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{
"abstract": "BACKGROUND\nThe Wiskott-Aldrich syndrome is a combined immunodeficiency associated with a syndrome linked to the X chromosome, which is characterized by eczema, recurrent infections, and thrombocytopenia. Other manifestations include autoimmune disorders such as hemolytic anemia or thrombocytopenic purpura mediated by the immune system, increased susceptibility to malignant tumors, including lymphoma or leukemia.\n\n\nMETHODS\nA 7-year-old male patient with a diagnosis of Wiskott-Aldrich syndrome who was treated with intravenous gamma globulin, antimicrobial prophylaxis with trimethoprim/sulfamethoxazole, and fluconazole, as well as with prednisone and cyclosporine due to hemolytic anemia and uveitis. Suddenly, he presented a deviation of the left labial commissure, so he was hospitalized. The studies showed a giant aneurysm of the aorta root, ascending aorta, descending aorta, and right coronary aorta, with insidious cardiac symptoms; therefore, he was referred to the vascular surgery department.\n\n\nCONCLUSIONS\nVasculitis in Wiskott-Aldrich syndrome is rare and it is usually asymptomatic in early stages, so an annual cardiovascular evaluation should be performed in order to avoid the complications of an aneurysm, which can be deleterious in this type of immunodeficiency where the possibility of death from bleeding is high.",
"affiliations": "Hospital Pediátrico de Sinaloa, Departamento de Inmunología y Alergia, Sinaloa, México. miguelgarcia.alergia@gmail.com.",
"authors": "García-Domínguez|Miguel|M|;De la O-Espinoza|Estivaliz Arizel|EA|;Cruz-Muñoz|Mario|M|",
"chemical_list": null,
"country": "Mexico",
"delete": false,
"doi": "10.29262/ram.v67i1.696",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-5151",
"issue": "67(1)",
"journal": "Revista alergia Mexico (Tecamachalco, Puebla, Mexico : 1993)",
"keywords": "Aortic aneurysm; Autoimmune disorders; Immunodeficiency; Vasculitis; Wiskott-Aldrich syndrome",
"medline_ta": "Rev Alerg Mex",
"mesh_terms": "D017545:Aortic Aneurysm, Thoracic; D002648:Child; D006801:Humans; D008297:Male; D014923:Wiskott-Aldrich Syndrome",
"nlm_unique_id": "9438824",
"other_id": null,
"pages": "87-93",
"pmc": null,
"pmid": "32447872",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aortic aneurysm in a patient with Wiskott-Aldrich syndrome.",
"title_normalized": "aortic aneurysm in a patient with wiskott aldrich syndrome"
} | [
{
"companynumb": "MX-NVP-000003",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo study the impact of therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, meloxicam, etoricoxib, and nimesulide, on systolic and diastolic blood pressure (BP) changes in a short period (3 days), as well as the risk of acute transient ischemic attack, ischemic and hemorrhagic stroke, and acute cardiovascular events within 6 months after NSAID use.\n\n\nMETHODS\nThe follow-up included 66 patients (34 women and 32 men) who took NSAIDs for emergent low back pain.\n\n\nRESULTS\nThe findings may suggest that etoricoxib-based therapy is highly effective and relatively safe for the management of acute nonspecific backache in patients with comorbidity. The important feature is the established tendency towards BP destabilization in patients with chronic cerebrovascular diseases treated with NSAIDs (diclofenac, meloxicam, to a lesser extent, nimesulide). After completion of drug intake for 14 days or longer, acute cerebral circulatory disorder and acute cerebrovascular event developed within 4.5 months in 3 and 2 patients, respectively.\n\n\nCONCLUSIONS\nThus, the spectrum of possible adverse cardiovascular effects of NSAIDs is rather broad. It is advisable to identify two major groups of NSAID-associated complications: 1) destabilized hypertension; 2) cardiovascular and cerebrovascular events.",
"affiliations": "Department of Neurology and Neurosurgery, Samara State Medical University, Samara.;Samara City Polyclinic Nine, Samara, Russia.",
"authors": "Poverennova|I E|IE|;Zolotovskaya|I A|IA|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal",
"country": "Russia (Federation)",
"delete": false,
"doi": "10.17116/terarkh201587553-57",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-3660",
"issue": "87(5)",
"journal": "Terapevticheskii arkhiv",
"keywords": null,
"medline_ta": "Ter Arkh",
"mesh_terms": "D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002318:Cardiovascular Diseases; D002561:Cerebrovascular Disorders; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D017116:Low Back Pain; D008297:Male; D008875:Middle Aged; D011379:Prognosis",
"nlm_unique_id": "2984818R",
"other_id": null,
"pages": "53-57",
"pmc": null,
"pmid": "26155619",
"pubdate": "2015",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Cerebrovascular risks and prediction of complications in patients with backache during therapy with nonsteroidal anti-inflammatory drugs.",
"title_normalized": "cerebrovascular risks and prediction of complications in patients with backache during therapy with nonsteroidal anti inflammatory drugs"
} | [
{
"companynumb": "RU-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-52254GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MELOXICAM"
},
... |
{
"abstract": "Fusobacterium nucleatum is a Gram-negative, obligate anaerobic bacterium which predominantly resides within the oral cavity and causes acute abscesses and venous thrombosis, primarily in the head and neck region, but could have unique clinical presentations in different anatomical regions of the body.\nWe present a case of subacute liver abscesses extending to the lung. The histopathological examination showed extensive necrosis and fibrosis. The chronic course, extensive fibrosis and extension across the anatomic barriers were suggestive of actinomycosis. two sets of blood cultures grew Fusobacterium nucleatum, only 16s rRNA analysis of the liver tissue and pleural fluid revealed F. nucleatum DNA without other organisms. The clinical and pathological features of our case illustrate that F. nucleatum may mimic actinomycosis.\nThis case illustrates that F. nucleatum should be considered in patients with subacute infections with extensive fibrosis that crosses anatomic barriers, mimicking actinomycosis.",
"affiliations": "MD, Division of Infectious Diseases, Department of Medicine, Ascension St John Hospital, 19251 Mack Ave, Suite 340, Grosse Pointe Woods, MI 48236, USA.;MD, Division of Infectious Diseases, Department of Medicine, Ascension St John Hospital, 19251 Mack Ave, Suite 340, Grosse Pointe Woods, MI 48236, USA.;MD, Department of Pathology, Ascension St John Hospital, 19251 Mack Ave, Suite 340, Grosse Pointe Woods, MI 48236, USA.;MD, Department of Pathology, Ascension St John Hospital, 19251 Mack Ave, Suite 340, Grosse Pointe Woods, MI 48236, USA.;MD, Department of Radiology, Ascension St John Hospital, 19251 Mack Ave, Suite 340, Grosse Pointe Woods, MI 48236, USA.",
"authors": "Hooshmand|Babak|B|;Khatib|Riad|R|;Hamza|Ameer|A|;Snower|Daniel|D|;Alcantara|Anthony L|AL|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": "10.18683/germs.2019.1164",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2248-2997",
"issue": "9(2)",
"journal": "Germs",
"keywords": "Fusobacterium nucleatum; Liver abscess; actinomycosis; fibrosis",
"medline_ta": "Germs",
"mesh_terms": null,
"nlm_unique_id": "101596099",
"other_id": null,
"pages": "102-105",
"pmc": null,
"pmid": "31341838",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": "11035583;18114452;22698087;24348321;25045274;25530149;25576662;25834342;26101735;2646510;27213146;28736715;28942408;29967887;4756858",
"title": "Fusobacterium nucleatum: A cause of subacute liver abscesses with extensive fibrosis crossing the diaphragm, mimicking actinomycosis.",
"title_normalized": "fusobacterium nucleatum a cause of subacute liver abscesses with extensive fibrosis crossing the diaphragm mimicking actinomycosis"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-212253",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
... |
{
"abstract": "BACKGROUND\nWe present the case of very early onset pre-eclampsia, possibly aggravated by liquorice consumption.\n\n\nMETHODS\nAn 18-year-old healthy primigravida presented with high blood pressure and proteinuria at 18 weeks gestation. She had a strong family history of pre-eclampsia and was consuming considerable amounts of liquorice. A diagnosis of severe pre-eclampsia/hemolysis, elevated liver enzymes, and low platelet count was confirmed. The pregnancy was terminated. Extensive investigation ruled out underlying diseases and autopsy revealed a normal fetus. In three consequtive pregnancies, she developed milder forms of pre-eclampsia.\n\n\nCONCLUSIONS\nIn healthy women with a familial/genetic susceptibility for pre-eclampsia, liquorice consumption may aggravate the course of the disease.",
"affiliations": "Department of Obstetrics and Gynecology .",
"authors": "Hauksdottir|Dögg|D|;Sigurjonsdottir|Helga Agusta|HA|;Arnadottir|Margret|M|;Geirsson|Reynir T|RT|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3109/10641955.2015.1009542",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1064-1955",
"issue": "34(2)",
"journal": "Hypertension in pregnancy",
"keywords": "Hypertension; Intrauterine growth restriction; Liqourice; Pre-eclampsia; Pregnancy",
"medline_ta": "Hypertens Pregnancy",
"mesh_terms": "D000032:Abortion, Therapeutic; D000293:Adolescent; D005260:Female; D020022:Genetic Predisposition to Disease; D006035:Glycyrrhiza; D006801:Humans; D011225:Pre-Eclampsia; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D011507:Proteinuria",
"nlm_unique_id": "9421297",
"other_id": null,
"pages": "221-6",
"pmc": null,
"pmid": "25774453",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe, very early onset pre-eclampsia associated with liquorice consumption.",
"title_normalized": "severe very early onset pre eclampsia associated with liquorice consumption"
} | [
{
"companynumb": "IS-BAYER-2015-182904",
"fulfillexpeditecriteria": "1",
"occurcountry": "IS",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Motor and non-motor manifestations are common and disabling features of hereditary spastic paraplegia (HSP). Botulinum toxin type A (Btx-A) is considered effective for spasticity and may improve gait in these patients. Little is known about the effects of Btx-A on non-motor symptoms in HSP patients. Objective To assess the efficacy of Btx-A on motor and non-motor manifestations in HSP patients. Methods Thirty-three adult patients with a clinical and molecular diagnosis of HSP were evaluated before and after Btx-A injections. Results Mean age was 41.7 ± 13.6 years and there were 18 women. Most patients had a pure phenotype and SPG4 was the most frequent genotype. The Btx-A injections resulted in a decrease in spasticity at the adductor muscles, and no other motor measure was significantly modified. In contrast, fatigue scores were significantly reduced after Btx-A injections. Conclusion Btx-A injections resulted in no significant functional motor improvement for HSP, but fatigue improved after treatment.",
"affiliations": "Departamento de Neurologia, Hospital de Clínicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.;Departamento de Neurologia, Hospital de Clínicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.;Departamento de Neurologia, Hospital de Clínicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.;Departamento de Medicina Interna, Serviço de Neurologia, Unidade de Distúrbios do Movimento, Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brasil.;Departamento de Medicina Interna, Serviço de Neurologia, Unidade de Distúrbios do Movimento, Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brasil.;Departamento de Medicina Interna, Serviço de Neurologia, Unidade de Distúrbios do Movimento, Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brasil.;Departamento de Medicina Interna, Serviço de Neurologia, Unidade de Distúrbios do Movimento, Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brasil.;Departamento de Medicina Interna, Serviço de Neurologia, Unidade de Distúrbios do Movimento, Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brasil.;Departamento de Medicina Interna, Serviço de Neurologia, Unidade de Distúrbios do Movimento, Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brasil.;Departamento de Medicina Interna, Serviço de Neurologia, Unidade de Distúrbios do Movimento, Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brasil.;Departamento de Neurologia, Hospital de Clínicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.",
"authors": "Servelhere|Katiane R|KR|;Faber|Ingrid|I|;Martinez|Alberto|A|;Nickel|Renato|R|;Moro|Adriana|A|;Germiniani|Francisco M B|FMB|;Moscovich|Mariana|M|;Blume|Tatiane R|TR|;Munhoz|Renato P|RP|;Teive|Hélio A G|HAG|;França|Marcondes C|MC|",
"chemical_list": "D009465:Neuromuscular Agents; D019274:Botulinum Toxins, Type A",
"country": "Brazil",
"delete": false,
"doi": "10.1590/0004-282x20180013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-282X",
"issue": "76(3)",
"journal": "Arquivos de neuro-psiquiatria",
"keywords": null,
"medline_ta": "Arq Neuropsiquiatr",
"mesh_terms": "D000328:Adult; D017668:Age of Onset; D019274:Botulinum Toxins, Type A; D005260:Female; D005684:Gait; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D008875:Middle Aged; D000068079:Motor Disorders; D018763:Muscle Fatigue; D009128:Muscle Spasticity; D009465:Neuromuscular Agents; D015203:Reproducibility of Results; D015419:Spastic Paraplegia, Hereditary; D016896:Treatment Outcome",
"nlm_unique_id": "0125444",
"other_id": null,
"pages": "183-188",
"pmc": null,
"pmid": "29809239",
"pubdate": "2018-03",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Botulinum toxin for hereditary spastic paraplegia: effects on motor and non-motor manifestations.",
"title_normalized": "botulinum toxin for hereditary spastic paraplegia effects on motor and non motor manifestations"
} | [
{
"companynumb": "BR-IPSEN BIOPHARMACEUTICALS, INC.-2018-05859",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ABOBOTULINUMTOXINA"
},
"dr... |
{
"abstract": "Purpose Docetaxel and cyclophosphamide (TC) was superior to doxorubicin and cyclophosphamide (AC) in a trial in early breast cancer. However, activity of TC relative to AC regimens with a taxane (TaxAC) is unknown. Methods In a series of three adjuvant trials, women were randomly assigned to TC for six cycles (TC6) or to a standard TaxAC regimen. US Oncology Research (USOR) 06-090 compared TC6 with docetaxel, doxorubicin, and cyclophosphamide (TAC6). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-46-I/USOR 07132 compared TC6, TAC6, or TC6 plus bevacizumab. NSABP B-49 compared TC6 with several standard AC and taxane combination regimens. Before any analysis of individual trials, a joint efficacy analysis of TC versus the TaxAC regimens was planned, with invasive disease-free survival (IDFS) as the primary end point. Patients who received TC6 plus bevacizumab on NSABP B-46-I/USOR 07132 were not included. A hazard ratio (HR) from a stratified Cox model that exceeded 1.18 for TC6 versus TaxAC was predefined as inferiority for TC6. The prespecified interim monitoring plan was to report for futility if the HR was > 1.18 when 334 IDFS events were observed (50% of 668 events required for definitive analysis). Results A total of 2,125 patients were randomly assigned to receive TC6 regimens and 2,117 patients were randomly assigned to receive TaxAC regimens. The median follow-up time was 3.3 years. There were 334 IDFS events, and the HR for TC6 versus TaxAC was 1.202 (95% CI, 0.97 to 1.49), which triggered early reporting for futility. The 4-year IDFS was 88.2% for TC6 and was 90.7% for TaxAC ( P = .04). Tests for treatment interaction by protocol, hormone receptor status, and nodal status were negative. Conclusion The TaxAC regimens improved IDFS in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer compared with the TC6 regimen.",
"affiliations": "Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.;Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.",
"authors": "Blum|Joanne L|JL|;Flynn|Patrick J|PJ|;Yothers|Greg|G|;Asmar|Lina|L|;Geyer|Charles E|CE|;Jacobs|Samuel A|SA|;Robert|Nicholas J|NJ|;Hopkins|Judith O|JO|;O'Shaughnessy|Joyce A|JA|;Dang|Chau T|CT|;Gómez|Henry Leonidas|HL|;Fehrenbacher|Louis|L|;Vukelja|Svetislava J|SJ|;Lyss|Alan P|AP|;Paul|Devchand|D|;Brufsky|Adam M|AM|;Jeong|Jong-Hyeon|JH|;Colangelo|Linda H|LH|;Swain|Sandra M|SM|;Mamounas|Eleftherios P|EP|;Jones|Stephen E|SE|;Wolmark|Norman|N|",
"chemical_list": "D018943:Anthracyclines; D001952:Bridged-Ring Compounds; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D043823:Taxoids; D000077143:Docetaxel; C080625:taxane; D004317:Doxorubicin; D003520:Cyclophosphamide; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2016.71.4147",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "35(23)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D018943:Anthracyclines; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D001952:Bridged-Ring Compounds; D018270:Carcinoma, Ductal, Breast; D002285:Carcinoma, Intraductal, Noninfiltrating; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D000077143:Docetaxel; D004317:Doxorubicin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis; D008408:Mastectomy; D008875:Middle Aged; D011446:Prospective Studies; D018719:Receptor, ErbB-2; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D043823:Taxoids",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "2647-2655",
"pmc": null,
"pmid": "28398846",
"pubdate": "2017-08-10",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "23940225;22152853;12637460;3519883;7877646;15930421;17135639;7973224;18159072;15897552;19204201;26077235;18420499;12668651;350254;22614988",
"title": "Anthracyclines in Early Breast Cancer: The ABC Trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology).",
"title_normalized": "anthracyclines in early breast cancer the abc trials usor 06 090 nsabp b 46 i usor 07132 and nsabp b 49 nrg oncology"
} | [
{
"companynumb": "US-JNJFOC-20170917172",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "From the beginning of COVID-19 pandemics, the involvement of patient's nervous system with this virus is increasingly reporting. Although various reports are published on affliction of multiple sclerosis (MS) patients with SARS-CoV-2, no report has been published on brain involvement by this virus in MS patients so far. Herein, a 34-year-old patient with MS who experienced the decreased level of consciousness and encephalopathy following COVID-19 involvement has been reported.",
"affiliations": "Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. abdorrezamoghadasi@gmail.com.",
"authors": "Naser Moghadasi|Abdorreza|A|0000-0002-8598-0911",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1007/s13365-020-00921-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-0284",
"issue": "26(6)",
"journal": "Journal of neurovirology",
"keywords": "COVID-19; Encephalopathy; IVIG; Multiple sclerosis; SARS-CoV-2",
"medline_ta": "J Neurovirol",
"mesh_terms": "D000328:Adult; D001921:Brain; D001927:Brain Diseases; D000086382:COVID-19; D015897:Comorbidity; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D009103:Multiple Sclerosis; D000086402:SARS-CoV-2",
"nlm_unique_id": "9508123",
"other_id": null,
"pages": "973-975",
"pmc": null,
"pmid": "33118141",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32447630;32409215;32590204;32474220;32895254;32283294",
"title": "Encephalopathy associated with COVID-19 in a patient with multiple sclerosis.",
"title_normalized": "encephalopathy associated with covid 19 in a patient with multiple sclerosis"
} | [
{
"companynumb": "IR-ROCHE-2716114",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "OBJECTIVE\nVitamin D is implicated in vascular health in CKD. This study compared placebo, calcifediol, and calcitriol treatment with changes in vascular stiffness, BP, proteinuria, mineral metabolism parameters, C-reactive protein, and fibroblast growth factor 23 in patients with stable CKD.\n\n\nMETHODS\nWe conducted a double-blind, randomized controlled trial in out-patient CKD clinics in Vancouver, Canada, from February of 2011 to August of 2014, enrolling 119 patients with an eGFR of 15-45 ml/min per 1.73 m2. Change in pulse wave velocity (PWV) was measured after 6 months of treatment with a fixed dose of oral calcifediol (5000 IU 25-hydroxyvitamin D3), calcitriol (0.5 µg 1,25-dihydroxyvitamin D3), or placebo, thrice weekly.\n\n\nRESULTS\nEighty-seven participants were evaluated. Mean age was 66 years, 71% were men, 40% were diabetic, and mean baseline PWV was 11.5 m/s (SD=3.9 m/s). After 6 months, the PWV decreased in the calcifediol group (mean change, -1.1; 95% confidence interval [95% CI], -2.2 to 0.1 m/s), remained unchanged in the calcitriol group (mean change, 0.2; 95% CI, -0.9 to 1.4 m/s), and increased in the placebo group (mean change, 1.1; 95% CI, -0.1 to 2.2 m/s). The overall P value for between-arm changes was 0.03. Absolute PWV change was significantly different between groups (P=0.04): the combined vitamin D treatment group saw decreased PWV (mean change, -0.4; 95% CI, -1.2 to 0.4 m/s) whereas the placebo group saw increased PWV (mean change, +1.1; 95% CI, -0.1 to 2.2 m/s). The treatment group demonstrated significantly decreased serum parathyroid hormone (mean difference, -0.5; 95% CI, -0.7 to -0.3 ln[pg/ml]; P<0.001) and increased calcium (mean difference, 0.4; 95% CI, -0.1 to 0.7 mg/dl; P=0.02). In observational analysis, participants in the highest 25-hydroxyvitamin D tertile at trial end had significant decreases in PWV (mean change, -1.0; 95% CI, -2.0 to 0.0 m/s) compared with the middle and lowest tertiles (P<0.01). Side effects were minor and rare.\n\n\nCONCLUSIONS\nSix months of supplemental vitamin D analogs at fixed doses may achieve a reduction of PWV in patients with advanced CKD. Because the treatment effect was attenuated when baseline PWV was included as a covariate, these findings should be replicated in larger populations and further studied.",
"affiliations": "Division of Nephrology, alevin@providencehealth.bc.ca.;Nephrology Research, St. Paul's Hospital, and.;Nephrology Research, St. Paul's Hospital, and.;Division of Nephrology.;Division of Nephrology.;Department of Medicine, and.;Department of Medicine, and.;BC Renal Agency, Vancouver, Canada.",
"authors": "Levin|Adeera|A|;Tang|Mila|M|;Perry|Taylor|T|;Zalunardo|Nadia|N|;Beaulieu|Monica|M|;Dubland|Joshua A|JA|;Zerr|Kelly|K|;Djurdjev|Ognjenka|O|",
"chemical_list": "D015415:Biomarkers; D014807:Vitamin D; C104450:25-hydroxyvitamin D; D002117:Calcitriol; D002112:Calcifediol",
"country": "United States",
"delete": false,
"doi": "10.2215/CJN.10791016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1555-9041",
"issue": "12(9)",
"journal": "Clinical journal of the American Society of Nephrology : CJASN",
"keywords": "Aged; Arm; C-Reactive Protein; Calcifediol; Calcitriol; Canada; Fibroblast Growth Factors; Humans; Male; Minerals; Outpatients; Pulse Wave Analysis; Renal Insufficiency, Chronic; Vascular Stiffness; Vitamin D; Vitamins; blood pressure; calcium; diabetes mellitus; fibroblast growth factor 23; mineral metabolism; parathyroid hormone; proteinuria; vascular calcification; vascular disease",
"medline_ta": "Clin J Am Soc Nephrol",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000554:Ambulatory Care Facilities; D015415:Biomarkers; D001955:British Columbia; D002112:Calcifediol; D002117:Calcitriol; D019587:Dietary Supplements; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D063177:Pulse Wave Analysis; D051436:Renal Insufficiency, Chronic; D013997:Time Factors; D059289:Vascular Stiffness; D014807:Vitamin D",
"nlm_unique_id": "101271570",
"other_id": null,
"pages": "1447-1460",
"pmc": null,
"pmid": "28550081",
"pubdate": "2017-09-07",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "27190394;24661355;23493381;26824510;25259743;21055801;21270766;21499117;18606901;26700109;24646518;25228838;21816525;21242674;26496210;25381032;21378153;27190390;20817560;22071357;25006678;21688248;25801871;25455721;22337679;22036893;24297817;23467111;22822092;24066946;17091124;17014561;20596692;23298824;27190392;16908915",
"title": "Randomized Controlled Trial for the Effect of Vitamin D Supplementation on Vascular Stiffness in CKD.",
"title_normalized": "randomized controlled trial for the effect of vitamin d supplementation on vascular stiffness in ckd"
} | [
{
"companynumb": "CA-VALIDUS PHARMACEUTICALS LLC-CA-2017VAL001686",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CALCITRIOL"
},
"drugadd... |
{
"abstract": "Acute fixed cervical kyphosis may be a rare presentation of conversion disorder, psychogenic dystonia, and potentially as a side effect from typical antipsychotic drugs. Haldol has been associated with acute dystonic reactions. In some cases, rigid deformities ensue. We are reporting a case of a fixed cervical kyphosis after the use of Haldol.\n\n\n\nTo present a case of a potential acute dystonic reaction temporally associated with Haldol ingestion leading to fixed cervical kyphosis.\n\n\n\nThis is a case report.\n\n\n\nA patient diagnosed with bipolar disorder presented to the emergency room several times with severe neck pain and stiffness. The neck appeared fixed in flexion with extensive osteophyte formation over a 3-month period.\n\n\n\nThe patient's condition was resolved by a posterior-anterior-posterior surgical approach. It corrected the patient's cervical curvature from 88° to 5°.\n\n\n\nAcute dystonic reactions have the potential to apply enough pressure on bone to cause rapid osteophyte formation.",
"affiliations": "Department of Spine Orthopaedics, Massachusetts General Hospital, Yawkey 3A, 55 Fruit St., Boston, MA 02114, USA. Electronic address: mamtharajMD@gmail.com.;Department of Spine Orthopaedics, Massachusetts General Hospital, Yawkey 3A, 55 Fruit St., Boston, MA 02114, USA.",
"authors": "Raj|Mamtha S|MS|;Schwab|Joseph H|JH|",
"chemical_list": "D014150:Antipsychotic Agents; D006220:Haloperidol",
"country": "United States",
"delete": false,
"doi": "10.1016/j.spinee.2016.09.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1529-9430",
"issue": "17(2)",
"journal": "The spine journal : official journal of the North American Spine Society",
"keywords": "Chin-to-chest deformity; Dystonic reaction; Fixed cervical kyphosis; Haloperidol; Osteophyte formation; Severe neck pain",
"medline_ta": "Spine J",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D002574:Cervical Vertebrae; D005260:Female; D006220:Haloperidol; D006801:Humans; D007738:Kyphosis",
"nlm_unique_id": "101130732",
"other_id": null,
"pages": "e7-e9",
"pmc": null,
"pmid": "27664338",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An unusual cause of cervical kyphosis.",
"title_normalized": "an unusual cause of cervical kyphosis"
} | [
{
"companynumb": "US-JNJFOC-20161220563",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": "1",
... |
{
"abstract": "Abiraterone acetate (AA) is licensed for treating metastatic castration-resistant prostate cancer (mCRPC). Real-world data on oncological outcome after AA are scarce. The current study assesses efficacy and safety of AA in mCRPC patients previously treated with docetaxel who started treatment during the Belgian compassionate use program (January 2011-July 2012).\n\n\n\nRecords from 368 patients with mCRPC from 23 different Belgian hospitals who started AA 1000mg per day with 10mg prednisone or equivalent were retrospectively reviewed (September 2013-December 2014). Prostate-specific antigen (PSA) response (decrease≥50%), time to PSA progression (increase>50% over PSA nadir in case of PSA response/>25% in absence of PSA response), time to radiographic progression (on bone scans or for soft tissue lesions using Response Evaluation Criteria In Solid Tumors 1.1), overall survival and adverse event rate (Common Terminology Criteria for Adverse Events v4.03) were analyzed. Kaplan-Meier statistics were applied.\n\n\n\nOverall, 92 patients (25%) had an Eastern Cooperative Oncology Group performance status≥2. Median age was 73 years, median PSA was 103ng/dl. PSA response was observed in 131 patients (37.4%). Median time to PSA and radiographic progression was 4.1 months (95% CI: 3.6-4.6) and 5.8 months (5.3-6.4), respectively. Median overall survival was 15.1 months (13.6-16.6). Most common grade 3 to 4 adverse events were anemia (13.9%), hypokalemia (7.3%), fatigue (6.8%), and pain (6.3%). Median duration of AA treatment was 5.3 months (interquartile range: 2.8-10.3). The main study limitation is its retrospective design.\n\n\n\nThese real-world data on post-docetaxel AA efficacy are in line with the COU-AA-301 trial. Importantly, incidence of severe anemia and hypokalemia is up to 50% higher than reported in previous studies.",
"affiliations": "Department of Urology, Ghent University Hospital, Ghent, Belgium. Electronic address: charles.vanpraet@uzgent.be.;Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium.;Department of Medical Oncology, University Hospital Leuven, Leuven, Belgium.;Department of Medical Oncology, AZ Turnhout, Turnhout, Belgium.;Department of Medical Oncology, AZ Klina, Kalmthout, Belgium.;Department of Medical Oncology, AZ Delta, Roeselare, Belgium.;Department of Medical Oncology, Imelda Hospital, Bonheiden, Belgium.;Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.;Department of Urology, Onze-Lieve-Vrouw Hospital, Aalst, Belgium.;Department of Medical Oncology, Hopital De Jolimont, Haine Saint Paul, Belgium.;Department of Medical Oncology, University Hospital Brussels, Jette, Belgium.;Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint Luc, Brussels, Belgium.;Department of Medical Oncology, Ziekenhuis Netwerk Antwerpen (ZNA) Middelheim, Antwerp, Belgium.;Department of Medical Oncology, AZ Nikolaas, Sint-Niklaas, Belgium.;Department of Medical Oncology, CHU Dinant-Godinne, Yvoir, Belgium.;Department of Urology, AZ Groeninge, Kortrijk, Belgium.;Department of Medical Oncology, ZNA Jan Palfijn, Merksem, Belgium.;Department of Medical Oncology, AZ Jessa, Hasselt, Belgium.;Department of Medical Oncology, St Luc Bouge, Namur, Belgium.;Department of Medical Oncology, UZA/AZ Monica, Antwerp, Belgium.;Department of Medical Oncology, Algemeen Stedelijk Ziekenhuis, Aalst, Belgium.;Department of Medical Oncology, AZ Sint-Trudo, Sint-Truiden, Belgium.;Department of Urology, AZ Sint-Andries, Tielt, Belgium.;Department of Medical Oncology, Sainte-Elisabeth, Namur, Belgium.;Department of Urology, Ghent University Hospital, Ghent, Belgium.",
"authors": "Van Praet|Charles|C|;Rottey|Sylvie|S|;Van Hende|Fransien|F|;Pelgrims|Gino|G|;Demey|Wim|W|;Van Aelst|Filip|F|;Wynendaele|Wim|W|;Gil|Thierry|T|;Schatteman|Peter|P|;Filleul|Bertrand|B|;Schallier|Dennis|D|;Machiels|Jean-Pascal|JP|;Schrijvers|Dirk|D|;Everaert|Els|E|;D'Hondt|Lionel|L|;Werbrouck|Patrick|P|;Vermeij|Joanna|J|;Mebis|Jeroen|J|;Clausse|Marylene|M|;Rasschaert|Marika|M|;Van Erps|Joanna|J|;Verheezen|Jolanda|J|;Van Haverbeke|Jan|J|;Goeminne|Jean-Charles|JC|;Lumen|Nicolaas|N|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D000069501:Abiraterone Acetate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1439",
"issue": "34(6)",
"journal": "Urologic oncology",
"keywords": "Abiraterone acetate; Castration-resistant; Compassionate use; Docetaxel; Prostatic neoplasms",
"medline_ta": "Urol Oncol",
"mesh_terms": "D000069501:Abiraterone Acetate; D000368:Aged; D001530:Belgium; D057176:Compassionate Use Trials; D000077143:Docetaxel; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant; D012189:Retrospective Studies; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "9805460",
"other_id": null,
"pages": "254.e7-254.e13",
"pmc": null,
"pmid": "26850781",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Abiraterone acetate post-docetaxel for metastatic castration-resistant prostate cancer in the Belgian compassionate use program.",
"title_normalized": "abiraterone acetate post docetaxel for metastatic castration resistant prostate cancer in the belgian compassionate use program"
} | [
{
"companynumb": "BE-JNJFOC-20160523823",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nIndividuals with HIV infection and peripheral metabolic complications have impaired basal myocardial insulin sensitivity that is related to left ventricular (LV) diastolic dysfunction. It is unknown whether interventions shown to be effective in improving peripheral insulin sensitivity can improve basal myocardial insulin sensitivity and diastolic function in people with HIV and peripheral metabolic complications.\n\n\nOBJECTIVE\nIn a pilot study, we evaluated whether the peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist pioglitazone or combined endurance and resistance exercise training improves basal myocardial insulin sensitivity and diastolic function in HIV+ adults with peripheral metabolic complications.\n\n\nMETHODS\nTwenty-four HIV+ adults with metabolic complications including peripheral insulin resistance were randomly assigned to 4 months of pioglitazone (PIO; 30 mg/d) or supervised, progressive endurance and resistance exercise training (EXS; 90-120 min/d, 3 d/wk). Basal myocardial substrate metabolism was quantified by radioisotope tracer methodology and positron emission tomography (PET) imaging, and LV function was measured by echocardiography.\n\n\nRESULTS\nTwenty participants completed the study. Neither PIO nor EXS resulted in a detectable improvement in basal myocardial insulin sensitivity or diastolic function. Post hoc analyses revealed sample sizes of more than 100 participants are needed to detect significant effects of these interventions on basal myocardial insulin sensitivity and function.\n\n\nCONCLUSIONS\nPIO or EXS alone did not significantly increase basal myocardial insulin sensitivity or LV diastolic function in HIV+ individuals with peripheral metabolic complications.",
"affiliations": "Program in Physical Therapy, Washington University School of Medicine, St. Louis, Missouri.;Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, Missouri.;Division of Infectious Disease, Washington University School of Medicine, St. Louis, Missouri.;Department of Radiology, Washington University School of Medicine, St. Louis, Missouri.;Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri.;Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine, St. Louis, Missouri.;Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine, St. Louis, Missouri.;Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine, St. Louis, Missouri.;Department of Radiology, Washington University School of Medicine, St. Louis, Missouri.;Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri.;Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine, St. Louis, Missouri.",
"authors": "Cade|W Todd|WT|;Reeds|Dominic N|DN|;Overton|E Turner|ET|;Herrero|Pilar|P|;Waggoner|Alan D|AD|;Laciny|Erin|E|;Bopp|Coco|C|;Lassa-Claxton|Sherry|S|;Gropler|Robert J|RJ|;Peterson|Linda R|LR|;Yarasheski|Kevin E|KE|",
"chemical_list": "D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077205:Pioglitazone",
"country": "England",
"delete": false,
"doi": "10.1310/hct1406-303",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1528-4336",
"issue": "14(6)",
"journal": "HIV clinical trials",
"keywords": "HIV; exercise; insulin resistance; left ventricular dysfunction; metabolic syndrome",
"medline_ta": "HIV Clin Trials",
"mesh_terms": "D000328:Adult; D015444:Exercise; D005260:Female; D015658:HIV Infections; D006801:Humans; D007004:Hypoglycemic Agents; D007333:Insulin Resistance; D008297:Male; D009206:Myocardium; D010865:Pilot Projects; D000077205:Pioglitazone; D011446:Prospective Studies; D045162:Thiazolidinediones; D016277:Ventricular Function, Left",
"nlm_unique_id": "100936377",
"other_id": null,
"pages": "303-12",
"pmc": null,
"pmid": "24334183",
"pubdate": "2013",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "17623815;9619798;17592090;16376782;16123370;11845124;12731756;17142348;16118251;11052966;21670229;15495092;10421244;7926289;2788669;18049834;11206679;15569129;16752430;10905472;11118392;18646086;17500064;18275343;16855995;18453807;18158644;12131567;18567700;22151886;11133903;16352676;9036802;20959530;1919738;8862319;17278068;18479224;11739286;10790352;20687068;18453813;12837664;9286964;19933410;16603854;16157765",
"title": "Pilot study of pioglitazone and exercise training effects on basal myocardial substrate metabolism and left ventricular function in HIV-positive individuals with metabolic complications.",
"title_normalized": "pilot study of pioglitazone and exercise training effects on basal myocardial substrate metabolism and left ventricular function in hiv positive individuals with metabolic complications"
} | [
{
"companynumb": "US-TAKEDA-2016TEU003296",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PIOGLITAZONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nEndometrial carcinoma is the most common gynecologic malignancy worldwide. Prognosis of patients with peritoneal carcinomatosis (PC) from endometrial carcinoma is deadly, with an estimated median survival not exceeding 12 months. The objective of this study was to report our experience with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for managing PC from primary and recurrent endometrial carcinoma.\n\n\nMETHODS\nA retrospective analysis of 6 patients with PC arising from endometrial cancer, who were managed with CRS and HIPEC at our referral tertiary care center, from November 2010 to August 2013.\n\n\nMETHODS\nSix patients underwent CRS and HIPEC. CRS was performed using standard peritonectomy procedures and visceral resections directed toward the complete elimination of tumors from ab.dominopelvic cavity. HIPEC was performed with cisplatin (50 mg/m2) and doxorubicin (15 mg/m2) and allowed to circulate in abdominopelvic cavity for 90 minutes at 41.0 to 42.2°C.\n\n\nRESULTS\nTwo patients with primary endometrial carcinoma and 4 patients with recurrent endometrial carcino.ma confined to peritoneal cavity were studied. Complete cytoreduction (CC-0) was achieved in 5 patients. The International Federation of Gynecology and Obstetrics (FIGO) stages and histopathological types were as follows: IB endometrioid adenocarcinomas (n=1), IC mesonephric carcinomas (n=1), IIIA endometrioid adenocarcino.mas (n=2), IIIA papillary serous carcinomas (n=1), and IIIC clear-cell carcinomas (n=1). Anastomotic leak (grade I) was the most commonly encountered postoperative complication. Two patients developed grade IV compli.cations due to septicemia and pulmonary embolism. No intraoperative mortality occurred. Postoperatively, all patients received chemotherapy (carboplatin and paclitaxel). In 1 patient, the clear-cell carcinoma histologic lesion relapsed within 6 months; the metastases spread to hepatic, pelvic, and mesenteric lymph nodes, and the patient died 5 months later. One patient with cytoreduction completeness of CC-2 developed hepatic metastases within 3 months and is still alive at a follow-up up 6 months. Remaining patients (n=4) are alive and disease free without evidence of recurrence of follow-ups at 35, 34, 19, and 7 months.\n\n\nCONCLUSIONS\nCRS and HIPEC are well-tolerated and feasibly promising management modalities in PC from primary and recurrent endometrial carcinoma. Further research is needed for in-depth analysis.",
"affiliations": "Dr. Ismail A. Al-Badawi, MBC 52 Department of Obstetrics and Gynecology,, PO Box 3354, King Faisal Specialist Hospital and Research Centre,, Riyadh 11211, Saudi Arabia, T: +966-11- 442-7392, F: +966-11-442-7393, ibadawi@kfshrc.edu.sa.",
"authors": "Abu-Zaid|Ahmed|A|;Azzam|Ayman Zaki|AZ|;AlOmar|Osama|O|;Salem|Hany|H|;Amin|Tarek|T|;Al-Badawi|Ismail A|IA|",
"chemical_list": "D016190:Carboplatin; D017239:Paclitaxel",
"country": "Saudi Arabia",
"delete": false,
"doi": "10.5144/0256-4947.2014.159",
"fulltext": "\n==== Front\nAnn Saudi MedAnn Saudi MedAnnals of Saudi Medicine0256-49470975-4466King Faisal Specialist Hospital and Research Centre 2489478610.5144/0256-4947.2014.159asm-2-159Brief ReportCytoreductive surgery and hyperthermic intraperitoneal chemotherapy for managing peritoneal carcinomatosis from endometrial carcinoma: a single-center experience of 6 cases Abu-Zaid Ahmed abAzzam Ayman Zaki acAlOmar Osama bSalem Hany bAmin Tarek aAl-Badawi Ismail A. b\na Oncology Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia\nb Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia\nc Faculty of Medicine, Alexandria University, Alexandria, EgyptCorrespondence: Dr. Ismail A. Al-Badawi, MBC 52 Department of Obstetrics and Gynecology, PO Box 3354, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia, T: +966-11- 442-7392. F: +966-11-442-7393, ibadawi@kfshrc.edu.saMar-Apr 2014 34 2 159 166 Copyright © 2014, Annals of Saudi Medicine2014This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.BACKGROUND AND OBJECTIVES\nEndometrial carcinoma is the most common gynecologic malignancy worldwide. Prognosis of patients with peritoneal carcinomatosis (PC) from endometrial carcinoma is deadly, with an estimated median survival not exceeding 12 months. The objective of this study was to report our experience with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for managing PC from primary and recurrent endometrial carcinoma.\n\nDESIGN AND SETTINGS\nA retrospective analysis of 6 patients with PC arising from endometrial cancer, who were managed with CRS and HIPEC at our referral tertiary care center, from November 2010 to August 2013.\n\nMATERIALS AND METHODS\nSix patients underwent CRS and HIPEC. CRS was performed using standard peritonectomy procedures and visceral resections directed toward the complete elimination of tumors from abdominopelvic cavity. HIPEC was performed with cisplatin (50 mg/m2) and doxorubicin (15 mg/m2) and allowed to circulate in abdominopelvic cavity for 90 minutes at 41.0 to 42.2°C.\n\nRESULTS\nTwo patients with primary endometrial carcinoma and 4 patients with recurrent endometrial carcinoma confined to peritoneal cavity were studied. Complete cytoreduction (CC-0) was achieved in 5 patients. The International Federation of Gynecology and Obstetrics (FIGO) stages and histopathological types were as follows: IB endometrioid adenocarcinomas (n=1), IC mesonephric carcinomas (n=1), IIIA endometrioid adenocarcinomas (n=2), IIIA papillary serous carcinomas (n=1), and IIIC clear-cell carcinomas (n=1). Anastomotic leak (grade I) was the most commonly encountered postoperative complication. Two patients developed grade IV complications due to septicemia and pulmonary embolism. No intraoperative mortality occurred. Postoperatively, all patients received chemotherapy (carboplatin and paclitaxel). In 1 patient, the clear-cell carcinoma histologic lesion relapsed within 6 months; the metastases spread to hepatic, pelvic, and mesenteric lymph nodes, and the patient died 5 months later. One patient with cytoreduction completeness of CC-2 developed hepatic metastases within 3 months and is still alive at a follow-up up 6 months. Remaining patients (n=4) are alive and disease free without evidence of recurrence of follow-ups at 35, 34, 19, and 7 months.\n\nCONCLUSION\nCRS and HIPEC are well-tolerated and feasibly promising management modalities in PC from primary and recurrent endometrial carcinoma. Further research is needed for in-depth analysis.\n==== Body\nEndometrial carcinoma is the most common gynecologic malignancy and generally carries a fortunate prognosis. This is because majority of patients (75%) present with vaginal bleeding early in the course of disease, without any clinical proof of extrauterine extension (the International Federation of Gynecology and Obstetrics [FIGO] stages I and II), and undergo largely curable total hysterectomy with bilateral salpingo-oophorectomy, which have been demonstrated to yield 5-year survival rates of roughly 80% to 90%.1,2 However, nearly 10% to 15% of patients with early-stage disease (stage I and II) develop recurrences.3,4 Conversely, a very small group of patients is unlucky and present with advanced-stage disease with unfortunate prognoses. The 5-year survival rates for regional disease (FIGO stage III) and distant disease (FIGO stage IV) are 57% and 19%, respectively.5\n\nThe prognosis of patients presenting with recurrent and advanced metastatic disease confined to peritoneal cavity is deadly, with an estimated median survival not exceeding 12 months.6,7 Patients with regional recurrence are most often managed with cytoreduction surgery— whenever technically feasible—and postoperative systemic therapy (chemotherapy or endocrine therapy).7 Despite advances in surgeries and systemic anticancer drugs, overall survival (OS) from advanced and recurrent endometrial carcinomas has not positively improved over the past 3 decades.7\n\nCytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been utilized in a chosen series of patients with peritoneal carcinomatosis (PC) arising from gynecological and non-gynecological malignancies.8 With respect to the gynecological cancers, the CRS and HIPEC have demonstrated fortunate results in ovarian carcinoma.9,10 The objective of this study is to report our experience with CRS and HIPEC for managing PC from primary and recurrent endometrial carcinoma.\n\nMATERIALS AND METHODS\nFrom November 2010 to August 2013, all patients who presented to our institution (King Faisal Specialist Hospital and Research Center [KFSHRC]) with PC from primary and recurrent endometrial carcinoma were included in the study and considered for CRS and perioperative HIPEC. The approval of Research Advisory Council was obtained to publish this study.\n\nPreoperatively, all patients were fully worked up. Workup included the following: physical examination, laboratory tests (hematological, hepatic, coagulation, renal, bone, and electrolyte profiles), serum tumor markers (cancer antigen [CA]-125, CA 19-9, and carcinoemberyonic antigen), electrocardiogram, echocardiography, spirometry, abdominopelvic ultrasonography, wholebody contrast-enhanced computed tomography (CT) scan, and whole-body positron emission tomography/computed tomography (PET/CT) scan. Furthermore, Karnofsky performance scale was used to assess physical/performance status of the patients.\n\nInclusion criteria for considering aggressive CRS and HIPEC included the following: (1) satisfactory physical status (Karnofsky performance status > 50%), (2) satisfactory hematological profile, (3) satisfactory hepatic and coagulation profiles, (4) satisfactory renal and electrolyte profiles, (5) proof of PC from primary or recurrent endometrial carcinoma, (6) no proof of distant endometrial carcinoma metastatic foci to brain, lungs, liver or bones, (7) no proof of other concurrent malignancies elsewhere, and (8) signed written informed consent by the patients.\n\nAll surgical procedures were carried out by surgeons from the departments of surgical oncology and gynecologic oncology at KFSHRC. Under general anesthesia, a midline incision extending from xiphoid process to pubic tubercle was performed to completely explore the abdominopelvic cavity for PC. The extent of PC was evaluated intraoperatively utilizing peritoneal cancer index (PCI).11\n\nAs previously outlined by Sugarbaker,8 CRS included a compilation of standard peritonectomy procedures and visceral resections directed toward the complete (optimal) elimination of tumors from abdominopelvic cavity. Standard peritonectomy procedures used in our study included the following: total peritonectomy, subtotal peritonectomy, right subdiaphragmatic peritonectomy, left subdiaphragmatic peritonectomy, greater omentectomy, lesser omentectomy, pelvic peritonectomy, mesenteric peritonectomy, Glisson capsule peritonectomy, and antrectomy. Furthermore, total abdominal hysterectomy (TAH) with bilateral salpingo-oophorectomy (BSO) was performed in all patients with primary endometrial carcinoma.\n\nAfter completing CRS, residual tumors were assessed intraoperatively using completeness of cytoreduction (CC) scores as follows: CC-0, no gross residual tumor remained in abdominopelvic cavity; CC-1, less than 2.5 mm residual tumor remained in abdominopelvic cavity; CC-2, 2.5 mm to 2.5 cm residual tumor remained in abdominopelvic cavity; and CC-3, more than 2.5 cm residual tumor or confluence of unresectable residual tumor remained in abdominopelvic cavity.11 Only CC-0 scores were regarded as CC.\n\nHIPEC was performed at the end of CRS. Abdominopelvic cavity was lavaged 15 times with 1 L of normal saline prior to HIPEC. Two inflow drains were positioned below hemidiaphragms, whereas 2 outflow drains were positioned in the pouch of Douglas. All drains were connected to an extracorporeal closed sterile circuit in which 2 L perfusate was circulated by means of 2 peristaltic rollup pumps (one inflow and the other outflow) at a flow rate of 2 L/min. Cisplatin (50 mg/m2 or) and doxorubicin (15 mg/m2) were supplemented to the perfusate and allowed to circulate in the abdominopelvic cavity for 90 min at 41.0 to 42.2°C. The heated perfusate and chemotherapy (41.0–42.2°C) were achieved by means of a heat exchanger connected to the sterile circuit. Intraperitoneal temperature was continuously checked by thermometers (thermal probes) situated in the abdominopelvic cavity to ensure the maintenance of temperature at 41.0 to 42.2°C. During the HIPEC procedure, hemodynamic and cardiopulmonary parameters were continuously and carefully monitored. At the end of HIPEC procedure, abdominopelvic cavity was again lavaged 15 times with 1 L of normal saline. Moreover, the left hemidiaphragmatic drain was kept for a couple of days to facilitate draining of residual perfusate. All other drains were taken out intraoperatively. All patients were moved to the intensive care unit for 2 days, and afterward transferred to the wards for recovery.\n\nPostoperative complications following the CRS and HIPEC were evaluated according to the Common Terminology Criteria for Adverse Events—version 4.0.12\n\nFollowing the CRS and HIPEC, all patients were considered for postoperative (adjuvant) systemic chemotherapy. As all patients were previously platinum sensitive, carboplatin and paclitaxel regimen were used. Platinum-resistant patients were defined as patients who did not respond or developed recurrences in less than 6 months following the primary platinum-based systemic chemotherapy.\n\nAll patients were followed up regularly. No patient was lost during the follow-up. During the first year following the CRS and HIPEC, patients were followed up every 3 months. During the second year and afterward, patients were followed up every 6 months. The follow-up workup included the following: physical examination, hematological profiles, biochemical profiles (hepatic, coagulation, bone, renal, and electrolyte), serum tumor marker (CA-125), whole-body CT scan, and PET/CT scan (whenever indicated).\n\nRESULTS\nBetween November 2010 and September 2013, a total of 6 patients (n=6) with PC from primary and recurrent endometrial carcinoma met the inclusion criteria for considering aggressive CRS and HIPEC. The characteristics of patients at the time of clinical presentation with primary and recurrent endometrial carcinoma confined to peritoneal cavity are depicted in Table 1. The mean age at the time of CRS and HIPEC was 55.5 years (range: 26—64 years). While 2 patients presented with PC from primary endometrial carcinoma, 4 patients presented with PC from recurrent endometrial carcinoma.\n\nAll patients with recurrent endometrial carcinoma (n=4) had only 1 prior laparotomy in the form of TAH and BSO. Postoperatively (following the initial laparotomy), 1 patient received abdominopelvic radiotherapy (n=1) while another patient received both abdominopelvic radiotherapy and chemotherapy (carboplatin and paclitaxel). Moreover, 1 patient received only adjuvant chemotherapy (carboplatin and paclitaxel), while 1 patient received no postoperative therapy.\n\nAs shown in Table 1, the FIGO stages and histopathological types were as follows: IB endometrioid adenocarcinomas (n=1), IC mesonephric (high-grade) adenocarcinomas (n=1), IIIA endometrioid adenocarcinomas (n=2), IIIA papillary serous carcinomas (n=1), and IIIC clear-cell carcinoma (n=1). The mean period from the initial laparotomy to recurrence and performing CRS and HIPEC was 9 months (range: 1—18 months).\n\nThe details of the CRS and HIPEC are described in Table 2. All 6 patients underwent multiple standard peritonectomies and visceral resections with intent to achieve complete (optimal) cytoreduction. The mean PCI was 19 (range: 9–26). While 5 patients achieved complete cytoreduction (CC-0), 1 patient achieved incomplete cytoreduction of CC-2. The mean duration of CRS and HIPEC combined was 9.5 hours (range: 8–11 hours), and the mean postop-50 days).\n\nThe details and grading of postoperative complications are shown in Table 3. Overall, postoperative complications were tolerable. Anastomotic leak (grade I) was the most commonly encountered postoperative complication. Two patients developed grade IV complications due to septicemia and pulmonary embolism. No grade V complication occurred.\n\nThe details of the postoperative therapy and outcomes following the CRS and HIPEC are demonstrated in Table 4. Following the CRS and HIPEC, all 6 patients (n=6) received chemotherapy (carboplatin and paclitaxel). In 1 patient, the complication that was a very aggressive and highly recurrent histological type relapsed within 6-months, developed metastases to hepatic, pelvic, and mesenteric lymph nodes, and eventually died 5 months later. In 1 patient with cytoreduction completeness of CC-2, the disease relapsed within 3 months following HIPEC; the patient developed hepatic metastases, but she was still alive at a follow up of 6 months. The rest of the 4 patients are alive and disease free without evidence of recurrence at 35, 34, 19, and 7 months follow-up. The overall range of follow-up after the CRS and HIPEC is 6 to 35 months. Using Kaplan–Meier estimates, the OS rate was 83.3% (Figure 1) whereas the disease-free survival rate was 66.7% (Figure 2).\n\nDISCUSSION\nRoughly 25%3 and 50%13 of endometrial cancer-related mortality are attributed to recurrent disease and advanced-stage disease (FIGO stages III and IV), respectively.\n\nAlso, 50% to 70% of patients present with recurrence of endometrial carcinoma within 24 months after the primary management.14 Recurrence rates range from 2% to 15% in patients with an early-stage disease (stage I and II) or with a biologically benign tumor histologic lesion (endometrioid histologic lesion grades 1 and 2). Conversely, recurrence rates can reach as high as 50% in patients with an advanced-stage disease (stages III and IV) or a biologically aggressive tumor histologic lesion (endometrioid histologic lesion grade 3, or non-endometrioid histologic lesion: serous, clear cell, mucinous, squamous, transitional cell, mesonephric, and undifferentiated).15,16\n\nThe most significant poor prognostic factors in setting of recurrent endometrial carcinoma include the following: shorter disease-free interval from the surgery to recurrence,17,18 advanced-stage disease,18 and high-grade endometrioid or non-endometrioid histologic lesion (clear-cell and papillary serous).17,18 Other factors are as follows: advanced age of patient; lymphovascular invasion; and adnexal, endocervical, lymph node, and peritoneal metastases.3\n\nThe development of PC from primary or recurrent endometrial carcinoma is not uncommon. The prognosis of patients presenting with advanced or recurrent widespread disease confined to peritoneal cavity is deadly, with an estimated median survival of less than 12 months.6,7\n\nConsidering PC is a locoregional disease, the combination of CRS and HIPEC has been utilized in a chosen series of patients with PC arising from gynecological and non-gynecological malignancies. This novel procedure (CRS and HIPEC) yielded a 5-year survival rate of 54% in patients with PC from ovarian cancers,9,10 27% in patients with PC from gastric cancers,19 45% in patients with PC from colon cancers,20 and 73% in patients with pseudomyxoma peritonei.21\n\nA recently published meta-analysis by Barlin et al.22 proposed that CRS to no gross residual disease offers survival benefits (ranging from 9–35 months) in patients with advanced or recurrent endometrial carcinoma.\n\nAside from this meta-analysis, Campagnutta and colleagues23 reported a series of 75 patients undertaking salvage CRS for managing advanced and recurrent disease. Complete resection of gross tumor and tumor resection to <1 cm residual disease were achieved in approximately 64% and 75% of patients, respectively. Optimal salvage (secondary) CRS was coupled with a median survival advantage of 53 months compared to only 9 months for patients left with gross residual disease.\n\nMoreover, Awtrey and associates24 reported a series of 27 patients undergoing non- exenterative CRS for recurrent endometrial carcinoma. The complete resection of macroscopic tumor and tumor resection to <2 cm residual disease were accomplished in nearly 56% and 67% of patients, respectively. Optimal CRS was associated with a much longer median survival interval of 43 months compared to 10 months for patients with suboptimal CRS and residual disease (P<.05).\n\nFurthermore, Bristow et al25 reported a series of 61 patients commencing secondary (salvage) CRS for recurrent endometrial carcinoma. Complete resection of macroscopic tumor without residual disease was attained in approximately 66% of patients. Optimal CRS was linked to a median post-recurrence survival benefit of 39 months in contrast to only 13 months for patients with macroscopic residual disease (P=.0005).\n\nIn all studies, the volume of residual disease was the most important predictor of post-recurrence progression- free and OS.23–25\n\nThe use of CRS and HIPEC for managing PC from primary and recurrent endometrial carcinoma is rather limited to 2 studies only.7,26\n\nRecently, Bakrin et al7 explored the combination of CRS and HIPEC for managing recurrent endometrial carcinoma confined to the peritoneal cavity. The study included 5 patients and showed promising results. Complete CRS (CC-0) was achieved in all patients. HIPEC was performed with cisplatin and mitomycin C. Postoperative complications were well tolerated. Two patients developed early recurrences at 2 and 10 months, respectively, and both died afterward. The rest of the 3 patients were alive and disease free at 7, 23, and 39 months from the time of CRS and HIPEC with a good performance status.\n\nAnother study by Helm et al26 showed promising results in 5 patients with recurrent endometrial carcinoma limited to peritoneal cavity. One patient developed recurrence carcinoma and eventually died. Two patients were alive and disease free at 28 and 32 months from the time of CRS and HIPEC with a good performance status. The remaining 2 patients were alive with disease at 12 and 36 months.\n\nThe rationale for utilizing HIPEC is principally based on the direct heat-enhanced deep penetration, cytotoxicity, and synergism of varying cancer chemotherapeutic agents on neoplastic cells.27,28 Following the aggressive CRS, intraperitoneal chemotherapy is directed at microscopic residual foci, which are the principal sources of surgical management failures.23–25 Intraperitoneal, as opposed to intravenous, chemotherapeutic administration offers much higher local concentrations and much lower unnecessary systemic toxicities and side effects.29 These advantages of HIPEC make the combination of the CRS and HIPEC very attractive and worth-experimenting modality for managing primary and recurrent endometrial carcinoma limited to the peritoneal cavity.\n\nThe preference of chemotherapeutic agents for HIPEC should be based on scientifically and clinically confirmed elevated heat-boosting effects on anticancer agents. Such anticancer agents include cisplatin,30 doxorubicin (adriamycin),31 and mitomycin C.32 The most frequently used regimen in HIPEC is cisplatin and doxorubicin. When doxorubicin is contraindicated for cardiotoxicity reasons,33 cisplatin and mitomycin C are the alternative chemotherapeutic regimens in HIPEC.\n\nA recent systematic review by Chua et al34 demonstrated that the morbidity rate following the CRS and HIPEC extend from nearly 12% to 52% in highvolume institutions. In our series, the most frequently reported postoperative complication was anastomotic leak, and this finding mirrored other studies published in the peer-reviewed published reports.35,36 Cisplatin has been studied to fail/interrupt anastomotic healing in animal studies.37 Moreover, it has been suggested that delaying fast restoration of gastrointestinal tract (by keeping patient NPO [nothing per oral]) is highly advised, 35 and this results in reduced rates of anastomotic impairments.38 Other severe complications such as sepsis, intrabdominal abscess, or postoperative hemorrhage requiring immediate interventions are uncommon.35,36\n\nIn our series, only 2 patients developed life-threatening complications requiring urgent interventions, namely pulmonary embolism and sepsis. In the same study by Chua et al,34 with respect to mortality associated with the CRS and HIPEC, it has been shown to range from 1% to 6%. In our series, no patient died intraoperatively or developed grade V postoperative complications resulting in death.\n\nGlehen et al39 and Elias et al21 documented that the degree of morbidity and mortality following the CRS and HIPEC are largely influenced by expertise of health care center in managing PC. Plus, it has been shown that learning curve of CRS and HIPEC is a significant factor to minimize the incidence of postoperative complications. 40,41 An average of 135 cases are anticipated to be sufficient to significantly reduce morbidity and mortality following the CRS and HIPEC.40,41 In our tertiary care center, till date, more than 160 cases of CRS and HIPEC were performed by surgeons from the departments of surgical oncology and gynecologic oncology. In our current study, the presented 6-patient series is just a subgroup analysis.\n\nSystemic chemotherapy remains the gold standard for managing patients with advanced-stage and recurrent endometrial carcinoma. The 2 most frequently used regimens are AP (doxorubicin and cisplatin) and TAP (paclitaxel, doxorubicin, and cisplatin). These 2 regimens were studied in phase III clinical trial by Gynecologic Oncologic Group (GOG) protocol 177 (AP versus TAP in managing patients with advanced-stage, metastatic, or recurrent endometrial carcinoma).42 The TAP regimen was coupled with an improved overall response rate (ORR)] (57% versus 34%; P<.01), progression-free survival (PFS) (median, 8.3 versus 5.3 months; P<.01), and OS (mean 15.3 versus 12.3 months; P=.37). Conversely, TAP versus AP regimen yielded increased occurrence of severe (grade 3) peripheral neuropathic toxicity (12% versus 1%, respectively: P<.01).\n\nIn view of the TAP-associated toxicity, the combination of paclitaxel and carboplatin (TC) remains the most frequently utilized regimen. Its administration is supported by phase III trial by the GOG protocol 209 (TAP versus TC in management of patients with advanced, metastatic, or recurrent endometrial carcinoma). 43 Approximately 50% of TAP and TC patients showed objective ORR, and roughly 30% experienced stable disease. Both TAP and TC patients had fairly comparable median PFS of 13 to 14 months. However, OS was a bit higher in TAP compared to TC patients (38 versus 32 months; no statistical significant difference: P>.05). Conversely, in patients receiving TAP versus TC, there were statistically significant decreases in the occurrence of peripheral neuropathic toxicity grade 2 or higher (19% versus 26%), vomiting (4% versus 7%), diarrhea (2% versus 6%), thrombocytopenia (12% versus 23%), and metabolic imbalances (8% versus 14%).\n\nSalvage radiotherapy (RT) is largely effective in managing isolated central pelvic recurrences confined to the vaginal region.44 For patients with locoregional endometrial carcinoma recurrences, utilization of salvage RT in managing naïve and previously irradiated fields is still debatable.22 It must be noted that with additional RT schedules (sessions), patients will be at relatively high increased risks for developing severe radiation-induced toxic side effects, such as fistulas, strictures, proctitis urinary/bowel incontinence, and others.\n\nLimitations to this study comprise the retrospective study design, relatively small sample size (case series of 6 patients), comparatively short period of follow-up, lack of uniform histopathological types, and lack of control group. Such limitations hinder our study to draw definitive and solid conclusions.\n\nThus, we conclude that, aggressive CRS supplemented with perioperative HIPEC emerges to be a well-tolerated, achievable, and feasibly promising treatment modality that yields favorable results in managing patients with PC from primary and recurrent endometrial carcinoma. Meticulous patient selection with highly optimal postoperative care is greatly recommended to prevent occurrence of undesirable complications associated with this novel treatment modality. Further research (uniform large-sized patient series and probably randomized clinical trials with control groups and longer follow-up data) is needed to draw definitive and concrete conclusions and validate the efficacy of this novel modality for managing PC from endometrial carcinoma.\n\nAcknowledgments\nAuthors sincerely acknowledge the editorial assistance of Ms. Evelyn Dinio, Academic and Training Affairs, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.\n\nFigure 1 Kaplan–Meier estimate for the overall survival (OS) rate.\n\nFigure 2 Kaplan–Meier estimate for the disease-free survival (DFS) rate.\n\nTable 1 Characteristics of patients at the time of clinical presentation.\n\nPatient no.\tAge (y) at CRS+HIPEC\tPrimary/Recurrent endometrial cancer\tCurrent/Original FIGO stage and histology\tNumber of prior laparotomy\tPostoperative radiotherapy and/or chemotherapy\tTime from initial laparotomy to CRS+HIPEC (mo)\t\n\n\t\n1\t26\tRecurrent\tIB endometrioid adenocarcinoma\t1\t—\t1\t\n2\t53\tRecurrent\tIIIA endometrioid adenocarcinoma\t1\tAbdominopelvic radiation\t6\t\n3\t62\tPrimary\tIIIC clear cell carcinoma\t0\t—\t—\t\n4\t43\tPrimary\tIIIA endometrioid adenocarcinoma\t0\t—\t—\t\n5\t55\tRecurrent\tIC mesonephric (high-grade) carcinoma\t1\tAbdominopelvic radiation and chemotherapy (carboplatin and paclitaxel)\t10\t\n6\t64\tRecurrent\tIIIA papillary serous carcinoma\t1\tChemotherapy (carboplatin and paclitaxel)\t18\t\nS: Cytoreductive surgery, HIPEC: hyperthermic intraperitoneal chemotherapy, FIGO: International Federation of Gynecology and Obstetrics; y: year; mo: month.\n\nTable 2 Details of the CRS and HIPEC.\n\nPatient no.\tPeritonectomy and visceral resections\tPeritoneal cancer index (PCI)\tCytoreduction completeness (CC)\tDuration of CRS+HIPEC (h)\tHospital stay (d)\t\n\n\t\n1\tResection of umbilicus, lesser/greater, omentectomy, total peritonectomy, cholecystectomy, subtotal colectomy with iliorectal anastomosis, splenectomy, distal pancreatectomy\t20\t0\t11\t26\t\n2\tSubtotal/Total peritonectomy, distal 2/3 gastrectomy, appendectomy, cholecystectomy, splenectomy, distal pancreatectomy, partial transverse colon resection, Glisson capsule resection\t9\t0\t8\t50\t\n3\tTotal abdominal hysterectomy with bilateral salpingo-oophorectomy, total peritonectomy, greater omentectomy, splenectomy, distal pancreatectomy, total colectomy and iliorectal anastomosis, resection of terminal ileum, resection of umbilicus\t23\t0\t10\t30\t\n4\tTotal abdominal hysterectomy with bilateral salpingo-oophorectomy, subtotal peritonectomy, lesser/greater omentectomy, splenectomy, right iliac and obturator lymph node dissections, appendectomy, Glisson capsule resection\t15\t0\t8\t35\t\n5\tSubtotal peritonectomy (right and left abdominal wall), pelvic peritonectomy, lesser/greater omentectomy, cholecystectomy, appendectomy, 4 small bowel resections, extended left colectomy and colorectal anastomosis\t26\t0\t11\t33\t\n6\tSubtotal peritonectomy, cholecystectomy, total colectomy and iliorectal anastomosis, lesser/greater omentectomy, splenectomy, distal pancreatectomy, resection of vaginal cuff, resection of segment of right ureter and re-anastomosis\t23\t2\t9\t23\t\nCRS: Cytoreductive surgery, HIPEC: hyperthermic intraperitoneal chemotherapy.\n\nTable 3 Postoperative complications following CRS and HIPEC.\n\nPatient no.\tPostoperative complication and grade\t\n\n\t\n1\tAnastomotic leak, grade I\t\n2\tAnastomotic leak, grade I\nRight deep vein thrombosis, grade II\nPulmonary embolism, grade IV\t\n3\tAnastomotic leak, grade I\nBilateral pleural effusion, grade II\nRight hydronephrosis, grade I\nIntestinal obstruction, grade I\t\n4\tAnastomotic leak, grade I\t\n5\tAnastomotic leak, grade II\nSepticemia, grade IV\t\n6\tAnastomotic leak, grade I\nUrinary tract infection, grade II\t\nCRS: Cytoreductive surgery, HIPEC: hyperthermic intraperitoneal chemotherapy.\n\nTable 4 Postoperative therapy and outcome following HIPEC.\n\nPatient no.\tAdjuvant therapy following HIPEC\tTime of relapse following CRS+HIPEC (mo)\tSite of recurrence\tTime since CRS and HIPEC; follow-up (mo)\tCurrent status\t\n\n\t\n1\tCarboplatin and paclitaxel\t—\t—\t35\tAlive, disease free\t\n2\tCarboplatin and paclitaxel\t—\t—\t34\tAlive, disease free\t\n3\tCarboplatin and paclitaxel\t6\tHepatic, mesenteric, and pelvic lymph nodes\t11\tDied\t\n4\tCarboplatin and paclitaxel\t—\t—\t19\tAlive, disease free\t\n5\tCarboplatin and paclitaxel\t—\t—\t7\tAlive, disease free\t\n6\tCarboplatin and paclitaxel\t3\tHepatic lymph nodes\t6\tAlive\t\nCRS: Cytoreductive surgery, HIPEC: hyperthermic intraperitoneal chemotherapy.\n==== Refs\nREFERENCES\n1 Lewin SN Herzog TJ Barrena Medel NI Comparative performance of the 2009 international Federation of gynecology and obstetrics’ staging system for uterine corpus cancer Obstet Gynecol 2010 116 5 1141 1149 20966700 \n2 Kao MS Management of recurrent endometrial carcinoma Chang Gung Med J 2004 27 9 639 45 15605903 \n3 Morrow CP Bundy BN Kurman RJ Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study Gynecol Oncol 1991 40 1 55 65 1989916 \n4 Hirahatake K Hareyama H Sakuragi N Nishiya M Makinoda S Fujimoto S A clinical and pathologic study on para-aortic lymph node metastasis in endometrial carcinoma J Surg Oncol 1997 65 2 82 7 9209518 \n5 Siegel R Naishadham D Jemal A Cancer statistics, 2013 CA Cancer J Clin 2013 63 1 11 30 23335087 \n6 Obel JC Friberg G Fleming GF Chemotherapy in endometrial cancer Clin Adv Hematol Oncol 2006 4 6 459 68 16981669 \n7 Bakrin N Cotte E Sayag-Beaujard A Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for the treatment of recurrent endometrial carcinoma confined to the peritoneal cavity Int J Gynecol Cancer 2010 20 5 809 14 20973274 \n8 Sugarbaker PH Peritonectomy procedures Ann Surg 1995 221 1 29 42 7826158 \n9 Cotte E Glehen O Mohamed F Cytoreductive surgery and intraperitoneal chemohyperthermia for chemo-resistant and recurrent advanced epithelial ovarian cancer: prospective study of 81 patients World J Surg 2007 31 9 1813 20 17629740 \n10 Jaaback K Johnson N Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer Cochrane Database Syst Rev 2006 1 CD005340 16437527 \n11 Sugarbaker PH Management of peritoneal-surface malignancy: the surgeon’s role Langenbecks Arch Surg 1999 384 6 576 87 10654274 \n12 Common Terminology Criteria for Adverse Events version 4.0 http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf \n13 Wolfson AH Sightler SE Markoe AM The prognostic significance of surgical staging for carcinoma of the endometrium Gynecol Oncol 1992 45 2 142 6 1592280 \n14 Sohaib SA Houghton SL Meroni R Rockall AG Blake P Reznek RH Recurrent endometrial cancer: patterns of recurrent disease and assessment of prognosis Clin Radiol 2007 62 1 28 34 17145260 \n15 Keys HM Roberts JA Bruneto VL A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group Study Gynecol Oncol 2004 92 3 744 751 14984936 \n16 Creutzberg CL van Putten WL Koper PC PORTEC Study Group Survival after relapse in patients with endometrial cancer: results from a randomized trial Gynecol Oncol 2003 89 2 201 209 12713981 \n17 Karagol H Saip P Uygun K Kucucuk S Aydiner A Topuz E Evaluation of prognostic factors and comparison of systemic treatment modalities in patients with recurrent or metastatic endometrial carcinoma Med Oncol 2006 23 4 543 548 17303913 \n18 Bradford LS Rauh-Hain JA Schorge J Birrer MJ Dizon DS Advances in the Management of Recurrent Endometrial Cancer Am J Clin Oncol 2013 6 11 [Epub ahead of print] \n19 Yonemura Y Endou Y Shinbo M Safety and efficacy of bidirectional chemotherapy for treatment of patients with peritoneal dissemination from gastric cancer: selection for cytoreductive surgery J Surg Oncol 2009 100 4 311 316 19697437 \n20 Sugarbaker PH Peritoneal surface oncology: review of a personal experience with colorectal and appendiceal malignancy Tech Coloproctol 2005 9 2 95 103 16007367 \n21 Elias D Gilly F Quenet F Pseudomyxoma peritonei: a French multicentric study of 301 patients treated with cytoreductive surgery and intraperitoneal chemotherapy Eur J Surg Oncol 2010 36 5 456 462 20227231 \n22 Barlin JN Puri I Bristow RE Cytoreductive surgery for advanced or recurrent endometrial cancer: a meta-analysis Gynecol Oncol 2010 118 1 14 8 20434198 \n23 Campagnutta E Giorda G De Piero G Surgical treatment of recurrent endometrial carcinoma Cancer 2004 100 1 89 96 14692028 \n24 Awtrey CS Cadungog MG Leitao MM Surgical resection of recurrent endometrial carcinoma Gynecol Oncol 2006 102 3 480 8 16490236 \n25 Bristow RE Santillan A Zahurak ML Gardner GJ Giuntoli RL 2nd Armstrong DK Salvage cytoreductive surgery for recurrent endometrial cancer Gynecol Oncol 2006 103 1 281 7 16631236 \n26 Helm CW Toler CR Martin RS 3rd Cytoreduction and intraperitoneal heated chemotherapy for the treatment of endometrial carcinoma recurrent within the peritoneal cavity Int J Gynecol Cancer 2007 Jan-Feb 17 1 204 9 17291254 \n27 Witkamp AJ de Bree E Van Goethem R Zoetmulder FA Rationale and techniques of intraoperative hyperthermic intraperitoneal chemotherapy Cancer Treat Rev 2001 27 6 365 74 11908929 \n28 Mohamed F Marchettini P Stuart OA Urano M Sugarbaker PH Thermal enhancement of new chemotherapeutic agents at moderate hyperthermia Ann Surg Oncol 2003 10 4 463 8 12734097 \n29 Glehen O Beaujard AC Arvieux C Huber O Gilly FN Peritoneal carcinomatosis. Surgical treatment, peritonectomy and intraperitoneal chemohyperthermia (In French) Gastroenterol Clin Biol 2002 26 3 210 5 11981459 \n30 Rietbroek RC van de Vaart PJ Haveman J Hyperthermia enhances the cytotoxicity and platinum-DNA adduct formation of lobaplatin and oxaliplatin in cultured SW 1573 cells J Cancer Res Clin Oncol 1997 123 1 6 12 8996534 \n31 Herman TS Henle KJ Nagle WA Moss AJ Monson TP Effect of step-down heating on the cytotoxicity of adriamycin, bleomycin, and cis-diamminedichloroplatinum Cancer Res 1984 44 5 1823 6 6201263 \n32 Teicher BA Kowal CD Kennedy KA Sartorelli AC Enhancement by hyperthermia of the in vitro cytotoxicity of mitomycin C toward hypoxic tumor cells Cancer Res 1981 41 3 1096 9 7459853 \n33 Samuel L Doxorubicin-induced cardiotoxicity Postgrad Med J 1995 71 835 318 \n34 Chua TC Yan TD Saxena A Morris DL Should the treatment of peritoneal carcinomatosis by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy still be regarded as a highly morbid procedure?: a systematic review of morbidity and mortality Ann Surg 2009 249 6 900 907 19474692 \n35 di Giorgio A Naticchioni E Biacchi D Cytoreductive surgery (peritonectomy procedures) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of diffuse peritoneal carcinomatosis from ovarian cancer Cancer 2008 113 2 315 325 18473354 \n36 Kusamura S Younan R Baratti D Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion: analysis of morbidity and mortality in 209 peritoneal surface malignancies treated with closed abdomen technique Cancer 2006 106 5 1144 1153 16456817 \n37 Makrin V Lev-Chelouche D Sapir EE Paran H Rabau M Gutman M Intraperitoneal heated chemotherapy affects healing of experimental colonic anastomosis: an animal study J Surg Oncol 2005 89 1 18 22 15612012 \n38 Verwaal VJ van Tinteren H Ruth SV Zoetmulder FAN Toxicity of cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy J Surg Oncol 2004 85 2 61 7 14755505 \n39 Glehen O Gilly FN Boutitie F Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy: a multi-institutional study of 1290 patients Cancer 2010 116 24 5608 5618 20737573 \n40 Smeenk RM Verwaal VJ Zoetmulder FA Learning curve of combined modality treatment in peritoneal surface disease Br J Surg 2007 11 94 11 1408 14 17631678 \n41 Kusamura S Baratti D Deraco M Multidimensional analysis of the learning curve for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal surface malignancies Ann of Surg 2012 255 2 348 356 22202584 \n42 Fleming GF Brunetto VL Celia D Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study J Clin Oncol 2004 22 11 2159 2166 15169803 \n43 Miller D Filiaci V Fleming G Late-breaking abstract 1: randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study Gynecol Oncol 2012 125 3 771 \n44 Pai HH Souhami L Clark BG Roman T Isolated vaginal recurrences in endometrial carcinoma: treatment results using high-dose-rate intracavitary brachytherapy and external beam radiotherapy Gynecol Oncol 1997 66 2 300 307 9264580\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "34(2)",
