GPA [21]. Besides the need for disease remission, the continued tobacco abuse and the incompliant drinking behaviour leading to over-hydration may have favoured infectious complications in this case as well.\n\nClinically, infections may have obscured GPA symptoms. To differentiate between infection and GPA progression, regular radiological and laboratory assessments are mandatory. Radiological signs and laboratory parameters including CRP and cANCA may raise suspicion for GPA progression. In addition, as an indirect proof, a set plasmapheresis sessions may help differentiate between GPA progression (responder of plasma exchange) and infection (elevated PCT). Here, plasmapheresis improved the clinical picture at first diagnosis of GPA and later on during hospitalisation for PCP indicating that GPA progression concurrently occurred.\n\nSide effects of immunosuppressive therapy for GPA are another concern. The timely relationship between cyclophosphamide therapy and the occurrence of acute right-heart failure and pericardial effusion suggested cyclophosphamide cardiotoxicity in analogy to previous reports [22-24]. Cyclophosphamide toxicity concerns arise in all patients with renal dysfunction even though the cyclophosphamide dose was relatively low (600 mg) in the present case. To safeguard for toxicity, the timing of hemodialysis (12 hours after cyclophosphamide exposure) is pertinent [25]. This requirement was not fulfilled here.\n\nIn summary, this case underlines the importance of disease remission in GPA, and supports the concept of PCP chemoprophylaxis with co-trimoxazole for up to 6 months after intensified medical immunosuppression. Co-trimoxazole as adjunct to maintenance therapy in GPA would serve both as life-long PCP prophylaxis and remission control [26,27]. In addition, the role of novel vasculitis activity markers such as circulating endothelial cells and endothelial microparticles [28] needs to be assessed in clinical medicine to detect relapses early and tailor immunosuppressive therapy accordingly. Together, comprehensive maintenance immunosuppressive therapy, monitoring of (emerging) vasculitis markers and determination of T-helper lymphocyte count may help guide GPA therapy to avoid relapses (Scylla) and over-immunosuppression (Charybdis).\n\nConsent\nWritten informed consent for publication of this Case Report and any accompanying images was obtained directly from the patient before his death. A copy of the written consent is available for review by the Editor of this journal.\n\nAbbreviations\nAKIN: Acute kidney injury network classification; cANCA: Antineutrophil cytoplasmic antibodies directed against cytosolic proteinase-3; COPD: Chronic obstructive pulmonary disease; CRP: C-reactive protein; GPA: Granulomatosis with polyangiitis; ICU: Intensive-care unit; PCP: Pneumocystis jirovecii pneumonia; PCT: Procalcitonin.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nEE made substantial contributions to conception, or acquisition of data. MG gave critical input in revising the manuscript. RUP drafted the manuscript. All authors contributed to the content and approved the final version of the manuscript to be published.\n\nPre-publication history\nThe pre-publication history for this paper can be accessed here:\n\nhttp://www.biomedcentral.com/1471-2369/15/28/prepub\n\nAcknowledgement\nThe authors wish to thank S. Theunert, MD (hemodialysis facility at Auenweg 38, Dessau-Rosslau, Germany) for her big support in providing patient records.\n==== Refs\nAhmed M Niffenegger JH Jakobiec FA Ben-Arie-Weintrob Y Gion N Androudi S Diagnosis of limited ophthalmic Wegener granulomatosis: distinctive pathologic features with ANCA test confirmation Int Ophthalmol 2008 28 35 46 10.1007/s10792-007-9109-y 17589807 \nBacon PA The spectrum of Wegener’s granulomatosis and disease relapse N Engl J Med 2005 352 330 332 10.1056/NEJMp048338 15673799 \nGhaussy NO Du Clos TW Ashley PA Limited Wegener’s granulomatosis presenting with complete heart block Scand J Rheumatol 2004 33 115 118 10.1080/03009740310004063 15163113 \nQian Q Cornell L Chandan V Hartman R Caples S Hemorrhagic colitis as a presenting feature of Wegener granulomatosis J Gastrointestin Liver Dis 2010 19 445 447 21188339 \nSarlon G Durant C Grandgeorge Y Bernit E Veit V Hamidou M Cardiac involvement in Wegener’s granulomatosis: report of four cases and review of the literature Rev Med Interne 2010 31 135 139 10.1016/j.revmed.2009.06.007 19783329 \nBacon PA The spectrum of Wegener’s granulomatosis and disease relapse N Engl J Med 2005 352 330 332 10.1056/NEJMp048338 15673799 \nMukhtyar C Guillevin L Cid MC Dasgupta B de GK Gross W EULAR recommendations for the management of primary small and medium vessel vasculitis Ann Rheum Dis 2009 68 310 317 10.1136/ard.2008.088096 18413444 \nGreen H Paul M Vidal L Leibovici L Prophylaxis of pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials Mayo Clin Proc 2007 82 1052 1059 10.4065/82.9.1052 17803871 \nStegeman CA Tervaert JW De Jong PE Kallenberg CG Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis. Dutch Co-Trimoxazole Wegener Study Group N Engl J Med 1996 335 16 20 10.1056/NEJM199607043350103 8637536 \nZycinska K Wardyn KA Zielonka TM Krupa R Lukas W Co-trimoxazole and prevention of relapses of PR3-ANCA positive vasculitis with pulmonary involvement Eur J Med Res 2009 14 Suppl 4 265 267 10.1186/2047-783X-14-S4-265 20156769 \nCettomai D Gelber AC Christopher-stine L A survey of RheumatologistsΓÇÖ practice for prescribing pneumocystis prophylaxis J Rheumatol 2010 37 792 799 10.3899/jrheum.090843 20194450 \nGrewal P Brassard A Fact or fiction: does the non-HIV/AIDS immunosuppressed patient need Pneumocystis jiroveci pneumonia prophylaxis? An updated literature review J Cutan Med Surg 2009 13 308 312 19919808 \nMehta R Kellum J Shah S Molitoris B Ronco C Warnock D Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury Crit Care 2007 11 R31 10.1186/cc5713 17331245 \nJayne DRW Gaskin G Rasmussen N Abramowicz D Ferrario F Guillevin L Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis J Am Soc Nephrol 2007 18 2180 2188 10.1681/ASN.2007010090 17582159 \nStamp LK Hurst M Is there a role for consensus guidelines for P. jiroveci pneumonia prophylaxis in immunosuppressed patients with rheumatic diseases? J Rheumatol 2010 37 686 688 10.3899/jrheum.091426 20360202 \nMukhtyar C Guillevin L Cid MC Dasgupta B de GK Gross W EULAR recommendations for the management of primary small and medium vessel vasculitis Ann Rheum Dis 2009 68 310 317 10.1136/ard.2008.088096 18413444 \nIssue S KDIGO clinical practice guideline for the care of kidney transplant recipients Am J Transplant 2009 9 S1 S155 \nEBPG Expert Group on Renal Transplantation European best practice guidelines for renal transplantation. Section IV: long-term management of the transplant recipient Nephrol Dial Transplant 2002 17 Suppl 4 1 67 \nGodeau B Mainardi JL Roudot-Thoraval F Hachulla E Guillevin L Du Huong LT Factors associated with pneumocystis carinii pneumonia in Wegener’s granulomatosis Ann Rheum Dis 1995 54 991 994 10.1136/ard.54.12.991 8546533 \nGirndt M Sester U Sester M Kaul H K+Âhler H Impaired cellular immune function in patients with end-stage renal failure Nephrol Dial Transplant 1999 14 2807 2810 10.1093/ndt/14.12.2807 10570074 \nHaubitz M Koch KM Brunkhorst R Survival and vasculitis activity in patients with end-stage renal disease due to Wegener’s granulomatosis Nephrol Dial Transplant 1998 13 1713 1718 10.1093/ndt/13.7.1713 9681717 \nGoldberg MA Antin JH Guinan EC Rappeport JM Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor Blood 1986 68 1114 1118 3533179 \nKatayama M Imai Y Hashimoto H Kurata M Nagai K Tamita K Fulminant fatal cardiotoxicity following cyclophosphamide therapy J Cardiol 2009 54 330 334 10.1016/j.jjcc.2009.01.006 19782276 \nTiersten A Wo J Jacobson C Weitzman A Horwich T Hesdorffer C Cardiac toxicity observed in association with high-dose cyclophosphamide-based chemotherapy for metastatic breast cancer Breast 2004 13 341 346 10.1016/j.breast.2004.02.007 15325671 \nHaubitz M Bohnenstengel F Brunkhorst R Schwab M Hofmann U Busse D Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency Kidney Int 2002 61 1495 1501 10.1046/j.1523-1755.2002.00279.x 11918757 \nStegeman CA Tervaert JW PE DJ Kallenberg CG Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis. Dutch Co-Trimoxazole Wegener Study Group N Engl J Med 1996 335 16 20 10.1056/NEJM199607043350103 8637536 \nZycinska K Wardyn KA Zielonka TM Krupa R Lukas W Co-trimoxazole and prevention of relapses of PR3-ANCA positive vasculitis with pulmonary involvement Eur J Med Res 2009 14 Suppl 4 265 267 10.1186/2047-783X-14-S4-265 20156769 \nErdbruegger U Grossheim M Hertel B Wyss K Kirsch T Woywodt A Diagnostic role of endothelial microparticles in vasculitis Rheumatology 2008 47 1820 1825 10.1093/rheumatology/ken373 18927191\n\n",
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"mesh_terms": "D000328:Adult; D003520:Cyclophosphamide; D003657:Decision Making; D014890:Granulomatosis with Polyangiitis; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D009229:Mythology; D009894:Opportunistic Infections; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D051437:Renal Insufficiency; D016896:Treatment Outcome",
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"title": "A case of granulomatosis with polyangiitis complicated by cyclophosphamide toxicity and opportunistic infections: choosing between Scylla and Charybdis.",
"title_normalized": "a case of granulomatosis with polyangiitis complicated by cyclophosphamide toxicity and opportunistic infections choosing between scylla and charybdis"
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"abstract": "Thymic carcinomas are extremely infrequent neoplasms (15% of all thymic epithelial tumors). Basaloid carcinoma is a peculiar tumor that represents no more than 2% of those infrequent thymic carcinomas. Surgical excision is the recommended treatment. As it's extremely rare, there is no evidence of the impact of different modalities of treatment. There are no reported cases that did not include surgery as part of their management. We herein present a case of an unresectable thymic basaloid carcinoma treated only with concurrent chemotherapy and radiotherapy that obtained a complete remission and free of disease after 2 years.",
"affiliations": "Department of Thoracic Surgery, Buenos Aires British Hospital, Buenos Aires, Argentina.;Department of Pneumonology, Buenos Aires British Hospital, Buenos Aires, Argentina.;Department of Thoracic Surgery, Buenos Aires British Hospital, Buenos Aires, Argentina.;Department of Pathology, Buenos Aires British Hospital, Buenos Aires, Argentina.",
"authors": "Buero|Agustín|A|;Quadrelli|Silvia|S|;Pankl|Leonardo German|LG|;Vigovich|Felix|F|",
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"doi": "10.11604/pamj.2019.33.53.12401",
"fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-33-5310.11604/pamj.2019.33.53.12401Case ReportTwo-year disease remission of an unresectable basaloid thymic carcinoma with second line chemotherapy drugs: report of a case Buero Agustín 1&Quadrelli Silvia 2Pankl Leonardo German 1Vigovich Felix 3\n1 Department of Thoracic Surgery, Buenos Aires British Hospital, Buenos Aires, Argentina\n2 Department of Pneumonology, Buenos Aires British Hospital, Buenos Aires, Argentina\n3 Department of Pathology, Buenos Aires British Hospital, Buenos Aires, Argentina& Corresponding author: Agustín Buero, Department of Thoracic Surgery, Buenos Aires British Hospital, Buenos Aires, Argentina24 5 2019 2019 33 5301 4 2017 27 12 2018 © Agustín Buero et al.2019The Pan African Medical Journal - ISSN 1937-8688. This is an Open Access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Thymic carcinomas are extremely infrequent neoplasms (15% of all thymic epithelial tumors). Basaloid carcinoma is a peculiar tumor that represents no more than 2% of those infrequent thymic carcinomas. Surgical excision is the recommended treatment. As it's extremely rare, there is no evidence of the impact of different modalities of treatment. There are no reported cases that did not include surgery as part of their management. We herein present a case of an unresectable thymic basaloid carcinoma treated only with concurrent chemotherapy and radiotherapy that obtained a complete remission and free of disease after 2 years.\n\nMediastinal tumorthymusbasaloid carcinoma\n==== Body\nIntroduction\nThymic neoplasms are rare tumors with an incidence of less than 1% of all adult cancers. Amongst those unusual tumors, thymic epithelial neoplasms include thymomas and thymic carcinomas. Carcinomas are extremely infrequent, representing only about 15% to 20% of all thymic epithelial tumors. Thymic basaloid carcinoma is a greatly peculiar tumor variant that represents no more than 2% of those infrequent thymic carcinomas and only a few cases have been reported in the literature. Surgical excision is the recommended treatment and has been performed for almost all previously published cases. In early studies [1], evaluation of various treatment modalities used to treat patients with all types of thymic carcinomas did not yield any statistically significant correlations with survival. As basaloid carcinoma is extremely rare, there is no evidence of the impact of different modalities of treatment. To our knowledge, there are no reported cases that did not include surgery as part of their management. We herein present a case of an unresectable thymic basaloid carcinoma treated only with concurrent chemotherapy and radiotherapy that obtained a complete remission and free of disease after 2 years.\n\nPatient and observation\nA 46-year-old woman without any known comorbidities presented with a three-month history of continuous pain in the right shoulder and chest. The physical examination showed significant facial oedema, erythema and engorgement of the jugular veins. There was evident collateral venous circulation. Enhanced computed tomography (CT) of the chest revealed a solid anterior mediastinal mass measuring 50 x 40 x 35mm in intimate contact with mediastinal vascular structures without cleavage plane and sternal commitment (Figure 1). Serum markers (including alpha-fetoprotein - human choriogonadotropin (HCG) - CA-19-9), human immunodeficiency virus (HIV) and myasthenia gravis markers were negative. Two incisional biopsies were performed (pre-sternal - right VATS). When videothoracoscopy was performed lung involvement was observed either by adhesions or tumor infiltration. Histology demonstrated a basaloid thymic carcinoma, with no lymphovascular invasion (Figure 2). Immunohistochemically, the tumor cells demonstrated positive reactivity to CK 5/6, CKAE1AE3, p63 and a Ki67 index of 30%. Distant metastasis had not occurred, but surgical resection was impossible because of invasion of surrounding organs including the sternum, trachea and large vessels. The patient received 4 series of platin based chemotherapy (doxorubicin 80 mgiv, cisplatin 80 mgiv and cyclophosphamide 800 mg iv), and the following post treatment CT-scan showed no response. Patient was then treated with carboplatin (320mg/week) plus paclitaxel (85mg/week) every 3 weeks for 4 cycles and concurrent radiation therapy (6120 GyE / 180 GyE). After the first cycle of this second line radio-chemotherapy the symptoms of superior venous cava (SVC) syndrome gradually improved. The patient experienced toxicity: alopecia, asthenia, neutropenia and thrombosis of neck vessels. After completing treatment, a new CT (Figure 3) showed a significant downsizing of the mediastinal mass with approximately an 81% reduction in tumor size. However, the tumor remained in close contact with vascular structures without a clear separation line. No sternal involvement was observed. The remaining tissue did not show FDG accumulation during FDG-PET. The multidisciplinary evaluation of the case concluded that the residual mass could not be removed with clear margins. The process would require SVC replacement and completeness of resection in the mediastinum down beside and behind the aorta would improbably be achieved. The differential diagnosis between non neoplastic fibrosis and remaining tumor was not definitive as the PET scan did not show FDG accumulation and the cost-effectiveness of a surgical exploration was not considered favourable (Figure 3). The patient was alive and with good performance status and no recurrence of symptoms 2 years after the initial diagnosis.\n\nFigure 1 Chest CT: solid anterior mediastinal mass measuring 50 x 40 x 35mm in intimate contact with mediastinal vascular structures without cleavage plane and sternal commitment\n\nFigure 2 Left image: HyE X 100: basaloid thymic carcinoma, with no lymphovascular invasion; right image: p53 determination (immunohistochemistry)\n\nFigure 3 Chest CT: downsizing of the mediastinal; remains in close contact with vascular structures without a clear separation line with no sternal involvement; PET-TC: not FDG accumulation in remaining tissue\n\nDiscussion\nThymic epithelial neoplasms are divided into thymomas and thymic carcinomas. Thymomas are epithelial tumors that still have the features of the thymic gland (well-developed lobular architecture, presence of neoplastic thymic epithelial cells but also lymphocytes, areas of medullary differentiation, lack of cytologic features of malignancy of neoplastic thymic epithelial cells). On the other hand, thymic carcinomas show cytologic atypia, invasive margins, and loss of the typical thymic appearance [2]. The histologic grade of thymic carcinoma has been reported to influence prognosis [3]. Initially, Levine and Rosai classified thymic carcinoma into five groups (squamous cell, lymphoepithelioma-like, clear cell, sarcomatoid and undifferentiated). In 1982, Snover and colleagues described three additional types of thymic carcinoma: mixed small cell undifferentiated squamous cell, mucoepidermoid, and basaloid. The subtype of basaloid thymic carcinoma is a very rare neoplasm. In the series of Weissferdt, amongst 65 thymic carcinomas only 3 were considered basaloid. Those tumors are morphologically defined as a thymic carcinoma composed of compact lobules of tumor cells with a prominent peripheral palisading pattern. Basaloid carcinoma can be presented in many other organs. Treatment will depend on the affected organ and may differ to treatment used for thymic affectation. In esophagus, it's similar to the treatment used in squamous cell carcinomas (SCCE) because of the difficulty in preoperative diagnosis. Cisplatin and 5-fluorouracil chemotherapy is concurrently used with conventional radiotherapy protocols developed for advanced or recurrent SCCE. In a retrospective analysis of 142 cases of basaloid carcinoma of the esophagus, Zhang et al reported that the incidence of locoregional recurrence was higher in patients who did not receive radiotherapy than that in patients receiving radiotherapy. In skin affectation there is no established consensus for treatment. Surgery of the tumor and the lymph nodes associated with radiotherapy is usually seen in most of the literature. Studies have proven that basaloid squamous cell carcinoma is a high-grade variant of conventional quamous cell carcinoma, associated with poorer prognosis and increased rate of recurrence. Well-differentiated squamous cell carcinoma, low-grade mucoepidermoid carcinoma and thymic basaloid carcinoma (TBC) have been categorized as low-grade malignant histology; however, in the few cases of basaloid carcinoma reported, distant metastasis has occurred in 30%. In the only published series of TBC, (12 cases) [4] amongst the 8 patients in which follow-up data were available, 5 died of their disease with an average life expectancy of 34 months. As those results were in marked contrast to the previously published literature (14 single cases with only 1 patient dead from the disease) the authors hypothesized that the smaller size or incorrect diagnoses of TBC were the cause of that apparently benign prognosis.\n\nThymic carcinomas are a very heterogeneous group of tumors whose course of disease can range from indolent to quite aggressive, making the analysis of outcomes extremely difficult. The few prospective trials that have included patients with advanced-stage disease involved heterogeneous treatments. It means that the treatment strategy, long-term surgical outcomes and clinical prognostic factors have yet to be fully elucidated. However, in most of thymic carcinomas, surgery is considered the main therapy. Complete tumor resection is achieved in less than 70% of patients even after the induction therapy [5], with a 5-year survival rate for all patients around 70-80%, being survival significantly better in patients who underwent a complete resection (R0 disease). Because of the absence of controlled trials, no definitive chemotherapeutic regimen has been established. Several reports have indicated the efficacy of different regimens including cisplatin + vincristine + doxorubicin + etoposide (CODE), cisplatin + doxorubicin + vincristine + cyclophosphamide (ADOC) and etoposide + ifosfamide + cisplatin (VIP) [6]. A Cochrane revision in 2013 [7] showed that the most common regimen for adult patients with thymic carcinoma or advanced thymoma is cisplatin-based chemotherapy but that there were no randomized control trials (RCTs) eligible for inclusion in that review. Recently, Song described seven patients who received paclitaxel plus carboplatin regimen as second-line and five as third-line chemotherapy with or without surgical resection (none of them TBC). They showed that the regimen of paclitaxel plus carboplatin was active for advanced thymic carcinoma patients as salvage chemotherapy with a response rate of 25.0% and median PFS of 3.5 months [8]. Nonaka et al showed in a study of 14 patients that those who received radiotherapy had a better outcome than the patients who did not, although the number of patients was too small and no patients who received radiotherapy to the mediastinum in the course of the initial treatment developed recurrence within the radiation field. The authors interpreted that these findings strongly suggest that radiotherapy plays an important role in treating thymic carcinoma and can reduce local recurrence. Only recently, a group of the Niigata University Medical and Dental Hospital, reported a case of thymic basaloid carcinoma [9] successfully treated with carboplatin (300 mg/m(2)/day) and paclitaxel (200 mg/m(2)/day) on day 1 for six three-week cycles. Our patient had at presentation an infiltrative tumor with no clear margins with the great vessels. Those conditions anticipated an incomplete resection, the need of SVC replacement and a surgical procedure potentially associated to high morbidity. As the clinical benefit of resection and of any adjuvant therapy (chemotherapy or radiotherapy) remains unclear for TBC, chemotherapy was administered as neoadjuvant therapy with the purpose of being able to undergo a complete resection after this treatment. However, after the two lines of chemotherapy and radiotherapy the tumor was still judged to be unresectable. Additionally, the lack of increased uptake of FDG might have represented substantial necrosis in the remaining tissue with a low or absent active tumor. It has been clearly demonstrated that thymic basaloid carcinoma seems to certainly be accompanied by strong inflammation process which could be responsible of the frequent cystic lesions and is that surrounding inflammation with formation of cysts which many times leads to the requirement of a combined resection of the adjacent structures even though no tumor invasion is observed [10]. The patient completed chemotherapy and is still alive with an unchanged CT scan and no recurrence was observed after 2 years of the initial diagnosis.\n\nConclusion\nThis case provides important information showing that concurrent chemo-radiotherapy can be effective against inoperable thymic basaloid carcinoma. It is also the second case in the literature giving evidence that paclitaxel plus carboplatin appears to have activity as second-line in advanced thymic basaloid carcinoma. We believe that the contribution of similar cases in the literature could provide interesting data on disease remission and long-term survival in patients with carcinomas not amenable to surgery getting similar results to those achieved by the gold standard treatment.\n\nCompeting interests\nThe authors declare no competing interests.\n\nAuthors’ contributions\nAgustin Buero drafted the manuscript and therefore made the major substantive contribution and was also assisting surgeon. Silvia Quadrelli revised the manuscript for intellectual content and coordinated the draft of the manuscript and helped to draft and revise the manuscript critically. Leonardo German Pankl was the operating surgeon and revised the manuscript critically. Felix Vigovich was the pathologist who evaluated the tumor and provided bibliography of the pathology exposed. All authors have read and agreed to the final version of this manuscript.\n==== Refs\nReferences\n1 Suster S Rosai J Thymic carcinoma: a clinicopathologic study of 60 cases Cancer 1991 2 15 67 4 1025 32 1991250 \n2 Travis W Brambilla W Müller-Hermelink H Harris C World Health Organization classification of tumors Pathology and genetics of tumors of the lung, pleura, thymus and heart 2004 Lyon IARC press 3 \n3 Okumura M Ohta M Tateyama H Nakagawa K Matsumura A Maeda H The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients Cancer 2002 2 1 94 3 624 32 11857293 \n4 Brown JG Familiari U Papotti M Rosai J Thymic basaloid carcinoma: a clinicopathologic study of 12 cases, with a general discussion of basaloid carcinoma and its relationship with adenoid cystic carcinoma Am J Surg Pathol 2009 8 33 8 1113 2 19461509 \n5 Shintani Y Inoue M Kawamura T Funaki S Minami M Okumura M Multimodality treatment for advanced thymic carcinoma: outcomes of induction therapy followed by surgical resection in 16 cases at a single institution Gen Thorac Cardiovasc Surg 2015 3 63 3 159 63 25311849 \n6 Rea F Marulli G Di Chiara F Multidisciplinary approach for advanced stage thymic tumors: long-term outcome Lung Cancer 2011 72 1 68 72 20708294 \n7 Wei ML Kang D Gu L Qiu M Zhengyin L Mu Y Chemotherapy for thymic carcinoma and advanced thymoma in adults Cochrane Database Syst Rev 2013 8 23 8 CD008588 \n8 Song Z Chemotherapy with paclitaxel plus carboplatin for relapsed advanced thymic carcinoma J Thorac Dis 2014 12 6 12 1808 12 25589977 \n9 Miura S Kagamu H Sakai T Nozaki K Asakawa K Moro H Okajima M Watanabe S Yamamoto S Iino N Goto S Kazama JJ Yoshizawa H Narita I Advanced thymic cancer treated with Carboplatin and Paclitaxel in a patient undergoing hemodialysis Intern Med 2015 54 1 55 8 25742894 \n10 Sakakura N Tateyama H Usami N Yokoi K Thymic basaloid carcinoma with pleural dissemination that developed after a curative resection: report of a case Surg Today 2010 11 40 11 1073 8 21046508\n\n",
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"title": "Two-year disease remission of an unresectable basaloid thymic carcinoma with second line chemotherapy drugs: report of a case.",
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"abstract": "OBJECTIVE\nThe aim of this article is to evaluate the rate of patients developing sustained elevated intraocular pressure (IOP) after ranibizumab (Lucentis) intravitreal (IVT) injections.\n\n\nMETHODS\nThis is a retrospective study.\n\n\nMETHODS\nCharts of 192 consecutive patients receiving Lucentis for age-related macular degeneration (AMD) were retrospectively reviewed.\n\n\nMETHODS\nWe enrolled patients with at least two IOP measurements between injections. Elevated IOP was defined as >21 mm Hg with an increase of at least 20% from baseline. Noninjected contralateral eyes of the same patient cohort were used as control.\n\n\nMETHODS\nPrimary outcome was defined as elevated IOP. Secondary outcomes were presence and type of glaucoma, number of injections, and time to IOP elevation.\n\n\nRESULTS\nElevated IOP occurred at a significantly higher rate in eyes receiving IVT ranibizumab (7.47%; n = 9) compared with control (0.93%; n = 1). Patients with preexisting glaucoma or ocular hypertension (OHT) were more likely to develop elevated IOP after IVT ranibizumab injection.\n\n\nCONCLUSIONS\nIntravitreal ranibizumab injections are associated with sustained IOP elevation in some eyes.\nReis GMSM, Grigg J, Chua B, Lee A, Lim R, Higgins R, Martins A, Goldberg I, Clement CI. The Incidence of Intraocular Pressure Elevation following Intravitreal Ranibizumab (Lucentis) for Age-related Macular Degeneration. J Curr Glaucoma Pract 2017;11(1):3-7.",
"affiliations": "Consultant, Glaucoma Unit, Sydney Eye Hospital, Sydney, New South Wales, Australia.;Associate Professor, Glaucoma Unit, Sydney Eye Hospital, Sydney; Discipline of Ophthalmology, Central Clinical School, University of Sydney Sydney, New South Wales, Australia.;Clinical Lecturer and Staff Specialist, Glaucoma Unit, Sydney Eye Hospital, Sydney; Discipline of Ophthalmology, Central Clinical School, University of Sydney Sydney, New South Wales, Australia.;Clinical Lecturer and Staff Specialist, Glaucoma Unit, Sydney Eye Hospital, Sydney; Discipline of Ophthalmology, Central Clinical School, University of Sydney Sydney, New South Wales, Australia.;Clinical Lecturer and Visiting Medical OfficerGlaucoma Unit, Sydney Eye Hospital, Sydney; Discipline of Ophthalmology, Central Clinical School, University of Sydney Sydney, New South Wales, Australia.;Visiting Medical Officer, Glaucoma Unit, Sydney Eye Hospital, Sydney; Discipline of Ophthalmology, Central Clinical School, University of Sydney Sydney, New South Wales, Australia.;Consultant, Department of Ophthalmology, Moorfields Eye Hospital London, United Kingdom.;Clinical Associate Professor, Glaucoma Unit, Sydney Eye Hospital, Sydney; Discipline of Ophthalmology, Central Clinical School, University of Sydney Sydney, New South Wales, Australia.;Clinical Lecturer and Staff Specialist, Glaucoma Unit, Sydney Eye Hospital, Sydney; Discipline of Ophthalmology, Central Clinical School, University of Sydney Sydney, New South Wales, Australia.",
"authors": "Reis|Gustavo Msm|GM|;Grigg|John|J|;Chua|Brian|B|;Lee|Anne|A|;Lim|Ridia|R|;Higgins|Ralph|R|;Martins|Alessandra|A|;Goldberg|Ivan|I|;Clement|Colin I|CI|",
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"fulltext": "\n==== Front\nJ Curr Glaucoma PractJ Curr Glaucoma PractJOCGPJournal of Current Glaucoma Practice0974-03330975-1947Jaypee Brothers Medical Publishers 10.5005/jp-journals-10008-1213Original ArticleIncidence of Intraocular Pressure Elevation following Intravitreal Ranibizumab (Lucentis) for Age-related Macular Degeneration Reis Gustavo MSM 1Grigg John 2Chua Brian 3Lee Anne 4Lim Ridia 5Higgins Ralph 6Martins Alessandra 7Goldberg Ivan 8Clement Colin I 91 Consultant, Glaucoma Unit, Sydney Eye Hospital, Sydney, New South Wales, Australia2 Associate Professor, Glaucoma Unit, Sydney Eye Hospital, Sydney; Discipline of Ophthalmology, Central Clinical School, University of Sydney Sydney, New South Wales, Australia3 Clinical Lecturer and Staff Specialist, Glaucoma Unit, Sydney Eye Hospital, Sydney; Discipline of Ophthalmology, Central Clinical School, University of Sydney Sydney, New South Wales, Australia4 Clinical Lecturer and Staff Specialist, Glaucoma Unit, Sydney Eye Hospital, Sydney; Discipline of Ophthalmology, Central Clinical School, University of Sydney Sydney, New South Wales, Australia5 Clinical Lecturer and Visiting Medical OfficerGlaucoma Unit, Sydney Eye Hospital, Sydney; Discipline of Ophthalmology, Central Clinical School, University of Sydney Sydney, New South Wales, Australia6 Visiting Medical Officer, Glaucoma Unit, Sydney Eye Hospital, Sydney; Discipline of Ophthalmology, Central Clinical School, University of Sydney Sydney, New South Wales, Australia7 Consultant, Department of Ophthalmology, Moorfields Eye Hospital London, United Kingdom8 Clinical Associate Professor, Glaucoma Unit, Sydney Eye Hospital, Sydney; Discipline of Ophthalmology, Central Clinical School, University of Sydney Sydney, New South Wales, Australia9 Clinical Lecturer and Staff Specialist, Glaucoma Unit, Sydney Eye Hospital, Sydney; Discipline of Ophthalmology, Central Clinical School, University of Sydney Sydney, New South Wales, AustraliaColin I Clement, Clinical Lecturer and Staff Specialist, Glaucoma Unit, Sydney Eye Hospital, Sydney New South Wales, Australia, Phone: +0293827111, e-mail: colinandkylie@me.comJan-Apr 2017 18 1 2017 11 1 3 7 15 6 2016 24 7 2016 Copyright © 2017; Jaypee Brothers Medical Publishers (P) Ltd.2017\nThis work is licensed under a Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit\nhttp://creativecommons.org/licenses/by/3.0/ABSTRACT\nAim\nThe aim of this article is to evaluate the rate of patients developing sustained elevated intraocular pressure (IOP) after ranibizumab (Lucentis) intravitreal (IVT) injections.\n\nDesign\nThis is a retrospective study.\n\nParticipants\nCharts of 192 consecutive patients receiving Lucentis for age-related macular degeneration (AMD) were retrospectively reviewed.\n\nMaterials and methods\nWe enrolled patients with at least two IOP measurements between injections. Elevated IOP was defined as >21 mm Hg with an increase of at least 20% from baseline. Noninjected contralateral eyes of the same patient cohort were used as control.\n\nMain outcome measures\nPrimary outcome was defined as elevated IOP. Secondary outcomes were presence and type of glaucoma, number of injections, and time to IOP elevation.\n\nResults\nElevated IOP occurred at a significantly higher rate in eyes receiving IVT ranibizumab (7.47%; n = 9) compared with control (0.93%; n = 1). Patients with preexisting glaucoma or ocular hypertension (OHT) were more likely to develop elevated IOP after IVT ranibizumab injection.\n\nConclusion\nIntravitreal ranibizumab injections are associated with sustained IOP elevation in some eyes.\n\nHow to cite this article\nReis GMSM, Grigg J, Chua B, Lee A, Lim R, Higgins R, Martins A, Goldberg I, Clement CI. The Incidence of Intraocular Pressure Elevation following Intravitreal Ranibizumab (Lucentis) for Age-related Macular Degeneration. J Curr Glaucoma Pract 2017;11(1):3-7.\n\nKeywords\nAge-related macular degenerationIntraocular pressureRanibizumab.\n==== Body\nINTRODUCTION\nAccording to the World Health Organization (WHO), age-related macular degeneration (AMD) is the primary cause of irreversible blindness in developed countries among people aged over 50, and the third leading cause of blindness worldwide.1 In the majority of patients with AMD, vision loss is due to the development of choroidal neovascularization (CNV), which is characterized by aberrant growth of new blood vessels from the choroid into or underneath the retina. These abnormal vessels leak blood and/ or fluid causing retinal damage by edema with cystic degeneration and fibrous scarring.\n\nRanibizumab is an antivascular endothelial growth factor (anti-VEGF) agent that was approved by the Food and Drug Administration in June 2006 for the treatment of CNV due to AMD.2 It is a recombinant humanized immunoglobulin monoclonal antibody fragment (Fab) directed against the receptor-binding domain of all active isoforms of VEGF-A inhibiting cell proliferation (angio-genesis) and reducing vascular leakage.3 It is initially used as a 0.05 mL (0.5 mg) intravitreal (IVT) injection every 4 weeks, with frequency thereafter tailored according to the clinical response.\n\nThe most common adverse ocular reactions reported in patients receiving ranibizumab included intraocular inflammation, cataract, vitreous hemorrhage, and increased intraocular pressure (IOP).3\n\nIt is known that an acute volume-related ocular hypertension (OHT) occurs transiently after IVT injections; however, within 30 to 60 minutes, the ocular pressure usually returns to baseline.4 Sustained OHT after anti-VEGF injections has been reported in both case series25 and retrospective studies67; the incidence ranges from 3 to 9%.\n\nOur study aims to establish the risk of sustained elevated IOP after ranibizumab injections in an Australian population in order to assess the safety profile of such treatment and whether presence of glaucoma or number of injections could be identified as a risk factor for IOP increase.\n\nMATERIALS AND METHODS\nThe medical records of consecutive patients receiving IVT ranibizumab (Lucentis, Genetech, San Francisco, CA, USA) for AMD at Sydney Eye Hospital were retrospectively reviewed. The study was approved by the South Eastern Sydney Local Health District Human Research Ethics Committee and conformed to tenants of the Declaration of Helsinki on Human Research.\n\nWe aimed to compare the highest recorded IOP after commencing IVT ranibizumab treatment with baseline IOP. Eyes were included for analysis if IOP, measured with Goldman tonometry, was clearly documented before commencing ranibizumab treatment and at all follow-up visits. As the contralateral noninjected eye was used as control, patients receiving bilateral treatment were excluded. Eyes with a history of IVT anti-VEGF treatment at another institution were also excluded. Demographic data, IOP, visual acuity, history of glaucoma or OHT, number of ranibizumab injections, time from onset of ranibizumab treatment, and IOP-reducing interventions were recorded. The IOP was considered elevated if at follow-up, a minimum 4 weeks following injection, measurement was >21 mm Hg with an increase of >20% from baseline on two consecutive visits.\n\nAll IVT injections were given using the same technique in an outpatient setting. In short, eyelids were cleaned with povidone-iodine after topical anesthesia with amethocaine hydrochloride 1% drops. A small bolus of subconjunctival lidocaine 1% was given immediately before ranibizumab (0.5 mg in 0.05 mL) was injected using a 30-gauge needle into the vitreous via either inferior or superior approach, 3.5 mm (pseudophakic eyes) or 4 mm (phakic eyes) from the corneoscleral limbus. Gentle local pressure with a cotton tip was applied for 10 seconds to avoid reflux, and chloramphenicol drops qid were routinely prescribed for a week following injection.\n\nStatistics\nCategorical and continuous data were compared using Chi-squared and Student t-test respectively, in Numbers (v 3.6.1). The effect of age, gender, preexisting glaucoma or OHT, and number of injections on final IOP was analyzed using linear regression modeling (Wizard for Mac, v 1.7.20). A p-value <0.05 was considered significant.\n\nRESULTS\nThe medical records of 192 patients were reviewed. From these, 107 patients met the inclusion criteria. Baseline characteristics are presented in Tables 1 and 2.\n\nBaseline acuity was significantly worse in control eyes compared with injected eyes (Table 2). This was, in part, due to the presence of end-stage AMD for which no IVT treatment was received. There was no significant difference in baseline IOP between injected and control eyes (Table 2). However, eyes receiving injections showed a statistically higher IOP compared with control eyes (17.13 vs 15.38 mm Hg; p = 0.02) at final follow-up.\n\nSignificantly more injected eyes displayed elevated IOP (>21 mm Hg and >20% from baseline) compared with controls (7.47 vs 0.93%; p = 0.03). In those eyes with IOP elevation, the mean highest IOP was 39.5 mm Hg. The number of injections given to eyes with elevated IOP was greater (19.43; 8-39) than eyes in which IOP did not rise (14.47; 2-62); however, there was considerable overlap and the difference was not significant.\n\nPreexisting glaucoma or OHT was identified in 15 of 107 eyes (14.0%) receiving ranibizumab [primary open angle glaucoma, n = 7; OHT n = 5; pseudoexfoliative syndrome (PXF), n = 3). The IOP elevation occurred in 4 of 15 (26.7%) glaucoma eyes and 4 of 92 (4.3%) nonglaucoma eyes following injection. The rate of IOP elevation in eyes with preexisting PXF was very high (100%), although the overall number was small (n = 3).\n\nLinear regression modeling revealed that age, baseline IOP, and preexisting glaucoma/OHT were significantly associated with highest recorded postinjection IOP (Table 3).\n\nTable 1: Baseline characteristics\n\nNumber\t \t \t107\t \t\nAge (years)\t \t \t76.87\t \t\nMale gender (%)\t \t \t52.3\t \t\nEthnicity (%)\t \t \t\t \t\nCaucasian\t \t \t68.2\t \t\nAsian\t \t \t19.6\t \t\nArabic\t \t \t7.5\t \t\nOther\t \t \t4.7\t \t\nTable 2: Acuity and IOP in injected and control eyes\n\n\t \tInjected\t \tControl\t \tp-value\t \t\nLogMAR acuity\t \t0.69 ± 0.09\t \t0.93 ± 0.18\t \t>0.01\t \t\nTotal number of\t \t1,583\t \t–\t \t–\t \t\ninjections (n)\t \t\t \t\t \t\t \t\nMean number of\t \t14.47 ± 1.84\t \t–\t \t–\t \t\ninjections (n)\t \t\t \t\t \t\t \t\nPreinjection IOP (mm Hg)\t \t15.26 ± 0.61\t \t15.32 ± 0.57\t \t0.45\t \t\nPostinjection IOP (mm Hg)\t \t17.13 ± 1.51\t \t15.38 ± 0.71\t \t0.02\t \t\nEyes with elevated IOP (%)\t \t7.47\t \t0.93\t \t0.03\t \t\nLogMAR: Logarithm of the minimum angle of resolution\n\nTable 3: Linear regression modeling of variables influencing final IOP following intravitreal ranibizumab injection\n\nVariable\t \tCoefficient\t \tStandard error\t \tp-value\t \t\nAge\t \t 0.063\t \t 0.029\t \t 0.031\t \t\nGender (male)\t \t–0.242\t \t 0.641\t \t 0.707\t \t\nBaseline IOP\t \t 0.384\t \t 0.098\t \t<0.001\t \t\nNumber of injections\t \t 0.045\t \t 0.033\t \t 0.176\t \t\nGlaucoma/OHT\t \t–2.44\t \t 0.873\t \t 0.007\t \t\nCASE REPORTS\nA summary of each case in which elevated IOP was documented following IVT ranibizumab follows.\n\nCase 1\nA 79-year-old phakic female was using latanoprost and brimonidine/timolol fixed combination daily in both eyes for PXF glaucoma and underwent left selective laser trabeculoplasty (SLT) in 2009, 1 year prior to commencing ranibizumab for AMD in April 2010. Pretreatment IOPs were 18/16 mm Hg with 0.7 and 0.9 cup/disk ratio. After three injections over 3 months, IOP was 18/36 on the same treatment. Oral acetazolamide 250 mg three times daily (TDS) was given with left IOP reducing to 20 mm Hg. Systemic anhydrase inhibitor was tapered and a month later she had another pressure spike - 27/36 mm Hg. Oral medication (250 mg BD) was recommenced, with IOP improving to 18/32 mm Hg. Left trabeculectomy was carried out. Six months following surgery, IOP was 22/6 mm Hg, and the patient was still receiving ranibizumab injections.\n\nCase 2\nA 78-year-old pseudophakic female with previous history of OHT commenced right eye ranibizumab in 2010. Pretreatment IOP was 19/18 mm Hg with latanoprost in both eyes. Following eight injections over 12 months, IOP was elevated to 62/14. Oral acetazolamide 250 mg TDS, apraclonidine TDS, and timolol maleate 0.5% BD were started, reducing IOP on the following day to 11/10 mm Hg. All medications except latanoprost were withdrawn. Two months later, following the ninth injection, IOP was 50/20 mm Hg. This improved to 17/10 with oral acet-azolamide 250 mg TDS and brimonidine/timolol fixed combination BD. After 2 weeks, SLT was performed. A month later, IOP was 18/17 on bimatoprost, brimonidine/ timolol fixed combination, and dorzolmaide BD. She continues to have IVT ranibizumab as needed, and IOP remains controlled.\n\nCase 3\nA 75-year-old pseudophakic male with no known history of glaucoma commenced ranibizumab in 2010 in the Right eye (RE) with baseline IOP of 16/16 mm Hg. Following eight injections over 10 months, IOP increased to 54/17 mm Hg. He was given acetazolamide 250 mg TDS, timolol maleate 0.5% BD, and iopidine TDS following which IOP reduced to 22 mm Hg. Oral medication was discontinued and ranibizumab resumed 3 weeks later. At review, IOP was 44/17 mm Hg requiring treatment with bimatoprost and brimonidine/timolol fixed combination BD with IOP coming down to 24/16 mm Hg. Another ranibizumab was given 2 months later, and the next week, the IOP was 32/19 mm Hg. He underwent SLT with IOP improving to 18/12 within 2 weeks. However, another ranibizumab injection 3 months after SLT was followed by and resulting in an IOP of 8/17 on no medication 6 months after surgery. Six further ranibizumab injections have been tolerated during that period with no change to the IOP.\n\nCase 4\nA 67-year-old phakic male with no history of glaucoma commenced left ranibizumab in 2009. The IOP increased from a baseline of 14/14 to 21/36 mm Hg after six injections over 7 months. With oral acetazolamide 500 mg, iopidine TDS, and pilocarpine TDS, IOP improved to 16/23 mm Hg. It remained controlled over the 18 months during which he had a further nine ranibizumab injections. However, after his 15th injection, IOP was elevated to 17/58 mm Hg. Back on maximum medical therapy, IOP only marginally improved to 47 mm Hg. The next day, he underwent a left combined phacoemulsification and viscocanalostomy. Three months after surgery, IOP was 18/18 mm Hg without medication. Three further ranibizumab injections have been given during this time.\n\nCase 5\nA 65-year-old pseudophakic male with no history of glaucoma commenced ranibizumab in February 2011 to the right eye for AMD. Past ocular history included a blind left eye secondary to chronic retinal detachment, high myopia, and right retinal tears treated with cryo-therapy. Baseline IOP was 11/12 mm Hg, but increased to 32/14 mm Hg after six injections. Right IOP improved to 21 mm Hg on latanoprost. He had a further six injections over 11 months after which IOP increased to 40 mm Hg in the right eye. Oral acetazolamide 250 mg TDS and brimonidine/timolol fixed combination BD was started and IOP remained at 10/10 mm Hg on topical hypotensive medication only 6 months later.\n\nCase 6\nA 67-year-old pseudophakic male with advanced PXF glaucoma started on ranibizumab treatment in 2008 had a baseline IOP at 16/16 mm Hg with travoprost/ timolol fixed combination daily and dorzolamide BD. Previous cyclodiode laser and tube implant surgery were performed years before commencing on ranibizumab. After 7 months of IVT injections, the IOP started to rise to 25/18 mm Hg and g. brimonidine was added on his RE. Pressure was well controlled since then when it rose to 26/17 mm Hg 3 months later requiring systemic acetazolamide 250 mg QID. It was then tapered to TDS, and the patient had a new IOP spike: 37/18 mm Hg. Cyclodiode laser was performed achieving good IOP control. The patient had another four injections between surgery and last follow-up, where IOP was 10/15 mm Hg on bimatoprost/timolol fixed combination daily and brimonidine BD.\n\nCase 7\nAn 84-year-old pseudophakic female with PXF glaucoma had baseline IOP of 15/12 on latanoprost. Ranibizumab injections were commenced for AMD in her RE in 2008. She had IOP ranging from 15 to 24 mm Hg within the next 4 years of follow-up, receiving a total of 36 injections during this period. However, on a routine visit, her IOP was 46/15 mm Hg without any symptoms. Oral acetazolamide 250 mg was started with topical brimo-nidine/timolol fixed combination as well as latanoprost. However, since she was unresponsive to medical treatment, an anterior chamber paracentesis was carried out to reduce the IOP to 12 mm Hg. She was sent home with acetazolamide 125 mg BD, g. latanoprost, and g. brimonidine/timolol. A week later, pressure levels were 11/10 mm Hg, and oral acetazolamide was replaced by brinzolamide. When assessed again, IOP was 42/14 mm Hg and oral acetazolamide was once again prescribed with SLT performed 180°. Three months after the SLT, IOP on medical therapy was 26/14 mm Hg. Due to her poor visual acuity (hand movements in both eyes) and advanced age, the patient’s relatives declined surgical intervention.\n\nCase 8\nAn 81-year-old pseudophakic female with no prior history of glaucoma commenced ranibizumab in 2010 to the right eye for AMD. Baseline IOP was 18/19 mm Hg on no treatment. Following five IVT injections of ranibizumab to the right eye over an 8-month period, the IOP rose to 27/20 mm Hg. After commencing latanoprost to the right eye, the IOP fell to 21 on that side. The patient remained on latanoprost and continued to have IVT ranibizumab to the right eye as required. No further significant elevations in IOP were recorded.\n\nDISCUSSION\nThe aim of this study was to assess the rate of sustained IOP elevation in eyes receiving IVT ranibizumab for AMD. Using IOP > 21 mm Hg and IOP > 20% from baseline as the definition of elevated IOP, this study has shown sustained IOP elevation in 7.47% of eyes receiving IVT ranibizumab. Preexisting glaucoma or OHT, higher baseline IOP, and increasing age were risk factors for sustained IOP elevation in this series.\n\nOur study results are consistent with the findings of a number of other studies. Using criteria of IOP of at least 22 mm Hg and elevation of at least 6 mm Hg at two consecutive visits, Bressler et al8 reported IOP elevation in 9.5% of participants receiving ranibizumab vs 3.4% receiving a sham injection. This is despite excluding eyes with preexisting glaucoma, a design that may result in an underestimation of the anti-VEGF effect. Another significant study by Freund et al,9 in which data from the VEGF Trap-Eye study and VIEW 1 and 2 studies were pooled, compared the effects of IVT aflibercept and ranibizumab. They report a higher rate of IOP > 21 mm Hg in eyes receiving 4-weekly ranibizumab compared with eyes receiving one of three aflibercept regimens (20.2 vs 14.2%, 12.1%, or 12.5%).\n\nSmaller studies like our own have reported similar findings, providing further evidence of an association. Adelman et al7 identified 4 eyes out of 116 (3.4%) treated for AMD with either bevacizumab or ranibizumab injections that developed sustained OHT after a mean of 13 treatments. Good et al6 found sustained IOP elevation in 13 of 215 eyes (6%) after a median of nine injections of ranibizumab and/or bevacizumab, noting a higher prevalence in eyes receiving only bevacizumab (9.9%) compared with those receiving only ranibizumab (3.1%). They further noted higher rates in patients with preexisting glaucoma (33 vs 3.1% in eyes without preexisting glaucoma). Agard et al10 found that 10 out of 217 eyes (4.6%) experienced IOP elevation above 25 mm Hg after a mean 6.7 IVT injections of an anti-VEGF agent.\n\nThe mechanism by which sustained IOP elevation occurs following IVT ranibizumab treatment is unknown. Currently three mechanisms seem likely; these may act in isolation or have a combined effect. The first is mic-roparticle obstruction, a process involving diffusion of the 48-kDa ranibizumab antibody fragment into the anterior chamber leading to physical obstruction and increased resistance within the trabecular meshwork. A similar process may occur due to the presence of silicone droplets or protein microaggregates from delivery equipment or packaging. Low-grade inflammation following injection is considered another potential cause, as it has the potential to alter fibroblast proliferation and scar deposition within the trabecular meshwork. Repeat trauma to the trabecular meshwork due to immediate and recurrent IOP spikes following injection has also been proposed.\n\nThe above-proposed mechanisms increase outflow resistance via changes to the trabecular meshwork. This is consistent with the finding of this study and others that glaucoma or OHT is a risk factor for sustained IOP elevation following IVT ranibizumab. It is likely eyes with glaucoma or OHT have reduced outflow facility compared with normotensive nonglaucomatous eyes. Further injury to trabecular meshwork from micropar-ticle obstruction, inflammation, or spiking IOP at the time of injection may compromise outflow further to the point that an IOP within the normal range cannot be maintained.\n\nOther risk factors for IVT ranibizumab have been reported and include number of injections, use of corti-costeroids, and phakic eyes.11 Again, these associations may be explained on the basis of effect on outflow facility. Number of injections could relate to IOP spiking with incremental increase in trabecular meshwork damage. Corticosteroids are well known to cause trabecular meshwork extracellular matrix remodeling. Phakic eyes have higher IOP than pseudophakic eyes. The mechanism for this observation is unknown, but changes to outflow facility have been implicated. Our finding that preexisting glaucoma or OHT, increasing age, and higher baseline IOP were positive predictors of developing sustained IOP is consistent with the theory that this response is mediated via an effect on outflow facility.\n\nIn this study, we used the contralateral noninjected eye as control. With this design, there is potential for the control eye to be exposed to ranibizumab via systemic absorption, as has been demonstrated in some animal models. For example, bilateral simultaneous IVT injection in monkeys of 0.5 mg ranibizumab is associated with ranibizumab antibody detection in serum peaking 3 hours after injection.12 However, a study in rabbits of monocular injections was not associated with serum ranibizumab antibody detection.13 These data suggest there is potential for systemic absorption, but the likelihood with monocular injection is uncertain. A recent meta-analysis suggests no increased risk of systemic cardiovascular events related to either ranibizumab or bevacizumab,14 implying that if systemic absorption occurs, its effect is minimal. That we observed a significant difference in the rate of IOP elevation between injected and control eyes is consistent with this. If anything, the control design in this study would serve to underestimate the effect on IOP. Interestingly, the only control eye that displayed elevated IOP in this study was in a patient who also displayed elevation in the injected eye.\n\nIn conclusion, this study found that sustained elevated IOP occurred in 7.47% of eyes receiving IVT ranibizumab for AMD. Risk factors for this finding included preexisting glaucoma/OHT, baseline IOP, and increasing age. This finding is consistent with similar studies and suggests repeat IVT ranibizumab has an effect on outflow facility in some eyes. The results highlight the importance of monitoring IOP in eyes receiving IVT ranibizumab.\n\nSource of support: Nil\n\nConflict of interest: None\n==== Refs\nREFERENCES\n1 Resnikoff S Pascolini D Etya’ale D Kocur I Pararajasegaram R Pokharel GP Mariotti SP Global data on visual impairment in the year 2002 Bull World Health Organ 2004 11 82 11 844 849 15640920 \n2 Bakri SJ McCannel CA Edwards AO Moshfeghi DM Persistent ocular hypertension following IVT ranibizumab. Graefes Arch Clin Exp Ophthalmol 2008 7 246 7 955 958 18425523 \n3 Hernandez-Pastor LJ Ortega A Garcia-Layana A Giraldez J Ranibizumab for neovascular age-related macular degeneration. Am J Health Syst Pharm 2008 10 1 65 19 1805 1814 18796421 \n4 Sharei V Hohn F Kohler T Hattenbach LO Mirshahi A Course of intraocular pressure after intravitreal injections of 0.05 mL ranibizumab (Lucentis). Eur J Ophthalmol 2010 Jan-Feb 20 1 174 179 19927267 \n5 Loukianou E Brouzas D Apostolopoulos M Sustained ocular hypertension following intravitreal injections of 0.5 mg/0.05 ml ranibizumab. Int Ophthalmol 2011 6 31 3 211 213 21611879 \n6 Good TJ Kimura AE Mandava N Kahook MY Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents. Br J Ophthalmol 2011 8 95 8 1111 1114 20702430 \n7 Adelman RA Zheng Q Mayer HR Persistent ocular hypertension following intravitreal bevacizumab and ranibizumab injections. J Ocul Pharmacol Ther 2010 2 26 1 105 110 20187807 \n8 Bressler SB Almukhtar T Bhorade A Bressler NM Gassman AR Huang SS Jampol LM Kim JE Melia M Diabetic Retinopathy Clinical Research Network Investigators. Repeated intravitreous ranibizumab injections for diabetic macular edema and the risk of sustained elevation of intraocular pressure or the need for ocular hypotensive treatment. JAMA Ophthalmol 2015 5 133 5 589 597 25719991 \n9 Freund KB Hoang QV Saroj N Thompson D Intraocular pressure in patients with neovascular age-related macular degeneration receiving intravitreal aflibercept or ranibi- zumab. Ophthalmology 2015 9 122 9 1802 1810 26025097 \n10 Agard E Elchehab H Ract-Madoux G Russo A Lagenaite C Dot C Repeated intravitreal anti-vascular endothelial growth factor injections can induce iatrogenic ocular hypertension, especially in patients with open-angle glaucoma. Can J Ophthalmol 2015 4 50 2 127 131 25863852 \n11 Dedania VS Bakri SJ Sustained elevation of intraocular pressure after intravitreal anti-VEGF agents: what is the evidence? Retina 2015 5 35 5 841 858 25905784 \n12 Gaudreault J Fei D Rusit J Suboc P Shiu V Preclinical pharmacokinetics of ranibizumab (rhuFabV2) after a single intravitreal administration. Invest Ophthalmol Vis Sci 2005 2 46 2 726 733 15671306 \n13 Bakri S Synder M Reid J Pulido JS Ezzat MK Singh RJ Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology 2007 12 114 12 2179 2182 18054637 \n14 Thulliez M Angoulvant D Le Lez ML Jonville-Bera AP Pisella PJ Gueyffier F Bejan-Angoulvant T Cardiovascular events and bleeding risk associated with intravitreal anti-vascular endothelial growth factor monoclonal antibodies: systematic review and meta-analysis. JAMA Ophthalmol 2014 11 132 11 1317 1326 25058694\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0974-0333",
"issue": "11(1)",
"journal": "Journal of current glaucoma practice",
"keywords": "Age-related macular degeneration; Intraocular pressure; Ranibizumab.",
"medline_ta": "J Curr Glaucoma Pract",
"mesh_terms": null,
"nlm_unique_id": "101492611",
"other_id": null,
"pages": "3-7",
"pmc": null,
"pmid": "28138211",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "20187807;18425523;26025097;18054637;15640920;21611879;25719991;25058694;25863852;20702430;19927267;15671306;25905784;18796421",
"title": "Incidence of Intraocular Pressure Elevation following Intravitreal Ranibizumab (Lucentis) for Age-related Macular Degeneration.",
"title_normalized": "incidence of intraocular pressure elevation following intravitreal ranibizumab lucentis for age related macular degeneration"
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... |
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"abstract": "BACKGROUND\nBeta blockers (BB) are used for very different indications in both adults and children. There can be mild adverse effects with normal doses. When taken in toxic doses, this can have fatal results in children. There are some standard therapies during BB poisoning such as insulin and glucagon but there is not enough knowledge concerning intravenous lipid infusion therapy (ILI).\n\n\nMETHODS\nHerein we present a case of propranolol poisoning in a previously healthy 2-year-old girl. In this patient, cardiac arrest developed twice, and cardiopulmonary resuscitation was performed for 5 and 20 minutes, respectively. We initiated inotropes, insulin, calcium and glucagon with a lack of response to all medical treatment. We used ILI and the patient improved after this treatment. She recovered without any disability.\n\n\nCONCLUSIONS\nILI treatment should be considered with life-threatening BB poisoning which is unresponsive to standard therapies.",
"affiliations": "Divsions of Pediatric Critical Care Unit, Department of Pediatrics, Ankara University Faculty of Medicine, Ankara, Turkey.;Divsions of Pediatric Critical Care Unit, Department of Pediatrics, Ankara University Faculty of Medicine, Ankara, Turkey.;Divsions of Pediatric Critical Care Unit, Department of Pediatrics, Ankara University Faculty of Medicine, Ankara, Turkey.;Divsions of Pediatric Critical Care Unit, Department of Pediatrics, Ankara University Faculty of Medicine, Ankara, Turkey.;Divsions of Pediatric Cardiology, Department of Pediatrics, Ankara University Faculty of Medicine, Ankara, Turkey.;Divsions of Pediatric Cardiology, Department of Pediatrics, Ankara University Faculty of Medicine, Ankara, Turkey.",
"authors": "Botan|Edin|E|;Kendirli|Tanıl|T|;Gün|Emrah|E|;Balsak|Serdar|S|;Ramoğlu|Mehmet|M|;Tutar|Ercan|E|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-4301",
"issue": "63(5)",
"journal": "The Turkish journal of pediatrics",
"keywords": "beta blockers; children; intravenous lipid infusion therapy; poisoning; propranolol",
"medline_ta": "Turk J Pediatr",
"mesh_terms": null,
"nlm_unique_id": "0417505",
"other_id": null,
"pages": "913-916",
"pmc": null,
"pmid": "34738374",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Cardiac arrest due to a fatal dose of propranolol successfully treated with intravenous lipid infusion.",
"title_normalized": "cardiac arrest due to a fatal dose of propranolol successfully treated with intravenous lipid infusion"
} | [
{
"companynumb": "TR-NORTHSTAR HEALTHCARE HOLDINGS-TR-2021NSR000178",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
},
... |
{
"abstract": "Primary immunodeficiencies with selective susceptibility to EBV infection are rare conditions associated with severe lymphoproliferation. We followed a patient, son of consanguineous parents, referred to our center for recurrent periodic episodes of fever associated with tonsillitis and adenitis started after an infectious mononucleosis and responsive to oral steroid. An initial diagnosis of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome was done. In the following months, recurrent respiratory infections and episodes of keratitis were also observed, together with a progressive reduction of immunoglobulin levels and an increase of CD20+ cells. Cell sorting and EBV PCR showed 25,000 copies for 100,000 leukocytes with predominant infection of B lymphocytes. Lymph node's biopsy revealed reactive lymphadenopathy with paracortical involvement consistent with a chronic EBV infection. Molecular analysis of XIAP, SHA2D1A, ITK, and CD27 genes did not detect any pathogenic mutation. The patients underwent repeated courses of anti-CD20 therapy with only a partial control of the disease, followed by stem cell transplantation with a complete normalization of clinical and immunological features. Whole exome sequencing of the trio was performed. Among the variants identified, a novel loss of function homozygous c.163-2A>G mutation of the CD70 gene, affecting the exon 2 AG-acceptor splice site, fit the expected recessive model of inheritance. Indeed, deficiency of both CD27, and, more recently, of its ligand CD70, has been reported as a cause of EBV-driven lymphoproliferation and hypogammaglobulinemia. Cell surface analysis of patient-derived PHA-T cell blasts and EBV-transformed lymphoblastoid cell lines confirmed absence of CD70 expression. In conclusion, we describe a case of severe chronic EBV infection caused by a novel mutation of CD70 presenting with recurrent periodic fever.",
"affiliations": "Clinica Pediatria e Reumatologia, Istituto Giannina Gaslini, Genova, Italy.;Division of Human Genetics, Istituto Giannina Gaslini, Genova, Italy.;Clinica Pediatria e Reumatologia, Istituto Giannina Gaslini, Genova, Italy.;Clinica Pediatria e Reumatologia, Istituto Giannina Gaslini, Genova, Italy.;Clinica Pediatria e Reumatologia, Istituto Giannina Gaslini, Genova, Italy.;Pathology Unit, Istituto Giannina Gaslini, Genova, Italy.;Centre for Advanced Studies, Research and Development in Sardinia (CRS4), Science and Technology Park Polaris, Pula, Italy.;Division of Human Genetics, Istituto Giannina Gaslini, Genova, Italy.;Bone Marrow Transplantation Unit, Istituto Giannina Gaslini, Genova, Italy.;Bone Marrow Transplantation Unit, Istituto Giannina Gaslini, Genova, Italy.;Clinica Pediatria e Reumatologia, Istituto Giannina Gaslini, Genova, Italy.;Clinica Pediatria e Reumatologia, Istituto Giannina Gaslini, Genova, Italy.;Clinica Pediatria e Reumatologia, Istituto Giannina Gaslini, Genova, Italy.;Clinica Pediatria e Reumatologia, Istituto Giannina Gaslini, Genova, Italy.;Division of Human Genetics, Istituto Giannina Gaslini, Genova, Italy.;Clinica Pediatria e Reumatologia, Istituto Giannina Gaslini, Genova, Italy.",
"authors": "Caorsi|Roberta|R|;Rusmini|Marta|M|;Volpi|Stefano|S|;Chiesa|Sabrina|S|;Pastorino|Claudia|C|;Sementa|Angela Rita|AR|;Uva|Paolo|P|;Grossi|Alice|A|;Lanino|Edoardo|E|;Faraci|Maura|M|;Minoia|Francesca|F|;Signa|Sara|S|;Picco|Paolo|P|;Martini|Alberto|A|;Ceccherini|Isabella|I|;Gattorno|Marco|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2017.02015",
"fulltext": "\n==== Front\nFront ImmunolFront ImmunolFront. Immunol.Frontiers in Immunology1664-3224Frontiers Media S.A. 10.3389/fimmu.2017.02015ImmunologyCase ReportCD70 Deficiency due to a Novel Mutation in a Patient with Severe Chronic EBV Infection Presenting As a Periodic Fever Caorsi Roberta 1†Rusmini Marta 2†Volpi Stefano 1Chiesa Sabrina 1Pastorino Claudia 1Sementa Angela Rita 3Uva Paolo 4Grossi Alice 2Lanino Edoardo 5Faraci Maura 5Minoia Francesca 1Signa Sara 1Picco Paolo 1Martini Alberto 1Ceccherini Isabella 2Gattorno Marco 1*1Clinica Pediatria e Reumatologia, Istituto Giannina Gaslini, Genova, Italy2Division of Human Genetics, Istituto Giannina Gaslini, Genova, Italy3Pathology Unit, Istituto Giannina Gaslini, Genova, Italy4Centre for Advanced Studies, Research and Development in Sardinia (CRS4), Science and Technology Park Polaris, Pula, Italy5Bone Marrow Transplantation Unit, Istituto Giannina Gaslini, Genova, ItalyEdited by: Isabelle Meyts, KU Leuven, Belgium\n\nReviewed by: Maria Pia Cicalese, Scientific Institute San Raffaele (IRCCS), Italy; Sylvain Latour, Centre national de la recherche scientifique (CNRS), France\n\n*Correspondence: Marco Gattorno, marcogattorno@gaslini.org†These authors have contributed equally to this work.\n\nSpecialty section: This article was submitted to Primary Immunodeficiencies, a section of the journal Frontiers in Immunology\n\n29 1 2018 2017 8 201505 9 2017 28 12 2017 Copyright © 2018 Caorsi, Rusmini, Volpi, Chiesa, Pastorino, Sementa, Uva, Grossi, Lanino, Faraci, Minoia, Signa, Picco, Martini, Ceccherini and Gattorno.2018Caorsi, Rusmini, Volpi, Chiesa, Pastorino, Sementa, Uva, Grossi, Lanino, Faraci, Minoia, Signa, Picco, Martini, Ceccherini and GattornoThis 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 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.Primary immunodeficiencies with selective susceptibility to EBV infection are rare conditions associated with severe lymphoproliferation. We followed a patient, son of consanguineous parents, referred to our center for recurrent periodic episodes of fever associated with tonsillitis and adenitis started after an infectious mononucleosis and responsive to oral steroid. An initial diagnosis of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome was done. In the following months, recurrent respiratory infections and episodes of keratitis were also observed, together with a progressive reduction of immunoglobulin levels and an increase of CD20+ cells. Cell sorting and EBV PCR showed 25,000 copies for 100,000 leukocytes with predominant infection of B lymphocytes. Lymph node’s biopsy revealed reactive lymphadenopathy with paracortical involvement consistent with a chronic EBV infection. Molecular analysis of XIAP, SHA2D1A, ITK, and CD27 genes did not detect any pathogenic mutation. The patients underwent repeated courses of anti-CD20 therapy with only a partial control of the disease, followed by stem cell transplantation with a complete normalization of clinical and immunological features. Whole exome sequencing of the trio was performed. Among the variants identified, a novel loss of function homozygous c.163-2A>G mutation of the CD70 gene, affecting the exon 2 AG-acceptor splice site, fit the expected recessive model of inheritance. Indeed, deficiency of both CD27, and, more recently, of its ligand CD70, has been reported as a cause of EBV-driven lymphoproliferation and hypogammaglobulinemia. Cell surface analysis of patient-derived PHA-T cell blasts and EBV-transformed lymphoblastoid cell lines confirmed absence of CD70 expression. In conclusion, we describe a case of severe chronic EBV infection caused by a novel mutation of CD70 presenting with recurrent periodic fever.\n\nCD70 deficiencyperiodic feveraphthous stomatitispharyngitiscervical adenitis syndromeperiodic feverEbstein–Barr virushematopoietic stem cell transplantation\n==== Body\nA number of different conditions are associated with the chronic activation of an EBV infection. Chronic active EBV (CABEV) was first described in 1975 (1), to describe a condition characterized by the presence of chronic symptoms of EBV infection in the absence of malignancy, autoimmunity, or a known immunodeficiency (2–4). This condition is heterogeneous from both the clinical and immunological point of view: in fact, while in some patients, EBV is nearly only detected in T or NK cells [more frequently in the Asian population (1–4)], in other patients, it is mostly detected in B cells [more common in the Caucasian population (5)].\n\nHowever, during the past years, it became evident that a relevant proportion of chronic EBV infections were secondary to genetic defects leading to a selective susceptibility to EBV-induced diseases. X-linked diseases caused by mutations in SH2D1A (6) (XLP), XIAP (7), and MAGT1 (8) or autosomal recessive diseases caused by mutation in ITK (9), CORO1A (10), and FCGR3A (11) are such an example. In this condition, patients develop various degrees of lymphoproliferation and immunodeficiency, with hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, and/or lymphoid malignancy secondary to chronic EBV infection as part of the clinical picture. Biallelic mutations of CD27, a tumor necrosis factor (TNF) receptor superfamily member expressed on cells of adaptive immunity and NK cells cause an EBV-associate lymphoproliferative disease with hypogammaglobulinemia (12–14). More recently, an autosomal recessive deficiency of CD70, the ligand of CD27, has been associated to a combined immunodeficiency with EBV-induced B-cell malignancy in humans (15, 16).\n\nThough presenting with a wide heterogeneity, most of the patients with chronic EBV infection share severe clinical manifestations with early onset and poor prognosis: common immunosuppressive and antiviral therapies are usually not effective, and most of the patients not treated with bone marrow transplantation die due to lymphoid malignancies (5). Here, we describe the genetic characterization of a patient with a severe chronic EBV infection due to a novel mutation of CD70, whose initial clinical picture resembled a periodic fever syndrome.\n\nThe patient, born to consanguineous parents, presented at the age of 15 months with a not-complicated infectious mononucleosis followed by the onset of recurrent episodes of fever associated with exudative tonsillitis, adenitis, splenomegaly, and sweating, lasting 3–5 days and treated with NSAIDS or, in some occasions, with antibiotics. Blood examination revealed neutrophilic leukocytosis and elevation of acute phase reactants, while serum immunoglobulins were within the normal range. An autoinflammatory condition, consistent with periodic fever, aphthosis stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome was suspected and on-demand steroidal treatment was suggested with a prompt response. In the following months, the child continued to present periodic fever episodes with a more clear association with respiratory viral and bacterial infections and more frequent use of antibiotics. Three episodes of anterior uveitis were also observed. The patient presented several destructive dental caries (Figure 1A) and hyper sensibility to mosquitoes’ bites was reported.\n\nFigure 1 (A) Multiple caries in CD70 deficient patient. (B) Histologic analysis of patient’s lymph node showing follicular hyperplasia with paracortical expansion (top left), germinal centers with normal appearance (top right), follicular lysis (lower panels). (C) Copies of EBV DNA (above) and number of CD20 cells (below) detected in the patient. Arrows represent the infusions of rituximab. (D) Family pedigree with the c.163-2A>G variant of the CD70 gene, heterozygous in carriers, and homozygous in the patient. (E)\nCD70 genomic region and cDNA sequence of the first 3 exons in the patient is depicted, revealing the exon 2 skipping in the electropherogram at the bottom.\n\nAt the age of 3, immunologic tests revealed a reduction in the level of serum immunoglobulins and a reduction of both T (in particular CD3+CD8+ cells) and B lymphocytes populations (Table 1). Quantitative PCR for EBV DNA revealed 21,935 copies for 100,000 leukocytes with prevalence of infection in the B cells (Table 2). Whole body positron emission tomography revealed a retroperitoneal formation of about 35 mm with an increased metabolism. At biopsy, staining was compatible with reactive lymphadenopathy with paracortical involvement associated with EBV infection (Figure 1B). No signs of lymphoma were observed. The cytofluorimetric characterization of the immunophenotype enlightened the presence of a mixed lymphocyte population composed of polyclonal T and B lymphocytes.\n\nTable 1 lymphocytes population detected in the patient.\n\nLymphocytes’ population\tPercentage of lymphocytes (absolute count/mmc)\t\nCD3+\t76 % (4071)\t\nCD3+ CD4+\t42.5 % (2246)\t\nCD3+ CD8+\t26.2 % (134)\t\nCD19+\t15.4 % (814)\t\nCD20+\t15 % (800)\t\nCD3– CD16+ CD56+\t7 % (370)\t\nTable 2 EBV DNA quantitative PCR in different lymphocytes populations.\n\nLymphocytes’ population\tEBV DNA quantitative PCR\t% of infected cells\t\nCD3+ CD8+\t8100 copies/ 1812200 cells\t0.4 %\t\nCD3+ CD4+\t10700 copies/ 4584300 cells\t0.2 %\t\nCD3– CD16+ CD56+\t1700 copies/ 367000 cells\t0.5 %\t\nCD19+\t386540 copies/ 4500000 cells\t8.6 %\t\nMost common genetic conditions possibly associated with chronic EBV infection and hypogammaglobulinemia were ruled out by molecular analysis of the coding sequence of target genes (SHA2D1A, XIAP, BAFF-R, and ICOS). In addition, the cytofluorimetric analysis of perforin, CD107, and 2B4 receptor was normal (data not shown). In light of these findings, a severe chronic EBV infection was suspected.\n\nTaking into consideration, the overall satisfactory general conditions and in light of the prevalent involvement of CD20+ lymphocytes, after informed consent approved by G. Gaslini ethical board, treatment with rituximab (375 mg/m2/dose) was started with a good clinical response and a dramatic reduction of viral load (Figure 1C). The patient was followed longitudinally with the indication to repeat rituximab whenever the viral load exceeded 20,000 copies/100,000 lymphomonocytic cells and/or the re-appearance of fever and other manifestations associated with EBV. During the following 2 years, the patient received only two administrations of rituximab, in association with i.v. immunoglobulin substitutive treatment every 6 weeks. The patient presented a general wellbeing with a regular growth, without severe infections, and with persistent control of the viral load and of the number of CD20 cells (Figure 1C). However, 3 years after the diagnosis a clear progression of the disease was observed, with subsequent elevations of the viral load and an increase in the frequency and severity of respiratory tract infections requiring, in some cases, prolonged hospitalization. In this period, the patient received three consecutive administrations of rituximab, with only a transient clinical response. On these bases, hematopoietic stem cell transplantation (HSCT) was planned.\n\nThe conditioning regimen consisted of Thiotepa (8 mg/kg, day −7), Fludarabine (40 mg/m2/day, from day −6 to day −3), and Treosulfan (14 gr/m2 from day −6 to day −4). Rabbit anti-thymocyte globulin (ATG, 30 mg/kg from day −4 to −2), micophenolyc acid (30 mg/kg from day 0), and cyclosporine (1 mg/kg until day −2 and 3 mg/kg from day −1) were administered as Graft-versus-Host Disease (GvHD) prophylaxis, whereas a single dose of rituximab (200 mg/sqm) was administered on day 0 for prevention of EBV-related lymphoprolipherative disease.\n\nA total of 2.88 × 108/kg mononuclear bone marrow cells were infused from an 8/10, EBV positive HLA-matched unrelated female donor (1 antigenic HLA-C mismatch in host-versus-graft direction, 1 bidirectional HLA-DQB1 mismatch). Neutrophils and platelets engraftment occurred on day +24 and +18 after HSCT, respectively. At first evaluation, chimerism analysis revealed a mixed pattern (88% donor cell), shown to be of full donor origin, which persisted at all subsequent evaluations. The early post-transplant phase was complicated by mild mucositis, multiple CMV reactivations successfully treated by Foscarnet and/or Gancyclovir, grade 2 acute GvHD (grade 2) responsive to corticosteroids. Immunosuppression was progressively tapered and eventually discontinued 16 months after HSCT in the absence of any manifestation of chronic GvHD. Blood EBV DNA never positivized after HSCT, and specific antibodies were detected since month +9. After 2 years and 6 months from HSCT, the patient persists in good health in the absence of any sign of the disease.\n\nHaving excluded some of the most common genetic causes of genetic susceptibility to EBV infections, and in light of the severity of the clinical picture, and the consanguinity of the parents (Figure 1D), a whole exome sequencing (WES) approach was undertaken in the patients and their parents. Variants were prioritized with a custom pipeline to identify the genetic cause of patient’s condition. In particular, only variants either unreported or already reported in the general population with a frequency lower than 1% were considered. Moreover, synonymous, intronic, and UTR variants were excluded, in addition to splicing variants not specifically affecting the donor and acceptor splice sites. Among the homozygous variants, thus identified (Table S1 in Supplementary Material), a splicing variant of the CD70 gene, fitting the expected recessive model of inheritance, with the parents being heterozygous for the same mutation (Figure 1D), was further investigated. In particular, the variant c.163-2A>G affects the exon 2AG-acceptor splice site of the CD70 gene (NM_001252). To analyze the effect of the mutation on the transcription of the gene, we sequenced the complementary DNA, revealing the skipping of exon 2 (Figure 1E).\n\nFlow cytometry analysis of CD70 expression of patient’s PHA-T cell blasts at 7 and 23 days of stimulation failed to detect even low amounts of CD70 protein. In contrast, expression of CD70 was detected on a fraction of PHA-stimulated T cells from healthy donors (Figure 2A). Similarly, CD70 was not detected on EBV-trasformed lymphoblastoid cells lines (EBV-LCL) derived from the patient, in contrast to EBV-LCL from healthy donors that expressed high levels of CD70 on their surface (Figure 2B). After HSCT, the expression of CD70 in patient’s PHA-T cell blasts at 12 days of culture was comparable to healthy donor (Figure 2C). These data demonstrate that c.163-2A>G mutation causes exon skipping and absence of CD70 protein expression in patient’s cells.\n\nFigure 2 CD70 expression. (A) FACS histograms showing CD70 expression detected with anti-CD70 antibody on PHA-stimulated CD3+ T cell blasts from patient (Pt) or healthy donor (Ctrl), at day 7 and 23 of culture. (B) FACS histograms showing CD70 expression on lymphoblastoid cell lines derived from the Pt or three healthy donors (Ctrl1, Ctrl2, and Ctrl3) detected with anti-CD70 antibody. (C) FACS histograms showing CD70 expression on PHA-stimulated CD3+CD4+ T cell blasts from Pt pre-HSCT (red line), Pt post-HSCT (black line), or healthy donor (dashed gray line), at day 12 of culture.\n\nCD70 is the ligand of the TNF superfamily member CD27 and is expressed by antigen-presenting cells upon triggering of CD40 and toll-like receptors (TLR), by T cells upon TCR activation, CD28 cross-linking, and cytokine exposure, and constitutively by thymic epithelial cells (17). CD27–CD70 binding provides a costimulatory signal for CD4 and CD8 activation (18, 19), and studies in mice have provided evidences for its role in memory expansion and protection upon reinfection (20, 21). Inborn errors of CD27 are a well-known cause of persistent symptomatic EBV viremia and hypogammaglobulinemia, thus making CD70 mutations the likely cause of our patient’s phenotype.\n\nWhile our characterization of this novel immune defect was on-going, two groups reported the association of CD70 mutations with combined immunodeficiency in a total of five patients affected by EBV-associated Hodking’s lymphoma and hypogammaglobulinemia (15, 16). The groups demonstrated that CD70 deficiency (16) causes a reduction of in vitro-generated EBV-specific cytotoxic T cell activity and to a decreased expression of 2B4 and NKG2D, receptors implicated in controlling EBV infection, on memory CD8+ T cells, consistent with their impaired capability to kill EBV-infected cells (15).\n\nFour of the five reported patients suffered by EBV-associated Hodgkin’s lymphoma with an onset at 2.5, 3 (two patients), and 17 years of age and hypogammaglobulinemia. The initial presentation was a severe varicella infection with pneumonia in one case, encephalitis of unknown cause in another one, and HL in the other three cases. Our patient uniquely presented with a subtle history of recurrent fever and inflammatory symptoms was similar to PFAPA syndrome. Of note, the patient reported by Izawa et al. following treatment for HL, also presented with recurrent fever and lymphoadenopathy, while P1 in Abolhassani et al. presented oral aphthous ulcers.\n\nIn conclusion, we report an early diagnosed case of CD70 deficiency with an onset of periodic fever, suggesting that in EBV positive patients with signs of PFAPA syndrome molecular analysis of CD70 gene should be performed.\n\nMaterials and Methods\nInformed Consent\nExperiments and molecular genetic analysis were performed, following informed consent and approval by the institute review board. The family gave permission for publication of clinical and laboratory data and photographic images.\n\nCell Culture\nWhole blood samples were collected from the patient and healthy donors. Peripheral blood mononuclear cells (PBMC) were isolated by Ficoll-Paque density gradient from blood samples using standard procedures. Expansion of T cell blasts were obtained by incubating PBMCs for 48 h with 1 µg/ml of phytohemagglutinin (PHA) (Sigma-Aldrich) in RPMI supplemented with 10% FBS serum, 1% penicillin, and 1% streptomycin. After 2 days, PHA-blasts were maintained in culture with 100 U/ml IL-2.\n\nEBV-trasformed cell lines were generated from the patient and control healthy donors with standard technique.\n\nLymph Node Histology\nLymph nodes from diagnostic biopsies were fixed in 4% formalin, paraffin embedded and sectioned for H&E staining with standard techniques. Images were recorded using a Zeiss Axioskop plus microscope mounting a digital microscopy camera AxioCam ICc5.\n\nFlow Cytometry\nCell staining and phenotype analyses of blast T cells and cell lines were performed according to standard flow cytometry methods.\n\nExpression of CD70 on PHA-T cell blasts pre- and post-HSCT and lymphoblastoid cell lines derived from the patient and four healthy donors was evaluated by flow cytometry. Anti-CD70 PE monoclonal antibody (clone: Ki-24, isotype: mouse IgG3, k, BD Biosciences), PeCy7 mouse anti-human CD3 (clone: SK7, isotype: mouse BALB/c IgG1, k, BD Biosciences), APC mouse anti-human CD4 (clone: RPA-T4, isotype: mouse IgG, k, BD Biosciences), and PC7 mouse anti-human CD19 (clone: J3-119, isotype: IgG1, mouse, Beckman Coulter) were used.\n\nWES and Sanger Sequencing Validation\nMolecular analysis of SHA2D1A, XIAP, BAFF-R, and ICOS genes was performed through Sanger sequencing in a CLIA certified laboratory.\n\nWhole exome sequencing consisted of several steps. Exome capture was performed on genomic DNA using the Nextera Rapid Capture Expanded Exome Kit (Illumina Inc., San Diego, CA, USA) according to manufacturer instructions. The enriched libraries were sequenced on the Hiseq3000 instrument with 100 bp paired-end reads. This approach achieved an 86× average coverage over the 62Mb of target regions sequenced, with more than 95% regions covered. Data analysis has been performed using an analysis pipeline implemented in Orione (22). Briefly, paired-end sequence reads were aligned to the human genome (hg19) with BWA-MEM [v.0.7.9a (23)]. Initial mappings were processed using the GATK framework [version 2.8.1 (24)], according to the GATK best practices recommendations (25, 26). Variants were classified as known or novel based on dbSNP146 and annotated using KGGSeq (27).\n\nAnnotations included positions in UCSC, RefGene, GENCODE and ENSEMBL transcripts, OMIM and ClinVar annotations, potential false positive signals, allele frequency in dbSNP, ESP6500, 1000 Genome Project (release 05/2013), and ExAC, functional predictions for the amino acid changes according to different models (SIFT, Polyphen2, LRT, MutationTaster, MutationAssessor, and FATHMM) retrieved from dbNSFP v 2.9 (database of human nonsynonymous SNPs and their functional predictions) (28).\n\nHomozygous missense and splicing mutations at ±2bp were taken into account and selected based on their allele frequency (variants unreported or reported with a frequency of <1% in the general population were selected). The identified CD70 variant was validated by Sanger sequencing both in the proband and in his parents. PCR products were purified by ExoSAP-IT (GE Healthcare) and directly sequenced using Big Dye v1.1 and an ABI3130 automated sequencer (Applied Biosystems, Foster City, CA, USA).\n\nCD70 Transcript Characterization\nTotal RNA from patient’s T cells and from three-unrelated controls was isolated by a commercial RNA purification kit (RNeasy Mini kit, Qiagen, GmbH, Germany) and 1 µg of total RNA was reverse transcribed by iScript cDNA synthesis kit (Bio-Rad Laboratories) according to the manufacturer’s protocol. DNA amplification followed by Sanger sequencing was carried out on the cDNA, thus obtained using CD70 specific primers designed on exon 1 (5′- GTGATCTGCCTCGTGGTGT-3′) and exon 3 (5′-AGGCAATGGTACAACCTTGG-3′).\n\nEthics Statement\nAll subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Regional Ethical Committee.\n\nAuthor Contributions\nRC, EL, MF, FM, SS, PP, AM, and MG clinically followed the patient. MR, PU, AG and IC performed genetic analysis. ARS performed pathological studies. SC and CP performed in vitro studies. RC, MR, and SV wrote the manuscript and prepared the figures. SC contributed to the writing and prepared the figures. IC and MG supervised all experiments and edited the manuscript.\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\nFunding. This work was funded by The INSAID Project (E-Rare 3 Program, grant no. 9003037603).\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at http://www.frontiersin.org/articles/10.3389/fimmu.2017.02015/full#supplementary-material.\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Horwitz CA Henle W Henle G Schmitz H . Clinical evaluation of patients with infectious mononucleosis and development of antibodies to the R component of the Epstein-Barr virus-induced early antigen complex . Am J Med (1975 ) 58 (3 ):330 –8 .10.1016/0002-9343(75)90599-9 163582 \n2 Tobi M Morag A Ravid Z Chowers I Feldman-Weiss V Michaeli Y \nProlonged atypical illness associated with serological evidence of persistent Epstein-Barr virus infection . Lancet (1982 ) 1 (8263 ):61 –4 .10.1016/S0140-6736(82)90210-0 6119490 \n3 Joncas JH Ghibu F Blagdon M Montplaisir S Stefanescu I Menezes J . A familial syndrome of susceptibility to chronic active Epstein-Barr virus infection . Can Med Assoc J (1984 ) 130 (3 ):280 –4 .6318944 \n4 DuBois RE Seeley JK Brus I Sakamoto K Ballow M Harada S \nChronic mononucleosis syndrome . South Med J (1984 ) 77 (11 ):1376 –82 .10.1097/00007611-198411000-00007 6093268 \n5 Cohen JI Jaffe ES Dale JK Pittaluga S Heslop HE Rooney CM \nCharacterization and treatment of chronic active Epstein-Barr virus disease: a 28-year experience in the United States . Blood (2011 ) 117 (22 ):5835 –49 .10.1182/blood-2010-11-316745 21454450 \n6 Coffey AJ Brooksbank RA Brandau O Oohashi T Howell GR Bye JM \nHost response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene . Nat Genet (1998 ) 20 (2 ):129 –35 .10.1038/2424 9771704 \n7 Rigaud S Fondanèche MC Lambert N Pasquier B Mateo V Soulas P \nXIAP deficiency in humans causes an X-linked lymphoproliferative syndrome . Nature (2006 ) 444 (7115 ):110 –4 .10.1038/nature05257 17080092 \n8 Li FY Lenardo MJ Chaigne-Delalande B . Loss of MAGT1 abrogates the Mg2+ flux required for T cell signaling and leads to a novel human primary immunodeficiency . Magnes Res (2011 ) 24 (3 ):S109 –14 .10.1684/mrh.2011.0286 21983175 \n9 Huck K Feyen O Niehues T Rüschendorf F Hübner N Laws HJ \nGirls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation . J Clin Invest (2009 ) 119 (5 ):1350 –8 .10.1172/JCI37901 19425169 \n10 Moshous D Martin E Carpentier W Lim A Callebaut I Canioni D \nWhole-exome sequencing identifies coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation . J Allergy Clin Immunol (2013 ) 131 (6 ):1594 –603 .10.1016/j.jaci.2013.01.042 23522482 \n11 Grier JT Forbes LR Monaco-Shawver L Oshinsky J Atkinson TP Moody C \nHuman immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity . J Clin Invest (2012 ) 122 (10 ):3769 –80 .10.1172/JCI64837 23006327 \n12 Alkhairy OK Perez-Becker R Driessen GJ Abolhassani H van Montfrans J Borte S \nNovel mutations in TNFRSF7/CD27: clinical, immunologic, and genetic characterization of human CD27 deficiency . J Allergy Clin Immunol (2015 ) 136 (3 ):703 –712.e10 .10.1016/j.jaci.2015.02.022 25843314 \n13 van Montfrans JM Hoepelman AI Otto S van Gijn M van de Corput L de Weger RA \nCD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia . J Allergy Clin Immunol (2012 ) 129 (3 ):787 –793.e6 .10.1016/j.jaci.2011.11.013 22197273 \n14 Salzer E Daschkey S Choo S Gombert M Santos-Valente E Ginzel S \nCombined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27 . Haematologica (2013 ) 98 (3 ):473 –8 .10.3324/haematol.2012.068791 22801960 \n15 Abolhassani H Edwards ES Ikinciogullari A Jing H Borte S Buggert M \nCombined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency . J Exp Med (2017 ) 214 (1 ):91 –106 .10.1084/jem.20160849 28011864 \n16 Izawa K Martin E Soudais C Bruneau J Boutboul D Rodriguez R \nInherited CD70 deficiency in humans reveals a critical role for the CD70-CD27 pathway in immunity to Epstein-Barr virus infection . J Exp Med (2017 ) 214 (1 ):73 –89 .10.1084/jem.20160784 28011863 \n17 Croft M . The role of TNF superfamily members in T-cell function and diseases . Nat Rev Immunol (2009 ) 9 (4 ):271 –85 .10.1038/nri2526 19319144 \n18 Nolte MA van Olffen RW van Gisbergen KP van Lier RA . Timing and tuning of CD27-CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology . Immunol Rev (2009 ) 229 (1 ):216 –31 .10.1111/j.1600-065X.2009.00774.x 19426224 \n19 Borst J Hendriks J Xiao Y . CD27 and CD70 in T cell and B cell activation . Curr Opin Immunol (2005 ) 17 (3 ):275 –81 .10.1016/j.coi.2005.04.004 15886117 \n20 Munitic I Kuka M Allam A Scoville JP Ashwell JD . CD70 deficiency impairs effector CD8 T cell generation and viral clearance but is dispensable for the recall response to lymphocytic choriomeningitis virus . J Immunol (2013 ) 190 (3 ):1169 –79 .10.4049/jimmunol.1202353 23269247 \n21 Allam A Swiecki M Vermi W Ashwell JD Colonna M . Dual function of CD70 in viral infection: modulator of early cytokine responses and activator of adaptive responses . J Immunol (2014 ) 193 (2 ):871 –8 .10.4049/jimmunol.1302429 24913981 \n22 Cuccuru G Orsini M Pinna A Sbardellati A Soranzo N Travaglione A \nOrione, a web-based framework for NGS analysis in microbiology . Bioinformatics (2014 ) 30 (13 ):1928 –9 .10.1093/bioinformatics/btu135 24618473 \n23 Li H Durbin R . Fast and accurate long-read alignment with Burrows-Wheeler transform . Bioinformatics (2010 ) 26 (5 ):589 –95 .10.1093/bioinformatics/btp698 20080505 \n24 McKenna A Hanna M Banks E Sivachenko A Cibulskis K Kernytsky A \nThe genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data . Genome Res (2010 ) 20 (9 ):1297 –303 .10.1101/gr.107524.110 20644199 \n25 DePristo MA Banks E Poplin R Garimella KV Maguire JR Hartl C \nA framework for variation discovery and genotyping using next-generation DNA sequencing data . Nat Genet (2011 ) 43 (5 ):491 –8 .10.1038/ng.806 21478889 \n26 Van der Auwera GA Carneiro MO Hartl C Poplin R Del Angel G Levy-Moonshine A \nFrom FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline . Curr Protoc Bioinformatics (2013 ) 43 :111011 –33 .10.1002/0471250953.bi1110s43 25431634 \n27 Li MX Gui HS Kwan JS Bao SY Sham PC . A comprehensive framework for prioritizing variants in exome sequencing studies of Mendelian diseases . Nucleic Acids Res (2012 ) 40 (7 ):e53 .10.1093/nar/gkr1257 22241780 \n28 Liu X Jian X Boerwinkle E . dbNSFP v2.0: a database of human non-synonymous SNVs and their functional predictions and annotations . Hum Mutat (2013 ) 34 (9 ):E2393 –402 .10.1002/humu.22376 23843252\n\n",
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"keywords": "CD70 deficiency; Ebstein–Barr virus; aphthous stomatitis; cervical adenitis syndrome; hematopoietic stem cell transplantation; periodic fever; pharyngitis",
"medline_ta": "Front Immunol",
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"title": "CD70 Deficiency due to a Novel Mutation in a Patient with Severe Chronic EBV Infection Presenting As a Periodic Fever.",
"title_normalized": "cd70 deficiency due to a novel mutation in a patient with severe chronic ebv infection presenting as a periodic fever"
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"abstract": "This case report describes a young, immunocompromised patient who presented with thoracic pain. After an extensive workup, she was diagnosed with a varicella zoster virus infection with involvement of the gastric mucosa, pancreas and lungs for which she was treated with acyclovir. Although the viral load decreased significantly, the patient had persistent postherpetic neuralgia and nausea.",
"affiliations": "Gastroenterology and Hepatology, Jeroen Bosch Ziekenhuis, Den Bosch, Noord-Brabant, The Netherlands.;Internal Medicine, Jeroen Bosch Ziekenhuis, Den Bosch, Noord-Brabant, The Netherlands.;Internal Medicine, Jeroen Bosch Ziekenhuis, Den Bosch, Noord-Brabant, The Netherlands.;Gastroenterology and Hepatology, Jeroen Bosch Ziekenhuis, Den Bosch, Noord-Brabant, The Netherlands.;Internal Medicine, Jeroen Bosch Ziekenhuis, Den Bosch, Noord-Brabant, The Netherlands.;Gastroenterology and Hepatology, Jeroen Bosch Ziekenhuis, Den Bosch, Noord-Brabant, The Netherlands.",
"authors": "Pavlov|Kirill|K|;Koehestanie|Parweez|P|;Beutler|Jaap J|JJ|;Römkens|Tessa E H|TEH|;Hoogeveen|Ellen K|EK|;Nissen|Loes H C|LHC|",
"chemical_list": null,
"country": "England",
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"doi": "10.1136/flgastro-2018-101025",
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"issue": "9(4)",
"journal": "Frontline gastroenterology",
"keywords": "acute pancreatitis; gastritis; immunodeficiency",
"medline_ta": "Frontline Gastroenterol",
"mesh_terms": null,
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"pages": "323-324",
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"pubdate": "2018-10",
"publication_types": "D002363:Case Reports",
"references": "11445106;17919788",
"title": "Thoracic and abdominal pain in a 28-year-old woman with a failing kidney transplant.",
"title_normalized": "thoracic and abdominal pain in a 28 year old woman with a failing kidney transplant"
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"abstract": "Aciclovir is effective in herpesvirus infections of the CNS. Aciclovir-induced neuropsychiatric symptoms (AINS) have been reported and are associated with high CSF concentrations of aciclovir metabolite 9-carboxymethoxymethylguanine (CMMG). Risk factors except for renal failure have not been explored, and disruption of the blood-brain barrier (BBB) in acute CNS infection may be of interest.\n\n\n\nTo investigate the impact of risk factors on aciclovir and CMMG concentrations, and to relate the results to AINS.\n\n\n\nWe investigated 21 consecutively included, consenting patients treated with aciclovir or valaciclovir for herpesvirus CNS infection. Regression models were constructed to study the impact of risk factors including BBB disruption, as measured with CSF:serum albumin ratio, on CSF aciclovir and CMMG concentrations. Medical records were assessed retrospectively to identify patients with AINS.\n\n\n\nIncreased CSF:serum albumin ratio, as well as decreased renal function and high aciclovir doses, was associated with increased aciclovir and CMMG concentrations in the CSF. We identified five patients with new neuropsychiatric symptoms; four of those were considered to have AINS and had increased CSF CMMG concentrations. Only one patient without suspicion of AINS had an increased CSF CMMG concentration.\n\n\n\nIn patients with herpesvirus CNS infections, BBB disruption is associated with increasing aciclovir and CMMG CSF concentrations. We also found an unexpectedly high number of patients with AINS. Evaluation of CSF:serum albumin ratios, renal function and CSF concentrations of aciclovir and CMMG may all contribute to the optimization of aciclovir dosing and avoidance of AINS.",
"affiliations": "Region Västra Götaland, Sahlgrenska University Hospital, Department of Infectious Diseases, Gothenburg, Sweden.;Department of Medical and Health Sciences, Division of Drug Research/Pharmacology, Linköping University Hospital, Linköping, Sweden.;Department of Clinical Neuroscience, Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Region Västra Götaland, Sahlgrenska University Hospital, Department of Infectious Diseases, Gothenburg, Sweden.;Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.",
"authors": "Lindström|Johan|J|;Helldén|Anders|A|;Lycke|Jan|J|;Grahn|Anna|A|;Studahl|Marie|M|",