"journal": "Annals of Saudi medicine",
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"medline_ta": "Ann Saudi Med",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002277:Carcinoma; D010478:Chemotherapy, Cancer, Regional Perfusion; D003131:Combined Modality Therapy; D065426:Cytoreduction Surgical Procedures; D018572:Disease-Free Survival; D016889:Endometrial Neoplasms; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D007274:Injections, Intraperitoneal; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel; D010534:Peritoneal Neoplasms; D012189:Retrospective Studies",
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"title": "Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for managing peritoneal carcinomatosis from endometrial carcinoma: a single-center experience of 6 cases.",
"title_normalized": "cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for managing peritoneal carcinomatosis from endometrial carcinoma a single center experience of 6 cases"
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"abstract": "Acute eosinophilic pneumonia is a severe syndrome characterized by fever, lung infiltrates, blood eosinophilia and respiratory failure. We describe a case of acute eosinophilic pneumonia associated with clomipramine and sertraline. A 40-year-old woman was admitted to the emergency department with 37.9 degrees C and respiratory rate of 35 respirations per minute. Blood analysis showed PaO2 = 57.6 mm Hg and HCO3- = 21.7 mmol/l and 12.2% eosinophils. Chest X-ray showed infiltrates in both lower lobes. She was taking clomipramine 25 mg bid for the last 4 weeks and sertraline 50 mg/day for the last week. Other causes of acute eosinophilic pneumonia such as parasitic and fungal infections or collagen diseases were discarded. Both antidepressant were stopped and the patient became afebrile and asymptomatic. A week later the patient was discharged from hospital. Physicians should be aware of this adverse antidepresant reaction which may result in severe pulmonary symptoms.",
"affiliations": "Hospital Severo-Ochoa, Madrid, Spain.",
"authors": "Barnés|M T|MT|;Bascuñana|J|J|;García|B|B|;Alvarez-Sala|J L|JL|",
"chemical_list": "D000928:Antidepressive Agents; D002997:Clomipramine; D020280:Sertraline",
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"issue": "21(5)",
"journal": "Pharmacy world & science : PWS",
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"medline_ta": "Pharm World Sci",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000928:Antidepressive Agents; D002997:Clomipramine; D005260:Female; D006801:Humans; D011657:Pulmonary Eosinophilia; D020280:Sertraline",
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"title": "Acute eosinophilic pneumonia associated with antidepressant agents.",
"title_normalized": "acute eosinophilic pneumonia associated with antidepressant agents"
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"companynumb": "ES-PFIZER INC-202200513389",
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"abstract": "Despite its' life-threatening potential due to cardiac severe dysrhythmia in the context of severe hypokalemia, thyrotoxic periodic paralysis (TPP) often goes unrecognized. Although classically confined to young Asian men, it can occur irrespective of age, sex, and race. We report a short series of three cases of TPP as first presentation of Graves' disease in a young Caucasian male and in two Caucasian elderly and middle-aged women, respectively. The first patient developed malignant ventricular arrhythmias due to severe hypokalemia and was defibrillated, with recovery after prompt potassium correction and administration of antithyroid agents and propranolol. The other two cases developed persistent hypokalemia despite adequate potassium chloride (KCl) repletion, with slow recovery of motor deficit and serum potassium normalization up to day 5. In the first case, long-term euthyroid state was achieved via total thyroidectomy due to the presence of a suspicious nodule that proved to be malignant. In the other two cases, medical treatment was the choice of therapy for thyrotoxicosis. None experienced recurrent TPP. Thyroid hormone evaluation is mandatory in the presence of hypokalemic paralysis, even in the absence of clinical signs of thyrotoxicosis. If TPP is confirmed, initial therapy should comprise antithyroid drugs and propranolol, besides hypokalemia correction.",
"affiliations": "Endocrinology Department, \"Grigore T. Popa\" University of Medicine and Pharmacy Iasi, 700111 Iasi, Romania.;Cardiology Department, \"Grigore T. Popa\" University of Medicine and Pharmacy Iasi, 700111 Iasi, Romania.;Endocrinology Department, \"Grigore T. Popa\" University of Medicine and Pharmacy Iasi, 700111 Iasi, Romania.;Cardiology Department, \"Grigore T. Popa\" University of Medicine and Pharmacy Iasi, 700111 Iasi, Romania.;Endocrinology Department, \"Grigore T. Popa\" University of Medicine and Pharmacy Iasi, 700111 Iasi, Romania.",
"authors": "Bilha|Stefana|S|;Mitu|Ovidiu|O|0000-0002-9438-8565;Teodoriu|Laura|L|;Haba|Cristian|C|;Preda|Cristina|C|",
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"doi": "10.3390/diagnostics10050316",
"fulltext": "\n==== Front\nDiagnostics (Basel)\nDiagnostics (Basel)\ndiagnostics\nDiagnostics\n2075-4418 MDPI \n\n10.3390/diagnostics10050316\ndiagnostics-10-00316\nCase Report\nThyrotoxic Periodic Paralysis—A Misleading Challenge in the Emergency Department\nBilha Stefana 1 https://orcid.org/0000-0002-9438-8565Mitu Ovidiu 2* Teodoriu Laura 1* Haba Cristian 2 Preda Cristina 1 1 Endocrinology Department, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, 700111 Iasi, Romania; stefanabilha@gmail.com (S.B.); cpreda1@yahoo.com (C.P.)\n2 Cardiology Department, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, 700111 Iasi, Romania; cristi.haba@gmail.com\n* Correspondence: mituovidiu@yahoo.co.uk (O.M.); lauraferaru89@yahoo.com (L.T.); Tel.: +40-745-279-714 (O.M.); Tel.: +40-773-969-025 (L.T.)\n18 5 2020 \n5 2020 \n10 5 31607 4 2020 14 5 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Despite its’ life-threatening potential due to cardiac severe dysrhythmia in the context of severe hypokalemia, thyrotoxic periodic paralysis (TPP) often goes unrecognized. Although classically confined to young Asian men, it can occur irrespective of age, sex, and race. We report a short series of three cases of TPP as first presentation of Graves’ disease in a young Caucasian male and in two Caucasian elderly and middle-aged women, respectively. The first patient developed malignant ventricular arrhythmias due to severe hypokalemia and was defibrillated, with recovery after prompt potassium correction and administration of antithyroid agents and propranolol. The other two cases developed persistent hypokalemia despite adequate potassium chloride (KCl) repletion, with slow recovery of motor deficit and serum potassium normalization up to day 5. In the first case, long-term euthyroid state was achieved via total thyroidectomy due to the presence of a suspicious nodule that proved to be malignant. In the other two cases, medical treatment was the choice of therapy for thyrotoxicosis. None experienced recurrent TPP. Thyroid hormone evaluation is mandatory in the presence of hypokalemic paralysis, even in the absence of clinical signs of thyrotoxicosis. If TPP is confirmed, initial therapy should comprise antithyroid drugs and propranolol, besides hypokalemia correction. \n\nthyrotoxic periodic paralysishypokalemiaventricular arrhythmiaGraves’ disease\n==== Body\n1. Introduction\nAlthough well described as a possible complication of Graves’ hyperthyroidism [1], thyrotoxic periodic paralysis (TPP) still represents a potential life-threatening and often misleading challenge in the Emergency Department (ED). The highest incidence (approximately 2%) is seen in the Asian population [2]. In contrast, the very low incidence of 0.1–0.2% in American Caucasians [3] makes the differential diagnosis a struggle: in Caucasians, primary forms (channelopathies) come first in the etiology of hypokalemic periodic paralysis, while other possible secondary causes besides TPP include gastrointestinal and renal pathologies, use of diuretics, etc. [2].\n\nAlthough Graves’ disease is the etiology of TPP in 96% of cases, nodular goiter, subacute thyroiditis, and thyrotoxicosis factitia have also been associated with TPP [1]. Unusual is also the disproportional occurrence of TPP in men compared to women (26: 1), despite Graves’ disease being predominantly encountered in women [1]. \n\nOnly 17–50% of TPP patients exhibit clinical signs of hyperthyroidism [1], making the diagnosis even more challenging. The sudden onset flaccid paralysis due to acute potassium shift (K+) in the intracellular space in the context of thyrotoxicosis can lead to cardiac arrhythmias and respiratory failure if not recognized and treated on time. The management of TPP is even more complicated by the thin line between refractory hypokalemia and rebound hyperkalemia, both predisposing to serious cardiac events [4]. Potassium chloride (KCl) supplementation is essential but often not enough to control TPP [5]. \n\nWe report three initially unapparent cases of TPP with severe and/or refractory hypokalemia as first presentation of hyperthyroidism (Graves’ disease).\n\n2. Case Presentation\nCase one: A 36-year-old male with negative personal medical history presented in the ED for an important malaise, a cutaneous erythematous eruption, and muscle pain which appeared after fast-food consumption. Clinical examination revealed an irregular peripheral pulse of 100 beats/min with an irregular central heart rate (HR) of 120 beats/min, blood pressure (BP) 160/80 mm Hg, systolic murmur 2/6 in the mitral area, hyperthermia (38.1 °C), and a pruritic maculopapular rash on the abdomen and lower limbs. The electrocardiogram (ECG) showed atrial fibrillation with rapid ventricular response (120/min), high R waves and negative T-waves in V4–V6, and ventricular premature beats. The echocardiography revealed a hyperkinetic heart with a slightly dilated left ventricle, moderately reduced left ventricle ejection fraction of 40%, and mild atrial dilation. Blood workup showed a low-normal serum K+ (3.6 mmol/L—normal range 3.5–5 mmol/L). The patient received 100 mg hydrocortisone due to the suspicion of an allergic reaction and was about to be admitted in the Cardiology Department when 1 h later he suddenly developed muscle weakness which evolved towards flaccid paralysis of the lower limbs in a matter of 30 min. Subsequently, his HR decreased to 25 bpm and the patient started experiencing syncopal episodes. Emergency ECG revealed complete atrioventricular (AV) block with escape ventricular beats that degenerated in multiple episodes of ventricular tachycardia and ventricular fibrillation (Figure 1)—in the context of severe hypokalemia of unknown etiology (serum K+ dropped to 1.2 mmol/L). After successful defibrillation and antiarrhythmic therapy, the patient was transferred to the Intensive Care Unit.\n\nEmergency thoracic and abdominal computer tomography (CT) scan revealed an enlarged right thyroid lobe (51/30/65 mm), which presented a cystic mass (30.5/26/22 mm) with a calcified thin wall. Thyroid evaluation showed: (1) thyroid stimulating hormone (TSH) = 0.017 mIU/L—normal range 0.4–4 mIU/L, free thyroxine (FT4) = 2.52 ng/dL—normal range 0.89–1.76 ng/dL, free tri-iodothyronine (FT3) = 4.1 pg/mL—normal range 2.3–4.9 pg/mL), thyroid peroxidase antibodies > 1000 IU/mL—normal range <36 IU/mL) and (2) thyroid ultrasound—increased volume of the right thyroid lobe (27 mL) with a cystic nodule of 2.75 cm in its largest diameter exhibiting punctate echogenic foci and peripheral rim calcifications (TI-RADS level 5—highly suspicious). TSH-receptor antibodies (TRAb) came back positive later on during hospitalization, thus confirming the diagnosis of Graves’ disease.\n\nThe evolution of the patient (Table 1) was favorable after prompt potassium correction and administration of antithyroid agents and nonselective beta-blockers, with rapid amelioration of cardiovascular and systemic symptoms. Due to the coexistence of Graves’ disease and a suspicious thyroid nodule, the patient subsequently underwent total thyroidectomy and the histological examination confirmed multifocal papillary carcinoma (T3bN0M0), stage I [6]. Radioiodine whole-body scintigraphy showed uptake in the cervical area and ablation with 2.56 GBq I-131 was performed (Figure 2). He is under hormonal suppressive dose of levothyroxine and ongoing observation.\n\nCase two: A 69-year-old woman, with no past medical history, was brought to the ED with severe proximal muscle weakness at the level of the lower limbs accompanied by nausea and vomiting of several hours’ onset. The patient also reported weight loss, palpitations and transient episodes of muscle weakness with difficulty in standing up that began 1 month before. On presentation, she had a regular HR of 100 beats/min and 160/80 mm Hg BP. A neurological examination revealed upper limb tremor, symmetrical hyporeflexia of the knees, and paraplegia. She also had a positive Giordano sign (costovertebral angle tenderness) on the right side. Remainder of the examination was normal.\n\nLaboratory data showed abnormal results for the white blood count (11,000/mm3, normal range 4000–10,000/mm3) and aminotransferases (ALAT = 65 U/L—normal range 2–55 U/L, ASAT = 45 U/L—normal range 5–34 U/L), and serum K+ (2.7 mmol/L—normal range 3.5–5 mmol/L). She had biochemical evidence of autoimmune thyrotoxicosis at the initial thyroid workup: TSH = 0.01 mIU/L—normal range 0.4–4 mIU/L, FT4 = 2.5 ng/dL—normal range 0.89—1.76 ng/dL, thyroid peroxidase antibodies = 240 IU/mL—normal range <100 U/mL, and thyroglobulin antibodies = 190 IU/mL—normal range <50 IU/mL. The thyroid ultrasound confirmed the diffuse hyperplasia of the thyroid gland (volume 43 mL). Urine culture was positive for Escherichia coli. The patient was admitted in the Internal Medicine Department and started on (1) thiamazole 30 mg q.i.d and propranolol 20 mg t.i.d. for the hyperthyroid state, (2) 1 g/day KCl for the hypokalemia, and (3) antibiotics for the urinary tract infection. The serum K+ normalized and the motor deficit regressed after 5 days of treatment (Table 1). Thyroid uptake and scintigraphy performed with 185 MBq Tc-99m pertechnetate (Tc-99m Pt) were suggestive of Graves’ disease.\n\nShe was discharged on day 25 after regaining full muscle power. Euthyroid state was achieved after 6 weeks of antithyroid medication and Graves’ disease was confirmed (positive TRAb). Our patient had no further episode of TPP.\n\nCase three: 51-year-old woman was brought to the ED with suspicion of leptospirosis due to acute onset complete flaccid quadriplegia, fever, recurrent episodes of loss of consciousness, and a positive epidemiological context. Physical examination revealed normal BP 120/80 mm Hg, tachycardia 110 beats/min, complete motor deficit with abolished deep tendon reflexes but no sensory deficits at the lower extremities, and mild exophthalmos.\n\nInitial serum potassium on presentation was 2.7 mmol/L (normal range 3.5–5 mmol/L) with normal acid–base, calcium, and magnesium status. Aminotransferases were slightly elevated (ASAT = 45 U/L—normal range 5–34 U/L and ALAT = 81 U/L—normal range 2–55 U/L). The remaining laboratory analyses, including blood count, inflammatory markers, muscle enzymes, and renal function were otherwise normal. Serological testing for leptospirosis proved negative. The patient was admitted in the Intensive Care Unit, where serum K+ normalized on day 5 (4 mmol/L, Table 1) and neurological signs improved after intravenous KCl supplementation.\n\nDue to the persistence of sinus tachycardia, thyroid hormones were tested: TSH = 0.2 mIU/L—normal range 0.4–4 mIU/L, FT4 = 2.1 ng/dL—normal range 0.89–1.76, thyroid peroxidase antibodies = 500 IU/mL—normal range <100 IU/mL, and thyroglobulin antibodies = 290 IU/mL—normal range <50 UI/mL. The appearance of the thyroid parenchyma at ultrasound was heterogenous, intense hypoechoic, and with increased blood flow. The patient was transferred to the Endocrinology Department where treatment with thiamazole 30 mg q.i.d and propranolol 20 mg t.i.d. was initiated. Thyroid scintigraphy with Tc-99m Pt showed increased diffuse uptake of the thyroid gland and TRAb were found positive, thus confirming the diagnosis of Graves’ disease. The patient was discharged on day 15 after complete remission of neuromuscular symptoms and improvement of hyperthyroid signs. She did not develop any further episode of TPP. The patients have approved this research and we have obtained their consent.\n\n3. Discussion\nTPP is a very rare complication of thyrotoxicosis which occurs more frequently in the Asian population, typically in young Asian men [2]. The presentation circumstances in the ED are variable and polymorphic, challenging the diagnostic and therapeutic approach.\n\nTPP is characterized by periodic, reversible attacks of muscle weakness, and paralysis due to intracellular blockade of K+ by the excessive thyroid hormones [7]. Thyroid hormones regulate the Na+-K+-ATP pump at a transcriptional and post-transcriptional level and also induce the release of catecholamines via beta 2 receptors, furthermore stimulating the Na+-K+-ATP pump [8]. TPP patients were shown to have 80% more Na+-K+-ATP pump activity than other thyrotoxic patients. In addition, insulin and testosterone increase the activity of the pump, which might explain the higher prevalence of TPP in males and the manifestation of symptoms after an intense workout and a high-carbohydrate meal. Mutations in the KCNJ18 gene, which encodes for the Kir channels, have been found in approximately 33% of patients with TPP. This massive cellular influx of potassium along with decreased outflow leads to hypokalemia and TPP [9].\n\nThyroid hormones also play an important role in gene regulation at the level of cardiac myocytes, especially during diastole as they affect the calcium uptake into the sarcoplasmic reticulum through the calcium adenosine triphosphatase (Ca2+-ATPase) and phospholamban [10]. The most frequent ECG changes in patients with TPP reflect the thyrotoxicosis and hypokalemia. In addition to the typical hypokalemia pattern, studies have also described the occurrence of both conduction disorders and supraventricular and ventricular arrhythmias in patients with TPP, such as sinus arrest, second-degree AV block, P-R prolongation, right bundle branch block, and up to total AV block (as in our first case) [11].\n\nVentricular arrhythmias are the most dangerous cardiovascular complications of TPP and are usually seen in patients with preexisting cardiac disease. Hypokalemia can be the cause of torsade de pointes or polymorphic ventricular tachycardia, which leads to ventricular fibrillation and death if untreated [12]. Hypokalemia delays repolarization and increases diastolic depolarization of pacemaker fibers, leading to tachycardia and increasing the likelihood of ectopic beat formation. The increase in automaticity predisposes the myocardium to arrhythmias, requiring immediate defibrillation if life-threatening or unstable [13]. Our first case experienced recurrent malignant ventricular arrhythmias in the context of sudden-onset severe hypokalemia.\n\nThe usually subtle presentation of thyrotoxicosis accompanying TPP challenges the diagnosis [14]. Increased and elevated BP are more sensitive indicators of TPP than other hyperthyroid signs (fever, moist skin, exophthalmos, and goiter) [3]. In the ED, one should think of TPP if in front of the following criteria: (1) clinical and/or biochemical signs of thyrotoxicosis: a tachycardic patient with systolic hypertension and abnormal ECG (AV block) and/or low TSH together with high FT4 and FT3, (2) hypokalemia with low urinary K+ excretion and normal blood acid–base status (hypophosphatemia and mild hypomagnesemia can also be encountered), and (3) negative family history for periodic paralysis [1,5,15]. Laboratory tests recommended in front of acute flaccid paralysis accompanied by hypokalemia are presented in Table 2. Thyroid hormones evaluation is mandatory, even in the absence of hyperthyroid clinical signs. If thyrotoxicosis is confirmed, then measurement of thyroid antibodies including TRAb should be carried out, especially as Graves’ disease is the most common cause of TPP [1]. Although predominantly encountered in young Asian males, we together with other authors [3,16] have shown that TPP can appear irrespective of age, sex, and race, and thus, one should stay alert when facing hypokalemic paralysis.\n\nThe differential diagnosis of TPP includes primary (genetic) forms of membrane excitability disorders (channelopathies such as hypo-, normo- and hyperkalemic periodic paralysis and Andersen–Tawil syndrome, respectively) as well as secondary causes of periodic paralysis [15]. \n\nPrimary hypokalemic periodic paralysis is caused by familial or de novo mutations in the CACNA1S gene (responsible for the synthesis of calcium channels) or SCN4A gene (encodes a critical part of sodium channels); it is characterized by hypokalemic muscle weakness episodes lasting from hours to days, usually appears under the age of 20 and is in most cases accompanied by positive family history (autosomal dominant transmission) [3,15]. Primary normo- and hyperkalemic periodic paralysis are caused by pathogenic variants in SCN4A, have similar clinical features as the hypokalemic form, but the age of onset is even lower, have normal or elevated serum K+ levels, and both exhibit myotonic discharges between attacks [15,17]. Andersen–Tawil syndrome is caused by pathogenic variants in KCNJ2 potassium channels and is characterized by episodic periodic paralysis with prolonged interictal muscle weakness and cardiac anomalies (ventricular arrhythmias and prolonged QT interval). The somatic dysmorphia (short stature, scoliosis, low-set ears, widely spaced eyes, and syndactyly) and neurocognitive deficits that are usually present (although variable) help the diagnosis, which is often made in the first two decades of life [18].\n\nSecondary (nonfamilial) hypokalemic paralysis causes also need to be excluded: (1) hyperaldosteronism—primary or secondary; (2) urinary losses, such as diuretics, hypomagnesemia, and Bartter and Gitelman syndromes; (3) gastrointestinal losses—vomiting, diarrhea, and laxative use; and (4) other causes of intracellular K+ shift—recovery from diabetic ketoacidosis, beta-agonists, and metabolic alkalosis [19].\n\nA 10-year analysis of 135 TPP patients found the presence of precipitating factors in approximately one-third of cases. The most prevalent were high carbohydrate ingestion (12%), followed by upper respiratory infections, strenuous exercise, high-salt diet, and trauma. The use of corticosteroids (1%)—such as in our first case—and beta-adrenergic bronchodilators have also been identified as trigger factors for TPP [1]. Our first patient had received hydrocortisone for the skin rash, but the other two patients did not exhibit any evident trigger factors. Corticosteroids were also reported to determine TPP in subclinical hyperthyroidism [20].\n\nTPP usually occurs as a first manifestation of thyrotoxicosis, as only one quarter of TPP patients are already diagnosed with hyperthyroidism prior to their first attack [1]. Once euthyroid state is obtained, TPP does not usually recur (highest rate of recurrence, approximately 62.2%, is in the first 3 months) [21,22]. One-third can still experience repetitive episodes during tapering or withdrawal of antithyroid drugs [1]—probably linked to recurrence of hyperthyroidism. In the absence of antithyroid and nonselective beta-blocker medication, our patients experienced persistent hypokalemia despite adequate KCl replacement. In a prospective interventional study on 78 TPP patients, approximately one-fourth developed paradoxical hypokalemia after KCl administration. These patients had more severe symptoms of thyrotoxicosis (higher HR, BP, and serum FT4) [4]. \n\nThe management of TPP is even more complicated as it also poses the risk of overcorrection and rebound hyperkalemia. Both paradoxical hypokalemia and rebound hyperkalemia are life-threatening situations due to potential serious cardiac arrhythmias (complete heart block and ventricular fibrillation) [23,24]. Little KCl is actually needed to correct the deficit in the absence of a true overall body depletion [24]. The risk of rebound hyperkalemia positively correlates with the dose of KCl received by the patient: administering more than 90 mEq KCl within the first 24 h or at a rate of more than 10 mEq/h poses the highest risk [5,24].\n\nThus, the main question in managing TPP-associated severe hypokalemia is how to find the balance between paradoxical hypokalemia and rebound hyperkalemia? Propranolol blunts the overstimulation of the Na+-K+-ATP pump, thus efficiently preventing the intracellular shift of K+ and reversing the paralysis without the need of excessively administering KCl [25]. Therefore, initial therapy for TPP should also include antithyroid drugs and propranolol which allow a rapid resolution of symptoms without the risk of rebound hyperkalemia [5]. Remission of thyrotoxicosis is the mainstay of therapy on the long term [26]. Other authors have also chosen surgical treatment (thyroidectomy) in the case of refractory TPP—like we did with our first patient—due the advantage of rapidly controlling the hyperthyroid state, especially if the patient has a large or suspicious goiter [21]. \n\nFinally, TPP is a well-known entity but since it is very rare and classically confined to a particular category of individuals, it still often goes underdiagnosed. Our experience emphasizes once more the need to bear in mind the diagnosis of TPP in every case of hypokalemic periodic paralysis, even in the absence of typical clinical signs and symptoms of thyrotoxicosis or when the clinical tableau suggests otherwise. Our first patient is even more interesting due to the debut of Graves’ disease and concomitant multifocal invasive thyroid papillary carcinoma via severe, life-threatening TPP in the absence of clinically apparent goiter or exophthalmos: to our knowledge, there are only three other papers [21,27,28] in the literature reporting the association TPP–thyrotoxicosis–thyroid carcinoma. Also, the occurrence of TPP in rather elderly Caucasian women—such as in our last two patients—makes this rare entity even rarer. We demonstrate that age, sex, and ethnicity should not be criteria to reckon on and that thyroid status evaluation should be promptly performed in order to avoid severe cardiac complications.\n\n4. Conclusions\nTPP is a rare, but life-threatening complication of hyperthyroidism that often goes under-recognized. In front of hypokalemic paralysis, thyroid hormone evaluation is mandatory, even in the absence of clinical signs of thyrotoxicosis and irrespective of age, sex, and race. If thyrotoxicosis is confirmed, thyroid antibodies including TRAb should be performed. Initial treatment of TPP should also include antithyroid drugs and propranolol besides KCl supplementation, as both refractory hypokalemia and rebound hyperkalemia can occur in the absence of thyroid and Na+-K+-ATP pump control. Long-term maintenance of euthyroid status is the keystone in preventing TPP recurrence.\n\nAuthor Contributions\nConceptualization, S.B. and C.P.; investigation, L.T., O.M., C.H., and C.P.; writing—original draft preparation, S.B. and O.M..; writing—review and editing, L.T. and C.P.; and supervision, C.P. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflicts of interest.\n\nFigure 1 Electrocardiogram (ECG) strip showing ventricular tachycardia.\n\nFigure 2 Remnant uptake in the thyroid area after iodine radiopharmaceutical washout in patient 1.\n\ndiagnostics-10-00316-t001_Table 1Table 1 Summary of TPP evolution in the presented patients. NI = not identified, TPP = thyrotoxic periodic paralysis.\n\nCase\tInitial Serum K+ (mmol/L)\tPrecipitating Factor\tThyrotoxic Signs\tAntithyroid and Propranolol Initiation\tK+ Normalization\tTPP Severe Complications\t\n1\t1.2\tHydrocortisone\tAtrial fibrillation\nSystolic hypertension\nFever\tDay 2\tDay 2\tResuscitated malignant ventricular arrhythmia\t\n2\t2.7\tNI\tSinus tachycardia\nSystolic hypertension\nGoiter\tDay 1\tDay 5\tNone\t\n3\t2.7\tNI\tTachycardia\nExophthalmos\tDay 5\tDay 5\tNone\t\ndiagnostics-10-00316-t002_Table 2Table 2 Laboratory workup for hypokalemic acute flaccid paralysis [5,15].\n\nLaboratory Tests Suggestive for TPP\t\nSerum electrolytes: hypokalemia < 3.5 mmol/L\nArterial blood gas analysis—normal acid–base balance\nSerum PO4, Mg: hypophosphatemia, hypomagnesemia\nUrine potassium excretion: urinary K+ <25 mmol/L or urinary K+-to-creatinine ratio <13\nThyroid function tests: low TSH, increased FT4, increased FT3\t\nPO4 = phosphate, Mg = magnesium, K+ = potassium, TSH = thyroid stimulating hormone, FT4 = free thyroxine, FT3 = free tri-iodothyronine, TPP = thyrotoxic periodic paralysis.\n==== Refs\nReferences\n1. 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"issn_linking": "2075-4418",
"issue": "10(5)",
"journal": "Diagnostics (Basel, Switzerland)",
"keywords": "Graves’ disease; hypokalemia; thyrotoxic periodic paralysis; ventricular arrhythmia",
"medline_ta": "Diagnostics (Basel)",
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"pubdate": "2020-05-18",
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"title": "Thyrotoxic Periodic Paralysis-A Misleading Challenge in the Emergency Department.",
"title_normalized": "thyrotoxic periodic paralysis a misleading challenge in the emergency department"
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"abstract": "Türe M, Bilici M, Akın A, Demir F, Balık H, Darakçı SM. Complete atrioventricular block associated with clozapine intoxication: case report. Turk J Pediatr 2019; 61: 618-621. Clozapine is one of the atypical anti-psychotic drugs used in the treatment of resistant schizophrenia. Although cardiac side-effects are rare, it has been reported that there may be development of myocarditis, dilated cardiomyopathy, postural orthostatic hypotension and prolonged QT duration. Complete atrioventricular (AV) block is characterized by the inability to transmit all of the atrial signal to the ventricles. Causes may be congenital, idiopathic or acquired which are associated with surgery, infection, or muscle disease. AV block is extremely serious and permanent pacemaker insertion is usually necessary for all patients. Complete AV block may develop due to clozapine intoxication through increase in vagal tonus, sinoatrial node (SN) and the inhibition of atrioventricular node signalling. The case presented here is of a 15-year old female patient who developed AV total cardiac block associated with the taking of clozapine in a suicide attempt.",
"affiliations": "Division of Pediatric Cardiology, Dicle University Faculty of Medicine, Diyarbakır, Turkey.;Division of Pediatric Cardiology, Dicle University Faculty of Medicine, Diyarbakır, Turkey.;Division of Pediatric Cardiology, Dicle University Faculty of Medicine, Diyarbakır, Turkey.;Division of Pediatric Cardiology, Dicle University Faculty of Medicine, Diyarbakır, Turkey.;Division of Pediatric Cardiology, Dicle University Faculty of Medicine, Diyarbakır, Turkey.;Department of Pediatrics, Dicle University Faculty of Medicine, Diyarbakır, Turkey.",
"authors": "Türe|Mehmet|M|;Bilici|Meki|M|;Akın|Alper|A|;Demir|Fikri|F|;Balık|Hasan|H|;Darakçı|Savaş Mert|SM|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
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"issue": "61(4)",
"journal": "The Turkish journal of pediatrics",
"keywords": "clozapine; complete atrioventricular block; intoxication",
"medline_ta": "Turk J Pediatr",
"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D054537:Atrioventricular Block; D001283:Atrioventricular Node; D003024:Clozapine; D004562:Electrocardiography; D005260:Female; D006801:Humans; D010138:Pacemaker, Artificial; D013406:Suicide, Attempted",
"nlm_unique_id": "0417505",
"other_id": null,
"pages": "618-621",
"pmc": null,
"pmid": "31990485",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
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"title": "Complete atrioventricular block associated with clozapine intoxication: case report.",
"title_normalized": "complete atrioventricular block associated with clozapine intoxication case report"
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"abstract": "BACKGROUND\nThyroid metastases from colorectal cancer are uncommon and few cases are described in literature.\n\n\nMETHODS\nA 64-year-old female patient presented with an asymptomatic right cervical nodule with a rapid growth six years after sigmoidectomy for cancer and two years after resection of colorectal lung metastases. Increased CA 19.9 was identified and a thoracoabdominal CT scan revealed the onset of new metastatic bilateral pulmonary lesions. Neck ultrasonography showed a suspicious nodule in the right thyroid lobe, and Fine-needle Aspiration Cytology (FNAC) of the nodule lead to the diagnosis of colorectal cancer metastasis. A right thyroid lobectomy with right central lymph node dissection was performed. The patient underwent chemotherapy with response, but this was posteriorly suspended due to haematological side effects, and the disease spread.\n\n\nCONCLUSIONS\nThyroid metastases from colorectal cancer are rare, but, with the improvement of radiologic exams and the higher survival rate of these patients, more cases are being described. The majority of the cases present pulmonary and hepatic metastases and the prognosis is poor. The decision to operate and the type of operation depend on the extent of the metastatic disease and the patient's overall condition.\n\n\nCONCLUSIONS\nA low threshold of suspicion is crucial to make a timely diagnosis of thyroid metastases from colorectal cancer. Treatment is controversial, but, without surgery, the need may arise for tracheostomy.",
"affiliations": "Centro Hospitalar e Universitário de Coimbra (Hospital Geral - Covões), S. Martinho de Bispo, 3041-853 Coimbra, Portugal. Electronic address: coelho.m.ines@gmail.com.;Centro Hospitalar e Universitário de Coimbra (Hospital Geral - Covões), S. Martinho de Bispo, 3041-853 Coimbra, Portugal. Electronic address: miguelalbano@gmail.com.;Centro Hospitalar e Universitário de Coimbra (Hospital Geral - Covões), S. Martinho de Bispo, 3041-853 Coimbra, Portugal. Electronic address: carloscostaalmeida@yahoo.com.;Centro Hospitalar e Universitário de Coimbra (Hospital Geral - Covões), S. Martinho de Bispo, 3041-853 Coimbra, Portugal. Electronic address: lfrs.reis@gmail.com.;Centro Hospitalar e Universitário de Coimbra (Hospital Geral - Covões), S. Martinho de Bispo, 3041-853 Coimbra, Portugal. Electronic address: nidia.moreira.22@gmail.com.;Centro Hospitalar e Universitário de Coimbra (Hospital Geral - Covões), S. Martinho de Bispo, 3041-853 Coimbra, Portugal. Electronic address: c.m.costa.almeida@gmail.com.",
"authors": "Coelho|M I|MI|;Albano|M N|MN|;Costa Almeida|C E|CE|;Reis|L S|LS|;Moreira|N|N|;Almeida|C M C|CMC|",
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"doi": "10.1016/j.ijscr.2017.06.035",
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(17)30288-210.1016/j.ijscr.2017.06.035Case ReportColon cancer metastasis to the thyroid gland: A case report Coelho M.I. coelho.m.ines@gmail.com⁎Albano M.N. miguelalbano@gmail.comCosta Almeida C.E. carloscostaalmeida@yahoo.comReis L.S. lfrs.reis@gmail.comMoreira N. nidia.moreira.22@gmail.comAlmeida C.M.C. c.m.costa.almeida@gmail.comCentro Hospitalar e Universitário de Coimbra (Hospital Geral – Covões), S. Martinho de Bispo, 3041-853 Coimbra, Portugal⁎ *Corresponding author. coelho.m.ines@gmail.com28 6 2017 2017 28 6 2017 37 221 224 20 4 2017 21 6 2017 21 6 2017 © 2017 The Author(s)2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Colorectal metastases to thyroid are rare.\n\n• The majority of the cases of colorectal thyroid metastases are diagnosed lately in the evolution of a known malignancy.\n\n• A low threshold of suspicion is crucial to make a timely diagnosis in order to avoid its high morbidity.\n\n• Colorectal thyroid metastization could be clinically silent and a raise in tumoral markers could be the only sign.\n\n• Treatment is controversial and the prognosis is usually poor. Without surgery, the need may arise for tracheostomy.\n\n\n\nIntroduction\nThyroid metastases from colorectal cancer are uncommon and few cases are described in literature.\n\nCase presentation\nA 64-year-old female patient presented with an asymptomatic right cervical nodule with a rapid growth six years after sigmoidectomy for cancer and two years after resection of colorectal lung metastases. Increased CA 19.9 was identified and a thoracoabdominal CT scan revealed the onset of new metastatic bilateral pulmonary lesions. Neck ultrasonography showed a suspicious nodule in the right thyroid lobe, and Fine-needle Aspiration Cytology (FNAC) of the nodule lead to the diagnosis of colorectal cancer metastasis. A right thyroid lobectomy with right central lymph node dissection was performed. The patient underwent chemotherapy with response, but this was posteriorly suspended due to haematological side effects, and the disease spread.\n\nDiscussion\nThyroid metastases from colorectal cancer are rare, but, with the improvement of radiologic exams and the higher survival rate of these patients, more cases are being described. The majority of the cases present pulmonary and hepatic metastases and the prognosis is poor. The decision to operate and the type of operation depend on the extent of the metastatic disease and the patient’s overall condition.\n\nConclusion\nA low threshold of suspicion is crucial to make a timely diagnosis of thyroid metastases from colorectal cancer. Treatment is controversial, but, without surgery, the need may arise for tracheostomy.\n\nKeywords\nColorectal cancerThyroidMetastasisCase report\n==== Body\n1 Introduction\nColorectal cancer is the second most common cancer worldwide and the second deadliest in Europe. If metastases are present, prognosis is poor [1]. Approximately 20% of patients with colon cancer have metastases at diagnosis, and the most common sites are: liver, lungs and peritoneum [2].\n\nThyroid metastases are rare. In autopsy series, thyroid metastases are mainly from lung cancer, whereas in clinical series, renal cell carcinoma is the most frequent cause [3]. Thyroid metastases from colorectal cancer are even rarer and occur late in the disease course. Liévre et al. identified 6 cases among 5862 patients with colorectal cancer (0.1%) between 1993 and 2004 [4].\n\nWe report a case of a patient with colon cancer with lung metastases who was diagnosed with a thyroid metastasis six years after the first cancer treatment.\n\nThis study has been reported in compliance with the SCARE criteria [5].\n\n2 Case presentation\nA 64-year-old female patient was submitted to sigmoidectomy in 2009 for sigmoid cancer, followed by adjuvant chemotherapy. The postoperative pathological diagnosis was a moderately differentiated sigmoid adenocarcinoma with regional ganglion metastases pT3 N1 M0, stage IIIB, KRAS wild type. In 2011, a right pulmonary metastasis was diagnosed and pulmonary metastasectomy was conducted. Two years later, a new lung metastasis was found on follow-up CT scan and a right inferior pulmonary lobectomy was performed, followed by adjuvant chemotherapy with FOLFOX. In 2015, an asymptomatic right cervical bump with rapid growth, without apparent cervical adenopathies, was detected. Additionally, an increasing CA 19.9 (57 ng/mL (<37)) with a normal CEA (5.14 ng/mL (<5.4)) was determined. Blood tests revealed no anaemia, but normal liver, renal and thyroid functions. A Thoracoabdominal CT scan was performed, revealing the onset of new metastatic pulmonary lesions in both lungs. No abdominal alterations were observed. In addition to confirming these pulmonary lesions, a PET scan diagnosed an enlargement of the thyroid gland due to a hypodense and hypermetabolic nodule in the right thyroid lobe measuring 38 × 21 × 45 mm. Cervical ultrasonography (US) showed a heterogeneous hypoechoic nodule with calcifications measuring 33 × 27 × 25 mm in the right thyroid lobe (Fig. 1) and a right internal jugular adenopathy (11 × 6 mm). FNAC of the nodule diagnosed a metastasis from colorectal cancer. At this time, CEA was increasing (9.5 ng/dL). Right thyroid lobectomy with right central lymph node dissection was performed (Fig. 2, Fig. 3). Surgical resection was difficult due to the strong adhesions of the tumor to the adjacent structures, namely the cricoid cartilage and cricopharyngeus muscle. No surgical complications occurred and the patient was discharged home 3 days after surgery. The pathology report revealed a tangential excision with the surgical margin of a diffuse carcinoma invasion with uncompleted glandular cell elements and associated necrosis infiltrating the thyroid capsule and surrounding muscular and fibroadipose tissues, as well as three metastatic adenopathies. Immunohistochemistry was positive for gastrointestinal markers CDX2 and CK20 and negative for CK7 and TTF-1, thus confirming colorectal origin. Adjuvant chemotherapy with FOLFIRI and Cetuximab was initiated. However, therapy was interrupted after six cycles due to haematological side effects and severe asthenia. At this time, the metastatic disease was limited to one right pulmonary nodule, with CEA and CA- 19.9 within normal values. Ten months after surgery and four months after chemotherapy suspension, hoarseness and intermittent dysphagia with recurrence of right cervical mass occurred. CEA and CA 19.9 levels were increased. The CT and PET scan revealed extensive right cervical metastatic disease with compression of the right internal jugular vein (Fig. 4) and bilateral pulmonary metastases (Fig. 5). Palliative cervical radiotherapy was not successful and the disease spread to the pleura, pericardium, liver and peritoneum. Palliative chemotherapy with capecitabine was initiated and fifteen months after thyroid surgery patient is still alive.Fig. 1 Cervical Ultrasonography: a heterogeneous hypoechoic nodule with calcifications measuring 33 × 27 × 25 mm in the right thyroid lobe.\n\nFig. 1Fig. 2 Intraoperative image from the right thyroid mass showing intense adhesions to the adjacent structures.\n\nFig. 2Fig. 3 Macroscopic aspect of the right thyroid lobe after excision.\n\nFig. 3Fig. 4 Cervical CT: extensive right cervical metastatic disease with compressing right jugular internal vein.\n\nFig. 4Fig. 5 Thoracic CT: right metastatic pulmonary nodules.\n\nFig. 5\n\n3 Discussion\nMetastases to the thyroid gland from non-thyroidal sites are an uncommon clinical presentation. In autopsy series, the lung is the most common site of primary tumor metastatic to the thyroid, whereas in clinical series, renal cell carcinoma is the most frequent, followed by breast and gastrointestinal neoplasms [6]. According to Nixon et al., the high oxygen and iodine environment may impair the ability of metastatic cells to settle and develop in the thyroid. Additionally, the fast blood flow could make adhesion and implantation of tumor cells difficult [7].\n\nAlthough thyroid metastases from colorectal cancer are rare, more cases are being described due to the emergence of more accurate image exams and the higher survival rate of patients. Lievre et al. described 6 cases (0.1%) of thyroid metastases among 5862 patients with colorectal cancer between January 1993 and June 2004 [4]. In 2013, Froylich et al. reviewed metachronous colon metastases to the thyroid and found 34 cases. In this study, two thirds of the patients were female, which suggests hormonal influence; the primary sites were the rectum (41%), the sigmoid colon (33%), the right colon (19%) and the left colon (11%); 75% of the patients had stage III or IV colon cancer; metastases to the thyroid were diagnosed 6 months to 8 years after colonic resection; and, in 29 patients, there was involvement of another organ [8]. Even though metastases to the thyroid might be the initial presentation of an occult primary tumor (20–40%), the majority of the cases are diagnosed in the setting of a known malignancy (60–80%) [4], [6], [9], [10], [11]. Therefore, the possibility of a metastasis to the thyroid should be considered in patients presenting a solitary thyroid nodule and a previous history of cancer [7,12]. Moreover, there is usually evidence of previous or concomitant pulmonary and/or hepatic secondary disease, which favors a hematogenous metastatic route [9], [13]. However, there are reports of right colon carcinoma with thyroid metastases without liver disease, which could be explained by the drainage of tumor cells to the inferior vena cava through the vertebral vessels [8]. In the reported case, the patient was a female with a past history of stage III sigmoid carcinoma with pulmonary metastases who was diagnosed with a thyroid metastasis 6 years after colon resection.\n\nMost patients with metastases to the thyroid are asymptomatic (31%) and the most common presentation is swelling or a cervical mass (26%) [14]. Lièvre et al. report that 50% of the patients were asymptomatic and the metastases were diagnosed by follow-up exams, and the remaining 50% had goiter-related symptoms [4]. Thyroid dysfunction is rare and usually appears late with thyrotoxicosis [6,15]. An increase in tumor markers (mostly CEA) is common and can be the first sign [16]. US, CT, magnetic resonance imaging (MRI) and PET are used to study thyroid nodules but only FNAC can differentiate a primary thyroid lesion from a metastasis, with positive and negative predictive values of 89 and 93%, respectively [6]. Nevertheless, not all cases of thyroid metastases are diagnosed, thus emphasizing the importance of a low threshold of suspicion [17]. According to some authors, increased thyroid 18-FDG uptake in the PET scan can be the first and only sign of thyroid neoplasm (including a colon metastasis). Hence, its use is advised in the initial staging of colorectal cancer [16], [17], [18]. Additionally, immunohistochemistry is crucial for the final diagnosis. Primary thyroid tumors are positive for CK7 and negative for CK20, in contrast to colon cancer metastases, which are positive for CK20 and negative for CK7 [6,11]. In line with literature data, our patient presented increased tumor markers without symptoms, and only four months later was the cervical nodule noticed by the patient. The diagnosis for colorectal cancer metastasis was then confirmed by cytology and immunohistochemistry (FNAC).\n\nThe decision to operate depends both on the extent of the metastatic disease in other sites and the medical condition of the patient [14], [17], [19]. Surgical treatment prevents asphyxiation [19], thus avoiding an emergent tracheostomy [20], [21], [22], [23]. However, the extent of surgical resection is not well defined, with some groups recommending total thyroidectomy based on the high rates of multicentric disease [6], [14], [19]. Although thyroid lobectomy alone could be associated with positive margins and therefore favor total thyroidectomy, this is not mandatory as long as adequate margins are achieved with lobectomy. Additionally, metastases to the thyroid gland are not sensitive to radioactive iodine, hence making total thyroidectomy not mandatory for this purpose [6]. Ten percent of the patients with metastases to the thyroid are found to be unresectable intra-operatively, and those who are resectable develop metastatic diseases in other sites [7]. Concomitant regional lymph node involvement is rare, therefore prophylactic neck dissection is not recommended [6]. However, Lièvre et al. advocate lymph node dissection, for they found lymph node metastases in all patients submitted to thyroidectomy with central and lateral neck lymph node dissection [4].\n\nChemotherapeutic drugs do not seem to have a good penetration into the thyroid gland, thus possibly making it a sanctuary for occult metastases [8]. A paper from Malani et al. supports these ideas [17], but there are other recent reports suggesting that combination chemotherapy is beneficial [22], and that radiotherapy may be advocated in case of life-threatening or disabling symptoms (e.g. dyspnea, dysphagia) [4]. In the presented case, we performed a right lobectomy because there was no evidence of contralateral disease, as well as a right central node dissection due to suspicion of lymph node metastasis.\n\nPrognosis depends on the grade of malignancy of the primary lesion and whether there are metastases in other organs rather than the thyroid [13], [21]. While Montero et al. report a cancer-related death rate of 50% in less than a year [24], Lievre et al. report a median overall survival of 12 months (8–18 months) and a postoperative survival of 10 months (which is lower than after resection of lung or liver metastases), with two patients dying from metastatic recurrence in other sites, hence suggesting that total thyroidectomy should only be indicated in selected cases [4]. Conservative management seems to be the most logical approach in patients with multi-metastatic disease [4].\n\nIn the reported case, the disease seemed to be controlled after surgery and chemotherapy. However, due to side effects, chemotherapy was stopped and the disease spread rapidly. There was evidence of metastatic disease on cervical lymph nodes, lungs, pleura, mediastinum, liver and peritoneum one year after surgery.\n\n4 Conclusion\nThe prevalence of thyroid metastases from colorectal cancer may be underestimated, as many patients are asymptomatic and these metastases are not commonly searched for. The possibility of metastases should be considered in patients presenting a solitary thyroid nodule and a past history of cancer. A low threshold of suspicion is crucial to make a timely diagnosis of thyroid metastases from colorectal cancer. Treatment is controversial, but, without surgery, the need may arise for tracheostomy.\n\nConflicts of interest\nAuthors declare no conflicts of interest\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\nEthical approval was not needed since this paper describes the use of a well-known technique. Thyroid lobectomy is a valid option to treat thyroid colon metastases.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\nM.I. Coelho – study concept and design, data collection and analysis, writing the paper, review.\n\nM.N. Albano – data analysis, writing the paper, review.\n\nC.E.C. Almeida – review.\n\nN. Moreira – review.\n\nGuarantor\nLuís S. Reis; Carlos M. Costa Almeida\n==== Refs\nReferences\n1 Ait Ouakrim D. Pizot C. Boniol M. Malvezzi M. Boniol M. Negri E. Bota M. Jenkins M.A. Bleiberg H. Autier P. Trends in colorectal cancer mortality in Europe: retrospective analysis of the WHO mortality database BMJ 2015 h4970 26442928 \n2 Riihimäki M. Hemminki A. Sundquist J. Hemminki K. Patterns of metastasis in colon and rectal cancer Sci. Rep. 6 2016 29765 27416752 \n3 Willis R.A. Metastatic tumours in the thyreoid gland Am. J. Pathol. 7 3 1931 187 208 (Accessed March 4, 2017) http://www.ncbi.nlm.nih.gov/pubmed/19969962 19969962 \n4 Lièvre A. Leboulleux S. Boige V. Travagli J.P. Dromain C. Elias D. Ducreux M. Malka D. Thyroid metastases from colorectal cancer: The Institut Gustave Roussy experience Eur. J. Cancer 42 2006 1756 1759 16762542 \n5 Agha R.A. Fowler A.J. Saeta A. Barai I. Rajmohan S. Orgill D.P. Afifi R. Al-Ahmadi R. Albrecht J. Alsawadi A. Aronson J. Ather M.H. Bashashati M. Basu S. Bradley P. Chalkoo M. Challacombe B. Cross T. Derbyshire L. Farooq N. Hoffman J. Kadioglu H. Kasivisvanathan V. Kirshtein B. Klappenbach R. Laskin D. Miguel D. Milburn J. Mousavi S.R. Muensterer O. Ngu J. Nixon I. Noureldin A. Perakath B. Raison N. Raveendran K. Sullivan T. Thoma A. Thorat M. Valmasoni M. Massarut S. D’cruz A. Baskaran V. Giordano S. Roy G. Machado- Aranda D. Healy D. Carroll B. Rosin D. The SCARE statement: consensus-based surgical case report guidelines Int. J. Surg. 34 2016 180 186 27613565 \n6 Nixon I.J. Coca-Pelaz A. Kaleva A.I. Triantafyllou A. Angelos P. Owen R.P. Rinaldo A. Shaha A.R. Silver C.E. Ferlito A. Metastasis to the thyroid gland: a critical review Ann. Surg. Oncol. 21 2016 (Epub ahead of print) \n7 Nixon I.J. Whitcher M. Glick J. Palmer F.L. Shaha A.R. Shah J.P. Patel S.G. Ganly I. Surgical management of metastases to the thyroid gland Ann. Surg. Oncol. 18 2011 800 804 21046263 \n8 Froylich D. Shiloni E. Hazzan D. Metachronous colon metastasis to the thyroid: a case report and literature review Case Rep. Surg. 2013 2013 1 5 \n9 Kumamoto K. Utsumi Y. Sugano K. Hoshino M. Suzuki S. Takenoshita S. Colon carcinoma metastasis to the thyroid gland: report of a case with a review of the literature Tumori 92 2006 252 256 (Accessed February 7, 2017) http://www.ncbi.nlm.nih.gov/pubmed/16869247 16869247 \n10 Cavanna L. Anselmi E. Palladino M. Pagani R. Colon carcinoma metastasis to the thyroid gland Tumori 92 2006 467 (Accessed February 7, 2017) http://www.ncbi.nlm.nih.gov/pubmed/17168448 17168448 \n11 Minami S. Inoue K. Irie J. Mine T. Tada N. Hirabaru M. Noda K. Ito S. Haraguchi M. Metastasis of colon cancer to the thyroid and cervical lymph nodes: a case report Surg. Case Rep. 2 108 2016 \n12 Roloff G.W. Yang Z. Wood L.V. Neychev V.K. Colon cancer metastasis to the thyroid gland: report of a case with unique molecular profile Key Clinical Message Clin. Case Rep. 4 2016 549 553 27398194 \n13 Nakamura K. Nozawa K. Aoyagi Y. Ishihara S. Matsuda K. Fukushima J. Watanabe T. A case report of thyroid gland metastasis associated with lung metastasis from colon cancer Tumori 97 2011 229 332 21617721 \n14 Romero Arenas M.A. Ryu H. Lee S. Morris L.F. Grubbs E.G. Lee J.E. Perrier N.D. The role of thyroidectomy in metastatic disease to the thyroid gland Ann. Surg. Oncol. 21 2014 434 439 24081800 \n15 Youn J.C. Rhee Y. Park S.Y. Kim W.H. Kim S.J. Chung H.C. Hong S.W. Lim S.-K. Severe hypothyroidism induced by thyroid metastasis of colon adenocarcinoma: a case report and review of the literature Endocr. J. 53 2006 339 343 (Accessed February 9, 2017) http://www.ncbi.nlm.nih.gov/pubmed/16714841 16714841 \n16 Iguchi T. Matsuoka J. Sato S. Okumura Y. Omori M. Mifune H. Akaki S. Kanazawa S. F-18 FDG PET demonstration of a thyroid metastasis in a patient with colon cancer Clin. Nucl. Med. 32 2007 361 362 17452862 \n17 Malani A.K. Gupta C. Rangineni S. Gupta V. Thyroid metastasis from colorectal cancer: role of [18F]-fluoro- 2-deoxy- D-glucose positron emission tomography Clin. Colorectal Cancer 5 2005 287 291 (Accessed February 9, 2017) http://www.ncbi.nlm.nih.gov/pubmed/16356308 16356308 \n18 Hanna W.C. Ponsky T.A. Trachiotis G.D. Knoll S.M. Colon cancer metastatic to the lung and the thyroid gland Arch. Surg. 141 2006 93 96 16415418 \n19 Nixon I.J. Whitcher M. Glick J. Palmer F.L. Shaha A.R. Shah J.P. Patel S.G. Ganly I. Surgical management of metastases to the thyroid gland Ann. Surg. Oncol. 18 2011 800 804 21046263 \n20 Alherabi A.Z. Marglani O.A. Gazzaz M.J. Abbas M.M. Colon cancer metastasis to the thyroid gland Saudi Med. J. 35 2014 868 871 (Accessed February 7, 2017) http://www.ncbi.nlm.nih.gov/pubmed/25129189 25129189 \n21 Goatman C. Goldsmith P.J. Antonopoulos V. Ali B. Metastasis of colorectal adenocarcinoma to the thyroid: a case report and review of the literature Case Rep. Surg. 2012 2012 1 3 \n22 Cheung W.Y. Brierley J. Mackay H.J. Treatment of rectal cancer metastases to the thyroid gland: report of two cases Clin. Colorectal Cancer 7 4 2008 Jul 280 282 18650197 \n23 Poon D. Toh H.C. Sim CS: Two case reports of metastases from colon carcinoma to the thyroid Ann. Acad. Med. Singapore 33 January (1) 2004 100 102 15008573 \n24 Montero P.H. Ibrahimpasic T. Nixon I.J. Shaha A.R. Thyroid metastasectomy J. Surg. Oncol. 2014 36 41 24122778\n\n",
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"title": "Colon cancer metastasis to the thyroid gland: A case report.",
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"abstract": "The use of immune checkpoint inhibitors has dramatically improved the chance of surviving malignant melanomas; however, the effect comes at the cost of toxicities that are difficult to predict. Immune-mediated hepatitis is the most common form of liver toxicity, but fatal outcome is uncommon. We report the case of a 70-year-old female with metastatic malignant melanoma who developed severe liver toxicity characterized by bile duct injury and cholestasis. The condition progressed despite potent immunosuppressive treatment, plasmapheresis, and intensive supportive care; and the patient died while still having tumor response.",
"affiliations": "Department of Oncology, Vestre Viken HF, Drammen, Norway.;Department of Gastroenterology, Vestre Viken HF, Drammen, Norway.;Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.;Department of Oncology, Vestre Viken HF, Drammen, Norway.",