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"fulltext": "\n==== Front\nJ Antimicrob ChemotherJ. Antimicrob. ChemotherjacJournal of Antimicrobial Chemotherapy0305-74531460-2091Oxford University Press 10.1093/jac/dkz357dkz357Original ResearchAn unexpectedly high occurrence of aciclovir-induced neuropsychiatric symptoms in patients treated for herpesvirus CNS infection: a prospective observational study https://orcid.org/0000-0003-3628-6189Lindström Johan 1Helldén Anders 2Lycke Jan 3Grahn Anna 1Studahl Marie 41 \nRegion Västra Götaland, Sahlgrenska University Hospital, Department of Infectious Diseases, Gothenburg, Sweden2 \nDepartment of Medical and Health Sciences, Division of Drug Research/Pharmacology, Linköping University Hospital, Linköping, Sweden3 \nDepartment of Clinical Neuroscience, Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden4 \nDepartment of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenCorresponding author. Department of Infectious Diseases, Sahlgrenska University Hospital, Diagnosvägen 21, SE-416 85 Göteborg, Sweden. Tel: +46 31 3439316; Fax: +46 31 847813; E-mail: johan.lindstrom@gu.se12 2019 25 8 2019 25 8 2019 74 12 3565 3572 30 4 2019 12 6 2019 13 7 2019 16 7 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nAciclovir is effective in herpesvirus infections of the CNS. Aciclovir-induced neuropsychiatric symptoms (AINS) have been reported and are associated with high CSF concentrations of aciclovir metabolite 9-carboxymethoxymethylguanine (CMMG). Risk factors except for renal failure have not been explored, and disruption of the blood–brain barrier (BBB) in acute CNS infection may be of interest.\n\nObjectives\nTo investigate the impact of risk factors on aciclovir and CMMG concentrations, and to relate the results to AINS.\n\nMethods\nWe investigated 21 consecutively included, consenting patients treated with aciclovir or valaciclovir for herpesvirus CNS infection. Regression models were constructed to study the impact of risk factors including BBB disruption, as measured with CSF:serum albumin ratio, on CSF aciclovir and CMMG concentrations. Medical records were assessed retrospectively to identify patients with AINS.\n\nResults\nIncreased CSF:serum albumin ratio, as well as decreased renal function and high aciclovir doses, was associated with increased aciclovir and CMMG concentrations in the CSF. We identified five patients with new neuropsychiatric symptoms; four of those were considered to have AINS and had increased CSF CMMG concentrations. Only one patient without suspicion of AINS had an increased CSF CMMG concentration.\n\nConclusions\nIn patients with herpesvirus CNS infections, BBB disruption is associated with increasing aciclovir and CMMG CSF concentrations. We also found an unexpectedly high number of patients with AINS. Evaluation of CSF:serum albumin ratios, renal function and CSF concentrations of aciclovir and CMMG may all contribute to the optimization of aciclovir dosing and avoidance of AINS.\n\nALF10.13039/100001424#ALFBGB-74050\n==== Body\nIntroduction\nAciclovir is the first-line treatment for patients with infections of the CNS caused by herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and varicella-zoster virus (VZV).1 The efficacy of treatment has only been studied in herpes simplex encephalitis (HSE). Intravenous (iv) aciclovir at 10 mg/kg q8h has in randomized trials been shown to decrease mortality in HSE markedly,2,3 but still the disease is associated with considerable morbidity.4\n\nWith the substantial morbidity taken into account, higher dosages than those used in studies on efficacy are sometimes considered in young patients with HSE without renal impairment, although studied retrospectively.5 Furthermore, several national guidelines and international expertise recommend treatment of VZV encephalitis with iv aciclovir at 10–15 mg/kg q8h,1,6 since VZV is less susceptible to aciclovir.7 However, the relationship between aciclovir concentrations, viral in vitro susceptibility and clinical efficacy is uncertain at best. Research on dosing and duration of aciclovir treatment is scarce, and increasing dosages may have negative consequences.\n\nAciclovir has the well-known and prevalent adverse effect of causing reversible nephrotoxicity, which can be prevented by adequate hydration and reducing the dosage.8 Less noticed is neurotoxicity related to aciclovir, aciclovir-induced neuropsychiatric symptoms (AINS), first reported in the 1980s.9 The AINS incidence in Sweden has been estimated to be at least one AINS case per million inhabitants, when retrospectively studied.10 A multitude of symptoms have been described, including confusion, hallucinations, ataxia, involuntary movements, somnolence and coma, mainly in patients with acute or chronic renal failure.11 However, symptoms occurring in HSE may be difficult to distinguish from AINS, and to date no systematic approach or scoring system to separate them has been published.\n\nThe association between AINS and aciclovir concentrations is not fully understood.12 Approximately 90% of aciclovir is excreted unchanged in the urine in patients with normal kidney function. The remaining part is metabolized by alcohol dehydrogenase and aldehyde dehydrogenase to the inactive main metabolite 9-carboxymethoxymethylguanine (CMMG). As renal function declines, metabolism to CMMG makes an increasing contribution to total clearance.13 More recent studies have shown an association between AINS and increased serum and CSF concentrations of CMMG in a more consistent manner compared with aciclovir concentrations,11,13 and as a result CMMG has been proposed as a more reliable marker of AINS than aciclovir.\n\nBesides decreased renal function, there may be other factors influencing CSF concentrations of aciclovir and CMMG. A few studies on CSF concentrations of aciclovir have been published, showing relatively stable aciclovir concentrations in CSF compared with serum, and lower AUC in CSF compared with serum,14–16 suggesting slow diffusion into and active transport out of CSF, substantiating the importance of the integrity of the blood–brain barrier (BBB) for aciclovir penetration to the CSF/CNS compartment. A damaged BBB, such as might occur in acute CNS infection, allows increased passage of molecules, usually accompanied by a decrease in functions of efflux mechanisms.17 Increased drug penetration due to BBB damage in CNS infections has been observed in studies of antiretrovirals18 and antibiotics.19,20 However, studies during aciclovir treatment are lacking.\n\nOur primary aim was to investigate the impact of different risk factors, including disruption of the BBB, on the concentrations of aciclovir and CMMG in patients treated for CNS infections. Our secondary aim was to relate our findings, including CMMG concentrations, to neuropsychiatric symptoms.\n\nPatients and methods\nPatients\nPatients (≥18 years of age) with suspected or confirmed herpes virus infection of the CNS, treated with iv aciclovir or oral valaciclovir, were consecutively enrolled in the study between 9 September 2013 and 20 January 2016 at the Department of Infectious Diseases at Sahlgrenska University Hospital, Gothenburg, Sweden. The Medical Ethics Committee at Gothenburg University approved the study (Dnr 407-13), and informed consent was obtained.\n\nSampling and analysis of serum and CSF\nPairs of serum and CSF were obtained on one or multiple occasions from each patient. The samples were obtained on days 1–2, 3–5, 6–9, 10–14, 15–21 and 22–30 after initiation of aciclovir treatment. Lag time between dose administration and sampling was not determined in advance, to enable analysis of the pharmacokinetic profile at group level in a scenario that mimics the clinical setting. CSF and blood samples were coded and stored at −70°C until further analysis.\n\nEstimation of renal function was determined from analysis of serum creatinine and serum cystatin C. CLCR was calculated using the Cockcroft–Gault formula,21 and glomerular filtration rate (GFR) based on cystatin C was calculated using the CAPA (Caucasian, Asian, paediatric and adult) formula.22 Development of acute kidney injury was further classified according to RIFLE (risk, injury, failure, loss of function, end-stage renal disease) criteria.23\n\nAlbumin levels in CSF and serum were measured by immunonephelometry on a Beckman image immunochemistry system (Beckman Instruments, Beckman Coulter, Brea, CA, USA). The albumin ratio was calculated [CSF albumin (mg/L)/serum albumin (g/L)] and used as an indicator of the integrity of the BBB,24 with normal upper limits of 6.8 × 10−3 for patients ≤45 years of age and 10.2 × 10−3 for patients >45 years of age,25 similar to the categorization suggested by Reiber and Felgenhauer.26 For ease of interpretation, albumin CSF:serum ratio is presented without adding the magnitude indicator of ×10−3 in the following sections.\n\nThe aciclovir and CMMG concentrations were determined at the Department of Clinical Pharmacology, Karolinska University Hospital, Huddinge, Stockholm, Sweden, using solid-phase extraction followed by HPLC with fluorescence detection. The limit of detection and the limit of quantification were 0.15 μmol/L. CMMG concentrations lower than the limit of detection of 0.15 μmol/L were assigned the value of 0.08 μmol/L for visualization purposes.\n\nAssessments of the risk of developing neuropsychiatric symptoms\nWe retrospectively studied the medical records of all included patients for neuropsychiatric symptoms previously associated with AINS, specifically generalized neuropsychiatric symptoms such as confusion, hallucinations, ataxia, involuntary movements, somnolence and coma.11 The study protocol did not include specific instructions on documentation, but documentation had been made on a daily basis according to standard procedure. Fever, headache and focal CNS symptoms, more typical of viral CNS infection, were considered unlikely to be associated with treatment.27 To further distinguish AINS from symptoms of viral CNS infection, symptoms needed to have developed during aciclovir treatment, and resolved at dose reduction or end of treatment. In addition, concomitant medications or pathologies needed to be ruled out as responsible for such symptoms. The risk assessment also included data on aciclovir doses and changes in serum creatinine, as decreased renal function has been previously associated with AINS. The assessments were performed blinded without knowledge of the aciclovir or CMMG concentrations by three of the authors: an experienced neurologist (J. Lycke) and two clinicians at the Department of Infectious Diseases (M. S., J. Lindström). The patient was considered to have suspected AINS if two or three of the raters were in agreement.\n\nStatistical analysis and subgrouping\nMultivariable regression models were constructed to study the impact of relevant independent variables on the studied dependent variables. The SAS procedure mixed was used, considering that some of the patients were sampled at more than one timepoint, using the autoregressive covariance pattern that was found optimal based on the lowest Akaike information criterion. The residual plots were reviewed for assumption of normal distribution. Standard errors and 95% CIs were estimated based on robust sandwich estimators in order to adjust for residuals’ potential deviation from a normal distribution. The mixed models were performed using SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA). Group comparisons were performed with the Mann–Whitney U-test, using GraphPad Prism 7.0 (GraphPad Software, San Diego, CA, USA). All tests were two-tailed and conducted at the 0.05 significance level.\n\nResults\nDuring the 29 month period of 2013–16, 21 patients were enrolled in the study. Overall, 34 CSF samples and 32 serum samples were obtained from the 21 patients. Patient data and characteristics are presented in Table 1. As treatment duration and timing of inclusion differed, the number of samplings for each patient varied from one to three. Owing to the study being performed at a referral clinic, all but one patient had their primary diagnostic CSF sampling made before inclusion in the study.\n\n\nTable 1. Characteristics of included patients, their treatment and CSF concentrations of aciclovir (ACV) and CMMG at all sampling timepoints\n\nPatient\tAge (years) \tGender\tWeight (kg)\tIndication for treatment\tACV dose q8h (mg/kg)\tLag time from dose to sampling (h)\tTreatment duration (days)\tEstimated CLCR (mL/min)\tRIFLE\tSerum concentration (μmol/L)\tCSF concentration (μmol/L)\tCSF:serum albumin ratio×10-3\tNeuropsychiatric symptoms during treatment\t\nACV\tCMMG\tACV\tCMMG\t\n1a\t70\tM\t56\therpes encephalitis\t10\t7.5\t13\t80\tR\t5.7\t0.74\t8.4\t0.15\tN/A\t\t\n1b\t\t\t\t\t10\t9\t20\t71\t\t2.7\t0.29\t7.1\t<0.15\t15.4\t\t\n1c\t\t\t\t\t10\t8.5\t27\t57\t\t5\t0.59\t8.5\t<0.15\t11.7\t\t\n2\t79\tF\t52\therpes encephalitis\t11\t6.5\t9\t61\tR\t70\t12\t11\t0.27\t7\t\t\n3\t66\tM\t89\tsuspected varicella meningitis\t1000d\t1\t14\t84\tF\t29\t1.7\t3.1\t<0.15\t6.9\t\t\n4a\t35\tM\t98\therpes encephalitis\t15\t6\t2\t30\tF\t110\t57\t40\t3.3\t29.4\tconfusion, improved at dose adjustment\t\n4b\t\t\t\t\t12\t7.5\t9\t125\t\t25\t2.8\t7.5\t0.15\t15.7\t\n4c\t\t\t\t\t12\t8\t16\t149\t\t10\t1.5\t10\t0.19\t23.8\t\n5\t30\tM\t100\tsuspected encephalitis\t10\t6\t3\t109\t\t9.6\t1.3\t6.7\t<0.15\t24.3\t\t\n6a\t64\tF\t60\therpes encephalitis\t12\t3.5\t3\t40\tR\t50\t9.7\t24\t0.68\t20.1\tconfusion, improved at end of treatment\t\n6b\t\t\t\t\t12\t4\t13\t65\t\t18.6\t2.7\t14\t0.3\t15.4\t\n6c\t\t\t\t\t12\t8\t21\t70\t\t11\t2.3\t12\t0.23\t11.9\t\n7a\t65\tM\t76\trecurrent herpes encephalitis\t15\t2.5\t8\t109\tI\t55\t18\t16\t0.29\t14.7\tconfusion, improved at end of treatment\t\n7b\t\t\t\t15\t4.5\t15\t51\t\t120\t38\t29\t1\t10.5\t\n7c\t\t\t\t15\t21\t29\t35\t\t11\t11\t8.2\t0.66\t14.6\t\n8\t55\tM\t77\therpes encephalitis\t10\t5.5\t13\t122\t\t11\t1\t6.7\t<0.15\t7.4\t\t\n9a\t58\tM\t68\tstroke\t11\t1\t5\t56\t\t75\t10\t12\t0.27\t9.3\t\t\n9b\t\t\t\t\t10\t6.5\t11\t52\t\t20\t5\t11\t0.26\t11.7\t\t\n10\t40\tM\t120\therpes meningoencephalitis\t10\t1\t12\t184\t\t13\t0.9\t8.5\t<0.15\t9.6\t\t\n11\t41\tF\t67\therpes meningitis\t10\t4.5\t7\t117\t\t14\t1.5\t17\t0.77\t26.7\t\t\n12\t67\tM\t78\tsuspected encephalitis\t9\t1.5\t5\t87\t\t31\t4.9\t8.9\t0.17\t13.8\t\t\n13\t26\tF\t50\tsuspected encephalitis\t15\t8\t3\t119\t\t6.1\t1.2\t5.9\t<0.15\t8.6\t\t\n14\t58\tM\t87\therpes meningitis\t1000d\t1\t10e\t115\t\t13\t2\t4.8\t<0.15\t8.6\t\t\n15a\t65\tF\t67\therpes encephalitis\t9\t6\t6\t73\t\t10\t2.3\t7.7\t0.16\t8.5\t\t\n15b\t\t\t\t\t9\t3\t11\t79\t\t40\t5.4\t7.6\t<0.15\t8.8\t\t\n16\t39\tF\t77\therpes encephalitis\t14\t1\t13\t131\t\tN/A\tN/A\t8\t<0.15\t22.5\t\t\n17\t49\tF\t72\therpes meningitis\t9\t1.5\t3\t129\t\t17\t1.6\t7.5\t<0.15\t4.1\t\t\n18\t53\tM\t85\tvaricella meningitis\t14\t5.5\t2\t123\t\tN/A\tN/A\t14\t0.24\t13.3\t\t\n19a\t75\tF\t57\tvaricella encephalitis\t10\t7\t7\t54\tRf\t15\t5.2\t28\t6.4\t162.4\tconfusion, improved at end of treatment\t\n19b\t\t\t\t\t10\t7\t14\t68\t\t13\t3.6\t27\t3.8\t108.1\t\n20a\t55\tF\t68\tRamsay Hunt syndrome\t14\t2.5\t2\t131\tF\t31\t3.8\t6.5\t<0.15\t1.7\tanxiety, improved slowly at end of treatment\t\n20b\t\t\t\t\t5\t3\t9\t60\t\t12\t3\t3.3\t<0.15\t1.4\t\n21a\t38\tM\t81\tvaricella encephalitis\t14\t4.5\t1\t141\t\t9.9\t1.1\t12\t0.2\t28.8\t\t\n21b\t\t\t\t\t14\t2.5\t3\t135\t\t19\t1.9\t14\t0.24\t18\t\t\nACV dose, mg iv aciclovir per kg body weight in a single dose, administered three times daily, except in patient 20b, where doses were administered twice daily; N/A, not available; M, male; F, female; (RIFLE column) R, risk; I, injury; F, failure; shaded areas indicate patients assessed to have AINS.\n\na First sampling in patient where repeated sampling was performed.\n\nb Second sampling.\n\nc Third sampling.\n\nd Treatment with oral valaciclovir in single dose (mg), three times daily.\n\ne Patient had previously received valaciclovir in a lower dose regimen as prophylaxis.\n\nf Patient did not fulfil RIFLE criteria based on creatinine, but calculation of GFR according to cystatin C CAPA estimated GFR at 30 mL/min, corresponding to at least risk of acute kidney failure.\n\nRisk factors and CSF concentrations of aciclovir and CMMG\nMedian aciclovir concentration in serum was 14.5 μmol/L (range 2.7–120) and in CSF 8.7 μmol/L (3.1–40). Median CMMG concentration measured in serum was 2.5 μmol/L (range 0.29–57) and in CSF 0.18 μmol/L (<0.15–6.4) (Figure 1).\n\n\nFigure 1. Distribution of aciclovir (left of divider) and CMMG (right of divider) in serum (n=32) and CSF (n=34) samples from patients (n=21) treated with aciclovir for herpesvirus CNS infection. Limit of detection is 0.15; values <0.15 are set to 0.08 for visualization purposes. Bar is set at median.\n\nIn our multiple linear regression model, significant associations were made between several independent risk factors and concentrations of aciclovir and CMMG in the CSF (Table 2).\n\n\nTable 2. Multiple linear regression models for aciclovir and CMMG CSF concentrations in 21 patients treated with aciclovir for CNS infection (34 samples)\n\nIndependent variable\tComparison\tAciclovir CSF concentration\tCMMG CSF concentration\t\nβ (95% CI)\t\nP value\tβ (95% CI)\t\nP value\t\nAlbumin ratio (×10−3)\tper 10 unit increase\t1.499 (1.290–1.709)\t<0.0001\t0.388 (0.356–0.421)\t<0.0001\t\nLag time dose to sampling (h)\tper 1 unit increase\t−0.779 (−1.350 to −0.208)\t0.015\t−0.046 (−0.072 to −0.020)\t0.0038\t\nCreatinine clearance (mL/min)\tper 10 unit increase\t−1.428 (−2.099 to −0.756)\t0.0015\t−0.161 (−0.245 to −0.077)\t0.0027\t\nDose (mg/kg)\tper 1 unit increase\t1.703 (1.215–2.190)\t<0.0001\t0.093 (0.022–0.163)\t0.017\t\nWeight (kg)\tper 10 unit increase\t1.996 (1.000–2.991)\t0.0005\t0.223 (0.052–0.394)\t0.013\t\nAge (years)\tper 10 unit increase\t0.042 (−1.402 to 1.487)\t0.95\t−0.026 (−0.198 to 0.147)\t0.74\t\nGender\twomen versus men\t0.774 (−2.276 to 3.824)\t0.60\t0.292 (−0.179 to 0.762)\t0.21\t\nBBB integrity\nAn increase of 10 in CSF:serum albumin ratio was associated with a mean increase in CSF aciclovir concentration of 1.50 μmol/L (95% CI 1.29–1.71, P<0.001) (Figure 2a) and a mean increase in CMMG CSF concentration of 0.39 μmol/L (95% CI 0.36–0.42, P<0.001) (Figure 3a).\n\n\nFigure 2. Aciclovir concentrations in serum (n=32) and CSF (n=34) samples from patients (n=21) treated with aciclovir for herpesvirus CNS infection. (a) Increased CSF:serum albumin ratio, interpreted as an indication of BBB damage, is associated with increased aciclovir CSF concentrations. The dotted vertical line represents the upper normal reference for CSF:serum albumin ratio (10.2). (b) Decreased creatinine clearance, calculated using the Cockcroft–Gault formula, is associated with increased aciclovir serum and CSF concentrations. (c) Increasing dose of aciclovir is associated with increased aciclovir serum and CSF concentrations.\n\nFigure 3. CMMG concentrations in serum (n=32) and CSF (n=34) samples from patients (n=21) treated with aciclovir for herpesvirus CNS infection. (a) Increased CSF:serum albumin ratio, interpreted as an indication of BBB damage, is associated with increased CMMG CSF concentrations. The dotted vertical line represents the upper normal reference for CSF:serum albumin ratio (10.2). The dotted horizontal line represents a CMMG CSF concentration of 0.5 μmol/L, previously associated with AINS. (b) Decreased creatinine clearance, calculated using the Cockcroft–Gault formula, is associated with increased CMMG serum and CSF concentrations. The dotted horizontal line represents a CMMG CSF concentration of 0.5 μmol/L, previously associated with AINS. (c) Increased dosing of aciclovir is associated with increased CMMG serum and CSF concentrations. The upper dotted horizontal line represents a CMMG serum concentration of 10 μmol/L, previously associated with AINS, and the lower dotted horizontal line represents a CMMG CSF concentration of 0.5 μmol/L, previously associated with AINS.\n\nRenal insufficiency\nA decrease in CLCR of 10 mL/min was associated with a mean increase in CSF aciclovir concentration of 1.43 μmol/L (95% CI 0.76–2.10, P=0.015) (Figure 2b) and a mean increase in CMMG CSF concentration of 0.16 μmol/L (95% CI 0.08–0.25, P=0.0027) (Figure 3b).\n\nAciclovir dosing\nAn increase in aciclovir dose of 1 mg/kg was associated with a mean increase in CSF aciclovir concentration of 1.70 μmol/L (95% CI 1.22–2.19, P<0.001) (Figure 2c) and a mean increase in CMMG CSF concentration of 0.09 μmol/L (95% CI 0.02–0.16, P=0.017) (Figure 3c).\n\nLag time\nCSF aciclovir concentration decreased by a mean of 0.78 μmol/L (95% CI 0.21–1.35, P=0.015) for every hour that passed between dose administration and sampling, and CSF CMMG concentrations decreased by 0.05 μmol/L (95% CI 0.02–0.07, P=0.0038).\n\nWeight\nA 10 kg increase in weight was associated with a mean increase in CSF aciclovir concentration of 2.00 μmol/L (95% CI 1.00–2.19, P=0.0005) and a mean increase in CSF CMMG concentration of 0.22 μmol/L (95% CI 0.05–0.39, P=0.013).\n\nAge and gender\nNeither age nor gender was significantly associated with changes in CSF aciclovir or CMMG concentrations.\n\nNeuropsychiatric symptoms\nFive out of 21 patients were identified with neuropsychiatric symptoms that developed after initiation of aciclovir treatment and subsided after a dose decrease or after the end of treatment (Table 1; see also the short descriptive case series available as Supplementary data at JAC Online). Four of the patients (Patients 4, 6, 7 and 19) deteriorated during treatment, with increased confusion, while one patient (Patient 20) presented with decreased muscle tonus and anxiety, not previously associated with AINS. None of the included patients was suspected to have AINS by the treating clinicians. Looking at expected risk factors, five out of five identified patients had decreased renal function, four out of five were treated with an aciclovir dose >10 mg/kg q8h and four out of five had indication of BBB damage with elevated CSF:serum albumin ratio (Table 1)\n\nExcluding Patient 20, who did not present a picture similar to earlier published cases, patients assessed with neuropsychiatric symptoms had higher peak CMMG concentrations in any CSF sample (n=4; median 2.15 μmol/L; range 0.68–6.4) compared with patients without typical neuropsychiatric symptoms (n=17; <0.15 μmol/L; <0.15–0.77) (P=0.0003) (Figure 4). Only one patient (Patient 11) had a CMMG concentration in CSF >0.5 μmol/L without recorded symptoms indicating AINS, and although this patient had BBB damage, he had a standard aciclovir dose of 10 mg/kg q8h and normal renal function. Peak serum CMMG concentration was also significantly higher in patients with AINS (n=4; median 23.85 μmol/L; range 5.2–57.0) compared with patients without typical neuropsychiatric symptoms (n=15; 1.7 μmol/L; 0.74–12.0) (P=0.0093).\n\n\nFigure 4. Comparison of peak CMMG concentrations in CSF samples from patients (n=21) treated with aciclovir for herpesvirus CNS infection. Comparison is made between patients with (n=4) and without (n=17) suspected AINS, previously associated with CMMG >0.5 μmol/L (upper dotted horizontal line). Bar is set at the median. The lower dotted horizontal line represents the CMMG analysis limit of quantification (LOQ) of 0.15 μmol/L.\n\nDiscussion\nIn this study, we show that damage to the BBB has a significant impact on aciclovir and CMMG pharmacokinetics in a clinical setting. We also reinforce the association between increased concentrations of CMMG in the CSF and neuropsychiatric symptoms, which were surprisingly prevalent.\n\nLooking at the results from our regression models, our findings demonstrate that damage to the BBB in the acute phase of CNS infection is associated with increased penetration of aciclovir and CMMG into the CNS/CSF compartment. The association was proportionally more pronounced when looking at CMMG compared with aciclovir, suggesting a larger impact of BBB damage on CMMG CNS pharmacokinetics, possibly owing to it being more difficult for CMMG to cross the BBB compared with aciclovir, consistent with pharmacokinetic data reported by Smith et al.16 The same study also describes that CMMG concentrations in the CSF do not vary considerably over time when in steady-state. This is not fully supported in our material since there is a change in CMMG concentration in relation to lag time from dose administration to sampling. However, the change is very small whereas the change in the aciclovir counterpart is more dynamic. Both CMMG and aciclovir concentrations were in some cases higher in CSF compared with serum, suggesting accumulation, and slow clearance out of the CNS for both molecules. In addition to BBB damage, and according to expectations, changes in CLCR had an impact on aciclovir and CMMG concentrations, as did increasing aciclovir doses. Notably, increased age was not associated with increased concentrations, possibly as an effect of decreased renal function already being considered in our models. Increased weight, on the other hand, was associated with increased concentrations, suggesting that dosing based on weight may be suboptimal. Patients that weigh more will receive larger doses of aciclovir, while the increase in weight is not necessarily reflected in an increase in renal elimination, resulting in a higher risk of aciclovir and CMMG accumulation. We found concentrations of CMMG in CSF >0.5 μmol/L, previously associated with toxicity,13 in 5/21 patients.\n\nIn our retrospective assessment, we were able to identify a surprisingly high number of patients with symptoms consistent with AINS, without taking aciclovir and CMMG concentrations into consideration. Although we identified five patients with neuropsychiatric symptoms, Patient 20 had anxiety as the main finding, a symptom that has not previously been described as typical of AINS. In addition, she did not have increased CMMG in the CSF samples, and we conclude that it is improbable that her anxiety was related to aciclovir treatment. Only in one patient with a CMMG level >0.5 μmol/L (Patient 11) were no neuropsychiatric symptoms found. However, it is possible that the patient may have had symptoms that were not noted in the medical records. Prospective, repeated assessments of neurological and psychiatric symptoms according to a protocol may have decreased the risk of missing such symptoms, but with the risk of impacting therapeutic decisions in this otherwise observational study.\n\nAn alternative explanation to impaired neurocognitive recovery could be autoimmune encephalitis. Recovery after cessation of aciclovir treatment, in combination with absence of anti-N-methyl-d-aspartate-receptor IgG antibodies in CSF and serum from the last sampling during admittance (data not shown), makes this highly unlikely. Autoimmune encephalitis is described as a later complication, with autoantibodies detected at 3 months after onset of HSE.28\n\nConsidering the invasiveness of CSF sampling, analysis of serum CMMG concentrations could be considered an attractive alternative if proven reliable. Although the patients with AINS had higher median peak serum concentrations of CMMG, there was an overlap between groups, and two out of four patients with suspected AINS had serum CMMG concentrations <10.8 μmol/L, previously associated with AINS.11 However, if CSF sampling is contraindicated, analysis of serum CMMG and aciclovir concentrations may still provide an indication of potentially harmful dosages if concentrations are high.\n\nAINS has in most cases previously been associated with chronic renal failure, which none of our patients with elevated CMMG had in their medical history. However, Patients 4, 6 and 7 could be classified with acute kidney injury according to RIFLE criteria, and Patient 19 had decreased GFR according to calculation based on cystatin C. Only Patient 11 had increased CSF CMMG without any indication of kidney injury, and considering he was not suspected to have AINS, it is possible that renal function may be related to AINS in some respect that is not yet fully understood. While high concentrations of aciclovir in the CSF have been associated with AINS, there are conflicting reports,12 and although CMMG has proven to be more reliable,13 it is unknown how it relates to the pathogenesis.\n\nIt is notable that none of the included patients was suspected to have AINS by the treating clinicians, highlighting the diagnostic difficulties and the need for additional diagnostic tools. Even though our assessment was retrospective, the patients were consecutively included, with a lower risk of selection bias when analysing CMMG compared with the previous studies.11,13 Considering the consistency in our study between neuropsychiatric symptoms and increased CMMG concentrations, we can assert that analysis of CMMG in the CSF may be a useful tool when considering aciclovir-induced neuropsychiatric toxicity, especially since a systematic approach is otherwise lacking.\n\nAlthough pharmacokinetic changes associated with BBB damage may be detrimental with regard to AINS, there may be positive effects associated with increased CNS penetration of aciclovir. Since BBB damage is most pronounced in the early stages of herpesvirus CNS infections, when viral replication is thought to play an important role in the pathogenesis,29 increased concentrations of aciclovir in the CSF might potentially be beneficial, similar to the rationale for consideration of increased aciclovir dosages in selected patients. In the retrospective study on patients with HSE by Stahl et al.5 where dosages of aciclovir were compared, a dosage of 15 mg/kg q8h did not increase the efficacy of treatment over a dosage of 10 mg/kg q8h, measured by looking at poor versus favourable outcome after treatment. Considering the increase in aciclovir concentrations in patients with BBB damage, a possible explanation for the lack of efficacy of increased dosages is that the increased dosages may be excessive. Although there is very little previous data on the penetration of aciclovir into the CNS in regard to BBB damage, a correlation between the albumin CSF:serum ratio and aciclovir CSF concentrations has previously been shown by Pouplin et al.30 in six patients treated with valaciclovir for HSE. In this context, it is proposed that BBB damage may have an impact on the feasibility of oral treatment of HSE, but, as discussed by Bodilsen et al.,31 drawing conclusions on efficacy based on aciclovir CSF concentrations is hazardous.\n\nAlthough AINS seem to be reversible, they are detrimental to the patient and may obscure the symptomatic progress of the treated disease. Since the morbidity after herpesvirus CNS disease is considerable, it is still possible that some patients may tolerate and benefit from increased doses of aciclovir. However, the recommendation of doses >10 mg/kg q8h in the initial stages of disease is debatable and should perhaps be reconsidered. Instead, it would be safer to consider an increase in dose after a few days of treatment, allowing time for adequate hydration and assurance of stable renal function, as well as factoring in the CSF:serum albumin ratio to identify patients who present with less-pronounced BBB damage, or patients in which the BBB heals over the course of treatment.\n\nIn summary, patients with compromised BBB, decreased renal function and high aciclovir doses have an increased risk of accumulating CMMG in the CSF, and increased concentrations of CMMG are associated with AINS. To optimize aciclovir dosing, we suggest that it may be advantageous to reconsider treatment with doses >10 mg/kg q8h, analyse CSF:serum albumin ratios in addition to evaluation of renal function, and, when available, measure CSF concentrations of both aciclovir and CMMG. This approach may be of particular interest when trying to discriminate between AINS and aggravated symptoms due to viral CNS disease.\n\nSupplementary Material\ndkz357_Supplementary_Data Click here for additional data file.\n\n Acknowledgements\nWe thank our colleagues and staff at the Department of Infectious Diseases at Sahlgrenska University Hospital, Gothenburg, for helpful assistance in including the patients in this study.\n\nFunding\nThe study was financed by grants from the Swedish state under the agreement between the Swedish government and the country councils, the ALF-agreement (#ALFBGB-74050).\n\nTransparency declarations\nNone to declare.\n==== Refs\nReferences\n1 \nGilden DH , Mahalingam R , Cohrs RJ \net al\nHerpesvirus infections of the nervous system . Nat Clin Pract Neurol 2007 ; 3 : 82 –94 .17279082 \n2 \nSkoldenberg B , Forsgren M , Alestig K \net al\nAcyclovir versus vidarabine in herpes simplex encephalitis. 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Crit Care 2004 ; 8 : R204 –12 .15312219 \n24 \nTibbling G , Link H , Ohman S. \nPrinciples of albumin and IgG analyses in neurological disorders. I. Establishment of reference values . Scand J Clin Lab Invest 1977 ; 37 : 385 –90 .337459 \n25 \nBlennow K , Fredman P , Wallin A \net al\nProtein analysis in cerebrospinal fluid. II. Reference values derived from healthy individuals 18-88 years of age . Eur Neurol 1993 ; 33 : 129 –33 .8467819 \n26 \nReiber H , Felgenhauer K. \nProtein transfer at the blood cerebrospinal fluid barrier and the quantitation of the humoral immune response within the central nervous system . Clin Chim Acta 1987 ; 163 : 319 –28 .3581475 \n27 \nRashiq S , Briewa L , Mooney M \net al\nDistinguishing acyclovir neurotoxicity from encephalomyelitis . J Intern Med 1993 ; 234 : 507 –11 .8228796 \n28 \nWestman G , Studahl M , Ahlm C \net al\nN-methyl-d-aspartate receptor autoimmunity affects cognitive performance in herpes simplex encephalitis . Clin Microbiol Infect 2016 ; 22 : 934 –40 .27497810 \n29 \nEsiri MM. \nHerpes simplex encephalitis. An immunohistological study of the distribution of viral antigen within the brain . J Neurol Sci 1982 ; 54 : 209 –26 .6284882 \n30 \nPouplin T , Pouplin JN , Van Toi P \net al\nValacyclovir for herpes simplex encephalitis . Antimicrob Agents Chemother 2011 ; 55 : 3624 –6 .21576427 \n31 \nBodilsen J , Nielsen H , Whitley RJ. \nValaciclovir therapy for herpes encephalitis: caution advised . J Antimicrob Chemother 2019 ; 74 : 1467 –8 .30668736\n\n",
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"title": "An unexpectedly high occurrence of aciclovir-induced neuropsychiatric symptoms in patients treated for herpesvirus CNS infection: a prospective observational study.",
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"abstract": "Recent advancements in multimodal therapy can provide oncologic benefits for patients with recurrent colorectal cancer. This report presents a case of locoregionally recurrent appendiceal cancer treated with neoadjuvant chemotherapy followed by surgical resection with vascular reconstruction. A 68-year-old Japanese woman was diagnosed with appendiceal cancer and underwent ileocecal resection. The pathological evaluation revealed KRAS-mutant adenocarcinoma with the final stage of T4bN1M0. She received oral fluorouracil-based adjuvant chemotherapy. One year later, she was found to have peritoneal dissemination in the pelvic cavity and vaginal metastasis. She received an oxaliplatin-based chemotherapy followed by surgical resection. One year after the second surgery, she developed a locoregional recurrence involving the right external iliac vessels and small intestine. She received an irinotecan-based regimen with bevacizumab as neoadjuvant chemotherapy, followed by surgical resection. At first, a femoro-femoral bypass was made to secure the blood supply to the right lower extremities. Subsequently, an en bloc resection including the recurrent tumor and the external iliac vessels was completed. Surgical resection for recurrent colorectal cancer is often technically challenging because of the tumor location and invasion to adjacent organs. In this case, a surgical approach with persistent chemotherapy achieved oncologic resection of locoregionally recurrent appendiceal cancer.",
"affiliations": "Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanumacho, Omiya, Saitama-shi, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanumacho, Omiya, Saitama-shi, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanumacho, Omiya, Saitama-shi, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanumacho, Omiya, Saitama-shi, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanumacho, Omiya, Saitama-shi, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanumacho, Omiya, Saitama-shi, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanumacho, Omiya, Saitama-shi, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanumacho, Omiya, Saitama-shi, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanumacho, Omiya, Saitama-shi, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanumacho, Omiya, Saitama-shi, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanumacho, Omiya, Saitama-shi, Saitama 330-8503, Japan.",
"authors": "Takahashi|Jun|J|;Tsujinaka|Shingo|S|0000-0002-8554-3869;Kakizawa|Nao|N|;Takayama|Noriya|N|;Machida|Erika|E|;Iseya|Kazuki|K|;Hasegawa|Fumi|F|;Kikugawa|Rina|R|;Miyakura|Yasuyuki|Y|;Suzuki|Koichi|K|;Rikiyama|Toshiki|T|",
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"doi": "10.1155/2018/1674279",
"fulltext": "\n==== Front\nCase Rep SurgCase Rep SurgCRISCase Reports in Surgery2090-69002090-6919Hindawi 10.1155/2018/1674279Case ReportSurgical Resection with Neoadjuvant Chemotherapy for Locoregionally Recurrent Appendiceal Cancer Invading the External Iliac Vessels Takahashi Jun http://orcid.org/0000-0002-8554-3869Tsujinaka Shingo tsujinakas@omiya.jichi.ac.jpKakizawa Nao Takayama Noriya Machida Erika Iseya Kazuki Hasegawa Fumi Kikugawa Rina Miyakura Yasuyuki Suzuki Koichi Rikiyama Toshiki Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanumacho, Omiya, Saitama-shi, Saitama 330-8503, JapanAcademic Editor: Christine Tunon-de-Lara\n\n2018 2 8 2018 2018 167427919 3 2018 10 6 2018 24 7 2018 Copyright © 2018 Jun Takahashi et al.2018This 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.Recent advancements in multimodal therapy can provide oncologic benefits for patients with recurrent colorectal cancer. This report presents a case of locoregionally recurrent appendiceal cancer treated with neoadjuvant chemotherapy followed by surgical resection with vascular reconstruction. A 68-year-old Japanese woman was diagnosed with appendiceal cancer and underwent ileocecal resection. The pathological evaluation revealed KRAS-mutant adenocarcinoma with the final stage of T4bN1M0. She received oral fluorouracil-based adjuvant chemotherapy. One year later, she was found to have peritoneal dissemination in the pelvic cavity and vaginal metastasis. She received an oxaliplatin-based chemotherapy followed by surgical resection. One year after the second surgery, she developed a locoregional recurrence involving the right external iliac vessels and small intestine. She received an irinotecan-based regimen with bevacizumab as neoadjuvant chemotherapy, followed by surgical resection. At first, a femoro-femoral bypass was made to secure the blood supply to the right lower extremities. Subsequently, an en bloc resection including the recurrent tumor and the external iliac vessels was completed. Surgical resection for recurrent colorectal cancer is often technically challenging because of the tumor location and invasion to adjacent organs. In this case, a surgical approach with persistent chemotherapy achieved oncologic resection of locoregionally recurrent appendiceal cancer.\n==== Body\n1. Introduction\nThe recurrence rate following curative resection with adjuvant chemotherapy for stage II or III colorectal cancer is approximately 30% [1]. Locoregional recurrence after curative resection for colon cancer is uncommon, with a reported incidence of 4.4% to 12.8% [2–5]. Although previous studies have demonstrated that complete surgical resection improved survival for locoregionally recurrent colon cancer (LRCC) [5–8], curative surgery is often challenging because it may lead to complex multivisceral resection. Neoadjuvant chemotherapy and/or radiotherapy may be considered for LRCC; however, little evidence is available due to a lack of prospective trials. Hence, we herein report a case of locoregionally recurrent appendiceal cancer treated by surgical resection with neoadjuvant chemotherapy.\n\n2. Case Presentation\nA 68-year-old Japanese woman with no significant medical history had suffered from pain in her right lower quadrant. She was examined at the regional cancer center and diagnosed with appendiceal cancer. She underwent ileocecal resection with lymph node dissection at the aforementioned hospital, and the postoperative course was uneventful. The pathological evaluation revealed KRAS-mutant (codon 12) moderately to poorly differentiated adenocarcinoma, and the final TNM stage was T4b (small intestine) N1M0 (stage IIIc). Thereafter, she received adjuvant chemotherapy with oral tegafur/uracil and leucovorin for one year.\n\nOne year after the surgery, a positron emission tomography/computed tomography (PET/CT) scan showed sporadic foci of intense tracer uptake in the pelvic cavity, consistent with peritoneal dissemination and vaginal metastasis. The recurrent tumor deposits were considered resectable. She received three courses of mFOLFOX6 regimen (oxaliplatin, folinic acid, and fluorouracil) as neoadjuvant chemotherapy, followed by resection of the peritoneal dissemination and partial resection of the vagina. The pathological diagnosis confirmed negative resection margins. Then, she resumed the mFOLFOX6 regimen as adjuvant chemotherapy; however, the regimen was discontinued after two courses for an allergic response to oxaliplatin.\n\nOne year after the second surgery, a surveillance abdominal ultrasonography showed a 27 × 16 mm irregular and low-echoic tumor around the right external iliac artery (Figure 1). A contrast-enhanced CT scan showed an irregularly enhanced tumor around the right external iliac artery and vein. In addition, the tumor appeared contiguous to the small intestine. These findings suggested tumor invasion to the right external iliac artery, the right external iliac vein, and the small intestine (Figure 2). A PET/CT scan showed tracer uptake (standardized uptake value max: 17.5) at the tumor (Figure 3). It also showed regional lymph node enlargement around the right iliac vessels and no findings of distant metastases. The patient was diagnosed with a locoregional recurrence after the first reoperative surgery for appendiceal cancer. She was then referred to our hospital for potential surgical resection.\n\nWe assumed that the tumor was resectable; however, the external iliac vessels also required resection during the surgery, which required a simultaneous procedure for vascular reconstruction. We proposed neoadjuvant chemotherapy and subsequent surgery for the patient because it was deemed important to control the tumor progression and increase tumor resectability.\n\nWe selected a FOLFIRI (irinotecan, folinic acid, and fluorouracil) plus bevacizumab regimen as neoadjuvant chemotherapy, considering the mutant KRAS status. We initially planned six courses of FOLFIRI plus bevacizumab therapy and assess the tumor progression and resectability every 3 months. We discussed with the patient, and she agreed with our proposed treatment strategy. Follow-up CT scans after three and six treatment courses showed no tumor progression. After six courses of the treatment, we recommended surgical resection for her as we planned, but she wanted to receive chemotherapy. FOLFIRI plus bevacizumab regimen was continued accordingly.\n\nAfter eight courses, she developed edema in the right lower extremities. A contrast-enhanced CT showed a narrowing of the right external iliac vein without any thromboemboli in both lower extremities; however, she was incidentally found to have suspicious emboli in her pulmonary arteries. The neoadjuvant chemotherapy was terminated, and she was administered an anticoagulant therapy (edoxaban). After two months, a contrast-enhanced CT was taken again and showed no thromboemboli and no significant tumor progression. Although she had been asymptomatic for the suspicious pulmonary embolism, her lower extremities remained edematous. We, thus, indicated surgical resection of the tumor. The tumor was considered to be resectable, and we asked cardiovascular surgeons for vascular reconstruction at the time of surgery.\n\nThe surgery was performed in the following sequence. At first, vascular reconstruction was performed by cardiovascular surgeons. A femoro-femoral arterial bypass with synthetic vascular graft (Gelsoft™ 8 mm, Vascutek Ltd., Renfrewshire, Scotland, UK) was made to secure the blood supply to the right lower extremities. Subsequently, a laparotomy was performed by colorectal surgeons. A fixed and solid tumor was observed at the right inguinal fossa, involving the external iliac artery, external iliac vein, ileum, and right obturator lymph nodes. En bloc tumor resection was successfully performed including a partial resection of the external iliac artery, external iliac vein, and ileum (Figure 4). The postoperative course was uneventful except for a prolonged ileus. She was discharged home 30 days after surgery. The leg edema was improved over time and did not recur during the follow-up.\n\nThe pathological evaluation revealed moderately and poorly differentiated adenocarcinoma consistent with rerecurrence of appendiceal cancer. Tumor invasion was extended to the external iliac vein with tumor embolus inside. The external iliac artery and ileum were free of tumor invasion but strongly attached to the tumor. The obturator lymph nodes and those in the resected mesentery of the ileum were positive for metastasis. Microscopically, cauterized cancer cells were present at the resection margin (R1 resection).\n\nShe received a FOLFIRI regimen as adjuvant chemotherapy. After six courses, a follow-up CT scan showed liver metastasis, para-aortic lymph node metastasis, and peritoneal dissemination. These recurrent lesions were considered unresectable. The chemotherapy regimen was altered to trifluridine/tipiracil. After seven courses, a follow-up CT scan showed a significant progression of the liver metastasis. Regorafenib was then administered for two weeks; however, it was discontinued because she denied further aggressive treatment. She had received palliative care and died one and half years after the last surgery.\n\n3. Discussion\nCurative surgical resection is crucial for the improved survival of LRCC. A systematic review concerning outcomes of resection for LRCC demonstrated that the R0 resection rate was 51%, and a five-year survival after R0 resection of 52% compared to 11% and 0% for R1 and R2 resection, respectively. They concluded that resection of LRCC is performed safely with long-term survival but that patients who could undergo resection had good performance status; therefore, the results may have been influenced by patient selection [9].\n\nSeveral studies have investigated the prognostic factors after surgery for LRCC by univariate and multivariate analysis. These factors include margin status [6, 7, 10, 11], number of LRCC [6, 7, 10], site of LRCC [6, 10], presence of distant metastasis [6, 7], age, stage of primary tumor, preoperative carcinoembryonic antigen (CEA) level [6], pathological grade, largest tumor diameter [7], time to first recurrence [10], nodal involvement of primary tumor, and vascular invasion of LRCC [11]. The locoregional recurrence rate of colon cancer is 4.4% to 12.8% [2–5]. The risk factors for locoregional recurrence include the stage of primary cancer [2–5], location of primary cancer, emergent surgery [2, 3], lymph-vascular invasion [4, 5], bowel perforation [3, 5], bowel obstruction, margin involvement, and local tumor invasion [5].\n\nLRCC often invades other organs such as the bladder, uterus, ovaries, and small intestine. Previous reports have shown that 26–100% of patients with LRCC undergo multivisceral resection [6–8, 11, 12]. In this case, the recurrent tumor involved the external iliac artery, external iliac vein, right obturator lymph nodes, and the small intestine. Before surgery, with careful assessment of the radiologic findings of the tumor extent, we consulted cardiovascular surgeons for reconstructive surgery involving the external iliac vessels. We suggest that preoperative consultations and discussions with surgical teams are extremely important for oncologic multivisceral resection for LRCC. Some authors suggested that resection of recurrent colorectal cancer with vascular involvement is contraindicated [13, 14]. Although there are limited numbers of publications, some authors suggested that aggressive resection of recurrent colon cancer with vascular excision is safe, contributing to longer survival and better quality of life [15–18]. For instance, Abdelsattar et al. reported 12 cases of surgery for LRCC involving the aortoiliac axis. They reported that seven of 12 patients who underwent arterial reconstruction had no graft complications, an R0 resection rate of 58%, and a four-year overall survival rate of 55% [19].\n\nCurrently, many patients receive systemic therapy including chemotherapy and radiotherapy before and/or after surgical resection for recurrent colorectal cancer. One advantage of preoperative chemotherapy is that we can evaluate the biological aggressiveness of metastatic colorectal cancer and choose appropriate patients who would receive long-term oncologic benefit from surgical resection [20]. In this case, the patient received multiple regimens of chemotherapy combined with the surgeries. She had pre- and postoperative mFOLFOX6 for the first tumor recurrence. Then, she had pre- and postoperative bevacizumab and/or FOLFIRI for the second tumor recurrence. For the recurrence after the last surgery, she sequentially received trifluridine/tipiracil and regorafenib. We used bevacizumab as molecular-targeted agents because of the KRAS mutant status. Some studies have advocated neoadjuvant therapy for colorectal cancer using bevacizumab [21–23]. These reports concluded that neoadjuvant chemotherapy with bevacizumab is oncologically feasible with good response, increased tumor resectability, and improved long-term survival.\n\nSome authors have reported the effect of surgical resection combined with systemic therapy on LRCC. Harji et al. showed that preoperative chemoradiotherapy and/or chemotherapy for LRCC improved the radical resection rate [11]. Ohira et al. reported 19 cases of neoadjuvant chemotherapy, and Hallet et al. reported 15 cases of neoadjuvant chemoradiotherapy followed by radical resection for LRCC [12, 24]. Despite the small numbers of cases, both reports demonstrated that neoadjuvant treatment increased the curative resection rate with long-term survival.\n\nHowever, the efficacy of systemic therapy on survival remains controversial. Kogler et al. reported that neoadjuvant or adjuvant therapy may influence median survival, although there was no statistical difference [8]. In contrast, Akiyoshi et al. and Bowne et al. showed that pre- and postoperative chemotherapy and radiotherapy for LRCC had no influence on disease-specific survival [6, 7].\n\nIn this case, we initially expected that the treatment strategy with sequential chemotherapy followed by surgical resection for LRCC would have provided long-term oncologic benefit. She survived two years and nine months since the diagnosis of rerecurrence. Because the rerecurrent tumor was locoregional, she might have survived for similar duration without surgical resection. Before the last surgery, she had suffered from leg edema, and symptomatic relief was achieved by the surgical resection. Afterwards, she never suffered from leg edema. Therefore, we assume that the surgical resection may have contributed to improved quality of life and better tolerability for the subsequent chemotherapy, rather than oncologic benefit.\n\nThe pathological evaluation revealed that cauterized cancer cells were present at the resection margin (R1 resection). Intraoperative radiotherapy with surgical resection has been shown to be beneficial for locoregionally advanced primary or recurrent colorectal cancer and other malignancies [25–27]. In our institution, intraoperative radiotherapy is not available; however, postoperative radiotherapy may have been another treatment option considering the resection margin was histologically positive.\n\nRecent reports have shown the efficacy of en bloc resection of primary pelvic tumors involving main iliac vessels [28, 29]. These reports suggested that surgery was feasibly performed in specialized institutions. To our knowledge, this is the first report that exhibited surgical resection with vascular reconstruction for recurrent appendiceal cancer following systemic chemotherapy.\n\nThere are concerns about the choice of vascular graft and the need for venous reconstruction during the surgery. In this case, we used a synthetic graft for arterio-arterial interposition. Autologous grafts are preferred in exenteration surgery where operative field may be contaminated by concomitant bowel resection [30]. We performed a femoro-femoral arterial bypass before laparotomy; therefore, we thought that there was less risk of graft infection. Tsukushi et al. compared the results between the patients of arterial reconstruction alone and those of arteriovenous reconstruction in limb-salvage surgery for soft tissue sarcoma [31]. They concluded that the results did not indicate the usefulness of additional venous reconstruction after vascular resection in the lower extremity.\n\nSystemic therapy for LRCC appears to contribute to the curative resection rate and long-term survival in selected patients. However, there are no generally accepted protocols for systemic therapy for LRCC. Further investigations including randomized trials are needed to elucidate a standardized treatment strategy for LRCC.\n\n4. Conclusion\nWe reported a case of locoregionally recurrent appendiceal cancer in which our multimodal treatment provided relatively a long survival after the diagnosis of recurrence. Multiple regimens of neo- and adjuvant chemotherapy with surgical resection contributed to the oncologic outcome. Patient selection with careful assessment, availability of appropriate expertise, and meticulous discussions is necessary for the optimal treatment of LRCC.\n\nConflicts of Interest\nThe authors declare that there is no conflict of interests regarding the publication of this article.\n\nFigure 1 Ultrasonography showing a 27 × 16 mm, irregular, low-echoic tumor (arrow). The tumor is located around the external iliac artery (a) and the external iliac vein (b).\n\nFigure 2 Contrast-enhanced CT scan showing an irregular tumor around the right external iliac vessels and the small intestine, contiguous to the small intestine (arrow).\n\nFigure 3 PET-CT showing intense tracer uptake (SUV max: 17.5) at the tumor (arrow).\n\nFigure 4 A femoro-femoral arterial bypass was performed, followed by an en bloc tumor resection. (a) The fixed solid tumor (∗) at the right inguinal fossa. The tumor involved the external iliac artery, external iliac vein (arrowhead), ileum (arrow), and right obturator lymph nodes. The broken lines with blue color indicate the proximal and distal resection margins of the bowel. The broken lines with black-colored circle indicate the resection margin of the vessels. (b) Surgical specimen of the resection tumor (∗) that invaded, including both the external iliac artery and vein (arrowhead) as well as the small intestine.\n==== Refs\n1 André T. Boni C. Navarro M. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial Journal of Clinical Oncology 2009 27 19 3109 3116 10.1200/JCO.2008.20.6771 2-s2.0-67650315187 19451431 \n2 Manfredi S. Bouvier A. M. Lepage C. Hatem C. Dancourt V. Faivre J. 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Surgery for locally recurrent rectal cancer Diseases of the Colon and Rectum 2005 48 5 929 937 10.1007/s10350-004-0909-0 2-s2.0-20844449051 15785880 \n15 Ali A. T. Clagett G. P. Edwards M. J. Complex venous and arterial reconstruction with deep vein after pelvic exenterative surgery: a case report The American Surgeon 2006 72 1 22 24 16494177 \n16 Hashimoto M. Komatsu H. Naruse Y. Sawada T. Watanabe G. Resection of paraaortic lymph node metastasis of colon cancer with graft replacement Hepato-Gastroenterology 2003 50 51 709 710 12828066 \n17 Tsarkov P. V. Belov Y. V. Skipenko O. G. En bloc resection of abdominal aorta and paraaortic lymph node metastasis of sigmoid cancer Techniques in Coloproctology 2007 11 4 346 349 10.1007/s10151-007-0379-1 2-s2.0-38649098785 18060362 \n18 Ueda K. Nagayama H. Narita K. Extended surgery with en bloc resection of the right common iliac vessels for lymph node metastasis of mucinous colon carcinoma: report of a case Surgery Today 2001 31 3 238 241 10.1007/s005950170176 2-s2.0-0035084709 11318128 \n19 Abdelsattar Z. M. Mathis K. L. Colibaseanu D. T. Surgery for locally advanced recurrent colorectal cancer involving the aortoiliac axis: can we achieve R0 resection and long-term survival? Diseases of the Colon and Rectum 2013 56 6 711 716 10.1097/DCR.0b013e31827dbcb0 2-s2.0-84879089126 23652744 \n20 Tosi F. Magni E. Amatu A. Effect of KRAS and BRAF mutations on survival of metastatic colorectal cancer after liver resection: a systematic review and meta-analysis Clinical Colorectal Cancer 2017 16 3 e153 e163 10.1016/j.clcc.2017.01.004 2-s2.0-85012875416 28216246 \n21 Wong R. Cunningham D. Barbachano Y. A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection Annals of Oncology 2011 22 9 2042 2048 10.1093/annonc/mdq714 2-s2.0-79959947067 21285134 \n22 Suenaga M. Fujimoto Y. Matsusaka S. Perioperative FOLFOX4 plus bevacizumab for initially unresectable advanced colorectal cancer (NAVIGATE-CRC-01) OncoTargets and Therapy 2015 8 1111 1118 10.2147/ott.s83952 2-s2.0-84929455899 26056475 \n23 Gruenberger B. Tamandl D. Schueller J. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer Journal of Clinical Oncology 2008 26 11 1830 1835 10.1200/JCO.2007.13.7679 2-s2.0-42949130734 18398148 \n24 Ohira G. Miyauchi H. Suzuki K. Nishimori T. Tohma T. Matsubara H. Neoadjuvant chemotherapy for recurrent colorectal cancer Gan to Kagaku Ryoho 2012 39 12 2189 2191 23268019 \n25 Abdelfatah E. Page A. Sacks J. Postoperative complications following intraoperative radiotherapy in abdominopelvic malignancy: a single institution analysis of 113 consecutive patients Journal of Surgical Oncology 2017 115 7 883 890 10.1002/jso.24597 2-s2.0-85020649609 28252805 \n26 Haddock M. G. Miller R. C. Nelson H. Combined modality therapy including intraoperative electron irradiation for locally recurrent colorectal cancer International Journal of Radiation Oncology, Biology, Physics 2011 79 1 143 150 10.1016/j.ijrobp.2009.10.046 2-s2.0-78650010351 \n27 Mirnezami R. Chang G. J. Das P. Intraoperative radiotherapy in colorectal cancer: systematic review and meta-analysis of techniques, long-term outcomes, and complications Surgical Oncology 2013 22 1 22 35 10.1016/j.suronc.2012.11.001 2-s2.0-84873708235 23270946 \n28 Schwarzbach M. H. M. Hormann Y. Hinz U. Clinical results of surgery for retroperitoneal sarcoma with major blood vessel involvement Journal of Vascular Surgery 2006 44 1 46 55 10.1016/j.jvs.2006.03.001 2-s2.0-33745671844 16828425 \n29 Brown K. G. M. Koh C. E. Solomon M. J. Qasabian R. Robinson D. Dubenec S. Outcomes after en bloc iliac vessel excision and reconstruction during pelvic exenteration Diseases of the Colon and Rectum 2015 58 9 850 856 10.1097/DCR.0000000000000421 2-s2.0-84940023326 26252846 \n30 Brown K. G. M. Koh C. E. Solomon M. J. Choy I. C. Dubenec S. Spiral saphenous vein graft for major pelvic vessel reconstruction during exenteration surgery Annals of Vascular Surgery 2015 29 6 1323 1326 10.1016/j.avsg.2015.01.028 2-s2.0-84938973571 25770390 \n31 Tsukushi S. Nishida Y. Sugiura H. Nakashima H. Ishiguro N. Results of limb-salvage surgery with vascular reconstruction for soft tissue sarcoma in the lower extremity: comparison between only arterial and arterovenous reconstruction Journal of Surgical Oncology 2008 97 3 216 220 10.1002/jso.20945 2-s2.0-39749088328 18161869\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2018()",
"journal": "Case reports in surgery",
"keywords": null,
"medline_ta": "Case Rep Surg",
"mesh_terms": null,
"nlm_unique_id": "101580191",
"other_id": null,
"pages": "1674279",
"pmc": null,
"pmid": "30155335",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "11318128;26056475;27169604;28252805;16804870;16828425;16494177;18161869;23536195;12828066;28216246;19451431;18688621;15785892;23270946;20864084;27812826;23652744;25159503;18398148;17139459;24534363;23268019;20041351;18060362;21285134;26252846;15785880;25770390;20395067;7684666",
"title": "Surgical Resection with Neoadjuvant Chemotherapy for Locoregionally Recurrent Appendiceal Cancer Invading the External Iliac Vessels.",
"title_normalized": "surgical resection with neoadjuvant chemotherapy for locoregionally recurrent appendiceal cancer invading the external iliac vessels"
} | [
{
"companynumb": "JP-ACCORD-071672",
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"activesubstancename": "FLUOROURACIL"
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"abstract": "The authors present a case of keratoprosthesis-associated cystoid macular edema (CME) responsive to subconjunctival bevacizumab (Avastin; Genentech, South San Francisco, CA). A 40-year-old woman with a history of Stevens-Johnson syndrome (SJS) and Boston keratoprosthesis type I implantation developed CME 10 months after surgery and received sub-Tenon's kenalog with minimal improvement. Sixteen months after surgery, she received a subconjunctival injection of bevacizumab and demonstrated visual and anatomic improvement. Ten weeks later, she received a second subconjunctival injection of bevacizumab for worsening CME and again demonstrated a favorable response. Subconjunctival bevacizumab may be an effective and less-invasive alternative to intravitreal injections for the treatment of postoperative CME.",
"affiliations": null,
"authors": "Muakkassa|Nora W|NW|;Klein|Kendra A|KA|;Hamrah|Pedram|P|;Reichel|Elias|E|",
"chemical_list": "D020533:Angiogenesis Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab",
"country": "United States",
"delete": false,
"doi": "10.3928/23258160-20160229-11",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-8160",
"issue": "47(3)",
"journal": "Ophthalmic surgery, lasers & imaging retina",
"keywords": null,
"medline_ta": "Ophthalmic Surg Lasers Imaging Retina",
"mesh_terms": "D000328:Adult; D020533:Angiogenesis Inhibitors; D001187:Artificial Organs; D000068258:Bevacizumab; D001705:Bioprosthesis; D003228:Conjunctiva; D003315:Cornea; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D056965:Injections, Intraocular; D008269:Macular Edema; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity",
"nlm_unique_id": "101599215",
"other_id": null,
"pages": "276-9",
"pmc": null,
"pmid": "26985802",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Subconjunctival Bevacizumab for the Treatment of Keratoprosthesis-Associated Cystoid Macular Edema.",
"title_normalized": "subconjunctival bevacizumab for the treatment of keratoprosthesis associated cystoid macular edema"
} | [
{
"companynumb": "US-ROCHE-1831931",
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"activesubstancename": "BEVACIZUMAB"
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"abstract": "OBJECTIVE\nTo describe clinical and radiological characteristics of seropositive neuromyelitis optica (NMO) in Emirati patients. While epidemiology of seropositive NMO in Abu Dhabi has been reported in a previous paper, its clinical and MRI profiles among Emirati patients have not been previously fully investigated.\n\n\nMETHODS\nIn our case series, we describe clinical and MRI characteristics of 5 Emirati patients with NMO, consecutively admitted at Cleveland Clinic Abu Dhabi, a major tertiary hospital in Abu Dhabi, United Arab Emirates.\n\n\nRESULTS\nPatients were all females, mean age of onset (SD) was 41 (11) years, and 67% had autoimmune comorbidities. Most patients initially presented with acute myelitis (80%) while 20% got optic neuritis. Mean (SD) number of further relapses after onset was 3 (1) and mean (SD) disease duration was 12 (11) years. At MRI, apparent longitudinal extensive transverse myelitis was present in all patients affecting mostly the central gray matter of the cervical cord but extending as well to the thoracic portion. Furthermore, seropositive NMO related brain lesions were also observed.\n\n\nCONCLUSIONS\nOur work provides valuable information regarding seropositive NMO with the potential to increase recognition of this disorder in Abu Dhabi and confirms NMO findings described in the other populations with this disorder. Further research is needed to advance clinical and MRI characterization of seronegative NMO in the region.",
"affiliations": "Neurological Institute, Cleveland Clinic Abu Dhabi, Sowwah Square, Al Maryah Island, PO Box 112412, Abu Dhabi, United Arab Emirates. Electronic address: ceccarelli.antonella@gmail.com.;Neurological Institute, Cleveland Clinic Abu Dhabi, Sowwah Square, Al Maryah Island, PO Box 112412, Abu Dhabi, United Arab Emirates.;Neurological Institute, Cleveland Clinic Abu Dhabi, Sowwah Square, Al Maryah Island, PO Box 112412, Abu Dhabi, United Arab Emirates.;Neurological Institute, Cleveland Clinic Abu Dhabi, Sowwah Square, Al Maryah Island, PO Box 112412, Abu Dhabi, United Arab Emirates.",
"authors": "Ceccarelli|Antonia|A|;Mifsud|Victoria Ann|VA|;Dogar|Amna|A|;Hussain|Syed Irteza|SI|",
"chemical_list": "D001323:Autoantibodies",
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2019.11.045",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "72()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Brain MRI; Diagnosis; Emirati; NMO; Spinal cord MRI",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D005260:Female; D066128:Gray Matter; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009188:Myelitis, Transverse; D009471:Neuromyelitis Optica; D012189:Retrospective Studies; D014479:United Arab Emirates; D055815:Young Adult",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "185-190",
"pmc": null,
"pmid": "31859181",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Seropositive neuromyelitis optica spectrum disorder in Emirati patients: A case series.",
"title_normalized": "seropositive neuromyelitis optica spectrum disorder in emirati patients a case series"
} | [
{
"companynumb": "NVSC2020AE056165",
"fulfillexpeditecriteria": "1",
"occurcountry": "AE",
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"actiondrug": "1",
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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... |
{
"abstract": "To report a case of 2-month-old boy with Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).\nA 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. A skin biopsy was performed which showed full-thickness epidermal necrosis. AMT was performed at the bedside under general anesthesia. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration.\nTo the best of our knowledge, our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.",
"affiliations": "Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.;Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.;Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.;Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.",
"authors": "Elhusseiny|Abdelrahman M|AM|;Gise|Ryan|R|;Scelfo|Christina|C|;Mantagos|Iason S|IS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2021.101017",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(21)00008-6\n10.1016/j.ajoc.2021.101017\n101017\nCase Report\nAmniotic membrane transplantation in a 2-month-old infant with toxic epidermal necrolysis\nElhusseiny Abdelrahman M. MD Gise Ryan MD Scelfo Christina MD Mantagos Iason S. MD, PhDjason.Mantagos@childrens.harvard.edu∗ Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA\n∗ Corresponding author. Department of Ophthalmology, Fegan 4, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA. jason.Mantagos@childrens.harvard.edu\n15 1 2021 \n3 2021 \n15 1 2021 \n21 10101725 6 2020 5 10 2020 11 1 2021 © 2021 The Authors2021This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo report a case of 2-month-old boy with Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).\n\nObservation\nA 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. A skin biopsy was performed which showed full-thickness epidermal necrosis. AMT was performed at the bedside under general anesthesia. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration.\n\nConclusion and importance\nTo the best of our knowledge, our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.\n\nKeywords\nStevens-Johnson syndromeToxic epidermal necrolysisAmniotic membrane transplantation\n==== Body\n1 Introduction\nStevens-Johnson syndrome (SJS) and its more severe variant toxic epidermal necrolysis (TEN) are serious life-threatening conditions that involve wide spread skin and mucous membrane destruction.1,2 We present a case of 2 month old boy with Stevens-Johnson syndrome/Toxic epidermal necrolysis and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).\n\n2 Case report\nA 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. One week prior to presentation, he developed non-specific viral prodromal symptoms including fever to102.6 F (39.2 °C), decreased urine output, emesis and decreased appetite. There was no history of any allergies. Family history was only significant for Sjögren's syndrome for his mother and recent pneumonia actively treated with azithromycin for the patient's older sister. A full sepsis work-up at outside hospital was performed and was negative. The patient was empirically started on acyclovir, vancomycin, ceftriaxone and acetaminophen. One day later, he developed a diffuse maculopapular rash with vesicles and desquamation involving head, trunk, upper and lower extremities (Fig. 1). The patient developed acute respiratory failure for which he was sedated and nasally intubated. At that time, he was transferred to Boston Children's Hospital with skin detachment involving more than 40% of his total body surface area (TBSA). A skin biopsy was performed which showed full-thickness epidermal necrosis. The adjacent epidermis demonstrated basal layer vacuolization and scattered dyskeratotic cells (Fig. 2). Special stains were performed including periodic acid Schiff (PAS), gram stain and Grocott-Gomori's (or Gömöri) methenamine silver which were all negative. No immunoreactivity was detected with IgG, IgA, IgM, C3 and fibrin. These findings were consistent with diagnosis of SJS/TEN. Systemic intravenous immunoglobulin (IVIG) was initiated.Fig. 1 External photo showing diffuse maculopapular rash with skin desquamation and epidermal detachment involving head, trunk and upper extremities with bilateral macerated upper and lower eye lids.\n\nFig. 1Fig. 2 Histopathology showing A-full thickness epidermal necrosis and separation (black arrow). B- The adjacent epidermis demonstrated scattered dyskeratotic cells (a) and basal layer vacuolization (b).\n\nFig. 2\n\nOcular evaluation by a senior faculty member at the time of initial presentation to our institution showed bilateral desquamated upper and lower eye lids (Fig. 1), mild conjunctival injection and bilateral corneal epithelial defects. No conjunctival staining was detected at that time. The anterior chamber was quiet bilaterally, the pupils were equal, round, regular and reactive to light. Dilated fundus examination disclosed normal disc, vessels, macula, and periphery. Erythromycin ointment and artificial tears were prescribed for the corneal epithelial defects which healed in two days. Five days later, diffuse perilimbal conjunctival staining was noted with early mild symblepharon formation nasally and temporally. AMT was performed at the bedside under general anesthesia using our previously described technique.3 In summary, intravenous tubing was used to create bolsters and a symblepharon ring, the diameter of which was estimated based on the distance between the superior and inferior orbital rims. A 5 × 5cm AM piece was then placed as a continuous sheet over the ocular surface. The symblepharon ring was inserted to push the AM into the fornices. Finally, the AM was anchored to the skin with 6–0 polypropylene sutures over the bolsters. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration. There was no evidence of limbal stem cell deficiency, and the tobramycin/dexamethasone drops were gradually tapered. The general condition of the patient continued to improve with signs of skin re-epithelization (Fig. 3). At the last follow-up, 2 months later, ocular examination showed normal anterior segment with no evidence of lid margin keratinization, entropion, trichiasis or any other complication (Fig. 4). Further follow-up visits have been scheduled for early detection of late complications.Fig. 3 External photo taken 2 weeks after initial presentation showing marked improvement in the patient's general condition with continued skin re-epithelization.\n\nFig. 3Fig. 4 External photo taken after discharge showing complete healing of lid desquamation and normal anterior segment.\n\nFig. 4\n\n3 Discussion\nOcular involvement in SJS/TEN occurs in 84% of patients during the acute stage, especially those with epidermal detachment >10% of TBSA.4 Our patient had more than 40% of TBSA involved, therefore it is better classified as TEN rather than SJS. Atypical cases of SJS/TEN may initially present with ocular signs only.5 Prompt diagnosis of ocular surface inflammation and early intervention are essential to avoid cicatricial keratoconjunctivitis and limbal stem cell deficiency that may lead to vision threatening complications. AMT performed in the first week after ocular involvement has been reported to be an effective treatment modality due to anti-inflammatory and anti-scarring effects mediated by anti-inflammatory cytokines, including interleukin-10 and anti-inflammatory protease inhibitors such as alpha 1 antitrypsin inhibitor. This can subsequently facilitate rapid epithelial healing preventing long-term ocular morbidity during the chronic stage.3,6, 7, 8 We present a rare case of TEN in a very young patient (2 months) that was successfully managed with AMT. The triggering factor for SJS/TEN in our case remained unclear, however it may be multifactorial. It may be a viral infection based on the history of fever and sick contact with pneumonia (patient's older sister). Our patient received acetaminophen one day before development of maculopapular rash and desquamation which raise the possibility that it may be one of the factors that lead to TEN. It has been previously reported to be associated with SJS/TEN with few reports in the literature, however it was started together with vancomycin, ceftriaxone and acyclovir and any one of them may be the triggering agent.9,10 Neonatal lupus presenting as TEN-like syndrome was considered initially given mother's history of Sjögren's syndrome, however the skin biopsy and overall clinical picture was consistent with TEN. Long-term follow-up of these cases is essential for early detection of complications. Catt and colleagues retrospectively evaluated the ocular manifestations of pediatric SJS/TEN and reported that the median time for development of corneal opacification was 4 months, of limbal stem cell deficiency was 7 months and of corneal neovascularization was 10 months after admission.11\n\nTo the best of our knowledge our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.\n\nPatient consent\nWritten informed consent was obtained from the patient's legal guardian.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for authorship.\n\nFunding\nChildren's Hospital Ophthalmology Foundation, Inc.\n\nDeclaration of competing interest\nThe following authors have no financial disclosures:\n\nAbdelrahman M. Elhusseiny, Ryan Gise, Christina Scelfo, Iason Mantagos.\n\nAcknowledgment\nNone.\n==== Refs\nReferences\n1 Miliszewski M.A. Kirchhof M.G. Sikora S. Stevens-johnson syndrome and toxic epidermal necrolysis: an analysis of triggers and implications for improving prevention Am J Med 129 11 2016 1221 1225 27086495 \n2 Kohanim S. Palioura S. Saeed H.N. Acute and chronic ophthalmic involvement in Stevens-Johnson syndrome/toxic epidermal necrolysis - a comprehensive review and guide to therapy. II. Ophthalmic disease Ocul Surf 14 2 2016 168 188 26882981 \n3 Ma K.N. Thanos A. Chodosh J. A novel technique for amniotic membrane transplantation in patients with acute Stevens-Johnson syndrome Ocul Surf 14 1 2016 31 36 26387869 \n4 Morales M.E. Purdue G.F. Verity S.M. Ophthalmic manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis and relation to SCORTEN Am J Ophthalmol 150 4 2010 505 510.e1 20619392 \n5 Chan F. Benson M.D. Plemel D.J.A. A diagnosis of Stevens-Johnson Syndrome (SJS) in a patient presenting with superficial keratitis Am J Ophthalmol Case Rep 11 2018 167 169 30128368 \n6 Shay E. Kheirkhah A. Liang L. Amniotic membrane transplantation as a new therapy for the acute ocular manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis Surv Ophthalmol 54 6 2009 686 696 19699503 \n7 Tseng S.C. Prabhasawat P. Barton K. Amniotic membrane transplantation with or without limbal allografts for corneal surface reconstruction in patients with limbal stem cell deficiency Arch Ophthalmol 116 4 1998 431 441 9565039 \n8 Eleiwa T. Ozcan E. Abdelrahman S. Case series of perforated keratomycosis after laser-assisted in situ keratomileusis Case Rep Ophthalmol Med 2020 2020 7237903 33014490 \n9 Rajput R. Sagari S. Durgavanshi A. Kanwar A. Paracetamol induced Steven-Johnson syndrome: a rare case report Contemp Clin Dent 6 Suppl 1 2015 S278 S281 26604588 \n10 Biswal S. Sahoo S.S. Paracetamol induced Stevens-Johnson syndrome--toxic epidermal necrolysis overlap syndrome Int J Dermatol 53 8 2014 1042 1044 24673330 \n11 Catt C.J. Hamilton G.M. Fish J. Ocular manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis in children Am J Ophthalmol 166 2016 68 75 27018234\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "21()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Amniotic membrane transplantation; Stevens-Johnson syndrome; Toxic epidermal necrolysis",
"medline_ta": "Am J Ophthalmol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101679941",
"other_id": null,
"pages": "101017",
"pmc": null,
"pmid": "33521381",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports",
"references": "30128368;33014490;19699503;27018234;24673330;26604588;20619392;26882981;27086495;26387869;9565039",
"title": "Amniotic membrane transplantation in a 2-month-old infant with toxic epidermal necrolysis.",
"title_normalized": "amniotic membrane transplantation in a 2 month old infant with toxic epidermal necrolysis"
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"abstract": "Mycobacterial spindle cell pseudotumor (MSP) is a non-neoplastic condition that is characterized by spindle-shaped histiocytes colonized by mycobacteria. MSP is most commonly diagnosed in the immunocompromised and, while MSP can occur throughout the body, the most common sites of MSP involvement are the lymph nodes and the skin. To diagnose MSP, histopathological analysis typically demonstrates the presence of inflammatory cells, in addition to spindle cells and the unequivocal mycobacteria, which guides the diagnosis away from potential neoplasms. If properly diagnosed and treated with appropriate antibiotic therapy, patients tend to experience almost complete resolution of their symptoms. MSP is a rare condition; to our knowledge, there have only been 11 documented cases of cutaneous MSP, including the one introduced in this report. Here, we present a unique case of a 50-year-old female on chronic immunosuppressive therapy diagnosed with cutaneous MSP in the absence of inflammatory cells on pathology.",
"affiliations": "University of Illinois College of Medicine, Chicago, Illinois, USA.;Skin MD LLC, Chicago, Illinois, USA.;Skin MD LLC, Chicago, Illinois, USA.;Skin MD LLC, Chicago, Illinois, USA.;Consolidated Pathology Consultants, Libertyville, Illinois, USA.",
"authors": "Kirchner|Allison|A|https://orcid.org/0000-0002-9453-768X;Sergeyenko|Artem|A|;Keane|Janice|J|;Belinski|Kenneth|K|;Liu|Wenhua|W|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/cup.14042",
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"issn_linking": "0303-6987",
"issue": "48(9)",
"journal": "Journal of cutaneous pathology",
"keywords": "dermatology; immunocompromised host; inflammation; mycobacterium infection; nontuberculous",
"medline_ta": "J Cutan Pathol",
"mesh_terms": null,
"nlm_unique_id": "0425124",
"other_id": null,
"pages": "1178-1181",
"pmc": null,
"pmid": "33948982",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Diagnosis of cutaneous mycobacterial spindle cell pseudotumor in the absence of typical inflammatory cells: A case report.",
"title_normalized": "diagnosis of cutaneous mycobacterial spindle cell pseudotumor in the absence of typical inflammatory cells a case report"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2022SP001427",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE"
},
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{
"abstract": "BACKGROUND\nConnatal cysts are rare but recognized periventricular cysts that represent anatomic variants and are associated with good neurological outcomes. These cysts can be differentiated from cysts that portend graver prognoses by their location in relation to the ventricles, size, laterality, and temporal resolution.\n\n\nMETHODS\nWe describe a preterm twin infant born to a mother with diabetes and cardiovascular disease who was found to have connatal cysts on head ultrasound at 3 days of age. These cysts were present again on head ultrasound at 12 days of age and on brain magnetic resonance imaging at 27 days of age. The infant had a normal neurological examination in the neonatal period and on follow-up at 3 and 6 months of age. Repeated head ultrasound at 3 months of age demonstrated near resolution of the cysts.\n\n\nCONCLUSIONS\nConnatal cysts are normal anatomic variants which clinicians should be able to distinguish from similar appearing cysts with less favorable outcomes. Although the etiology of connatal cysts remains unknown, this case raises the possibility of maternal comorbidities or perinatal hypoperfusion playing a role in their formation.",
"affiliations": "Division of Pediatric Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Neurosciences Intensive Care Nursery, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: lsun20@jhmi.edu.;The Neurosciences Intensive Care Nursery, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Section of Pediatric Neuroradiology, Division of Pediatric Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.;The Neurosciences Intensive Care Nursery, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Eudowood Neonatal Pulmonary Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland.;Division of Pediatric Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Neurosciences Intensive Care Nursery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.",
"authors": "Sun|Lisa R|LR|;Tekes|Aylin|A|;Golden|W Christopher|WC|;Oakley|Christopher|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-8994",
"issue": "51(3)",
"journal": "Pediatric neurology",
"keywords": "frontal horn cyst; newborn; periventricular cyst; prematurity",
"medline_ta": "Pediatr Neurol",
"mesh_terms": "D000328:Adult; D001921:Brain; D001927:Brain Diseases; D020863:Central Nervous System Cysts; D015897:Comorbidity; D004200:Diseases in Twins; D004453:Echoencephalography; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases; D008279:Magnetic Resonance Imaging; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011254:Pregnancy in Diabetics; D014427:Twins",
"nlm_unique_id": "8508183",
"other_id": null,
"pages": "444-7",
"pmc": null,
"pmid": "25023976",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Connatal cyst in a preterm twin infant with maternal comorbidities.",
"title_normalized": "connatal cyst in a preterm twin infant with maternal comorbidities"
} | [
{
"companynumb": "PHHY2014US086586",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nInterleukin-6 (IL6) blockage is a treatment strategy used in many inflammatory conditions. Trials in Neuromyelitis Optica Spectrum Disorder (NMOSD) are ongoing. Secondary auto-immunity affecting the central nervous system (CNS) is well described with some biologic agents, mainly tumor necrosis factor (TNF)-alpha inhibitors. These treatments can also aggravate patients with known multiple sclerosis (MS).\n\n\nOBJECTIVE\nTo describe a case of a patient who developed MS using another biologic, IL6 receptor antibody Tocilizumab.\n\n\nRESULTS\nA 48-year-old woman developed MS while on treatment with Tocilizumab for Rheumatoid Arthritis (RA). This is the first published report of this association. It has obvious implications for NMOSD patients receiving anti-IL6 therapy. Development of new white matter lesions suggestive of MS in a patient treated with anti-IL6 therapy might represent an important complication of therapy.\n\n\nCONCLUSIONS\nThis case illustrates that Tocilizumab might cause secondary auto-immunity in CNS. It is important to be aware of this potential complication as anti-IL6 therapy might become an option for the treatment NMOSD.",
"affiliations": "Hôpital de l'Enfant-Jésus du CHU de Québec, Département des sciences neurologiques, Université Laval/UBC MS Clinic, Department of Neurology, UBC, Vancouver, BC, Canada philippe.beauchemin.1@ulaval.ca.;UBC MS Clinic, Department of Neurology, UBC, Vancouver, BC, Canada.",
"authors": "Beauchemin|Philippe|P|;Carruthers|Robert|R|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D019947:Receptors, Interleukin-6; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.1177/1352458515623862",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-4585",
"issue": "22(2)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "CNS demyelinating disease; Devic’s syndrome; MRI; Tocilizumab; autoimmune diseases; multiple sclerosis",
"medline_ta": "Mult Scler",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D015551:Autoimmunity; D005260:Female; D006801:Humans; D008875:Middle Aged; D009103:Multiple Sclerosis; D019947:Receptors, Interleukin-6",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "254-6",
"pmc": null,
"pmid": "26743640",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "MS arising during Tocilizumab therapy for rheumatoid arthritis.",
"title_normalized": "ms arising during tocilizumab therapy for rheumatoid arthritis"
} | [
{
"companynumb": "PHHY2018CA007240",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXLANSOPRAZOLE"
},
"drugadditional": "3",
"... |
{
"abstract": "Rituximab safety and efficacy in patients with renal impairment have not been established, nor have the effects of hemodialysis on serum rituximab level. There are only a few published case reports assessing serum rituximab level pre- and postdialysis. No data have been published regarding the usage of rituximab in patients with continuous renal replacement therapy. The authors present a case of a 59-year-old female patient who presented with paraneoplastic tetraparesis. She was admitted to the intensive care unit due to alveolar hemorrhage with respiratory failure and acute kidney injury requiring continuous renal replacement therapy. After a diagnostic workup, the diagnosis of lymphoplasmacytic lymphoma was established. Therapy with rituximab and cyclophosphamide was started. Rituximab levels were determined in serum and dialysate. No rituximab was found in the dialysate. The patient died after 2 months in the intensive care unit from nosocomial pneumonia due to multidrug-resistant Pseudomonas aeruginosa.",
"affiliations": "Centro Hospitalar e Universitário de Coimbra EPE - Coimbra, Portugal.;Centro Hospitalar e Universitário de Coimbra EPE - Coimbra, Portugal.;Centro Hospitalar e Universitário de Coimbra EPE - Coimbra, Portugal.;Centro Hospitalar e Universitário de Coimbra EPE - Coimbra, Portugal.;Centro Hospitalar e Universitário de Coimbra EPE - Coimbra, Portugal.",
"authors": "Simões|Marco|M|;Miranda|Marisa|M|;Carda|José|J|;Carmo|Anália|A|;Martins|Paulo|P|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000069283:Rituximab",
"country": "Brazil",
"delete": false,
"doi": "10.5935/0103-507X.20190040",
"fulltext": "\n==== Front\nRev Bras Ter IntensivaRev Bras Ter IntensivarbtiRevista Brasileira de Terapia Intensiva0103-507X1982-4335Associação de Medicina Intensiva Brasileira -\nAMIB 3127162810.5935/0103-507X.20190040Case ReportRituximab use for lymphoplasmacytic lymphoma during continuous renal\nreplacement therapy Uso de rituximabe no tratamento de linfoma linfoplasmocítico\ndurante terapia de substituição renal\ncontínua Simões Marco 1Miranda Marisa 1Carda José 1Carmo Anália 1Martins Paulo 1\n1 Centro Hospitalar e Universitário de Coimbra EPE -\nCoimbra, Portugal.Corresponding author: Marco Simões, Centro\nHospitalar e Universitário de Coimbra EPE, Praceta Prof. Mota Pinto,\nCoimbra 3000-075, PortugalApr-Jun 2019 Apr-Jun 2019 31 2 258 261 25 8 2018 02 1 2019 This is an Open Access article distributed under the terms of the\nCreative Commons Attribution License, which permits unrestricted use,\ndistribution, and reproduction in any medium, provided the original work is\nproperly cited.Rituximab safety and efficacy in patients with renal impairment have not been\nestablished, nor have the effects of hemodialysis on serum rituximab level.\nThere are only a few published case reports assessing serum rituximab level pre-\nand postdialysis. No data have been published regarding the usage of rituximab\nin patients with continuous renal replacement therapy. The authors present a\ncase of a 59-year-old female patient who presented with paraneoplastic\ntetraparesis. She was admitted to the intensive care unit due to alveolar\nhemorrhage with respiratory failure and acute kidney injury requiring continuous\nrenal replacement therapy. After a diagnostic workup, the diagnosis of\nlymphoplasmacytic lymphoma was established. Therapy with rituximab and\ncyclophosphamide was started. Rituximab levels were determined in serum and\ndialysate. No rituximab was found in the dialysate. The patient died after 2\nmonths in the intensive care unit from nosocomial pneumonia due to\nmultidrug-resistant Pseudomonas aeruginosa.\n\nA segurança e a eficácia do rituximabe em pacientes com\ncomprometimento renal não foram estabelecidas, e o mesmo ocorre com os\nefeitos da hemodiálise nos níveis séricos de rituximabe.\nAtualmente, apenas alguns relatos de caso avaliaram o nível sérico\nde rituximabe antes e após a diálise. Não foram até\naqui publicados dados relativos ao uso de rituximabe em pacientes sob terapia de\nsubstituição renal contínua. Os autores apresentam um caso\nreferente a uma mulher com 59 anos de idade atendida com quadro de tetraparesia\nparaneoplásica. Ela foi admitida no serviço de medicina intensiva\ndevido a hemorragia alveolar com insuficiência respiratória e\nlesão renal aguda, que necessitou da utilização de terapia\nde substituição renal contínua. Após os\nprocedimentos diagnósticos, estabeleceu-se o diagnóstico de\nlinfoma linfoplasmocítico. Deu-se início ao tratamento com\nrituximabe e ciclofosfamida. Os níveis de rituximabe foram determinados\nno soro e no dialisato. Não se encontrou qualquer nível de\nrituximabe no dialisato. A paciente faleceu após 2 meses no\nserviço de medicina intensiva por pneumonia nosocomial causada por\nPseudomonas aeruginosa resistente a múltiplos\nfármacos.\n\nRituximabLymphomaRenal replacement therapyRenal insufficiencyPolyradiculoneuropathyCritical careRituximabeTerapia de substituição renalInsuficiência renalPolirradiculoneuropatiaCuidados críticos\n==== Body\nINTRODUCTION\nRituximab safety and efficacy in patients with renal impairment has not been\nestablished, nor have the effects of hemodialysis on serum rituximab level. There\nare only a few published case reports assessing serum rituximab level pre- and\npostdialysis.(1-4) No data have been published\nregarding the usage of rituximab in patients with continuous renal replacement\ntherapy (CRRT).\n\nCASE REPORT\nThe authors present the case of a 59-year-old female patient. She came to the\nEmergency Department in April 2017 with back pain, lower limb pain, dysesthesia and\ndiminished strength on the lower limbs, which impaired orthostatism and gait. These\ncomplaints had been evolving for 5 days. The clinical examination confirmed the\ndiminished strength in her limbs, with distal predominance accompanied by sensitive\ndeficit and the absence of some osteotendinous reflexes. Her past medical history\nrevealed leukocytoclastic vasculitis diagnosed in 2014, treated with dapsone 100mg\ni.d.\n\nThe patient was admitted with a suspected diagnosis of Guillain-Barré syndrome\nand was treated with i.v. immunoglobulin for 5 days. Although she had slight\nclinical improvement, she still had severe motor impairment. Therapy with\nplasmapheresis was initiated but had to be suspended due to acute facial nerve\nparesis. Cranial, spinal and thoraco-abdominal examinations were normal. Spinal\nmagnetic resonance imaging revealed minor degenerative changes without medullar\ncompression. Laboratory examination revealed slight microcytic anemia and elevation\nof erythrocyte sedimentation rate, angiotensin-converting enzyme, ferritin and\nrheumatoid factor. Tumor markers were negative. Serum protein electrophoresis\nrevealed diminished albumin and elevated gamma fraction. She had immunofixation\nwithout a monoclonal component and negative autoimmune markers. Serologies were also\nnegative for acute infection. Electromyography was suggestive of axonal\npolyneuropathy.\n\nAfter one month, she was discharged home. However, she was readmitted due to\nworsening of motor complaints. Nerve, skin and muscle biopsy was suggestive of\nvasculitis. The first bone marrow examination revealed 1.5% clonal B cells with a\nphenotype similar to lymphoplasmacytic lymphoma (LPL).\n\nThe patient's clinical status worsened during the second hospital stay, with alveolar\nhemorrhage, acute kidney injury and acute respiratory failure, requiring invasive\nmechanical ventilation and intensive care unit (ICU) admission. On day 6 of her ICU\nstay, CRRT was initiated.\n\nThe diagnosis of LPL was established based on the results of diagnostic exams. Bone\nmarrow aspirate with morphology as well as the bone marrow biopsy showed an\ninfiltrate composed of small lymphocytes admixed with variable numbers of plasma\ncells and plasmacytoid lymphocytes, some of them with nuclear pseudoinclusions.\nImmunophenotyping by 8-color flow cytometry and the presence of the MYD88 L265P\nmutation helped to confirm the diagnosis. Therapy with the alkylating agent\ncyclophosphamide 0.75g/m2 every 3 weeks and the anti-CD20 monoclonal\nantibody rituximab (MabThera®) 375mg/m2 weekly was\nstarted on the 10th day of her ICU stay. She developed pancytopenia after treatment,\nrequiring blood and platelet transfusion. As the patient was under CRRT, the\nefficacy and safety of rituximab and the ideal administration protocol were\nquestioned. Rituximab's phase II and III trials excluded patients with renal\nimpairment. The recommended dosage and safety for patients under hemodialysis had\nnot been established. All published data on this subject came from sporadic case\nreports, in which the drug was not found in the dialysate, the therapeutic plasma\nlevels were reached and the treatment was effective. There were no published data on\nthe usage of rituximab during CRRT. We decided upon off-label usage of rituximab as\na potential lifesaving therapy (considering the LPL diagnosis and the related\nneuropathy). No dosage adjustment was made (375mg/m2 weekly). In the\nsecond rituximab cycle, serum levels were determined before and after drug\nadministration. No drug was found in the dialysate (Table 1). Serum anti-rituximab antibody and rituximab levels were\ndetermined in serum using the Lisa-Tracker Duo Rituximab enzyme-linked immunosorbent\nassay (ELISA) kit (Theradiag, France). Rituximab was considered undetectable at\nconcentrations under 2µg/mL. The limit of detection of anti-rituximab\nantibodies reported by the manufacturer was 5ng/mL.\n\nTable 1 Rituximab blood and dialysate levels\n\n \tBefore drug infusion\tAfter drug infusion (1 hour)\tDialysate\tLaboratory reference\t\nRituximab (µg/mL)\t43.6\t72.7\t< 2.5\t> 25\t\nRituximab, Ab. (ng/mL)\t< 10 \t< 10\t< 10\t< 10\t\nContinuous renal replacement therapy was performed on a Baxter\nPrismaflex® CRRT machine using AN69 membranes (filter\nreference ST150) and citrate regional anticoagulation. The filter was replaced just\nprior to drug infusion and 5 days after infusion due to clotting. The dialytic\nsolution used was Phoxilium®. The CRRT settings used are presented\nin table 2.\n\nTable 2 Continuous renal replacement therapy settings used\n\n Blood flow rate \t110mL/minute\t\nPreblood pump (Citrate)\t1100mL/hour\t\nDialysate\t500mL/hour\t\nReplacement\t400mL/hour\t\nUltrafiltration\t150mL/hour\t\nDialysis dose\t32mL/kg/hour\t\nFiltration fraction\t28%\t\nThere was no improvement in the polyneuropathy symptoms. She died on the 65th day of\nthe ICU stay from nosocomial multidrug-resistant Pseudomonas\naeruginosa pneumonia.\n\nDISCUSSION\nLymphoplasmacytic lymphoma is a neoplasm of small B monoclonal plasmacytoid\nlymphocytes and plasma cells, usually with focal or diffuse bone marrow\ninfiltration. Sometimes lymph nodes and the spleen are also involved.(5) The majority (up to 95%) of LPLs\nhave MYD88 L265P mutations, but these are absent or rare in other IgM-secreting\nB-cell malignancies. The new mutant protein triggers tumor growth and resistance to\ncell death. Although LPL is often associated with a paraprotein, usually of the IgM\ntype, this is not required for the diagnosis and sometimes can be absent.(6,7) Although patients with asymptomatic disease can maintain a\nwatchful waiting strategy, LPL with cytopenias or symptomatic disease manifested by\nhyperviscosity from IgM paraprotein, amyloidosis, cryoglobulinemia, central nervous\nsystem involvement or severe and/or advancing peripheral neuropathy should be\nconsidered for therapy. For symptomatic patients with LPL, options include rituximab\nmonotherapy or rituximab in combination with alkylating agents (bendamustine or\ncyclophosphamide), proteasome inhibitors (bortezomib) or nucleoside analogs\n(fludarabine). Rituximab alone is well suited for more indolent disease and for\nthose for whom aggressive chemotherapy is inappropriate.(8)\n\nRituximab safety and efficacy in patients with renal impairment has not been\nestablished. In the pivotal phase III trial, relapsed or refractory low-grade or\nfollicular non-Hodgkin lymphoma (NHL) patients with serum creatinine > 2.0mg/dL\nwere excluded from enrollment.(9)\nSimilar exclusion criteria were applied in the 2 first-line therapy trials for\nlow-grade or follicular NHL and in the 3 diffuse large B-cell lymphoma (DLBCL)\ntrials. In the CLL8 trial of previously untreated patients with chronic lymphocytic\nleukemia (CLL), patients were required to have a creatinine clearance (CrCl)\n≥ 70mL/min for enrollment.(10) In the REACH trial of previously treated CLL patients,\npatients with a CrCl < 60mL/min were excluded from the study. No reason was\npresented for the exclusion of patients with renal impairment in these trials. \n\nThe effects of hemodialysis on serum rituximab level have not been established.\nPublished data are limited to a small study and case reports assessing serum\nrituximab level pre- and postdialysis in patients with renal impairment requiring\ndialysis.\n\nOchi et al. conducted a retrospective study including 8 patients treated with\nrituximab and chemotherapy while receiving dialysis.(1) Rituximab 375mg/m2 (no dose reduction)\nwas given as part of the R-CVP, R-CHOP, or R-THPCOP regimen. Patients received\nhemodialysis 24 hours after chemotherapy. Overall, 7 patients had a complete\nresponse, 1 patient had a partial response after a median follow-up of 20 months, 1\npatient died due to lymphoma at 45 months, and 1 patient died from hepatocellular\ncarcinoma at 18 months. All patients experienced neutropenia. Other adverse events\nincluded anemia (n = 4), thrombocytopenia (n = 3), infection (n = 3), febrile\nneutropenia (n = 2), and peripheral neuropathy (n = 2).\n\nSerum rituximab level and its elimination were evaluated in a 54-year-old male with\nlow-grade NHL and immune thrombocytopenic purpura receiving thrice-weekly\nhemodialysis for end-stage renal disease (ESRD) by Jillella et al.(2) Rituximab 375mg/m2 was\nadministered weekly for 8 cycles. There was a resolution of lymphadenopathy and\nnormalization of platelet counts. Serum rituximab level was measured before and\nafter each rituximab treatment. In addition, rituximab level was measured pre- and\npostdialysis following rituximab therapy. The results suggested that these levels\nwere comparable to levels reported in patients with normal renal function. Rituximab\nwas not found in the dialysate fluid. No infusion-related adverse events were\nobserved besides one event of life-threatening hyperkalemia, probably in the context\nof tumor lysis syndrome.\n\nGupta et al. compared rituximab levels before and after dialysis in an ESRD patient\non thrice-weekly hemodialysis.(3) A\n65-year-old patient was treated with rituximab and CHOP for DLBCL. Rituximab levels\npre- and postdialysis were 128,000ng/mL and 150,000ng/mL, respectively. The higher\npostdialysis levels were thought to be due to hemoconcentration. Rituximab was not\ndetected in the dialysate fluid.\n\nMorita et al. described a 76-year-old male on hemodialysis with B-cell primary\ncardiac lymphoma treated with biweekly rituximab monotherapy.(4) The patient received rituximab\n375mg/m2 followed by hemodialysis 1 hour later. His serum rituximab\nconcentration was higher compared with that of a DLBCL patient with normal renal\nfunction. The rituximab concentration was maintained at a therapeutic level during\ndialysis. During the 6 cycles of rituximab, no infusion-related reaction occurred,\nand the patient experienced complete remission. A relapse occurred 10 months after\ndiagnosis; the patient died 4 months later from progressive disease.\n\nCONCLUSION\nIn our research, we found no published data on rituximab usage during continuous\nrenal replacement therapy. We decided to apply an off-label usage of rituximab as a\npotential life-saving therapy. We cannot prove its efficacy for the treatment of\nthis patient's lymphoplasmacytic lymphoma because she died due to nosocomial\npneumonia. Nevertheless, we verified by serum and dialysate analysis that rituximab\nwas nondialyzable using these settings. This can probably be explained by\nrituximab's molecular weight and the dialyzer membrane used. We cannot exclude other\nmechanisms that could have contributed to the removal of rituximab, such as\nunspecific adsorption to the tubing and dialyzer membrane. However, there was an\neffective increase in its serum level after drug infusion despite ongoing continuous\nrenal replacement therapy.\n\nConflicts of interest: None.\n\nResponsible editor: Fernando Godinho Zampieri\n==== Refs\nREFERENCES\n1 Ochi Y Hiramoto N Ono Y Yoshioka S Tabata S Yonetani N Tolerability and efficacy of rituximab-containing\nimmunochemotherapy in patients with B-cell non-Hodgkin lymphoma receiving\nhemodialysis Leuk Lymphoma 2016 57 8 1945 1948 26689650 \n2 Jillella AP Dainer PM Kallab AM Ustun C Treatment of a patient with end-stage renal disease with\nRituximab: pharmacokinetic evaluation suggests Am J Hematol 2002 71 3 219 222 12410580 \n3 Gupta N El-Tarabily M Bedient S Rituximab can be safely administered in patients with endstage- renal\ndisease on hemodialysis without dose-modification [Abstract] 2003 45th Annual Meeting of the American Society of Hematology San Diego, California December 6-9, 2003 ASH Abstract #4916 \n4 Morita Y Matsuda M Yamaguchi T Sakaguchi M Rai S Kanai Y Efficacy of rituximab monotherapy for an elderly hemodialysis\npatient with primary cardiac lymphoma Intern Med 2010 49 19 2163 2166 20930448 \n5 Swerdlow SH Campo E Harris NL Jaffe ES Pileri SA Stein H Thiele J WHO classification of tumours of haematopoietic and lymphoid\ntissues 2017 4th ed Lyon International Agency for Research on Cancer \n6 Xu L Hunter ZR Yang G Zhou Y Cao Y Liu X MYD88 L265P in Waldenström macroglobulinemia,\nimmunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative\ndisorders using conventional and quantitative allele-specific polymerase\nchain reaction Blood 2013 121 11 2051 2058 Erratum in Blood. 2013;121(26):5259. Varettoni, Maria [corrected to\nVarettoni, Marzia] 23321251 \n7 Varettoni M Arcaini L Zibellini S Boveri E Rattotti S Riboni R Prevalence and clinical significance of the MYD88 (L265P) somatic\nmutation in Waldenstrom's macroglobulinemia and related lymphoid\nneoplasms Blood 2013 121 13 2522 2528 23355535 \n8 Treon SP How I treat Waldenström macroglobulinemia Blood 2015 126 6 721 732 26002963 \n9 McLaughlin P Grillo-López AJ Link BK Levy R Czuczman MS Williams ME Rituximab chimeric anti-CD20 monoclonal antibody therapy for\nrelapsed indolent lymphoma: half of patients respond to a four-dose\ntreatment program J Clin Oncol 1998 16 8 2825 2833 9704735 \n10 Hallek M Fischer K Fingerle-Rowson G Fink A Busch R Mayer J Hensel M Hopfinger G Hess G von Grünhagen U Bergmann M Catalano J Zinzani PL Caligaris-Cappio F Seymour JF Berrebi A Jäger U Cazin B Trneny M Westermann A Wendtner CM Eichhorst BF Staib P Bühler A Winkler D Zenz T Böttcher S Ritgen M Mendila M Kneba M Döhner H Stilgenbauer S International Group of Investigators German Chronic Lymphocytic Leukaemia Study Group Addition of rituximab to fludarabine and cyclophosphamide in\npatients with chronic lymphocytic leukaemia: a randomised, open-label, phase\n3 trial Lancet 2010 376 9747 1164 1174 20888994\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0103-507X",
"issue": "31(2)",
"journal": "Revista Brasileira de terapia intensiva",
"keywords": null,
"medline_ta": "Rev Bras Ter Intensiva",
"mesh_terms": "D058186:Acute Kidney Injury; D000074322:Antineoplastic Agents, Immunological; D000079664:Continuous Renal Replacement Therapy; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008875:Middle Aged; D000069283:Rituximab",
"nlm_unique_id": "9506692",
"other_id": null,
"pages": "258-261",
"pmc": null,
"pmid": "31271628",
"pubdate": "2019-06-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12410580;20888994;20930448;23321251;23355535;26002963;26689650;9704735",
"title": "Rituximab use for lymphoplasmacytic lymphoma during continuous renal replacement therapy.",
"title_normalized": "rituximab use for lymphoplasmacytic lymphoma during continuous renal replacement therapy"
} | [
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"companynumb": "PT-CELLTRION INC.-2019PT023117",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "DAPSONE"
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{
"abstract": "We report a patient who presented a non-ST segment elevation myocardial infarction in the context of severe normocytic hypochromic anemia related to gastrointestinal bleeding, 3 months after switching anticoagulant from the vitamin K antagonist acenocoumarol to the direct oral anticoagulant rivaroxaban. High levels of both anti-Xa activity and rivaroxaban plasma concentrations were measured despite rivaroxaban withdrawal, suggesting reduced elimination/drug clearance. Estimated half-life was 2-3 times longer than usually reported. The patient is a homozygous carrier of ABCB1 variant alleles, which could have participated to reduced elimination of rivaroxaban. Furthermore, CYP3A4/5 phenotyping showed moderately reduced enzyme activity. Drug-drug interaction with simvastatin may have contributed to decreased rivaroxaban elimination. Although in the present case moderate acute renal failure probably played a role, more clinical data are required to elucidate the impact of ABCB1 polymorphism on rivaroxaban pharmacokinetics and bleeding complications.",
"affiliations": "Division of Clinical Pharmacology and Toxicology, University Hospitals of Geneva Geneva, Switzerland.;Division of Clinical Pharmacology and Toxicology, University Hospitals of Geneva Geneva, Switzerland.;Division of Angiology and Haemostasis, University Hospitals of Geneva Geneva, Switzerland.;Division of Clinical Pharmacology and Toxicology, University Hospitals of Geneva Geneva, Switzerland.;Division of Clinical Pharmacology and Toxicology, University Hospitals of Geneva Geneva, Switzerland.",
"authors": "Ing Lorenzini|Kuntheavy|K|;Daali|Youssef|Y|;Fontana|Pierre|P|;Desmeules|Jules|J|;Samer|Caroline|C|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.3389/fphar.2016.00494",
"fulltext": "\n==== Front\nFront PharmacolFront PharmacolFront. Pharmacol.Frontiers in Pharmacology1663-9812Frontiers Media S.A. 10.3389/fphar.2016.00494PharmacologyCase ReportRivaroxaban-Induced Hemorrhage Associated with ABCB1 Genetic Defect Ing Lorenzini Kuntheavy 1*Daali Youssef 1Fontana Pierre 2Desmeules Jules 1Samer Caroline 11Division of Clinical Pharmacology and Toxicology, University Hospitals of GenevaGeneva, Switzerland2Division of Angiology and Haemostasis, University Hospitals of GenevaGeneva, SwitzerlandEdited by: Vita Dolzan, University of Ljubljana, Slovenia\n\nReviewed by: Erik Eliasson, Karolinska Institutet, Sweden; Farhad Kamali, Newcastle University, UK\n\n*Correspondence: Kuntheavy Ing Lorenzini, kuntheavy-roseline.ing@hcuge.chThis article was submitted to Pharmacogenetics and Pharmacogenomics, a section of the journal Frontiers in Pharmacology\n\n19 12 2016 2016 7 49407 10 2016 02 12 2016 Copyright © 2016 Ing Lorenzini, Daali, Fontana, Desmeules and Samer.2016Ing Lorenzini, Daali, Fontana, Desmeules and SamerThis 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) or licensor 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.We report a patient who presented a non-ST segment elevation myocardial infarction in the context of severe normocytic hypochromic anemia related to gastrointestinal bleeding, 3 months after switching anticoagulant from the vitamin K antagonist acenocoumarol to the direct oral anticoagulant rivaroxaban. High levels of both anti-Xa activity and rivaroxaban plasma concentrations were measured despite rivaroxaban withdrawal, suggesting reduced elimination/drug clearance. Estimated half-life was 2–3 times longer than usually reported. The patient is a homozygous carrier of ABCB1 variant alleles, which could have participated to reduced elimination of rivaroxaban. Furthermore, CYP3A4/5 phenotyping showed moderately reduced enzyme activity. Drug-drug interaction with simvastatin may have contributed to decreased rivaroxaban elimination. Although in the present case moderate acute renal failure probably played a role, more clinical data are required to elucidate the impact of ABCB1 polymorphism on rivaroxaban pharmacokinetics and bleeding complications.\n\ndirect oral anticoagulantsadverse drug reactiongenetic polymorphismABCB1CYP3A4/5drug-drug interaction\n==== Body\nIntroduction\nRivaroxaban is a direct Factor Xa inhibitor which has been approved for specific thromboembolic disorders such as the prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation (Mueck et al., 2014). Rivaroxaban is both excreted as unchanged drug in urine and through metabolic transformation. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), as well as cytochrome P450 (CYP) 3A4/5 have been shown to play major roles in rivaroxaban transport and metabolism, respectively (Mueck et al., 2014). The administration of strong inhibitors of CYP3A4/5 and P-gp/BCRP such as ritonavir and ketoconazole has been shown to increase rivaroxaban exposure and cases of severe bleeding have been reported (Mueck et al., 2013). However, to the best of our knowledge, no human data has described the impact of genetic polymorphism of ABCB1 and/or ABCG2 on the pharmacokinetics and safety of rivaroxaban. ABCB1 and ABCG2 genes encode for P-gp and BCRP efflux transporter, respectively, (Hodges et al., 2011; Giacomini et al., 2013). We report here a rivaroxaban-treated patient who presented with severe anemia related to gastrointestinal bleeding and in whom ABCB1 genetic polymorphism and drug-drug interaction (DDI) may have been contributing factors. The patient gave his written informed consent for publication of this report.\n\nCase Presentation\nOur patient is a 79-year-old male suffering from systolic cardiac failure (ischemic, rhythmic, and valvular) and type 2 diabetes mellitus. The patient had received rivaroxaban 20 mg q.d. since September 2015 for cardioembolic strokes and atrial fibrillation. Before the introduction of rivaroxaban, he had been treated with acenocoumarol for years. The patient was hospitalized on December 15th 2015 for non-ST segment elevation myocardial infarction (NSTEMI). At hospital admission, laboratory testing showed severe normocytic hypochromic anemia with a hemoglobin level at 70 g/l (normal range: 140–180 g/l), without hemodynamic instability. The patient received erythrocyte transfusions, which raised the hemoglobin to 105–110 g/l. Acute renal failure was also diagnosed with a CLCR value at 39 ml/min using the Cockcroft–Gault equation at admission. Renal function improved at 57 ml/min 4 days later. Due to the presence of fecal occult blood on two occasions, iron loss from gastrointestinal bleeding was suspected. The colonoscopy did not show any evidence of colon injury; however, inadequate bowel preparation was highlighted by the examinator. Gastroscopy could not be performed because the patient’s comorbidities exposed him to high risks in case of general anesthesia. Rivaroxaban was stopped at admission; enoxaparin was introduced 4 days later and then switched to acenocoumarol.\n\nThe other patient medications before hospitalization were: insulin, simvastatin 40 mg q.d., levothyroxine 75 μg q.d., extended-release metoprolol 25 mg q.d., and enalapril 10 mg q.d.\n\nInvestigations\nClinical investigations were performed to assess for causes of potential increased rivaroxaban effects at therapeutic doses. They included anti-Xa activity measurement, rivaroxaban plasma concentrations measurement, as well as ABCB1 genotyping, and CYP3A4/5 phenotyping.\n\nAnti-Xa Activity\nAnti-Xa activity was measured with a chromogenic assay using the DiXal® kit (Hyphen Biomed, Neuville-Sur-Oise, France) and a BCS XP instrument (Siemens, Marburg, Germany). This method has a limit of detection of 10 ng/ml. No information is given by the manufacturer regarding the limit of quantification (LOQ). However, previous studies have shown a LOQ of 20–30 ng/ml (Douxfils et al., 2013). The accuracy and precision calculated from the quality controls (QCs) were 107.0 and 8.8%, respectively, (Asmis et al., 2012). An excellent correlation between this method and liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been shown (Spearman correlation coefficient of 0.96) (Douxfils et al., 2013).\n\nRivaroxaban Plasma Concentrations\nRivaroxaban determination was performed using a fully validated LC-MS/MS method according to guidelines of the US Food and Drug Administration and the International Conference on Harmonization. The method was accurate and precise across the dynamic range of 0.5–1000 ng/ml. The LOQ was 0.5 ng/ml. The mean precision and accuracy, calculated from the QCs, were 10.2 and 112%, respectively.\n\nA plasma sample of 40 μl was processed by protein precipitation extraction using acetonitrile (200 μL). Separation was performed on a C18 column (50 mm × 2.1 mm ID; 2.6 μm particle size) and under gradient conditions using formic acid 10 mM in water and formic acid 10 mM in acetonitrile. Detection was by tandem-MS in positive mode using a Qtrap API 6500 from AB sciex (Ontario, Canada) using rivaroxaban-d4 as internal standard (20 ng/ml).\n\nABCB1 Genotyping\nGenomic DNA was extracted from whole blood (200 μl) using the QIAamp DNA blood mini kit (QIAGEN, Hombrechtikon, Switzerland). ABCB1 c.3435C>T and c.2677G>T polymorphisms were determined in a single multiplex PCR, with fluorescent probe melting temperature analysis on a LightCycler (Roche, Rotkreuz, Switzerland) as previously described (Ansermot et al., 2008).\n\nCYP3A4/5 Phenotyping\nMidazolam was used as a probe to measure the joint activity of CYP3A4/5 as previously described (Bosilkovska et al., 2014). Phenotyping was performed 8 days after hospital admission with concomitant treatment of insulin, enoxaparin 60 mg b.i.d., atorvastatin 40 mg q.d. (replacing simvastatin from the day of hospital admission), esomeprazole 40 mg q.d., levothyroxine 75 μg q.d., lisinopril 10 mg q.d., extended-release metoprolol 50 mg q.d., picosulfate 5 mg q.d., and spironolactone 25 mg q.d.\n\nResults\nResults from anti-Xa activity and rivaroxaban plasma concentrations are presented in Table 1. The patient was a homozygous carrier of both tested ABCB1 variant alleles. His genotype was TT for the c.2677G>T single nucleotide polymorphism (SNP) and TT for the c.3435C>T SNP. CYP3A4/5 phenotyping showed moderately decreased enzymatic activity, with OH-midazolam/midazolam metabolic ratio of 0.31.\n\nTable 1 Anti-Xa activity and rivaroxaban plasma concentrations.\n\nTime after the lastrivaroxaban dose\tAnti-Xa activity (ng/ml)\tRivaroxaban plasmaconcentrations (ng/ml)\t\n24 h\t231\tnot performed\t\n48 h\t110\t88.3\t\n60 h\t81\tnot performed\t\n72 h\t66\t70.5\t\n84 h\t66\tnot performed\t\n96 h\t34\t35.6\t\nDiscussion\nWe described the case of a rivaroxaban-treated patient who presented a non-ST segment elevation myocardial infarction in the context of a severe anemia probably due to a gastrointestinal bleeding, 3 months after switching anticoagulant treatment from acenocoumarol to rivaroxaban. Laboratory investigations showed high levels of anti-Xa activity and rivaroxaban plasma concentrations at trough level (24 h after the last dosing) and an unexpected delay for rivaroxaban clearance, suggesting impaired rivaroxaban elimination. Our hypothesis is that both genetic and environmental factors might have contributed to an increased susceptibility to rivaroxaban in this patient, e.g., the homozygous presence of ABCB1 variant alleles and reduced CYP3A4/5 activity due to DDI with simvastatin. Given that more than one third of the dose is eliminated as unchanged active drug in the urine (Mueck et al., 2014), acute renal failure was probably also a contributing factor. However, renal impairment at admission was moderate (39 ml/min), not requiring dose adjustment according to the summary of product characteristics. In a physiologically based pharmacokinetic (PBPK) model simulating the combined effect of renal impairment and concomitant erythromycin (combined P-gp and moderate CYP3A4/5 inhibitor) administration on rivaroxaban pharmacokinetics, concurrent renal impairment plus erythromycin resulted in a 2.5–3 fold increase in rivaroxaban exposure in elderly (Grillo et al., 2012). However, in vivo data showed that the impact of concomitant renal impairment and erythromycin administration was less than expected by the PBPK model. Indeed, a clinical study showed that in subjects with moderate renal impairment receiving concomitant erythromycin, rivaroxaban AUC, and Cmax values increased by approximately 99 and 64%, as compared with subjects with normal renal function receiving rivaroxaban 10 mg alone (Moore et al., 2014).\n\nRivaroxaban belongs to the recently developed class of direct oral anticoagulants (DOACs). Older OACs such as vitamin K antagonists (VKAs) are characterized by extensive hepatic metabolism by CYP450, narrow therapeutic window and the need for routine coagulation monitoring for dose adjustment. Their extensive hepatic metabolism implies multiple potential DDI and an impact of CYP2C9 genetic polymorphism on their pharmacokinetics (Scaglione, 2013). DOACs are given at fixed doses without the need for routine monitoring (Mueck et al., 2014). However, these compounds are also subject to DDI due to CYP450-mediated metabolism and/or P-gp and/or BCRP-mediated transport (Scaglione, 2013). About one third of a rivaroxaban dose is renally excreted as an unchanged form (Mueck et al., 2014) via glomerular filtration and tubular secretion (Scaglione, 2013). P-gp and BCRP have been shown to be the major transporters involved in the active renal secretion of rivaroxaban (Mueck et al., 2014). The remaining part of the dose is eliminated after hepatic metabolism. CYP3A4/5 and CYP2J2 are the isoenzymes involved in rivaroxaban metabolism, while CYP-independent mechanisms are also contributing (Mueck et al., 2014).\n\nTo the best of our knowledge, no human data have yet described the impact of CYP3A4/5 and/or ABCB1 (MDR1) and ABCG2 gene polymorphism on the pharmacokinetics and safety of rivaroxaban. More than 100 single nucleotide polymorphisms (SNPs) of the ABCB1 gene region occurring at a >5% frequency have been described. For the most common coding SNPs (c.2677G>T, c.3435C>T), allele frequencies exhibits large interethnic differences, ranging between 2 and 90% across populations and depending on the SNP (Hodges et al., 2011). These SNPs are in high linkage disequilibrium and are therefore observed most frequently as haplotypes. In the Caucasian population, the TT TT haplotype frequency ranges from 15 to 25% (Marzolini et al., 2004).\n\nAn animal study showed that Mdr1a/Mdr1b/Bcrp triple knockout mice exhibited higher rivaroxaban plasma levels than wild type mice, with a 1.7 fold increase in plasma concentration 4 h after administration (Gong et al., 2013). The observed effect was explained by decreased excretion of rivaroxaban via P-gp and/or BCRP rather than increased absorption as rivaroxaban oral bioavailability is high (80–100%; Mueck et al., 2014). ABCB1 genotype of our patient was a homozygous carrier for both tested SNP (c.2677G>T: TT; and c.3435C>T: TT). This genotype might have contributed to the high levels of anti-Xa activity and rivaroxaban plasma concentrations measured. Indeed, levels of anti-Xa activity as determined by a chromogenic assay were higher than expected. The trough level of anti-Xa activity measured 24 h after last drug administration (231 ng/ml) was in the range of expected Cmax levels (Groupe de travail RivaMoS Suisse, 2013). The level measured 4 days after last drug administration (34 ng/ml) was in the range of expected trough levels (Groupe de travail RivaMoS Suisse, 2013). Rivaroxaban plasma concentration measured by LC/MS-MS 48 h after administration (88 ng/ml) was comparable to approximately 8–16 h post-dose predicted levels based on a population pharmacokinetic model (20 mg q.d. administration) (Mueck et al., 2011). The plasma concentration measured 4 days after last drug administration (36 ng/ml) was comparable to expected trough concentrations. The estimated half-life was increased by threefold in our patient, approximately 24–30 h as compared to 11–13 h in the literature for old patients (Mueck et al., 2014).\n\nDrug-Drug Interaction probably also played a role in rivaroxaban high levels. Crossover studies in healthy volunteers have shown significant increases in rivaroxaban systemic exposure during concomitant administration with strong inhibitors of CYP3A4/5 (and possibly CYP2J2), P-gp and BCRP. Steady state administration of ketoconazole led to a dose-dependent increase in rivaroxaban AUC and Cmax. AUC and Cmax increased by, respectively, 82% (90% CI 59%, 108%) and 53% (90% CI 27%, 85%) with ketoconazole 200 mg q.d. compared with rivaroxaban alone. With a higher dose of 400 mg q.d., the measured increases in AUC and Cmax were 158% (90% CI 136%, 182%) and 72% (90% CI 61%, 83%) (Mueck et al., 2013). As a consequence, the concomitant use of rivaroxaban with strong CYP3A4/5 and P-gp/BCRP inhibitors should be avoided due to a potential increase in the risk of bleeding (Mueck et al., 2013). According to the data from the ROCKET AF study (Prevention of Stroke and Embolism Trial in Atrial Fibrillation), the presence of combined CYP3A4/5 and P-gp inhibitors did not have any impact on safety outcomes such as bleeding events when comparing the rivaroxabanand warfarin groups (Piccini et al., 2016). However, key exclusion criteria included use of a strong CYP3A4/5 inhibitors or inducers. As recently underscored by Bouatou et al. (2016) this represents a major bias when analyzing the impact of polypharmacy pharmacokinetic interactions on the efficacy and safety of rivaroxaban. Moreover, the prescription of P-gp affecting drugs in heart failure patients is as frequent as 40–50% as shown by Jungbauer et al. (2010).\n\nIn the present case, our patient was receiving long-term treatment with simvastatin. Recently, an in vitro study has shown that simvastatin inhibited CYP3A4/5 and P-gp activity (Lee et al., 2015). An in vivo animal study performed by the same authors showed that concomitant administration of simvastatin with nifedipine, a CYP3A/5 and P-gp substrate, significantly increased the absolute bioavailability of nifedipine by 150% (Lee et al., 2015). On the other hand, atorvastatin inhibited CYP3A/5 but not P-gp activity in vitro, and had no impact on nifedipine pharmacokinetics in vivo (Lee et al., 2015). According to the FDA classification1, simvastatin would therefore be considered as a weak CYP3A/5 inhibitor (≥1.25 but <2-fold increase in AUC). CYP3A4/5 phenotyping, which was performed 8 days after the patient had been switched from simvastatin to atorvastatin, showed moderately decreased enzymatic activity as compared to our study population of healthy volunteers (Bosilkovska et al., 2014), which could be attributed at least in part to inhibition by atorvastatin. Although the enzymatic activity was only modestly decreased with a OH-midazolam/midazolam metabolic ratio of 0.31, compared to 0.50 in healthy volunteers without enzyme inhibitor/inducer, and 0.22 in the presence of a CYP inhibitor (voriconazole) (Bosilkovska et al., 2014), the measured phenotype allowed to rule out an ultrarapid metabolism.\n\nThe present case has some limitations. We did not investigate ABCG2 and CYP2J2 gene polymorphism. Indeed, CYP2J2 is also subject to genetic variations and the promoter region SNP (CYP2J2-76G>T; ∗7 allele) reportedly decreases epoxygenase activity in vivo (Murray, 2016). Moreover, we did not evaluate P-gp activity in vivo through phenotyping and the DDI with simvastatin has not been thoroughly investigated. Finally, the moderate acute renal failure at admission was probably a contributing factor to rivaroxaban high levels.\n\nConcluding Remarks\nOur patient presented severe normocytic hypochromic anemia probably due to gastrointestinal bleeding, 3 months after switching his anticoagulant treatment from acenocoumarol to rivaroxaban.\n\nLaboratory investigations showed high levels of anti-Xa activity and rivaroxaban plasma concentrations after rivaroxaban withdrawal, suggesting reduced rivaroxaban elimination (estimated half-life: 24–30 h). We suggest that the homozygous presence of ABCB1 variant alleles and possibly altered CYP3A4/5 activity due to DDI with simvastatin were possible contributing factors, in addition to the moderate decreased renal function.\n\nMore clinical data are required to elucidate the impact of genetic polymorphism on rivaroxaban pharmacokinetics and bleeding complications. The impact of ABCB1, ABCG2, and CYP2J2 gene polymorphism on rivaroxaban pharmacokinetics should be investigated in a phase 1 clinical study in healthy volunteers. The impact of genetic polymorphism on the susceptibility to DDI should also be further investigated. Indeed, the presence of a variant allele could predispose to DDI, as suggested between warfarin and simvastatin (Andersson et al., 2012).\n\nAuthor Contributions\nKIL was in charge of the pharmacological investigations done in the patient, interpreted the results, and wrote the manuscript. YD measured the rivaroxaban plasma concentrations and performed the phenotyping test. PF was involved in the care of the patient and was in charge of the anti-Xa measurements and of interpretation of the results. JD supervised the investigations and the redaction of the manuscript. CS interpreted the results and wrote the manuscript. All authors read and approved the manuscript.\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\nThe authors would like to thank the patient for allowing publication of this case.\n\n1 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm\n==== Refs\nReferences\nAndersson M. L. Eliasson E. Lindh J. D. (2012 ). 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"issn_linking": "1663-9812",