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"doi": "10.1159/000507695",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000507695\ncro-0013-0659\nCase Report\nFatal Cholestatic Liver Injury during Treatment with PD1 Immune Checkpoint Inhibitor for Malignant Melanoma: A Case Report\nThorsteinsdottir Thuridur a Løitegård Teje b Reims Henrik Mikael c Porojnicu Alina Carmen a* aDepartment of Oncology, Vestre Viken HF, Drammen, Norway\nbDepartment of Gastroenterology, Vestre Viken HF, Drammen, Norway\ncDepartment of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway\n*Dr. Alina Carmen, Porojnicu Department of Oncology, Vestre Viken HF, Wergelands gate 10, NO–3019 Drammen (Norway), alinacp@vestreviken.no\nMay-Aug 2020 \n15 6 2020 \n15 6 2020 \n13 2 659 663\n2 4 2020 2 4 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.The use of immune checkpoint inhibitors has dramatically improved the chance of surviving malignant melanomas; however, the effect comes at the cost of toxicities that are difficult to predict. Immune-mediated hepatitis is the most common form of liver toxicity, but fatal outcome is uncommon. We report the case of a 70-year-old female with metastatic malignant melanoma who developed severe liver toxicity characterized by bile duct injury and cholestasis. The condition progressed despite potent immunosuppressive treatment, plasmapheresis, and intensive supportive care; and the patient died while still having tumor response.\n\nKeywords\nImmune checkpoint inhibitorsVanishing bile duct syndromeMalignant melanoma\n==== Body\nIntroduction\nThe use of immune checkpoint inhibitors (ICPIs) has dramatically improved the chance of surviving malignant melanomas. Pembrolizumab is a monoclonal antibody that selectively inhibits programmed cell death-1 (PD1) activity at the tumor site, thus being able to restore anti-tumor immune response. In metastatic disease, pembrolizumab significantly improves overall survival, with 55% of all treated patients still being alive 24 months after treatment start.\n\nLiver toxicity is a rare complication of pembrolizumab, with 2% of all patients included in the Checkpoint 006 study experiencing grade 3–4 injury [1]. A recent meta-analysis suggests that the risk of hepatotoxicity related to ICPIs largely depends on the type of cancer treated, dosing schedule, and the regimen used, with the combination of ipilimumab and nivolumab posing the highest risk [2].\n\nThe pathophysiological mechanisms of immune-related adverse events (irAEs) are poorly understood. Immune-mediated hepatitis is believed to be mediated by an immune-related T-cell activation, but it differs in several respects from both drug-induced and idiopathic autoimmune hepatitis [3]. Details in the reporting of hepatotoxicity vary widely across publications, with some studies registering isolated elevations of various liver tests, for example, alanine aminotransferase (ALT), aspartate aminotransferase, alkaline phosphatase (ALP), γ-glutamyl transpeptidase, or bilirubin, while others use general terms such as “liver toxicity” or “hepatitis.”\n\nMortality due to liver toxicity is a rare event in prospective studies, but in a retrospective analysis of individual safety data from the World Health Organization database VigiLyze, approximately 22% of all irAE-related deaths in patients on anti-PD1/PD-L1 monotherapy were caused by liver injury [4].\n\nThe general algorithm for managing irAEs is based on treatment with high-dose steroids with prompt conversion to other immunosuppressants in case of treatment failure [5]. A thorough investigation to exclude other causes of liver dysfunction should be performed before or simultaneously with immunosuppressive treatments, and this should include virology tests, radiological assessment, and liver biopsy. Liver-specific autoimmune antibody tests are not always elevated in case of irAEs.\n\nCase Report\nA 70-year-old Caucasian female with no prior history of cancer was examined in December 2017, after the discovery of a growing lump in her left axilla. Her past medical history included hypertension, paroxysmal tachycardia, and gout. Her medication was lisinopril dehydrate, verapamil colchicine, and allopurinol. A biopsy of the axillary mass revealed lymph node metastasis from a malignant melanoma, BRAF wild type. A CT scan showed several small lung nodules and enlarged lymph nodes on the left side of her neck, giving suspicion of disseminated malignancy. No primary tumor was identified at skin checkup.\n\nAt assessment in our outpatient clinic, she was in good clinical condition (ECOG 1) and her blood tests revealed activated inflammatory parameters (CRP 103 mg/L, leukocytes 11.8 × 109/L, granulocytes 8 × 109/L), normal liver function (ALT, γ-glutamyl transpeptidase, bilirubin, and ALP), and normal kidney function (creatinine). LDH was moderately elevated at 353 U/L.\n\nShe was offered treatment with pembrolizumab 2 mg/kg every 3 weeks and received the regimen as scheduled. Reimaging after 5 cycles of treatment showed good partial response and her CRP and LDH had normalized. At that time point, she was experiencing itching and skin rash corresponding to grade 2 toxicity [6] that were successfully managed with topical corticosteroid as well as hypothyroidism that was corrected with levothyroxine.\n\nDuring treatment, her laboratory results including liver tests were followed every 3 weeks and were normal until symptom onset.\n\nAfter the twelfth infusion with pembrolizumab, she was admitted to the hospital in poor clinical condition; she had developed jaundice and suffered from painful joints and inspiratory chest pain. Her blood examinations showed: CRP 19 mg/L, hemoglobin 15 g/dL, leukocytes 15.1 × 109/L, Na 132 mmol/L, creatinine 137 μmol/L, ALT 217 U/L, ALP 417 U/L, LD 369 U/L, bilirubin 216 μmol/L, and S-glucose 22 mmol/L.\n\nThe tentative diagnosis upon admission was irAEs affecting the liver, kidney, pancreas, joints, and possibly lungs and/or pleura. The patient received intravenous treatment with methyl prednisolone 125 mg daily and insulin along with adequate supportive care according to international guidelines [5]. Imaging with liver ultrasound and CT of the chest and abdomen excluded tumor progression or other organ-related causes. Serum virology test (hepatitis B and C, HBV, cytomegalovirus) were normal. Magnetic resonance cholangiopancreatography was not considered necessary based on previous radiology findings.\n\nThree days after admission, her symptoms improved; and creatinine was normalized, while ALT, ALP, and bilirubin levels continued to rise (Fig. 1). Given the lack of improvement in her liver tests, mycophenolate 1 g twice daily was added to her corticosteroid treatment. A liver biopsy was obtained and showed portal fibrosis and inflammation dominated by lymphocytes, with scattered histiocytes and a few plasma cells and only focal interface activity. The most striking finding was the lack of identifiable bile ducts in the majority of the portal tracts, as well as the absence of ductular proliferation. In the lobules, there was extensive intracellular and intracanalicular cholestasis, mild lymphocytic inflammation, and mild microvesicular steatosis (Fig. 2).\n\nTen days after admission and despite high-dose corticosteroids and mycophenolate, her liver tests continued to worsen, and plasmapheresis was instituted along with doubling of the mycophenolate dose. She received 8 cycles in total of plasmapheresis that were given daily in the early phase. All her liver tests improved slightly, but we observed a rapid deterioration when plasmapheresis was delayed (e.g., during weekends), thus indicating a short-lived effect of this treatment modality. Her clinical condition eventually worsened with no signs of reversible cause, and she died on day 26 after symptom onset.\n\nDiscussion\nWe present here the case of an atypical form of liver toxicity associated with ICPIs therapy, histologically characterized by severe ductopenia and cholestasis. According to previous reports, the predominant histopathological findings in liver injury associated with ICPIs, including pembrolizumab, include hepatitis with lobular inflammation and some degree of portal and/or periportal inflammation, sometimes with bile duct injury [3, 7, 8]. The biopsy findings in the present case are suggestive of a rare form of liver injury known as vanishing bile duct syndrome (VBDS). This type of injury may be caused by an infection, autoimmune disease, ischemia, and drugs, or it may occur as a paraneoplastic event. This condition is characterized by a progressive destruction of intrahepatic bile ducts resulting in severe cholestasis. The prognosis is largely dependent on the underlying cause and whether epithelial regeneration occurs.\n\nA retrospective register-based analysis [9] showed a mortality rate of 20% among patients with drug-related VBDS, with the extent of ductopenia being the most important predictive factor for outcome. Doherty et al. [10] reported a series of 3 cases of severe intrahepatic biliary injury that occurred under treatment with ICPIs, one of which presented as VBDS after a single infusion of pembrolizumab. The pathogenesis of this type of ICPI-related biliary injury is unknown, but the lack of autoimmune hepatitis-like features, and the apparently poor effect of immunosuppressive treatment, suggests involvement of mechanisms distinct from those of immune-mediated hepatitis.\n\nLiver toxicity due to ICPIs is treated with high-dose corticosteroids (1–2 mg prednisolone/kg/day). In the event of treatment failure, mycophenolate should be added. The TNF-alpha inhibitor infliximab, which is commonly used to treat gastrointestinal immunological side effects, is not recommended due to concerns regarding added liver toxicity. Other immunosuppressive alternatives are tacrolimus or anti-thymocyte globulin. Our patient showed no treatment response to either corticosteroids or mycophenolate. Due to the rapid aggravation of her liver function, plasmapheresis was started with the intention of reducing exposure to pathogenic autoantibodies. We observed a slight but only temporary improvement in her liver parameters with this treatment modality (Fig. 1).\n\nThe median time from onset of symptoms to death from irAEs due to ICPIs (all toxicities analyzed together) is 40 days in the retrospective analysis of Wang et al. [4]. In the other reported case of VBDS due to pembrolizumab, toxicity occurred after the first infusion [10]. In the case of our patient, liver injury became manifest almost 10 months after treatment initiation. We also noticed several other toxicities occurring prior to or concurrently with liver toxicity (dermatitis, hypothyroidism, arthritis, diabetes, and possibly pneumonitis/pleuritis).\n\nClinical features, time to onset and severity of liver injury associated with ICPIs vary widely and make prediction and management of these conditions challenging. To our knowledge, this is the second reported case of VBDS associated with treatment with ICPIs, and the first case with fatal outcome. With the dramatic increase in the use of checkpoint inhibitors across cancer types, efforts should be made to improve the understanding of toxicities and to optimize their treatment, especially in the context of complex, severe irAEs. The identification of cases with severe biliary ductal injury may be particularly important, as these may require other treatment regimens than patients with immune-mediated hepatitis.\n\nStatement of Ethics\nPublication of these data was approved post mortem by the patient's closest family and by the Data Security Office at Vestre Viken HF, Norway.\n\nDisclosure Statement\nT.T., T.L., and H.M.R. have nothing to declare. A.C.P. has received honorarium from Brystol-Myers Squibb Norway for scientific lectures.\n\nFunding Sources\nNone.\n\nAuthor Contributions\nAll authors contributed to the treatment and clinical evaluation of this patient as well as to the preparation of this manuscript.\n\nFig. 1 Graph showing the changes in liver tests over time. Start and stop of plasmapheresis is depicted on the graph.\n\nFig. 2 Photomicrographs showing liver biopsy findings, including a mild portal and lobular inflammation, b small portal tract with bile duct loss, and c marked intracanalicular and intracellular cholestasis.\n==== Refs\nReferences\n1 Schachter J Ribas A Long GV Arance A Grob JJ Mortier L Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006) Lancet 2017 Oct 21 390 (10105) 1853 62 28822576 \n2 Wang W Lie P Guo M He J Risk of hepatotoxicity in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis of published data Int J Cancer 2017 Sep 1 141 (5) 1018 28 28263392 \n3 Jennings JJ Mandaliya R Nakshabandi A Lewis JH Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies Expert Opin Drug Metab Toxicol 2019 3 15 (3) 231 44 30677306 \n4 Wang DY Salem JE Cohen JV Chandra S Menzer C Ye F Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis JAMA Oncol 2018 Dec 1 4 (12) 1721 8 30242316 \n5 Haanen JBAG Carbonnel F Robert C Kerr KM Peters S Larkin J Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2017 Jul 1 28 (Suppl l_4) iv119 iv42 \n6 US Department of Health and Human Services Common Terminology Criteria for Adverse Events (CTCAE) 2017 Available from: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf \n7 Aivazian K Long GV Sinclair EC Kench JG McKenzie CA Histopathology of pembrolizumab-induced hepatitis: a case report Pathology 2017 12 49 (7) 789 2 29079004 \n8 De Martin E Michot JM Papouin B Champiat S Mateus C Lambotte O Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors J Hepatol 2018 6 68 (6) 1181 90 29427729 \n9 Bonkovsky HL Kleiner DE Gu J Odin JA Russo MW Navarro VM Clinical presentations and outcomes of bile duct loss caused by drugs and herbal and dietary supplements Hepatology 2017 4 65 (4) 1267 7 27981596 \n10 Doherty GJ Duckworth AM Davies SE Mells GF Brais R Harden SV Severe steroid-resistant anti-PD1 T-cell checkpoint inhibitor-induced hepatotoxicity driven by biliary injury ESMO open 2017 2 (4) e000268 29081991\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "13(2)",
"journal": "Case reports in oncology",
"keywords": "Immune checkpoint inhibitors; Malignant melanoma; Vanishing bile duct syndrome",
"medline_ta": "Case Rep Oncol",
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"pages": "659-663",
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"pmid": "32774252",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "29081991;30242316;27981596;29427729;28263392;29079004;28822576;28881921;30677306",
"title": "Fatal Cholestatic Liver Injury during Treatment with PD1 Immune Checkpoint Inhibitor for Malignant Melanoma: A Case Report.",
"title_normalized": "fatal cholestatic liver injury during treatment with pd1 immune checkpoint inhibitor for malignant melanoma a case report"
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"abstract": "Pancreatic ductal adenocarcinoma (PDAC) has a bleak prognosis, especially for the majority of patients diagnosed with metastatic disease. The primary option for palliative treatment is chemotherapy, and responses beyond first-line treatment are rare and typically short. Here, we report a case of a 63-year-old woman with PDAC in the head of the pancreas who was initially successfully treated by pancreaticoduodenectomy followed by adjuvant chemotherapy with gemcitabine. However, disease recurrence with liver and para-aortic lymph node metastases was detected only two months after the completion of adjuvant chemotherapy. First-line palliative chemotherapy with gemcitabine-nab/paclitaxel was commenced. The results were discouraging, with disease progression (liver and lung metastases) detected at the first evaluation; the progression-free survival was just two months (64 days). Surprisingly, the response to second-line palliative chemotherapy with 5-fluorouracil-oxaliplatin was excellent; in combination with the ablation of a liver metastasis, this treatment regimen resulted in a complete radiological response and an 11-month treatment-free interval with a sustained good performance status.",
"affiliations": "Department of Clinical Pathology and Department of Clinical and Experimental Medicine, Linköping University, 58183 Linköping, Sweden.;Department of Oncology, Ryhov County Hospital, 55305 Jönköping, Sweden.;Department of Surgery and Department of Clinical and Experimental Medicine, Linköping University, 58183 Linköping, Sweden.;Department of Surgery and Department of Clinical and Experimental Medicine, Linköping University, 58183 Linköping, Sweden.",
"authors": "Blomstrand|Hakon|H|https://orcid.org/0000-0002-9845-1410;Adolfsson|Karin|K|;Sandström|Per|P|;Björnsson|Bergthor|B|https://orcid.org/0000-0001-9704-1260",
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"doi": "10.1155/2020/4138215",
"fulltext": "\n==== Front\nCase Rep Gastrointest MedCase Rep Gastrointest MedCRIGMCase Reports in Gastrointestinal Medicine2090-65282090-6536Hindawi 10.1155/2020/4138215Case ReportComplete Radiologic Response of Metastatic Pancreatic Ductal Adenocarcinoma to Microwave Ablation Combined with Second-Line Palliative Chemotherapy https://orcid.org/0000-0002-9845-1410Blomstrand Hakon \n1\nAdolfsson Karin \n2\nSandström Per \n3\nhttps://orcid.org/0000-0001-9704-1260Björnsson Bergthor bergthor.bjornsson@liu.se\n3\n\n1Department of Clinical Pathology and Department of Clinical and Experimental Medicine, Linköping University, 58183 Linköping, Sweden\n2Department of Oncology, Ryhov County Hospital, 55305 Jönköping, Sweden\n3Department of Surgery and Department of Clinical and Experimental Medicine, Linköping University, 58183 Linköping, SwedenAcademic Editor: Shiro Kikuchi\n\n2020 31 1 2020 2020 413821518 8 2019 7 1 2020 13 1 2020 Copyright © 2020 Hakon Blomstrand et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Pancreatic ductal adenocarcinoma (PDAC) has a bleak prognosis, especially for the majority of patients diagnosed with metastatic disease. The primary option for palliative treatment is chemotherapy, and responses beyond first-line treatment are rare and typically short. Here, we report a case of a 63-year-old woman with PDAC in the head of the pancreas who was initially successfully treated by pancreaticoduodenectomy followed by adjuvant chemotherapy with gemcitabine. However, disease recurrence with liver and para-aortic lymph node metastases was detected only two months after the completion of adjuvant chemotherapy. First-line palliative chemotherapy with gemcitabine-nab/paclitaxel was commenced. The results were discouraging, with disease progression (liver and lung metastases) detected at the first evaluation; the progression-free survival was just two months (64 days). Surprisingly, the response to second-line palliative chemotherapy with 5-fluorouracil-oxaliplatin was excellent; in combination with the ablation of a liver metastasis, this treatment regimen resulted in a complete radiological response and an 11-month treatment-free interval with a sustained good performance status.\n==== Body\n1. Background\nPancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in Sweden and the USA [1, 2]. Initial symptoms are often nonspecific, and most patients are diagnosed with locally advanced pancreatic cancer (LAPC) and/or metastatic disease.\n\nPDAC without distant metastasis is divided into resectable PDAC, borderline resectable pancreatic cancer (BRPC), and LAPC, largely dependent on the extent of vessel involvement [3]. For resectable PDAC without vessel involvement, the standard treatment is initial surgery with pancreaticoduodenectomy or distal resection, depending on tumour location, followed by single-agent adjuvant chemotherapy with 5-fluorouracil (5FU) or gemcitabine [4]. This subgroup of PDAC patients has the best outcome, but the frequency of recurrence is high, and long-term survival at five years is only 15–20% [5]. Adjuvant combination chemotherapy with gemcitabine-5FU appears to improve outcomes [6], and neoadjuvant chemotherapy is being evaluated in several ongoing trials [7]. For the BRPC subgroup with tumour infiltration of local major vessels (mainly the celiac trunk, superior mesenteric artery, and hepatic artery), the risk of microscopically positive resection margins (R1 resection) following surgery is substantial; therefore, combination chemotherapy and multimodal treatments (e.g., chemotherapy with sequential or concomitant radiotherapy) have been tested in numerous trials, but the results on the most effective strategy are contradictory (reviewed in [8]). The LAPC subgroup with extensive vessel engagement has a high risk of macroscopically positive resection margins (R2 resection), and surgery should not be considered unless conversion to BRPC is achieved during palliative treatment [9].\n\nIn nonresponding LAPC or primary metastatic disease, resection of the primary tumour is not possible or not indicated, respectively, and the treatment option is palliative care. According to current guidelines, the only treatment modalities for patients with this disease are chemotherapy and radiation therapy for severe and refractory pain [10, 11]. The prognosis of patients with metastatic pancreatic cancer is poor, with an expected five-year survival rate of 8% in Sweden [12]. Histological subtypes other than ductal adenocarcinoma are rare, and signet ring cell carcinoma appears to have a similar prognosis [13], while the colloid variant (mucinous noncystic adenocarcinoma) has a markedly better prognosis [14].\n\n2. Case Presentation\nA 63-year-old Swedish woman consulted her local health centre due to nausea, bright coloured stools, and 4 kg weight loss. Laboratory tests revealed elevated aminotransferases and bilirubinaemia, and the patient was referred to the local surgical department. Abdominal ultrasound and computed tomography (CT) of the abdomen and thoracic cavity revealed a tumour in the pancreatic head measuring 25 mm, a borderline enlarged lymph node in the liver hilum, and dilation of the pancreatic and common bile ducts but no evidence of distant metastases. CA19-9 was elevated to 2741 kU/L (<35 kU/L) (Figure 1). Internal bile duct drainage via endoscopic retrograde cholangiopancreatography (ERCP) failed; thus, the patient underwent percutaneous transhepatic cholangiography (PTC) drainage and was treated twice for cholangitis with intravenous antibiotics before undergoing surgery at the regional university hospital. The surgical procedure was a standard pancreaticoduodenectomy with an uneventful recovery. The patient was discharged to the local hospital on the fourth postoperative day (POD) and to the home on POD 15. The histopathological examination confirmed moderately to poorly differentiated PDAC. Although minor sections of the tumour had mucinous and signet ring cell-like histology, the diagnosis was not changed. Perineural and lymphovascular invasion was evident. Carcinoma involvement was seen in two pancreaticoduodenal lymph nodes out of a total of 20 examined lymph nodes. The tumour grade was pT3N1MX (Figure 2). Postoperative CA19-9 was 6 kU/L. Six months of adjuvant treatment with gemcitabine (intravenous infusions on days 1, 8, and 15 in a four-week cycle at 1000 mg/m2) was initiated. The patient completed the entire treatment regimen, except the dose on cycle 4 day 15 due to E. coli septicaemia, which was successfully treated with antibiotics. At the evaluation at the end of adjuvant treatment, 7.5 months after surgery, there were no signs of radiological recurrence on CT; however, CA19-9 was increased to 229 kU/L.\n\nAfter an additional two months of observation, CA19-9 increased to 3026 kU/L, and CT revealed one liver metastasis in segment 6 (Figure 3) and multiple enlarged para-aortic lymph nodes. The patient was treated with two full cycles of gemcitabine/nab-paclitaxel as first-line palliative chemotherapy according to regional guidelines. The treatment was administered by intravenous infusions on days 1, 8, and 15 in a four-week cycle at 1000 mg/m2 gemcitabine and 125 mg/m2 nab-paclitaxel. The response was evaluated with positron emission tomography (PET)-CT, which revealed no change in the liver metastasis in segment 6 or in lymph nodes without uptake; however, a new paravertebral tumour with FDG uptake was detected in the lower right lobe of the lungs (Figures 4 and 5). CA19-9 was 6628 kU/L. The diagnosis was progressive disease, and second-line palliative 5FU-based chemotherapy was commenced. The first cycle was given as FLV (500 mg/m2 5FU bolus plus 60 mg/m2 leucovorin on days 1 and 2 in a two-week cycle) due to persistent chemotherapy-induced polyneuropathy (CIPN) from the first-line treatment. The CIPN decreased to CTCAE grade 1, allowing for the administration of FLOX (FLV plus the infusion of 85 mg/m2 oxaliplatin on day 1 of the two-week cycle) from the second cycle. Repeated CT scans showed a partial response, and CA19-9 decreased to 44 kU/L during 17 cycles over a 9-month treatment period. The oxaliplatin dose was reduced because of CIPN and discontinued from cycle 14 due to an adverse drug reaction; drug hypersensitivity could not be ruled out. PET-CT and contrast-enhanced ultrasound of the liver showed a complete response in the thoracic cavity (Figure 6) and one 13-mm liver metastasis in segment 6 as the only remaining radiological evidence of disease.\n\nDue to the earlier adverse reaction to oxaliplatin, persistent CIPN, and chemotherapy-related fatigue, continued palliative chemotherapy was difficult and had no curative potential. In part based on the patient's request, alternative treatment strategies were considered, and local treatment with microwave ablation (MWA) was offered after discussion at a multidisciplinary conference. The patient underwent MWA of the liver lesion 22 months after surgery for the primary tumour, and CA19-9 levels were normalized after MWA. Due to the presence of a postablation liver abscess, continued chemotherapy was contraindicated, and an active monitoring strategy was chosen. The patient was evaluated every second month and showed a slow increase in CA19-9 to 151 kU/L by 30 months after surgery for the primary tumour but no radiological evidence of relapse. CA19-9 further increased to 3182 kU/L after an additional 2 months, and PET-CT showed one liver metastasis in segment 5 measuring 15 mm (Figure 3) without additional dissemination; thus, the patient, after discussion at a multidisciplinary conference, underwent successful radiofrequency ablation (RFA) 33 months after surgery for the primary tumour.\n\nAt the next evaluation visit 3 months later (i.e., 36 months after primary surgery), a relapse was found both biochemically, with a further increase in CA19-9 to 4692 kU/L, and radiologically, with PET-CT showing three suspicious 4 to 8 mm lung metastases without FDG uptake and two metastases in the right liver lobe measuring 25 and 30 mm. Third-line palliative chemotherapy with FLIRI (FLV plus the intravenous infusion of 180 mg/m2 irinotecan on day 1 in the two-week cycle) was started.\n\nExcept during the initial adverse event of a liver abscess following the MWA, which was successfully treated with antibiotics, the patient did not suffer from any side effects after local treatment. During the eleven-month relapse-free interval and until the start of third-line palliative chemotherapy with FLIRI, the patient reported a WHO performance status of 0. The patient experienced normal health and pursued physical activity and hobbies as before the cancer diagnosis.\n\n3. Discussion\nThe frequently observed course of metastatic PDAC is rapid progression, but there is now a fairly good chance for a response to first-line palliative combination chemotherapy [15]; in the South East Region of Sweden, the median overall survival of this patient group is approximately 9 months [16]. Based on the results of the phase III MPACT trial [15], many guidelines advocate the use of gemcitabine-nab/paclitaxel as first-line palliative treatment in patients with metastatic PDAC and ECOG PS 0-1, as is the case in the South East Region of Sweden. This case illustrates that even in PDAC, some patients who are nonresponders to the recommended treatment do experience a response to alternative chemotherapy treatments, indicating the need for therapy-specific predictive factors to optimize oncologic treatment decision-making.\n\nIn treating patients with metastatic PDAC with second- or even third-line chemotherapy, there is a fine balance between patient frailty and drug toxicity. In Sweden, platinum-based combination chemotherapy (in this case, FLOX) is often offered to patients with a good performance status based on the survival benefit seen in previous small phase II studies and a phase III study [17]. These data have since been questioned as the results from a more recent phase III study were contradictory, with a shorter median OS in the platinum-based therapy (FOLFOX) group than in the FLV only group [18]. In addition, the objective response rate on second-line therapy is often less than 10% [19], indicating the importance of appropriate patient selection. As predictors of the outcome of individual chemotherapy regimens are lacking, clinical parameters and the ECOG or Karnofsky performance status are often used, and a nomogram to help choose the right patients for second-line treatment has been proposed [20].\n\nWith the abovementioned data in mind, this case illustrates an example of an exceptional response to second-line palliative chemotherapy. Although limited conclusions can be drawn from a single case, this patient had several prognostic factors associated with a poor outcome in the previously reported nomogram, such as liver metastasis, advanced age, and a very short duration of first-line chemotherapy. The factors that contributed to the therapeutic response in this patient are unknown, but the current report illustrates that second-line therapy can be effective and should be considered, even in motivated patients with multiple aggravating clinical factors.\n\nIn metastatic PDAC, clinical guidelines do not include surgery or local treatment modalities, which is in contrast to colorectal cancer, for which the surgical approach (with a curative intention) to liver and lung metastases is routine [21, 22]. For PDAC, the ablative modality of irreversible electroporation (IRE) has been evaluated as a first-line treatment for LAPC but has not shown a significant survival benefit [23]. IRE could theoretically be used for hilar liver metastases [24], but this was not an option in this case due to the location of the liver metastasis. Concerning the choice between RFA or MWA, data on hepatocellular carcinoma and colorectal liver metastases suggest similar efficacy, with a tendency towards better local control with MWA, especially in cases of large lesions [25, 26]. In the case presented herein, ablation of the liver metastasis was used in conjunction with chemotherapy and achieved an 11-month treatment-free interval without radiologically detectable disease and with a subjective and objective (WHO PS) good quality of life. The duration was far longer than expected, considering the unambiguous histopathological diagnosis of PDAC and the immediate progression on first-line palliative chemotherapy. This, together with the recurrence in another liver lobe and the absence of evidence for the curative potential of chemotherapy in metastatic PDAC, points towards an actual treatment effect of MWA. Though not possible in this case due to infectious complications of MWA, the effect could hypothetically have been prolonged by “adjuvant” chemotherapy, considering the previous response to second-line chemotherapy. However, as the overall intention was palliative, the value of the treatment-free period should not be underestimated.\n\nThe choice of a second liver ablation over chemotherapy was based on the treatment-free interval after the initial ablation, the good quality of life reported by the patient in the chemotherapy-free interval, and the radiological finding of a single new lesion in the liver.\n\n4. Conclusion\nThis case illustrates that a treatment-free interval with a sustained good performance status can be achieved with second-line palliative chemotherapy in combination with the ablation of liver metastases in patients with pancreatic cancer and that local therapies should therefore be considered in select cases.\n\nConsent\nWritten informed consent was obtained from the patient for the writing of this case report.\n\nConflicts of Interest\nThe authors declare no conflicts of interest regarding the publication of this article.\n\nFigure 1 Variation over time in CA19-9 levels and the ECOG PS in relation to treatment. Abbreviations: ECOG, Eastern Cooperative Oncology Group; PS, performance status; Gem, gemcitabine; NabP, nab-paclitaxel; FLOX, bolus 5-FU plus oxaliplatin; FLIRI, bolus 5-FU plus irinotecan.\n\nFigure 2 Histologic haematoxylin- and eosin-stained paraffin section of the patient's primary tumour (a) and detailed image of lymphatic invasion and tumour morphology (b).\n\nFigure 3 Liver metastases: the lesion in segment 6 was treated with microwave ablation (a), and the lesion in segment 5 was treated with RFA (b).\n\nFigure 4 PET-CT evaluation of the response to first-line palliative chemotherapy showed disease progression with lung metastasis. PET-CT (left column) and CT (middle column) images. Top right inset: higher magnification image and measurement of the lesion. The SUVmax of the lesion was 9.7.\n\nFigure 5 No change in the liver metastasis in segment 6 was observed upon evaluation of the response to first-line palliative chemotherapy. PET-CT (left column) and CT (right column) images. The SUVmax was 5.5 for the lesion and 3.1 for the surrounding liver.\n\nFigure 6 PET-CT images showing a complete radiological response of the lung metastasis. PET-CT (left column) and CT (right column) images.\n==== Refs\n1 Siegel R. L. Miller K. D. Jemal A. Cancer statistics, 2017 CA: A Cancer Journal for Clinicians 2017 67 1 7 30 10.3322/caac.21387 2-s2.0-85008220577 28055103 \n2 Bergman O. Jaresand M. Cancerfondsrapporten 2018 Stockholm, Sweden The Swedish Cancer Society \n3 Katz M. H. G. Pisters P. W. T. Lee J. E. Fleming J. B. Borderline resectable pancreatic cancer: what have we learned and where do we go from here? Annals of Surgical Oncology 2011 18 3 608 610 10.1245/s10434-010-1460-y 2-s2.0-79955707335 21136179 \n4 Neoptolemos J. P. Stocken D. D. Bassi C. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection JAMA 2010 304 10 1073 1081 10.1001/jama.2010.1275 2-s2.0-77956416112 20823433 \n5 Hishinuma S. Ogata Y. Tomikawa M. Ozawa I. Hirabayashi K. Igarashi S. Patterns of recurrence after curative resection of pancreatic cancer, based on autopsy findings Journal of Gastrointestinal Surgery 2006 10 4 511 518 10.1016/j.gassur.2005.09.016 2-s2.0-33646055453 16627216 \n6 Neoptolemos J. P. Palmer D. Ghaneh P. ESPAC-4: a multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine (GEM) and capecitabine (CAP) versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma Journal of Clinical Oncology 2016 34 18_suppl LBA4006 10.1200/jco.2016.34.18_suppl.lba4006 \n7 Silvestris N. Longo V. Cellini F. Neoadjuvant multimodal treatment of pancreatic ductal adenocarcinoma Critical Reviews in Oncology/Hematology 2016 98 309 324 10.1016/j.critrevonc.2015.11.016 2-s2.0-84957638630 26653573 \n8 Silvestris N. Brunetti O. Vasile E. Multimodal treatment of resectable pancreatic ductal adenocarcinoma Critical Reviews in Oncology/Hematology 2017 111 152 165 10.1016/j.critrevonc.2017.01.015 2-s2.0-85014128206 28259290 \n9 Tol J. A. M. G. Eshuis W. J. Besselink M. G. H. van Gulik T. M. Busch O. R. C. Gouma D. J. Non-radical resection versus bypass procedure for pancreatic cancer—a consecutive series and systematic review European Journal of Surgical Oncology (EJSO) 2015 41 2 220 227 10.1016/j.ejso.2014.11.041 2-s2.0-84921607762 25511567 \n10 Ducreux M. Cuhna A. S. Caramella C. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Annals of Oncology 2015 26 Suppl 5 v56 v68 10.1093/annonc/mdv295 2-s2.0-84941646402 26314780 \n11 Tempero M. A. Malafa M. P. Al-Hawary M. Pancreatic adenocarcinoma, version 2.2017, NCCN clinical practice guidelines in oncology Journal of the National Comprehensive Cancer Network 2017 15 8 1028 1061 10.6004/jnccn.2017.0131 2-s2.0-85027279361 28784865 \n12 Bergman O. Johansson E. Cancer I Siffror 2018 2018 Stockholm, Sweden Socialstyrelsen \n13 Patel M. The impact of epidemiological factors and treatment interventions on survival in patients with signet ring cell carcinoma of the pancreas American Journal of Clinical Oncology 2018 41 12 1176 1184 10.1097/COC.0000000000000447 2-s2.0-85056802150 29672365 \n14 Poultsides G. A. Reddy S. Cameron J. L. Histopathologic basis for the favorable survival after resection of intraductal papillary mucinous neoplasm-associated invasive adenocarcinoma of the pancreas Annals of Surgery 2010 251 3 470 476 10.1097/sla.0b013e3181cf8a19 2-s2.0-77649125847 20142731 \n15 Von Hoff D. D. Ervin T Arena F. P Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine The New England Journal of Medicine 2013 369 369 1691 1703 10.1056/NEJMoa1304369 2-s2.0-84886741654 24131140 \n16 Blomstrand H. Scheibling U. Bratthäll C. Green H. Elander N. O. Real world evidence on gemcitabine and nab-paclitaxel combination chemotherapy in advanced pancreatic cancer BMC Cancer 2019 19 1 p. 40 10.1186/s12885-018-5244-2 2-s2.0-85059796050 \n17 Oettle H. Riess H. Stieler J. M. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial Journal of Clinical Oncology 2014 32 23 2423 2429 10.1200/jco.2013.53.6995 2-s2.0-84905817411 24982456 \n18 Gill S. Ko Y.-J. Cripps C. PANCREOX: a randomized phase III study of fluorouracil/leucovorin with or without oxaliplatin for second-line advanced pancreatic cancer in patients who have received gemcitabine-based chemotherapy Journal of Clinical Oncology 2016 34 32 3914 3920 10.1200/jco.2016.68.5776 2-s2.0-84995527140 27621395 \n19 Rahma O. E. Duffy A. Liewehr D. J. Steinberg S. M. Greten T. F. Second-line treatment in advanced pancreatic cancer: a comprehensive analysis of published clinical trials Annals of Oncology 2013 24 8 1972 1979 10.1093/annonc/mdt166 2-s2.0-84881239893 23670093 \n20 Vienot A. Beinse G. Louvet C. Overall survival prediction and usefulness of second-line chemotherapy in advanced pancreatic adenocarcinoma JNCI: Journal of the National Cancer Institute 2017 109 10 10.1093/jnci/djx037 2-s2.0-85029679945 \n21 Lykoudis P. M. O’Reilly D. Nastos K. Fusai G. Systematic review of surgical management of synchronous colorectal liver metastases British Journal of Surgery 2014 101 6 605 612 10.1002/bjs.9449 2-s2.0-84898541040 24652674 \n22 Sun Z. Thacker J. M. Contemporary surgical options for metastatic colorectal cancer Current Oncology Reports 2015 17 4 p. 13 10.1007/s11912-015-0437-1 2-s2.0-84923667111 \n23 Månsson C. Brahmstaedt R. Nygren P. Nilsson A. Urdzik J. Karlson B.-M. Percutaneous irreversible electroporation as first-line treatment of locally advanced pancreatic cancer Anticancer Research 2019 39 5 2509 2512 10.21873/anticanres.13371 2-s2.0-85066440309 31092446 \n24 Scheffer H. J. Melenhorst M. C. A. M. Echenique A. M. Irreversible electroporation for colorectal liver metastases Techniques in Vascular and Interventional Radiology 2015 18 3 159 169 10.1053/j.tvir.2015.06.007 2-s2.0-84941267640 26365546 \n25 Facciorusso A. Di Maso M. Muscatiello N. Microwave ablation versus radiofrequency ablation for the treatment of hepatocellular carcinoma: a systematic review and meta-analysis International Journal of Hyperthermia 2016 32 3 339 344 10.3109/02656736.2015.1127434 2-s2.0-84955083837 26794414 \n26 Takahashi H. Kahramangil B. Kose E. Berber E. A comparison of microwave thermosphere versus radiofrequency thermal ablation in the treatment of colorectal liver metastases HPB 2018 20 12 1157 1162 10.1016/j.hpb.2018.05.012 2-s2.0-85048760605 29929785\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2020()",
"journal": "Case reports in gastrointestinal medicine",
"keywords": null,
"medline_ta": "Case Rep Gastrointest Med",
"mesh_terms": null,
"nlm_unique_id": "101580185",
"other_id": null,
"pages": "4138215",
"pmc": null,
"pmid": "32099693",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "16627216;24652674;27621395;28784865;25511567;20823433;26365546;28259290;31092446;29929785;23670093;26653573;29672365;28055103;24131140;26314780;28383673;24982456;21136179;30621618;26794414;25708798;20142731",
"title": "Complete Radiologic Response of Metastatic Pancreatic Ductal Adenocarcinoma to Microwave Ablation Combined with Second-Line Palliative Chemotherapy.",
"title_normalized": "complete radiologic response of metastatic pancreatic ductal adenocarcinoma to microwave ablation combined with second line palliative chemotherapy"
} | [
{
"companynumb": "SE-ACCORD-175589",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "Niemann-Pick disease type C (NPC) is a rare, autosomal recessive neurodegenerative disease, characterized by progressive psychiatric and neurological deficits. Neurological symptoms include cognitive decline and dysphagia. Aspiration pneumonia secondary to dysphagia is a leading cause of death in NPC. Miglustat is currently the only approved disease-specific treatment shown to be effective in stabilizing neurological symptoms. Miglustat has previously been reported to halt or improve early dysphagia and cognitive symptoms. Here we examine the characteristics of dysphagia, the relationship between dysphagia and the presence of cognitive impairment, and longitudinal changes in swallowing function during miglustat treatment in adult-and-adolescent-onset NPC. Retrospective analysis of videofluoroscopic swallow studies (VFSS) was completed for ten adults with NPC (mean age 28.44 years ± 9.34 years). Participants were recruited through the Royal Melbourne Hospital in Australia between 2008 and 2015. The Bethlehem Swallowing Scale and the Penetration-Aspiration Scale were used to quantify VFSS data. Dysphagia was present in 90% of participants at baseline with reduced lingual function and a delayed swallowing reflex as the most common symptoms. Swallow impairment appeared to stabilize during miglustat therapy for periods up to 66 months, with no significant changes in scores (p > 0.05). Data were in accordance with the literature and support the use of miglustat as an efficacious treatment for reducing swallowing impairment and stabilizing cognitive function. Findings provide detailed information on the impairments experienced by patients, give context to events leading to aspiration in NPC and, importantly, inform how management of dysphagia can complement pharmaceutical treatment.",
"affiliations": "Centre for Neuroscience of Speech, The University of Melbourne, 550 Swanston Street, Parkville, Melbourne, VIC, 3010, Australia.;Centre for Neuroscience of Speech, The University of Melbourne, 550 Swanston Street, Parkville, Melbourne, VIC, 3010, Australia.;Centre for Neuroscience of Speech, The University of Melbourne, 550 Swanston Street, Parkville, Melbourne, VIC, 3010, Australia.;Department of Speech Pathology, Monash Health, Melbourne, Australia.;Neuropsychiatry Unit, Royal Melbourne Hospital, Parkville, Australia.;Neuropsychiatry Unit, Royal Melbourne Hospital, Parkville, Australia.;Centre for Neuroscience of Speech, The University of Melbourne, 550 Swanston Street, Parkville, Melbourne, VIC, 3010, Australia. vogela@unimelb.edu.au.",
"authors": "Lewis|Courtney|C|;Keage|Megan|M|;Watanabe|Miyuki|M|;Schubiger|Danielle|D|;Velakoulis|Dennis|D|;Walterfang|Mark|M|;Vogel|Adam P|AP|0000-0002-3505-2631",
"chemical_list": "D004791:Enzyme Inhibitors; D017485:1-Deoxynojirimycin; C059896:miglustat",
"country": "United States",
"delete": false,
"doi": "10.1007/s00455-020-10145-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0179-051X",
"issue": "36(3)",
"journal": "Dysphagia",
"keywords": "Cognition; Deglutition; Deglutition disorders; Niemann-Pick disease type C; Treatment; Videofluoroscopy",
"medline_ta": "Dysphagia",
"mesh_terms": "D017485:1-Deoxynojirimycin; D000293:Adolescent; D000328:Adult; D003679:Deglutition; D003680:Deglutition Disorders; D004791:Enzyme Inhibitors; D006801:Humans; D019636:Neurodegenerative Diseases; D052556:Niemann-Pick Disease, Type C; D012189:Retrospective Studies",
"nlm_unique_id": "8610856",
"other_id": null,
"pages": "362-373",
"pmc": null,
"pmid": "32562141",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Characterization of Dysphagia and Longitudinal Changes in Swallowing Function in Adults with Niemann-Pick Disease Type C Treated with Miglustat.",
"title_normalized": "characterization of dysphagia and longitudinal changes in swallowing function in adults with niemann pick disease type c treated with miglustat"
} | [
{
"companynumb": "AU-JNJFOC-20210613778",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MIGLUSTAT"
},
"drugadditional": null,
"... |
{
"abstract": "Acute myeloid leukemia (AML) is primarily a disease of older adults. Many older patients with AML are not candidates for intensive chemotherapy regimens aimed at inducing remission before transplantation. The prognosis for this patient population remains poor, with 5-year overall survival (OS) rates of less than 10 %. At present, there is no standard of care, and clinical trials should be considered. Hypomethylating agents often are the mainstay of treatment in this setting; however, improved genetic profiling and risk stratification based on molecular, biological, and clinical characteristics of AML enhance the ability to identify an individual patient's risk and can refine therapeutic options. Over the past 2 years, several novel agents have been approved for AML patients in either the frontline or relapsed settings. Additional agents have also shown promising activity. It is becoming a challenge for physicians to navigate these different options and select the optimal therapy or combination of therapies. The aim of this review is to summarize the available information to assist with treatment decisions for leukemia patients who are not suitable for intensive chemotherapy.",
"affiliations": "Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, USA. Electronic address: Elizabeth.Griffiths@RoswellPark.org.;Taussig Cancer Institute, Cleveland Clinic, 10900 Euclid Ave, Cleveland, OH, USA. Electronic address: carrawh@ccf.org.;University of Miami, Coral Gables, FL, USA. Electronic address: nxc691@med.miami.edu.;Smilow Cancer Center at Yale New Haven Hospital, 35 Park Street, New Haven, CT, USA. Electronic address: thomas.prebet@yale.edu.",
"authors": "Griffiths|Elizabeth A|EA|;Carraway|Hetty E|HE|;Chandhok|Namrata S|NS|;Prebet|Thomas|T|",
"chemical_list": "D001562:Benzimidazoles; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010671:Phenylurea Compounds; D011725:Pyridines; D013449:Sulfonamides; D003561:Cytarabine; D000077209:Decitabine; D000079982:Gemtuzumab; D019311:Staurosporine; C059539:midostaurin; C000592580:glasdegib; D001374:Azacitidine; C579720:venetoclax; C000627630:ivosidenib; D005998:Glycine",
"country": "England",
"delete": false,
"doi": "10.1016/j.leukres.2020.106339",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-2126",
"issue": "91()",
"journal": "Leukemia research",
"keywords": "Acute myeloid leukemia; Elderly; Hypomethylating agents; Mutations; Targeted agents",
"medline_ta": "Leuk Res",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine; D001562:Benzimidazoles; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003561:Cytarabine; D000077209:Decitabine; D000079982:Gemtuzumab; D005998:Glycine; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D058990:Molecular Targeted Therapy; D010671:Phenylurea Compounds; D057285:Precision Medicine; D011725:Pyridines; D012008:Recurrence; D012074:Remission Induction; D019311:Staurosporine; D013449:Sulfonamides",
"nlm_unique_id": "7706787",
"other_id": null,
"pages": "106339",
"pmc": null,
"pmid": "32146154",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Advances in non-intensive chemotherapy treatment options for adults diagnosed with acute myeloid leukemia.",
"title_normalized": "advances in non intensive chemotherapy treatment options for adults diagnosed with acute myeloid leukemia"
} | [
{
"companynumb": "US-BAYER-2020-053006",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAnalysis of K- and N-RAS mutations is mandatory before planning treatment of metastatic colorectal cancer, because only RAS wild-type (WT) patients can benefit from treatment with anti-EGFR monoclonal antibodies (cetuximab and panitumumab).\n\n\nMETHODS\nHere we report the case of a 69-year-old male patient affected by metastatic sigmoid cancer. He underwent left hemicolectomy, and histology diagnosed a well-differentiated, pT4, node-positive adenocarcinoma; KRAS analysis performed with direct sequencing identified a mutation in exon 2 of the KRAS gene (GGT->GTT). After first-line chemotherapy with FOLFOX6 plus bevacizumab, the patient underwent surgical resection of residual liver metastases. Histology showed metastatic deposits from colic adenocarcinoma with extensive coagulative necrosis. Mutational analysis of the KRAS gene was also performed on liver metastases by pyrosequencing assay, and no mutation was identified. Due to the discordant results (GGT->GTT exon 2 KRAS mutation in the primary tumor, and KRAS-WT in the liver metastases), mutational analysis on liver metastasis was repeated using next-generation sequencing and enriching the sample in tumor cells by manual microdissection; the same type of mutation of the primary tumor (GGT->GTT exon 2 KRAS gene) was confirmed.\n\n\nCONCLUSIONS\nAccurate tissue sampling and adequately sensitive assays are essential to correctly identify colorectal cancer patients who can be treated with an anti-EGFR monoclonal antibody.",
"affiliations": "Department of Clinical Medicine and Surgery, Federico II University, Naples - Italy.;Department of Clinical Medicine and Surgery, Federico II University, Naples - Italy.;Department of Public Health, Federico II University, Naples - Italy.;Division of Pathological Anatomy and Histology, Catholic University of the Sacred Heart, Rome - Italy.;Department of Clinical Medicine and Surgery, Federico II University, Naples - Italy.;Department of Clinical Medicine and Surgery, Federico II University, Naples - Italy.;Department of Clinical Medicine and Surgery, Federico II University, Naples - Italy.;Division of Pathological Anatomy and Histology, Catholic University of the Sacred Heart, Rome - Italy.;Department of Public Health, Federico II University, Naples - Italy.;Department of Clinical Medicine and Surgery, Federico II University, Naples - Italy.;Department of Public Health, Federico II University, Naples - Italy.;Department of Clinical Medicine and Surgery, Federico II University, Naples - Italy.",
"authors": "De Stefano|Alfonso|A|;Rosanova|Mario|M|;Malapelle|Umberto|U|;Martini|Maurizio|M|;De Falco|Stefano|S|;Attademo|Laura|L|;Fiore|Giovanni|G|;Cenci|Tonia|T|;Bellevicine|Claudio|C|;De Placido|Sabino|S|;Troncone|Giancarlo|G|;Carlomagno|Chiara|C|",
"chemical_list": "C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002955:Leucovorin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.5301/ijbm.5000273",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0393-6155",
"issue": "32(4)",
"journal": "The International journal of biological markers",
"keywords": null,
"medline_ta": "Int J Biol Markers",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003110:Colonic Neoplasms; D005091:Exons; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D009154:Mutation; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins",
"nlm_unique_id": "8712411",
"other_id": null,
"pages": "e474-e477",
"pmc": null,
"pmid": "28665451",
"pubdate": "2017-10-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Discordance in RAS mutations between primary colon tumor and metastases: a real event or a matter of methodology?",
"title_normalized": "discordance in ras mutations between primary colon tumor and metastases a real event or a matter of methodology"
} | [
{
"companynumb": "IT-PFIZER INC-2017516579",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AFLIBERCEPT"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nAcute pulmonary thromboembolism (PTE) is a life-threatening disease. Mortality in PTE still remains very high in spite of progress in diagnostic tools. Mortality rate is about 30% in patients with unrecognized acute PTE.\n\n\nMETHODS\nIt is a single center observational study of 31 consecutive patients who were hospitalized in the Department of Cardiology at MS Ramaiah Memorial hospital between January 1, 2010 and June 2015. All the patients confirmed with diagnosis of acute PTE by CT scan (either HRCT or CTPA) were included in the study. Following relevant investigations chosen patients were risk stratified as per standard guidelines into massive, sub massive or low risk and treated accordingly. The included patients were followed up for a period of 1 year with 2D-echocardiogram and other relevant investigations for comparison to assess improvement. Mortality due to either acute PTE or other causes was noted in the study.\n\n\nRESULTS\nOf the 31 patients enrolled in our study, 71% (n=22) of the patients belonged to the age range 20-50 years with those in the age group 31-40 years comprising 39% (n=12) of the total. Elderly people over 65 years of age comprised only 19% (n=6) of the total number of patients. Dyslipidemia, prolonged immobilization, deep vein thrombosis, post-operative state, malignancy and post-partum period were the commonly reported risk factors. We thrombolysed a total of 18 (58%) patients with massive and submassive PTE, of which 12 (39%) received tenecteplase and 6 patients received streptokinase (19%). Three (9%) patients required repeat thrombolysis with streptokinase due to failed thrombolytic therapy with tenecteplase.\n\n\nCONCLUSIONS\nOur study reported higher incidence of acute PTE in the middle age group population. Prevalence of dyslipidemia was high in this cohort of patients studied although the exact association of it in APE could not be determined. Thrombolytic therapy can be considered for patients with both massive and submassive pulmonary thromboembolism. Repeat thrombolysis can be considered in case one thrombolytic agent failed to give the desirable results.",
"affiliations": "Department of Cardiology, MS Ramaiah Medical College, MS Ramaiah Memorial Hospital, Bangalore, Karnataka, India. Electronic address: nmalesh@yahoo.co.in.;Department of Cardiology, MS Ramaiah Medical College, MS Ramaiah Memorial Hospital, Bangalore, Karnataka, India.;Department of Cardiology, MS Ramaiah Medical College, MS Ramaiah Memorial Hospital, Bangalore, Karnataka, India.;Department of Cardiology, MS Ramaiah Medical College, MS Ramaiah Memorial Hospital, Bangalore, Karnataka, India.;Department of Cardiology, MS Ramaiah Medical College, MS Ramaiah Memorial Hospital, Bangalore, Karnataka, India.;Department of Cardiology, MS Ramaiah Medical College, MS Ramaiah Memorial Hospital, Bangalore, Karnataka, India.",
"authors": "Nagamalesh|U M|UM|;Prakash|V S|VS|;Naidu|K C Karthik|KCK|;Sarthak|S|S|;Hegde|Anupama V|AV|;Abhinay|T|T|",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "India",
"delete": false,
"doi": "10.1016/j.ihj.2016.08.010",
"fulltext": "\n==== Front\nIndian Heart JIndian Heart JIndian Heart Journal0019-4832Elsevier S0019-4832(16)30397-210.1016/j.ihj.2016.08.010Original ArticleAcute pulmonary thromboembolism: Epidemiology, predictors, and long-term outcome – A single center experience Nagamalesh U.M. nmalesh@yahoo.co.in⁎Prakash V.S. Naidu K.C. Karthik Sarthak S. Hegde Anupama V. Abhinay T. Department of Cardiology, MS Ramaiah Medical College, MS Ramaiah Memorial Hospital, Bangalore, Karnataka, India⁎ Corresponding author at: Department of Cardiology, MS Ramaiah Memorial Hospital, MSRIT Post, Bangalore, Karnataka 560054, India.Department of Cardiology, MS Ramaiah Memorial HospitalMSRIT PostBangaloreKarnataka560054India nmalesh@yahoo.co.inMar-Apr 2017 12 10 2016 69 2 160 164 31 3 2016 23 8 2016 © 2016 Published by Elsevier B.V. on behalf of Cardiological Society of India.2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nAcute pulmonary thromboembolism (PTE) is a life-threatening disease. Mortality in PTE still remains very high in spite of progress in diagnostic tools. Mortality rate is about 30% in patients with unrecognized acute PTE.\n\nMethods\nIt is a single center observational study of 31 consecutive patients who were hospitalized in the Department of Cardiology at MS Ramaiah Memorial hospital between January 1, 2010 and June 2015. All the patients confirmed with diagnosis of acute PTE by CT scan (either HRCT or CTPA) were included in the study. Following relevant investigations chosen patients were risk stratified as per standard guidelines into massive, sub massive or low risk and treated accordingly. The included patients were followed up for a period of 1 year with 2D-echocardiogram and other relevant investigations for comparison to assess improvement. Mortality due to either acute PTE or other causes was noted in the study.\n\nResults\nOf the 31 patients enrolled in our study, 71% (n = 22) of the patients belonged to the age range 20–50 years with those in the age group 31–40 years comprising 39% (n = 12) of the total. Elderly people over 65 years of age comprised only 19% (n = 6) of the total number of patients. Dyslipidemia, prolonged immobilization, deep vein thrombosis, post-operative state, malignancy and post-partum period were the commonly reported risk factors. We thrombolysed a total of 18 (58%) patients with massive and submassive PTE, of which 12 (39%) received tenecteplase and 6 patients received streptokinase (19%). Three (9%) patients required repeat thrombolysis with streptokinase due to failed thrombolytic therapy with tenecteplase.\n\nConclusions\nOur study reported higher incidence of acute PTE in the middle age group population. Prevalence of dyslipidemia was high in this cohort of patients studied although the exact association of it in APE could not be determined. Thrombolytic therapy can be considered for patients with both massive and submassive pulmonary thromboembolism. Repeat thrombolysis can be considered in case one thrombolytic agent failed to give the desirable results.\n\nKeywords\nAcute pulmonary embolismDeep vein thrombosisRisk stratificationTroponin TThrombolysis\n==== Body\n1 Introduction\nAcute pulmonary embolism (PE) is a common and potentially lethal form of venous thromboembolism (VTE) which is commonly encountered in clinical practice. Most patients die of this fatal condition usually within the first 1 h of the event with mortality rate reaching nearly 10% during this period.1 Mortality rate of diagnosed and treated pulmonary embolism ranges from 3 to 8%, but increases to about 30% in untreated pulmonary embolism.1 In the United States, acute pulmonary embolism afflicts 500,000–600,000 persons annually and is either a primary or secondary cause of death in 150,000–200,000 of these individuals.2 The 1-year mortality rate in the PIOPED study was reported as ≈25%, with 2.5% dying from primary cause as pulmonary embolism itself.3 Other studies have reported that in patients without preexisting cardiac or pulmonary disease, the 1-year mortality rate ranged from 3% to 9%.4, 5 Mortality in APE is mainly reported to be due the associated comorbid conditions like cancer, infections, cardiovascular diseases, and other pulmonary diseases.6\n\nThe varied clinical presentation of this condition makes the diagnosis challenging, treatment diverse and results unpredictable with subsequent high morbidity and mortality. The condition is often suspected in patients who present with unexplained dyspnea, tachypnea, or chest pain. Further, a background of high risk predisposing conditions like malignancy, immobilization, recent major surgery, orthopedic surgeries and others warrant an urgent investigation when APE is clinically suspected.\n\nDespite therapeutic and diagnostic advances, the data from developing countries are largely lacking with respect to diagnostic and treatment efficacy and also there is insufficient data of long-term follow-up of those treated.\n\nOur study was conducted to understand the clinical profile of patients with APE and its response to standard guideline based treatment. Further, the patients who were successfully treated were followed up long-term to understand the overall long-term benefit achieved.\n\n2 Methods\nIt was a single center observational study conducted at MS Ramaiah Memorial hospital. The study began in January 2010 and recruitment of patients concluded on June 2014. However, data collection on long-term follow-up concluded on June 2015, i.e., after 1 year of the last date of recruitment period.\n\nAll the patients with clinically suspected APE were assessed with Well's Criteria. Those with likely APE on Well's criteria were investigated further with D-dimer testing and diagnosis of APE was finally confirmed by CT scan (either HRCT or CTPA). Patients who were admitted in our cardiac intensive care following an established diagnosis were only included for the study as it needed close monitoring of treatment response of these patients. Also it enabled us to study the clinical parameters in greater detail at baseline and further helped to enroll them for long-term follow-up. Patients with diagnosis of APE who had already received treatment before reaching the study center, those with previous diagnosis of Acute PTE irrespective of their current treatment status, patients with suspected diagnosis of APE who died before a diagnosis could be established, those who did not consent for CT imaging and patients with non-availability of baseline data or long-term follow-up data were again excluded.\n\nA total of 38 patients with suspected PTE were identified during the study period. Out of this, two patients did not consent for enrollment. Five patients were critically ill with significant co-morbidities (mainly renal dysfunction) which made them unsuitable for CTPA and were treated on the basis of clinical suspicion only. After satisfying the necessary criteria we were able to recruit 31 patients during the study period. A detailed record of clinical profile of all the patients included in the study was done. Baseline record of following investigations were made in common in all patients: complete hemogram, renal function tests, serum electrolyte assay, liver function tests, fasting lipid profile, thyroid profile, coagulation profile, ECG, 2D-echocardiogram, ultrasonography of abdomen and chest X-ray. Additional investigations were done as deemed necessary for identification of etiology and/or complications in specific group of patients. Chosen patients were risk stratified as per standard guidelines into massive, sub massive or low risk and treated as per current guidelines. The included patients were followed up for a period of 1 year with 2D-echocardiogram and other relevant investigations for comparison to assess improvement. Mortality due to either acute PTE or other causes was noted in the study.\n\nStatistical analysis was done and continuous variables were presented as mean, and ordinal variables as percentages.\n\n3 Results\nOf the 31 patients enrolled in our study, 71% (n = 22) of the patients belonged to the age range 20–50 years (Table 1). 39% (n = 12) of the total belonged to age range 31–40 years. Elderly over 65 years of age comprised 19% (n = 6) of the total. Sex difference was also noticed with APE being observed to be more common among male patients (58%) (Fig. 1).\n\nDyslipidemia, prolonged immobilization, deep vein thrombosis, post-operative state, malignancy and post-partum period were the commonly reported risk factors in our study population (Fig. 2). Dyslipidemia was identified in 42% (n = 13) of our patients although the clinical significance of dyslipidemia as a risk factor is yet to be clearly established. 35% (n = 11) of the patients reported prolonged immobilization prior to the event with over 50% (n = 6) of them being the elderly over 65 years of age. The reasons for prolonged immobilization were mainly recent long travels, serious illnesses, and musculoskeletal causes with the latter being more commonly reported among the elderly.\n\nDyspnea was the most common symptom reported at presentation in all the 31 patients. Additionally reported symptoms included palpitations (71%, n = 22) syncope (32%, n = 10) and chest pain (29%, n = 9) (Fig. 3). The most common clinical sign was tachycardia (58%, n = 18) and tachypnea (32%, n = 10). Patients with dyspnea on clinical assessment had NYHA Class II or more symptoms at presentation. Following treatment when these patients were reassessed for NYHA functional class at the end of 1 year, 74% (n = 23) of the patients showed significant improvement of their functional class to NYHA Class I. Out of the 35% (n = 11) patients who were in NYHA Class IV at admission, nearly 81.8% patients (n = 9) showed significant improvement of their functional status to NYHA III or less at 1 year (Table 2; Fig. 4).\n\n2D echocardiography was used for assessing the parameters like pulmonary artery pressure and RV dilatation. These parameters were easily available for comparison during future follow-up. During follow-up 26% (n = 8) of patients had persistently elevated pulmonary artery pressure and 32% (n = 10) patients had RV dilatation even after 1 year of treatment of APE (Table 3). Out of this, three patients had clinical features of progressive right heart failure.\n\nIn our study all the patients with suspected APE on initial assessment were subjected to CTPA, Echocardiography and troponin T. Based on the findings patients were classified as massive, sub-massive and low risk groups.\n\nAcute PE with sustained hypotension with SBP <90 mmHg for at least 15 min or requiring inotropic support were considered as massive PTE, which consists of 26% (08) of patients. Submissive PE patients were those with APE without systemic hypotension (SBP ≥90 mmHg) but with either RV dysfunction or myocardial necrosis, which consisted 32% of patients (10). Mild APE formed the remainder group of patients (41%, n = 13) (Fig. 5).\n\nWe thrombolysed a total of 18 (58%) patients majority of whom had massive or submassive PTE, of which 12 (39%) received tenecteplase and 6 patients received streptokinase (19%). Three (9%) patients required repeat thrombolysis with streptokinase due to failed thrombolytic therapy with tenecteplase (Table 4).\n\nIn view of persistent elevated PA pressure and early RV dysfunction two patients underwent pulmonary endarterectomy after 6 months of index event. They are under follow-up with normal PA pressure and normal RV function. None of them were sent for surgical embolectomy. 16% (n = 5) patients were put IVC Filter after careful clinical assessment to prevent recurrent PE (Table 5).\n\nOverall reported mortality rate was 6% (n = 2). One patient with massive pulmonary embolism died in hospital after thrombolysis due to persistent hypoxia, bleeding and shock. The second patient died after few weeks at home. He had minor PTE with no DVT and was on oral anticoagulation. The exact cause of death in him could not be reached. Overall 52% (n = 16) of the subjects presented with shock at admission or within 48 h following admission. Out this 50% (n = 8) required inotropic support to maintain stable hemodynamics (Table 4). The duration of requirement of inotropic support varied from 24 h to 96 h with mean of 48 h. Inotropic support for maintaining blood pressure was common in patients with massive and sub massive APE (n = 6). One patient developed profound irreversible shock and respiratory failure requiring inotropic support and mechanical ventilation. This patient had massive APE and was treated with thrombolytic therapy. Overall, 10% (n = 3) of the patients with massive APE required mechanical ventilation with one reported mortality. Bleeding following intravenous thrombolysis was noted in four patients (13%) with one patient having massive bleeding episode requiring blood transfusion.\n\n4 Discussion\nThe incidence of venous thromboembolism (VTE), which includes PE and deep venous thrombosis (DVT), has remained relatively constant, with age- and sex-adjusted rates of 117 cases per 100,000 person-years.7, 8 VTE incidence rises sharply after age 60 in both men and women, with PE accounting for the majority of the increase.7, 8 Acute pulmonary embolism (APE) is a major cause of death associated with surgery, injury, and medical illnesses. The mortality rate associated with PE is underappreciated; if untreated, acute PE is associated with a significant mortality rate (as high as 30%) with two of three such people dying of APE die within the first 2 h of presentation.1 Mortality rate is up to 8% among those diagnosed and treated.1 In nearly 25% of patients with PE, the initial clinical manifestation is sudden death.7\n\nNumerous published studies have shown that the incidence of first-time VTE rises exponentially with age. In the patients between 50 and 59 years, Anderson reported the incidence of first time VTE of 62 per 100,000, and Silverstein et al. observed a much higher incidence of 122 per 100,000 among women and 147 per 100,000 among men.8 Between 70 and 79 years age group Anderson et al. reported 316 cases per 100,000 per year (35% recurrent); Silverstein et al. reported 440 cases per 100,000 per year.8 Nordström et al. overall estimated the cumulative probability of developing VTE between ages 50 and 80 at 10.7% for Swedish men.8 In our study, 71% of the patients belonged to age group 20–50 years with remaining 29% being over 50 years of age. In those patients over 50 years the pre-disposing factors leading to APE could be ascertained in most cases. However, the cause remained elusive many a times among the group <50 years of age.\n\nSex predilections for VTE have shown consistent differences in the incidence of VTE among both the sexes across different subsets of age groups. Anderson et al. found a similar incidence in both sexes.9, 10 Silverstein et al. reported slightly higher incidence rate among younger women, and a modest predilection among older men.8 Cushman et al. reported similar incidences among men and women except for a 2-fold higher rate in men over age 75.8 The ICOPER study had male predominance in incidence of pulmonary thromboembolism.11 Overall our study reported higher incidence of PTE among the male population (58% in males as against 42% in females). However, majority of this difference was due to higher incidence rates of PTE in elderly males. Among the young patient population of our study, there was no significant difference in PTE incidence in either population group.\n\nRisk factors that have been consistently associated with VTE include advanced age, prolonged immobility, malignancy, major surgery, polytrauma, prior VTE, and chronic heart failure. Major risk factors for pulmonary thromboembolism in our study were dyslipidemia 42%, prolonged immobilization 35% and DVT 26%.\n\nDue to lack of direct evidence for dyslipidemia it is difficult to attribute dyslipidemia as risk factor for PTE. However, the effects of circulating lipid molecules on the vascular endothelium, platelet function, and coagulation factors in DVT are yet to be elaborated. Better epidemiologic evidence is required to establish whether dyslipidemia is a risk factor for venous thromboembolism.\n\nThe clinical presentation of PE varies widely with dyspnea being most frequent presenting symptom. Symptoms vary from severe dyspnea, cyanosis, or syncope suggesting a massive PE while pleuritic pain, cough, or hemoptysis indicating a smaller peripherally located PE. On physical examination, tachypnea is the most common sign. All the patients in our study with APE presented with dyspnea with NYHA Class II or >. Palpitations (71%), chest pain (29%) and syncope (32%) were the other commonly reported symptoms. Tachycardia (58%, n = 18) and tachypnea (32%, n = 10) were the common signs noted. The presence of initial presenting symptoms and signs from our study were similar to most of the landmark trials. Following successful therapy, at the end of 1 year study period majority of the patients reported significant improvement in their symptoms with dyspnea improving from NYHA Class II or > to NYHA Class I (74%).\n\nRV dysfunction has been shown to predict disease recurrence and mortality. In a randomized controlled trial, Goldhaber et al.12 found RV function improved at 24 h in 16/18 thrombolysed patients compared with 8/18 treated with heparin.\n\nOn admission 26% of patients were classified as massive, 32% were submissive and 41% were low risk. In the ICOPER study, the 90-day mortality rate for patients with acute PE and systolic blood pressure <90 mmHg at presentation (108 patients) was 52.4% (95% confidence interval [CI] 43.3–62.1%).13 Similarly, in the Germany-based Management Strategy and Prognosis of Pulmonary Embolism Registry (MAPPET) of 1001 patients with acute PE, in-hospital mortality was 8.1% for hemodynamically stable patients versus 25% for those presenting with cardiogenic shock and 65% for those requiring cardiopulmonary resuscitation.14 In patients with low risk pulmonary embolism short-term mortality approach ≈1%. Risk stratification of the patients with APE helped define the population suitable for thrombolytic therapy. Data from four registries MAPPET, ICOPER, RIETE, and, EMPEROR have suggested a trend toward decrease in all-cause mortality from PE, especially massive PE in those patients treated with fibrinolysis.15 Konstantinides et al.15 found a 30 day mortality of 4.7% in 169 patients who received thrombolysis, compared with 11.1% in 550 who were treated with heparin. Recurrence rates were 7.7% and 18.7% respectively.\n\nIn our study, both massive and submissive group received thrombolytic therapy and low risk patients received low molecular weight heparin.\n\nSix trials with 481 patients have compared various thrombolytic regimens using rTPA, streptokinase, and urokinase, with rTPA being delivered over 2 h and urokinase and streptokinase delivered over 2–24 h.15, 16, 17, 18, 19, 20, 21 No agent has proved superior.\n\nAmong the 18 (58%) patients in our study, 39% received tenecteplase and 19% of patients received Streptokinase. In the tenecteplase group three patients (10%) had failed thrombolysis that was then treated with streptokinase. All those patients were maintaining normal pulmonary artery pressure and functional class at the end of study period. One of the single center study reported failed thrombolysis in 40 patients (8.2%) among the 488 APE patients who underwent thrombolysis.22 Out of this 14 patients were treated by rescue surgical embolectomy, and 26 were treated by repeat thrombolysis.22 There was no significant difference in the baseline characteristics of the two groups. However, there was significantly more recurrent PEs (fatal and nonfatal) in the repeat-thrombolysis group (35% versus 0%).22 The rate of uneventful long-term evolution was the same in the two groups.22 The questions whether thrombolytic therapy was really successful in our cohort of patients and whether failed thrombolytic therapy can be treated again with repeat thrombolysis with the different agent still remains to be answered. The small sample size of the study made it difficult to address the above issue clearly although clinically a benefit was noted in patients who were managed accordingly.\n\nTwo of the patients who received heparin therapy followed by oral anticoagulants for low risk PTE, later developed chronic PTE with severe PAH with exertional dyspnea Class III (NYHA) and RV dysfunction. These patients underwent pulmonary endarterectomy. They now have exertional dyspnea Class I/II (NYHA) and normal PA pressures. In a recent series >91.3% of the patients were in NYHA Functional Class III or IV before procedure and at 1 year after operation, 91.4% of patients were reclassified as NYHA Functional Class I or II.23 In addition, with the elimination of sustained pressure overload, RV geometry rapidly reverts toward normal.23\n\n5 Limitations\nThe small sample size and single center observation were the main limiting factors of our study. However, successful attempts were made to elaborately discuss most of the clinico-epidemiologic issues concerned with diagnosis and treatment of acute pulmonary thromboembolism. We also tried to address some of the key controversial issues concerned with failed thrombolytic therapy. Also, the role of other surgical and non-surgical interventions also could not be elaborated completely due to small sample size again.\n\nNevertheless, our study shows the potential for a future large scale multi-center trial in this regard and also gives a basic framework on which it can be further improvised to understand the clinico-epidemiologic aspects of APE.\n\n6 Conclusion\nAPE which was once a disease of the old and frail is now increasingly becoming common among the young and middle aged. APE still masquerades itself presenting in various clinical settings, and posing a great diagnostic challenge to the physician. A high degree of clinical suspicion with close observation of key clinical signs is needed to identify this entity. Diagnosed cases need to be risk stratified into mild, moderate and massive to plan appropriate treatment strategy. In case of failed thrombolysis a repeat thrombolysis can be considered before subjecting to definitive surgical approach, however, it needs further validation from more large scale studies.\n\nConflicts of interest\nThe authors have none to declare.\n\nFig. 1 Sex disribution.\n\nFig. 2 Risk factors for APE.\n\nFig. 3 Clinical features at presentation.\n\nFig. 4 NYHA class at admission and at 1 year.\n\nFig. 5 Classification of APE.\n\nTable 1 Age distribution of patients.\n\nTable 1Age group\tNumber of patients\tPercentage (%)\t\n20–30\t05\t16\t\n31–40\t12\t39\t\n41–50\t05\t16\t\n51–60\t03\t10\t\n>60\t06\t19\t\n\n\n\t\nTotal\t31\t100\t\nTable 2 NYHA class at admission and at 1-year follow-up.\n\nTable 2Functional class\tOn admission\tPercentage (%)\tAfter 1 year\tPercentage (%)\t\nNYHA I\t00\t00\t23\t74\t\nNYHA II\t08\t26\t03\t9\t\nNYHA III\t12\t39\t05\t16\t\nNYHA IV\t11\t35\t00\t00\t\nTable 3 Complications in ape.\n\nTable 3Sl. no.\tComplications\tNumber (n)\tPercentage (%)\t\n1\tReversible shock on admission\t8\t26\t\n2\tMechanical ventilation\t3\t10\t\n3\tAborted sudden cardiac death\t1\t3\t\n4\tShock requiring inotropic use\t8\t26\t\n5\tBleeding\t4\t13\t\n6\tElevated PA pressure after 1 year\t8\t26\t\n7\tRV dilatation/dysfunction after 1 year\t10\t32\t\nTable 4 Thrombolytic therapy.\n\nTable 4Thrombolytic drug\tNumber of patient\tPercentage (%)\t\nStreptokinase\t06\t19\t\nTenecteplase\t12\t39\t\nRepeat thrombolysis\t03\t10\t\nTable 5 Surgical management.\n\nTable 5Type of procedure\tNumber of patients\tPercentage (%)\t\nSurgical thrombectomy\t–\t–\t\nPulmonary endartectomy\t02\t6\t\nIVC filter\t05\t16\n==== Refs\nReferences\n1 Belohlávek J. Dytrych V. Linhart A. Pulmonary embolism. Part I. Epidemiology, risk factors and risk stratification, pathophysiology, clinical presentation, diagnosis and nonthrombotic pulmonary embolism Exp Clin Cardiol 18 Spring (2) 2013 129 138 23940438 \n2 Ansari A. Acute and chronic pulmonary thromboembolism: current perspectives. I. Glossary of terms, historic evolution and prevalence Clin Cardiol 9 1986 398 402 3524936 \n3 Worsley D.F. Alavi A. Comprehensive analysis of the results of the PIOPED study. Prospective Investigation of Pulmonary Embolism Diagnosis study J Nucl Med 36 December (12) 1995 2380 2387 8523135 \n4 Sutton G.C. Hall R.J.C. Kerr I.H. Clinical course and late prognosis of treated subacute massive, acute minor, and chronic pulmonary thromboembolism Br Heart J 39 1977 1135 1142 911566 \n5 MacIntyre D. Banham S.W. Moran F. Pulmonary embolism: long-term follow-up Postgrad Med J 58 1982 222 225 7111102 \n6 Carson J.L. Kelley M.A. Duff A. The clinical course of pulmonary embolism N Engl J Med 326 1992 1240 1245 1560799 \n7 Piazza G. Goldhaber S.Z. Acute pulmonary embolism. Part I. Epidemiology and diagnosis Circulation 114 2006 e28 e32 16831989 \n8 White R.H. The epidemiology of venous thromboembolism Circulation 107 2003 1 14 \n9 Anderson F.A. Jr. Wheeler H.B. Goldberg R.J. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT study Arch Intern Med 151 1991 933 938 2025141 \n10 Robert-Ebadi H. Gal G.L. Carrier M. Differences in clinical presentation of pulmonary embolism in women and men J Thromb Haemost 8 April (4) 2010 693 698 20096004 \n11 Goldhaber S.Z. Visani L. De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER) Lancet 353 April (9162) 1999 1386 1389 10227218 \n12 Goldhaber S.Z. Haire W.D. Feldstein M.L. Alteplase versus heparin in acute pulmonary embolism: randomized trial assessing right ventricular function and pulmonary perfusion Lancet 341 1993 507 511 8094768 \n13 Kucher N. Rossi E. De Rosa M. Goldhaber S.Z. Massive pulmonary embolism Circulation 113 2006 577 582 16432055 \n14 Kasper W. Konstantinides S. Geibel A. Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry J Am Coll Cardiol 30 1997 1165 1171 9350909 \n15 Konstantinides S. Giebel A. Oleschewski M. Association between thrombolytic treatment and the prognosis of haemodynamically stable patients with major pulmonary embolism – results of a multicenter registry Circulation 96 1997 882 888 9264496 \n16 USET phase 2 – urokinase–streptokinase trial: phase 2 results JAMA 229 1974 1606 1613 4408392 \n17 Goldhaber S. Kessler C. Heit J. Randomized controlled trial of rtPA versus urokinase in the treatment of acute pulmonary embolism Lancet 2 1988 293 298 2899718 \n18 Meyer G. Surs H. Charbonnier B. Effects of intravenous urokinase versus alteplase on the total pulmonary resistance in acute massive pulmonary embolism: a European double blind trial J Am Cardiol 19 1992 239 245 \n19 Goldhaber S. Kessler C. Heit J. Recombinant tissue-type plasminogen activator versus a novel dosing regimen of urokinase in acute pulmonary embolism: a randomized controlled multicenter trial J Am Coll Cardiol 20 1992 24 30 1607532 \n20 Meneveau N. Schiele F. Vuillemenot A. Streptokinase versus alteplase in massive PE: a randomized trial assessing right heart haemodynamics and pulmonary vascular obstruction Eur Heart J 18 1997 1141 1148 9243149 \n21 Meneveau N. Schiele F. Metz D. Comparative efficiency of a 2 hour regimen of streptokinase versus alteplase in acute massive pulmonary embolism: immediate clinical and haemodynamic outcomes and one year follow up J Am Coll Cardiol 31 1998 1057 1063 9562007 \n22 Meneveau N. Séronde M.F. Blonde M.C. Management of unsuccessful thrombolysis in acute massive pulmonary embolism Chest 129 April (4) 2006 1043 1050 16608956 \n23 Blanchard D.G. Malouf P.J. Gurudevan S.V. Utility of right ventricular Tei index in the noninvasive evaluation of chronic thromboembolic pulmonary hypertension before and after pulmonary thromboendarterectomy JACC Cardiovasc Imaging 2 2009 143 149 19356547\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0019-4832",