"issue": "7()",
"journal": "Frontiers in pharmacology",
"keywords": "ABCB1; CYP3A4/5; adverse drug reaction; direct oral anticoagulants; drug-drug interaction; genetic polymorphism",
"medline_ta": "Front Pharmacol",
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"pages": "494",
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"pmid": "28066243",
"pubdate": "2016",
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"title": "Rivaroxaban-Induced Hemorrhage Associated with ABCB1 Genetic Defect.",
"title_normalized": "rivaroxaban induced hemorrhage associated with abcb1 genetic defect"
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"abstract": "BACKGROUND\nThe combination of vinblastine and mammalian target of rapamycin (mTOR) inhibitor sirolimus inhibits the growth of neuroblastoma xenografts through pro-apoptotic and anti-angiogenic mechanisms. This phase I study aimed to explore the safety and toxicity of this combination in pediatric patients with advanced solid tumors.\n\n\nMETHODS\nPatients ≤21 years of age with recurrent/refractory solid tumors (including CNS) were eligible. Sirolimus was administered daily by mouth or nasogastric (NG) tube, with doses adjusted to achieve a target trough concentration of 10-15 ng/ml, with weekly intravenous vinblastine (dose escalated 4-6 mg/m(2)/dose according to 3 + 3 phase I design).\n\n\nRESULTS\nFourteen patients were enrolled (median age 8.7 years; range 2.3-19) of whom 12 were evaluable for toxicity and 11 for response. One patient experienced a dose-limiting toxicity (grade 3 mucositis) at the highest vinblastine dose level. Myelosuppression was the most common toxicity. Dose-adjusted sirolimus trough concentrations were significantly lower in patients receiving drug via NG tube (1.50 ± 0.75 ng/ml/mg vs. 2.25 ± 1.07 ng/ml/mg for oral administration). Correlative biomarker analysis demonstrated a significant reduction in serum concentration of soluble vascular endothelial growth factor receptor (sVEGFR2) at 28 days compared to baseline consistent with inhibition of angiogenesis. One patient had a partial response and three had stable disease for more than 3 months.\n\n\nCONCLUSIONS\nThe combination of mTOR inhibitor and vinblastine given over an extended continuous schedule is safe, associated with a reduction in circulating angiogenic factor (CAF) VEGFR2 and resulted in clinical responses. Future studies using the intravenously administered mTOR inhibitor temsirolimus are planned.",
"affiliations": "Department of Paediatrics, University of Toronto and New Agent and Innovative Therapy Programme, The Hospital for Sick Children, Toronto, Ontario, Canada.",
"authors": "Morgenstern|Daniel A|DA|;Marzouki|Monia|M|;Bartels|Ute|U|;Irwin|Meredith S|MS|;Sholler|Giselle L S|GL|;Gammon|Janet|J|;Yankanah|Rosanna|R|;Wu|Bing|B|;Samson|Yvan|Y|;Baruchel|Sylvain|S|",
"chemical_list": "D042461:Vascular Endothelial Growth Factor A; D014747:Vinblastine; D040262:Receptors, Vascular Endothelial Growth Factor; D020123:Sirolimus",
"country": "United States",
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"doi": "10.1002/pbc.24656",
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"issn_linking": "1545-5009",
"issue": "61(1)",
"journal": "Pediatric blood & cancer",
"keywords": "Phase I; anti-angiogenesis; mTOR; rapamycin; sirolimus; vinblastine",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local; D009369:Neoplasms; D040262:Receptors, Vascular Endothelial Growth Factor; D020123:Sirolimus; D042461:Vascular Endothelial Growth Factor A; D014747:Vinblastine; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "128-33",
"pmc": null,
"pmid": "23956145",
"pubdate": "2014-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase I study of vinblastine and sirolimus in pediatric patients with recurrent or refractory solid tumors.",
"title_normalized": "phase i study of vinblastine and sirolimus in pediatric patients with recurrent or refractory solid tumors"
} | [
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"companynumb": "CA-PFIZER INC-2013060262",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
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"activesubstancename": "VINBLASTINE"
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{
"abstract": "We discovered a rare cause of pleural effusion, chemothorax. In this case, a patient with invasive ductal breast carcinoma was admitted for a large and symptomatic pleural effusion. The radiology report obtained prior to admission did not describe the location of the Infuse-a-Port catheter. After a bedside thoracentesis demonstrated results consistent with chemotherapy infusate in the pleural space, further review of the medical imaging demonstrated that the catheter was in the pleural space.",
"affiliations": "Department of Internal Medicine, Wright State School of Medicine, Dayton, Ohio, USA.;Department of Internal Medicine, Wright State School of Medicine, Dayton, Ohio, USA.;Department of Internal Medicine, Wright State School of Medicine, Dayton, Ohio, USA.",
"authors": "Kelly|Devin|D|;Geottman|David|D|;Sarodia|Bipin|B|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008875:Middle Aged; D010996:Pleural Effusion; D011859:Radiography; D062666:Vascular Access Devices",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26655229",
"pubdate": "2015-12-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16302239;23845616;6415832;23605827;9517694;2626123;22563269;25261677;22813785;23871236;25390061",
"title": "Chemothorax: a rare cause of a transudative pleural effusion.",
"title_normalized": "chemothorax a rare cause of a transudative pleural effusion"
} | [
{
"companynumb": "US-HOSPIRA-3160672",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
"dru... |
{
"abstract": "Background and study aims To investigate bleeding risk and thromboembolic risk in patients receiving antithrombotic therapy who underwent endoscopic ultrasound-guided fine-needls aspiration (EUS-FNA). Patients and methods A single-center retrospective study of 908 consecutive patients undergoing EUS-FNA for pancreatic and non-pancreatic lesions patients between March 2013 and March 2017 was performed. Antithrombotic management was classified into three groups: continuous, discontinuation, and heparin replacement. Results A total of 114 patients (12.6 %) were on antithrombotic drugs and 794 (84.6 %) were not. There were six cases of significant bleeding (0.7 %) four in the antithrombotic group (0.4 %) and two (0.2 %) in the non-antithrombotic group, (odds ratio, 9.59; 95 % confidence interval, 2.12 - 43.1; P = 0.006). Of the four cases in the antithrombotic group, two were on continuous treatment, one was on discontinuation treatment and one was on heparin replacement. All cases of non-significant bleeding occurred in the non-antithrombotic group (3 peri-tumoral hematomas, 1 submucosal hematoma, and 1 intraluminal bleed). The sole thromboembolic event (0.9 %) was a cerebral infarction in the antithrombotic group in a patient on thienopyridine who switched to aspirin before the procedure. Conclusions There was a slight increase in risk of bleeding in patients receiving antithrombotic therapy especially postoperative bleeding; however, there were no cases of severe bleeding was seen and only one case of cerebral infarction which occurred in a high-risk thromboembolic patients. We concluded that EUS-FNA in a safe procedure for patients on antithrombotics, even when antithrombotic therapy is not discontinued during EUS-FNA.",
"affiliations": "Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan.",
"authors": "Polmanee|Petcharee|P|;Hara|Kazuo|K|;Mizuno|Nobumasa|N|;Hijioka|Susumu|S|;Kuwahara|Takamichi|T|;Okuno|Nozomi|N|;Iwaya|Hiromichi|H|;Tajika|Masahiro|M|;Tanaka|Tsutomu|T|;Ishihara|Makoto|M|;Hirayama|Yutaka|Y|;Ohnishi|Sachiyo|S|;Toriyama|Kazuhiro|K|;Bhanthomkomol|Patommatat|P|;Ito|Ayako|A|;Kuraoka|Naosuke|N|;Matsumoto|Shinpei|S|;Niwa|Yasumasa|Y|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/a-0735-9107",
"fulltext": "\n==== Front\nEndosc Int OpenEndosc Int Open10.1055/s-00025476Endoscopy International Open2364-37222196-9736© Georg Thieme Verlag KG Stuttgart · New York 10.1055/a-0735-9107Original articleOutcomes of EUS-FNA in patients receiving antithrombotic therapy Polmanee Petcharee 12Hara Kazuo 1Mizuno Nobumasa 1Hijioka Susumu 1Kuwahara Takamichi 1Okuno Nozomi 1Iwaya Hiromichi 1Tajika Masahiro 1Tanaka Tsutomu 1Ishihara Makoto 1Hirayama Yutaka 1Ohnishi Sachiyo 1Toriyama Kazuhiro 1Bhanthomkomol Patommatat 1Ito Ayako 1Kuraoka Naosuke 1Matsumoto Shinpei 1Niwa Yasumasa 11 Department of Gastroenterology Aichi Cancer Center Hospital, Nagoya, Japan2 Department of Internal Medicine, Bhumibol Adulyadej Hospital, Saimai, Bangkok, ThailandCorresponding author Kazuo Hara, MD Department of GastroenterologyAichi Cancer Center Hospital 1-1 KanokodenChikusa-ku, Nagoya 464-8681Japan+81-52-764-2942+81-52-764-2963khara@aichi-cc.jp1 2019 03 1 2019 7 1 E15 E25 07 12 2017 \naccepted after revision\n21 6 2018 This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.\nBackground and study aims \nTo investigate bleeding risk and thromboembolic risk in patients receiving antithrombotic therapy who underwent endoscopic ultrasound-guided fine-needls aspiration (EUS-FNA).\n\n\n\nPatients and methods\n A single-center retrospective study of 908 consecutive patients undergoing EUS-FNA for pancreatic and non-pancreatic lesions patients between March 2013 and March 2017 was performed. Antithrombotic management was classified into three groups: continuous, discontinuation, and heparin replacement.\n\n\n\nResults\n A total of 114 patients (12.6 %) were on antithrombotic drugs and 794 (84.6 %) were not. There were six cases of significant bleeding (0.7 %) four in the antithrombotic group (0.4 %) and two (0.2 %) in the non-antithrombotic group, (odds ratio, 9.59; 95 % confidence interval, 2.12 – 43.1;\nP\n = 0.006). Of the four cases in the antithrombotic group, two were on continuous treatment, one was on discontinuation treatment and one was on heparin replacement. All cases of non-significant bleeding occurred in the non-antithrombotic group (3 peri-tumoral hematomas, 1 submucosal hematoma, and 1 intraluminal bleed). The sole thromboembolic event (0.9 %) was a cerebral infarction in the antithrombotic group in a patient on thienopyridine who switched to aspirin before the procedure.\n\n\n\nConclusions\n There was a slight increase in risk of bleeding in patients receiving antithrombotic therapy especially postoperative bleeding; however, there were no cases of severe bleeding was seen and only one case of cerebral infarction which occurred in a high-risk thromboembolic patients. We concluded that EUS-FNA in a safe procedure for patients on antithrombotics, even when antithrombotic therapy is not discontinued during EUS-FNA.\n==== Body\nIntroduction\n\nAntithrombotic drugs, which are classified as either anticoagulants or antiplatelets, are widely prescribed for patients with a range of cardiovascular and thromboembolic conditions. These drugs increase bleeding risk during therapeutic endoscopic procedures\n1\n2\n3\n, and risk of thromboembolic events increases when they are discontinued\n4\n. There are very few reports on the association between antithrombotic agents and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) procedures. One prospective controlled study comparing EUS-FNA and/or Trucut biopsy (TCB) in patients taking acetylsalicylic acid (ASA),non-steroidal anti-inflammatory drugs (NSAIDs) and low-molecular-weight heparin (LMWH) found that risk of bleeding in patients on antithrombotics was 33.3 %, compared to 3.7 % in a control group\n5\n. A recent retrospective study from Japan included 746 patients, of whom 130 were receiving antithrombotic therapy (ASA or cilostazol), and recorded only 1 case of bleeding in the antithrombotic group\n6\n.\n\n\n\nIn addition to risk of bleeding during EUS-FNA in patients taking antithrombotic drugs, discontinuation of these agents before or during procedures is significantly associated with an increase in thromboembolic events, such as stroke or pulmonary embolism. A recent retrospective study of 2,197 cases of ischemic stroke identified from hospital discharge records found that stroke ocurred in 114 patients (5.2 %) who had stopped taking warfarin or antiplatelet agents in the previous 60 days\n7\n.\n\n\n\nSeveral guidelines for antithrombotic management in endoscopy have been proposed, including guidelines from the British Society of Gastroenterology, the American Society of Gastrointestinal Endoscopy, the European Society of Gastrointestinal Endoscopy\n8\n9\n10\nand the Japan Gastroenterological Endoscopy Society (JGES)\n11\n. All guidelines have classified EUS-FNA as a high-risk procedure and peri-procedural management is based on antithrombotic groups and patient risk. The most recent Japanese guidelines (JGES) came after a consensus meeting in June 2011 where evidence-based guidelines on management of antithrombotic therapy in endoscopy incorporate use of oral antiplatelets and direct oral anticoagulant drugs (DOACs). These guidelines were published in\nGastroenterological Endoscopy\n(Japanese) in 2012 and in\nDigestive Endoscopy\nin 2014\n12\n. The guidelines classified patients as high and low bleeding risk after endoscopic procedures and investigated the factors associated with thromboembolism associated with withdrawal of antithrombotic therapy. However, since then, very few studies have been conducted. One retrospective study examined risk factors for early and delayed postoperative bleeding after endoscopic submucosal dissection (ESD) of gastric neoplasms. In patients who continued using low-dose aspirin, the bleeding risk of 9.5 %\n13\nwas comparable to other patients.\n\n\nOur study sought to evaluate the outcome of EUS-FNA, especially bleeding and thromboembolic events, in patients receiving antithrombotic therapy, following revision of the 2011 JGES guidelines. We aimed to investigate how the relative risks of bleeding and ischemia can be balanced after discontinuation of antithrombotic drugs.\n\nPatients and methods\nPatients\n\nThe records of 1,244 patients who were scheduled to undergo FNA between March 2013 and March 2017 at Aichi Cancer Center Hospital were reviewed and data from 908 patients who met the inclusion criteria were analyzed. Data were collected from a computerized database of all patients who registered and had provided written informed consent for EUS-FNA. EUS-FNA procedures were performed by gastroenterologists or under the supervision of a senior gastroenterologist who had been performing EUS procedures for more than 10 years. A total of 114 patients had been taking antithrombotic drugs, such as ASA, clopidogrel, cilostazol, dipyridamole, ticlopidine, warfarin, another antiplatelet agent, or DOACs, for more than 1 month (\nFig. 1\n). We excluded patients who had undergone an invasive high-risk endoscopic procedure in the month prior to EUS-FNA (endoscopic retrograde cholangiopancreatography, EUS-guided drainage, endobronchial ultrasound endoscopy, endoscopic submucosal dissection, endoscopic mucosal resection, EUS-guided cystic analysis, etc.), because adverse events (AEs) usually occur within this period\n14\n. We also excluded patients at high risk of bleeding due to bleeding disorders such as aplastic anemia, idiopathic thrombocytopenia, thrombocytopenia, and hemophilia, as well as those with coagulopathy or platelet dysfunction from end-stage renal disease requiring dialysis, and those with decompensated cirrhosis.\n\n\nFig. 1 \n Flow diagram of patients who underwent endoscopic ultrasound-guided fine needle aspiration and received antithrombotic therapy. ERCP, endoscopic retrograde cholangiopancreatography; EBUS, endobronchial ultrasound bronchoscopy; EUS-guided, endoscopic ultrasound-guided; ESD, endoscopic submucosal dissection; EMR, endoscopic mucosal resection; ASA, acetylsalicylic acid; DOACs, direct oral anticoagulants\n1\nOther antiplatelets (10 ASA + thienopyridines, 10 prostaglandin, 7 ASA with thienopyridines + eicosapentane, 6 eicosapentane, 3 ASA or thienopyridines + prostaglandin, 2 cilostazol, 2 saprogrelate),\n\n\n\nBefore any decisions were made on administration of antithrombotic drugs, cases were discussed with the primary physician before the procedure and the coagulogram (international normalized ratio [INR] ≥ 1.5) and platelet number (> 80,000/mL) were normalized. All patients on antithrombotic drugs were managed according to the JGES guidelines depending on the type of drug and thromboembolic risks\n11\n12\n. EUS-FNA was considered to be a high-risk procedure. Patients in the antithrombotic group were further classified into three subgroups: 1) continuous treatment group with patients receiving monotherapy of ASA/cilostazol and in whom non-aspirin non-thienopyridines antiplatelets were discontinued the day of the procedure; 2) a discontinuous treatment group, which included some patients on warfarin or DOACs who were at high risk of bleeding but low risk of thromboembolism plus the thienopyridines group (e. g. clopidogrel was discontinued 5 – 7 days before the procedure and ASA/cilostazol was continued or patients switched to ASA if monotherapy); and 3) a heparin replacement group in which warfarin was suspended and replaced with unfractionated intravenous or subcutaneous heparin 3 to 5 days before endoscopy and then heparin suspended at least 3 to 6 hours before endoscopy. Patients in this group who were taking warfarin or DOAC were considered at high risk of thromboembolism. DOACs should be suspended 24 to 48 hours before the procedure, and heparin replacement introduced 12 hours later. After temporary withdrawal of antithrombotics, the same regimen was reestablished as soon as hemostasis was confirmed. Generally, administration of aspirin, non aspirin antiplatelets, warfarin and heparin should be resumed after the procedure, with warfarin or DOAC resumed when oral intake which re-established.\n\n\nThe study was approved by the institutional review board of Aichi Cancer Center Hospital (approval no. 2016-1-363).\n\nMethods\n\nEUS-FNA was performed with the patient in the left lateral position under conscious sedation using intravenous midazolam (5 mg) and pethidine (25 – 100 mg). An Aloka Prosound Alpha 10 or EU-ME2 compact ultrasound processor was used with a GF-UCT 240 or GF-UCT 260 linear array echoendoscope, (Olympus Medical Systems Corp., Tokyo, Japan). A 19-G, 20-G, 22-G, or 25-G needle was used to perform EUS-FNA after target lesion confirmation. During and after FNA, color Doppler imaging was performed to rule out intervening blood vessels and signs of bleeding (new hypoechoic or hyperechoic areas)\n15\n. Intraluminal bleeding was defined as blood loss from the puncture site. Negative pressure was used with or without a 20-mL syringe in cases with an increased bleeding risk, such as hypervascular tumors. Patient characteristics recorded included the maximal diameter of lesions, site of lesions, route of puncture, needle size, the number of FNA passes, underlying diseases, age, sex, lab chemistry, indication for antithrombotic drugs, other predictive risk factors for bleeding, and length of hospital stay. After the procedure patients’ clinical events (especially hematemesis, melena, and thromboembolic events), vital signs, lab chemistry hemoglobin, ultrasound, computed tomography imaging (or other imaging) were recorded within 2 to 4 weeks.\n\n\n\nWe focused on outcomes in terms of bleeding and thromboembolic events, especially stroke and pulmonary emboli. Bleeding events and severity grading were defined according to the definitions of the American Society for Gastrointestinal Endoscopy\n14\n. Significant bleeding events were defined as follows: > 2 g/dL drop in hemoglobin level compared with baseline and/or a history of melena, hematemesis, hematochezia with no other cause of upper gastrointestinal bleeding, or evidence of intra-abdominal bleeding on imaging (ultrasonographic imaging reveal new hyper or hypo-echoic lesions or bleeding evidence from computed tomography (CT) imaging. In addition, severe bleeding was defined as cases where a transfusion and/or hemostasis by endoscopic procedure, radiological intervention, or surgery was required. Bleeding events relating to the procedure (classified as intraoperative bleeding) were defined as events occurring during the procedure and up to 1 hour after the procedure. Postoperative bleeding was defined as bleeding detected within 14 days post-procedure and delayed bleeding after 14 days\n14\n. Adverse events (AEs) were graded as follow: Grade 1 mild (needs medication); Grade 2 moderate (needs ventilation, intervention, or surgery and prolonged hospital stay of 4 – 10 days); Grade 3, severe (prolonged hospital stay of > 10 days, intensive care unit stay of > 1 day, needs surgery, or causes disability); and Grade 4 fatal\n14\n.\n\n\nStatistical analysis\n\nCategorical variables were analyzed using Fisher’s exact test or the Chi-square Χ\n2\ntest. The independent sample\nt\n-test was used to compare continuous variables. Odds ratios (ORs) and 95 % confidence intervals (95 % CI) were calculated to evaluate predictors of complications. Two-tailed\nP\nvalues less than 0.05 were considered statistically significant. All calculations were performed using SPSS version 20 (IBM Corporation, Armonk, New York, United States).\n\n\nResults\n\nOf the 908 patients undergoing EUS-FNA, 114 (12.6 %) were receiving antithrombotic therapy while 794 (84.6 %) were not, and management of antithrombotic agents during the EUS procedure is shown in\nFig. 1\n. Baseline demographic data are shown in\nTable 1\n. Median age of patients in the antithrombotic group was 72 years (range, 64 – 80 years) and most were male (76 males, 38 females). The non-antithrombotic group had a mean age of 63 years (range, 52 – 74 years) with 439 males and 355 females.\n\n\nTable 1 Baseline characteristics of patients.\nPatients data\t\nATD group (n = 114)\nMean ± SD\n\t\nNon ATD group (n = 794)\nMean ± SD\n\t\nP\nvalue\n2\n\t\nAge\t72 (64 – 80)\t 63 (52 – 74)\t\n < 0.001\n1\n\t\nMale/Female\t76/38\t439/355\t\n0.022\n1\n\t\n\nBMI (kg/m\n2\n)\n\t21.62 ± 2.84\t 21.82 ± 3.48\t0.557\t\n\nUnderlying disease\n1\n\t\t\t\n < 0.001\n1\n\t\nDM\t38\t347\t\t\nHT\t 8\t 81\t\t\nDM, HT\t28\t 98\t\t\nESRD without hemodialysis\t 4\t 8\t\t\nDecompensated Cirrhosis\t 1\t 9\t\t\nCAD\t21\t 1\t\t\nCVA\t 4\t–\t\t\nAF\t 4\t–\t\t\nDVT\t 3\t–\t\t\nPVD\t 2\t–\t\t\nPE\t 1\t–\t\t\n\nPlatelet count (× 10\n4\n/ul)\n\t21.87 ± 7.05\t 23.79 ± 12.34\t0.105\t\nINR\t 1.15 ± 0.15\t 1.05 ± 0.09\t\n0.007\n1\n\t\nHemoglobin before FNA (g/dl)\t12.53 ± 1.79\t 13.14 ± 1.72\t\n0.001\n1\n\t\nHemoglobin after FNA (g/dl)\t11.90 ± 1.66\t 12.47 ± 1.68\t\n0.001\n1\n\t\nLength of hospital stay\t 5.52 ± 7.76\t 4.30 ± 6.98\t0.088\t\nDM, diabetes mellitus; HT, hypertension; CAD, coronary arterial disease; ESRD, End-stage renal disease; CVA, cerebrovascular disease; PE, pulmonary embolism; PVD, peripheral vascular disease; DVT, deep vein thrombosis; Hb, hemoglobin; ATD, antithrombotic drugs; SD, standard deviation; FNA, fine needle aspiration\n\n1 Important underlying disease-related antithrombotic treatment. Some patients had multiple underlying diseases\n\n2 \nStatistically significant (\nP\n < 0.05)\n\n\n\nOf the 114 patients taking antithrombotics, 42 were on ASA, 10 on clopidogrel, 2 on ticlopidine, 10 on warfarin, 40 on other antiplatelets (10 ASA + thienopyridines, 10 prostaglandin, 7 ASA with thienopyridines + eicosapentane, 6 eicosapentane, 3 ASA or thienopyridines + prostaglandin, 2 cilostazol, 2 saprogrelate), 8 on DOACs, and 2 on both antiplatelets and anticoagulants. Patients were divided into 3 groups based on pharmaceutical management: 1) continuation (n = 63); 2) discontinuation (n = 41); 3) heparin replacement (n = 10) ( \nFig. 1\n). Age, male sex, comorbidity, hemoglobin before and after the procedure, and INR were significantly different in the two groups (\nP\n < 0.05); however, body mass index, platelet count, and length of hospital stay were not (\nTable 1\n).\n\n\n\nLesion and procedure characteristics were not significantly different in the two groups. The most common lesion puncture site was the pancreas (n = 513,56.5 %), which included 381 pancreatic cancers (42 %). The other 132 pancreatic lesions (14.5 %) comprised 53 pancreatic neuroendocrine tumors (PNETs), 30 cases of chronic pancreatitis and benign masses, 18 of autoimmune pancreatitis, 21 macrocystis lesions (intraductal papillary mucinous neoplasms, and solid pseudopapillary tumors), and 10 microcystic lesions (PNETs, serous cystic neoplasms). Non-pancreatic lesions included 164 lymph node lesions, 88 hepatobiliary tract lesions, and 143 lesions of the non-gastrointestinal tract. Maximal diameter, puncture route, number of EUS passes, suction technique, cystic nature, presence of ascites, and lesion vascularity were not statistically significant between the two groups (\nTable 2\n).\n\n\nTable 2 Baseline characteristic of procedure and final diagnosis.\n\t\nATD group\nn = 114 (%)\n\t\nNon ATD group\nn = 794 (%)\n\t\nTotal\nn = 908\n\t\nP\nvalue\n\t\nDiagnosis\t114\t794\t908\t0.280\t\nPancreatic lesions\t 73 (64.0)\t440 (55.4)\t513 (56.5)\t\t\nPancreatic CA\t 57 (50)\t324 (40.8)\t381 (42)\t\t\nOther pancreatic disease\t 16 (14.0)\t116 (14.6)\t132 (14.5)\t\t\nAIP\n\n\t 5\t 13\t 18\t\t\nChronic pancreatitis/benign mass\n\n\t 3\t 27\t 30\t\t\nPNETs\n\n\t 3\t 50\t 53\t\t\nIPMC/SPN\n\n\t 5\t 16\t 21\t\t\nMicro-cystic lesion (SCA, PNETs)\n\n\t–\t 10\t 10\t\t\nHepatobiliary tract disease\t 11 (9.6)\t 77 (9.7)\t 88 (9.7)\t\t\nLiver metastasis\t 4\t 25\t 29\t\t\nCCC\t 2\t 27\t 29\t\t\nHCC\t 1\t 3\t 4\t\t\nGB mass/cancer\t 2\t 6\t 7\t\t\nOther benign liver mass/cystic lesion\t 2\t 16\t 19\t\t\nGastroinestinal/Non-gastroinestinal mass or cancer\t 10 (8.8)\t133 (16.8)\t143 (15.7)\t\t\nGastrointestinal SMT/GIST\t 2\t 54\t 56\t\t\nGastroinestinal mass/cancer\t 1\t 11\t 12\t\t\nIntra-abdominal mass/cancer\t 5\t 40\t 45\t\t\nIntra-abdominal GIST/NET\t 2\t 11\t 13\t\t\nSpleen/adrenal gland/lung mass\t–\t 17\t 17\t\t\nLN\t 20 (17.5)\t144 (18.5)\t164 (18.1)\t\t\nLN metastasis\t 10\t 74\t 84\t\t\nOther LN disease\t 7\t 47\t 54\t\t\nLymphoma\t 3\t 23\t 26\t\t\nPancreas site\t 72 (63.2)\t444 (55.9)\t516 (56.8)\t0.145\t\nHead and neck\t 26\t167\t193\t\t\nBody\t 33\t168\t201\t\t\nTail\t 10\t 86\t 96\t\t\nMultiple sites\t 3\t 23\t 26\t\t\nNon pancreas site\t 42 (36.8)\t350 (44.1)\t392 (43.1)\t\t\nMaximal diameter (Mean ± SD) (mm)\t 28.52 ± 17.43\t 28.12 ± 22.92\t\t0.860\t\n ≤ 20 mm\t 45 (39.5)\t316 (39.8)\t361\t\t\n > 20 mm\t 69 (60.5)\t478 (60.2)\t547\t\t\nPuncture route\t\t\t\t0.147\t\nStomach\t 64 (7)\t504 (55.5)\t568 (62.6)\t\t\nDuodenum\t 36 (4)\t185 (20.4)\t221 (24.3)\t\t\nEsophagus\t 7 (0.8)\t 64 (7.0)\t 71 (7.8)\t\t\nOther\t 7 (0.8)\t 41 (4.5)\t 48 (5.3)\t\t\nCystic lesion\t 15 (13.2)\t 81 (10.2)\t 96 (10.5)\t0.337\t\nMicro-cyst\t 0\t 11\t 11\t\t\nMacro-cyst\t 10\t 54\t 64\t\t\nCystic- necrosis/degeneration/retention\t 5\t 16\t 21\t\t\nNo cystic lesion\t 99 (86.8)\t713 (89.8)\t812 (89.4)\t\t\nAscites\t\t\t\t\t\nNo\t106 (11.7)\t770 (84.8)\t876\t0.082\t\nSmall\t 6 (5.3)\t 16 (2)\t 22\t\t\nModerate\t 2 (1)\t 8 (1)\t 10\t\t\nNeedle size\t\t\t\t\t\n19G\t 8\t 58\t 66 (7.2)\t0.554\t\n20G\t 2\t 19\t 21 (2.4)\t\t\n22G\t 93\t668\t761 (83.8)\t\t\n25G\t 11\t 49\t 60 (6.6)\t\t\nNumber of needle passes (Mean ± SD)\t 2.90 ± 1.30\t 2.77 ± 1.24\t\t0.453\t\n ≤ 2\t 51 (44.7)\t385 (48.5)\t436\t\t\n > 2\t 63 (55.3)\t409 (51.5)\t472\t\t\n\nSuction\nYes\n\t107 (11.8)\t712 (78.4)\t819\t0.180\t\nNo\t 7 (0.8)\t 82 (9.0)\t 89\t\t\nHypervascular lesion\t\t\t\t\t\nYes\t 6 (0.7)\t 83 (11.9)\t 89\t0.092\t\nNo\t108 (9.1)\t711 (78.3)\t819\t\t\nATD, antithrombotic drug; AIP, autoimmune pancreatitis; PNETs, pancreatic neuroendocrine tumors; IPMC, Intraductal papillary mucinous carcinoma; SPN, solid pseudopapillary neoplasm; SCA, serous cystadenoma; CCC, cholangiocarcinoma; HCC, hepatocellular carcinoma; GB, gallbladder; GI, gastrointestinal ; GIST, gastrointestinal stromal tumor; NET, neuroendocrine tumor; LN, lymph node\n\n\nSignificant bleeding occurred in six patients (0.7 %); four in the antithrombotic group (0.4 %) and two in the non-antithrombotic group (0.2 %) (univariate OR, 9.59; 95 % CI, 2.12 – 43.1;\nP\n = 0.006; multivariate OR, 14.4; 95 % CI, 2.6 – 79.54;\nP\n = 0.002) (\nTable 4\n). All cases of bleeding cases occurred postoperation and all were confirmed by hemoglobin drops and ultrasound or CT. None of these patients required blood transfusion and were treated conservatively until clinical improvement and bleeding stoppage. The four cases of bleeding (3.4 %,4/114) in the antithrombotic group (1 on ASA, 1 on ASA/clopidogrel, 1 on another oral antiplatelet, and 1 on warfarin) occurred in the continuation (3.2 %,2/63), discontinuation(2.4 %,1/41) and heparin subgroups (10 %, 1/10)(\nTable 3\n).\n\n\nTable 3 Significant bleeding events according to antithrombotic management.\nATD management\tBleeding case\tTotal\t% Bleed/group\t\nP\nvalue\n\t\nYes\tNo\t\nAntithrombotic group\t4\t110\t114\t(3.4 %,4/114)\t0.601\t\n1. Continue\t2\t 61\t 63\t(3.2 %,2/63)\t\t\nASA,cilostazol,other antiplatelet\n\n\t2\t 61\t 63\t\t\t\n2. Discontinue\t1\t 40\t 41\t(2.43 %,1/41)\t\t\n\nSwitched to ASA\n1\n\n\n\t0\t 14\t 14\t\t\t\n\nContinued ASA\n1\n\n\n\t1\t 10\t 11\t\t\t\nOther\n\n\t0\t 16\t 16\t\t\t\n3. Heparin replacement\t1\t 9\t 10\t(10 %,1/10)\t\t\nNon-Antithrombotic group\t2\t792\t794\t(0.2 %,2/794)\t\t\nTotal\t6\t902\t908\t(0.7 %,6/908)\t\t\nASA, aspirin;\n\n1 withdrew thienopyridine\n\nTable 4 Bleeding events and other adverse events.\nComplication of EUS-FNA\t\nATD\nn = 114 (%)\n\t\nNon-ATD\nn = 794 (%)\n\t\nTotal\nn = 908\n\t\nSeverity\n(ASGE)\n\tUnivariate analysis\tMultivariate analysis\t\nOR(95 %CI)\t\nP\nvalue\n2\n\tOR(95 %CI)\t\nP\nvalue\n2\n\t\n\nSignificant bleeding\n(Hb drop > 2 g/dL)\n\t4 (0.4)\t2 (0.2)\t6 (0.7)\t\nMild = 5\nMod = 1\n\t\n9.59\n(2.12 – 43.1)\n\t\n0.006\n1\n\t\n14.4\n(2.6 – 79.54)\n\t\n0.002\n1\n\t\n\nNon-significant bleeding\n(Hb drop ≤ 2 g/dL)\n\t–\t5 (0.6)\t5 (0.6)\tMild = 5\t\n1.14\n(1.11 – 1.17)\n\t1.000\t–\t0.997\t\nTotal bleeding\t4 (0.4)\t7 (0.8)\t11 (1.2)\t\nMild = 10\nMod = 2\n\t\n4.08\n(1.17 – 14.19)\n\t\n0.039\n1\n\t\n0.24\n(0.07 – 0.85)\n\t\n0.027\n1\n\t\nCerebral infarction\t1 (0.9)\t–\t1 (0.1)\t\nSevere\n1\n\t–\t0.126\t–\t–\t\nHypotension\t1 (0.9)\t–\t1 (0.1)\tMild\t–\t0.126\t–\t–\t\nFever\t2 (0.2)\t9 (1)\t11 (1.2)\tMild\t\n1.56\n(0.33 – 7.30)\n\t0.638\t–\t0.571\t\nAcute pancreatitis\t–\t1 (0.1)\t1 (0.1)\tMod\t–\t0.100\t–\t–\t\nATD, antithrombotic drugs; EUS-FNA endoscopic-guided fine-needle aspiration; Hb, hemoglobin; ASGE, American Society of Gastrointestinal Endoscopy; OR, odds ratio; CI, confidence interval; Mod, moderate\n\n1 Severe (disability and prolonged)\n\n2 \nStatistically significant (\nP\n < 0.05)\n\n\n\nThere were five cases of non-significant bleeding (Hb drop ≤ 2 g/dL) in the non-antithrombotic group. Most were intraoperative bleeds confirmed by Doppler ultrasound, Three cases had enhanced echogenicity of the peritumoral lesions, one had a submucosal hematoma, elevated gastric mucosa at the puncture site, and a hypoechoic lesion in the gastric mucosal layer, and one was bleeding from the puncture site accompanied by a spontaneous self-limiting bleed. There was no need for endoscopic or surgical intervention. The total number of bleeding events was 11, four in the antithrombotic group, and seven in the non-antithrombotic group. The difference in bleeding rates between the antithrombotic and non-antithrombotic groups was significantly different on univariate (\nP\n = 0.039) and multivariate analysis (\nP\n = 0.027\n)\n(\nTable 4\n).\n\n\nOther adverse events recorded included one cerebral infarction, one case of acute pancreatitis, 11 postoperative fever (infection unknown source), and one case of hypotension. The patient who developed the acute cerebral infarction in the antithrombotic group (0.9 %) was on thienopyridine due to concurrent diabetes mellitus, hypertension, and cerebral vascular disease and switched to ASA before EUS-FNA for pancreatic cancer. This patients restarted thienopyridine 1 day after the procedure. Four days after the procedure, the patient developed left hemiparesis and brain magnetic resonance imaging showed acute right middle cerebral infarction. The patient received palliative care for 2 weeks before returning to their original hospital. The patient with hypotension was in the anticoagulant group and was normotensive during the procedure. However, within 24 hours, the blood pressure had dropped to 80/50 mm Hg and pulse rate to 70 to 88/min without an apparent cardiac cause or blood loss. The patient’s symptoms resolved after appropriate hydration. The patient with acute pancreatitis developed typical abdominal pain with an amylase level three times the upper normal limit and CT showed diffuse pancreatic swelling, leading to a prolonged hospital stay of 4 to 10 days.\n\n\nIn addition, postoperative fever developed in 11 patients, two in the antithrombotic and nine in the non-antithrombotic group (\nP\n = 0.571). The patients with significant bleeding had diagnoses of pancreatic duct carcinoma (3 cases), PNET (2 cases), and lymphoma (1 case).\n\n\n\nFactors associated with bleeding were analyzed (\nTable 5\n). Only antithrombotic use (\nP\n = 0.003) and INR (\nP\n = 0.007) were significantly higher in patients who experienced bleeding. No bleeding events occurred in patients who were punctured with 20G and 25G needles. Length of hospital stays was significantly longer in the significant bleeding group (13.1 days) than the non-bleeding group (4.4 days;\nP\n = 0.003). Subgroup analysis of all bleeding cases is shown in\nTable 6\n.\n\n\nTable 5 Analysis of factors associated with bleeding.\nFactors\t\nBleed (%)\nn = 6\n\t\nNo bleed (%)\nn = 902\n\t\nP\nvalue\n2\n\tOR(95 %CI)\t\nAge, mean ± SD\t65.71 ± 7.41\t64.63 ± 11.43\t0.909\t\t\n ≥ 60 Y\t6 (0.7)\t642 (70.7)\t0.680\t\n2.42\n(0.29 – 20 – 20)\n\t\n < 60 Y\t1 (0.1)\t259 (28.5)\t\t\t\n\nSex\nMale\n\t2 (0.2)\t513 (56.5)\t0.412\t0.38 (0.06 – 2.08)\t\nFemale\t4 (0.4)\t389 (42.8)\t\t\t\nATD group\t4 (0.4)\t110 (12.1)\t\n0.003\n1\n\t\n14.4\n(2.60 – 79.54)\n\t\nNon-ATD\t2 (0.2)\t792 (87.2)\t\t\t\nHb (g/dl)\t13.26 ± 1.86\t13.06 ± 1.74\t0.779\t\t\nWBC (/mm3)\t7710 ± 2383\t6873 ± 2683\t0.446\t\t\n\nPlatelets (× 10\n4\n/mm\n3\n)\n\t23.15 ± 6.79\t23.55 ± 11.85\t0.934\t\t\nINR\t1.15 ± 0.152\t1.05 ± 0.091\t\n0.007\n1\n\t\t\nOrgan of puncture\t\t\t\t\t\nPancreas\t5 (0.6)\t511 (56.3)\t0.705\t1.90 (0.37 – 9.89)\t\nNon pancreas\t2 (0.2)\t390 (43.0)\t\t\t\nRoute of puncture\t\t\t\t\t\nStomach\t5 (0.6)\t563 (62)\t0.419\t\n3.01\n(0.35 – 25.87)\n\t\nOther\t1 (0.1)\t339 (37.3)\t\t\t\nMaximal diameter, mean ± SD (mm)\t\t\t\t\t\n ≤ 20 mm\t2 (0.2)\t359 (39.5)\t1.000\t0.75 (0.14 – 4.15)\t\n > 20 mm\t4 (0.4)\t542 (59.8)\t\t\t\nCystic lesion\t\t\t\t\t\nYes\t2 (0.2)\t86 (9.5)\t0.108\t\n0.108\n(0.03 – 1.16)\n\t\nNo\t4 (0.4)\t816 (89.9)\t\t\t\nAscites\t\t\t\t\t\nNo\t6 (0.7)\t870 (95.8)\t1.000\t1.02 – 1.05\t\nMild\t0\t22 (2.4)\t\t\t\nModerate\t0\t10 (1.1)\t\t\t\nNumber of passes\t\t\t\t\t\n ≤ 2\t3 (0.3)\t433 (47.7)\t1.000\t\n1.08\n(0.217 – 3.395)\n\t\n > 2\t3 (0.3)\t469 (51.7)\t\t\t\nNeedle size\t\t\t\t\t\n22G\t5 (0.6)\t756 (83.3)\t1.000\t0.96 (0.11 – 8.32)\t\n19G\t1 (0.1)\t65 (7.2)\t\t\t\n20G\t0\t21 (2.3)\t\t\t\n25G\t0\t60 (6.6)\t\t\t\nNo. lesion punctures, mean ± SD\t1.15 ± 0.83\t1.19 ± 0.51\t0.956\t\t\n < 2\t4 (0.4)\t769 (84.7)\t0.220\t0.34 (0.63 – 1.90)\t\n ≥ 2\t2 (0.2)\t133 (14.6)\t\t\t\nSuction technique\t\t\t\t\t\nYes\t4 (0.4)\t827 (91.1)\t0.085\t\n0.085\n(0.033 – 1.007)\n\t\nNo\t2 (0.2)\t75 (8.3)\t\t\t\n\nHyper-vascular tumor\n1\n\t\t\t\t\t\nYes\t2 (0.2)\t815 (89.6)\t0.110\t\n4.68\n(0.85 – 25.94)\n\t\nNo\t4 (0.6)\t87 (9.6)\t\t\t\nLength of hospital stay\t13.17 ± 22.49\t4.40 ± 6.88\t\n0.003\n1\n\t3.08 – 14.45\t\nOR, odds ratio; CI, confidence interval; SD, standard deviation; ATD, antithrombotic drug; HB, hemoglobin; WBC, white blood cells; INR, international normalized ratio\n\n1 Hypervascular tumor included hepatocellular carcinoma, neuroendocrine tumors, gastrointestinal stromal tumors and carcinoid tumor\n\n2 \nStatistically significant (\nP\n < 0.05)\n\n\nTable 6 Subgroup analysis of bleeding patients.\nBleeding\tSex\tAge (y)\tU/D\tManagement ATD\tBleeding\tLOS (day)\tBlood Tx\tSeverity\tDiagnosis\t\nOrgan\npuncture\n\tDiameter (mm)\tCyst\tAscites\tRoute\tNeedle\tNo. FNA\tNo. lesion\tSuction\tHypervascular tumor\t\nSignificant bleeding\tF\t72\tDM\t–\tPost op\t 4\tNo\tMild\tPDAC\tPancreas\t 10\tY\tN\tStomach\t22G\t2\t1\tY\tN\t\nF\t60\tDM,HT, DVT\tHeparin\tPostop\t 6\tNo\tModerate\tPNETs\tPancreas\t 50\tN\tN\tStomach\t19G\t4\t1\tN\tY\t\nF\t56\tDM\t–\tPost op\t 3\tNo\tMild\tPDAC\tPancreas\t 19.3\tY\tN\tDuodenum\t22G\t1\t1\tY\tN\t\nM\t75\tDM,HT\tcontinue\tPost op\t 2\tNo\tMild\tLymphoma\tLN\t 55\tN\tN\tStomach\t22G\t4\t3\tY\tN\t\nF\t67\tDM\tcontinue\tPost op\t 5\tNo\tModerate\tPNETs\tPancreas\t 30\tN\tN\tStomach\t22G\t5\t2\tN\tY\t\nM\t61\tDM,HT, CVA\tcontinue\tPost op\t 3\tNo\tMild\tPDAC\tPancreas\t 29\tN\tN\tStomach\t22G\t2\t1\tY\tN\t\nNon-significant bleeding\tF\t64\tNo\t–\tIntraop\t 3\tNo\tMild\tSCN\tPancreas\t 30\tY\tN\tStomach\t22G\t3\t1\tY\tY\t\nM\t45\tNo\t–\tIntraop (Submucosal hematoma)\t 3\tNo\tMild\tOther lesion (sarcoid)\tBile duct\t 30.4\tN\tN\tStomach\t20G\t3\t1\tY\tN\t\nM\t60\tNo\t–\tPost op\t 2\tNo\tMild\tRCC LN metastasis\tLN\t 13.5\tN\tN\tEsophagus\t22G\t5\t1\tY\tN\t\nM\t59\tHT\t–\tIntra op\t 2\tNo\tMild\tPancreatic Benign\tPancreas\t 13.6\tN\tN\tStomach\t22G\t1\t1\tY\tN\t\nF\t67\tDM,HT\t–\tIntra op (Intraluminal bleeding)\t11\tNo\tMild\tIntra-abdominal carcinoma\tIntra-abdominal soft tissue\t106.5\tN\tY\tStomach Duodenum\t22G\t1\t1\tY\tN\t\nLOS, length of hospital stay; M, male; F, female; N, no; Y, yes; DM, Diabetes mellitus; HT, hypertension; DVT, deep vein thrombosis; CAD, coronary arterial disease; PDAC, pancreatic duct adenocarcinoma; PNETs, pancreatic neuroendocrine tumor; SCN, serous cystic neoplasm; RCC, renal cell carcinoma; LN, lymph node; Post op, postoperative bleeding; Intraop, Intraoperative bleeding; Blood Tx, blood transfusion.\n\nDiscussion\n\nA previous large systematic review of 22 studies had suggested that risk of bleeding associated with gastrointestinal procedures in patients receiving antiplatelet therapy was not significantly higher than in patients with interrupted antiplatelet therapy or in those with no bleeding at all. Only five studies showed a higher risk of bleeding during continuous antiplatelet therapy and there was only one prospective study of 241 EUS-FNA and/or TCB procedures that found bleeding in 0/26 of the ASA/NSAIDs group, 2/6 of the LMWH group, and 7/190 in the control group with no statistically significant difference (\nP\n = 0.023). In addition, the mean number of FNA passes, applications of suction, blood specimens, and cellular yield were not significantly different. EUS-FNA or TCB is safe in patients taking ASA or NSAIDs\n16\n.\n\n\n\nIn addition, bleeding risk was found to be increased according to specific types of antithrombotic drugs, such as warfarin and heparin. A recent meta-analysis showed that periprocedural bridging therapy with heparin increased overall risk of major bleeding without a significant decrease in risk of thromboembolic events\n16\n17\n.\n\n\n\nA previous study from Japan on EUS-FNA for solid lesions in patients on antithrombotic therapy found that the overall bleeding event rate was 0.9 % and that all bleeding events were intraoperative. Subgroup analysis according to antithrombotic agent revealed bleeding event rates of 1.0 % (6/611), 0 % (0/62), 1.6 % (1/61), and 0 % (0/8) in non-administration, discontinuation, continuation of ASA or cilostazol, and heparin replacement groups, respectively\n6\n. The antithrombotic therapy group had only one case of intraoperative bleeding in the continuous group, and bleeding risk was not related to the type or size of the lesion, needle size, needle pass route, the number of passes, or the type of antithrombotic therapy.\n\n\n\nIn this study the overall significant bleeding rate was 0.7 %, 0.4 % in the antithrombotic group and 0.2 % in the non-antithrombotic group. According to subgroup classification using the updated JGES guidelines, significant bleeding in the antithrombotic group occurred in two cases, one case and one case of the continuation, discontinuation, and heparin replacement groups, respectively and two cases in the non-antithrombotic group. All bleeding in the antithrombotic group occurred postoperatively (within 1 – 14 days).Bleeding risk from antithrombotics was significantly higher (\nP\n = 0.003). Our results differ from the outcomes of a previous study\n6\nin that postoperative significant bleeding occurred in four cases in the antithrombotic group and two cases in the non-antithhrombotic group. One prospective study of EUS-FNA or Trucut biopsy in EUS-FNA reported one case of immediate bleeding and one case of late bleeding from six cases (33.3 %) in a heparin/LMWH group but no bleeding in continued ASA or NSAID group\n5\n. Another retrospective study of endoscopic submucosal dissection reported a delayed bleeding rate in patients taking antithrombotic drugs of 11.6 %(\nP\n = 0.013)\n18\n. Continuation of antithrombotics in EUS-FNA may present a risk of operative or delayed bleeding and care should be taken after the procedure.\n\n\nThe non-significant bleeding rate was 0.6 % and the total bleeding event rate was 1.2 %, all of which were found in the non-antithrombotic group. There were no incidences of severe bleeding in our study. Both significant and total bleeding events were more common in the antithrombotic group. We found that patients in the antithrombotic group in this study were older, more commonly male, and had higher rates of comorbidity and lower hemoglobin levels at baseline than those in the non-antithrombotic group. In addition, one patient who was on ASA and discontinuation of thienopyridine developed cerebral infarction. This patient had a high thromboembolism risk and restarted thienopyridine 1 day after the procedure.\n\nThere are concerns about postprocedural follow-up and length of hospital stay in patients who experience bleeding after medication adjustment, especially when switching from warfarin to heparin, and the need for close observation in these cases. However, after 1 month of follow-up, we recorded no instances of late death and only one case of major morbidity (the aforementioned cerebral infarction. Factors such as maximal diameter of the lesion, puncture route, number of EUS passes, suction technique, cystic nature, presence of ascites, and lesion vascularity were not associated with bleeding risk.\n\nThe major limitation of this study was the low number of patients in the antithrombotic group, especially the anticoagulant subgroup. In the future, larger prospective studies of patients with high-risk factors such as antithrombotic therapy, especially those taking thienopyridines or anticoagulants and those with hypervascular masses, are needed.\n\nConclusion\nThe bleeding risk in the antithrombotic group was higher than in the non-antithrombotic group. However, no severe bleeding was found in patients who continued or discontinued antithrombotic therapy and only one thromboembolic event occurred. Relative risks of bleeding and thrombosis should be carefully assessed during the preprocedural decision-making process.\n\nAcknowledgements\nThe authors would like to thank the staff residents and statisticians of the Department of Gastroenterology of Aichi Cancer Center Hospital and Bhumibol Adulyadej Hospital for their assistance in performing this study.\n\nCompeting interests None\n==== Refs\nReference\n1 Hamada T Yasunaga H Nakai Y Severe bleeding and perforation are rare complications of endoscopic ultrasound-guided fine needle aspiration for pancreatic masses: an analysis of 3,090 patients from 212 hospitals Gut Liver 2014 8 215 218 24672664 \n2 Wang K X Ben Q W Jin Z D Assessment of morbidity and mortality associated with EUS-guided FNA: a systematic review Gastrointest Endosc 2011 73 283 290 21295642 \n3 Varadarajulu S Eloubeidi M A Frequency and significance of acute intracystic hemorrhage during EUS-FNA of cystic lesions of the pancreas Gastrointest Endosc 2004 60 631 635 15472697 \n4 Oprea A D Noto C J Halaszynski T M Risk stratification, perioperative and periprocedural management of the patient receiving anticoagulant therapy J Clin Anesth 2016 34 586 599 27687455 \n5 Kien-Fong Vu C Chang F Doig L A prospective control study of the safety and cellular yield of EUS-guided FNA or Trucut biopsy in patients taking aspirin, nonsteroidal anti-inflammatory drugs, or prophylactic low molecular weight heparin Gastrointest Endosc 2006 63 808 813 16650543 \n6 Inoue T Okumura F Sano H Bleeding risk of endoscopic ultrasound-guided fine-needle aspiration in patients undergoing antithrombotic therapy Dig Endosc 2016 10.1111/den.12687 \n7 Burger W Chemnitius J M Kneissl G D Low-dose aspirin for secondary cardiovascular prevention - cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation - review and meta-analysis J Intern Med 2005 257 399 414 15836656 \n8 Boustière C Veitch A Vanbiervliet G Endoscopy and antiplatelet agents. European Society of Gastrointestinal Endoscopy (ESGE) Guideline Endoscopy 2011 43 445 461 21547880 \n9 Committee ASoP Anderson M A Ben-Menachem T Management of antithrombotic agents for endoscopic procedures Gastrointest Endosc 2009 70 1060 1070 19889407 \n10 Veitch A M Baglin T P Gershlick A H Guidelines for the management of anticoagulant and antiplatelet therapy in patients undergoing endoscopic procedures Gut 2008 57 1322 18469092 \n11 Fujimoto K Fujishiro M Katou M Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment Gastroenterol Endosc 2012 54 2075 2102 (in Japanese)\n12 Fujimoto K Fujishiro M Kato M Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment Dig Endosc 2014 26 1 14 \n13 Matsumura T Arai M Maruoka D Risk factors for early and delayed post-operative bleeding after endoscopic submucosal dissection of gastric neoplasms, including patients with continued use of antithrombotic agents BMC Gastroenterology 2014 14 172 25280756 \n14 Cotton P B Eisen G M Aabakken L A lexicon for endoscopic adverse events: report of an ASGE workshop Gastrointest Endosc 2010 71 446 454 20189503 \n15 Affi A Vazquez-Sequeiros E Norton I D Acute extraluminal hemorrhage associated with EUS-guided fine needle aspiration: Frequency and clinical significance Gastrointestinal Endoscopy 2001 53 221 225 11174300 \n16 Baron T H Kamath P S McBane R D Management of antithrombotic therapy in patients undergoing invasive procedures N Engl J Med 2013 368 2113 2124 23718166 \n17 Kowalewski M Suwalski P Raffa G M Meta-analysis of uninterrupted as compared to interrupted oral anticoagulation with or without bridging in patients undergoing coronary angiography with or without percutaneous coronary intervention Int J Cardiol 2016 223 186 194 27541652 \n18 Koh R Hirasawa K Yahara S Antithrombotic drugs are risk factors for delayed postoperative bleeding after endoscopic submucosal dissection for gastric neoplasms Gastrointest Endosc 2013 78 476 483 23622974\n\n",
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"title": "Outcomes of EUS-FNA in patients receiving antithrombotic therapy.",
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"abstract": "We report a case of acquired factor V inhibitors (AFVIs) in a patient with end-stage renal disease receiving warfarin therapy for atrial fibrillation. A 72-year-old Japanese man was admitted to our hospital complaining of tarry stools and abdominal pain. The laboratory findings revealed eosinophilia (52.1%), prolonged activated partial thromboplastin time (APTT) (98 s), PT (84 s), a factor V (FV) activity of <3%, and an FV inhibitor level of 6 Bethesda units/mL. After administration of prednisolone was started, his coagulation findings improved. However, his renal failure progressed, and he ultimately required chronic hemodialysis. This is the first case of AFVIs in a patient starting hemodialysis for end-stage renal disease.",
"affiliations": "Nephrology, Dokkyo Medical University Koshigaya Hospital, Japan.",
"authors": "Kitazawa|Atsushi|A|;Misawa|Hideo|H|;Nagahori|Katsuhiro|K|;Koda|Ryo|R|;Yoshino|Atsunori|A|;Kawamoto|Shinya|S|;Takeda|Tetsuro|T|",
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"fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.55.7369Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 27904118Case ReportAcquired Factor V Inhibitors in a Patient with End-stage Renal Disease Kitazawa Atsushi 1Misawa Hideo 1Nagahori Katsuhiro 1Koda Ryo 1Yoshino Atsunori 1Kawamoto Shinya 1Takeda Tetsuro 11 Nephrology, Dokkyo Medical University Koshigaya Hospital, JapanCorrespondence to Dr. Atsushi Kitazawa, atsukitaaq@gmail.com\n\n1 12 2016 55 23 3505 3509 7 3 2016 20 4 2016 The Internal Medicine is an Open Access article 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/).We report a case of acquired factor V inhibitors (AFVIs) in a patient with end-stage renal disease receiving warfarin therapy for atrial fibrillation. A 72-year-old Japanese man was admitted to our hospital complaining of tarry stools and abdominal pain. The laboratory findings revealed eosinophilia (52.1%), prolonged activated partial thromboplastin time (APTT) (98 s), PT (84 s), a factor V (FV) activity of <3%, and an FV inhibitor level of 6 Bethesda units/mL. After administration of prednisolone was started, his coagulation findings improved. However, his renal failure progressed, and he ultimately required chronic hemodialysis. This is the first case of AFVIs in a patient starting hemodialysis for end-stage renal disease. \n\nfactor V inhibitoreosinophiliawarfarin\n==== Body\nIntroduction\nAcquired coagulation factor deficiency is a rare autoimmune disease in which inhibitory autoantibodies to coagulation factors are produced. These antibodies reduce the activity of coagulation factors, leading to a bleeding tendency. Most autoantibodies are to factor VIII (F8), referred to as acquired hemophilia A, and occur at a frequency of 1:100 million people. In Japan, the incidence of acquired factor V inhibitors (AFVIs) has been reported as 1:50 relative to acquired hemophilia A (1).\n\nCase Report\nA 72-year-old man with end-stage renal disease (resulting from nephrosclerosis) was admitted to our hospital with fatigue, abdominal pain, and tarry stools in the middle of September. His medical history included chronic atrial fibrillation (AF), congestive heart failure with massive aortic regurgitation (AR), and peptic ulcer disease. He was taking the following chronic medications: warfarin, carvedilol, amlodipine, olmesartan, febuxostat, furosemide, and lansoprazole.\n\nA physical examination at the time of admission revealed pale-colored conjunctivae and epigastric tenderness. The laboratory findings on admission are summarized in Table 1. In brief, the eosinophil count was markedly increased (52.1%), and the hemoglobin level was reduced (9.7 g/dL). The prothrombin time-international normalized ratio (PT-INR) was increased to 7.27, but the D-dimer value (0.45 μg/mL) was within the normal range. A chest X-ray showed cardiomegaly, with a cardiothoracic ratio of 66% (Fig. 1). A computed tomography (CT) scan of his abdomen showed bilateral renal atrophy and a mass, 38 mm in diameter, in the right kidney (Fig. 2).\n\nTable 1. Laboratory Findings on Admission.\n\nPeripheral blood\t\t\tBlood chemistry\t\t\tImmuno-serological findings\t\t\t\nWBC\t 5,600 \t/μL\tTP \t 7.9 \tg/dL\tIgG\t 3,049 \tmg/dL\t\n(neutro)\t 33.3 \t%\tAlb\t 3.49 \tg/dL\tIgA\t 409 \tmg/dL\t\n(lym)\t 8.3 \t%\tT-bil\t 0.53 \tmg/dL\tIgM\t 83 \tmg/dL\t\n(mono)\t 4.7 \t%\tAST\t 13 \tIU/L\tIgE\t 2,840 \tIU/mL\t\n(eosino)\t 52.1 \t%\tALT\t 12 \tIU/L\tIgG4\t 142 \tmg/dL\t\nRBC\t 323 ×104\t/μL\tLDH\t 260 \tIU/L\tCH50\t 33.3 \tIU/mL\t\nHb\t 9.7 \tg/dL\tALP\t 215 \tIU/L\tC3\t 63 \tmg/dL\t\nHt\t 30.1 \t%\tγ-GTP\t 25 \tIU/L\tC4\t 13.4 \tmg/dL\t\nPlt\t 10.8 ×104\t/μL\tCh-E\t 163 \tIU/L\tANA \t ×40\t\t\nCoagulation test\t\t\tFerritin\t 233 \tng/mL\tds-DNA IgG\t×2.8 \t\t\nPT(S)\t 84.6 \tsec\tBUN\t 79 \tmg/dL\tMPO-ANCA\t<1.0 \t IU/mL\t\nPT(%)\t9.0 \t%\tCr\t 7.1 \tmg/dL\tPR3-ANCA\t <1.0\tIU/mL\t\nPT-INR\t7.27 \t\tNa\t 136 \tmEq/L\tanti-GBM Ab\t <2.0 \tIU/mL\t\nAPTT (day6)\t 98.5 \tsec\tK\t 4.8 \tmEq/L\tanti-SS-A Ab\t <7.0 \tIU/mL\t\nFib\t 462 \tmg/dL\tCl\t 110 \tmEq/L\tanti-SS-B Ab\t <7.0 \tIU/mL\t\nFDP \t 4.1 \tng/mL\tCa \t 8.2 \tmg/dL\tRF \t <3 \tIU/mL\t\nD-dimer \t 0.45 \tμg/mL\tIP \t 4.1 \tmg/dL\tanti-CCP Ab \t 0.6 \tIU/mL\t\nTumor marker\t\t\tUA \t 6.0 \tmg/dL\tsIL-2R\t 5,780 \tIU/mL\t\nCEA \t 3.3 \tng/mL\tCK \t 48 \tIU/L\tHBs Ag \t (-)\t\t\nCA19-9 \t 19.8 \tIU/mL\tCRP \t 0.81 \tmg/dL\tHCV Ab \t (-)\t\t\nPSA \t 0.407 \tng/mL\t\t\t\tT-spot \t (-)\t\t\nFigure 1. A chest X-ray on admission showed cardiomegaly, with a cardiothoracic ratio of 66%.\n\nFigure 2. Abdominal computed tomography on admission revealing bilateral renal atrophy and a mass, 38 mm in diameter, in the right kidney.\n\nThe patient's clinical course is illustrated in Fig. 3. Initially, warfarin toxicity was suspected. Thus, the warfarin was stopped, and vitamin K was administered intravenously, with a subsequent temporary improvement in his PT values. Although upper and lower gastrointestinal tract endoscopy was performed, no obvious source of bleeding was identified. However, on Day 14 of admission, a CT scan of the chest showed bilateral massive infiltrative shadows in the right middle and lower lobes of the lung, suggesting an alveolar hemorrhage. On Day 15, the PT-INR value had increased to 5.76, and the activated partial thromboplastin time (APTT) was markedly prolonged (>180 s). His findings for lupus anticoagulant diluted Russell's viper venom time (dRVVT) were positive (>1.33, normal range: 0-1.3 s), and his level of anti-β2-glycoprotein 1 (aB2GP1) IgG antibody was 3.2 U/mL (normal range: <3 U/mL) and anti-cardiolipin (aCL) IgG antibody was 38 U/mL (normal range: <10 U/mL). A plasma cross-mixing test was then performed and revealed no factor deficiency, but suggested a delayed-type inhibitor pattern (Fig. 4). We suspected acquired hemophilia and carried out tests to detect the coagulation factor activity and inhibitor presence (Table 2). The activity of factor V (FV) was quite low (<3%). The specific inhibitor for FV was present, with a titer of 6 Bethesda units/mL (BU/mL). Thus, prednisolone was initiated, starting at a dose of 60 mg/day (1.0 mg/kg/day). The patient's eosinophilia soon improved. The findings from his coagulation studies improved markedly, but his renal failure progressed with oliguria, and he ultimately required chronic hemodialysis.\n\nFigure 3. Clinical course. Horizontal axis: hospital days, APTT: activated partial thromboplastin time (s), PT-INR: international normalized ratio of prothrombin time, Hb: hemoglobin (g/dL), Vit K: Vitamin K (Menatetrenone), PSL: prednisolone (mg/day), FFP: Fresh frozen plasma, RCC-LR: red cells concentrates-leukocytes reduced\n\nFigure 4. Cross-mixing test. Plasma from the patient and normal were mixed at various rations after incubation for 2 h at 37˚C. It demonstrated no factor deficiency but suggested a delayed-type inhibitor pattern.\n\nTable 2. Coagulation Factor Assay.\n\n\tactivity\tinhibitor\t\nFactor II\t46% (75-135)\tnegative\t\nFactor V\t<3% (70-135)\t6 BU/mL\t\nFactor VII\t101% (75-140)\tno data\t\nFactor VIII\t63% (60-150)\tnegative\t\nFactor IX\t84% (70-130)\tnegative\t\nFactor X\t67% (0-50)\tnegative\t\nFactor XI\t56% (75-145)\tno data\t\nFactor XII\t104% (50-150)\tno data\t\nBy Day 34 of admission, the findings from his coagulation studies had normalized (PT-INR: 1.22, APTT: 30.1 s), so an arteriovenous fistula was surgically created for ongoing hemodialysis. On Day 40, the FV activity increased to 61%, and the test for FV inhibitors was negative. Prednisolone was thus tapered to 50 mg/day. On Day 42, capsule endoscopy revealed a wide area of redness and erosion in the small intestine. This was considered to be the source of the bleeding that resulted in the tarry stool and anemia.\n\nThe patient had experienced pain in both upper limbs on Day 15 and thereafter had some numbness in the upper and lower limbs. A nerve conduction test showed multiple mononeuropathies. Once prednisolone was started, the upper limb pain improved, although the numbness remained. The prednisolone dosage was gradually reduced. The levels of the coagulation markers remained stable, and the FV inhibitors remained undetectable. The patient was discharged after 91 days in the hospital. The prednisolone dosage was tapered to 7.5 mg/day. One year later, the prednisolone had been tapered to 1 mg/day, the FV inhibitors remained undetectable, and he continued hemodialysis without complications.\n\nDiscussion\nAFVI was first reported by Hörder et al. in 1955. According to a systematic review by Franchini, by 2010, there had been 159 reported cases, 70 of which were associated with previous exposure to topical bovine thrombin. In the remainder of cases, the underlying causes were reported to be autoimmune (13%), tumor-associated (22%), and antibacterial drug-induced, notably β-lactam antibiotics (42%); 21% were classified as idiopathic (2). In the present case, several causes were considered, including tumor-associated (renal cell carcinoma was suspected, given the kidney mass identified on CT), warfarin, eosinophilia-related, and autoimmune (aCL-positive).\n\nMore than one year later, the kidney mass had neither increased in size nor metastasized, and the AFVIs did not recur. Given that we were unable to find any previous reports of renal cell carcinoma as a cause of AFVIs, we believe the renal mass was unlikely to be the underlying cause of the AFVI in the present patient.\n\nFour cases of AFVI related to warfarin therapy have been reported, but none identified the cause (3-6). In the present case, despite a two-week interval between the withdrawal of warfarin and the initiation of prednisolone, the coagulation abnormalities and eosinophilia did not improve spontaneously on withdrawal of the warfarin. In addition, 8 days before warfarin was started, the proportion of eosinophils had already increased to 15%. Thus, whether or not warfarin was the underlying cause is unclear.\n\nAll three cases of acquired coagulation factor inhibitor associated with eosinophilia had FVIs (7-9). Interestingly, these three cases also suffered from kidney diseases. One case was a maintenance dialysis patient, and the other two had membranous nephropathy, which is caused by immune complex formation in the glomerulus. The present case had bilateral renal atrophy, and from the clinical course, he was considered to have nephrosclerosis, but further details were unclear, as renal biopsy had not been performed. In addition to marked eosinophilia, our patient also was positive for antiphospholipid antibodies (aCL and aB2GP1) and had elevated serum IgG levels and multiple mononeuropathies, suggesting the presence of an immunological disorder. However, the diagnostic criteria for systemic lupus erythematosus, eosinophilic granulomatous vasculitis, and polyarteritis nodosa were not met.\n\nThe relationship between renal disease or renal failure and AFVIs is unclear for rare diseases, but some as-yet-unknown immunological mechanism causing eosinophilia might be involved in the production of the FV inhibitors.\n\nThe mucosal erosion observed in the present patient was confined to the small intestine and not biopsied. A diagnosis of eosinophilic gastroenteritis was suggested, given the eosinophilia, elevated serum IgG levels, diarrhea, and the wide range of small bowel erosions. Further, the patient's gastrointestinal symptoms (abdominal pain, tarry stool, and diarrhea) resolved with steroid therapy. With the use of capsule endoscopy and double-balloon enteroscopy spreading, reports have begun to appear in the literature of eosinophilic enteritis localized to the small intestine (10-12).\n\nThere is no well-established treatment for AFVIs, but immunosuppressive therapy (including corticosteroids and cyclophosphamide), intravenous immunoglobulins, and plasmapheresis are reported to be effective, similar to the treatment for acquired hemophilia (2). Some reports suggest that rituximab is effective in patients presenting with severely bleeding diathesis (13-16).\n\nThe findings from the cross-mixing test provided a clue to the diagnosis in this particular case, prompting us to start treatment with prednisolone, which rapidly improved the patient's coagulation abnormalities. Given that the coagulation factor activity and inhibitor presence take a long time to evaluate, the cross-mixing test is helpful in obtaining an early diagnosis.\n\nAlthough there have been two reported cases of AFVIs occurring in patients on maintenance hemodialysis (7,17), this is the first case of AFVIs in a patient initiating hemodialysis for end-stage renal disease.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nTamai Y , Takami H \nAcquired hemophilia . Nihon Naika Gakkai Zasshi \n103 : 1622 -1630 , 2014 (in Japanese).25154257 \n2. \nFranchini M , Lippi G \nAcquired factor V inhibitors. A systematic review . J Thromb Thrombolysis \n31 : 449 -457 , 2011 .21052780 \n3. \nNozu T , Mita H , Okumura T \nAcquired factor V inhibitor in a patient with a mechanical aortic valve under warfarin therapy . Intern Med \n49 : 2229 -2233 , 2010 .20962441 \n4. \nGartrell B \nAcquired factor V inhibitor complicating warfarin therapy . Am J Hematol \n86 : 710 -712 , 2011 .21761437 \n5. \nKhalafallah A , Grabek J , Hayes R , Mohamed M \nBleeding associated with acquired factor V inhibitor in a patient on warfarin treated successfully with prednisolone . BMJ Case Reports \n6 : bcr2013010018 , 2013 .\n6. \nKinjo Y , Yoshimura K , Suzuki T , et al \nDevelopment of asymptomatic acquired factor V inhibitor after the administration of antibiotic . Rinsho Ketsueki \n55 : 2311 -2315 , 2014 (in Japanese, Abstract in English).25501413 \n7. \nIino N , Maruyama H , Gejo F \nAcquired coagulation abnormality due to factor V inhibitor . Nihon Naika Gakkai Zasshi \n92 : 3295 -3297 , 2002 (in Japanese).\n8. \nKitamura S , Misawa M , Namba S , et al \nMembranous nephropathy with acquired factor V inhibitor: a case report . BMC Research Notes \n6 : 553 , 2013 .24360027 \n9. \nTakahashi H , Fuse I , Abe T , Yoshino N , Aizawa Y \nAcquired factor V inhibitor complicated by Hashimoto's thyroditis, primary biliary cirrhosis and membranous nephropathy . Blood Coagul Fibrinolysis \n14 : 87 -93 , 2003 .12544735 \n10. \nMatsui T , Murata K , Kaneko M , et al \nA case of ensinophilic enteritis successfully observed by capsule endoscopy before and after treatment . Nihon Syoukaki Naisikyou Gakkai Zasshi \n55 : 3394 -3400 , 2013 (in Japanese, Abstract in English).\n11. \nEndo H , Hosono K , Inamori M , et al \nCapsule endoscopic evaluation of eosinophilic enteritis before and after treatment . Digestion \n83 : 134 -135 , 2011 .21042024 \n12. \nOkada K , Daimon Y , Iwase T , Mitsufuji S \nNovel findings of capsule endoscopy and double-ballon enteroscopy in a case of eosinophilic gastroenteritis . Clin J Gastroenterol \n6 : 16 -19 , 2013 .26181398 \n13. \nLian EC , Tzakis AG , Andrews D \nResponse of factor V inhibitor to Rituximab in a patient who receive liver transplantation for primary biliary cirrhosis . Am J Hematol \n77 : 363 -365 , 2004 .15551286 \n14. \nPerdekamp MT , Rubenstein DA , Jesty J , Hultin MB \nPlatelet factor V supports hemostasis in a patient with an acquired factor V inhibitor, as shown by prothrombinase and tenase assys . Blood Coagul Fibrinolysis \n17 : 593 -597 , 2006 .16988558 \n15. \nLebrun A , Leroy-Matheron C , Arlet JB , Bartolucci P , Michel M \nSuccessful treatment with rituximab in a patient with an acquired factor V inhibitor . Am J Hematol \n83 : 163 -164 , 2008 .17849464 \n16. \nYamada Y , Miyakawa Y , Sawano M , Okano Y \nSuccessful treatment of severe lung hemorrhage caused by acquired factor V inhibitor with rituximab . Intern Med \n53 : 1083 -1085 , 2014 .24827490 \n17. \nIshizu M , Kuroiwa M , Tanaka K , Hasegawa Y \nSevere hemorrhagic tendency due to factor V inhibitor in a hemodialysis patient: a case report . Nihon Toseki Igakkai Zasshi \n36 : 1285 -1288 , 2003 (in Japanese, Abstract in English).\n\n",
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"issue": "55(23)",
"journal": "Internal medicine (Tokyo, Japan)",
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"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001777:Blood Coagulation; D001780:Blood Coagulation Tests; D005165:Factor V; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male; D010314:Partial Thromboplastin Time",
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"title": "Acquired Factor V Inhibitors in a Patient with End-stage Renal Disease.",
"title_normalized": "acquired factor v inhibitors in a patient with end stage renal disease"
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"abstract": "BACKGROUND\nAcute severe ulcerative colitis is a high stakes event with significant numbers still requiring emergent colectomy, representing a need to establish alternative medical management options. We report a case series of tofacitinib as rescue therapy in biologic-experienced patients with acute severe ulcerative colitis.\n\n\nMETHODS\nFour patients were identified over a 1-year period at our institution who initiated tofacitinib for acute severe ulcerative colitis. All four had previously failed at least two biologics, including infliximab, and were failing high-dose oral prednisone therapy before admission. All patients had Mayo disease activity index of at least 10 at admission. After no significant improvement despite receiving a minimum of 3 days of intravenous methylprednisolone and based on elevated Ho and Travis indices at Day 3, patients were offered rescue tofacitinib for induction of remission, or colectomy. Standard induction of tofacitinib was used [10 mg twice daily], and one patient was escalated to 15 mg twice daily after inadequate response.\n\n\nRESULTS\nAll patients experienced improvement in objective symptoms and laboratory markers, and were discharged without colectomy on tofacitinib as maintenance therapy and prednisone taper; 30-day and 90-day colectomy rates on tofacitinib maintenance therapy were zero and 90-day readmission rate was also zero. Two of four patients achieved steroid-free remission on maintenance tofacitinib monotherapy based on clinical symptoms and follow-up endoscopy. No major adverse reaction was reported during induction or maintenance therapy.\n\n\nCONCLUSIONS\nTofacitinib may be an acceptable rescue agent in biologic-experienced patients with acute severe ulcerative colitis. Tofacitinib may also be safely continued as maintenance therapy once remission has been achieved.",
"affiliations": "University of California San Francisco, Department of Medicine, Division of Gastroenterology, San Francisco, CA, USA.;University of California San Francisco, Department of Medicine, Division of Gastroenterology, San Francisco, CA, USA.;University of California San Francisco, Department of Medicine, Division of Gastroenterology, San Francisco, CA, USA.",
"authors": "Kotwani|Prashant|P|;Terdiman|Jonathan|J|;Lewin|Sara|S|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C479163:tofacitinib; D000069285:Infliximab; D011241:Prednisone",
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"issue": "14(7)",
"journal": "Journal of Crohn's & colitis",
"keywords": "Tofacitinib; acute severe ulcerative colitis; remission; rescue",
"medline_ta": "J Crohns Colitis",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D003082:Colectomy; D003093:Colitis, Ulcerative; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D011241:Prednisone; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019233:Retreatment; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101318676",
"other_id": null,
"pages": "1026-1028",
"pmc": null,
"pmid": "32020189",
"pubdate": "2020-07-30",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Tofacitinib for Rescue Therapy in Acute Severe Ulcerative Colitis: A Real-world Experience.",
"title_normalized": "tofacitinib for rescue therapy in acute severe ulcerative colitis a real world experience"
} | [
{
"companynumb": "US-MYLANLABS-2021M1051400",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VEDOLIZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Eating disorders (EDs) are complex and difficult to treat illnesses that are often chronic and disabling on their own accord or due to comorbidity with other psychiatric conditions. Historically, EDs have been viewed as illnesses of heterosexual, affluent white females. This stereotype increases the likelihood that these disorders will be underrecognized in the lesbian, gay, bisexual, and transgender community, as well as in different gender, socioeconomic, and ethnic populations. Our case report illustrates the clinical difficulties of managing a patient who presented to inpatient treatment with complaints of depression and suicidality, but who also had an active ED and was transgender.",
"affiliations": "WAGNER and STEVENS: The Menninger Clinic and Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX.",
"authors": "Wagner|Rebecca|R|;Stevens|Jonathan R|JR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/PRA.0000000000000248",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-4160",
"issue": "23(4)",
"journal": "Journal of psychiatric practice",
"keywords": null,
"medline_ta": "J Psychiatr Pract",
"mesh_terms": "D000328:Adult; D015897:Comorbidity; D003866:Depressive Disorder; D001068:Feeding and Eating Disorders; D005260:Female; D006801:Humans; D008297:Male; D063106:Transgender Persons; D055815:Young Adult",
"nlm_unique_id": "100901141",
"other_id": null,
"pages": "284-289",
"pmc": null,
"pmid": "28749833",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clinical Barriers to Effective Treatment of Eating Disorders and Co-occurring Psychiatric Disorders in Transgendered Individuals.",
"title_normalized": "clinical barriers to effective treatment of eating disorders and co occurring psychiatric disorders in transgendered individuals"
} | [
{
"companynumb": "US-009507513-1809USA002891",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MIRTAZAPINE"
},
"drugadditional": "3",
... |
{
"abstract": "Here, we describe a case of primary graft failure with severe sepsis in a boy who experienced frequent relapses of osteosarcoma. The patient had undergone haploidentical bone marrow transplant after engraftment of unrelated cord blood transplant performed 10 months earlier. Considering his severe condition, we transfused autologous peripheral stem cells along with a single dose of etoposide (50 mg/m2). Granulocyte engraftment was confirmed on human leukocyte antigen-microsatellite analysis of bone marrow on day 14. Although the patient died due to respiratory failure, transfusion of autologous hematopoietic stem cells is a reasonable rescue option for graft failure even in patients whose background hematopoiesis is reconstituted by a first donor.",
"affiliations": "From the Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.",
"authors": "Watanabe|Atsushi|A|;Inukai|Takeshi|T|;Akahane|Koshi|K|;Somazu|Shinpei|S|;Oshiro|Hiroko|H|;Goi|Kumiko|K|;Koizumi|Keiichi|K|;Harii|Norikazu|N|;Matsuda|Kenichi|K|;Sugita|Kanji|K|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2016.0315",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "17(2)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D001859:Bone Neoplasms; D002648:Child; D017809:Fatal Outcome; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D012516:Osteosarcoma; D036102:Peripheral Blood Stem Cell Transplantation; D012086:Reoperation; D013977:Tibia; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous; D017211:Treatment Failure",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "281-283",
"pmc": null,
"pmid": "28760119",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Autologous Stem Cell Rescue for Graft Failure of Second Allogeneic Stem Cell Transplant After Engraftment of Primary Allogeneic Transplant.",
"title_normalized": "autologous stem cell rescue for graft failure of second allogeneic stem cell transplant after engraftment of primary allogeneic transplant"
} | [
{
"companynumb": "JP-ACCORD-057264",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"dr... |
{
"abstract": "We present the case of a 3-year-old female liver transplant recipient with a history of Caroli disease who presented with positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction (RT-PCR) test and was ultimately diagnosed with multisystem inflammatory syndrome in children (MIS-C) complicated by portal vein thrombosis. To the best of our knowledge, this is the first case report of MIS-C in a pediatric solid organ transplant (SOT) recipient. Based on our patient, MIS-C could be a potential complication of Coronavirus disease 2019 (COVID-19) in SOT recipients and may have a negative outcome on transplant graft function.",
"affiliations": "Section of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.;Texas Children's Hospital, Houston, Texas.;Section of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.;Texas Children's Hospital, Houston, Texas.;Texas Children's Hospital, Houston, Texas.;Department of Pediatrics, The University of Mississippi Medical Center, Jackson, Mississippi.;Department of Pediatrics, The University of Mississippi Medical Center, Jackson, Mississippi.;Texas Children's Hospital, Houston, Texas.",
"authors": "Petters|Leanne M|LM|0000-0002-0208-4581;Vogel|Tiphanie P|TP|;Munoz|Flor M|FM|;Hernandez|Jose A|JA|;Koohmaraie|Sarah|S|;Nowicki|Michael J|MJ|;Zumbro|Caleb E|CE|;Mysore|Krupa R|KR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.16572",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "21(7)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; complication; infection and infectious agents - viral; infectious disease; liver transplantation/hepatology; pediatrics",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000086382:COVID-19; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D016377:Organ Transplantation; D000086402:SARS-CoV-2; D018746:Systemic Inflammatory Response Syndrome; D066027:Transplant Recipients",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "2596-2599",
"pmc": null,
"pmid": "33754452",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "32406181;33518372;32386565;32179660;28913888;32838102;32410760;32816964;32949098;32790663;32598831;32705809",
"title": "Multisystem inflammatory syndrome in children associated with SARS-CoV-2 in a solid organ transplant recipient.",
"title_normalized": "multisystem inflammatory syndrome in children associated with sars cov 2 in a solid organ transplant recipient"
} | [
{
"companynumb": "US-ASTELLAS-2021US038238",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
... |
{
"abstract": "The present multicenter phase II study evaluated the efficacy and safety of weekly docetaxel as second-line chemotherapy for metastatic urothelial carcinoma. Weekly docetaxel was well tolerated but demonstrated modest activity, with a response rate of 6%, a median progression-free survival (PFS) of 1.4 months, and a median overall survival (OS) of 8.3 months. The dichotomy between PFS and OS was likely associated with subsequent platinum-based chemotherapy received by 58% of the patients.\n\n\nBACKGROUND\nDocetaxel is commonly used for second-line therapy for metastatic urothelial carcinoma (UC). However, myelosuppression is a substantial concern when the traditional 3-week docetaxel cycle is used. The present multicenter phase II study evaluated the efficacy and safety of weekly docetaxel as second-line chemotherapy for metastatic UC.\n\n\nMETHODS\nPatients with progression after previous platinum-based chemotherapy for advanced or metastatic disease were treated with docetaxel 30 mg/m(2) on days 1 and 8 every 21 days. The primary endpoint was the response rate.\n\n\nRESULTS\nThe study enrolled 31 patients. Their median age was 64 years (range, 40-79 years). An Eastern Cooperative Oncology Group performance status of 1, liver metastasis, and a hemoglobin level < 10 g/dL were observed in 100%, 32%, and 23% of patients, respectively. Previous platinum-based chemotherapy had been administered for metastatic disease in 29 patients (94%). Although fatigue (13%) and anorexia (6%) were the most frequently observed grade 3 to 4 toxicities, the safety profiles were generally mild and manageable. Two patients (6%) achieved an objective response, which was maintained for 3.0 to 7.8 months. Eight patients experienced disease stabilization (disease control rate, 32%). The median progression-free survival (PFS) and overall survival (OS) were 1.4 months (95% confidence interval [CI], 1.3-1.6) and 8.3 months (95% CI, 5.9-10.6), respectively. A relatively long OS was associated with further salvage platinum-based chemotherapy (n = 18, 58%) showing an encouraging activity (response rate, 44%; median PFS, 4.0 months).\n\n\nCONCLUSIONS\nSecond-line chemotherapy with weekly docetaxel was well tolerated but demonstrated modest activity in patients with metastatic UC. A platinum-based combination as second-line treatment might be considered for selected patients.",
"affiliations": "Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea.;Division of Hematology-Oncology, Department of Medicine, Dankook University Hospital, Dankook University College of Medicine, Cheonan, Republic of Korea. Electronic address: avnrt@hanmail.net.;Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Division of Hematology/Oncology, Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Soonchunhyang University Hospital Cheonan, Cheonan, Republic of Korea.;Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.",
"authors": "Kim|Young Saing|YS|;Lee|Soon Il|SI|;Park|Se Hoon|SH|;Park|Silvia|S|;Hwang|In Gyu|IG|;Lee|Sang-Cheol|SC|;Sun|Jong-Mu|JM|;Lee|Jeeyun|J|;Lim|Ho Yeong|HY|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1558-7673",
"issue": "14(1)",
"journal": "Clinical genitourinary cancer",
"keywords": "Bladder cancer; Chemotherapy; Docetaxel; Phase II; Second-line; Urothelial carcinoma",
"medline_ta": "Clin Genitourin Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002295:Carcinoma, Transitional Cell; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D016879:Salvage Therapy; D043823:Taxoids; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "101260955",
"other_id": null,
"pages": "76-81",
"pmc": null,
"pmid": "26454620",
"pubdate": "2016-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "A Phase II Study of Weekly Docetaxel as Second-Line Chemotherapy in Patients With Metastatic Urothelial Carcinoma.",
"title_normalized": "a phase ii study of weekly docetaxel as second line chemotherapy in patients with metastatic urothelial carcinoma"
} | [
{
"companynumb": "KR-SA-2015SA222924",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
"dru... |
{
"abstract": "OBJECTIVE\nINFLOW (INdacaterol eFfectiveness and utiLizatiOn in COPD: real World evaluation) was a prospective, noninterventional study assessing the effectiveness and safety of long-acting bronchodilators in patients with chronic obstructive pulmonary disease (COPD) from the Middle East, Asia, and South Africa.\n\n\nMETHODS\nPatients newly prescribed or switched to indacaterol or other long-acting β2-agonist (LABA), or tiotropium (monotherapy or in combination) were evaluated over 6 months. The primary endpoint was the clinical COPD questionnaire overall score at the end of the study.\n\n\nRESULTS\nData were analyzed from 1,710 patients (mean postbronchodilator forced expiratory volume in 1 second, 59% predicted) who received indacaterol (n=1,179), other LABA (n=68), tiotropium (n=271), indacaterol plus tiotropium (n=167), or other LABA plus tiotropium (n=25). Across treatments, clinical COPD questionnaire overall score improved from baseline by 0.81-1.26 points (all P<0.0001), 63%-84% of patients were satisfied/very satisfied, and physicians rated effectiveness as good/very good in 63%-80% of cases. The indacaterol inhaler was rated easy/very easy to use by the majority of patients, and physicians considered its use clearly understood by most patients. All treatments had acceptable tolerability.\n\n\nCONCLUSIONS\nIn real life clinical practice across a diverse region, indacaterol and other long-acting bronchodilators improved health status and were well regarded by patients and physicians.",
"affiliations": "St Georges Hospital University Medical Center, Ashrafieh, Beirut, Lebanon.;Chest Department, Faculty of Medicine, Helwan University, Cairo, Egypt.;Division of Pulmonary and Critical Care, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.;Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, University of Indonesia, Persahabatan Hospital, Jakarta Timur, Indonesia.;Department of Pulmonary Medicine, Philippine Heart Center, Quezon City, Philippines.;Linkou Chang Gun Memorial Hospital, Taoyuan Hsien, Taiwan, ROC.;Novartis Healthcare Pvt Ltd, Rangareddy, Telangana, India.;Novartis Pharma AG, Basel, Switzerland.",
"authors": "Juvelekian|Georges|G|;El-Sorougi|Waleed|W|;Pothirat|Chaicharn|C|;Yunus|Faisal|F|;De Guia|Teresita|T|;Kuo|Han-Pin|HP|;Basu Patnaik|Shalma|S|;Pilipovic|Virginia|V|",
"chemical_list": "D001993:Bronchodilator Agents; D003692:Delayed-Action Preparations; D007189:Indans; D015363:Quinolones; C510790:indacaterol; D000069447:Tiotropium Bromide",
"country": "New Zealand",
"delete": false,
"doi": "10.2147/COPD.S83071",
"fulltext": "\n==== Front\nInt J Chron Obstruct Pulmon DisInt J Chron Obstruct Pulmon DisInternational Journal of COPDInternational Journal of Chronic Obstructive Pulmonary Disease1176-91061178-2005Dove Medical Press 10.2147/COPD.S83071copd-10-2109Original ResearchA real-world evaluation of indacaterol and other bronchodilators in COPD: the INFLOW study Juvelekian Georges 1El-Sorougi Waleed 2Pothirat Chaicharn 3Yunus Faisal 4De Guia Teresita 5Kuo Han-Pin 6Basu Patnaik Shalma 7Pilipovic Virginia 81 St Georges Hospital University Medical Center, Ashrafieh, Beirut, Lebanon2 Chest Department, Faculty of Medicine, Helwan University, Cairo, Egypt3 Division of Pulmonary and Critical Care, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand4 Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, University of Indonesia, Persahabatan Hospital, Jakarta Timur, Indonesia5 Department of Pulmonary Medicine, Philippine Heart Center, Quezon City, Philippines6 Linkou Chang Gun Memorial Hospital, Taoyuan Hsien, Taiwan, ROC7 Novartis Healthcare Pvt Ltd, Rangareddy, Telangana, India8 Novartis Pharma AG, Basel, SwitzerlandCorrespondence: Georges Juvelekian, St Georges Hospital University Medical Center, Post Box 166378, Ashrafieh, Beirut 11002807, Lebanon, Tel +961 3 497 574, Fax +961 1 582 560, Email juveleg@hotmail.com2015 05 10 2015 10 2109 2120 © 2015 Juvelekian et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2015The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Aim\nINFLOW (INdacaterol eFfectiveness and utiLizatiOn in COPD: real World evaluation) was a prospective, noninterventional study assessing the effectiveness and safety of long-acting bronchodilators in patients with chronic obstructive pulmonary disease (COPD) from the Middle East, Asia, and South Africa.\n\nMethods\nPatients newly prescribed or switched to indacaterol or other long-acting β2-agonist (LABA), or tiotropium (monotherapy or in combination) were evaluated over 6 months. The primary endpoint was the clinical COPD questionnaire overall score at the end of the study.\n\nResults\nData were analyzed from 1,710 patients (mean postbronchodilator forced expiratory volume in 1 second, 59% predicted) who received indacaterol (n=1,179), other LABA (n=68), tiotropium (n=271), indacaterol plus tiotropium (n=167), or other LABA plus tiotropium (n=25). Across treatments, clinical COPD questionnaire overall score improved from baseline by 0.81–1.26 points (all P<0.0001), 63%–84% of patients were satisfied/very satisfied, and physicians rated effectiveness as good/very good in 63%–80% of cases. The indacaterol inhaler was rated easy/very easy to use by the majority of patients, and physicians considered its use clearly understood by most patients. All treatments had acceptable tolerability.\n\nConclusion\nIn real life clinical practice across a diverse region, indacaterol and other long-acting bronchodilators improved health status and were well regarded by patients and physicians.\n\nKeywords\nlong-acting bronchodilatorindacaterolchronic obstructive pulmonary diseasenoninterventional studyMiddle EastAsia\n==== Body\nIntroduction\nChronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable disease and a leading cause of morbidity and mortality worldwide.1,2 COPD prevalence varies in different regions.3 A large epidemiological study of >60,000 interviewees from 11 countries of the Middle East, North Africa, and Pakistan (BREATHE study)4 reported an overall prevalence of 3.6%, while the Asia-Pacific regional working group reported an overall prevalence of 6.3% across 12 Asian countries.5 Prevalence may differ not only between but also within countries.6 The prevalence of COPD in India is unknown, but chronic bronchitis has been estimated to affect 6.5%–7.7% of the rural population.7 The BREATHE study also reported a high burden of disease, with a large proportion of patients experiencing exacerbations, comorbidities, limitations in work, difficulties in social and family activities, and psychological distress.8\n\nBronchodilators are the cornerstone of COPD treatment.2 Long-acting β2-agonists (LABAs), such as indacaterol, and long-acting muscarinic antagonists (LAMAs), such as tiotropium, are recommended as first choice or alternative treatments, either as monotherapies or in combination, for patients with all severities of COPD.2 Indacaterol maleate (Onbrez® Breezhaler®, Novartis, Basel, Switzerland) is a once-daily LABA, delivered by a low-resistance dry-powder inhaler, indicated for the maintenance treatment of airflow obstruction in adult COPD patients.9,10 In Phase III studies, indacaterol provided sustained 24-hour bronchodilation and significantly better efficacy in terms of lung function, symptom control, and health status compared with placebo, and comparable or superior efficacy compared with twice-daily LABAs (double blinded) and/or tiotropium (open label or blinded),11–15 and was well tolerated.16,17\n\nAlthough very important, efficacy and safety data from clinical trials may not accurately reflect outcomes observed in routine clinical practice owing to their study designs and stringent inclusion/exclusion criteria. Noninterventional studies provide useful complementary information on real-world effectiveness and safety of treatments when prescribed in routine clinical practice and in particular circumstances, for example in different geographical regions and in ethnically diverse patient populations.\n\nDespite the high COPD prevalence in the Middle East and North Africa,4 the BREATHE study reported that in these countries COPD is underdiagnosed and inadequately treated.18 The present study was designed to assess the effectiveness, treatment satisfaction, and safety of indacaterol and other long-acting inhaled bronchodilator therapies in COPD patients from the Middle East, Asia, and South Africa.\n\nMethods\nStudy design\nThis was a 6-month, multicenter, prospective, noninterventional, real-world study, conducted between July 2011 and January 2014, to assess the effectiveness and safety of indacaterol and other inhaled long-acting bronchodilators in 12 countries in Asia, the Middle East, and South Africa. Therapy was prescribed according to the physician’s judgment and clinical indication based on local prescribing information in the respective countries and was independent of the decision to include the patient in the study. Enrolled patients were observed over 6 months (±4 weeks) with recommended data-collection time points at baseline (study entry) and at months 1, 3, and 6/end of study. As the study was noninterventional, only data originating from routine clinical practice were collected, and there was no mandate for study-specific patient visits, tests, or monitoring. The study was conducted according to the declaration of Helsinki, the International Conference on Harmonisation Tripartite Guidelines for Good Clinical Practice, the Guidelines for Good Pharmacoepidemiology Practices of the International Society for Pharmacoepidemiology, and with applicable local regulations. The study protocol was approved by local ethics committees at participating centers. (Supplementary materials S1).\n\nPatients\nThe study population consisted of male and female patients aged ≥40 years, with mild-to-severe COPD (according to the Global initiative for chronic Obstructive Lung Disease [GOLD] 2009 strategy document),19 who were symptomatic, and were receiving indacaterol or other long-acting bronchodilators as monotherapy or in combination. Patients were current or ex-smokers with a smoking history of ≥10 pack-years. Eligible patients must have been either on 1) newly prescribed LABA or tiotropium as monotherapy or in combination, or 2) switched from one LABA to another or from a LABA to tiotropium (or vice versa). Patients gave their written informed consent for participation in the study.\n\nPatients were not included if they had drug contraindications, a previous diagnosis of asthma, acute exacerbations (requiring antibiotics or hospitalizations) at study entry, unwillingness or inability to comply with the study requirements, treatment with inhaled corticosteroids (ICS) at study entry or within 3 months prior to study entry, or treatment with two different LABAs, LABA + ICS, tiotropium + ICS or triple therapy (tiotropium + LABA + ICS). However, new bronchodilator or ICS treatment could be initiated if required by the patient during the study.\n\nObjectives\nThe objectives were to assess the effectiveness of treatments using the clinical COPD questionnaire (CCQ) to measure health status, to describe the characteristics of COPD patients treated with indacaterol and other long-acting bronchodilators, to evaluate patients’ and physicians’ satisfaction with treatment, to describe patients’ and physicians’ assessment of the inhaler used with indacaterol (Breezhaler®), to evaluate persistence with treatment, and to assess safety and tolerability of treatment.\n\nAssessments\nHealth status was measured using the CCQ at baseline and end of study or at treatment change if the patient switched treatment (last observation carried forward). The CCQ was developed for use with COPD patients and comprises ten items divided into three domains: symptoms, functional state, and mental state. It generates an overall clinical COPD control score (as well as domain scores) between 0 (very good control) and 6 (extremely poor control). The questionnaire is short and easy to administer in the clinical practice setting, as required for a noninterventional study. The instrument has been shown to be valid, reliable, and responsive to change in COPD patients20,21 and has a minimal clinically important difference (MCID) of 0.4 points.22 The 7-day recall version, validated in local languages, was used.\n\nPersistence was defined as the percentage of patients receiving the treatment prescribed at baseline at each subsequent data collection time point until the end of study. Global satisfaction with treatment at end of study was recorded by patients on a four-point scale; physicians also rated treatment satisfaction based on assessment of effectiveness, tolerability, and compliance on a four-point scale. The inhaler used with indacaterol was assessed by patients as the percentage of patients reporting it as being very difficult, difficult, easy, or very easy to use, and by physicians in terms of the percentage of patients who clearly understood the use of the inhaler, used the device correctly but required further explanation, needed to have a number of technical points reviewed, and needed to have the use of the device explained again.\n\nSafety and tolerability of treatment were assessed by patient- and physician-reported adverse events and serious adverse events, and the percentage of patients with adverse events and serious adverse events was determined.\n\nData were collected using paper case report forms designed for the study.\n\nStatistical analyses\nData from studies across 12 countries (Bahrain, Egypt, India, Indonesia, Kuwait, Lebanon, Oman, Philippines, South Africa, Taiwan, Thailand, and the United Arab Emirates), conducted under one umbrella protocol, were pooled. The sample size for each country was based on the feasible numbers of patients treated with the respective drugs, rather than on statistical considerations; a ratio of 2:1 (indacaterol:other long-acting bronchodilators) was planned. The sample size calculation was set to test the primary endpoint, CCQ (end of study vs baseline in each arm; within-treatment comparisons) with a standard deviation estimated at 1.0 point.23 The precision was expressed in terms of the width of the 95% confidence interval.\n\nThe estimated CCQ total score precision was calculated for the respective sample sizes of each country. Changes from baseline in the CCQ total and domain scores were analyzed by a two-sided t-test; a P-value <0.05 indicates a significant difference from baseline. If no CCQ value was available at end of study, then the last postbaseline observation was carried forward. Differences between treatments were not analyzed.\n\nTwo populations were defined for analysis. The full analysis set comprised all patients who started treatment. The per-protocol population comprised the full analysis set, but excluded patients who deviated from the protocol-specified criteria of age ≥40 years or baseline forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) <70%. The CCQ analysis was performed on the per-protocol population. Where ICS treatment was initiated during the study, additional CCQ assessments were carried out at the time of medication change; the study did not evaluate effectiveness postinitiation of ICS for these patients. Thus the effectiveness analysis is based on the population without ICS. All other analyses are based on the full analysis set, including patients treated with ICS during the study.\n\nResults\nData were analyzed from 1,710 patients from 12 countries (Table 1). Indacaterol was most commonly used in the Middle East/Lebanon, while indacaterol + tiotropium was most commonly used in India. Most of the “other LABA” use (generally formoterol) occurred in the Middle East/Lebanon, as was the case for tiotropium. The majority of the use of “other LABA + tiotropium” (mostly concurrent formoterol and tiotropium) occurred in Egypt.\n\nOf the 1,710 patients analyzed, 1,535 (90%) completed the study. Most discontinuations (n=129/175; 74%) were due to patients being lost to follow-up, other reasons included withdrawal of consent, adverse events, unsatisfactory therapeutic effect, death, protocol deviations, the condition no longer requiring the study drug, administrative problems, or missing data.\n\nPatient demographics and baseline characteristics are shown in Table 2. Spirometry was available for approximately half of the total patients, as the preexisting diagnosis of COPD (according to GOLD 2009) did not have to be confirmed before study enrollment. Most patients (n=1,337; 78%) had GOLD Stage II airflow limitation, as reported by the study physician, and the mean rate of exacerbations in the year prior to enrollment was 1.8. The two concurrent bronchodilator treatment groups contained the highest proportions of patients with severe/very severe airflow limitation (46% and 24% vs 12%–15% in other treatment groups) and had the worst overall CCQ scores at baseline (mean 2.7 and 3.3 vs 2.2–2.4 in other treatment groups).\n\nOverall, 40% (n=677/1,710) of patients had switched treatment at baseline, prior to study entry, generally for reasons of insufficient disease control (77% of switched patients; n=520/677).\n\nEfficacy\nThe overall CCQ score improved significantly from baseline in all treatment groups (all P<0.0001; Figure 1). In each case, the level of improvement exceeded the MCID of 0.4 points. A similar pattern of significant improvements was observed for scores in the individual domains (symptoms, functional state, and mental state) in each treatment group (Figure S2).\n\nPersistence with the assigned treatment to end of study was >80% for all treatments except for the indacaterol + tiotropium combination, for which 66% of patients were persistent. Overall, 78% of patients were satisfied/very satisfied with their current treatment (Figure 2). In terms of physicians’ opinions (Figure 3), the effectiveness of treatment was rated good/very good for 76% of patients, the tolerability of treatment was rated good/very good for 79%, and the adherence to treatment was judged good/very good in 78% of patients.\n\nThe inhaler used with indacaterol was rated as easy/very easy to use by the majority of patients receiving indacaterol either as monotherapy (n=1,008; 85%) or concurrently with tiotropium (n=113; 68%) (Figure 4). Most physicians considered the use of this device to be clearly understood by their patients when receiving indacaterol as monotherapy (n=918; 78%) or concurrently with tiotropium (n=105; 63%) (Figure 5).\n\nSafety\nAdverse events were reported by 15% of all patients, ranging from 10% to 36% across the treatments. Cough was the most commonly reported adverse event (n=68; 4% of total patients; Table 3). Serious adverse events were reported by 1.5% of all patients (Table 3). Five patients died during the study; four from the indacaterol treatment group (myocardial infarction, paracetamol overdose, prostate cancer, and sudden death) and one from the tiotropium group (reason unknown). Ten patients discontinued treatment because of adverse/serious adverse events.\n\nDiscussion\nDespite the high prevalence of COPD in this geographical region, little is known about disease management and treatment in these countries. Data from the BREATHE study suggest that as few as 29% of COPD patients in the Middle East and North Africa receive respiratory treatment and that only 54% of those receive β2-agonists, anticholinergics, and/or ICS.18 This large, noninterventional study is the first to evaluate the effects of long-acting bronchodilators in real-life clinical practice in a diverse region of 12 countries, nearly all from the Middle East and Asia. Most patients (83%) had mild or moderate airflow limitation (GOLD Stages I and II), although the frequency of exacerbations appears higher than that reported in clinical trials in patients with more severe disease,24,25 and this may be reflected in the moderately high baseline CCQ scores.26 The mean baseline scores would categorize the patients as having “more symptoms” according to the current GOLD model for patient risk assessment, which states an approximate CCQ cutoff value of 1.0–1.5 points.2\n\nIndacaterol and other long-acting bronchodilators improved health status in these patients, as shown by reductions from baseline in the overall and individual CCQ scores, by a level greater than the MCID. They were also regarded as effective treatments by most patients and physicians. The change from baseline CCQ score was numerically greatest in the concurrent indacaterol/tiotropium treatment group compared with all other subgroups. Although the differences between treatments were not subject to formal statistical analysis, and patient numbers in this group were small, this interesting observation seems to be validated by a recent study evaluating the efficacy of combination LABA/LAMA treatments.27 However, the concurrent indacaterol/tiotropium treatment in the present study also attracted the lowest ratings for patient and physician satisfaction compared with the other subgroups, for reasons that are unknown but may have involved the need to use two different inhalers.\n\nThe inhaler used with indacaterol was rated as easy/very easy to use by 85% of patients using indacaterol as monotherapy and by 68% using it with concurrent tiotropium, perhaps again because patients found two inhalers harder to manage. Physicians also rated the inhaler highly in terms of how well patients understood its use. This was shown previously by Chapman et al28 who reported that 81% of patients used the indacaterol inhaler without a critical error on the first day of use, compared with 70% of patients when they used the single-dose, dry-powder inhaler for tiotropium. Additionally, in that study, significantly more patients chose the indacaterol inhaler as their preferred inhaler to use on a daily basis (61% of patients vs 31% for the tiotropium device).28 In a study of patients’ and physicians’ preferences for inhaler devices, ease-of-use was reported by 66% of patients as the most important attribute for an inhaler.29\n\nIndacaterol and other long-acting bronchodilators had acceptable safety and tolerability profiles. The only possible exception was in the “other LABA + tiotropium” group, where the frequency of adverse events was notably higher, but the number of patients was small, and so it may be a random finding. While adverse event reporting procedures were standardized across the different participating countries, the difference may reflect national variations (most of the patients in this treatment group were from Egypt) rather than any real safety differences. The treatments evaluated in this study have all previously been shown in clinical trials to have acceptable safety and tolerability profiles that were comparable with placebo data.17\n\nRandomized clinical trials provide most of the scientific evidence to guide treatment recommendations and decisions. However, one study suggests that patients included in COPD clinical trials may represent only 17% of the real-life COPD patient population,30 which makes it difficult to extrapolate clinical trial data to real-life prescribing and outcomes. Real-life studies have an increasingly valuable role in respiratory medicine, to complement the results from clinical studies.31 To date, several small observational studies of indacaterol treatment in COPD patients have been conducted and have reported results broadly consistent with our findings. A study of 28 outpatients in Japan showed indacaterol to be effective and well tolerated; all participants found the indacaterol inhaler easy to use.32 In the UK, a small cohort of patients who were not well controlled on current therapy (ICS-based in 8 of 15 patients) fared better in terms of exacerbations and health status after switching to indacaterol alone or in combination with tiotropium.33 Another small study in 23 Japanese patients found improved physical activity in patients who received indacaterol for 4 weeks.34 In comparison with these studies, our own study is notable both for its size and for the diverse region covered.\n\nAlthough the study included patients from 12 countries, the majority were from the Middle East, notably Lebanon, and Egypt. Our results will therefore be more specific to these two countries rather than to all countries involved with the study. In future studies, it may be more appropriate to stratify enrollment by country according to the population size and COPD prevalence in each country.\n\nIt should be noted that the intended ratio of 2:1 for patients on indacaterol:other long-acting bronchodilators was not achieved in this real-life study. However, as the study was not designed for between-group comparisons but for within-treatment comparisons (end of study vs baseline), we did not feel that this imbalance would influence the study results.\n\nA small number of never-smokers (1% of total) were enrolled in the study despite the requirement for patients to have a minimum smoking history. These patients were included because they had been diagnosed by the treating physicians as having COPD. While exposure to tobacco smoke is a strong risk factor for COPD, exposure to smoke from home cooking and indoor fuels, and to occupational dust and chemicals and air pollution, are also important contributory factors to the disease.2,5\n\nThis study was designed and conducted when COPD severity was determined solely by airflow limitation, according to the 2009 version of GOLD. Since 2011, GOLD has recommended that patients are assessed in terms of exacerbation risk according to airflow limitation, symptom severity, and history of exacerbations.2 Some of the patients in the present study with more severe airflow limitation may have approximated to the current higher-risk GOLD groups, for which the GOLD-recommended first choice treatments are ICS + LABA + LAMA, ICS + LABA, or LAMA.2 Treatments in this study were given according to local prescribing information and at the discretion of the treating physician, independently of the inclusion of the patients in the study. Patients treated with ICS at study entry, or within 3 months prior to study entry, were not eligible for inclusion; however, ICS treatment could have been initiated during the study, if the treating physician felt that it was required. Furthermore, combinations of long-acting bronchodilators are listed as alternative choices in the current GOLD treatment recommendations,2 and baseline data show that these treatments were being given appropriately to patients with more severe disease, in terms of both airflow limitation and symptoms, compared with the other treatment groups.\n\nIt should also be noted that exacerbations were not recorded during the study period as they were not an endpoint in the study. This may be a limitation of the study as the possibility of an exacerbation coinciding with the patient’s visit for assessment of CCQ scores, and therefore potentially impacting the CCQ scores, cannot be excluded.\n\nIn conclusion, the present results support previous findings from randomized controlled clinical trials demonstrating the efficacy and safety of indacaterol and build on these in a geographical region that has been sparsely studied thus far. In a real-world setting, indacaterol and other long-acting bronchodilators provided a substantial and clinically important improvement in health status, and the indacaterol treatment and inhaler were well received by both patients and physicians.\n\nSupplementary materials\nSupplementary S1\nEthics Committees and Institutional Review Boards\nThe following Ethics Committees and Institutional Review Boards approved the study protocol: MOHP-RHD-REC, Cairo, Egypt; Institutional Review Board of the Hammoud Hospital University Medical Center, Saida, Lebanon; Dubai Heath Authority Ethics Committee, Dubai, United Arab Emirates; Joint Committee for the Protection of Human Subjects in Research of the Health Sciences Center (HSC) & Kuwait Institute for Medical Specialization (KIMS), Safat, Kuwait; American Mission Hospita, Manama, Kingdome of Bahrain; National Health Regulatory Authority, Manama, Kingdome of Bahrain; Sultanate of Oman, Ministry of Health – Division General of Planning, Muscat, Oman; The Ethic Committee of the Faculty of Medicine, University of Indonesia, Jawa Barat, Indonesia; CLINICOM “SUSH-RUTA”, Bangalore, India; Ethics Committee, Fortis Hospitals, Kolkata, West Bengal, India; Philippine Heart Center (PHC) Ethics Review Committee, Quezon City, Philippines; Mary Mediatrix Medical Center (MMMC), Batangas, Phil-ippines; St. Luke's Institutional Ethics Review Committee, Quezon City, Philippines; UPM Research Ethics Board (UPMREB), Manila, Philippines; Office of the Khon Kaen University Ethics Committee for Human Research, Khon Kaen, Thailand; Institutional Review Board, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Office of Research Administration, Faculty of Medicine, Thammasat University Hospital, Pathum Thani, Thailand; The Research Ethics Committee, Faculty of Medicine, Prince of Songkla University, Songkla, Thailand; Research Ethics Committee, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Institutional Review Board, Royal Thai Army Medical Department, Bangkok, Thailand; Ethics Committee Institute for the Development of Human Research Protections (IHRP), Nonthaburi, Thailand; Research Ethics Committee, Department of Medical Science, Ministry of Public Health Chest Disease Institute, Nonthaburi, Thai-land; Institutional Review Board Committee B, Changhua Christian Hospital, Changhua, Taiwan; Institutional Review Board, Chung Shan Medical University Hospital, Chung Shan, Taiwan; Institutional Review Board, Cheng Hsin General Hospital, Taipei, Taiwan; Chang Gung Memorial Foundation Institutional Review Board, Linkou, Taiwan; Institutional Review Board, Cathay General Hospital, Taipei, Taiwan; Institutional Review Board I, Tri-Service General Hospital, Taipei, Taiwan; Institutional Review Board, Taichung Veteran's General Hospital, Taichung, Taiwan; Institutional Review Board, China Medical University Hospital, Taichung, Taiwan; Institutional Review Board, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan; Pharma-Ethics (Pty) Ltd, Centurion, South Africa.\n\nSupplementary Figure S2\nFigure S2 Change from baseline in CCQ (A) symptoms score, (B) functional state score and (C) mental state score.\n\nNotes: Data are mean ± standard error. Last observation was carried forward. All P<0.0001 for change in CCQ from baseline to end of study. Per-protocol population.\n\nAbbreviations: CCQ, clinical COPD questionnaire; LABA, long-acting β2-agonist.\n\n Acknowledgments\nThe authors acknowledge Sashka Hristoskova (Novartis Pharma AG) for critical review of the manuscript. Lietta Nicolaides and Sarah Filcek (CircleScience, an Ashfield Company, part of UDG Healthcare plc) provided medical writing assistance. This was funded by Novartis, the INFLOW study sponsor.\n\nDisclosure\n\nGJ has received payments from AstraZeneca and Novartis (fees and honoraria for lecturing, advisory membership); MSD (fees and honoraria for lecturing, advisory membership, speakers’ bureau); Abbott, Boehringer Ingelheim, and Takeda (fees and honoraria for lecturing). WE-S has received lecturing honoraria from AstraZeneca, GlaxoSmithKline, MSD, and Pfizer. CP has received consultancy and speaker fees from Novartis, and speaker fees from AstraZeneca and GlaxoSmithKline. FY has received speaker and advisory board fees from AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, and Novartis; and speaker fees from Takeda and Zambon. TdeG has received advisory board fees from Novartis. H-PK has received speaker and advisory board fees from Novartis, and speaker fees from Bayer, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Pfizer, Roche, and Takeda. All investigators (GJ, WE-S, CP, FY, TdeG, and H-PK) received fees from Novartis for conducting the study. SBP and VP are Novartis employees. VP is also a Novartis shareholder. The authors report no other conflicts of interest in this work.\n\nFigure 1 Changes from baseline in CCQ overall score.\n\nNotes: Data are mean ± standard error. Last observation was carried forward. All P<0.0001 for change in CCQ overall score from baseline to end of study.\n\nAbbreviations: CCQ, clinical COPD questionnaire; LABA, long-acting β2-agonist.\n\nFigure 2 Patient satisfaction with current treatment at end of study.\n\nNotes:\naPatients who changed treatment during the observational period; treatment satisfaction was assessed until the time of treatment change in these patients.\n\nAbbreviation: LABA, long-acting β2-agonist.\n\nFigure 3 Physician satisfaction with current treatment at end of study.\n\nNote: Patients who changed treatment cohort during the observational period were not included in the analysis.\n\nAbbreviation: LABA, long-acting β2-agonist.\n\nFigure 4 Patient assessment of ease of use of indacaterol inhaler at end of study.\n\nNotes:\naPatients who changed treatment during the observational period; inhaler ease of use was assessed until the time of treatment change in these patients.\n\nFigure 5 Physician assessment of indacaterol inhaler ease of use at end of study.\n\nNote: Patients who changed treatment cohort during the observational period were not included in the analysis.\n\nTable 1 Participating patients (n, %) by country and treatment\n\n\tIndacaterol (n=1,179)\tIndacaterol + tiotropium (n=167)\tOther LABA (n=68)\tTiotropium (n=271)\tOther LABA + tiotropium (n=25)\tTotal (N=1,710)\t\nEgypt\t103 (8.7)\t32 (19.2)\t7 (10.3)\t14 (5.2)\t22 (88.0)\t178 (10.4)\t\nIndia\t34 (2.9)\t88 (52.7)\t0\t0\t0\t122 (7.1)\t\nIndonesia\t22 (1.9)\t0\t0\t12 (4.4)\t0\t34 (2.0)\t\nMiddle East\t844 (71.6)\t43 (25.7)\t61 (89.7)\t184 (67.9)\t3 (12.0)\t1,135 (66.4)\t\n Lebanon\t678 (57.5)\t25 (15.0)\t54 (79.4)\t139 (51.3)\t3 (12.0)\t899 (52.6)\t\n Bahrain\t20 (1.7)\t11 (6.6)\t0\t3 (1.1)\t0\t34 (2.0)\t\n United Arab Emirates\t114 (9.7)\t0\t1 (1.5)\t38 (14.0)\t0\t153 (8.9)\t\n Oman\t22 (1.9)\t0\t6 (8.8)\t2 (0.7)\t0\t30 (1.8)\t\n Kuwait\t10 (0.8)\t7 (4.2)\t0\t2 (0.7)\t0\t19 (1.1)\t\nPhilippines\t40 (3.4)\t0\t0\t9 (3.3)\t0\t49 (2.9)\t\nTaiwan\t70 (5.9)\t3 (1.8)\t0\t24 (8.9)\t0\t97 (5.7)\t\nThailand\t61 (5.2)\t0\t0\t26 (9.6)\t0\t87 (5.1)\t\nSouth Africa\t5 (0.4)\t1 (0.6)\t0\t2 (0.7)\t0\t8 (0.5)\t\nAbbreviation: LABA, long-acting β2-agonist.\n\nTable 2 Patient demographics and baseline characteristics\n\n\tIndacaterol\tIndacaterol + tiotropium\tOther LABA\tTiotropium\tOther LABA + tiotropium\tTotal\t\n\t(n=1,179)\t(n=167)\t(n=68)\t(n=271)\t(n=25)\t(N=1,710)\t\nAge, years\t\n Mean (SD)\t58.6 (11.79)\t62.5 (10.36)\t55.3 (9.77)\t57.6 (12.29)\t59.8 (9.37)\t58.7 (11.71)\t\nAge group, n (%)\t\n <65 years\t818 (69.4)\t94 (56.3)\t56 (82.4)\t192 (70.8)\t16 (64.0)\t1,176 (68.8)\t\n ≥65 years\t361 (30.6)\t73 (43.7)\t12 (17.6)\t79 (29.2)\t9 (36.0)\t534 (31.2)\t\nSex, n (%)\t\n Male\t875 (74.2)\t143 (85.6)\t51 (75.0)\t218 (80.4)\t22 (88.0)\t1,309 (76.5)\t\nRace, n (%)\t\n Caucasian\t819 (69.5)\t75 (44.9)\t62 (91.2)\t163 (60.1)\t25 (100)\t1,144 (66.9)\t\n Asian\t320 (27.1)\t92 (55.1)\t5 (7.4)\t97 (35.8)\t0\t514 (30.1)\t\n Other\t35 (3.0)\t0\t1 (1.5)\t11 (4.1)\t0\t47 (2.7)\t\n Black\t5 (0.4)\t0\t0\t0\t0\t5 (0.3)\t\nSmoking history, pack-years\t\n n\t1,168\t145\t68\t268\t25\t1,674\t\n Mean (SD)\t39.3 (28.03)\t34.0 (23.71)\t33.3 (13.90)\t34.2 (18.90)\t42.0 (28.6)\t37.8 (26.05)\t\nSmoking history, n (%)\t\n Never smoked\t6 (0.5)\t9 (5.4)\t0\t3 (1.1)\t0\t18 (1.1)\t\n Ex-smoker\t361 (30.6)\t88 (52.7)\t13 (19.1)\t81 (29.9)\t10 (40.0)\t553 (32.3)\t\n Current smoker\t812 (68.9)\t70 (41.9)\t55 (80.9)\t187 (69.0)\t15 (60.0)\t1,139 (66.6)\t\nPostbronchodilator FEV1, % predicted\t\n n\t520\t120\t27\t109\t22\t798\t\n Mean (SD)\t60.8 (19.23)\t52.4 (18.10)\t64.5 (12.06)\t60.8 (20.97)\t54.7 (15.47)\t59.5 (19.25)\t\nPostbronchodilator FEV1/FVC, %\t\n n\t517\t110\t27\t111\t22\t787\t\n Mean (SD)\t61.2 (8.97)\t60.0 (12.16)\t61.1 (8.29)\t62.2 (9.13)\t60.6 (11.08)\t61.2 (9.53)\t\nGOLD stage airflow limitation at study entry (based on GOLD 2009), n (%)\t\n GOLD I\t52 (4.4)\t15 (9.0)\t4 (5.9)\t7 (2.6)\t0\t78 (4.6)\t\n GOLD II\t957 (81.2)\t76 (45.5)\t54 (79.4)\t231 (85.2)\t19 (76.0)\t1,337 (78.2)\t\n GOLD III\t135 (11.5)\t57 (34.1)\t9 (13.2)\t27 (10.0)\t5 (20.0)\t233 (13.6)\t\n GOLD IV\t35 (3.0)\t19 (11.4)\t1 (1.5)\t6 (2.2)\t1 (4.0)\t62 (3.6)\t\nCOPD exacerbations in past 12 months\t\n Number\t2,191\t316\t144\t378\t43\t3,072\t\n Mean (SD)\t1.9 (3.35)\t1.9 (5.45)\t2.1 (2.28)\t1.4 (2.20)\t1.7 (1.43)\t1.8 (3.41)\t\nHospitalizations due to COPD exacerbations in past 12 months\t\n Number\t553\t51\t21\t99\t7\t731\t\n Mean (SD)\t0.5 (0.91)\t0.3 (0.82)\t0.3 (0.63)\t0.4 (0.77)\t0.3 (0.68)\t0.4 (0.87)\t\n\n\t\n\t(n=1,103)\t(n=142)\t(n=68)\t(n=250)\t(n=25)\t(N=1,588)\t\nCCQ overall score, points\t\n n\t1,079\t142\t65\t245\t25\t1,556\t\n Mean (SD)\t2.4 (1.02)\t2.7 (1.01)\t2.2 (1.04)\t2.3 (0.94)\t3.3 (1.14)\t2.4 (1.02)\t\nCCQ symptoms domain score, points\t\n n\t1,083\t142\t65\t246\t25\t1,561\t\n Mean (SD)\t2.9 (1.03)\t2.9 (1.20)\t2.6 (1.08)\t2.7 (1.09)\t3.7 (0.98)\t2.8 (1.06)\t\nNote: GOLD staging was based on information reported by the study physician at the baseline visit. The bold letters indicate the total number of participants in each group.\n\nAbbreviations: CCQ, clinical COPD questionnaire; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global initiative for chronic Obstructive Lung Disease; LABA, long-acting β2-agonist; SD, standard deviation.\n\nTable 3 Patients (n, %) with AEs and SAEs\n\n\tIndacaterol (n=1,179)\tIndacaterol + tiotropium (n=167)\tOther LABA (n=68)\tTiotropium (n=271)\tOther LABA + tiotropium (n=25)\tTotal (N=1,710)\t\nTotal AEs, n (%)\t183 (15.5)\t16 (9.6)\t10 (14.7)\t43 (15.9)\t9 (36.0)\t261 (15.3)\t\nNumber (%) of patients with most frequent AEs (occurring in ≥3.0% of patients in any group)\t\n Cough\t50 (4.2)\t7 (4.2)\t3 (4.4)\t8 (3.0)\t0\t68 (4.0)\t\n COPD worsening\t17 (1.4)\t1 (0.6)\t2 (2.9)\t3 (1.1)\t4 (16.0)\t27 (1.6)\t\n Productive cough\t7 (0.6)\t0\t0\t2 (0.7)\t1 (4.0)\t10 (0.6)\t\n Dyspepsia\t3 (0.3)\t0\t1 (1.5)\t1 (0.4)\t2 (8.0)\t7 (0.4)\t\n Headache\t5 (0.4)\t0\t0\t1 (0.4)\t1 (4.0)\t7 (0.4)\t\n LRTI\t2 (0.2)\t2 (1.2)\t0\t1 (0.4)\t1 (4.0)\t6 (0.4)\t\n Infection\t4 (0.3)\t0\t0\t0\t1 (4.0)\t5 (0.3)\t\n Chest pain\t2 (0.2)\t0\t1 (1.5)\t0\t1 (4.0)\t4 (0.2)\t\n Tonsillitis\t1 (0.1)\t0\t0\t0\t2 (8.0)\t3 (0.2)\t\n Diarrhea\t1 (0.1)\t0\t0\t0\t1 (4.0)\t2 (0.1)\t\nDiscontinuation due to\t5 (0.4)\t0\t0\t5 (1.8)\t0\t10 (0.6)\t\nAE/SAE, n (%)\t\nSAEs, n (%)\t15 (1.3)\t4 (2.4)\t0\t7 (2.6)\t0\t26 (1.5)\t\n Deaths, n (%)\t4 (0.3)\t0\t0\t1 (0.4)\t0\t5 (0.3)\t\nAbbreviations: AE, adverse event; COPD, chronic obstructive pulmonary disease; LABA, long-acting β2-agonist; LRTI, lower respiratory tract infection; SAE, serious adverse event.\n==== Refs\nReferences\n1 World Health Organization (WHO) Burden of COPD Available from: http://www.who.int/respiratory/copd/burden/en/ Accessed October 29, 2014 \n2 Global Initiative for Chronic Obstructive Lung Disease (GOLD 2014) Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (Updated 2014) Available from: http://www.goldcopd.org/uploads/users/files/GOLD_Report_2014.pdf Accessed November 13, 2014 \n3 Buist AS McBurnie MA Vollmer WM International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study Lancet 2007 370 9589 741 750 17765523 \n4 Tageldin MA Nafti S Khan JA Distribution of COPD-related symptoms in the Middle East and North Africa: results of the BREATHE study Respir Med 2012 106 Suppl 2 S25 S32 23290701 \n5 Regional COPD Working Group COPD prevalence in 12 Asia-Pacific countries and regions: projections based on the COPD prevalence estimation model Respirology 2003 8 2 192 198 12753535 \n6 Idolor LF DE Guia TS Francisco NA Burden of obstructive lung disease in a rural setting in the Philippines Respirology 2011 16 7 1111 1118 21801277 \n7 McKay AJ Mahesh PA Fordham JZ Majeed A Prevalence of COPD in India: a systematic review Prim Care Respir J 2012 21 3 313 321 22790612 \n8 Uzaslan E Mahboub B Beji M The burden of chronic obstructive pulmonary disease in the Middle East and North Africa: results of the BREATHE study Respir Med 2012 106 Suppl 2 S45 S59 23290704 \n9 Onbrez Breezhaler® 150 and 300 microgram inhalation powder, hard capsules [UK Summary of Product Characteristics] Updated October 23, 2014 Surrey, UK Novartis Pharmaceuticals UK Ltd Available from: http://www.medicines.org.uk/EMC/medicine/23260/SPC/Onbrez+Breezhaler+150+and+300+microgram+inhalation+powder%2c+hard+capsules/ Accessed October 29, 2014 \n10 Pavkov R Mueller S Fiebich K Characteristics of a capsule based dry powder inhaler for the delivery of indacaterol Curr Med Res Opin 2010 26 11 2527 2533 20843166 \n11 Kornmann O Dahl R Centanni S Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison Eur Respir J 2011 37 2 273 279 20693243 \n12 Korn S Kerwin E Atis S Indacaterol once-daily provides superior efficacy to salmeterol twice-daily in COPD: a 12-week study Respir Med 2011 105 5 719 726 21367594 \n13 Donohue JF Fogarty C Lötvall J Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium Am J Respir Crit Care Med 2010 182 2 155 162 20463178 \n14 Dahl R Chung KF Buhl R Efficacy of a new once-daily long-acting inhaled β2 -agonist indacaterol versus twice-daily formoterol in COPD Thorax 2010 65 6 473 479 20522841 \n15 Buhl R Dunn LJ Disdier C Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD Eur Respir J 2011 38 4 797 803 21622587 \n16 Chapman KR Rennard SI Dogra A Long-term safety and efficacy of indacaterol, a long-acting β2 -agonist, in subjects with COPD: a randomized, placebo-controlled study Chest 2011 140 1 68 75 21349928 \n17 Donohue JF Singh D Kornmann O Lawrence D Lassen C Kramer B Safety of indacaterol in the treatment of patients with COPD Int J Chron Obstruct Pulmon Dis 2011 6 477 492 22003293 \n18 Idrees M Koniski ML Taright S Management of chronic obstructive pulmonary disease in the Middle East and North Africa: results of the BREATHE study Respir Med 2012 106 Suppl 2 S33 S44 23290703 \n19 Global Initiative for Chronic Obstructive Lung Disease (GOLD 2009) Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (Updated 2009) Available from: http://www.goldcopd.com Accessed October 29, 2014 \n20 Kocks JW Kerstjens HA Snijders SL Health status in routine clinical practice: validity of the clinical COPD questionnaire at the individual patient level Health Qual Life Outcomes 2010 8 135 21080960 \n21 van der Molen T Willemse BW Schokker S ten Hacken NH Postma DS Juniper EF Development, validity and responsiveness of the Clinical COPD Questionnaire Health Qual Life Outcomes 2003 1 13 12773199 \n22 Kocks JW Tuinenga MG Uil SM van den Berg JW Ståhl E van der Molen T Health status measurement in COPD: the minimal clinically important difference of the clinical COPD questionnaire Respir Res 2006 7 62 16603063 \n23 Ställberg B Nokela M Ehrs PO Hjemdal P Jonsson EW Validation of the clinical COPD Questionnaire (CCQ) in primary care Health Qual Life Outcomes 2009 7 26 19320988 \n24 Calverley PM Anderson JA Celli B Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease N Engl J Med 2007 356 8 775 789 17314337 \n25 Wedzicha JA Calverley PM Seemungal TA The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide Am J Respir Crit Care Med 2008 177 1 19 26 17916806 \n26 Kocks JW van den Berg JW Kerstjens HA Day-to-day measurement of patient-reported outcomes in exacerbations of chronic obstructive pulmonary disease Int J Chron Obstruct Pulmon Dis 2013 8 273 286 23766644 \n27 Bateman ED Ferguson GT Barnes N Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study Eur Respir J 2013 42 6 1484 1494 23722616 \n28 Chapman KR Fogarty CM Peckitt C Delivery characteristics and patients’ handling of two single-dose dry-powder inhalers used in COPD Int J Chron Obstruct Pulmon Dis 2011 6 353 363 21760722 \n29 Molimard M Colthorpe P Inhaler devices for chronic obstructive pulmonary disease: insights from patients and healthcare practitioners J Aerosol Med Pulm Drug Deliv 2015 28 3 219 228 25265316 \n30 Herland K Akselsen JP Skjønsberg OH Bjermer L How representative are clinical study patients with asthma or COPD for a larger “real life” population of patients with obstructive lung disease? Respir Med 2005 99 1 11 19 15672843 \n31 Saturni S Bellini F Braido F Randomized controlled trials and real life studies. Approaches and methodologies: a clinical point of view Pulm Pharmacol Ther 2014 27 2 129 138 24468677 \n32 Ohno T Wada S Hanada S Sawaguchi H Muraki M Tohda Y Efficacy of indacaterol on quality of life and pulmonary function in patients with COPD and inhaler device preferences Int J Chron Obstruct Pulmon Dis 2014 9 107 114 24489464 \n33 Singh MP Indacaterol therapy in moderate-to-severe chronic obstructive pulmonary disease: findings from a single-center primary care cohort Int J Chron Obstruct Pulmon Dis 2013 8 613 619 24353411 \n34 Hataji O Naito M Ito K Watanabe F Gabazza EC Taguchi O Indacaterol improves daily physical activity in patients with chronic obstructive pulmonary disease Int J Chron Obstruct Pulmon Dis 2013 8 1 5 23293514\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-9106",
"issue": "10()",
"journal": "International journal of chronic obstructive pulmonary disease",
"keywords": "Asia; Middle East; chronic obstructive pulmonary disease; indacaterol; long-acting bronchodilator; noninterventional study",
"medline_ta": "Int J Chron Obstruct Pulmon Dis",
"mesh_terms": "D000280:Administration, Inhalation; D000328:Adult; D000349:Africa; D000368:Aged; D001208:Asia; D001993:Bronchodilator Agents; D003692:Delayed-Action Preparations; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007189:Indans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive; D015363:Quinolones; D000069447:Tiotropium Bromide; D016896:Treatment Outcome",
"nlm_unique_id": "101273481",
"other_id": null,
"pages": "2109-20",
"pmc": null,
"pmid": "26491281",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "12753535;15672843;16603063;17314337;17765523;17507545;17916806;12773199;19320988;20522841;20463178;20843166;21080960;20693243;21367594;21349928;21760722;21801277;21622587;22003293;22790612;23293514;23290701;23290703;23290704;23766644;23722616;24353411;24489464;24468677;25265316",
"title": "A real-world evaluation of indacaterol and other bronchodilators in COPD: the INFLOW study.",
"title_normalized": "a real world evaluation of indacaterol and other bronchodilators in copd the inflow study"
} | [
{
"companynumb": "LB-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-63319BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "LB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TIOTROPIUM BROMIDE MONOHYDRATE"
... |
{
"abstract": "OBJECTIVE\nTo report a case of pelvic angiosarcoma in a 27-year-old man with Li-Fraumeni Syndrome (LFS) and evaluate the presentation and timeline of genitourinary (GU) tract involvement in LFS patients.\n\n\nMETHODS\nWe retrospectively identified 39 LFS patients treated at our institution between 2000 and 2014; 7 (18%) had experienced a GU malignancy or an LFS-related malignancy involving the GU tract. Clinical characteristics, including dates of onset of first GU tract malignancies; pathologic findings; multimodal management; and familial history of LFS were reviewed.\n\n\nRESULTS\nMedian age at first malignancy was 14.0 years (interquartile range [IQR] 5.5-24.0). There was a slight male predominance (4 of 7). Median time between first malignancy and the malignancy involving the GU tract was 10.1 years (IQR 8.0-19.5). Six of the 7 patients (86%) had a form of sarcoma involving the GU tract; 1 developed adrenocortical carcinoma. The cancer pedigree of all patients showed LFS-associated malignancies in family members. Multimodal management included surgical resection in 6 patients with adjuvant chemotherapy or radiotherapy in 1 patient each. One patient received chemotherapy only. Following diagnosis of malignancy involving the GU tract, 5 of the 7 patients developed additional primary malignancies. At a median follow-up of 4.7 years (IQR 3.0-12.1), 2 patients are alive, 3 died of disease, and 1 died of unknown cause. One patient was lost at follow-up.\n\n\nCONCLUSIONS\nContinued follow-up of LFS cancer patients aimed at the determination of optimal screening, management, and surveillance protocols is recommended and may result in longer survival expectations.",
"affiliations": "Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Surgery, Division of Urology, University of Missouri, Columbia, MO. Electronic address: murraykat@health.missouri.edu.;Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; Stony Brook Medicine, SUNY at Stony Brook, Stony Brook, NY.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY.;Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, NY.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY; Duke Cancer Institute, Durham, NC.;Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY.;Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY.",
"authors": "Murray|Katie S|KS|;Spaliviero|Massimiliano|M|;Tonorezos|Emily S|ES|;Lacouture|Mario E|ME|;Tap|William D|WD|;Oeffinger|Kevin C|KC|;Vargas|Hebert Alberto|HA|;Eastham|James A|JA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.urology.2018.06.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-4295",
"issue": "119()",
"journal": "Urology",
"keywords": null,
"medline_ta": "Urology",
"mesh_terms": "D000328:Adult; D017809:Fatal Outcome; D006801:Humans; D016864:Li-Fraumeni Syndrome; D008297:Male; D012189:Retrospective Studies; D014565:Urogenital Neoplasms",
"nlm_unique_id": "0366151",
"other_id": null,
"pages": "55-61",
"pmc": null,
"pmid": "29935265",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10617473;11474498;11498785;15643668;16370914;17483435;19086841;19204208;1933872;1978757;20478780;20522432;21601526;22313396;23584479;23670029;24642672;24651012;25896519;25982339;26580448;26793489;26833171;3409256;5360287;8516323;8611417;9764816",
"title": "Li-Fraumeni Syndrome-related Malignancies Involving the Genitourinary Tract: Review of a Single-institution Experience.",
"title_normalized": "li fraumeni syndrome related malignancies involving the genitourinary tract review of a single institution experience"
} | [
{
"companynumb": "PHHY2018US142300",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "OBJECTIVE\nSeveral guidelines recommend erlotinib, pemetrexed, or docetaxel for second-line chemotherapy in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). The aim of this study was to retrospectively evaluate the efficacy of erlotinib, pemetrexed, and docetaxel in epidermal growth factor receptor (EGFR) mutation-negative patients with previously treated advanced non-squamous NSCLC.\n\n\nMETHODS\nWe analyzed the efficacy of these agents in patients with previously treated advanced non-squamous NSCLC who had EGFR wild-type tumors, performance status (PS) of 0, 1, or 2 and received erlotinib, pemetrexed, or docetaxel between December 2007 and September 2011. Variability among patient backgrounds was evaluated using propensity scores to assess comparability. The efficacy of these agents was evaluated in patient subgroups with low variability.\n\n\nRESULTS\nThe propensity scores showed that the backgrounds of the groups that received second-line therapy with each agent had low variability and were adequate for comparison. Patients were divided into the PS0/1 and PS2 groups for analysis. The median progression-free survival (PFS) in patients treated with erlotinib was 2.8 months in the PS0/1 group, as compared with 1.0 month in the PS0/1/2 group and 0.90 months in the PS2 group. PFS in PS0/1 patients who received erlotinib was comparable to that in PS0/1 patients who received pemetrexed (2.5 months) or docetaxel (1.9 months). Overall survival (OS) in erlotinib-, pemetrexed-, and docetaxel-treated PS0/1 patients was 16.1, 7.4 and 10.0 months, respectively. The study had limited power to detect differences in PFS and OS because of the small sample size.\n\n\nCONCLUSIONS\nErlotinib appears to be a useful second-line option in PS0/1 patients with EGFR mutation-negative advanced non-squamous NSCLC given its mild adverse effects. The results should be carefully interpreted because of the small sample size, limited power, and retrospective nature of the study.",
"affiliations": "Department of Respiratory Medicine, Kurashiki Central Hospital, Japan.;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Japan. Electronic address: kabu568459@yahoo.co.jp.;Department of Respiratory Medicine, Kurashiki Central Hospital, Japan.;Department of Respiratory Medicine, Kurashiki Central Hospital, Japan.;Department of Respiratory Medicine, Kurashiki Central Hospital, Japan.;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Japan.;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Japan.;Division of Pulmonary Medicine, Kobe City Medical Center General Hospital, Japan.;Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Japan.;Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Japan.;Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Japan.;Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Japan.;Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Japan.;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Japan.;Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Japan.",
"authors": "Nishiyama|Akihiro|A|;Katakami|Nobuyuki|N|;Yoshioka|Hiroshige|H|;Iwasaku|Masahiro|M|;Korogi|Yohei|Y|;Hata|Akito|A|;Takeshita|Jumpei|J|;Otsuka|Kojiro|K|;Nishino|Kazumi|K|;Uchida|Junji|J|;Okuyama|Takako|T|;Namba|Yoshinobu|Y|;Mori|Masahide|M|;Fujita|Shiro|S|;Morita|Satoshi|S|",
"chemical_list": "D043823:Taxoids; D000068437:Pemetrexed; D000077143:Docetaxel; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "89(3)",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "Docetaxel; EGFR mutation-negative; Erlotinib; Non-squamous non-small-cell lung cancer; Pemetrexed; Performance status; Second-line treatment",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D000077143:Docetaxel; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D000068437:Pemetrexed; D012189:Retrospective Studies; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "301-5",
"pmc": null,
"pmid": "26141215",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Retrospective efficacy and safety analyses of erlotinib, pemetrexed, and docetaxel in EGFR-mutation-negative patients with previously treated advanced non-squamous non-small-cell lung cancer.",
"title_normalized": "retrospective efficacy and safety analyses of erlotinib pemetrexed and docetaxel in egfr mutation negative patients with previously treated advanced non squamous non small cell lung cancer"
} | [
{
"companynumb": "JP-ASTELLAS-2013US003209",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ERLOTINIB"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nDrug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction.\n\n\nMETHODS\nWe performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background.\n\n\nRESULTS\nAC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P=4.8×10(-14)), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10(-4)). An independent association was observed in the class I region (rs2523822, P=1.8×10(-10)), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10(-6)) and HLA-DQB1*0602 (P=5×10(-10)) and their interaction (P=.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10(-4)).\n\n\nCONCLUSIONS\nClass I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values.",
"affiliations": "Facultad de Medicina, Hospital Universitario Virgen de la Victoria, Campus Universitario s/n, Málaga and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.",
"authors": "Lucena|M Isabel|MI|;Molokhia|Mariam|M|;Shen|Yufeng|Y|;Urban|Thomas J|TJ|;Aithal|Guruprasad P|GP|;Andrade|Raúl J|RJ|;Day|Christopher P|CP|;Ruiz-Cabello|Francisco|F|;Donaldson|Peter T|PT|;Stephens|Camilla|C|;Pirmohamed|Munir|M|;Romero-Gomez|Manuel|M|;Navarro|Jose Maria|JM|;Fontana|Robert J|RJ|;Miller|Michael|M|;Groome|Max|M|;Bondon-Guitton|Emmanuelle|E|;Conforti|Anita|A|;Stricker|Bruno H C|BH|;Carvajal|Alfonso|A|;Ibanez|Luisa|L|;Yue|Qun-Ying|QY|;Eichelbaum|Michel|M|;Floratos|Aris|A|;Pe'er|Itsik|I|;Daly|Mark J|MJ|;Goldstein|David B|DB|;Dillon|John F|JF|;Nelson|Matthew R|MR|;Watkins|Paul B|PB|;Daly|Ann K|AK|;|||;|||;|||;|||;|||",
"chemical_list": "D000900:Anti-Bacterial Agents; D015234:HLA-A Antigens; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D019980:Amoxicillin-Potassium Clavulanate Combination",
"country": "United States",
"delete": false,
"doi": "10.1053/j.gastro.2011.04.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-5085",
"issue": "141(1)",
"journal": "Gastroenterology",
"keywords": null,
"medline_ta": "Gastroenterology",
"mesh_terms": "D056704:Adaptive Immunity; D000368:Aged; D000369:Aged, 80 and over; D019980:Amoxicillin-Potassium Clavulanate Combination; D000900:Anti-Bacterial Agents; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury; D016009:Chi-Square Distribution; D005060:Europe; D005260:Female; D005787:Gene Frequency; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015234:HLA-A Antigens; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D014481:United States; D044465:Whites",
"nlm_unique_id": "0374630",
"other_id": null,
"pages": "338-47",
"pmc": null,
"pmid": "21570397",
"pubdate": "2011-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "17006920;17924348;16753010;8651842;19733727;19132805;16083708;19018717;19643668;18955056;12484709;18075792;18760391;20435227;16998491;15931258;10535882;20800921;12143055;15608640;8229110;11034591;2791808;15206996;17133470;16187174;18758442;21245432;19458352;17505501;15185301;17701901;20639878;20126254;19483685;17339877",
"title": "Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles.",
"title_normalized": "susceptibility to amoxicillin clavulanate induced liver injury is influenced by multiple hla class i and ii alleles"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-06482",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDRALAZINE HYDROCHLORIDE"
},
... |
{
"abstract": "Calciphylaxis is a rare and severe condition, characterized by calcification and thrombosis of small vessels, mainly affecting the skin. It is most often described in patients with end-stage renal disease on dialysis. Rarer cases of non-uremic calciphylaxis are reported. The prognosis is grim and the treatment is not well codified. Sodium thiosulfate has been used for more than a decade in the treatment of uremic calciphylaxis and has been shown to be effective. Its use in non-uremic cases has been reported in a few rare observations. Rheopheresis is a technique very recently used as an adjuvant treatment in uremic calciphylaxis. We describe a case of non-uremic calciphylaxis in a patient with normal renal function and with calcium supplementation. Sodium thiosulfate was introduced, then discontinued due to the patient's poor tolerance for this treatment. Rheopheresis was then used and allowed the acceleration of healing process and a significant reduction in pain. These two treatments are promising, larger studies are needed to establish their effectiveness in non-uremic calciphylaxis.",
"affiliations": "Service de dermatologie, centre hospitalier Henri-Duffaut, 84000 Avignon, France; Service de dermatologie et de vénéréologie, CHU Ibn Sina, Université Mohamed V, 10100 Rabat, Maroc. Electronic address: hamich.soumaya@gmail.com.;Service de rhumatologie-médecine interne, CHU Morafeno, 501 Toamasina, Madagascar.;Service de dermatologie, centre hospitalier Henri-Duffaut, 84000 Avignon, France.;Service d'anatomopathologie, centre hospitalier Henri-Duffaut, 84000 Avignon, France.;Service de néphrologie, centre hospitalier Henri-Duffaut, 84000 Avignon, France.;Service de dermatologie, centre hospitalier Henri-Duffaut, 84000 Avignon, France.;Service de dermatologie, centre hospitalier Henri-Duffaut, 84000 Avignon, France.",
"authors": "Hamich|Soumaya|S|;Rakotoson|Julien|J|;Mazereeuw|Martin|M|;Tristani|Hugo|H|;Lavelle|Olivier|O|;Sanchez|Michèle|M|;Lagrange|Brigitte|B|",
"chemical_list": "D000077264:Calcium-Regulating Hormones and Agents; D002117:Calcitriol; D002118:Calcium",
"country": "France",
"delete": false,
"doi": "10.1016/j.nephro.2020.09.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1769-7255",
"issue": "16(7)",
"journal": "Nephrologie & therapeutique",
"keywords": "Calciphylaxie non urémique; Calciphylaxie urémique; Non-uremic calciphylaxis; Rheopheresis; Rhéophérèse; Sodium; Thiosulfate; Thiosulfate de sodium; Uremic calciphylaxis",
"medline_ta": "Nephrol Ther",
"mesh_terms": "D000368:Aged; D001781:Blood Component Removal; D002115:Calciphylaxis; D002117:Calcitriol; D002118:Calcium; D000077264:Calcium-Regulating Hormones and Agents; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D007011:Hypoparathyroidism; D007049:Iatrogenic Disease",
"nlm_unique_id": "101248950",
"other_id": null,
"pages": "431-436",
"pmc": null,
"pmid": "33177014",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Iatrogenic non uremic calciphylaxis: A case report.",
"title_normalized": "iatrogenic non uremic calciphylaxis a case report"
} | [
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"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
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"abstract": "BACKGROUND\nVertebral artery dissection is an uncommon, but potentially fatal, vascular event. This case aimed to describe the pathogenesis and clinical presentation of vertebral artery dissection in a term pregnant patient. Moreover, we focused on the differential diagnosis, reviewing the available evidence.\n\n\nMETHODS\nA 39-year-old Caucasian woman presented at 38 + 4 weeks of gestation with a short-term history of vertigo, nausea, and vomiting. Symptoms appeared a few days after cervical spine manipulation by an osteopathic specialist. Urgent magnetic resonance imaging of the head was obtained and revealed an ischemic lesion of the right posterolateral portion of the brain bulb. A subsequent computed tomography angiographic scan of the head and neck showed a right vertebral artery dissection. Based on the correlation of the neurological manifestations and imaging findings, a diagnosis of vertebral artery dissection was established. The patient started low-dose acetylsalicylic acid and prophylactic enoxaparin following an urgent cesarean section.\n\n\nCONCLUSIONS\nVertebral artery dissection is a rare but potential cause of neurologic impairments in pregnancy and during the postpartum period. It should be considered in the differential diagnosis for women who present with headache and/or vertigo. Women with a history of migraines, hypertension, or autoimmune disorders in pregnancy are at higher risk, as well as following cervical spine manipulations. Prompt diagnosis and management of vertebral artery dissection are essential to ensure favorable outcomes.",
"affiliations": "Obstetrics and Gynecology Unit, Mother - Infant and Adult Department of Medical and Surgical Sciences, University Hospital Policlinico of Modena, Via del Pozzo 71, 41124, Modena, Italy. francesca.monari@unimore.it.;Department of Anaesthesia and Intensive Care, University Hospital of Modena, Modena, Italy.;Obstetrics and Gynecology Unit, Mother - Infant and Adult Department of Medical and Surgical Sciences, University Hospital Policlinico of Modena, Via del Pozzo 71, 41124, Modena, Italy.;Obstetrics and Gynecology Unit, Mother - Infant and Adult Department of Medical and Surgical Sciences, University Hospital Policlinico of Modena, Via del Pozzo 71, 41124, Modena, Italy.;Department of Anaesthesia and Intensive Care, University Hospital of Modena, Modena, Italy.;Department of Anaesthesia and Intensive Care, University Hospital of Modena, Modena, Italy.;Department of Neuroradiology, University Hospital Policlinico of Modena, Via del Pozzo 71, 41124, Modena, Italy.;Obstetrics and Gynecology Unit, Mother - Infant and Adult Department of Medical and Surgical Sciences, University Hospital Policlinico of Modena, Via del Pozzo 71, 41124, Modena, Italy.",
"authors": "Monari|Francesca|F|http://orcid.org/0000-0002-1831-3086;Busani|Stefano|S|;Imbrogno|Maria Giovanna|MG|;Neri|Isabella|I|;Girardis|Massimo|M|;Ghirardini|Annamaria|A|;Cavalleri|Francesca|F|;Facchinetti|Fabio|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13256-021-03090-z",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n3090\n10.1186/s13256-021-03090-z\nCase Report\nVertebral artery dissection in term pregnancy after cervical spine manipulation: a case report and review the literature\nhttp://orcid.org/0000-0002-1831-3086\nMonari Francesca francesca.monari@unimore.it\n\n1\nBusani Stefano 2\nImbrogno Maria Giovanna 1\nNeri Isabella 1\nGirardis Massimo 2\nGhirardini Annamaria 2\nCavalleri Francesca 3\nFacchinetti Fabio 1\n1 grid.413363.0 0000 0004 1769 5275 Obstetrics and Gynecology Unit, Mother - Infant and Adult Department of Medical and Surgical Sciences, University Hospital Policlinico of Modena, Via del Pozzo 71, 41124 Modena, Italy\n2 grid.413363.0 0000 0004 1769 5275 Department of Anaesthesia and Intensive Care, University Hospital of Modena, Modena, Italy\n3 grid.413363.0 0000 0004 1769 5275 Department of Neuroradiology, University Hospital Policlinico of Modena, Via del Pozzo 71, 41124 Modena, Italy\n20 10 2021\n20 10 2021\n2021\n15 5308 2 2021\n2 9 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nVertebral artery dissection is an uncommon, but potentially fatal, vascular event. This case aimed to describe the pathogenesis and clinical presentation of vertebral artery dissection in a term pregnant patient. Moreover, we focused on the differential diagnosis, reviewing the available evidence.\n\nCase presentation\n\nA 39-year-old Caucasian woman presented at 38 + 4 weeks of gestation with a short-term history of vertigo, nausea, and vomiting. Symptoms appeared a few days after cervical spine manipulation by an osteopathic specialist. Urgent magnetic resonance imaging of the head was obtained and revealed an ischemic lesion of the right posterolateral portion of the brain bulb. A subsequent computed tomography angiographic scan of the head and neck showed a right vertebral artery dissection. Based on the correlation of the neurological manifestations and imaging findings, a diagnosis of vertebral artery dissection was established. The patient started low-dose acetylsalicylic acid and prophylactic enoxaparin following an urgent cesarean section.\n\nConclusion\n\nVertebral artery dissection is a rare but potential cause of neurologic impairments in pregnancy and during the postpartum period. It should be considered in the differential diagnosis for women who present with headache and/or vertigo. Women with a history of migraines, hypertension, or autoimmune disorders in pregnancy are at higher risk, as well as following cervical spine manipulations. Prompt diagnosis and management of vertebral artery dissection are essential to ensure favorable outcomes.\n\nKeywords\n\nVertebral artery dissection\nPregnancy\nVertebrobasilar ischemia\nCervical spine manipulation\nOsteopathy\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nVertebral arterial dissection (VAD) is a rare complication of pregnancy and puerperium. A data registry reported that 2.4% of symptomatic, spontaneous VADs occurred in the postpartum period [1]. Aortic, coronary, and cervical/vertebral artery dissection was reported to be associated with preeclampsia in the antenatal setting [1]. On the other hand, VAD incidence in hypertensive disorders of pregnancy is unknown, due to the paucity of reports documenting only adverse outcomes [1]. Hormonal and mechanical factors might increase the risk of VAD during pregnancy and puerperium [2]. Indeed, identified predisposing factors of VAD include intimal injury related to Valsalva maneuvers during labor, and alterations in arterial wall integrity due to hormonal or vasoactive substances, in addition to an overall state of hypercoagulability [3]. Another possible condition that can lead to VAD is cervical spine manipulation [4]. It is known that any type of trauma can cause a dissection such as cervical manipulation. Therefore, in nonpregnant patients, it is not uncommon, but most patients are asymptomatic, and this serious accident after manipulation has an underestimated incidence. Nevertheless, the risk related to the development of VAD is decidedly low if the manipulation maneuvers are carried out according to good clinical practice [4]. Several vascular and connective tissue disorders have also been associated with dissection; in particular, migraines, fibromuscular hyperplasia, and vascular Ehlers–Danlos syndrome [5]. As previously stated, the etiology of VAD is complex and often multifactorial, especially when trivial trauma and manipulations are involved. Other risk factors or conditions, such as fibromuscular dysplasia, Marfan’s syndrome, migraines, use of oral contraceptives, recent infections, and mild hyperhomocysteinemia, should be considered in any given case [6]. There exists uncertainty of how to counsel women with a previous VAD, regarding the risk of recurrence during pregnancy [2].\n\nWe aim to describe a 39-year-old female who presented with vertigo, nausea, and vomiting and was found to have a VAD. We discuss the presentation, differential diagnosis, and pathogenesis of this uncommon, but clinically significant, vascular event. Finally, we briefly review other described VAD cases.\n\nCase presentation\n\nA 39-year-old pregnant Caucasian woman presented to the Obstetric Emergency Room reporting vertigo, vomiting, nystagmus, dizziness, and hindrance in the execution of fine movements of the right arm. The maternal parameters on admission are regular: pulse 98 beats per minute, pressure 110/68 mmHg, and temperature of 36.2 °C. She had an obstetric history of a first-trimester spontaneous abortion and a medical history of tension headache. She is married and graduated. She has a high socioeconomic status and is employed as an engineer.\n\nThe ongoing pregnancy coursed physiologically until that moment. The fetus was screened for aneuploidy with a noninvasive prenatal test (NIPT), while second- and third-trimester ultrasounds for the study of malformations were both normal. The oral glucose tolerance test at 24 weeks was negative. At 38 + 4-week gestation, the patient was hospitalized due to suspected vestibular neuritis diagnosed by an otolaryngology (ORL) specialist. Following diagnosis, the patient started therapy with corticosteroids, including prednisone 5 mg two times per day and levosulpiride 25 mg two times per day, that continued for 3 days.\n\nOn day 2, the patient developed diplopia and worsening of vomiting and dizziness, with improvement of symptoms in left lateral decubitus. The ORL revaluation excluded peripheral vestibulopathy and progressed to an urgent brain computed tomography (CT) scan without contrast that excluded ischemic or hemorrhagic brain lesions.\n\nOn day 3, due to further worsening of symptoms, urgent neurological counseling was performed. Viral examinations of herpes simplex I and II, herpes zoster, and herpes virus VI were negative. The neurologic examination showed the left eye adducted and elevated, vertical diplopia, and presence of rotatory nystagmus accentuated on the right gaze and dyssynergia in the cerebellar maneuvers of the right upper limb. After a detailed medical history, the patient stated for the first time that she had undergone cervical spine manipulations by an osteopathic specialist in the days preceding the beginning of the symptoms. Magnetic resonance imaging (MRI) of the brain was urgently performed, showing a punctate lesion hyperintense on diffusion-weighted imaging (DWI) (Fig. 1A–B), characterized by a reduction of apparent diffusion coefficient (ADC) on the colorimetric maps. This finding was suggestive of ischemia in the posterolateral right medulla oblongata, which is consistent with the symptoms of Wallenberg syndrome, although the patient did not have the full spectrum of symptoms. On MR angiography, the intracranial V4 segment was normal, but the right posteroinferior cerebellar artery (PICA) was not present (Fig. 1E). Urgent thrombolytic therapy or emergency revascularization was not deemed necessary by the neurologist colleague. Acetylsalicylic acid (ASA), 100 mg, therapy was then prescribed. Subsequently, echo-color Doppler ultrasound of the supra-aortic trunk detected no alterations of the cervical vessels, and transthoracic echocardiogram with exclusion of patency of the foramen ovale was performed. During this observation period, the patient was continuously monitored with noninvasive blood pressure monitor and pulse oximeter to detect hypotensive state and/or desaturation episodes early. Considering the clinical condition of the patient, the term gestational age, and initial onset of prodromal contractions, an elective cesarean section (CS) under subarachnoid anesthesia was performed, given the inability of the patient to deliver vaginally because of the ischemic cerebral event and obligatory left lateral decubitus, diplopia, and dizziness. The intraoperative and postoperative courses were uneventful. Six hours after the CS, prophylaxis with low-molecular-weight heparin was prescribed.Fig. 1 Right vertebral artery dissection with ischemia in the posterolateral medulla oblongata. In DWI (a) and ADC map (b) the arrow shows a punctate, shiny ischemic lesion, with typical reduction of ADC in the right posterolateral medulla oblongata. c and d CT angiography (axial and 3D reformat, c and d, respectively) showing a focal dissection of the V2 distal segment of the right vertebral artery, with the arrow in figure c pointing to the dissection. e MRI angiography (time of flight, TOF) showing the absence of visualization of right PICA\n\nThe neonate showed good adaptation to postnatal life with an Apgar score of 9 at 1′, 10 at 5′, and 10 at 10′; blood gas analysis was regular both in the artery and vein. Normal anthropometric parameters were present: 3250 g (52nd centile), length of 49 cm, and cranial circumference of 36 cm.\n\nOn day 4, for better study suspected dissection on small vertebral vessels, the patient underwent CT angiography of the neck, which showed a focal dissection at the V2 distal segment of the right vertebral artery (Fig. 1C–D). The puerperium course was normal, and the midwife helped the patient during breastfeeding because of the difficulty of standing up and walking due to the diplopic symptom. Psychological support was offered during the hospitalization, with daily physiotherapy rehabilitation and orthoptic evaluation. Congenital and acquired thrombophilia tested negative. After 12 days of rehabilitation, the patient was discharged with continued complaints of diplopia and a walker for mobility. After the VAD diagnosis and for the entire length of hospitalization, the patient was treated with Cardioaspirin 100 mg/day and prophylactic enoxaparin 4000 UI/day subcutaneous injection for 60 days. At the subsequent neurological evaluation, during the follow-up of 2 and 4 months, the patient showed persistence of vertical diplopia and a circumspect and wide gait, and life-long ASA was prescribed. A follow-up MRI was scheduled for 6 months after the stroke, which confirmed the signs of the previous ischemic lesion on the posterolateral right medulla oblongata. The remaining findings are unchanged.\n\nEthical approval was obtained, and the patient gave written informed consent to publish this case and any accompanying images.\n\nDiscussion and conclusion\n\nTo our knowledge, this is one of the rare reports of an ischemic lesion due to VAD in low-risk pregnancy secondary to cervical spine manipulation. Cervical artery dissection (CAD), including VAD, is a rare complication of pregnancy; however, Salehi Omran et al. recently demonstrated that the incidence in pregnancy is twice as common as in the rest of the female population [7]. VAD has typically been associated with hypertensive disorder of pregnancy (HDP) [1, 8], autoimmune disease [9], and migraines [10]. A recent nationwide American cohort study on pregnancy-associated arterial dissection showed that VAD is the fourth most common dissection after or prior birth and found a significant association with older maternal age, chronic hypertension, dyslipidemia, tobacco use, alcohol use, obesity, heart failure, chronic liver disease, arthritis, depression, Marfan syndrome, and Ehlers–Danlos syndrome [11]. However, one recent meta-analysis demonstrated that nearly 50% of cases occur in the absence of such risk factors [12, 13]. To date, the etiology of VAD is not well established. Borelli et al. proposed a dual mechanism of pathogenesis occurring in the postpartum period: (1) advanced age, causing increased arterial stiffness, and (2) hormone fluctuations, inducing structural vascular changes [14], which may also happen at the end of pregnancy in our patient. McKinney et al. also suggested that endothelial damage may occur due to the release of vasoactive or angiogenic substances during pregnancy [15].\n\nVAD should be considered in the differential diagnosis of women who present with nonspecific symptoms, such as headache, vomiting, and/or vertigo, particularly in the context of HDP [1]. Women older than 35 years and those with a history of HDP or autoimmune disease (that is, systemic lupus erythematosus, anti-phospholipid syndrome) are particularly at high risk. Other predisposing factors of arterial dissection in the peripartum period include intimal injury related to Valsalva maneuvers during labor, alterations in arterial wall integrity due to pregnancy-related hormonal or vasoactive substances [9], and reactive thrombocytosis (subsequent to postpartum hemorrhage), which may all play potential roles in this process and require further investigation [16]. Moreover, prompt diagnosis and management of VAD are essential to ensure favorable patient outcomes.\n\nOne recent report discussed the contributing factors in a case of VAD following chiropractic treatment in a pregnant woman with systemic lupus erythematosus [4]. Migraine disorder was shown to be associated with a twofold increased risk of VAD in a recent meta-analysis [9] and has been frequently reported in several case series [17–19]. Stuber et al. recently published a review of the literature regarding adverse effects of spinal manipulation in the pregnant and postpartum periods [20], identifying adverse events in five pregnant women and two postpartum women.\n\nTable 1 summarizes all cases of VAD reported both prior and after delivery, with 24 cases distributed with a prevalence during the postpartum period (19 of the 24 cases). The clinical presentation is varied, with a higher frequency of headaches, vertigo, and diplopia, and the risk factors most represented are hypertension and migraines.Table 1 Review of literature: cases of vertebral artery dissection VAD reported in pregnancy and postpartum period\n\nCases\tAge\tPresentation\tRisk factors\tVAD affected\tMode of delivery\tTime to and from delivery (days)\t\nCurrent report\t39\tVertigo, vomiting, nystagmus, dizziness, and hindrance in the execution of fine movements with the right arm\tMigraine\tRight\tCesarean section\tAntepartum, 39 w\t\nGasecki et al. (1999)\t34\tNeck pain, headache, 1 week later: right facial numbness, left-sided weakness, and vertigo, right. Horner’s syndrome, right-side ataxia,\tHealthy\tRight\tVaginal delivery\t14 days postpartum\t\nMcKinney et al. (2002)\t41\tSevere headache, blurred vision, HTN\tPreeclampsia\tLeft\tCesarean section\t5 days postpartum\t\nTuluc (2006)\t39\tHeadache preceding loss of consciousness\tHTN\tRight\tSubsequent massive subarachnoid hemorrhage with death\tAntepartum\t\nArnold et al. (2008)\t41\tBilateral neck pain\tMigraine, hyperlipidemia\tLeft\tVaginal delivery\t18 days postpartum\t\n27\tIpsilateral neck pain, thunderclap headache\tMigraine, HTN, hyperlipidemia\tRight\tVaginal delivery\t11 days postpartum\t\n\t38\tThunderclap headache\tMigraine, hyperlipidemia\tBilateral\tVaginal delivery\t7 days postpartum\t\n\t34\tIpsilateral neck pain, headache\tChiropractor neck manipulation\tRight\tVaginal delivery\t7 days postpartum\t\nSharma et al. (2010) [29]\t28\tNon-exertional, intermittent, substernal, sharp chest pain, and left arm numbness, intermittent bifrontal headache\tAtherosclerotic risk factors\tLeft\tVaginal delivery\t10 days postpartum\t\nCenkowski et al. (2012) [30]\t35\tSudden-onset retrosternal chest pain radiating to the jaw, nausea, vomiting (7 months postpartum), diplopia, numbness to left arm and face (8 months postpartum)\tNone\tRight\tVaginal delivery\t7 months postpartum\t\nDrazin et al. (2012)\t37\tThunderclap headache, neck pain\tMigraine, hHigh pressure during labor\tBilateral\tVaginal delivery\t3 days postpartum\t\nMorton A. (2012)\t38\tOccipital headache, severe right-sided anterior neck pain, ipsilateral Horner’s syndrome (after chiropractic treatment: spinal manipulation)\tMigraine, SLE, HTN, heterozygous for prothrombin gene mutation\tRight\t4 days after the onset of neurological symptoms intrauterine fetal demise\tAntepartum 16 weeks was noted\t\nKelly et al. (2014)\t39\tThunderclap headache, ipsilateral neck pain, blurred vision, and horizontal diplopia\tHTN, hyperlipidemia\tBilateral\tVaginal delivery\t24 days postpartum\t\n39\tRight eyelid ptosis, headache, and bilateral neck pain\tHealthy\tRight\tVaginal delivery\t11 days postpartum\t\n29\tRight-sided weakness, sensory loss, and expressive aphasia, followed by severe headache and right-sided hemiplegia\tMigraine\tLeft\tVaginal delivery\t53 days postpartum\t\n32\tSevere headache and neck pain, followed by left-sided facial droop and left arm weakness\tMigraine\tRight\tVaginal delivery\t0 days postpartum\t\n28\tSevere headache, neck\n\npain, bilateral leg\n\nweakness\n\n\tHTN\tLeft\tCesarean section\t4 days postpartum\t\nFinley et al. (2015)\t35\tThunderclap headache, intractable vertigo\tMigraine\tRight\tVaginal delivery\t21 days postpartum\t\nNishimura et al. (2015)\t35\tThunderclap headache\tEclampsia, PRES\tRight\t\t8 days postpartum\t\nShanmugalingam et al. (2016)\t32\tLeft-sided neck pain\tPreeclampsia/eclampsia\tLeft\tCesarean section\tAntepartum, 38 + 2 weeks\t\n33\tRight-sided neck pain\tPreeclampsia\tRight\tCesarean section\tAntepartum, 36 weeks\t\n30\tHeadache with left-sided neck pain\tNSAID-induced postpartum HTN, migraines, obesity\tRight\tVaginal delivery\t3 days postpartum\t\n30\tLeft-sided neck pain\tPrevious IUGR and postpartum hemorrhage with DIC\tLeft\tVaginal delivery\t6 days postpartum,\t\nManasewitsch et al. (2020)\t31\tFrontal headache, vertigo, nausea, vomiting\tPreeclampsia, smoking\tLeft\tCesarean section\t10 days postpartum\t\nHTN hypertension, SLE systemic lupus erythematosus, PRES posterior reversible encephalopathy syndrome, NSAID nonsteroidal antiinflammatory drug, IUGR intrauterine growth restriction, DIC disseminated intravasal coagulation\n\nThe association between cervical spine manipulation and neurovascular complications is still strongly debated [21, 22]. CAD is thought to occur spontaneously, but neck trauma, especially in hyperextension and rotation, has been reported as a trigger [23]. A population-based, case–control study found no evidence of excess risk of vertebrobasilar stroke associated with chiropractic care compared with controls [24]. A recent retrospective case–control study, however, found a significantly increased risk of VAD in individuals less than 55 years of age with recent neck manual therapy [25]. A recent multivariable regression analysis of a retrospective study assessed the risk factors and clinical outcomes associated with CAD-related strokes. Patients with CAD were younger and more likely to have a history of migraines and recent neck manipulation [26]. A systematic review and meta-analysis of chiropractic care and CAD concluded that the quality of the published data was very low, and the authors showed a small association between chiropractic neck manipulation and CAD [27, 28].\n\nFinally, the future of these women is somewhat debated. They should be advised about their increased risk of developing a new stroke, so these patients will need to continue Cardioaspirin prophylaxis for life [2]. Regarding reproductive future, a recent observational German study concluded that the risk of recurrent VAD may not be significantly increased with pregnancies, starting at least 12 months after the event, in women without connective tissue disease, such as our patient [2].\n\nDespite the absence of hypertension and autoimmune diseases in our patient, previous chiropractic treatment, pregnancy hormonal condition, and advanced age (39 years) may have contributed to vessel fragility. The risk of VAD was also increased due to the history of tensive headache/migraine. Osteopathy practitioners should be aware of the possible complications of neck manipulation in pregnancy and the postpartum period, particularly in mothers with underlying medical disorders that may predispose to vessel fragility and VAD.\n\nIn conclusion, we recommend that obstetric professionals carefully consider VAD as a differential diagnosis when evaluating women with dizziness, headache, and neck pain with or without a recent history of spinal manipulation, both in pregnancy and in the postpartum period. Moreover, they should consider with caution the risks and benefits of any cervical osteopathy practice in pregnant women with risk factors for VAD (hypertension and autoimmune diseases, history of tensive headache/migraine).\n\nAbbreviations\n\nVAD Vertebral artery dissection\n\nCAD Cervical artery dissection\n\nNIPT Noninvasive prenatal test\n\nORL Otolaryngologist\n\nCT Computed tomography\n\nMRI Magnetic resonance imaging\n\nASA Acetylsalicylic acid\n\nCS Cesarean section\n\nHDP Hypertensive disorder of pregnancy\n\nDWI Diffusion-weighted imaging\n\nADC Apparent diffusion coefficient\n\nPICA Posteroinferior cerebellar artery\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nFM and SB contributed to the clinical management of the patient and the literature review, and wrote the initial draft of this manuscript and subsequent revisions. MGI, FF, IN, FC, MG, AG, and FC contributed to the clinical management and manuscript preparation. All authors have read and approved the final manuscript.\n\nFunding\n\nThere was no funding for the research for this manuscript for any author.\n\nAvailability of data and materials\n\nThis is a case report of a single patient. To protect privacy and respect confidentiality, none of the raw data has been made available in any public repository. The original reports, laboratory studies, imaging studies, and outpatient clinic records are retained, as per normal procedure, within the medical records of our institution.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNo ethics approval was required, as this is a case report. Written and verbal consent was obtained from the patient discussed in this case report.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare they have no financial or other conflicts of interest concerning this research and its publication.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Shanmugalingam R Reza Pour N Chuah SC Vo TM Beran R Hennessy A Vertebral artery dissection in hypertensive disorders of pregnancy: a case series and literature review BMC Pregnancy Childbirth 2016 16 1 164 10.1186/s12884-016-0953-5 27422677\n2. Reinhard M Munz M von Kannen AL Griesser-Leute HJ Dittrich R Engelter ST Risk of recurrent cervical artery dissection during pregnancy, childbirth and puerperium Eur J Neurol 2015 22 4 736 739 10.1111/ene.12602 25444227\n3. Baffour FI Kirchoff-Torres KF Einstein FH Karakash S Miller TS Bilateral internal carotid artery dissection in the postpartum period Obstet Gynecol 2012 119 2 Pt 2 489 492 10.1097/AOG.0b013e318242d8d4 22270449\n4. Tinel D Bliznakova E Juhel C Gallien P Brissot R Vertebrobasilar ischemia after cervical spine manipulation: a case report Ann Readapt Med Phys 2008 51 5 403 414 10.1016/j.annrmp.2008.04.010 18586346\n5. Ohshima T Miyachi S Isaji T Matsuo N Kawaguchi R Takayasu M Bilateral vertebral artery dissection and unilateral carotid artery dissection in case of Ehlers-Danlos syndrome type IV World Neurosurg. 2019 121 83 87 10.1016/j.wneu.2018.09.236 30315974\n6. Gdynia HJ Kühnlein P Ludolph AC Huber R Connective tissue disorders in dissections of the carotid or vertebral arteries J Clin Neurosci 2008 15 5 489 494 10.1016/j.jocn.2007.10.001 18343117\n7. Salehi Omran S Parikh NS Poisson S Armstrong J Merkler AE Prabhu M Association between pregnancy and cervical artery dissection Ann Neurol 2020 88 3 596 602 10.1002/ana.25813 32525238\n8. Leffert LR Clancy CR Bateman BT Bryant AS Kuklina EV Hypertensive disorders and pregnancy-related stroke: frequency, trends, risk factors, and outcomes Obstet Gynecol 2015 125 1 124 131 10.1097/AOG.0000000000000590 25560114\n9. Morton A Internal carotid artery dissection following chiropractic treatment in a pregnant woman with systemic lupus erythematosus Chiropr Man Therap. 2012 20 1 38 10.1186/2045-709X-20-38 23254252\n10. Rist PM Diener HC Kurth T Schürks M Migraine, migraine aura and cervical artery dissection: a systemic review and meta-analysis Cephalalgia 2011 31 8 886 896 10.1177/0333102411401634 21511950\n11. Beyer SE Dicks AB Shainker SA Feinberg L Schermerhorn ML Secemsky EA Pregnancy-associated arterial dissections: a nationwide cohort study Eur Heart J 2020 41 44 4234 4242 10.1093/eurheartj/ehaa497 32728725\n12. Gottesman RF Sharma P Robinson KA Arnan M Tsui M Ladha K Clinical characteristics of symptomatic vertebral artery dissection: a systematic review Neurologist 2012 18 5 245 254 10.1097/NRL.0b013e31826754e1 22931728\n13. Gasecki AP Kwiecinski H Lyrer PA Lynch TG Baxter T Dissections after childbirth J Neurol 1999 246 8 712 715 10.1007/s004150050437 10460450\n14. Borelli P Baldacci F Nuti A Lucetti C Berti C Logi C Postpartum headache due to spontaneous cervical artery dissection Headache 2011 51 5 809 813 10.1111/j.1526-4610.2011.01881.x 21457234\n15. McKinney JS Messé SR Pukenas BA Satti SR Weigele JB Hurst RW Intracranial vertebrobasilar artery dissection associated with postpartum angiopathy Stroke Res Treat. 2010 2010 320627 10.4061/2010/320627 20700423\n16. Manasewitsch NT Hanfy AA Beutler BD Antwi-Amoabeng D Taha M Elnaggar M Postpartum vertebral artery dissection: case report and review of the literature Thromb J 2020 18 1 30 10.1186/s12959-020-00243-w 33292273\n17. Finley A Rogers B Richards T Jr Vogel H Postpartum vertebral artery dissection BMJ Case Rep 2015 10.1136/bcr-2015-211872 26604230\n18. Kelly JC Safain MG Roguski M Edlow AG Malek AM Postpartum internal carotid and vertebral arterial dissections Obstet Gynecol 2014 123 4 848 856 10.1097/AOG.0000000000000189 24785614\n19. Drazin D Rosner J Shirzadi A Phuphanich S Postpartum extracranial bilateral vertebral artery dissection mimicking subarachnoid hemorrhage Neurologist 2012 18 3 149 151 10.1097/NRL.0b013e318247bb59 22549357\n20. Stuber KJ Wynd S Weis CA Adverse events from spinal manipulation in the pregnant and postpartum periods: a critical review of the literature Chiropr Man Ther 2012 20 8 10.1186/2045-709X-20-8\n21. Cassidy JD Bronfort G Hartvigsen J Should we abandon cervical spine manipulation for mechanical neck pain? BMJ 2012 344 e3680 10.1136/bmj.e3680 22677797\n22. Wand BM Heine PJ O'Connell NE Should we abandon cervical spine manipulation for mechanical neck pain? BMJ 2012 344 e3679 10.1136/bmj.e3679 22677796\n23. Chaibi A Russell MB A risk-benefit assessment strategy to exclude cervical artery dissection in spinal manual-therapy: a comprehensive review Ann Med 2019 51 2 118 127 10.1080/07853890.2019.1590627 30889367\n24. Cassidy JD Boyle E Côté P He Y Hogg-Johnson S Silver FL Risk of vertebrobasilar stroke and chiropractic care: results of a population-based case–control and case-crossover study J Manip Physiol Ther 2009 32 2 Suppl S201 S208 10.1016/j.jmpt.2008.11.020\n25. Thomas LC Rivett DA Attia JR Parsons M Levi C Risk factors and clinical features of craniocervical arterial dissection Man Ther 2011 16 4 351 356 10.1016/j.math.2010.12.008 21256072\n26. Garg A Bathla G Molian V Limaye K Hasan D Leira EC Differential risk factors and outcomes of ischemic stroke due to cervical artery dissection in young adults Cerebrovasc Dis 2020 49 5 509 515 10.1159/000510437 32980848\n27. Church EW Sieg EP Zalatimo O Hussain NS Glantz M Harbaugh RE Systematic review and meta-analysis of chiropractic care and cervical artery dissection: no evidence for causation Cureus. 2016 8 2 e498 10.7759/cureus.498 27014532\n28. Haneline MT Lewkovich GN An analysis of the etiology of cervical artery dissections: 1994 to 2004 J Manip Physiol Ther 2005 28 8 617 622 10.1016/j.jmpt.2005.08.016\n29. Sharma AM Herrera B Aronow HD Simultaneous spontaneous coronary and vertebral artery dissection in a postpartum woman J Invasive Cardiol 2010 22 12 E229 E232 21127377\n30. Cenkowski M daSilva M Bordun KA Hussain F Kirkpatrick ID Jassal DS Spontaneous dissection of the coronary and vertebral arteries post-partum: case report and review of the literature BMC Pregnancy Childbirth 2012 12 122 10.1186/1471-2393-12-122 23121892\n\n",
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"keywords": "Cervical spine manipulation; Osteopathy; Pregnancy; Vertebral artery dissection; Vertebrobasilar ischemia",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000328:Adult; D000792:Angiography; D002574:Cervical Vertebrae; D002585:Cesarean Section; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D011247:Pregnancy; D020217:Vertebral Artery Dissection",
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"title": "Vertebral artery dissection in term pregnancy after cervical spine manipulation: a case report and review the literature.",
"title_normalized": "vertebral artery dissection in term pregnancy after cervical spine manipulation a case report and review the literature"
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"abstract": "Sclerotherapy is used to treat varicosities and telangiectases. Glycerin is a sclerosing agent that has been used off-label for years with a favorable adverse effect profile. However, the treatment of facial telangiectases with sclerotherapy is controversial given the potential for necrosis and embolization in relation to the complex vascular anatomy of the face.\n\n\n\nTo determine the safety and efficacy of glycerin sclerotherapy for the treatment of facial telangiectases.\n\n\n\nThe authors report a series of 8 patients with facial telangiectases treated with glycerin sclerotherapy. Glycerin mixed with lidocaine and epinephrine was used. The telangiectases were measured and identified as targets for treatment.\n\n\n\nThe patients ranged in age from 45 to 88 years. Between 0.5 and 1 mL was used to treat telangiectases of the nose and malar cheek area per session. Five of the patients achieved satisfactory results after 1 treatment, whereas patients with more extensive telangiectases required up to 3 sessions with 4-week intervals between each session. Injection site pain was the only reported adverse effect, and no evidence of necrosis or blindness was observed.\n\n\n\nGlycerin sclerotherapy seems to be a safe and effective modality for the treatment of facial telangiectases.",
"affiliations": "Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, North Carolina.;Park Avenue Dermatology, Orange Park, Florida.;Park Avenue Dermatology, Orange Park, Florida.",
"authors": "McGregor|Sean|S|;Miceli|Alyssa|A|;Krishnamurthy|Karthik|K|",
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"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000779:Anesthetics, Local; D015331:Cohort Studies; D005148:Facial Dermatoses; D005260:Female; D005990:Glycerol; D006801:Humans; D008012:Lidocaine; D008297:Male; D008875:Middle Aged; D012597:Sclerosing Solutions; D015911:Sclerotherapy; D013684:Telangiectasis; D016896:Treatment Outcome",
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"abstract": "To describe a case of massive spontaneous subconjunctival hemorrhage in a patient taking warfarin with a therapeutic international normalized ratio (INR).\nMassive circumferential hemorrhagic chemosis, extensive periorbital and facial ecchymosis, and active arterial extravasation in the subconjunctiva which required cessation and reversal of anticoagulation. Findings gradually resolved over several months after discharge.\nWhile subconjunctival hemorrhage, even in anticoagulated patients, is usually benign, rare examples of severe presentations exist. We present, to our knowledge, the first documented case of a subconjunctival hemorrhage necessitating cessation and reversal of anticoagulation in the setting of a therapeutic INR.",
"affiliations": "College of Medicine, University of Cincinnati, 3230 Eden Ave, Cincinnati, OH, 45267, USA.;College of Medicine, University of Cincinnati, 3230 Eden Ave, Cincinnati, OH, 45267, USA.;Department of Ophthalmology, University of Cincinnati, 3230 Eden Ave, Cincinnati, OH, 45267, USA.;Department of Ophthalmology, University of Cincinnati, 3230 Eden Ave, Cincinnati, OH, 45267, USA.",
"authors": "Philip|Andrew M|AM|;Fry|Matthew V|MV|;Hermanson|Meghan E|ME|;Kelly|Lisa D|LD|",
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"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936\nElsevier\n\nS2451-9936(21)00040-2\n10.1016/j.ajoc.2021.101049\n101049\nCase Report\nMassive spontaneous subconjunctival hemorrhage in a patient on therapeutic warfarin: A case report\nPhilip Andrew M. a\nFry Matthew V. a\nHermanson Meghan E. b\nKelly Lisa D. KellyL5@ucmail.uc.edu\nb∗\na College of Medicine, University of Cincinnati, 3230 Eden Ave, Cincinnati, OH, 45267, USA\nb Department of Ophthalmology, University of Cincinnati, 3230 Eden Ave, Cincinnati, OH, 45267, USA\n∗ Corresponding author. KellyL5@ucmail.uc.edu\n26 2 2021\n6 2021\n26 2 2021\n22 1010497 9 2020\n3 1 2021\n21 2 2021\n© 2021 The Authors. Published by Elsevier Inc.\n2021\n\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nPurpose\n\nTo describe a case of massive spontaneous subconjunctival hemorrhage in a patient taking warfarin with a therapeutic international normalized ratio (INR).\n\nObservations\n\nMassive circumferential hemorrhagic chemosis, extensive periorbital and facial ecchymosis, and active arterial extravasation in the subconjunctiva which required cessation and reversal of anticoagulation. Findings gradually resolved over several months after discharge.\n\nConclusions and importance\n\nWhile subconjunctival hemorrhage, even in anticoagulated patients, is usually benign, rare examples of severe presentations exist. We present, to our knowledge, the first documented case of a subconjunctival hemorrhage necessitating cessation and reversal of anticoagulation in the setting of a therapeutic INR.\n\nKeywords\n\nWarfarin\nAnticoagulation\nSubconjunctival hemorrhage\nReversal\nSpontaneous\n==== Body\n1 Introduction\n\nSubconjunctival hemorrhage (SCH) is a typically benign process characterized by acute, painless bleeding into the subconjunctival space.1 It is a common ocular condition with risk factors that include hypertension, hyperlipidemia, diabetes mellitus, anticoagulation therapy, and increased age (particularly over 50-years old given the previously mentioned risk factors).2 While often spontaneous, SCH can be caused by Valsalva maneuvers, ocular and orbital trauma, and potentially serious systemic causes of coagulopathy.3 Warfarin, the most prescribed outpatient anticoagulant in North America, is a known cause of spontaneous SCH, with an incidence of 0.35–1.56%.4,5\n\nWhile a supratherapeutic international normalized ratio (INR) has not been shown to increase the risk of SCH, patients on warfarin with SCH should have their INR and prothrombin time (PT) checked to evaluate systemic coagulation status.1,5 Warfarin-associated SCH usually resolves spontaneously after 5–10 days and rarely requires more than supportive care.5 Documented cases of severe warfarin-associated SCH requiring cessation of anticoagulation,6 cessation and surgical evacuation,7 or cessation and reversal of supratherapeutic anticoagulation are extremely rare in the literature.8 Usually, SCH are self-limiting, not overly severe, and do not require intervention. Therefore, formalized guidelines for proper anticoagulation management in warfarin-associated SCH do not exist and clinical judgement usually dictates treatment strategy.\n\nHerein, we present a case that, to our knowledge, is the only reported occurrence of a warfarin-associated SCH in which the severity of presentation necessitated inpatient admission with cessation and reversal of anticoagulation in the setting of a therapeutic INR. This uniquely severe presentation of a condition universally regarded as benign provides the opportunity to examine the current literature regarding warfarin-associated SCH and offer insights to management strategies.\n\n2 Case report\n\nAn 86-year-old Caucasian male presented to our institution's Emergency Department (ED) in May 2020 with progressive swelling and bleeding of his right eye with visual obstruction. His medical history was significant for hypertension, grade III chronic kidney disease, and atrial fibrillation. His ocular history was significant for bilateral cataract extractions with PCIOL implantation in 2013 and bilateral YAG laser capsulotomies in 2013. His medications were significant for Aspirin-CaCO3 81–300 mg daily, metoprolol ER 50 mg daily, and warfarin 2.5 mg daily with two days of 3.75 mg dosing. The rest of his history was non-contributory.\n\nOne week prior to presentation, the patient noticed an initially small, but slowly progressive, amount of blood overlying the sclera of his right eye. He eventually experienced slight obstruction of his vision from the blood as well as minor periorbital ecchymosis. Two days prior to presentation, the patient was diagnosed with a small SCH by an outside ophthalmologist and was instructed to discontinue his warfarin and was told to not worry about the bleeding. After two days of progressive bleeding, he presented to an outside hospital ED, where active subconjunctival bleeding and hemorrhagic chemosis were documented. Laboratory evaluation at that time showed an INR of 2.85 with a PT of 32.9. Due to this atypical presentation, the patient was referred to our institution for further management.\n\nOn presentation to our ED, the patient denied any pain, dizziness, blurry vision, or history of recent trauma to the eye or face. Of note, the patient was normotensive with a blood pressure of 120/81 mmHg. Best visual acuity sans correction was found to be 20/80 in the right eye and 20/40 in the left eye. Intraocular pressure and pupillary exam were both within normal limits. External examination revealed periorbital ecchymosis with trace edema, massive 360-degree hemorrhagic chemosis, and active bleeding from the subconjunctiva with overflow onto the patient's face (Fig. 1A, Fig. 1BA, B). Extraocular movements in the right eye were restricted 50% in all quadrants, while there were no restrictions in the left eye. Slit lamp and fundus examinations revealed no further abnormalities.Fig. 1A Right eye, upper lid manually retracted superiorly. Active extravasation and massive hemorrhagic chemosis can be seen, with blood overflowing the lower lid and draining down the patient's face.\n\nFig. 1A\n\nFig. 1B Extensive periorbital ecchymosis can be appreciated with inferior extension to the right jaw.\n\nFig. 1B\n\nLaboratory workup was significant for an INR of 2.7 (normal range of 0.9–1.1, and 2.0–3.0 with therapeutic anticoagulation), a PT of 32.9 s (normal range of 12.1–15.1 s), and an initial hemoglobin of 14.3 g/dL which decreased to 13.6 g/dL 4 h later. Due to the active nature of the bleeding, a CT-Angiogram of the head with/without contrast was ordered, which revealed a small preseptal hematoma anterior to the right globe with a focus of active arterial extravasation of unclear source. No vascular malformations or large lacerations corresponding to the area of bleeding were noted. After discussion with the patient's internal medicine team, the decision was made to reverse the warfarin with 2.5 mg of Vitamin K and 1 unit of fresh frozen plasma. At this point, copious erythromycin ointment and pressure patches were applied to the right eye.\n\nSeveral hours after admission the source of bleeding was identified as a small artery in the superficial inferonasal bulbar conjunctiva near the medial canthus and finally controlled with application of focal pressure patches for 25 and then 15 minutes. No additional management was necessary for several hours until the patient snorted and began actively bleeding again. Focal pressure patches were again applied to the source, twice for 30 minutes each, with subsequent hemostasis. Although surgical management and cautery were discussed with the patient, due to the recurrent severe bleeding, the patient was hesitant to pursue surgical measures and ultimately elected to continue patching upon further bleeding.\n\nRegular ophthalmic examinations continued for two more days, with no further bleeding or ophthalmic complications, at which point the patient was cleared by Ophthalmology for discharge. The patient was medically managed for several more days due to episodes of atrial fibrillation and was discharged from the hospital five days after admission. At his final follow-up appointment, 3 months post-discharge, the patient had no recurrence of bleeding or other related complications, except for a mild contact dermatitis from the initial choice of antibiotic ointment. The patient's SCH and periorbital ecchymosis completely resolved over the course of follow-up and corrected vision in the right eye improved to baseline acuity of 20/40.\n\n3 Discussion\n\nThis case demonstrates an atypically massive spontaneous SCH in a patient on therapeutic warfarin. With no reported trauma, previous occurrence of similar bleeds, or known lesions near the site of the bleed, this presentation is disproportionately severe and markedly inconsistent in magnitude compared to the expectedly small SCH in patients taking warfarin.4, 5, 6 While the exact cause of this patient's bleed may never be fully known, it is possible that the small bulbar vessel was initially damaged by a strong Valsalva maneuver since the patient denied any obvious trauma or eye rubbing. While the difference between therapeutic and supratherapeutic INR has not been shown to increase the risk of SCH in patients taking warfarin,1,5 the impressive amount of hemorrhage was certainly more suggestive of a further hypocoagulable state than the therapeutic INR found on laboratory examination. The only other documented case of warfarin cessation and reversal due solely to an SCH was in a patient with a supratherapeutic INR, further highlighting the distinctiveness of this presentation.8\n\nDue to the lack of formal guidelines on managing an SCH of such atypical severity, clinical judgement was the sole determinant of management course. Discontinuation and reversal of warfarin was deemed necessary in this case due to the severity of the bleeding and mass effect on surrounding tissues. Had the bleeding not been so robust as to threaten the patient's vision, it may have been possible to manage the bleeding while maintaining anticoagulation. Once the bleeding vessel was identified, cautery versus surgical repair of the vessel was strongly considered due to the quantity of hemorrhage and fear of further recurrence leading to blood loss or visual impairment. However, due to the patient's choice for non-surgical management, conservative therapy with focal tamponade was further trialed with clear success as described. While the viability of anticoagulation reversal and conservative management of such a severe SCH is supported by this particular case report, it should be recognized as preliminary at this time. It may serve as an initial data point for future practitioners when faced with an SCH of this magnitude in an anticoagulated patient.\n\n4 Conclusions\n\nThis case report highlights that, while extremely rare, spontaneous SCH in patients anticoagulated with warfarin may present with severity requiring focal tamponade, cessation and/or reversal of anticoagulation, or surgical management. To our knowledge, this is the first report to describe a warfarin-associated SCH of sufficient severity to require cessation and reversal of anticoagulation in a patient with a therapeutic INR. This report may also serve as a cautionary tale that even the most apparently benign condition, such as a SCH, can have atypical and severe presentations, and as such should not be dismissed without thorough examination or workup.\n\nPatient consent\n\nThe patient provided both verbal and written consent for the use of his medical history and images to be written and submitted as a case report.\n\nFunding\n\nNo funding or grant support.\n\nAuthorship\n\nAll authors attest that they meet the current ICMJE criteria.\n\nDeclaration of competing interest\n\nNone.\n==== Refs\nReferences\n\n1 Tarlan B. Kiratli H. Subconjunctival hemorrhage: risk factors and potential indicators Clin Ophthalmol 7 2013 1163 1170 10.2147/OPTH.S35062 23843690\n2 Fukuyama J. Hayasaka S. Yamada K. Setogawa T. Causes of subconjunctival hemorrhage Ophthalmologica 200 2 1990 63 67 https://doi:10.1159/000310079 2338986\n3 Taamallah-Malek I. Chebbi A. Bouladi M. Massive bilateral subconjunctival hemorrhage revealing acute lymphoblastic leukemia J Fr Ophtalmol 36 3 2013 Mar e45 e48 10.1016/j.jfo.2012.03.013 23122838\n4 Superstein R. Gomolin J.E.S. Hammouda W. Rosenberg A. Overbury O. Arsenault C. Prevalence of ocular hemorrhage in patients receiving warfarin therapy Can J Ophthalmol 35 7 2000 385 389 10.1016/S0008-4182(00)80126-X 11192447\n5 Leiker L.L. Mehta B.H. Pruchnicki M.C. Rodis J.L. Risk factors and complications of subconjunctival hemorrhages in patients taking warfarin Optometry 80 5 2009 227 231 https://doi:10.1016/j.optm.2008.10.018 19410227\n6 Bodack M.I. A warfarin-induced subconjunctival hemorrhage Optometry 78 3 2007 113 118 10.1016/j.optm.2006.10.015 17321459\n7 Shaikh M.Y. Bodla A.A. An unusual presentation of spontaneous sub-conjunctival haematoma in a patient receiving warfarin Clin Exp Optom 89 3 2006 169 170 10.1111/j.1444-0938.2006.00034.x 16637972\n8 Kleis W. Hernández-Denton G. Hernández-Morales F. An unusual complication of anticoagulant therapy: bloody tears Bol Asoc Med P R 81 7 1989 275 276 2775404\n\n",
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"issue": "22()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Anticoagulation; Reversal; Spontaneous; Subconjunctival hemorrhage; Warfarin",
"medline_ta": "Am J Ophthalmol Case Rep",
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"pmid": "33732947",
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"title": "Massive spontaneous subconjunctival hemorrhage in a patient on therapeutic warfarin: A case report.",
"title_normalized": "massive spontaneous subconjunctival hemorrhage in a patient on therapeutic warfarin a case report"
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"abstract": "BACKGROUND\nDespite the efficacy of raltegravir in reducing viral load in HIV-infected patients, evidence for its safety in late pregnancy is lacking. A high rate of placental transfer was recently demonstrated.\n\n\nMETHODS\nA treatment-naïve 34-year-old HIV-1-positive woman of African origin began treatment with zidovudine/lamivudine, lopinavir/ritonavir, and raltegravir at 35 weeks of pregnancy. After 11 days of treatment with raltegravir, a substantial reduction in viral load was achieved. Concurrently, she had a 23-fold increase in serum alanine aminotransferase and a 10-fold increase in serum aspartate aminotransferase, both of which returned to normal when raltegravir treatment was discontinued. A healthy boy was delivered at term. The infant's tests for HIV were negative at five months, and he had no health problems at eight months.\n\n\nCONCLUSIONS\nThis is the first case report, to our knowledge, of increased maternal serum transaminase levels following the use of raltegravir in a woman at a late stage of pregnancy.",
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"mesh_terms": "D000328:Adult; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D005260:Female; D005865:Gestational Age; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011256:Pregnancy Outcome; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D019562:Viral Load",
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"abstract": "Kawasaki disease (KD) is an acute febrile multisystem vasculitis and has been recognized to be one of the most common causes of acquired heart disease in children. Although gastrointestinal symptoms including vomiting, diarrhea, and abdominal pain are not uncommon in KD patients, KD with lower gastrointestinal bleeding is quite rare. Here, we describe a 3-year-old boy with typical KD who had lower gastrointestinal bleeding caused by rectal ulcers on the third day of aspirin therapy.",
"affiliations": "Department of Pediatrics, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.;Department of Pediatrics, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.;Department of Pediatrics, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China. yyp757605@163.com.",
"authors": "Han|Yong|Y|;Hu|Chenmin|C|;Yu|Yanping|Y|http://orcid.org/0000-0001-9006-8479",
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"fulltext": "\n==== Front\nPediatr Rheumatol Online J\nPediatr Rheumatol Online J\nPediatric Rheumatology Online Journal\n1546-0096 BioMed Central London \n\n414\n10.1186/s12969-020-0414-6\nLetter to the Editor\nA case of rectal ulcers during aspirin therapy in acute Kawasaki disease\nHan Yong 49738515@qq.com Hu Chenmin hcmsmn0306@126.com http://orcid.org/0000-0001-9006-8479Yu Yanping yyp757605@163.com grid.13402.340000 0004 1759 700XDepartment of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China \n17 3 2020 \n17 3 2020 \n2020 \n18 245 10 2019 2 3 2020 © The Author(s). 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Kawasaki disease (KD) is an acute febrile multisystem vasculitis and has been recognized to be one of the most common causes of acquired heart disease in children. Although gastrointestinal symptoms including vomiting, diarrhea, and abdominal pain are not uncommon in KD patients, KD with lower gastrointestinal bleeding is quite rare. Here, we describe a 3-year-old boy with typical KD who had lower gastrointestinal bleeding caused by rectal ulcers on the third day of aspirin therapy.\n\nKeywords\nKawasaki diseaseGastrointestinal hemorrhageRectal ulcerAspirinissue-copyright-statement© The Author(s) 2020\n==== Body\nDear Editor,\n\nKawasaki disease (KD) is a febrile multisystem vasculitis of unknown etiology, especially involving coronary arteries. Although the prevalence of gastrointestinal involvement in KD is unknown, gastrointestinal symptoms including vomiting, diarrhea, and abdominal pain are relatively common. However, KD with lower gastrointestinal bleeding is quite rare. Here, we describe a 3-year-old boy with typical KD who had lower gastrointestinal bleeding caused by rectal ulcers on the third day of aspirin therapy.\n\nA 3-year-old boy was first seen on day 2 of high fever. On physical examination, enlarged tonsil, pharyngeal hyperemia, and coarse respiratory sounds of both lungs were noted. No other abnormal finding was present at that time. Laboratory findings were as follows: white blood cell count 14.8*10^9/L, neutrophil 84.8%, hemoglobin 131 g/L, platelet count 228*10^9/L, C-reactive protein 122 mg/L. He was admitted and treated with intravenous antibiotics empirically. The boy remained febrile. Three day later (day 5), the onset of maculopapular rash on the trunk and limbs, nonexudative conjunctivitis, strawberry tongue, edema of hands and feet, and an enlarged right cervical lymph node led to the diagnosis of KD. Fortunately, echocardiography (Fig. 1A1, A2 )revealed no dilatation of coronary arteries (2.2 mm left and 2.0 mm right). Then, intravenous immunoglobulin (IVIG, 2 g/kg) and oral aspirin (50 mg/kg per day) were administered. After IVIG, his fever resolved rapidly. However, hematochezia occurred on day 3 of aspirin. Repeated laboratory examinations revealed white blood cell count of 7.1 × 10^9/L with predominance of neutrophil 51.2%, hemoglobin level of 118 g/L, platelet count of 378 × 10^9/L, and C-reactive protein of 57 mg/L. Colonoscopy revealed multiple superficial active ulcers in the rectum (Fig. 1B). Microscopic examination of a specimen from rectal biopsy revealed focal active colitis. There was predominantly neutrophilic infiltration within the lamina propria along with hemorrhage and crypt abscess formation (Fig. 1C). Thus, high-dose aspirin was stopped and intravenous methylprednisolone (30 mg per day) was given. Three days later, bloody stool disappeared. The intravenous methylprednisolone was changed to methylprednisolone tablets with gradually decreased dosage. Simultaneously, low-dose aspirin (4 mg/kg per day) was started. On day 15, most of the laboratory parameters were normal except for elevated platelet count of 623 × 10^9/L. The next day, he was discharged and continued with low-dose aspirin (4 mg/kg per day) for 8 weeks. Further follow-up showed that the patient recovered without sequelae.\nFig. 1 A, Echocardiography shows no dilatation of left coronary artery (A1) and right coronary artery (A2). B, Colonoscopy results showing multiple superficial active ulcers covered with thick “white moss” in rectum. C, Histologic examination of biopsy shows prominent neutrophilic infiltration within the lamina propria along with hemorrhage and crypt abscess formation (green arrow), indicating focal active colitis (hematoxylin-eosin, magnification × 100)\n\n\n\nOnly 5 cases of KD with gastrointestinal hemorrhage have been previously documented in the English literature (Table 1). Two cases with upper gastrointestinal bleeding occurred before the use of aspirin [1, 2]. Three cases of upper gastrointestinal hemorrhage complicating high-dose aspirin therapy might be iatrogenic [3, 4]. Adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the lower gastrointestinal tract are also common; however, symptomatic NSAID-induced colitis is rare. Usually, histologically, there is no predominant cell type producing infiltration in colitis associated with NSAIDs [5]. Although the duration of exposure to NSAIDs before the development of symptoms of colitis is variable; most of the patients with NSAID-induced colitis have been taking these drugs for more than 6 months [6]. Our patient developed lower gastrointestinal bleeding on day 3 of aspirin, due to active rectal ulcers. Histological examination of a colonoscopic biopsy specimen revealed prominent neutrophilic infiltration and crypt abscess formation, indicating focal active colitis. In light of clinical details and histological features, we suspect that aspirin may not be the primary cause of rectal ulcers in our patient. Vasculitis of the submucosal artery in the rectum together with the local pathogens might play an important role. Undoubtedly, we can not rule out that high-dose aspirin may play a promoting role. As a matter of fact, the role of high-dose aspirin in KD remains controversial. Kuo et al. [7] demonstrated that high-dose aspirin in KD did not confer any benefit with regards to inflammation and it did not appear to improve treatment outcomes. A recent meta-analysis revealed that low-dose aspirin (3–5 mg/kg/d) may be as effective as the use of high-dose aspirin (> 30 mg/kg/d) for the initial treatment of KD [8]. In summary, pediatricians should be aware of the risk of gastrointestinal bleeding in KD children, especially in those receiving high-dose aspirin.\nTable 1 Clinical characteristics of the reported patients with gastrointestinal hemorrhage in Kawasaki disease\n\nRef\tFirst author\tAge/sex\tClinical onset\tDetails of gastrointestinal bleeding\tBlood transfusion\tEndoscopy\tSurgery\t\n1\tZulian\t20 m/M\tFever\tHematemesis on day 7 of illness without aspirin\tYes\tShowed diffuse hemorrhagic duodenitis\tNone\t\n2\tSingh\t4.5 y/M\tNausea, vomiting, diarrhea and fever\tHemorrhagic shock with hematemesis and hematochezia at 2 months after onset (without aspirin)\tYes\tFailed because of the massive bleeding\tRevaeled a 1.5 cm duodenal ulcer with active bleeding\t\n3\tMatsubara\t2 y/M\tFever\tHematemesis on day 19 of illness (day 13 of aspirin)\tYes\tRevealed a 2 cm duodenal ulcer\tNone\t\n4 y/F\tFever\tMelanotic stools followed by emesis of blood on day 31 of illness (day 26 of aspirin)\tYes\tNone\tNone\t\n4\tChang\t5 y/M\tFever, cervical lymphadenitis\tTarry stool on day 6 of illness; Massive gastrointestinal bleeding on day 14 of illness (day 5 of aspirin)\tYes\tNA\tNA\t\nRef Reference, y Year, m Month, M Male, F Female, NA Not available\n\n\n\nAbbreviations\nIVIGIntravenous immunoglobulin\n\nKDKawasaki disease\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe are grateful to Zhejiang Medical and Health Science and Technology Plan for establishing the project (2019321962/2019KY485), although there is no funding.\n\nAuthors’ contributions\nYH collected and interpreted the patient data and was a major contributor in revising the manuscript. CH collected literatures and was a contributor in drafting the manuscript. YY designed the work and drafted the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThis work did not receive funding.\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\nThe study protocol was approved by the Ethics Commission of Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine. Permission to carry out the study and access patient records was sought from the respective hospital administrators.\n\nConsent for publication\nWritten consent for publication of this anonymous information was obtained from the patient’s parents and the proof of consent can be requested at any time.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Zulian F Falcini F Zancan L Martini G Secchieri S Luzzatto C Acute surgical abdomen as presenting manifestation of Kawasaki disease J Pediatr 2003 142 731 735 10.1067/mpd.2003.232 12838207 \n2. Singh R Ward C Walton M Persad R Atypical Kawasaki disease and gastrointestinal manifestations Paediatr Child Health 2007 12 235 237 10.1093/pch/12.3.235 19030366 \n3. Matsubara T Mason W Kashani IA Kligerman M Burns JC Gastrointestinal hemorrhage complicating aspirin therapy in acute Kawasaki disease J Pediatr 1996 128 701 703 10.1016/S0022-3476(96)80140-5 8627447 \n4. Chang CH Chen MH Yang W Kawasaki disease presenting with lymphadenopathy and gastrointestinal hemorrhage: report of one case Acta Paediatr Taiwan 2004 45 171 173 15493738 \n5. Sherid M Ehrenpreis ED Types of colitis based on histology Dis Mon 2011 57 457 489 10.1016/j.disamonth.2011.05.004 21944389 \n6. Shibuya T Ohkusa T Yokoyama T Harada A Beppu K Sakamoto N Colonic mucosal lesions associated with long-term or short-term administration of nonsteroidal anti-inflammatory drugs Color Dis 2010 12 1113 1121 10.1111/j.1463-1318.2009.01948.x \n7. Kuo HC Lo MH Hsieh KS Guo MM Huang YH High-Dose Aspirin is Associated with Anemia and Does Not Confer Benefit to Disease Outcomes inKawasaki Disease PLoS One 2015 10 e0144603 10.1371/journal.pone.0144603 26658843 \n8. Zheng X Yue P Liu L Tang C Ma F Zhang Y Efficacy between low and high dose aspirin for the initial treatment of Kawasaki disease: Current evidence based on a meta-analysis PLoS One 2019 14 5 e0217274 10.1371/journal.pone.0217274 31117119\n\n",
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"keywords": "Aspirin; Gastrointestinal hemorrhage; Kawasaki disease; Rectal ulcer",
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"title": "A case of rectal ulcers during aspirin therapy in acute Kawasaki disease.",
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"abstract": "We encountered 2 cases of drug-induced intrathoracic lesions caused by allergic reactions to mesalazine in patients with ulcerative colitis. Case 1: A 26-year-old man had a fever, cough and exertional dyspnea after 1 month of mesalazine treatment. He was hospitalized because of bilateral pulmonary infiltrates on a chest X-ray film. Case 2: A 27-year-old woman complained of fever and left back pain that exacerbated after 2 weeks of mesalazine treatment. She was hospitalized because of bilateral pulmonary effusions on chest CT. Both patients showed a positive reaction to a drug lymphocyte stimulation tests (DLST) for mesalazine. The first case was given a diagnosis of eosinophilic pneumonia by bronchoscopic examination, and responded to steroid therapy after discontinuation of mesalazine. The second case was given a diagnosis of pleuritis and improved on cessation of Mesalazine treatment.",
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"authors": "Machida|Hisanori|H|;Shinohara|Tsutomu|T|;Hatakeyama|Nobuo|N|;Inayama|Mami|M|;Hosokawa|Emiko|E|;Ogushi|Fumitaka|F|",
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"title": "Two cases of drug-induced intrathoracic lesions caused by mesalazine in patients with ulcerative colitis.",
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"abstract": "Carfilzomib is a proteasome inhibitor and immunomodulator used to treat patients with multiple myeloma who have disease progression refractory to bortezomib. The difference in agents is that carfilzomib is an irreversible inhibitor of 20 s proteasome. The most common side effects of carfilzomib are fatigue, nausea, diarrhea, anemia, thrombocytopenia, dyspnea, and pyrexia. Less frequent side effects include cardiac manifestations for which we will explore with more detail. In this case report, we describe a 70-year-old female with multiple myeloma presenting to the emergency department with complaint of dyspnea. Patient was discovered to be in heart failure with atrioventricular block necessitating placement of a pacemaker.",
"affiliations": "Department of Emergency Medicine, Hackensack University Medical Center, Hackensack, NJ, USA.;Department of Emergency Medicine, Hackensack University Medical Center, Hackensack, NJ, USA.",
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"title": "Heart failure secondary to carfilzomib-induced heart block in multiple myeloma patients.",
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"abstract": "Pembrolizumab is an immune checkpoint inhibitor used in many different cancers. Several immune-related adverse events (irAEs) have been associated with pembrolizumab, including toxic epidermal necrolysis. Here, we are presenting a patient with non-small cell lung cancer that developed toxic epidermal necrolysis 3-days following initiation of pembrolizumab. Following high-dose steroid therapy, intravenous immunoglobulin 2 g/kg was initiated and resulted in complete resolution of all his irAEs. To our knowledge, this is the first reported case of total re-epithelialization and resolution of immune checkpoint inhibitor-induced toxic epidermal necrolysis following the use of intravenous immunoglobulin.",
"affiliations": "The Legacy Heritage Oncology Center & Dr. Larry Norton Institute, Soroka Medical Center and Ben-Gurion University Medical School for International Health, Ben-Gurion University of the Negev Dermatology Department Soroka Medical Center & Ben-Gurion University Internal Medicine Ward, Soroka Medical Center & Ben-Gurion University Faculty of Health Sciences, Ben-Gurion University of the Negev Medical Intensive care Unit, Soroka University Medical Center, Beer-Sheva, Israel.",
"authors": "Kian|Waleed|W|;Zemel|Melanie|M|;Elobra|Firas|F|;Sharb|Adam A|AA|;Levitas|Dina|D|;Assabag|Yarden|Y|;Alguayn|Farouq|F|;Yakobson|Alexander|A|;Rouvinov|Keren|K|;Fuchs|Lior|L|",
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"fulltext": "\n==== Front\nAnticancer Drugs\nAnticancer Drugs\nACD\nAnti-Cancer Drugs\n0959-4973\n1473-5741\nLippincott Williams & Wilkins\n\n34321417\n00096\n10.1097/CAD.0000000000001162\nCase Reports\nIntravenous immunoglobulin efficacy on pembrolizumab induced severe toxic epidermal necrolysis\nKian Waleed a\nZemel Melanie b*\nElobra Firas c\nSharb Adam A. d\nLevitas Dina a\nAssabag Yarden d\nAlguayn Farouq e\nYakobson Alexander a\nRouvinov Keren a\nFuchs Lior f\na The Legacy Heritage Oncology Center & Dr. Larry Norton Institute, Soroka Medical Center and Ben-Gurion University\nb Medical School for International Health, Ben-Gurion University of the Negev\nc Dermatology Department Soroka Medical Center & Ben-Gurion University\nd Internal Medicine Ward, Soroka Medical Center & Ben-Gurion University\ne Faculty of Health Sciences, Ben-Gurion University of the Negev\nf Medical Intensive care Unit, Soroka University Medical Center, Beer-Sheva, Israel\nCorrespondence to Waleed Kian, MD, The Legacy Heritage Oncology Center & Dr. Larry Norton Institute, Soroka Medical Center & Ben-Gurion University, Beer-Sheva, Israel, Tel: +972 (0)52 8686663; e-mail: waleedkian77@gmail.com\n30 7 2021\n1 2022\n33 1 e738e740\n29 4 2021\n30 5 2021\nCopyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nPembrolizumab is an immune checkpoint inhibitor used in many different cancers. Several immune-related adverse events (irAEs) have been associated with pembrolizumab, including toxic epidermal necrolysis. Here, we are presenting a patient with non-small cell lung cancer that developed toxic epidermal necrolysis 3-days following initiation of pembrolizumab. Following high-dose steroid therapy, intravenous immunoglobulin 2 g/kg was initiated and resulted in complete resolution of all his irAEs. To our knowledge, this is the first reported case of total re-epithelialization and resolution of immune checkpoint inhibitor-induced toxic epidermal necrolysis following the use of intravenous immunoglobulin.\n\nintravenous immunoglobulin\npembrolizumab\nprogrammed cell death ligand-1\ntoxic epidermal necrolysis\nOPEN-ACCESSTRUE\nSTATUSONLINE-ONLY\n==== Body\npmcIntroduction\n\nPembrolizumab has been approved by the Food and Drug Administration and belongs to a group of drugs termed immune checkpoint inhibitors. Pembrolizumab specifically is an anti-programmed death-1 (PD-1) receptor mAb that is used in several different cancers, including but not limited to, non-small cell lung cancer, endometrial cancer, breast cancer and melanoma [1]. Since checkpoint inhibitors interfere with the body’s normal immune system, it has been shown that they are frequently associated with immune-related adverse events (irAEs). These can include dermatitis, pneumonitis, hypothyroidism and colitis [2].\n\nCutaneous irAEs are quite frequent in patients that are treated with PD-1 inhibitors and are commonly described as maculopapular rashes [3]. Other severe dermatologic complications can occur, including erythema multiforme, lichenoid and morbilliform reactions [4]. Rarely, Steven–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported as irAEs. SJS/TEN are life-threatening bullous drug eruptions that on a few occasions have been linked to anti-PD-1 antibodies [4,5]. Finally, approximately 23% of patients with SJS/TEN following the initiation of PD-1/programmed cell death ligand-1 (PD-L1) inhibitors died following the onset of a reaction [6].\n\nHere, we are reporting on a severe case of TEN 3-days following the initiation of pembrolizumab for the treatment of non-small cell lung cancer (NSCLC) with complete resolution of symptoms after intravenous immunoglobulin (IVIG) therapy.\n\nCase presentation\n\nA 65-year-old Caucasian male was diagnosed with metastatic NSCLC squamous type. PD-L1 status expression was <1% while, epidermal growth factor receptor, ROS1 and ALK were wild-type. Next-generation sequencing on his tumor sample revealed different somatic mutations as seen in Tables 1 and 2. His medical history is significant for hypertension and smoking. His medications include ramipril and amlodipine. There is no personal or family history for dermatologic or autoimmune diseases. This patient received two cycles of combination chemotherapy, including carboplatin and paclitaxel without any significant side effects. On 3 December he received his first dose of pembrolizumab 200 mg.\n\nTable 1 Genomic alterations found in tumor sample\n\nGene\tMutation\tAmino acid change\t% Frequency\t\nMYCN\tc.691G>C\tp. Ala231Pro\t28.26\t\nMAP3K1\tc.365C>T\tp. Ala122Val\t61.19\t\nCSMD3\tc.2246G>C\tp. Arg749Pro\t15.32\t\nOR4M2\tc.347C>A\tp. Thr116Lys\t8.49\t\nTP53\tc.746G>T\tp. Arg249Met\t18.03\t\n\nTable 2 Copy number variants found in tumor sample\n\nGene\tVariant class\tCopy number variants\t\nCOL11A1\tAmplification\t6.28\t\n\nOn 11 December, he presented to the hospital with chest pain, nausea, vomiting and a whole-body maculopapular erythematous skin rash that first appeared on 6 December (3-days following drug initiation). He was then admitted for myocarditis, gastritis, esophagitis and suspected SJS/TEN. Gastritis and esophagitis were then confirmed by gastroscopy. Electrocardiogram and troponin levels confirmed myocarditis. Intravenous (i.v.) steroid therapy with methylprednisolone 2 mg/kg was initiated without significant improvement. Therefore, pulse steroid therapy with methylprednisolone 500 mg was given for 3 days with mild improvement. He was then transferred to the ICU due to widespread epidermal detachment which involved the face, chest, back, upper and lower limbs (Fig. 1a). In the ICU, he was treated with high-dose steroid therapy and IVIG total dose of 2 g/kg with an impressive clinical improvement (Fig. 1b). He showed complete re-epithelialization on 30 December. The skin punch biopsy confirmed the diagnosis of TEN.\n\nFig. 1 (a) Widespread epidermal detachment involving the face, chest, upper and lower limbs with a positive Nikolsky sign. (b) Resolution of skin lesions 2-weeks following intravenous immunoglobulin therapy.\n\nDiscussion\n\nToxic epidermal necrolysis is a life-threatening bullous drug reaction that begins as an erythematous maculopapular rash that leads to epidermal detachment. By definition, TEN involves >30% of body surface area. TEN is thought to be due to apoptosis of epithelial keratinocytes by cytotoxic CD8+ T lymphocytes [7]. TEN is most commonly linked to nonsteroidal anti-inflammatory drugs, antibiotics and allopurinol [8].\n\nHere we present a very interesting case of an NSCLC patient with PD-L1 status less than 1%. Following one cycle of pembrolizumab, he developed early onset irAEs in multiple organs, including esophagitis, gastritis, myocarditis and life-threatening toxic epidermal necrolysis. After high-dose steroidal therapy and IVIG treatment, the patient experienced complete resolution of all his irAE including TEN.\n\nThe guidelines for the treatment of immune-checkpoint inhibitor adverse events related to TEN include intravenous methylprednisolone 1–2 mg/kg and for corticosteroid-unresponsive cases, IVIG or cyclosporin can be considered [4].\n\nAfter review of the literature, there have only been two reported cases of IVIG use in patients unresponsive to high-dose steroidal therapy, all of which died [9,10]. To our knowledge, this is the first reported case of complete resolution of irAEs after initiation of IVIG therapy.\n\nConclusion\n\nHere we described a case of life-threatening pembrolizumab-induced TEN. To our knowledge, this is the first reported case of pembrolizumab-induced TEN with complete resolution following the use of IVIG. Therefore, physicians should be made aware of this life-threatening drug reaction and its association with this widely used medication.\n\nAcknowledgements\n\nConflicts of interest\n\nThere are no conflicts of interest.\n\n* Dr.Melanie Zemel equally contributed to this work and should be considered as a First author.\n==== Refs\nReference\n\n1 du Rusquec P de Calbiac O Robert M Campone M Frenel JS . Clinical utility of pembrolizumab in the management of advanced solid tumors: an evidence-based review on the emerging new data. Cancer Manag Res 2019; 11 :4297–4312.31190995\n2 Baxi S Yang A Gennarelli RL Khan N Wang Z Boyce L Korenstein D . Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ 2018; 360 :k793.29540345\n3 Michot JM Bigenwald C Champiat S Collins M Carbonnel F Postel-Vinay S . Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 2016; 54 :139–148.26765102\n4 Brahmer JR Lacchetti C Schneider BJ Atkins MB Brassil KJ Caterino JM .; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018; 36 :1714–1768.29442540\n5 Haanen JBAG Carbonnel F Robert C Kerr KM Peters S Larkin J, Jordan K ; ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28 (suppl 4 ):iv119–iv142.28881921\n6 Cai ZR Lecours J Adam JP Marcil I Blais N Dallaire M . Toxic epidermal necrolysis associated with pembrolizumab. J Oncol Pharm Pract 2020; 26 :1259–1265.31810421\n7 Lerch M Mainetti C Terziroli Beretta-Piccoli B Harr T . Current perspectives on Stevens-Johnson syndrome and toxic epidermal necrolysis. Clin Rev Allergy Immunol 2018; 54 :147–176.29188475\n8 Ward KE Archambault R Mersfelder TL . Severe adverse skin reactions to nonsteroidal antiinflammatory drugs: a review of the literature. Am J Health Syst Pharm 2010; 67 :206–213.20101062\n9 Griffin LL Cove-Smith L Alachkar H Radford JA Brooke R Linton KM . Toxic epidermal necrolysis (TEN) associated with the use of nivolumab (PD-1 inhibitor) for lymphoma. JAAD Case Rep 2018; 4 :229–231.29687056\n10 Vivar KL Deschaine M Messina J Divine JM Rabionet A Patel N . Epidermal programmed cell death-ligand 1 expression in TEN associated with nivolumab therapy. J Cutan Pathol 2017; 44 :381–384.28000240\n\n",
"fulltext_license": "CC BY-NC-ND",
"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": "34321417",
"pubdate": "2021-07-30",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intravenous immunoglobulin efficacy on pembrolizumab induced severe toxic epidermal necrolysis.",
"title_normalized": "intravenous immunoglobulin efficacy on pembrolizumab induced severe toxic epidermal necrolysis"
} | [
{
"companynumb": "IL-009507513-2108ISR006935",
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"activesubstancename": "RAMIPRIL"
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... |
{
"abstract": "Nosocomial catheter-related and Arteriovenous fistula (AV)-related infections are significant concern in patients undergoing haemodialysis. These infections are associated with multiple complications as well as mortality and demands immediate and appropriate management. While coagulase-negative staphylococci, S.aureus, and Escherichia coli are the most common causes of catheter-related infections in haemodialysis patients, such infections caused by Pseudomonas aeruginosa are relatively rare. Here, we present an unusual case of 36-year-old male patient with chronic renal failure, who developed endocarditis and sepsis from Pseudomonas aeruginosa infection of the left hand arteriovenous fistula. The bacteraemia in the present case caused multiple complications including dry gangrene of bilateral lower limbs, stroke, endophthalmitis, left brachial artery thrombosis and vegetations on the interventricular septum and aortic wall. Despite antibiotic treatment, the patient suffered a cardiac arrest and could not be revived.",
"affiliations": "Consultant, Department of Cardiology, Amrita Institute of Medical Sciences (AIMS), Amrita Vishwa Vidyapeetham University , Kochi, Kerala, India .;Consultant, Department of Cardiology, Amrita Institute of Medical Sciences (AIMS), Amrita Vishwa Vidyapeetham University , Kochi, Kerala, India .;Consultant, Department of Cardiology, Amrita Institute of Medical Sciences (AIMS), Amrita Vishwa Vidyapeetham University , Kochi, Kerala, India.;Technician, Department of Cardiology, Amrita Institute of Medical Sciences (AIMS), Amrita Vishwa Vidyapeetham University , Kochi, Kerala, India .;Professor, Department of Cardiology, Amrita Institute of Medical Sciences (AIMS), Amrita Vishwa Vidyapeetham University , Kochi, Kerala, India .",
"authors": "Aggarwal|Manav|M|;Vijan|Vikrant|V|;Vupputuri|Anjith|A|;Nandakumar|Sandya|S|;Mathew|Navin|N|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2016/20220.8175",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "10(7)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Arteriovenous fistula infections; Embolectomy; Endophthalmitis; Gangrene",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "OD12-3",
"pmc": null,
"pmid": "27630891",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports",
"references": "25024944;24151435;17237890;21642365;17532401;26299166;25442867;22017567;23399454",
"title": "A Rare Case of Fatal Endocarditis and Sepsis Caused by Pseudomonas aeruginosa in a Patient with Chronic Renal Failure.",
"title_normalized": "a rare case of fatal endocarditis and sepsis caused by pseudomonas aeruginosa in a patient with chronic renal failure"
} | [
{
"companynumb": "IN-PFIZER INC-2016379868",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFEPIME HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "BACKGROUND\nImmune checkpoint inhibitors (ICIs) have emerged as a promising class of cancer immunotherapies. Neurotoxicities are uncommon, but often severe, and potentially fatal complications of ICIs, and clinical experience is limited. The aim of this study is to further define the clinical spectrum and outcome of ICI-mediated neurotoxicities.\n\n\nMETHODS\nPatients with ICI-associated neurotoxicities were identified from retrospective review of the quality control database at a single institution. Data regarding demographics, medical history, clinical presentation, diagnosis, management and outcome were recorded.\n\n\nRESULTS\nWe identified 18 patients with neurotoxicity following ICI therapy with pembrolizumab, nivolumab, atezolizumab, or ipilimumab for a diverse set of malignancies. Neurotoxicities comprised central demyelinating disorder (28%), autoimmune encephalitis predominantly affecting the grey matter (17%), aseptic meningitis (6%), myasthenia gravis (MG) (17%) with concurrent myositis (6%), sensorimotor polyneuropathy (11%) and hypophysitis (17%). Median time to onset of neurotoxicities was 5 weeks (range 1-72). All patients discontinued ICIs and received steroids with additional immunomodulation required in 9 patients, resulting in improvement for 16 of 18 patients. Grade 3-4 neurotoxicity developed in 14 patients, of whom 6 had died at database closure. Grade 3-4 severity negatively impacted overall survival (OS) (p = 0.046).\n\n\nCONCLUSIONS\nICI-mediated neurotoxicities present early, are rapidly progressive and include a diverse phenotype affecting the CNS, PNS and neuroendocrine system. A high level of vigilance is warranted, as early diagnosis and targeted treatment can substantially prevent morbidity and mortality. Prospective clinical trials are warranted to assess optimized management of ICI-induced neurotoxicities.",
"affiliations": "Department of Neurology, Yale School of Medicine, New Haven, CT, USA.;Department of Neurology, Yale School of Medicine, New Haven, CT, USA.;Department of Neurology, Yale School of Medicine, New Haven, CT, USA.;Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA. joachim.baehring@yale.edu.",
"authors": "Duong|Sophie L|SL|;Barbiero|Frank J|FJ|;Nowak|Richard J|RJ|;Baehring|Joachim M|JM|http://orcid.org/0000-0001-7755-6793",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000082082:Immune Checkpoint Inhibitors; D000074324:Ipilimumab; D000077594:Nivolumab; C000594389:atezolizumab; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.1007/s11060-021-03695-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-594X",
"issue": "152(2)",
"journal": "Journal of neuro-oncology",
"keywords": "CTLA4; Cancer; Immunotherapy; Neurologic immune-related adverse events; PD1",
"medline_ta": "J Neurooncol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D000074324:Ipilimumab; D009369:Neoplasms; D020258:Neurotoxicity Syndromes; D000077594:Nivolumab; D012189:Retrospective Studies",
"nlm_unique_id": "8309335",
"other_id": null,
"pages": "265-277",
"pmc": null,
"pmid": "33454891",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": "26027431;27718847;26406148;30482962;22437870;28064139;28666240;28938341;28973656;27271951;28426103;28873125;26984943;29567705;28889792;25795410;27653290;31405908;28495807;30170622;29872177;14561798;28821685;27084345;28765062;6481621;26282644;31423344;26115796",
"title": "Neurotoxicities associated with immune checkpoint inhibitor therapy.",
"title_normalized": "neurotoxicities associated with immune checkpoint inhibitor therapy"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-014801",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nTo evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin.\n\n\nMETHODS\nAflibercept was administered at escalating doses of 2, 4, or 6 mg kg(-1) in combination with fixed doses of pemetrexed (500 mg m(-2)) plus cisplatin (75 mg m(-2)) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations.\n\n\nRESULTS\nEighteen patients were enrolled. One patient dosed at 4 mg kg(-1) experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg(-1) cohort or the 6 mg kg(-1) dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ≥ 3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted.\n\n\nCONCLUSIONS\nThe results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg(-1), to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.",
"affiliations": "Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Hospital, University Health Network, University of Toronto, 610 University Avenue, 5-700, Toronto, Ontario M5G 2M9, Canada. ivan.padilla@uhn.ca",
"authors": "Diaz-Padilla|I|I|;Siu|L L|LL|;San Pedro-Salcedo|M|M|;Razak|A R A|AR|;Colevas|A D|AD|;Shepherd|F A|FA|;Leighl|N B|NB|;Neal|J W|JW|;Thibault|A|A|;Liu|L|L|;Lisano|J|J|;Gao|B|B|;Lawson|E B|EB|;Wakelee|H A|HA|",
"chemical_list": "D005971:Glutamates; D011993:Recombinant Fusion Proteins; D000068437:Pemetrexed; C533178:aflibercept; D006147:Guanine; D040262:Receptors, Vascular Endothelial Growth Factor; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1038/bjc.2012.319",