"issue": "69(2)",
"journal": "Indian heart journal",
"keywords": "Acute pulmonary embolism; Deep vein thrombosis; Risk stratification; Thrombolysis; Troponin T",
"medline_ta": "Indian Heart J",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D004562:Electrocardiography; D005260:Female; D005343:Fibrinolytic Agents; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007194:India; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011655:Pulmonary Embolism; D012189:Retrospective Studies; D012307:Risk Factors; D015912:Thrombolytic Therapy; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D014463:Ultrasonography; D055815:Young Adult",
"nlm_unique_id": "0374675",
"other_id": null,
"pages": "160-164",
"pmc": null,
"pmid": "28460762",
"pubdate": "2017",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "2899718;12814979;8523135;3524936;16432055;9243149;16608956;20096004;1607532;4408392;1732347;16831989;7111102;9264496;911566;23940438;9350909;8094768;1560799;2025141;9562007;19356547;10227218",
"title": "Acute pulmonary thromboembolism: Epidemiology, predictors, and long-term outcome - A single center experience.",
"title_normalized": "acute pulmonary thromboembolism epidemiology predictors and long term outcome a single center experience"
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"abstract": "To estimate the incidence of serious infections in patients with HIV infection and autoimmune disease who were treated with tumor necrosis factor (TNF) inhibitors, and to compare these rates by stratified viral load levels.\n\n\n\nUsing a unified search strategy, 4 centers identified HIV-infected patients exposed to TNF inhibitors. Patient characteristics and infection data were assessed via chart review in all patients who were ≥18 years old and who received TNF inhibitor therapy after HIV diagnosis, between January 1999 and March 2015.\n\n\n\nWe studied 23 patients with 26 uses of TNF inhibitor therapy (86.7 person-years of followup). Two (8.7%) experienced at least 1 serious infection episode, for an overall incidence rate of 2.55 per 100 patient-years (95% confidence interval [95% CI] 0.28-9.23). The incidence rate per 100 patient-years was 3.28 (95% CI 0.04-18.26) among patients with a viral load >500 copies/ml at therapy initiation and 2.09 (0.03-11.65) among patients with a viral load ≤500 copies/ml.\n\n\n\nThis study suggests that the rate of serious infections in patients with HIV infection under active care who have received treatment with TNF inhibitors may be comparable to the rates observed in registry databases.",
"affiliations": "Chiang Mai University, Chiang Mai, Thailand.;Johns Hopkins School of Medicine, Baltimore, Maryland.;Brigham and Women's Hospital, Boston, Massachusetts.;University of Miami School of Medicine, Miami, Florida.;Cleveland Clinic Foundation, Cleveland, Ohio.;Johns Hopkins School of Medicine, Baltimore, Maryland.;University of Miami School of Medicine, Miami, Florida.;Cleveland Clinic Foundation, Cleveland, Ohio.",
"authors": "Wangsiricharoen|Sintawat|S|;Ligon|Colin|C|;Gedmintas|Lydia|L|;Dehrab|Admad|A|;Tungsiripat|Marisa|M|;Bingham|Clifton|C|;Lozada|Carlos|C|;Calabrese|Leonard|L|",
"chemical_list": "D001688:Biological Products; D014409:Tumor Necrosis Factor-alpha",
"country": "United States",
"delete": false,
"doi": "10.1002/acr.22955",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2151-464X",
"issue": "69(3)",
"journal": "Arthritis care & research",
"keywords": null,
"medline_ta": "Arthritis Care Res (Hoboken)",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D000368:Aged; D001327:Autoimmune Diseases; D001688:Biological Products; D005260:Female; D015658:HIV Infections; D006801:Humans; D016867:Immunocompromised Host; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha; D014481:United States; D019562:Viral Load; D055815:Young Adult",
"nlm_unique_id": "101518086",
"other_id": null,
"pages": "449-452",
"pmc": null,
"pmid": "27332039",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "16325657;8656014;26774690;11040859;18079191;20674669;18093266;12079562;18657708;15075543;21172278;23467774;22776851;25632071;19940946",
"title": "Rates of Serious Infections in HIV-Infected Patients Receiving Tumor Necrosis Factor Inhibitor Therapy for Concomitant Autoimmune Diseases.",
"title_normalized": "rates of serious infections in hiv infected patients receiving tumor necrosis factor inhibitor therapy for concomitant autoimmune diseases"
} | [
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"companynumb": "PHHY2017US131053",
"fulfillexpeditecriteria": "1",
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"drug... |
{
"abstract": "Toxic epidermal necrolysis (TEN) is a severe, life-threatening disorder that usually affects adults. It is often drug induced. We report an instance of a severe case of TEN in a 6-year-old boy, probably induced by acetaminophen, and less likely by codeine. A lymphocyte stimulation test could not identify the culprit drug. Treatment with intravenous immunoglobulin seemed to halt the disease progression.",
"affiliations": "Department of Dermatology, Aarhus Amtssygehus, Skejby Hospital, Aarhus, Denmark.",
"authors": "Bygum|Anette|A|;Gregersen|Jon Waarst|JW|;Buus|Sanne Krogsbøll|SK|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D016756:Immunoglobulins, Intravenous; D000082:Acetaminophen",
"country": "United States",
"delete": false,
"doi": "10.1111/j.0736-8046.2004.21309.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "21(3)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D002648:Child; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "236-8",
"pmc": null,
"pmid": "15165202",
"pubdate": "2004",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acetaminophen-induced toxic epidermal necrolysis in a child.",
"title_normalized": "acetaminophen induced toxic epidermal necrolysis in a child"
} | [
{
"companynumb": "DK-RANBAXY-2014R1-91343",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CODEINE"
},
"drugadditional": null,
"... |
{
"abstract": "Primary pulmonary lymphoma is a rare entity. Furthermore, simultaneous bilateral spontaneous pneumothorax (SBSP) is a very rare condition which is often related to therapeutic complications. We present, to the best of our knowledge, the first case of primary pulmonary mucosa associated lymphoid tissue (MALT) lymphoma revealed by SBSP. A 50-year-old female was diagnosed with organizing pneumonia. One month later, she presented with sudden chest pain and shortness of breath due to SBSP. Bilateral chest tubes were inserted. A scan- guided right lung biopsy led to the diagnosis of primary pulmonary MALT lymphoma. The patient was treated with R-CHOP chemotherapy. The association between lymphoma and pneumothorax is extremely rare, often related to therapeutic toxicity. We report the case of SBSP as the first manifestation of primary pulmonary MALT lymphoma.",
"affiliations": "Pneumology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia.;Hematology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia.;Pathology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia.;Radiology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia.;Pneumology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia.;Hematology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia.;Pneumology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia.;Hematology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia.;Hematology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia.;Pneumology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia.;Pneumology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia.;Pneumology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia.",
"authors": "Migaou|Asma|A|;Slama|Nader|N|;Njima|Manel|M|;Achour|Asma|A|;Saad|Ahmed Ben|AB|;Boukhris|Sarra|S|;Fahem|Nesrine|N|;Dimassi|Sabrine|S|;Laatiri|Adnene|A|;Mhammed|Saoussen Cheikh|SC|;Rouatbi|Naceur|N|;Joobeur|Sameh|S|",
"chemical_list": "C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Uganda",
"delete": false,
"doi": "10.11604/pamj.2020.37.11.24494",
"fulltext": "\n==== Front\nPan Afr Med J\nPAMJ\nThe Pan African Medical Journal\n1937-8688 The African Field Epidemiology Network \n\nPAMJ-37-11\n10.11604/pamj.2020.37.11.24494\nCase Report\nSimultaneous bilateral spontaneous pneumothorax as the first manifestation of primary pulmonary MALT lymphoma\nMigaou Asma 1& Slama Nader 2 Njima Manel 3 Achour Asma 4 Saad Ahmed Ben 1 Boukhris Sarra 2 Fahem Nesrine 1 Dimassi Sabrine 2 Laatiri Adnene 2 Mhammed Saoussen Cheikh 1 Rouatbi Naceur 1 Joobeur Sameh 1 1 Pneumology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia,\n2 Hematology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia,\n3 Pathology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia,\n4 Radiology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia\nCorresponding author: Asma Migaou, Pneumology Department, Fattouma Bourguiba Hospital of Monastir, Avenue Farhat Hached, Monastir 5000, Tunisia. migaou.asma@gmail.com\n03 9 2020 \n2020 \n37 1122 6 2020 20 7 2020 Copyright: Asma Migaou et al.2020The Pan African Medical Journal (ISSN: 1937-8688). This is an Open Access article distributed under the terms of the Creative Commons Attribution International 4.0 License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Primary pulmonary lymphoma is a rare entity. Furthermore, simultaneous bilateral spontaneous pneumothorax (SBSP) is a very rare condition which is often related to therapeutic complications. We present, to the best of our knowledge, the first case of primary pulmonary mucosa associated lymphoid tissue (MALT) lymphoma revealed by SBSP. A 50-year-old female was diagnosed with organizing pneumonia. One month later, she presented with sudden chest pain and shortness of breath due to SBSP. Bilateral chest tubes were inserted. A scan- guided right lung biopsy led to the diagnosis of primary pulmonary MALT lymphoma. The patient was treated with R-CHOP chemotherapy. The association between lymphoma and pneumothorax is extremely rare, often related to therapeutic toxicity. We report the case of SBSP as the first manifestation of primary pulmonary MALT lymphoma.\n\nBilateral pneumothoraxpneumothoraxMALT lymphomaorganizing pneumonia\n==== Body\nIntroduction\nPrimary pulmonary lymphoma is a rare entity, which accounts for less than 1% of Non-Hodgkin´s lymphoma (NHL) and only 0.5 to 1% of primary pulmonary malignancies [1]. Primary pulmonary mucosa associated lymphoid tissue (MALT) lymphoma is the most common sub type of low grade primary pulmonary lymphoma [2]. Simultaneous bilateral spontaneous pneumothorax (SBSP) is usually due to an underlying lung disease which is rarely neoplastic (0.05%) dominated by sarcoma [3]. To the best of our knowledge, no cases of SBSP as the first manifestation of NHL have been reported. In this report, we present an unusual presentation of primary pulmonary MALT lymphoma revealed by SBSP.\n\nPatient and observation\nA 50-year-old non-smoker woman followed for bipolar disorder treated with Depakote and Prazepam for 7 months was, a month ago, diagnosed with organizing pneumonia. The diagnosis was based on the presence of a dry cough with stage 2 dyspnea on exertion and unexplained weight loss. Chest computed tomography (CT) scan showed bilateral and peripheral alveolar condensations with 2 left posterior basal air cysts. Laboratory tests did not objectify inflammatory syndrome. A compete blood count revealed lymphopenia. Serum protein electrophoresis, liver and renal function tests were unremarkable. Lactate dehydrogenase test and calcium levels were normal. Immunological assessment and the infectious disease tests were negative. No significant improvement was noted after antibiotherapy with levofloxacin. Divalproex Sodium induced organizing pneumonia was suspected and the treatment was stopped. In the presence of severe restriction in spirometry and hypoxemia on exertion, steroids were prescribed.\n\nBronchoalveolar lavage was not carried out due to significant respiratory repercussions. A slight improvement was noted under corticotherapy. One month later, she presented with sudden chest pain and shortness of breath due to SBSP (Figure 1, Figure 2). Immediately after diagnosis, bilateral chest tubes were inserted. The right one was removed after 24 hours and the left one after 48 hours when no air leak was evident. A scan-guided right lung biopsy was performed before the ablation of the drain, which led to the diagnosis of primary pulmonary MALT lymphoma. On immunohistochemistry, the tumor cells expressed CD20 (strong membrane positivity). They were immunonegative for CD3, CD5, CD10, CD23 and Cyclin D1 (Figure 3, Figure 4). Left pneumothorax recurred 7 days after. Left chest tube was inserted followed by pleurodesis by left pleural abrasion with partial thoracoscopic pleurectomy. The cervical and abdomino-pelvic CT scan did not show any other ganglionic or extra ganglionic lesions and the bone marrow biopsy was negative. The patient was treated with R-CHOP chemotherapy.\n\nFigure 1 A) bilateral pneumothorax on chest radiograph (arrows); B) chest radiograph after chest tubes removal; C) recurrence of the left pneumothorax\n\nFigure 2 (A+B+C) coronal and (D+E) transverse computed tomography chest scan after bilateral drainage: bilateral pulmonary consolidation associated to bilateral air cysts and bilateral residual pneumothorax\n\nFigure 3 diffuse tumor proliferation of small lymphoid cells resembling mature lymphocytes (A:HEx100, B:HEx400)\n\nFigure 4 positivity of tumor cells for CD20 (A), CD3 (B) and CD5 (C) are negative\n\nDiscussion\nIn this report, we present a case of SBSP as the first manifestation of primary pulmonary MALT lymphoma. SBSP is a very rare condition which often occurs on a pathological lung [4]. Underlying lung disease is rarely neoplastic. The association between lymphoma and spontaneous pneumothorax is extremely rare. The appearance of the pneumothorax is often related to therapeutic complications [5-7]. In patients with pulmonary lymphoma, rapid chemotherapy induces tumor lysis resulting in tissue necrosis and excavation of tumor nodules. The rupture of these tumor nodules in the pleural space results in pneumothorax [8]. The association of unilateral spontaneous pneumothorax and lymphoma at diagnosis is a very rare event. A total of three cases have been reported in the literature [8-10]. Okam et al. [8] and Wolf et al. [10] reported two cases of spontaneous pneumothorax revealing a lung lymphoma. Emanuele et al. noted that a previous history of lymphocytic interstitial pneumonia or other rare pulmonary lymphoid proliferations support the potential pathogenic role of these inflammatory process in the development of pulmonary MALT lymphoma [2]. Thus, organizing pneumonia may be a pre-neoplastic condition of lymphoma in our case.\n\nConclusion\nThe association between lymphoma and pneumothorax is extremely rare, often related to therapeutic toxicity. We report the case of SBSP as the first manifestation of primary pulmonary MALT lymphoma.\n\nCite this article: Asma Migaou et al. Simultaneous bilateral spontaneous pneumothorax as the first manifestation of primary pulmonary MALT lymphoma. Pan African Medical Journal. 2020;37(11). 10.11604/pamj.2020.37.11.24494\n\nCompeting interests\nThe authors declare no competing interests.\n\nAuthors' contributions\nAM and NS wrote the case. NF and SB participated in its English translation. MN prepared the anatomopathological figures. AC elaborated the radiological iconography. AB, SD and SC contributed to the writing of the discussion. AL, NR and SJ corrected and revised the manuscript. All authors read and approved the final version of this manuscript and equally contributed to its content.\n==== Refs\n1 Wislez M Bernier C Antoine M Cadranel J Lymphome Pulmonaire Emc Pneumologie 2002 6-002-H-05 \n2 Emanuele Z Francesco B The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance Blood 2016 127 17 2082 209 26989205 \n3 Sayar A Turna A Metin M Küçükyağci N Solak O Gürses A Simultaneous bilateral spontaneous pneumothorax report of 12 cases and review of the literature Acta Chir Belg 2004 10 104 5 572 6 15571026 \n4 Steinhäuslin CA Cuttat JF Spontaneous pneumothorax: A complication of lung cancer Chest 1985 11 88 5 709 13 2996838 \n5 Upadya A Recurrent bilateral spontaneous pneumothorax complicating chemotherapy for metastatic sarcoma Southern Med J 2003 96 8 821 3 14515929 \n6 Kitagawa M Tanaka I Takemura T Matsubara O Kasuga T Angiosarcoma of the scalp: report of two cases with fatal pulmonary complications and a review of Japanese autopsy registry data Virchows Arch A Pathol Anat Histopathol 1987 412 1 83 7 3120405 \n7 Stein ME Shklar Z Drumea K Goralnik L Ben-Arieh Y Haim N Chemotherapy-induced spontaneous pneumothorax in a patient with bulky mediastinal lymphoma: a rare oncologic emergency Oncology 1997 54 1 15 8 \n8 Okam M Alsolaiman M Brau A Austin M Plymyer M Spontaneous pneumothorax as the first manifestation of lymphoma: a rare presentation and the importance of diagnostic biopsy South Med J 2003 96 1 99 100 \n9 Hsu JR Chang SC Perng RP Pneumothorax following cytotoxic chemotherapy in malignant lymphoma Chest 1990 12 98 6 1512 3 1700945 \n10 Wolf KM Inclement weather, pneumothorax, and a cavitary apical infiltrate Am J Med 1990 89 6 828 830 2252055\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "37()",
"journal": "The Pan African medical journal",
"keywords": "Bilateral pneumothorax; MALT lymphoma; organizing pneumonia; pneumothorax",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002637:Chest Pain; D015505:Chest Tubes; D003520:Cyclophosphamide; D004317:Doxorubicin; D004417:Dyspnea; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D018442:Lymphoma, B-Cell, Marginal Zone; D008875:Middle Aged; D011030:Pneumothorax; D011241:Prednisone; D000069283:Rituximab; D014750:Vincristine",
"nlm_unique_id": "101517926",
"other_id": null,
"pages": "11",
"pmc": null,
"pmid": "33062114",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "15571026;14515929;2252055;26989205;8978586;12602730;3120405;2996838;1700945",
"title": "Simultaneous bilateral spontaneous pneumothorax as the first manifestation of primary pulmonary MALT lymphoma.",
"title_normalized": "simultaneous bilateral spontaneous pneumothorax as the first manifestation of primary pulmonary malt lymphoma"
} | [
{
"companynumb": "TN-UNICHEM PHARMACEUTICALS (USA) INC-UCM202102-000107",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DIVALPROEX SODIUM"
},
... |
{
"abstract": "BACKGROUND\nNew treatments are needed for patients with drug-resistant epilepsy to improve seizure control without decreasing quality of life.\n\n\nOBJECTIVE\nIn Belgium, a Medical Need Program (MNP) was initiated to make a new antiepileptic drug (brivaracetam; high-affinity synaptic vesicle protein 2A ligand) available as adjunctive therapy to treat focal seizures in patients failing treatment with three or more different antiepileptic drugs. This is a real-world chart review of the majority of patients (71%) enrolled in the MNP.\n\n\nMETHODS\nRetention and seizure outcomes of brivaracetam adjunctive treatment were evaluated in 175 patients aged ≥ 16 years enrolled in the MNP between June 2016 and May 2017 at six centers; 95.4% were previously/concomitantly treated with levetiracetam. Safety events data were also collected.\n\n\nRESULTS\nIn this highly drug-resistant population, 85.8%, 73.9%, and 64.9% of patients remained on brivaracetam, while seizure frequency decreased from baseline in 32.0%, 37.1%, and 37.3% of patients after 3, 6, and 9 months' treatment, respectively. Patients achieving 3-month seizure freedom increased from 3.2% after 3 months' treatment to 10.2% and 10.7% after 6 and 9 months' treatment, respectively. Six-month seizure freedom was achieved by 5.7% of patients at any time. Qualitative evaluation of seizures by physicians demonstrated 44.2%, 38.8%, and 43.2% of patients improved and 42.8%, 50.9%, and 50.6% remained unchanged during 3, 6, and 9 months' follow-up, respectively. No safety signals were identified.\n\n\nCONCLUSIONS\nRetention was high during 9 months of brivaracetam treatment in drug-resistant patients, including those previously/concomitantly treated with levetiracetam; 3-month seizure freedom increased from 3.2% after 3 months to 10.7% after 9 months of treatment.",
"affiliations": "Reference Center for the Treatment of Refractory Epilepsy, Hôpital Erasme, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium.;Refractory Epilepsy Center, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.;Centre Hospitalier Neurologique William Lennox, Allée de Clerlande 6, 1340, Ottignies, Belgium.;UCB Pharma, Alfred-Nobel-Straße 10, 40789, Monheim am Rhein, Germany.;UCB Pharma, Allée de la Recherche 60, 1070, Brussels, Belgium. france.ferriere@ucb.com.",
"authors": "Depondt|Chantal|C|;Van Paesschen|Wim|W|http://orcid.org/0000-0002-8535-1699;van Rijckevorsel|Kenou|K|;Leunikava|Iryna|I|;Ferrière|France|F|http://orcid.org/0000-0003-4371-9253",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40801-021-00246-7",
"fulltext": "\n==== Front\nDrugs Real World Outcomes\nDrugs Real World Outcomes\nDrugs - Real World Outcomes\n2199-1154\n2198-9788\nSpringer International Publishing Cham\n\n34060026\n246\n10.1007/s40801-021-00246-7\nOriginal Research Article\nBrivaracetam Retention Rate and Seizure Outcomes in Patients with Drug-Resistant Focal Epilepsy Included in the Medical Need Program in Belgium: A Real-World, Multicenter, Chart Review\nDepondt Chantal 1\nhttp://orcid.org/0000-0002-8535-1699\nVan Paesschen Wim 2\nvan Rijckevorsel Kenou 3\nLeunikava Iryna 4\nhttp://orcid.org/0000-0003-4371-9253\nFerrière France france.ferriere@ucb.com\n\n5\n1 grid.4989.c 0000 0001 2348 0746 Reference Center for the Treatment of Refractory Epilepsy, Hôpital Erasme, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium\n2 grid.410569.f 0000 0004 0626 3338 Refractory Epilepsy Center, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium\n3 Centre Hospitalier Neurologique William Lennox, Allée de Clerlande 6, 1340 Ottignies, Belgium\n4 grid.420204.0 0000 0004 0455 9792 UCB Pharma, Alfred-Nobel-Straße 10, 40789 Monheim am Rhein, Germany\n5 grid.421932.f 0000 0004 0605 7243 UCB Pharma, Allée de la Recherche 60, 1070 Brussels, Belgium\n31 5 2021\n31 5 2021\n9 2021\n8 3 407415\n30 3 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial 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-nc/4.0/.\nBackground\n\nNew treatments are needed for patients with drug-resistant epilepsy to improve seizure control without decreasing quality of life.\n\nObjective\n\nIn Belgium, a Medical Need Program (MNP) was initiated to make a new antiepileptic drug (brivaracetam; high-affinity synaptic vesicle protein 2A ligand) available as adjunctive therapy to treat focal seizures in patients failing treatment with three or more different antiepileptic drugs. This is a real-world chart review of the majority of patients (71%) enrolled in the MNP.\n\nPatients and Methods\n\nRetention and seizure outcomes of brivaracetam adjunctive treatment were evaluated in 175 patients aged ≥ 16 years enrolled in the MNP between June 2016 and May 2017 at six centers; 95.4% were previously/concomitantly treated with levetiracetam. Safety events data were also collected.\n\nResults\n\nIn this highly drug-resistant population, 85.8%, 73.9%, and 64.9% of patients remained on brivaracetam, while seizure frequency decreased from baseline in 32.0%, 37.1%, and 37.3% of patients after 3, 6, and 9 months’ treatment, respectively. Patients achieving 3-month seizure freedom increased from 3.2% after 3 months’ treatment to 10.2% and 10.7% after 6 and 9 months’ treatment, respectively. Six-month seizure freedom was achieved by 5.7% of patients at any time. Qualitative evaluation of seizures by physicians demonstrated 44.2%, 38.8%, and 43.2% of patients improved and 42.8%, 50.9%, and 50.6% remained unchanged during 3, 6, and 9 months’ follow-up, respectively. No safety signals were identified.\n\nConclusions\n\nRetention was high during 9 months of brivaracetam treatment in drug-resistant patients, including those previously/concomitantly treated with levetiracetam; 3-month seizure freedom increased from 3.2% after 3 months to 10.7% after 9 months of treatment.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1007/s40801-021-00246-7.\n\nUCB Pharmaissue-copyright-statement© The Author(s) 2021\n==== Body\nKey Points\n\nIn patients with drug-resistant epilepsy, retention rate was high after brivaracetam treatment initiation (85.8% after 3 months, 73.9% after 6 months, and 64.9% after 9 months).\t\nSeizure frequency decreased from baseline in 32.0%, 37.1%, and 37.3% of patients after 3, 6, and 9 months’ treatment, respectively.\t\nThe percentage of patients with 3-month seizure freedom increased from 3.2% after 3 months’ treatment to 10.2% and 10.7% after 6 and 9 months’ treatment, respectively.\t\nQualitative seizure improvements were reported in 61/138, 45/116, and 35/81 of patients after 3, 6, and 9 months, respectively.\t\n\nIntroduction\n\nApproximately one-third of epilepsy patients develop drug resistance, defined as “failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drug (AED) schedules (as monotherapies or in combination) to achieve sustained seizure freedom” [1, 2]. Moreover, about a half of treated patients experience mild to moderately severe adverse reactions [3, 4]. Therefore, new treatments are needed for patients with drug-resistant epilepsy to improve seizure control without decreasing their quality of life.\n\nIn this context, brivaracetam, a synaptic vesicle protein 2A (SV2A) ligand differing from levetiracetam by its rapid brain penetration, lack of direct effect on AMPA receptors, and higher affinity for SV2A, was developed [5, 6]. Brivaracetam showed higher potency and efficacy as an anti-seizure and antiepileptogenic agent than levetiracetam in preclinical epilepsy models [7, 8]. Clinical trials have shown that brivaracetam used as an adjunctive therapy reduced seizure frequency and had a favorable safety profile [9]. Moreover, brivaracetam was associated with fewer behavioral adverse events than levetiracetam [10]. In the European Union, brivaracetam is approved as adjunctive therapy in the treatment of focal seizures with or without secondary generalization (new terminology of the International League Against Epilepsy: evolution to bilateral tonic-clonic seizures) in epilepsy patients from the age of 4 years [11–13].\n\nIn Belgium, a Medical Need Program (MNP) was initiated as an early access program to make brivaracetam available before commercialization for adolescents and adults with epilepsy who could benefit from this AED as adjunctive therapy in the treatment of focal seizures [14]. To meet the Belgian eligibility criteria for reimbursement of the most recently licensed AEDs, including brivaracetam, lacosamide, and perampanel, all patients included in the MNP had failed treatment with three or more different AEDs due to a lack of efficacy or occurrence of unacceptable adverse events [15]. Here, we present the results of a real-world chart review based on data from the MNP, which primarily evaluated brivaracetam retention rates after 3, 6, and 9 months of treatment. Additional data collected were seizure frequency and qualitative clinical seizure evaluation after 3, 6, and 9 months of treatment, and changes in AEDs. Safety information was collected as additional data and analyzed post hoc.\n\nMethods\n\nDesign and Population\n\nThis retrospective, longitudinal, multicenter chart review was based on data from the MNP collected in six centers, representing 71% of the total MNP population: Universitair Ziekenhuis Leuven (Leuven), Centrum voor Epilepsie en Psycho-Organische Stoornissen (Duffel), Hôpital Erasme (Brussels), Cliniques Universitaires Saint-Luc (Brussels), Centre Hospitalier Universitaire de Liège (Liège), and Centre Hospitalier Neurologique William Lennox (Ottignies-Louvain-la-Neuve).\n\nEligible patients were enrolled in the MNP to initiate brivaracetam treatment between 10 June 2016 and 31 May 2017. All patients were ≥ 16 years of age, had uncontrolled focal seizures despite previous treatments with three or more AEDs (in monotherapy or adjunctive therapy, concomitant or life‐time used; due to therapeutic failure or adverse events), of which one was levetiracetam (except when levetiracetam was not considered appropriate in the opinion of the treating physician).\n\nThe Ethics Committees of all participating centers were approached for their consent of the MNP and to inform them of the data collection.\n\nData Collection and Analysis\n\nData were collected from patients’ records and anonymized by either the treating physicians or designated personnel. Data entry was conducted by site personnel or data entry assistants upon request of the treating physicians and approval by Ethics Committees.\n\nAt baseline (day of brivaracetam initiation), year of birth, gender, lifetime history of AEDs prescribed before brivaracetam, non-drug treatment (e.g., epilepsy surgery, vagus nerve stimulation, deep brain stimulation), monthly seizure frequency during 6 months before brivaracetam initiation, brivaracetam initiation date, and AEDs concomitant to brivaracetam, were collected. At 3, 6, and 9 months after brivaracetam initiation, the monthly seizure frequency, qualitative clinical seizure evaluation (changes in seizure frequency according to routine clinical physician’s assessment), treatment continuation/discontinuation status, and treatment end date, if applicable, were collected. Monthly seizure frequency was collected and analyzed in categories to ease the evaluation of disease evolution, as follows: (1) seizure-free, (2) < 6 per month, (3) 6–15 per month, (4) 16–30 per month, and (5) > 30 per month. At last follow-up, the numbers of lifetime AEDs and AEDs concomitant to brivaracetam were collected.\n\nSafety information was not initially the focus of this chart review but was collected during the MNP, based on a spontaneous reporting system. As such, safety events were analyzed post hoc. Psychiatric, central nervous system-related, and other treatment-emergent safety events were reported to UCB Patient Safety by the treating physicians.\n\nStatistical Analysis\n\nThe number of patients analyzed was based on the number of patients included in the MNP in the six participating centers. Analyses were performed on the entire chart review population and the subpopulation of patients on concomitant levetiracetam at last follow-up.\n\nStatistical analyses were descriptive (mean, standard deviation (SD), median, and range for quantitative variables; frequencies for categorical variables). Retention rates were calculated as proportion of patients maintaining brivaracetam at 3, 6, and 9 months and using Kaplan-Meier estimates. The number of censored observations, i.e., last observation for each patient after which no data were available, was recorded at baseline, and at 3, 6, and 9 months. No correction methods were used to complete missing values. Percentages of seizure‐free patients were calculated during the first 3 months, between 3 and 6 months, and between 6 and 9 months after brivaracetam initiation. Statistical analyses were performed using a proprietary macro-enriched Excel file (XDUstat v1.3), which was run under Microsoft Excel 2016 MSO 32-bit.\n\nResults\n\nDemographic Characteristics of the Population\n\nData from 178 patients were collected. Three patients were excluded from all analyses: two due to off-label brivaracetam use (one treated for progressive myoclonic epilepsy and one treated with brivaracetam as monotherapy) and one due to unknown brivaracetam initiation date (Fig. 1). After 3, 6, and 9 months of treatment, data from 169, 161, and 131 patients were included in analyses, respectively. After 9 months, data were no longer available for 44 patients due to absence of follow-up data or patient lost to follow-up (n = 23) or patients having a shorter observation period due to later enrollment (n = 21) (Fig. 1). In the latter 21 patients, the observation period was less than 9 months because patients were enrolled between June 2016 and May 2017, and data were collected between October 2017 and November 2017. Patients enrolled towards the end of the inclusion period therefore received brivaracetam for less than 9 months at the time of data collection (end of their observation period). The mean follow-up duration was 9 months (SD 1.5 months), starting at the inclusion in the MNP.Fig. 1 The STROBE flow chart. FU follow-up\n\nThe median age of patients was 37 years (range 16–71 years) and 54.9% were female (Table 1). Patients had highly drug-resistant epilepsy as reflected by the 85 patients (48.6%) who had used non-drug treatments (mainly vagus nerve stimulation (72 patients) and epilepsy surgery (25 patients)), a median number of eight lifetime AEDs prescribed, and 36% of patients with ten or more lifetime AEDs prescribed (Table 1). A median of three concomitant AEDs were used at brivaracetam initiation. The most frequently prescribed lifetime AED (in combination or monotherapy) was levetiracetam (95.4% of patients), followed by valproic acid (84.6%), lamotrigine (72.6%), and carbamazepine (72.0%). Among patients with concomitant AED data available at last follow-up, 24/166 (14.5%) received concomitant levetiracetam.Table 1 Baseline demographic characteristics\n\nCharacteristics\tReal-life data in Belgium (N = 175)\t\nGender\t\n Female, n (%)\t96 (54.9)\t\n Male, n (%)\t79 (45.1)\t\nAge (years)\t\n Mean (SD)\t38.0 (13.4)\t\n Median (range)\t37.0 (16–71)\t\nAge group\t\n 16–25 years, n (%)\t35 (20.0)\t\n 26–45 years, n (%)\t93 (53.1)\t\n 46–65 years, n (%)\t44 (25.1)\t\n > 65 years, n (%)\t3 (1.7)\t\nNon-drug treatment\t\n Yes, n (%)\t85 (48.6)\t\n No, n (%)\t90 (51.4)\t\nDistribution of the non-drug treatment (N = 85)\t\n Epilepsy surgery, n (%)\t25 (29)\t\n Vagus nerve stimulation, n (%)\t72 (85)\t\n Deep brain stimulation, n (%)\t4 (5)\t\n Atkins diet, n (%)\t1 (1)\t\nNumber of lifetime AEDs\t\n Mean (SD)\t8.3 (3.4)\t\n Median (range)\t8 (2–18)\t\nNumber of lifetime AEDs\t\n 2–5 AEDs, n (%)\t45 (25.7)\t\n 6–10 AEDs, n (%)\t89 (50.9)\t\n > 10 AEDs, n (%)\t41 (23.4)\t\nAED antiepileptic drug, N total number of patients included in the analyses, n/% number/percentage of patients within each category, SD standard deviation\n\nOutcomes\n\nRetention\n\nPercentages of patients still on brivaracetam were 85.8% (145/169), 73.9% (119/161), and 64.9% (85/131) after 3, 6, and 9 months (Fig. 1). Retention rates of brivaracetam using Kaplan-Meier estimates were 88.8%, 78.8%, and 69.7% after 3, 6, and 9 months (Fig. 2). Numbers of censored observations were 6, 8, 30, and 85 after the baseline, 3-, 6-, and 9-month visits, respectively. Among the 175 patients included in analyses, 24 (13.7%) stopped their treatment during the first 3 months, 18 (10.3%) between 3 and 6 months, and four (2.3%) between 6 and 9 months after brivaracetam initiation (Fig. 1).Fig. 2 Retention rate of brivaracetam using the Kaplan-Meier estimate in the 175 patients included in the main analysis and in the 24 patients on concomitant levetiracetam at last follow-up. LEV levetiracetam\n\nSeizure Frequency\n\nThe percentage of patients with fewer than six seizures per month increased from 32.7% at baseline to 41.3%, 42.6%, and 50.7% after 3, 6, and 9 months, respectively (Fig. 3a). Compared with baseline, seizure frequency decreased in 32.0–37.3% and remained stable in 49.5–54.1% of patients after 3–9 months (Fig. 4a).Fig. 3 Percentage of patients according to the monthly seizure frequency reported before treatment initiation and after 3, 6, and 9 months of brivaracetam treatment (a) in all the patients included in the main analyses and (b) in the patients on concomitant levetiracetam at last follow-up. N total number of patients for whom information on quantitative seizure frequency is available, % percentage of patients within each category. aIncluding one patient who interrupted brivaracetam for 49 days. bIncluding one patient who underwent epilepsy surgery after start of brivaracetam\n\nFig. 4 Monthly seizure frequency evolution after 3, 6, and 9 months of brivaracetam treatment in the patients without seizure freedom (a) included in the main analyses and (b) on concomitant levetiracetam at last follow-up. N total number of patients without seizure freedom at the specified timepoint for whom information on seizure frequency is available at the specified timepoint and at baseline, % percentage of patients within each category\n\nAmong the 126 patients with available information on seizure frequency during the first 3 months of brivaracetam treatment, four (3.2%) achieved 3-month seizure freedom (Fig. 3a): one (0.8%) remained seizure-free during the entire observation period, one (0.8%) until 6 months and was subsequently lost to follow-up, one (0.8%) was lost to follow-up after 3 months, and one (0.8%) had seizures between 3 and 6 months after brivaracetam initiation.\n\nAmong the 108 patients with available information on seizure frequency between 3 and 6 months after brivaracetam initiation, 11 (10.2%) achieved 3-month seizure freedom (Fig. 3a): six (5.6%) remained seizure-free between 6 and 9 months, three (2.8%) were lost to follow-up after 6 months, and two (1.9%) had new seizures between 6 and 9 months.\n\nAmong the 75 patients with available information on seizure frequency between 6 and 9 months after brivaracetam initiation, eight (10.7%) achieved 3-month seizure freedom (Fig. 3a): six (8.0%) were already registered as seizure-free from previous timepoints and two (2.7%) had seizures at previous timepoints.\n\nSix-month seizure freedom was achieved by 7/122 (5.7%) patients with available information on seizure frequency for two or more consecutive visits.\n\nQualitative Seizure Evaluation\n\nRegarding the qualitative evaluation of seizures by the physicians, 61/138 (44.2%), 45/116 (38.8%), and 35/81 (43.2%) patients had improved, 59/138 (42.8%), 59/116 (50.9%), and 41/81 (50.6%) patients were considered unchanged, and 18/138 (13.0%), 12/116 (10.3%), and 5/81 (6.2%) patients had worsened at 3, 6, and 9 months after treatment start compared with baseline, respectively (Fig. 5a).Fig. 5 Qualitative seizure evaluation after 3, 6, and 9 months of brivaracetam treatment (a) in the patients included in the main analyses and (b) in the patients on concomitant levetiracetam at last follow-up. N total number of patients for whom information on qualitative seizure frequency is available, % percentage of patients within each category. aIncluding one patient who interrupted brivaracetam for 49 days. bIncluding one patient who underwent epilepsy surgery after the start of brivaracetam\n\nBrivaracetam Treatment Regimen\n\nThe mean number of concomitant AEDs was 2.8 (range 1–7) at brivaracetam initiation and 2.4 (range 1–6) at last follow-up. Most patients received two or three concomitant AEDs. The concomitant AEDs used were similar at brivaracetam initiation and last follow-up, except for a lower proportion of levetiracetam (14.5% vs. 33.7%) and perampanel (7.2% vs. 11.4%) at last follow-up compared with baseline as shown in the table (Online Supplemental Material, Resource 1).\n\nOutcomes in the Subpopulation on Concomitant Levetiracetam at Last Follow-Up\n\nAt 3 and 6 months, data were available for all 24 patients on concomitant levetiracetam at last follow-up. At 9 months, data were available for 18 patients due to loss to follow-up for six patients after 6 months.\n\nRetention\n\nPercentages of patients remaining on brivaracetam while on concomitant levetiracetam at last follow-up were 79.2% (19/24 patients), 70.8% (17/24), and 55.6% (10/18) after 3, 6, and 9 months, respectively. Retention rates of brivaracetam in patients on concomitant levetiracetam using Kaplan-Meier estimates were 83.3%, 75.0%, and 62.5% after 3, 6, and 9 months, respectively (Fig. 2). Among the 24 patients included in analyses, five (20.8%) stopped their brivaracetam treatment during the first 3 months, two (8.3%) between 3 and 6 months, and one (4.2%) between 6 and 9 months after brivaracetam initiation.\n\nSeizure Frequency\n\nIn patients on concomitant levetiracetam at last follow-up, the percentage of patients with fewer than six seizures per month increased from 39.1% at baseline to 55.0%, 52.9%, and 80.0% after 3, 6, and 9 months of treatment (Fig. 3b). Compared with baseline, seizure frequency decreased in 20–30% and remained stable in 50–65% of patients after 3–9 months (Fig. 4b). Three-month seizure freedom was achieved by 3/17 (17.6%) patients (all between 3 and 6 months after brivaracetam initiation); no patient achieved 6-month seizure freedom (Fig. 3b).\n\nQualitative Seizure Evaluation\n\nRegarding the qualitative evaluation of seizures by the physicians in patients on concomitant levetiracetam at last follow-up, seven (33.3%), eight (44.4%), and four (40.0%) patients had improved, nine (42.9%), eight (44.4%), and four (40.0%) patients were considered stable, and five (23.8%), two (11.1%), and two (20.0%) patients had worsened at 3, 6, and 9 months after treatment initiation compared with baseline, respectively (Fig. 5b).\n\nBrivaracetam Treatment Regimen\n\nIn patients on levetiracetam at last follow-up, the mean number of concomitant AEDs prescribed in addition to brivaracetam was 2.9 (range 1–5) at treatment start and last follow-up visit. Most patients received between two and four concomitant AEDs in addition to brivaracetam.\n\nSafety\n\nFour patients reported severe safety events: one reported suicidal thoughts, hetero aggression, and increased seizure frequency; one reported suicidal thoughts; one reported exacerbation of seizures, decreased activity, and loss of appetite; and one reported headache.\n\nThe most frequent psychiatric safety events were aggression (15 events) and mood change (depression) (five events). The most common central nervous system-related safety events were dizziness and headache (five events each). The most common other safety events were thrombocytopenia (six events), loss of appetite, and nausea (three events each) as shown in Online Supplemental Material (Resource 2).\n\nDiscussion\n\nIn this chart review based on data from the MNP in Belgium, we evaluated retention rate and seizure outcomes following brivaracetam as adjunctive therapy for the treatment of focal seizures with or without secondary generalization. The vast majority (95.4%) of patients evaluated had been treated previously or concomitantly with levetiracetam. These real-life data are useful to evaluate brivaracetam utility in a broader population than patients enrolled in clinical trials, who are often not representative of everyday clinical practice because of strict inclusion and exclusion criteria [16]. The study population was highly drug resistant, with a median of eight previously used AEDs and three concomitant AEDs at treatment initiation. In addition, almost half of the total study population (48.6%) had previously received unsuccessful non-drug treatments, including epilepsy surgery (14.3% of total population), vagus nerve stimulation (41.1% of total population), and deep brain stimulation (2.3% of total population).\n\nIn these drug-resistant patients, retention rates of brivaracetam, used as indicators of effectiveness and tolerability, were high, with 85.8%, 73.9%, and 64.9% of patients still on brivaracetam after 3, 6, and 9 months. Our results are in line with other published retrospective data showing that brivaracetam is effective in difficult-to-treat epilepsy patients [17–21], including those who have undergone unsuccessful epilepsy surgery or neurostimulation [17, 19]. In two retrospective studies in Germany, retention rates at 6 months were 75.8% in patients who failed a median of four previous AEDs (post-marketing study) [19] and 80.4% in patients with a median of five previously used AEDs [17]. In another retrospective study in Spain, retention rates were 80.2% at 6 months and 70.4% at 1 year in patients with a median of eight previously used AEDs [20]. A lower retention rate (51.5%) was obtained in a monocenter survey in highly intractable patients with a median of ten previously used AEDs in Germany [18]. In another monocenter, retrospective analysis in Germany (median of five previously used AEDs), the retention rate was 72% during an average period of 5.3 months after brivaracetam initiation [21].\n\nIn our chart review, seizure frequency tended to decrease after brivaracetam initiation. Although this is an encouraging finding, these results should be interpreted with caution since patients with inadequate seizure control may have discontinued their treatment before the end of the follow-up (excluded from analyses at subsequent timepoints). Nevertheless, treating physicians also considered that 38.8–44.2% of patients presented a qualitative seizure improvement and 42.8–50.9% of patients remained unchanged during the 9-month follow-up. Moreover, 10.2% of patients achieved 3-month seizure freedom after 6 months of treatment, and 5.7% of patients achieved 6-month seizure freedom at any time. Although these rates are good for highly drug-resistant epilepsy patients given that the probability of achieving seizure freedom diminishes substantially with each subsequent AED regimen [22], they should be interpreted cautiously because they depend on baseline seizure frequencies. Three-month seizure freedom rates after 6 months of brivaracetam treatment were 17.2% in a previous retrospective study in Spain (median of eight previous AEDs) [20], 15.3% in a retrospective cohort study in Germany (median of four previous AEDs) [19], and 7.0% in a monocenter survey in Germany (median of ten previous AEDs) [18]. In a monocenter study in Germany, 21.7% of patients became newly seizure-free after 6 months (median of five previous AEDs) [17]. In another retrospective study in Germany, the seizure freedom rate was 8.8% during an average period of 5.3 months after brivaracetam initiation (median of five previous AEDs) [21].\n\nFour patients reported severe safety events, including suicidal thoughts (n = 2), aggression (n = 1), decreased activity (n = 1), loss of appetite (n = 1), and headache (n = 1). Besides these, the most frequently reported safety events were aggression (15 events), thrombocytopenia (six events), mood change (depression) (five events), dizziness (five events), and headache (five events). These safety events are generally in line with previous reports, although the most common safety events in the previously mentioned studies also included somnolence, irritability, fatigue, cognitive decline, and nausea [17–21].\n\nThe results of this chart review suggest that brivaracetam may be a suitable treatment option for drug-resistant epilepsy patients previously or concomitantly treated with levetiracetam. Indeed, 95.4% of patients in this chart review were previously or concomitantly treated with levetiracetam (as per eligibility criteria). The good retention and seizure freedom rates observed up to 9 months post-brivaracetam initiation are in line with a previous analysis showing that intolerability or ineffectiveness of prior levetiracetam treatment did not preclude a good response to brivaracetam [17]. In the previous study, the incidence of psychiatric and behavioral problems was lower in patients who switched from levetiracetam to brivaracetam [17]. A potential explanation is that levetiracetam inhibits AMPA receptors, an effect that has been associated with behavioral events for some drugs, whereas brivaracetam does not [23, 24]. Based on our results in the subpopulation of patients on levetiracetam at the last follow-up visit, the combination of these two drugs did not appear to be detrimental: the retention rate at 6 months was 70.8%, and the proportion of patients who reported fewer than six seizures per month increased from 39.1% at baseline to 55.0%, 52.9%, and 80.0% after 3, 6, and 9 months of treatment.\n\nThe strengths of this retrospective chart review include its follow-up duration, and the systematic and uniform data collection. Nevertheless, the results should be interpreted cautiously because of the limitations associated with its retrospective design: some data were missing from patient records, such as the exact numbers and types of seizures, and the reasons for previous levetiracetam treatment failures (therapeutic failure and/or adverse effects). A further limitation of the study is that the reason for treatment discontinuation was not collected, nor were brivaracetam doses (although it should be noted that the analysis only included patients using brivaracetam on-label). Furthermore, the high proportion of patients in our study sample previously or concomitantly treated with levetiracetam is not representative of general clinical practice. The safety evaluation was beyond the scope of this chart review, and therefore, safety events reported are most likely incomplete and probably only include those of greatest severity. Finally, the results for the subpopulation of patients on levetiracetam at the last follow-up visit should be interpreted with caution due to the low number of patients included in the subanalysis.\n\nConclusions\n\nIn our highly drug-resistant population that predominantly included patients treated previously or concomitantly with levetiracetam, retention rate was high during 9 months after brivaracetam treatment initiation. Quantitative and qualitative seizure improvements were also observed: around 10% achieved 3-month seizure freedom after 6 and 9 months of treatment, and qualitative seizure improvements were reported in around 40% of patients. The results suggest that brivaracetam adjunctive therapy may be a suitable treatment option in patients with drug-resistant epilepsy, including those with previous or concomitant levetiracetam treatment.\n\nSupplementary Information\n\nBelow is the link to the electronic supplementary material.Supplementary file1 (PDF 405 KB)\n\nAcknowledgements\n\nThe authors thank the physicians from the six centers who participated in the data collection: Prof. Lieven Lagae (Refractory Epilepsy Center, University Hospitals Leuven), Prof. Susana Ferrao Santos (Centre Hospitalier Neurologique William Lennox, Ottignies and Cliniques Universitaires Saint-Luc, Brussels), Dr. Pascal Vrielynck, Dr. Françoise Liénard (Centre Hospitalier Neurologique William Lennox, Ottignies), Dr. Henri Hauman (Centrum voor Epilepsie en Psycho-Organische Stoornissen, Duffel), Prof. Bernard Sadzot, Dr. Estelle Rikir (Centre Hospitalier Universitaire de Liège), Dr. Benjamin Legros (Hôpital Erasme, Brussels), Dr. Riëm El Tahry (Cliniques Universitaires Saint-Luc, Brussels). The authors thank Claire Verbelen, PhD (Modis, Wavre, Belgium) and Nicole Meinel, PhD (Evidence Scientific Solutions, London, UK) for writing assistance, which was funded by UCB Pharma.\n\nDeclarations\n\nFunding\n\nThe Medical Need Program as well as this retrospective data collection and related publications were sponsored by UCB Pharma.\n\nConflicts of Interest\n\nCD received grants paid to the institution from UCB Pharma during the conduct of the study as well as grants, speaker’s fees, and conference support from UCB Pharma outside the submitted work. WVP received nonfinancial support from UCB Pharma during the conduct of the study as well as personal fees and nonfinancial support from UCB Pharma, grants from EIT Health, and personal fees from Idorsia outside the submitted work. KvR has no relevant relationships to disclose. IL and FF are employees of UCB Pharma.\n\nEthics Approval\n\nThe Ethics Committees of all participating centers were approached for their consent of the MNP and to inform them of the data collection. Anonymized data entry was conducted by site personnel or data entry assistants upon request of the treating physicians and approval by Ethics Committees.\n\nConsent to Participate/Consent for Publication\n\nIn the context of this real-life data collection, no informed consent was required due to the retrospective design and the nature of the information collected. The sponsor only had access to fully anonymized data.\n\nData Availability\n\nThe datasets generated and/or analyzed during the current study are not publicly available as data from non-interventional studies is outside of UCB’s data sharing policy.\n\nCode availability\n\nNot applicable.\n\nAuthor Contributions\n\nFF and IL were responsible for the study conception. CD, WVP, and KvR contributed to the study conception, were participating investigators in the data collection, and members of the Medical Need Program. All authors were responsible for data interpretation. Medical writing assistance (funded by UCB Pharma) was provided under the direction of the authors. All authors reviewed and commented on previous versions of the manuscript. All authors read and approved the final manuscript and agreed to the submission to Drugs-Real World Outcomes.\n==== Refs\nReferences\n\n1. Kwan P Arzimanoglou A Berg AT Brodie MJ Allen Hauser W Mathern G Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies Epilepsia 2010 51 1069 1077 10.1111/j.1528-1167.2009.02397.x 19889013\n2. Kwan P Brodie MJ Early identification of refractory epilepsy N Engl J Med. 2000 342 314 319 10.1056/NEJM200002033420503 10660394\n3. Schmidt D Schachter SC Drug treatment of epilepsy in adults BMJ 2014 348 g254 10.1136/bmj.g254 24583319\n4. Ventola CL Epilepsy management: newer agents, unmet needs, and future treatment strategies P T. 2014 39 776 792 25395820\n5. Klitgaard H Matagne A Nicolas JM Gillard M Lamberty Y De Ryck M Brivaracetam: rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment Epilepsia 2016 57 538 548 10.1111/epi.13340 26920914\n6. Stephen LJ Brodie MJ Brivaracetam: a novel antiepileptic drug for focal-onset seizures Ther Adv Neurol Disord. 2018 11 1756285617742081 10.1177/1756285617742081 29399049\n7. Matagne A Margineanu DG Kenda B Michel P Klitgaard H Anti-convulsive and anti-epileptic properties of brivaracetam (ucb 34714), a high-affinity ligand for the synaptic vesicle protein, SV2A Br J Pharmacol. 2008 154 1662 1671 10.1038/bjp.2008.198 18500360\n8. Gillard M Fuks B Leclercq K Matagne A Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: relationship to anti-convulsant properties Eur J Pharmacol. 2011 664 36 44 10.1016/j.ejphar.2011.04.064 21575627\n9. Feyissa AM Brivaracetam in the treatment of epilepsy: a review of clinical trial data Neuropsychiatr Dis Treat. 2019 15 2587 2600 10.2147/NDT.S143548 31571877\n10. Yates SL Fakhoury T Liang W Eckhardt K Borghs S D'Souza J An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam Epilepsy Behav. 2015 52 165 168 10.1016/j.yebeh.2015.09.005 26432008\n11. European Medicines Agency (EMA). Committee for Medicinal Products for Human Use (CHMP). Summary of opinion (post authorisation)—Briviact (brivaracetam). 2018. https://www.ema.europa.eu/documents/smop/chmp-post-authorisation-summary-positive-opinion-briviact_en.pdf. Accessed 12 Feb 2019.\n12. Zaccara G Brivaracetam: new compound approved for the treatment of epilepsy Drugs Today (Barc). 2016 52 219 227 27252986\n13. European Medicines Agency (EMA). Summary of product characteristics—Briviact. https://www.ema.europa.eu/en/documents/product-information/briviact-epar-product-information_en.pdf. Accessed 19 Aug 2019.\n14. Federal Agency for Medicines and Health Products. Compassionate use—medical need—Briviact—summarized information for publication. https://www.famhp.be/sites/default/files/content/annex_i_summarized_information_for_publication_en_fr_nl_5.pdf. Accessed 29 Aug 2019.\n15. Institut national d'assurance maladie-invalidité (INAMI). Autorisations—formulaires de demande réglementaires—Formulaire de demande de remboursement de la spécialité BRIVIACT en tant que thérapie d'association. 2019. https://ondpanon.riziv.fgov.be/SSPWebApplicationPublic/fr/Public/RequestForm. Accessed 4 Feb 2019.\n16. Blonde L Khunti K Harris SB Meizinger C Skolnik NS Interpretation and impact of real-world clinical data for the practicing clinician Adv Ther. 2018 35 1763 1774 10.1007/s12325-018-0805-y 30357570\n17. Hirsch M Hintz M Specht A Schulze-Bonhage A Tolerability, efficacy and retention rate of brivaracetam in patients previously treated with levetiracetam: a monocenter retrospective outcome analysis Seizure. 2018 61 98 103 10.1016/j.seizure.2018.07.017 30118932\n18. Steinhoff BJ Bacher M Bucurenciu I Hillenbrand B Intravooth T Kornmeier R Real-life experience with brivaracetam in 101 patients with difficult-to-treat epilepsy: a monocenter survey Seizure. 2017 48 11 14 10.1016/j.seizure.2017.03.010 28364655\n19. Steinig I von Podewils F Moddel G Bauer S Klein KM Paule E Postmarketing experience with brivaracetam in the treatment of epilepsies: a multicenter cohort study from Germany Epilepsia 2017 58 1208 1216 10.1111/epi.13768 28480518\n20. Villanueva V Lopez-Gonzalez FJ Mauri JA Rodriguez-Uranga J Olive-Gadea M Montoya J BRIVA-LIFE: a multicenter retrospective study of the long-term use of brivaracetam in clinical practice Acta Neurol Scand. 2018 139 360 368 10.1111/ane.13059 30506559\n21. Zahnert F Krause K Immisch I Habermehl L Gorny I Chmielewska I Brivaracetam in the treatment of patients with epilepsy—first clinical experiences Front Neurol. 2018 9 38 10.3389/fneur.2018.00038 29467714\n22. Chen Z Brodie MJ Liew D Kwan P Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study JAMA Neurol. 2018 75 279 286 10.1001/jamaneurol.2017.3949 29279892\n23. Coppola G Iapadre G Operto FF Verrotti A New developments in the management of partial-onset epilepsy: role of brivaracetam Drug Des Devel Ther 2017 11 643 657 10.2147/DDDT.S103468\n24. Hansen CC Ljung H Brodtkorb E Reimers A Mechanisms underlying aggressive behavior induced by antiepileptic drugs: focus on topiramate, levetiracetam, and perampanel Behav Neurol 2018 2018 2064027 10.1155/2018/2064027 30581496\n\n",
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"references": "29399049;29467714;21575627;24583319;28293101;28480518;30118932;30506559;10660394;30581496;29279892;25395820;26920914;30357570;28364655;27252986;19889013;31571877;18500360;26432008",
"title": "Brivaracetam Retention Rate and Seizure Outcomes in Patients with Drug-Resistant Focal Epilepsy Included in the Medical Need Program in Belgium: A Real-World, Multicenter, Chart Review.",
"title_normalized": "brivaracetam retention rate and seizure outcomes in patients with drug resistant focal epilepsy included in the medical need program in belgium a real world multicenter chart review"