"fulltext": "\n==== Front\nBr J Cancer\nBr J Cancer\nBritish Journal of Cancer\n0007-0920\n1532-1827\nNature Publishing Group\n\nbjc2012319\n10.1038/bjc.2012.319\n22805331\nClinical Study\nA phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours\nAflibercept in combination with cisplatin and pemetrexed\nDiaz-Padilla I 1*\nSiu L L 1\nSan Pedro-Salcedo M 2\nRazak A R A 1\nColevas A D 2\nShepherd F A 1\nLeighl N B 1\nNeal J W 2\nThibault A 3\nLiu L 3\nLisano J 3\nGao B 3\nLawson E B 3\nWakelee H A 2\n1 Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Hospital, University Health Network, University of Toronto, 610 University Avenue, 5-700, Toronto, Ontario M5G 2M9, Canada\n2 Division of Oncology, Department of Medicine, Stanford University and Stanford Cancer Institute, Stanford, CA, USA\n3 Regeneron Pharmaceuticals, Tarrytown, NY, USA\n* E-mail: ivan.padilla@uhn.ca\n07 08 2012\n17 07 2012\n107 4 604611\n12 04 2012\n21 06 2012\n26 06 2012\nCopyright © 2012 Cancer Research UK\n2012\nCancer Research UK\nhttps://creativecommons.org/licenses/by-nc-sa/3.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/\nBackground:\n\nTo evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin.\n\nMethods:\n\nAflibercept was administered at escalating doses of 2, 4, or 6 mg kg−1 in combination with fixed doses of pemetrexed (500 mg m−2) plus cisplatin (75 mg m−2) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations.\n\nResults:\n\nEighteen patients were enrolled. One patient dosed at 4 mg kg−1 experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg−1 cohort or the 6 mg kg−1 dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ⩾3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted.\n\nConclusion:\n\nThe results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg−1, to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.\n\naflibercept\nphase I\ncisplatin\npemetrexed\nangiogenesis\npharmacokinetic\n==== Body\npmcVascular endothelial growth factor (VEGF) is a promoter of tumour angiogenesis (Kowanetz and Ferrara, 2006). Vascular endothelial growth factor signals through its receptors (VEGFR) including VEGFR-1 (FLT-1) and VEGFR-2 (FLK 1/KDR), which are expressed in normal and tumour vasculature endothelia. Vascular endothelial growth factor-mediated signalling is thought to be important in the development and progression of multiple solid tumours, and VEGF mRNA and protein overexpression are prognostic of poor outcome (Bonnesen et al, 2009; Delli Carpini et al, 2010). Thus, the use of VEGF- and VEGFR-targeted agents as cancer therapy has increased dramatically in recent years (Cook and Figg, 2010).\n\nAflibercept (VEGF Trap; Regeneron Pharmaceuticals, Tarrytown, NY, USA, and Sanofi Oncology, Cambridge, MA, USA) is a recombinant protein consisting of domain 2 from VEGFR-1 fused to domain 3 from VEGFR-2, attached to the hinge region of the Fc(a) domain of human immunoglobulin IgG1. Aflibercept binds all isoforms of VEGF-A, VEGF-B, and placental growth factor. Aflibercept exerts its antiangiogenic effects through regression in the normalisation and remodelling of surviving tumour vessels, and inhibition of neovascularisation (Holash et al, 2002).\n\nPreviously reported clinical trials have shown that aflibercept has antitumour activity both as a single agent and in combination with chemotherapy (Holash et al, 2002; Tang et al, 2008; Lockhart et al, 2010; Coleman et al, 2011; Tabernero et al, 2011). The recommended phase II dose (RP2D) is 4 mg kg−1 intravenously (i.v.) every 2 weeks when given as a single agent and either 4 mg kg−1 administered every 2 weeks or 6 mg kg−1 administered every 3 weeks in combination with chemotherapy (Lockhart et al, 2010). The most common treatment-related toxicities were consistent with prior studies of anti-VEGF agents, and included proteinuria, hypertension, fatigue, and hoarseness. Combination studies with cytotoxic chemotherapy have shown some increase in chemotherapy-related toxicities (Freyer et al, 2008; Limentani et al, 2008; Rixe et al, 2008; Kuhnowski et al, 2010; Novello et al, 2011; Tabernero et al, 2011).\n\nPemetrexed in combination with cisplatin is used first-line in the treatment of patients with locally advanced or metastatic non-squamous non-small-cell lung cancer (NSCLC) (Scagliotti et al, 2008), and in patients with advanced malignant pleural mesothelioma (MPM) (Vogelzang et al, 2003). The addition of a VEGF inhibitor, such as bevacizumab, to chemotherapy has proven to be effective in non-squamous NSCLC, with an acceptable toxicity profile (Sandler et al, 2006; Spigel et al, 2012).\n\nThe primary objective of this phase I combination trial was to determine the dose-limiting toxicities (DLTs) and RP2D of aflibercept administered i.v. every 3 weeks in combination with pemetrexed and cisplatin. Secondary objectives were to assess the safety profile of the combination, to characterise the pharmacokinetics (PKs) of aflibercept and pemetrexed, and to evaluate the immunogenicity of aflibercept.\n\nMaterials and methods\n\nPatient eligibility\n\nPatients were required to have a histologically confirmed advanced, incurable malignancy that was refractory to conventional therapy, or for which treatment with pemetrexed and/or cisplatin was considered appropriate. Patients had to have measurable disease by Response Evaluation Criteria in Solid Tumours (RECIST) (version 1.1), (Eisenhauer et al, 2009) an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ⩽1, and adequate haematological, hepatic, and renal function. Prior anti-VEGF therapy ⩾4 weeks from initial administration of aflibercept was allowed. Key exclusion criteria included: (a) prior treatment with aflibercept or pemetrexed; (b) patients whose disease had progressed during cisplatin administration or relapsed within 6 months of completion of cisplatin-based therapy; (c) surgery within the last 28 days; (d) uncontrolled hypertension defined as systolic blood pressure (BP) ⩾150 mm Hg and/or diastolic pressure ⩾100 mm Hg (prior antihypertensive medication was allowed); (e) bleeding diathesis or coagulopathy; (f) brain or leptomeningeal metastases (brain imaging was mandatory for study participation).\n\nThe study was conducted at two sites and the institutional review board of both participating centres approved the study.\n\nStudy design\n\nThis was an open-label, dose-escalation phase I trial; three dose levels were planned for aflibercept: (a) 2 mg kg−1, (b) 4 mg kg, and (c) 6 mg kg−1. No intra-patient dose escalation was permitted. In the event patients experienced a DLT at the first dose level, a dose level −1 (aflibercept given at 1 mg kg−1) was planned. Aflibercept, pemetrexed, and cisplatin were administered i.v. on day 1 of each 3-week cycle. Aflibercept was administered over 1 h, followed in sequence by fixed doses of pemetrexed (500 mg m2 i.v. over 10 min) and cisplatin (75 mg m2 i.v. administered as per institutional practice; typically 2 h). Patients were supplemented with vitamin B12 (1000 mcg intramuscularly) 1 week before the first pemetrexed dose and every three cycles thereafter. A low-dose folic acid preparation or multivitamin with folic acid was administered by mouth daily at doses ranging from 350 to 1000 mcg. This supplementation started at least 5 days before the first dose of pemetrexed, continued throughout the treatment period, and for 30 days after the last dose of pemetrexed. Oral or i.v. dexamethasone (4 mg) was given twice daily the day before, the day of, and the day after pemetrexed administration unless medically contraindicated. Three patients were enrolled in the first-dose level; dose escalation proceeded, following the standard 3+3 rule, until>one patient experienced a DLT during the first cycle of therapy. The RP2D was then selected as the dose level at which ⩽1 of 6 patients encountered a DLT during the first cycle of therapy.\n\nToxicity was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v.3.0). Dose-limiting toxicities were defined as adverse events (AEs) attributed as being possibly, probably, or definitely related to the study agents, and fulfilling one of the following criteria: (a) grade 3 or 4 neutropenia complicated by fever ⩾38.5 °C or infection, or grade 4 neutropenia of at least 7 days duration, (b) grade 3 thrombocytopenia complicated by haemorrhage or grade 4 thrombocytopenia, or (c) any grade 3 or higher non-haematologic toxicity (except fatigue, anorexia, nausea, vomiting, or diarrhoea that was not optimally controlled with appropriate medical intervention). Grade 3 hypertension (BP ⩾150/100 mm Hg), or BP ⩾180/100 mm Hg (if the patient had a history of isolated systolic hypertension) that could be controlled within 3 weeks of initiation of oral antihypertensive therapy was not considered a DLT. Likewise, grade 3 proteinuria (>3.5 grams per 24 h) that recovered to <2 grams per 24 h within 3 weeks of onset and/or grade 3 laboratory abnormalities that could reflect tumour burden were not considered as DLTs.\n\nPatient evaluation\n\nPre-treatment evaluations were performed within 2 weeks of treatment initiation and included history and physical examination, ECOG PS, haematology, serum chemistry, prothrombin time/INR, PTT, and urinalysis. Physical examinations were repeated on day 1 of each subsequent cycle; haematology, chemistry, and urinalysis were measured weekly for the entire study duration.\n\nBaseline radiological investigations were performed within 28 days of treatment initiation. Objective tumour response was assessed by RECIST (version 1.1) every two cycles (Eisenhauer et al, 2009). Complete and partial responses (PR) had to be confirmed at least 4 weeks after the initial observation.\n\nDose modifications\n\nPatients were required to meet the following criteria to receive study drugs on day 1 of a treatment cycle: absolute neutrophil count ⩾1.5 × 109 l−1, platelets ⩾100 × 109 l−1, creatinine clearance (CrCl) ⩾60 ml/min, and non-haematologic toxicity recovered to grade ⩽1.\n\nIn the event a DLT occurred during cycle 1 or later, treatment with the triplet regimen was interrupted temporarily. A recovery period of up to 6 weeks was allowed. Patients could resume dosing at a lower dose level upon recovery to grade 2 or better. Recurrence of a drug-related DLT after one dose reduction led to withdrawal of the patient from the study. Patients who required permanent discontinuation from aflibercept were withdrawn from the study. If either cisplatin or pemetrexed was permanently discontinued, the administration of aflibercept and the remaining chemotherapeutic agent was allowed to continue at the same (or lower) dose.\n\nDuration of therapy\n\nStudy treatment continued until disease progression, an unacceptable AE, patient’s decision to withdraw from the study, or changes in the patient’s condition rendering further treatment unacceptable.\n\nPharmacokinetic analysis\n\nBlood samples were collected to characterise the plasma PK profiles of aflibercept and pemetrexed. For aflibercept, samples were collected on cycle 1 day 1 before aflibercept infusion, at the end of aflibercept infusion, and at 1, 2, 4 and 8 h after completion of pemetrexed infusion; day 2 (24 h), day 8, and day 15. For cycle 2 and beyond, trough samples for aflibercept were taken before aflibercept infusion. For pemetrexed, samples were collected on cycle 1 day 1 before aflibercept infusion, at the end of pemetrexed infusion, and at 0.25, 0.5, 1, 2, and 4 h after completion of pemetrexed infusion, and on day 2 (24 h).\n\nAflibercept (bound to VEGF or free) in plasma samples was quantified using a validated, direct enzyme-linked immunosorbent assay, with a lower limit of quantification of 15.6 ng ml−1 in human plasma for free aflibercept and 43.9 ng ml−1 in human plasma for bound aflibercept (Tew et al, 2010). To calculate the total aflibercept concentration, the amount of aflibercept present in the bound complex needed to be determined. As 1 ng of complex contains 0.717 ng of aflibercept and 0.283 ng of human VEGF, the concentration of the complex was multiplied by 0.717 to give the adjusted-bound aflibercept concentration (Equation 1).\n\nTotal aflibercept concentrations were calculated by adding the adjusted-bound aflibercept concentrations to the free aflibercept concentrations at the corresponding time points (Equation 2). Total aflibercept concentrations were only calculated for samples for which both free and bound aflibercept concentrations were available.\n\nPemetrexed plasma concentration determination was performed by LC-MS/MS. Briefly, pemetrexed and its internal standard was extracted from a 0.050 ml aliquot of human K2-EDTA plasma using an automated protein precipitation procedure. The lower limit of quantitation of the assay is 1.00 mcg ml−1. Detection of antiaflibercept antibodies was performed in acid-treated serum samples using an electrochemiluminescence bridging immunoassay (Tew et al, 2010).\n\nObserved PK parameters were calculated using non-compartmental analysis (WinNonLin v. 5.3, Pharsight Corporation, Mountain View, CA, USA). Observed half-life (t½), clearance (CL), volume of distribution (Vss), maximum plasma concentration (Cmax), dose-adjusted Cmax (Cmax/D), last observed concentration (Clast), time of maximum plasma concentration (tmax), time of last observed concentration (tlast), area under the concentration-time curve (AUCinf), and dose-adjusted AUCinf (AUCinf/D) were calculated for free aflibercept and for pemetrexed. Cmax, Cmax/D, Clast, tmax, and tlast were calculated for adjusted-bound aflibercept–VEGF complex. AUCinf was calculated using the log-linear trapezoidal rule.\n\nResults\n\nPatient demographics\n\nBetween October 2008 and November 2010, 18 patients were enrolled at the two participating institutions. A median of four cycles of aflibercept (range 1–12) were administered for the entire group. Treatment duration of the 18 patients ranged from 21 days to 315 days (0.7–10 months). At the time of this report, all patients are off study treatment. Table 1 shows their baseline demographics.\n\nDose escalation and maximum tolerated dose\n\nFour, seven, and seven patients were enrolled in dose levels 1, 2, and 3, respectively. Treatment is summarised in Table 2. Two patients (1 in the 4 mg kg−1 cohort and 1 in the 6 mg kg−1 cohort) were replaced owing to disease progression before cycle 1 completion (without experiencing a DLT). No cycle 1 DLT was observed at the first dose level (2 mg kg−1). One patient at the 4 mg kg−1 dose level experienced treatment-related grade 3 hypophosphatemia (DLT), thus prompting a cohort expansion with an additional three patients. No additional DLT was observed in the expansion cohort allowing for further dose escalation. When aflibercept was dosed at 6 mg kg−1 in the next cohort, no DLTs were observed. Thus, aflibercept 6 mg kg−1 i.v. every 3 weeks was selected as the RP2D in combination with pemetrexed and cisplatin.\n\nSafety and compliance\n\nAll 18 treated patients were evaluable for toxicity and experienced at least one AE during the course of the study. The most frequently reported treatment-related AEs are listed in Table 3.\n\nFatigue (89%) and nausea (83%) were the most frequently reported non-haematologic all grade AEs. Three patients (17%) treated at higher doses of aflibercept had grade 3 fatigue. Nausea (83%), constipation (61%), anorexia (61%), and vomiting (56%) were the most relevant gastrointestinal toxicities. These were grade 1 and 2 in all cases, and were managed with supportive care measures. Other toxicities, commonly associated with antiangiogenic therapy, were hypertension (56%), dysphonia (39%), thromboembolic-related events (TREs, 17%), and proteinuria (6%). Hypertension seemed to be more frequent with increasing doses of aflibercept. Four patients (22%) experienced grade 3 hypertension (one patient treated at 2 mg kg−1 and three patients treated at 6 mg kg−1), which was managed with oral antihypertensive medication. No patient discontinued study treatment owing to this AE. Dysphonia was mild, and did not lead to dose modification, delay, or treatment discontinuation. Two patients, both treated in the 4 mg kg−1 cohort, had grade 4 pulmonary embolism (PE). One patient had a bilateral PE as well as deep vein thrombosis and was withdrawn from the study; the other was asymptomatic and had an incidental unilateral PE documented on a restaging computed tomography scan showing progressive disease (PD). No major haemorrhagic events were observed. One episode of reversible grade 2 proteinuria was observed, in the 6 mg kg−1 cohort. It did not require modification of the treatment dose.\n\nFive patients (28%) experienced mild neurocognitive disturbance. These symptoms mostly consisted of a vague sensation of dizziness and mild headache. All episodes were grade 1 in intensity, and mostly observed in female patients. Four patients were treated at dose level 1 (2 mg kg−1 of aflibercept) and one patient was at dose level 2 (4 mg kg−1 of aflibercept). There was no apparent association with hypertension, or with the cumulative dose of aflibercept. Magnetic resonance imaging (MRI) of the brain was performed in two of these patients and results were normal. The development of these symptoms did not correlate with a specific number of cycles and, after its resolution, patients who were rechallenged did not experience a recurrence of their symptoms. There were no grade 3 or 4 events. These symptoms did not lead to treatment cessation and were reversible in three of the five patients (60%). One patient reported mild cognitive impairment at the end of the study but did not have a formal neurocognitive assessment, and the other patient was lost to follow-up.\n\nA summary of the most common laboratory abnormalities observed throughout the study can be found in Table 3. Grade 3 neutropenia was observed in six patients (33%), leading to dose delay and/or dose reduction of the chemotherapy part of the regimen in the majority of cases. No episodes of febrile neutropenia were documented. Three patients died during the study: two of disease progression and one patient of a pleural effusion, assessed as unrelated to the study treatment.\n\nDose delays and dose modifications for pemetrexed and cisplatin are provided in Table 4. There were no dose delays or reductions for aflibercept.\n\nActivity\n\nTwo patients (11%) achieved a confirmed PR, both treated at the 6 mg kg−1 cohort. One patient, a 56-year-old male, with a previously untreated NSCLC achieved PR at cycle 6, and discontinued treatment owing to an inflammatory cholangitis (unrelated to study treatment). A 65-year-old male with a chemo-naïve mesothelioma achieved a PR at cycle 8, and received 12 cycles of therapy, until PD was documented. Eleven (61%) patients had SD as their best response.\n\nPharmacokinetic analysis\n\nThe PK parameters for unbound (free) and adjusted-bound aflibercept are shown in Table 5. The mean Cmax of free aflibercept increased in a dose-proportional manner when comparing the 2, 4, and 6 mg kg−1 cohorts. The concentration–time profiles of free aflibercept are characterised by a consistent t½ over the dosing interval at all three dose levels (Figure 1). The mean CL and Vss of free aflibercept did not change over the 2–6 mg kg−1 dose range, suggesting target (endogenous VEGF) saturation. The mean dose-adjusted AUC during the first dosing interval (AUC0-21 day/dose) of free aflibercept was dose-proportional at the two higher dose levels of 4 and 6 mg kg−1, indicating near-target saturation in the systemic circulation after one dose. Following i.v. administration, free aflibercept binds endogenous VEGF to form a monomeric aflibercept–VEGF complex. The complex reaches a plateau, and the concentration of adjusted-bound complex remains constant with repeat dosing of aflibercept at 2, 4, and 6 mg kg−1 over the 21-day dosing interval. Bound aflibercept concentrations were comparable at all three dose levels, suggesting saturation of endogenous VEGF binding (Figure 1). The cohorts differed only in their time-to-plateau, which was longest for the 2 mg kg−1 cohort and shorter for the 4 and 6 mg kg−1 cohorts.\n\nPemetrexed PK parameters were calculated to assess the effect, if any, of aflibercept administration on systemic pemetrexed concentrations (Table 5). The systemic concentration of and exposure to pemetrexed were not altered by concomitant administration of aflibercept. In particular, the kinetics of pemetrexed were linear over the first dosing interval, consistent with literature values of pemetrexed PK parameters when pemetrexed is administered with cisplatin in the same study population composition as this study (Dickgreber et al, 2009). The pemetrexed Cmax, AUC, tmax, and t½ were not statistically different (P<0.05) between the 2, 4, and 6 mg kg−1 aflibercept cohorts. In addition, the mean plasma concentration of pemetrexed at any given time point was the same regardless of aflibercept dose. Further, free and bound aflibercept drug concentrations in combination with pemetrexed are comparable to those observed with aflibercept monotherapy (Tew et al, 2010), suggesting that aflibercept PK are not affected by concomitant pemetrexed administration.\n\nNo antiaflibercept antibodies were detected in analysed samples.\n\nConclusion\n\nThis study has evaluated the feasibility of the combination of i.v. aflibercept in conjunction with cisplatin and pemetrexed in patients with advanced solid tumours. The RP2D of aflibercept was determined to be 6 mg kg−1 i.v. every 3 weeks. The most common treatment-related clinical AEs were fatigue and nausea. Fatigue was observed more frequently than in prior studies with cisplatin and pemetrexed combinations both in NSCLC and MPM patients (Shepherd et al, 2001; Vogelzang et al, 2003; Scagliotti et al, 2008). The most frequently reported haematologic toxicities (i.e., neutropenia and thrombocytopenia) do not appear to differ significantly from previous studies (Vogelzang et al, 2003; Kim et al, 2008; Scagliotti et al, 2008).\n\nAnti-VEGF therapy has been associated with several side effects common to this class of agents. The incidence of vascular-related toxicities (i.e., hypertension, proteinuria, thrombosis, and haemorrhage) in this study was generally similar to that previously reported in prior studies of anti-VEGF therapy (Kuenen et al, 2002), including aflibercept with chemotherapy (Freyer et al, 2008; Limentani et al, 2008; Rixe et al, 2008; Kuhnowski et al, 2010). Prior reports have indicated a potential negative interaction between VEGF modulators and cisplatin (Kuenen et al, 2002; Marx et al, 2002). As VEGF has an important role in endothelial cell homeostasis and modulates the production of nitric oxide, deprivation of VEGF can potentially lead to a shift in endothelial cells to a prothrombotic state (Li and Keller, 2000). Chemotherapeutic agents, especially cisplatin, can induce activation of platelets, monocytes, and endothelial cells (Togna et al, 2000); as such, further exacerbation of hypercoagulability could potentially occur, resulting in a high rate of thromboembolic events. Two patients (11%) experienced three TREs in this study (two episodes of PE and one episode of DVT) deemed to be at least possibly related to the study treatment. The reported incidence of TREs in prior studies of aflibercept and chemotherapy ranges from 3 to 22% (Tabernero et al, 2012). In addition, a meta-analysis of anti-VEGF class AEs in three placebo-controlled phase III trials with aflibercept demonstrated that venous thrombotic events were not increased with aflibercept (Tabernero et al, 2012). The incidence of TREs in unselected patient populations with NSCLC and/or mesothelioma is 3–31% (Chew et al, 2008). It is therefore difficult to ascertain whether the addition of aflibercept to the cisplatin–pemetrexed combination actually poses a higher risk of developing TREs.\n\nVascular endothelial growth factor has an important role in regulating glomerular permeability (Kanellis et al, 2004). Thus, the inhibition of VEGF in the kidney glomeruli can result in proteinuria. Several clinical trials of aflibercept have confirmed that proteinuria is a potential toxicity, with an overall incidence of grade 3/4 up to 8% (Tabernero et al, 2012). Nephrotoxicity is one of the major side effects of cisplatin, which occurs in a dose-dependent manner in 25–30% of patients receiving a single dose of cisplatin. Renal toxicity is also accumulative. Glomerular injury is one of the potential mechanisms of nephrotoxicity when cisplatin is used (Sanchez-Gonzalez et al, 2011). Although glomerular injury occurs less frequently (because it is associated with high drug exposures) than tubular toxicity, vascular or interstitial damage, it may lead to proteinuria. Cisplatin-induced glomerular injury is characterised by a marked fall in the glomerular filtration rate. In this study, the frequencies of decreased CrCl and of proteinuria were both low (n=1 each, 6%) and no grade ⩾3 of such events were observed (Table 3).\n\nIn this study, we observed an increased rate of neurological symptoms, particularly in the form of a poorly defined, mild neurocognitive disturbance, often described by patients as dizziness or lightheadedness. There was no apparent dose dependence, as four episodes of this neurocognitive disturbance were documented when aflibercept was administered at 2 mg kg−1, and only one patient reported it in the 4 mg kg−1 cohort. Evaluation of these vague neurological symptoms steered towards the consideration of RPLS, which has been associated with the administration of anti-VEGF agents and/or cisplatin (Ito et al, 1998; Marinella and Markert, 2009; Leighl et al, 2010). However, differences between the symptoms observed in this patient subgroup and the most commonly reported characteristics of RPLS were noted. First, most cases of RPLS reported in the literature have been associated with severe and often acute hypertension; this was not the case in our study. All patients had their BP monitored on a weekly basis. For those who developed these mild neurocognitive symptoms, no significant changes were observed between BP reading before and after the development of symptoms (data not shown). Endothelial dysfunction has been implicated in the pathophysiology of RPLS, and has been observed in other, nontumoral, clinical settings, such as chronic renal failure, nephritis, haemolytic uraemic syndrome, and/or metabolic disturbances (e.g., hypomagnesemia) (Hinchey et al, 1996). Therefore, we further investigated if the development of this cognitive disorder was associated with decreased CrCl, the onset of proteinuria, or the presence of electrolyte abnormalities. All patients who developed neurocognitive symptoms had a normal CrCl at baseline, and no changes were observed in association with the onset of symptoms (data not shown). Second, other potentially serious neurological symptoms (e.g., alteration in mental status, hallucinations, and seizures) are usually present in the development of RPLS. These symptoms were not observed in patients in our study though reports of mild headache and memory impairment were noted in several patients. Finally, abnormalities in MRI, including vasogenic oedema, have been described consistently and are key to diagnosis in patients affected by RPLS (Hinchey et al, 1996). In this phase I study, in those patients who had MRI scans (n=2) after developing neurocognitive symptoms, no MRI abnormalities were noted.\n\nPharmacokinetic analysis showed that trough concentrations of free (unbound) aflibercept were higher than adjusted-bound aflibercept trough concentrations in patients receiving either 4 or 6 mg kg−1 aflibercept. Maintenance of systemic free aflibercept concentration above the adjusted-bound aflibercept trough concentration ensures maintenance of target saturation. As target saturation is thought to parallel clinical efficacy, PK analysis suggests that a dose of 6 mg kg−1 i.v. every 3 weeks has the best chance of clinical efficacy via maintenance of target saturation over the entire dosing interval. With respect to the potential impact of aflibercept administration on pemetrexed concentrations, the systemic concentration of and exposure to pemetrexed were not altered by concomitant administration of aflibercept.\n\nIn summary, this study showed that the administration of aflibercept 6 mg kg−1 i.v. every 3 weeks in combination with cisplatin and pemetrexed led to a slightly higher than expected rate of the side effects (mainly increased fatigue) than that observed with the chemotherapy regimen alone. The mild neurocognitive disturbances seen in five patients were investigated and did not suggest RPLS at this stage, but led to a higher level of observation for this toxicity in the phase II study. The phase II study of this regimen was conducted in previously untreated nonsquamous NSCLC (clinicaltrials.gov identifier: NCT00794417) and results will be reported separately, but it is noted that the study was discontinued early owing to a higher than anticipated incidence of RPLS.\n\nThe present study has been supported by Regeneron Pharmaceuticals and SanofiOncology.\n\nFigure 1 (A) Mean aflibercept (free and adjusted-bound) concentration–time profiles after first, single i.v. administration of aflibercept. (B) Mean aflibercept (free and adjusted-bound) concentration–time profiles after i.v. administration of multiple doses of aflibercept.\n\nTable 1 Patient characteristics\n\n \tPatients (n=18), n (%)\t\nAge, years\t \t\n Median\t61\t\n Range\t37–73\t\n \t \t\nGender\t\n Male\t9 (50)\t\n Female\t9 (50)\t\n \t \t\nECOG PS\t\n 0\t2 (11)\t\n 1\t16 (89)\t\n \t \t\nType of tumour\t\n Mesothelioma\t5 (28)\t\n Non-small-cell lung cancer\t4 (22)\t\n Angiosarcoma\t1 (6)\t\n Breast cancer\t1 (6)\t\n Cholangiocarcinoma\t1 (6)\t\n Endometrial stromal sarcoma\t1 (6)\t\n Appendiceal adenocarcinoma\t1 (6)\t\n Carcinoma of unknown origin\t1 (6)\t\n Rectal cancer\t1 (6)\t\n Thyroid poorly differentiated carcinoma\t1 (6)\t\n \t \t\nPrior treatment\t\n Surgery\t13 (72)\t\n Chemotherapy\t8 (44)\t\n Radiotherapy\t7 (39)\t\n \t \t\nNo. of prior chemotherapy regimens\t\n 0\t10\t\n 1\t3\t\n 2\t1\t\n 3\t2\t\n 4\t2\t\nAbbreviation: ECOG PS=Eastern Cooperative Oncology Group performance status.\n\nTable 2 Dose level evaluated and DLT encountered\n\nDose level\tAflibercept dose (mg kg−1)\tNo. of patients treated\tNo. of patients with DLT\tDLT\t\n1\t2\t4\t0\t \t\n2\t4\t7\t1\tGrade 3 hypophosphatemia\t\n3\t6\t7\t0\t \t\nAbbreviation: DLT=dose-limiting toxicity.\n\nTable 3 Treatment-related adverse events and laboratory abnormalities\n\nDose level\tDose level 1\tDose level 2\tDose level 3\t \t \t\nDose\t2 mg kg−1\t4 mg kg−1\t6 mg kg−1\tAll\t\nNo. of patients\t4\t7\t7\t18\t\nGrades\tAll grades\tGrades 3/4\tAll grades\tGrades 3/4\tAll grades\tGrades 3/4\tAll grades (%)\tGrades 3/4 (%)\t\nFatigue\t4\t0\t6\t1\t6\t2\t16 (89)\t3 (17)\t\nNausea\t4\t0\t5\t0\t6\t0\t15 (83)\t0\t\nConstipation\t3\t0\t3\t0\t5\t0\t11 (61)\t0\t\nAnorexia\t3\t0\t4\t0\t4\t0\t11 (61)\t0\t\nVomiting\t4\t0\t3\t0\t3\t0\t10 (56)\t0\t\nHypertension\t2\t1\t3\t0\t5\t3\t10 (56)\t4 (22)\t\nDysphonia\t1\t0\t3\t0\t3\t0\t7 (39)\t0\t\nHeadache\t3\t0\t1\t0\t3\t0\t7 (39)\t0\t\nDizziness\t1\t0\t2\t0\t4\t0\t6 (33)\t0\t\nEpistaxis\t2\t0\t1\t0\t3\t0\t6 (33)\t0\t\nDiarrhoea\t2\t0\t2\t0\t1\t0\t5 (28)\t0\t\nMucositis\t1\t0\t3\t0\t1\t0\t5 (28)\t0\t\nWeight loss\t0\t0\t1\t0\t3\t0\t4 (22)\t0\t\nMemory impairment\t1\t0\t2\t0\t0\t0\t3 (17)\t0\t\nArthralgia\t0\t0\t0\t0\t2\t0\t2 (11)\t0\t\nPulmonary embolism\t0\t0\t2\t2\t0\t0\t2 (11)\t2 (11)\t\nDVT\t0\t0\t1\t1\t0\t0\t1 (6)\t1 (6)\t\nRash\t0\t0\t0\t0\t1\t0\t1 (6)\t0\t\nSensory neuropathy\t1\t0\t0\t0\t0\t0\t1 (6)\t0\t\n \t \t \t \t \t \t \t \t \t\nHaematology\t\n Neutropenia\t2\t2\t4\t2\t7\t2\t13 (72)\t6 (33)\t\n Thrombocytopenia\t2\t0\t4\t0\t2\t0\t8 (44)\t0\t\n Anaemia\t3\t0\t7\t0\t6\t0\t3 (17)\t0\t\n \t \t \t \t \t \t \t \t \t\nChemistry\t\n Hyponatremia\t3\t1\t6\t3\t5\t2\t14 (78)\t6 (33)\t\n Hypomagnesemia\t2\t0\t4\t0\t2\t0\t8 (44)\t0\t\n Hypophosphatemia\t1\t1\t2\t1\t4\t1\t7 (39)\t3 (17)\t\n Hypokalemia\t0\t0\t1\t1\t1\t0\t2 (11)\t1 (6)\t\n AST (raised)\t2\t0\t5\t0\t5\t0\t12 (67)\t0\t\n ALT (raised)\t2\t0\t3\t0\t5\t0\t10 (56)\t0\t\n ALP (raised)\t2\t0\t2\t0\t3\t1\t7 (39)\t1 (6)\t\n Decreased CrCl\t1\t0\t0\t0\t0\t0\t1 (6)\t0\t\n Proteinuria\t0\t0\t0\t0\t1\t0\t1 (6)\t0\t\nAbbreviations: ALP=Alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CrCl=creatinine clearance; DVT=deep venous thrombosis,\n\nTable 4 Dose delays and reductions due to adverse events per dose level and drug\n\n \t \t \t \t \tAny dose reduction\t \t\nPt ID\tDose level\tAny delay (yes/no)\tMain reason of delay\tTotal length of delay (week)\tC\tP\tA\tNumber/timing of dose reductions\t\n001\t1\tNo\tNA\tNA\tNo\tNA\t\n002\t1\tYes\tG3 neutropenia\t2\tYes\tYes\tNo\tC4D1,\t\n003\t1\tYes\tG3 neutropenia, G2 thrombocytopenia, G2 CrCl decreased\t1\tYes\tNo\tNo\tC5D1, C7D1\t\n004\t1\tYes\tG3 nonneutropenic fever\t1\tNo\tNA\t\n005\t2\tNo\tNA\tNA\tNo\tNA\t\n006a\t2\tNo\tNA\tNA\tNo\tNA\t\n007\t2\tNo\tNA\tNA\tNo\tNA\t\n008\t2\tYes\tG3 fatigue, G3 neutropenia, G2 thrombocytopenia\t1\tYes\tYes\tNo\tC2D1, C3D1\t\n009\t2\tNo\tNA\tNA\tNo\tNA\t\n010\t2\tNo\tNA\tNA\tNo\tNA\t\n011\t2\tYes\tG3 neutropenia, G2 anaemia, decreased CrCl\t3\tYes\tYes\tNo\tC2D1, C3D1, C4D1\t\n012\t3\tYes\tG1 anaemia\t2\tNo\tNA\t\n013\t3\tNo\tNA\tNA\tNo\tNA\t\n014\t3\tYes\tG3 neutropenia, G2 fatigue, G1 anaemia\t3\tNo\tNA\t\n015\t3\tYes\tG2 pneumonia (non-related)\t2\tNo\tNA\t\n016a\t3\tNo\tNA\tNA\tNo\tNA\t\n017\t3\tYes\tG1 neutropenia, decreased CrCl\t1\tYes\tNo\tNo\tC4D1\t\n018\t3\tNo\tNA\tNA\tNo\tNA\t\nAbbreviations: A=aflibercept; C=cisplatin; CrCl=creatinine clearance; NA=not applicable; P=pemetrexed.\n\na Patient(s) nonevaluable.\n\nTable 5 Pharmacokinetic parameters of pemetrexed, free and adjusted-bound aflibercept in the 2, 4, and 6 mg kg−1 cohorts\n\n \tPemetrexed\tFree aflibercept\tAdjusted-bound aflibercept\t\n \t2 mg kg−1 cohort\t4 mg kg−1 cohort\t6 mg kg−1 cohort\t2 mg kg−1 cohort\t4 mg kg−1 cohort\t6 mg kg−1 cohort\t2 mg kg−1 cohort\t4 mg kg−1 cohort\t6 mg kg−1 cohort\t\nNumber of patients included in the analysis\t4\t7\t7\t4\t7\t7\t4\t7\t7\t\nMean Cmax (mg l−1)\t124±0.02\t112±0.07\t113±0.05\t53.6±7.14\t68.6±18.7\t148±108\t1.73±0.12\t2.28±1.03\t2.14±0.74\t\nMean AUC0–21 d (hr*mg l−1)\t151±30.1\t151±32.7\t162±12.5\t4824±2316\t7920±6024\t10608±3648\tNC\tNC\tNC\t\nMean tmax (h)\t0.010±0.0\t0.010±0.0\t0.010±0.0\t1.75±1.51\t0.912±1.01\t0.912±1.01\t300±200\t386±179\t432±132\t\nMean clearancea\t56.7±9.73\t57.8±14.0\t51.7±3.62\t0.00764±0.003\t0.0111±0.005\t0.0111±0.006\tNC\tNC\tNC\t\nMean t1/2 (h)\t1.47±0.39\t1.63±0.22\t1.73±0.37\t75.8±13.7\t133±130\t89.3±25.0\tNC\tNC\tNC\t\nAbbreviations: AUC=area under the curve; Cmax=maximum plasma concentration; NC=not calculated; tmax=time of maximum plasma concentration; t½=observed half-life.\n\nThe mean±s.d. is reported.\n\na Units of clearance are ml min−1 m−2 for pemetrexed, and ml min−1 kg−1 for free aflibercept and adjusted-bound aflibercept.\n\nThis work is published under the standard license to publish agreement. 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N Engl J Med 334 (8): 494–5008559202\nHolash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, Boland P, Leidich R, Hylton D, Burova E, Ioffe E, Huang T, Radziejewski C, Bailey K, Fandl JP, Daly T, Wiegand SJ, Yancopoulos GD, Rudge JS (2002) VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 99 (17): 11393–1139812177445\nIto Y, Arahata Y, Goto Y, Hirayama M, Nagamutsu M, Yasuda T, Yanagi T, Sobue G (1998) Cisplatin neurotoxicity presenting as reversible posterior leukoencephalopathy syndrome. AJNR Am J Neuroradiol 19 (3): 415–4179541291\nKanellis J, Levidiotis V, Khong T, Cox AJ, Stacker SA, Gilbert RE, Cooper ME, Power DA (2004) A study of VEGF and its receptors in two rat models of proteinuria. Nephron Physiol 96 (1): P26–P3614752241\nKim YH, Chung HC, Kang WK, Park SR, Kim CS, Kim TY, Shin SW, Park BJ, Cha SJ, Bang YJ (2008) Pemetrexed and cisplatin in patients with advanced gastric cancer: a Korean cancer study group multicenter phase II study. Cancer Chemother Pharmacol 62 (2): 263–27017960386\nKowanetz M, Ferrara N (2006) Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin Cancer Res 12 (17): 5018–502216951216\nKuenen BC, Rosen L, Smit EF, Parson MR, Levi M, Ruijter R, Huisman H, Kedde MA, Noordhuis P, van der Vijgh WJ, Peters GJ, Cropp GF, Scigalla P, Hoekman K, Pinedo HM, Giaccone G (2002) Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors. J Clin Oncol 20 (6): 1657–166711896117\nKuhnowski F, Thieblemont C, Jardin F, Broussais-Guillemot F, Meignan M, Cabecadas J, Gaulard P, Tilly H, Oprea C, Haioun C (2010) A phase I study of IV aflibercept (Afl) in combination with R-CHOP in untreated patients (pts) with B-cell lymphoma. J Clin Oncol 28 (Suppl 15s): abstr 8010\nLeighl NB, Raez LE, Besse B, Rosen PJ, Barlesi F, Massarelli E, Gabrail N, Hart LL, Albain KS, Berkowitz L, Melnyk O, Shepherd FA, Sternas L, Ackerman J, Shun Z, Miller VA, Herbst RS (2010) A multicenter, phase 2 study of vascular endothelial growth factor trap (Aflibercept) in platinum- and erlotinib-resistant adenocarcinoma of the lung. J Thorac Oncol 5 (7): 1054–105920593550\nLi W, Keller G (2000) VEGF nuclear accumulation correlates with phenotypical changes in endothelial cells. J Cell Sci 113 (Part 9): 1525–153410751144\nLimentani S, Just R, Purdham A, Mulay M, Bair A, Tamby JF, Chap LI, Rosen LS (2008) A phase I dose escalation and pharmacokinetic (PK) study of intravenous (iv) aflibercept (VEGF Trap) plus FOLFOX4 in patients (pts) with advanced solid tumors: preliminary results. J Clin Oncol 26 (Suppl): abstr 3556\nLockhart AC, Rothenberg ML, Dupont J, Cooper W, Chevalier P, Sternas L, Buzenet G, Koehler E, Sosman JA, Schwartz LH, Gultekin DH, Koutcher JA, Donnelly EF, Andal R, Dancy I, Spriggs DR, Tew WP (2010) Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol 28 (2): 207–21419949018\nMarinella MA, Markert RJ (2009) Reversible posterior leucoencephalopathy syndrome associated with anticancer drugs. Intern Med J 39 (12): 826–83419220526\nMarx GM, Steer CB, Harper P, Pavlakis N, Rixe O, Khayat D (2002) Unexpected serious toxicity with chemotherapy and antiangiogenic combinations: time to take stock!. J Clin Oncol 20 (6): 1446–144811896090\nNovello S, Ramlau R, Gorbunova VA, Ciuleanu TE, Ozgurolu M, Goksel T, Baldotto C, Bennouna J, Shepherd FA, Scagliotti G (2011) Aflibercept in combination with docetaxel for second-line treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC): final results of a multinational placebo-controlled phase III trial (EFC10261-VITAL). 14th World Conference on Lung Cancer. Abstract O4302. 3–7 July 2011 Amsterdam, The Netherlands\nRixe O, Verslype C, Khayat D, Tejpar S, Billemont B, Crabbe M, Meric JB, Assadourian S, Van Cutsem E (2008) A phase I dose escalation (DE) and pharmacokinetics (PK) study of intravenous aflibercept (VEGF Trap) plus irinotecan, 5-fluorouracil, and leucovorin (I-LV5FU2) in patients with advanced solid tumors (STs). J Clin Oncol 26 (Suppl): abstr 3557\nSanchez-Gonzalez PD, Lopez-Hernandez FJ, Lopez-Novoa JM, Morales AI (2011) An integrative view of the pathophysiological events leading to cisplatin nephrotoxicity. Crit Rev Toxicol 41 (10): 803–82121838551\nSandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355 (24): 2542–255017167137\nScagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26 (21): 3543–355118506025\nShepherd FA, Dancey J, Arnold A, Neville A, Rusthoven J, Johnson RD, Fisher B, Eisenhauer E (2001) Phase II study of pemetrexed disodium, a multitargeted antifolate, and cisplatin as first-line therapy in patients with advanced nonsmall cell lung carcinoma: a study of the National Cancer Institute of Canada Clinical Trials Group. Cancer 92 (3): 595–60011505404\nSpigel DR, Hainsworth JD, Shipley DL, Ervin TJ, Kohler PC, Lubiner ET, Peyton JD, Waerhouse DM, Burris HA, Greco FA (2012) A randomized phase II trial of pemetrexed/gemcitabine/bevacizumab or pemetrexed/carboplatin/bevacizumab in the first-line treatment of elderly patients with advanced non-small cell lung cancer. J Thor Oncol 7 (1): 196–202\nTabernero J, Allegra CJ, Rougier PR, Scagliotti G, Philip PA, Lakomy R, Ramlau R, Assadourian S, Chevalier S, Van Cutsem E (2012) Meta-analysis of anti-VEGF class adverse events from three double-blind (db), placebo (pbo)-controlled phase III trials with IV aflibercept (Afl). J Clin Oncol 30 (Suppl): abstr 3579\nTabernero J, Van Cutsem E, Lakomy R, Prausova J, Ruff P, Van Hazel G, Moisevenko V, Ferry D, Mckendrick J, Soussan-Lazard K, Boelle E, Allegra C (2011) Results from VELOUR, a phase 3 study of aflibercept versus placebo in combination with FOLFIRI for the treatment of patients with previously treated metastatic colorectal cancer. European Multidisciplinary Congress. Abstract 6LBA, Stockholm, 23–27 September 2011\nTang P, Cohen SJ, Bjarnason GA, Kollmannsberger C, Virik K, MacKenzie MJ, Brown J, Wang L, Chen AP, Moore MJ (2008) Phase II trial of aflibercept (VEFG Trap) in previously treated patients with metastatic colorectal cancer (MCRC): a PMH phase II consortium trial. J Clin Oncol 26 (Suppl): abstr 4027\nTew WP, Gordon M, Murren J, Dupont J, Pezzulli S, Aghajanian C, Sabbatini P, Mendelson D, Schwartz L, Gettinger S, Psyrri A, Cedarbaum JM, Spriggs DR (2010) Phase 1 study of aflibercept administered subcutaneously to patients with advanced solid tumors. Clin Cancer Res 16 (1): 358–36620028764\nTogna GI, Togna AR, Franconi M, Caprino L (2000) Cisplatin triggers platelet activation. Thrombosis Res 99 (5): 503–509\nVogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P (2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21 (14): 2636–264412860938\n\n",
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"journal": "British journal of cancer",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D004334:Drug Administration Schedule; D005221:Fatigue; D005260:Female; D005971:Glutamates; D006147:Guanine; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea; D009369:Neoplasms; D000068437:Pemetrexed; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins",
"nlm_unique_id": "0370635",
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"title": "A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours.",
"title_normalized": "a phase i dose escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours"
} | [
{
"companynumb": "CA-MYLANLABS-2017M1008125",
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"abstract": "Pneumomediastinum has been described in patients with asthma. In this case report, we describe a young patient who presented to our medical assessment unit with an asthma exacerbation and progressive dyspnea. The patient developed pneumomediastinum, a rare complication of an asthma exacerbation. Pneumomediastinum is usually characterized by chest pain, dyspnea, and neck swelling caused by subcutaneous emphysema. Although the condition is usually benign and treatment is primarily supportive, surgical intervention may be needed if the patient develops hemodynamic compromise or respiratory failure through mechanisms similar to those seen in a tension pneumothorax.",
"affiliations": "Department of Endocrinology and General Internal Medicine, St Columcille's Hospital, Loughlinstown, County Dublin, Ireland. patrickdavidmitchell@gmail.com.;Department of Endocrinology and General Internal Medicine, St Columcille's Hospital, Loughlinstown, County Dublin, Ireland.;Department of Endocrinology and General Internal Medicine, St Columcille's Hospital, Loughlinstown, County Dublin, Ireland.",
"authors": "Mitchell|Patrick D|PD|;King|Thomas J|TJ|;O'Shea|Donal B|DB|",
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"country": "United States",
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"doi": "10.4187/respcare.03750",
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"issue": "60(8)",
"journal": "Respiratory care",
"keywords": "asthma; dyspnea; pneumomediastinum",
"medline_ta": "Respir Care",
"mesh_terms": "D002637:Chest Pain; D018450:Disease Progression; D004417:Dyspnea; D006801:Humans; D008297:Male; D008478:Mediastinal Emphysema; D012131:Respiratory Insufficiency; D013224:Status Asthmaticus; D055815:Young Adult",
"nlm_unique_id": "7510357",
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"pages": "e141-3",
"pmc": null,
"pmid": "25605959",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Subcutaneous Emphysema in Acute Asthma: A Cause for Concern?",
"title_normalized": "subcutaneous emphysema in acute asthma a cause for concern"
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"companynumb": "IE-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-64340BI",
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"activesubstancename": "ALBUTEROL SULFATE\\IPRATROPIUM BROM... |
{
"abstract": ": Loperamide hydrochloride is an over-the-counter anti-diarrheal agent, acting via mu-opioid receptor agonist effects in the intestinal myenteric plexus. Although preclinical investigations suggested that abuse liability associated with loperamide use is low, there are increasing numbers of cases reported to the US Food and Drug Administration, of abuse, dependence, and withdrawal associated with loperamide use. A case of a patient with opioid use disorder, that is, in the form of protracted loperamide excess use, requiring management of withdrawal with methadone is presented. Management of withdrawal from abrupt loperamide discontinuation has not been discussed in the literature. Long-term treatment issues are also described.",
"affiliations": "Department of Psychiatry (RJL, KSJ); Department of Family Medicine (MAG), University at Buffalo, Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, NY.",
"authors": "Leo|Raphael J|RJ|;Ghazi|Muhammad A|MA|;Jaziri|Kelly S|KS|",
"chemical_list": "D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D008139:Loperamide; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1097/ADM.0000000000000325",
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"issn_linking": "1932-0620",
"issue": "11(5)",
"journal": "Journal of addiction medicine",
"keywords": null,
"medline_ta": "J Addict Med",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D005260:Female; D006801:Humans; D008139:Loperamide; D008691:Methadone; D009293:Opioid-Related Disorders; D017450:Receptors, Opioid, mu",
"nlm_unique_id": "101306759",
"other_id": null,
"pages": "402-404",
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"pmid": "28574864",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Methadone Management of Withdrawal Associated With Loperamide-related Opioid Use Disorder.",
"title_normalized": "methadone management of withdrawal associated with loperamide related opioid use disorder"
} | [
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"companynumb": "US-JNJFOC-20171004555",
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"activesubstancename": "LOPERAMIDE HYDROCHLORIDE"
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{
"abstract": "SGLT-2 (sodium-glucose cotransporter-2) inhibitors are a novel class of oral hypoglycemic agents for the management of type 2 diabetes mellitus (T2DM). Herein, we aimed to assess the long-term effectiveness and safety of SGLT-2 inhibitors in a Southern Italy population of subjects affected by T2DM.\n408 diabetic patients treated with one of the three SGLT-2 inhibitors currently available in Italy (dapagliflozin, empagliflozin, and canagliflozin), either alone or in combination with other antidiabetic drugs, were retrospectively assessed at baseline, during, and after 18 months of continuous therapy.\nTreatment with SGLT-2 inhibitors resulted in a median decrease in HbA1c of 0.9%, with a percentage of decrement of 12 in relation to the baseline value, followed by a significant reduction (P < 0.001) in fasting plasma glucose. Variations in HbA1c occurred independently of the baseline clinical or biochemical characteristics. In addition, treatment with SGLT-2 inhibitors reduced body weight (P < 0.008) and decreased diastolic blood pressure (P = 0.004). With regard to safety outcomes, 66 patients out of 91 stopped SGLT-2 inhibitors during follow-up because of chronic or recurring genital infections, while the rest experienced other adverse events, such as urinary tract infections, polyuria, nausea, hypotension, dizziness, acute coronary event, worsening of glycemic control status, and rapid deterioration of renal function.\nIn our patients' population, the glycometabolic effects of SGLT-2 inhibitors were durable and comparable to those observed in multicenter randomized controlled trials. This notwithstanding safety concerns must be raised regarding the frequent occurrence of genitourinary infections and the risk of a rapid decline of renal function in patients with evidence of volume depletion and/or receiving other medications which can adversely affect kidney function.",
"affiliations": "Department of Health Sciences, University \"Magna Græcia\" of Catanzaro, Catanzaro, Italy.;Department of Health Sciences, University \"Magna Græcia\" of Catanzaro, Catanzaro, Italy.;Complex Operative Structure Endocrinology-Diabetology, Hospital Pugliese-Ciaccio, Catanzaro, Italy.;Complex Operative Structure Endocrinology-Diabetology, Hospital Pugliese-Ciaccio, Catanzaro, Italy.;Department of Health Sciences, University \"Magna Græcia\" of Catanzaro, Catanzaro, Italy.;Department of Health Sciences, University \"Magna Græcia\" of Catanzaro, Catanzaro, Italy.;Department of Health Sciences, University \"Magna Græcia\" of Catanzaro, Catanzaro, Italy.;Department of Health Sciences, University \"Magna Græcia\" of Catanzaro, Catanzaro, Italy.;Complex Operative Structure Endocrinology-Diabetology, Hospital Pugliese-Ciaccio, Catanzaro, Italy.;Department of Health Sciences, University \"Magna Græcia\" of Catanzaro, Catanzaro, Italy.",
"authors": "Mirabelli|Maria|M|https://orcid.org/0000-0002-6427-7186;Chiefari|Eusebio|E|https://orcid.org/0000-0001-5329-3124;Caroleo|Patrizia|P|;Vero|Raffaella|R|;Brunetti|Francesco Saverio|FS|;Corigliano|Domenica Maria|DM|https://orcid.org/0000-0002-5493-9318;Arcidiacono|Biagio|B|https://orcid.org/0000-0003-4343-678X;Foti|Daniela Patrizia|DP|https://orcid.org/0000-0002-9536-5736;Puccio|Luigi|L|;Brunetti|Antonio|A|https://orcid.org/0000-0003-1533-8779",
"chemical_list": "D001559:Benzhydryl Compounds; D015415:Biomarkers; D001786:Blood Glucose; D005960:Glucosides; D006442:Glycated Hemoglobin A; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C517652:hemoglobin A1c protein, human; D000068896:Canagliflozin; C529054:dapagliflozin; C570240:empagliflozin",
"country": "England",
"delete": false,
"doi": "10.1155/2019/3971060",
"fulltext": "\n==== Front\nJ Diabetes ResJ Diabetes ResJDRJournal of Diabetes Research2314-67452314-6753Hindawi 10.1155/2019/3971060Research ArticleLong-Term Effectiveness and Safety of SGLT-2 Inhibitors in an Italian Cohort of Patients with Type 2 Diabetes Mellitus https://orcid.org/0000-0002-6427-7186Mirabelli Maria \n1\nhttps://orcid.org/0000-0001-5329-3124Chiefari Eusebio \n1\nCaroleo Patrizia \n2\nVero Raffaella \n2\nBrunetti Francesco Saverio \n1\nhttps://orcid.org/0000-0002-5493-9318Corigliano Domenica Maria \n1\nhttps://orcid.org/0000-0003-4343-678XArcidiacono Biagio \n1\nhttps://orcid.org/0000-0002-9536-5736Foti Daniela Patrizia \n1\nPuccio Luigi \n2\nhttps://orcid.org/0000-0003-1533-8779Brunetti Antonio brunetti@unicz.it\n1\n\n1Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy\n2Complex Operative Structure Endocrinology-Diabetology, Hospital Pugliese-Ciaccio, Catanzaro, ItalyAcademic Editor: Raffaele Marfella\n\n2019 4 11 2019 2019 397106011 7 2019 14 10 2019 Copyright © 2019 Maria Mirabelli et al.2019This 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.Background\n SGLT-2 (sodium-glucose cotransporter-2) inhibitors are a novel class of oral hypoglycemic agents for the management of type 2 diabetes mellitus (T2DM). Herein, we aimed to assess the long-term effectiveness and safety of SGLT-2 inhibitors in a Southern Italy population of subjects affected by T2DM. \n\nPatients and Methods\n 408 diabetic patients treated with one of the three SGLT-2 inhibitors currently available in Italy (dapagliflozin, empagliflozin, and canagliflozin), either alone or in combination with other antidiabetic drugs, were retrospectively assessed at baseline, during, and after 18 months of continuous therapy. \n\nResults\n Treatment with SGLT-2 inhibitors resulted in a median decrease in HbA1c of 0.9%, with a percentage of decrement of 12 in relation to the baseline value, followed by a significant reduction (P < 0.001) in fasting plasma glucose. Variations in HbA1c occurred independently of the baseline clinical or biochemical characteristics. In addition, treatment with SGLT-2 inhibitors reduced body weight (P < 0.008) and decreased diastolic blood pressure (P = 0.004). With regard to safety outcomes, 66 patients out of 91 stopped SGLT-2 inhibitors during follow-up because of chronic or recurring genital infections, while the rest experienced other adverse events, such as urinary tract infections, polyuria, nausea, hypotension, dizziness, acute coronary event, worsening of glycemic control status, and rapid deterioration of renal function. \n\nConclusion\n In our patients' population, the glycometabolic effects of SGLT-2 inhibitors were durable and comparable to those observed in multicenter randomized controlled trials. This notwithstanding safety concerns must be raised regarding the frequent occurrence of genitourinary infections and the risk of a rapid decline of renal function in patients with evidence of volume depletion and/or receiving other medications which can adversely affect kidney function.\n==== Body\n1. Introduction\nOver the last four decades, the global prevalence of type 2 diabetes mellitus (T2DM) has quadrupled, in parallel to that of obesity [1], because of a more westernized lifestyle, responsible for most of the excess weight in the modern adult's life [2]. Although with wide regional differences, in 2016, 5.3% of the entire Italian population (16.5% among people aged 65 and over) was affected by diabetes, with a negative record in the Calabrian Region of Southern Italy with ~33% obese people and 8% diabetics [3]. Although adequate glycemic control remains the main therapeutic goal in patients with T2DM, more than half of diabetics do not reach the optimal glycemic target (HbA1c < 7%) recommended by the American Diabetes Association [4], which would significantly reduce the incidence and progression of microvascular complications [5–8].\n\nSGLT-2 (sodium-glucose cotransporter-2) inhibitors are the last class of antidiabetic drugs approved by FDA and EMA regulatory agencies, which could be used in any stage of T2DM, irrespective of comedications. By lowering the renal threshold for glucose excretion, SGLT-2 inhibitors suppress renal glucose reabsorption with insulin-independent mechanisms and are therefore suitable for patients with long-standing diabetes and impairment of β-cell function [9]. However, their unique glycosuric mechanism is dependent on the glomerular filtration rate so that in patients with chronic kidney disease (estimated GFR < 45 ml/min/1.73 m2), SGLT-2 inhibitors do not increase the urinary glucose excretion and, therefore, are not recommended. Beyond glycemic control, SGLT-2 inhibitors have also the potential of reducing weight, due to the calorie loss through glycosuria, and be beneficial for lowering blood pressure, due to their osmotic diuretic effect [10]. Furthermore, EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event in type 2 diabetes mellitus) [11–13] and CANVAS (CANagliflozin cardioVascular Assessment Study) [14] have shown that treatment with SGLT-2 inhibitors may reduce cardiovascular morbidity and mortality, as well as the onset and/or progression of nephropathy in high-risk T2DM patients, when compared to standard care. SGLT-2 inhibitors share these glycometabolic and cardio-renal-protective effects with the glucagon-like peptide 1 receptor agonist (GLP1-RA), liraglutide [15, 16]. From a pharmacoeconomics perspective, if the efficacy and safety results of EMPA-REG OUTCOME, CANVAS, and LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) were confirmed by real-world evidence, treatment with SGLT-2 inhibitors would become a more cost-effective strategy to achieve glycemic control and prevent cardiovascular death and nephropathy in T2DM patients [17], with the advantage of oral administration. Nonetheless, many questions remain regarding the safety and tolerability of SGLT-2 inhibitors. Clinical trials and preliminary postmarketing research have highlighted the risk of genitourinary infections, urosepsis, diabetic ketoacidosis, volume depletion, and amputation, especially in the most vulnerable categories of patients with diabetes [18–22]. This notwithstanding, so far, only a few observational studies have been conducted on the effectiveness and safety of SGLT-2 inhibitors at a median follow-up of more than one year [23, 24].\n\nThe purpose of this study was to evaluate the long-term safety and efficacy of three SGLT-2 inhibitors (empagliflozin, dapagliflozin, and canagliflozin) administered to Calabrian patients with T2DM, attending our endocrinology/diabetology outpatient clinics.\n\n2. Patients and Methods\n2.1. Participants\nIn this study, we retrospectively analyzed the safety and efficacy of SGLT-2 inhibitors in a Southern Italy population of subjects affected by T2DM. Data were collected from 408 diabetic patients who started treatment with one of the three SGLT-2 inhibitors currently available in Italy: dapagliflozin 10 mg/day (Forxiga® and Xigduo®), empagliflozin 10 mg and 25 mg/day (Jardiance®, Synjardy®, and Glyxambi®), and canagliflozin 100 mg and 300 mg/day (Invokana® and Vokanamet®), either alone or in combination with other antidiabetic drugs (including insulin), on the basis of the international clinical practice recommendations for the management of hyperglycemia in T2DM [25]. Participants were recruited from the Operative Units of Endocrinology and Diabetes (AOU “Mater Domini” and the AO Pugliese-Ciaccio in Catanzaro) during the period November 2012 to August 2018, after marketing authorization approval of dapagliflozin (Forxiga®) in Italy. Age, sex, body mass index (BMI), blood pressure (BP), lipid profile, fasting plasma glucose (FPG), HbA1c, aspartate aminotransferase/alanine aminotransferase (AST/ALT), serum creatinine, duration of diabetes, micro- and macrovascular complications of T2DM, and any concomitant pharmacological therapy were recorded at baseline for all patients.\n\n2.2. Data Collection\nData collection was approved by the ethics committee of Regione Calabria Sezione Area Centro (protocol registry number 26 of January 17, 2019). As the data were analyzed anonymously, there was no need for written informed consent. Study was performed in accordance with the Declaration of Helsinki.\n\n2.3. Assessments\nAll patients underwent periodical clinical and biochemical evaluation to monitor the safety and efficacy of SGLT-2 inhibitors therapy. The variables analyzed to assess efficacy included: HbA1c, FPG, body weight, BMI, systolic and diastolic BP, and total daily insulin dose (TDI). Safety variables included fasting lipid profile, AST and ALT liver enzymes, serum creatinine, estimated glomerular filtration rate (eGFR) using both the CKD-EPI creatinine equation and the MDRD study equation, genitourinary infections, hypoglycemic episodes, dehydration, and volume depletion symptoms. Any medical problems, including possible adverse events, were recorded on diary cards, and the entries were reviewed at each study visit.\n\n2.4. Outcome Measures\nThe primary outcome was to test the safety and tolerability of SGLT-2 inhibitors in our patients' population. The primary efficacy outcome measure was the change from baseline in HbA1c after 18 months of treatment. The secondary outcome measures included changes in body weight, BMI, BP, FPG, lipid profile, AST and ALT, TDI, and proportion of participants achieving HbA1c level < 7.0%. In addition, we searched for potential baseline predictors of a better response to therapy.\n\n2.5. Statistical Analysis\nInitially, each quantitative trait was tested for normality of distribution, using the Shapiro-Wilk normality test. Continuous variables were expressed as median and interquartile range (IQR) and categorical variables as numbers and percentages. The nonparametric Wilcoxon signed-rank test was used for within-group quantitative differences, whereas the two-tailed Fisher's exact test was used for comparisons of proportions. Spearman's rank correlation analysis was used to explore the correlation between safety and efficacy of SGLT-2 inhibitors with clinical and biochemical parameters. A P value of <0.05 (two-tailed) was considered statistically significant. Data were analyzed with SPSS 20.0 software (SPSS Inc., Chicago, IL, USA).\n\n3. Results\n3.1. VClinical and Biochemical Baseline Characteristics of SGLT-2 Inhibitor-Treated Patients\nA total of 408 diabetic patients started the treatment with SGLT-2 inhibitors. Out of these patients, 246 (60.3%) were treated with empagliflozin, 107 (26.2%) with dapagliflozin, and 55 (13.5%) with canagliflozin. Table 1 shows the main clinical and biochemical characteristics of these subjects.\n\n3.2. Safety of SGLT-2 Inhibitors\n27 patients were lost to follow-up after a median duration of 3 months (0-9 IQR), while 98 (24%) individuals (54 females and 44 males) stopped SGLT-2 inhibitors during follow-up because of adverse events. As reported in Table 2, most of them (N = 66) discontinued treatment at 7.5 (3-12 IQR) months for chronic or recurring genital yeast infections, whereas 11 patients stopped therapy at 6 (3-12 IQR) months for persistent or recurrent urinary tract infections. 21 patients stopped using SGLT-2 medications for other adverse events, including polyuria (6 patients), nausea (1 patient), hypotension (1 patient), dizziness (1 patient), acute coronary event (1 patient), worsening of glycemic control status (3 patients), rapid deterioration of renal function as defined by a rising of serum creatinine levels (4 patients), and other side effects (4 patients). In 4 individuals, therapy was discontinued for lack of compliance. There were neither lower-extremity amputations nor episodes of stroke during the study period. In terms of percentage, women (31.2%) were more likely to discontinue SGLT-2 inhibitor therapy than men (18.7%) (P = 0.005), mainly because of chronic or recurring genital yeast infections (P = 0.020) (Table 3). On Spearman's univariate correlation analysis, patients' age was significantly correlated with interruption for side effects (ρ = −0.119, P = 0.016). No other correlation was detected. As shown in Figure 1, side effects appeared during the first year of treatment, while the three SGLT-2 inhibitors had about the same risk of side effects (Table 4).\n\n3.3. Efficacy of SGLT-2 Inhibitors\nAs the study progressed, we have been able to follow 101 treated patients for at least 18 months. During this 18 months of treatment, a significant reduction in HbA1c was observed over the course of the study period, with a more pronounced decrease in HbA1c during the first six months of drug use (Figure 2(a)). A slight trend towards an increase in HbA1c levels was noted following 18 months of treatment (not shown). Overall, HbA1c decreased from 8.4% (7.7 to 9.4) to 7.5% (6.9 to 8.2) (P < 0.001). In details, we observed a reduction of 0.9% (0.3-1.7), with a percentage of decrement of 12 (3.5-20.1) with respect to the baseline value (Figure 2(b)). Spearman's univariate correlation analysis was employed in order to identify the existence of better predictors of response to therapy. However, neither biochemical findings nor clinical determinants of SGLT-2 efficacy were identified.\n\nConsidering the secondary outcomes, levels of FPG decreased from 182 mg/dL (160 to 208) to 144 mg/dL (121 to 168) (P < 0.001, Figure 2(c)). Also, body weight decreased from 83 kg (75 to 92) to 80 kg (73 to 91) (P = 0.008), and this decrease paralleled the reduction in BMI: from 30.2 kg/m2 (27.8 to 33.0) to 29.4 kg/m2 (26.8 to 32.2) (P = 0.009). The decreasing trend in systolic BP, from 135 mmHg (120 to 150) to 130 mmHg (120 to 140), did not reach conventional levels of statistical significance (P = 0.111), whereas diastolic BP significantly decreased from 80 mmHg (70 to 80) to 70 mmHg (70 to 80) (P = 0.004). Instead, a significant increase emerged in HDL cholesterol after treatment: from 43 mg/dL (36 to 48) to 45 mg/dL (40 to 55) (P = 0.004). No significant differences were observed in other serum and urinary parameters, as well as in eGFR and TDI. When determinants of these differences were explored, only the use of sulfonylureas inversely correlated with body weight reduction (ρ = −0.551, P = 0.001). Finally, 25 further patients (26.3%) reached ADA target for glycemic control (HbA1c < 7%) (31 versus 6, P < 0.001). Among them, 11 patients (44%), who were on insulin therapy, held stable or lower daily insulin requirements following combination with SGLT-2 inhibitors: from 26 UI (17 to 32) to 20 UI (10 to 32).\n\n4. Discussion\nFrom the results of the present study, it can be concluded that treatment with SGLT-2 inhibitors can significantly lower FPG and HbA1c in T2DM patients over 18 months of follow-up in real-life clinical practice. As seen in our case, patients using SGLT-2 inhibitors showed a reduction in HbA1c of about 1% at the end of the study period, and over a quarter of participants achieved the ADA glycemic targets, thus closely resembling the efficacy results of randomized clinical trials with these agents [26, 27]. Improvement in glycemic control was independent of baseline HbA1c levels, BMI, and other clinical and biochemical parameters, indicating that treatment with SGLT-2 inhibitors can be initiated in diabetic patients independent of the duration of diabetes and the baseline levels of HbA1c. In our patients, apart from durability of glycemic efficacy, SGLT-2 inhibitors provided weight loss, as well as a considerable reduction in diastolic BP and a slight declining tendency for systolic BP, thereby supporting the pleiotropic effects of this novel class of antidiabetic agents [10, 28]. However, our results about BP are partially inconsistent with those reported in recent meta-analyses of clinical trials, which demonstrate modest reductions in both systolic and diastolic BP with the use of SGLT-2 inhibitors [29–31]. Differences in background antihypertensive regimens, small sample sizes, short follow-up periods, methods for assessing BP, and assessment of antihypertensive effects as secondary outcomes in most studies may explain these discrepancies. Also, discrepancies might arise from population-specific genetic heterogeneity, which may influence distinct BP variations in response to environmental or pharmacological interventions [32].\n\nOnly the concomitant use of SGLT-2 inhibitors with sulfonylureas was inversely correlated with weight reduction, making this combination therapy less suitable for overweight and obese patients as it may encourage weight gain [33]. Also, for the first time in a real-world setting, we investigated the long-term impact of SGLT-2 inhibitors on insulin therapy, showing no differences in TDI up to 18 months treatment. The tendency to maintain constant TDI up to 18 months, with significant improvement in both glycemic control and weight loss, should be considered when assessing T2DM patients on insulin therapy.\n\nConsistent with previous studies [29], our findings indicate that SGLT-2 inhibitors cause a modest but significant increase in HDL cholesterol, with no effect on serum creatinine levels and eGFR. These findings complement those of the landmark cardiovascular outcomes trial on empagliflozin [13], in which the eGFR remained fairly stable through 6 years of follow-up, while gradually declining with placebo. A major decline in renal function occasionally occurs during SGLT-2 inhibitor therapy, often associated with specific coadministered medications. In March 2016, the FDA reinforced the existing warning on the potential risk of acute renal failure with SGLT-2 inhibitors, following numerous postmarketing case reports [34]. This adverse event is probably the expression of the intrarenal hemodynamic changes occurring during the first weeks of treatment with SGLT-2 inhibitors, which result in a transient eGFR reduction [35–37]. These intrarenal hemodynamic changes may be accentuated in susceptible patients, as a consequence of volume depletion induced by glucose-induced osmotic diuresis [38], reduced angiotensin II-mediated efferent arteriolar vascular tone [39], and concurrent use of nonsteroidal anti-inflammatory drugs or radiocontrast agents [40].\n\nWith regard to safety issues with SGLT-2 inhibitors, our data are in contrast to other postmarketing observational studies [23, 41]. Chronic or recurring genital yeast infections were the main cause of treatment discontinuation in our patient population, with a clear female preponderance. Most infectious events occurred within the first year of treatment, in line with a pooled analysis of phase III clinical studies [22]. SGLT-2 inhibitor-treated patients improved glycemic control with respect to baseline, supporting the idea that genitourinary tract infections were not correlated with poorly controlled hyperglycemia [42], but rather with increased urinary glucose excretion, that may enhance Candida colonization of genital tissues [43] and the growth rate of potential uropathogens [44].\n\nOne strength of the present study is the large subset of adult patients with T2DM who received at least one dose of SGLT-2 inhibitors from a single tertiary care center, regardless of previous and/or concomitant antidiabetic agents, duration and severity of disease, comorbidities, and follow-up time. The study reflects real-life clinical practice, partially avoiding the selection bias that is common in randomized clinical trials. All patients were recruited in Calabria, Southern Italy, a region with limited genetic diversity [45], which lowers interindividual variability among people, including variability in drug response [46]. Improved long-term efficacy outcomes following treatment with the GLP-1RA, liraglutide, were reported by us before, in this region, in terms of reduced HbA1c, FPG, body weight, and systolic BP, throughout a follow-up period of 18 months [47]. For the first time, herein, we focused on the long-term effectiveness of SGLT-2 inhibitors. However, caution should be taken when evaluating the degree of benefit from SGLT-2 inhibitors in this study, owing to its retrospective observational nature.\n\n5. Conclusions\nOur study indicates that the beneficial durable effects of SGLT-2 inhibitors in Calabrian patients with T2DM are comparable to those from multicenter randomized controlled trials. Safety concerns must be raised regarding the occurrence of genitourinary infections, which, although generally mild or moderate in intensity, tend to recur and eventually lead to treatment discontinuation. A warning should also be issued about the risk of rapid deterioration of renal function in patients prone to volume depletion and/or receiving medications, such as nonsteroidal anti-inflammatory drugs and renin-angiotensin-aldosterone system blockers. So, it is recommended that renal function should be monitored closely during SGLT-2 inhibitor therapy.\n\nAcknowledgments\nWe thank the staff of the Operative Units of Endocrinology and Diabetes, AOU “Mater Domini”, and the AO Pugliese-Ciaccio in Catanzaro, Italy.\n\nData Availability\nThe data used to support the findings of this study are included within the article.\n\nConflicts of Interest\nThe authors declare that there is no conflict of interest regarding the publication of this paper.\n\nAuthors' Contributions\nMaria Mirabelli and Eusebio Chiefari contributed equally to this work.\n\nFigure 1 Adverse events. Onset of adverse events over the course of the treatment period. Other adverse events are polyuria, nausea, hypotension, dizziness, acute coronary event, worsening of glycemic control, and rapid deterioration of renal function. GI: genital infections; UTI: urinary tract infections.\n\nFigure 2 Glycemic efficacy. (a) Trend of HbA1c over the course of the 18-month treatment period. The differences between pre- and posttreatment were evaluated by the Wilcoxon nonparametric test. ∗P < 0.001 with respect to basal values. (b) Changes in HbA1c from baseline to 18 months, in absolute number (left) and percentage (right). Baseline values are indicated as median. Changes in HbA1c are indicated as median and IQR. (c) Changes in FPG from baseline to 18 months. Baseline values are indicated as median. Changes in FPG are indicated as median and IQR. ∗P < 0.001.\n\nTable 1 Baseline clinical and biochemical characteristics of all 408 T2DM patients treated with SGLT-2 inhibitors.\n\nBaseline features\t\nN (%)\t\nFemale gender\t173 (42.4)\t\nAge (years)\t62 (55-68)a\t\nDiabetes duration (years)\t12 (7-19)a\t\nDiabetes duration ≥10 years\t254 (62.3)\t\nBody weight (kg)\t83 (74-92.5)a\t\nBMI (kg/m2)\t30.1 (27.2-36.6)a\t\nBP (mmHg)\t\t\n Systolic\t130 (120-146)a\t\n Diastolic\t80 (70-80)a\t\nFPG (mg/dL)\t180 (152-213)a\t\nHbA1c (%)\t8.3 (7.6-9.6)a\t\nSerum creatinine (mg/dL)\t0.8 (0.7-0.95)a\t\neGFR (ml/min/m2)\t90.6 (77.8-105.3)a\t\nTotal cholesterol (mg/dL)\t166 (141.5-191)a\t\nHDL-C (mg/dL)\t42 (35-50)a\t\nTriglycerides (mg/dL)\t142 (98.2-191.5)a\t\nAST (UI)\t23 (19-32)a\t\nALT (UI)\t24 (19-34)a\t\n\n\n\t\nComorbidities\t\n\n\n\t\nHypertension\t333 (81.6)\t\nCoronary artery disease\t78 (19.1)\t\nHistory of stroke/TIA\t13 (3.2)\t\nPeripheral artery disease\t21 (5.1)\t\nObesity (BMI ≥ 30 kg/m2)\t210 (52.2)\t\nOverweight (BMI ≥ 25 kg/m2)\t147 (36.7)\t\nOther comorbidities\t264 (64.7)\t\nDiabetic microvascular complications\t160 (39.2)\t\n Diabetic retinopathy\t88 (21.6)\t\n Early diabetic nephropathy\t47 (11.5)\t\n Overt diabetic nephropathy\t25 (6.1)\t\n Diabetic neuropathy (autonomic/peripheral)\t55 (13.5)\t\n\n\n\t\nConcomitant medications\t\t\n\n\n\t\nACE inhibitors\t129 (31.6)\t\nAngiotensin II receptor blockers\t149 (36.5)\t\nCalcium channel blockers\t90 (22.1)\t\nBeta blockers\t117 (28.7)\t\nDiuretics\t117 (28.7)\t\nLoop diuretics\t33 (8.1)\t\nAlpha 1 blockers\t21 (5.1)\t\nStatins\t241 (59.1)\t\nEzetimibe\t24 (5.9)\t\nCardioaspirin\t111 (27.2)\t\nNSAIDs\t13 (3.2)\t\nMetformin\t320 (78.4)\t\nSulphonylureas\t49 (12.0)\t\nMeglitinides\t38 (9.3)\t\nDPP-4 inhibitors\t14 (3.4)\t\nGLP-1 receptor agonists\t12 (2.9)\t\nPioglitazone\t9 (2.2)\t\nAcarbose\t6 (1.5)\t\nInsulin\t238 (58.3)\t\n\naMedian (IQR) values. BMI: body mass index; BP: blood pressure; FPG: fasting plasma glucose; HbA1c: glycated hemoglobin; eGFR: estimated glomerular filtration rate (MDRD formula); HDL-C: high-density lipoprotein-cholesterol; ALT: alanine aminotransferase; AST: aspartate aminotransferase; NSAIDs: nonsteroidal anti-inflammatory drugs; DPP-4: dipeptidyl peptidase 4; GLP-1: glucagon-like peptide 1.\n\nTable 2 Reasons and time for treatment discontinuation in patients who were treated with SGLT-2 inhibitors.\n\n\tPatients, N (%)\tMonths, median (IQR)\t\nChronic or recurring genital yeast infections\t66 (67.4)\t7.5 (3-12)\t\nPersistent or recurring urinary tract infections\t11 (11.2)\t6 (3-12)\t\nOther adverse eventsa\t21 (21.4)\t3 (1-9)\t\nOverall\t98 (100)\t6 (2-12)\t\n\naPolyuria, nausea, hypotension, dizziness, acute coronary event, worsening of glycemic control, and rapid deterioration of renal function.\n\nTable 3 Gender differences in treatment interruption due to adverse events.\n\n\tFemales, N = 173 (%)\tMales, N = 235 (%)\t\nP value\t\nChronic or recurring genital yeast infections\t37 (21.4)\t29 (12.3)\t0.020\t\nPersistent or recurring urinary tract infections\t7 (4.0)\t4 (1.7)\t0.216\t\nOther adverse eventsa\t10 (5.8)\t11 (4.7)\t0.655\t\nOverall\t54 (31.2)\t44 (18.7)\t0.005\t\n\naPolyuria, nausea, hypotension, dizziness, acute coronary event, worsening of glycemic control, and rapid deterioration of renal function. Statistical analysis was performed using Fisher's exact test.\n\nTable 4 Interdrug differences in terms of adverse events.\n\n\tEmpagliflozin, N = 62 (%)\tDapagliflozin, N = 25 (%)\tCanagliflozin, N = 11 (%)\t\nChronic or recurring genital yeast infections\t41 (66.1)\t16 (64.0)\t9 (81.8)\t\nPersistent or recurring urinary tract infections\t7 (11.3)\t3 (12.0)\t1 (9.1)\t\nOther adverse eventsa\t14 (22.6)\t6 (24.0)\t1 (9.1)\t\n\naPolyuria, nausea, hypotension, dizziness, acute coronary event, worsening of glycemic control, and rapid deterioration of renal function.\n==== Refs\n1 NCD Risk Factor Collaboration (NCD-RisC) Worldwide trends in diabetes since 1980: a pooled analysis of 751 population- based studies with 4·4 million participants The Lancet 2016 387 10027 1513 1530 10.1016/S0140-6736(16)00618-8 2-s2.0-84994417475 27061677 \n2 Brunetti A. Chiefari E. Foti D. 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Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis Annals of Internal Medicine 2013 159 4 262 274 10.7326/0003-4819-159-4-201308200-00007 2-s2.0-84882251091 24026259 \n27 Nauck M. A. del Prato S. Durán-García S. Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add‐on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin Diabetes, Obesity and Metabolism 2014 16 11 1111 1120 10.1111/dom.12327 2-s2.0-84914144323 \n28 van Baar M. J. B. van Ruiten C. C. Muskiet M. H. A. van Bloemendaal L. IJzerman R. G. van Raalte D. H. SGLT-2 inhibitors in combination therapy: from mechanisms to clinical considerations in type 2 diabetes management Diabetes Care 2018 41 8 1543 1556 10.2337/dc18-0588 2-s2.0-85053563266 30030256 \n29 Monami M. Nardini C. Mannucci E. Efficacy and safety of sodium glucose co‐transport‐2 inhibitors in type 2 diabetes: a meta‐analysis of randomized clinical trials Diabetes, Obesity and Metabolism 2014 16 5 457 466 10.1111/dom.12244 2-s2.0-84898791935 \n30 Baker W. L. Smyth L. R. Riche D. M. Bourret E. M. Chamberlin K. W. White W. B. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis Journal of the American Society of Hypertension 2014 8 4 262 275.e9 10.1016/j.jash.2014.01.007 2-s2.0-84898854471 24602971 \n31 Mazidi M. Rezaie P. Gao H. K. Kengne A. P. Effect of sodium-glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22 528 patients Journal of the American Heart Association 2017 6 6, article e004007 10.1161/JAHA.116.004007 2-s2.0-85020460150 28546454 \n32 Franceschini N. Chasman D. I. Cooper-DeHoff R. M. Arnett D. K. Genetics, ancestry, and hypertension: implications for targeted antihypertensive therapies Current Hypertension Reports 2014 16 8 p. 461 10.1007/s11906-014-0461-9 2-s2.0-84901734335 24903233 \n33 Apovian C. M. Okemah J. O'Neil P. M. Body weight considerations in the Management of Type 2 diabetes Advances in Therapy 2019 36 1 44 58 10.1007/s12325-018-0824-8 2-s2.0-85057074843 30465123 \n34 US Food and Drug Administration FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR) 2016 Silver Spring (MD) FDA Drug Safety Communication https://www.fda.gov/Drugs/DrugSafety/ucm505860.htm \n35 Škrtić M. Cherney D. Z. I. Sodium–glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathy Current Opinion in Nephrology and Hypertension 2015 24 1 96 103 10.1097/MNH.0000000000000084 2-s2.0-84918531200 25470017 \n36 Fioretto P. Zambon A. Rossato M. Busetto L. Vettor R. SGLT2 inhibitors and the diabetic kidney Diabetes Care 2016 39 Supplement 2 S165 S171 10.2337/dcS15-3006 2-s2.0-84979582003 27440829 \n37 Heerspink H. J. Perkins B. A. Fitchett D. H. Husain M. Cherney D. Z. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications Circulation 2016 134 10 752 772 10.1161/CIRCULATIONAHA.116.021887 2-s2.0-84980320178 27470878 \n38 Johnsson K. Johnsson E. Mansfield T. A. Yavin Y. Ptaszynska A. Parikh S. J. Osmotic diuresis with SGLT-2 inhibition: analysis of events related to volume reduction in dapagliflozin clinical trials Postgraduate Medicine 2016 128 4 346 355 10.1080/00325481.2016.1153941 2-s2.0-84978402704 26878357 \n39 Schoolwerth A. Sica D. A. Ballermann B. J. Wilcox C. S. Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the council on the kidney in cardiovascular disease and the council for high blood pressure research of the American Heart Association Circulation 2001 104 16 1985 1991 10.1161/hc4101.096153 2-s2.0-0035899896 11602506 \n40 Heyman S. N. Khamaisi M. Rosen S. Rosenberger C. Abassi Z. Potential hypoxic renal injury in patients with diabetes on SGLT-2 inhibitors: caution regarding concomitant use of NSAIDs and iodinated contrast media Diabetes Care 2017 40 4 e40 e41 10.2337/dc16-2200 2-s2.0-85019567416 28130255 \n41 Hong A. R. Koo B. K. Kim S. W. Yi K. H. Moon M. K. Efficacy and safety of sodium-glucose cotransporter-2 inhibitors in Korean patients with type 2 diabetes mellitus in real-world clinical practice Diabetes & Metabolism Journal 2019 43 10.4093/dmj.2018.0134 \n42 Benfield T. Jensen J. S. Nordestgaard B. G. Influence of diabetes and hyperglycaemia on infectious disease hospitalisation and outcome Diabetologia 2007 50 3 549 554 10.1007/s00125-006-0570-3 2-s2.0-33846842006 17187246 \n43 Yokoyama H. Nagao A. Watanabe S. Honjo J. Incidence and risk of vaginal candidiasis associated with sodium–glucose cotransporter 2 inhibitors in real‐world practice for women with type 2 diabetes Journal of Diabetes Investigation 2019 10 2 439 445 10.1111/jdi.12912 2-s2.0-85055269879 30136398 \n44 Geerlings S. E. Brouwer E. C. Gaastra W. Verhoef J. Hoepelman A. I. Effect of glucose and pH on uropathogenic and non-uropathogenic Escherichia coli : studies with urine from diabetic and non-diabetic individuals Journal of Medical Microbiology 1999 48 6 535 539 10.1099/00222615-48-6-535 2-s2.0-0032846814 10359302 \n45 Chiefari E. Tanyolaç S. Iiritano S. A polymorphism of HMGA1 is associated with increased risk of metabolic syndrome and related components Scientific Reports 2013 3 1, article 1491 10.1038/srep01491 2-s2.0-84875795546 \n46 Brunetti A. Chiefari E. Foti D. P. Pharmacogenetics in type 2 diabetes: still a conundrum in clinical practice Expert Review of Endocrinology & Metabolism 2017 12 3 155 158 10.1080/17446651.2017.1316192 2-s2.0-85017509123 30063457 \n47 Chiefari E. Capula C. Vero A. Add-on treatment with liraglutide improves glycemic control in patients with type 2 diabetes on metformin therapy Diabetes Technology & Therapeutics 2015 17 7 468 474 10.1089/dia.2014.0412 2-s2.0-84982732820 25844858\n\n",
"fulltext_license": "CC BY",
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"issue": "2019()",
"journal": "Journal of diabetes research",
"keywords": null,
"medline_ta": "J Diabetes Res",
"mesh_terms": "D000368:Aged; D001559:Benzhydryl Compounds; D015415:Biomarkers; D001786:Blood Glucose; D000068896:Canagliflozin; D003924:Diabetes Mellitus, Type 2; D004334:Drug Administration Schedule; D000081206:Duration of Therapy; D005260:Female; D005960:Glucosides; D006442:Glycated Hemoglobin A; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D061214:Patient Safety; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101605237",
"other_id": null,
"pages": "3971060",
"pmc": null,
"pmid": "31781664",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "28130255;30075890;25470017;30877709;25488697;27299675;10860187;30063457;25844858;23512162;27862830;9742976;27449721;26878357;24919526;28546454;28605608;11602506;21403038;30136398;24903233;24748926;26378978;9742977;27470878;30030256;21680987;28854085;27061677;30207040;29547044;23614587;27806225;24517339;24602971;24026259;27440829;17187246;10359302;29213337;30465123;29222379;24320621;26819227",
"title": "Long-Term Effectiveness and Safety of SGLT-2 Inhibitors in an Italian Cohort of Patients with Type 2 Diabetes Mellitus.",
"title_normalized": "long term effectiveness and safety of sglt 2 inhibitors in an italian cohort of patients with type 2 diabetes mellitus"
} | [
{
"companynumb": "IT-JNJFOC-20191225490",
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"activesubstance": {
"activesubstancename": "CANAGLIFLOZIN"
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"abstract": "OBJECTIVE\nTo discuss two cases of life-threatening serotonin toxicity due to a drug interaction between citalopram and fluconazole and to review the pertinent literature.\n\n\nMETHODS\nA Medline search without date limitation was conducted using the terms serotonin syndrome, serotonin toxicity, fluconazole and citalopram.\n\n\nCONCLUSIONS\nFluconazole inhibits CYP2C19. Citalopram is a substrate for 2C19 and inhibition of its metabolism may result in serotonin toxicity. Serotonin toxicity in oncology patients may not present with the classic constellation of signs typically described in the literature. Delirium may be the only presenting feature. Current level of evidence for treatment of serotonin toxicity is level 4 or 5 (case series and expert opinion). Nevertheless, there is a strong theoretical basis for treating serotonin toxicity in medical patients with a 5H(2A) blocker such as cyproheptadine.\n\n\nCONCLUSIONS\nConsultation-liaison psychiatrists and oncologists should be aware of this preventable and underrecognized interaction. Citalopram should be stopped or substituted prior to the concurrent administration of fluconazole, and in the event of toxicity, treatment with cyproheptadine has a favorable risk-benefit ratio despite a lack of randomized controlled data to support its use.",
"affiliations": "Department of Psychiatry and Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY 10022, USA. levint@mskcc.org",
"authors": "Levin|Tomer T|TT|;Cortes-Ladino|Alberto|A|;Weiss|Mark|M|;Palomba|M Lia|ML|",
"chemical_list": "D000935:Antifungal Agents; D012702:Serotonin Antagonists; D017367:Serotonin Uptake Inhibitors; D015283:Citalopram; D003533:Cyproheptadine; D015725:Fluconazole; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19",
"country": "United States",
"delete": false,
"doi": "10.1016/j.genhosppsych.2008.03.008",
"fulltext": null,
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"issn_linking": "0163-8343",
"issue": "30(4)",
"journal": "General hospital psychiatry",
"keywords": null,
"medline_ta": "Gen Hosp Psychiatry",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D001189:Aryl Hydrocarbon Hydroxylases; D015283:Citalopram; D003533:Cyproheptadine; D065731:Cytochrome P-450 CYP2C19; D003693:Delirium; D003866:Depressive Disorder; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole; D006801:Humans; D008875:Middle Aged; D012702:Serotonin Antagonists; D020230:Serotonin Syndrome; D017367:Serotonin Uptake Inhibitors; D012720:Severity of Illness Index",
"nlm_unique_id": "7905527",
"other_id": null,
"pages": "372-7",
"pmc": null,
"pmid": "18585543",
"pubdate": "2008",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Life-threatening serotonin toxicity due to a citalopram-fluconazole drug interaction: case reports and discussion.",
"title_normalized": "life threatening serotonin toxicity due to a citalopram fluconazole drug interaction case reports and discussion"
} | [
{
"companynumb": "US-BAXTER-2019BAX010292",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "ETOPOSIDE"
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{
"abstract": "A 25-year-old woman in her 30th week of pregnancy presented with a 3-day history of fevers, productive cough and dyspnoea. On presentation she was tachypnoeic, tachycardic and hypoxic. Auscultation of the chest revealed widespread wheeze and crepitations at the right mid-zone. Despite initial treatment with intravenous antibiotics, nebulised bronchodilators and oral corticosteroids, the patient continued to deteriorate and required transfer to intensive care. Serial chest radiographs showed increasing bilateral alveolar densities consistent with acute respiratory distress syndrome (ARDS). The only positive investigation was a nasopharyngeal swab which revealed rhinovirus RNA. With supportive management, the patient made a full recovery and went on to deliver a healthy infant at 36 weeks gestation. This case explores human rhinoviruses-induced ARDS and highlights the clinical and diagnostic challenges posed by pregnancy in the critically unwell patient.",
"affiliations": "Department of Internal Medicine, Gisborne Hospital, Gisborne, New Zealand elliotrevell@doctors.org.uk.;Department of Internal Medicine, Gisborne Hospital, Gisborne, New Zealand.;Department of Internal Medicine, Gisborne Hospital, Gisborne, New Zealand.",
"authors": "Revell|Elliot|E|http://orcid.org/0000-0001-6025-094X;Glasbey|Madeleine|M|;Brown|Peter|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-246927",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(12)",
"journal": "BMJ case reports",
"keywords": "adult intensive care; bronchiolitos; obstetrics and gynaecology; respiratory medicine",
"medline_ta": "BMJ Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34880041",
"pubdate": "2021-12-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rhinovirus induced bronchiolitis and ARDS in pregnancy: a case report.",
"title_normalized": "rhinovirus induced bronchiolitis and ards in pregnancy a case report"
} | [
{
"companynumb": "NZ-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-338111",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MAGNESIUM"
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{
"abstract": "To report retinal findings in two patients with mucopolysaccharidosis type I (MPS I) receiving human recombinant alpha-l-iduronidase (Laronidase) as enzyme replacement therapy.\nPatient 1 had visual acuity 20/20 right eye, 20/25 left eye and unremarkable anterior segment and retinal examination. Optical coherence tomography (OCT) scanning demonstrated parafoveal thinning and subfoveal hyperreflectant material. Patient 2 had visual acuity 20/20 both eyes, with dense nuclear cataract both eyes. Retinal examination demonstrated bull's eye maculopathy both eyes. OCT scanning confirmed parafoveal atrophy and demonstrated similar appearing subfoveal hyperreflectant material, more prominent than in case 1.\nThese two patients with MPS I receiving Laronidase treatment have developed bull's eye maculopathy changes and subfoveal deposition of hyperreflectant material despite excellent compliance and good tolerance of the standard dose of enzyme therapy for this disorder. Further studies are required to determine the nature of the material, the incidence and the effect of enzyme replacement therapy on these findings in patients with MPS I.",
"affiliations": "Department of Surgery (Ophthalmology), University of Melbourne, Grattan St, Parkville, Victoria 3052, Australia.;Department of Surgery (Ophthalmology), University of Melbourne, Grattan St, Parkville, Victoria 3052, Australia.;Melbourne Health, 300 Grattan St, Parkville, Victoria 3052, Australia.",
"authors": "Mack|Heather G|HG|;Symons|R C Andrew|RCA|;de Jong|Gerard|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2017.10.006",
"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(16)30309-710.1016/j.ajoc.2017.10.006Case reportBull's eye maculopathy and subfoveal deposition in two mucopolysaccharidosis type I patients on long-term enzyme replacement therapy Mack Heather G. hmack@eyesurgery.com.auabc∗Symons R.C. Andrew abde Jong Gerard bda Department of Surgery (Ophthalmology), University of Melbourne, Grattan St, Parkville, Victoria 3052, Australiab Melbourne Health, 300 Grattan St, Parkville, Victoria 3052, Australiac Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australiad Department of Medicine, University of Melbourne, Grattan St, Parkville, Victoria 3052, Australia∗ Corresponding author. 2/232 Victoria Parade, East Melbourne 3002, Australia.2/232 Victoria ParadeEast Melbourne3002Australia hmack@eyesurgery.com.au04 10 2017 3 2018 04 10 2017 9 1 6 20 12 2016 1 8 2017 2 10 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo report retinal findings in two patients with mucopolysaccharidosis type I (MPS I) receiving human recombinant alpha-l-iduronidase (Laronidase) as enzyme replacement therapy.\n\nObservations\nPatient 1 had visual acuity 20/20 right eye, 20/25 left eye and unremarkable anterior segment and retinal examination. Optical coherence tomography (OCT) scanning demonstrated parafoveal thinning and subfoveal hyperreflectant material. Patient 2 had visual acuity 20/20 both eyes, with dense nuclear cataract both eyes. Retinal examination demonstrated bull's eye maculopathy both eyes. OCT scanning confirmed parafoveal atrophy and demonstrated similar appearing subfoveal hyperreflectant material, more prominent than in case 1.\n\nConclusions and importance\nThese two patients with MPS I receiving Laronidase treatment have developed bull's eye maculopathy changes and subfoveal deposition of hyperreflectant material despite excellent compliance and good tolerance of the standard dose of enzyme therapy for this disorder. Further studies are required to determine the nature of the material, the incidence and the effect of enzyme replacement therapy on these findings in patients with MPS I.\n\nKeywords\nEnzyme replacement therapyScheieMaculaMucopolysaccharidosis type IIduronidase\n==== Body\n1 Introduction\nMucopolysaccharidosis type I (MPS I, OMIM #607016) is an autosomal recessive lysosomal storage disorder due to deficiency of α-l-iduronidase (IDUA),1 of prevalence approximately 1 per 88,000 live births in Australia.2 Gradual lysosomal accumulation of metabolites of IDUA glycosaminoglycan (GAG) substrates heparan and dematan sulfate eventually interferes with cellular function. Although this process occurs in all cells, it is pathophysiologically most apparent in terminally differentiated, long-lived cells such as neurons, cardiomyocytes, and retinal pigment epithelium, underpinning the multisystem and progressive nature of the disorder.\n\nInterference with normal bone development is clinically apparent in the dysostosis multiplex and typical facial dysmorphism that is characteristically developed in this disorder. Cardiorespiratory disease in the context of skeletal deformities and bronchial, pulmonary and cardiac pathology imparts significant morbidity and mortality. Interminable neurodegeneration, retinal degeneration, corneal clouding and cataracts contribute importantly to lifelong morbidity.\n\nPhenotypic variability is wide, varying from severely affected individuals (Hurler syndrome, MPS I-H) to attenuated forms (Scheie syndrome, MPS I-S). Significant restrictive pulmonary disease and progressive neurodegeneration heralded in early childhood characteristically complicates the severe, Hurler phenotype, as opposed to the normal neurological development and sparing of cognition in the attenuated, Scheie phenotype.\n\nHeterologous hematopoietic stem cell transplant (HSCT) has become the gold standard treatment for patients with the severe phenotype diagnosed under 2.5 years of age. Enzyme replacement therapy (ERT) with human recombinant IDUA (Laronidase, Genzyme, Cambridge MA) has demonstrated efficacy in mitigating a number of the clinical effects of the enzyme deficiency, most notably the effects on cardiopulmonary function, and is used for patients diagnosed later in life, as well as pre- and peri-HSCT.3, 4\n\nReported ocular features of MPS I include corneal clouding, pigmentary retinopathy, optic nerve abnormalities including glaucoma, papilledema and atrophy, ocular motility and refractive problems.5 There is one report of macular edema-like change observed on stereoscopic fundus photography.6 Between 44% and 79% of MPS I patients have visual acuity less than 20/40 in their better eye.7 Retinal involvement, when present, has been described as a progressive rod-cone retinal degeneration with attenuated electroretinographic (ERG) amplitude with relatively mild clinically apparent retinal pigment epithelial (RPE) change in the mid periphery8, 9 and typical degeneration of the outer retinal layers on histopathological examination. Patients without clinical retinal degeneration have been shown to have fine fibrillary inclusions in the RPE and retinal ganglion cells, and multimembranous inclusions in retinal ganglion cells.10 We are not aware of any published reports of macular histopathology in untreated patients with MPS I. Optical coherence tomography (OCT) studies have demonstrated thinning of the parafoveal ellipsoid line, thickening of the central foveal external limiting membrane (ELM), parafoveal retinal folds, retinal cysts and fluid in the outer nuclear layer in MPS I patients,11, 12 some of whom received ERT.13 A recent report demonstrated improved vision in 42% of patients receiving Laronidase treatment; the study recorded visual acuity and corneal clouding, but not retinal structure or function.14 There are no reports of improved retinal function in patients receiving Laronidase treatment. ERT does not cross the blood-brain barrier and presumably does not cross the blood-retina barrier either, given the ultrastructural similarity between the two.\n\nWe report macular changes in two patients with MPS I receiving ERT. Case 2 is the oldest reported patient, and the first report of a patient undergoing cataract surgery. We also report the first multifocal ERG analysis of MPS I patients. An earlier version of this work was published as a meeting abstract.15\n\n2 Findings\n2.1 Case 1\nA twenty-one year old Caucasian male was referred for baseline ophthalmological monitoring during ERT. He complained of glare. He had been diagnosed with MPS I 15 years prior, at the age of 6 when his mother sought clarification for his impaired mobility. He had the typical although relatively mild facial dysmorphic features, severe obstructive pulmonary disease, mild mitral valve stenosis and trace mitral regurgitation, hepatosplenomegaly and bilateral carpal tunnel syndrome. He had received IDUA at the regular dose of 0.58 mg/kg for 8.75 years with excellent compliance and tolerance. On examination, best corrected visual acuity was right 20/20 and left 20/25. Corneae demonstrated Ashworth mild grade5 corneal haze bilaterally. The anterior chambers were deep, with clear lenses. Optic discs had cup to disc ratios of 0.1 and appeared healthy; the retinal examination was clinically normal (Fig. 1). OCT scanning (Cirrus, Zeiss Meditec, Germany) demonstrated parafoveal thinning of retinal layers and subfoveal increased hyperreflectance at the level of the external limiting membrane (ELM, Fig. 1), with outer retinal layers intact. Full-field electroretinogram (ERG, RETI-port/scan, Roland Consult, Brandenburg, Germany) was modestly reduced in amplitude, but essentially normal (Table 1); multifocal ERG showed reproducible signals in ring 1 only in the right eye, with no reproducible signals in any test sector in the left eye.Fig. 1 A twenty-one year old male with mucopolysaccharidosis type I undergoing Laronidase enzyme replacement therapy.\n\nA Color fundus photographs of the right and B left eye, showing slight foveal reddening, but no bull's’ eye macular appearance. Images are blurred by corneal clouding. C Optical coherence tomography (OCT) scanning (Cirrus, Zeiss, Germany) of the right, and D left eye showing subfoveal hyperreflectant material at the level of the external limiting membrane. The key OCT features of photoreceptor structure appear intact. Inset OCT cube views demonstrate in both eyes parafoveal thinning. E Multifocal ERG responses (Roland, Brandenburg, Germany) showing reproducible response only in ring 1 in the right eye (red arrow), and F no reproducible responses in the left eye. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)\n\nFig. 1Table 1 Clinical characteristics of two patients with mucopolysaccharidosis type I.\n\nTable 1\tPatient 1\tPatient 2\t\nAge at case report (years)\t21\t59\t\nGender\tMale\tFemale\t\nAge at start of ERT (years)\t14\t51\t\nMucopolysaccharidosis type\tI Scheie\tI Scheie\t\nVisual acuity right eye, left eye\t20/20, 20/25\t20/20, 20/20\t\nRefraction right, left\t+2.5–4.75 × 84; +3.0–4.25 × 82\t+8.5–0.50 × 76; +7.50–1.0 × 88\t\nERG findings\t\nDA 0.01 amplitude right, left (94.2–202 μV)\t119, 193\tNM, NM\t\nDA 0.01 latency right, left (68.5–97.5 msec)\t77.3, 92.8\tNM, NM\t\nDA 10 b-wave amplitude right, left (194.2–385.7 μV)\t111, 203\t20.8, 48.6\t\nDA 10b-wave latency right, left (31.3–55.8 msec)\t53.2, 52.7\t67.3, 73.3\t\nDA b-/a-wave ratio (1.2–1.9)\t1.92, 1.75\t0.79; 3.6\t\n30 Hz flicker amplitude right, left (46.6–130.1 μV)\t42, 53.6\t25.6, 21.1\t\n30 Hz flicker latency right, left (25.0–29.7 msec)\t25.8, 26.6\t32.2, 35.7\t\nMultifocal ERG findings\tReproducible P1 responses only in ring 1 in the right eye (31.7 nV/deg2; lower limit of normal 42.5)\tReproducible responses only in ring 1 in both eyes (right 25.8, left 31.2 nV/deg2; lower limit of normal 21.6)\t\nDA, dark-adapted; ERG, electroretinogram; ERT, enzyme replacement therapy; NM, not measurable.\n\n\n\n2.2 Case 2\nA fifty-nine year old Caucasian female was referred for ophthalmological monitoring during ERT. She complained of nyctalopia onset aged 31 years. She was diagnosed with MPS I in 2011 at age fifty-four years, and has involvement of bones and joints, with relatively mild facial dysmorphism which had been interpreted as acromegalic in years previous to the diagnosis of MPS1, obstructive pulmonary disease, aortic valve disease and bilateral carpal tunnel syndrome. In keeping with the Australian Life Saving Drugs Program guidelines, she has received IDUA at a dose of 0.58 mg/kg ideal body weight (adjusted for BMI 27) for 5 years with excellent compliance and tolerance. On examination, best visual acuity was 20/20 in both eyes. Corneae demonstrated Ashworth mild grade corneal haze bilaterally and were thin right 425 μm, left 415 μm (Pentacam, Oculus, USA). Anterior chamber depth was right 1.5 mm, left 1.46 mm. Many posterior synechiae were present, and minimal pupil dilation could be induced pharmacologically. On fundoscopy optic discs demonstrated cup to disc ratios of 0.3 and appeared healthy, a bull's eye maculopathy pattern was noted along with sparse patches of intraretinal pigment migration (Fig. 2). She readily dissociated to a large alternating exotropia. OCT scanning demonstrated parafoveal thinning of all layers, particularly the ellipsoid line and other photoreceptor components, with subfoveal increased hyperreflectance at the level of the ELM, and peripheral macular photoreceptor lines fragmented. Full-field ERG (Table 1) showed no reproducible pure rod responses, with attenuated responses, negative in waveform in the right eye, to brighter dark-adapted stimuli. Photopic responses were reduced in amplitude and prolonged in latency. Multifocal ERG showed reproducible responses only in ring 1 in both eyes.Fig. 2 A fifty-nine year old female with mucopolysaccharidosis type I undergoing Laronidase enzyme replacement therapy.\n\nA Color fundus photographs of the right and B left eye, showing bilateral bull's’ eye macular appearance. Images are blurred by corneal clouding. C Optical coherence tomography (OCT) scanning (Cirrus, Zeiss, Germany) of the right, and D left eye showing subfoveal hyperreflectant material at the level of the external limiting membrane, with parafoveal thinning of the outer nuclear layers and loss of the ellipsoid lines. Multifocal ERG responses (Roland, Brandenburg, Germany) showing reproducible response only in ring 1 in the E right eye and F left eye (red arrows). Automated visual field analysis (Humphrey, Germany) of the G right and H left eye showing fields constricted to about 20° diameter. OCT scanning of the I right, and J left eye at 8 weeks post-operatively demonstrating cystoid macular edema; and K right, L left eye 8 weeks later showing response to treatment. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)\n\nFig. 2\n\nShe was monitored annually for three years. Nuclear sclerosis developed in both eyes, and anterior chambers progressively shallowed. She underwent uneventful bilateral YAG laser peripheral iridotomy. Her clinical examination and electrophysiology testing was otherwise stable. She developed blurred vision and visual acuity fell to right 20/32 and left 20/40 due to cataract. She underwent laser-assisted cataract surgery in both eyes, with implantation of Rayner C-Flex 970C posterior chamber lenses right eye +39D and left eye +38D. Post-operatively best visual acuity was right 20/32 and left 20/25, however cystoid macular edema (CME) developed at post-operative week 8 (Fig. 2), treated with topical prednisolone acetate 1% and ketorolac 0.5%, with slow improvement in visual acuity and OCT signs. At last review, visual acuity was right 20/32, left 20/25 and topical treatment was slowly withdrawn.\n\n3 Discussion\nIn this study, we report parafoveal thinning, particularly at the level of the ellipsoid line, and thickening of the foveal ELM, similar to previous reports. Case 2 is one of the oldest patients reported to date, and the first reported patient to undergo cataract surgery. We also include the first multifocal ERG investigation of macular dysfunction. The older of the two patients (59 years) reported on here has more marked findings with a frank bull's eye maculopathy and mild CME, which worsened immediately following cataract surgery. Additionally, results consistent with a typical rod-cone dystrophy were evident on ERG testing. Both patients show preservative of function in ring 1 only on multifocal ERG (very poor function), similar to earlier reports describing the clinical appearance to be more benign than the more severe functional abnormality detected with electrophysiology testing.\n\nThe retinal changes reported here bear some similarity to changes reported in hydroxychloroquine (HCQ) macular toxicity (“flying saucer sign’ on OCT scanning).16, 17 Neither of our patients received HCQ treatment for their MPS related arthropathy. The reported changes differ from typical HCQ toxicity by being symmetrical vertically around the fovea, rather than more prominent inferiorly, and by ERG features of rod-cone dystrophy rather than affecting rods and cones to a similar degree as occurs in advanced HCQ toxicity.18\n\nThe cause of macular and retinal abnormality in patients with MPS I has not been definitively proven, but is thought to be secondary to GAG production by the RPE,19 failure of GAG metabolism leading to its accumulation, and subsequent cellular death occurring in phagocytic Müller cells and/or RPE. This is consistent with findings that gene therapy in murine models of MPS VII has been shown to reverse GAG accumulation in RPE and subsequent retinal degeneration20, 21 Bull's eye maculopathy has not been definitively demonstrated to date in untreated MPS patients or in foveated animal models, using histopathological examination or OCT scanning. Wide phenotypic variation is well recognised in patients and families with the same genetic mutation in mucopolysaccharidoses,22 similar to retinal degenerative disease, best exemplified by PRPH223 and ABCA424 and we hypothesise that the bull's eye maculopathy may be a previously unrecognised phenotypic variant of retinal degeneration occurring in MPS I patients. Our younger patient does not have rod-cone dystrophy and follow-up will be important to determine whether the maculopathy is isolated or is associated with widespread dystrophy.\n\nThe cause of increased hyperreflectance in the region of the ELM, and whether it is intracellular or extracellular, is not known. It may represent undigested abnormal photoreceptor outer segments, although this is unlikely given that it is anterior to the ellipsoid line zone, or abnormal collagen deposition, which has been recently proposed to cause corneal clouding in MPS I-H.25 Seok et al.13 proposed the material to be degraded GAG accumulating in Müller cells. The reason for deposition in the fovea with sparing of the remaining retina is not known. IDUA does not cross the blood-retina barrier. We propose that our patients with a clinically mild phenotype have some attenuated enzyme action in Müller cells allowing clearing of degraded GAG, but in the subfoveal location the increased number of photoreceptors results in a higher load of GAG and the limited enzyme capacity is overwhelmed. Also, foveal astrocytes have different structural26, 27 and presumably functional properties to Müller cells; the enzymic activity is not known, but may be less in these more primitive retinal astrocytes. It is also possible that there is an inflammatory component to maculopathy from activated Muller cells, as activated microglia have been shown to be inflammatory in the cortex in murine models of MPS I.28\n\n4 Conclusions\nWe report macular changes in patients with MPS I undergoing ERT, with clinical changes less significant than functional abnormality detected with ERG. This is the first report of a patient undergoing cataract surgery and the first report of multifocal ERG assessment. Further studies of untreated patients, and patients treated with both ERT and HSCT are needed to elucidate the nature of the macular changes and their relationship to treatment.\n\nPatient consent\nBoth patients gave written consent to publish case details.\n\nFunding\nNo funding or grant support.\n\nConflicts of interest\nAll authors have no financial disclosures: HGM, RCAS, GdJ.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nAcknowledgements\nNone.\n\nAcknowledgements and disclosures\nThe abstract was presented at The Royal Australian and New Zealand College of Ophthalmologists, 48th Annual Scientific Congress, Melbourne, 19–23 November 2016, and published in Poster Abstracts, Clinical & Experimental Ophthalmology, 2016; 44: 80–140. Permission to reproduce the abstract here has been obtained from the copyright holder, the Royal Australian and New Zealand College of Ophthalmologists.\n==== Refs\nReferences\n1 Beesley C.E. Meaney C.A. Greenland G. Mutational analysis of 85 mucopolysaccharidosis type I families: frequency of known mutations, identification of 17 novel mutations and in vitro expression of missense mutations Hum Genet 109 5 2001 503 511 11735025 \n2 Meikle P.J.1 Hopwood J.J. Clague A.E. Carey W.F. Prevalence of lysosomal storage disorders JAMA 28 1999 249 254 \n3 de Ru M.H.1 Boelens J.J. Das A.M. Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure Orphanet J Rare Dis 6 2011 55 21831279 \n4 Jameson E. Jones S. Remmington T. Enzyme replacement therapy with laronidase (Aldurazyme) for treating mucopolysaccharidosis type I Cochrane Database Syst Rev 4 2016 Art. No.: CD009354 \n5 Ashworth J.L. Kruse F.E. Bachmann B. Ocular manifestations in the mucopolysaccharidoses – a review Clin Exp Ophthal 38 2010 12 22 \n6 Usui T.1 Shirakashi M. Takagi M. Abe H. Iwata K. Macular edema-like change and pseudopapilledema in a case of Scheie syndrome J Clin Neuroophthalmol 11 1991 183 185 PMID:1836802 1836802 \n7 Ashworth J.L. Biswas S. Wratih E. Lloyd I.C. The ocular features of the mucopolysaccharisoses Eye 20 2006 553 563 15905869 \n8 Gills J.P. Hobson R. Hanley W.B. McKusick V.A. Electroretinography and fundus oculi findings in Hurler's disease and allied mucopolysaccharidoses JAMA Ophthalmol 74 1965 596 603 \n9 Caruso R.C. Kaiser-Kupfer M.I. Muenzer J. Electroretinographic findings in the mucopolysaccharidoses Ophthalmol 93 1986 1612 1616 \n10 Chan C.C. Green W.R. Maumenee I.H. Sack G.H. Ocular ultrastructural studies of two cases of the Hurler syndrome (systemic mucopolysaccharisosis I0H) Ophthalmic Paediatr Genet 2 1983 3 19 \n11 Huang C.T. Chu S.Y. Lee Y.C. Optical coherence tomography of chorioretinopathy caused by mucopolysaccharidoses Ophthalmol 122 2015 1535 1537 \n12 Javed A. Aslam T. Ashworth J. Use of new imaging in detecting and monitoring ocular manifestations of the mucopolysaccharidoses Acta Ophthalmol 94 2016 e676 e682 27273899 \n13 Seok S. Lyu I.J. Park K.A. Oh S.Y. Spectral domain optical coherence tomography imaging of mucopolysaccharidoses I, II, and VI A Graefes Arch Clin Exp Ophthalmol 253 2015 2111 2119 25690978 \n14 Laraway S. Mercer J. Jameson E. Ashworth J. Hensman P. Jones S.A. Outcomes of long-term treatment with laronidase in patients with mucopolysaccharidosis type I J Pediatr 178 2016 219 226 27788836 \n15 Mack H.G. Symons R.C.A. de Jong G. Bull's eye maculopathy and subfoveal deposition in two Mucopolysaccharidosis type I patients on long-term enzyme replacement therapy Clin Exp Ophthalmol 44 Suppl 1 2016 127 \n16 Chen E. Brown D.M. Benz M.S. Spectral domain optical coherence tomography as an effective screening test for hydroxychloroquine retinopathy (the “flying saucer” sign) Clin Ophthalmol 4 2010 1151 1158 21060664 \n17 Marmor M.F. Kellner U. Lai T.Y.Y. Melles R.B. Mieler W.F. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision) Ophthalmology 123 2016 1386 1394 26992838 \n18 Nair A.A. Marmor M.F. ERG and other discriminators between advanced hydroxychloroquine retinopathy and retinitis pigmentosa Doc Ophthalmol 134 2017 175 183 28451987 \n19 deS Senanayake P. Calabro A. Nishiyama K. Hu J.G. Bok D. Hollyfield J.G. Glycosaminoglycan synthesis and secretion by the retinal pigment epithelium: polarized delivery of hyaluronan from the apical surface J Cell Sci 114 Pt 1 2001 199 205 11112703 \n20 Li T. Davidson B.L. Phenotype correction in retinal pigment epithelium in murine mucopolysaccharidosis VIII by adenovirus-mediated gene transfer Proc Natl Acad Sci U. S. A 92 1995 7700 7704 7644479 \n21 Hennig A.K. Ogilvie J.M. Ohlemiller K.K. Timmers A.M. Hauswirth W.W. Sands M.S. Aav-Mediated intravitreal gene therapy reduces lysosomal storage in the retinal pigmented epithelium and improves retinal function in adult MPS VII mice Mol Ther 10 2004 106 116 15233947 \n22 Cimaz R. La Torre F. Mucopolysaccharidoses Curr Rheumatol Rep 16 2014 389 24264718 \n23 Apfelstedt-Sylla E. Theischen M. Rüther K. Wedemann H. Gal A. Zrenner E. Extensive intrafamilial and interfamilial phenotypic variation among patients with autosomal dominant retinal dystrophy and mutations in the human RDS/peripherin gene Br J Ophthalmol 79 1995 28 34 7880786 \n24 Burke T.R. Tsang S.H. Allelic and phenotypic heterogeneity in ABCA4 mutations Ophthalmic Genet 32 2011 165 174 21510770 \n25 Yuan C. Bothun E.D. Hardten D.R. Tolar J. McLoon L.K. A novel explanation of corneal clouding in a bone marrow transplant-treated patient with Hurler syndrome Exp Eye Res 148 2016 83 89 27235795 \n26 Ramírez J.M. Triviňo A. Ramírez A.I. Structural specializations of human retinal glial cells Vis Res 36 1996 2029 2036 8776469 \n27 Reichenbach A. Bringmann A. Müller cells in the healthy retina Müller Cells in the Healthy and Diseased Retina 2010 Springer New York 35 214 \n28 Ohmi K. Greenberg D.S. Rajavel K.S. Ryazantsev S. Li H.H. Neufeld E.F. Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB PNAS 100 2003 1902 1907 12576554\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "9()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Enzyme replacement therapy; Iduronidase; Macula; Mucopolysaccharidosis type I; Scheie",