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"abstract": "BACKGROUND\nThe authors report a case of a rare complication that occurred after botulinum toxin injection to the extraocular muscle, which was easily overlooked and successfully corrected by surgery.\n\n\nMETHODS\nA 34-year-old female patient visited our clinic for diplopia and ocular motility disorder after removal of an epidermoid tumor of the brain. At her initial visit, her best-corrected visual acuity (BCVA) was 20/20 for both eyes. An alternate cover test showed 45 prism-diopter esotropia and 3 prism-diopter hypertropia in the right eye. Following 6 months of observation, the deviation of the strabismus did not improve, and botulinum toxin was injected into the right medial rectus (RMR). After 6 days, she visited our clinic with decreased visual acuity of her right eye. The BCVA was found to be 20/50 for her right eye. Funduscopic examination presented a retinal tear inferonasal to the optic disc with preretinal hemorrhage. Subretinal fluid nasal to the fovea was seen on optical coherence tomography (OCT). Barrier laser photocoagulation was done around the retinal tear; however, her visual acuity continued to decrease, and vitreous hemorrhage and subretinal fluid at the lesion did not improve. In addition, a newly developed epiretinal membrane was seen on OCT. An alternate cover test presented 30 prism-diopter right esotropia. 19 weeks after RMR botulinum toxin injection, she received pars plana vitrectomy, membranectomy, endolaser barrier photocoagulation, and intravitreal bevacizumab (Avastin®) injection. After 4 months, her visual acuity improved to 20/20, and only 4 prism-diopter of right hypertropia and 3 prism-diopter of exotropia were noted. Vitreous opacity and the epiretinal membrane were completely removed, as confirmed by funduscopic and examination.\n\n\nCONCLUSIONS\nSudden loss of vision after injection of botulinum toxin into the extraocular muscle may suggest a serious complication, and a prompt, thorough ophthalmic examination should be performed. If improvements are not observed, rapid surgical intervention is recommended to prevent additional complications.",
"affiliations": "Institute of Vision Research, Department of Ophthalmology, Severance Eye and ENT Hospital, Yonsei University College of Medicine, Seoul, South Korea.;Institute of Vision Research, Department of Ophthalmology, Severance Eye and ENT Hospital, Yonsei University College of Medicine, Seoul, South Korea.;Institute of Vision Research, Department of Ophthalmology, Severance Eye and ENT Hospital, Yonsei University College of Medicine, Seoul, South Korea.;Institute of Vision Research, Department of Ophthalmology, Severance Eye and ENT Hospital, Yonsei University College of Medicine, Seoul, South Korea.;Department of Ophthalmology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea. minkim76@gmail.com.",
"authors": "Lee|Dong Hyun|DH|;Han|Jinu|J|;Han|Sueng-Han|SH|;Lee|Sung Chul|SC|;Kim|Min|M|http://orcid.org/0000-0003-1873-6959",
"chemical_list": "D009498:Neurotoxins; D001905:Botulinum Toxins",
"country": "England",
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"doi": "10.1186/s12886-017-0649-2",
"fulltext": "\n==== Front\nBMC OphthalmolBMC OphthalmolBMC Ophthalmology1471-2415BioMed Central London 64910.1186/s12886-017-0649-2Case ReportVitreous hemorrhage and Rhegmatogenous retinal detachment that developed after botulinum toxin injection to the extraocular muscle: case report Lee Dong Hyun wizmeca@live.co.kr 1Han Jinu jinuhan@yuhs.ac 1Han Sueng-Han shhan222@yuhs.ac 1Lee Sung Chul sunglee@yuhs.ac 1http://orcid.org/0000-0003-1873-6959Kim Min +82-2-2019-3445minkim76@gmail.com 21 0000 0004 0470 5454grid.15444.30Institute of Vision Research, Department of Ophthalmology, Severance Eye and ENT Hospital, Yonsei University College of Medicine, Seoul, South Korea 2 0000 0004 0470 5454grid.15444.30Department of Ophthalmology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea 13 12 2017 13 12 2017 2017 17 24912 7 2017 5 12 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\nThe authors report a case of a rare complication that occurred after botulinum toxin injection to the extraocular muscle, which was easily overlooked and successfully corrected by surgery.\n\nCase presentation\nA 34-year-old female patient visited our clinic for diplopia and ocular motility disorder after removal of an epidermoid tumor of the brain. At her initial visit, her best-corrected visual acuity (BCVA) was 20/20 for both eyes. An alternate cover test showed 45 prism-diopter esotropia and 3 prism-diopter hypertropia in the right eye. Following 6 months of observation, the deviation of the strabismus did not improve, and botulinum toxin was injected into the right medial rectus (RMR). After 6 days, she visited our clinic with decreased visual acuity of her right eye. The BCVA was found to be 20/50 for her right eye. Funduscopic examination presented a retinal tear inferonasal to the optic disc with preretinal hemorrhage. Subretinal fluid nasal to the fovea was seen on optical coherence tomography (OCT). Barrier laser photocoagulation was done around the retinal tear; however, her visual acuity continued to decrease, and vitreous hemorrhage and subretinal fluid at the lesion did not improve. In addition, a newly developed epiretinal membrane was seen on OCT. An alternate cover test presented 30 prism-diopter right esotropia. 19 weeks after RMR botulinum toxin injection, she received pars plana vitrectomy, membranectomy, endolaser barrier photocoagulation, and intravitreal bevacizumab (Avastin®) injection. After 4 months, her visual acuity improved to 20/20, and only 4 prism-diopter of right hypertropia and 3 prism-diopter of exotropia were noted. Vitreous opacity and the epiretinal membrane were completely removed, as confirmed by funduscopic and examination.\n\nConclusions\nSudden loss of vision after injection of botulinum toxin into the extraocular muscle may suggest a serious complication, and a prompt, thorough ophthalmic examination should be performed. If improvements are not observed, rapid surgical intervention is recommended to prevent additional complications.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12886-017-0649-2) contains supplementary material, which is available to authorized users.\n\nKeywords\nBotulinum toxinRetinal detachmentVitreous hemorrhageStrabismusissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nBotulinum toxin is a widely used drug for the treatment of various ophthalmologic disease. In addition to cosmetic uses, botulinum toxin injection can be useful in the treatment of a variety of ocular muscle disorders, including strabismus [1], blepharospasm [2], upper eye lid retraction [3], entropion [4] and facial paralysis [5]. Botulinum toxin acts by blocking the release of acetylcholine from the synaptic cleft of the neuromuscular junction, thereby leading to chemical denervation of the muscle and reduced muscle activity. Further, during strabismus surgery, botulinum toxin acts to weaken the antagonist muscle and correct the deviation of the eyeball [6].\n\nRhegmatogenous retinal detachment (RRD) occurs when liquefied vitreous enters a previously created retinal hole or tear and causes detachment between the neurosensory retina and the retinal pigment epithelium (RPE). The detached retina should be reattached promptly to avoid severe vision loss. Surgical interventions to treat RRD include pars plana vitrectomy (PPV), scleral buckle (SB), PPV with a SB, and pneumatic retinopexy [7]. Proliferative vitreoretinopathy (PVR), a major complication of chronic RRD, is a common cause for the failure of surgical repairs. The prognosis of patients with PVR is poor because many cytokines derived from the vitreous trigger proliferation and migration of the RPE, leading to epithelial-mesenchymal transition and formation of a fibrous membrane that aggravates retinal detachment [8–11].\n\nAlthough complications, including edema, bruising, pain, and headache, can occur as a result of botulinum toxin injection, most are self-limited and only last a short period [12]. However, severe complications, such as perforation of the globe, may develop inadvertently as a result.\n\nThe authors report a case of a young female who was diagnosed with RRD with PVR 6 days after botulinum toxin injection into the extraocular muscle. The patient was healed completely through surgical intervention.\n\nCase presentation\nA 34-year-old female patient, with a history of laser epithelial keratomileusis, visited our clinic for diplopia and ocular motility disorder after removal of an epidermoid tumor at the prepontine cistern of the brain because of right 6th nerve palsy. At her initial visit, her best-corrected visual acuity (BCVA) was 20/20 for both eyes. An alternate cover test showed 45 prism-diopter esotropia and 3 prism-diopter hypertropia in the right eye. The patient was diagnosed with paralytic strabismus, and we planned to observe her for about two to three months to check changes in the amount of deviation. However, as the patient failed to visit outpatient clinic since then, further follow-up was unavailable. She revisited at 6 months after the development of her first symptom. Following 6 months of observation, angle of deviation did not improve, and 0.2 cm3 of botulinum toxin (2.5 international units) were injected into the right medial rectus (RMR). After 6 days, she visited our clinic complaining of decreased visual acuity of her right eye. The BCVA and intraocular pressure (IOP) for her right eye were found to be 20/50 and 15 mmHg, respectively. Based on funduscopic examination, a retinal hole was located 4 DD (disc diameter) inferonasally from the optic disc, and both preretinal and vitreous hemorrhages were present in front of the lesion (Fig. 1a). Optical coherence tomography (OCT) examination revealed subretinal fluid nasal to the fovea, but central fovea was attached (Fig. 1b, c). The patient was diagnosed with RRD with macula off, but because of small subretinal fluid and tiny retinal break, we decided to observe it first. Barrier laser photocoagulation around the retinal hole was performed (Fig. 1d). However, the patient’s visual acuity continued to decrease without improvement of vitreous hemorrhage, and at 12 weeks after botulinum toxin injection, a newly developed tractional membrane from macula to inferonasal periphery was noted, suggesting PVR development (Fig. 2a, b). An alternate cover test presented 30 prism-diopter right esotropia. 19 weeks following RMR botulinum toxin injection, she received PPV, membranectomy, peeling of the internal limiting membrane, and endolaser barrier photocoagulation. After 4 months, her visual acuity improved to 20/20, and only 4 prism-diopter of right hypertropia and 3 prism-diopter of exotropia were noted. Vitreous opacity and the epiretinal membrane were completely removed (Fig. 2c, d). Serious adverse complications, including endophthalmitis, retinal re-detachment, and increased IOP, were not observed.Fig. 1 6 days after botulinum toxin injection to the right medial rectus muscle. a A wide-field color fundus photo shows a retinal tear inferonasal to the optic disc with preretinal hemorrhage nearly blocking the site. b, c SD-OCT B-scan images reveal subretinal fluid nasal to the fovea; however, the central fovea was intact. d One week after application of barrier laser photocoagulation around the retinal tear, the preretinal hemorrhage remained inferior to the optic disc\n\n\nFig. 2 \na 11 weeks after botulinum toxin injection. Note the fibrous membrane extending from the macula to the nasal mid-periphery and the vitreous hemorrhage that remained at the inferonasal quadrant. b A SD-OCT cross-sectional image reveals a thick epiretinal membrane corresponding to the fibrous membrane adherent to the central macula. c 18 weeks after PPV with visual acuity of 20/20. The scar change nasal to the optic disc remained, but the overall retina was remarkably flattened. d A SD-OCT B-scan image showed the flattened retina with minimal intraretinal cystic changes and a recovered photoreceptor layer\n\n\n\n\nDiscussion and conclusions\nAlthough botulinum toxin is a relatively safe medication with few complications, some unexpected, adverse events can occur after injection. And a majority of those adverse events occurred immediately after or during procedure [13–15]. Liu M et al. reported a case in which the botulinum toxin was improperly injected into the vitreous cavity of a patient receiving treatment to the right medial rectus, resulting in increased IOP, decreased visual acuity, and retinal detachment [13]. The patient received topical and oral antibiotic treatment and spontaneously recovered without any further complications. In our case, however, the retinal detachment did not improve spontaneously, and the development of PVR necessitated surgical intervention.\n\nMost studies have found intraocular botulinum toxin injection to be safe. Kutlut S et al. reported no difference in the retinal function of rabbit eyes that received intraocular botulinum toxin injection versus controls that received only intraocular saline injection, as confirmed by visual evoked potential and electroretinogram (ERG) test [16]. Likewise, Gatzioufas Z et al. reported IOP immediately increased after intravitreal botulinum toxin injection in normotensive rats; however, the density of retinal ganglion cells and immunostaining pattern of rhodopsin and retinal glial fibrillary acidic protein showed no difference between the group injected with botulinum toxin and the control group injected with balanced salt solution [17]. Pehere N et al. reported a case of unintentional injection of botulinum toxin into the eyeball that recovered without any complications other than a slight increase in intraocular pressure [18]. In our case, small amount of botulinum toxin, which might have been injected into the eyeball, did not affect the final visual acuity or intraocular pressure. To sum up, these reports suggest that, in most cases, botulinum toxin injected inadvertently into the eyeball does not appear to be toxic. However, periorbital botulinum toxin injection can cause mydriasis of the pupil, resulting in acute angle closure attack [19]. Further, spreading of the botulinum toxin to adjacent muscles, including the levator and inferior rectus muscles, can lead to the development of ptosis or vertical strabismus [20]. To solve these problems, peri- or retrobulbar anesthesia should be considered when electromyography (EMG) is not available [14]. By stretching the extraocular muscle slightly to make a free space between the extraocular muscle and the ocular surface [21], unintentional perforation of the globe can be prevented.\n\nAlthough the procedure was done under EMG guidance, the patient underwent scleral perforation. Her axial length which was taken before PPV was 25.15 mm, which suggests that the patient might have had moderate myopia. Myopia is known to be a risk factor for scleral perforation in various surgical interventions, including strabismus surgery [22] and retro- or peribulbar anesthesia [23]. Therefore, we concluded that the risk factor was obscured due to past history of refractive surgery. Accordingly, when planning botulinum toxin injection into extraocular muscle, surgeon should be fully aware of patient’s refractive error as well as history of any kind of refractive surgery, in order to prevent inadvertent scleral perforation (Additional file 1 and Additional file 2).\n\nIn this case, the procedure was performed under EMG guidance, and no immediate problems were observed. However, after 6 days, the patient visited our clinic because of decreased visual acuity, and retinal detachment with preretinal hemorrhage was present. And the patient eventually had to undergo surgery to correct for the anatomical abnormality. Thus, the authors suggest that if a patient comes to the hospital presenting with a sudden loss of vision after botulinum toxin injection, a thorough ophthalmic examination, which includes a funduscopic examination, should be performed. If improvement is not observed, prompt surgical intervention must be executed to avoid more serious complications. To prevent such serious complications, surgeons should thoroughly review the patient’s past history and perform detailed examination to identify various risk factors, such as myopia and scleral scar, when planning botulinum toxin injection into extraocular muscle.\n\nIn conclusion, physicians should pay close attention to the uncommon complications that may arise during botulinum toxin injection, and respond properly in a suspicious situation with a variety of methods including either medical or surgical intervention. Moreover, knowing the patient’s risk factors before treatment helps to reduce such complications.\n\nAdditional files\n\nAdditional file 1: Patient Perspective. This document has been confirmed to the patient who was the subject of this case report. (DOCX 17 kb)\n\n \nAdditional file 2: Timeline Picture of Our Case Report. This document is a simple diagram that shows a patient’s visit to our hospital, a series of tests that she had received, and healed course. (DOCX 46 kb)\n\n \n\n\nAbbreviations\nBCVABest-corrected visual acuity\n\nDDDisc diameter\n\nEMGElectromyography\n\nERGElectroretinogram\n\nIOPIntraocular pressure\n\nOCTOptical coherence tomography\n\nPPVPars plana vitrectomy\n\nPVRProliferative vitreoretinopathy\n\nRMRRight medial rectus\n\nRPERetinal pigment epithelium\n\nRRDRhegmatogenous retinal detachment\n\nSBScleral buckle\n\nElectronic supplementary material\n\nThe online version of this article (10.1186/s12886-017-0649-2) contains supplementary material, which is available to authorized users.\n\nAcknowledgements\nNot applicable.\n\nFunding\nThe authors declare that they have no sources of funding.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nInvolved in Conception and design of study (DHL, JH, SHH, MK); and Writing the article (DHL, MK); Critical revision of the article (SCL); and final approval of the manuscript (all authors).\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient.\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. Donahue SP Botulinum toxin treatment for esotropia Am Orthopt J 2013 63 29 31 10.3368/aoj.63.1.29 24260805 \n2. Sung Y Nam SM Lew H Clinical outcomes of individualized botulinum neurotoxin type a injection techniques in patients with essential blepharospasm Korean J Ophthalmol 2015 29 2 115 120 10.3341/kjo.2015.29.2.115 25829828 \n3. Chuenkongkaew W Botulinum toxin treatment for upper lid retraction of dysthyroidism J Med Assoc Thail 2003 86 11 1051 1054 \n4. Deka A Saikia SP Botulinum toxin for lower lid entropion correction Orbit 2011 30 1 40 42 10.3109/01676830.2010.544443 21281080 \n5. Cooper L Lui M Nduka C Botulinum toxin treatment for facial palsy: a systematic review J Plast Reconstr Aesthet Surg 2017 70 6 833 841 10.1016/j.bjps.2017.01.009 28389084 \n6. Akbari MR Ameri A Keshtkar Jaafari AR Mirmohammadsadeghi A Botulinum toxin injection for restrictive myopathy of thyroid-associated orbitopathy: success rate and predictive factors J aapos 2016 20 2 126 130 10.1016/j.jaapos.2016.01.007 27079592 \n7. Haugstad M, Moosmayer S, Bragadόttir R. Primary rhegmatogenous retinal detachment - surgical methods and anatomical outcome. Acta Ophthalmol. 2017;95(3):247–51.\n8. Ciprian D The Pathogeny of proliferative Vitireoretinopathy Rom J Ophthalmol 2015 59 2 88 92 26978867 \n9. Danielescu C Zugun-Eloae F Zlei M Concentrations of Vitreal cytokines in Rhegmatogenous retinal detachment Rev Med Chir Soc Med Nat Iasi 2016 120 1 124 129 27125084 \n10. Yang S Li H Li M Wang F Mechanisms of epithelial-mesenchymal transition in proliferative vitreoretinopathy Discov Med 2015 20 110 207 217 26562474 \n11. Charteris DG Proliferative vitreoretinopathy: pathobiology, surgical management, and adjunctive treatment Br J Ophthalmol 1995 79 10 953 960 10.1136/bjo.79.10.953 7488586 \n12. Basar E Arici C Use of Botulinum neurotoxin in ophthalmology Turk J Ophthalmol 2016 46 6 282 290 28050326 \n13. Liu M Lee HC Hertle RW Ho AC Retinal detachment from inadvertent intraocular injection of botulinum toxin a Am J Ophthalmol 2004 137 1 201 202 10.1016/S0002-9394(03)00837-7 14700677 \n14. Agrawal S Singh V Gupta SK Kumar BV Vitreous hemorrhage following inadvertent intra-ocular injection of botulinum toxin Oman J Ophthalmol 2015 8 1 79 80 10.4103/0974-620X.149905 25709290 \n15. Mohan M Fleck BW Globe perforation during botulinum toxin injection Br J Ophthalmol 1999 83 4 503 504 10.1136/bjo.83.4.501d 10434880 \n16. Kutluk S Akar S Topcu M Kural G Effect of botulinum toxin injections into rabbit eye Strabismus 1999 7 4 221 226 10.1076/stra.7.4.221.625 10694913 \n17. Gatzioufas Z Stupp T Moschos MM Kopsidas K Charalambous P Thanos S Effect of botulinum toxin a on the intraocular pressure and the retina in an animal model Cutan Ocul Toxicol 2013 32 2 107 111 10.3109/15569527.2012.713419 22917001 \n18. Pehere N Jalali S Mathai A Naik M Ramesh K Inadvertent intraocular injection of botulinum toxin a J Pediatr Ophthalmol Strabismus 2011 48 Online e1 e3 21261223 \n19. Zheng L Azar D Angle-closure glaucoma following periorbital botulinum toxin injection Clin Exp Ophthalmol 2014 42 7 690 693 10.1111/ceo.12293 24373149 \n20. Lennerstrand G Nordbo OA Tian S Eriksson-Derouet B Ali T Treatment of strabismus and nystagmus with botulinum toxin type A. An evaluation of effects and complications Acta Ophthalmol Scand 1998 76 1 27 10.1034/j.1600-0420.1998.760106.x 9541431 \n21. Wan XM Chu RX Gong HQ Minimally invasive botulinum toxin type a injection from the ocular surface to extraocular muscles Int J Ophthalmol 2011 4 2 179 181 22553637 \n22. Park K Hong S Chung W Kim SS Byeon SH Seong GJ Lee JB Han SH Inadvertent scleral perforation after strabismus surgery: incidence and association with refractive error Can J Ophthalmol 2008 43 6 669 672 10.3129/i08-151 19020632 \n23. Schrader WF Schargus M Schneider E Josifova T Risks and sequelae of scleral perforation during peribulbar or retrobulbar anesthesia J Cataract Refract Surg 2010 36 6 885 889 10.1016/j.jcrs.2009.12.029 20494757\n\n",
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"issue": "17(1)",
"journal": "BMC ophthalmology",
"keywords": "Botulinum toxin; Retinal detachment; Strabismus; Vitreous hemorrhage",
"medline_ta": "BMC Ophthalmol",
"mesh_terms": "D000328:Adult; D001905:Botulinum Toxins; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D056965:Injections, Intraocular; D009498:Neurotoxins; D012163:Retinal Detachment; D014823:Vitreous Hemorrhage",
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"title": "Vitreous hemorrhage and Rhegmatogenous retinal detachment that developed after botulinum toxin injection to the extraocular muscle: case report.",
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"abstract": "A previous study suggested that a thymine (THY) challenge dose could detect aberrant pharmacokinetics in known cases of fluoropyrimidine toxicity compared with healthy volunteers. The preliminary data suggested that urine sampling also could detect this aberrant disposition. The aim of this case-control study was to assess the ability of the urinary THY challenge test to discriminate cases of severe gastrointestinal toxicity in a cohort of patients treated with 5-fluorouracil or capecitabine.\n\n\n\nPatients (n = 37) received a 250 mg (per os) dose of THY and a cumulative urine sample was collected for 0-4 h. The urinary amounts of THY and metabolite dihydrothymine (DHT) were determined by liquid chromatography/mass spectrometry. Genomic DNA was analysed for DPYD gene variants. Renal function was estimated from blood creatinine levels. Cases (n = 9) and noncases (n = 23) of severe (grade ≥ 3) gastrointestinal toxicity were defined based on Common Terminology Criteria for Adverse Events.\n\n\n\nThe median THY/DHT ratios were 6.2 (interquartile range 2.9-6.4) in cases, including the 2 patients who were DPYD heterozygous carriers. However, this was not significantly different (P = .07) from the THY/DHT in noncases (median 2.6, interquartile range 2.8-4.2). Although creatinine clearance was lower (P = .001) in cases, renal function could not discriminate cases from noncases. However, logistic regression analysis using both of these explanatory variables could discriminate most cases (receiver operating characteristic area 0.8792, 95% confidence interval 0.72-1.00).\n\n\n\nThe THY challenge test combined with a patient's renal function may be useful as a phenotypic diagnostic test to detect risk of life-threatening fluoropyrimidine gastrointestinal toxicity.",
"affiliations": "Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.;School of Pharmacy, University of Queensland, Australia.;Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.;Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.;Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.;Blood and Cancer, Auckland City Hospital, Grafton, Auckland, New Zealand.;Blood and Cancer, Auckland City Hospital, Grafton, Auckland, New Zealand.;Department of Mathematics and Statistics, University of Otago, New Zealand.;Blood and Cancer, Auckland City Hospital, Grafton, Auckland, New Zealand.;Blood and Cancer, Auckland City Hospital, Grafton, Auckland, New Zealand.",
"authors": "Helsby|Nuala A|NA|0000-0001-6570-5368;Duley|John|J|;Burns|Kathryn E|KE|0000-0003-4951-3539;Bonnet|Claire|C|;Jeong|Soo Hee|SH|;Brenman|Elliott|E|;Barlow|Paula|P|;Sharples|Katrina|K|;Porter|David|D|;Findlay|Michael|M|",
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"mesh_terms": "D000069287:Capecitabine; D016022:Case-Control Studies; D003955:Diagnostic Tests, Routine; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil; D006801:Humans; D013941:Thymine",
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"title": "A case-control study to assess the ability of the thymine challenge test to predict patients with severe to life threatening fluoropyrimidine-induced gastrointestinal toxicity.",
"title_normalized": "a case control study to assess the ability of the thymine challenge test to predict patients with severe to life threatening fluoropyrimidine induced gastrointestinal toxicity"
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"abstract": "Staphylococcus aureus as a pathogen in human gestational membranes, a rather rare phenomenon, has recently been the focus of several researches. S. aureus forms biofilms on these membranes and potentially causes chorioamnionitis in pregnant women. We report a case of persistent methicillin-resistant S. aureus (MRSA) bacteremia owing to placental infection, causing chorioamnionitis and preterm birth. A 29-year-old Japanese woman at the 27th gestational week was diagnosed with acute promyelocytic leukemia and underwent all-trans retinoic acid therapy. Soon after hospitalization, the patient presented with persistent MRSA bacteremia of unknown origin. Despite various antimicrobial therapies, she experienced 12 MRSA bacteremia episodes over 6 weeks. However, after child birth, MRSA bacteremia disappeared without any complications. A pathologic examination of her placenta revealed placenta abscess, resulting in a diagnosis of MRSA-associated chorioamnionitis. Molecular analysis proved that a single MRSA strain (SCCmec Type IVa), which tested negative for Panton-Valentine leukocidin and toxic shock syndrome toxin-1, caused the obstinate infection. We should be aware that persistent MRSA bacteremia in pregnant women can originate from placental abscess.",
"affiliations": "Division of Infection Control and Prevention, Osaka University Hospital, Japan.;Division of Infection Control and Prevention, Osaka University Hospital, Japan. Electronic address: highgear@hp-infect.med.osaka-u.ac.jp.;Department of Obstetrics and Gynecology, Osaka University Hospital, Japan.;Department of Hematology, Osaka University Hospital, Japan.;Department of Hematology, Osaka University Hospital, Japan.;Laboratory for Clinical Investigation, Osaka University Hospital, Japan.;Department of Obstetrics and Gynecology, Osaka University Hospital, Japan.;Department of Pathology, Osaka University Hospital, Japan.;Department of Pathology, Osaka University Hospital, Japan.;Department of Pathology, Osaka University Hospital, Japan.;Department of Hematology, Osaka University Hospital, Japan.;Department of Obstetrics and Gynecology, Osaka University Hospital, Japan.;Division of Infection Control and Prevention, Osaka University Hospital, Japan.",
"authors": "Maeda|Naomi|N|;Hagiya|Hideharu|H|;Takiuchi|Tsuyoshi|T|;Kusakabe|Shinsuke|S|;Maeda|Tetsuo|T|;Kimura|Keigo|K|;Iwai|Sayuri|S|;Kawasaki|Keisuke|K|;Hori|Yumiko|Y|;Morii|Eiichi|E|;Kanakura|Yuzuru|Y|;Kimura|Tadashi|T|;Tomono|Kazunori|K|",
"chemical_list": "D001427:Bacterial Toxins; D005098:Exotoxins; D007956:Leukocidins; C078284:Panton-Valentine leukocidin; D014212:Tretinoin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2018.05.001",
"fulltext": null,
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"issn_linking": "1341-321X",
"issue": "24(12)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Chorioamnionitis; Febrile neutropenia; Leukemia; Methicillin-resistant Staphylococcus aureus; Persistent bacteremia; Staphylococcus aureus bacteremia",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D018784:Abdominal Abscess; D000328:Adult; D016470:Bacteremia; D001427:Bacterial Toxins; D002821:Chorioamnionitis; D005098:Exotoxins; D005260:Female; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D007956:Leukocidins; D055624:Methicillin-Resistant Staphylococcus aureus; D010198:Pancytopenia; D010920:Placenta; D011247:Pregnancy; D013203:Staphylococcal Infections; D014212:Tretinoin",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "975-979",
"pmc": null,
"pmid": "29804839",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Persistent methicillin-resistant Staphylococcus aureus bacteremia owing to placental abscess.",
"title_normalized": "persistent methicillin resistant staphylococcus aureus bacteremia owing to placental abscess"
} | [
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"companynumb": "JP-TEVA-2018-JP-988582",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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"activesubstancename": "METHYLPREDNISOLONE"
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{
"abstract": "Subacute cutaneous lupus erythematosus (SCLE) is a well-defined subtype of lupus erythematosus, characterised by photosensitivity, annular and/or psoriasiform lesions, variable systemic involvement and presence of circulating SSA/anti-Ro antibodies. SCLE may be idiopathic or drug-induced. Both the idiopathic and drug-induced forms of SCLE are analogous in their clinical, serological and histological features. Drug-induced SCLE has been reported with various oral agents, but to our knowledge this is the first reported case due to a topical medication. A 34-year-old female foot masseuse presented with a 2-month history of scaly, erythematous lesions isolated to the dorsal hands and interdigital spaces. She had used topical terbinafine, a topical antifungal cream, to her clients' feet for a number of years. ANA and anti-SSA/Ro antibodies were positive. Physical examination, serology and histopathology were consistent with SCLE. We propose that our patient's unique presentation of SCLE may be explained by a prolonged occupational exposure to topical terbinafine as a foot masseuse. While oral terbinafine is a drug known to cause drug-induced SCLE, to our knowledge, this is the first topically induced form of the disease.",
"affiliations": "The Ronald O. Perelman Department of Dermatology , New York University School of Medicine , New York, New York , USA.;The Ronald O. Perelman Department of Dermatology , New York University School of Medicine , New York, New York , USA.;The Ronald O. Perelman Department of Dermatology , New York University School of Medicine , New York, New York , USA.;The Ronald O. Perelman Department of Dermatology , New York University School of Medicine , New York, New York , USA.;The Ronald O. Perelman Department of Dermatology , New York University School of Medicine , New York, New York , USA.;The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA; Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, New York, USA.",
"authors": "Ramachandran|Sarika M|SM|;Leventhal|Jonathan S|JS|;Franco|Loren G|LG|;Mir|Adnan|A|;Walters|Ruth F|RF|;Franks|Andrew G|AG|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/lupus-2017-000207",
"fulltext": "\n==== Front\nLupus Sci MedLupus Sci MedlupusscimedlupusLupus Science & Medicine2053-8790BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR lupus-2017-00020710.1136/lupus-2017-000207Case Report1506Topical drug-induced subacute cutaneous lupus erythematosus isolated to the hands Ramachandran Sarika M 1Leventhal Jonathan S 1Franco Loren G 1Mir Adnan 1Walters Ruth F 1Franks Andrew G Jr121 The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA2 Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, New York, USACorrespondence to Professor Andrew G Franks, Jr; andrew.franks@nyumc.org2017 13 3 2017 4 1 e00020717 1 2017 11 2 2017 14 2 2017 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/2017This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Subacute cutaneous lupus erythematosus (SCLE) is a well-defined subtype of lupus erythematosus, characterised by photosensitivity, annular and/or psoriasiform lesions, variable systemic involvement and presence of circulating SSA/anti-Ro antibodies. SCLE may be idiopathic or drug-induced. Both the idiopathic and drug-induced forms of SCLE are analogous in their clinical, serological and histological features. Drug-induced SCLE has been reported with various oral agents, but to our knowledge this is the first reported case due to a topical medication. A 34-year-old female foot masseuse presented with a 2-month history of scaly, erythematous lesions isolated to the dorsal hands and interdigital spaces. She had used topical terbinafine, a topical antifungal cream, to her clients’ feet for a number of years. ANA and anti-SSA/Ro antibodies were positive. Physical examination, serology and histopathology were consistent with SCLE. We propose that our patient's unique presentation of SCLE may be explained by a prolonged occupational exposure to topical terbinafine as a foot masseuse. While oral terbinafine is a drug known to cause drug-induced SCLE, to our knowledge, this is the first topically induced form of the disease.\n\nAutoimmune DiseasesSystemic Lupus ErythematosusAutoantibodies\n==== Body\nIntroduction\nCutaneous lupus erythematosus (CLE) is an autoimmune disease characterised by a wide spectrum of skin lesions that typically occur on sun-exposed areas of the skin. In addition to the classical forms of CLE, which include discoid lupus erythematosus and subacute cutaneous lupus erythematosus (SCLE), there are uncommon subsets and atypical clinical variants, which may be diagnostically challenging.1 Furthermore, different forms of cutaneous lupus may be induced by various drugs. Drug-induced SCLE has been associated with common systemic medications such as hydrochlorothiazide, calcium channel blockers, angiotensin-converting enzyme inhibitors, proton pump inhibitors, tumour necrosis factor (TNF)-α inhibitors, chemotherapy agents and terbinafine.1–3\n\nWe report the case of a foot masseuse with an unusual presentation of SCLE isolated to the dorsum of the hands and interdigital spaces. We propose that occupation as a foot masseuse may have predisposed the patient to sensitisation to topical terbinafine and may explain the patient's condition. The diagnosis, aetiological factors and pathophysiology will be discussed.\n\nCase report\nAn otherwise healthy foot masseuse presented to the Dermatology Clinic at Bellevue Hospital Center with a chief complaint of hand lesions for 2 months, associated with skin peeling and itchiness. The patient had no other medical complaints, no significant medical history and was on no other medications. The patient reported working as a foot masseuse for many years and admitted to regularly applying topical terbinafine to the clients' feet without gloves. The patient denied any history of hand lesions prior to entering this profession.\n\nPhysical examination revealed well-demarcated, scaling, erythematous plaques with hyperpigmented borders and some erosive, indurated plaques interdigitally and on the dorsum of the hands (figure 1). The lesions were confined to the dorsum of the hands and interdigital spaces. No similar lesions were found elsewhere on the body. A Potassium hydroxide (KOH) was negative, and the patient's hand dermatitis was treated as a contact dermatitis with clobetasol 0.05% ointment. On return visit 1 month later, there was no improvement and fungal culture was also negative. Two skin biopsies were then performed on the left fourth digit and left dorsal hand.\n\nFigure 1 Topical terbinafine-induced subacute cutaneous lupus erythematosus. Scaling erythematous plaques with hyperpigmented borders and erosive, indurated plaques interdigitally.\n\nHistopathology of both skin biopsies revealed superficial and deep perivascular, periadnexal and band-like infiltrate comprised of lymphocytes, histiocytes and rare plasma cells. Lymphocytes extended to the overlying, slightly hyperplastic epidermis with vacuolar changes, numerous necrotic keratinocytes and hyperkeratosis with foci of parakeratosis. A Periodic acid-Schiff (PAS)-D stain revealed slight thickening of the basement membrane and no evidence of fungal hyphae. A colloidal iron stain revealed increased deposits of connective tissue mucin throughout the dermis, most prominent in the reticular dermis. No spongiosis was noted (figure 2A,B). These findings were most consistent with a connective tissue disease such as discoid lupus or SCLE.\n\nFigure 2 (A) Topical terbinafine-induced subacute cutaneous lupus erythematosus (SCLE). H&E stain revealed hyperkeratosis, superficial and deep perivascular lymphohistiocytic infiltrate, vacuolar changes and deposits of connective tissue mucin in dermis. (B) Topical terbinafine-induced SCLE. Colloidal iron stain revealed increased deposits of connective tissue mucin throughout the dermis, most prominent in the reticular dermis.\n\nLaboratory evaluation performed after biopsy revealed normal complete blood count, kidney function, hepatic panel and urinalysis. ANA was positive in a speckled pattern at a titre of 1:40, anti-Anti-Sjögren's syndrome type A (SSA)/Ro antibody was positive at 1.6 Antibody Index (AI) and anti-Anti-Sjögren's syndrome type B (SSB)/La antibody was negative. Based on the clinical history, physical examination, histopathology and serology, the diagnosis of acral SCLE was made. After discontinuation of topical terbinafine, the lesions gradually resolved, and on telephone follow-up 6 months later there has been no further recurrence of the illness.\n\nDiscussion\nCLE is a highly photosensitive condition that usually affects sun-exposed areas of the face and scalp.1 It does not commonly affect the hands in isolation without any other lesions in more photosensitive areas of the body. A literature search disclosed many reports on CLE and involvement of acral surfaces, none of which described this rare and atypical clinical presentation of isolated dorsal and interdigital SCLE.4\n5 Of those cases reported in the literature, the majority presented with discoid lesions.4\n5 Our patient had primarily scaly, erythematous lesions of the fingers and interdigital spaces that were clinically most consistent with SCLE and supported by positive speckled ANA and positive anti-SSA/Ro antibodies.1\n2\n6\n7 SCLE may be induced by various oral medications, most commonly antihypertensive agents and oral terbinafine.2 One study found that patients with drug-induced SCLE were older, had more extensive skin involvement and had an increased incidence of bullous, erythema multiforme-like and vasculitic lesions compared with individuals with idiopathic SCLE.7 Photodistribution is characteristic as in our patient, and resolution occurred within a few months without treatment as noted in the literature.8 Interestingly, our patient's unusual presentation of localised SCLE lesions on the hands may be explained by an occupational exposure to a topical drug, namely terbinafine.\n\nAs a foot masseuse, the patient was exposed almost daily to topical terbinafine. Systemic administration of this agent is a well-known cause of drug-induced SCLE, but there are no reports of topical induction of SCLE.1\n2\n6\n8\n9 Terbinafine is an allylamine with antimycotic effects that is used in the treatment of fungal foot and nail infections.10 It is a highly lipophilic substance that may concentrate in the skin, nails and fatty tissue for a prolonged period of time10 While topical terbinafine is not readily absorbed into the systemic circulation and therefore would unlikely cause systemic lupus flare, the possibility arises that if locally absorbed it may induce focal development of SCLE10 Studies have demonstrated that the average incubation time for terbinafine-induced SCLE was 5.1 weeks (range 1–12 weeks).6\n9 Our patient's initial lesions on the dorsal hand and interdigital spaces may have resulted from prolonged exposure to topical terbinafine.\n\nOur patient's cutaneous manifestation of SCLE on the hands is noteworthy because of the sparing of the palmar surfaces. In an occupational exposure as a foot masseuse, one would expect lesions on the volar surfaces as well. One possible explanation is that the thickness of the palmar surface of the hand limited the permeability of topical terbinafine, as opposed to the thinner skin on the dorsum of the hand. Studies have shown that skin permeability is variable in different areas of the body, being generally greatest in thin-skinned surfaces.11 Another explanation for involvement of the dorsum of the hand versus the palmar surface is increased exposure to ambient Ultraviolet (UV) radiation. Whether the UV radiation, medication or a combination of these exogenous factors precipitated the patient's condition is not clear.\n\nThere are suggested hypotheses for the pathogenesis of idiopathic and drug-induced SCLE. Genetics have been shown to play an important role in the development of SCLE, specifically in individuals with human leucocyte antigen (HLA) B8, HLA-DR3, HLA-DRw52 and HLA-DQ1.12 It is speculated that UV radiation stimulates keratinocytes and dermal fibroblasts to release cytokines such as TNF-α and interleukins involved in immunomodulation and apoptotic pathways in SCLE.13 In addition, nuclear antigens (including anti-SSA/Ro) in keratinocytes that have been translocated to the cell surface may be targeted by circulating anti-SSA/Ro antibodies and cytotoxic T cells.7\n13 In drug-induced SCLE, the induction of a photosensitivity state by certain medications may induce skin lesions via an isomorphic (Köebner) response in predisposed individuals.2 Terbinafine is capable of producing a photosensitivity state and is speculated to induce SCLE through this mechanism.2 The pathogenesis of drug-induced SCLE may vary according to individual medications.2 For example, hydrochlorothiazide is hypothesised to enhance the cytotoxicity of anti-Ro antibodies and induce epidermal cytotoxicity through direct phototoxicity.3\n\nThis case represents a rare and interesting instance of SCLE isolated to the dorsum of the hand and interdigital spaces. We propose that localised exposure of the hands to topical terbinafine in an occupational setting was the cause of this unusual presentation. Although little is known about the absorption and pharmacodynamics of topical terbinafine, its potential to induce SCLE topically deserves further investigation.\n\nContributors: JSL, LGF, AM, SMR, RFW and AGF had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: SMR and AGF. Acquisition, analysis and interpretation of data: JSL, AGF, AM, SMR, RFW and AGF. Drafting of the manuscript: JSL, LGF, SMR and AGF. Critical revision of the manuscript for important intellectual content: SMR and AGF. Obtained funding: AGF. Study supervision: AGF.\n\nFunding: The Frances and Benjamin Benenson Foundation and Lynn and William M. Silverman Donation Fund.\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData sharing statement: No additional data are available.\n==== Refs\nReferences\n1 Werth VP \nClinical manifestations of cutaneous lupus erythematosus . Autoimmun Rev \n2005 ;4 :296 –302 . doi:10.1016/j.autrev.2005.01.00315990077 \n2 Lowe GC , Henderson CL , Grau RH \nA systematic review of drug-induced subacute cutaneous lupus erythematosus . Br J Dermatol \n2011 ;164 :465 –72 . doi:10.1111/j.1365-2133.2010.10110.x21039412 \n3 Shapiro M , Sosis AC , Junkins-Hopkins JM \nLupus erythematosus induced by medications, ultraviolet radiation, and other exogenous agents: a review, with special focus on the development of subacute cutaneous lupus erythematosus in a genetically predisposed individual . Int J Dermatol \n2004 ;43 :87 –94 . doi:10.1111/j.1365-4632.2004.02013.x15125497 \n4 Ashinoff R , Werth VP , Franks AG Jr \nResistant discoid lupus erythematosus of palms and soles: successful treatment with azathioprine . J Am Acad Dermatol \n1988 ;19 :961 \ndoi:10.1016/S0190-9622(88)70259-53192780 \n5 Prystowsky SD , Herndon JH Jr, Gilliam JN \nChronic cutaneous lupus erythematosus (DLE)—a clinical and laboratory investigation of 80 patients . Medicine (Baltimore) \n1976 ;55 :183 –91 . doi:10.1097/00005792-197603000-000061082971 \n6 Lorentz K , Booken N , Goerdt S \nSubacute cutaneous lupus erythematosus induced by terbinafine: case report and review of literature . J Dtsch Dermatol Ges \n2008 ;6 :823 –7 , 823–8 \ndoi:10.1111/j.1610-0387.2008.06806.x18564209 \n7 Marzano AV , Lazzari R , Polloni I \nDrug-induced subacute cutaneous lupus erythematosus: evidence for differences from its idiopathic counterpart . Br J Dermatol \n2011 ;165 :335 –41 . doi:10.1111/j.1365-2133.2011.10397.x21564069 \n8 Srivastava M , Rencic A , Diglio G \nDrug-induced, Ro/SSA-positive cutaneous lupus erythematosus . Arch Dermatol \n2003 ;139 :45 –9 .12533163 \n9 Kasperkiewicz M , Anemüller W , Angelova-Fischer I \nSubacute cutaneous lupus erythematosus associated with terbinafine . Clin Exp Dermatol \n2009 ;34 :e403 –4 . doi:10.1111/j.1365-2230.2009.03380.x19549237 \n10 Hill S , Thomas R , Smith SG \nAn investigation of the pharmacokinetics of topical terbinafine (Lamisil) 1% cream . Br J Dermatol \n1992 ;127 :396 –400 . doi:10.1111/j.1365-2133.1992.tb00461.x1419761 \n11 Cronin E , Stoughton RB \nPercutaneous absorption. Regional variations and the effect of hydration and epidermal stripping . Br J Dermatol \n1962 ;74 :265 –72 .13882336 \n12 Lin JH , Dutz JP , Sontheimer RD \nPathophysiology of cutaneous lupus erythematosus . Clin Rev Allergy Immunol \n2007 ;33 :85 –106 . doi:10.1007/s12016-007-0031-x18094949 \n13 Werth VP , Zhang W , Dortzbach K \nAssociation of a promoter polymorphism of tumor necrosis factor-alpha with subacute cutaneous lupus erythematosus and distinct photoregulation of transcription . J Invest Dermatol \n2000 ;115 :726 –30 . doi:10.1046/j.1523-1747.2000.00118.x10998151\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2053-8790",
"issue": "4(1)",
"journal": "Lupus science & medicine",
"keywords": "Autoantibodies; Autoimmune Diseases; Systemic Lupus Erythematosus",
"medline_ta": "Lupus Sci Med",
"mesh_terms": null,
"nlm_unique_id": "101633705",
"other_id": null,
"pages": "e000207",
"pmc": null,
"pmid": "28331627",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "1082971;15990077;13882336;3192780;10998151;21039412;15125497;12533163;18094949;21564069;19549237;18564209;1419761",
"title": "Topical drug-induced subacute cutaneous lupus erythematosus isolated to the hands.",
"title_normalized": "topical drug induced subacute cutaneous lupus erythematosus isolated to the hands"
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"companynumb": "US-CIPLA LTD.-2017US24457",
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"abstract": "Scedosporium apiospermum complex as a ubiquitous environmental mold is increasingly reported to cause an invasive fungal infection in immunosuppressive hosts. Herein, we present the case of an immunosuppressive 54 - year-old man who developed S. apiospermum complex lung infection and pulmonary adenocarcinoma.\nThe patient had some complaints of dyspnea and cough during a neutropenic episode. The computed tomography (CT) scan of the patient revealed pleural effusion. After culturing the pleural fluid sample, the fungus was identified by microscopic examination and ITS sequencing. In addition, antifungal susceptibility testing was performed using the M38-A2 microdilution method. The minimum inhibitory concentrations of amphotericin B, voriconazole, posaconazole, and caspofungin were obtained as > 64, 0.06, 0.06, and 0.03 µg/mL, respectively. Voriconazole (administered in two doses of 6 mg/kg and a maximum of 250 mg) was preferred for treatment. The patient received antifungal treatment for 2 months; however, he was lost to follow-up.\nScedosporium apiospermum complex should be considered a cause of systemic fungal infections in neutropenic patients. Furthermore, the determination of the in vitro antifungal susceptibilities of clinical strains may contribute to the development of therapeutic approaches.",
"affiliations": "Department of Mycology, Kayseri City Hospital, Kayseri, Turkey.;Department of Mycology, Eskisehir City Hospital, Eskisehir, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Kayseri City Hospital, Kayseri, Turkey.",
"authors": "Sav|Hafize|H|;Altinbas|Rabiye|R|;Bestepe Dursun|Zehra|Z|",
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"country": "Iran",
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"doi": "10.18502/cmm.6.3.3982",
"fulltext": "\n==== Front\nCurr Med Mycol\nCurr Med Mycol\nCurrent Medical Mycology\n2423-3439\n2423-3420\nIranian Society of Medical Mycology Iran, Sari\n\nCMM-6-3\n10.18502/cmm.6.3.3982\nCase Report\nA fatal invasive Scedosporium apiospermum pulmonary infection in an adult patient with malignant lung adenocarcinoma\nSav Hafize 1*\nAltinbas Rabiye 2\nBestepe Dursun Zehra 3\n1 Department of Mycology, Kayseri City Hospital, Kayseri, Turkey\n2 Department of Mycology, Eskisehir City Hospital, Eskisehir, Turkey\n3 Department of Infectious Diseases and Clinical Microbiology, Kayseri City Hospital, Kayseri, Turkey\n*Corresponding author: Hafize Sav; Department of Mycology, Kayseri City Hospital, Kayseri, Turkey.\nhafize.sav@hotmail.com\n9 2020\n6 3 6164\n17 4 2020\n19 4 2020\n06 3 2020\nCopyright: © 2020, Published by Mazandaran University of Medical Sciences on behalf of Iranian Society of Medical Mycology and Invasive Fungi Research Center.\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 Unported License, ( http://creativecommons.org/licenses/by/4.0/ ) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground and Purpose:\n\nScedosporium apiospermum complex as a ubiquitous environmental mold is increasingly reported to cause an invasive fungal infection in immunosuppressive hosts. Herein, we present the case of an immunosuppressive 54 - year-old man who developed S. apiospermum complex lung infection and pulmonary adenocarcinoma.\n\nCase report:\n\nThe patient had some complaints of dyspnea and cough during a neutropenic episode. The computed tomography (CT) scan of the patient revealed pleural effusion. After culturing the pleural fluid sample, the fungus was identified by microscopic examination and ITS sequencing. In addition, antifungal susceptibility testing was performed using the M38-A2 microdilution method. The minimum inhibitory concentrations of amphotericin B, voriconazole, posaconazole, and caspofungin were obtained as > 64, 0.06, 0.06, and 0.03 µg/mL, respectively. Voriconazole (administered in two doses of 6 mg/kg and a maximum of 250 mg) was preferred for treatment. The patient received antifungal treatment for 2 months; however, he was lost to follow-up.\n\nConclusion:\n\nScedosporium apiospermum complex should be considered a cause of systemic fungal infections in neutropenic patients. Furthermore, the determination of the in vitro antifungal susceptibilities of clinical strains may contribute to the development of therapeutic approaches.\n\nFebrile neutropenia\nİnvasive fungal disease\nScedosporium apiospermum\n==== Body\nIntroduction\n\nInvasive fungal infections are on a growing trend due to the increasing number of immunosuppressed and critically ill patients.\n\nSuch risk factors as neutropenia or use of corticosteroid and cytotoxic agents play an important role in the development of invasive fungal infections [ 1 ]. The protective layers of the body, such as the mucosa and skin, are strengthened by body pH and enzymatic defenses against fungal agents. Spores and hyphae can reach the deeper tissues as a result of some invasive interventions, surgical operations, catheters, and use of the therapeutic agents of radiotherapy and chemotherapy. In this regard, the environmental fungi can cause invasive fungal infections in the host by impairing the immune system [ 2 ].\n\nScedosporium species are environmental filamentous fungi present in the soil and dirty water, which account for the development of endophthalmitis, mycetoma, osteomyelitis, and disseminated infections [ 3 - 6 ]. These species are rarely identified by the routine diagnostic mycological tests and are difficult to treat, especially when considering the optimal treatment, intrinsic resistance to systemic antifungals (e.g., fluconazole and amphotericin B) reduces the success rate of the treatment [ 7 ].\n\nBased on the evidence, S. prolificans is resistant to caspofungin [ 8 ]. However, some studies have reported voriconazole as an effective option for the invasive fungal infections caused by Scedosporium species [ 9 , 10 ]. Limited clinical experience exists regarding the diagnosis of fungal infections caused by Scedosporium species. Therefore, in the present case report, we aimed to report the development of invasive S. apiospermum pulmonary infection in an adult patient with malignant lung adenocarcinoma. In addition, it was aimed to present data related to the diagnosis of this infection, alongside a pleural effusion, and investigate the in vitro antifungal susceptibility of the given species.\n\nCase report\n\nA 54-year-old male patient with pneumonia prediagnosis referred to our hospital with such complaints as the shortness of breath and fever (day 0). The laboratory study revealed the white blood cell count of 8.540 mm3, C-reactive protein level of 112 mg/L, and hemoglobin level of 10.6 g/dL. Among the radiological examinations, positron emission tomography indicated parenchymal mass in the left lung lobe. In addition, metastatic lymph nodes were detected in the left hilar region. The pathological examination of the left lung as a result of bronchoscopic biopsy (day+7) led to the diagnosis of adenocarcinoma. Adenocarcinoma was found to be at stage III, accompanied by the spread of the bronchoalveolar lavage. Following the diagnosis, the patient was put on paclitaxel plus carboplatin chemotherapy and simultaneous radiotherapy.\n\nThe patient did not receive steroid treatment; however, he developed neutropenia during the chemotherapy (absolute neutrophil count: 279/µL, day +72) and complained of coughing. The thoracic CT revealed 2.5 cm-thick pleural effusion in the left hemithorax. In addition, a mass lesion reaching 3.5 cm in thickness was observed in the left lobe apicoposterior segment, which resulted in the loss of calibration in the vascular structures. The comparison of the mass size with that of the previous year was indicative of the regression of the lesion size. However, pleural effusion reaching up to 7 cm was observed in the thickest area extending to the left apex (figures 1 & 2).\n\nFigure 1 Presence of a mass lesion a year ago in the left lung lobe\n\nFigure 2 Presence of a mass lesion in the left lung lobe\n\nWhile on the treatment, the patient's complaints of coughing and shortness of breath increased (day +92). Accordingly, to drain pleural effusion, a chest tube was placed, and chemotherapy was continued. Fungal growth was detected in the pleural fluid culture. Thoracic CT scan showed no changes in the basic mass lesion. Furthermore, changes in lesion densities were consistent with those occurring at the beginning of cavitation. The recovery of a hyaline mold by culturing a pleural mai was evaluated, and the patient was classified as a proven case according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group [ 11 ].\n\nThe duration of neutropenia was calculated for the patient with an absolute neutrophil count of < 500/μL, at least once during the 3 months before the onset of invasive pulmonary disease. Voriconazole (in two doses of 6 mg/kg and a maximum of 250 mg) was preferred for treatment according to the results of antifungal susceptibility testing.\n\nMycological examination\n\nPleural fluid was cultured on two Sabouraud dextrose agar (SDA; Oxoid, England) media with cycloheximide and without cycloheximide slants and then incubated at 25°C and 37°C for 7 days. This led to the detection of rapidly growing fungal colonies. Initially, the colony appearance was cottony and velvety with the color being changed from white to grey (Figure 3). Septate hyaline hyphae were observed in the culture by microscopic examination with lactophenol. Conidia were observed to have an oval shape. They were placed onto conidiophore as small groups or solitarily (Figure 4).\n\nFigure 3 Colony of Scedosporium apiospermum complex on Sabouraud dextrose agar medium (The colony appearance is cottony and velvety, with the color being changed from white to grey.)\n\nFigure 4 Microscopic examination of the slide culture stained with lactophenol cotton blue staining and branching septated hyphae and ovale sesile conidia\n\nMolecular Identification\n\nThe DNA analysis of the clinical species was performed at a private laboratory (Bioeksen) using polymerase chain reaction (PCR) products, primers, and ABI Prism 377 DNA Sequencer (Applied Biosystems, USA). The identification of S. apiospermum complex was finally accomplished based on the sequencing of the PCR amplicons of the internal transcribed spacer 1 and internal transcribed spacer 2 [ 12 ]. The data of sequence analysis were analyzed using the “National Center for Biotechnology Information (Bethesda, ABD)” BLAST system ( http://www. ncbi.nlm.nih.gov/BLAST/). The GenBank accession number was determined as MT338936.\n\nAntifungal susceptibility\n\nThe stock solutions of amphotericin B, voriconazole, posaconazole (Sigma, St. Louis, MO, USA), and caspofungin (Merck Sharp & Dohme BV, Haarlem, The Netherlands) were prepared using the M38-A2 reference microdilution method [ 13 ]. The serial two-fold dilutions of each antifungal were prepared in RPMI 1640 medium with L-glutamine and without sodium bicarbonate (Sigma Chemical Co., USA) and then buffered to a pH of 7.0 with 0.165 M MOPS (Sigma Chemical Co., USA).\n\nFungal suspensions were adjusted spectropho- tometrically to an optical density of 0.15-0.17 (68-70% transmittance) for S. apiospermum complex. These suspensions were diluted to 1:50 in RPMI. Each well of the microtiter plates was inoculated with 0.1 mL of the inoculum fungal suspension and then incubated at 35°C. The minimum inhibitory concentrations (MICs) were read at 48 h. Susceptibility testing revealed the MIC values of > 64, 0.06, 0.06, and 0.03 μg/mL for amphotericin B, voriconazole, posaconazole, and caspofungin, respectively. Consequently, voriconazole (administered in two doses of 6 mg/kg and a maximum of 250 mg) was preferred for treatment according to these results.\n\nEthical Statements\n\nAs this manuscript is a case report, ethical rules were not violated; therefore, there was no need to request any ethical certificate.\n\nDiscussion\n\nScedosporium infections are rare conditions that generally cause disseminated infections in immunocompromised patients or local infections in immunocompetent patients [ 5 ]. The most notable risk factors for immunocompromised patients are prolonged neutropenia and corticosteroid therapy. Howden et al. reported the incidence of S. prolificans-induced disseminated infection in a patient after a bone marrow transplantation [ 6 ]. Furthermore, in another case report, Scedosporium was isolated from the culture of a clinical sample of a patient being treated for asthma with low- dose corticosteroids [ 9 ]. In an epidemiological study, Rodriguez-Tudela et al. investigating P. boydii infections, introduced neutropenia as a notable risk factor for the development of Scedosporium species infections [ 14 ]. Accordingly, in the present case report, the duration of neutropenia in the patient was proposed to be dependent on the usage of chemotherapeutic agents, which are known to play a role in the development of Scedosporium fungal infections.\n\nAntifungal susceptibility tests were performed using the reference test method as Scedosporium species have intrinsic resistance to many antifungal agents. Based on the results, the isolated S. apiospermum complex sample had higher MIC values for amphotericin B and fluconazole, while showing lower MIC values for voriconazole, posaconazole, and caspofungin. There is no well-established standard of care for the management of these fungal infections. The reported MIC values of antifungals against the Scedesporium species are higher in many in vitro studies.\n\nBased on the evidence, triazoles are more effective against S. apiospermum and P. boydii infections [ 15 , 16 ]. In our case, antifungal susceptibility was studied and following the results of this test, voriconazole (administered in two doses of 6 mg/kg and a maximum of 250 mg) was initiated. However, the patient did not respond to antifungal treatments, and he was lost to follow-up.\n\nConclusion\n\nAs the present study indicated, S. apiospermum complex had the ability to cause an invasive pulmonary fungal infection in an adult patient with malignant lung adenocarcinoma. Based on the evidence, neutropenia is a risk factor for the development of this disease. Our patient was subjected to voriconazole as primary therapy. Although the patient was given appropriate antifungal therapy, the treatment was not successful. Consequently, in order to improve the mortality rate, it is necessary to establish rapid diagnostic methods and efficient therapeutic approaches.\n\nAuthor’s contribution\n\nZ. B. D. analyzed and interpreted the clinical data, H. S. wrote the manuscript, and R. A. performed routine laboratory examinations.\n\nConflicts of interest\n\nThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFinancial disclosure\n\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n==== Refs\nReferences\n\n1 Webb BJ Ferraro JP Rea S Kaufusi S Goodman BE Spalding J Epidemiology and clinical features of invasive fungal infection in a US health care network Open Forum Infect Dis 2018 5 8 ofy187 30151412\n2 Low CY Rotstein C Emerging fungal infections in immunocompromised patients F1000 Med Rep 2011 3 14 21876720\n3 Vanzzini-Zago V Corredor-Casas S Rodríguez-Reyes A Hernández-Hernández F Manzano-Gayosso P Martínez RL et al Endophthalmitis of probable endogenous origin caused by Scedosporium boydii: a case report Rev Iberoam Micol 2016 33 2 122 5 26874584\n4 Uenotsuchi T Moroi Y Urabe K Tsuji G Koga T Matsuda T et al Cutaneous Scedosporium apiospermum infection in an immunocompromised patient and a review of the literature Acta Derm Venereol 2005 85 2 156 9 15823912\n5 Steinbach WJ Schell WA Miller JL Perfect JR Scedosporium prolificans osteomyelitis in an immunocompetent child treated with voriconazole and caspofungin, as well as locally applied polyhexamethylene biguanide J Clin Microbiol 2003 41 8 3981 5 12904435\n6 Howden BP Slavin MA Schwarer AP Mijch AM Successful control of disseminated Scedosporium prolificans infection with a combination of voriconazole and terbinafine Eur J Clin Microbiol Infect Dis 2003 22 2 111 3 12627286\n7 Tortorano AM Richardson M Roilides E van Diepeningen A M, Munoz P et al ESCMID and ECMM joint guidelines on diagnosis and management of hyalohyphomycosis: Fusarium spp. , Scedosporium spp. and others Clin Microbiol Infect 2014 20 Suppl 3 27 46\n8 Cuenca-Estrella M Gomez-Lopez A Mellado E Buitrago MJ Monzon A Rodriguez-Tudela JL Head-to-head comparison of the activities of currently available antifungal agents against 3,378 Spanish clinical isolates of yeasts and filamentous fungi Antimicrob Agents Chemother 2006 50 3 917 21 16495251\n9 Muñoz P Marín M Tornero P Martín Rabadán P Rodríguez- Creixéms M Bouza E Successful outcome of Scedosporium apiospermum disseminated infection treated with voriconazole in a patient receiving corticosteroid therapy Clin Infect Dis 2000 31 6 1499 501 11096022\n10 Stripeli F Pasparakis D Velegraki A Lebessi E Arsenis G Kafetzis D et al Scedosporium apiospermum skeletal infection in an immunocompetent child Med Mycol 2009 47 4 441 4 19191169\n11 De Pauw B Walsh TJ Donnelly JP Stevens DA Edwards JE Calandra T et al Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group Clin Infect Dis 2008 46 12 1813 21 18462102\n12 Schoch CL Seifert KA Huhndorf S Robert V Spouge JL Levesque CA et al Nuclear ribosomal internal transcribed spacer (ITS) region as a universal DNA barcode marker for Fungi Proc Natl Acad Sci U S A 2012 109 16 6241 6 22454494\n13 National Committee for Clinical Laboratory Standards Reference method for broth dilution antifungal susceptibility testing of filamentous fungi; approved standard-second edition. CLSI Document M38-A2. Wane, PA, USA: National Committee for Clinical Laboratory Standards; 2008\n14 Rodriguez-Tudela JL Berenguer J Guarro J Kantarcioglu AS Horre R de Hoog GS et al Epidemiology and outcome of Scedosporium prolificans infection, a review of 162 cases Med Mycol 2009 47 4 359 70 19031336\n15 Cortez KJ Roilides E Quiroz-Telles F Antachopoulos C Knudsen T Buchanan W et al Infections caused by Scedosporium spp Clin Microbiol Rev 2008 21 1 157 97 18202441\n16 Rynga D Capoor MR Varshney S Naik M Gupta V Scedosporium apiospermum, an emerging pathogen in India: case series and review of literature Indian J Pathol Microbiol 2007 60 4 550 5\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2423-3420",
"issue": "6(3)",
"journal": "Current medical mycology",
"keywords": " İnvasive fungal disease ; Febrile neutropenia ; Scedosporium apiospermum",
"medline_ta": "Curr Med Mycol",
"mesh_terms": null,
"nlm_unique_id": "101647935",
"other_id": null,
"pages": "61-64",
"pmc": null,
"pmid": "33834145",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": "21876720;16495251;30151412;18202441;29323071;19031336;18462102;15823912;26874584;24548001;12627286;22454494;19191169;11096022;12904435",
"title": "A fatal invasive Scedosporium apiospermum pulmonary infection in an adult patient with malignant lung adenocarcinoma.",
"title_normalized": "a fatal invasive scedosporium apiospermum pulmonary infection in an adult patient with malignant lung adenocarcinoma"
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"abstract": "Depression is a complex disorder with heterogeneous clinical anomalies whose neurobiological understanding still remains unclear. Medications have been implicated as potential causes of depression but for many of them, data are controversial. The present study aims to investigate association bet ween drugs and reports of depression. We used the case/non case method in the French pharmacovigilance database (FPVD) to identify drugs associated with depression. Cases were reports of depression in the FPVD between January 2007 and December 2011. Non cases were all other reports during the same period. Data were expressed as reporting odds ratio (ROR) with their 95% confidence interval. Of the 114,692 reports recorded in the FPVD during the studied period, we identified 474 cases of depression. For the majority of the patients, they were considered as \"non serious\" (56%) and evolution was favorable (64%). Significant RORs were found for antiepileptics (topiramate, levetiracetam), anti-infective and especially anti-retroviral drugs (efavirenz, emtricitabine, tenofovir, etravirine, raltegravir), interferons and other agents including isotretinoin, methylphenidate, sodium oxybate, varenicline, montelukast, flunarizine, adalimumab, anastrozole. Taking into account the limits of the methodology, the present study described associations with mainly expected drugs belonging to various therapeutic classes but it also found a signal with some anti-retrovirals. On the contrary, we did not find some assumed associations like cardiovascular medications, antimalarial. For most of the drugs, one or more mechanisms were found to explain these depressogenic effects on the basis of animal and human literature. Even if such associations need to be confirmed by further prospective studies, cautions are necessary for many drugs to early detect depressive symptoms.",
"affiliations": "CHU de Poitiers, Service de Pharmacologie Clinique et Vigilances, Poitiers, France.;CHU de Poitiers, Service de Pharmacologie Clinique et Vigilances, Poitiers, France.;CHU de Poitiers, Service de Pharmacologie Clinique et Vigilances, Poitiers, France.;Agence Nationale de Sécurité du Médicament et des produits de santé (ANSM), Direction de la Surveillance, Saint-Denis, France.;CHU de Poitiers, Service de Pharmacologie Clinique et Vigilances, Poitiers, France.",
"authors": "Lafay-Chebassier|Claire|C|;Chavant|François|F|;Favrelière|Sylvie|S|;Pizzoglio|Véronique|V|;Pérault-Pochat|Marie-Christine|MC|;|||",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.2515/therapie/2015026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-5957",
"issue": "70(5)",
"journal": "Therapie",
"keywords": null,
"medline_ta": "Therapie",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D016208:Databases, Factual; D003863:Depression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D055815:Young Adult",
"nlm_unique_id": "0420544",
"other_id": null,
"pages": "425-32",
"pmc": null,
"pmid": "26056040",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Drug-induced Depression: a Case/Non Case Study in the French Pharmacovigilance Database.",
"title_normalized": "drug induced depression a case non case study in the french pharmacovigilance database"
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"activesubstancename": "CYAMEMAZINE"
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"abstract": "BACKGROUND\nIn the last 10 years, multiple new targeted agents have been developed for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. Up to 55% of patients with HER2+ breast cancer will develop brain metastases requiring some form of radiation therapy. The interaction between radiation and these targeted agents is unknown and previously unreported.\n\n\nMETHODS\nIn this series, we describe 4 patients who developed clinically significant brain edema at sites of treated brain metastases. These patients were treated with stereotactic radiosurgery and trastuzumab emtansine, the newest FDA-approved agent for metastatic HER2+ breast cancer. Additionally, we present rates of clinically significant radiation necrosis among all breast cancer patients treated during this same time period.\n\n\nRESULTS\nUsing previously published clinical and preclinical data, we then hypothesize possible mechanisms for this striking interaction.\n\n\nCONCLUSIONS\nIncreased awareness of potential interactions between targeted agents and radiation to the brain is crucial.",
"affiliations": null,
"authors": "Carlson|Julie A|JA|;Nooruddin|Zohra|Z|;Rusthoven|Chad|C|;Elias|Anthony|A|;Borges|Virginia F|VF|;Diamond|Jennifer R|JR|;Kavanagh|Brian|B|;Kabos|Peter|P|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D008453:Maytansine; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine",
"country": "England",
"delete": false,
"doi": "10.1093/neuonc/not329",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1522-8517",
"issue": "16(7)",
"journal": "Neuro-oncology",
"keywords": null,
"medline_ta": "Neuro Oncol",
"mesh_terms": "D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001921:Brain; D001929:Brain Edema; D001932:Brain Neoplasms; D001943:Breast Neoplasms; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008453:Maytansine; D008875:Middle Aged; D009336:Necrosis; D016634:Radiosurgery; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"nlm_unique_id": "100887420",
"other_id": null,
"pages": "1006-9",
"pmc": null,
"pmid": "24497407",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article",
"references": "10829059;23382472;12066192;20887087;23352568;19010901;15140287;12571445;18165625;17159499;21509760;23020162;11248153;21510863;21924310;10802351;15774813;15073860;23311575;22234627;2470152;22727691;23100438;17192538;20197459;19013723;22188921",
"title": "Trastuzumab emtansine and stereotactic radiosurgery: an unexpected increase in clinically significant brain edema.",
"title_normalized": "trastuzumab emtansine and stereotactic radiosurgery an unexpected increase in clinically significant brain edema"
} | [
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"companynumb": "US-ROCHE-1352983",
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"activesubstancename": "ADO-TRASTUZUMAB EMTANSINE"
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{
"abstract": "BACKGROUND\nPulmonary nocardiosis is an opportunistic infection in an immunocompromised patient; however, often neglected in the immunocompetent patient from the diagnosis considerations.\n\n\nMETHODS\nWe describe a case of pulmonary nocardiosis masquerading renascence of tuberculosis, in a 51-years-Nepali farmer. After a 6 month of presumed successful antitubercular therapy; the patient develops the clinical presentations and radiological features showing similarities with that of tuberculosis and malignancy. MTB complex was not detected with Xpert MTB/RIF assay and cytological examinations were negative for the malignant cells, however. The Ziehl-Neelsen staining of the broncho-alveolar-lavage revealed acid-fast, thin branching filamentous organisms suggestive Nocardia spp. Further, identifications and susceptibility pattern against recommended antibiotics were assessed as per the CLSI guidelines. The case was then, subsequently, diagnosed as pulmonary nocardiosis. Trimethoprim-sulfamethoxazole was prescribed for 12 months. The patient underwent progressive changes and no relapse was noted in a periodic follow-up.\n\n\nCONCLUSIONS\nThis case underscores that pulmonary nocardiosis requires diagnostic considerations, regardless of a patient's immunologic status and other mimicking infections.",
"affiliations": "Tribhuvan University Teaching Hospital, Kathmandu, Nepal. khadka.priyatam@gmail.com.;Tribhuvan University Teaching Hospital, Kathmandu, Nepal.;Tribhuvan University Teaching Hospital, Kathmandu, Nepal.;Tribhuvan University Teaching Hospital, Kathmandu, Nepal.",
"authors": "Khadka|Priyatam|P|http://orcid.org/0000-0002-1525-8130;Basnet|Ramesh Bahadur|RB|;Rijal|Basista Parsad|BP|;Sherchand|Jeevan Bahadur|JB|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13104-018-3604-2",
"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central London 360410.1186/s13104-018-3604-2Case ReportPulmonary nocardiosis masquerading renascence of tuberculosis in an immunocompetent host: a case report from Nepal http://orcid.org/0000-0002-1525-8130Khadka Priyatam khadka.priyatam@gmail.com 12Basnet Ramesh Bahadur ramesh.basnet@yahoo.com 1Rijal Basista Parsad basistarijal@yahoo.com 1Sherchand Jeevan Bahadur jevanbsherchand@yahoo.com 11 0000 0004 0635 3456grid.412809.6Tribhuvan University Teaching Hospital, Kathmandu, Nepal 2 0000 0001 2114 6728grid.80817.36Trichandra Multiple Campus, Tribhuvan University, Ghantaghar, Kathmandu, Nepal 17 7 2018 17 7 2018 2018 11 48831 1 2018 13 7 2018 © The Author(s) 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPulmonary nocardiosis is an opportunistic infection in an immunocompromised patient; however, often neglected in the immunocompetent patient from the diagnosis considerations.\n\nCase presentations\nWe describe a case of pulmonary nocardiosis masquerading renascence of tuberculosis, in a 51-years-Nepali farmer. After a 6 month of presumed successful antitubercular therapy; the patient develops the clinical presentations and radiological features showing similarities with that of tuberculosis and malignancy. MTB complex was not detected with Xpert MTB/RIF assay and cytological examinations were negative for the malignant cells, however. The Ziehl–Neelsen staining of the broncho-alveolar-lavage revealed acid-fast, thin branching filamentous organisms suggestive Nocardia spp. Further, identifications and susceptibility pattern against recommended antibiotics were assessed as per the CLSI guidelines. The case was then, subsequently, diagnosed as pulmonary nocardiosis. Trimethoprim–sulfamethoxazole was prescribed for 12 months. The patient underwent progressive changes and no relapse was noted in a periodic follow-up.\n\nConclusions\nThis case underscores that pulmonary nocardiosis requires diagnostic considerations, regardless of a patient’s immunologic status and other mimicking infections.\n\nKeywords\nImmunocompetent hostPulmonary nocardiosisTuberculosisissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nPulmonary nocardiosis often imitates pulmonary tuberculosis in both clinical presentations and radiological characteristics [1]. Consequently, the diagnosis of nocardiosis can be overlooked and treated empirically with anti-tuberculosis regimens; when in fact pulmonary nocardiosis should have been treated [2]. The condition is more common in developing countries where the diagnosis is rely based on these findings [3, 4]. Pulmonary nocardiosis is an opportunistic infection in an immunocompromised patient; however, often neglected in the immunocompetent patient from the diagnosis considerations [5]. Herein, we report a case of pulmonary nocardiosis in an immunocompetent host featuring as a relapse case of tuberculosis.\n\nCase presentations\nA 51-year-old man presented in Tribhuvan University teaching hospital (TUTH); with chief complain of fever, severe chest pain and dry cough for 3 weeks. The patient denied any history of diabetes, hypertension, and asthma. Neither breathlessness nor hemoptysis was reported. At that time, he underwent chest radiography and sputum examination. The posterior–anterior (PA) view of chest x-ray was suggestive of pulmonary tuberculosis. However, no acid-fast bacilli found in two consecutive sputum samples. Later on, the case diagnosed as pulmonary tuberculosis (rifampicin sensitive) with Xpert MT/RIF Assay. The patient received HRZE for 2 months, followed by HR for 4 months as followed by antitubercular therapy in a government-run tuberculosis center (DOTS). After a subsequent antitubercular therapy for 6 months, the symptoms subsided, chest Xray showed a decreased size of opacity and no AFB seen on smear microscopy. Hence, declared cured and remained asymptomatic succeeding 4 months.\n\nNearly after 4 months of presumed successful treatment, the sequel resumed with similar clinical presentations but this time with worsened cough including hemoptysis. On posterior–anterior (PA) view chest x-ray, left perihilar opacity with fibrotic changes was seen (Fig. 1). Based on clinical manifestation, radiological features and AFB positive reported on smear microscopy, relapse of pulmonary tuberculosis was assumed. Further, GeneXpert test was done to rule out MDR TB or mutation on genome if present; nevertheless, no MTB complex was detected. On general examination, he was conscious, oriented and well nourished; no clubbing and cervical lymphadenopathy noted.Fig. 1 posterior–anterior (PA) view chest x-ray: left perihilar opacity with fibrotic changes\n\n\n\n\nInvestigation\nA complete blood count reveals: Haemoglobin: 10.0 gm/dl; white blood cell (WBC) count: 14,500/mm3; platelets 150 × 109/L; neutrophils: 85%; lymphocytes: 8%; monocytes: 5%; eosinophils: 2; ESR: 45 mm in the first hour. A peripheral blood smear for haemoparasite was negative. Serological marker (HIV/HBsAg/HCV) and Widal test were negative. Similarly, renal function, liver function, blood glucose were normal.\n\nSputum grew non-significant bacterial, while Xpert MTB/RIF Assay detects no MTB complex. Since the patient was unable to expectorate the patient underwent bronchoscopy; broncho-alveolar-lavage was aspirated then sent for cytological and microbiological analysis. No associated malignancy reported on histopathological examinations. However, Ziehl Neelsen staining of the broncho-alveolar-lavage revealed acid-fast thin branching filamentous organisms suggestive of nocardiosis (Fig. 2). The species are grown on Blood agar, Chocolate agar, and LJ media after 72 h of incubations with a chalky white appearance on blood agar, chocolate agar and LJ media (Fig. 3).Fig. 2 AFB staining: partially acid-fast branching rod suggestive Nocardia species on modified. Kinyounstain (×1000 orginal magnification)\n\n\nFig. 3 Colonial morphology of Nocardia species on a LJ media; b Blood Agar; c Chocolate agar: whitish chalky adherent colonies of Nocardia species\n\n\n\n\nFurther, identification of the isolate was done with standard microbiological culture methods recommended by American Society for Microbiology [6]. In brief, colony morphology (chalky, matt, dry, crumbly, adherent or velvety in appearances; 0.5–1.0 mm in diameter with fine intertwining, branching filaments with delicate aerial hyphae were seen); in-house set of biochemical test: catalase (positive), Urea hydrolysis test (positive), Bile esculin (positive), Acid production on rhamnose (positive), Acid production sorbitol (positive), Simmon’s citrate (negative), Nitrate reduction (negative), no gelatin liquefaction and hydrolysis of casein, tyrosine, and xanthine seen; varied incubation temperature of the isolates (under incubation with temperature variation at 46 and 10 °C, no growth was seen at 10 °C but seen at 46 °C). The antibiotic sensitivity test was performed by Kirby Bauer disc diffusion method following CLSI guidelines [7]. The isolate was sensitive to Amikacin, Imipenem, Cotrimoxazole, while Amoxicillin, Ceftriaxone, and Cefotaxime were found intermediate.\n\nTreatment\nThe patient was treated with BACTRIM-DS (PO × BD), 2 double strength tablets each containing 800 mg sulfamethoxazole and 160 mg trimethoprim. Fever and cough subsided within 6 days of antimicrobial therapy.\n\nOutcomes and follow-up\nThe patient recovered well, on medication with BACTRIM-DS (PO × BD), 2 double strength tablets each containing 800 mg sulfamethoxazole and 160 mg trimethoprim and was prescribed for 3 months then to follow. The same medication was continued for 12 months, the patient underwent progressive changes and no relapse was noted. He is under regular follow-up, from then and we found him asymptomatic, with limited side effects—possibly due to prolonged antimicrobial therapy.\n\nDiscussion and conclusion\nNocardiosis is an opportunistic infection profoundly affects the immunocompromised patient; however, often neglected in an immunocompetent patient from the diagnosis considerations [5]. It has been reviewed in a study, that 15% of patients with nocardiosis do not have a predisposing immunosuppressive condition and the figure ranges from 10 to 25% on other studies [8]. This case underscores, regardless of a patient’s immunologic status, the isolation of Nocardia from the respiratory tract or other body sources should not be regarded as a contaminant or commensal organism [9].\n\nThe infection result due to inhalation (pulmonary nocardiosis-pneumonia, lung abscess, and cavitary lesions) or contact with the bacteria via a cut or abraded skin (cutaneous nocardiosis-cellulitis, ulcers); and possibly metastasizes haematogenously into distant organs system (lungs, central nervous system, eyes, kidneys, skin, subcutaneous tissue and bone) [10]. Relating to our case, probably the inhalation of the pathogen attribute for the progressive pulmonary nocardiosis.\n\nThe clinical syndromes vary and range from pulmonary, disseminated, cutaneous form involving eyes, kidneys, skin, bone, and CNS. The lungs, however, are the most common site of involvement and are affected in 70% of all cases of nocardiosis [11]. The clinical presentations of pulmonary nocardiosis are nonspecific and erratic with a chronic course resulting diagnostic stalemate. Consequently, delay and the high propensity of misdiagnosis may be attributed, as the clinical features—fever, cough, breathlessness, hemoptysis, and weight loss—mimic pulmonary tuberculosis, invasive fungal disease, community-acquired pneumonia, and lungs cancer [12].\n\nIn a diagnostic perspective of pulmonary nocardiosis, the chest radiographic indices are pleomorphic and nonspecific. The radiological picture revealing, consolidations and large irregular nodules, often cavitary, are most common; however, nodules, masses, and interstitial patterns may also be seen [13]. The case we present found obscured apart, with similar clinical presentations and radiological features show semblance to pulmonary tuberculosis.\n\nThe identification of the isolate was done with standard microbiological culture methods recommended by American Society for Microbiology based on phenotypic characteristics, biochemical interpretations, and varied incubation temperatures since molecular analysis and sequencing was not accessible in our laboratory settings. The microbiological diagnosis, however, is often difficult owing to the longer incubation periods to cultivate the pathogen in vitro and variable characteristics on gram staining, acid-fast-stain negative as if positive, also in the distorted branching forms mimicking Mycobacterium tuberculosis [2]. Henceforward, PCR and molecular-based diagnostic tools are of utmost importance in an early diagnosis of the nocardiosis. Therefore, a high index of clinical suspicion together with close collaboration with microbiological and radiological interpretations allows the more precise diagnosis to initiate appropriate therapy.\n\nThe implicated clinical management, nevertheless, of nocardiosis is the stereotaxic aspiration or surgical resection, and a course of appropriate antibiotics therapy for several months [14]. Unfolding of our case, the patient was treated with trimethoprim–sulfamethoxazole which undergoes a better prognosis of the condition. Furthermore, to limit the possibility of late relapse of nocardiosis the treatment regimen was extended to 12 months. The alternative parenteral antimicrobial therapies of carbapenems (imipenem or meropenem, but not ertapenem), third-generation cephalosporins (cefotaxime or ceftriaxone), and amikacin, alone or in combination were presumed unnecessary to include in regimen, though recommended by some author [15, 16]. Nonetheless, the likelihood of late recurrent nocardiosis could be a pitfall to the successful outcomes [12, 17]. Hereafter, clinical management along with the consistent follow up is crucial in the elimination of the infection.\n\nHowever, the adverse reactions, owing to prolonged and high-dose TMP-SMX therapy, are frequent including: myelosuppression, hepatoxicity, immune hypersensitivity reactions and renal insufficiency [14]. Nonetheless, no such complications were found to be associated with our case. As a minimal side effect, the patient complained a few episodes of nausea, vomiting, and anorexia during 12 months of medications.\n\nThe anti-tubercular drugs have their own spectrum of hematological toxicity and blood cell abnormalities along with drug-induced syndrome—hemolytic anemia, methemoglobinemia, red cell aplasia, sideroblastic anemia, megaloblastic anemia, polycythemia and aplastic anemia—affecting natural immune functions to acquire the pulmonary nocardiosis [18]. Relating to our case, possibly the antitubercular drugs could be a potent risk factor for the successive pulmonary nocardiosis.\n\nThe burden and case associated with pulmonary nocardiosis—particularly in an immunocompetent host—in developing countries like Nepal are undetermined and unkempt. The exoticism with the case, nonspecific or lack of pathognomonic clinical presentation, diagnostic intricacies, and lack of systematic reporting impede further workup for nocardiosis [19, 14]. To our knowledge, this is the first case of pulmonary nocardiosis of different clinical type—masquerading renascence of pulmonary tuberculosis—in an immunocompetent host from Nepal, although nocardiosis in the immunocompromised has been reported elsewhere.\n\nThis case underscores that pulmonary nocardiosis requires diagnostic considerations if patients’ condition exacerbates despite optimum antitubercular therapy or in presumed relapse cases. Regardless of a patient’s immunologic status, the isolation of Nocardia sps from the respiratory tract or other body sources, should not be overlooked as a contaminant or commensal organism.\n\nAbbreviations\nAFBacid fast bacilli\n\nCLSIClinical & Laboratory Standards Institute\n\nCNScentral nervous system\n\nDOTSdirectly observed therapy short-course\n\nESRerythrocyte sedimentation rate\n\nHIVhuman immune defeciency virus\n\nHBsAghepatitis B surface antigen\n\nHCVhepatitis C virus\n\nLJLöwenstein–Jensen medium\n\nMDRmulti drug resistant\n\nMTB\nMycobacterium tuberculosis\n\n\nPCRpolymerase chain reaction\n\nTUTHTribhuvan University Teaching Hospital\n\nAuthors’ contributions\nPK made the diagnosis, designed the manuscript, reviewed the literature and prepared the article for submission. RBB, BPR, and JBS helped for literature review, gave the concept of research paper and critically reviewed the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe would like to thank Prof. Bharat Mani Pokharel for the constant support and guidance.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and materials\nData generated or analyzed during this study are included in this published article and remaining are available from the corresponding author on reasonable request.\n\nConsent to publish\nWritten informed consent was taken from the patient for publication of this case report and any accompanying images.\n\nEthics approval and consent to participate\nThere is no need for ethical approval for a case report according to the local ethical guidelines (not applicable).\n\nFunding\nNot applicable (nil).\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Ojha N Bista KDB Torres OH Domingo P Pericas R Boiron P Clinical and radiographic characteristics of pulmonary nocardiosis: clues to earlier diagnosis PLoS ONE 2014 57 3 807 812 \n2. De S Desikan P Pulmonary nocardiosis mimicking relapse of tuberculosis BMJ Case Rep. 2009 \n3. Castellana G Grimaldi A Castellana M Farina C Castellana G Respiratory medicine case reports pulmonary nocardiosis in chronic obstructive pulmonary disease: a new clinical challenge Respir Med Case Rep. 2016 18 14 21 27144111 \n4. Alavi Darazam I Shamaei M Mobarhan M Ghasemi S Tabarsi P Motavasseli M Nocardiosis: risk factors, clinical characteristics and outcome Iran Red Crescent Med J. 2013 15 5 436 439 10.5812/ircmj.2384 24349735 \n5. Qureshi S Pandey A Sirohi TR Verma SR Sardana V Agrawal C Mixed pulmonary infection in an immunocompromised patient: a rare case report Indian J Med Microbiol. 2014 32 1 79 81 10.4103/0255-0857.124330 24399397 \n6. Isenberg HD Clinical microbiology procedures handbook 2004 2 Washington Dc ASM Press \n7. CLSI. Performance standards for antimicrobial disk susceptibility tests; approved standard, M02-A12, 12th ed, vol. 35. Clinical and Laboratory Standards Institute; 2015. p. 73.\n8. Matulionyte R Rohner P Uçkay I Lew D Garbino J Secular trends of Nocardia infection over 15 years in a tertiary care hospital J Clin Pathol 2004 57 8 807 812 10.1136/jcp.2004.016923 15280400 \n9. Beaman BL Burnside J Edwards B Causey W Nocardial infections in the United States, 1972–1974 J Infect Dis 1976 789786 \n10. Kandi V Human Nocardia infections: a review of pulmonary Nocardiosis Cureus 2015 7 8 10 15 \n11. Cort Marcelo E Maria F Villafafie fioti. Nocardiosis: a review Int J Infect Dis 2003 7 243 250 10.1016/S1201-9712(03)90102-0 14656414 \n12. Aggarwal D Garg K Chander J Saini V Janmeja AK Pulmonary nocardiosis revisited: a case series Lung India Off Organ Indian Chest Soc India 2015 32 165 168 10.4103/0970-2113.152638 \n13. Yaşar Z Acat M Onaran H Özgül MA Fener N Talay F Case report an unusual case of pulmonary nocardiosis in immunocompetent patient Case Rep Pulmonol. 2014 2014 963482 25506020 \n14. Wilson JW Nocardiosis: updates and clinical overview JMCP. 2012 87 4 403 407 \n15. Kassa E Enawgaw B Gelaw A Gelaw B Effect of anti-tuberculosis drugs on hematological profiles of tuberculosis patients attending at University of Gondar Hospital, Northwest Ethiopia BMC Hematol 2016 26751690 \n16. Khadka P Basnet RB Khadka P Shah DS Pokhrel BM Disseminated Nocardiosis in renal transplant recipient under therapy for pulmonary tuberculosis: a case report BMC Res Notes 2017 \n17. Shariff M Gunasekaran J Presentation C Clinico-pathologic conferences pulmonary Nocardiosis : review of cases and an update Can Respir J. 2016 27445562 \n18. Boubaker K Gargah T Abderrahim E Abdallah TB Kheder A Mycobacterium tuberculosis infection following kidney transplantation Biomed Res Int. 2013 2013 347103 10.1155/2013/347103 24222903 \n19. Khadka P Mishra SK Shah DS Rijal BP Case report: primary pulmonary nocardiosis and candidosis with cutaneous involvement in nephrotic syndrome patient under steroid therapy Int J Clin Case Rep 2016 6 11 1 7\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1756-0500",
"issue": "11(1)",
"journal": "BMC research notes",
"keywords": "Immunocompetent host; Pulmonary nocardiosis; Tuberculosis",
"medline_ta": "BMC Res Notes",
"mesh_terms": "D003937:Diagnosis, Differential; D000067565:Farmers; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D009390:Nepal; D009615:Nocardia; D009617:Nocardia Infections; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "101462768",
"other_id": null,
"pages": "488",
"pmc": null,
"pmid": "30016976",
"pubdate": "2018-07-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25814804;789786;24349735;15280400;26751690;21686892;25506020;22469352;24399397;27144111;24222903;14656414;28159010;27445562;26430578",
"title": "Pulmonary nocardiosis masquerading renascence of tuberculosis in an immunocompetent host: a case report from Nepal.",
"title_normalized": "pulmonary nocardiosis masquerading renascence of tuberculosis in an immunocompetent host a case report from nepal"
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"activesubstancename": "RIFAMPIN"
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"abstract": "A drug rape facilitated with the sedative antipsychotic drug quetiapine is presented here. A teenage girl and her girlfriend went to the home of an adult couple they had met at a bar. Here, the teenage girl (victim) felt tired after consuming some alcoholic drinks and fell asleep. While she was asleep, the others left her at the house alone and returned to the bar. Later, the girl woke up to witness the adult male having intercourse with her, but she was not able to resist the attack. She fell asleep again and slept through the next day and a half, after which she left the house. Forty-three hours after the suspected drug-facilitated sexual assault (DFSA), blood and urine samples were collected and the initial toxicological screening detected quetiapine. Confirmation and quantification by ultra high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) revealed a concentration of 0.007mg/kg quetiapine in blood and 0.19mg/l in urine. Six months after the DFSA, a hair sample was collected and segmental hair analysis was performed on four washed segments (0-3cm, 3-5cm, 5-7cm, and 7-9cm). The last segment contained 0.011ng/mg of quetiapine, whereas the other segments were negative. The low level of quetiapine in the hair segment and its absence in the other segments indicate that the victim had only consumed one or a few doses of quetiapine within that period and was not a regular user. This study describes the first drug-facilitated assault involving a single dose of quetiapine that was detected by hair, blood and urine analysis. This case illustrates the importance of having very sensitive analytical methods for measurement of a single dose in blood and urine and how the extended detection window for hair analysis can reveal more information in such cases.",
"affiliations": "Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Frederik V's vej 11, DK-2100, Denmark. Electronic address: Sys.johansen@sund.ku.dk.",
"authors": "Johansen|Sys Stybe|SS|",
"chemical_list": "D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2016.12.010",
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"issn_linking": "0379-0738",
"issue": "270()",
"journal": "Forensic science international",
"keywords": "Drug-facilitated assault; Hair; Quetiapine; UHPLC–MS/MS; Urine; Whole blood",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D002851:Chromatography, High Pressure Liquid; D019548:Crime Victims; D005260:Female; D006197:Hair; D006801:Humans; D000069348:Quetiapine Fumarate; D011902:Rape; D053719:Tandem Mass Spectrometry",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "e12-e15",
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"pmid": "28012825",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Detection of the antipsychotic drug quetiapine in the blood, urine and hair samples of the victim of a drug-facilitated sexual assault.",
"title_normalized": "detection of the antipsychotic drug quetiapine in the blood urine and hair samples of the victim of a drug facilitated sexual assault"
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"companynumb": "DK-TEVA-756693ACC",
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{
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"activesubstance": {
"activesubstancename": "QUETIAPINE"
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{
"abstract": "We present a case of necrotizing fasciitis in a 66-year-old Caucasian woman with rheumatoid arthritis receiving tocilizumab, and provide a review of published cases. The patient exhibited no systemic symptoms and discreet cutaneous inflammatory signals at presentation. She was successfully treated with broad-spectrum empiric antibiotic therapy and surgical debridement.",
"affiliations": "Rheumatology Department, Centro Hospitalar São João, Portugal. Electronic address: di9_goncalves@hotmail.com.;Rheumatology Department, Centro Hospitalar São João, Portugal.;Rheumatology Department, Centro Hospitalar São João, Portugal.",
"authors": "Rosa-Gonçalves|Diana|D|;Bernardes|Miguel|M|;Costa|Lúcia|L|",
"chemical_list": "D000900:Anti-Bacterial Agents; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; C502936:tocilizumab",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.reuma.2016.10.008",
"fulltext": null,
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"issn_linking": "2173-5743",
"issue": "14(3)",
"journal": "Reumatologia clinica",
"keywords": "Antagonistas del factor de necrosis tumoral alfa; Artritis reumatoide; Fascitis necrosante; Infección; Infection; Necrotizing fasciitis; Piel; Rheumatoid arthritis; Skin; Tocilizumab; Tumor necrosis factor antagonists",
"medline_ta": "Reumatol Clin (Engl Ed)",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D003131:Combined Modality Therapy; D003646:Debridement; D019115:Fasciitis, Necrotizing; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents",
"nlm_unique_id": "101717526",
"other_id": null,
"pages": "168-170",
"pmc": null,
"pmid": "28041910",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Necrotizing fasciitis in a patient receiving tocilizumab for rheumatoid arthritis - Case report.",
"title_normalized": "necrotizing fasciitis in a patient receiving tocilizumab for rheumatoid arthritis case report"
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{
"companynumb": "PT-EDENBRIDGE PHARMACEUTICALS, LLC-PT-2018EDE000159",
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{
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"activesubstancename": "LEFLUNOMIDE"
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"abstract": "Pregabalin is often used for the treatment of neuropathic pain in patients with spinal cord injury (SCI). We reported a patient with C5 [S(C5/C6)] ASIA Impairment Scale C SCI due to cervical myelopathy who presented CO2 retention when taking a therapeutic dosage of pregabalin. An 88-year-old patient with cervical SCI was transferred to the department of physical medicine and rehabilitation. When he had transferred, his neuropathic pain had been treated with 150-mg pregabalin per day (75 mg twice a day); however, he still exhibited severe neuropathic pain with a Numeric Pain Rating Scale score of 7 to 8. Dosage for the pregabalin increased from 150 mg/d (75 mg twice a day) to 225 mg/d (150 mg at morning and 75 mg at dinner). That afternoon, he presented drowsiness and confusion, and arterial blood gas analysis (ABGA) demonstrated respiratory acidosis with CO2 retention; pH, 7.312; PaCO2, 62.8 mm Hg; PaO2,58.9 mm Hg; HCO3 concentration, 30.8 mmol/L; base excess, 3.2 mmol/L; and oxygen saturation, 90.4%. Finally, he required tracheal intubation and ventilation. After 6 weeks, the patient was transferred to a general ward, and the follow-up ABGA and end-tidal CO2 showed normal range with the discontinuation of pregabalin. We demonstrated CO2 retention via ABGA in a patient with SCI due to cervical myelopathy who developed hypercapnia after taking a therapeutic dose of pregabalin. Physicians should pay particular attention to CO2 retention when prescribing a therapeutic dosage of pregabalin in a patient with cervical SCI.",
"affiliations": "From the Department of Physical Medicine and Rehabilitation, Veterans Health Service Medical Center, Seoul, Korea (KHD, EJC, H-EY); and Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University, Daegu, Korea (MCC).",
"authors": "Do|Kyung Hee|KH|;Choi|Eun Jung|EJ|;Chang|Min Cheol|MC|;Yang|Hea-Eun|HE|",
"chemical_list": "D000069583:Pregabalin",
"country": "United States",
"delete": false,
"doi": "10.1097/PHM.0000000000000735",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0894-9115",
"issue": "96(12)",
"journal": "American journal of physical medicine & rehabilitation",
"keywords": null,
"medline_ta": "Am J Phys Med Rehabil",
"mesh_terms": "D000369:Aged, 80 and over; D002574:Cervical Vertebrae; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D006935:Hypercapnia; D008297:Male; D009437:Neuralgia; D010147:Pain Measurement; D000069583:Pregabalin; D011782:Quadriplegia; D012129:Respiratory Function Tests; D018570:Risk Assessment; D013119:Spinal Cord Injuries; D016896:Treatment Outcome",
"nlm_unique_id": "8803677",
"other_id": null,
"pages": "e223-e226",
"pmc": null,
"pmid": "28323759",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypercapnia Caused by a Therapeutic Dosage of Pregabalin in a Tetraplegic Patient With Cervical Spinal Cord Injury.",
"title_normalized": "hypercapnia caused by a therapeutic dosage of pregabalin in a tetraplegic patient with cervical spinal cord injury"
} | [
{
"companynumb": "KR-PFIZER INC-2017144124",
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"occurcountry": "KR",
"patient": {
"drug": [
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"drugautho... |
{
"abstract": "OBJECTIVE\nSequential chemotherapy with doxorubicin and gemcitabine (AG) followed by ifosfamide, paclitaxel, and cisplatin (ITP) was previously demonstrated to be well tolerated in patients with advanced transitional cell carcinoma (TCC). This study sought to evaluate the efficacy and to additionally define toxicity.\n\n\nMETHODS\nSixty patients with advanced TCC received AG every 2 weeks for five or six cycles followed by ITP every 21 days for four cycles. Granulocyte colony-stimulating factor was given between cycles.\n\n\nRESULTS\nMyelosuppression was seen with 68% of patients who experienced grades 3 to 4 neutropenia and with 25% who experienced febrile neutropenia. Grade 3 or greater nonhematologic toxicities were infrequent. Forty (73%) of 55 evaluable patients (95% CI, 59% to 84%) demonstrated a major response (complete, n = 19; partial, n = 21) and had a median response duration of 11.3 months (range, 1.7 to >or= 105.6 months). Twenty-seven (79%) of 34 patients with locally advanced disease (ie, T4, N0, M0) or with regional lymph node involvement (ie, T3-4, N1, M0) and 10 (56%) of 18 patients with distant metastases achieved a major response. The median progression-free survival was 12.1 months (95% CI, 9.0 to 14.8 months), and the median overall survival was 16.4 months (95% CI, 14.0 to 22.5 months). At a median follow-up of 76.4 months, seven (11.7%) patients remain alive, and all were disease free.\n\n\nCONCLUSIONS\nAG plus ITP is an active regimen in previously untreated patients with advanced TCC; however, it is associated with toxicity and does not clearly offer a benefit compared with other nonsequential, cisplatin-based regimens.",
"affiliations": "Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA. milowskm@mskcc.org",
"authors": "Milowsky|Matthew I|MI|;Nanus|David M|DM|;Maluf|Fernando C|FC|;Mironov|Svetlana|S|;Shi|Weiji|W|;Iasonos|Alexia|A|;Riches|Jamie|J|;Regazzi|Ashley|A|;Bajorin|Dean F|DF|",
"chemical_list": "D003841:Deoxycytidine; D004317:Doxorubicin; C056507:gemcitabine; D017239:Paclitaxel; D002945:Cisplatin; D007069:Ifosfamide",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2008.21.2241",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "27(25)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002295:Carcinoma, Transitional Cell; D002945:Cisplatin; D003841:Deoxycytidine; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006801:Humans; D007069:Ifosfamide; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D017239:Paclitaxel; D013997:Time Factors; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms; D019459:Urothelium",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "4062-7",
"pmc": null,
"pmid": "19636012",
"pubdate": "2009-09-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": "3510732;8683681;2452983;10673526;7680373;9345341;10738226;9704723;9215826;16034041;10506615;11001674;9053481;7509853;2189954;8353075;9314292;12668651;7525883;1607913;2706136;22370319;2819654;7666085",
"title": "Final results of sequential doxorubicin plus gemcitabine and ifosfamide, paclitaxel, and cisplatin chemotherapy in patients with metastatic or locally advanced transitional cell carcinoma of the urothelium.",
"title_normalized": "final results of sequential doxorubicin plus gemcitabine and ifosfamide paclitaxel and cisplatin chemotherapy in patients with metastatic or locally advanced transitional cell carcinoma of the urothelium"
} | [
{
"companynumb": "US-JNJFOC-20130709469",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MESNA"
},
"drugadditional": null,
"dru... |
{
"abstract": "OBJECTIVE\nTo compare the hemostatic effect of hematostatic agent Surgiflo and absorbable gelatin sponge (AGS) in posterior lumbar surgery.\n\n\nMETHODS\nA total of 60 cases were recruited during August 2016 and June 2017 according to the inclusion and exclusion criteria. Patients were randomly allocated to the Surgiflo Haemostatic Matrix (SHM) group or the AGS group (AGS) by computer-generated randomization codes. The success rates of hemostasis for 3 minutes and 5 minutes, the time of operation, the amount of intraoperative bleeding, the volume of autogenously blood transfusion, the amount of blood during hemostasis, the amount of blood transfusion, and BP, RBC, HCT, HB of preoperative, 2 to 3 days, and 5 to 7 days following operation were recorded to compare. Daily drainage and all adverse events after operation were also compared.\n\n\nRESULTS\nAll the patients were followed up for at least 1 month. The RBC and HCT of the AGS group before operation were lower than those in the control group (P = .039, P = .029), but there was no difference after operation (P >.05). In the control group, 19 cases were successfully hemostatic in 3 minutes, 4 cases were successful in 5 minutes, and 7 cases were combined with hemostasis. In the SHM group, it was 22, 3, and 5 cases respectively. There was significant difference in blood loss during hemostatic process between the 2 groups (P <.001). There was no difference in the amount of blood loss and autologous blood transfusion between the 2 groups, and there was no difference in the operation time between the 2 groups. In the AGS group, allogeneic blood was infused in 1 case during operation, and no allogeneic blood was infused in the other patients. The drainage volume on the 1st day and the 2nd to 4th day after operation in the AGS group was less than that in the control group (P = .015, P = .010).\n\n\nCONCLUSIONS\nCompared with AGS, SHM could decrease the blood loss during hemostatic process and the postoperative drainage volume in posterior operation of lumbar degenerative disease. SHM is a safe and effective hemostatic agent in lumbar posterior surgery.",
"affiliations": "Department of Orthopedics, West China Hospital, Sichuan University.;College of Computer Science, Sichuan University, Sichuan Province, P. R. China.;Department of Orthopedics, West China Hospital, Sichuan University.;Department of Orthopedics, West China Hospital, Sichuan University.",
"authors": "Ma|Litai|L|;Dai|Lijuan|L|;Yang|Yi|Y|;Liu|Hao|H|",
"chemical_list": "D006490:Hemostatics; C000629581:Surgiflo; D005780:Gelatin; D013917:Thrombin",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30544449D-18-0254910.1097/MD.0000000000013511135117100Research ArticleClinical Trial/Experimental StudyComparison the efficacy of hemorrhage control of Surgiflo Haemostatic Matrix and absorbable gelatin sponge in posterior lumbar surgery A randomized controlled studyMa Litai MDaDai Lijuan PhDbYang Yi MDaLiu Hao MD, PhDa∗Xiong. Xiaoxing a Department of Orthopedics, West China Hospital, Sichuan Universityb College of Computer Science, Sichuan University, Sichuan Province, P. R. China.∗ Correspondence: Hao Liu, Department of Orthopedics, West China Hospital, Sichuan University, Guoxuexiang, No. 37, Chengdu 610041, Sichuan Province, P. R. China (e-mail: liuhao6304@hotmail.com).12 2018 10 12 2018 97 49 e135119 4 2018 7 11 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nObjective:\nTo compare the hemostatic effect of hematostatic agent Surgiflo and absorbable gelatin sponge (AGS) in posterior lumbar surgery.\n\nMethods:\nA total of 60 cases were recruited during August 2016 and June 2017 according to the inclusion and exclusion criteria. Patients were randomly allocated to the Surgiflo Haemostatic Matrix (SHM) group or the AGS group (AGS) by computer-generated randomization codes. The success rates of hemostasis for 3 minutes and 5 minutes, the time of operation, the amount of intraoperative bleeding, the volume of autogenously blood transfusion, the amount of blood during hemostasis, the amount of blood transfusion, and BP, RBC, HCT, HB of preoperative, 2 to 3 days, and 5 to 7 days following operation were recorded to compare. Daily drainage and all adverse events after operation were also compared.\n\nResults:\nAll the patients were followed up for at least 1 month. The RBC and HCT of the AGS group before operation were lower than those in the control group (P = .039, P = .029), but there was no difference after operation (P >.05). In the control group, 19 cases were successfully hemostatic in 3 minutes, 4 cases were successful in 5 minutes, and 7 cases were combined with hemostasis. In the SHM group, it was 22, 3, and 5 cases respectively. There was significant difference in blood loss during hemostatic process between the 2 groups (P <.001). There was no difference in the amount of blood loss and autologous blood transfusion between the 2 groups, and there was no difference in the operation time between the 2 groups. In the AGS group, allogeneic blood was infused in 1 case during operation, and no allogeneic blood was infused in the other patients. The drainage volume on the 1st day and the 2nd to 4th day after operation in the AGS group was less than that in the control group (P = .015, P = .010).\n\nConclusion:\nCompared with AGS, SHM could decrease the blood loss during hemostatic process and the postoperative drainage volume in posterior operation of lumbar degenerative disease. SHM is a safe and effective hemostatic agent in lumbar posterior surgery.\n\nKeywords\nabsorbable fluid gelatinabsorbable gelatin spongehemostatic materialspinesurgerySurgifloOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nPosterior lumbar fusion surgery has a high rate of success, although intraoperative concerns and complications exist. Bleeding during surgery was one of the most important problems that spinal surgeons often faced. The degree and location of bleeding in different spinal surgery are different. The main bleeding in the operation of epidural cavity is the rupture of the intraspinal venous plexus. Patients with lumbar spinal stenosis often suffer from long-term compression of the spinal canal. The vascular wall of the intraspinal venous plexus is thinner than normal. After decompression, the blood vessels of the veins are irritated and easily ruptured, which lead to bleeding. The improper hemostasis may lead to cauda equine syndrome, nerve root injury because of the small space operation. In elderly patients, the blood vessel sclerosis, the coagulation function is slightly abnormal, it is more difficult to stop bleeding of the intervertebral venous plexus bleeding during intervertebral decompression, which can lead to incomplete hemostasis during the operation, massive drainage of the wound after operation, and the need for continuous prevention of infection and blood transfusion treatment. This not only increases the economic burden of patients but also increases the risk of infection of blood-borne diseases. Prolonged use of antimicrobial agents may lead to a variety of adverse events as a result of a decrease in the patient's body resistance.\n\nAt present, the main hemostatic method for intervertebral venous plexus hemorrhage is filling of gelatin sponge, however, too much gelfoam may lead to compression of spinal cord, cauda equina nerve and nerve root,[1] there are also reported cases of emergency removal surgery due to gelfoam compression. Therefore, it is very important to find a convenient, fast and effective hemostatic method in posterior lumbar surgery. Absorbable hemostatic products, a new kind of hemostatic materials, have been widely used in various surgical operations to assist hemostasis.[2–9] Surgiflo Haemostatic Matrix (SHM) plus flextip (Surgiflo, Johnson & Johnson Wound Management, Somerville, NJ) is an absorbable gelatin matrix hemostatic material that has been widely used in other surgical procedures.[10–13] The liquid form allows injection to the place where hemostasis is required, and the fluid state can be dispersed into the local irregular cavity to have hemostatic effect on the local area. However, this new product has been little reported to be used in posterior lumbar surgery and the safety and efficacy remains controversial. A prospective, randomized and controlled study was conducted in our hospital to compare the hemostatic effect of hematostatic agent Surgiflo and absorbable gelatin sponge (AGS) (Fukangsen, Guilin fukangsen medical equipment co. LTD) in posterior lumbar surgery.\n\n2 Materials and methods\nAll participants signed the informed consent form, applied and recorded to the ethics committee, fully respecting the principle of voluntary participation and withdrawal of the patients. This study was approved by medical ethical committee of our hospital.\n\nInclusion criteria: lumbar 3 to sacral segment 1 patients who underwent posterior spinal canal decompression, bone grafting, and internal fixation, the hemostatic material is fluid gelatin or gelatin sponge only. The operation is performed by a doctor only. Exclusion criteria: BMD ≤−2.0, platelet <50 /109 / L, coagulation index more than normal 20%. Cerebrospinal fluid leakage patients were found during and after operation.\n\nFrom August 2016 to June 2017, a total of 60 cases that underwent posterior lumbar decompression and fusion, and meet the inclusion and exclusion criteria were recruited at last. Patients were randomly allocated to the Surgiflo group or the control group. The random and blind methods were as follows: The number of patients undergoing posterior spinal surgery in the study was numbered in the order of operation. The sequence was randomly divided by statistical experts into 2 groups (the SHM group and the AGS group), the patient then enters the corresponding grouping, it was only before the operation began that the surgeon knew the hemostatic material used for the patient, if cerebrospinal fluid leakage occurred after operation, the patient will automatically be excluded until all effective patients have 60 cases. Blind method to a patient and a statistician. The SHM group (30 cases) was treated with absorbable fluid gelatin Surgiflo for hemostasis. The AGS group (30 cases) was treated with AGS Fukangsen for hemostasis. Fluid gelatin is a sterilized and absorbable porcine gel fluid matrix of 8 mL. After mixed evenly with 2 mL saline during the operation, it is sprayed on the wound to stop bleeding. The basic ingredient is porcine gelatin extract. The principle of hemostasis is to form a fluid gelatin matrix, which can be completely absorbed in the human body within 4 to 6 weeks by physical compression and physical stent for platelet aggregation. There is no compression effect on the spinal cord or cauda equina. Gelatin sponge is 60 mm × 20 mm × 5 mm in size. It is a white, sterile, absorbable sponge made of gelatin. It is hydrophilic and collagen for the common use of hemostatic materials in surgical procedures.\n\n2.1 Surgical procedures and hemostasis\nAfter general anesthesia, the patient was put in a prone position with abdominal suspension. The anesthesia used for 2 groups were same, the operation position was same, and the hypertension was adjusted to normal. All patients received the same degree of controlled hypotension during surgery. The lesion was marked with the help of X-rays, the electric knife dissects the paraspinal muscles on the spinous process and strips the paravertebral muscles along the surface of the vertebral lamina to both sides of the articular process joints and transverse processes. The pedicle screw was placed and the position of pedicle screw was confirmed by X-rays. The spinous process and ligamentum flavum were removed. The affected disc was removed and cartilage endplate was scraped off. Appropriately sized cage filled with autologous bone was inserted and confirmed by X-rays. Then the titanium rod was properly connected. Again, the fluoroscopy was used to finally confirm the position of implants. Bipolar electrocoagulation was used for hemostasis when bleeding during soft tissue incision. Autologous blood transfusion device is used during the operation, but another suction device is used during the hemostasis process to facilitate the collection of bleeding during the hemostasis process, meanwhile, it also helps to avoid hemostatic products from entering autologous blood recovery system so as to avoid patients with abnormal coagulation function. Internal bleeding in the spinal canal is hemostatic with gelatin sponge or fluid gelatin. Gelatin sponge hemostasis is as follows: assistant pruning gelatin sponge into long or square shape. Place 1 or more gelatin sponges on the lateral margin of the posterior spinal canal to avoid direct compression of the dura mater, and then apply 1:200 thousand epinephrine cotton slice to stop bleeding. Use the hemostatic product for 3 minutes and 5 minutes to observe the hemostatic effect. If 1 hemostasis is unsuccessful, repeat the procedure again, and if the hemostasis is still unsuccessful, use a combination of gelatin sponge and fluid gelatin to hemostasis until the hemostasis is successful. No matter which hemostatic material, the hemostatic material is not removed, the excess part is removed. After hemostasis, gelatin sponge covers the exposed dura. Drainage tubes were placed beside the incision to drain the hemorrhage in the incision. The muscle layer was sutured loosely and the deep fascia was sutured continuously to avoid the bleeding from the deep incision.\n\nIf the bleeding rate gradually slows so that there is no more obvious bleeding, the hemostasis is considered successful; otherwise, it is regarded as a hemostatic failure. The success rate of hemostasis for 3 minutes and 5 minutes is recorded, the operation time, the blood loss during the operation, and the amount of bleeding during the hemostasis process are recorded. Blood transfusion volume within 1 week after operation. The changes of systolic blood pressure (SBP), diastolic blood pressure (DBP), erythrocyte count (RBC), hematocrit (HCT), hemoglobin, platelet count, white blood cell count (WBC), neutrophil percentage (neutrophil) and lymphocyte percentage were recorded on the 2 to 3 days and 5 to 7 weeks after operation. The drainage volume was also recorded. All adverse events were recorded.\n\nThe data were managed by a single person. This study was based on the observation of different materials to hemostasis of intraoperative bleeding, followed up for 1 month, and observed the occurrence of adverse events after discharge.\n\n2.2 Statistical analysis\nThe data were analyzed using statistical software (IBM SPSS Statistics for Windows, Version 17.0). The chi-square test was used to classify variables, and the measured data were expressed as mean ± standard deviation. The Anova variance analysis was used to test the statistical significance of all the measured data (P <. 05).\n\n3 Results\nIn the SHM group, there were 12 male cases and 18 female cases; and there were 22 cases operated on 1 segment, 8 cases operated on 2 segments. In the AGS group there were 14 male cases, 16 female cases; 1 segment fusion in 21 cases, 2 segmental fusion in 9 cases; the gender, age, BMI, fusion level, length of hospital stay, surgical segment of 2 groups were not statistically significant, P >.05 (Table 1).\n\nTable 1 The basis data of 2 groups.\n\nThe RBC in the SHM group before operation was less than that in the AGS group (P = .039), the HCT was less than that in the AGS group (P = .029), the SBP in the SHM group was higher than that in the AGS group on the 2 to 3 days after operation (P = .006), and the 5th to 7th day after operation(P = .037). The other laboratorial data were no difference between 2 groups. See Table 2.\n\nTable 2 The blood pressure and laboratorial data of 2 groups in preoperative and postoperative time.\n\nIn the AGS group, the bleeding could not stop completely during the hemostasis process, and always found a little exudation, there were 7 cases with more exudation and with combined hemostasis in them. In the SHM group, there will be some cases that the bleeding is stopped immediately when the fluid gelatin is injected into the hemostatic par, without the need cotton flake to compress. And some needs local compression to stop bleeding and then no re-bleeding. However, few patients had the phenomenon of fluid gelatin being washed away by blood. At this time, only 3 cases successfully stopped hemostatic with fluid gelatin again, while the others (5 cases) needed to be filled with small pieces of gelatin sponge first and then taken the fluid gelatin on it and stop bleeding immediately (Table 3).\n\nTable 3 Success rates of hemostasis in 2 groups.\n\nOne patient in the AGS group transfused red blood cell of 2u and 150 mL fresh frozen plasma during operation, and none of the other patients received allogeneic blood transfusion. The amount of bleeding during the hemostasis process of the SHM group is less than that of the AGS group (P < .001). Patients in both groups were treated with subfascial wound continuous drainage and the drainage tube was removed if the drainage volume/24 hours is less than 50 mL. All drainage tubes were removed 2 to 4 days after operation. The patients were discharged from hospital on 5 to 7 days after operation. The drainage volume of the SHM group was less than that of the AGS group at first 24 hours after operation (P = .015), and the amount of drainage was also less than that of AGS group on the 2 to 4 day after the operation (P = .010). There was no statistical difference in the amount of bleeding, blood transfusion and operation time between the 2 groups, but the SHM group was less than the AGS group (Table 4).\n\nTable 4 The blood loss, transfusion, drainage volume and operation time between the 2 groups.\n\nAdverse events: the comorbidities in 2 groups were not significantly different. One case of intermuscular vein thrombosis in both groups disappeared after anticoagulant therapy. Cerebrospinal fluid leakage was observed in 3 cases in the AGS group and 2 cases in the AGS group after operation and they were excluded. All patients were followed up for at least 1 month. Including the 5 patients excluded, no patients were re-admitted to hospital because of postoperative complications and no adverse effects of fluid gelatin were observed in both groups.\n\n4 Discussion\nThe intraspinal venous plexus, also known as the Batson venous plexus, is a part of the vertebral venous system and consists of a number of small valvular veins. These veins surround the ventral and dorsal side of the dural sac and then converge at the intervertebral foramen to form the extramedullary venous plexus. When the intervertebral disc is herniated and the vertebral canal is narrow, the Batson venous plexus in the spinal canal is compressed and the reflux is limited, which results in the venous irritation. It is inevitable to touch or cut the vein of the angry opening during the operation, and the bleeding is difficult to control. The commonly used method of hemostasis is bipolar electrocoagulation. On the one hand, the effect on venous plexus hemorrhage is limited, and on the other hand, the local heat-producing effect has the risk of damaging the peripheral nerve. Local hemostatic preparation can achieve satisfactory hemostatic effect.[14]\n\nThe AGS, which is supported by gelatin in animal skin, is baked into a sponge. Although it is derived from animals, it has basically no antigenicity. It has a large absorbent surface and can inhale blood several times the weight of itself. The effect of local hemostasis was achieved by solidifying it in the sea surface.[15,16] Gelatin sponges can be absorbed in the body after 4 to 6 weeks, but since gelatin sponge absorbs more than 30 times its own volume, it is not recommended to keep it in the spinal canal. In order to avoid the nerve compression caused by blood-sucking swelling, the cases of postoperative acute paraplegia caused by gelatin sponge have been reported abroad.[17] Alander et al reported a case of acute quadriplegia after ACCF.[18] During the exploration, it was found that the blood-sucking swelling gelfoam filled the whole decompression area. Part of the gelatin sponge was removed after hemostasis, but the removal process often resulted in rebleeding and repeated hemostasis was required.\n\nAbsorbable hemostatic gelatin sponge (SurgifloTM), (short for short: fluid gelatin) is a sterile and absorbable porcine gel fluid matrix. After mixed evenly with 2 mL saline during the operation, it is sprayed on the wound for hemostasis. Stop the bleeding by physical compression and provide a physical scaffold for platelet aggregation, without forming a knot, without oppressive effects on the spinal cord or cauda equina nerve. The fluid matrix provides an environment in which platelets are adhered to and polymerized. In turn, a natural platelet-coagulation waterfall reaction occurs, and the patient's endogenous thrombin is activated, the particle state of gelatin matrix is consistent with the irregular wound, and the filling effect is produced in the expansion of the surgical site.[19] The hemostatic matrix is hydrophilic and melts well with the wet tissue. In contrast, other materials such as fibrin glue require a dry surface, and the fluid gelatin has a fluid state which allows it to enter an irregular cavity. The filling fluid gelatin fills the irregular gap between the dura mater and the spinal canal to stop bleeding. So, we found that the amount of bleeding during the hemostasis process of the SHM group is less than that of the AGS group. The preoperative RBC and HCT in the experiment group were less than those in the AGS group, but RBC and HCT were the same after operation, indicating that less RBC was lost during operation in the experiment group, The early postoperative SBP in the AGS group was lower than that in the AGS group, which may be related to more intraoperative bleeding. At the same time, the amount of intraoperative bleeding, the volume of autologous blood transfusion and the time of operation in the trial group were less than those in the AGS group, although the difference was not statistically significant, the postoperative drainage volume in the trial group was less than that in the AGS group. It shows that fluid gelatin has more advantages than gelatin sponge in hemostasis of spinal canal. In fact, solid hemostatic material cannot well touch or contact the errhysis wound compared with the liquid hemostatic material during the lumbar spine surgery, because hemostasis by compression is very dangerous for nerve and spinal cord. In a very small and irregular space, liquid hemostatic material has the theoretical superiority than solid hemostatic material. However, because of the hydrophilicity and fluid state of fluid gelatin, if the speed of bleeding in the spinal canal is very fast, the blood will be “washed away” because of the dilution of the fluid gelatin, which will not stop the bleeding. And in this case, a combination of Surgiflo and AGS can be used theoretically.\n\nSome limitations should not be ignored. First, the sample size of this study is relatively small, the base line of 2 groups was approximately matched because of random allocation, but it is not completely matched since the limited sample size; Second, the hemostatic process is not blind because of different type of hemostatic material is so obvious to distinguish and observer bias may existed. Third, the hemostasis is influenced by so many factors and the confounding factors may have an impact on the results in this study.\n\nIn conclusion, compared with gelatin sponge, Surgiflo can decrease the blood loss during hemostatic process and the postoperative drainage volume in posterior operation of lumbar degenerative disease. Surgiflo is a safe and effective hemostatic agent in lumbar posterior surgery. Future prospective, randomized, controlled studies with larger sample sizes were needed for further investigation.\n\nAuthor contributions\nConceptualization: Yi Yang.\n\nData curation: Litai Ma, Lijuan Dai.\n\nFormal analysis: Yi Yang, Hao Liu.\n\nFunding acquisition: Hao Liu.\n\nMethodology: Litai Ma.\n\nProject administration: Hao Liu.\n\nResources: Litai Ma, Lijuan Dai.\n\nSoftware: Lijuan Dai, Yi Yang.\n\nSupervision: Litai Ma, Hao Liu.\n\nValidation: Hao Liu.\n\nWriting – original draft: Litai Ma.\n\nWriting – review & editing: Lijuan Dai.\n\nAbbreviations: AGS = absorbable gelatin sponge, HCT = hematocrit, RBC = erythrocyte count, SBP = systolic blood pressure, SHM = Surgiflo Haemostatic Matrix.\n\nThis work was supported by foundation of Science & Technology Department of Sichuan Province, PR China (NO. 0040205301F19).\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Wu J Jin Y Zhang J \nHemostatic techniques following multilevel posterior lumbar spine surgery: a randomized control trial . J Spinal Disord Tech \n2014 ;27 :442–6 .24335723 \n[2] Ellis-Behnke RG Liang YX Tay DK \nNano hemostat solution: immediate hemostasis at the nanoscale . Nanomed Nanotechnol Biol Med \n2006 ;2 :207–15 .\n[3] Fraga GP Bansal V Coimbra R \nTransfusion of blood products in trauma: an update . J Emerg Med \n2010 ;39 :253–60 .19345046 \n[4] Alonso F Rustagi T Iwanaga J \nSelf-made, cost-reducing hemostatic agent for use in spine surgery . World Neurosurg \n2017 ;108 :90–3 .28870821 \n[5] Seon GM Lee MH Kwon BJ \nFunctional improvement of hemostatic dressing by addition of recombinant batroxobin . Acta Biomater \n2017 ;48 :175–85 .27769944 \n[6] Hanisch ME Baum N Beach PD \nA comparative evaluation of Avitene and gelfoam for hemostasis in experimental canine prostatic wounds . Invest Urol \n1975 ;12 :333–6 .1112663 \n[7] Cassano R Di Gioia ML Mellace S \nHemostatic gauze based on chitosan and hydroquinone: preparation, characterization and blood coagulation evaluation . J Mater Sci Mater Med \n2017 ;28 :190.29116465 \n[8] Benesch J Tengvall P \nBlood protein adsorption onto chitosan . Biomaterials \n2002 ;23 :2561–8 .12033604 \n[9] Li G Quan K Xu C \nSynergy in thrombin-graphene sponge for improved hemostatic efficacy and facile utilization . Colloids Surf B Biointerfaces \n2018 ;161 :27–34 .29040831 \n[10] Nagele U Schilling D Anastasiadis AG \nClosing the tract of mini-percutaneous nephrolithotomy with gelatine matrix hemostatic sealant can replace nephrostomy tube placement . Urology \n2006 ;68 :489–93 .16979734 \n[11] Lattouf JB Beri A Klinger CH \nPractical hints for hemostasis in laparoscopic surgery . Minim Invasive Ther Allied Technol \n2007 ;16 :45–51 .17365676 \n[12] van Dijk JH Pes PL \nHaemostasis in laparoscopic partial nephrectomy: current status . Minim Invasive Ther Allied Technol \n2007 ;16 :31–44 .17365675 \n[13] Gazzeri R De Bonis C Galarza M \nUse of a thrombin-gelatin Hemostatic Matrix (Surgiflo) in spinal surgery . Surg Technol Int \n2014 ;25 :280–5 .25419955 \n[14] Sabel M Stummer W \nThe use of local agents: Surgicel and Surgifoam . Eur Spine J \n2004 ;13 suppl 1 :S97–101 .15480824 \n[15] Cho SK Yi JS Park MS \nHemostatic techniques reduce hospital stay following multilevel posterior cervical spine surgery . J Bone Jt Surg Am Vol \n2012 ;94 :1952–8 .\n[16] Renkens KL JrPayner TD Leipzig TJ \nA multicenter, prospective, randomized trial evaluating a new hemostatic agent for spinal surgery . Spine \n2001 ;26 :1645–50 .11474348 \n[17] Friedman J Whitecloud TS 3rd \nLumbar cauda equina syndrome associated with the use of gelfoam: case report . Spine \n2001 ;26 :E485–7 .11598530 \n[18] Alander DH Stauffer ES \nGelfoam-induced acute quadriparesis after cervical decompression and fusion . Spine \n1995 ;20 :970–1 .7644964 \n[19] Bak JB Singh A Shekarriz B \nUse of gelatin matrix thrombin tissue sealant as an effective hemostatic agent during laparoscopic partial nephrectomy . J Urol \n2004 ;171 :780–2 .14713810\n\n",
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"mesh_terms": "D016063:Blood Loss, Surgical; D001803:Blood Transfusion; D005260:Female; D005780:Gelatin; D005781:Gelatin Sponge, Absorbable; D006487:Hemostasis; D006490:Hemostatics; D006801:Humans; D008159:Lumbar Vertebrae; D008297:Male; D008875:Middle Aged; D061646:Operative Time; D013917:Thrombin",
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"title": "Comparison the efficacy of hemorrhage control of Surgiflo Haemostatic Matrix and absorbable gelatin sponge in posterior lumbar surgery: A randomized controlled study.",
"title_normalized": "comparison the efficacy of hemorrhage control of surgiflo haemostatic matrix and absorbable gelatin sponge in posterior lumbar surgery a randomized controlled study"
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"abstract": "Micafungin is recommended especially in patients with liver and kidney failure and in the presence of other side effects due to antifungals apart from its known priority indications such as invasive candidiasis. The aim of this study was to evaluate the children who have received micafungin treatment. In the study, 125 children who were hospitalized in the pediatric wards and intensive care units of our hospital and had used micafungin between November 2016 and January 2019 were analyzed retrospectively. Clinical data, micafungin indication, blood values on the first and fourth days of the treatment, side effects of the drug and efficacy were evaluated. Sixty percent (75/125) of the patients were male and the mean age of all the patients were 58 ± 67 (0-215, 30) months. Approximately half of the cases (48%) had malignancy and 13% of them were premature. Sixty-two percent (n= 37) of the malignencies were hematological (27 acute lymphocytic leukemia, nine acute myeloid leukemia, one myelodysplastic syndrome) and 38% (n= 23) were oncological (six neuroblastoma, four Hodgkin lymphoma, two Non-Hodgkin's lymphoma, five sarcomas, one hepatoblastoma, five others) malignencies. The major cause of hospitalization was sepsis (53%). The patients had several risk factors like immunosuppressive therapy (n= 68, 54%), neutropenia (n= 61, 49%), central venous catheter (n= 102, 82%), nasogastric tube (n= 63, 50%), endotracheal intubation tube (n= 49, 39%), urinary catheter (n= 14, 11%) and total parenteral nutrition (n= 81, 65%). Thirteen percent (n= 16) of the cases were post-operative patients. Candida species were cultivated in 97 clinical specimens (blood, endotracheal aspirate, sputum, urine, etc.) among 23 (18%) of the patients. Thirteen (10%) of the patients had candidemia and 62% of them were non-albicans strains. In all candidemias, strains were echinocandin susceptible, and blood cultures were negative within four days. When all the patients (n= 125) were evaluated, a significant decrease in C-reactive protein, an increase in sodium, and a decrease in alanine aminotransferase were observed on the fourth day of micafungin treatment (p<0.05). A total of 39 (31%) patients underwent various antifungal treatments for median seven (1-60) days prior to micafungin treatment. Fourteen (36%) of these 39 patients, had elevated liver function tests (LFT), 10 (26%) of them had hypokalemia, and five (13%) of them had elevated renal function tests. Ten (26%) patients had antifungal-induced hypokalemia previously; and potassium levels were normalized after micafungin treatment (p= 0.0001). The patients for which micafungin treatment was chosen due to elevated liver function tests (n= 47, 38%), whether the antifungalinduced or not; alanine aminotransferase and aspartate aminotransferase levels were decreased after micafungin treatment (p= 0.0001 and p= 0.0001, respectively). Nineteen (15%) of the patients have died within the first 30 days of micafungin treatment and one of them had candidemia. No micafungin treatment related significant side effects were observed in any of the patients. Our study showed that micafungin could be a safe and effective option in pediatric cases including newborns with high liver and kidney function tests.",