"medline_ta": "Am J Ophthalmol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101679941",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "29468207",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports",
"references": "1836802;11735025;7880786;15905869;21060664;24264718;8776469;7644479;26992838;27273899;12576554;9918480;11112703;4954407;21831279;15233947;3101020;27235795;27788836;29468207;25690978;27033167;25864794;28451987;21510770",
"title": "Bull's eye maculopathy and subfoveal deposition in two mucopolysaccharidosis type I patients on long-term enzyme replacement therapy.",
"title_normalized": "bull s eye maculopathy and subfoveal deposition in two mucopolysaccharidosis type i patients on long term enzyme replacement therapy"
} | [
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"companynumb": "AU-SA-2016SA221875",
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"activesubstancename": "LARONIDASE"
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"abstract": "BACKGROUND\nPreclinical studies have suggested that the oral antifungal agent itraconazole specifically inhibits proliferation, migration, and tube formation of endothelial cells. Itraconazole has potent antiangiogenic activity and enhances the efficacy of cytotoxic chemotherapy in multiple primary xenograft lung cancer models. On the basis of these data, we performed an exploratory clinical study, assessing the efficacy of itraconazole with cytotoxic chemotherapy in the treatment of patients with advanced lung cancer.\n\n\nMETHODS\nThe study enrolled patients with progressive nonsquamous non-small-cell lung cancer after one prior cytotoxic therapy for metastatic disease, randomized 2:1 to intravenous administration of pemetrexed 500 mg/m2 on day 1, with or without itraconazole 200 mg orally daily, on a 21-day cycle. Outcome measures included percent progression-free at 3 months, progression-free survival, overall survival, and observed toxicity.\n\n\nRESULTS\nA total of 23 patients were enrolled; the study was stopped early because of increasing use of pemetrexed in the first-line setting. At 3 months, 67% of the patients on itraconazole plus pemetrexed were progression-free versus 29% on the control arm of pemetrexed alone (p = 0.11). Median progression-free survivals were 5.5 months (itraconazole) versus 2.8 months (control) (hazard ratio = 0.399, p = 0.089). Overall survival was longer in patients receiving itraconazole (median 32 months) versus control (8 months) (hazard ratio = 0.194, p = 0.012). There were no evident differences in toxicity between the study arms.\n\n\nCONCLUSIONS\nItraconazole is well tolerated in combination with pemetrexed. Consistent with our preclinical data, daily itraconazole administration is associated with trends suggestive of improved disease control in patients receiving chemotherapy for advanced lung cancer.",
"affiliations": "The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1550 Orleans Street, Baltimore, MD 21231, USA. rudin@jhmi.edu",
"authors": "Rudin|Charles M|CM|;Brahmer|Julie R|JR|;Juergens|Rosalyn A|RA|;Hann|Christine L|CL|;Ettinger|David S|DS|;Sebree|Rosa|R|;Smith|Ruth|R|;Aftab|Blake T|BT|;Huang|Peng|P|;Liu|Jun O|JO|",
"chemical_list": "D005971:Glutamates; D000068437:Pemetrexed; D017964:Itraconazole; D006147:Guanine",
"country": "United States",
"delete": false,
"doi": "10.1097/JTO.0b013e31828c3950",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-0864",
"issue": "8(5)",
"journal": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer",
"keywords": null,
"medline_ta": "J Thorac Oncol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D018572:Disease-Free Survival; D057239:Early Termination of Clinical Trials; D005260:Female; D005971:Glutamates; D006147:Guanine; D006801:Humans; D017964:Itraconazole; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed",
"nlm_unique_id": "101274235",
"other_id": null,
"pages": "619-23",
"pmc": null,
"pmid": "23546045",
"pubdate": "2013-05",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "17167137;19204576;22237781;19188680;21914503;7082756;20610543;10655437;22330688;17178843;17909198;15166262;21896639;16697074;11252008;15117980;17432820",
"title": "Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer.",
"title_normalized": "phase 2 study of pemetrexed and itraconazole as second line therapy for metastatic nonsquamous non small cell lung cancer"
} | [
{
"companynumb": "US-JNJFOC-20130504881",
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... |
{
"abstract": "Amantadine has been reported to cause various corneal complications, such as superficial punctate keratitis, corneal endothelial dysfunction, and corneal edema. However, there have been no reports of amantadine-induced deposits in the corneal epithelium. Here, we describe the first case with amantadine-induced deposits in the corneal epithelium proved by confocal biomicroscopy.\nAn 81-year-old woman presented with impaired vision in both eyes. She had been treated with amantadine for 9 years. Corrected visual acuity was 0.8 in both eyes. Furthermore, both eyes showed opacities in the corneal epithelial corneal layer. On confocal biomicroscopy, there were highly reflective deposits in corneal epithelial cells. There were no pathological findings in the stroma and endothelium. Two months after discontinuation of amantadine, corneal opacities disappeared, and visual acuity was 1.0 in both eyes.\nAdministration of amantadine can cause deposits in corneal epithelial cells.",
"affiliations": "Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, 1-9-6 Sendamachi, Naka-ku, Hiroshima-shi, Hiroshima, 730-0052, Japan.;Department of Ophthalmology and Visual Science, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima-shi, Hiroshima, 734-8551, Japan.;Department of Ophthalmology and Visual Science, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima-shi, Hiroshima, 734-8551, Japan.",
"authors": "Yoshinaka|Asayo|A|;Chikama|Taiichiro|T|;Kiuchi|Yoshiaki|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2020.100852",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(20)30167-5\n10.1016/j.ajoc.2020.100852\n100852\nCase Report\nAmantadine can induce intra-epithelial deposition in the cornea\nYoshinaka Asayo asayo@hiroshima-u.ac.jpa∗ Chikama Taiichiro b Kiuchi Yoshiaki b a Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, 1-9-6 Sendamachi, Naka-ku, Hiroshima-shi, Hiroshima, 730-0052, Japan\nb Department of Ophthalmology and Visual Science, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima-shi, Hiroshima, 734-8551, Japan\n∗ Corresponding author. 1-9-6 Sendamachi, Naka-ku, Hiroshima, Hiroshima, 730-0052, Japan. asayo@hiroshima-u.ac.jp\n05 8 2020 \n9 2020 \n05 8 2020 \n19 10085212 2 2020 5 7 2020 26 7 2020 © 2020 Published by Elsevier Inc.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nAmantadine has been reported to cause various corneal complications, such as superficial punctate keratitis, corneal endothelial dysfunction, and corneal edema. However, there have been no reports of amantadine-induced deposits in the corneal epithelium. Here, we describe the first case with amantadine-induced deposits in the corneal epithelium proved by confocal biomicroscopy.\n\nObservations\nAn 81-year-old woman presented with impaired vision in both eyes. She had been treated with amantadine for 9 years. Corrected visual acuity was 0.8 in both eyes. Furthermore, both eyes showed opacities in the corneal epithelial corneal layer. On confocal biomicroscopy, there were highly reflective deposits in corneal epithelial cells. There were no pathological findings in the stroma and endothelium. Two months after discontinuation of amantadine, corneal opacities disappeared, and visual acuity was 1.0 in both eyes.\n\nConclusions\nAdministration of amantadine can cause deposits in corneal epithelial cells.\n\nKeywords\nAmantadineCorneal opacityConfocal microscopyCorneal epithelial cell deposits\n==== Body\n1 Introduction\nAmantadine was developed as a treatment for influenza A infection, and later found to exhibit anti-parkinsonian effects.1 Since that discovery in 1969, it has been widely used in the management of Parkinson's disease.\n\nThere have been several reports regarding amantadine-associated ocular complications, such as superficial punctate keratitis, corneal endothelial dysfunction, epithelial edema, and stromal edema.2, 3, 4, 5 However, there have been no reports regarding amantadine-induced deposits in corneal epithelial cells.\n\nHere, we describe a patient who exhibited bilateral corneal epithelial opacities following treatment of Parkinson's disease with amantadine.\n\n2 Case report\nAn 81-year-old woman with bilateral corneal opacities was referred to the Hiroshima University hospital. At the first visit, her corrected visual acuity was 0.8 in both eyes. Intraocular pressures were 15 mmHg in the right eye and 16 mmHg in the left eye. Slit-lamp examination revealed bilateral belt-shaped epithelial opacities in the central part of the cornea (Fig. 1). She had no dry eye findings, such as superficial punctate keratitis or short tear break-up times. There were no signs of inflammatory findings in the anterior chamber, vitreous or retina. The endothelial cell density at the center cornea was 3017 cells/mm2 in the right eye and 2297 cells/mm2 in the left eye. On anterior segment optical coherence tomography examination, there was no opacity and edema in the corneal stroma of either eye (Fig. 2). Confocal biomicroscopy showed high-density plaques in the basal layer of corneal epithelial cells in both eyes (Fig. 3).Fig. 1 Slit-lamp examination of the anterior segment at the first visit. There were intra-epithelial opacities in the right cornea (a, c) and left cornea (b, d). There was no fluorescein staining in either cornea (c, d).\n\nFig. 1Fig. 2 Anterior segment optical coherence tomography examination of the right cornea (a) and left cornea (b) at the first visit. There was no opacity or edema in either cornea.\n\nFig. 2Fig. 3 Confocal biomicroscopic findings of the right cornea (a, b) and left cornea (c, d) at the first visit. The basal layers of corneal epithelial cells around the border between the opaque and clear portions of the cornea are shown, and the dotted line represents the border between the normal and abnormal areas. Epithelial cells in the upper area were normal. In the lower area, reflective abnormal epithelial cells were observed (a, c). In the basal layer of the opaque cornea, highly reflective round shaped deposits were observed (b, d) (arrow head).\n\nFig. 3\n\nThe patient's medical history included Parkinson's disease, insomnia, hypertension, hypercholesterolemia, osteoporosis, hypothyroidism, and constipation. She was taking amantadine, clotiazepam, milnacipran, carvedilol, lovastatin, levothyroxine, alfacalcidol, alendronate, rabeprazole, and irsogladine. Amantadine had been started 9 years prior for treatment of Parkinson's disease. Her daily dose of amantadine was 300 mg. She had no history of the use of any eye drops. The patient's ocular history was unremarkable, and she had no family history of corneal disease.\n\nWe suspected that the corneal opacities might be associated with the use of systemic drugs. Among the drugs that the patient was taking, amantadine has reportedly induced several corneal complications; thus, amantadine was suspected as the probable cause of her corneal opacities. After consultation with her neurologist, amantadine therapy was discontinued. Two months after discontinuation of amantadine, the patient's corneal opacities had disappeared (Fig. 4), and visual acuity had returned to 1.0 in both eyes. Furthermore, there were no high-density deposits in corneal epithelial cells on confocal biomicroscopy (Fig. 5). The patient was returned to her referring ophthalmologist for continued follow-up care.Fig. 4 Slit-lamp examination of the anterior segment at 2 months after discontinuation of amantadine. Corneal intra-epithelial opacities disappeared in the right cornea (a, c) and left cornea (b, d). There was no fluorescein staining in either cornea (c, d).\n\nFig. 4Fig. 5 Confocal biomicroscopy of the right cornea (a) and the left cornea (b) at 2 months after discontinuation of amantadine. These images show almost the same areas as seen in Fig. 3. There were no high-density deposits in the corneal epithelial cells in either cornea.\n\nFig. 5\n\n3 Discussion\nAmantadine has been reported to cause various corneal complications, such as superficial punctate keratitis, corneal endothelial dysfunction, and corneal edema.2, 3, 4, 5 However, these reports did not clearly show that amantadine can induce deposits in corneal epithelial cells. We report here on amantadine-induced deposits in corneal epithelial cells; notably, confocal biomicroscopy was useful for observation of highly reflective deposits in the basal layer of corneal epithelium.\n\nA number of systemic drugs, such as amiodarone, are known to induce deposits in corneal epithelial cells6; these drugs tend to induce a vortex pattern of deposits. This vortex pattern of corneal deposits is the result of the centripetal migration of cells from the limbal stem cells to the center of the cornea. The epithelial cells in the central area of the cornea are exposed to drugs for a longer period of time, and tend to form opacities due to accumulation of drug inside affected cells. Therefore, in the present case, we speculate that the corneal opacities appeared in the central area of the cornea due to drug exposure.\n\nThe patient in the present case, however, did not show a vortex pattern of corneal deposits, but rather a belt-shaped epithelial opacity at the center of each cornea. The mechanism for the formation of amantadine-induced deposits may differ from that in amiodarone-induced keratopathy. The belt-shaped opacities matched with the eyelid apertures, thus the exposure to air may have caused some kind of reaction and induced belt-shaped opacities.\n\nWe propose the following two possible mechanisms for the formation of amantadine-induced corneal deposits. First, phospholipidosis (PLD) in the cells of the corneal epithelium may be related to the occurrence of amiodarone-induced keratopathy; notably, amiodarone is the most widely studied systemic drug that causes corneal epithelial changes. Amiodarone belongs to the family of cationic-amphiphilic drugs (CADs), and has been shown to induce PLD in various organs.8 The cornea is a potential target of PLD. Corneal PLD is termed drug-induced keratopathy and involves formation of corneal deposits. The precise mechanism for CAD-induced corneal toxicity is not well-known, but PLD in the cells of corneal epithelium may be related to amiodarone-induced toxicity. In addition, other CADs (e.g., chloroquine, chlorpromazine and indomethacin) have been reported to cause corneal PLD.9,10 Amantadine also belongs on the list of CADs,11 and has been reported to cause phospholipid storage in various organs and tissues in rats, as well as in cultured cells.12 It is not yet known whether amantadine causes phospholipid storage in corneal epithelial cells, but amantadine might be associated with drug-induced PLD, similar to the effects of other CADs.\n\nThere have also been several reports regarding confocal biomicroscopic observations of amiodarone-induced keratopathy.13,14 Those studies showed highly reflective epithelial cells, which were morphologically similar to those in the present case. However, some of the highly reflective materials inside the epithelial cells in the present case were hard to explain, because they varied in contrast and shape. A possible reason is that different doses of amantadine or different densities of the cytoplasmic deposits may affect the reflective materials. It is also possible that the highly reflective materials that did not seem to be located inside the epithelial cells may be the result of epithelial cell degeneration after the accumulation of amantadine. However, the resolution of the current confocal biomicroscope limited our ability to obtain a more-detailed image of the morphology of the corneal epithelial cells. Further studies with a larger number of patients are needed to be able to understand the morphological mechanisms.\n\nSecond, organic cation transporters (OCTs) may be related to amantadine-induced keratopathy. OCTs constitute broad-specificity transporters for the excretion of endogeneous organic cations, as well as the uptake, elimination, and distribution of cationic drugs, toxins, and environmental waste products. OCT1 and OCT2 are members of a solute carrier superfamily of OCTs; notably, OCT1 and OCT2 are primarily expressed in the basolateral membrane of renal tubules, where they aid in renal secretion and reabsorption.15 Structurally, amantadine is a substrate of both OCT1 and OCT2.16 Furthermore, several transporters are expressed in various ocular tissues, such as the cornea, iris, ciliary body, conjunctiva, and retina; in these tissues, facilitate the transport of many drugs, toxins, and endogenous compounds.17 OCT1 mRNA has been detected in human cornea.18 These findings suggest that OCTs may contribute to the transport of amantadine into corneal epithelial cells.\n\nAdditionally, the patient was using many drugs, and the interactions of these drugs or their metabolites may have contributed to the formation of corneal deposits. Further studies are needed to elucidate the underlying mechanism in amantadine-induced formation of corneal deposits.\n\n4 Conclusions\nAmantadine can induce deposits in corneal epithelial cells, and should be considered in the differential diagnosis of corneal opacity.\n\nPatient consent\nConsent to publish the case report was not obtained. This report does not contain any personal information that could lead to the identification of the patient.\n\nFunding\nNo funding was received for this work.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nDeclaration of competing interest\nNo conflict of interest exists.\n\nAcknowledgments\nWe thank Ryan Chastain-Gross, Ph.D., from Edanz Group (https://en-author-services.edanzgroup.com/) for editing a draft of this manuscript.\n==== Refs\nReferences\n1 Schwab R.S. England A.C. Poskanzer D.C. Young R.R. Amantadine in the treatment of Parkinson's disease J Am Med Assoc 208 7 1969 1168 1170 10.1001/jama.1969.03160070046011 \n2 Nogaki H. Morimatsu M. Superficial punctate keratitis and corneal abrasion due to amantadine hydrochloride J Neurol 240 6 1993 388 389 10.1007/BF00839973 8336180 \n3 Kubo S. Iwatake A. Ebihara N. Murakami A. Hattori N. Visual impairment in Parkinson's disease treated with amantadine: case report and review of the literature Park Relat Disord 14 2 2008 166 169 10.1016/j.parkreldis.2007.03.003 \n4 Jeng B.H. Galor A. Lee M.S. Amantadine-associated corneal edema. Potentially irreversible even after cessation of the medication Ophthalmology 115 9 2008 1540 1544 10.1016/j.ophtha.2008.03.011 18501429 \n5 Chang K.C. Jeong J.H. Kim M.K. Wee W.R. Lee J.H. Jeon B.S. The effect of amantadine on corneal endothelium in subjects with Parkinson's disease Ophthalmology 117 6 2010 1214 1219 10.1016/j.ophtha.2009.10.039 20153901 \n6 Kaplan L.J. William E. Cappaert. Amiodarone keratopathy Arch Ophthalmol 100 4 1982 601 602 10.1001/archopht.1982.01030030603011 7073573 \n8 D'Amico D.J. Kenyon K.R. Ruskin J.N. Amiodarone keratopathy: drug-induced lipid storage disease Arch Ophthalmol 99 1981 257 261 10001/archopht.1981.03930010259007 6258544 \n9 Halliwell W.H. Cationic amphiphilic drug-induced phospholipidosis Toxicol Pathol 25 1997 53 60 10.1177/019262339702500111 9061852 \n10 Raizman M.B. Hamrah P. Holland E.J. Drug-induced corneal epithelial changes Surv Ophthalmol 62 3 2017 286 301 10.1016/j.survophthal.2016.11.008 27890620 \n11 Lüllmann-Rauch R. Drug-induced lysosomal storage disorders Front Biol 48 1979 49 130 387466 \n12 Burmester J. Hanpft R. Kröplin K. Lüllmann-Rauch R.P.M. Amantadine-induced lipidosis. A cytological and physicochemical study Toxiclogoy 44 1987 45 59 10.1016/0300-483x(87)90045-x \n13 Ciancaglini M. Carpineto P. Zuppardi E. Nubile M. Doronzo E. Mastropasqua L. In vivo confocal microscopy of patients with amiodarone-induced keratopathy Cornea 20 4 2001 368 373 10.1097/00003226-200105000-00007 11333323 \n14 Ikegawa Y. Shiraishi A. Hayashi Y. Ogimoto A. Ohashi Y. In vivo confocal microscopic observations of vortex keratopathy in patients with Amiodarone-induced Keratopathy and Fabry disease J Ophthalmol 2018 2018 10.1155/2018/5315137 \n15 Karbach U. Kricke J. Meyer-Wentrup F. Localization of organic cation transporters OCT1 and OCT2 in rat kidney Am J Physiol Ren Physiol 279 4 48-4 2000 679 687 10.1152/ajprenal.2000.279.4.F679 \n16 Goralski K.B. Lou G. Prowse M.T. The cation transporters rOCT1 and rOCT2 interact with bicarbonate but play only a minor role for amantadine uptake into rat renal proximal tubules J Pharmacol Exp Therapeut 303 3 2002 959 968 10.1124/jpet.102.038885 \n17 Zhang T. Xiang C.D. Gale D. Carreiro S. Wu E.Y. Zhang E.Y. Drug transporter and cytochrome P450 mRNA expression in human ocular barriers: Implications for ocular drug disposition Drug Metab Dispos 36 7 2008 1300 1307 10.1124/dmd.108.021121 18411399 \n18 Xiang C.D. Batugo M. Gale D.C. Characterization of human corneal epithelial cell model as a surrogate for corneal permeability assessment: metabolism and transport Drug Metab Dispos 37 5 2009 10.1124/dmd.108.026286 992 LP - 998\n\n",
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"title": "Amantadine can induce intra-epithelial deposition in the cornea.",
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"abstract": "Posterior pituitary injection is an extract prepared from the dried posterior lobe of the pituitary gland from domestic animals containing two octapeptide hormones, oxytocin and vasopressin. Posterior pituitary injection carries an approved therapeutic indication as an adjunct measure for achieving surgical hemostasis. We report a case of cerebral edema and death attributed to water intoxication in a child who had received a large volume of free water concurrent with posterior pituitary injection to control bleeding after tonsillectomy and adenoidectomy.",
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"abstract": "BCR-ABL inhibitors administered in conjunction with chemotherapy have significantly improved outcomes in Philadelphia chromosome-positive acute lymphoblastic leukemia but, for patients diagnosed during pregnancy, data on risks to the fetus are limited. We report a woman treated with chemotherapy and imatinib mesylate who delivered a healthy baby at 30 weeks, and we discuss available data.",
"affiliations": "Department of Medicine, University of Maryland School of Medicine, Baltimore, USA cmainor@umm.edu.;Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore, USA.;Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, USA.;Department of Medicine, University of Maryland School of Medicine, Baltimore, USA Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, USA.;Department of Medicine, University of Maryland School of Medicine, Baltimore, USA Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, USA.",
"authors": "Mainor|Candace B|CB|;Duffy|Alison P|AP|;Atkins|Kristin L|KL|;Kimball|Amy S|AS|;Baer|Maria R|MR|",
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"abstract": "Refractory metastatic rhabdomyosarcoma is largely incurable. Here we analyze the response of a child with refractory bone marrow metastatic rhabdomyosarcoma to autologous HER2 CAR T cells. Three cycles of HER2 CAR T cells given after lymphodepleting chemotherapy induces remission which is consolidated with four more CAR T-cell infusions without lymphodepletion. Longitudinal immune-monitoring reveals remodeling of the T-cell receptor repertoire with immunodominant clones and serum autoantibodies reactive to oncogenic signaling pathway proteins. The disease relapses in the bone marrow at six months off-therapy. A second remission is achieved after one cycle of lymphodepletion and HER2 CAR T cells. Response consolidation with additional CAR T-cell infusions includes pembrolizumab to improve their efficacy. The patient described here is a participant in an ongoing phase I trial (NCT00902044; active, not recruiting), and is 20 months off T-cell infusions with no detectable disease at the time of this report.",
"affiliations": "Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. mghegde@bcm.edu.;Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.;Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.;Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.;Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.;Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.;Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.;Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.;Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.;Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.;Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.;Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.;Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.;Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.;Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.;Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.;Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.;Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.;Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.;Department of Microbiology and Immunology at University of North Carolina, Chapel Hill, NC, USA.;Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.;Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.;Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany.;Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.;Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. nahmed@bcm.edu.",
"authors": "Hegde|Meenakshi|M|http://orcid.org/0000-0002-7778-7871;Joseph|Sujith K|SK|;Pashankar|Farzana|F|http://orcid.org/0000-0003-2883-0957;DeRenzo|Christopher|C|;Sanber|Khaled|K|;Navai|Shoba|S|http://orcid.org/0000-0003-1220-2788;Byrd|Tiara T|TT|;Hicks|John|J|;Xu|Mina L|ML|;Gerken|Claudia|C|;Kalra|Mamta|M|;Robertson|Catherine|C|;Zhang|Huimin|H|;Shree|Ankita|A|;Mehta|Birju|B|;Dakhova|Olga|O|;Salsman|Vita S|VS|;Grilley|Bambi|B|;Gee|Adrian|A|;Dotti|Gianpietro|G|;Heslop|Helen E|HE|;Brenner|Malcolm K|MK|;Wels|Winfried S|WS|;Gottschalk|Stephen|S|http://orcid.org/0000-0003-3991-7468;Ahmed|Nabil|N|http://orcid.org/0000-0002-0982-8424",
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"fulltext": "\n==== Front\nNat Commun\nNat Commun\nNature Communications\n2041-1723 Nature Publishing Group UK London \n\n17175\n10.1038/s41467-020-17175-8\nArticle\nTumor response and endogenous immune reactivity after administration of HER2 CAR T cells in a child with metastatic rhabdomyosarcoma\nhttp://orcid.org/0000-0002-7778-7871Hegde Meenakshi mghegde@bcm.edu 123 Joseph Sujith K. 123 http://orcid.org/0000-0003-2883-0957Pashankar Farzana 4 DeRenzo Christopher 123 Sanber Khaled 1235 http://orcid.org/0000-0003-1220-2788Navai Shoba 123 Byrd Tiara T. 123 Hicks John 6 Xu Mina L. 7 Gerken Claudia 123 Kalra Mamta 123 Robertson Catherine 2 Zhang Huimin 2 Shree Ankita 123 Mehta Birju 2 Dakhova Olga 2 Salsman Vita S. 123 Grilley Bambi 123 Gee Adrian 123 Dotti Gianpietro 89 Heslop Helen E. 1235 Brenner Malcolm K. 1235 Wels Winfried S. 101112 http://orcid.org/0000-0003-3991-7468Gottschalk Stephen 1236 http://orcid.org/0000-0002-0982-8424Ahmed Nabil nahmed@bcm.edu 1236 1 0000 0001 2160 926Xgrid.39382.33Texas Children’s Cancer and Hematology Centers, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX USA \n2 0000 0001 2160 926Xgrid.39382.33Center for Cell and Gene Therapy, Texas Children’s Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX USA \n3 0000 0001 2160 926Xgrid.39382.33Department of Pediatrics, Baylor College of Medicine, Houston, TX USA \n4 0000000419368710grid.47100.32Department of Pediatrics, Yale University School of Medicine, New Haven, CT USA \n5 0000 0001 2160 926Xgrid.39382.33Department of Medicine, Baylor College of Medicine, Houston, TX USA \n6 0000 0001 2160 926Xgrid.39382.33Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX USA \n7 0000000419368710grid.47100.32Department of Pathology, Yale University School of Medicine, New Haven, CT USA \n8 0000 0001 1034 1720grid.410711.2Department of Microbiology and Immunology at University of North Carolina, Chapel Hill, NC USA \n9 0000000122483208grid.10698.36Lineberger Cancer Center at University of North Carolina, Chapel Hill, NC USA \n10 0000 0001 1088 7029grid.418483.2Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany \n11 0000 0004 0492 0584grid.7497.dGerman Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt, Germany \n12 0000 0004 1936 9721grid.7839.5Frankfurt Cancer Institute, Goethe University, Frankfurt, Germany \n15 7 2020 \n15 7 2020 \n2020 \n11 354928 5 2019 13 6 2020 © The Author(s) 2020\nOpen Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Refractory metastatic rhabdomyosarcoma is largely incurable. Here we analyze the response of a child with refractory bone marrow metastatic rhabdomyosarcoma to autologous HER2 CAR T cells. Three cycles of HER2 CAR T cells given after lymphodepleting chemotherapy induces remission which is consolidated with four more CAR T-cell infusions without lymphodepletion. Longitudinal immune-monitoring reveals remodeling of the T-cell receptor repertoire with immunodominant clones and serum autoantibodies reactive to oncogenic signaling pathway proteins. The disease relapses in the bone marrow at six months off-therapy. A second remission is achieved after one cycle of lymphodepletion and HER2 CAR T cells. Response consolidation with additional CAR T-cell infusions includes pembrolizumab to improve their efficacy. The patient described here is a participant in an ongoing phase I trial (NCT00902044; active, not recruiting), and is 20 months off T-cell infusions with no detectable disease at the time of this report.\n\nRecurrent metastatic rhabdomyosarcoma remains largely incurable. Here, the authors describe a child with metastatic rhabdomyosarcoma who has durable response to HER2-specific CAR T cells and shows endogenous immune reactivity.\n\nSubject terms\nCancerImmunologyOncologySarcomahttps://doi.org/10.13039/100009730EIF | Stand Up To Cancer (SU2C)SU2C-AACR-DT1113Hegde Meenakshi https://doi.org/10.13039/100000043American Association for Cancer Research (American Association for Cancer Research, Inc.)SU2C-AACR-DT1113Hegde Meenakshi https://doi.org/10.13039/100000054U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)1U54CA232568-01K12CA090433Hegde Meenakshi https://doi.org/10.13039/100001445Alex's Lemonade Stand Foundation for Childhood Cancer (Alex's Lemonade Stand Foundation)https://doi.org/10.13039/100004917Cancer Prevention and Research Institute of Texas (Cancer Prevention Research Institute of Texas)RP101335RP160283Hegde Meenakshi U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)issue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nRhabdomyosarcoma (RMS) is the most common malignant soft-tissue tumor in children and adolescents. There is no effective treatment for patients with metastatic RMS refractory to standard cytotoxic chemotherapy1,2. We have previously reported on a favorable safety profile of autologous HER2 CAR T cells in patients with advanced sarcoma whose tumors lack HER2 gene-amplification and are thus not amenable to HER2-specific monoclonal antibody therapy3–5. Although clinical benefit was achieved in a subset of patients after HER2 CAR T cells, with 4 of 17 evaluable patients having durable stable disease and 1 patient with partial response (PR), no measurable complete tumor response was observed3. A major limitation identified in the study was the lack of T-cell expansion and persistence in all treated patients. Lymphodepletion prior to T-cell administration improves the expansion of adoptively transferred T cells, in part due to increased availability of homeostatic cytokines such as IL-7 and IL-15. In addition, lymphodepleting chemotherapy decreases both regulatory T cells and myeloid-derived suppressor cells, thereby augmenting the expansion of T cells and consequently their antitumor activity6–10.\n\nAn ongoing phase I trial (NCT00902044; active, not recruiting) is designed to evaluate the safety of autologous HER2 CAR T cells after lymphodepletion in patients with advanced sarcoma and incorporates multiple CAR T-cell infusions to improve their persistence. Here, we report on an exceptional tumor response observed in a child with refractory bone marrow-metastatic RMS enrolled on this phase I trial. Furthermore, we describe the longitudinal analysis of immune-monitoring studies and show evidence of endogenous immune reactivity accompanying CAR T-cell therapy, which may have contributed to this favorable clinical outcome11.\n\nResults\nClinical history and infusion of autologous HER2 CAR T cells\nA 7-year-old boy presenting with severe pancytopenia was diagnosed with metastatic RMS after bilateral bone marrow aspiration and biopsy (BMAB) revealed infiltration with alveolar-pattern RMS cells, which were immunoreactive to desmin and myogenin (Fig. 1a). A whole-body positron emission tomography–computed tomography (PET-CT) revealed extensive BM involvement and a primary tumor in the right calf muscle (Fig. 1b). Surgical resection of the primary tumor confirmed the diagnosis of RMS with alveolar histology (Fig. 1c) but without evidence of FOXO1-gene rearrangement. Tumor DNA sequencing detected a somatic variant of PIK3CA Q546R. The child completed intense systemic chemotherapy lasting for 13 months and radiation therapy to the primary site (4140 cGy in 23 fractions) according to the Children’s Oncology Group’s (COG) co-operative trial ARST0431 for upfront treatment of high-risk RMS (Supplementary Table 1), resulting in local control12. After 9 months of chemotherapy, the PET-CT showed no FDG-avid disease, but at the conclusion of treatment, BMAB showed ~10% of the cellularity comprised of metastatic RMS. By the specific protocol criteria, the child was considered to have PR at the end of first-line therapy and subsequently received salvage therapy per the COG protocol ARST0921 (Supplementary Table 1)13. Restaging evaluation after two cycles of chemotherapy showed persistent metastatic RMS aggregates comprised of atypical cells with abundant pale eosinophilic cytoplasm and large eccentric, irregular nuclei with inconspicuous nucleoli in the bone marrow. Because of the chemotherapy-refractory metastatic disease, the child was evaluated for phase I trials. After confirming HER2 surface expression on both the primary tumor and BM metastasis by immunohistochemistry (IHC; grade 3, intensity score 3; Fig. 1d)14, the child was enrolled on our phase I trial of autologous HER2 CAR T cells in patients with advanced sarcoma. An autologous HER2 CAR T-cell product was manufactured and contained a majority of CD8+ T cells with an effector memory profile (CD45RO+/CCR7−/CD62L−; Supplementary Fig. 1a). The FRP5 antibody-based HER2-specific CAR molecule containing a CD28 co-stimulatory endo-domain (Fig. 1e) was detected in 72.9% of the patient’s T cells (Fig. 1f; gating strategy shown in Supplementary Fig. 2) and induced specific lysis of the HER2-positive sarcoma cells LM7 but not of the HER2-negative cell line K562 (Supplementary Fig. 1b)5. After a 4-week washout period and recovery from prior cytotoxic chemotherapy, the child received three intravenous infusions of 1 × 108 cells/m2 autologous HER2 CAR T cells ~10 weeks apart, each after lymphodepletion with cyclophosphamide and fludarabine (Cy/Flu)6,7. At the end of this induction phase, no morphologic or imaging evidence of RMS was present. Thereafter, the same dose of HER2 CAR T cells was administered approximately every 10 weeks without Cy/Flu for 6 additional months with the intent of consolidating the disease response (Fig. 1g).Fig. 1 Clinical and pathological findings prior to enrollment, and the CAR T-cell infusion regimen.\na Histological examination showing hypocellular bone marrow (BM) containing alveolar-patterned rhabdomyosarcoma (RMS) cells on routine hematoxylin and eosin (H&E) staining and immunoreactivity to desmin and myogenin. b Positron emission tomography–computed tomography showing extensive BM involvement (upper panel) and a primary tumor in the right calf (lower panel). c Histological examination of the primary tumor showing RMS cells that are immunoreactive to desmin and myogenin. d HER2 immunoreactivity (grade 3, intensity score 3+) of the primary tumor and BM metastasis at baseline prior to study enrollment. Panels (a, c, d) show representative microscopic images; scale bar 100 µm. e Schematic outline of components of the HER2 CAR transgene introduced by retroviral vector transduction. TM transmembrane. f HER2 CAR expression in the autologous T-cell product released from the good manufacturing practice (GMP) laboratories for infusion. g Treatment regimen, including the induction and consolidation phases. Autologous HER2 CAR T-cell dose was 1 × 108 cells/m2 for each infusion. H&E hematoxylin and eosin stain. Cy/Flu cyclophosphamide and fludarabine.\n\n\n\nHER2 CAR T cells expand safely after lymphodepletion\nThe Cy/Flu regimen induced grade 4 lymphopenia, with an absolute lymphocyte count of 11–19 cells/mm3 on the day of HER2 CAR T-cell infusion (day 0). Analysis of the child’s serum after conditioning chemotherapy but prior to T-cell infusions revealed an increase in the homeostatic cytokine IL-15, with peak levels on the day of T-cell infusion that declined to low but detectable levels by 6 weeks post-infusion (Fig. 2a, b)10. HER2 CAR T cells were detected in the peripheral blood using quantitative polymerase chain reaction (qPCR) starting at 3 h and up to 8 weeks after each infusion during induction, with the peak in vivo expansion (152–747 copies/μg of DNA) occurring 7 days post infusion (Fig. 2c). Matched 6-week post infusion BMAB samples, when available, were analyzed for the presence of the HER2 CAR transgene (Fig. 2d).Fig. 2 Measurement of serum cytokines and monitoring of HER2 CAR T cells after infusion.\na Analysis of serum cytokines after Cy/Flu administration and prior to T-cell infusion on day 0 showing the difference in IL-15 levels with (n = 3 infusion cycles, data presented as mean values ± standard deviation) and without (n = 2 infusions) lymphodepletion. b Kinetics of serum IL-15 levels prior to and after T-cell infusions given with cytoreducing chemotherapy (n = 3 infusion cycles). c Trends in the absolute lymphocyte count (ALC; shaded gray area) and levels of the HER2 CAR transgene detected by quantitative polymerase chain reaction (qPCR; solid black line) in the peripheral blood during the induction and consolidation phase leading to the initial complete response (CR1). d Detection of the HER2 CAR transgene in the peripheral blood and corresponding bone marrow levels at 6 weeks after infusions 2 and 5. e Analysis of pro-inflammatory cytokines (IL-6, GM-CSF, IFNγ, and TNFα) in the patient’s serum before and after CAR T-cell infusion given with (n = 3 infusion cycles) and without (n = 2 infusions) lymphodepletion. In panels (a, b, e), each dot in the graph represents an average of technical replicates from a biologically distinct serum sample. Inf CAR T-cell infusion, Cy/Flu cyclophosphamide and fludarabine.\n\n\n\nDuring induction, the child developed grade 1 cytokine release syndrome (CRS) with fever, malaise, chills, and nausea within 12 h of each infusion, which resolved completely with supportive care within 72 h of onset (other adverse events are detailed in Supplementary Table 2)15. We detected a rise in C-reactive protein (range: 3.9–8.4 mg/dL) within 24 h of T-cell infusions given after Cy/Flu that trended down with resolution of the fever. GM-CSF and IFN-γ were elevated in the peripheral blood at 4 h post infusion when T cells were administered after lymphodepletion, and a small but sustained increase in the serum IFN-γ (but not IL-6 or TNFα) was noted between days 7–14, which corresponded to the peak of CAR T-cell expansion (Fig. 2e). In addition to lymphopenia, the child developed grades 3–4 neutropenia (absolute neutrophil count: 180–747 cells/mm3) lasting up to day 14 with each Cy/Flu conditioning during induction. No cardiac or pulmonary toxicities were observed despite the CAR T-cell expansion achieved and the repeated infusions given. Echocardiograms performed 6 weeks after each HER2 CAR T-cell infusion showed normal left ventricular ejection fraction.\n\nExceptional tumor response to HER2 CAR T cells\nBilateral BMABs, standard of care for the assessment of BM metastatic RMS, were obtained prior to initiation of study treatment (Fig. 3a) and 6 weeks after each CAR T-cell infusion. Stable disease was observed following the first and the second CAR T-cell infusions with 10–20% of the bone marrow cellularity comprised of metastatic tumor aggregates. The BMAB following the third CAR T-cell infusion demonstrated recovery of trilineage hematopoiesis and no morphological evidence of RMS cells (Fig. 3b). The whole-body PET-CT remained negative with no evidence of FDG-avid disease (Fig. 3c). The child was considered to have a complete response (CR) as per the study-specific criteria. CAR T cells were detected in the peripheral blood by flow cytometry only during peak expansion (day 7) and constituted 1.5–2.2% of the T lymphocytes (Fig. 3d, e; gating strategy shown in Supplementary Fig. 3). Further analysis of the CD8+ T-cell subset revealed higher intensity of surface expression of PD-1 and LAG3 in CAR-positive T cells compared to CAR-negative T cells (Fig. 3f, g; gating strategy shown in Supplementary Fig. 4). Subsequently, the child received four additional CAR T-cell infusions ~10 weeks apart without lymphodepletion over 6 months, with the intent of consolidating the tumor response. To account for the potential sampling error from patchy involvement of the bone marrow, bilateral BMAB and PET-CT were done 6 weeks after each T-cell infusion throughout the treatment period and every 12 weeks during the follow-up. These evaluations continued to show no evidence of disease, and the response was sustained for 12 months.Fig. 3 Clinical and pathological findings after autologous HER2 CAR T-cell infusions.\na Histological examination of the bone marrow 4 weeks after the salvage chemotherapy (ARST0921) and prior to initiating CAR T-cell infusions showing hypocellularity and presence of rhabdomyosarcoma (RMS) cells on hematoxylin and eosin (H&E) staining and immunoreactivity to desmin and myogenin, b complete disease response (CR1), evidenced by recovery of trilineage hematopoiesis and absence of immunoreactivity to desmin and myogenin after three HER2 CAR T-cell infusions. Panels (a, b) show representative microscopic images; scale bar 100 µm. c Representative image from positron emission tomography–computed tomography (PET-CT) with no evidence of FDG-avid disease in bone marrow or other sites 6 weeks after the third HER2 CAR T-cell infusion. d Detection of HER2 CAR-expressing T cells in the peripheral blood 7 days after the second infusion using flow cytometry. HER2 CAR was specifically recognized using HER2.Fc chimeric protein followed by a goat anti-human Fc conjugated with PE as a secondary antibody. SSC side scatter. e The proportion of CD3+ HER2 CAR-expressing T cells on day +7 after each infusion during the induction period. f Histograms showing the PD-1 and LAG3 surface expression in CAR-positive CD8+ (in blue) in comparison to CAR-negative CD8+ T cells (in black) at peak expansion (day +7) after each infusion during induction, and g the corresponding median fluorescence intensity (MFI) of PD-1 and LAG3 surface expression in CAR-positive and CAR-negative CD8+ T cells.\n\n\n\nRemodeling of T-cell receptor repertoire after CAR T-cell therapy\nResolution of the metastatic disease was achieved in this child after the initial disease stabilization despite heterogeneous HER2 expression. To evaluate whether CAR T cells initiated an endogenous immune response that could have potentially contributed to tumor control, we carried out a longitudinal sequencing of the CDR3 region of TCRβ in the peripheral blood mononuclear cells before and after the initiation of CAR T-cell therapy16. The pre-infusion peripheral blood sample was obtained at study entry, 4 weeks after recovering from the prior chemotherapy. The post-infusion peripheral blood and the time-matched bone marrow aspiration samples representing the metastatic disease sites were analyzed at 6 weeks after the CAR T-cell infusions. During the course of induction, T cells represented an increasing proportion of the peripheral blood mononuclear cells (Supplementary Fig. 5a) comprised more of oligoclonally expanded populations after the second and third CAR T-cell infusions (sample clonality 0.332 and 0.331, respectively), compared to pre-infusion baseline (sample clonality 0.19; Supplementary Table 3). Six weeks after the second and third CAR T-cell infusions, the immunodominant clonotypes (hyperexpanded clones, defined as having >1% rearrangement frequency) occupied more of the peripheral blood clonal homeostatic space (43.93% and 44.34%, respectively) as compared to 25.66% at the pre-infusion time point (Fig. 4a). The T cells in the peripheral blood also had a high degree of clonal similarity with the time-matched bone marrow samples (Fig. 4b and Supplementary Fig. 5b), and the distribution of the clonal space homeostasis was comparable between the left and the right bone marrow metastatic disease sites (Supplementary Fig. 5c). Analysis of the in-frame CDR3 loop amino acid sequence length to evaluate the patterns of TCR utilization demonstrated diversity in the peripheral repertoire between CAR T-cell infusions (Supplementary Table 4a). A marked perturbation in the CDR3 length distribution was observed after the second and third infusions (Fig. 4c), further suggesting a differential expansion of unique TCRβ clonotypes17. The CDR3 length distribution patterns are primarily determined by the variable-region gene assembly18, and in this child, we found distinct alterations in the TCRβV family gene usage after CAR T-cell infusions (predominantly TCRβV02, TCRβV06, TCRβV27, and TCRβV28) in comparison to pre-infusion (predominantly TCRβV09 and TCRβV10) peripheral blood (Fig. 4d and Supplementary Table 4b). Similarly, utilization of TCRβJ family genes varied between pre- (predominantly TCRβJ01-02) and post-CAR T-cell infusion (predominantly TCRβJ01-01 and TCRβJ02-01) peripheral blood T cells (Fig. 4d and Supplementary Table 4c).Fig. 4 Remodeling of TCRβ repertoire following HER2 CAR T-cell infusions.\na Longitudinal homeostatic space distribution of T-cell clones from the peripheral blood (PB) categorized as hyperexpanded/large (>1% frequency of productive rearrangements), medium (0.1–1% frequency), small (more than single event, but <0.1% frequency) and rare (single rearrangement events) before and 6 weeks after the first, second and third HER2 CAR T-cell infusions. The pre-infusion sample (Pre) was obtained at 4 weeks from the prior cyclophosphamide containing chemotherapy and serves as a chemotherapy only control. b Heat map representing Morisita’s overlap index of TCRβ CDR3 rearrangements between time-matched samples from the PB and bone marrow (BM) obtained 6 weeks after the second and third CAR T-cell infusions. The overlap index has values ranging from 0 to 1 representing low to high degree of overlap, respectively. c Amino acid (AA) length distribution of the TCRβ CDR3 in peripheral blood before and 6 weeks after the first, second and third HER2 CAR T-cell infusions. d TCRβV family genes and TCRβJ family genes in the CDR3 region of peripheral blood T cells before and 6 weeks after the first, second and third HER2 CAR T-cell infusions. Only TCRβV genes with >1% of cumulative productive frequencies are represented. Complete TCRβV family gene use is provided as Supplementary Table 4. Inf infusion, L left, R right.\n\n\n\nThe appearance of unique productive TCRβ rearrangements in the peripheral blood after each CAR T-cell infusion during induction (Fig. 5a and Supplementary Fig. 5d) suggests remodeling of the T-cell repertoire (Fig. 5b), primarily consisting of high frequency clones (Supplementary Fig. 5e). Upon longitudinal tracking of the productive TCRβ rearrangements, we noted an overall declining trend in the immunodominant clones that were present prior to the initiation of CAR T-cell infusions (Fig. 5c and Supplementary Table 5a). While a few pre-existing clones (detected in the pre-infusion sample) expanded during the course of treatment, of the 20 immunodominant clones identified, 8 were not detectable in the peripheral blood prior to initiation of CAR T-cell infusions or in the infused CAR T-cell product (Fig. 5d and Supplementary Table 5b). Comparing the frequency of distribution of the top 10 CDR3 rearrangements identified in each sample demonstrated progressive TCRβ repertoire remodeling after CAR T-cell infusions during induction (with Cy/Flu) that persisted through consolidation (without Cy/Flu) at a lower frequency (Fig. 5e). These repertoire patterns were distinct from that of pre-infusion peripheral blood and of the infused CAR T-cell product. The productive CDR3 rearrangements and the frequency of their distribution were largely comparable between the peripheral blood and the time-matched bone marrow samples.Fig. 5 Longitudinal tracking of productive TCRβ CDR3 rearrangements.\na Fate of TCRβ CDR3 rearrangements which developed after the initiation of HER2 CAR T-cell infusions, from top 250 rearrangements (n = 127). b Heat map representing Morisita’s overlap index of TCRβ rearrangements between the infused CAR T-cell product and longitudinal samples from the peripheral blood demonstrating restructuring of the T-cell repertoire with each CAR T-cell infusion. The overlap index has values ranging from 0 to 1 depicting low to high degree of overlap, respectively. c Hyperexpanded (defined as having >1% frequency) TCRβ CDR3 rearrangements present in the peripheral blood prior to initiation of CAR T-cell infusions and their fate over the course of induction. d Longitudinal tracking of the productive TCRβ CDR3 rearrangements expanding in the peripheral blood analyzed 6 weeks after HER2 CAR T-cell infusions given during induction phase. Eight T-cell clones that were not detected pre-infusion or in the infused T-cell product were detected in the peripheral blood following CAR T-cell infusions (highlighted in blue). e Frequency distribution of top 10 TCRβ CDR3 rearrangements present in each peripheral blood (PB) and bone marrow (BM) sample 6 weeks after the T-cell infusion, with (induction) or without (consolidation) Cy/Flu lymphodepletion, in comparison to that of pre-infusion peripheral blood and the infused CAR T-cell product. Pre-infusion peripheral blood was obtained at study entry, 4 weeks after the prior cyclophosphamide containing chemotherapy. BM samples were unavailable for analysis after infusions 1 and 6. Pre pre-infusion, Inf infusion, Cy/Flu cyclophosphamide and fludarabine, L left, R right.\n\n\n\nAntibody responses against oncogenic pathway proteins\nDue to the intense lymphodepleting chemotherapy administered prior to CAR T-cell infusions, we monitored the immunoglobulin (IgG) levels in this child which paradoxically showed an increasing trend during induction (Fig. 6a). We then examined the child’s serum using ProtoArray™ proteomic analysis and identified specific post-infusion autoantibody responses that were largely directed against intracellular components involved in cell-cycle regulation, cell-signaling, and tumor-associated processes (Supplementary Fig. 6a and Supplementary Table 6)19. In particular, autoantibodies against four proteins (including FUT8, USP2, SULT1B1, and RAB7B), implicated in tumor invasion and metastasis20, were consistently high 6 weeks after the first, second, and third infusions (Supplementary Table 7). The reactivity of the child’s serum to FUT8, USP2, and RAB7B at different dilutions was validated using indirect ELISA (Fig. 6b). A marked post-infusion autoantibody response observed against GSK3α, a downstream target in the PI3K/AKT signaling pathway, was also confirmed using indirect ELISA (Fig. 6b)21. The serum autoantibody target profile at tumor recurrence (detailed below), 6 months after stopping CAR T-cell infusions (day 546), was noted to be distinct from that at remission (day 425; Fig. 6c and Supplementary Data 1), with a corresponding increase in the child’s serum IgG and IgM levels detected using indirect ELISA (Supplementary Fig. 6b).Fig. 6 Autoantibody responses identified in the patient’s serum before and after CAR T-cell infusions.\na Serum IgG levels obtained in the clinical laboratory prior to initiation of CAR T-cell infusion and 10 weeks after each infusion during the first induction period. b Indirect ELISA confirming serum antibody reactivity with recombinant FUT8, USP2, RAB7B, and GSK3A post HER2 CAR T-cell infusions during the first induction, in comparison to pre-infusion sample. Serum samples from each time point were tested in four dilutions as shown. c Waterfall plot depicting proteins with ≥2 fold change in autoantibody binding signal identified by ProtoArrayTM Human Protein Microarray analysis in the patient’s serum at tumor recurrence 6 months after stopping T-cell infusions (day 546) compared to the sample obtained during remission (day 425). Pre pre-infusion, Inf infusion.\n\n\n\nBone marrow relapse and a sustained second remission\nSix months after the last dose of CAR T cells and following multiple disease evaluations confirming remission, surveillance bone marrow biopsy showed hypocellularity and the presence of small aggregates of neoplastic cells with positive desmin immunostaining, indicating relapsed RMS. HER2 expression was maintained on the recurrent BM metastatic disease, although at a lower level by IHC (grade 2, intensity score 2; Fig. 7a). The child was re-enrolled on the trial and infused with the same dose of autologous HER2 CAR T cells (1 × 108 cells/m2) after lymphodepletion. Bilateral BMAB evaluation and PET-CT done 6 weeks after re-treatment with CAR T cells showed no morphologic (Fig. 7b) or imaging evidence of RMS, respectively, indicating a CR per the study-specific criteria. After achieving the second CR (CR2), the child completed re-induction with two additional cycles of Cy/Flu and CAR T-cell infusion. Four weeks after the BM demonstrated resolution of metastatic disease, the PD-1-blocking antibody pembrolizumab was added, as allowed on the study protocol, with the intent of promoting the CAR T-cell function. The first dose of pembrolizumab (2 mg/kg/dose) was administered 2 weeks following the second CAR T-cell infusion and every 3 weeks thereafter. The serum IL-15 kinetics during re-induction (Fig. 7c) were comparable to that of the first CR (CR1). The cryopreserved first T-cell product was depleted at the end of re-induction; therefore, a new product was manufactured for infusions during consolidation. The HER2 CAR transduction efficiency (Fig. 7d; gating strategy shown in Supplementary Fig. 7), phenotype (Supplementary Fig. 1c), and cytotoxicity (Supplementary Fig. 1d) were comparable between the two products except for the higher proportion of CD4+ T cells in the second product. During consolidation of CR2, the child received five additional CAR T-cell infusions (1 × 108 cells/m2) without lymphodepletion. The total duration of CAR T-cell infusions was 12 months from the attainment of CR2 (Fig. 7e). Bilateral BMAB and whole-body PET-CT were performed 6 weeks after each CAR T-cell infusion during the treatment period and per clinical guidelines thereafter, with no evidence of disease recurrence.Fig. 7 HER2 CAR T-cell infusions after bone marrow relapse and monitoring during the second remission.\na Surveillance bone marrow (BM) at 6 months after stopping HER2 CAR T-cell infusions showing hypocellularity and presence of HER2-expressing RMS cells (grade 2, intensity score 2+ by immunohistochemistry). b BM showing restoration of trilineage hematopoiesis and no morphological evidence of RMS (CR2) 6 weeks after one cycle of lymphodepletion and HER2 CAR T cells (1 × 108 cells/m2). Panels (a, b) show representative microscopic images; scale bar 100 µm. c Kinetics of serum IL-15 levels before and after HER2 CAR T-cell infusions given with Cy/Fly lymphodepletion (n = 3 infusion cycles). d HER2 CAR expression in the second autologous T-cell product manufactured and infused during consolidation of CR2. e Timeline of the initial treatment course, disease relapse, re-induction of CR2, and consolidation of the response shown in a schematic diagram. PD-1 antibody, pembrolizumab, was initiated 4 weeks after confirming the CR2 and continued every 3 weeks thereafter. f Analysis of pro-inflammatory cytokines (IFN-γ, TNFα, and GM-CSF) in the patient’s serum before and after CAR T-cell infusion given with (n = 3 infusion cycles) and without (n = 2 infusions) lymphodepletion. g Longitudinal monitoring of serum IL-6 and IL-4 levels during CR2, before and after adding PD-1-blocking antibody to the CAR T-cell infusion regimen, in comparison to CR1. Solid lines represent the mean values of sample duplicates tested. h Trends in the absolute lymphocyte count (ALC; shaded gray area) and levels of the HER2 CAR transgene detected by quantitative polymerase chain reaction (qPCR; solid black line) in the peripheral blood during the treatment phase of CR2 and the follow-up period. i Detection of HER2 CAR transgene in the matched BM and peripheral blood samples at 6 weeks after T-cell infusions during CR2. In panels (c, f), each dot in the graph represents an average of technical replicates from a biologically distinct serum sample. H&E hematoxylin and eosin stain, Cy/Flu cyclophosphamide and fludarabine.\n\n\n\nDuring re-induction, the child developed fever within 12 h of the first and second CAR T-cell infusions, and the grade 1 CRS resolved within 72 h of onset with supportive care. Analysis of serum cytokines showed peripheral blood GM-CSF and IFN-γ levels peak at 4 h after the CAR T-cell infusions given with Cy/Flu, whereas lymphodepletion did not influence the post-infusion TNFα levels (Fig. 7f). In comparison to the induction and consolidation phases of CR1 wherein only CAR T cells were infused, the serum IL-6 and IL-4 levels were substantially higher when the CAR T cells were combined with pembrolizumab during CR2 (Fig. 7g). HER2 CAR T cells expanded in the peripheral blood when infused after Cy/Flu during induction, were better sustained during the consolidation of CR2, and continued to be detected at low levels during off-therapy follow-up (Fig. 7h). The BMAB samples obtained 6 weeks after CAR T-cell infusions showed the presence of the HER2 CAR transgene, but the levels did not directly correlate with that detected in the time-matched peripheral blood (Fig. 7i). The child did not develop a detectable human anti-mouse antibody response despite multiple CAR T-cell infusions. The CR2 is ongoing at the time of this report, 20 months after stopping CAR T-cell infusions.\n\nDiscussion\nWe report on a child with metastatic RMS who achieved a durable remission after experimental treatment using CAR T cells. Children with high-risk RMS have very poor outcomes2,12,13. This child had high-risk RMS at diagnosis based on the unfavorable extremity location of the primary tumor, alveolar-pattern histology, and extensive BM involvement22. Treatment with intensive first and second line COG regimens for high-risk RMS could not achieve remission of metastatic disease in this child as evidenced by the detection of neoplastic cells on multiple BM biopsies. This course is consistent with data from previous clinical trials, which showed that intensification of therapy in patients with high-risk RMS failed to improve outcomes2,22,23. In children with high-risk disease and CR to upfront therapy, early results from the COG study ARST0431 showed 3-year event-free survival of 20% for those with two or more Oberlin risk factors12. In a large cohort of children with metastatic RMS (n = 788) treated on nine American and European co-operative group studies, the presence of RMS cells in the BM was shown to be an independent poor prognostic factor2,22. The poor prognostic significance of BM metastatic disease in pediatric RMS at diagnosis (n = 27) was confirmed in a recent single-institution retrospective study, which found a median survival of 1.5 years from diagnosis in these children24. However, 4.3 years after initiating infusions of HER2 CAR T cells, this child with two Oberlin risk factors and chemotherapy-refractory metastatic RMS in the bone marrow remains in remission.\n\nIn our preceding dose-escalation study of HER2 CAR T cells3, a major limitation identified was the poor expansion and persistence after adoptive transfer. Therefore, we used a combination of Cy/Flu for creating a favorable homeostatic space prior to administering autologous HER2 CAR T cells to this child with refractory disease. This led to an increase in the serum levels of the homeostatic cytokine IL-15 after Cy/Flu and improved expansion of the infused HER2 CAR T cells. The child developed fever and a rise in serum inflammatory markers after each HER2 CAR T-cell infusion during induction, consistent with mild CRS15. However, we did not observe any on-target, off-tumor toxicities, and there were no adverse events indicative of lung injury or cardiotoxicity, providing yet another layer of safety data for targeting HER2 with the FRP5-derived CAR T cells3,25.\n\nIn B cell malignancies, a single dose of CD19-targeted CAR T cells infused after Cy/Flu can show marked expansion, and these cells can subsequently persist at lower frequencies which may be maintained, in part, by sustained exposure to normal CD19-positive B cells26–28. These kinetics were predictive of durable remission in CD19-CAR T-cell treated patients29. Although BM could represent a favorable disease site due to its accessibility to the circulating CAR T cells, attaining the optimal kinetics needed for disease clearance and durable response is a greater challenge in solid tumors. We initially used Cy/Flu lymphodepletion to facilitate the expansion of HER2 CAR T cells. Then, to consolidate the remission, we used repeated infusions of HER2 CAR T cells alone to sustain their persistence over time. Although this child had a lasting response using our induction and consolidation strategy, recurrent disease was observed 6 months after stopping HER2 CAR T-cell infusions. Tumor recurrence following treatment with CAR T cells targeting a single antigen could result from the emergence of antigen loss variants, and multivalent CAR T cells are being explored as a potential approach to decrease treatment failures30–35. Interestingly, the HER2 expression was lower at recurrence, but it remained targetable with CAR T cells in this child and resulted in a CR2 which is currently ongoing.\n\nCAR T cells have direct cytotoxic effects on tumor cells through engagement of the target antigen. Therefore, the disease response achieved here despite the antigenic heterogeneity of the tumor may reflect the dynamic state of HER2 expression and/or the engagement of the host immune response. We examined whether the CAR T-cell therapy altered the adaptive T-cell responses in this child and observed considerable remodeling of the TCRβ repertoire with immunodominant clones during the course of induction. This was accompanied by perturbations of CDR3 loop length distribution and altered TCRβV and TCRβJ gene utilization, suggesting expansion of previously undetected T-cell clonotypes. In a patient with chronic lymphocytic leukemia responding to CTL019 therapy, peripheral expansion of a single T-cell clone with disruption of the TET2-gene due to CD19-CAR transgene integration (and hypomorphic mutation in the second allele) was thought to be the predominant mediator of the observed antitumor response36. In our patient with RMS, while some pre-existing T-cell clones were sustained through multiple infusions during induction and increased in frequency to >1% of the homeostatic space, we observed bursts of unique TCRβ productive rearrangements occupying a substantial percentage of the clonal space after subsequent infusions of the same CAR T-cell product. Specifically, eight immunodominant clones identified post infusion were not detected in the CAR T-cell product or the pre-infusion peripheral blood, which may indicate an adaptive immune response37. Theoretically, lymphodepletion with Cy/Flu could have contributed to the changes in TCRβ rearrangements noted between infusions38. However, a recent study of adult patients with hematological or solid malignancies found that the age-specific pre-treatment TCR repertoire is restored after recovery from lymphodepleting chemotherapy39. In this child, the distribution of productive CDR3 rearrangements after CAR T-cell infusions given with and without Cy/Flu was distinct in comparison to the pre-infusion peripheral blood obtained 4 weeks after prior cytotoxic chemotherapy only. Given the lack of primary tumor cells and reliable technology to determine the TCR-specificity of the immunodominant clones identified after HER2 CAR T-cell infusion in this patient, our observations currently remain descriptive but warrant further studies, ideally in a larger cohort of responding and non-responding patients.\n\nFurther evaluation of the humoral immune response based on the trend in serum IgG level demonstrated an elevated autoantibody response after HER2 CAR T-cell infusions compared to their reactivity in the pre-infusion sample obtained after prior chemotherapy alone. This finding suggests HER2 CAR T-cell-augmented endogenous immune reactivity against various molecules, including those implicated in tumor invasion and metastasis (e.g., FUT8 and USP2)20,40. Interestingly, a spike in the serum IgM level was detected at the time of relapse, which was accompanied by a concomitant waning of the autoantibody responses that were present during remission. These changes correlated with the distinct serum IgG autoantibody profile identified during relapse using the proteomic analysis. Taken together, these observations may indicate a unique antigenic profile of the relapsed tumor11,41. As antitumor responses are largely mediated by T cells, the autoantibody responses to intracellular proteins such as FUT8, USP2, and GSK3A may represent an ongoing multi-faceted immune response against the tumor, although their functional significance remains uncertain42.\n\nThe inflammatory milieu resulting from repeated CAR T-cell infusions may have contributed to the upregulation of the immune-modulatory receptors, PD-1 and LAG3, on CAR-expressing CD8+ cytotoxic T cells. The cell-surface upregulation of these receptors likely indicates an activated state of CAR T cells at the time of peak expansion, 7 days after each infusion during the induction phase. PD-1 blockade was reported to reinvigorate CD19-CAR T cells and induce clinical response in an adult patient with B cell lymphoma43. In sarcomas, despite pre-clinical studies suggesting a potential role for checkpoint inhibitor therapy, early clinical trials using pembrolizumab or nivolumab as single agents have shown very limited efficacy44,45. There are no reports of pediatric sarcoma with CR to anti-PD-1 therapy alone, and pre-clinical studies on expression of PD-L1 in pediatric RMS are limited46. In view of the upregulation of PD-1 on CD8+ CAR+ T cells following repeat infusions during CR1, we reasoned that incorporating pembrolizumab with CAR T cells could improve CAR T-cell function and lead to clinical benefit in our patient. During the combinatorial treatment, we observed higher serum levels of Th2 cytokines IL-6 and IL-4, the source and implications of which need to be evaluated in additional patients. As the HER2 CAR T-cell product infused during the consolidation of CR2 was different from that of CR1, it is unclear whether PD-1 blockade had a role in improved sustenance of CAR T cells in the peripheral blood. Now, 20 months after stopping CAR T-cell infusions, this child remains in disease remission.\n\nIn conclusion, we report on attaining a durable disease remission in a child with refractory metastatic RMS by safely enhancing the expansion and persistence of autologous HER2-specific CAR T cells. In-depth analysis of the described infusion regimen in a larger cohort of patients with RMS is needed to further evaluate the antitumor efficacy of HER2-specific CAR T cells and the potential contribution of an endogenous immune response against non-targeted proteins in achieving tumor control.\n\nMethods\nStudy design and evaluations\nThis phase I, open-label, dose-escalation trial (ClinicalTrials.gov identifier: NCT00902044) for advanced sarcoma is designed to primarily assess the safety of one intravenous injection of autologous HER2-specific CAR T cells administered after lymphodepleting chemotherapy. Assessment of in vivo expansion, persistence, and antitumor activity of infused CAR T cells were secondary objectives of the study. Patients who tolerated the initial infusion well and had no clinical decline were eligible to receive additional HER2 CAR T-cell infusions 6–12 weeks apart. The clinical trial protocol is approved by Baylor College of Medicine’s Institutional Review Board (IRB), the recombinant DNA advisory committee of the National Institutes of Health, and the US Food and Drug Administration (FDA). Patients with refractory or recurrent HER2-positive sarcoma are eligible. Concurrent treatment with antineoplastic agents is not allowed 4 weeks before and 6 weeks after the CAR T-cell infusions except for PD-1 or PDL-1 inhibitors. The interim analysis of the phase I study is conducted and reported to the IRB and FDA on an ongoing basis in accordance with the pre-defined study criteria and the regulatory guidelines. The Data Safety Monitoring Committee of the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine is informed of this single patient report from an ongoing clinical trial. This publication describes an exceptional antitumor response observed in one patient following the CARE guidelines for transparency and accuracy of health research reporting and is in line with the study consent obtained at the time of enrollment. The parent(s) of this child provided a written informed consent for participation and reporting of this research study.\n\nHER2 CAR T cells were manufactured from ~60 mL autologous peripheral blood using a gamma-retrovirus delivery system as previously described3. The CAR T cells were evaluated for sterility, HLA identity, immunophenotype, and HER2-specific cytotoxicity (4-h chromium-51 release assay) prior to cryopreservation. Lymphodepletion consisted of Cy (30 mg/kg/day) for 2 days followed by Flu (25 mg/m2/day) for 5 days (Cy/Flu)6. The prescribed HER2 CAR T-cell dose was 1 × 108 cells/m2, the highest dose previously tested without lymphodepletion3,25. The T-cell dose was based on the total number of cells infused. Study-related adverse events were collected and analyzed as per Common Terminology Criteria for Adverse Events with the exception of CRS, which was graded according to Lee et al.15. Disease evaluation was performed with whole-body PET-CT and bilateral BMAB prior to study entry and at 6 weeks after each T-cell infusion to assess the treatment response. Histologic BMAB response was tested and interpreted by an independent clinical pathologist per standard of care. Radiographic responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST)47. Soluble serum cytokines were quantified using the Luminex® Multiplex Assay (Cat# HCYTOMAG-60K, Lot# 2977010, Millipore, Austin, TX)3.\n\nImmunohistochemistry\nHER2 expression was evaluated using immunohistochemistry (mouse monoclonal to ErbB2 [CB11] ab8054; Abcam Inc, Cambridge, MA)3,48. HER2 expression was graded for percent positive tumor cells (grade 0, no staining; grade 1, 1–25%; grade 2, 26–50%; grade 3, 51–75%; grade 4, 76–100%) and intensity of staining (0, 1+, 2+, or 3+) as scored by an independent pathologist and compared to HER2-positive breast cancer density gradient tissue microarrays as positive controls. To meet study entry eligibility, tumors were required to have at least grade 1 (1–25% positive) and intensity score 1+ for HER2 staining. Desmin and myogenin immunohistochemistry were performed per standard of care in a CLIA-certified clinical laboratory and were interpreted by an independent pathologist.\n\nQuantitative polymerase chain reaction\nWe used qPCR amplification to detect HER2 CAR T cells in patient samples3. Briefly, DNA was extracted (QIAamp DNA Blood Mini Kit, Quiagen, Hilden, Germany) from peripheral blood or bone marrow; using FRP5-specific primers (forward primer: 5′-CCACGGTCACCGTTTCCT-3′ 18 bp, reverse primer: 5′-GGGTCAGCTGGATGTCAGAAC-3′ 21 bp, probe (on reverse strand): 5′-FAM-CCGCCACCAGAACCG-NFQ-3′ 15 bp) and TaqMan probe (Applied Biosystems, Waltham, MA). qPCR was performed in triplicates using the ABI 7900HT Sequence Detection System (Applied Biosystems). The baseline range was set at cycles 6–15, with the threshold 10 standard deviations above the baseline fluorescence. Serial dilution of DNA plasmids encoding each cassette was used to generate DNA standards.\n\nFlow cytometry\nA BD AccuriTM C6 (BD Accuri C6 Software, Becton Dickinson, San Jose, CA) or a Gallios flow cytometer (Kaluza Analysis Software, Beckman Coulter, Indianapolis, IN) and FlowJo software v10 (FlowJo LLC, Ashland, OR) were used for flow cytometric analysis of peripheral blood and bone marrow samples. The following monoclonal antibodies were used: mouse anti-human CD3 FITC (stock solution, 5 µL/100 µL test at 1:20 dilution, clone: SK7, Cat# 349201, Lot# 7221481, Becton Dickinson Biosciences, San Jose, CA), mouse anti-human CD8 Pacific Blue (stock solution, 5 µL/100 µL test at 1:20 dilution, clone: B9.11, Cat# A82791, Lot# 38, Beckman Coulter, Indianapolis, IN), mouse anti-human CD279 (PD-1) APC (stock solution, 5 µL/100 µL test at 1:20 dilution, clone: MIH4, Cat# 558694, Lot# 8012764, Becton Dickinson Biosciences, San Jose, CA), mouse anti-human CD223 (LAG3) FITC (stock solution, 5 µL/100 µL test at 1:20 dilution, clone: 3DS223H, Cat# 11-2239-42, Lot# 4337363, Thermo Fisher Scientific, Waltham, MA). HER2 CAR expression in the T-cell product was detected using Alexa Fluor® 647 AffiniPure Goat Anti-Mouse IgG, F(ab′)2 fragment specific (reconstituted, 1:100 to 1:800 dilution, 0.5–1 µL/100 µL test, polyclonal, Cat# 115-605-006, Lot# 122475, The Jackson Laboratory, Bar Harbor, ME), and in the peripheral blood T cells using a recombinant human ErbB2/HER2 Fc chimeric protein (100 µg/mL concentration, 5 µL/100 µL test at 1:20 dilution, Cat# 1129-ER, Lot# FXR0917071, R&D Systems, Minneapolis, MN) followed by a goat anti-human IgG Fc secondary antibody PE (pre-titrated, 1 uL/100 µL test at 1:100 dilution, polyclonal, Cat# 12-4998-82, Lot# 2070588, Thermo Fisher Scientific, Waltham, MA). Negative controls included isotype antibodies and where appropriate, non-transduced T cells stained with the test antibodies. Gating strategy for all flow cytometry experiments is included in Supplementary Information.\n\nTCRβ CDR3 sequencing\nGenomic DNA was extracted using the DNeasy Blood & Tissue Kit (Qiagen, Germantown, MD) per manufacturer’s instructions. The immunosequencing of the CDR3 regions of human TCRβ chains was performed using the ImmunoSEQTM Assay (Adaptive Biotechnologies, Seattle, WA)49. Briefly, genomic DNA was amplified in an unbiased multiplex PCR assay with a mixture of primers (Adaptive Biotechnologies, Seattle, WA)49 targeting the rearranged variable and joining segments and a high-throughput DNA sequencing was performed. The sequences were quantitated and analyzed to identify frequency of productive TCRβ CDR3 rearrangements in samples using the ImmunoSEQ Analyzer 3.0 software provided by Adaptive Biotechnologies. Sample clonality and Morisita index were calculated using the ImmunoSEQ Analyzer 3.0 software. For other graphical presentations, data were exported as a tab-separated values file and graphs were plotted on Microsoft Excel. All associated Venn plots were created from the exported data using the webtool found at http://bioinformatics.psb.ugent.be/webtools/Venn/.\n\nProtoArrayTM human protein microarray\nHigh-throughput serological analysis for autoantibody generation was performed on patient serum samples using the ProtoArrayTM Human Protein Microarray (Thermo Fisher Scientific, Rockford, IL)50. The reactivity of antibodies present in the patient’s serum to 9480 unique protein probes was investigated by the manufacturer’s antibody profiling services. Briefly, the patient’s serum at pre infusion and 6 weeks post infusions #1, #2, #3, #7 (remission) and relapse at day 546 was profiled at 1:500 dilution and bound antibodies were developed with AF647 goat anti-human IgG. Negative controls were incubated with buffer containing no serum prior to incubation with the Alexa Fluor™647-anti-human IgG detection reagent. The background values for the assay ranged from 39 to 61 RFU. Pixel intensities for each spot were determined using GenePix 7 software and analyzed using Thermo Fisher Scientific’s proprietary ProtoArray™ Prospector software.\n\nIn conducting the analyses comparing selected individual serum samples, the data from one sample were filtered to remove proteins that were bound by the anti-human IgG detection reagent alone and compared in pairwise fashion to a second sample. Proteins were defined as eliciting an increased signal from serum autoantibody binding if they met the following criteria: (1) the Signal Used value, or background-subtracted signal, on the array probed with one sample under comparison was at least 5000 RFU; (2) the ratio of the Signal Used value on the array probed with one sample under comparison to the Signal Used value on the other array under comparison was >2; (2) the z-score, or normalized signal intensity, was <1.0 on the negative control array. The z-score indicates the number of standard deviations above or below the median signal value for all human protein features on the array; (4) the Z-factor, or signal-to-noise ratio, was >0.5 on the corresponding array, indicating a signal greater than twofold above the noise; (5) the coefficient of variation was <50% for the adjacent replicate spots on the corresponding array; and (6) a CI P value < 0.05 as calculated by the ProtoArray® Prospector software. The CI P value assigns a probability that an observed signal is derived from the distribution of signals arising from a set of defined negative controls. Typically, a CI P value < 0.05 correlates with a visually confirmable signal on the array. Cytoscape maps depicting nodes of genes and informative functional terms were visualized using the WebGIVI tool (http://raven.anr.udel.edu/webgivi/)51.\n\nIndirect ELISA\nThe serum IgG and IgM levels at various time points over the course of treatment (pre-infusion, 6 weeks post each infusion during CR1 and at relapse) were determined using IgG (total) Human uncoated ELISA kit (Cat# 88-50550-22, Lot# 175941117) and IgM Human uncoated ELISA kit (Cat# 88-50620-22, Lot# 1666010115), respectively, as per manufacturer’s instructions (Invitrogen, Carlsbad, CA). Indirect ELISA was performed to validate the reactivity of patient serum to rFUT8, rUSP2, rRAB7B, and rGSK3A. Briefly, 96-well ELISA plates were coated with recombinant proteins (1 µg/ml; 100 µl/well; Abcam, Cambridge, MA) in carbonate buffer. After blocking with 2.5% Milk-PBS-T20, the patient’s plasma collected at pre infusion and post infusion time points was incubated for an hour at 1:125, 1:250, 1:500, and 1:1000 dilutions. Goat anti-human IgG (γ-chain specific) conjugated to HRP (1:2500 dilution; Cat# A8419-2ML, Lot# 077M4873V, Sigma-Aldrich, St. Louis, MO) was used as secondary antibody and the assay was developed with TMB substrate (BioLegend, San Diego, CA). The reaction was stopped after 15 min with 2.5 M sulfuric acid and read at 450 nm using an Infinite® F50 microplate reader (Tecan, Switzerland).\n\nStatistical analysis and reproducibility\nData were generated using biologically distinct samples when possible, employing technical replicates in each experiment as indicated. All experimental results were appropriately repeated for validation except in the scenarios where the patient sample was limited. Specifically, flow cytometry analysis of the post-infusion PBMC was optimized and repeated using donor PBMC with decreasing concentrations of CAR T cells to ensure reproducibility prior to testing of patient sample(s). Disease evaluation with histopathological examination of the bone marrow and whole-body PET-CT was done as part of patient care following standard clinical guidelines. GraphPad Prism 8.0 or Microsoft Excel 2013 was used for data analysis and graphical presentation. All data were summarized using descriptive statistics as mean ± SD.\n\nReporting summary\nFurther information on research design is available in the Nature Research Reporting Summary linked to this article.\n\nSupplementary information\n\nSupplementary Information\n\n \nReporting Summary\n\n \n\n\nSource data\n\nSource Data\n\n\n\n\nPeer review information\nNature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary information is available for this paper at 10.1038/s41467-020-17175-8.\n\nAcknowledgements\nWe thank the patient and his family as well as the physicians and nursing staff involved in this child’s care. The trial was supported by Stand Up To Cancer (SU2C)—St. Baldrick’s Pediatric Cancer Dream Team Translational Research Grant (SU2C-AACR-DT1113); SU2C is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research (AACR). This work was also supported by Alex’s Lemonade Stand Pediatric Cancer Foundation, Cancer Prevention Research Institute of Texas (CPRIT) grant (RP101335), The V Foundation for Cancer Research, Triumph Over Kid Cancer Foundation, and Cookies for Kids’ CancerTM Foundation. Further support was provided by the Clinical Research Center at Texas Children’s Hospital and by shared resources through Dan L. Duncan Cancer Center Support Grant P30CA125123. M.H., S.K.J., K.S., and N.A. were supported by the National Cancer Institute of the National Institute for Health under the Cancer Moonshot U54 project 1U54CA232568-01. K.S. was supported by the State of Texas CPRIT training program RP160283—Baylor College of Medicine Comprehensive Cancer Training Program. S.N. was supported by the National Cancer Institute of the National Institutes for Health under award number K12CA090433. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.\n\nAuthor contributions\nM.H., B.G., A.G., G.D., H.E.H., M.K.B., W.S.W., S.G., and N.A. developed the clinical trial concept, design and provided supervision. M.H., F.P., C.D., S.N., J.H., M.X., C.G., M.K., C.R., H.Z., A.S., B.M., O.D., V.S.S., B.G., S.G., and N.A. were involved in study implementation, acquisition, analysis, and interpretation of clinical data. M.H., S.K.J., K.S., T.T.B., S.G., and N.A. designed methods and experiments. S.K.J., K.S., T.T.B., C.G., and A.S. performed the laboratory experiments. M.H., S.K.J., and N.A. interpreted laboratory data and carried out statistical analysis. M.H. and N.A. had access to all the data and wrote the paper. S.K.J., K.S., and S.N. contributed to paper writing. All authors were involved in the critical review and editing of the paper.\n\nData availability\nThe source data underlying Figs. 1f, 2a–e, 3d–g, 4–6, 7c, d, f–i and Supplementary Figs. 1a–d, 2a–e, and 3a, b are provided as a Source Data file. ProtoArrayTM data in this publication are deposited in NCBI’s functional genomic data repository Gene Expression Omni3a, bbus (GEO) and are accessible through GEO series accession number GSE152029. Figures 1g and 7e are created by S.N. using BioRender.com (purchased license). For these figures, timeline from initial study enrollment is provided without the dates to protect the research participant’s privacy, and to align with the study consent. All the other data supporting the findings of this study are available within the article, supplementary information, source files, and from the corresponding author upon reasonable request. Source data are provided with this paper.\n\nCompeting interests\nM.H., S.K.J., T.T.B., and V.S.S. are named inventors on patent applications in the field of CAR T-cell therapy owned by Baylor College of Medicine (BCM). B.G. owns QBRegulatory Consultants, LLC (QBR) which provides clinical research regulatory and project management support to companies inclusive of Allovir, TESSA therapeutics, Marker Therapeutics Inc, and LOKON Pharma AB. H.E.H. reports ownership equity in Marker Therapeutics and Allovir, consulting with Tessa Therapeutics, Kiadis, Novartis, Gilead Biosciences, PACT Pharma, Marker Therapeutics, and Allovir, and research grants from Tessa Therapeutics and Cell Medica, outside the submitted work. M.K.B. reports ownership equity in Marker Therapeutics, Tessa Therapeutics, and Allovir, consulting with Tessa Therapeutics, Walking Fish Therapeutic, Memgen, TScan, Allogene, Marker Therapeutics, and Allovir, outside the submitted work. W.S.W. is named as an inventor on patents and patent applications in the field of cancer immunotherapy owned by Georg-Speyer-Haus. S.G. has patent applications in the fields of T-cell and/or gene therapy for cancer and a research collaboration with TESSA Therapeutics, is a DSMB member of Immatics, and on the scientific advisory board of Tidal. N.A. is named inventor on patents and patent applications owned by Baylor College of Medicine. N.A. received one-time royalties from Celgene and Cell Medica, consulted in the past for Adaptimmune and continues to consult for Equillium (pro bono) and The Children’s Cancer Hospital Egypt 57357 on medical education and research development. None of these relationships conflict with the published work. The remaining authors declare no competing financial interests.\n==== Refs\nReferences\n1. Linch M Miah AB Thway K Judson IR Benson C Systemic treatment of soft-tissue sarcoma-gold standard and novel therapies Nat. Rev. Clin. Oncol. 2014 11 187 202 24642677 \n2. Pappo, A. S. & Dirksen, U. Rhabdomyosarcoma, Ewing sarcoma, and other round cell sarcomas. J. Clin. Oncol. JCO2017747402, 10.1200/JCO.2017.74.7402 (2017).\n3. Ahmed N Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma J. Clin. Oncol. 2015 33 1688 1696 25800760 \n4. Ebb D Phase II trial of trastuzumab in combination with cytotoxic chemotherapy for treatment of metastatic osteosarcoma with human epidermal growth factor receptor 2 overexpression: a report from the children’s oncology group J. Clin. Oncol. 2012 30 2545 2551 22665540 \n5. Ahmed N Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression Mol. Ther. 2009 17 1779 1787 19532139 \n6. Dudley ME Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma J. Clin. Oncol. 2005 23 2346 2357 15800326 \n7. Dudley ME Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens J. Clin. Oncol. 2008 26 5233 5239 18809613 \n8. Wrzesinski C Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells J. Immunother. 2010 33 1 7 19952961 \n9. Wrzesinski C Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells J. Clin. Investig. 2007 117 492 501 17273561 \n10. Kochenderfer JN Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels J. Clin. Oncol. 2017 35 1803 1813 28291388 \n11. Gulley, J. L. et al. Role of antigen spread and distinctive characteristics of immunotherapy in cancer treatment. J. Natl Cancer Inst.10910.1093/jnci/djw261 (2017).\n12. Weigel BJ Intensive multiagent therapy, including dose-compressed cycles of ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide, irinotecan, and radiation, in patients with high-risk rhabdomyosarcoma: a report from the Children’s Oncology Group J. Clin. Oncol. 2016 34 117 122 26503200 \n13. Malempati S Hawkins DS Rhabdomyosarcoma: review of the Children’s Oncology Group (COG) Soft-tissue Sarcoma Committee experience and rationale for current COG studies Pediatr. Blood Cancer 2012 59 5 10 22378628 \n14. 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Agrawal P A systems biology approach identifies FUT8 as a driver of melanoma metastasis Cancer Cell 2017 31 804 819.e807 28609658 \n21. Manning BD Toker A AKT/PKB Signaling: Navigating the Network Cell 2017 169 381 405 28431241 \n22. Oberlin O Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European cooperative groups J. Clin. Oncol. 2008 26 2384 2389 18467730 \n23. Rudzinski, E. R. et al. Histology, fusion status, and outcome in metastatic rhabdomyosarcoma: a report from the Children’s Oncology Group. Pediatr. Blood Cancer6410.1002/pbc.26645 (2017).\n24. Bailey, K. A. & Wexler, L. H. Pediatric rhabdomyosarcoma with bone marrow metastasis. Pediatr. Blood Cancer, e28219 10.1002/pbc.28219 (2020).\n25. Ahmed, N. et al. HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: a phase 1 dose-escalation trial. JAMA Oncol.10.1001/jamaoncol.2017.0184 (2017).\n26. Lee DW T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial Lancet 2015 385 517 528 25319501 \n27. Maude SL Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia N. Engl. J. Med 2018 378 439 448 29385370 \n28. Grupp SA Chimeric antigen receptor-modified T cells for acute lymphoid leukemia N. Engl. J. Med. 2013 368 1509 1518 23527958 \n29. Fraietta JA Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia Nat. Med. 2018 24 563 571 29713085 \n30. Sotillo E Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy Cancer Discov. 2015 5 1282 1295 26516065 \n31. Brown CE Mackall CL CAR T cell therapy: inroads to response and resistance Nat. Rev. Immunol. 2019 19 73 74 30631206 \n32. Hegde M Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma Mol. Ther. 2013 21 2087 2101 23939024 \n33. Hegde M Tandem CAR T cells targeting HER2 and IL13Ralpha2 mitigate tumor antigen escape J. Clin. Investig. 2016 126 3036 3052 27427982 \n34. Fry TJ CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy Nat. Med. 2018 24 20 28 29155426 \n35. O’Rourke, D. M. et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci. Transl Med.910.1126/scitranslmed.aaa0984 (2017).\n36. Fraietta JA Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells Nature 2018 558 307 312 29849141 \n37. Schumacher TN Schreiber RD Neoantigens in cancer immunotherapy Science 2015 348 69 74 25838375 \n38. Gassner FJ Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia Cancer Immunol. Immunother. 2011 60 75 85 20857100 \n39. Simnica D T cell receptor next-generation sequencing reveals cancer-associated repertoire metrics and reconstitution after chemotherapy in patients with hematological and solid tumors Oncoimmunology 2019 8 e1644110 31646093 \n40. Zhao Y USP2a supports metastasis by tuning TGF-beta signaling Cell Rep. 2018 22 2442 2454 29490279 \n41. GuhaThakurta D Humoral immune response against nontargeted tumor antigens after treatment with sipuleucel-T and its association with improved clinical outcome Clin. Cancer Res. 2015 21 3619 3630 25649018 \n42. Renshaw J Dual blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) pathways synergistically inhibits rhabdomyosarcoma cell growth in vitro and in vivo Clin. Cancer Res. 2013 19 5940 5951 23918606 \n43. Chong EA PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR Blood 2017 129 1039 1041 28031179 \n44. Tawbi HA Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial Lancet Oncol. 2017 18 1493 1501 28988646 \n45. D’Angelo SP Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials Lancet Oncol. 2018 19 416 426 29370992 \n46. Bertolini G PD-L1 assessment in pediatric rhabdomyosarcoma: a pilot study BMC Cancer 2018 18 652 29898687 \n47. Therasse P 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 \n48. Gorlick R Expression of HER2/erbB-2 correlates with survival in osteosarcoma J. Clin. Oncol. 1999 17 2781 2788 10561353 \n49. Carlson CS Using synthetic templates to design an unbiased multiplex PCR assay Nat. Commun. 2013 4 2680 24157944 \n50. Predki PF Mattoon D Bangham R Schweitzer B Michaud G Protein microarrays: a new tool for profiling antibody cross-reactivity Hum. Antibodies 2005 14 7 15 16424595 \n51. Sun L WebGIVI: a web-based gene enrichment analysis and visualization tool BMC Bioinform. 2017 18 237\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2041-1723",
"issue": "11(1)",
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"mesh_terms": "D001706:Biopsy; D001853:Bone Marrow; D002648:Child; D017321:Clinical Trials, Phase I as Topic; D006801:Humans; D016219:Immunotherapy, Adoptive; D008297:Male; D019042:Muscle Neoplasms; D009364:Neoplasm Recurrence, Local; D018719:Receptor, ErbB-2; D000076962:Receptors, Chimeric Antigen; D012074:Remission Induction; D012208:Rhabdomyosarcoma; D013601:T-Lymphocytes; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "24642677;25800760;22665540;19532139;15800326;18809613;19952961;17273561;28291388;26503200;22378628;9242460;24876563;27587469;16930714;12778474;24579088;28609658;5546324;18467730;25319501;29385370;23527958;29713085;26516065;30631206;23939024;27427982;29155426;29849141;25838375;20857100;31646093;29490279;25649018;23918606;28031179;28988646;29370992;29898687;10655437;10561353;24157944;16424595",
"title": "Tumor response and endogenous immune reactivity after administration of HER2 CAR T cells in a child with metastatic rhabdomyosarcoma.",
"title_normalized": "tumor response and endogenous immune reactivity after administration of her2 car t cells in a child with metastatic rhabdomyosarcoma"
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"abstract": "Priapism is rarely related to use of non-erectile related medications. The objective was to educate about the multiple possible causes of priapism and to provide treatment recommendations for the different types of priapism. We present the case of a 43-year-old African American male with a history of schizoaffective disorder who presented to our emergency department multiple times over a three year period with priapism, each episode related to the ingestion of quetiapine. Following penile aspiration and intercavernosal injection of phenylephrine, this patient had resolution of his priapism. This case demonstrates an unusual case of recurrent priapism.",
"affiliations": "Department of Emergency Medicine, Denver Health Residency Program, Denver, Colorado.;Exempla Emergency Physicians, Denver, Colorado.;Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado.",
"authors": "Saghafi|Omeed|O|;Kao|Amanda|A|;Druck|Jeffrey|J|",
"chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate",
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"fulltext": "\n==== Front\nWest J Emerg MedWest J Emerg MedWestJEMWestern Journal of Emergency Medicine1936-900X1936-9018Department of Emergency Medicine, University of California, Irvine School of Medicine 2457877710.5811/westjem.2013.8.18548wjem-15-114Diagnostic AcumenCase ReportRecurrent Priapism from Therapeutic Quetiapine Saghafi Omeed MD*Kao Amanda MD†Druck Jeffrey MD‡\n* Department of Emergency Medicine, Denver Health Residency Program, Denver, Colorado\n† Exempla Emergency Physicians, Denver, Colorado\n‡ Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, ColoradoAddress for Correspondence: Jeffrey Druck, MD. Department of Emergency Medicine, Campus Box B-215, 12401 E. 17th Avenue, Aurora, CO 80045. Email: jeffrey.druck@ucdenver.edu.Supervising Section Editor: Rick McPheeters, DO\n\nFull text available through open access at http://escholarship.org/uc/uciem_westjem\n\n2 2014 15 1 114 116 13 6 2013 09 8 2013 19 8 2013 Copyright © 2014 the authors.2014This is an open access article distributed in accordance with the terms of the Creative Commons\nAttribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by-nc/4.0/.Priapism is rarely related to use of non-erectile related medications. The objective was to educate about the multiple possible causes of priapism and to provide treatment recommendations for the different types of priapism. We present the case of a 43-year-old African American male with a history of schizoaffective disorder who presented to our emergency department multiple times over a three year period with priapism, each episode related to the ingestion of quetiapine. Following penile aspiration and intercavernosal injection of phenylephrine, this patient had resolution of his priapism. This case demonstrates an unusual case of recurrent priapism.\n==== Body\nINTRODUCTION\nPriapism is defined as persistent penile erection or clitoral engorgement not accompanied by sexual desire or stimulation, usually lasting more than 4 to 6 hours. It is considered a urologic emergency that should be treated promptly as it can lead to erectile dysfunction in 30–90% of patients.1 In general, priapism is divided into 2 types: high-flow and low-flow. High-flow priapism is non-ischemic and is often caused by increased flow through arteries due to trauma. Low-flow priapism is a result of blood collecting within the corpora and is caused by erectile dysfunction medications, hyperviscosity syndromes, trauma, tumor, neurologic conditions, and medication side effects. Variouos psychoactive medications are also known to cause low-flow priapism, with trazodone the most commonly implicated member of this group. Quetiapine is an atypical antipsychotic originally designed for use in schizophrenia, but it is now also used to treat a multitude of other psychiatric disorders, including schizoaffective disorder, bipolar disorder, anxiety, and depression.2 We report the first case of recurrent priapism as a result of standard doses of quetiapine after first use and with multiple subsequent uses.\n\nCASE REPORT\nA 43-year-old African American man with a history of schizoaffective disorder and ulcerative colitis presented to the emergency department (ED) for a painful erection lasting 15 hours. He reported noncompliance with sulfasalazine for ulcerative colitis but intermittent use of quetiapine, 100 mg every morning and 200 mg every evening, for his schizoaffective disorder. Prior to the ED visit, previous doses of quetiapine resulted in erections lasting 3 hours every morning that resolved spontaneously. He denied any history of trauma, sickle cell disease or trait, illicit drug use, vasoactive agents, including nitrates, recent intercourse, or use of any medications or devices for sexual enhancement. Examination demonstrated a tender and erect phallus without evidence of injury, fibrosis, angulation, lesions, or discharge. Testicles were normal, and no hernias were present.\n\nSubcutaneous terbutaline and oral pseudoephedrine were administered with no effect. Aspiration of 10 cc of intracavernosal blood followed by intracavernosal phenylephrine injection led to successful detumescence. The patient was advised to discontinue use of quetiapine and arrange follow-up with his primary care physician.\n\nThe patient returned to the ED 4 times over the course of the next year. Each time the patient had a morning erection lasting 6 to 9 hours following 200 mg of quetiapine ingestion the prior evening. Detumescence was achieved successfully with aspiration and intracavernosal phenylephrine injection. The patient was ultimately transitioned from quetiapine to ziprasidone and amitriptyline with resolution of his recurrent priapism.\n\nThree years after his initial presentation, the patient returned to the ED with yet another episode of priapism. He reported accidentally taking 100 mg of quetiapine instead of his normal dose of amitriptyline the evening prior to presentation. He awoke with an erection and came to the ED after the erection failed to resolve spontaneously after 8 hours. Detumescence was again achieved with intracavernosal aspiration and injection of phenylephrine. Intracavernosal blood was found to contain quetiapine with a level of 502 ng/ml. The patient was discharged home and advised to dispose of any excess quetiapine.\n\nDISCUSSION\nThe case presented is the first reported case of recurrent priapism due to therapeutic doses of quetiapine. There have been several previous case reports implicating quetiapine as a cause of priapism. Quetiapine was initially approved by the U.S. Food and Drug Administration for the treatment of schizophrenia in 1997. The first report of priapism was in 2001 by Pais and Ayvazian;3 a 45-year-old male attempted suicide by ingesting 27 quetiapine (65 mg/tablet) pills, which resulted in priapism requiring a cavernosal-glanular shunt to achieve detumescence.\n\nDu Toit et al reported priapism due to therapeutic doses of quetiapine in 2004.4 Their patient developed priapism 24 hours after being transitioned from risperidone and trazodone to quetiapine. Symptoms resolved after being started on loxapine, an antipsychotic with minimal alpha1 adrenoreceptor blockade. The patient had no difficulty with risperidone and trazodone for 2 years prior to the event but developed diabetes over the course of his 2 years of treatment. Thus, Du Toit et al concluded that the “risk of ischemic (low-flow) priapism from a range of atypical antipsychotics is aggravated by diabetes.”\n\nIn a letter to the editor, Harrison et al describe a 46-year-old African American/Native American man on mirtazepine and quetiapine who developed priapism requiring surgical intervention after taking amphetamines 24 to 48 hours prior to presentation.5,6\n\nThe case presented by Davol and Rukstalis provided the best evidence for therapeutic quetiapine alone as a cause of priapism.7 They described priapism in a 25-year-old African American man without a history of sickle cell disease or trait, who had been taking quetiapine for over a year, was taking no other medications, and received his medications at the prison infirmary.\n\nThe pharmacologic mechanism of drug-induced priapism is believed to be related to the blockade of alpha1 adrenoreceptors. Alpha-adrenergic blockade allows for relaxation of cavernosal trabecular smooth muscle resulting in engorgement of the corpora cavernosa. Examples of medications that act via this mechanism include yohimbine or delequamine.\n\nAntipsychotics are also believed to cause priapism by blocking alpha1 adrenoreceptors. A study of reports of antipsychotic-induced priapism in the United Sates Adverse Event Reporting System database found that high alpha1 affinty antipsychotics (quetiapine, chlorpromazine, risperidone, ziprasidone) were associated with priapism requiring medical intervention (reporting odds ratio 13.7; 10.1–18.5) while low and medium affinity antipsychotics such as loxapine, haloperidol, and aripiprazole were not associated with priapism requiring intervention (reporting odds ratio 2.2; 0.9–4.1).8\n\nOur patient developed recurrent priapism after taking relatively low (100 to 200 mg) doses of quetiapine. Transition to another antipsychotic resulted in resolution of symptoms. After not using quetiapine and being symptom free for over two years, the patient developed priapism after a single dose of quetiapine. The expected therapeutic serum steady-state level of quetiapine is 100–1000 ng/ml. While an intercavernosal level is not directly comparable to serum levels and serum levels were not measured in this case, the intracavernosal level of 502 ng/ml demonstrates the presence of quetiapine within the corpora after only a single dose.\n\nOne possible difficulty in interpretation of reported cases is that most cases of priapism due to quetiapine use are African American patients. All of the patients described denied a history of sickle cell disease or trait and any other symptoms consistent with such a history, yet none of the case patients were ever tested for sickle cell trait or disease. However, development of priapism during adulthood in sickle cell disease is uncommon: 75% of male sickle cell patients have the first occurrence of priapism before the age of 20 with a mean age of 12 to 15 years.9 In vitro studies of quetiapine metabolism have shown that quetiapine is metabolized by both CYP3A4 and to a lesser degree CYP3A5, which is expressed in 60% of African Americans versus only 10–30% of whites.10 This raises the possibility that priapism due to quetiapine use may be affected by differences in metabolism.\n\nKnowing that priapism is rare, practitioners may be unfamiliar with the standard therapeutic treatment plan for priapism. High-flow versus low-flow states may be established by history and physical exam, cavernosal blood gas or color duplex ultrasonography of the penis.11 High-flow priapism is most commonly caused by penile arterial laceration and resultant excessive inflow of arterial blood. Low-flow priapism presents with a painful erection, engorged corpora cavernosa and (in contrast to normal erection) a flaccid corpus spongiosum and glans penis. While the diagnosis and treatment of priapism is similar in both adults and children, causes of low-flow priapism that must be elucidated through careful history and physical examination in children include bleeding disorders, Kawasaki disease, leukemia, and sickle cell disease. For cases in which differentiating high- versus low-flow priapism is challenging, intracavernosal blood gas analysis will demonstrate arterial blood in high-flow priapism versus low pH, low oxygen tension, and high carbon dioxide in low-flow priapism.\n\nInitial treatment should include analgesia. Opioids and anxiolytics may be used parentally. A dorsal penile nerve block using local anesthesia using a wheal of lidocaine without epinephrine dorsally one centimeter distal to the pubic bone and scrotal insertion may be a helpful adjunct in pain control.\n\nTreatment of any primary disorder that may be causing the priapism is integral to the initial therapy. In sickle cell disease, this treatment includes hydration and oxygenation.\n\nFor high-flow priapism, arterial flow is maintained and there is no concern for immediate ischemia; as a result, a period of observation is appropriate prior to selective arterial embolization.12 Another option that has been attempted successfully in case reports includes applying direct pressure to the arteriovenous fistula under Doppler ultrasound guidance.13,14 Regardless, urologic consultation should be made from the ED and will likely guide treatment in high-flow priapism.\n\nFor low-flow priapism, the most proven treatment requires aspiration of cavernosal blood and direct caversonal injection of phenylephrine (or epinephrine in some reports).15,16 For phenylephrine, 1 mg of 1 mg/mL phenylephrine can be mixed into a syringe with either 9 or 99 cc of normal saline thereby creating a 100 mcg/1cc or 100 mcg/10cc concentration respectively.17 A butterfly needle should be placed perpendicularly to the penis into the corpora cavernosa (the two corpora cavernosa are connected and therefore only a single side approach is necessary). Five to 10 cc of blood should be aspirated using an empty syringe, and 100–200 mcg of phenyephrine should be injected. This can be repeated every 5–10 minutes to a maximum dose of 1000 mcg. Vital signs including blood pressure should be monitored, as some phenylephrine will be absorbed systemically. If aspiration fails, the next step is surgical intervention and the creation of a cavernosal-corpora spongiosa shunt.\n\nConsultation with a urologist is recommended in all cases of pediatric priapism, persistent low-flow priapism, and high-flow priapism. Patients with persistent priapism or underlying disorders such as leukemia or sickle cell disorder require inpatient hospitalization. If the priapism is treated successfully, then the patient can be observed and discharged home with urologic specialist follow-up as an outpatient.\n\nCONCLUSION\nUse of quetiapine continues to increase. While initially approved for schizophrenia, quetiapine is now approved for mania-associated bipolar disorder, and has also been used in the treatment of myriad disorders including depression, obsessive-compulsive disorder, post-traumatic stress disorder, restless leg syndrome, Tourette’s syndrome, and as a sedative. Given past case reports and our case of recurrent priapism, it is important that physicians come to recognize priapism as a serious side effect of quetiapine and are prepared to treat it appropriately when diagnosed.\n\nConflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.\n==== Refs\nREFERENCES\n1 Burnett AL Bivalacqua TJ Priapism: current principles and practice Urol Clin North Am 2007 631 642 viii 17983902 \n2 Ravindran AV Al-Subaie A Abraham G Quetiapine: novel uses in the treatment of depressive and anxiety disorders Expert Opin Investig Drugs 2010 19 1187 1204 \n3 Pais VM Ayvazian PJ Priapism from quetiapine overdose: first report and proposal of mechanism Urology 2001 462 \n4 du Toit RM Millson RC Heaton JP Priapism Can J Psychiatry 2004 49 868 869 \n5 Harrison G Dilley JW Loeb L Priapism and quetiapine in an HIV-positive male J Clin Psychopharmacol 2006 100 101 16415722 \n6 Harrison G Dilley JW Loeb L Priapism and quetiapine: a case report Psychopharmacol Bull 2006 39 117 119 17065976 \n7 Davol P Rukstalis D Priapism associated with routine use of quetiapine: case report and review of the literature Urology 2005 880 \n8 Andersohn F Schmedt N Weinmann S Priapism associated with antipsychotics: role of alpha1 adrenoceptor affinity J Clin Psychopharmacol 2010 68 71 20075651 \n9 Adeyoju AB Olujohungbe AB Morris J Priapism in sickle-cell disease; incidence, risk factors and complications - an international multicentre study BJU Int 2002 90 898 902 12460353 \n10 Bakken GV Rudberg I Christensen H Metabolism of quetiapine by CYP3A4 and CYP3A5 in presence or absence of cytochrome B5 Drug Metab Dispos 2009 37 254 258 19022943 \n11 Bassett J Rajfer J Diagnostic and therapeutic options for the management of ischemic and nonischemic priapism Rev Urol 2010 12 56 63 20428295 \n12 Kessler CS Bauml J Non-traumatic urologic emergencies in men: a clinical review West J Emerg Med 2009 10 281 287 20046251 \n13 Sancak T Conkbayir I Post-traumatic high-flow priapism: management by superselective transcatheter autologous clot embolization and duplex sonography-guided compression J Clin Ultrasound 2001 29 349 353 11424101 \n14 Imamoglu A Bakirtas H Conkbayir I An alternative noninvasive approach for the treatment of high-flow priapism in a child: duplex ultrasound-guided compression J Pediatr Surg 2006 41 446 448 16481268 \n15 Vilke GM Harrigan RA Ufberg JW Emergency evaluation and treatment of priapism J Emerg Med 2004 26 325 329 15028333 \n16 Roberts JR Price C Mazzeo T Intracavernous epinephrine: a minimally invasive treatment for priapism in the emergency department J Emerg Med 2009 36 285 289 18996674 \n17 Marx JA Hockberger RS Walls RM Rosen’s emergency medicine: concepts and clinical practice 7th ed Philadelphia Mosby/Elsevier 2010\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1936-900X",
"issue": "15(1)",
"journal": "The western journal of emergency medicine",
"keywords": null,