"affiliations": "Uludag University Faculty of Medicine, Department of Pediatric Infectious Diseases, Bursa, Turkey.;Uludag University Faculty of Medicine, Department of Pediatric Infectious Diseases, Bursa, Turkey.;Uludag University Faculty of Medicine, Department of Pediatric Hematology, Bursa, Turkey.;Uludag University Faculty of Medicine, Department of Pediatric Infectious Diseases, Bursa, Turkey.;Uludag University Faculty of Medicine, Department of Pediatric Infectious Diseases, Bursa, Turkey.;Uludag University Faculty of Medicine, Department of Medical Mycology, Bursa, Turkey.;Uludag University Faculty of Medicine, Department of Neonatology, Bursa, Turkey.;Uludag University Faculty of Medicine, Department of Pediatric Infectious Diseases, Bursa, Turkey.;Uludag University Faculty of Medicine, Department of Medical Mycology, Bursa, Turkey.;Uludag University Faculty of Medicine, Department of Pediatric Hematology, Bursa, Turkey.;Uludag University Faculty of Medicine, Department of Neonatology, Bursa, Turkey.;Uludag University Faculty of Medicine, Department of Neonatology, Bursa, Turkey.;Uludag University Faculty of Medicine, Department of Pediatric Oncology, Bursa, Turkey.;Celal Bayar University Faculty of Medicine, Department of Pediatric Endocrinology, Manisa, Turkey.;Uludag University Faculty of Medicine, Department of Pediatric Infectious Diseases, Bursa, Turkey.",
"authors": "Yeşil|Edanur|E|;Çelebi|Solmaz|S|;Sezgin Evim|Melike|M|;Özer|Arife|A|;Turan|Cansu|C|;Timur|Demet|D|;Çakır|Salih Çağrı|SÇ|;Bülbül|Beyhan|B|;Ener|Beyza|B|;Güneş|Adalet Meral|AM|;Köksal|Nilgün|N|;Özkan|Hilal|H|;Sevinir|Betül|B|;Düzcan Kilimci|Duygu|D|;Hacımustafaoğlu|Mustafa|M|",
"chemical_list": "D000935:Antifungal Agents; D055666:Lipopeptides; D000077551:Micafungin",
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"mesh_terms": "D000935:Antifungal Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D055666:Lipopeptides; D008297:Male; D000077551:Micafungin; D012189:Retrospective Studies",
"nlm_unique_id": "7503830",
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"pages": "120-134",
"pmc": null,
"pmid": "32050883",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluation of Micafungin Use in Children.",
"title_normalized": "evaluation of micafungin use in children"
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"abstract": "Tacrolimus has been used in pregnant women following transplantation and for management of lupus nephritis. We report a case of successful control of nephrotic syndrome due to membranous glomerulonephritis during pregnancy using tacrolimus.\nA 26-year-old female presented with severe nephrotic syndrome in her first pregnancy. Post-partum renal biopsy confirmed idiopathic membranous glomerulonephritis. She had persistent proteinuria of 6 g/day with hypoalbuminaemia despite angiotensin receptor blockade. Treatment with tacrolimus monotherapy led to remission of proteinuria, three months prior to conceiving again. She maintained remission with tacrolimus therapy in pregnancy, resulting in a successful birth outcome.\nMembranous glomerulonephritis can be successfully and safely managed with tacrolimus monotherapy during pregnancy. This provides an alternative immunosuppressant with a favourable side effect profile suitable for use in women planning a pregnancy when other immunosuppressive drugs should be avoided.",
"affiliations": "Central and Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, Australia.;Central and Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, Australia.",
"authors": "Irish|G L|GL|https://orcid.org/0000-0003-0758-1867;Jesudason|S|S|",
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"issue": "13(3)",
"journal": "Obstetric medicine",
"keywords": "Membranous glomerulonephritis; nephrotic syndrome; proteinuria; tacrolimus",
"medline_ta": "Obstet Med",
"mesh_terms": null,
"nlm_unique_id": "101464191",
"other_id": null,
"pages": "148-150",
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"pubdate": "2020-09",
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"title": "Case study of tacrolimus as an effective treatment for idiopathic membranous glomerulonephritis in pregnancy.",
"title_normalized": "case study of tacrolimus as an effective treatment for idiopathic membranous glomerulonephritis in pregnancy"
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"abstract": "HRS is a rare and poor prognosis complication of chronic acetaminophen toxicity, which presents by progressive decline in renal function secondary to liver failure.",
"affiliations": "Department of Clinical Pharmacy Faculty of Pharmacy Mazandaran University of Medical Sciences Sari Iran.;Department of Clinical Pharmacy Faculty of Pharmacy Mazandaran University of Medical Sciences Sari Iran.;Toxoplasmosis Research Center Communicable Diseases Institute Iranian National Registry Center for Lophomoniasis and Toxoplasmosis Mazandaran University of Medical Sciences Sari Iran.;Toxoplasmosis Research Center Communicable Diseases Institute Iranian National Registry Center for Lophomoniasis and Toxoplasmosis Mazandaran University of Medical Sciences Sari Iran.;Toxoplasmosis Research Center Communicable Diseases Institute Iranian National Registry Center for Lophomoniasis and Toxoplasmosis Mazandaran University of Medical Sciences Sari Iran.",
"authors": "Nekoukar|Zahra|Z|https://orcid.org/0000-0003-2663-9024;Moghimi|Minoo|M|;Zakariaei|Zakaria|Z|https://orcid.org/0000-0003-4835-9349;Fakhar|Mahdi|M|;Tabaripour|Rabeeh|R|",
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"doi": "10.1002/ccr3.4037",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4037\nCCR34037\nCase Report\nCase Reports\nFulminant hepatorenal syndrome due to Acetaminophen toxicity: A case report\nNEKOUKAR et al.\nNekoukar Zahra https://orcid.org/0000-0003-2663-9024\n1\nMoghimi Minoo 1\nZakariaei Zakaria https://orcid.org/0000-0003-4835-9349\n2 3 ali.zakariaei@yahoo.com\n\nFakhar Mahdi 2\nTabaripour Rabeeh 2\n1 Department of Clinical Pharmacy Faculty of Pharmacy Mazandaran University of Medical Sciences Sari Iran\n2 Toxoplasmosis Research Center Communicable Diseases Institute Iranian National Registry Center for Lophomoniasis and Toxoplasmosis Mazandaran University of Medical Sciences Sari Iran\n3 Toxicology and Forensic Medicine Division Orthopedic Research Center Imam Khomeini Hospital Mazandaran University of Medical Sciences Sari Iran\n* Correspondence\nZakaria Zakariaei, Toxicology and Forensic Medicine Division, Orthopedic Research Center, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari, P.O box: 48166‐33131, Iran.\nEmail: ali.zakariaei@yahoo.com\n\n24 3 2021\n5 2021\n9 5 10.1002/ccr3.v9.5 e0403722 2 2021\n15 1 2021\n25 2 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nHRS is a rare and poor prognosis complication of chronic acetaminophen toxicity, which presents by progressive decline in renal function secondary to liver failure.\n\nHRS is a rare and poor prognosis complication of chronic acetaminophen toxicity, which presents by progressive decline in renal function secondary to liver failure.\n\nacetaminophen\nhepatorenal syndrome\nmetabolic acidosis\nsource-schema-version-number2.0\ncover-dateMay 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:24.05.2021\nNekoukar Z , Moghimi M , Zakariaei Z , Fakhar M , Tabaripour R . Fulminant hepatorenal syndrome due to Acetaminophen toxicity: A case report. Clin Case Rep. 2021;9 :e04037. 10.1002/ccr3.4037\n==== Body\n1 INTRODUCTION\n\nHepatorenal syndrome is a rare life‐threatening complication of acetaminophen toxicity. It is not responsive to fluid therapy and needs performing an emergent liver transplantation. Here, we introduce a 24‐year‐old woman with a history of chronic high doses of acetaminophen consumption, presenting with nausea, vomiting, lethargy, oliguria, and severe metabolic acidosis.\n\nAcetaminophen [(N‐acetyl‐p‐aminophenol or APAP], also known as paracetamol, is used for its antipyretic and analgesic properties. 1 It is widely available as single‐ingredient or combination formulations with other medications for over‐the‐counter use which accounts for its high prevalence of toxicity. 2 Although acetaminophen is safely used in therapeutic doses, severe and life‐threatening toxicities including renal injury and acute liver failure (ALF) potentially may occur with doses higher than recommended. 3 , 4\n\nAcetaminophen dose‐dependent hepatotoxicity is the most frequent cause of ALF (about 50%) in the United States. 5 With doses less than 4 g/d, about 97% of acetaminophen is metabolized by glucuronidation and sulfation to eliminate safely through the kidney. 6 When higher doses of acetaminophen was ingested, its metabolism pathway change to cytochrome P450 system in which acetaminophen metabolized to [N‐acetyl‐p‐benzoquinone imine] (NAPQI), a reactive metabolite leading to irreversible hepatocellular damage. 7 , 8\n\nAcute kidney injury (AKI) is another complication of acetaminophen toxicity that happens in less than 2% of cases and may occur either in the presence or in the absence of ALF. While necrosis is responsible for cell death in AKI, it seems that apoptosis is the major cause of hepatocellular damage in acetaminophen ALF. ALF‐related hepatorenal syndrome (HRS) also may be involved in acute kidney injury (AKI) in acetaminophen overdose. 9 , 10\n\n2 CASE PRESENTATION\n\nThis study was conducted according to the Declaration of Helsinki principles. Also, CARE guidelines and methodology have been followed in this study. A 24‐year‐old woman with nausea, vomiting, dizziness, and anorexia was referred to the emergency room (ER) of Imam Khomeini Hospital, Sari, Iran, on December 20, 2020. She had no history of underlying disease. Due to emotional problems, she had been taking 50 to 100 tablets of clonazepam 1 mg and alprazolam 0.5 mg daily for two years. Eight months ago, regardless of the importance of tapering down, she stopped taking these drugs straight off and started to take 50 to 60 tablets of acetaminophen/codeine 300/20 mg and 500 mg daily. Almost from the same time, she gradually became weak and lethargic leading to hospital admission. According to the history of acetaminophen overdose, she consulted a clinical toxicologist.\n\nIn the clinical examination, the conjunctiva and skin were pale. The heart rate of 110 beats per minute, blood pressure of 80/50 mm Hg, respiratory rate of 24 per minute, and arterial O2 saturation of 97% were recorded. On physical examination, the abdomen was soft with tenderness in the right upper quadrant. There was bleeding from the mucosa of the mouth. She was oliguric and underwent urine catheterization. Hydration was started, and a blood sample was sent to the laboratory for routine tests on admission and evaluation of the acetaminophen plasma level. On ultrasound sonography, an increase in the size of the spleen was notable. Space‐occupying lesions were not seen in the parenchyma of the liver, spleen, kidneys, and pancreas. Liver echography and bile ducts were normal. No mass and free fluid was visible inside the abdomen. On ECG, sinus tachycardia was detected. Viral markers including HIV, HBsAg, and HCV Ab were negative. ABG showed severe metabolic acidosis. Other laboratory data are in Table 1.\n\nTABLE 1 Baseline laboratory data\n\nHemoglobin\t7.9 g/dL\t\nWhite blood cells\t9000/mm3\t\nPlatelet\t142000/mm3\t\nSodium\t143 mmol/L\t\nPotassium\t3.5 mmol/L\t\nALT\t2030 IU/L\t\nAST\t1691 IU/L\t\nALP\t303 IU/L\t\nBilirubin\t\nTotal\t2.3 mg/dL\t\nDirect\t0.8 mg/dL\t\nLactate dehydrogenase\t5400 IU/L\t\nPT\t39.2 sec\t\nPTT\t58 sec\t\nINR\t4.8\t\nAlbumin\t2.5 g/dL\t\nCalcium\t7.9 mg/dL\t\nMagnesium\t1.6 g/dL\t\nBlood urea nitrogen\t16.82 mg/dL\t\nCreatinine\t3 mg/dL\t\npH\t7.19 mmHg\t\nHCO3\t9.6 mmol/L\t\nPCO2\t24.7 mmHg\t\nBase excess\t−18.6 mmol/L\t\nBlood sugar\t50 mg/dL\t\nJohn Wiley & Sons, Ltd\n\nShe was immediately transferred from the emergency room to the ICU. She had hematemesis consisting of acetaminophen tablet residues which explained upper gastrointestinal bleeding. Tachypnea and loss of consciousness secondary to the hepatic encephalopathy resulted in intubation. According to the metabolic acidosis and raised creatinine, the three‐hour hemodialysis was performed. Treatment was started with N‐acetylcysteine (NAC), pantoprazole, norepinephrine, albumin, fresh‐frozen plasma, packed cell, vitamin K, magnesium sulfate, and sodium bicarbonate. Dextrose water 50% was also administered to improve her hypoglycemic state. Based on the impaired LFT profile and her coagulopathy, she consulted a gastrointestinal specialist and a surgeon for an urgent liver transplantation. Despite the intensive supportive therapy during the first 24 hours and efforts to correct the metabolic acidosis and electrolyte disorders, no response was detected, and unfortunately, she died.\n\n3 DISCUSSION\n\nAcetaminophen, a safe and effective analgesic, and antipyretic agent can cause irreversible, even fatal damage to the liver and kidney with chronic high‐dose consumption. Early presentation and diagnosis of acetaminophen overdose are critical for successful management. Acetaminophen is rapidly absorbed after oral administration with the onset of action 30 minutes to 2 hours. Peak plasma levels reach 4 hours after overdoses, which could prolong in gastrointestinal hypomotility or administration of extended‐release formulation. 1 , 11 In acute situations, during the first 4‐6 hours after consumption, oral activated charcoal reduces the gastrointestinal absorption and subsequent acetaminophen plasma level. A free radical scavenger, NAC, is also effective against the replenishing glutathione stores caused by oxidative metabolite of acetaminophen and could prevent or reduce the severity of acetaminophen hepatotoxicity. 12\n\nThe normal elimination half‐life of 2 hours could prolong to 17 hours in severe hepatic dysfunction. 13 It is well known that in acute ingestion of acetaminophen, Rumack‐Matthew nomogram is used to make decisions about initiation and to evaluate the treatment trend. This nomogram cannot be used in chronic toxicity to predict the time of treatment initiation due to the lack of correlation between plasma levels and the degree of acetaminophen ingestion. However, treatment is indicated in such patients with concurrent elevated transaminases regardless of acetaminophen plasma level. It has been recommended to treat patients either with acetaminophen plasma levels of more than 20 mcg/mL or with increased transaminases. 1 Accordingly, NAC was started for this case, with acetaminophen plasma level of 84.7 mcg/mL, but it could not be effective based on the extensive liver and kidney oxidative injuries.\n\nLate presentation, like our case, may manifest as a rise in alanine transaminase (ALT), aspartate transaminase (AST), and bilirubin that represents the hepatic phase of acetaminophen toxicity. 14 Actually, this case was on chronic acetaminophen abuse and presented by both liver and kidney dysfunction which did not respond to any treatment options. About this patient, chronic consumption of acetaminophen had led to the impairment of hepatic metabolism pathways; therefore, prolonged half‐life of acetaminophen had been caused further hepatic injury.\n\nIn overdoses, the acetaminophen metabolic pathway shifted to produce more oxidative NAPQI metabolites that could be excreted in urine. As a result, glutathione stores of the kidney will be reduced and tubular injury occurs. 15\n\nShe also became oliguric with a creatinine level of 3 mg/dl, representing acetaminophen renal injury. Acetaminophen‐related renal injury occurs more in chronic users with significant elevation in liver transaminases. 16 There are some situations of concurrent kidney and liver involvements that are necessary to be differentiated from HRS. Regarding no history of fever and blood and ascites cultures; no history of bleeding and NSAIDs consumption; and no history of infections, injection of dye, intake of nephrotoxic agents such as aminoglycosides in this case that are associated with infection, prerenal acute kidney injury, and parenchymal renal disease, respectively, HRS could be considered. Also, it is important to differentiate acute tubular necrosis (ATN) that is the most common type of acetaminophen‐induced nephrotoxicity, from HRS. 6 Since the patient did not respond to fluid replacement (that is not common in ATN), and among her liver failure, increased serum creatinine, oliguric state, and lethargy, HRS was considered as a consequence of chronic acetaminophen hepatotoxicity. HRS is described as a progressive reduction in renal function resulting from severe liver failure, which often happens in cirrhotic patients. HRS has a poor prognosis, particularly in type 1, and its mortality rate is high within 2 weeks unless performing an urgent liver transplantation. 17 This case was also a candidate for liver transplantation but unfortunately died before any preparations.\n\n4 CONCLUSION\n\nIt is important to distinguish HRS from ATN, which is the most reported cause of acetaminophen‐induced nephrotoxicity, to select a certain treatment strategy. HRS is a rare and poor prognosis complication of chronic acetaminophen toxicity, which presents by progressive decline in renal function secondary to liver failure. The curable treatment option in this situation may be liver transplantation, the same as HRS in cirrhotic patients.\n\nCONFLICT OF INTEREST\n\nThe authors confirm that this article content has no conflict of interest.\n\nAUTHOR CONTRIBUTIONS\n\nZZ: involved in interpretation and collecting of data, and editing the manuscript. MM: involved in drafting first version of manuscript and editing. ZN: involved in writing, editing, and preparing the final version of manuscript. MF: involved in critical revising. RT is responsible for collecting data and submitting the manuscript. All authors reviewed the paper and approved the final version of the manuscript.\n\nINFORMED CONSENT\n\nInformed consent for the publication was taken from the patient's parents.\n\nACKNOWLEDGMENTS\n\nPublished with written consent of the patient.\n\nDATA AVAILABILITY STATEMENT\n\nThe data are available with the correspondence author and can be gained on request.\n==== Refs\nREFERENCES\n\n1 Agrawal S , Khazaeni B . Acetaminophen toxicity. Statpearls [internet]. 2020.\n2 Gummin DD , Mowry JB , Spyker DA , Brooks DE , Osterthaler KM , Banner W . 2017 annual report of the American association of poison control centers’ National Poison Data System (NPDS): 35th annual report. Clin Toxicol. 2018;56 (12 ):1213‐1415.\n3 Stollings JL , Wheeler AP , Rice TW . Incidence and characterization of acute kidney injury after acetaminophen overdose. J Crit Care. 2016;35 :191‐194.27481758\n4 Michaut A , Moreau C , Robin MA , Fromenty B . Acetaminophen‐induced liver injury in obesity and nonalcoholic fatty liver disease. Liver Int. 2014;34 (7 ):171‐179.24164713\n5 Larson AM , Polson J , Fontana RJ , et al. Acetaminophen‐induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42 (6 ):1364‐1372.16317692\n6 Mazer M , Perrone J . Acetaminophen‐induced nephrotoxicity: pathophysiology, clinical manifestations, and management. J Med Toxicol. 2008;4 (1 ):2‐6.18338302\n7 More SS , Nugent J , Vartak AP , Nye SM , Vince R . Hepatoprotective effect of ψ‐glutathione in a murine model of acetaminophen‐induced liver toxicity. Chem Res Toxicol. 2017;30 (3 ):777‐784.28165728\n8 Jiang Y , Zhang T , Kusumanchi P , Han S , Yang Z , Liangpunsakul S . Alcohol metabolizing enzymes, microsomal ethanol oxidizing system, cytochrome P450 2E1, catalase, and aldehyde dehydrogenase in alcohol‐associated liver disease. Biomedicines. 2020;8 (3 ):50.\n9 Lancaster EM , Hiatt JR , Zarrinpar A . Acetaminophen hepatotoxicity: an updated review. Arch Toxicol. 2015;89 (2 ):193‐199.25537186\n10 Inoue D , Usui R , Nitta K , Koike M . A case of acetaminophen‐induced acute tubulointerstitial nephritis in adult. CEN Case Rep. 2017;6 (2 ):185‐188.28801780\n11 Ye H , Nelson LJ , del Moral MG , Martínez‐Naves E , Cubero FJ . Dissecting the molecular pathophysiology of drug‐induced liver injury. World J Gastroenterol. 2018;24 (13 ):1373.29632419\n12 Heard KJ . Acetylcysteine for acetaminophen poisoning. N Engl J Med. 2008;359 (3 ):285‐292.18635433\n13 Yu‐Xin WANG , Yi DU , Xia‐Fei LIU , et al. A hepatoprotection study of Radix Bupleuri on acetaminophen‐induced liver injury based on CYP450 inhibition. Chinese J Nat Med. 2019;17 (7 ):517‐524.\n14 Khandelwal N , James LP , Sanders C , Larson AM , Lee WM . Unrecognized acetaminophen toxicity as a cause of indeterminate acute liver failure. Hepatology. 2011;53 (2 ):567‐576.21274877\n15 Saleem M , Iftikhar H . A rare case of acetaminophen toxicity leading to severe kidney injury. Cureus. 2019;11 (6 ):e5003.31497434\n16 McClain C , Holtzman J , Allen J , Kromhout J , Shedlofsky S . Clinical features of acetaminophen toxicity. J Clin Gastroenterol. 1988;10 (1 ):76‐80.3356889\n17 Ginès P , Guevara M , Arroyo V , Rodés J . Hepatorenal syndrome. Lancet. 2003;362 (9398 ):1819‐1827.14654322\n\n",
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"keywords": "acetaminophen; hepatorenal syndrome; metabolic acidosis",
"medline_ta": "Clin Case Rep",
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"title": "Fulminant hepatorenal syndrome due to Acetaminophen toxicity: A case report.",
"title_normalized": "fulminant hepatorenal syndrome due to acetaminophen toxicity a case report"
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"abstract": "A 36-week gestation newborn was admitted to the neonatal intensive care unit for treatment of primary pulmonary hypertension and possible sepsis. The infant developed hyperbilirubinemia on day 4 of life and peaked on day 5 at a total serum bilirubin of 19 mg/dL. Phototherapy was started on day 4 and continued for 5 days. On day 8 of life, ibuprofen was started for fever; a concurrent total serum bilirubin was 15.7 mg/dL. The subsequent hospital course was uneventful, and discharge occurred on day 22 of life. Because the patient failed a hearing screen at discharge, he was referred for a diagnostic audiology workup. He subsequently failed formal audiometric testing on two occasions one week apart, and was given a diagnosis of auditory dys-synchrony and/or auditory neuropathy, consistent with kernicterus. At 5½ months of age, he was reported to be hypotonic and to have frequent arching movements. Since the total serum bilirubin did not exceed 19 mg/dL, concern was raised that ibuprofen may have caused displacement of bilirubin from its albumin binding site, resulting in kernicterus due to excessive unbound bilirubin concentrations. Ibuprofen should be administered with caution in preterm infants at risk for kernicterus.",
"affiliations": "Women's Hospital, Moses Cone Health System ; School of Pharmacy, University of North Carolina at Chapel Hill ; Greensboro Area Health Education Center.",
"authors": "Gal|Peter|P|;Ransom|J Laurence|JL|;Davis|Sherri A|SA|",
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"journal": "The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG",
"keywords": "adverse effect; bilirubin; ibuprofen; kernicterus; neonate; non-steroidal anti-inflammatory drugs",
"medline_ta": "J Pediatr Pharmacol Ther",
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"publication_types": "D002363:Case Reports",
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"title": "Possible Ibuprofen-induced kernicterus in a near-term infant with moderate hyperbilirubinemia.",
"title_normalized": "possible ibuprofen induced kernicterus in a near term infant with moderate hyperbilirubinemia"
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"abstract": "Spontaneous expulsive suprachoroidal hemorrhage is a rare ocular condition, which usually occurs after sudden decompression of the eyewall. Most of the cases of expulsive hemorrhage reported had a predisposing glaucoma with the combination of corneal pathology. We are reporting a case of spontaneous expulsive suprachoroidal hemorrhage in a glaucoma patient probably due to perpetuated inflammatory reaction and frequent eye rubbing induced by allergic reaction to topical alpha adrenergic agonist in a compromised cornea.",
"affiliations": "Department of Glaucoma Services, 29954Aravind Eye Hospital, Madurai, TN, India.;Department of Glaucoma Services, 29954Aravind Eye Hospital, Madurai, TN, India.;Department of Glaucoma Services, 29954Aravind Eye Hospital, Madurai, TN, India.;Department of Glaucoma Services, 29954Aravind Eye Hospital, Madurai, TN, India.",
"authors": "Pillai|Manju R|MR|https://orcid.org/0000-0002-3522-0877;Kasthuribai|Hariharasubramanian|H|;Ishrath|Deeba|D|https://orcid.org/0000-0001-6074-4456;Gnanavelu|Subathra|S|https://orcid.org/0000-0002-4275-5802",
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"issue": null,
"journal": "European journal of ophthalmology",
"keywords": "Brimonidine; Spontaneous expulsive suprachoroidal hemorrhage; drug allergy; glaucoma",
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "9110772",
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"publication_types": "D016428:Journal Article",
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"title": "A rare case of spontaneous expulsive suprachoroidal haemorrhage in a glaucomatous eye treated with topical alpha-adrenergic agonist.",
"title_normalized": "a rare case of spontaneous expulsive suprachoroidal haemorrhage in a glaucomatous eye treated with topical alpha adrenergic agonist"
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"abstract": "To report our experience with adult patients with spinal muscular atrophy (SMA), some of whom were treated with nusinersen.\n\n\n\nWe reviewed charts of adult patients with SMA seen in our neuromuscular clinic between 2017 and 2019 and noted their demographics, clinical characteristics, treatment, and side effects.\n\n\n\nTwenty-two patients were included. Nine had type 2 and 13 type 3 SMA. Median age was 36 years (range 20-71). Most could not walk unassisted. Ten patients had significant respiratory impairment necessitating ventilation and 2 had tracheostomy. Seventeen had severe scoliosis. Ten patients were treated with nusinersen for 6-24 months (median 12 months), 3 of whom required bone laminectomy for intrathecal access. One developed bowel and bladder incontinence following the procedure. In the treated group, on average, % Medical Research Council change was 2.5% at 12 months and 3.9% at 24 months. Most untreated patients remained stable; 3 had slightly declined. Five treated patients reported subjective improvement. Treatment side effects included post lumbar puncture headache in 5 patients, 2 of whom needed blood patch, and 1 bacterial meningitis requiring inpatient treatment. Three patients stopped treatment after 12-24 months due to lack of improvement, recurrent pneumonia, or proteinuria.\n\n\n\nSide effects of nusinersen can be serious. Whereas half of treated patients reported modest improvement in function, there were no significant objective changes, which may point largely to a placebo effect.\n\n\n\nThis study provides Class IV evidence that for some adult patients with SMA, nusinersen improves subjective function and causes serious adverse effects.",
"affiliations": "From the Department of Neurology, Oregon Health & Science University, Portland.;From the Department of Neurology, Oregon Health & Science University, Portland.;From the Department of Neurology, Oregon Health & Science University, Portland.;From the Department of Neurology, Oregon Health & Science University, Portland.;From the Department of Neurology, Oregon Health & Science University, Portland.;From the Department of Neurology, Oregon Health & Science University, Portland. chafickaram@gmail.com.",
"authors": "Moshe-Lilie|Orly|O|0000-0001-9773-5246;Visser|Amy|A|;Chahin|Nizar|N|;Ragole|Thomas|T|;Dimitrova|Diana|D|;Karam|Chafic|C|",
"chemical_list": "D009841:Oligonucleotides; C000590926:nusinersen",
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0000000000009914",
"fulltext": null,
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"issn_linking": "0028-3878",
"issue": "95(4)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D008875:Middle Aged; D009134:Muscular Atrophy, Spinal; D009841:Oligonucleotides; D055815:Young Adult",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "e413-e416",
"pmc": null,
"pmid": "32665408",
"pubdate": "2020-07-28",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Nusinersen in adult patients with spinal muscular atrophy: Observations from a single center.",
"title_normalized": "nusinersen in adult patients with spinal muscular atrophy observations from a single center"
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"abstract": "There is paucity of literature available on Raoultella terrigena infection. Microbiological identification of Raoultella terrigena is difficult and isolates are frequently misidentified as Klebsiella species. This series of 3 cases with Raoultella terrigena septicemia provides a description of the pitfalls and challenges in the diagnosis and management of the highly resistant strains isolated and to the best of our knowledge, is the first report from Pakistan.\nThe medical records of 3 cases of R. terrigena reported in the hospital over two months were reviewed retrospectively to record all relevant clinical information. Organism was identified by using Analytical profile index (API) 20 E with 90-95% successful identification and the sensitivity testing was performed by disc diffusion method.\nThis organism caused fulminant sepsis in case 2 resulting in mortality and complicated urinary tract infection in the third, while in case 1 it preceded the fatal candidemia. All three patients were females who had multiple co-morbid and had a history of protracted hospital stay and antibiotic usage elsewhere before being shifted to our hospital. The isolates were resistant to all beta lactams and were even colistin resistant in two patients, creating challenges and suboptimal response for effective antibiotic therapy.\nThe purpose of this case series is to highlight the highly drug resistant profile of this organism and the fulminant infection it can cause, which if spreads in our hospitals due to breaches in infection control practices, can pose risk as a deadly and untreatable nosocomial infection.",
"affiliations": "Department of Microbiology, The Indus Hospital, Karachi, Pakistan.;Department of Infectious Disease, The Indus Hospital, Karachi, Pakistan.;Department of Internal Medicine, The Indus Hospital, Karachi, Pakistan.;Indus Hospital Research Center, Indus Health Network, Karachi, Pakistan.",
"authors": "Mal|Pushpa Bhawan|PB|;Sarfaraz|Samreen|S|;Herekar|Fivzia|F|;Ambreen|Rakhshinda|R|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2019.e00628",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(19)30124-610.1016/j.idcr.2019.e00628e00628ArticleClinical manifestation and outcomes of multi-drug resistant (MDR) Raoultella terrigena infection – A case series at Indus Health Network, Karachi, Pakistan Mal Pushpa Bhawan pushpa.saajan@gmail.coma⁎Sarfaraz Samreen bHerekar Fivzia cAmbreen Rakhshinda da Department of Microbiology, The Indus Hospital, Karachi, Pakistanb Department of Infectious Disease, The Indus Hospital, Karachi, Pakistanc Department of Internal Medicine, The Indus Hospital, Karachi, Pakistand Indus Hospital Research Center, Indus Health Network, Karachi, Pakistan⁎ Corresponding author at: Department of Microbiology, The Indus Hospital, Plot C-76, Sector 31/5, Opposite Darussalam Society, Korangi Crossing, Karachi, 75190, Pakistan. pushpa.saajan@gmail.com20 8 2019 2019 20 8 2019 18 e0062814 5 2019 18 8 2019 18 8 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background and objectives\nThere is paucity of literature available on Raoultella terrigena infection. Microbiological identification of Raoultella terrigena is difficult and isolates are frequently misidentified as Klebsiella species. This series of 3 cases with Raoultella terrigena septicemia provides a description of the pitfalls and challenges in the diagnosis and management of the highly resistant strains isolated and to the best of our knowledge, is the first report from Pakistan.\n\nMethods\nThe medical records of 3 cases of R. terrigena reported in the hospital over two months were reviewed retrospectively to record all relevant clinical information. Organism was identified by using Analytical profile index (API) 20 E with 90–95% successful identification and the sensitivity testing was performed by disc diffusion method.\n\nResults\nThis organism caused fulminant sepsis in case 2 resulting in mortality and complicated urinary tract infection in the third, while in case 1 it preceded the fatal candidemia. All three patients were females who had multiple co-morbid and had a history of protracted hospital stay and antibiotic usage elsewhere before being shifted to our hospital. The isolates were resistant to all beta lactams and were even colistin resistant in two patients, creating challenges and suboptimal response for effective antibiotic therapy.\n\nConclusions\nThe purpose of this case series is to highlight the highly drug resistant profile of this organism and the fulminant infection it can cause, which if spreads in our hospitals due to breaches in infection control practices, can pose risk as a deadly and untreatable nosocomial infection.\n\nKeywords\nRaoultella terrigenaExtensively drug resistantNosocomial infection\n==== Body\nIntroduction\nRaoultella terrigena (formally identified as Klebsiella terrigena) are gram-negative, non-motile, facultative anaerobic, encapsulated bacilli belonging to family Enterobacteriaceae and closely linked to genus Klebsiella [1]. Raoultella includes four species: Raoultella ornithinolytica, Raoultella planticola, Raoultella terrigena and Raoultella electrica. They are principally found in water, plants and soil. Raoultella ornithinolytica and Raoultella planticola are frequently isolated and reported from human samples but Raoultella terrigena and Raoultella electrica are rarely reported from clinical samples [2]. There is scanty data available on. R. terrigena septicemia [3]. Moreover, exact identification of R. terrigena is difficult in many clinical microbiology laboratories, and isolates can be simply misidentified as Klebsiella species [4]. Up till now, only four case reports with clinically important infections caused by R. terrigena have been published. First case was R. terrigena infective endocarditis in a forty five year-old liver transplant recipient [5]. In the second case, R. terrigena caused sepsis in a sixty nine year-old male who underwent major surgery (Whipple’s procedure). Third reported case showed urinary tract infection in a premature newborn caused by R. terrigena.(3)The fourth case described a subdural abscess due to R. terrigena [6].The isolates in all these cases were sensitive to multiple antibiotics and easily treatable. No other case reports of infections caused by this organism have been published, and there is limited data about the disease spectrum and pathogenesis caused by this bacteria [7]. Over a period of 2 months (December 2018 to January 2019), three cases of R. terrigena infection, with a multidrug resistant profile, were diagnosed and treated at our institute, two of whom expired. The aim of this case series study is to share our experiences of the difficulties encountered in the diagnosis and management of R. terrigena infection and to provide a thorough review of the literature.\n\nCase history\nCase 1\nA thirty years old female with uncontrolled diabetes and history of recurrent miscarriages presented with altered mentation and sepsis. Two months back she had been managed elsewhere for diabetic ketoacidosis and urosepsis. Post discharge she became bed bound with worsening generalized weakness, undocumented intermittent fever, anorexia and mental obtundation with delayed responses and difficulty to recognize family members. She was initially managed as diabetic ketoacidosis with acute kidney injury and septic shock and later diagnosed as having acute motor-sensory axonal neuropathy subtype of Guillain–Barré syndrome for which 5 alternate day sessions of plasmapheresis were conducted with no resulting improvement in lower limb power. Her blood and urine cultures sent on admission reported Raoultella terrigena sensitive only to fosfomycin and co-trimoxazole with intermediate zone for tigecycline. She was started on IV fosfomycin, tigecycline and co-trimoxazole as targeted therapy. She temporarily improved, achieved blood culture clearance but subsequently succumbed to candidaemia. Her terminal event was refractory hypocalcemia due to plasmapheresis leading to cardiac arrhythmias and death on her fourteenth day of admission.\n\nCase 2\nA sixty three years old female known case of diabetes, hypertension, rheumatoid arthritis and iatrogenic Cushing's syndrome due to steroid self-medication, recently treated for falciparum malaria, became bed bound for eight days due to generalized oedema. She subsequently presented elsewhere with shortness of breath and left lower limb swelling and was diagnosed with deep venous thrombosis leading to saddle shaped pulmonary embolism involving bilateral pulmonary arteries. She was ventilated and underwent cardiac catheterization with tissue plasminogen activator (TPA) for thrombolysis followed by streptokinase infusion. Subsequently the patient had bleeding from multiple orifices and had to be given cryoprecipitate and fresh frozen plasma (FFP) infusions. She contracted ventilator associated pneumonia caused by Acinetobacter spp. for which meropenem and colistin were administered. The patient was, there off transferred to the Indus hospital due to affordability issues. Her femoral line was removed and the catheter tip grew Candida non albicans spp, while her peripheral blood cultures sent on admission, and grew Raoultella terrigena sensitive only to colistin and tigecycline and Stenotrophomonas sensitive to co-trimoxazole. Her tracheal aspirate also grew Raoultella terrigena with same sensitivities as the blood isolate. She was started on IV colistin, tigecycline, co-trimoxazole and fluconazole. Her line was replaced, following which Stenotrophomonas cleared immediately. Delayed clearance was observed for Raoultella bacteremia, as the blood showed no growth of the organism on the 9th day of antibiotics. The possibility of infected thrombus could not be ruled out. The patient remained septic despite culture clearance and expired from disseminated intravascular coagulation (DIC) and multiple organ dysfunction syndrome (MODS) on the 26th day of admission.\n\nCase-3\nA sixty three years old female known case of hypertension, ischemic heart disease with heart failure (ejection fraction of 35%), chronic obstructive pulmonary disease (requiring long term oxygen therapy and BIPAP) with secondary pulmonary artery hypertension and chronic kidney disease, had a recent prolonged admission of 2 months elsewhere, for lower respiratory tract and urinary tract infections. During the course of this illness she underwent seven sessions of hemodialysis through perma catheter for acute on chronic kidney injury complicated by pulmonary oedema and received meropenem and vancomycin. She was shifted to the Indus hospital due to financial constraints. Two blood cultures from perma catheter on admission at our hospital grew methicillin resistant Staphylococcus epidermidis (MRSE) for which vancomycin was continued. Peripheral blood culture grew Pseudomonas spp and based on the sensitivity pattern antibiotic was de-escalated from meropenem to ceftazidime. Urine culture grew Raoultella terrigena sensitive only to colistin and fosfomycin, hence considering her recent hospitalization, catheterization history and acute on chronic kidney injury, oral fosfomycin was started to treat Raoultella infection. She cleared all 3 cultures but deteriorated due to multiple comorbidities and patient's attendants shifted her to another tertiary care hospital.\n\nMicrobiological analysis\nMicrobiological culture and sensitivities were performed as per the standard operating procedures. Blood gram staining showed gram negative rods as shown in Fig. A1. Positive blood culture was inoculated on chocolate, blood agar and MacConkey agar (Oxoid, UK). Chocolate blood agar and MacConkey agar were incubated at 37 °C aerobically for 24–48 hours. After 24 h of incubation there were lactose fermenter mucoid colonies on MacConkey agar Fig. A2. Biochemical tests showed citrate utilization was positive but indole, motility, hydrogen sulphide production as well as urease was negative and acidic / acidic on triple sugar iron test (Oxoid, UK). For further identification API 20 E (bioMérieux) was set and incubated at 370C for 24 h. This gram negative rod was identified as Raoultella terrigena 91% in two cases and 95% in third case by standard conventional biochemical method.\n\nAntibiotic susceptibility\nAntimicrobial susceptibility was performed on Mueller-Hinton agar using Kirby-Bauer disk diffusion method and the results were determined according to the Clinical and Laboratory Standards Institute (CLSI) antibiotic guideline as shown in Fig. A3. The antimicrobial tests and the disc content used included, trimethoprim-sulfamethoxazole (1.25ug/23.75ug), chloramphenicol (30 μg), Ciprofloxacin (10 μg), Fosfomycin (200 μg), Gentamicin (10 μg), amikacin (30 μg), ampicillin (10 μg) ceftriaxone (30 μg), meropenem (30 μg), imipenem (10 μg), ertapenem (10 μg), piperacillin-tazobactam (100/10 μg), tigecycline (15 μg), cefoperazone-sulbactam (30/10 μg)) and colistin (10 μg). All plates for antimicrobial susceptibility testing were incubated at 35–37 °C in 5% CO2 for 24 h. E.coli (ATCC 25,922) was used as control strain. Zone diameters were measured and interpreted as per Clinical and Laboratory Standards Institute (CLSI 2018) guidelines.\n\nDiscussion\nLiterature review of data from Pakistan revealed no previous reporting of R. terrigena. In fact there is limited relevant clinical data for R. terrigena globally. The main purpose of reporting this case series was to highlight the limited antibiotic options available for treatment and the suboptimal response and high mortality observed despite targeted therapy. This organism was originally called Klebsiella terrigena, reclassified as R. terrigena in 2001 after 16SrDNA and rpoB gene sequencing studies [3].Current gold standard for identification of this species is gene sequencing, however, in this case series due to resource limitations, conventional identification by using API 20 E was done with 91 to 95% successful identification.\n\nOur two cases developed sepsis due to R. terrigena and one case developed urinary tract infection by this organism (shown in Table A1). All three cases grew extensively drug resistant isolate. First case was sensitive only to fosfomycin and co-trimoxazole, second case was sensitive only to tigecycline and colistin whereas third case was resistant to all antibiotics except fosfomycin as shown in Table A2. Literature review revealed that previously reported R. terrigena were more sensitive as compared to our study [[3], [4], [5], [6], [7]].This highlights the threat posed by rising antimicrobial resistance (AMR) where the antimicrobial arsenal to treat extensively drug resistant bacteria is fast depleting with an imminent post antibiotic era in sight. Rampant injudicious use of broad spectrum empirical antibiotics is a major contributor to AMR. Broad spectrum antibiotics coupled with a prolonged ICU stay causes a number of bacteria to develop resistance genes which they readily transfer to other bacteria, increasing chances of colonization and subsequent infection with different multi drug resistant organisms (MDRO’s) [3]. All patients in our case series had been transferred from various high dependency or intensive care units and had been heavily pretreated with multiple broad spectrum antimicrobials.\n\nRaoultella spp carries a chromosomal beta- lactamase that makes this agent inherently resistant to several antimicrobial agents [8]. All our patients were put on contact precaution by our infection control department to prevent its transmission to other patients. Yu Wang et al described case of subdural abscess due to R. terrigena in 2016 and this patient recovered with imipenem. This isolate was pan sensitive [6]. Demiray Tet al published three case report with R. terrigena. Two cases were extended -spectrum beta-lactamase (ESBL) negative and both cases were recovered with targeted therapy but one case was ESBL positive which was not responded to therapy and patient died. In contrast to our cases whereby two ended in mortalities, all of Demiray’s cases responded well with cefoperazone/sulbactam, piperacillin/tazobactam [3]. Conversely, our patients were not responding adequately to given treatment because of highly resistant antibiotics profile of this bug which left limited option for cure and eradication of infection. Clinical course and outcome of human infection cannot be predicted with very few case reports [6]. Infections with rare bacteria and high antibiotic resistance profile should always be dealt with collaboration of microbiology and infectious diseases as there is no clear understanding of their behaviour and pathogenesis in vivo while specimen reporting. Laboratory staff should be on alert to find out source of the specimen and interpret bacterial identification with the utmost care wherever a rare organism is concerned [3]. There is need to actively monitor and identify such organisms to establish its pathogenic role and antibiotics resistance profile.\n\nLimitations\nDue to limited resources our study cannot identify R. terrigena by genome sequencing and sensitivity testing was performed by disk diffusion testing. It was desirable to have minimum inhibitory concentration (MIC) in all cases but we could outsource and perform colistin MIC in only one case\n\nConclusion\nR. terrigena is a potential emerging pathogen and its incidence and pathogenic role is not well reported. There is need of active monitoring and reporting of this bug to establish its antibiogram and clinical significance.\n\nSources of funding\nNone.\n\nDeclaration of Competing Interest\nThere are no conflict of interests in this study.\n\nAppendix A Fig. A1 Gram stain of blood sample showing Gram negative rods.\n\nFig. A1Fig. A2 Growth of lactose fermenter on MacConkey agar.\n\nFig. A2Fig. A3 Sensitivity testing by disc diffusion method.\n\nFig. A3Table A1 Table showing different characteristics of patients.\n\nTable A1Identified cases\tAge (years)\tGender\tComorbid\tPrevious hospitalization\tSource of Raoultella\tOutcome\t\nCase 1\t30\tFemale\tUncont. DM*\tMultiple prolong hospitalization\tBlood and urine culture\tExpired\t\nCase 2\t63\tFemale\tDM*\nHTN*\nRA*\nCS*\tMultiple prolong hospitalization\tBlood\tExpired\t\nCase 3\t63\tFemale\tHTN*\nIHD*\nCOPD*\nCKD*\tMultiple prolong hospitalization\tUrine\tPatient shifted to other hospital\t\n* Uncont. DM: Uncontrolled diabetes mellitus, DM: Diabetes Mellitus, HTN: hypertension, RA: rheumatoid arthritis, CS: Cushing syndrome, IHD: ischemic heart disease, COPD: chronic pulmonary disease, CKD: chronic kidney disease.\n\nTable A2 Antibiotics susceptibility pattern of the three isolates of organism. Raoultella terrigena from disc diffusion testing.\n\nTable A2no\tAntibiotics\tCase 1\tCase2\tCase3\t\n1\tAmpicillin\tR\tR\tR\t\n2\tCo-Amoxiclav\tR\tR\tR\t\n3\tPiperacillin-Tazobactam\tR\tR\tR\t\n4\tSulbactam-Cefperazone\tR\tR\tR\t\n5\tCeftriaxone\tR\tR\tR\t\n6\tImipenem\tR\tR\tR\t\n7\tMeropenem\tR\tR\tR\t\n8\tErtapenem\tR\tR\tR\t\n9\tAmikacin\tR\tR\tR\t\n10\tGentamicin\tR\tR\tR\t\n11\tCiprofloxacin\tR\tR\tR\t\n12\tLevofloxacin\tR\tR\tR\t\n13\tTigecycline\tR\tS\tS\t\n14\tCo-trimoxazole\tS\tR\tR\t\n15\tChloramphenicol\tS\tR\t–\t\n16\tFosfomycin\tS\tR\tS\t\n17\tNitrofurantoin\t–\t–\tR\t\n18\tColistin\t*R (MIC > 16 μg/ml)\tS\tR\t\nS: Sensitive, R: Resistant.\n\nAll cases have extensively drug resistant profile.\n\n* Colistin Minimum Inhibitory Concentration was performed by broth microdilution method from Aga Khan Laboratory only on one case.\n\n\n\nAcknowledgements\nThere are no acknowledgements.\n==== Refs\nReferences\n1 Drancourt M. Bollet C. Carta A. Rousselier P. Phylogenetic analyses of Klebsiella species delineate Klebsiella and Raoultella gen. nov., with description of Raoultella ornithinolytica comb. nov., Raoultella terrigena comb. nov. and Raoultella planticola comb. nov Int J Syst Evol Microbiol 51 Pt 3 2001 925 932 11411716 \n2 Ponce-Alonso M. Rodriguez-Rojas L. Del Campo R. Canton R. Morosini M.I. Comparison of different methods for identification of species of the genus Raoultella: report of 11 cases of Raoultella causing bacteraemia and literature review Clin Microbiol Infect 22 3 2016 252 257 26577139 \n3 Demiray T. Koroglu M. Ozbek A. Hafizoglu T. Altindis M. The first case of Raoultella terrigena infection in an infant Turk J Pediatr 57 6 2015 624 628 27735805 \n4 Monnet D. Freney J. Method for differentiating Klebsiella planticola and Klebsiella terrigena from other Klebsiella species J Clin Microbiol 32 4 1994 1121 1122 8027329 \n5 Goegele H. Ruttmann E. Aranda-Michel J. Kafka R. Stelzmueller I. Hausdorfer H. Fatal endocarditis due to extended spectrum betalactamase producing Klebsiella terrigena in a liver transplant recipient Wien Klin Wochenschr 119 11 2007 385 386 17634898 \n6 Wang Y. Jiang X. Xu Z. Ying C. Yu W. Xiao Y. Identification of Raoultella terrigena as a rare causative agent of subungual abscess based on 16S rRNA and housekeeping gene sequencing Can J Infect Dis Med Microbiol 2016 2016 \n7 Shaikh M.M. Morgan M. Sepsis caused by Raoultella terrigena JRSM Short Rep 2 6 2011 1 3 21286224 \n8 Podschun R. Isolation of Klebsiella terrigena from human feces: biochemical reactions, capsule types, and antibiotic sensitivity Zentralblatt fur Bakteriologie 275 1 1991 73 78 1930567\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "18()",
"journal": "IDCases",
"keywords": "Extensively drug resistant; Nosocomial infection; Raoultella terrigena",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e00628",
"pmc": null,
"pmid": "31485415",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "11411716;27735805;26577139;8027329;1930567;17634898;27379169;21731819",
"title": "Clinical manifestation and outcomes of multi-drug resistant (MDR) Raoultella terrigena infection - A case series at Indus Health Network, Karachi, Pakistan.",
"title_normalized": "clinical manifestation and outcomes of multi drug resistant mdr raoultella terrigena infection a case series at indus health network karachi pakistan"
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"abstract": "Roseomonas species is rarely found to be pathogenic to humans and there are few clinical cases that have been described in the literature. We report a case of Roseomonas mucosa bacteremia that involved a 9-year-old Japanese boy who was in a condition of febrile neutropenia caused by chemotherapy for cerebellar medulloblastoma. Conventional phenotyping failed to identify the organism; however, genetic analysis using 16S rDNA sequencing confirmed the pathogen to be R. mucosa. The patient recovered following treatment by meropenem without any complications. A literature review of pediatric cases of Roseomonas bacteremia identified 12 other documented cases, and these revealed that a common clinical situation for the infection is an immunocompromised state with malignancy and/or an indwelling intravenous catheter. Because of the low number of cases, the overall picture of Roseomonas bacteremia in children remains to be elucidated; however, the prognosis of the infection appears to be satisfactory.",
"affiliations": "Laboratory for Clinical Investigation, Osaka University Hospital, Japan.;Division of Infection Control and Prevention, Osaka University Hospital, Japan.;Laboratory for Clinical Investigation, Osaka University Hospital, Japan.;Division of Infection Control and Prevention, Osaka University Hospital, Japan.;Division of Infection Control and Prevention, Osaka University Hospital, Japan.",
"authors": "Kimura|Keigo|K|;Hagiya|Hideharu|H|;Nishi|Isao|I|;Yoshida|Hisao|H|;Tomono|Kazunori|K|",
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"doi": "10.1016/j.idcr.2018.e00469",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(18)30155-010.1016/j.idcr.2018.e00469e00469ArticleRoseomonas mucosa bacteremia in a neutropenic child: A case report and literature review Kimura Keigo aHagiya Hideharu highgear@hp-infect.med.osaka-u.ac.jpb⁎Nishi Isao aYoshida Hisao bcTomono Kazunori ba Laboratory for Clinical Investigation, Osaka University Hospital, Japanb Division of Infection Control and Prevention, Osaka University Hospital, Japanc Department of Pediatrics, Osaka University Hospital, Japan⁎ Corresponding author: Division of Infection Control and Prevention, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan. highgear@hp-infect.med.osaka-u.ac.jp13 11 2018 2018 13 11 2018 14 e00469 e00469 15 8 2018 9 11 2018 9 11 2018 © 2018 The Authors. Published by Elsevier Ltd.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Roseomonas species is rarely found to be pathogenic to humans and there are few clinical cases that have been described in the literature. We report a case of Roseomonas mucosa bacteremia that involved a 9-year-old Japanese boy who was in a condition of febrile neutropenia caused by chemotherapy for cerebellar medulloblastoma. Conventional phenotyping failed to identify the organism; however, genetic analysis using 16S rDNA sequencing confirmed the pathogen to be R. mucosa. The patient recovered following treatment by meropenem without any complications. A literature review of pediatric cases of Roseomonas bacteremia identified 12 other documented cases, and these revealed that a common clinical situation for the infection is an immunocompromised state with malignancy and/or an indwelling intravenous catheter. Because of the low number of cases, the overall picture of Roseomonas bacteremia in children remains to be elucidated; however, the prognosis of the infection appears to be satisfactory.\n\nKeywords\nBloodstream infectionFebrile neutropeniaRoseomonas mucosa\n==== Body\nIntroduction\nMembers of the genus Roseomonas, which was first reported by Rihs et al. in 1993 [1], are slow-growing, aerobic, non-fermentative Gram-negative bacteria, which appear as pink-pigmented colonies. More than 20 Roseomonas species have been isolated from environmental samples, including water, soil, and plants [[2], [3], [4], [5]]. These species are opportunistic pathogens with low pathogenicity to humans; however, the occurrence of human infections has increasingly been reported over the last two decades, predominantly in immunocompromised patients [[6], [7], [8]]. These organisms frequently cause central line-associated bloodstream infections, but potentially give rise to respiratory, skin and soft tissue, peritoneal, and urinary tract infections, as well as spondylitis and subretinal abscesses [[9], [10], [11]].\n\nThe major human pathogens of Roseomonas species are Roseomonas gilardii subsp. gilardii, Roseomonas gilardii subsp. rosea, and Roseomonas mucosa [2,8,12]. Of these, R. mucosa appears to be the most frequently identified in clinical samples [8] and has the ability to cause infections in immunocompetent patients [8,13] and even life-threatening diseases [14]. However, the clinical picture of the infection caused by the pathogen remains to be fully elucidated because of the paucity of reported cases. Here, we report a case of R. mucosa bacteremia, with a literature review of pediatric cases of bacteremia caused by Roseomonas species.\n\nCase\nA 9-year-old Japanese boy (body weight, 27 kg) diagnosed with cerebellar medulloblastoma was admitted to our hospital. He had undergone cranial surgery for tumor resection and had subsequently undergone monthly cancer chemotherapy with a combination of cisplatin, cyclophosphamide, and vincristine. For the infusion of anticancer drugs, an indwelling central line catheter was placed. Three days subsequent to the third course, the patient developed febrile neutropenia, for which meropenem (2.7 g per day) was empirically initiated. His vital signs remained stable, but high fever accompanying diarrhea persisted. Whole-body tomography did not reveal any abnormal findings. Four days later, the patient’s laboratory findings revealed Grade 4 neutropenia (40 cells/μL), a mild elevation in C-reactive protein levels (2.77 mg/dL), and decreased serum gamma globulin levels (immunoglobulin G, 493 mg/dL). Following the collection of blood through the central line for culture, teicoplanin was administered. In addition, his stool specimen was positive for Clostridium difficile toxins, and treatment with intravenous metronidazole was initiated.\n\nBlood was collected into in BD BACTEC™ Peds Plus/F culture vials (Becton Dickinson, Sparks, MD, USA) and was incubated in a BD BACTEC™ FX blood culture system (Becton Dickinson). After 48 h at 35 °C, there was a positive signal from the automated blood culture apparatus; however, no organisms were detected under microscopic examination. The fluid was centrifuged to collect bacteria, and Gram-negative plump coccoid rods were successfully confirmed (Fig. 1A). These were subcultured on trypticase soy agar with 5% sheep blood (Becton Dickinson) and on chocolate agar (Kyokuto Pharmaceutical Industrial, Tokyo, Japan) in 5% CO2 at 35 °C. Over subsequent days, colonies on the chocolate agar demonstrated a pink color (Fig. 1B). The organism, which was positive for catalase, oxidase, and urease in biochemical identification tests, could not be identified using Neg Combo Panel NNFC1J (Beckman Coulter, Brea, CA, USA).Fig. 1 Gram staining of blood culture fluid (A) and pink-pigmented colonies on a chocolate agar plate (B). A, stained following centrifugation. B, incubated in 5% CO2 at 35 °C for 2 days.\n\nFig. 1\n\nFull-base 16S rDNA polymerase chain reaction analysis was conducted and 1,411 base pairs of the targeted gene were amplified using the universal primers 8UA (5'-AGA GTT TGA TCM TGG CTC AG-3') and 1485B (5'-TAC GGT TAC CTT GTT ACG AC-3'). The sequence data were analyzed using BLAST sequence homology search programs (GenBank, EzBioCloud, and leBIBI), and the pathogen was finally confirmed to correspond with the type strain of R. mucosa (ATCC BAA-692; accession number, AF538712) with an accuracy of 100%. The organism was also identified as R. mucosa by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry using a MALDI Biotyper (Bruker Daltonics, Bremen, Germany), with a score of 2.378. The isolate showed resistance to piperacillin, aztreonam, and ceftazidime, and was susceptible to carbapenems, aminoglycosides, minocycline, fluoroquinolones, and trimethoprim/sulfamethoxazole (Table 1).Table 1 Antimicrobial susceptibility testing of the pathogen after 48-hour incubation in ambient air at 35 °C.\n\nTable 1\tMIC (μg/mL)\tSusceptibility\t\nPiperacillin\t>64\tR\t\nCeftazidime\t>16\tR\t\nCefepime\t16\tI\t\nImipenem\t≤1\tS\t\nMeropenem\t≤1\tS\t\nAztreonam\t>16\tR\t\nGentamicin\t≤2\tS\t\nTobramycin\t≤2\tS\t\nAmikacin\t≤8\tS\t\nMinocycline\t≤2\tS\t\nCiprofloxacin\t0.5\tS\t\nLevofloxacin\t≤0.5\tS\t\nTrimethoprim/sulphamethoxazole\t≤2\tS\t\nMIC, minimum inhibitory concentration. Antimicrobial susceptibility was interpreted on the basis of Clinical & Laboratory Standards Institute Guideline (M100-S27, other non-Enterobacteriaceae).\n\n\n\nThe patient gradually recovered from the neutropenia, and a subsequent blood culture examination was negative. He was treated with meropenem for 2 weeks with a satisfactory clinical course.\n\nDiscussion\nBecause of their low pathogenicity, Roseomonas species rarely cause infections in humans; thus, its clinical features are not yet fully understood. To elucidate the clinical characteristics of Roseomonas bacteremia in children, we reviewed previous literature (Table 2) [8,9,[14], [15], [16], [17], [18]]. A search of MEDLINE from its inception in 1996 revealed only 12 such cases. Of the 13 cases, including our patient, the majority of cases had any underlying diseases (11 cases, 84.6%); almost half of the cases had malignancies (6 cases, 46.2%) and neutropenia was observed in at least three cases (23.1%). Only one child was free from any underlying disease [8]. Since the characterization of R. mucosa in 2003 [12], this species has accounted for the majority of clinical cases (6/8 cases, 75%). According to a 16S rDNA-based study in Taiwan, R. mucosa was the most prevalent strain among various Roseomonas species [8]. Central lines appear to be common infectious sites for Roseomonas bacteremia in children, as has been described in adult cases [[7], [8], [9],16]. A recent investigation found that opportunistic infections due to R. mucosa are associated with skin microbiota rather than the environment [2]. Considering these findings, Roseomonas bacteremia may occur as a result of the direct invasion of the pathogen through a catheter penetration site, particularly when the patient’s neutrophil immunity has decreased. All of the pediatric patients were reported to be recovered from the infection, suggesting a preferable prognosis for cases of Roseomonas bacteremia.Table 2 Summary of Roseomonas species bacteremia in pediatric cases.\n\nTable 2No\tAge\tSex\tUnderlying diseases\tNeutropenia at the onset\tSpecies\tInfectious sites\tTreatment\tPrognosis\tyear\tRef\t\n1\t1m\tn.d.\tPremature\tn.d.\tR. gilardii\tn.d.\tn.d.\tn.d.\t1996\t9\t\n2\t2m\tn.d.\tnone\tn.d.\tRoseomonas (not identified)\tn.d.\tn.d.\tTransient Colonization\t1996\t9\t\n3\t6y\tF\tCystic fibrosis\tn.d.\tRoseomonas (not identified)\tn.d.\tn.d.\tTransient Colonization\t1996\t9\t\n4\t15y\tF\tALL\t<100 /μL\tRoseomonas (not identified)\tn.d.\tGM, CAZ\t“Response was positive”\t1996\t9\t\n5\t2y\tM\tALL\tNo\tR. gilardii\tCVC\tAMK, CAZ\tRecover\t2001\t15\t\n6\t11m\tM\tALL\tNo\tR. gilardii\tCVC\tGM, CAZ\tRecover\t2006\t16\t\n7\t18y\tM\tTPN dependence\tn.d.\tR. mucosa\tCVC\tCPFX\tRecover\t2010\t14\t\n8\t8m\tM\tTethered cord syndrome with dermal tract\tNo\tR. mucosa\tSoft tissue infection\tCTX\tRecover\t2012\t8\t\n9\t1y\tF\tnone\tNo\tRoseomonas genomospecies 5\tPrimary bacteremia\tABPC/SBT\tRecover\t2012\t8\t\n10\t3y\tF\tPompe disease\tNo\tR. mucosa\tPrimary bacteremia\tABPC/SBT\tRecover\t2012\t8\t\n11\t3y\tn.d.\tALL\t385 /μL\tR. mucosa\tProbably CVC\tIPM, AMK\tRecover\t2014\t17\t\n12\t17y\tM\tAML\tn.d.\tR. mucosa\tProbably CVC\tcarbapenem\tRecover\t2016\t18\t\n13\t9y\tM\tCerebellar medulloblastoma\t40 /μL\tR. mucosa\tProbably CVC\tMEM\tRecover\t2017\tPresent\ncase\t\nABPC/SBT, ampicillin/sulbactam; ALL, acute lymphoblastic leukemia; AMK, amikacin; AML, acute myeloid leukemia; CAZ, ceftazidime; CPFX, ciprofloxacin; CTX, cefotaxime; CVC, central venous catheter; GM, gentamicin; IPM, imipenem; MEM, meropenem; NB, neuroblastoma. n.d., not described; TPN, total parenteral neutrition.\n\n\n\nThe choice of treatment for Roseomonas species is difficult as there is no standard laboratory method at present, and drug susceptibility varies between species. Of note, the majority of previously reported isolates were not susceptible to third- or fourth-generation cephalosporins [12], as was the case in the patient described here. Among the Roseomonas species, R. mucosa, the most frequent isolate in clinical settings, exhibits the highest antimicrobial resistance [8,12]. The result of whole-genome sequencing for a clinical isolate of R. mucosa in a previous study indicated that the organism possesses innate antimicrobial-resistant characteristics [19]. However, Roseomonas species usually show in vitro susceptibility to other antimicrobial classes, such as carbapenems, aminoglycosides, and fluoroquinolones, and the clinical outcome with these antimicrobials has been reported to be satisfactory in adult cases [8].\n\nRoseomonas organisms form characteristic pink-pigmented colonies on agar plates [11], which show positive reactions to catalase and urease, and thus identification at the genus level is not such difficult. However, commercial microbiologic kits using a phenotypic approach may result in misidentification, and accurate bacterial identification of the organisms at the species level requires genetic techniques. As in previous cases [14,17,20], we identified the R. mucosa strain using 16S rDNA sequencing.\n\nTo conclude, we described a case of R. mucosa bacteremia in a Japanese boy with febrile neutropenia following chemotherapy for cerebellar medulloblastoma. A literature review revealed that a common clinical feature of bacteremia caused by Roseomonas in children is a healthcare-associated catheter-related infection in an immunocompromised child with an underlying disease, particularly a malignancy. Roseomonas species are comparatively resistant to various antimicrobials; however, good outcomes can be expected, even in pediatric cases.\n\nDeclarations of interest\nNone.\n\nConsent\nWritten informed consent was obtained from the parents for publication. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nContribution\nWriting, H. Hagiya and K. Kimura. Supervision, I. Nishi, H. Yoshida, and K. Tomono.\n\nAcknowledgments\nThis study was supported by the Center for Medical Research and Education, Graduate School of Medicine, Osaka University. We would like to thank enago (www.enago.jp/) for English language editing.\n==== Refs\nReferences\n1 Rihs J.D. Brenner D.J. Weaver R.E. Steigerwalt A.G. Hollis D.G. Yu V.L. Roseomonas, a new genus associated with bacteremia and other human infections J Clin Microbiol 31 1993 3275 3283 8308122 \n2 Romano-Bertrand S. Bourdier A. Aujoulat F. Skin microbiota is the main reservoir of Roseomonas mucosa, an emerging opportunistic pathogen so far assumed to be environmental Clin Microbiol Infect 22 737 2016 e731 e737 \n3 Chung E.J. Yoon H.S. Kim K.H. Jeon C.O. Chung Y.R. Roseomonas oryzicola sp. Nov., isolated from the rhizosphere of rice (Oryza sativa L.) Int J Syst Evol Microbiol 65 2015 4839 4844 26443678 \n4 Gallego V. Sanchez-Porro C. Garcia M.T. Ventosa A. Roseomonas Aquatica sp. Nov., isolated from drinking water Int J Syst Evol Microbiol 56 2006 2291 2295 17012549 \n5 Zhang Y.Q. Yu L.Y. Wang D. Roseomonas Vinacea Sp. Nov., a gram-negative coccobacillus isolated from a soil sample Int J Syst Evol Microbiol 58 2008 2070 2074 18768606 \n6 Shokar N.K. Shokar G.S. Islam J. Cass A.R. Roseomonas gilardii infection: case report and review J Clin Microbiol 40 2002 4789 4791 12454198 \n7 De I. Rolston K.V. Han X.Y. Clinical significance of Roseomonas species isolated from catheter and blood samples: analysis of 36 cases in patients with Cancer Clin Infect Dis 38 2004 1579 1584 15156446 \n8 Wang C.M. Lai C.C. Tan C.K. Clinical characteristics of infections caused by Roseomonas species and antimicrobial susceptibilities of the isolates Diagn Microbiol Infect Dis 72 2012 199 203 22209515 \n9 Struthers M. Wong J. Janda J.M. An initial appraisal of the clinical significance of Roseomonas species associated with human infections Clin Infect Dis 23 1996 729 733 8909835 \n10 Bhende M. Karpe A. Arunachalam S. Therese K.L. Biswas J. Endogenous endophthalmitis due to Roseomonas mucosa presenting as a subretinal abscess J Ophthalmic Inflamm Infect 7 2017 5 28130734 \n11 Wallace P.L. Hollis D.G. Weaver R.E. Moss C.W. Biochemical and chemical characterization of pink-pigmented oxidative Bacteria J Clin Microbiol 28 1990 689 693 2332467 \n12 Han X.Y. Pham A.S. Tarrand J.J. Rolston K.V. Helsel L.O. Levett P.N. Bacteriologic characterization of 36 strains of Roseomonas species and proposal of Roseomonas mucosa sp. Nov. and Roseomonas gilardii Subsp. Rosea subsp. nov Am J Clin Pathol 120 2003 256 264 12931556 \n13 Kim K.Y. Hur J. Jo W. Infectious spondylitis with bacteremia caused by Roseomonas mucosa in an immunocompetent patient Infect Chemother 47 2015 194 196 26483995 \n14 Bard J.D. Deville J.G. Summanen P.H. Lewinski M.A. Roseomonas mucosa isolated from bloodstream of pediatric patient J Clin Microbiol 48 2010 3027 3029 20534804 \n15 Marin M.E. Marco Del Pont J. Dibar E. Catheter-related bacteremia caused by Roseomonas gilardii in an immunocompromised patient Int J Infect Dis 5 2001 170 171 11724677 \n16 McLean T.W. Rouster-Stevens K. Woods C.R. Shetty A.K. Catheter-related bacteremia due to Roseomonas species in pediatric hematology/oncology patients Pediatr Blood Cancer 46 2006 514 516 15782406 \n17 Michon A.L. Saumet L. Bourdier A. Haouy S. Sirvent N. Marchandin H. Bacteremia due to imipenem-resistant Roseomonas mucosa in a child with acute lymphoblastic leukemia J Pediatr Hematol Oncol 36 2014 e165 168 23669726 \n18 Kim Y.K. Moon J.S. Song K.E. Lee W.K. Two cases of bacteremia due to Roseomonas mucosa Ann Lab Med 36 2016 367 370 27139611 \n19 Abu Choudhury M. Wailan A.M. Sidjabat H.E. Draft genome sequence of Roseomonas mucosa strain Au37, isolated from a peripheral intravenous catheter Genome Announc 5 2017 \n20 Fanella S. Schantz D. Karlowsky J. Rubinstein E. Septic arthritis due to Roseomonas gilardii in an immunocompetent adolescent J Med Microbiol 58 2009 1514 1516 19574413\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "14()",