"medline_ta": "West J Emerg Med",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D004636:Emergency Service, Hospital; D006801:Humans; D008297:Male; D011317:Priapism; D011618:Psychotic Disorders; D000069348:Quetiapine Fumarate; D012008:Recurrence",
"nlm_unique_id": "101476450",
"other_id": null,
"pages": "114-6",
"pmc": null,
"pmid": "24578777",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16415722;16481268;20795889;16230163;11549503;12460353;15028333;19022943;18996674;20075651;11424101;15679220;17983902;17065976;20046251;20428295",
"title": "Recurrent priapism from therapeutic quetiapine.",
"title_normalized": "recurrent priapism from therapeutic quetiapine"
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{
"companynumb": "TR-ALKEM LABORATORIES LIMITED-TR-ALKEM-2018-07527",
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"activesubstancename": "QUETIAPINE FUMARATE"
},
... |
{
"abstract": "To highlight the role of azacytidine (AZA) in patients with myeloproliferative neoplasms developing blast phase (MPN-BP), we evaluated retrospectively 19 patients [M/F 15/4, median age 71.3 years, interquartile range (IQR) 64.5-77.7] reported in the database of our cooperative group. Median time from diagnosis to BP evolution was 52.7 months (IQR 11.2-181.8). All patients were treated with AZA at the standard dosage of 75 mg/m(2). Two patients died early after 5-AZA initiation from pulmonary fungal infection and respiratory failure respectively, 4 patients had a disease progression, 4 patients a stable disease, 3 patients had an hematological improvement, 1 patient a partial response and 5 pts (26.3%) a complete response (CR) after 4, 4, 4, 5, and 12 months. The median cumulative survival from BP evolution was 9.9 months (95%CI 6.6-13.1): the comparison with an historical cohort of 72 patients with MPN-BP treated with approaches other than AZA (median cumulative survival 3.1 months, 95%CI 1.1-5.0) showed a significant advantage for patients treated with AZA (p=0.02). Our data confirm the relative efficacy and safety of AZA in this group of patients with otherwise dismal prognosis, underlining the possible achievement of long-lasting responses in a sizeable portion of them.",
"affiliations": "UOSA di Ematologia, Ospedale Nuovo Regina Margherita, Roma, Italy. Electronic address: alessandro.andriani1@tin.it.;UOC di Ematologia, ASL VT, Viterbo, Italy.;Cattedra di Ematologia, Università Cattolica, Policlinico Gemelli, Roma, Italy.;UOSA di Ematologia, Ospedale Nuovo Regina Margherita, Roma, Italy.;UOC di Ematologia, Ospedale S. Maria Goretti, Latina, Italy.;UOS di Ematologia, Ospedale Santo Spirito, Roma, Italy.;UOC di Ematologia, ASL VT, Viterbo, Italy.;Cattedra di Ematologia, Università \"Tor Vergata\", Roma, Italy.;Cattedra di Ematologia, Università \"Tor Vergata\", Roma, Italy.;Dipartimento di ematologia e biotecnologie, Università \"La Sapienza\", Roma, Italy.;Dipartimento di ematologia e biotecnologie, Università \"La Sapienza\", Roma, Italy.",
"authors": "Andriani|Alessandro|A|;Montanaro|Marco|M|;Voso|Maria Teresa|MT|;Villivà|Nicoletta|N|;Ciccone|Fabrizio|F|;Andrizzi|Cristina|C|;De Gregoris|Cinzia|C|;Di Veroli|Ambra|A|;Maurillo|Luca|L|;Alimena|Giuliana|G|;Latagliata|Roberto|R|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-2126",
"issue": "39(8)",
"journal": "Leukemia research",
"keywords": "Azacytidine; Blastic phase; MPN",
"medline_ta": "Leuk Res",
"mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D001752:Blast Crisis; D018450:Disease Progression; D005260:Female; D006801:Humans; D054438:Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "7706787",
"other_id": null,
"pages": "801-4",
"pmc": null,
"pmid": "26065981",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Azacytidine for the treatment of retrospective analysis from the Gruppo Laziale for the study of Ph-negative MPN.",
"title_normalized": "azacytidine for the treatment of retrospective analysis from the gruppo laziale for the study of ph negative mpn"
} | [
{
"companynumb": "IT-CELGENE-083-50794-14010258",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
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"activesubstance": {
"activesubstancename": "AZACITIDINE"
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"drugadditional": null,
... |
{
"abstract": "Ciprofloxacin is increasingly used as oral suppressive therapy for musculoskeletal infections. Delirium and acute hypoglycemia are little-known, severe potential adverse drug reactions. We report here on a patient who experienced both complications. The patient is a 56-year-old woman with no psychiatric history who was managed for left lower extremity chronic osteomyelitis after fracture fixation. She developed significant, prolonged delirium and intermittent hypoglycemia within 24 hours of starting ciprofloxacin; both symptoms remitted within 24 hours of drug discontinuation.\n\n\n\nThe neuropsychiatric complications of ciprofloxacin are under-discussed, given its frequency of use, and merit greater awareness for the prevention of postoperative delirium.",
"affiliations": "Department of Orthopaedic Surgery, University of California, San Francisco, California.;Department of Orthopaedic Surgery, University of California, San Francisco, California.",
"authors": "Stroud|Sarah G|SG|;Kandemir|Utku|U|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin",
"country": "United States",
"delete": false,
"doi": "10.2106/JBJS.CC.19.00603",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2160-3251",
"issue": "10(2)",
"journal": "JBJS case connector",
"keywords": null,
"medline_ta": "JBJS Case Connect",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin; D003693:Delirium; D005260:Female; D006801:Humans; D008875:Middle Aged; D010019:Osteomyelitis; D051436:Renal Insufficiency, Chronic",
"nlm_unique_id": "101596828",
"other_id": null,
"pages": "e0603",
"pmc": null,
"pmid": "32243279",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Delirium Induced by Ciprofloxacin in a Patient With Chronic Kidney Disease: A Case Report.",
"title_normalized": "acute delirium induced by ciprofloxacin in a patient with chronic kidney disease a case report"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-283793",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYCODONE"
},
"drug... |
{
"abstract": "Objective Although modified FOLFIRINOX (mFOLFIRINOX, mFFX) is widely used for patients with advanced pancreatic ductal adenocarcinoma (PDAC), maintenance of the standard dose intensity is often difficult due to the high incidence of neutropenic events. Pegylated granulocyte colony-stimulating factor (G-CSF) (Peg G) is a long-lasting G-CSF agent that is applicable for prophylaxis against neutropenic complications. The aim of this study was to assess the clinical safety and efficacy of mFFX combined with secondary prophylaxis using Peg G in advanced PDAC patients. Methods Advanced PDAC patients who had received more than two cycles of mFFX were analyzed. The clinical safety and efficacy were compared between patients in the Peg G group and those in the non-Peg G group in a retrospective manner. Results Among 45 patients treated with mFFX, 28 exhibited grade 3-4 neutropenia or febrile neutropenia. Among these 28 patients, 4 who received only 1 or 2 mFFX cycles were excluded from this study. Finally, 11 patients in the Peg G group and 13 in the non-Peg G group were enrolled. The combination therapy with Peg G and mFFX markedly prolonged the progression-free survival compared with the non-Peg G group, and its effects were associated with a reduced incidence of neutropenic events as well as lower rates of dosage reduction, delayed chemotherapy due to neutropenic events and altered blood cell counts after chemotherapy. Conclusion The scheduled administration of secondary prophylactic Peg G prolonged the progression-free survival in patients treated with mFFX. The combination therapy of Peg G and mFFX may be recommended in patients who exhibit grade 3-4 neutropenic events after prior mFFX cycles.",
"affiliations": "Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan.;Clinical Research Center, Kindai University Hospital, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan.;Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan.",
"authors": "Yamao|Kentaro|K|;Takenaka|Mamoru|M|;Yoshikawa|Tomoe|T|;Ishikawa|Rei|R|;Okamoto|Ayana|A|;Yamazaki|Tomohiro|T|;Nakai|Atsushi|A|;Omoto|Shunsuke|S|;Kamata|Ken|K|;Minaga|Kosuke|K|;Hagiwara|Satoru|S|;Sakurai|Toshiharu|T|;Nishida|Naoshi|N|;Chiba|Yasutaka|Y|;Watanabe|Tomohiro|T|;Kudo|Masatoshi|M|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.2234-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3099616410.2169/internalmedicine.2234-18Original ArticleClinical Safety and Efficacy of Secondary Prophylactic Pegylated G-CSF in Advanced Pancreatic Cancer Patients Treated with mFOLFIRINOX: A Single-center Retrospective Study Yamao Kentaro 1Takenaka Mamoru 1Yoshikawa Tomoe 1Ishikawa Rei 1Okamoto Ayana 1Yamazaki Tomohiro 1Nakai Atsushi 1Omoto Shunsuke 1Kamata Ken 1Minaga Kosuke 1Hagiwara Satoru 1Sakurai Toshiharu 1Nishida Naoshi 1Chiba Yasutaka 2Watanabe Tomohiro 1Kudo Masatoshi 1\n1 Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan\n2 Clinical Research Center, Kindai University Hospital, JapanCorrespondence to Dr. Kentaro Yamao, yamaken_volvo@yahoo.co.jp\n\n17 4 2019 15 7 2019 58 14 1993 2002 4 10 2018 27 1 2019 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/).Objective \nAlthough modified FOLFIRINOX (mFOLFIRINOX, mFFX) is widely used for patients with advanced pancreatic ductal adenocarcinoma (PDAC), maintenance of the standard dose intensity is often difficult due to the high incidence of neutropenic events. Pegylated granulocyte colony-stimulating factor (G-CSF) (Peg G) is a long-lasting G-CSF agent that is applicable for prophylaxis against neutropenic complications. The aim of this study was to assess the clinical safety and efficacy of mFFX combined with secondary prophylaxis using Peg G in advanced PDAC patients. \n\nMethods \nAdvanced PDAC patients who had received more than two cycles of mFFX were analyzed. The clinical safety and efficacy were compared between patients in the Peg G group and those in the non-Peg G group in a retrospective manner. \n\nResults \nAmong 45 patients treated with mFFX, 28 exhibited grade 3-4 neutropenia or febrile neutropenia. Among these 28 patients, 4 who received only 1 or 2 mFFX cycles were excluded from this study. Finally, 11 patients in the Peg G group and 13 in the non-Peg G group were enrolled. The combination therapy with Peg G and mFFX markedly prolonged the progression-free survival compared with the non-Peg G group, and its effects were associated with a reduced incidence of neutropenic events as well as lower rates of dosage reduction, delayed chemotherapy due to neutropenic events and altered blood cell counts after chemotherapy. \n\nConclusion \nThe scheduled administration of secondary prophylactic Peg G prolonged the progression-free survival in patients treated with mFFX. The combination therapy of Peg G and mFFX may be recommended in patients who exhibit grade 3-4 neutropenic events after prior mFFX cycles. \n\npegylated G-CSFmFOLFIRINOXpancreatic cancer\n==== Body\nIntroduction\nPancreatic ductal adenocarcinoma (PDAC) has the worst survival rate among common cancers; the 3-year survival rate of unresectable PDAC is approximately 3% (1). The efficacy of FOLFIRINOX (FFX), a regimen consisting of leucovorin (I-LV), 5-fluorouracil (5-FU), irinotecan (CPT-11), and oxaliplatin (L-OHP), was first reported in 2011 for advanced-staged PDAC patients in a phase III trial (ACCORD-11) (2). Although FFX exhibited survival advantages compared with gemcitabine, more adverse events occurred in the FFX group than in the gemcitabine group (2). These adverse events included severe neutropenia [grade 3-4 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4. (3)] and febrile neutropenia (FN), both of which reduce the patients' quality of life. Indeed, grade 3-4 neutropenia and FN occurred in 37.3-77.8% and 5.4-22.2% of cases, respectively, in previous FFX trials in which patients did not receive prophylactic granulocyte colony-stimulating factor (G-CSF) (2, 4, 5). Such a high incidence of hematotoxicity by FFX prompted oncologists to develop a modified FFX regimen (mFFX) that lacks bolus 5-FU administration and has a decreased CPT-11 dose to reduce neutropenia and FN (6-10). It should be noted, however, that the incidences of grade 3-4 neutropenia and FN were comparable between mFFX and the original full-dose FFX trials in the absence of primary prophylactic G-CSF (11, 12). Furthermore, strong myelosuppressive effects, which often accompany the mFFX regimen, require clinicians to reduce the dosage and/or delay the administration of the next chemotherapy cycle (4, 8, 12). Maintaining the dose intensity (DI) and chemotherapy schedule is therefore important for maximizing the therapeutic effects.\n\nPegylated G-CSF (Peg G) is G-CSF that is applicable for prophylaxis against neutropenic complications. Peg G has a longer half-life than non-pegylated (conventional) G-CSF due to the conjugation of polyethylene glycol (13). Such long-lasting effects of G-CSF on hematopoietic stem cells have been shown to reduce the incidence of neutropenia and FN in patients undergoing moderate- or high-dose myelotoxic chemotherapy (14-24). The American Society of Clinical Oncology (ASCO) (25) and the European Organization for Research and Treatment of Cancer (EORTC) guidelines (26) have recently recommended secondary prophylaxis with G-CSF in patients who exhibit neutropenic events caused by prior cycles of chemotherapy or who require DI maintenance. The purpose of chemotherapy combined with prophylactic G-CSF is to prevent neutropenic events and to ensure that chemotherapy is performed safely and on schedule without dose reductions. In this regard, chemotherapy combined with prophylactic Peg G may prolong the progression-free survival (PFS) and overall survival (OS), as the long-lasting effects of G-CSF by pegylation lead to sustained numbers of functional hematopoietic cells. In fact, the PFS in patients with hematological malignancies was improved by prophylactic Peg G (27, 28). However, the clinical safety and efficacy of secondary prophylactic Peg G for mFFX in PDAC remain to be studied.\n\nIn this study, we retrospectively investigated the clinical safety and efficacy of mFFX combined with secondary prophylaxis with Peg G in PDAC patients. We explored whether or not combination therapy with mFFX and Peg G prolonged the PFS in PDAC patients who exhibited neutropenic events in previous mFFX cycles.\n\nMaterials and Methods\nPatients\nA total of 336 PDAC patients at Kindai University Hospital between January 2014 and July 2018 were identified by medical records. Patients were enrolled if they met all of the following criteria: 1) a pathological PDAC diagnosis; 2) PDAC considered unresectable due to tumor progression; and 3) received more than 2 mFFX cycles and exhibited grade 3-4 neutropenia as defined by ＜1,000 neutrophils per mm3 and/or FN. Patients were excluded if they met any of the following criteria: 1) received full-dose FFX; 2) received 1 or 2 mFFX cycles and had a neutrophil count ＜2,000 per mm3 before mFFX; or 3) had uridine diphosphate glucuronosyltransferase (UGT) A1 genetic polymorphisms (homozygous UGT1A1*28 or UGT1A1＊6 or heterozygous UGT1A1*6 or UGT1A1＊28) (29, 30).\n\nThis was a retrospective study, and ethical permission for its performance was obtained from the Review Boards of Kindai University Faculty of Medicine (Registration number: 29-141).\n\nThe mFOLFIRINOX regimen\nPatients were treated with mFFX every 2 weeks as follows: L-OHP (85 mg/m2), I-LV (200 mg/m2) and CPT-11 (150 mg/m2) on day 1, and then 5-FU (2,400 mg/m2) on days 1, 2, and 3. Prior to L-OHP administration, the 5-hydroxytryptamine (HT) receptor antagonist dexamethasone and a selective neurokinin 1 receptor antagonist were given to all patients for nausea and vomiting. Patients received the mFFX regimen repeatedly, and treatment was repeated unless serious toxicity was observed; discontinuation was decided by the investigators.\n\nAdministering Peg G and dose reductions in the mFOLFIRINOX-Peg G group\nPeg G (3.6 mg) administration was initiated 24-72 hours after the 5-FU infusion of the cycle following the observation of a grade 3-4 neutropenic event (neutropenia or FN) in a previous mFFX cycle. Patients who received Peg G were defined as the mFFX-Peg G group (Peg G group). Peg G administration was left to the discretion of each physician and was continued until the final mFFX cycle. Dose reductions of chemotherapeutic agents were performed when grade 3-4 neutropenic events occurred despite Peg G administration or when other adverse events, such as thrombocytopenia, anemia, diarrhea, mucositis, hand and foot syndrome, elevated total bilirubin, or neuropathy, were observed.\n\nDose reductions were carried out based on the modified criteria of Conroy et al. (2) (Supplementary material). The details of dose reductions and the criteria for reductions are shown in the Supplementary material. In brief, dose reductions of chemotherapeutic agents were performed based on hematological and non-hematological toxicities. Toxicities were assessed using the National Cancer Institute CTCAE, version 4, as described previously (3). In cases of hematological toxicities, dose reductions were performed in accordance with the criteria shown in Supplementary Tables 1 and 2. In cases of non-hematological toxicities, dose reductions were performed in accordance with the criteria shown in Supplementary Table 3. Chemotherapy was delayed until the recovery status met all of the following criteria: neutrophil count ＞1,500 per mm3, platelet count ＞75,000 per mm3, total bilirubin ＜1.5 mg/dL, grade ≤ 2 peripheral sensory neuropathy, and grade ≤ 2 diarrhea and watery stool.\n\nDose reductions in the mFOLFIRINOX-non-Peg G group\nIn response to various adverse events, including neutropenic events, dose reductions of chemotherapeutic agents were performed without secondary prophylactic Peg G; this group was defined as the mFFX-non-Peg G group (non-Peg G group). The application criteria of dose reductions and delays were the same as for the Peg G group described above (Supplementary Table 1-3).\n\nThe PFS and OS\nTo clarify the therapeutic effects of secondary prophylactic Peg G in advanced PDAC patients treated with mFFX, we compared the PFS and OS between the Peg G and non-Peg G groups. The PFS was defined as the time from the initiation of the third cycle to the earliest date of disease progression or death. Cases were censored when tumors were reduced in size enough to allow surgery. The OS was defined as the time from the initiation of the third cycle to death from any cause.\n\nProportion of adverse events\nThe incidence of adverse events, dose reductions, chemotherapy delays, and hospitalizations due to adverse events were compared between the Peg G and non-Peg G groups. The proportion of dose reductions was defined as the proportion of patients who needed dose reductions after the third mFFX cycle. The proportion of chemotherapy delays was defined as the proportion of patients whose chemotherapy could not be started on the prescribed start date after the third cycle. The proportion of hospitalizations was defined as the proportion of patients requiring hospital admission after the third cycle.\n\nCalculating the relative dose intensity (RDI) for each cycle\nThe RDI in each cycle was calculated as the ratio of the actual DI in each cycle to the planned DI, as follows: RDI in each cycle (%) = actual dose in each cycle (mg/m2) / planned dose (mg/m2) ×100 (%).\n\nChanges in blood cell counts\nPeripheral blood cell counts were compared with the absolute blood cell counts on day 1 of each cycle. Numbers of white blood cells (WBCs), neutrophils, monocytes, lymphocytes, basophils, eosinophils, and platelets were determined as previously described (31).\n\nStatistical analyses\nCategorical variables were summarized as the number of events and proportions (%), and p values are calculated using Fisher's exact test. Continuous variables were summarized as the means (± standard error), and p values were calculated using Wilcoxon's rank sum test. Time-to-event variables (OS and PFS) were assessed using the Kaplan-Meier method, and p values were calculated using the log-rank test. All statistical analyses were performed using GraphPad Prism v.5 software program (GraphPad Software, San Diego, USA).\n\nResults\nPatient characteristics\nThe details of patient selection and clinical characteristics of the enrolled cohort are shown in Fig. 1 and Table 1. Grade 3-4 neutropenia or FN occurred in 28 of the 45 PDAC patients who received mFFX. Among these 28 patients, 12 received Peg G (Peg G group), and 16 did not (non-Peg G group). One in the Peg G group and three in the non-Peg G group received only one or two mFFX cycles and were excluded from this study. Ultimately, 11 patients in the Peg G group and 13 in the non-Peg G group were included in the final analysis (Fig. 1).\n\nFigure 1. Study flow chart. Forty-five advanced pancreatic ductal adenocarcinoma (PDAC) patients received mFOLFIRINOX (mFFX), with 28 (62.2%) exhibiting grade 3-4 neutropenia or febrile neutropenia (FN). Twelve of these patients were treated with pegylated G-CSF (Peg G group), and 16 were not (non-Peg G group). One patient in the Peg G group and three in the non-Peg G group received only one or two mFFX cycles and were excluded. Ultimately, 11 patients in the Peg G group and 13 in the non-Peg G group were included in the final analysis.\n\nTable 1. Patient Characteristics.\n\n\tPeg G group (n=11)\tNon-Peg G group (n=13)\tp value\t\nSex, n (%)\t\t\t\t\nMale\t8 (72.7)\t11 (84.6)\t0.83\t\nFemale\t3 (27.2)\t2 (15.4)\t\t\nAge, years\t\t\t\t\nMedian (range)\t66 (53-74)\t64 (52-70)\t0.26\t\nECOG performance status, n (%)\t\t\t\t\n0\t7 (63.6)\t9 (69.2)\t0.88\t\n1\t4 (36.3)\t4 (30.8)\t\t\nTumor location, n (%)\t\t\t\t\nHead\t3 (27.2)\t4 (30.8)\t0.94\t\nBody\t3 (27.2)\t3 (23.1)\t\t\nTail\t2 (18.2)\t1 (7.7)\t\t\nResected\t3 (27.2)\t5 (38.5)\t\t\nBody surface area\t\t\t\t\nMedian (range)\t1.58 (1.21-1.91)\t1.73 (1.51-2.0)\t0.14\t\nUICC stage, n (%)\t\t\t\t\nIII (Locally advanced)\t3 (27.2)\t1 (7.7)\t0.46\t\nIV (Metastatic)\t8 (72.7)\t12 (92.3)\t\t\nMetastatic sites, n (%)\t\t\t\t\nNo metastasis\t3 (27.2)\t1 (7.7)\t0.17\t\nLiver\t6 (54.5)\t5 (38.5)\t\t\nOther site\t2 (18.2)\t7 (53.8)\t\t\nBaseline neutrophil count\t\t\t\t\nMedian (range)\t2,543 (2,790-10,400)\t3,884 (1,577-8,484)\t0.31\t\nCEA at start of FOLFIRINOX\t\t\t\t\nMedian (range)\t3.3 (1.2-226)\t4.2 (1.6-37.2)\t0.29\t\nCA19-9 at start of FOLFIRINOX\t\t\t\t\nMedian (range)\t63 (4-83,895)\t458 (9-50,081)\t0.38\t\n\nUGT1A1 (*6 /*28), n (%)\t\t\t\t\nWild-type/wild-type\t5 (45.5)\t6 (46.2)\t1.00\t\nWild-type/heterozygous\t4 (36.3)\t5 (38.5)\t\t\nHeterozygous/wild-type\t2 (18.2)\t2 (15.4)\t\t\nmFOLFIRINOX cycles\t\t\t\t\nMedian (range)\t9 (4-27)\t7 (3-16)\t0.11\t\nChemotherapy, n (%)\t\t\t\t\nFirst line\t3 (27.2)\t5 (38.5)\t0.86\t\nSecond line\t6 (54.5)\t7 (53.8)\t\t\nThird line\t2 (18.1)\t1 (7.7)\t\t\nThe characteristics of the patients in the Peg G and non-Peg G groups are shown in Table 1. The peripheral blood neutrophil count before mFFX was significantly lower in the Peg G group than in the non-Peg G group, but no significant differences were found between the two groups regarding age, sex, performance status, tumor location, tumor stage, serum levels of carcinoembryonic antigen (CEA) and CA19-9, or UGT1A1 polymorphisms. The median number of mFFX cycles was 8 (range: 4-36) in the Peg G group and 7 (range: 3-17) in the non-Peg G group. In the Peg G group, 11 and 4 patients exhibited grade 3-4 neutropenia and/or FN in the first and second cycles, respectively. Peg G administration was initiated in the third cycle and continued to the end of treatment in all cases in the Peg G group.\n\nThe PFS and OS after the third chemotherapy cycle\nTo assess the clinical efficacy of combined mFFX and Peg G, we first estimated the PFS and OS after the third chemotherapy cycle in the Peg G and non-Peg G groups. As shown in Fig. 2A, the median PFS after the third chemotherapy cycle in the Peg G-group was 7.0 months, whereas that of the non-Peg G group was 3.1 months. Thus, the combination therapy markedly prolonged the PFS compared with mFFX alone (p=0.02). mFFX was continued in four Peg G patients after the observation period, and one Peg G patient underwent surgical resection after their eighth cycle because of a massive reduction in their primary tumor.\n\nFigure 2. Kaplan-Meier curves of the progression-free survival and overall survival after the third chemotherapy cycle. The progression-free survival (PFS, A) and overall survival (OS, B) in pancreatic ductal adenocarcinoma patients treated with (Peg G group) or without (non-Peg G group) pegylated G-CSF (Peg G). The PFS in the Peg G group was significantly longer than in the non-Peg G group; *p<0.05.\n\nIn the Peg G group, the median OS was not reached after the third chemotherapy cycle (survival rates at 6 and 12 months were 81.8% and 72.7%, respectively), and 7 patients were still alive at the end of the observation period. Conversely, in the non-Peg G group, the median OS after the third chemotherapy cycle was 10.0 months, and only 1 patient was still alive. As shown in Fig. 2B, the OS in the Peg G group was better than that in the non-Peg G group, although this difference was not statistically significant (p=0.19).\n\nTaken together, these results strongly suggest that combination therapy with mFFX and Peg G prolonged the PFS in PDAC patients.\n\nAdverse hematological events after the third chemotherapy cycle\nWe next compared incidences of adverse hematological events, as hematotoxicity is a major adverse event of mFFX (11, 12). As shown in Table 2, 11 cases (84.6%) of neutropenic events, including 8 cases of grade 3-4 neutropenia and 3 cases of FN, were seen in the non-Peg G group after the third chemotherapy cycle, while neutropenia was only observed in 1 patient (9.1%) with no patients exhibiting grade 3-4 neutropenia or FN in the Peg G group. Thus, the incidence of neutropenic events was much lower in the Peg G group than in the non-Peg G group (0% vs. 61.5%; p＜0.01).\n\nThe incidence of grade 3-4 thrombocytopenia was comparable between the Peg G and non-Peg G groups. Severe anemia (grade 3-4) was not observed after the third chemotherapy cycle in either group. Thus, scheduled Peg G administration prevented the development of mFFX-induced neutropenia and FN.\n\nTable 2. Hematological and Non-hematological Adverse Events after the Third Chemotherapy Cycle.\n\n\tPeg G group (n=11)\tNon-Peg G group (n=13)\tp value\t\nAll grades\tGrade 3-4\tAll grades\tGrade 3-4\tGrade 3-4\t\nHematological event\t\t\t\t\t\t\nNeutropenia\t1 (9.1)\t0 (0)\t11 (84.6)\t8 (61.5)\t<0.01\t\nFebrile neutropenia\t0 (0)\t0 (0)\t3 (23.1)\t3 (23.1)\t0.28\t\nThrombocytopenia\t4 (36.3)\t2 (18.2)\t5 (38.5)\t0 (0)\t0.39\t\nAnemia\t2 (18.2)\t0 (0)\t1 (7.7)\t0 (0)\tNA\t\nNon-hematological event\t\t\t\t\t\t\nAnorexia\t7 (63.4)\t0 (0)\t10 (76.9)\t0 (0)\tNA\t\nFatigue\t8 (72.7)\t1 (9.1)\t7 (53.8)\t2 (15.4)\t0.93\t\nNausea\t4 (36.3)\t1 (9.1)\t6 (46.2)\t1 (9.1)\t0.54\t\nVomiting\t0 (0)\t0 (0)\t0 (0)\t0 (0)\tNA\t\nDiarrhea\t6 (54.5)\t2 (18.2)\t6 (46.2)\t3 (23.1)\t0.83\t\nMucositis\t1 (9.1)\t0 (0)\t3 (23.1)\t0 (0)\tNA\t\nNeuropathy\t5 (54.5)\t2 (18.2)\t6 (46.2)\t2 (15.4)\t0.71\t\nHyperglycemia\t1 (9.1)\t1 (9.1)\t0 (0)\t0 (0)\t0.89\t\nNon-hematological adverse events after the third chemotherapy cycle\nNon-hematological adverse events after the third mFFX cycle are listed in Table 2. Anorexia, fatigue, nausea, diarrhea, and neuropathy were observed in approximately 40-70% of cases in both groups. There was no significant difference in the incidence of non-hematological adverse events between the two groups. No side effects related to Peg G were observed in the 11 patients in the Peg G group in this study.\n\nDose reductions, chemotherapy delays, and hospitalizations after the third chemotherapy cycle\nThe numbers and percentages of patients who required dose reductions, chemotherapy delays, and hospitalizations after the third chemotherapy cycle are shown in Table 3. Four patients (36.3%) in the Peg G group required dose reductions: 2 because of thrombocytopenia and 2 because of neuropathy. Chemotherapy was delayed in three of these four patients (for the same reasons). Eight patients (61.5%) in the non-Peg G group required dose reductions and chemotherapy delays because of neutropenic events: 6 because of neutropenia and 2 because of FN. Thus, the incidences of dose reductions and chemotherapy delays were lower in the Peg G group than in the non-Peg G group, probably because scheduled Peg G administration effectively prevented neutropenia and FN development. Of note, the incidence of dose reductions and chemotherapy delays due to neutropenic events was significantly different between the two groups.\n\nTable 3. Dose Reductions, Chemotherapy Delays and Hospitalizations after the Third Chemotherapy Cycle.\n\n\tPeg G group (n=11)\tNon-Peg G group (n=13)\tp value\t\nDose reductions for any reason\t4 (36.3)\t8 (61.5)\t0.41\t\nDose reductions because of neutropenic events*\t0 (0)\t8 (61.5)\t<0.01\t\nDose delays for any reason\t3 (27.2)\t8 (61.5)\t0.20\t\nDose delays because of neutropenic events*\t0 (0)\t8 (61.5)\t<0.01\t\nHospitalizations for any reason\t1 (9.1)\t5 (38.5)\t0.24\t\nHospitalizations for neutropenic events*\t0 (0)\t2 (15.4)\t0.54\t\n*Neutropenia and febrile neutropenia\n\nOne patient (9.1%) in the Peg G group required hospitalization because of hyperglycemia, whereas 5 (38.5%) in the non-Peg G group required hospitalization. The reasons for hospitalization in the non-Peg G group included FN (two cases), cholangitis without a neutropenic event (one case), small bowel obstruction due to tumor invasion (one case), and cerebral infarction (one case). Collectively, these data suggest that combination therapy of mFFX and Peg G reduced the incidences of dose reductions, chemotherapy delays, and hospitalizations by preventing neutropenic events.\n\nRDI of chemotherapeutic agents\nWe next compared the RDI in each cycle between the Peg G and non-Peg G groups. As shown in Fig. 3, no significant difference was seen in the RDI of L-OHP, I-LV, or 5-FU between these two groups throughout the observation period. In contrast, the RDI of CPT-11 was significantly higher in the Peg G group than in the non-Peg G group at the 6th-9th chemotherapy cycles. These RDI data suggest that the prolonged PFS of PDAC patients treated with both mFFX and Peg G was associated with a higher CPT-11 RDI.\n\nFigure 3. Changes in the relative dose intensity at each mFOLFIRINOX cycle. The relative dose intensities (RDIs) of the four chemotherapeutic agents of mFFX were determined at each chemotherapy cycle. The RDIs for leucovorin (I-LV), 5-fluorouracil (5-FU), irinotecan (CPT-11), and oxaliplatin (L-OHP) are shown. Results are shown as the mean ± standard error; *p<0.05.\n\nAltered blood cell counts after chemotherapy\nAs scheduled Peg G administration markedly reduced neutropenic events and maintained the CPT-11 RDI, we next determined the effects of Peg G on the numbers of peripheral blood hematopoietic cells. As shown in Fig. 4A and B, the numbers of WBCs and neutrophils were significantly higher in the Peg G group than in the non-Peg G group throughout the observation period. Interestingly, the numbers of monocytes were also significantly higher in the Peg G group than in the non-Peg G group throughout the observation period (Fig. 4C). In contrast, no significant differences were seen in the numbers of lymphocytes, basophils, eosinophils, or platelets between the two groups (Fig. 4D-G). Thus, scheduled Peg G administration sustained the numbers of peripheral blood neutrophils and monocytes but not lymphocytes. Together, these data suggest that the sustained numbers of peripheral blood neutrophils and monocytes induced by Peg G are associated with a prolonged PFS in PDAC patients treated with mFFX due to maintenance of the high RDI of CPT-11.\n\nFigure 4. Changes in peripheral blood hematopoietic cells at each mFOLFIRINOX cycle. Numbers of peripheral blood white blood cells (WBCs), neutrophils, monocytes, lymphocytes, basophils, eosinophils, and platelets are shown. Results are shown as the mean ± standard error; *p<0.05.\n\nDiscussion\nIn this study, we showed that scheduled secondary prophylactic Peg G administration prolonged the PFS in advanced PDAC patients treated with mFFX. The prolonged PFS due to scheduled Peg G administration was accompanied by sustained numbers of peripheral blood neutrophils and monocytes, which might prevent neutropenic events as well as allow for a high RDI of CPT-11, a key component of the mFFX regimen.\n\nShort-half-life G-CSF (non-pegylated) is widely used as a supportive therapy for recovery from neutropenia and FN in cancer patients receiving moderate- or high-dose myelotoxic agents (15, 32). The clinical guidelines from the ASCO and EORTC recommend primary prophylaxis with G-CSF when a patient's overall FN risk is greater than 20%. In addition to primary prophylaxis, secondary prophylaxis with G-CSF is recommended when patients experience neutropenic events from prior chemotherapy cycles and require high-level RDIs to obtain maximal therapeutic effects from chemotherapy (25, 26). It is generally established that maximal therapeutic effects of chemotherapy can be obtained by preventing adverse effects, such as neutropenia and FN, as well as by maintaining high RDIs. The scheduled secondary administration of prophylactic Peg G may be attractive for preventing neutropenic events, as this treatment leads to sustained numbers of peripheral blood neutrophils through the long-lasting effects of G-CSF (13). Indeed, scheduled Peg G administration prolonged the PFS in patients with hematological malignancies (27, 28). Although the mFFX regimen is widely used because of its efficacy in PDAC patients, dose reductions and/or chemotherapy delays are often required due to the high incidence of adverse events, especially neutropenia and FN. In this study, we tried to retrospectively determine the clinical safety and efficacy of scheduled secondary prophylactic Peg G administration in PDAC patients who received mFFX. Surprisingly, we found that scheduled Peg G administration markedly reduced the incidences of neutropenic events associated with mFFX due to the sustained numbers of peripheral blood neutrophils and ultimately prolonged the PFS (Table 2 and Fig. 2A). Previous reports have shown that repeated Peg G administration caused severe adverse events specific to Peg G, such as spontaneous splenic rupture (33), musculoskeletal pain (34-38), and interstitial pneumonia. These severe adverse effects were not observed in the Peg G group in this study.\n\nTo our knowledge, this is the first report to show the clinical advantages of scheduled Peg G administration in mFFX-treated PDAC patients. The OS was also longer in the Peg G group than in the non-Peg G group, although this was not statistically significant. However, it should be noted that a significant number of patients in the Peg G group continued mFFX after the observation period, whereas most of the patients in the non-Peg G group died. Therefore, it may be too early to determine the OS in this study. Whether or not scheduled Peg G administration prolongs not only the PFS but also the OS will be explored in our ongoing, large-scale prospective study.\n\nAchieving the planned RDI is important for obtaining the maximum therapeutic effects of chemotherapy (39). In fact, a high chemotherapy RDI has been shown to be associated with improved clinical outcomes in a few previous reports (40, 41). Consistent with this idea, the RDI of a key mFFX component, CPT-11, showed higher trends in the Peg G group than in the non-Peg G group (Fig. 3). In contrast, the RDIs of the other three components-L-OHP, I-LV, and 5-FU-were comparable between the two groups. The higher CPT-11 RDI may be explained by the fact that dose reductions of CPT-11 are required upon encountering neutropenia and FN (Supplementary Table 2). Therefore, it is likely that preventing neutropenia and FN through scheduled Peg G administration resulted in a prolonged PFS for PDAC patients partially through the achievement of a higher CPT-11 RDI.\n\nAs expected, scheduled Peg G administration induced an expansion of peripheral blood neutrophils throughout the observation period. Our extensive analysis regarding changes in the peripheral blood immune cell subpopulations revealed that scheduled Peg G administration led to expansions of neutrophils and monocytes but not lymphocytes, basophils, or eosinophils (Fig. 4). Thus, sustained numbers of peripheral blood neutrophils and monocytes are a characteristic alteration of peripheral blood immune cells associated with scheduled Peg G administration. It is without a doubt that the Peg G-mediated expansion of neutrophils contributed to the clinical advantage and maintenance of high RDIs in this study. However, whether or not the prolonged PFS observed in this study can be solely attributed to the ability to maintain high-level RDIs is unclear.\n\nIn this regard, the Peg G-induced expansion of peripheral blood neutrophils and monocytes prompted us to speculate that long-lasting G-CSF might promote the differentiation of myeloid cells with potent antitumor immunity. Tumor-infiltrating myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), both of which are characterized by the capacity to suppress T and natural killer (NK) cell cancer immune surveillance, promote cancer progression (42, 43). In fact, MDSCs and TAMs are key players in the pancreatic cancer microenvironment that support tumor progression and dissemination (44, 45). Monocytes are immature myeloid cells that can differentiate into macrophages and dendritic cells (46, 47). Cytokines and chemokines released into the cancer microenvironment regulate the differentiation of monocytes into M1 macrophages and M2 macrophages, with tumor-suppressive and tumor-promoting activities, respectively (42-47). Given the fact that scheduled Peg G administration led to an expansion of not only neutrophils but also monocytes, it would be interesting to see which types of macrophages (M1 vs. M2) accumulated in the tumors of PDAC patients treated with mFFX and Peg G.\n\nTwo concerns need to be addressed before the scheduled administration of secondary prophylactic Peg G is applied to PDAC patients treated with mFFX. First, the cost of repeated Peg G administration cannot be ignored, as it is an expensive agent. For this reason, Peg G application as primary prophylaxis may not be feasible for all patients receiving mFFX. Second, patients are usually required to revisit the hospital for Peg G administration. To overcome this issue, Peg G has been administered on the same day as chemotherapy in some clinical trials, which resulted in a higher incidence of FN than with administration a few days after completing chemotherapy (48, 49).\n\nDespite the careful and intense analysis performed in this study, some limitations bear mentioning, and we need to be cautious regarding the interpretation of the results in this study. First, this was a non-randomized, retrospective study. Second, the sample size was relatively small. Therefore, a prospective study with a larger number of patients is required to verify that the scheduled administration of secondary prophylactic Peg G prolongs the PFS in mFFX-treated PDAC patients. Third, the administration of Peg G depended on each physician's decision in this study. There might therefore have been some degree of selection bias for the patients. Whether or not mFFX combined with Peg G prolongs the PFS and/or OS in patients with advanced PDAC should be explored in prospective studies enrolling a large number of patients.\n\nIn conclusion, the scheduled administration of secondary prophylactic Peg G prolonged the PFS in PDAC patients treated with the mFFX regimen by preventing dose reductions and chemotherapy delays. The RDI of a key mFFX component, CPT-11, was maintained at high levels due to the sustained numbers of neutrophils in PDAC patients who received scheduled Peg G administration. The scheduled administration of secondary prophylactic Peg G may be recommended for PDAC patients who exhibit grade 3-4 neutropenic events after previous mFFX cycles.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nSupplementary Material\nDose adjustment guidelines for toxicity Click here for additional data file.\n\n Acknowledgement\nWe thank Hitoshi Imaoka for editing a draft of this manuscript.\n==== Refs\n1. \nEgawa S , Toma H , Ohigashi H , et al \nJapan Pancreatic Cancer Registry; 30th year anniversary: Japan Pancreas Society . Pancreas \n41 : 985 -992 , 2012 .22750974 \n2. \nConroy T , Desseigne F , Ychou M , et al \nFOLFIRINOX versus gemcitabine for metastatic pancreatic cancer . N Engl J Med \n364 : 1817 -1825 , 2011 .21561347 \n3. \nNational Cancer Institute Common Terminology Criteria for Adverse Events v.\nhttps://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf\n\n4. \nOkusaka T , Ikeda M , Fukutomi A , et al \nPhase II study of FOLFIRINOX for chemotherapy-naive Japanese patients with metastatic pancreatic cancer . Cancer Sci \n105 : 1321 -1326 , 2014 .25117729 \n5. \nChllamma MK , Cook N , Dhani NC , et al \nFOLFIRINOX for advanced pancreatic cancer: the Princess Margaret Cancer Centre experience . Br J Cancer \n115 : 649 -654 , 2016 .27467054 \n6. \nBai X , Su R , Ma T , et al \nModified FOLFIRINOX for advanced pancreatic cancer: a tertiary center experience from China . Zhonghua Wai Ke Za Zhi [Chinese Journal of Surgery] \n54 : 270 -275 , 2016 (in Chinese, Abstract in English).\n7. \nBlazer M , Wu C , Goldberg RM , et al \nNeoadjuvant modified (m) FOLFIRINOX for locally advanced unresectable (LAPC) and borderline resectable (BRPC) adenocarcinoma of the pancreas . Ann Surg Oncol \n22 : 1153 -1159 , 2015 .25358667 \n8. \nGhorani E , Wong HH , Hewitt C , Calder J , Corrie P , Basu B \nSafety and efficacy of modified FOLFIRINOX for advanced pancreatic adenocarcinoma: a UK single-centre experience . Oncology \n89 : 281 -287 , 2015 .26372905 \n9. \nStein SM , James ES , Deng Y , et al \nFinal analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer . Br J Cancer \n114 : 737 -743 , 2016 .27022826 \n10. \nUmemura A , Nitta H , Sasaki A , Takahara T , Hasegawa Y , Wakabayashi G \nModified FOLFIRINOX for locally advanced and metastatic pancreatic cancer patients resistant to gemcitabine and S-1 in Japan: a single institutional experience . Hepatogastroenterology \n61 : 814 -820 , 2014 .26176079 \n11. \nLi X , Ma T , Zhang Q , et al \nModified-FOLFIRINOX in metastatic pancreatic cancer: a prospective study in Chinese population . Cancer Lett \n406 : 22 -26 , 2017 .28729048 \n12. \nYoshida K , Iwashita T , Uemura S , et al \nA multicenter prospective phase II study of first-line modified FOLFIRINOX for unresectable advanced pancreatic cancer . Oncotarget \n8 : 111346 -111355 , 2017 .29340058 \n13. \nYang BB , Kido A \nPharmacokinetics and pharmacodynamics of pegfilgrastim . Clin Pharmacokinet \n50 : 295 -306 , 2011 .21456630 \n14. \nVose JM , Crump M , Lazarus H , et al \nRandomized, multicenter, open-label study of pegfilgrastim compared with daily filgrastim after chemotherapy for lymphoma . J Clin Oncol \n21 : 514 -519 , 2003 .12560443 \n15. \nVogel CL , Wojtukiewicz MZ , Carroll RR , et al \nFirst and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study . J Clin Oncol \n23 : 1178 -1184 , 2005 .15718314 \n16. \nPinter T , Klippel Z , Cesas A , et al \nA phase III, randomized, double-blind, placebo-controlled trial of pegfilgrastim in patients receiving first-line FOLFOX/bevacizumab or FOLFIRI/bevacizumab for locally advanced or metastatic colorectal cancer: final results of the pegfilgrastim and anti-VEGF evaluation study (PAVES) . Clin Colorectal Cancer \n16 : 103 -114.e103 , 2017 .28038865 \n17. \nNaeim A , Henk HJ , Becker L , et al \nPegfilgrastim prophylaxis is associated with a lower risk of hospitalization of cancer patients than filgrastim prophylaxis: a retrospective United States claims analysis of granulocyte colony-stimulating factors (G-CSF) . BMC Cancer \n13 : 11 , 2013 .23298389 \n18. \nKosaka Y , Rai Y , Masuda N , et al \nPhase III placebo-controlled, double-blind, randomized trial of pegfilgrastim to reduce the risk of febrile neutropenia in breast cancer patients receiving docetaxel/cyclophosphamide chemotherapy . Support Care Cancer \n23 : 1137 -1143 , 2015 .25576433 \n19. \nHolmes FA , O'Shaughnessy JA , Vukelja S , et al \nBlinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer . J Clin Oncol \n20 : 727 -731 , 2002 .11821454 \n20. \nHolmes FA , Jones SE , O'Shaughnessy J , et al \nComparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer . Ann Oncol \n13 : 903 -909 , 2002 .12123336 \n21. \nGrigg A , Solal-Celigny P , Hoskin P , et al \nOpen-label, randomized study of pegfilgrastim vs. daily filgrastim as an adjunct to chemotherapy in elderly patients with non-Hodgkin's lymphoma . Leuk Lymphoma \n44 : 1503 -1508 , 2003 .14565651 \n22. \nGreen MD , Koelbl H , Baselga J , et al \nA randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy . Ann Oncol \n14 : 29 -35 , 2003 .12488289 \n23. \nBondarenko I , Gladkov OA , Elsaesser R , Buchner A , Bias P \nEfficacy and safety of lipegfilgrastim versus pegfilgrastim: a randomized, multicenter, active-control phase 3 trial in patients with breast cancer receiving doxorubicin/docetaxel chemotherapy . BMC Cancer \n13 : 386 , 2013 .23945072 \n24. \nBalducci L , Al-Halawani H , Charu V , et al \nElderly cancer patients receiving chemotherapy benefit from first-cycle pegfilgrastim . Oncologist \n12 : 1416 -1424 , 2007 .18165618 \n25. \nSmith TJ , Bohlke K , Lyman GH , et al \nRecommendations for the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline Update . J Clin Oncol \n33 : 3199 -3212 , 2015 .26169616 \n26. \nAapro MS , Bohlius J , Cameron DA , et al \n2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours . Eur J Cancer \n47 : 8 -32 , 2011 .21095116 \n27. \nPfreundschuh M , Trumper L , Kloess M , et al \nTwo-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL . Blood \n104 : 634 -641 , 2004 .15016643 \n28. \nGruber M , Fleiss K , Porpaczy E , et al \nProlonged progression-free survival in patients with chronic lymphocytic leukemia receiving granulocyte colony-stimulating factor during treatment with fludarabine, cyclophosphamide, and rituximab . Ann Hematol \n90 : 1131 -1136 , 2011 .21617923 \n29. \nYamamoto N , Takahashi T , Kunikane H , et al \nPhase I/II pharmacokinetic and pharmacogenomic study of UGT1A1 polymorphism in elderly patients with advanced non-small cell lung cancer treated with irinotecan . Clin Pharmacol Ther \n85 : 149 -154 , 2009 .18685565 \n30. \nMinami H , Sai K , Saeki M , et al \nIrinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1*6 and ＊28 . Pharmacogenet Genomics \n17 : 497 -504 , 2007 .17558305 \n31. \nChung H , Watanabe T , Kudo M , Chiba T \nCorrelation between hyporesponsiveness to Toll-like receptor ligands and liver dysfunction in patients with chronic hepatitis C virus infection . J Viral Hepat \n18 : e561 -e567 , 2011 .21914077 \n32. \nTimmer-Bonte JN , Adang EM , Smit HJ , et al \nCost-effectiveness of adding granulocyte colony-stimulating factor to primary prophylaxis with antibiotics in small-cell lung cancer . J Clin Oncol \n24 : 2991 -2997 , 2006 .16682725 \n33. \nArshad M , Seiter K , Bilaniuk J , et al \nSide effects related to cancer treatment: case 2. Splenic rupture following pegfilgrastim . J Clin Oncol \n23 : 8533 -8534 , 2005 .16293882 \n34. \nGavioli E , Abrams M \nPrevention of granulocyte-colony stimulating factor (G-CSF) induced bone pain using double histamine blockade . Support Care Cancer \n25 : 817 -822 , 2017 .27817104 \n35. \nMoukharskaya J , Abrams DM , Ashikaga T , et al \nRandomized phase II study of loratadine for the prevention of bone pain caused by pegfilgrastim . Support Care Cancer \n24 : 3085 -3093 , 2016 .26894485 \n36. \nBondarenko IM , Bias P , Buchner A \nIncidence of bone pain in patients with breast cancer treated with lipegfilgrastim or pegfilgrastim: an integrated analysis from phase II and III studies . Support Care Cancer \n24 : 267 -273 , 2016 .26024743 \n37. \nKubista E , Glaspy J , Holmes FA , Green MD , Hackett J , Neumann T \nBone pain associated with once-per-cycle pegfilgrastim is similar to daily filgrastim in patients with breast cancer . Clin Breast Cancer \n3 : 391 -398 , 2003 .12636878 \n38. \nMoore DC , Pellegrino AE \nPegfilgrastim-induced bone pain: a review on incidence, risk factors, and evidence-based management . Ann Pharmacother \n51 : 797 -803 , 2017 .28423916 \n39. \nLyman GH \nImpact of chemotherapy dose intensity on cancer patient outcomes . J Natl Compr Canc Netw \n7 : 99 -108 , 2009 .19176210 \n40. \nChirivella I , Bermejo B , Insa A , et al \nOptimal delivery of anthracycline-based chemotherapy in the adjuvant setting improves outcome of breast cancer patients . Breast Cancer Res Treat \n114 : 479 -484 , 2009 .18463977 \n41. \nBudman DR , Berry DA , Cirrincione CT , et al \nDose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia group B . J Nati Cancer Inst \n90 : 1205 -1211 , 1998 .\n42. \nZhao Y , Wu T , Shao S , Shi B , Zhao Y \nPhenotype, development, and biological function of myeloid-derived suppressor cells . Oncoimmunology \n5 : e1004983 , 2016 .27057424 \n43. \nGabrilovich DI , Nagaraj S \nMyeloid-derived suppressor cells as regulators of the immune system . Nat Rev Immunol \n9 : 162 -174 , 2009 .19197294 \n44. \nStromnes IM , Brockenbrough JS , Izeradjene K , et al \nTargeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity . Gut \n63 : 1769 -1781 , 2014 .24555999 \n45. \nZhu Y , Herndon JM , Sojka DK , et al \nTissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression . Immunity \n47 : 323 -338.e326 , 2017 .28813661 \n46. \nSolinas G , Germano G , Mantovani A , Allavena P \nTumor-associated macrophages (TAM) as major players of the cancer-related inflammation . J Leukoc Biol \n86 : 1065 -1073 , 2009 .19741157 \n47. \nTakeya M , Komohara Y \nRole of tumor-associated macrophages in human malignancies: friend or foe? \nPathol Int \n66 : 491 -505 , 2016 .27444136 \n48. \nHayama T , Sakurai K , Miura K , et al \nOptimal timing for pegfilgrastim administration in Japanese breast cancer patients receiving intermediate-risk chemotherapies . Int J Clin Pharm \n40 : 997 -1000 , 2018 .29855985 \n49. \nWeycker D , Li X , Figueredo J , Barron R , Tzivelekis S , Hagiwara M \nRisk of chemotherapy-induced febrile neutropenia in cancer patients receiving pegfilgrastim prophylaxis: does timing of administration matter? \nSupport Care Cancer \n24 : 2309 -2316 , 2016 .26607482\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(14)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "mFOLFIRINOX; pancreatic cancer; pegylated G-CSF",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001772:Blood Cell Count; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D010190:Pancreatic Neoplasms; D012189:Retrospective Studies",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1993-2002",
"pmc": null,
"pmid": "30996164",
"pubdate": "2019-07-15",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "11821454;12123336;12488289;12560443;12636878;14565651;15016643;15718314;16293882;16682725;17558305;18165618;18463977;18685565;19176210;19197294;19741157;21095116;21456630;21561347;21617923;21914077;22750974;23298389;23945072;24555999;25117729;25358667;25576433;26024743;26169616;26176079;26372905;26607482;26894485;27022826;27029201;27057424;27444136;27467054;27817104;28038865;28423916;28729048;28813661;29340058;29855985;9719081",
"title": "Clinical Safety and Efficacy of Secondary Prophylactic Pegylated G-CSF in Advanced Pancreatic Cancer Patients Treated with mFOLFIRINOX: A Single-center Retrospective Study.",
"title_normalized": "clinical safety and efficacy of secondary prophylactic pegylated g csf in advanced pancreatic cancer patients treated with mfolfirinox a single center retrospective study"
} | [
{
"companynumb": "PHHY2019JP227799",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "LEUCOVORIN CALCIUM"
},
"drugadditional": null,
... |
{
"abstract": "The most frequent clinical manifestation of cardiovascular diseases in patients with AIDS is pericarditis. Indomethacin is a well tolerated non-steroidal inflammatory drug (NSAID) widely used in the treatment of pericarditis but it can provoke acute renal failure. Tenofovir has also been associated with chronic renal dysfunction. Liver damage can occur during treatment with NSAIDs. We describe the first case of acute renal failure and cholestatic hepatitis occurring in an HIV-naive patient with pericarditis starting HAART (highly active antiretroviral therapy) and assuming indomethacin and antibiotic therapy for opportunistic infections (OIs) at the same time. Based on our case we suggest that attention be paid to drug-drug interactions in such patients.",
"affiliations": "Dipartimento di Scienze per la Promozione della Salute, Universita di Palermo, Palermo, Italy.;Dipartimento di Scienze per la Promozione della Salute, Universita di Palermo, Palermo, Italy.;Dipartimento di Scienze per la Promozione della Salute, Universita di Palermo, Palermo, Italy.;Dipartimento di Scienze per la Promozione della Salute, Universita di Palermo, Palermo, Italy.;Dipartimento di Scienze per la Promozione della Salute, Universita di Palermo, Palermo, Italy.",
"authors": "Colomba|Claudia|C|;Siracusa|Lucia|L|;Madonia|Simona|S|;Bonura|Silvia|S|;Rubino|Raffaella|R|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007213:Indomethacin",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1124-9390",
"issue": "22(3)",
"journal": "Le infezioni in medicina",
"keywords": null,
"medline_ta": "Infez Med",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D058186:Acute Kidney Injury; D000894:Anti-Inflammatory Agents, Non-Steroidal; D023241:Antiretroviral Therapy, Highly Active; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis; D006505:Hepatitis; D006801:Humans; D007213:Indomethacin; D008297:Male; D008875:Middle Aged; D010493:Pericarditis",
"nlm_unique_id": "9613961",
"other_id": null,
"pages": "247-9",
"pmc": null,
"pmid": "25269969",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Irreversible acute renal failure and cholestatic hepatitis following therapy with indomethacin in an HIV-naive patient with pericarditis: a case report.",
"title_normalized": "irreversible acute renal failure and cholestatic hepatitis following therapy with indomethacin in an hiv naive patient with pericarditis a case report"
} | [
{
"companynumb": "IT-TEVA-525921ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INDOMETHACIN"
},
"drugadditional": "1",
"dr... |
{
"abstract": "Renal Cell Carcinoma (RCC) is the most common type of cancer in the kidney and is mostly asymptomatic. Previous studies have supported the important role of sex hormones in RCC pathophysiology and that targeted hormone receptor therapy, such as estrogen receptor targeting, is a promising treatment strategy. However, to the best of our knowledge, it remains unknown whether hormonal therapy, such as controlled ovarian stimulation for in vitro fertilization, serves a role in the development and progression of RCC. The present report describes a case of RCC developed after a fertility stimulation therapy and provides a summary of the known literature on the role of hormone receptors in the development and progression of RCC. A 35-year-old woman received fertility stimulation treatment with follitropin alfa 900 units, human chorionic gonadotropic hormone 5,000 units, injectable leuprolide 1 mg/0.2 ml and cetrotide 0.25 mg. The patient presented to the hospital with shortness of breath and weight loss. The patient had no known genetic predisposition or family history of malignancies and no exposure to chemicals. The patient never used tobacco, alcohol or recreational drugs. Imaging revealed a 17x19 mm, heterogeneously enhancing, and partially exophytic mass in the right kidney. After partial nephrectomy, the pathological evaluation confirmed the diagnosis of clear cell RCC. To the best of our knowledge, this was the first time that a case of ovarian stimulation therapy was associated with the development of RCC. This case raises concerns about the potential oncogenic effect of controlled ovarian stimulation therapy in RCC promotion, suggesting a need for systematic research to clarify the clinical significance of existing pre-clinical data.",
"affiliations": "Department of Medicine, Rutgers/Saint Peter's University Hospital, New Brunswick, NJ 08901, USA.;Department of Medicine, Rutgers/Saint Peter's University Hospital, New Brunswick, NJ 08901, USA.;Department of Medicine, Rutgers/Saint Peter's University Hospital, New Brunswick, NJ 08901, USA.;The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA.",
"authors": "Doukas|Sotirios G|SG|;Martinez|Boris|B|;Rosenthal|Marnie E|ME|;Vageli|Dimitra P|DP|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2021.2302",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "15(1)",
"journal": "Molecular and clinical oncology",
"keywords": "estrogens; in vitro fertilization; ovarian stimulation therapy; renal cell carcinoma",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "140",
"pmc": null,
"pmid": "34094538",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": "30470497;27247714;11821091;20961245;18642351;28492542;23688201;19574399;24971815;30171816;24509264;24988820;29108248;22787479;23211423;12638782;15271872;15221985;28326246;26131816;16061872;31938447;29969209;15217997;20448658;11986344;22129368;23943232;24467919;25676433;32409702;698974;30105850;18711701;29088109;20161981;30788497;25449206;9797090;29789714;27035677;21779010;26411204",
"title": "Controlled ovarian stimulation therapy as a potential risk for the development and progression of renal cell carcinomas: A case report and literature review.",
"title_normalized": "controlled ovarian stimulation therapy as a potential risk for the development and progression of renal cell carcinomas a case report and literature review"
} | [
{
"companynumb": "US-TOLMAR, INC.-21US028530",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FOLLITROPIN ALFA"
},
"drugadditional": "3",
... |
{
"abstract": "The outcome of children, adolescents and young adults (CAYA) with poor-risk recurrent/refractory lymphoma is dismal (⩽30%). To overcome this poor prognosis, we designed an approach to maximize an allogeneic graft vs lymphoma effect in the setting of low disease burden. We conducted a multi-center prospective study of myeloablative conditioning (MAC) and autologous stem cell transplantation (AutoSCT), followed by a reduced intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (AlloHCT) in CAYA, with poor-risk refractory or recurrent lymphoma. Conditioning for MAC AutoSCT consisted of carmustine/etoposide/cyclophosphamide, RIC consisted of busulfan/fludarabine. Thirty patients, 16 Hodgkin lymphoma (HL) and 14 non-Hodgkin lymphoma (NHL), with a median age of 16 years and median follow-up of 5years, were enrolled. Twenty-three patients completed both MAC AutoSCT and RIC AlloHCT. Allogeneic donor sources included unrelated cord blood (n=9), unrelated donor (n=8) and matched siblings (n=6). The incidence of transplant-related mortality following RIC AlloHCT was only 12%. In patients with HL and NHL, 10 year EFS was 59.8% and 70% (P=0.613), respectively. In summary, this approach is safe, and long-term EFS with this approach is encouraging considering the poor-risk patient characteristics and the use of unrelated donors for RIC AlloHCT in the majority of cases.",
"affiliations": "Department of Pediatrics, Columbia University, New York, NY, USA.;Department of Biostatistics, Columbia University, New York, NY, USA.;Department of Pediatrics, Duke University, Durham, NC, USA.;Department of Pediatrics, Columbia University, New York, NY, USA.;Department of Pediatrics, Columbia University, New York, NY, USA.;Department of Pediatrics, Columbia University, New York, NY, USA.;Department of Pediatrics, Northwestern University, Chicago IL, USA.;Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.;Depatment of Pediatrics, New York Medical College, Valhalla, NY, USA.;Depatment of Pediatrics, New York Medical College, Valhalla, NY, USA.;Department of Pediatrics, Columbia University, New York, NY, USA.;Department of Pediatrics, Duke University, Durham, NC, USA.;Depatment of Pediatrics, New York Medical College, Valhalla, NY, USA.;Depatment of Pediatrics, New York Medical College, Valhalla, NY, USA.;Department of Pediatrics, Duke University, Durham, NC, USA.;1] Depatment of Pediatrics, New York Medical College, Valhalla, NY, USA [2] Departments of Medicine, Pathology, Microbiology and Anatomy, New York Medical College, Valhalla, NY, USA.",
"authors": "Satwani|P|P|;Jin|Z|Z|;Martin|P L|PL|;Bhatia|M|M|;Garvin|J H|JH|;George|D|D|;Chaudhury|S|S|;Talano|J|J|;Morris|E|E|;Harrison|L|L|;Sosna|J|J|;Peterson|M|M|;Militano|O|O|;Foley|S|S|;Kurtzberg|J|J|;Cairo|M S|MS|",
"chemical_list": "D006680:HLA Antigens",
"country": "England",
"delete": false,
"doi": "10.1038/leu.2014.194",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "29(2)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005312:Fetal Blood; D020350:Graft vs Tumor Effect; D006680:HLA Antigens; D018380:Hematopoietic Stem Cell Transplantation; D006689:Hodgkin Disease; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D011379:Prognosis; D011446:Prospective Studies; D012008:Recurrence; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "448-55",
"pmc": null,
"pmid": "24938649",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "11368367;21133886;19835971;19800015;10071273;20733154;21079154;15542804;19433688;18084337;21848882;23253557;16972242;8049425;19087093;22215753;21047225;20220116;11099321;15077223;19528536;1991174;20637881;21282545;16611309;18785912;20818441;21993674;2474058;12456505;17514732;19438504;8246023;22260323;10905766;16135485;4153799;17660841;17132719;18816698;19498021;17138821",
"title": "Sequential myeloablative autologous stem cell transplantation and reduced intensity allogeneic hematopoietic cell transplantation is safe and feasible in children, adolescents and young adults with poor-risk refractory or recurrent Hodgkin and non-Hodgkin lymphoma.",
"title_normalized": "sequential myeloablative autologous stem cell transplantation and reduced intensity allogeneic hematopoietic cell transplantation is safe and feasible in children adolescents and young adults with poor risk refractory or recurrent hodgkin and non hodgkin lymphoma"
} | [
{
"companynumb": "PHHY2018US065036",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": "3",
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"abstract": "Ovarian cancer is the eighth most common cancer and the seventh highest cause of cancer-associated mortality in women worldwide. It is the second highest cause of mortality among female reproductive malignancies. The current standard first-line treatment for advanced ovarian cancer includes a combination of surgical debulking and standard systemic platinum-based chemotherapy with carboplatin and paclitaxel. Although a deeper understanding of this disease has been attained, relapse occurs in 70% of patients 18 months subsequent to the first-line treatment. Therefore, it is crucial to develop a novel drug that effectively affects ovarian cancer, particularly tumors that are resistant to current chemotherapy. The aim of the present study was to identify genes whose expression may be used to predict survival time or prognosis in ovarian cancer patients treated with chemotherapy. Gene or protein expression is an important issue in chemoresistance and survival prediction in ovarian cancer. In the present study, the research group consisted of patients treated at the Surgical Clinic of the Gynecology and Obstetrics Gynecological Clinical Hospital, Poznan University of Medical Sciences (Poznan, Poland) between May 2006 and November 2014. Additional eligibility criteria were a similar severity (International Federation of Gynecolgy and Obstetrics stage III) at the time of diagnosis, treatment undertaken in accordance with the same schedule, and an extremely good response to treatment or a lack of response to treatment. The performance of the OncoScan® assay was evaluated by running the assay on samples obtained from the four patients and by following the recommended protocol outlined in the OncoScan assay manual. The genomic screening using Affymetrix OncoScan Arrays resulted in the identification of large genomic rearrangements across all cancer tissues. In general, chromosome number changes were detected in all examined tissues. The OncoScan arrays enabled the identification of ~100 common somatic mutations. Chemotherapy response in ovarian cancer is extremely complex and challenging to study. The present study identified specific genetic alterations associated with ovarian cancer, but not with response for treatment.",
"affiliations": "Surgical Gynecology Clinic of The Gynecological and Obstetrics Clinical Hospital, Poznan University of Medical Sciences, 60-535 Poznan, Poland.;Surgical Gynecology Clinic of The Gynecological and Obstetrics Clinical Hospital, Poznan University of Medical Sciences, 60-535 Poznan, Poland.;Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-535 Poznan, Poland.;Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-535 Poznan, Poland.;Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-535 Poznan, Poland.;Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-535 Poznan, Poland.;Gynecological and Obstetrics Clinical Hospital, Poznan University of Medical Sciences, 60-535 Poznan, Poland.;Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-535 Poznan, Poland.;Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-535 Poznan, Poland.;Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-535 Poznan, Poland.;Surgical Gynecology Clinic of The Gynecological and Obstetrics Clinical Hospital, Poznan University of Medical Sciences, 60-535 Poznan, Poland.",
"authors": "Englert-Golon|Monika|M|;Burchardt|Bartosz|B|;Budny|Bartlomiej|B|;Dębicki|Szymon|S|;Majchrzycka|Blanka|B|;Wrotkowska|Elzbieta|E|;Jasiński|Piotr|P|;Ziemnicka|Katarzyna|K|;Słopień|Radosław|R|;Ruchała|Marek|M|;Sajdak|Stefan|S|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2017.6590",
"fulltext": "\n==== Front\nOncol LettOncol LettOLOncology Letters1792-10741792-1082D.A. Spandidos 10.3892/ol.2017.6590OL-0-0-6590ArticlesGenomic markers of ovarian adenocarcinoma and its relevancy to the effectiveness of chemotherapy Englert-Golon Monika 1*Burchardt Bartosz 12*Budny Bartlomiej 3Dębicki Szymon 3Majchrzycka Blanka 3Wrotkowska Elzbieta 3Jasiński Piotr 4Ziemnicka Katarzyna 3Słopień Radosław 5Ruchała Marek 3Sajdak Stefan 11 Surgical Gynecology Clinic of The Gynecological and Obstetrics Clinical Hospital, Poznan University of Medical Sciences, 60-535 Poznan, Poland2 Department of Forensic Sciences, Poznan University of Medical Sciences, 60-535 Poznan, Poland3 Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-535 Poznan, Poland4 Gynecological and Obstetrics Clinical Hospital, Poznan University of Medical Sciences, 60-535 Poznan, Poland5 Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-535 Poznan, PolandCorrespondence to: Professor Stefan Sajdak or Mr. Bartosz Burchardt, Surgical Gynecology Clinic of The Gynecological and Obstetrics Clinical Hospital, Poznan University of Medical Sciences, Ul. Polna 33, 60-535 Poznan, Poland, E-mail: kgo.ela@wp.pl, E-mail: bartosz.jan.burchardt@gmail.com* Contributed equally\n\n9 2017 17 7 2017 17 7 2017 14 3 3401 3414 22 11 2016 13 4 2017 Copyright: © Englert-Golon et al.2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Ovarian cancer is the eighth most common cancer and the seventh highest cause of cancer-associated mortality in women worldwide. It is the second highest cause of mortality among female reproductive malignancies. The current standard first-line treatment for advanced ovarian cancer includes a combination of surgical debulking and standard systemic platinum-based chemotherapy with carboplatin and paclitaxel. Although a deeper understanding of this disease has been attained, relapse occurs in 70% of patients 18 months subsequent to the first-line treatment. Therefore, it is crucial to develop a novel drug that effectively affects ovarian cancer, particularly tumors that are resistant to current chemotherapy. The aim of the present study was to identify genes whose expression may be used to predict survival time or prognosis in ovarian cancer patients treated with chemotherapy. Gene or protein expression is an important issue in chemoresistance and survival prediction in ovarian cancer. In the present study, the research group consisted of patients treated at the Surgical Clinic of the Gynecology and Obstetrics Gynecological Clinical Hospital, Poznan University of Medical Sciences (Poznan, Poland) between May 2006 and November 2014. Additional eligibility criteria were a similar severity (International Federation of Gynecolgy and Obstetrics stage III) at the time of diagnosis, treatment undertaken in accordance with the same schedule, and an extremely good response to treatment or a lack of response to treatment. The performance of the OncoScan® assay was evaluated by running the assay on samples obtained from the four patients and by following the recommended protocol outlined in the OncoScan assay manual. The genomic screening using Affymetrix OncoScan Arrays resulted in the identification of large genomic rearrangements across all cancer tissues. In general, chromosome number changes were detected in all examined tissues. The OncoScan arrays enabled the identification of ~100 common somatic mutations. Chemotherapy response in ovarian cancer is extremely complex and challenging to study. The present study identified specific genetic alterations associated with ovarian cancer, but not with response for treatment.\n\novarian adenocarcinomapoint gene mutationsefficacy of the treatmentmicroarrays\n==== Body\nIntroduction\nOvarian cancer is the eighth most common cancer and the seventh leading cause of cancer-associated mortality in women worldwide. It is the second highest cause of mortality among female reproductive malignancies and accounts for 140,200 mortalities each year. The estimated incidence and number of mortalities in the USA from ovarian cancer is 21,980 cases and 14,270 mortalities, respectively, for 2014 (1,2). Ovarian cancer is the fourth most common malignancy in women and is the leading cause of gynecological cancer-associated mortality. Poland is one of the countries with high morbidity rates for ovarian carcinoma. Epidemiological data show steady rise of ovarian cancer incidence. Due to late-onset symptoms, ovarian cancer is mainly diagnosed in an advanced stage. In total, 60–70% of patients present with stage III or IV disease and are therefore associated with poor survival. The International Federation of Gynecology and Obstetrics (FIGO) staging classification in ovarian cancer has an independent prognostic role. The major role of the staging system is not only to provide universal terminology that may be used in different oncological hospitals worldwide, but it also informs us about the prognosis and outcome prediction subsequent to specific treatment. The majority of ovarian cancer patients are diagnosed with late-stage disease as the asymptomatic progression is poorly understood, and an efficient screening strategy is not presently available (3–5). The current standard first-line treatment for advanced ovarian cancer includes a combination of surgical debunking and standard systemic platinum-based chemotherapy with carboplatin and paclitaxel (6,7). This standard treatment results in >80% response rates and 40–60% complete responses; however, the majority of patients with advanced disease (stages III–IV) will eventually relapse, even with initial disease response. Improvement in survival has also been poor in ovarian cancer. Gene expression-based tools for the prediction of patient prognosis subsequent to surgery or chemotherapy are currently available for certain cancers. The prediction of cancer prognosis using molecular signatures is a popular research field, within which a wide variety of approaches have been considered (7). Popular RNA or protein expression measurement techniques include cDNA hybridization microarrays, end-point and quantitative reverse transcription polymerase chain reaction (PCR), and immunohistochemistry approaches (8). Although a deeper understanding of this disease has been attained, relapse continues to occur in 70% of patients 18 months following the first-line treatment. Therefore, it is crucial to develop a novel drug that effectively impacts on ovarian cancer, particularly one that is resistant to current chemotherapy. The 5-year survival rate of ovarian cancer patients with stage I is 92%. However, patients diagnosed in the late stage have poor prognosis, with a 5-year survival rate of only 19% for stage IV patients. The median progression-free survival time ranges between 16 and 21 months, and the median overall survival time ranges between 24 and 60 months (9,10). Subsequent to repeated cycles of chemotherapy, recurrent ovarian cancer eventually develops resistance to numerous available cytotoxic agents. As a result, studies into the mechanisms of drug-resistance, biomarkers for drug resistance, and the development of new-targeted therapies have been the subject of numerous ovarian cancer studies (11). Although patients receiving standard therapy, including surgical cytoreduction and platinum-based combination chemotherapies, may have an initial favorable response, the majority of patients experience relapse within 5 years (12). Consequently, there is an urgent requirement for novel treatments for this deadly disease.\n\nThe aim of the present study was to identify genes of which the expression may be used to predict survival time or prognosis in ovarian cancer patients treated witch chemotherapy. As aforementioned, the presence of resistance to the chemotherapy agent administered dramatically affects the survival of a patient. It is therefore reasonable to expect the gene signatures identified to include genes responsible for chemoresistance, which will affect the mechanism of action of the drug. Gene or protein expression is an important issue of chemoresistance and survival prediction in ovarian cancer. The concept of identifying gene signatures is popular, but requires careful handling to extract the information required for this to be successful. There are certain previous studies that investigated the differing response of different types of ovarian cancer to chemotherapy (13). Identification of biomarkers that can reliably predict drug sensitivity and resistance is extremely important.\n\nMaterials and methods\nIn the present study, the research group consisted of patients treated at the Surgical Clinic of the Gynecology and Obstetrics Gynecological Clinical Hospital, Poznan University of Medical Sciences (Poznan, Poland) between May 2006 and November 2014. Of the 2,000 patients, four who suffered from ovarian serum carcinoma were chosen. Additional eligibility criteria were a similar severity (FIGO stage IIIC) at the time of diagnosis, treatment undertaken in accordance with the same schedule, and an extremely good response to treatment or a lack of response to treatment. Finally, two patients who had an exceptionally good response to treatment and two patients who did not respond to treatment were selected. A detailed description of the therapeutic effects of the patients enrolled in the present study is subsequently reported. Informed consent was obtained from all patients, and ethical approval was provided by the Bioethics Committee of Poznan University of Medical Sciences.\n\nThe tissue samples were collected from neoplastic lesions removed during surgery prior to starting drug therapy. The tissues were stored in paraffin blocks.\n\n\nCase reports\nCase 1\nPatient 1 (48 years of age) was classified as having a good response to treatment. The patient was referred from a gynecological ward of Gniezno County Hospital (Gniezo, Poland) in October 2007 with a suspected neoplastic process that extended from the ovary, for treatment at the. Surgical Gynecology Clinic of the Gynecological and Obstetrics Clinical Hospital (Poznan, Poland). On admission, vaginal and transabdominal ultrasounds were performed, which showed conglomerate tumors occupying the pelvis. This ovarian tumor had the following dimensions, 7×8 and 6×5.9 cm infiltrated the large intestine (descending colon and anus) and bladder. The level of the marker cancer antigen (CA) 125 was 207 IU/ml in the blood (normal reference values are <35 IU ml). Subsequent to preparation, partial excision of the pelvic tumor, with reconstruction of the walls of the bladder and anastomosis of the proximal descending colon and the rectum was performed. Unfortunately, due to infiltration of the tumor into the left iliac vessels, the whole tumor was not removed Subsequent to a period of recuperation in November 2007, treatment was commenced with first-line chemotherapy, consisting of paclitaxel and cisplatin (intravenous infusion of paclitaxel 175 mg/m2 and 75 mg/m2 cisplatin per cycle lasting 3 h with 3 weeks break between chemotherapy cycles) which lasted continuously until February 2008. At the start of this stage of treatment, a lesion in the vicinity of the left iliac vessels were visible on transvaginal ultrasound, 1.0×0.7 cm in size, while the CA125 level was 50 IU/ml in the blood. Subsequent to a cycle of paclitaxel and cisplatin chemotherapy (intravenous infusion of paclitaxel 175 mg/m2 and 75 mg/m2 cisplatin per cycle lasting 3 h with 3 weeks break between chemotherapy cycles.), this lesion was invisible and the CA125 level was 13 IU/ml in the blood. At a follow-up in late April 2008, ultrasound examinations found recurrence in the vicinity of the left iliac vessels, with a dimension of 4×4×5 cm and the patient was admitted to the oncology clinic of the Gynecology and Obstetrics Gynecological Clinical Hospital (Poznan, Poland). It was decided to perform surgery to remove the lesion. Considering the high infiltration of the left iliac vessels and subsequent to consultation with a vascular surgeon, the lesion was not entirely removed, leaving a fragment of a tumor measuring ~0.5×0.5 cm around the left common iliac artery. The next stage of treatment was second-line chemotherapy consisting of cyclophosphamide and cisplatin (intravenous infusion of cyclophosphamide 750 mg/m2 and 75 mg/m2 cisplatin per cycle lasting 3 h with 3 weeks break between chemotherapy cycles, which started at the end of May 2008. However, subsequent to 2 cycles of chemotherapy, the patient had a strong anaphylactic reaction to the chemotherapy, which resulted in a change to topotecan (to 1.5 mg/m2 for 5 days every 3 weeks). The level of CA125 (7 IU/ml) in the blood had decreased to 3 IU/ml at the end of therapy, the baseline was following completion of the topotecan treatment. Chemotherapy was completed in late October/November 2008, with the ultrasound also revealing no pelvic lesions; it was decided to continue treatment on an outpatient basis, with one follow-up every 3 weeks. During a follow-up in late December 2008, a recurrence 7×5×5 cm in size was observed around the left iliac vessels. In addition, the patient experienced deterioration in general condition, including a lack of appetite, weakness and weight loss (12 kg within 7 weeks). At the request of the patient, further treatment was not commenced, and it was decided in consultation with the patient for palliative care to be administered at their place of residence. The patient succumbed in mid-January 2009. At the request of the family, no autopsy was performed.\n\nCase 2\nPatient 2 (50 years of age) was classified as having a good response to treatment. The patient presented to the gynecological clinic of the local hospital in Kościan (Kościan County Hospital) in February 2009 subsequent to the accidental detection of a polycystic solid tumor in the pelvic cavity, posterior to the uterus, during abdominal ultrasound. The patient was urgently admitted to the Surgical Gynecology Clinic of the Gynecological and Obstetrics Clinical Hospital in March 2009 and a transvaginal ultrasonography revealed a tumor 9×5×5 cm in size that was in contact with the ascending colon and bladder. The patient reported a history of partial hysterectomy in July 2007. The CA125 level in the blood was 175 IU/ml. Subsequent to preparation, surgery was performed to remove the lesions originating from the right ovary, with the macroscopically unchanged left ovary. Following a period of recovery, first-line chemotherapy consisting of paclitaxel and carboplatin (6 cycles intravenous infusion of paclitaxel, 175 mg/m2 lasting 3 h, followed by 400 mg/m2 carboplatin per cycle, with 3 weeks between cycles.) was commenced in mid-April 2009. Throughout the administration of chemotherapy, there were no lesions in the pelvic cavity and the level of the marker CA125 in the blood dropped between 40 IU/ml at the start of chemotherapy and 13 IU/ml at its completion. In the period between September 2009 and February 2013, the patient was admitted to the Surgical Gynecology Clinic of the Gynecological and Obstetrics Clinical Hospital. In March 2013 during a routine follow-up, a pelvic lesion 7×10×5 cm in size was identified in the right ovary. The patient was admitted to the clinic in order to perform surgery to remove the lesion. The CA125 level was 51 IU/ml. Underwent radical changes and the removal of deciding to start at the beginning of March 2013 chemotherapy (3 cycles of intravenous infusion of paclitaxel 175 mg/m2 and carboplatin 400 mg/m2 per cycle lasting 3 h with 3 weeks break between chemotherapy cycles). During the third course of chemotherapy, the patient developed an adverse reaction to carboplatin (palmar-plantar erythrodysesthesia) that resulted in carboplatin being replaced by cisplatin (3 cycles of intravenous infusion of 75 mg/m2 cisplatin per cycle; 3 weeks break between chemotherapy cycles). Chemotherapy was completed in August 2014, and the patient was referred for follow-up. The last follow-up took place in October 2014. No lesions were detected in the pelvic cavity and the level of CA125 in the blood was 10 IU/ml. The patient succumbed to cardiogenic shock in mid-December 2014. At the request of the family, no autopsy was performed.\n\nCase 3\nPatient 3 (49 years of age) was classified as being unresponsive to treatment. In October 2009, the patient was admitted to the Department of Gynecology, Konin district hospital (Konin, Poland) due to a pelvic tumor. On admission to the Surgical Gynecology Clinic of the Gynecological and Obstetrics Clinical Hospital, transvaginal ultrasonography revealed a solid lesion with multiple compartments that filled the entire pelvis, with smaller dimensions totaling 12×10×17 cm. The tumor infiltrated the bladder and bowel. There was no point in time at which the point where the cancer lesion came from could be reached. The level of CA125 in the blood was 156 IU/ml. Subsequent to preparation, non-radical resection of the tumor was performed, including the uterus and ovaries, a fragment of the wall of the bladder and a section of the descending colon. Among the surgically reconstructed section, colon end-to-side colon anastomosis was performed. However, a small residual section infiltrating the jejunum was left. Following a period of recuperation in mid-November 2009, first-line chemotherapy consisting of paclitaxel and carboplatin (6 cycles of intravenous infusion of paclitaxel 175 mg/m2 and 400 mg/m2 carboplatin per cycle lasting 3 h with 3 weeks break between chemotherapy cycles) was commenced. During the examination prior to the first treatment cycle, lesions were detected in the pelvis and the blood CA125 level was 21 IU/ml. Following 3 cycles of chemotherapy, pelvic free fluid appeared, and the amount of fluid increased in the following cycle. Prior to the last cycle of (February 2010) chemotherapy, a lesion that involved the bladder wall, 2×2×3 cm in size, was observed during the ultrasound. Due to the poor condition and increasing shortness of breath of the patient, the peritoneal cavity was punctured, and over 3 days, 5 l of fluid were removed. Subsequent to another week of hospitalization and further deterioration in the general condition of the patient, further treatment was not administered at the patient's request, and the patient was discharged. Palliative care was administered between discharge (beginning of April 2010) and early June 2010, when the patient succumbed to ovarian cancer.\n\nCase 4\nPatient 4 (49 years of age) was classified as being unresponsive to treatment. In November 2010, the patient was referred to Surgical Gynecology Clinic of the Gynecological and Obstetrics Clinical Hospital by a physician, due to the detection of bilateral ovarian tumors by screening ultrasound. On admission, transvaginal ultrasound was performed, and a solid tumor with central vascularization, measuring 2×1×2 cm, was identified in the left ovary, and a multi-element solid tumor located centrally with peripheral vasculature, measuring 4×3×5 cm, was identified in the right ovary. The level of CA125 in the blood was 410 IU/ml. A radical hysterectomy with removal of the two ovaries, tumors and lymph nodes was performed. Following a period of recovery, first-line chemotherapy consisting of carboplatin and paclitaxel (6 cycles of intravenous infusion of paclitaxel 175 mg/m2 and 400 mg/m2 carboplatin per cycle lasting 3 h with 3 weeks break between chemotherapy cycles) was commenced in mid-December 2010. At the starting of chemotherapy, the CA125 level in the blood was 47 IU/ml, and subsequent to the completion of chemotherapy, it was 46 IU/ml. In May 2011, subsequent to finishing the whole course of treatment, the patient was referred to the Surgical Gynecology Clinic of the Gynecological and Obstetrics Clinical Hospital for follow-up. In June 2011, ultrasound examinations observed a lesion 2×2×0.5 cm in size, which gradually widened (between December 2010 and May 2011) to 7×10×6 cm in size. There was also an increase in the level of CA125 in the blood to 211 IU/ml in February 2013. The patient did not agree to the proposed hospitalizations and surgical procedures. In February 2013, a painful lump 2×2 cm in size was observed in the postoperative scar. Subsequent to obtaining consent from the patient to perform the surgery, a localized lesion in the vagina was removed. In addition, a partly invasive bladder recurrence was removed by local resection of the bladder wall, and a tumor located in the subcutaneous tissue, which was identified as metastasis, was also removed. Following a period of recuperation, second-line chemotherapy consisting of paclitaxel and carboplatin (6 cycles of intravenous infusion of paclitaxel 175 mg/m2 and 400 mg/m2 carboplatin per cycle lasting 3 h with 3 weeks break between chemotherapy cycles) was commenced in April 2013. Prior to the fourth cycle of chemotherapy, transvaginal ultrasound was performed, and identified a localized bladder lesion 2×1×1 cm in size, which, despite treatment, gradually increased in size over 3 cycles (13 weeks). Subsequent to completion of chemotherapy treatment for the localized lesion (4×4×3 cm above the vagina) and the level of CA125 in the blood increased from the initial 13 IU/ml to 97 IU/ml subsequent to treatment. In April 2014, the patient refused to consent to the subsequent chemotherapy and self-discharged. In December 2014, the patient was presented again to the Surgical Gynecology Clinic of the Gynecological and Obstetrics Clinical Hospital with weight loss and weakness and was immediately admitted for treatment. Subsequent to improvement of blood morphology, renal function and the general condition of the patient, the proposed chemotherapy regimen Caelyx (doxorubicin) (6 cycles of 50 mg/m2 doxorubicin per cycle, with 3 weeks between chemotherapy cycles) was administered. In total, six cycles of chemotherapy were administered, which did not stop the growth of the localized lesions in the pelvic cavity. At the end of administrations, the dimensions were 7×5×5 cm and CA125 from level had increased from the original 136 IU/ml to 192 IU/ml. In May 2015, chemotherapy was again attempted, with the fourth-line chemotherapy consisting of paclitaxel and carboplatin (6 cycles of intravenous infusion of paclitaxel 175 mg/m2 and 400 mg/m2 carboplatin per cycle lasting 3 h with 3 weeks break between chemotherapy cycles), which was stopped after 3 courses due to the absence of treatment effects, and the request of the patient to be discharged and discontinue treatment. During the last follow-up, the lesion was 10×9×8 cm in size and the blood CA125 level was 625 IU/ml. The patient succumbed to ovarian cancer in late November 2015.\n\nGenetic examination\nThe proceeding of a genetic examination was performed as previously described (14). Four formalin-fixed paraffin-embedded (FFPE) ovarian carcinoma tissue samples were obtained from the Cancer Pathology Department at Poznan University of Medical Sciences. The FFPE blocks were no older than 5 years.\n\nIn order to obtain a high content of cancer cells for DNA extraction, 5–10 sections (5-µm thick) were cut from each paraffin block, and a set of slides was prepared. One slide per patient was then stained routinely with hematoxylin and eosin to identify regions containing a high concentration of cancer cells. Based on this estimation, regions of interest were dissected from the unstained slides. The dissected cells were then put into a 1.5 Eppendorf tube and DNA was extracted using QIAamp DNA FFPE Tissue kit (Qiagen GmbH, Hilden, Germany), according to the manufacturer's protocol. Following the extraction, DNA was inspected using NanoDrop spectrophotometer (NanoDrop; Thermo Fisher Scientific, Inc.) and the Qubit 2.0, Quant-iT™ PicoGreen® dsDNA Assay kit (Thermo Fisher Scientific, Inc.). A final concentration of 12 ng/µl DNA in Tris-EDTA buffer (10 mM Tris-HCl, 0.1 mM disodium EDTA, pH 8) was than utilized for the OncoScan® assay (Affymetrix, Inc., Santa Clara, CA, USA). In total, 80 ng of DNA (in 6.6 µl) from each sample were processed. The advantage of the OncoScan assay is possibility of simultaneous identification of copy number alterations, loss of heterozygosity (LOH) and somatic mutations (SMs) in a single experiment. This is possibly due to the use of molecular inversion probe (MIP) technology, and capturing >220,000 small nucleotide polymorphism (SNP) genotypes focused on ~900 cancer locations, distributed across the genome. Another advantage is the ability to identify selected ‘hotspot’ somatic mutations in nine genes that particularly contribute to the development of various cancers [tumor protein p53, B-Raf proto-oncogene, serine/threonine kinase, KRAS proto-oncogene, GTPase, epidermal growth factor receptor, isocitrate dehydrogenase 1, isocitrate dehydrogenase 2, phosphatase and tensin homolog, phosphoinositide-3-kinase catalytic subunit α (PIK3CA) and NRAS proto-oncogene, GTPase]. The experimental procedure includes several steps. Probes were added to the sample DNA, and allowed to anneal at 58°C overnight (16–18 h) subsequent to an initial denaturation (95°C for 5 min). Samples was then split into two separate reactions, and proceeded as follows: dATP (A) and dTTP (T) (A/T) were added to one reaction, and dGTP (G) and dCTP (C) (G/C) were added to the second in order to conduct gap fill.\n\nUnincorporated and non-circularized MIPs, as well as the remains of the genomic template, were removed by treatment with exonucleases (Affymetrix, Inc.). The circular MIPs that were gap-filled by the A/T or G/C nucleotides were cleaved using the HaeIII enzyme, and their linear form was amplified by PCR. Subsequently, the 120-bp PCR product was cut and the smaller (44-bp) fragment containing the specific SNP genotype was subjected for hybridization onto array. Prior to this, samples were mixed with hybridization buffer and injected into the cartridges for 16–18 h at 49°C and 0.013 × g. Following hybridization, cartridges were removed from the oven, and stained using the GeneChip® Fluidics Station 450 (Affymetrix, Inc.), according to the manufacturer's protocol. Subsequent to staining and washing, arrays were scanned in GeneChip Scanner 3000 7G (Affymetrix, Inc.) and the fluorescence of clusters was measured in order to generate a DAT file. Cluster intensities values were automatically calculated using built-in algorithm from DAT files by the Affymetrix GeneChip Command Console software, version 4.0 (Affymetrix, Inc.), and a CEL file was created.\n\nGenomic data analysis\nCEL files were processed using OncoScan Console software, version 1.1.034 (Affymetrix, Inc.), to recalculate probe intensities into genomic landscape (OSCHP file) as well as a set of QC metrics (MAPD SNPQC and waviness). For each sample, a profile of copy number alterations was created, expressed by numerical values. The LOH profile was created for all samples, assuming a high confidence interval of ≥3 Mbp (ChAS option). The TuScan algorithm was also used for calculation of ploidy (i.e. 0, 66 or 100%). Somatic mutations were evaluated and viewed in the ChAS browser (Affymetrix, Inc.). The reliability of calls for SMs depends on the SNPQC parameter, and therefore it was necessary to obtain ndSNPQC ≥26 (‘in-bounds’) for all tested samples. The OncoScan assays are able to detect mutations by relying on the signal intensity of designed clusters, which is translated into the mutation score. This algorithm recognizes three basic thresholds for calls, termed ‘Undetected’ for an absence of SMs, and ‘Lower confidence’ or ‘High confidence’ for detected changes. In the present study, the default mutation score thresholds supplied in the software were used.\n\nResults\n\nGenomic studies\nGenomic screening using Affymetrix OncoScan arrays resulted in the identification of large genomic rearrangements across all of the cancer tissues. In general, chromosome number changes were detected in all examined tissues. Ploidies were found in three out of four examined samples. Patients 1 and 2 showed incomplete tetraploidy, whereas patient 3 showed incomplete triploidy. Patient 4 showed diploidy, according to the TuScan algorithm, with hypoploidy of chromosomes 13 and 15. The detailed analysis of regions presenting LOH resulted in the detection of 152 LOH segments with a minimum 3 Mbp size (Table I). These findings are shown in Fig. 1, and the location of each altered segment was depicted. Subsequently, unique overlapping regions in patients presenting sensitivity for treatment (patients 1 and 2) vs. patients showing resistance (patients 3 and 4) were assessed. For the first cohort, only 5 segments on chromosomes 4, 6, 8, 9 and 16 were identified (Table II; Fig. 2). Within those regions, 10 cancer genes were identified using the COSMIC database. For the second cohort, 20 regions on chromosomes 3–5, 7–9, 10, 11, 14–16 and 19 were identified. Within the selected segments, 45 different cancer genes were found (Table III; Fig. 3). The identified LOH regions for all patients are presented in Fig. 1.\n\nThe OncoScan arrays enabled the identification of ~100 common somatic mutations (Table IV). In the present study, only one mutation was identified, in patient 4. The mutation affected the PIK3CA gene and lead to a glutamic acid-lysine substitution (p.E542K, c.1624G>A; Cosmic ID, COSM760). Notably, the mutation was found in cancer tissue that was diploid and was showing only a hypoploidy of acrocentric chromosomes (chromosomes 13, 15, 18 and 22).\n\nDiscussion\nOvarian cancer has the highest mortality rate among reproductive cancers and currently ranks as the fifth leading cause of cancer-associated mortalities among women. Despite the improvements achieved in ovarian cancer therapy over previous decades, the overall 5-year survival rate remains <50% (15). Therefore, novel agents are necessary to improve the outcomes for ovarian cancer patients. In addition, it is important to understand and define the patients that are likely to be sensitive to treatment and have resistant disease. Ovarian cancer is a lethal gynecological disease that is characterized by peritoneal metastasis and increased resistance to conventional chemotherapies (16). This increased resistance and the ability of the cancer to spread is often attributed to the formation of multicellular aggregates or spheroids in the peritoneal cavity, which seed to abdominal surfaces and organs (17). Since the presence of metastatic implants is a predictor of poor survival, a better understanding of how spheroids form is critical to improving patient outcome, and may result in the identification of novel therapeutic targets (16). The most widely used tumor marker in ovarian cancer, often considered the ‘gold standard’, is CA125, which is elevated in 80% of epithelial ovarian cancers (EOCs) (18). CA125 is elevated in 50–60% of patients with stage I EOC and 75–90% of patients with advanced stage EOC (19). The sensitivity of CA125 to identify early stage disease is limited as a screening tool (20). Reliable clinical evidence demonstrates that human epididymis protein (HE4), used alone or in combination with CA125, substantially improves the accuracy of screening and/or disease monitoring (21). HE4, found primarily in the epithelia of normal genital tissues is elevated in EOC (22). HE4 has greater specificity in the premenopausal age group than CA125, since it does not appear to be expressed at high levels in benign conditions (23–25). The strongest risk factor of developing ovarian cancer is a family history of breast and ovarian cancer. It is known that ~15% of ovarian cancer patients in the Polish population carry mutations in the BRCA1 and BRCA2 genes (26). A small number of cases are also associated with Lynch syndrome and mutations in hMLH1, hMSH2, hMSH6, PMS1 and PMS2 in mismatch repair genes (27). Chemotherapy resistance is a common problem faced by patients diagnosed with EOC (28,29). Currently there are no specific or sensitive clinical biomarkers that may be implemented to identify chemotherapy resistance and provide insight into prognosis. Resistance of tumors to chemotherapeutic drugs remains a major clinical challenge for ovarian cancer treatment. The limitations of clinical chemotherapy have been ascribed primarily to mechanisms that mediate drug resistance at the cellular level (30). Previous studies suggest that tumor cells have the ability to regulate genes that help to export, decrease uptake, or increase the metabolism of chemotherapeutic drugs. Newer data also suggest that interactions between tumor cells and the surrounding microenvironment allow for increased resistance of tumor cells to chemotherapy (31). It has been observed that although 40–60% of patients achieve a complete clinical response to first-line chemotherapy treatment ~50% of these patients relapse within 5 years and only 10–15% of patients presenting with advanced stage disease achieve long-term remission (32). It is hypothesized that the high relapse rate is, at least in part, due to resistance to chemotherapy, which may be inherent or acquired by altered gene expression. The patient response to chemotherapy for ovarian cancer is extremely heterogeneous and there are currently no tools to aid the prediction of sensitivity or resistance to chemotherapy and allow treatment stratification (8). Such a tool may markedly improve patient survival by identifying the most appropriate treatment on a patient-specific basis. A clinically applicable gene signature capable of predicting patient response to chemotherapy has not yet been identified. Research into a predictive model, as opposed to a prognostic model, may be highly beneficial and aid the identification of the most suitable treatment for patients. Although it has not yet been accomplished, progress within the field suggests that the development of a predictive model is possible (8). There is considerable variability between the approaches and success of existing studies in the literature, and there have been high levels of variation in the explanatory genes identified (13). The present study hypothesizes that, if more attention is paid to selecting the patients included, to control for treatment history, these gene signatures may be simplified and models that are able to predict the response to treatment may be developed.\n\nTargeting molecular signatures, as well as signal transduction pathways for tumor sensitivity and resistance is essential for treatment and improving overall survival in patients with ovarian cancer (33). At present, an efficient molecular diagnostics for patients has not been established. The major goal of the present study was to reveal molecular hallmarks associated with, or even responsible for, the response of a patient to standard treatment. This knowledge facilitates the design and implementation of new therapies based on the genetic defect type. The identification of molecular signatures associated with chemo-response is a recent area of investigation. In ovarian adenocarcinoma, the OncoScan microarray technology has been performed to find genetic markers and locations that would be relevant in the prediction of response to chemotherapy. The OncoScan assay is efficient for the analysis of FFPE samples (14).\n\nFor the purposes of the present study, patients were divided into two categories, according to responsiveness to chemotherapy. In microarray analysis, the distribution of specific genetic factors between patients was compared. Significant variances in the occurrence of rearrangements were detected for both amplifications (gains) and deletions (losses). Deletions were more frequent in patients showing chemoresistance (14 losses) than in patients presenting with chemosensitivity (1 loss). However, none of the deletions were present in both patients in the same group. This discrepancy between the two patients in each cohort shows a high genetic heterogeneity of tumors. Detailed mapping data also revealed information on the LOH. The LOH phenomenon is of particular importance since it enables the tracing of loss of the normal alleles of tumor suppressor genes, to determine the tumor phenotype. Therefore, locations presenting high frequency of LOH are attractive candidates for harboring tumor suppressor mutations. In the present study, similar amounts of LOH were present in the two cohorts. In addition, the majority of the samples showed LOH at several loci. Numerous loci with LOH were common between the two cohorts. However, certain LOH were typical for patients with resistance to chemotherapy or patients presenting with chemosensitivity. Regions of typical LOH for chemosensitivity were located on chromosomes 4 (p16.3, q11) and 6 (p25.3) in the present study, whereas LOH associated with loci 3p21.3, 3p26.3, 6q23.3 and 11q14.1 were found exclusively in the chemoresistant cases.\n\nThe assessment of LOH in EOC focused on the role of genes located on the short arm of chromosome 3 (3p) in the development of disease. Deletions in regions 3p21.3 and 3p26.3 are common for such cases (34).\n\nLOH in 6q23.3 affects the genes MYB, TNFAIP3 and ECT2 L. Only TNFAIP3 has been implicated in the inhibition of programmed cell death is and suggested to be a tumor suppressor gene (35). At present, the function the remaining genes is not associated with the pathogenesis of ovarian cancer. Furthermore, Shridhar et al (36) reported that deletion of the 6q23.3 region, which commonly presents LOH in ovarian cancer.\n\nNotably, the commonly mutated genes for EOC, namely: CDH1; PRKN; BRCA1/2; and AKT1 were not identified in the present study. However, in patient 4, who showed chemotherapy resistance, a somatic PIK3CA mutation was identified. Mutation in this gene has been previously associated with ovarian cancer (37). Certain studies have confirmed that the PIK3CA/Akt/mammalian target of rapamycin pathway is commonly dysregulated in ovarian cancers (38,39).\n\nChemotherapy response in ovarian cancer is a complex and unpredictable process that determines the course of the disease. In the present study, genetic regions associated with ovarian cancer that may play an important role in the context of treatment response were identified. However, additional studies on a larger cohort of patients are required, in order to reveal crucial pathways and molecular determinants that directly influence the disease course and its aggressiveness.\n\nAcknowledgements\nThis study was supported by the Polish Ministry of Science and Education (grant no. 789/FNiTP/162/2013).\n\nFigure 1. Loss of heterozygosity regions identified in all examined patients. Bars next to the ideogram indicate patients 1–4.\n\nFigure 2. A karyogram showing the chromosomal alterations identified in patients 1 and 2, who showed chemosensitivity.\n\nFigure 3. A karyogram showing the chromosomal regions with chromosomal alterations identified in patients 3 and 4, who showed chemoresistance.\n\nTable I. LOH regions identified in all examined patients.\n\nNo.\tSample\tType\tChrom.\tCytoband\tGenomic location start\tGenomic location end\tSize (Kbp)\tGene count\t\n 1\t1_189975.OSCHP\tLOH\t1\tp21.3\t115837919\t96311795\t19526.124\t161\t\n 2\t4_208156_15.OSCHP\tLOH\t1\tp31.3\t89473522\t68095206\t21378.316\t96\t\n 3\t3_8376_10.OSCHP\tLOH\t1\tp36.23\t33275981\t7892870\t25383.111\t392\t\n 4\t3_8376_10.OSCHP\tLOH\t1\tp36.33\t4738355\t754191\t3984.164\t97\t\n 5\t1_189975.OSCHP\tLOH\t1\tp36.33\t33760197\t754191\t33006.006\t524\t\n 6\t3_8376_10.OSCHP\tLOH\t1\tq23.3\t180377339\t163377535\t16999.804\t144\t\n 7\t3_8376_10.OSCHP\tLOH\t1\tq31.2\t197574134\t191510124\t6064.01\t24\t\n 8\t2_203344_15.OSCHP\tLOH\t1\tq32.1\t216605071\t200649365\t15955.706\t180\t\n 9\t2_203344_15.OSCHP\tLOH\t1\tq43\t249212878\t237257823\t11955.055\t102\t\n 10\t3_8376_10.OSCHP\tLOH\t2\tp21\t90245035\t42993165\t47251.87\t302\t\n 11\t3_8376_10.OSCHP\tLOH\t2\tp25.3\t39767074\t21493\t39745.581\t250\t\n 12\t2_203344_15.OSCHP\tLOH\t2\tq11.2\t112928815\t101831270\t11097.545\t79\t\n 13\t1_189975.OSCHP\tLOH\t2\tq13\t141463604\t114138191\t27325.413\t127\t\n 14\t2_203344_15.OSCHP\tLOH\t2\tq36.1\t228157661\t224463413\t3694.248\t18\t\n 15\t3_8376_10.OSCHP\tLOH\t2\tq36.3\t243052331\t230641762\t12410.569\t154\t\n 16\t2_203344_15.OSCHP\tLOH\t2\tq36.3\t243052331\t230903874\t12148.457\t152\t\n 17\t3_8376_10.OSCHP\tLOH\t3\tp21.31\t51927415\t46001062\t5926.353\t143\t\n 18\t4_208156_15.OSCHP\tLOH\t3\tp21.31\t53323914\t50248426\t3075.488\t82\t\n 19\t3_8376_10.OSCHP\tLOH\t3\tp26.3\t11539955\t63410\t11476.545\t69\t\n 20\t4_208156_15.OSCHP\tLOH\t3\tp26.3\t49346130\t63410\t49282.72\t368\t\n 21\t4_208156_15.OSCHP\tLOH\t3\tq22.3\t164972840\t138296967\t26675.873\t147\t\n 22\t3_8376_10.OSCHP\tLOH\t3\tq25.32\t168219437\t157426328\t10793.109\t39\t\n 23\t3_8376_10.OSCHP\tLOH\t3\tq27.1\t197852564\t184416008\t13436.556\t129\t\n 24\t3_8376_10.OSCHP\tLOH\t4\tp15.1\t35668267\t29950964\t5717.303\t1\t\n 25\t2_203344_15.OSCHP\tLOH\t4\tp16.3\t8060637\t71565\t7989.072\t107\t\n 26\t1_189975.OSCHP\tLOH\t4\tp16.3\t49092454\t71565\t49020.889\t278\t\n 27\t1_189975.OSCHP\tLOH\t4\tq11\t190915650\t52684890\t138230.76\t611\t\n 28\t2_203344_15.OSCHP\tLOH\t4\tq11\t190915650\t52684890\t138230.76\t611\t\n 29\t3_8376_10.OSCHP\tLOH\t4\tq22.3\t114068306\t97748435\t16319.871\t90\t\n 30\t4_208156_15.OSCHP\tLOH\t4\tq24\t190915650\t103271887\t87643.763\t337\t\n 31\t3_8376_10.OSCHP\tLOH\t4\tq26\t177478156\t119815943\t57662.213\t207\t\n 32\t4_208156_15.OSCHP\tLOH\t5\tp14.1\t33066481\t28142098\t4924.383\t12\t\n 33\t3_8376_10.OSCHP\tLOH\t5\tq11.1\t68828372\t49441965\t19386.407\t87\t\n 34\t4_208156_15.OSCHP\tLOH\t5\tq11.2\t68828372\t51164114\t17664.258\t83\t\n 35\t1_189975.OSCHP\tLOH\t5\tq11.2\t68828372\t52864364\t15964.008\t77\t\n 36\t2_203344_15.OSCHP\tLOH\t5\tq11.2\t68828372\t55081693\t13746.679\t56\t\n 37\t3_8376_10.OSCHP\tLOH\t5\tq13.2\t90049057\t70306677\t19742.38\t109\t\n 38\t2_203344_15.OSCHP\tLOH\t5\tq13.2\t119919958\t70306677\t49613.281\t206\t\n 39\t1_189975.OSCHP\tLOH\t5\tq13.2\t180698312\t70306677\t110391.635\t749\t\n 40\t4_208156_15.OSCHP\tLOH\t5\tq13.2\t180698312\t70306677\t110391.635\t749\t\n 41\t3_8376_10.OSCHP\tLOH\t5\tq21.1\t106861975\t101206368\t5655.607\t9\t\n 42\t3_8376_10.OSCHP\tLOH\t5\tq21.3\t114957561\t107853410\t7104.151\t33\t\n 43\t3_8376_10.OSCHP\tLOH\t5\tq22.3\t121539398\t115180415\t6358.983\t20\t\n 44\t2_203344_15.OSCHP\tLOH\t5\tq23.2\t124880865\t121481182\t3399.683\t11\t\n 45\t3_8376_10.OSCHP\tLOH\t5\tq23.3\t132783187\t129632862\t3150.325\t34\t\n 46\t2_203344_15.OSCHP\tLOH\t5\tq31.1\t136935228\t133568504\t3366.724\t33\t\n 47\t3_8376_10.OSCHP\tLOH\t5\tq31.2\t142559092\t138965375\t3593.717\t106\t\n 48\t2_203344_15.OSCHP\tLOH\t5\tq32\t150654481\t147480079\t3174.402\t48\t\n 49\t2_203344_15.OSCHP\tLOH\t5\tq33.1\t154336832\t150789050\t3547.782\t21\t\n 50\t3_8376_10.OSCHP\tLOH\t5\tq33.1\t176675423\t151738611\t24936.812\t137\t\n 51\t2_203344_15.OSCHP\tLOH\t5\tq33.2\t180698312\t155277214\t25421.098\t200\t\n 52\t2_203344_15.OSCHP\tLOH\t6\tp25.3\t21704602\t204908\t21499.694\t116\t\n 53\t1_189975.OSCHP\tLOH\t6\tp25.3\t58770502\t204908\t58565.594\t708\t\n 54\t3_8376_10.OSCHP\tLOH\t6\tq11.1\t69746054\t61886392\t7859.662\t8\t\n 55\t1_189975.OSCHP\tLOH\t6\tq11.1\t170913051\t61886392\t109026.659\t512\t\n 56\t2_203344_15.OSCHP\tLOH\t6\tq22.32\t170913051\t126471760\t44441.291\t261\t\n 57\t3_8376_10.OSCHP\tLOH\t6\tq23.3\t170913051\t135739354\t35173.697\t205\t\n 58\t4_208156_15.OSCHP\tLOH\t6\tq23.3\t170913051\t138266430\t32646.621\t189\t\n 59\t3_8376_10.OSCHP\tLOH\t7\tp15.3\t35873540\t21882560\t13990.98\t118\t\n 60\t4_208156_15.OSCHP\tLOH\t7\tp22.3\t50700153\t41420\t50658.733\t348\t\n 61\t1_189975.OSCHP\tLOH\t8\tp23.1\t26419805\t8094762\t18325.043\t147\t\n 62\t4_208156_15.OSCHP\tLOH\t8\tp23.1\t27024823\t8094762\t18930.061\t148\t\n 63\t3_8376_10.OSCHP\tLOH\t8\tp23.1\t30191040\t8094762\t22096.278\t182\t\n 64\t1_189975.OSCHP\tLOH\t8\tp23.3\t7004147\t172416\t6831.731\t36\t\n 65\t3_8376_10.OSCHP\tLOH\t8\tp23.3\t7004147\t172416\t6831.731\t36\t\n 66\t4_208156_15.OSCHP\tLOH\t8\tp23.3\t7004147\t172416\t6831.731\t36\t\n 67\t4_208156_15.OSCHP\tLOH\t8\tq11.21\t53114569\t49845207\t3269.362\t5\t\n 68\t4_208156_15.OSCHP\tLOH\t8\tq12.1\t117682009\t59515755\t58166.254\t254\t\n 69\t2_203344_15.OSCHP\tLOH\t8\tq12.3\t66046002\t62996038\t3049.964\t12\t\n 70\t1_189975.OSCHP\tLOH\t8\tq13.3\t111154532\t71428716\t39725.816\t192\t\n 71\t3_8376_10.OSCHP\tLOH\t8\tq24.22\t140789847\t134986490\t5803.357\t10\t\n 72\t2_203344_15.OSCHP\tLOH\t9\tp22.3\t24559653\t14364589\t10195.064\t59\t\n 73\t1_189975.OSCHP\tLOH\t9\tp24.3\t33434153\t204737\t33229.416\t138\t\n 74\t4_208156_15.OSCHP\tLOH\t9\tq21.11\t78561334\t70984371\t7576.963\t37\t\n 75\t1_189975.OSCHP\tLOH\t9\tq21.12\t141054761\t73134143\t67920.618\t659\t\n 76\t3_8376_10.OSCHP\tLOH\t9\tq21.13\t99234997\t74937502\t24297.495\t145\t\n 77\t2_203344_15.OSCHP\tLOH\t9\tq21.13\t93599890\t79064623\t14535.267\t67\t\n 78\t3_8376_10.OSCHP\tLOH\t9\tq31.1\t136241639\t107839840\t28401.799\t301\t\n 79\t4_208156_15.OSCHP\tLOH\t9\tq33.2\t141054761\t125422864\t15631.897\t316\t\n 80\t1_189975.OSCHP\tLOH\t10\tp15.3\t32764613\t126069\t32638.544\t188\t\n 81\t1_189975.OSCHP\tLOH\t10\tq23.1\t135434303\t82575777\t52858.526\t437\t\n 82\t4_208156_15.OSCHP\tLOH\t10\tq23.1\t135434303\t82843903\t52590.4\t437\t\n 83\t3_8376_10.OSCHP\tLOH\t10\tq23.1\t114381720\t87268004\t27113.716\t267\t\n 84\t3_8376_10.OSCHP\tLOH\t11\tp11.2\t51575951\t46089775\t5486.176\t59\t\n 85\t1_189975.OSCHP\tLOH\t11\tp11.2\t51575951\t48040260\t3535.691\t18\t\n 86\t1_189975.OSCHP\tLOH\t11\tp15.5\t3789206\t192763\t3596.443\t112\t\n 87\t4_208156_15.OSCHP\tLOH\t11\tp15.5\t27025877\t192763\t26833.114\t361\t\n 88\t3_8376_10.OSCHP\tLOH\t11\tp15.5\t38786252\t192763\t38593.489\t422\t\n 89\t4_208156_15.OSCHP\tLOH\t11\tq12.2\t63386750\t60212296\t3174.454\t108\t\n 90\t1_189975.OSCHP\tLOH\t11\tq13.4\t80566396\t70719896\t9846.5\t108\t\n 91\t4_208156_15.OSCHP\tLOH\t11\tq14.1\t134938847\t82560444\t52378.403\t405\t\n 92\t3_8376_10.OSCHP\tLOH\t11\tq14.1\t93535839\t84664703\t8871.136\t56\t\n 93\t3_8376_10.OSCHP\tLOH\t11\tq22.1\t118473385\t99519603\t18953.782\t155\t\n 94\t1_189975.OSCHP\tLOH\t11\tq22.3\t116216759\t108306235\t7910.524\t62\t\n 95\t1_189975.OSCHP\tLOH\t12\tp13.33\t12919325\t189399\t12729.926\t215\t\n 96\t3_8376_10.OSCHP\tLOH\t12\tq13.13\t133818115\t52051129\t81766.986\t724\t\n 97\t2_203344_15.OSCHP\tLOH\t12\tq14.1\t62234495\t59059674\t3174.821\t3\t\n 98\t2_203344_15.OSCHP\tLOH\t12\tq21.33\t133818115\t89779996\t44038.119\t388\t\n 99\t4_208156_15.OSCHP\tLOH\t12\tq23.1\t133818115\t96564524\t37253.591\t340\t\n100\t3_8376_10.OSCHP\tLOH\t13\tq11\t111956103\t19084822\t92871.281\t429\t\n101\t2_203344_15.OSCHP\tLOH\t13\tq11\t115103150\t19084822\t96018.328\t460\t\n102\t4_208156_15.OSCHP\tLOH\t13\tq11\t115103150\t19084822\t96018.328\t460\t\n103\t3_8376_10.OSCHP\tLOH\t14\tq11.2\t35930195\t23299134\t12631.061\t116\t\n104\t4_208156_15.OSCHP\tLOH\t14\tq23.1\t107282024\t60071277\t47210.747\t465\t\n105\t1_189975.OSCHP\tLOH\t14\tq23.1\t99873891\t60436201\t39437.69\t283\t\n106\t3_8376_10.OSCHP\tLOH\t14\tq32.2\t107282024\t100785616\t6496.408\t170\t\n107\t1_189975.OSCHP\tLOH\t15\tq11.2\t78938567\t22752398\t56186.169\t617\t\n108\t3_8376_10.OSCHP\tLOH\t15\tq11.2\t79548077\t22752398\t56795.679\t624\t\n109\t4_208156_15.OSCHP\tLOH\t15\tq11.2\t102397317\t22752398\t79644.919\t807\t\n110\t2_203344_15.OSCHP\tLOH\t15\tq24.2\t79167603\t75948670\t3218.933\t42\t\n111\t2_203344_15.OSCHP\tLOH\t16\tp11.2\t35271725\t31842847\t3428.878\t16\t\n112\t3_8376_10.OSCHP\tLOH\t16\tp13.3\t23792157\t83886\t23708.271\t366\t\n113\t1_189975.OSCHP\tLOH\t16\tp13.3\t35271725\t83886\t35187.839\t535\t\n114\t1_189975.OSCHP\tLOH\t16\tq11.2\t90158005\t46461308\t43696.697\t420\t\n115\t3_8376_10.OSCHP\tLOH\t16\tq11.2\t90158005\t46461308\t43696.697\t420\t\n116\t1_189975.OSCHP\tLOH\t17\tp13.3\t22217883\t400958\t21816.925\t399\t\n117\t2_203344_15.OSCHP\tLOH\t17\tp13.3\t22217883\t400958\t21816.925\t399\t\n118\t3_8376_10.OSCHP\tLOH\t17\tp13.3\t22217883\t400958\t21816.925\t399\t\n119\t4_208156_15.OSCHP\tLOH\t17\tp13.3\t22217883\t400958\t21816.925\t399\t\n120\t1_189975.OSCHP\tLOH\t17\tq11.1\t45863219\t25326940\t20536.279\t472\t\n121\t2_203344_15.OSCHP\tLOH\t17\tq11.1\t80263427\t25326940\t54936.487\t952\t\n122\t3_8376_10.OSCHP\tLOH\t17\tq11.1\t80263427\t25326940\t54936.487\t952\t\n123\t4_208156_15.OSCHP\tLOH\t17\tq11.1\t80263427\t25326940\t54936.487\t952\t\n124\t1_189975.OSCHP\tLOH\t17\tq23.2\t80263427\t58390959\t21872.468\t320\t\n125\t2_203344_15.OSCHP\tLOH\t18\tp11.32\t10493077\t2063183\t8429.894\t44\t\n126\t4_208156_15.OSCHP\tLOH\t18\tq12.1\t78007784\t26057436\t51950.348\t215\t\n127\t2_203344_15.OSCHP\tLOH\t18\tq12.2\t78007784\t36335674\t41672.11\t172\t\n128\t3_8376_10.OSCHP\tLOH\t18\tq12.3\t78007784\t38349307\t39658.477\t169\t\n129\t1_189975.OSCHP\tLOH\t18\tq12.3\t78007784\t42908725\t35099.059\t162\t\n130\t1_189975.OSCHP\tLOH\t19\tp13.3\t4448843\t247231\t4201.612\t154\t\n131\t4_208156_15.OSCHP\tLOH\t19\tp13.3\t6222353\t247231\t5975.122\t196\t\n132\t3_8376_10.OSCHP\tLOH\t19\tp13.3\t9033548\t247231\t8786.317\t277\t\n133\t2_203344_15.OSCHP\tLOH\t19\tq13.11\t59093239\t35366074\t23727.165\t924\t\n134\t4_208156_15.OSCHP\tLOH\t19\tq13.2\t56731955\t42241444\t14490.511\t616\t\n135\t1_189975.OSCHP\tLOH\t19\tq13.32\t59093239\t46416646\t12676.593\t561\t\n136\t4_208156_15.OSCHP\tLOH\t20\tp13\t16811434\t69093\t16742.341\t139\t\n137\t1_189975.OSCHP\tLOH\t20\tq11.22\t60126157\t34313296\t25812.861\t250\t\n138\t2_203344_15.OSCHP\tLOH\t20\tq13.2\t58259236\t52721955\t5537.281\t49\t\n139\t3_8376_10.OSCHP\tLOH\t20\tq13.2\t60139227\t52771260\t7367.967\t57\t\n140\t1_189975.OSCHP\tLOH\t21\tq11.2\t48097610\t14344536\t33753.074\t295\t\n141\t1_189975.OSCHP\tLOH\t22\tq11.1\t51213826\t16054712\t35159.114\t549\t\n142\t4_208156_15.OSCHP\tLOH\t22\tq11.1\t51213826\t16054712\t35159.114\t549\t\n143\t3_8376_10.OSCHP\tLOH\t22\tq11.21\t51213826\t19939352\t31274.474\t492\t\n144\t2_203344_15.OSCHP\tLOH\t22\tq11.21\t51213826\t21028945\t30184.881\t467\t\n145\t1_189975.OSCHP\tLOH\tX\tp22.33\t58412929\t177941\t58234.988\t396\t\n146\t3_8376_10.OSCHP\tLOH\tX\tp22.33\t58412929\t177941\t58234.988\t396\t\n147\t2_203344_15.OSCHP\tLOH\tX\tq11.1\t65127774\t61732393\t3395.381\t12\t\n148\t3_8376_10.OSCHP\tLOH\tX\tq11.1\t76001785\t61732393\t14269.392\t102\t\n149\t1_189975.OSCHP\tLOH\tX\tq11.1\t155219364\t61732393\t93486.971\t623\t\n150\t4_208156_15.OSCHP\tLOH\tX\tq11.2\t67429457\t63554561\t3874.896\t12\t\n151\t3_8376_10.OSCHP\tLOH\tX\tq21.31\t92806132\t88265772\t4540.36\t3\t\n152\t3_8376_10.OSCHP\tLOH\tX\tq25\t129607422\t125678360\t3929.062\t18\t\nLOH, loss of heterozygosity; Chrom., chromosome\n\nTable II. The chromosomal regions showing chromosomal alterations identified in patients 1–2 showing sensitiveness for chemotherapy.\n\nNo.\tType\tSegment\tChrom.\tGenomic location start\tGenomic location end\tSize (Kbp)\tCancer genes\t\n1\tloh\tLOH_2_15.OSCHP\t 4\t52684890\t97836479\t45151.589\tFIP1L1, CHIC2, PDGFRA, KIT, KDR\t\n2\tloh\tLOH_2_15.OSCHP\t 6\t 204908\t21704602\t21499.694\tIRF4, DEK,\t\n3\tloh\tLOH_2_15.OSCHP\t 9\t14364589\t24559653\t10195.064\tNFIB, MLLT3, CDKN2A\t\n4\tloh\tLOH_2_15.OSCHP\t16\t31842847\t35271725\t3428.878\t–\t\n5\tloss\tLoss1.5_2_15.OSCHP\t 8\t89900441\t95759698\t5859.257\t–\t\nLOH, loss of heterozygosity; Chrom., chromosome.\n\nTable III. The chromosomal regions with alterations identified in patients 3 and 4, who showed chemoresistance.\n\nNo.\tType\tSegment\tChrom.\tGenomic location start\tGenomic location end\tSize\tGenes\t\n 1\tloh\tLOH_3_10.OSCHP\t3\t63410\t11539955\t11476.545\tSRGAP3, FANCD2, VHL\t\n 2\tloh\tLOH_3_10.OSCHP\t3\t46001062\t51927415\t5926.353\tSETD2\t\n 3\tloh\tLOH_3_10.OSCHP\t3\t157426328\t168219437\t10793.109\tMLF1\t\n 4\tloss\tLoss1.0_4_15.OSCHP\t4\t104892789\t126864721\t21971.932\tTET2, IL2\t\n 5\tloss\tLoss1.0_4_15.OSCHP\t4\t160026316\t190915650\t30889.334\t\t\n 6\tloss\tLoss1.0_4_15.OSCHP\t5\t51505664\t113875957\t62370.293\tIL6ST, PIK3R1, APC\t\n 7\tloh\tLOH_3_10.OSCHP\t7\t21882560\t35873540\t13990.98\tHNRN, PA2B1, HOXA9, HOXA11, HOXA13, JAZF1\t\n 8\tloss\tLoss1.3_3_10.OSCHP\t7\t23008207\t27115718\t4107.511\t\t\n 9\tloss\tLoss1.7_3_10.OSCHP\t7\t27127230\t32219657\t5092.427\t\t\n10\tloss\tLoss1.3_3_10.OSCHP\t7\t32240424\t32817742\t577.318\t\t\n11\tloss\tLoss1.0_4_15.OSCHP\t8\t172416\t26170975\t25998.559\tPCM1\t\n12\tloss\tLoss1.5_4_15.OSCHP\t9\t126044009\t136147702\t10103.693\tSET, FNBP1, ABL1, NUP214, TSC1, RALGDS\t\n13\tloss\tLOH_3_8376_10.OSCHP\t10\t87268004\t114381720\t27113.716\tBMPR1A, PTEN, TLX1, NFKB2, SUFU, NT5C2, VTI1A, TCF7L2, FGFR2\t\n14\tloh\tLOH_4_15.OSCHP\t11\t192763\t27025877\t26833.114\tHRAS, CARS, NUP98, LMO1, FANCF\t\n15\tloh\tLOH_3_10.OSCHP\t11\t84664703\t93535839\t8871.136\tPICALM\t\n16\tloss\tLOH_3_8376_10.OSCHP\t14\t100785616\t107282024\t6496.408\t\t\n17\tloss\tLoss1.3_3_10.OSCHP\t15\t71156952\t79214215\t8057.263\tPML\t\n18\tloss\tLoss1.5_4_15.OSCHP\t16\t18069547\t19266457\t1196.91\t\t\n19\tloss\tLoss1.0_4_15.OSCHP\t19\t247231\t5655792\t5408.561\tFSTL3, STK11, TCF3, GNA11, MAP2K2, SH3GL1, MLLT1\t\n20\tloss\tLoss1.7_3_10.OSCHP\t19\t1550649\t8086055\t6535.406\t\t\nLOH, loss of heterozygosity; Chrom., chromosome.\n\nTable IV. List of the drivers somatic mutations implemented into Affymetrix OncoScan Arrays.\n\nMutation\tType\tAA change\tCDS change\tCosmic ID\t\nNRAS:p.Q61R:c.182A>G\tMissense\tp.Q61R\tc.182A>G\tCOSM584\t\nNRAS:p.Q61L:c.182A>T\tMissense\tp.Q61L\tc.182A>T\tCOSM583\t\nNRAS:p.Q61K:c.181C>A\tMissense\tp.Q61K\tc.181C>A\tCOSM580\t\nNRAS:p.G12V:c.35G>T\tMissense\tp.G12V\tc.35G>T\tCOSM566\t\nNRAS:p.G12D:c.35G>A\tMissense\tp.G12D\tc.35G>A\tCOSM564\t\nNRAS:p.G12S/C:c.34G>A/T\tMissense\tp.G12S||p.G12C\tc.34G>A||c.34G>T\tCOSM563||COSM562\t\nIDH1:p.R132H:c.395G>A\tMissense\tp.R132H\tc.395G>A\tCOSM28746\t\nPIK3CA:p.E542K:c.1624G>A\tMissense\tp.E542K\tc.1624G>A\tCOSM760\t\nPIK3CA:p.E545K:c.1633G>A\tMissense\tp.E545K\tc.1633G>A\tCOSM763\t\nPIK3CA:p.Q546K:c.1636C>A\tMissense\tp.Q546K\tc.1636C>A\tCOSM766\t\nPIK3CA:p.H1047R:c.3140A>G\tMissense\tp.H1047R\tc.3140A>G\tCOSM775\t\nPIK3CA:p.H1047L:c.3140A>T\tMissense\tp.H1047L\tc.3140A>T\tCOSM776\t\nEGFR:p.G719S:c.2155G>A\tMissense\tp.G719S\tc.2155G>A\tCOSM6252\t\nEGFR:p.G719C:c.2155G>T\tMissense\tp.G719C\tc.2155G>T\tCOSM6253\t\nEGFR:p.G719A:c.2156G>C\tMissense\tp.G719A\tc.2156G>C\tCOSM6239\t\nEGFR:p.E746_A750del:c.2235_2249del15\tIn-frame\tp.E746_A750delELREA\tc.2235_2249del15\tCOSM6223\t\nEGFR:p.E746_A750del:c.2236_2250del15\tIn-frame\tp.E746_A750delELREA\tc.2236_2250del15\tCOSM6225\t\nEGFR:p.E746_T751>A:c.2237_2251del15\tDeletion In-frame\tp.E746_T751>A\tc.2237_2251del15\tCOSM12678\t\nEGFR:p.L747_E749P/del:c.2239_2248>C/G\tVarious\tp.L747_A750>P||p.L747_E749delLRE\tc.2239_2248TTAAGAGAAG >C||c.2239_2247 delTTAAGAGAA\tCOSM12 382||COSM6218\t\nEGFR:p.L747_T751del:c.2240_2254del15\tIn-Frame\tp.L747_T751delLREAT\tc.2240_2254del15\tCOSM12369\t\nEGFR:p.L747_P753>S:c.2240_2257del18\tDeletion In-frame\tp.L747_P753>S\tc.2240_2257del18\tCOSM12370\t\nEGFR:p.V769_D770insASV:c.2307_2308ins9\tIn-frame\tp.V769_D770insASV\tc.2307_2308ins GCCAGCGTG\tCOSM12376\t\nEGFR:p.D770_N771insSVD:c.2311_2312ins9\tIn-frame\tp.D770_N771insSVD\tc.2311_2312ins GCGTGGACA\tCOSM13428\t\nEGFR:p.H773_V774insNPH:c.2319_2320ins9\tIn-frame\tp.H773_V774insNPH\tc.2319_2320ins AACCCCCAC\tCOSM12381\t\nEGFR:p.T790M:c.2369C>T\tMissense\tp.T790M\tc.2369C>T\tCOSM6240\t\nEGFR:p.L858R:c.2573T>G\tMissense\tp.L858R\tc.2573T>G\tCOSM6224\t\nEGFR:p.L861Q:c.2582T>A\tMissense\tp.L861Q\tc.2582T>A\tCOSM6213\t\nBRAF:p.V600K:c.1798_1799GT>AA\tMissense\tp.V600K\tc.1798_1799GT>AA\tCOSM473\t\nBRAF:p.V600E:c.1799T>A\tMissense\tp.V600E\tc.1799T>A\tCOSM476\t\nBRAF:p.G469E:c.1406G>A\tMissense\tp.G469E\tc.1406G>A\tCOSM461\t\nBRAF:p.G469A:c.1406G>C\tMissense\tp.G469A\tc.1406G>C\tCOSM460\t\nPTEN:p.R130G:c.388C>G\tMissense\tp.R130G\tc.388C>G\tCOSM5219\t\nPTEN:p.R130*:c.388C>T\tNonsense\tp.R130*\tc.388C>T\tCOSM5152\t\nPTEN:p.R130Q/fs*4:c.389G>A/delG\tVarious\tp.R130Q||p.R130fs*4\tc.389G>A||c.389delG\tCOSM5033||COSM5817\t\nPTEN:p.R159S:c.477G>T\tMissense\tp.R159S\tc.477G>T\tCOSM5287\t\nPTEN:p.R233*:c.697C>T\tNonsense\tp.R233*\tc.697C>T\tCOSM5154\t\nPTEN:p.P248fs*5:c.741_742insA\tFrame-Shift\tp.P248fs*5\tc.741_742insA\tCOSM4986\t\nPTEN:p.K267fs*9:c.800delA\tFrame-Shift\tp.K267fs*9\tc.800delA\tCOSM5809\t\nKRAS:p.A146P:c.436G>C\tMissense\tp.A146P\tc.436G>C\tCOSM19905\t\nKRAS:p.Q61H:c.183A>T\tMissense\tp.Q61H\tc.183A>T\tCOSM555\t\nKRAS:p.Q61H:c.183A>C\tMissense\tp.Q61H\tc.183A>C\tCOSM554\t\nKRAS:p.Q61K/K:c.180_181TC>TA/AA\tMissense\tp.Q61K\tc.181C>A||c. 180_181TC>AA\tCOSM549||COSM87298\t\nKRAS:p.G13D:c.38G>A\tMissense\tp.G13D\tc.38G>A\tCOSM532\t\nKRAS:p.G12D/V:c.35G>A/T\tMissense\tp.G12D||p.G12V\tc.35G>A||c.35G>T\tCOSM521||COSM520\t\nKRAS:p.G12A:c.35G>C\tMissense\tp.G12A\tc.35G>C\tCOSM522\t\nKRAS:p.G12C/S:c.34G>T/A\tMissense\tp.G12C||p.G12S\tc.34G>T||c.34G>A\tCOSM516||COSM517\t\nIDH2:p.R172K:c.515G>A\tMissense\tp.R172K\tc.515G>A\tCOSM33733\t\nIDH2:p.R140Q:c.419G>A\tMissense\tp.R140Q\tc.419G>A\tCOSM41590\t\nTP53:p.R306*:c.916C>T\tNonsense\tp.R306*\tc.916C>T\tCOSM10663\t\nTP53:p.R282W:c.844C>T\tMissense\tp.R282W\tc.844C>T\tCOSM10704\t\nTP53:p.R273H/L:c.818G>A/T\tMissense\tp.R273H||p.R273L\tc.818G>A||c.818G>T\tCOSM10660||COSM10779\t\nTP53:p.R273C/S:c.817C>T/A\tMissense\tp.R273C||p.R273S\tc.817C>T||c.817C>A\tCOSM10659||COSM43909\t\nTP53:p.R249S:c.747G>T\tMissense\tp.R249S\tc.747G>T\tCOSM10817\t\nTP53:p.R248Q/L:c.743G>A/T\tMissense\tp.R248Q||p.R248L\tc.743G>A||c.743G>T\tCOSM10662||COSM6549\t\nTP53:p.R248W:c.742C>T\tMissense\tp.R248W\tc.742C>T\tCOSM10656\t\nTP53:p.G245S/C:c.733G>A/T\tMissense\tp.G245S||p.G245C\tc.733G>A||c.733G>T\tCOSM6932||COSM11081\t\nTP53:p.Y220C:c.659A>G\tMissense\tp.Y220C\tc.659A>G\tCOSM10758\t\nTP53:p.R213*:c.637C>T\tNonsense\tp.R213*\tc.637C>T\tCOSM10654\t\nTP53:p.R196*:c.586C>T\tNonsense\tp.R196*\tc.586C>T\tCOSM10705\t\nTP53:p.H179R:c.536A>G\tMissense\tp.H179R\tc.536A>G\tCOSM10889\t\nTP53:p.C176F:c.527G>T\tMissense\tp.C176F\tc.527G>T\tCOSM10645\t\nTP53:p.R175H:c.524G>A\tMissense\tp.R175H\tc.524G>A\tCOSM10648\t\nTP53:p.Y163C:c.488A>G\tMissense\tp.Y163C\tc.488A>G\tCOSM10808\t\nTP53:p.V157F:c.469G>T\tMissense\tp.V157F\tc.469G>T\tCOSM10670\n==== Refs\nReferences\n1 Jemal A Bray F Center MM Ferlay J Ward E Forman D Global cancer statistics CA Cancer J Clin 61 69 90 2011 10.3322/caac.20107 21296855 \n2 Siegel R Ma J Zou Z Jemal A Cancer statistics, 2014 CA Cancer J Clin 64 9 29 2014 10.3322/caac.21208 24399786 \n3 Potrykowska A Strzelecki Z Szymborski J Witkowski J Cancer incidence and mortality versus the demographic situation of Poland Rządowa Rada Ludnościowa Warsaw 117 130 2014 (In Polish) \n4 Paik ES Lee YY Lee EJ Choi CH Kim TJ Lee JW Bae DS Kim BG Survival analysis of revised 2013 FIGO staging classification of epithelial ovarian cancer and comparison with previous FIGO staging classification Obstet Gynecol Sci 58 124 134 2015 10.5468/ogs.2015.58.2.124 25798426 \n5 Suh DH Kim TH Kim JW Kim SY Kim HS Lee TS Chung HH Kim YB Park NH Song YS Improvements to the FIGO staging for ovarian cancer: Reconsideration of lymphatic spread and intraoperative tumor rupture J Gynecol Oncol 24 352 358 2013 10.3802/jgo.2013.24.4.352 24167671 \n6 van der Burg ME van Lent M Buyse M Kobierska A Colombo N Favalli G Lacave AJ Nardi M Renard J Pecorelli S The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological cancer cooperative group of the European Organization for research and treatment of cancer N Engl J Med 332 629 634 1995 10.1056/NEJM199503093321002 7845426 \n7 Raja FA Chopra N Ledermann JA Optimal first-line treatment in ovarian cancer Ann Oncol 23 (Suppl 10) x118 x127 2012 10.1093/annonc/mds315 22987945 \n8 Lloyd KL Cree IA Savage RS Prediction of resistance to chemotherapy in ovarian cancer: A systematic review BMC Cancer 15 117 2015 10.1186/s12885-015-1101-8 25886033 \n9 Pliarchopoulou K Pectasides D Epithelial ovarian cancer: Focus on targeted therapy Crit Rev Oncol Hematol 79 17 23 2011 10.1016/j.critrevonc.2010.07.004 20674385 \n10 Zhu LC Gao J Hu ZH Schwab CL Zhuang HY Tan MZ Yan LM Liu JJ Zhang DY Lin B Membranous expressions of Lewis y and CAM-DR-related markers are independent factors of chemotherapy resistance and poor prognosis in epithelial ovarian cancer Am J Cancer Res 5 830 843 2015 25973320 \n11 Vinogradov S Wei X Cancer stem cells and drug resistance: The potential of nanomedicine Nanomedicine (Lond) 7 597 615 2012 10.2217/nnm.12.22 22471722 \n12 Markman M Bookman MA Second-line treatment of ovarian cancer Oncologist 5 26 35 2000 10.1634/theoncologist.5-1-26 10706647 \n13 Cooley M Fang P Fang F Nephew KP Chien J Molecular determinants of chemotherapy resistance in ovarian cancer Pharmacogenomics 16 1763 1767 2015 10.2217/pgs.15.130 26554863 \n14 Foster JM Oumie A Togneri FS Vasques FR Hau D Taylor M Tinkler-Hundal E Southward K Medlow P McGreeghan-Crosby K Cross-laboratory validation of the OncoScan® FFPE Assay, a multiplex tool for whole genome tumour profiling BMC Med Genomics 8 5 2015 10.1186/s12920-015-0079-z 25889064 \n15 Bast RC Jr Hennessy B Mills GB The biology of ovarian cancer: New opportunities for translation Nat Rev Cancer 9 415 428 2009 10.1038/nrc2644 19461667 \n16 Musrap N Tuccitto A Karagiannis GS Saraon P Batruch I Diamandis EP Comparative proteomics of ovarian cancer aggregate formation reveals an increased expression of calcium-activated chloride channel regulator 1 (CLCA1) J Biol Chem 290 17218 17227 2015 10.1074/jbc.M115.639773 26004777 \n17 Burleson KM Casey RC Skubitz KM Pambuccian SE Oegema TR Jr Skubitz AP Ovarian carcinoma ascites spheroids adhere to extracellular matrix components and mesothelial cell monolayers Gynecol Oncol 93 170 181 2004 10.1016/j.ygyno.2003.12.034 15047232 \n18 Høgdall E Cancer antigen 125 and prognosis Curr Opin Obstet Gynecol 20 4 8 2008 10.1097/GCO.0b013e3282f2b124 18196998 \n19 Gadducci A Cosio S Fanucchi A Negri S Cristofani R Genazzani AR The predictive and prognostic value of serum CA 125 half-life during paclitaxel/platinum-based chemotherapy in patients with advanced ovarian carcinoma Gynecol Oncol 93 131 136 2004 10.1016/j.ygyno.2003.12.043 15047226 \n20 Menon U Skates SJ Lewis S Rosenthal AN Rufford B Sibley K Macdonald N Dawnay A Jeyarajah A Bast RC Jr Prospective study using the risk of ovarian cancer algorithm to screen for ovarian cancer J Clin Oncol 23 7919 7926 2005 10.1200/JCO.2005.01.6642 16258091 \n21 Hasanbegovic L Alicelebic S Sljivo N Comparison of specific ovarian tumor markers by elecsys analyzer 2010 Acta Inform Med 23 86 89 2015 10.5455/aim.2015.23.86-89 26005273 \n22 Hellström I Raycraft J Hayden-Ledbetter M Ledbetter JA Schummer M McIntosh M Drescher C Urban N Hellström KE The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma Cancer Res 63 3695 3700 2003 12839961 \n23 Moore RG MacLaughlan S Bast RC Jr Current state of biomarker development for clinical application in epithelial ovarian cancer Gynecol Oncol 116 240 245 2010 10.1016/j.ygyno.2009.09.041 19879639 \n24 Huhtinen K Suvitie P Hiissa J Junnila J Huvila J Kujari H Setälä M Härkki P Jalkanen J Fraser J Serum HE4 concentration differentiates malignant ovarian tumours from ovarian endometriotic cysts Br J Cancer 100 1315 1319 2009 10.1038/sj.bjc.6605011 19337252 \n25 Moore RG Miller MC Steinhoff MM Skates SJ Lu KH Lambert-Messerlian G Bast RC Jr Serum HE4 levels are less frequently elevated than CA125 in women with benign gynecologic disorders Am J Obstet Gynecol 206 351 e1 8 2012 \n26 Górski B Byrski T Huzarski T Jakubowska A Menkiszak J Gronwald J Pluzańska A Bebenek M Fischer-Maliszewska L Grzybowska E Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer Am J Hum Genet 66 1963 1968 2000 10.1086/302922 10788334 \n27 Herman JG Umar A Polyak K Graff JR Ahuja N Issa JP Markowitz S Willson JK Hamilton SR Kinzler KW Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma Proc Natl Acad Sci USA 95 6870 6875 1998 10.1073/pnas.95.12.6870 9618505 \n28 Curia MC Palmirotta R Aceto G Messerini L Verì MC Crognale S Valanzano R Ficari F Fracasso P Stigliano V Unbalanced germ-line expression of hMLH1 and hMSH2 alleles in hereditary nonpolyposis colorectal cancer Cancer Res 59 3570 3575 1999 10446963 \n29 Debniak T Kurzawski G Gorski B Kladny J Domagala W Lubinski J Value of pedigree/clinical data, immunohistochemistry and microsatellite instability analyses in reducing the cost of determining hMLH1 and hMSH2 gene mutations in patients with colorectal cancer Eur J Cancer 36 49 54 2000 10.1016/S0959-8049(99)00208-7 10741294 \n30 Ali AY Farrand L Kim JY Byun S Suh JY Lee HJ Tsang BK Molecular determinants of ovarian cancer chemoresistance: New insights into an old conundrum Ann N Y Acad Sci 1271 58 67 2012 10.1111/j.1749-6632.2012.06734.x 23050965 \n31 Thibault B Castells M Delord JP Couderc B Ovarian cancer microenvironment: Implications for cancer dissemination and chemoresistance acquisition Cancer Metastasis Rev 33 17 39 2014 10.1007/s10555-013-9456-2 24357056 \n32 Li M Yin J Mao N Pan L Upregulation of phosphorylated cofilin 1 correlates with taxol resistance in human ovarian cancer in vitro and in vivo Oncol Rep 29 58 66 2013 23064469 \n33 Mok SC Bonome T Vathipadiekal V Bell A Johnson ME Wong KK Park DC Hao K Yip DK Donninger H A gene signature predictive for outcome in advanced ovarian cancer identifies a survival factor: Microfibril-associated glycoprotein 2 Cancer Cell 16 521 532 2009 10.1016/j.ccr.2009.10.018 19962670 \n34 Fullwood P Marchini S Rader JS Martinez A Macartney D Broggini M Morelli C Barbanti-Brodano G Maher ER Latif F Detailed genetic and physical mapping of tumor suppressor loci on chromosome 3p in ovarian cancer Cancer Res 59 4662 4667 1999 10493522 \n35 Chng HW Camplejohn RS Stone MG Hart IR Nicholson LJ A new role for the anti-apoptotic gene A20 in angiogenesis Exp Cell Res 312 2897 2907 2006 10.1016/j.yexcr.2006.05.015 16824518 \n36 Shridhar V Staub J Huntley B Cliby W Jenkins R Pass HI Hartmann L Smith DI A novel region of deletion on chromosome 6q23.3 spanning less than 500 Kb in high grade invasive epithelial ovarian cancer Oncogene 18 3913 3918 1999 10.1038/sj.onc.1202756 10445856 \n37 Shayesteh L Lu Y Kuo WL Baldocchi R Godfrey T Collins C Pinkel D Powell B Mills GB Gray JW PIK3CA is implicated as an oncogene in ovarian cancer Nat Genet 21 99 102 1999 10.1038/5042 9916799 \n38 Cheaib B Auguste A Leary A The PI3K/Akt/mTOR pathway in ovarian cancer: Therapeutic opportunities and challenges Chin J Cancer 34 4 16 2015 10.5732/cjc.014.10289 25556614 \n39 Friedlander ML Russell K Millis S Gatalica Z Bender R Voss A Molecular profiling of clear cell ovarian cancers: Identifying potential treatment targets for clinical trials Int J Gynecol Cancer 26 648 654 2016 10.1097/IGC.0000000000000677 26937756\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1792-1074",
"issue": "14(3)",
"journal": "Oncology letters",
"keywords": "efficacy of the treatment; microarrays; ovarian adenocarcinoma; point gene mutations",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "3401-3414",
"pmc": null,
"pmid": "28927094",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": "22987945;25556614;24167671;10445856;25973320;9916799;20674385;26005273;16258091;19337252;16824518;26937756;24357056;10788334;18196998;15047226;25889064;7845426;15047232;10706647;26554863;10446963;25798426;26004777;23064469;12839961;9618505;10741294;19879639;24399786;21296855;23050965;19962670;19461667;22471722;22284961;10493522;25886033",
"title": "Genomic markers of ovarian adenocarcinoma and its relevancy to the effectiveness of chemotherapy.",
"title_normalized": "genomic markers of ovarian adenocarcinoma and its relevancy to the effectiveness of chemotherapy"
} | [
{
"companynumb": "PL-JNJFOC-20190539937",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "The most common type of infective endocarditis is bacterial endocarditis. However, fungal infections have been seen more frequently, mostly in the immunocompromised population. We report a case of invasive Aspergillus fumigatus native mitral valve endocarditis. The patient received appropriate empiric antifungal treatment with a combination of liposomal amphotericin B and flucytosine, associated with surgical debridement, valve replacement and chordae tendineae repair. Despite receiving the standard treatment of Aspergillus endocarditis, and susceptibility of the microorganism to the antifungal regimen, the patient, unexpectedly, developed early-onset septic emboli. It is surprising to see that the patient had developed such complications early, despite attempts to eliminate the source of infection with surgical intervention.",
"affiliations": "Department of Medicine, Western University, London, Ontario, Canada.;Department of Cardiology, Western University, London, Ontario, Canada.;Department of Cardiology, Western University, London, Ontario, Canada.;Department of Medicine, Western University, London, Ontario, Canada.",
"authors": "Rofaiel|Rymon|R|;Turkistani|Yosra|Y|;McCarty|David|D|;Hosseini-Moghaddam|Seyed M|SM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-217281",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001228:Aspergillosis; D001230:Aspergillus; D004452:Echocardiography; D004697:Endocarditis, Bacterial; D005260:Female; D006801:Humans; D008875:Middle Aged; D008943:Mitral Valve",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27932432",
"pubdate": "2016-12-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": "11431671;3935042;11999005;8635345;7695378;16585653;21036091;10770721;22644820;4206485;26373316;9352973;11118386;8838182;20061772;18331447;10685447;6340215;18491965;8838195;15975413;3934969;10914055;23466974;18397213;10941355;9100737;17420802;2003709;11846535;17710627;22086858;19191635",
"title": "Fungal mobile mass on echocardiogram: native mitral valve Aspergillus fumigatus endocarditis.",
"title_normalized": "fungal mobile mass on echocardiogram native mitral valve aspergillus fumigatus endocarditis"
} | [
{
"companynumb": "CA-FRESENIUS KABI-FK201702173",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IDARUBICIN HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "Anti-PD-L1/PD-1 immunotherapy has improved survival for certain patients with metastatic urothelial carcinoma. However, the mechanisms of resistance to these agents have not been fully elucidated. We report the first combined analysis using RNA sequencing, whole-exome sequencing (WES), and flow cytometry of multiple tumor specimens over a 5-yr period for a patient undergoing anti-PD-L1 therapy. Initial sensitivity to anti-PD-L1 immunotherapy was associated with conversion to a basal molecular subtype and a rising tumor mutational burden. We found that as the tumor became more resistant to anti-PD-L1, the proportion of regulatory T cells and CD8+ T cells expressing alternative immune checkpoints including CTLA-4, TIM-3, and LAG-3 increased. This suggests that alternative immune checkpoint upregulation may be one form of anti-PD-L1 resistance in urothelial carcinoma. These data support the concept of combined immune checkpoint blockade for urothelial carcinoma, a concept that is being evaluated in prospective clinical trials. PATIENT SUMMARY: In this study we characterized how a patient with metastatic urothelial cancer became resistant to anti-PD-L1 immunotherapy. By tracking changes in protein and gene expression over time, we found that as urothelial carcinoma becomes resistant to PD-L1 blockade, additional immune checkpoints may be upregulated. These data support the concept of combined checkpoint blockade for urothelial carcinoma.",
"affiliations": "Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Greenberg Bladder Cancer Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA. Electronic address: mkates@jhmi.edu.;Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.;Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.;Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.;Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Greenberg Bladder Cancer Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.;Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX, USA.;Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX, USA.;Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.;Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Greenberg Bladder Cancer Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.;Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Greenberg Bladder Cancer Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.;Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.;Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Greenberg Bladder Cancer Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.",
"authors": "Kates|Max|M|;Nirschl|Thomas R|TR|;Baras|Alex S|AS|;Sopko|Nikolai A|NA|;Hahn|Noah M|NM|;Su|Xiaoping|X|;Zhang|Jiexin|J|;Kochel|Christina M|CM|;Choi|Woonyoung|W|;McConkey|David J|DJ|;Drake|Charles G|CG|;Bivalacqua|Trinity J|TJ|",
"chemical_list": "D060890:B7-H1 Antigen; D000082082:Immune Checkpoint Inhibitors",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.euo.2019.01.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2588-9311",
"issue": "4(1)",
"journal": "European urology oncology",
"keywords": "Bladder cancer; Immune checkpoint blockade",
"medline_ta": "Eur Urol Oncol",
"mesh_terms": "D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes; D002295:Carcinoma, Transitional Cell; D005434:Flow Cytometry; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D011446:Prospective Studies; D050378:T-Lymphocytes, Regulatory; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "101724904",
"other_id": null,
"pages": "117-120",
"pmc": null,
"pmid": "31411999",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Combined Next-generation Sequencing and Flow Cytometry Analysis for an Anti-PD-L1 Partial Responder over Time: An Exploration of Mechanisms of PD-L1 Activity and Resistance in Bladder Cancer.",
"title_normalized": "combined next generation sequencing and flow cytometry analysis for an anti pd l1 partial responder over time an exploration of mechanisms of pd l1 activity and resistance in bladder cancer"
} | [
{
"companynumb": "US-CIPLA LTD.-2021US01389",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"drugadditional": "3",
... |
{
"abstract": "The development of trastuzumab and other targeted systemic therapies has transformed the management of HER-2 positive breast cancers. However, as patients live longer and systemic therapies may not cross the blood brain barrier a rising number of patients are developing leptomeningeal metastases and brain metastases as a sanctuary site of disease. Intrathecal trastuzumab has been reported to treat these. We describe a breast cancer patient with HER-2 positive leptomeningeal disease in the spinal cord successfully treated with intrathecal trastuzumab and methotrexate, alongside systemic anti-HER-2 therapy and radiotherapy. We also review the literature to date on the efficacy and safety of intrathecal trastuzumab, and recent evidence suggesting that intrathecal trastuzumab passes via the blood brain barrier into the serum to achieve intravenous concentrations similar to that seen with systemic therapy alone. Overall, intrathecal trastuzumab appears to be a safe and often effective treatment for leptomeningeal metastases in HER-2 positive breast cancer. Ongoing phase I and II studies are required to determine optimum dosing schedules, validate CSF and CSF-to-serum pharmacokinetics, determine efficacy, and to assess the added benefits or disadvantages of prior radiotherapy and concomitant systemic therapy.",
"affiliations": "The Royal Marsden, London, UK. Electronic address: tianakordbacheh@nhs.net.;The Royal Marsden, London, UK.;The Royal Marsden, London, UK.",
"authors": "Kordbacheh|T|T|;Law|W Y|WY|;Smith|I E|IE|",
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"keywords": "HER-2 positive; Intrathecal trastuzumab (Herceptin); Leptomeningeal metastases; Metastatic breast cancer",
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"mesh_terms": "D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D008577:Meningeal Neoplasms; D008727:Methotrexate; D008875:Middle Aged; D018719:Receptor, ErbB-2; D013120:Spinal Cord Neoplasms; D000068878:Trastuzumab",
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"title": "Sanctuary site leptomeningeal metastases in HER-2 positive breast cancer: A review in the era of trastuzumab.",
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"abstract": "Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by abnormal proliferation of skin and osseous tissue frequently associated with underlying pulmonary disorders. Cardinal features include digital clubbing, periostitis and significant joint and bone pain. A number of recent reports have emerged of HOA and periostitis occurring in association with the antifungal agent voriconazole.\n\n\n\nWe present two additional cases of voriconazole-induced HOA and periostitis in lung transplant recipients with a review the medical literature.\n\n\n\nIn both cases, symptoms were painful and severe enough to require opioid medication. Rapid improvement occurred within days of voriconazole cessation. A review of existing literature revealed an additional 17 cases of voriconazole-induced HOA and periostitis in lung transplant patients.\n\n\n\nWe highlight the importance of recognizing the association of voriconazole with painful HOA and periostitis in lung transplant patients receiving antifungal therapy. Management of this painful condition involves cessation of voriconazole therapy, which may necessitate alternative anti-fungal drug therapies as well as adjustment of immunosuppressive drug dosage since voriconazole is a strong drug-inducer.",
"affiliations": "Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 822, Charleston, SC 29401, USA.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Medical University of South Carolina, Charleston, SC 29401, USA.;Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC 29401, USA.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Medical University of South Carolina, Charleston, SC 29401, USA.;Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 822, Charleston, SC 29401, USA. Electronic address: silverr@musc.edu.",
"authors": "Elmore|Stephen|S|;Wisse|Amy|A|;Chapin|Russell W|RW|;Whelan|Timothy P|TP|;Silver|Richard M|RM|",
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"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D003550:Cystic Fibrosis; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D017563:Lung Diseases, Interstitial; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D010005:Osteoarthropathy, Secondary Hypertrophic; D010522:Periostitis; D011183:Postoperative Complications; D065819:Voriconazole",
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"title": "Voriconazole-associated periostitis presenting as hypertrophic osteoarthropathy following lung transplantation report of two cases and review of the literature.",
"title_normalized": "voriconazole associated periostitis presenting as hypertrophic osteoarthropathy following lung transplantation report of two cases and review of the literature"
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"abstract": "Radioligand therapy with 177Lu-PSMA-617 has emerged as a promising treatment modality for patients with mCRPC (metastatic castration resistant prostate cancer). However, genomic defects in DNA damage repair mechanisms have been proposed to affect the radiosensitivity of prostate cancers. Patients harboring such deleterious mutations are, thus, unlikely to respond to 177Lu-PSMA-617 alone and would need a more tailored therapeutic approach. We report the case of a 68-year-old man with ATM mutation-positive mCRPC who showed exceptional response to concomitant administration of enzalutamide with 177Lu-PSMA-617.",
"affiliations": "From the Department of Nuclear Medicine.;Medical Oncology, Regional Cancer Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;From the Department of Nuclear Medicine.;From the Department of Nuclear Medicine.;From the Department of Nuclear Medicine.",
"authors": "Satapathy|Swayamjeet|S|;Das|Chandan Krushna|CK|;Parihar|Ashwin Singh|AS|;Sood|Ashwani|A|;Mittal|Bhagwant R|BR|",
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"title": "Response to Concomitant Enzalutamide and 177Lu-PSMA-617 Radioligand Therapy in ATM-Mutated Metastatic Castration Resistant Prostate Cancer.",
"title_normalized": "response to concomitant enzalutamide and 177lu psma 617 radioligand therapy in atm mutated metastatic castration resistant prostate cancer"
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"abstract": "The coexistence of multiple myeloma and chronic myeloid leukemia in a single patient is a very rare event that has been reported very infrequently in the literature. We report a case of a patient who developed chronic myeloid leukemia four years after his diagnosis with multiple myeloma. Historically, no link between the two malignancies has been identified. This synchronous existence complicates the treatment plan for these patients, and there is a lack of evidence on the best therapeutic approach. Our patient was successfully treated with a combination of bortezomib, dexamethasone, and dasatinib, which he tolerated well for eleven months until he eventually succumbed to cardiac complications and pulmonary hypertension leading to his death.",
"affiliations": "Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.;Division of Hematology-Oncology, Department of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.;Department of Pathology, University of Cincinnati, Cincinnati, OH 45267, USA.;Division of Hematology-Oncology, Department of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.",
"authors": "Alsidawi|Samer|S|0000-0002-8440-5587;Ghose|Abhimanyu|A|0000-0001-6524-0476;Qualtieri|Julianne|J|0000-0003-1005-622X;Radhakrishnan|Neetu|N|",
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"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi Publishing Corporation 10.1155/2014/962526Case ReportA Case of Multiple Myeloma with Metachronous Chronic Myeloid Leukemia Treated Successfully with Bortezomib, Dexamethasone, and Dasatinib http://orcid.org/0000-0002-8440-5587Alsidawi Samer \n1\nhttp://orcid.org/0000-0001-6524-0476Ghose Abhimanyu \n2\nhttp://orcid.org/0000-0003-1005-622XQualtieri Julianne \n3\nRadhakrishnan Neetu \n2\n\n*\n1Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA2Division of Hematology-Oncology, Department of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA3Department of Pathology, University of Cincinnati, Cincinnati, OH 45267, USA*Neetu Radhakrishnan: radhaknu@ucmail.uc.eduAcademic Editor: Josep M. Ribera\n\n2014 2 12 2014 2014 9625262 9 2014 15 11 2014 Copyright © 2014 Samer Alsidawi et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The coexistence of multiple myeloma and chronic myeloid leukemia in a single patient is a very rare event that has been reported very infrequently in the literature. We report a case of a patient who developed chronic myeloid leukemia four years after his diagnosis with multiple myeloma. Historically, no link between the two malignancies has been identified. This synchronous existence complicates the treatment plan for these patients, and there is a lack of evidence on the best therapeutic approach. Our patient was successfully treated with a combination of bortezomib, dexamethasone, and dasatinib, which he tolerated well for eleven months until he eventually succumbed to cardiac complications and pulmonary hypertension leading to his death.\n==== Body\n1. Introduction\nMultiple myeloma (MM) is a plasma cell dyscrasia characterized by an uncontrolled proliferation of a single plasma cell clone leading to overproduction of a monoclonal immunoglobulin. MM is an overall uncommon malignancy accounting for approximately 1% of all cancers in the Unites States [1]. Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by uncontrolled proliferation of mature granulocytes. CML is associated with the fusion of two genes: BCR (on chromosome 22) and ABL1 (on chromosome 9) resulting in the BCR-ABL1 fusion gene which gives rise to an abnormal chromosome 22 known as the Philadelphia chromosome which is closely linked to the pathogenesis of this malignancy. CML is also considered an uncommon malignancy with an annual incidence of 1 to 2 cases per 100.000 [2]. About 10 to 15 percent of patients with CML initially present in the accelerated phase or blast phase of the disease which resembles an acute leukemia. The cooccurrence of MM and CML in one patient is an extremely rare incident that has been reported in less than 20 cases in the literature and their simultaneous presence or management is not yet fully understood. Here we present the case of a patient who achieved good response to his MM treatment but presented with CML four years after his MM diagnosis which further complicated his treatment plan.\n\n2. Case Presentation\nA 60-year-old African American male with beta-thalassemia minor, diabetes mellitus, and hypertension was diagnosed with IgG Kappa multiple myeloma (MM) in 2008 after a minor mechanical fall resulted in a right femur fracture. His X-rays showed multiple lytic lesions of the right femur. Labs at diagnosis were significant for microcytic anemia with a hemoglobin of 12.3 g/dL and a mean corpuscular volume (MCV) of 67 fL, normal white blood cells (WBC) and platelet counts, an M-spike of 3.9 g/dL on his serum protein electrophoresis (SPEP) with the immunofixation significant for a monoclonal IgG Kappa, and a high Kappa/Lambda ratio. There was 70% involvement of the bone marrow with plasma cells and the cytogenetic analysis was significant for male karyotype with trisomy of chromosome 3 and deletion of Y chromosome in 4 out of 20 cells. The patient was treated with radiation to his femur after an orthopedic procedure and this was followed by five cycles of lenalidomide 25 mg daily on days 1–21 and dexamethasone 40 mg daily on days 1, 8, 15, and 22 every 4 weeks followed by bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 every 3 weeks. The patient achieved stable disease with this regimen and he received no further treatment for almost four years. Meanwhile, he was being followed up regularly with clinical and laboratory assessments, serial serum protein electrophoresis with immunofixation, and free light chains. In 2012, four years after his initial diagnosis and treatment, the patient was found to have a relapse of his MM with an increase in his M-spike to >2 g/dL. Labs showed hemoglobin of 9.5 g/dL, WBC of 11.2 × 103/mm3 with a normal differential except for slightly elevated eosinophils, and platelet count of 509 × 103/mm3. Skeletal survey showed increase in his myeloma lytic bone lesions. A bone marrow aspirate and biopsy was done which demonstrated a hypercellular marrow with trilineage hematopoiesis, increased myeloid cell series (M : E ratio 4 : 1) with eosinophilia, and 15–20% monoclonal plasmacytosis based on CD138 immunostaining (Figure 1). The cytogenetics showed 46 XY t(9;22) (q34;q11.2) in 8 out of 15 cells and the fluorescent in situ hybridization (FISH) was consistent with BCR/ABL translocation in 72.8% of cells. Interestingly, no trisomy of chromosome 3 or deletion of Y chromosome was detected in the cells examined—which could be explained by their low levels and the small number of metaphases examined. It was decided to control the patient's myeloma first prior to starting a tyrosine kinase inhibitor (TKI) for his CML as there was evidence of an aggressive myeloma progression with the sudden increase in his bony lesions, while his WBC was normal at the time. He was started again on lenalidomide 25 mg every 3 weeks and dexamethasone 20 mg weekly. Three months later, the patient presented with symptoms of fatigue, malaise, abdominal discomfort, and generalized weakness. The M spike was 1.8 g/dL, WBC count 42.7 103/mm3, and platelet count of 2472 103/mm3. There was an increased number of myelocytes, metamyelocytes, bands, mature neutrophils with rare blasts (approximately 1% of total cells), and increased basophils (4.2%). He underwent a bone marrow aspirate and biopsy that showed a hypercellular bone marrow with significantly increased myeloid progenitor population with a blast count of 37% in background of a myeloproliferative disorder, favoring transformation to acute myeloid leukemia (Figure 2). Unfortunately, the initial bone marrow biopsy from his MM diagnosis was not available to be examined for CML. A diagnosis of chronic myeloid leukemia in blast phase was made and cytoreductive treatment was started with hydration and hydroxyurea (up to 4 g/days) and subsequently he was started on dasatinib 140 mg daily. The patient reached major molecular response four months after treatment and complete molecular response four months after that. He was kept on maintenance treatment with dasatinib 100 mg daily. The treatment for the MM with lenalidomide was stopped when the patient presented in blast crisis. In 3 months, the patient had a quick progression of multiple myeloma with an increase of his M-spike to 2.5 g/dL and new diffuse lytic bone lesions. Treatment with weekly bortezomib 0.7 mg/m2 which was later increased to 1.3 mg/m2 weekly and dexamethasone 20 mg on days 1, 4, 8, and 11 of a 21-day cycle was restarted, concurrent with dasatinib. The patient tolerated the treatment combination of bortezomib and dasatinib well. He continued to show complete molecular response of his CML and he initially showed a good response of his MM as his M-spike stabilized around 1.9 g/dL transiently before increasing back to 2.3 g/dL again. One year from the start of dasatinib, the patient had an acute myocardial infarction. Dasatinib was continued while bortezomib and dexamethasone were discontinued which resulted in an improvement in his anemia while his M-spike remained stable. About five months later, he was admitted with pulmonary artery hypertension (PAH) with a mean pulmonary arterial pressure of 50–55 mm Hg on right heart catheterization. It was assumed that this was due to either the dasatinib or a diet pill that he admitted to taking over the counter or due to a combination of his comorbidities. Although dasatinib was stopped, he eventually succumbed to respiratory failure due to PAH 18 months after his CML diagnosis.\n\n3. Discussion\nThe cooccurrence of MM and CML is a very rare entity that has been reported in less than twenty cases in the literature. There are only four reported cases where the diagnosis of MM preceded the diagnosis of CML [3–6]. Many of the reported cases in which the diagnosis of MM followed a long treatment course of CML [7–11] with the tyrosine kinase inhibitor, imatinib, suggested a link between this treatment and the development of MM. However, almost half of the reported cases of these two entities coexisting in a single patient are of patients who either developed MM first or were diagnosed with the two malignancies simultaneously [12–17]. This makes a link between imatinib and the development of MM very unlikely. Similarly, MM treatment does not seem to lead to the development of CML as the reported patients were treated for MM using regimens consisting of multiple different and unrelated agents. There is no evidence in the literature to suggest that either lenalidomide or bortezomib can lead to the development of CML. Lenalidomide is now known to be a risk factor for secondary malignancies, but it is usually nonmelanoma skin cancers and myelodysplastic syndromes [18]. The finding of Philadelphia chromosome in the bone marrow is an indicator of a myeloproliferative disease; however, there are reported cases of patients with MM with this translocation [19, 20]. The significance of such finding is unknown.\n\nIn the case presented above, we show that the combination of bortezomib and dasatinib was well tolerated. This represents the first case in which a patient with MM and CML received concurrent treatment with bortezomib, dexamethasone, and dasatinib. Pulmonary arterial hypertension is a known complication of dasatinib and is commonly seen after 8 to 48 months of treatment [21–24]. Although less common, pulmonary arterial hypertension has been reported with bortezomib as well [25, 26]. It was unclear if dasatinib was the only culprit in our patient's pulmonary hypertension as he also sustained a cardiac event and he later admitted to taking an unknown “diet pill” which might have all contributed to developing pulmonary hypertension. Most cases of pulmonary hypertension after dasatinib described near complete regression of this side effect after cessation of the drug. However, there are cases of refractory pulmonary hypertension that required treatment despite the withdrawal of dasatinib [27].\n\n4. Conclusion\nThe cooccurrence of MM and CML is an extremely rare entity that creates dilemmas in the management of these two separate malignancies. We present our experience in a patient whose treatment of MM was complicated by the development of CML that quickly progressed into the blast phase. We found that the combination of bortezomib, dexamethasone, and dasatinib was well tolerated; however, special attention needs to be paid to the individual side effects of these medications.\n\nDisclosure\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Bone marrow aspirate showing a hypercellular marrow with trilineage hematopoiesis and increased myeloid cell series (M : E ratio 4 : 1) with eosinophilia and plasmacytosis (approximately 15 to 20%).\n\nFigure 2 Bone marrow with markedly increased population of cells >20%, morphologically consistent with blasts.\n==== Refs\n1 Siegel R. Ma J. Zou Z. Jemal A. Cancer statistics, 2014 CA Cancer Journal for Clinicians 2014 64 1 9 29 10.3322/caac.21208 2-s2.0-84892805731 \n2 Chen Y. Wang H. Kantarjian H. Cortes J. Trends in chronic myeloid leukemia incidence and survival in the United States from 1975 to 2009 Leukemia and Lymphoma 2013 54 7 1411 1417 10.3109/10428194.2012.745525 2-s2.0-84877736487 23121646 \n3 Nitta M. Tsuboi K. Yamashita S. Kato M. Hayami Y. Harada S. Komatsu H. Iida S. Banno S. Wakita A. Ueda R. Multiple myeloma preceding the development of chronic myelogenous leukemia International Journal of Hematology 1999 69 3 170 173 2-s2.0-0033113498 10222655 \n4 Klenn P. J. Hyun B. H. Lee Y. H. Zheng W. Y. Multiple myeloma and chronic myelogenous leukemia: a case report with literature review Yonsei Medical Journal 1993 34 3 293 300 10.3349/ymj.1993.34.3.293 2-s2.0-0027655660 8259707 \n5 Ragupathi L. Najfeld V. Chari A. Petersen B. Jagannath S. Mascarenhas J. A case report of chronic myelogenous leukemia in a patient with multiple myeloma and a review of the literature Clinical Lymphoma Myeloma and Leukemia 2012 13 2 175 179 10.1016/j.clml.2012.09.010 \n6 Caparrotti G. Esposito D. Graziani F. De F. G. Pagiani D. Development of chronic myeloid leukemia in a patient with multiple myeloma: a case report Haematologica 2007 92 183 \n7 Derghazarian C. Whittemore N. B. Multiple myeloma superimposed on chronic myelocytic leukemia Canadian Medical Association Journal 1974 110 9 1047 1050 2-s2.0-0016231288 4522851 \n8 Ide M. Kuwahara N. Matsuishi E. Kimura S. Gondo H. Uncommon case of chronic myeloid leukemia with multiple myeloma International Journal of Hematology 2010 91 4 699 704 2-s2.0-77954540630 10.1007/s12185-010-0546-4 20352382 \n9 Michael M. Antoniades M. Lemesiou E. Papaminas N. Melanthiou F. Development of multiple myeloma in a patient with chronic myeloid leukemia while on treatment with imatinib mesylate for 65 months Oncologist 2009 14 12 1198 1200 2-s2.0-75449085967 10.1634/theoncologist.2009-0165 19955186 \n10 Galanopoulos A. Papadhimitriou S. I. Kritikou-Griva E. Georgiakaki M. Anagnostopoulos N. I. Multiple myeloma developing after imatinib mesylate therapy for chronic myeloid leukemia Annals of Hematology 2009 88 3 281 282 10.1007/s00277-008-0597-2 2-s2.0-59049083736 18726593 \n11 Garipidou V. Vakalopoulou S. Tziomalos K. Development of multiple myeloma in a patient with chronic myeloid leukemia after treatment with imatinib mesylate The Oncologist 2005 10 6 457 458 10.1634/theoncologist.10-6-457 2-s2.0-22244458317 15967839 \n12 Schwarzmeier J. D. Shehata M. Ackermann J. Hilgarth M. Kaufmann H. Drach J. Simultaneous occurrence of chronic myeloid leukemia and multiple myeloma: evaluation by FISH analysis and in vitro expansion of bone marrow cells Leukemia 2003 17 7 1426 1428 10.1038/sj.leu.2402971 2-s2.0-0037765477 12835740 \n13 Alvarez-Larrán A. Rozman M. Cervantes F. Simultaneous occurrence of multiple myeloma and chronic myeloid leukemia Haematologica 2001 86 8 894 2-s2.0-0034847778 11524262 \n14 Tanaka M. Kimura R. Matsutani A. Zaitsu K. Oka Y. Oizumi K. Coexistence of chronic myelogenous leukemia and multiple myeloma: case report and review of the literature Acta Haematologica 1998 99 4 221 223 10.1159/000040843 2-s2.0-0031982372 9644301 \n15 Boots M. A. Pegrum G. D. Simultaneous presentation of chronic granulocytic leukaemia and multiple myeloma Journal of Clinical Pathology 1982 35 3 364 365 10.1136/jcp.35.3.364 2-s2.0-0020111359 6950954 \n16 Offiah C. Murphy P. T. Quinn J. P. Thornton P. Co-existing chronic myeloid leukaemia and multiple myeloma: rapid response to lenalidomide during imatinib treatment International Journal of Hematology 2012 95 4 451 452 10.1007/s12185-012-1038-5 2-s2.0-84862894516 22426625 \n17 Romanenko N. A. Bessmel'tsev S. S. Udal'eva V. I. Zenina M. N. Martynkevich I. S. Rugal' V. I. Abdulkadyrov K. M. The combination of chronic myeloid leukemia and multiple myeloma in one patient Voprosy Onkologii 2013 59 2 103 110 2-s2.0-84880837898 23814859 \n18 Dimopoulos M. A. Richardson P. G. Brandenburg N. Yu Z. Weber D. M. Niesvizky R. Morgan G. J. A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide Blood 2012 119 12 2764 2767 10.1182/blood-2011-08-373514 2-s2.0-84858858229 22323483 \n19 Ranni N. S. Slavutsky I. Wechsler A. de Salum S. B. Chromosome findings in multiple myeloma Cancer Genetics and Cytogenetics 1987 25 2 309 316 10.1016/0165-4608(87)90192-0 2-s2.0-0023121035 3470119 \n20 Martiat P. Mecucci C. Nizet Y. Stul M. Philippe M. Cassiman J. J. Michaux J. L. Van den Berghe H. Sokal G. P190 BCR/ABL transcript in a case of Philadelphia-positive multiple myeloma Leukemia 1990 4 11 751 754 2-s2.0-0025076983 2232886 \n21 Montani D. Bergot E. Günther S. Savale L. Bergeron A. Bourdin A. Bouvaist H. Canuet M. Pison C. MacRo M. Poubeau P. Girerd B. Natali D. Guignabert C. Perros F. O'Callaghan D. S. Jaïs X. Tubert-Bitter P. Zalcman G. Sitbon O. Simonneau G. Humbert M. Pulmonary arterial hypertension in patients treated by dasatinib Circulation 2012 125 17 2128 2137 10.1161/CIRCULATIONAHA.111.079921 2-s2.0-84860346274 22451584 \n22 Mattei D. Feola M. Orzan F. Mordini N. Rapezzi D. Gallamini A. Reversible dasatinib-induced pulmonary arterial hypertension and right ventricle failure in a previously allografted CML patient Bone Marrow Transplantation 2009 43 12 967 968 10.1038/bmt.2008.415 2-s2.0-67649882756 19104491 \n23 Dumitrescu D. Seck C. Ten Freyhaus H. Gerhardt F. Erdmann E. Rosenkranz S. Fully reversible pulmonary arterial hypertension associated with dasatinib treatment for chronic myeloid leukaemia European Respiratory Journal 2011 38 1 218 220 2-s2.0-79960181854 10.1183/09031936.00154210 21719499 \n24 Rasheed W. Flaim B. Seymour J. F. Reversible severe pulmonary hypertension secondary to dasatinib in a patient with chronic myeloid leukemia Leukemia Research 2009 33 6 861 864 10.1016/j.leukres.2008.09.026 2-s2.0-63349083357 18986702 \n25 Ghose A. Tariq Z. Taj A. Chaudhary R. Acute dyspnea from treatment of al amyloidisis with bortezomib The American Journal of Therapeutics 2011 18 4 e123 e125 10.1097/MJT.0b013e3181cea0ef 2-s2.0-79960557976 20335791 \n26 Akosman C. Ordu C. Eroglu E. Oyan B. Development of acute pulmonary hypertension after bortezomib treatment in a patient with multiple myeloma: a case report and the review of the literature American Journal of Therapeutics 2013 2-s2.0-84884947515 10.1097/01.mjt.0000433941.91996.5f \n27 Groeneveldt J. A. Gans S. J. M. Bogaard H. J. Vonk-Noordegraaf A. Dasatinib-induced pulmonary arterial hypertension unresponsive to PDE-5 inhibition European Respiratory Journal 2013 42 3 869 870 10.1183/09031936.00035913 2-s2.0-84883528181 24000257\n\n",
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"other_id": null,
"pages": "962526",
"pmc": null,
"pmid": "25544920",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "20335791;19955186;9644301;20352382;23168212;11524262;18986702;21719499;15967839;10222655;8259707;18726593;24000257;22451584;12835740;3470119;22323483;22426625;24100255;23121646;24399786;2232886;23814859;4522851;6950954;19104491",
"title": "A case of multiple myeloma with metachronous chronic myeloid leukemia treated successfully with bortezomib, dexamethasone, and dasatinib.",
"title_normalized": "a case of multiple myeloma with metachronous chronic myeloid leukemia treated successfully with bortezomib dexamethasone and dasatinib"
} | [
{
"companynumb": "US-TAKEDA-2014MPI003433",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": "1",
... |
{
"abstract": "An 81-year-old woman presented with blurred vision in the left eye. Best corrected visual acuity was 20/100. Ophthalmologic examination in the left eye revealed tilted disc syndrome with exudative change at the margin of inferior staphyloma. The exudative change persisted despite monthly intravitreal ranibizumab injections for 5 months. Subsequently, two intravitreal aflibercept injections 1 month apart were substituted for the ranibizumab injections, resulting in successful resolution of the exudative change.",
"affiliations": null,
"authors": "Hirano|Yoshio|Y|;Yasukawa|Tsutomu|T|;Tsukada|Akiyo|A|;Yokoyama|Sachiko|S|;Ito|Yuya|Y|;Nakazawa|Yoko|Y|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D004396:Coloring Agents; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D007208:Indocyanine Green; D000069579:Ranibizumab",
"country": "United States",
"delete": false,
"doi": "10.3928/23258160-20150323-16",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-8160",
"issue": "46(3)",
"journal": "Ophthalmic surgery, lasers & imaging retina",
"keywords": null,
"medline_ta": "Ophthalmic Surg Lasers Imaging Retina",
"mesh_terms": "D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D004396:Coloring Agents; D057915:Drug Substitution; D019773:Epiretinal Membrane; D005124:Eye Abnormalities; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D007208:Indocyanine Green; D058449:Intravitreal Injections; D008269:Macular Edema; D009898:Optic Disk; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D012163:Retinal Detachment; D012164:Retinal Diseases; D055213:Retinal Pigment Epithelium; D058471:Subretinal Fluid; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A",
"nlm_unique_id": "101599215",
"other_id": null,
"pages": "384-6",
"pmc": null,
"pmid": "25856827",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Resolution of exudative changes refractory to ranibizumab after aflibercept injections at the margin of inferior staphyloma in tilted disc syndrome.",
"title_normalized": "resolution of exudative changes refractory to ranibizumab after aflibercept injections at the margin of inferior staphyloma in tilted disc syndrome"
} | [
{
"companynumb": "JP-ROCHE-1584774",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": null,
"dr... |
{
"abstract": "The antibiotic minocycline is virtually pathognomonic for brown-black discoloration of the thyroid gland referred to as 'black thyroid'. Black thyroid' is an incidental finding in patients taking the drug who undergo thyroid surgery for another indication and is not of known clinical significance. However, its recognition is important so as not to raise concern for a disease process. Here, we present the first case of 'black thyroid' attributable to the iodine-containing compound indocyanine green. Intraoperative indocyanine green was administered as part of a research protocol transoral robotic-assisted surgery for a base of tongue cancer in a 44-year-old man. Hemithyroidectomy was subsequently performed during the same operation for further evaluation of an indeterminate thyroid nodule. The resected thyroid lobe was dark, nearly black in color, and histologically showed extensive brown pigment deposition in the follicular epithelial cells and colloid, mimicking minocycline-induced 'black thyroid'. In this case, however, the patient was not taking minocycline; instead the 'black thyroid' was attributed to the iodine-containing compound indocyanine green. Indocyanine green is a hereto unreported cause of 'black thyroid' with histopathologic features that are remarkably similar to that induced by minocycline. Indocyanine green should be included the differential diagnosis of 'black thyroid'. Clinical history is important so as not to raise concern for a disease process.",
"affiliations": "Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8118, St. Louis, MO, USA. rchernock@path.wustl.edu.;Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, USA.",
"authors": "Chernock|Rebecca D|RD|;Jackson|Ryan S|RS|",
"chemical_list": "D004396:Coloring Agents; D007208:Indocyanine Green",
"country": "United States",
"delete": false,
"doi": "10.1007/s12022-016-9458-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1046-3976",
"issue": "28(3)",
"journal": "Endocrine pathology",
"keywords": "Black thyroid; Fluorescence imaging; Indocyanine green; Minocycline; Thyroid pigment",
"medline_ta": "Endocr Pathol",
"mesh_terms": "D000328:Adult; D002294:Carcinoma, Squamous Cell; D004396:Coloring Agents; D005927:Glossectomy; D006801:Humans; D007208:Indocyanine Green; D008297:Male; D037981:Neck Dissection; D065287:Robotic Surgical Procedures; D013961:Thyroid Gland; D014062:Tongue Neoplasms",
"nlm_unique_id": "9009288",
"other_id": null,
"pages": "244-246",
"pmc": null,
"pmid": "27797004",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25397396;17519514;18631011;5435292;22577366;25427416;27039880;990789;23165392",
"title": "Novel Cause of 'Black Thyroid': Intraoperative Use of Indocyanine Green.",
"title_normalized": "novel cause of black thyroid intraoperative use of indocyanine green"
} | [
{
"companynumb": "US-DIAGNOSTIC GREEN GMBH-2026108",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "INDOCYANINE GREEN"
},
"drugadditional"... |
{
"abstract": "Patients with multi-system Langerhans cell histiocytosis (LCH) who progress on frontline therapy have a dismal outcome. Responses to cladribine have been reported in relapsed LCH, but there are no well defined salvage regimens for LCH is refractory to therapy. The next generation deoxyadenosine analog, clofarabine, has demonstrated activity in patients with leukemia that is refractory to salvage regimens, including other nucleotide congeners; however, no experience exist on the use of clofarabine in LCH. In this report we describe significant single agent activity of clofarabine in disseminated LCH refractory to salvage regimens, including cladribine.",
"affiliations": "Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. carlos.rodriguez-galindo@stjude.org",
"authors": "Rodriguez-Galindo|Carlos|C|;Jeng|Michael|M|;Khuu|Phuong|P|;McCarville|M Beth|MB|;Jeha|Sima|S|",
"chemical_list": "D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D000077866:Clofarabine",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.21668",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "51(5)",
"journal": "Pediatric blood & cancer",
"keywords": null,
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D002675:Child, Preschool; D000077866:Clofarabine; D005260:Female; D006646:Histiocytosis, Langerhans-Cell; D006801:Humans; D007223:Infant",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "703-6",
"pmc": null,
"pmid": "18623218",
"pubdate": "2008-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Clofarabine in refractory Langerhans cell histiocytosis.",
"title_normalized": "clofarabine in refractory langerhans cell histiocytosis"
} | [
{
"companynumb": "US-JNJFOC-20130608739",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOFARABINE"
},
"drugadditional": null,
... |
{
"abstract": "Carboplatin, a cisplatinum analogue, has no reported nephrotoxicity in phase I/II studies, assessed by creatinine clearance. We prospectively determined renal function in 10 untreated lung cancer patients with normal baseline renal function, treated with carboplatin 400 mg m-2 day 1 and vincristine 2 mg day 1 and 8 every 4 weeks (max. five cycles) by means of clearance studies with 125I-sodium thalamate and 131I-hippurate to determine GFR and ERPF respectively. Tubular damage was monitored by excretion of tubular enzymes and relative beta 2-microglobulin clearance. During the first course no changes in renal function were seen. After the second course a significant fall in GFR and ERPF started, ultimately leading to a median decrease in GFR of 19.0% (range 6.8-38.7%) and in ERPF of 14% (range 0-38.9%). No increases in the excretion of tubular enzymes or changes in the relative beta 2-microglobulin clearances were seen. We conclude from our data that carboplatin causes considerable loss of renal function. Monitoring renal function in patients treated with multiple courses of carboplatin is warranted.",
"affiliations": "Department of Internal Medicine, University Hospital, Groningen, The Netherlands.",
"authors": "Sleijfer|D T|DT|;Smit|E F|EF|;Meijer|S|S|;Mulder|N H|NH|;Postmus|P E|PE|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D016190:Carboplatin",
"country": "England",
"delete": false,
"doi": "10.1038/bjc.1989.233",
"fulltext": "\nC The Macmillan Press Ltd.. 1989\n\nAcute and cumulative effects of carboplatin on renal function\n\nD.Th. Sleijfer, E.F. Smit, S. Meijer, N.H. Mulder & P.E. Postmus\n\nDepartment of Internal Medicine, Divisions of Medical Oncologv, Nephrologv and Pulmonology, University Hospital\nGroningen, Oostersingel 59, 9713 EZ Groningen, The Netherlands.\n\nSummanr Carboplatin. a cisplatinum analogue, has no reported nephrotoxicity in phase I'II studies, assessed\nby creatinine clearance. We prospectively deterniined renal function in 10 untreated lung cancer patients with\nnormal baseline renal function, treated with carboplatin 400mgm 2 day 1 and vincristine 2mg day 1 and 8\nevery 4 weeks (max. five cycles) by means of clearance studies with 1251-sodium thalamate and 1311-hippurate\n\nto determine GFR and ERPF respectively. Tubular damage was monitored by excretion of tubular enzymes\nand relative f2-microglobulin clearance. During the first course no changes in renal function were seen. After\nthe second course a significant fall in GFR and ERPF started, ultimately leading to a median decrease in\nGFR of 19.0% (range 6.8-38.7%) and in ERPF of 14% (range 0-38.9%). No increases in the excretion of\ntubular enzymes or changes in the relative fi-microglobulin clearances were seen. We conclude from our data\nthat carboplatin causes considerable loss of renal function. Monitoring renal function in patients treated with\nmultiple courses of carboplatin is warranted.\n\nThe introduction of cisplatin (CDDP) in the early seventies\nresulted in a major step forward in anticancer chemotherapy\n(Carter et al., 1984). However. cisplatin has a narrow\ntherapeutic index especially in regard to nephrotoxicity,\nlimiting the clinical utility of this agent (Madias &\nHarrington. 1978). Several ways have been employed to\novercome this problem. Although therapeutic index of\nCDDP has improved with the use of such manoeuvres, the\ndrug does remain nephrotoxic (Al-Sarraf et al., 1983; Ozols\net al.. 1984; Markham et al., 1985; Bodenner et al., 1986;\nElfenrnk et al., 1986; Offerman et al., 1985). An alternative\napproach was the synthesis of analogues of cisplatin with the\naim to find Pt-complexes with less nephrotoxicity and more\nor comparable antitumour activity (Burchenal et al., 1979).\nAbout 2,000 second generation Pt-compounds have been\nsynthesised and screened for cytotoxicity. Only a few have\nbeen selected for clinical evaluation, of which carboplatin\n(CBDCA, JM8) probably is the most promising. In human\nand animal studies carboplatin has demonstrated increased\nhaematological toxicity compared to CDDP, but it is less\nemetogenic and has little or no oto- or neurotoxicity and no\nnephrotoxicity even in the absence of forced diuresis\n(Lelieveld et al.. 1984: Van Glabbeke et al., 1988). In these\nstudies the renal function was measured by monitoring\nserum creatinine and creatinine clearances. However, the\ndetermination of creatinine as a reflection of the glomerular\nfiltration rate has proved to be a relatively insensitive\nmethod to monitor CDDP-induced renal damage (Meijer et\nal., 1983; Daugaard et al., 1988). Moreover, using 52Cr\nEDTA clearances, Calvert et al. (1982) were also unable to\nidentify CBDCA as a nephrotoxic drug.\n\nIn this study we prospectively determined changes in\nglomerular filtration rate and effective renal plasma flow by\nthe more sensitive method developed by Donker et al. (1977)\nin 10 patients treated with standard dose carboplatin. The\npossible tubular damage was monitored by measuring the\nexcretion of tubular enzymes.\n\nMethods\n\nPatients and therapy\n\nTen patients, one female, nine male, were studied. All had\nhistologically proved lung cancer (eight small cell lung\ncancer, one squamous cell carcinoma, one endobronchial\ncarcinoid). One patient was pretreated with s.c. infusion of\ninterferon, all others were previously untreated. Their age\nranged from 48 to 69 years (mean 58). All had a normal\nCorrespondence: D.Th. Sleijfer.\n\nReceived 23 November 1988. and accepted in revised form 6 March\n1989.\n\nserum creatimne level < 120 ,umol 1 '. were normotensive,\nnot salt restricted, and did not use other potentially nephro-\ntoxic medication.\n\nAll patients were treated with carboplatin 400mgm 2 day\n1 and vincristine 2mg day 1 and 8 every 4 weeks. Carbo-\nplatin was dissolved in 250 ml of glucose 5% and given as a\n30 mn i.v. infusion on day 1. Vincristine was given as bolus\ninjection. No pre- or post-hydration was given.\n\nSeven responding patients received the maximum of five\ncourses. The treatment had to be stopped in two patients\nafter three and in one patient after two courses. because of\ntumour progression.\n\nRenal function studies\n\nGlomerular filtration rate (GFR) and effective renal plasma\nflow (ERPF) were measured simultaneously in supine\nposition with radioisotopes. ERPF was determined by\nmeasuring the clearance of 1311-hippuran (I x V P) and GFR\nby the clearance of '251-iothalamate (Ux V P) (I= counts per\nminute of I ml sustaining solution, V= infusion volume or\nurine volume in ml per minute, P =counts per minute in 2 ml\nof plasma and U=counts per minute in 2ml urine). After a\nstandard pnrmary dose and sustaining infusion for 2h, 1-h\nclearances were determined for acute effects and 2-h clear-\nances for cumulative effects. For the latter. values are the\nmean of two 2-h clearances, which were corrected for\nstandard body surface area. Errors in GFR introduced by\nincomplete collection of urine were corrected to a method\npreviously described. The day to day variation of GFR is\n\n2O2% and of ERPF <5% (Donker et al., 1977). Filtration\nfraction (FF) was calculated as the quotient of GFR and\nERPF.\n\nCreatinine clearances were also corrected for incomplete\ncollection of urine, using the same method as mentioned\nabove.\n\nThese vanrables were studied before and during four hours\nafter the first carboplatin infusion in order to determine\nacute effects on renal function. Cumulative effects were also\nmeasured during 4h 4 weeks after each course, just before\nthe administration of the following courses, i.e. on days 29,\n57, 85. 113 and 141.\n\nDuring renal function studies urine was collected hourly\nfor the determination of creatinine, LDH, alkaline phospha-\ntase (ALP), gamma-GT and #2-microglobulin. Serum and\nurine creatinine, urine LDH, ALP and gamma-GT were\ndetermined with standard automatic techniques. f2-Micro-\nglobulin concentration in plasma and urine was determined\nby a radioimmnunosorbent technique according to Evnrn et al.\n(1971). Next the ratio of respectively LDH, ALP, gamma-\nGT and creatinine (U per gram) were calculated. For fl2-\n\nBr. J. Cancer (I 989), 60, 116-120\n\nCARBOPLATIN AND RENAL FUNCTION 117\n\nmicroglobulin the relative clearance in respect to creatinine\nclearance was calculated.\n\nStatistics\n\nStatistical analysis was performed with Wilcoxon's test for\npaired observations (two-sided); P< 0.05 was considered\nindicative of a significant difference between groups.\n\nResults\n\nAcute effects\n\nThe pretreatment values (A) of ERPF, GFR and FF of all\npatients are listed in Table I. Also depicted are the nadir\nvalues of ERPF and values of GFR and FF corresponding\nwith the nadir values of ERPF after the first carboplatin\ninfusion (B). Also, corresponding creatinine clearances are\nlisted in Table I. There were no statistically significant\nchanges in the GFR, either by the radiochemical method or\ncreatinine clearances, and ERPF. For tubular enzymes no\nchanges were seen. Relative clearance of #2-microglobulin\nincreased in the 4h after carboplatin infusion, but remained\nwithin the normal range.\nCumulative effects\n\nAbsolute and relative changes in GFR and ERPF during the\nwhole treatment are given in Table II and Figure 1, respec-\ntively. Corresponding creatinine clearances are also given.\nFour weeks after the first administration of carboplatin there\nis still no significant change in ERPF, GFR and FF, but\ndeterioration of the renal function as measured by the\nradioisotope clearances occurs after the second course. Out\nof nine patients still on study 4 weeks after two courses,\nseven had a fall in GFR >2% (P<0.02), median -7.5%,\nrange + 1.9% to -36.1%. In three patients ERPF decreased\n>5% as opposed to pretreatment values; median -3.4%,\nrange + 24.1% to -40.0% (P<0.05). The ultimate decrease\nafter five courses (n = 7) ranges from 6.8% to 38.7% for\nGFR (median 19.0%) (P<0.02) and for ERPF 1.6% to\n38.9% (median 14%) (P<0.02). These changes could not be\nexplained by alteration in body weight of individual patients.\n\nAlthough creatinine clearances showed a tendency to\ndecrease after course 2, this change was not significant\n(P>0.1). Moreover, 4 weeks after the fourth course creati-\nnine clearances retuned to baseline values, with the exception\nof those in patient number 10. After five courses no\nsignificant difference as opposed to pre-treatment values\nwere found.\n\nDuring the observation period no significant changes in\nserum creatinine were found. In regard to tubular enzymes\n\nand relative f2 clearance we could not detect significant\nchanges. Also, none of the patients developed proteiniiria.\n\nThe most serious side effect of cisplatin is nephrotoxicity.\nAfter multiple courses of CDDP, a decrease of about 40% in\ncreatinine clearance has been reported (Meijer et al., 1983;\nDentino et al., 1978). The study of Meijer et al. (1983), using\nthe same method as used in this report, showed a median\ndecrease in GFR and ERPF of both 23% after induction\nchemotherapy containing CDDP for non-seminomatous tes-\nticular cancer. The cisplatin analogue carboplatin has no\nreported nephrotoxicity at conventional dose levels. The\nreduced protein binding (Van Echo et al., 1984; Gaver et al.,\n1987) and greater stability of carboplatin in body fluids and\ntherefore increased renal excretion compared to cisplatin are\nsupposed to account for the absence of nephrotoxicity\n(Harland et al., 1984; Sharma et al., 1983). Also, in animal\nmodels, carboplatin enhanced nuclear protein phos-\nphorylation in tumour cells more than CDDP did, but\ncaused much less protein phosphorylation in the normal liver\nand kidney cells. This suggests some selective toxicity to-\nwards tumour cells and may in part explain the decreased\nnephrotoxicity of carboplatin (Harrap et al., 1980). There-\nfore, carboplatin has been recommended as an alternative to\ncisplatin in patients with impaired renal function or in those\nwho cannot receive the hydration required for conventional\ncisplatin administration (Von Hoff, 1987).\n\nThere have been sporadic observations of renal function\ndeterioration after multiple courses of carboplatin (Calvert et\nal., 1982; Van Glabbeke et al., 1988; Rozenczweig et al.,\n1983; Leyvraz et al., 1985). Also, the high dose\n(>800mgm-2) study of Gore et al. (1987) showed a fall in\nGFR of >25% in 55% of courses, as measured by (5\"Cr)\nEDTA clearances.\n\nSince vincristine has no reported nephrotoxicity (Schilsky,\n1982; Weis & Poster, 1982), we conclude from the data of\nour study that carboplatin has a cumulative dose related\nnephrotoxic effect, as there was no decrease in renal function\nparameters after the first course, but an impressive fall in\nGFR and ERPF after the second course, ultimately leading\nto a decrease of 38% after five courses in some patients. The\nfall in GFR may be clinically important because the degree\nof myelosuppression probably depends on GFR (Egorin et\nal., 1984; Fish et al., 1987; Egorin et al., 1985). In our\npatients, however, we did not find cumulative haemato-\nlogical toxicity despite this decrease in GFR. Even the\npatient with a 38% reduction in GFR did not have severe\nmyelosuppression.\n\nThis study also shows the superiority of the radiochemical\n\nTable I ERPF and GFR (creatinine clearance), all in mlmin-' 1.73m -2 before (A) and after (B) first\n\ncarboplatin infusion\n\nPatient\n\n3\n4\n5\n6\n7\n8\n9\n10\n\nMedian\nMean\ns.d.\n\ns.e.m.\n\nERPF\n\nA B\n\n660\n375\n401\n293\n312\n271\n319\n599\n301\n558\n388\n\n408.9\n\n143.06\n45.24\n\n601\n395\n397\n309\n322\n235\n315\n517\n309\n526\n\n358.5\n398\n\n125.88\n39.81\n\nGFR (creatinine clearance)\n\n121\n118\n155\n87\n83\n80\n105\n123\n102\n143\n\nA\n\n(106)\n(107)\n(115)\n\n(80)\n(98)\n(82)\n(116)\n(118)\n(110)\n(134)\n\n111.5 (108.5)\n111.7 (106.6)\n25.14 (16.5)\n\n7.95 (5.21)\n\n119\n136\n158\n92\n94\n81\n102\n130\n113\n154\n\nB\n\n(96)\n(95)\n(131)\n\n(75)\n(82)\n(72)\n(107)\n(116)\n(122)\n(114)\n\n121.5 (101.5)\n117.9 (101)\n\n26.39 (20.3)\n\n8.34 (6.42)\n\nFF\n\nA B\n\n0.18\n0.30\n0.39\n0.28\n0.27\n0.30\n0.33\n0.21\n0.34\n0.26\n0.29\n0.286\n0.0615\n0.0194\n\n0.20\n0.35\n0.39\n0.30\n0.29\n0.34\n0.32\n0.23\n0.37\n0.29\n0.31\n\n0.308\n\n0.0596\n0.0188\n\n118 D.TH. SLEIJFER et al.\n\nTable I Absolute changes in GFR (creatinine clarance) and ERPF, all in mlmin-I 1.73m-2 after multiple courses\n\nCourse nunber\n\nPatient 0 1 2 3 4 5\nGFR (creatinine clearance)\n\n1 121 (106) 124 (112) 95 (79) 98 (93) 101 (105) 96 (129)\n2 118 (107) 137 (124) 113 (101)\n\n3 155 (115) 116 (100) 99 (116) 97 (109) 94 (179) 95 (68)\n4 87 (80) 97 (125) 82 (93) 91 (97) 87 (111) 81 (59)\n5 83 (98) 90 (114) 78 (101)\n\n6 80 (82) 79 (85) 74 (87) 73 (84) 72 (81) 62 (91)\n7 105 (116) 102 (113) 107 (72) 101 (109) 89 (107) 85 (91)\n8 123 (118) 131 (102) 124 (143) 120 (145) 119 (123) 114 (127)\n9 102 (110) 116 (120)\n\n10 143 (134) 111 (90) 110 (90) 98 (79) 103 (50) 122 (116)\nMedian 111.5 (110) 116 (112.5) 99 (93) 98 (97) 94 (111) 95 (91)\nMean 111.7 (106.5) 110.3 (108.5) 98 (99) 96.9 (102.3) 95.0 (108) 93.6 (97)\n\ns.d. 25.14 (16.5) 18.35 (13.8) 17.20 (22.5) 13.90 (22.0) 14.75 (39.5) 10.26 (27.8)\ns.e.m. 7.95 (5.21) 5.80 (4.37) 5.73 (7.49) 5.25 (8.31) 5.58 (14.94) 7.66 (10.5)\nERPF\n\n1 660 540 396 413 423 403\n2 375 492 424\n\n3 401 470 407 360 320 310\n4 293 331 283 350 288 290\n5 312 376 302\n\n6 271 260 260 254 249 234\n7 319 354 3% 372 330 314\n8 599 554 499 531 558 555\n9 301 452\n\n10 558 385 374 348 382 398\nMedian 388 418.5 396 360 330 314\n\nMean 408.9 421.4 371.2 375.4 364.3 357.7\ns.d. 143.06 95.50 76.30 83.67 102.90 105.41\ns.e.m. 45.24 30.20 25.43 31.63 38.89 39.84\n\n20\n10\n\n0\n-10\n\n-20\n\n20\n10\n0\n-10\n-20\n\na\n\nb\n\nFgwe 1 Mean percent changes in GFR (mlmin-' 1.73m-2)\n(a) and ERPF (mlmin - 1.73 m-2) (b) after multiple courses\nof carboplatin (mean + s.e.).\n\nmethod to determine GFR as opposed to creatinine clear-\nance in order to monitor Pt induced renal damage. The\nlatter method failed to detect a significant change in GFR\nafter multiple courses of carboplatin. A possible explanation\nfor this finding is provided by Meyer et al. (1983). A\nsignificant fall in GFR (median 23%) was seen after com-\nbination chemotherapy containing CDDP, without a rise in\nserum creatinine. They suggested that the chemotherapy\ninterfered with enzymic systems required for creatinine\nproduction.\n\nThe mode of action of Pt-induced nephrotoxicity remains\nunknown. Offerman et al. (1984) have shown that the acute\neffect of CDDP on renal function is a fall in ERPF\npreceding a similar change in GFR. Also, in experimental\nmodels of renal failure following intoxication with heavy\nmetals, in the initial phase a reduction of renal blood flow\ncan be found. In our study no such phenomenon could be\nfound, as during the first course neither a fall in GFR nor in\nERPF was seen. Since a simultaneous decrease in both GFR\nand ERPF occurred 4 weeks after course 2, we can only\nspeculate, but not exclude, whether such a sequence of\nevents did take place. Also, the intracellular presence of\nreactive Pt-compounds in the kidney is suggested to relate to\nthis toxicity (Harland et al., 1984; Stewart et al., 1985).\nTherefore tubular damage might play an important role in\nPt-induced nephrotoxicity. The reported renal uptake of\ncarboplatin does not differ substantially from that for\nCDDP (Lelieveld et al., 1984; Owens et al., 1985). CDDP\ninduces tubular damage in most patients but we could not\nfind signs of tubular damage after carboplatin adminis-\ntration as measured by the urinary excretion of tubular\nenzymes, because of infrequent sampling. For the evaluation\nof tubular damage timing of specimen collection plays an\nimportant role (Goren et al., 1987). As reported for cisplatin\n(Goren et al., 1986) and carboplatin (Egorin et al., 1984),\nurinary enzymes can peak as late as several days after the\nadministration of the drug. Shillen et al. (1988) collected\nweekly specimens for the evaluation of excretion of urinary\n\n0\n\nCARBOPLATIN AND RENAL FUNCTION 119\n\nprotein and enzymes in patients receiving multiple courses of\ncarboplatin 400mg m .2 In some of their patients urinary\nenzymes peaked 2 weeks after the administration of the\ndrug. Therefore, our results might be misleading in tha they\nwere obtained for a period of only 4 h after administration.\n\nWe conclude from our data that carboplatin exerts dose-\nrelated cumulative renal damage. Careful monitoring,\nespecially with regard to myelosuppression, in patients with\nimpaired renal function or those pretreated with Pt contain-\ning regimens is therefore warranted. The observed reduction\nin renal function after carboplatin is in the same range\n\ncompared to patients treated with cisplatin with saline\ndiuresis (Meijer et al., 1983). Although it has not been\nexcluded that hyperhydration during carboplatin treatment\ncould prevent the nephrotoxic effects, the value of adminis-\ntering this cytostatic drug on an outpatient base would\ndisappear.\n\nThis study was supported by grant C84-503 of the Dutch Kidney\nFoundation (Nierstichting Nederland). The authors thank Willy\nBruins-van der Weij for secretarial support and Aly Drent-Bremer\nfor technical assistance.\n\nReferces\n\nAL-SARRAF, M. FLETCHER. W. OISHI, H. and 5 others (1983).\n\nCisplatin hydration with and without mannitol diuresis in refrac-\ntory disseminated malignant melanoma: a southwest oncology\ngroup study. Cancer Treat. Rep., 66, 31.\n\nBODENNER, D.L.. DEDON, P.C., KENG. P.C.. KATZ, JC. & BORCH.\n\nR.F. (1986). Selective protection against cis-diamminechloride-\nplatinum (II)-induced toxicity in kidney, gut and bone marrow\nby diethyldithiocarbamate. Cancer Res., 46, 2751.\n\nBURCHENAL. J.H., KALAHER. K_. DEW. K. & LOKYS. L. (1979).\n\nRationale for development of platinum analogs. Cancer Treat.\nRep., 65, 1493.\n\nCALVERT. A.H.. HARLAND. SJ., NEWELL. D.R. and 9 others (1982).\n\nEarly clinical studies with cis-diammine-l,l-cyclobutane di-\ncarboxylate platinum II. Cancer Chemother. Pharmacol., 9, 140.\nCARTER. SK. (1984). Cisplatin - past, present and future. In\n\nPlatinum Coordination Complexes in Cancer Chemotherapy,\nHacker, M.P., Douple, E.B. & Krakoff, I.H. (eds) p. 359.\nMartinus Nijhoff: Boston.\n\nDAUGAARD. G. ROSSING. N. & RORTH. M. (1988). Effects of\n\ncisplatin on different measures of glomerular function in the\nhuman kidney with special emphasis on high dose. Cancer\nChemother. Pharmacol., 21, 163.\n\nDENTINO. M_. LUFT. F.C_. YUM. M.N.. WILLLIMS. S.D. & EINHORN.\n\nL.H. (1978). Long term effect of cis-diamminochloride platinum\n(CDDP) on renal function and structure in man. Cancer. 41,\n1274.\n\nDONKER, AiJ.M.. VWs DER HEM. G.K.. SLUITER. WJ. & BEEKHUIS. A.\n\n(1977). A radioisotope method for simultaneous determination of\nthe glomerular filtration rate and the effective renal plasma flow.\nNeth. J. Med.. 20, 97.\n\nEGORIN. MJ. VAN ECHO. DA.. TIPPING. SJ. and 4 others (1984).\n\nPharmacokinetics and dosage reduction of cis-diammine( 1.1-\ncyclobutanedicarboxylato) platinum in patients with impaired\nrenal function. Cancer Res., 44, 5432.\n\nEGORIN. MJ.. VAN ECHO. D-A.. OLMAN. E_A.. WHITACRE. M.Y-.\n\nFORREST, A. & AISNER. J. (1985). Prospective validation of a\npharmacologically based dosing scheme for the cis-diammine\ndichloroplatinum (II) analogue cis(dianmnine (1,1) cyclobutane-\ndicarboxylatoplatinum. Cancer Res., 45, 6502.\n\nELFERINK. F.. VAN DER VIJGH. WJ.F. KLEIN. I. & PINEDO. H.M.\n\n(1986). Interaction of cisplatin and carboplatin with sodium\nthiosulfate: reaction rates and protein binding. Clin. Chem., 32,\n641.\n\nEVRIN. P_E.. PETERSON. PA_. WIDE. L. & BERGGARD. 1. (1971).\n\nRadioimmunoassay of f2 microglobulin in human biological\nfluids. Scand. J. Clin. Lab. Invest.. 28, 439.\n\nFISH. R.G.. SHELLEY, M.D.. GRIFFITH. H. & ADAMS. M. (1987).\n\nLetter. Cancer Res., 47, 3606.\n\nGAVER. R.C.. GEORGE, AMM. & DAB. G. (1987). In vitro stability,\n\nplasma protein binding and blood cell partitioning of \"4C\ncarboplatin. Cancer Chemother. Pharmacol., 20, 271.\n\nGORE. M.E. CALVERT. A.H. & SMITH, I.E. (1987). High dose\n\ncarboplatin in the treatment of lung cancer and mesothelioma: a\nphase I dose escalation study. Eur. J. Cancer Clin. Oncol., 23,\n1391.\n\nGOREN. M.P.. WRIGHT, R.K & HOROWITZ, M.E. (1986). Cumulative\n\nrenal tubular damage associated with cisplatin nephrotoxicity.\nCancer Chemother. Pharmacol., 18, 69.\n\nGOREN. M.P., FORASTIERE, AA., WRIGHT, R.K. and 5 others\n\n(1987). Carboplatin (CBDCA), iproplatin (CHIP) and high dose\ncisplatin in hypertonic saline evaluated for tubular nephro-\ntoxicity. Cancer Chemother. Pharmacol., 19, 57.\n\nHARLAND. SJ., NEWELL, DR_. SIDDIK, Z_H., CHADWICK. R_\n\nCALVERT. A.H_ & HARRAP. K.R (1984). Pharmacokinetics of cis-\ndiammine-l,1-cyclobutane dicarboxylate platinum (II) in patients\nwith normal and impaired renal function. Cancer Res., 44, 1693.\nHARRAP, K.R.. JONES, M., WILKINSON, C.R. and 5 others (1980).\n\nAntitumor, toxic and biochemical properties of cisplatin and\neight other platinum complexes. In Cisplatin Current Status and\nNew Developments, Prestayko, A.W., Crooke, S.T. & Carter,\nS.K. (eds). Academic Press: London.\n\nLELIEVELD, P. N-AvN DER VIJGH, WJ-F.. VELDHUIZEN. R_W_ and 4\n\nothers (1984). Preclinical studies on toxicity, antitumour activity\nand pharmacokinetics of cisplatin and three recently developed\nderivates. Eur. J. Cancer Clin. Oncol., 20, 1087.\n\nLEYVRAZ, S. OHNUMA, T., LASSUS, M. & HOLLAND. J.F. (1985).\n\nPhase I study of carboplatin in patients with advanced cancer,\nintermittent intravenous bolus and 24-hour infusion. J. Clin.\nOncol., 3, 1385.\n\nMADIAS. N.E. & HARRINGTON, J.T. (1978). Platinum nephro-\n\ntoxicity. Am. J. Med., 65, 307.\n\nMARKMAN. M.. CLEARY. S. & HOWELL, SB. (1985). Nephrotoxicity\n\nof high-dose intracavitary cisplatin with intravenous thiosulfate\nprotection. Eur. J. Cancer Clin. Oncol., 21, 1015.\n\nMEIJER. S.. SLEIJFER. D.TH-, MULDER. NH. and 7 others (1983).\n\nSome effects of combination chemotherapy with cis-platinum on\nrenal function in patients with nonseminomatous testicular carci-\nnoma. Cancer, 51, 2035.\n\nOFFERMAN. JJ-G.. MEYER. S., SLEIJFER, DTH. and 5 others (1984).\n\nAcute effects of cisdiamminedichloroplatinum (CDDP) on renal\nfunction. Cancer Chemother. Pharmacol., 12, 36.\n\nOFFERMAN. JJ.G.. MULDER, N.H.. SLEUFER, DTH. and 4 others\n\n(1985). Influence of captopril on cis-diammine-dichloro-platinum\ninduced renal toxicity. Am. J. Nephrol., 5, 433.\n\nOWENS. SE., THATCHER. N. SHARMA. H. and 8 others (1985). In\n\nvitro distribution studies of radioactively labelled platinum com-\nplexes: cis-dichlorodiammine platinum (H), cis-trans-dichlorodi-\nhydroxy-bis-(isopropylamine) platinum (IV), cis-dichloro-bis-\ncyclo-propylamine platinum (II) and cis-diammuine 1. 1-cyclo-\nbutanedicarboxylate platinum (II) in patients with malignant\ndisease, using a gamma camera. Cancer Chemother. Pharmacol.,\n14, 253.\n\nOZOLS, R.F. CORDON. BJ.. JACOB. J., WESLEY. M-M-. OSTCHEGA.\n\nY. & YOUNG. R.C. (1984). High-dose cisplatin in hypertonic\nsaline. Ann. Intern. Med., 100, 19.\n\nROZENCZWEIG. M_. NICAISE, C. & BEIR, M. (1983). Phase I study of\n\ncarboplatin given on a five-day intravenous schedule. J. Clin.\nOncol., 1, 621.\n\nSHILLEN, A-W.. BUAMAH, P.K., CANTWELL. B.MJ.. CORNELL. C..\n\nHODSON, A-W. & HARRIS, A.L. (1988). Urinary protein and\nenzyme excretion in patients receiving chemotherapy with the cis-\nplatin analogs carboplatin (CBDCA, JM8) and iproplatin\n(CHIP. JM9). Cancer Chemother. Pharmacol., 22, 228.\n\nSCHILSKY. R.L. (1982). Renal and metabolic toxicities of cancer\n\nchemotherapy. Semin. Oncol.. 9, 75.\n\nSHARMA. H. THATCHER. N.. BEAR. J. and 6 others (1983). Blood\n\nclearance of radioactively labelled cis-diammine 1.1-cyclobutane\ndicarboxylate platinum (HI) (CBDCA) in cancer patients. Cancer\nChemother. Pharmacol., 11, 5.\n\nSTEWART. DJ.. MIKHAEL. N-Z., NANJI. A.A. and 5 others (1985).\n\nRenal and hepatic concentrations of platinum: relationship to\ncisplatin time, dose and nephrotoxicity. J. Clin. Oncol., 3, 1251.\n\n120 D.TH. SLEUFER et al.\n\nVAN ECHO, DA-, EGORIN, MJ., WHITACRE, M.Y., OLMAN, EAL &\n\nAISNER, J. (1984). Phase I clinical and pharmacologic trial of\ncarboplatin daily for 5 days. Cancer Treat. Rep., 68, 1103.\n\nVAN GLABBEKE, M., RENARD, J., PINEDO, H.M. and 7 others\n\n(1988). Iproplatin and carboplatin induced toxicities: overview of\nphase II clnical trial conducted by the EORTC Early Clinical\nTnrals Cooperative Group (ECTG). Eur. J. Cancer Clin. Oncol.,\n24, 255.\n\nVON HOFF, D.D. (1987). Whither carboplatin - a replacement for or\n\nan alternative to cisplatin. J. Clin. Oncol., 5, 169 (editorial).\n\nWEIS, RB. & POSTER, D.S. (1982). The renal toxicity of cancer\n\nchemotherapeutic agents. Cancer Treat. Rev., 9, 37.\n\n",
"fulltext_license": "CC BY",
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"issue": "60(1)",
"journal": "British journal of cancer",
"keywords": null,
"medline_ta": "Br J Cancer",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D016190:Carboplatin; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007668:Kidney; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D011446:Prospective Studies; D012079:Renal Circulation",
"nlm_unique_id": "0370635",
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"pages": "116-20",
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"pmid": "2679841",
"pubdate": "1989-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "2824209;3581092;3280153;3281842;3044631;3319277;4110090;638991;99034;498148;6761010;6340821;6366128;6367971;6381064;6383605;6386150;3888431;4040958;3900302;3904984;4065175;3909819;3513991;3009000;2875808;3543240",
"title": "Acute and cumulative effects of carboplatin on renal function.",
"title_normalized": "acute and cumulative effects of carboplatin on renal function"
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"abstract": "Although subacute sclerosing panencephalitis is almost exclusively a childhood disease, it can occur in adults as well. We present an atypical case of adult-onset subacute sclerosing panencephalitis. The disease was characterized by prolonged insidious course followed by accelerated and aggressive phase, atypical EEG findings, and absence of myoclonic jerks. The diagnostic and treatment-related pitfalls are discussed.",
"affiliations": "1School of Dental Medicine, University of Zagreb, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 2School of Dental Medicine, University of Zagreb, Department of Microbiology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 3Department of Radiology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 4Department of Neurology, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 5Department of Pathology, Dubrava University Hospital, Zagreb, Croatia; 6School of Dental Medicine, University of Zagreb, Department of Intensive Care Medicine and Neuroinfectology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia.;1School of Dental Medicine, University of Zagreb, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 2School of Dental Medicine, University of Zagreb, Department of Microbiology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 3Department of Radiology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 4Department of Neurology, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 5Department of Pathology, Dubrava University Hospital, Zagreb, Croatia; 6School of Dental Medicine, University of Zagreb, Department of Intensive Care Medicine and Neuroinfectology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia.;1School of Dental Medicine, University of Zagreb, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 2School of Dental Medicine, University of Zagreb, Department of Microbiology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 3Department of Radiology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 4Department of Neurology, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 5Department of Pathology, Dubrava University Hospital, Zagreb, Croatia; 6School of Dental Medicine, University of Zagreb, Department of Intensive Care Medicine and Neuroinfectology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia.;1School of Dental Medicine, University of Zagreb, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 2School of Dental Medicine, University of Zagreb, Department of Microbiology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 3Department of Radiology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 4Department of Neurology, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 5Department of Pathology, Dubrava University Hospital, Zagreb, Croatia; 6School of Dental Medicine, University of Zagreb, Department of Intensive Care Medicine and Neuroinfectology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia.;1School of Dental Medicine, University of Zagreb, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 2School of Dental Medicine, University of Zagreb, Department of Microbiology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 3Department of Radiology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 4Department of Neurology, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 5Department of Pathology, Dubrava University Hospital, Zagreb, Croatia; 6School of Dental Medicine, University of Zagreb, Department of Intensive Care Medicine and Neuroinfectology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia.;1School of Dental Medicine, University of Zagreb, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 2School of Dental Medicine, University of Zagreb, Department of Microbiology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 3Department of Radiology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 4Department of Neurology, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 5Department of Pathology, Dubrava University Hospital, Zagreb, Croatia; 6School of Dental Medicine, University of Zagreb, Department of Intensive Care Medicine and Neuroinfectology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia.",
"authors": "Stemberger Marić|Lorna|L|;Đaković Rode|Oktavija|O|;Višković|Klaudija|K|;Hećimović|Hrvoje|H|;Lambaša|Smiljka|S|;Lepur|Dragan|D|",
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"doi": "10.20471/acc.2020.59.03.21",
"fulltext": "\n==== Front\nActa Clin Croat\nActa Clin Croat\nACC\nActa Clinica Croatica\n0353-9466\n1333-9451\nSestre Milosrdnice University Hospital and Institute of Clinical Medical Research, Vinogradska cesta c. 29 Zagreb\n\nACC-59-543\n10.20471/acc.2020.59.03.21\nCase Reports\nAtypical adult-onset subacute sclerosing panencephalitis\nStemberger Marić Lorna 1\nĐaković Rode Oktavija 2\nVišković Klaudija 3\nHećimović Hrvoje 4\nLambaša Smiljka 5\nLepur Dragan 6\n1School of Dental Medicine, University of Zagreb, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 2School of Dental Medicine, University of Zagreb, Department of Microbiology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 3Department of Radiology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia; 4Department of Neurology, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 5Department of Pathology, Dubrava University Hospital, Zagreb, Croatia; 6School of Dental Medicine, University of Zagreb, Department of Intensive Care Medicine and Neuroinfectology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia\nCorrespondence to: Dragan Lepur, MD, PhD, Department of Intensive Care Medicine and Neuroinfectology, Dr Fran Mihaljević University Hospital for Infectious Diseases, Mirogojska 8, HR-10000 Zagreb, Croatia, E-mail: dragan.lepur@xnet.hr\n9 2020\n9 2020\n59 3 543548\n13 4 2016\n08 12 2016\n2020\nSestre Milosrdnice University Hospital\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND) 4.0 License.\nSUMMARY\n\nAlthough subacute sclerosing panencephalitis is almost exclusively a childhood disease, it can occur in adults as well. We present an atypical case of adult-onset subacute sclerosing panencephalitis. The disease was characterized by prolonged insidious course followed by accelerated and aggressive phase, atypical EEG findings, and absence of myoclonic jerks. The diagnostic and treatment-related pitfalls are discussed.\n\nKey words:\n\nAdult onset\nMRZ (measles, rubella, varicella-zoster) reaction\nMultiple sclerosis\nSubacute sclerosing panencephalitis\n==== Body\nIntroduction\n\nSubacute sclerosing panencephalitis (SSPE) is traditionally described as a devastating childhood and early adolescence disease caused by persistent mutated measles virus. The diagnosis is based on characteristic clinical presentation, electroencephalographic (EEG) findings and increased antibody titer to measles both in serum and cerebrospinal fluid (CSF) (1). However, the majority of patients (78.8%) are initially incorrectly diagnosed even in developing countries with a high annual incidence of SSPE (up to 21 cases per million in general population) (2). The diagnosis of adult-onset SSPE, particularly in those patients with insidious course of the disease, can be quite challenging (3, 4). We present an atypical case of adult-onset SSPE and detailed discussion of diagnostic and treatment-related pitfalls.\n\nCase Report\n\nA 42-year-old Caucasian male with suspected Creutzfeldt-Jakob disease was transferred to our Hospital from the Department of Neurology in October 2011. He was born in 1969 in an urban community in Croatia and had been vaccinated according to the national immunization schedule that included measles vaccine. Measles vaccination was introduced to the Croatian mandatory immunization program in 1968. His past medical history was unremarkable. There was no history of fever, arthritis, arthralgias, myalgias or rash. In addition, there were no recent measles epidemics recorded in Croatia.\n\nThe disease had started two years before hospitalization with bilateral decreased visual acuity attributed to optic neuropathy and macular dystrophy followed by depression. Magnetic resonance imaging (MRI) of the brain in 2009 showed demyelination changes (details unknown). He was taking drugs prescribed by a psychiatrist (alprazolam and paroxetine). Eighteen months later, he developed left-sided hemiparesis and was hospitalized in June 2011. The initial MRI of the brain performed on a 1.5 T unit revealed symmetric, scattered, high signal intensity areas on T2 weighted image (WI) and fluid attenuation inversion recovery (FLAIR) sequence in the periventricular white matter, as well as in the frontal and temporal subcortical gray matter (Fig. 1). There was no enhancement on postcontrast T1 WI. Diffuse brain atrophy was present. Lumbar puncture revealed 1 cell per cubic millimeter, glucose level of 4.3 mmol/L and total protein level of 0.64 g/L. The function of the blood-brain barrier (BBB) was normal with intrathecal synthesis of IgG. Oligoclonal IgG bands (OCB) were found in CSF with additional identical bands in CSF and serum (OCB type 3). In order to detect polyspecific intrathecal antibody response to neurotropic viruses, the so-called MRZ (measles, rubella, varicella-zoster) reaction revealed positive antibody index (AI 6.2) for measles but negative for rubella (AI 0.6), varicella-zoster (AI 0.6) and herpes simplex virus (AI 0.9). EEG was normal. Visual evoked response (VER) revealed a mild right-sided delay in conduction at the pre-chiasmatic level. Brainstem auditory evoked response (BAER) revealed a right-sided delay in conduction at the brainstem level.\n\nFig. 1 Axial fluid attenuation inversion recovery (FLAIR) sequence of the brain: (a) hyperintensity in subcortical gray matter of temporal lobes; and (b) in periventricular white matter (arrows) with diffuse brain atrophy.\n\nDespite nonspecific MRI findings and unusual OCB pattern, the diagnosis of probable multiple sclerosis (MS) was made and the patient was started on a high dose of methylprednisolone with certain clinical improvement. Two weeks later, his condition progressively aggravated with severe cognitive decline accompanied by increased fatigue, lethargy, pyramidal and extrapyramidal signs, but without myoclonic jerks. Follow-up MRI examination performed one month after the initial one was described as progression of hyperintensity lesions on T2 WI and FLAIR sequences in subcortical temporal, occipital and parietal lobes, bilaterally and symmetrically, without enhancement on postcontrast T1 WI. The radiological differential diagnosis included MS, acute disseminated encephalomyelitis and finally posterior reversible leukoencephalopathy. However, the substantial progress of initially described MRI changes was not confirmed by other MRI experts during the revision process.\n\nThe patient was consecutively treated with a high dose of steroids (methylprednisolone), intravenous immunoglobulins and finally plasmapheresis (total plasma exchange, TPE). All these treatments turned out to be completely ineffective.\n\nThe extensive diagnostic workup including autoimmune, metabolic and endocrine screening was negative. Funduscopy revealed chorioretinal degeneration on the right eye and decolorized optic papilla on the left eye. After consulting infectious disease specialists, additional tests were conducted. Treponema pallidum hemagglutination assay was negative. Tests for antibodies to measles, HIV 1 and 2, Mycoplasma pneumoniae and Borrelia burgdorferi were also negative. Protein 14-3-3 in CSF was positive and the patient was ultimately transferred to our Department.\n\nRepeated lumbar puncture revealed 2 cells per cubic millimeter, glucose level of 3.5 mmol/L and total protein level of 1.0 g/L. The BBB dysfunction with intrathecal synthesis of IgG was found. CSF concentration of neuron-specific enolase was 7.6 µg/L (normal <15.5 µg/L), protein Tau 505 pg/mL (normal <150 pg/mL) and S-100 4.05 µg/L (normal <2.5 µg/L). Polymerase chain reaction (PCR) of CSF for JC virus, human herpesvirus 6, Epstein-Barr virus, cytomegalovirus and measles virus was negative. The EEG taken on admission showed pseudoperiodic biphasic and triphasic delta waves over the left temporo-occipital region with irregular background rhythm. Finally, brain biopsy was performed due to the progressive course of the disease, the possibility of primary CNS angiitis, and nonspecific and inconclusive previous diagnostic tests. Unfortunately, PCR for measles virus detection from brain tissue was not done because of inadequate sample. Histopathologic examination revealed perivascular infiltration of T-lymphocytes, microglial nodules, neuronophagia and astrogliosis compatible with viral encephalitis (Fig. 2).\n\nFig. 2 Histopathologic examination revealed perivascular infiltration of T-lymphocytes (hemalaun-eosin, X20) (a); microglial nodules, reactive astrogliosis (hemalaun-eosin, X40) (b); and neuronophagia, marked with asterisks (hemalaun-eosin, X40) (c), compatible with viral encephalitis.\n\nFour weeks later, repeated EEG showed periodic high-amplitude biphasic and triphasic delta wave discharges bilaterally and synchronously, larger in amplitude over the left temporo-occipital region, occurring at intervals of 3-4 s (Fig. 3). Because of that, the diagnosis of SSPE was reconsidered and measles antibodies testing was repeated in the serum and CSF with enzyme immunoassay (Measles Virus IgG/IgM SERION ELIA classic Institut Virion/Serion GmbH, Leipzig, Germany) according to the manufacturer’s instructions. Serum and CSF anti-measles IgG antibodies titers were >5000 IU/L and >5000 IU/L, respectively (positive IgG >200 IU/L). The calculated CSF IgG antibody index was 28.3 indicating intrathecal synthesis of measles IgG. SSPE was definitely diagnosed and the patient was transferred to the county hospital where he died two and a half years after the initial onset of symptoms.\n\nFig. 3 Electroencephalography showing periodic biphasic and triphasic delta wave discharges bilaterally and synchronously, larger in amplitude over the left temporo-occipital region, occurring at intervals of 3-4 s.\n\nDiscussion\n\nWe have described a case of an unusual form of SSPE in an adult patient characterized by atypical EEG findings and absence of myoclonic jerks. In spite of numerous diagnostic pitfalls, he ultimately met diagnostic criteria for SSPE. The possibility of Creutzfeldt-Jakob disease was immediately discarded at admission to our Department because of the long period between visual impairment and cognitive dysfunction, as well as the absence of myoclonic jerks, typical EEG and MRI findings. Positive 14-3-3, Tau and S-100 proteins in the CSF indicated severe but not specific neuronal damage.\n\nAfter careful revision of his medical history, we recognized several misleading factors. Above all, it was an insidious course of disease which started with visual disturbance and depression syndrome for 18 months. The new-onset motor symptoms with initial MRI findings suggested a relapse of MS. The history of optic neuropathy, VER and BAER findings, positive OCB, together with certain improvements after steroid treatment, supported the clinical diagnosis. However, the unfavorable disease course despite the immunosuppressive treatment with a lack of evidence for infectious disease supported the idea of primary CNS vasculitis refractory to steroids.\n\nCommon MRI findings in patients with SSPE are cortical and subcortical asymmetric hyperintense lesions on T2 WI in the posterior brain regions. Basal ganglia are usually affected after the cortex. However, MRI can be normal or may show asymmetric changes in the early stages of the disease, and changes do not always correlate with the clinical stage (5, 6). With the disease progression, the lesions may disappear and new lesions may occur symmetrically in the periventricular white matter, associated with cortical atrophy (7). In our patient, the initial MRI finding available showed signs of already advanced disease, which is difficult to distinguish from a wide spectrum of other white matter diseases including acute disseminated encephalomyelitis, acute viral encephalitis, MS and metabolic white matter disease. Taking in consideration the revised and modified McDonald’s criteria for MS, it was not possible to exclude MS based only on imaging criteria (8).\n\nThe antibody indices of specific IgG antibodies, the so-called MRZ reaction (MRZR) was recently introduced to the methods used to diagnose MS. MRZR reflects the intrathecal synthesis of specific IgG antibodies to measles (M), rubella (R) and varicella-zoster (Z) viruses. MRZR was shown to be a valuable paraclinical examination tool, detectable in CSF of 80%-100% of MS patients and more specific compared to OCB (9). However, careful assessment of MRZR is advised, particularly in cases where it is positive for only one virus and associated with OCB type 3. When MRZR score does not surpass the cut-off value of 10 (if antibody index is positive: 9 points for measles, 8 points for rubella and 1 point for varicella-zoster virus), as it was in this patient, then chronic viral encephalitis including SSPE should be taken in consideration. According to the literature, the antibody indices for measles in patients with definitive SSPE were found to be in a range of 2.3-36.9 (mean 12.9) (10). Because MRZR has been considered as a substantial contribution to the diagnosis of MS, it represented a confounding factor in this case. Furthermore, the slow forms of SSPE with initial visual manifestations that may precede other neurological signs by several years, as well as depression syndrome have been previously reported (11-14).\n\nNot only delayed, but also atypical EEG findings considerably affected the diagnostic procedure. The first EEG changes, which provoked suspicion of SSPE, were seen as late as 5 months after the onset of the accelerated phase (one month before definitive diagnosis). Atypical EEG findings in SSPE are very rare, regardless of the course of the disease or patient age (15). Atypical EEG findings could be associated with the absence of myoclonic jerks.\n\nThe major misleading finding probably was the absence of myoclonic jerks during the fully developed disease. Even though the series of immunosuppressive treatments had questionable effect on the course of the disease, they manifestly affected the diagnosis. We believe that the use of TPE resulted in false-negative serology for measles and postponed the opportunity to make an accurate diagnosis. This was supported by seroconversion in this patient with advanced disease in the weeks following TPE. Since immunosuppressants commonly and logically aggravated the course of the disease, transitory improvement noted after the first steroid pulse treatment was quite unusual. The prolonged indolent course of the disease followed by accelerated and aggressive phase in the reported patient was expected due to his old age (1, 16).\n\nIn conclusion, we would like to highlight several points. First, despite the fact that SSPE is almost exclusively a disease of childhood, it can occur in adults as well. Second, the diagnosis of adult-onset SSPE can be especially challenging because of atypical clinical presentation and broadened differential diagnosis compared to the pediatric population. Finally, the employment of unnecessary treatments such as plasmapheresis accompanied by the lack of typical EEG findings and myoclonic jerks can result in missing the correct diagnosis due to false-negative serology for measles.\n\nAcknowledgments\n\nWe thank Mrs. Arijana Pavelić and Mrs. Marija Fijucek for their help in preparation of the manuscript.\n==== Refs\nReferences\n\n1 Garg RK . Subacute sclerosing panencephalitis. Postgrad Med J. 2002;78 :63–70. 10.1136/pmj.78.916.63 11807185\n2 Saha V John TJ Mukundan P . High incidence of subacute sclerosing panencephalitis in South India. Epidemiol Infect. 1990;104 :151–6. 10.1017/S0950268800054637 2307182\n3 Prashanth LK Taly AB Sinha S Ravi V . Subacute sclerosing panencephalitis (SSPE): an insight into the diagnostic errors from a tertiary care university hospital. J Child Neurol. 2007;22 (6 ):683–8. 10.1177/0883073807303999 17641252\n4 Prashanth LK Taly AB Ravi V Sinha S Arunodaya GR . Adult onset subacute sclerosing panencephalitis: clinical profile of 39 patients from a tertiary care centre. J Neurol Neurosurg Psychiatry. 2006;77 :630–3. 10.1136/jnnp.2005.085829 16464898\n5 Sharma P Singh D Singh MK Garg RK Kohli N . Brainstem involvement in subacute sclerosing panencephalitis. Neurol India. 2011;59 :273–5. 10.4103/0028-3886.79146 21483132\n6 Schiffmann R Van der Knaap MS . An MRI-based approach to the diagnosis of white matter disorders. Neurology. 2009;72 :750–9. 10.1212/01.wnl.0000343049.00540.c8 19237705\n7 Gutierrez J Issacson RS Koppel BS . Subacute sclerosing panencephalitis: an update. Dev Med Child Neurol. 2010;52 (10 ):901–7. 10.1111/j.1469-8749.2010.03717.x 20561004\n8 Przybek J Gniatkowska I Mirowska-Guzel D Członkowska A . Evolution of diagnostic criteria for multiple sclerosis. Neurol Neurochir Pol. 2015;49 (5 ):313–21. 10.1016/j.pjnns.2015.07.006 26377983\n9 Brecht I Weissbrich B Braun J Toyka KV Weishaupt A Buttmann M . Intrathecal, polyspecific antiviral immune response in oligoclonal band negative multiple sclerosis. PLoS One. 2012;7 (7 ):e40431. 10.1371/journal.pone.0040431 22792316\n10 Samlıoğlu P Unalp A Gökçay A Altuğlu I Oztürk A Zeytinoğlu A . Subacute sclerosing panencephalitis cases diagnosed by increased CSF/serum measles antibody indices. Mikrobiyol Bul. 2012;46 :716–8.23188587\n11 Green SH Wirtschafter J . Ophthalmoscopic findings in subacute sclerosing panencephalitis. Br J Ophthalmol. 1973;57 :780–7. 10.1136/bjo.57.10.780 4784213\n12 Caruso JM Robbins-Tien D Brown WD Antony JH Gascon GG . Atypical chorioretinitis as an early presentation of subacute sclerosing panencephalitis. J Pediatr Ophthalmol Strabismus. 2000;37 (2 ):119–22.10779273\n13 Datta SS Jacob R Kumar S Jeyabalan S . A case of subacute sclerosing panencephalitis presenting as depression. Acta Neuropsychiatr. 2006;18 :55–7. 10.1111/j.0924-2708.2006.00117.x 26991986\n14 Prashanth LK Taly AB Ravi V Sinha S Rao S . Long term survival in subacute sclerosing panencephalitis: an enigma. Brain Dev. 2006;28 (7 ):447–52. 10.1016/j.braindev.2006.01.008 16554134\n15 Markand ON Panszi JG . The electroencephalogram in subacute sclerosing panencephalitis. Arch Neurol. 1975;32 :719–26. 10.1001/archneur.1975.00490530041002 1180740\n16 Gagnon A Bouchard RW . Fulminating adult-onset subacute sclerosing panencephalitis in a 49-year-old man. Arch Neurol. 2003;60 (8 ):1160–1. 10.1001/archneur.60.8.1160 12925376\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0353-9466",
"issue": "59(3)",
"journal": "Acta clinica Croatica",
"keywords": "Adult onset; MRZ (measles, rubella, varicella-zoster) reaction; Multiple sclerosis; Subacute sclerosing panencephalitis",
"medline_ta": "Acta Clin Croat",
"mesh_terms": "D000328:Adult; D002648:Child; D004569:Electroencephalography; D006801:Humans; D013344:Subacute Sclerosing Panencephalitis",
"nlm_unique_id": "9425483",
"other_id": null,
"pages": "543-548",
"pmc": null,
"pmid": "34177067",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": "10779273;26377983;21483132;12925376;2307182;19237705;1180740;20561004;23188587;16464898;16554134;26991986;11807185;4784213;22792316;17641252",
"title": "Atypical adult-onset subacute sclerosing panencephalitis.",
"title_normalized": "atypical adult onset subacute sclerosing panencephalitis"
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