"journal": "IDCases",
"keywords": "Bloodstream infection; Febrile neutropenia; Roseomonas mucosa",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e00469",
"pmc": null,
"pmid": "30479963",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D002363:Case Reports",
"references": "26483995;28408667;12454198;8909835;27269884;20534804;17012549;15156446;11724677;12931556;19574413;26443678;27139611;23669726;22209515;8308122;2332467;18768606;15782406;28130734",
"title": "Roseomonas mucosa bacteremia in a neutropenic child: A case report and literature review.",
"title_normalized": "roseomonas mucosa bacteremia in a neutropenic child a case report and literature review"
} | [
{
"companynumb": "JP-HQ SPECIALTY-JP-2018INT000289",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
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{
"abstract": "RAS short variant (SV) mutations in colorectal cancer (CRC) are associated with lack of benefit from epidermal growth factor receptor (EGFR) monoclonal antibody (EGFRmAb). However, the clinical implications for RAS amplification (RASa) as a biomarker for anti-EGFR therapy in CRC remain ill defined.\n\n\n\nGenomic analysis was performed using the Foundation Medicine (FM) comprehensive genomic profiling database of 37,233 CRC cases. Clinical outcomes were assessed using two independent cohorts: the City of Hope (COH) cohort of 338 patients with metastatic CRC (mCRC) and the Flatiron Health-FM real-world clinicogenomic database (CGDB) of 3,904 patients with mCRC.\n\n\n\nRASa was detected in 1.6% (614/37,233) of primarily mCRC. RASa 6-9 (n = 241, 39%), 10-19 (n = 165, 27%), and ≥ 20 (n = 209, 34%) copy number subsets had co-RAS SV/BRAF V600E in 63%/3%, 31%/0.6%, and 4.8%/0% of cases, respectively. In the COH cohort, six patients with RASa (13-54 copies) received EGFRmAb, four of six had progressive disease, two had stable disease, and median time to treatment discontinuation (TTD) was 2.5 months. Of the CGDB EGFRmAb-treated patients, those with RASa (n = 9) had median TTD of 4.7 months and overall survival (OS) of 11.4 months, those with RAS SV (n = 101) had median TTD and OS of 5.3 and 9.4 months, and those with RAS/BRAF wild-type (n = 608) had median TTD and OS of 7.6 and 13.7 months.\n\n\n\nPatients with RASa without RAS mutations (1.1% of mCRC) may have poor outcomes on EGFRmAb, although numbers herein were small, and interpretation is confounded by combination chemotherapy. Larger independent studies are warranted to determine if RASa, including degree of amplification, may act similarly to RAS mutation as a resistance mechanism to EGFRmAb therapies.\n\n\n\nGenomic data suggest that RAS amplification occurs as the sole RAS/RAF alteration in >1% of colorectal cancer cases and that degree of amplification inversely correlates with co-occurring MAPK pathway alterations. Preliminary clinical evidence suggests that RAS amplification may function similarly to RAS mutation as a negative predictor of benefit from anti-epidermal growth factor receptor therapies in colorectal cancer. More clinical data are needed, and comprehensive genomic profiling, including detection of RAS amplification, should be used in trial design to inform therapy selection.",
"affiliations": "Foundation Medicine, Inc., Cambridge, Massachusetts, USA.;Foundation Medicine, Inc., Cambridge, Massachusetts, USA.;Department of Medical Oncology, City of Hope National Medical Center, Duarte, California, USA.;Foundation Medicine, Inc., Cambridge, Massachusetts, USA.;Flatiron Health, Inc., New York, New York, USA.;Flatiron Health, Inc., New York, New York, USA.;Flatiron Health, Inc., New York, New York, USA.;Foundation Medicine, Inc., Cambridge, Massachusetts, USA.;Department of Medical Oncology, City of Hope National Medical Center, Duarte, California, USA.",
"authors": "Schrock|Alexa B|AB|0000-0003-0106-9096;Lee|Jessica K|JK|;Sandhu|Jaideep|J|;Madison|Russell|R|;Cho-Phan|Cheryl|C|;Snider|Jeremy W|JW|;Castellanos|Emily|E|;Venstrom|Jeffrey M|JM|;Fakih|Marwan|M|",
"chemical_list": "D000911:Antibodies, Monoclonal; D066246:ErbB Receptors; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab",
"country": "United States",
"delete": false,
"doi": "10.1002/onco.13679",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "26(6)",
"journal": "The oncologist",
"keywords": "Colorectal cancer; Copy number; EGFR antibody; Genomic profiling; RAS amplification",
"medline_ta": "Oncologist",
"mesh_terms": "D000911:Antibodies, Monoclonal; D000068818:Cetuximab; D003110:Colonic Neoplasms; D015179:Colorectal Neoplasms; D066246:ErbB Receptors; D006801:Humans; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "469-475",
"pmc": null,
"pmid": "33465286",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "31445211;25605843;28420421;28747067;29128267;24024839;24142049;29703606;25323927;26030179;27004837;31427573;22589270;22722830;23404247;27784278",
"title": "RAS Amplification as a Negative Predictor of Benefit from Anti-EGFR-Containing Therapy Regimens in Metastatic Colorectal Cancer.",
"title_normalized": "ras amplification as a negative predictor of benefit from anti egfr containing therapy regimens in metastatic colorectal cancer"
} | [
{
"companynumb": "US-SHILPA MEDICARE LIMITED-SML-US-2021-01052",
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"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
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{
"abstract": "Background Hereditary vitamin D resistant rickets (HVDRR) is a bone disorder characterized by a phenotype of rickets with onset at early stage of life with elevated alkaline phosphatase, hypocalcemia, hypophosphatemia, hyperparathyroidism and elevated levels of 1,25-dihydroxyvitamin D (calcitriol) as a consequence of the resistance of the vitamin D receptor (VDR). Mutations in the DNA-binding domain of the VDR of the vitamin D receptor have been characterized by a lack of response to traditional treatment with calcium and calcitriol. Secondary hyperparathyroidism and hypophosphatemia are the main factors in its pathogenesis. Cinacalcet is a calciomimetic drug that reproduces the action of calcium by increasing the sensitivity of the calcium-sensitive receptors (CASR) of the parathyroid glands that regulate the secretion of the parathyroid hormone (PTH). Case presentation We describe its effectiveness and safety in a patient with HVDRR and review other published report cases in the literature. According to published experience, cinacalcet could be used as an adjunctive treatment for the HVDRR with mutations in the DNA-binding domain of the VDR refractory to traditional treatment. Due to lack of knowledge of possible effects of cinacalcet on CASR in the skeleton, long-term use should be avoided. Conclusions The optimal dose of cinacalcet for treatment of HVDRR ranges between 0.25 and 0.5 mg/kg/day. Serious side effects of cinacalcet have not been published in this type of patient, although we considered that a close monitoring is necessary in order to detect hypocalcemia.",
"affiliations": "Pediatric Nephrology, General University Hospital of Castellón, Castellón, Spain.;Pediatric Nephrology, General University Hospital of Castellón, Castellón, Spain.;Hospital of Manises, Manises, Spain.;Pediatric Nephrology, General University Hospital of Castellón, Castellón, Spain.",
"authors": "Lucas|Jesús|J|https://orcid.org/0000-0001-7842-6624;Badia|Jose Luis|JL|;Lucas|Elena|E|;Remon|Ana|A|",
"chemical_list": "D000077264:Calcium-Regulating Hormones and Agents; D014815:Vitamins; D014807:Vitamin D; D000069449:Cinacalcet",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0334-018X",
"issue": "33(2)",
"journal": "Journal of pediatric endocrinology & metabolism : JPEM",
"keywords": "cinacalcet; hereditary vitamin D resistant rickets; vitamin D",
"medline_ta": "J Pediatr Endocrinol Metab",
"mesh_terms": "D000077264:Calcium-Regulating Hormones and Agents; D002675:Child, Preschool; D000069449:Cinacalcet; D004351:Drug Resistance; D053098:Familial Hypophosphatemic Rickets; D006801:Humans; D008297:Male; D011379:Prognosis; D016879:Salvage Therapy; D014807:Vitamin D; D014815:Vitamins",
"nlm_unique_id": "9508900",
"other_id": null,
"pages": "313-318",
"pmc": null,
"pmid": "31926093",
"pubdate": "2020-02-25",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Cinacalcet treatment experience in hereditary vitamin D resistant rickets.",
"title_normalized": "cinacalcet treatment experience in hereditary vitamin d resistant rickets"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP000164",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "CALCIUM"
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"drugadditional": ... |
{
"abstract": "Allogeneic hematopoietic cell transplant (HCT) is often the only curative therapy for patients with nonmalignant diseases; however, many patients do not have an HLA-matched donor. Historically, poor survival has been seen after HLA-haploidentical HCT because of poor immune reconstitution, increased infections, graft-versus-host disease (GVHD), and graft failure. Encouraging results have been reported using a nonmyeloablative T cell-replete HLA-haploidentical transplant approach in patients with hematologic malignancies. Here we report the outcomes of 23 patients with various nonmalignant diseases using a similar approach. Patients received HLA-haploidentical bone marrow (n = 17) or granulocyte colony-stimulating factor-mobilized peripheral blood stem cell (n = 6) grafts after conditioning with cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, and 2 or 4 Gy total body irradiation. Postgrafting immunosuppression consisted of cyclophosphamide, mycophenolate mofetil, tacrolimus, ± sirolimus. Median patient age at HCT was 10.8 years. Day 100 transplant-related mortality (TRM) was 0%. Two patients died at later time points, 1 from intracranial hemorrhage/disseminated fungal infection in the setting of graft failure and 1 from infection/GVHD. The estimated probabilities of grades II to IV and III to IV acute GVHD at day 100 and 2-year National Institutes of Health consensus chronic GVHD were 78%, 26%, and 42%, respectively. With a median follow-up of 2.5 years, the 2-year overall and event-free rates of survival were 91% and 78%, respectively. These results are encouraging and demonstrate favorable disease-specific lineage engraftment with low TRM in patients with nonmalignant diseases using nonmyeloablative conditioning followed by T cell-replete HLA-haploidentical grafts. However, additional strategies are needed for GVHD prevention to make this a viable treatment approach for patients with nonmalignant diseases.",
"affiliations": "Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington; Division of Hematology and Oncology, Seattle Children's Hospital, Seattle, Washington.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington; Division of Hematology and Oncology, Seattle Children's Hospital, Seattle, Washington.;Clinical Biostatistics, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.;Children's Hospital at TriStar Centennial and Sarah Cannon Research Institute, Nashville, Tennessee.;Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington; Division of Immunology, Seattle Children's Hospital, Seattle, Washington.;Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington; Division of Immunology, Seattle Children's Hospital, Seattle, Washington.;Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington; Division of Hematology and Oncology, Seattle Children's Hospital, Seattle, Washington.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington; Division of Hematology and Oncology, Seattle Children's Hospital, Seattle, Washington.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington; Division of Hematology and Oncology, Seattle Children's Hospital, Seattle, Washington.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington; Division of Hematology and Oncology, Seattle Children's Hospital, Seattle, Washington.;Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington; Division of Immunology, Seattle Children's Hospital, Seattle, Washington.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington; Division of Hematology and Oncology, Seattle Children's Hospital, Seattle, Washington.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington; Division of Hematology and Oncology, Seattle Children's Hospital, Seattle, Washington. Electronic address: lburroug@fredhutch.org.",
"authors": "Mallhi|Kanwaldeep K|KK|;Srikanthan|Meera A|MA|;Baker|Kelsey K|KK|;Frangoul|Haydar A|HA|;Torgerson|Troy R|TR|;Petrovic|Aleksandra|A|;Geddis|Amy E|AE|;Carpenter|Paul A|PA|;Baker|K Scott|KS|;Sandmaier|Brenda M|BM|;Thakar|Monica S|MS|;Skoda-Smith|Suzanne|S|;Kiem|Hans-Peter|HP|;Storb|Rainer|R|;Woolfrey|Ann E|AE|;Burroughs|Lauri M|LM|",
"chemical_list": "D006680:HLA Antigens; D003520:Cyclophosphamide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2020.03.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "26(7)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Haploidentical transplantation; Nonmalignant diseases; Nonmyeloablative conditioning; Post-transplant cyclophosphamide",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D003520:Cyclophosphamide; D006086:Graft vs Host Disease; D006680:HLA Antigens; D006239:Haplotypes; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1332-1341",
"pmc": null,
"pmid": "32234377",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "21228326;22796535;12791654;19897573;25648539;22839094;21527516;9573000;30770870;28013015;7022832;27241891;28288951;7703498;19855248;23462188;25682602;27846611;16338616;29656137;25862589;23206845;8937413;22110248;30846493;31248843;12393457;7581076;27217372;2230693;29021228;17825895;27821503;23355537;29440002;29360162;2911570;25730184;27832981;25085357;21659547;26130705;18489989;18940683;25054717;17660844;12171484;25529383;9108426;20089963;22955919;24797180;18927240;20673987;30878319;27856368",
"title": "HLA-Haploidentical Hematopoietic Cell Transplantation for Treatment of Nonmalignant Diseases Using Nonmyeloablative Conditioning and Post-Transplant Cyclophosphamide.",
"title_normalized": "hla haploidentical hematopoietic cell transplantation for treatment of nonmalignant diseases using nonmyeloablative conditioning and post transplant cyclophosphamide"
} | [
{
"companynumb": "US-TEVA-2020-US-1846364",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
... |
{
"abstract": "Trichilemmal carcinoma (TC) is described as a very rare cancer of the skin adnexa.1 2 Ninety per cent of the lesions present on the scalp. Prognostic factors in TC are limited to lymph node status and surgical margins, with no statistical significance observed for age or gender of the patient, size of tumour or locoregional recurrence. We present a 46-year-old black patient who developed TC during treatment for breast cancer. Postoperative histology of the scalp lesion excision confirmed no involved margins. At the three monthly appointment, the patient was reviewed and multiple, new scalp lesions were noted. A CT scan of the head, neck found multiple lesions on the scalp, limited to the soft tissue, not involving the outer table of the skull. There was bilateral invasion of the parotid glands. To the best of our knowledge, no syndromes or associations between breast cancer and adnexal skin tumours exist.",
"affiliations": "Department of Plastic and Reconstructive Surgery, University of the Witwatersrand, Johannesburg, South Africa.;Department of Plastic and Reconstructive Surgery, University of the Witwatersrand, Johannesburg, South Africa.;Department of Plastic and Reconstructive Surgery, University of the Witwatersrand, Johannesburg, South Africa.",
"authors": "Sofianos|Chrysis|C|http://orcid.org/0000-0002-3438-508X;Chauke|Nkhensani Y|NY|;Grubnik|Alexandra|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-217661",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D018294:Neoplasms, Adnexal and Skin Appendage; D012535:Scalp",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27872134",
"pubdate": "2016-11-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25645796;14692940;1597565;793411;10658141;10699898;8349925;11896784;19405112;9870149;23686402;25313781;1360441;19115489;27303183;15487455;6852333;12859393;8468416;23605822;14746636;24649199;20948924;25370551",
"title": "Metastatic trichilemmal carcinoma in a patient with breast cancer.",
"title_normalized": "metastatic trichilemmal carcinoma in a patient with breast cancer"
} | [
{
"companynumb": "ZA-ACCORD-047297",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
"druga... |
{
"abstract": "Hydroxychloroquine is an oral antimalarial medication commonly used off-label for a variety of rheumatological conditions, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and dermatomyositis. We present a case of a 64-year-old woman who presented with acute onset headache, bilateral tinnitus, and left-sided facial numbness and tingling in the setting of accidentally overdosing on hydroxychloroquine. By the next morning, the patient began to experience worsening in the tingling sensation and it eventually spread to her left arm, thigh and distal extremities. The patient also complained of new onset blurring of her peripheral vision and feeling 'off balance.' Despite a complete neurological and ophthalmological work-up with unremarkable imaging and blood work, the patient has had no improvement in her tinnitus, left-sided paresthesias, visual disturbance or ataxia. This is a unique case of hydroxychloroquine overdose resulting in permanent neurotoxic vestibulopathy.",
"affiliations": "Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.;Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA werth@mail.med.upenn.edu.",
"authors": "Chansky|Peter B|PB|;Werth|Victoria P|VP|",
"chemical_list": "D006886:Hydroxychloroquine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-218786",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Emergency medicine; Neurological injury; Rheumatology; Sjogren's syndrome",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001259:Ataxia; D062787:Drug Overdose; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D008875:Middle Aged; D010292:Paresthesia; D014012:Tinnitus; D014786:Vision Disorders",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28404567",
"pubdate": "2017-04-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "102610;10630270;11555803;12098196;12355560;14982575;16495267;18180661;19157361;22494697;2263276;23771936;25057461;26351590;26793391;26992838;27323674;8806147",
"title": "Accidental hydroxychloroquine overdose resulting in neurotoxic vestibulopathy.",
"title_normalized": "accidental hydroxychloroquine overdose resulting in neurotoxic vestibulopathy"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-17-01978",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
... |
{
"abstract": "Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. L-dopa-carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG-J), which reduces L-dopa-plasma-level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day \"off\" time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, \"on\" time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l-dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks.",
"affiliations": "Center for Neurological Restoration, Cleveland Clinic, Cleveland, Ohio, USA.",
"authors": "Fernandez|Hubert H|HH|;Standaert|David G|DG|;Hauser|Robert A|RA|;Lang|Anthony E|AE|;Fung|Victor S C|VS|;Klostermann|Fabian|F|;Lew|Mark F|MF|;Odin|Per|P|;Steiger|Malcolm|M|;Yakupov|Eduard Z|EZ|;Chouinard|Sylvain|S|;Suchowersky|Oksana|O|;Dubow|Jordan|J|;Hall|Coleen M|CM|;Chatamra|Krai|K|;Robieson|Weining Z|WZ|;Benesh|Janet A|JA|;Espay|Alberto J|AJ|",
"chemical_list": "D000978:Antiparkinson Agents; D004338:Drug Combinations; D005782:Gels; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D002230:Carbidopa",
"country": "United States",
"delete": false,
"doi": "10.1002/mds.26123",
"fulltext": "\n==== Front\nMov DisordMov. DisordmdsMovement Disorders0885-31851531-8257Blackwell Publishing Ltd Oxford, UK 10.1002/mds.26123Research ArticlesLevodopa-Carbidopa Intestinal Gel in Advanced Parkinson'd Disease: Final 12-Month, Open-Label Results Fernandez Hubert H MD1*Standaert David G MD, PhD2Hauser Robert A MD3Lang Anthony E MD, FRCPC4Fung Victor SC PhD, FRACP5Klostermann Fabian PhD6Lew Mark F MD7Odin Per MD, PhD8Steiger Malcolm MBBS, MD, FRCP9Yakupov Eduard Z MD, PhD, DMSc10Chouinard Sylvain MD, FRCPC11Suchowersky Oksana MD, FRCPC, FCCMG12Dubow Jordan MD13Hall Coleen M MS13Chatamra Krai PhD13Robieson Weining Z PhD13Benesh Janet A BSMT13Espay Alberto J MD, MSc141 Center for Neurological Restoration, Cleveland ClinicCleveland, Ohio, USA2 University of Alabama at BirminghamBirmingham, Alabama, USA3 Department of Neurology, University of South FloridaTampa, Florida, USA4 University of TorontoToronto, Ontario, Canada5 Movement Disorders Unit, Westmead Hospital and Sydney Medical SchoolSydney, Australia6 Charité-University Medicine BerlinBerlin, Germany7 Keck/USC School of MedicineLos Angeles, California, USA8 Klinikum-Bremerhaven, Bremerhaven, Germany and Skane University HospitalLund, Sweden9 Walton Center for Neurology and NeurosurgeryLiverpool, United Kingdom10 Kazan State Medical UniversityKazan, Russia11 University of MontrealMontreal, Quebec, Canada12 University of AlbertaEdmonton, Alberta, Canada13 AbbVie Inc., North ChicagoIllinois, USA14 University of Cincinnati Academic Health CenterCincinnati, Ohio, USA*Correspondence to: Dr. Hubert H. Fernandez, Center for Neurological Restoration, Cleveland Clinic, 9500 Euclid Avenue, U-2, Cleveland, OH 44195, USA; fernanh@ccf.org or Dr. David G. Standaert, Department of Neurology, 1719 6th Avenue South, CIRC 516, Birmingham, AL 35294, USA; dstandaert@uab.eduFunding agencies: This study was sponsored by AbbVie Inc. (North Chicago, IL, USA), which participated in the study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. Funding for editorial and graphic support was provided by AbbVie Inc. to The Curry Rockefeller Group, LLC; medical writing assistance was provided by Michael Feirtag, Susan Kralian, PhD, Paul V. Shea, Jennifer Kuo, PharmD, and John Norwood of The Curry Rockefeller Group, LLC.\n\nRelevant conflicts of interest/financial disclosures: H.H.F. was a study investigator and has served as a consultant for AbbVie Inc. through a contract between AbbVie Inc. and Cleveland Clinic Foundation; he has not received any personal compensation from AbbVie Inc. D.G.S. was a study investigator for, and has received compensation from, AbbVie Inc. for serving as a consultant and/or participating in scientific advisory boards. R.A.H. was a study investigator for AbbVie Inc. and has received honoraria or payments for consulting, advisory services, or speaking services over the past 12 months from AbbVie Inc. A.E.L. was a study investigator for AbbVie Inc. and has received compensation from AbbVie Inc. for participating in scientific advisory boards. V.S.C.F. was a study investigator for, and has also received compensation from, AbbVie Inc. for participating in scientific advisory boards; AbbVie Inc. contributed to funding for a Parkinson's disease nurse specialist in the form of a grant to his institution. F.K. was a study investigator for, and has received compensation from, AbbVie Inc. for participating in scientific advisory boards and for serving as a lecturer. M.F.L. was a study investigator for AbbVie Inc. P.O. was a study investigator in AbbVie Inc.-sponsored studies and has received compensation from AbbVie Inc. for serving as a consultant and lecturer. M.S. was a study investigator in AbbVie Inc.-sponsored studies and has received compensation from AbbVie Inc. for participating in scientific advisory boards. E.Z.Y. was a study investigator for, and has received compensation from, AbbVie Inc. for serving as a lecturer. S.C. was a study investigator for, and has received compensation from, AbbVie Inc. for serving as a consultant, lecturer, and/or participating in scientific advisory boards. O.S. was a study investigator for, and has received compensation from, AbbVie Inc. for serving as a consultant and/or participating in scientific advisory boards. J.D., C.M.H., K.C., W.Z.R., and J.A.B. are employees of AbbVie Inc. A.J.E. was a study investigator for, and has received compensation from, AbbVie Inc. for serving as a consultant, lecturer, and/or participating in scientific advisory boards.\n\nFull financial disclosures and author roles may be found in the online version of this article.\n\n4 2015 24 12 2014 30 4 500 509 28 8 2014 07 11 2014 18 11 2014 © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.2014This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. l-dopa-carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG-J), which reduces l-dopa-plasma–level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day “off” time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, “on” time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l-dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.\n\ndyskinesiainfusionlevodopa-carbidopa intestinal gel“off” timepercutaneous endoscopic gastrojejunostomy\n==== Body\nOral levodopa (L-dopa) is one of the most effective therapies for Parkinson's disease (PD).1–4 During early disease stage, motor symptoms are well controlled with 3 to 4 daily doses. As PD progresses, however, oral l-dopa's effect may not be sustained between doses and symptoms may re-emerge.3–6 Adjunctive therapies may initially reduce the duration of motor complications (i.e., decrease “off” time by approximately 1-2 hours per day); however, dyskinesia and other adverse events (AEs) increase.7–9 Oral l-dopa pharmacokinetic properties contribute to oscillations in plasma l-dopa levels,3–5 which may be compounded by variability of gastric emptying and l-dopa absorption.10,11\n\nEstablishing stable plasma l-dopa levels may provide more continuous dopaminergic stimulation, resulting in decreased motor fluctuations.4,6\nl-dopa-carbidopa intestinal gel (LCIG) offers continuous drug delivery and may provide a closer approximation of physiological continuous dopaminergic stimulation through its amelioration of plasma-level fluctuations, including the depth and frequency of serum troughs.5 LCIG is delivered continuously by portable pump through a percutaneous endoscopic gastrojejunostomy (PEG-J) tube,1,6,12 bypassing the stomach to eliminate variability associated with gastric emptying,4,10 resulting in a significant decrease in off time duration.5,12–15\n\nThe efficacy of LCIG as an adjunctive therapy was evaluated in a double-blind, double-dummy, phase III study, which showed a 4.0-hour reduction from baseline in off time among patients randomized to LCIG and a 1.9-hour difference in off time reduction versus optimized oral l-dopa (P = 0.0015).15 Previous open-label studies also showed statistically significant reductions in off time and/or dyskinesia versus baseline.13,14,16–21 However, these studies were small by design, comprised of 5 to 91 patients. This large study was designed to provide needed longer-term safety and efficacy results with clinical applicability to an international patient population with advanced PD. Furthermore, the study investigated the initiation and maintenance of LCIG as monotherapy, replacing adjunctive PD therapy.\n\nPatients and Methods\nThe safety and efficacy of LCIG were evaluated in patients with advanced PD experiencing motor fluctuations despite optimized medical therapy in an open-label, phase III, 12-month study (http://ClinicalTrials.gov: NCT00335153). The study methodology has been reported on22 and is summarized below. The study protocol was approved by the institutional review board/ethics committee at all 86 centers in 16 countries. All patients provided written informed consent.\n\nStudy Design\nThe study included a screening period (≤28 days), baseline assessments, a nasojejunal (NJ) titration period (2-14 days), a PEG-J titration period (2-14 days), and a 54-week treatment period (Fig. 1A). The starting infusion dose was based on each patient's previous daily dose of oral l-dopa. Usage of other PD medications that required tapering off was compensated for at the investigator's discretion. Patients were hospitalized for NJ tube placement and initiation of LCIG titration as well as PEG-J tube placement and further dose optimization by PEG-J, if required. At the end of titration, patients entered long-term PEG-J treatment and assessments began on day 28. LCIG was administered by a portable pump during waking hours; a morning dose/bolus was followed by continuous infusion for approximately 16 hours with additional rescue doses during the day, if clinically indicated. The use of oral immediate-release l-dopa-carbidopa was permitted only when the pump was turned off at night. Use of other PD medications was permitted after 28 days post-LCIG initiation at the investigator's discretion. Apomorphine and controlled-release l-dopa-carbidopa were not permitted.\n\nFig. 1 (A) Study design. (B) Patient disposition.\n\nSafety and tolerability provided the primary endpoint whereas efficacy assessments provided the secondary endpoints.\n\nPatients\nEligible patients were ≥30 years old, l-dopa responsive, met UK Parkinson's Disease Society Brain Bank diagnostic criteria, and had severe motor fluctuations defined as ≥3 hours of daily off time at baseline (confirmed by the PD symptom diary), despite optimized treatment with available PD medications.\n\nSafety\nSafety measures included AEs, infusion device complications, and tolerability assessed by number of patients completing the study. Laboratory results, vital signs, and electrocardiogram (ECG) were monitored.\n\nAEs were coded according to Medical Dictionary for Regulatory Activities (MedDRA) version 14.0. Each event could be coded to one or more terms descriptive of the event. Planned hospitalization for baseline assessment and treatment initiation was not considered a serious AE (SAE) unless hospitalization was prolonged as a result of complications. All AEs reported are treatment-emergent AEs, which were defined as those that began or worsened from the time of NJ tube insertion until 30 days after PEG-J removal. AEs of special interest were monitored. These were AEs associated with neuropathy, the procedure and device (e.g., PEG-J placement), respiratory tract aspiration, weight loss, and cardiovascular fatalities.\n\nEfficacy\nEfficacy outcomes included assessed mean change from baseline to last visit in patient-diary off time, “on” time with troublesome dyskinesia, and on time without troublesome dyskinesia (on time without dyskinesia plus on time with nontroublesome dyskinesia, i.e., does not interfere with function or cause meaningful discomfort); the investigator-rated Clinical Global Impression-Improvement (CGI-I) scale; the UPDRS23 Parts II, III, total score (Parts I–III), and the dyskinesia items from Part IV (questions 32-34); the 39-item PD Questionnaire (PDQ-39)24; the EuroQoL-5D (EQ-5D) Summary Index25; and the EuroQoL visual analog scale (EQ-VAS).26 Efficacy assessments were collected during post-PEG-J weeks 4, 12, 24, and 54; PD diary and CGI-I were also collected at post-PEG-J week 36. PDQ-39 was administered during screening visit 1 rather than at baseline.\n\nPatients were trained to record their motor states every 30 minutes throughout the waking day using a 24-hour diary (Hauser diary)27 over the 3 consecutive days preceding baseline and each scheduled visit. PD diary variables were normalized to a 16-hour waking day and averaged over the 3 consecutive days. At baseline, clinicians rated the severity of patients' symptoms with the Clinical Global Impression-Severity (CGI-S) scale. During treatment, clinicians used the CGI-I scale. The UPDRS was administered by the investigator during the best on state (usually 2-4 hours after the morning dose).\n\nStatistical Analyses\nEfficacy analyses included all patients who received LCIG during the post-PEG-J period and completed ≥1 postbaseline efficacy assessment. Safety analysis included all patients who had NJ placement and completed ≥1 postbaseline safety evaluation. The within-group magnitude of change for all efficacy outcome measures was tested using a one-sample t test. Multiple testing procedures were not used to control for study-wise type I error rate. Planned enrollment was 320 patients to provide a sufficient sample to satisfy regulatory requirements for exposure assessments at 6 and 12 months.\n\nResults\nPatient Disposition and Baseline Measures\nOf 354 enrolled patients, 324 (91.5%) completed the NJ phase and 272 completed the study (76.8% of all patients enrolled, 84.0% of those who proceeded to PEG-J treatment; Fig. 1B).\n\nEighty-two patients (23.2%) prematurely discontinued, of whom 27 (7.6%) discontinued as the result of an AE. Other reasons for withdrawal were administrative reasons (4.0%; e.g., protocol-specified discontinuations for timely study closure), major protocol violations (2.5%), lack of efficacy (2.0%), and withdrawal of consent (7.1%; reasons for withdrawal of consent were not collected).\n\nAt baseline, patients had a mean ± standard deviation (SD) age of 64.1 ± 9.1 years, PD duration of 12.5 ± 5.5 years, and off time of 6.75 ± 2.35 hours per day (Table 1). Ninety-four patients (26.6%) were on l-dopa (or l-dopa derivative) monotherapy, whereas 259 (73.2%) were receiving ≥2 PD medications (including l-dopa for all patients) in any combination (primarily dopamine agonists [55.4% of all patients], amantadine [29.9%], and catechol-O-methyltransferase (COMT) inhibitors [28.2%]), all of which were discontinued before LCIG treatment.\n\nTABLE 1 Baseline characteristics (n = 354)\n\nCharacteristic\tValue\t\nAge, years\t\t\n Mean ± SD\t64.1 ± 9.1\t\nSex, males, n (%)\t202 (57.1)\t\nRace, n (%)\t\t\n White\t328 (92.7)\t\n Asian\t22 (6.2)\t\n Black\t4 (1.1)\t\nWeight, kg\t\t\n Mean ± SD\t70.8 ± 15.8\t\n Median (range)\t69.5 (39.7-123.0)\t\nPD duration in years, mean ± SD\t12.5 ± 5.5\t\nl-dopa dose at screening, mg/day, mean ± SD\t1,082.9 ± 582.1\t\nPD medications, n (%)a\t\t\n Number of PD medication classes received\t\t\n One (all l-dopa or derivative alone)\t94 (26.6)\t\n Two\t112 (31.6)\t\n Three\t87 (24.6)\t\n More than three\t60 (16.9)\t\n Medication classes of those receiving ≥2 PD medications\t\t\n l-dopa or derivatives\t259 (73.2)\t\n Dopamine agonists\t196 (55.4)\t\n COMT inhibitors\t100 (28.2)\t\n Amantadine\t106 (29.9)\t\n MAO-B inhibitors\t45 (12.7)\t\n Tertiary amines\t11 (3.1)\t\n Not recorded\t1 (0.3)\t\nOff time in hours/day,b mean ± SD\t6.75 ± 2.35\t\nOn time without troublesome dyskinesia in hours/day,b mean ± SD\t7.65 ± 2.45\t\nOn time with troublesome dyskinesia in hours/day,b mean ± SD\t1.61 ± 2.03\t\nCGI-S scale,b,c mean ± SD\t4.85 ± 0.84\t\nUPDRS scores,d mean ± SD\t\t\n Total (sum of Parts I, II and III)e\t48.4 ± 18.9\t\n Part II (activities of daily living)f\t17.4 ± 6.6\t\n Part III (motor symptoms)g\t28.8 ± 13.7\t\n Part IV (dyskinesia items nos. 32, 33 and 34 only)e\t3.7 ± 2.4\t\nPDQ-39 Summary Index score,h mean ± SD\t42.8 ± 15.1\t\nEQ-5D Summary Index score,i mean ± SD\t0.588 ± 0.195\t\nEQ-VAS score,i mean ± SD\t50.2 ± 21.0\t\na Some patients' medications were tapered and discontinued before baseline; listed drug categories are those used by ≥3.0% of all patients.\n\nb n = 316.\n\nc The CGI-S is a 7-point Likert scale ranging from 1 (normal) to 7 (most ill).\n\nd Higher UPDRS scores are associated with more disability.\n\ne n = 292.\n\nf n = 293.\n\ng n = 291.\n\nh n = 320; Higher PDQ-39 scores are associated with more severe symptoms.\n\ni n = 318; Higher EQ scores are associated with better health.\n\nTotal Daily l-dopa Dose\nAll patients were converted to l-dopa-carbidopa monotherapy based on the l-dopa component of their previous PD therapy. On the last titration day (NJ or PEG-J, whichever was a patient's final titration period), the mean total daily l-dopa dose was 1,547.4 mg, which included a mean of 1,537.0 mg from LCIG; only 4.4% (15 of 338) of patients received oral immediate-release l-dopa-carbidopa at nighttime, with an average dose of 235 mg. Initial titration during the NJ period was completed in a mean of 4.5 ± 2.2 days. The mean LCIG dose remained relatively constant throughout the study, ranging from 1,551.0 to 1,630.5 mg, depending on time point, and was 1,572.4 mg at last visit (Supporting Fig. 1). In the post-PEG-J phase, 76.5% (n = 248) of patients received only l-dopa-carbidopa, as LCIG with or without oral l-dopa-carbidopa, including 27.8% (n = 90) who received LCIG monotherapy. Among patients receiving adjunctive medications, 12.7% (n = 41) received dopamine agonists, 9.6% (n = 31) amantadine, 3.7% (n = 12) COMT inhibitors, and 1.5% (n = 5) monoamine oxidase (MAO)-B inhibitors (Supporting Table 1). At last visit, 27.8% (n = 88) of patients received immediate-release l-dopa-carbidopa (mean total dosage: 174.6 mg/night).\n\nSafety\nAEs were reported in 166 (46.9%) patients during the NJ period; the most common AEs were insomnia (7.9%), complication of device insertion (7.3%), and oropharyngeal pain (6.5%). During the post-PEG-J period, 298 (92.0%) patients experienced AEs (Table 2). The most common were complication of device insertion (34.9%), abdominal pain (31.2%), and procedural pain (20.7%). For the majority of subjects, AEs were mild (18.5%) or moderate (43.8%) and transient, with the highest incidence occurring during week 1 post-PEG-J (Supporting Fig. 2), with 65.1% of patients experiencing an AE at week 1 post-PEG-J, compared with 24.4%, 15.4%, and 17.1% by weeks 2, 3, and 4, respectively. SAEs were reported in 105 (32.4%) patients; the most common included complication of device insertion (6.5%), abdominal pain (3.1%), and peritonitis and polyneuropathy (each 2.8%; Table 2). There were no clinically meaningful changes in laboratory values, vital signs, or ECG.\n\nFig. 2 Mean ± SD daily “off” and “on” times as assessed by a Parkinson's disease diary. *P < 0.05; **P < 0.01; ***P<0.001 versus baseline.\n\nTABLE 2 AEs and SAEs in the percutaneous endoscopic gastrojejunostomy treatment period (n = 324)\n\nMedDRA Preferred Terma\tNo. of Patients (%)\t\nAny AE\t298 (92.0)\t\nAEs reported in ≥10%\t\t\n Complication of device insertionb\t113 (34.9)\t\n Abdominal pain\t101 (31.2)\t\n Procedural pain\t67 (20.7)\t\n Nausea\t54 (16.7)\t\n Excessive granulation tissue\t52 (16.0)\t\n Postoperative wound infection\t50 (15.4)\t\n Fall\t49 (15.1)\t\n Constipation\t47 (14.5)\t\n Insomnia\t44 (13.6)\t\n Incision site erythema\t42 (13.0)\t\n Urinary tract infection\t37 (11.4)\t\nAny SAE\t105 (32.4)\t\nSAEs reported in ≥1%\t\t\n Complication of device insertionb\t21 (6.5)\t\n Abdominal pain\t10 (3.1)\t\n Peritonitis\t9 (2.8)\t\n Polyneuropathy\t9 (2.8)\t\n PDc\t8 (2.5)\t\n Pneumoperitoneum\t8 (2.5)\t\n Hip fracture\t6 (1.9)\t\n Pneumonia\t6 (1.9)\t\n Device dislocation\t5 (1.5)\t\n Depression\t4 (1.2)\t\na A single event could be coded to >1 preferred term.\n\nb Events with this term were most often additionally coded to abdominal pain, abdominal discomfort, abdominal distension, flatulence, and pneumoperitoneum.\n\nc Patients requiring hospitalization or extended hospitalization resulting from PD.\n\nAmong AEs of special interest, procedure-/device-related AEs were reported for 68.5% of patients, primarily complication of device insertion (33.6%), abdominal pain (26.5%), procedural pain (20.4%), excessive granulation tissue (15.4%), postoperative wound infection (15.1%), incision-site erythema (12.7%), procedural-site reaction (9.3%), postprocedural discharge (7.7%), incision-site pain (6.2%), and pneumoperitoneum (5.9%). There were no treatment-emergent cardiovascular fatalities. Aspiration-related AEs (14.8% of patients) were primarily dyspnea (4.0%), pneumonia (3.1%), gastroesophageal reflux disease (2.2%), pyrexia (2.2%), dysphagia (1.9%), and atelectasis (1.5%). Fourteen aspiration events occurred within 7 days of initial PEG placement and 3 within 7 days of tube replacement/repositioning that required endoscopy. AEs related to polyneuropathy (6.8% of patients) were coded to the following MedDRA preferred terms: polyneuropathy (3.1% [which led to discontinuation for 1 patient]); peripheral sensory neuropathy (0.9%); Guillain-Barré syndrome-like neuropathy (coded as Guillain-Barré Syndrome; see Discussion; 0.6%); mononeuropathy (0.6%); neuralgia (0.6%); neuropathy peripheral (0.6%); and peripheral sensorimotor neuropathy (0.6%). Weight-loss–related AEs occurred in 15.4% of patients.\n\nTwenty-seven (7.6%) patients had an AE leading to withdrawal, 5 during the NJ period, and 22 patients post-PEG-J. Withdrawals during the NJ period were the result of dysphagia, vomiting, and complication of device insertion in 1 patient as well as pneumonia, QT prolongation, anxiety, and hallucination (1 patient each). In the post-PEG-J period, the most common reasons were complication of device insertion (n = 6), abdominal pain (n = 3), dyskinesia (n = 2), death of unknown etiology (n = 2), and completed suicide (n = 2; both patients had a history of depression). There were 8 subjects who had procedure-/device-related AEs resulting in discontinuation.\n\nA total of 8 deaths (2.3%) were reported; none were considered treatment related. Seven of these deaths occurred during the LCIG treatment period or within 30 days after PEG-J removal and included deaths attributed to suicide (n = 2), unknown etiology (n = 2), multiple complications (n = 1), cerebrovascular accident (n = 1), and cachexia (n = 1). One patient with a history of deep vein thrombosis (DVT) died 93 days post-PEG-J removal (i.e., not treatment emergent) as a result of DVT.\n\nDevice complications (i.e., related to device function, but not necessarily associated with an AE) were reported for 87.0% of patients: intestinal tube complication (50.9%); pump or stoma complication (35.8% each); and PEG-J or other complication (35.2% each).\n\nEfficacy\nOff time was significantly decreased from baseline to last visit by 4.4 ± 2.9 hours per day, or 65.6% (P < 0.001; Fig. 2 and Supporting Table 2). This improvement was sustained throughout all post-PEG-J visits (weeks 4-54; P < 0.001). Similarly, on time without troublesome dyskinesia increased by 4.8 ± 3.4 hours per day, or 62.9% (P < 0.001), and on time with troublesome dyskinesia decreased by 0.4 ± 2.8 hours per day, or 22.5% (P = 0.023). These improvements were sustained at all visits (P < 0.05).\n\nOn the CGI-I scale at end of treatment, 22.4% of patients were “very much improved,” 55.5% “much improved,” and 13.7% “minimally improved.” There was no change for 3.1% of patients, whereas 2.8% were “minimally worse,” 1.0% “much worse,” and none were “very much worse.”\n\nOn the efficacy measures commonly associated with function and health-related quality of life (HRQoL), significant improvement (P < 0.001) was noted by week 4 of long-term treatment and was maintained through the end of the study (Fig. 3). From baseline to last visit, the mean change was −4.4 ± 6.5 points for the UPDRS Part II (activities of daily living), +0.064 ±0.203 points for the EQ-5D Summary Index, and +14.0 ± 24.8 points for the EQ-VAS. From screening to last visit, the mean ± SD change in the PDQ-39 Summary Index was −6.9 ± 14.1 points. Seven of the eight PDQ-39 domains (except social support) showed statistically significant mean improvements (Supporting Table 3).\n\nFig. 3 Mean ± SD changes from baseline on other efficacy measures including function and health-related quality of life. aBaseline value from screening. ***P < 0.001 versus baseline, one-sample t test.\n\nDiscussion\nThis prospective study provides long-term safety and efficacy data for over 12 months in the largest cohort to date of patients with advanced PD treated with LCIG. Here, LCIG was initiated as monotherapy, replacing both oral l-dopa and other adjunctive PD medications in patients with PD who experienced severe motor complications despite optimized pharmacological therapy. Continuous infusion of LCIG throughout the day led to significant improvements in off time of −4.4 hours per day (65.6%), as assessed by patient-completed diary, which were sustained throughout the 54-week trial. This outcome is of a magnitude expected to be clinically meaningful to patients, well beyond the 1-hour change in off time deemed clinically important in the literature.28 Of note, the reduction in off time corresponded to a significant increase in on time without troublesome dyskinesia. Even with optimized LCIG, there was some residual off time (approximately 2.5 hours in this cohort), but both the physician- and patient-perceived improvements were robust, with significant and enduring improvements in motor function as assessed by the UPDRS and CGI-I, as well as HRQoL as assessed by the PDQ-39 and EuroQoL. In fact, HRQoL improvements began as early as week 4 and were maintained through the duration of the 54-week study period. Furthermore, total daily dosing, after initial titration/optimization, was stable throughout the study, suggesting that patients do not develop tolerance to LCIG. Moreover, although adjunctive therapies were permitted after 28 days, there was low use of these therapies and 76.5% of patients remained on l-dopa-carbidopa monotherapy. This is valuable given that it simplifies patient treatment regimens and could decrease AEs resulting from multiple dopaminergic medications.\n\nThe most common AEs in this study were associated with device insertion, were generally transient, and decreased substantially after the first week post-PEG-J tube placement. Device complications were most common in the first week after PEG-J placement. In the NJ phase, insomnia may have been related to causes including hospitalization itself and was deemed not related to the system in the majority of cases. SAEs occurred in 105 (32.4%) patients; the most common included complication of device insertion (6.5%), abdominal pain (3.1%), and peritonitis and polyneuropathy (each 2.8%). There were 2 SAEs of suicide, both in subjects under the age of 65 with a medical history of depression; neither reported suicidal ideation, but patients with PD as a group are at increased risk of suicide (by 5.3-fold in one study),29 and clinically relevant depression has been reported in 35% of patients with PD.30 In a study employing multivariable regression, the only factor associated with suicidal ideation or behavior in advanced PD was severity of depression,31 so physicians should be vigilant about the emotional state of all patients with advanced PD. Considering the patient population in our study (mean 64.1 years old, mean PD duration of 12.5 years; baseline CGI-S of “markedly ill” or worse for approximately two thirds), the procedure was generally well tolerated with few discontinuations resulting from AEs (7.6%). Of the 272 subjects who completed this study, 203 (74.6%) enrolled in the extension study, 66 (24.3%) transitioned to commercial LCIG, and 3 (1.1%) discontinued treatment.\n\nTo further examine procedure-related AEs, an adjudication committee consisting of independent expert gastroenterologists reviewed treatment-emergent AEs and SAEs categorized as “procedure and device-associated events” in the ongoing LCIG phase III program, including this study. The committee found that the rate of gastrointestinal AEs was generally consistent with ranges reported in the literature32,33 for the PEG-J procedure.34\n\nPatients with PD are at increased risk of neuropathy. The cause of this is uncertain, but it has been suggested that it may be related to the metabolic effects of long-term l-dopa therapy.35 The rate in our study is consistent with reports in the literature for patients with PD receiving l-dopa.36 In the LCIG phase III program, an independent committee adjudicated cases associated with polyneuropathy and determined that the cases observed were predominantly subacute or chronic, the severity mild to moderate, the phenotype sensory or sensorimotor, and the neurophysiology was typically consistent with axonal polyneuropathy.37 No patients were deemed to fulfill the criteria for Guillain-Barré syndrome despite 2 AEs being coded as Guillain-Barré syndrome. Although neuropathy screening and monitoring was not standardized at the outset, decreased vitamin B6, vitamin B12, folic acid, and increased homocysteine and methylmalonic acid appear to have emerged as risk factors for polyneuropathy,36,38 and measurements at baseline and every 3 months were added by amendment to the LCIG phase III protocols. Future prospective studies examining the incidence of neuropathy would be valuable.\n\nThe open-label design of this trial and lack of a control group are study limitations, in that the potential contributions of placebo effect cannot be assessed. However, the present trial is the largest sample of LCIG-treated patients studied worldwide thus far, which is a key strength. Moreover, these results demonstrate the maintenance of LCIG effects over 12 months, which is consistent with the recently reported 12-week, double-blind, double-dummy, phase III study comparing LCIG with optimized oral immediate-release l-dopa-carbidopa (both treatments concomitant with unchanged adjunctive therapies).15 The double-blind study showed that the difference in off time decrease was significant at −1.91 hours (P = 0.0015; least squares [LS] mean of −4.04 hours for LCIG [n = 35] vs. −2.14 hours for oral l-dopa-carbidopa [n = 31] over an “optimized” baseline). Also in line with our study, the median CGI-I endpoint score was “much improved” for LCIG versus “minimally improved” for oral therapy, the mean UPDRS Part II score changed by −1.8 points (LS mean) in the LCIG arm (3.0-point improvement over oral therapy; P = 0.0086), and the PDQ-39 Summary Index score changed by −10.9 points (LS mean) with LCIG (7-point improvement over oral therapy; P = 0.0155).\n\nSafety results in the double-blind study were consistent with our study. The most common AEs were related to the procedure, device, oral l-dopa, or underlying disease, most commonly abdominal pain (42%), procedural pain (32%), and nausea (25%). AEs were generally mild to moderate and declined within the first 2 weeks following the PEG-J procedure. Gastrointestinal AEs were typical for a PEG-J procedure.\n\nContinuous drug delivery is integral to the therapeutic profile of LCIG. In countries where it is approved, LCIG is indicated for the treatment of advanced l-dopa-responsive PD with severe motor fluctuations and dyskinesia when available combinations of oral PD medications have not given satisfactory results.39 In this setting, the restricted mean duration of LCIG treatment in Sweden was approximately 7.8 years; 60% of patients were ongoing, and the most common reason for discontinuation was death (unrelated to LCIG).40 Furthermore, when LCIG is initiated, the large majority of patients do not require adjunctive agents and can be maintained on l-dopa-carbidopa monotherapy, facilitating dose adjustment for efficacy or managing AEs14 and simplifying patients' therapeutic regimens. Overall, our safety and efficacy results are further reinforced by results from these and other LCIG studies that have been systematically compiled and published.41\n\nApomorphine infusion and DBS are also associated with significant reductions in off time and with HRQoL improvements.13,42–50 LCIG will provide another treatment option for patients with motor complications despite optimized therapy, offering an additional treatment option suiting patient-specific needs and contraindications.50\n\nIn summary, in this long-term, open-label study, LCIG demonstrated sustained, significant, and clinically meaningful improvements not only in motor complications, but also in HRQoL in advanced PD. LCIG was associated with robust improvements in off and on time, at a consistent mean daily dose throughout the study period, and without worsening dyskinesia throughout 54 weeks. As assessed by the low rate of study withdrawal resulting from AEs (7.6%), LCIG was generally well tolerated. Nonetheless, 92% of the patients reported ≥1 AE, most commonly associated with PEG-J tube placement during the first week post-PEG-J placement. LCIG provides an effective therapeutic option for advanced PD patients with severe motor complications despite optimized oral pharmacologic therapy.\n\nAbbVie Inc. funded the study (NCT00335153). AbbVie Inc. participated in the study design, research, analysis, data collection and interpretation, reviewing, and approval of the publication. Funding for editorial, design, and production support was provided by AbbVie Inc. to The Curry Rockefeller Group, LLC; medical writing assistance was provided by Michael Feirtag, Susan Kralian, PhD, Paul V. Shea, Jennifer Kuo, PharmD, and John Norwood of The Curry Rockefeller Group, LLC.\n\nStudy Investigators\nThe authors thank the following study investigators for their contributions to this study: Prof. Giovanni Abbruzzese (Universita degli Studi di Genova, Genova, Italy); Alina Agafina, MD, PhD (St. Petersburg City Hospital, St. Petersburg, Russia); Tim Anderson, FRACP, MD (University of Otago, Christchurch, New Zealand); Roongroj Bhidayasiri, MD, FRCP (King Chulalongkom Memorial Hospital, Bangkok, Thailand); Prof. Andrzej Bogucki, MD, PhD (Medical University of Lodz, Lodz, Poland); Prof. Ubaldo Bonuccelli (University of Pisa, Pisa, Italy); James T. Boyd, MD (University of Vermont College of Medicine, Burlington, VT, USA); Dr. Roger Clarnette (Fremantle Hospital, Fremantle, Australia); Dr. Luis Cunha (Hospital da Universidade de Coimbra, Coimbra, Portugal); Dr. Oriol de Fàbregues (Universitat Autonoma de Barcelona, Barcelona, Spain); Prof. Dr. Günther Deuschl (Kiel University, Kiel, Germany); Dirk Dressler, MD, PhD (Hannover Medical School, Hannover, Germany); Andrew Feigin, MD (The Feinstein Institute for Medical Research, Manhasset, NY, USA); Prof. Joaquim J. Ferreira, MD, PhD (Instituto de Medicina Molecular, Lisbon, Portugal); Tanya Gurevich, MD (Tel Aviv Medical Center, Tel Aviv, Israel); Jonathan Harris, MD (Neurologic Consultants, Ft. Lauderdale, FL, USA); Neal Hermanowicz, MD (University of California Irvine, Irvine, CA, USA); Dr. Donald S. Higgins, Jr. (Albany Medical College, Albany, NY, USA); Dr. Andrew Hughes (Austin Health, Melbourne, Australia); Keith L. Hull, Jr., MD (Wake Med Health and Hospitals at Raleigh, Raleigh, NC, USA); Dr. Zygmunt Jamrozik (Samodzielny Publiczny Centralny Szpital, Warsaw, Poland); Thomas E. Kimber, MBBS (Hons), PhD (Royal Adelaide Hospital, Adelaide, Australia); Jaime Kulisevsky, MD, PhD (Sant Pau Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain); Rajeev Kumar, MD (Colorado Neurological Institute, Englewood, CO, USA); Laura Kupila, MD, PhD (Päijät-Häme Central Hospital, Lahti, Finland); Prof. Patricia Limousin (Institute of Neurology, London, UK); Michael A. Lobatz, MD (The Neurology Center and Scripps Health, Encinitas, CA, USA); Dr. Zoltan Mari (John Hopkins Neurology, Baltimore, MD, USA); Juan Carlos Martinez-Castrillo, MD, PhD (Hospital Ramon y Cajal, IRYCIS, Madrid, Spain); Leo Verhagen Metman, MD, PhD (Rush University Medical Center, Chicago, IL, USA); Stuart Mossman, MD, FRACP (Wellington Hospital, Wellington, New Zealand); Prof. Thomas Müller (St. Joseph Hospital Berlin-Weißensee, Berlin, Germany); Prof. Giuseppe Orefice (Azienda Ospedaliera Universitaria, Napoli, Italy); Fernando L. Pagan, MD (Georgetown University Hospital, Washington, DC, USA); Nicolas Phielipp, MD (Toronto Western Hospital, Tornonto, Ontario, Canada); Niphon Poungvarin, MD, FRCP (Siriraj Hospital, Bangkok, Thailand); Dr. Victor Puente (Hospital del Mar, Barcelona, Spain); Brad A. Racette, MD (Washington University School of Medicine, St. Louis, MO, USA); Prof. Ivan Rektor, MD, CSc (Masaryk University, Hospital Sv. Anna, CEITEC, Brno, Czech Republic); Ramon L. Rodriguez, MD (University of Florida, Gainesville, FL, USA); Maria Jose Rosas, MD (Hospital S. João, Porto, Portugal); Evzen Ruzicka, MD, DSc (Vseobecna Fakultnin Nemocnice Praha, Praha, Czech Republic); Joseph M. Savitt, MD, PhD (Parkinson's and Movement Disorders Center of Maryland, Elkridge, MD, USA); Johannes Schwarz, MD (Geriatric Hospital Haag, Haag, Germany); Mustafa S. Siddiqui, MD (Wake Forest University School of Medicine, Winston-Salem, NC, USA); Barry J. Snow, MBChB, FRACP, FRCPC (Auckland City Hospital, Auckland, New Zealand); Martin Sommer, MD (University of Goettingen, Goettingen, Germany); David G. Standaert, MD, PhD (University of Alabama at Birmingham, Birmingham, AL, USA); Fabrizio Stocchi, MD, PhD (IRCCS San Raffaele, Rome, Italy); Oksana Suchowersky, MD, FRCPC (University of Alberta, Edmonton, Alberta, Canada); Paul L. Timmings, MBChB, MD, FRACP (Waikato Hospital, Hamilton, New Zealand); Prof. Eduardo Tolosa (Universitat de Barcelona, Barcelona, Spain); Associate Prof. Martin Vališ, MD, PhD (Charles University, Faculty Hospital, Hradec Kralove, Czech Republic); C.C.P. Verstappen, PhD, MD (Canisius Wilhelmina Hospital, Nijmegen, The Netherlands); Thomas Vogt, MD (University Medical Center, Mainz, Germany); Richard Walsh, MD (Toronto Western Hospital, Toronto, Ontario, Canada); Cheryl Waters, MD (Columbia University, New York, NY, USA); William J. Weiner, MD† (University of Maryland, Baltimore, MD); Christian Winkler, MD, PhD (University Hospital Freiburg, Freiburg, Germany); Jaroslaw Wronka, MD (NZOZ CMHCP Oddzial Neurologiczny, Poznan, Poland); Prof. Eduard Yakupov (LLC Research Medical Complex, Kazan, Russia); Cindy Zadikoff, MD (Northwestern University, Chicago, IL, USA); Mario Zappia, MD (University of Catania, Catania, Italy); Katerina Zarubova, MD (Fakultni Nemocnice Motol, Praha, Czech Republic); and Richard M. Zweig, MD (LSU Health Sciences Center, Shreveport, LA, USA). †29 December 2012.\n\nAuthor Roles\n(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.\n\nH.H.F.: 1A, 1B, 1C, 2C, 3A, 3B\n\nD.G.S.: 1A, 1B, 1C, 2C, 3A, 3B\n\nR.A.H.: 1A, 1B, 1C, 2C, 3A, 3B\n\nA.E.L.: 1B, 1C, 3B\n\nV.S.C.F.: 1B, 1C, 3A, 3B\n\nF.K.: 1B, 1C, 3B\n\nM.F.L.: 1B, 1C, 3B\n\nP.O.: 1A, 1B, 2A, 2C, 3A, 3B\n\nM.S.: 1B, 1C, 3B\n\nE.Z.Y.: 1B, 1C, 3B\n\nS.C.: 1B, 1C, 3B\n\nO.S.: 1B, 1C, 3B\n\nJ.D.: 1B, 1C, 3B\n\nC.M.H.: 2A, 2B, 3B\n\nK.C.: 1A, 1B, 1C, 2A, 2C, 3A, 3B\n\nW.Z.R.: 1A, 1B, 1C, 2A, 2B, 3B\n\nJ.A.B.: 1A, 1B, 1C, 2A, 2C, 3A, 3B\n\nA.J.E.: 1A, 1B, 1C, 2C, 3A, 3B\n\nFinancial Disclosures\nH.H.F. was a study investigator and has served as a consultant for AbbVie Inc. through a contract between AbbVie Inc. and Cleveland Clinic Foundation; he has not received any personal compensation from AbbVie Inc. D.G.S. was a study investigator and has received compensation from AbbVie Inc. for serving as a consultant and/or participating in scientific advisory boards and from Auspex Inc., Teva Neurosciences, and Serina Therapeutics for serving as a consultant. R.A.H. has received honoraria or payments for consulting, advisory services, or speaking services over the past 12 months from AbbVie Inc., Allergan, AstraZeneca, Biotie Therapeutics, Ceregene, Chelsea Therapeutic, Cleveland Clinic, Eli Lilly, GE Healthcare, Impax Laboratories, Neurocrine, Indus, Ipsen Biopharmaceuticals, Lundbeck, Merck/MSD, Noven Pharmaceuticals, Pfizer, Straken Pharmaceuticals, Targacept, Teva Pharmaceuticals Industries, Ltd., Teva Neuroscience, Upsher-Smith Laboratories, UCB, UCB Pharma SA, University of Houston, US World Meds, Xenoport, and Zambon Company SpA. His institution has received research support over the past 12 months from Abbott Laboratories, Addex Therapeutics, Allergan, AstraZeneca, Biotie Therapeutics, Chelsea Therapeutics, Civitas, GE Healthcare, Impax Laboratories, Ipsen Biopharmaceuticals, Merck/MSD, Merz, the Michael J. Fox Foundation for Parkinson's Research, the National Institute of Neurological Disorder and Stroke, Parkinson Study Group, Schering-Plough, Teva Neuroscience, UCB, and Vita-Pharm. He has received royalties in the last 12 months from the University of South Florida and is supported in part by a Center grant from the National Parkinson Foundation. A.E.L. has served as an advisor for Abbott, AbbVie, Allon Therapeutics, Avanir Pharmaceuticals, Biogen Idec, Boehringer Ingelheim, Ceregene, Lilly, Medtronic, Merck, Novartis, NeuroPhage Pharmaceuticals, Teva, and UCB; received honoraria from Teva, UCB, and AbbVie; received grants from Brain Canada, Canadian Institutes of Health Research, the Edmond J. Safra Philanthropic Foundation, the Michael J. Fox Foundation, the National Parkinson Foundation, Parkinson Society Canada, the Tourette Syndrome Association, and the W. Garfield Weston Foundation; received publishing royalties from Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press; and has served as an expert witness in cases related to the welding industry. V.S.C.F. was a study investigator for, and has also received compensation from, AbbVie Inc. for participating in scientific advisory boards; AbbVie Inc. contributed to funding for a Parkinson disease nurse specialist in the form of a grant to his institution. F.K. was a study investigator for, and has received compensation from, AbbVie Inc. for participating in scientific advisory boards and for serving as a lecturer. M.F.L. has been a study investigator and a speaker for Teva, USWM, Ipsen, and UCB; an advisor/consultant to Teva, USWM, Ipsen, Schering-Plough, Merz, Abbott, Impax, and Baxter; a researcher for the National Institutes of Health ///NIH, Abbott/AbbVie, Schering-Plough, the Parkinson Study Group, USWM, the Michael J. Fox Foundation for Parkinson's Research, Synosia Pharmaceuticals, Merz, and Ipsen; and received foundation grants from the National Parkinson Foundation, the HollyRod Foundation, and the Gene and Kathy Monroe Foundation. P.O. has been a study investigator in AbbVie Inc.– and Britannia-sponsored studies and has received compensation from AbbVie Inc., Britannia, ESP, and Leading Edge for serving as a consultant and lecturer. M.S. was a study investigator in AbbVie Inc.–sponsored studies and has received compensation from AbbVie Inc. for participating in scientific advisory boards. M.S. has also received honoraria for scientific advisory boards and lecture fees from Teva Pharmaceuticals and Britannia Pharmaceuticals. E.Z.Y. was a study investigator and has received compensation from AbbVie Inc. for serving as a lecturer. S.C. was a study investigator and has received compensation from AbbVie Inc. for serving as a consultant, lecturer, and/or participating in scientific advisory boards. O.S. was a study investigator and has received compensation from AbbVie Inc. for serving as a consultant and/or participating in scientific advisory boards. O.S. serves on an advisory board for Allergan and receives honoraria from UpToDate. J.D., C.M.H., K.C., W.Z.R., and J.A.B. are employees of AbbVie Inc. A.J.E. is supported by the K23 career development award (National Institute of Mental Health ///NIMH, 1K23MH092735); has received grant support from CleveMed/Great Lakes NeuroTechnologies and the Michael J. Fox Foundation; has received personal compensation as a consultant/scientific advisory board member for Solvay (now AbbVie), Chelsea Therapeutics, Teva, Impax, Merz, Pfizer, Solstice Neurosciences, Eli Lilly, and US WorldMeds; has received royalties from Lippincott Williams & Wilkins and Cambridge University Press; and has received honoraria from Novartis, UCB, Teva, the American Academy of Neurology, and International Parkinson and Movement Disorder Society. He serves as Associate Editor of Movement Disorders and Frontiers in Movement Disorders and on the editorial board of Parkinsonism & Related Disorders and The European Neurological Journal.\n\nSupporting Data\nAdditional Supporting Information may be found in the online version of this article at the publisher's web-site.\n\nSupplementary Information Table 1.\n\n Supplementary Information Table 2.\n\n Supplementary Information Table 3.\n\n Supplementary Figure 1. Mean total daily dose of levodopa (LCIG plus immediate-release levodopa). SD, standard deviation; NJ, nasojejunal; PEG-J, percutaneous endoscopic gastrojejunostomy.\n\n Supplementary Figure 2. Incidence of AEs (≥10% during any time interval) over time. A single event could be coded to >1 preferred term. NJ, nasojejunal; PEG-J, percutaneous endoscopic gastrojejunostomy.\n==== Refs\nReferences\n1 Hauser RA Levodopa: past, present, and future Eur Neurol 2009 62 1 8 19407449 \n2 Hornykiewicz O A brief history of levodopa J Neurol 2010 257 Suppl 2 S249 S252 21080185 \n3 Lundqvist C Continuous levodopa for advanced Parkinson's disease Neuropsychiatr Dis Treat 2007 3 335 348 19300565 \n4 Antonini A Chaudhuri KR Martinez-Martin P Odin P Oral and infusion levodopa-based strategies for managing motor complications in patients with Parkinson's disease CNS Drugs 2010 24 119 129 20088619 \n5 Olanow CW Obeso JA Stocchi F Continuous dopamine-receptor treatment of Parkinson's disease: scientific rationale and clinical implications Lancet Neurol 2006 5 677 687 16857573 \n6 Chaudhuri KR Rizos A Sethi KD Motor and nonmotor complications in Parkinson's disease: an argument for continuous drug delivery? J Neural Transm 2013 120 1305 1320 23456290 \n7 Mouradian MM Heuser IJ Baronti F Fabbrini G Juncos JL Chase TN Pathogenesis of dyskinesias in Parkinson's disease Ann Neurol 1989 25 523 526 2774496 \n8 Chase TN The significance of continuous dopaminergic stimulation in the treatment of Parkinson's disease Drugs 1998 55 1 9 9483164 \n9 Stowe R Ives N Clarke CE Meta-analysis of the comparative efficacy and safety of adjuvant treatment to levodopa in later Parkinson's disease Mov Disord 2011 26 587 598 21370258 \n10 Antonini A Odin P Pros and cons of apomorphine and L-dopa continuous infusion in advanced Parkinson's disease Parkinsonism Relat Disord 2009 15 Suppl 4 S97 S100 20123567 \n11 Deleu D Northway MG Hanssens Y Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease Clin Pharmacokinet 2002 41 261 309 11978145 \n12 Nyholm D Askmark H Gomes-Trolin C Optimizing levodopa pharmacokinetics: intestinal infusion versus oral sustained-release tablets Clin Neuropharmacol 2003 26 156 163 12782919 \n13 Abbruzzese G Barone P Bonuccelli U Lopiano L Antonini A Continuous intestinal infusion of levodopa/carbidopa in advanced Parkinson's disease: efficacy, safety and patient selection Funct Neurol 2012 27 147 154 23402675 \n14 Nyholm D Nilsson Remahl AI Dizdar N Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease Neurology 2005 64 216 223 15668416 \n15 Olanow CW Kieburtz K Odin P Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study Lancet Neurol 2014 13 141 149 24361112 \n16 Eggert K Schrader C Hahn M Continuous jejunal levodopa infusion in patients with advanced Parkinson's disease. Practical aspects and outcome of motor and non-motor complications Clin Neuropharmacol 2008 31 151 166 18520982 \n17 Antonini A Isaias IU Canesi M Duodenal levodopa infusion for advanced Parkinson's disease: 12-month treatment outcome Mov Disord 2007 22 1145 1149 17661426 \n18 Antonini A Mancini F Canesi M Duodenal levodopa infusion improves quality of life in advanced Parkinson's disease Neurodegener Dis 2008 5 244 246 18322402 \n19 Puente V De Fabregues O Oliveras C Eighteen month study of continuous intraduodenal levodopa infusion in patients with advanced Parkinson's disease: impact on control of fluctuations and quality of life Parkinsonism Relat Disord 2010 16 218 221 19762271 \n20 Honig H Antonini A Martinez-Martin P Intrajejunal levodopa infusion in Parkinson's disease: a pilot multicenter study of effects on nonmotor symptoms and quality of life Mov Disord 2009 24 1468 1474 19425079 \n21 Devos D French DUODOPA Study Group Patient profile, indications, efficacy and safety of duodenal levodopa infusion in advanced Parkinson's disease Mov Disord 2009 24 993 1000 19253412 \n22 Fernandez HH Vanagunas A Odin P Levodopa-carbidopa intestinal gel in advanced Parkinson's disease open-label study: interim results Parkinsonism Relat Disord 2013 19 339 345 23287001 \n23 Fahn S Elton RL Fahn S Marsen CD Calne DB Goldstein M UPDRS Program Members Unified Parkinson's Disease Rating Scale Recent Developments in Parkinson's Disease 1987 Florham Park, NJ, USA Macmillan 153 163 \n24 Jenkinson C Fitzpatrick R Peto V Greenhall R Hyman N The PDQ-8: development and validation of a short-form Parkinson's Disease Questionnaire Psychol Health 1997 12 805 814 \n25 Schrag A Selai C Jahanshahi M Quinn NP The EQ-5D—a generic quality of life measure—is a useful instrument to measure quality of life in patients with Parkinson's disease J Neurol Neurosurg Psychiatry 2000 69 67 73 10864606 \n26 EuroQoL Group EuroQoL: a new facility for the measurement of health-related quality of life Health Policy 1990 16 199 208 10109801 \n27 Hauser RA Friedlander J Zesiewicz TA A home diary to assess functional status in patients with Parkinson's disease with motor fluctuations and dyskinesia Clin Neuropharmacol 2000 23 75 81 10803796 \n28 Hauser RA Auinger P Parkinson Study Group Determination of minimal clinically important change in early and advanced Parkinson's disease Mov Disord 2011 26 813 818 21437987 \n29 Kostić VS Perkmezović T Tomić A Suicide and suicidal ideation in Parkinson's disease J Neurol Sci 2010 289 40 43 19737673 \n30 Reijnders JS Ehrt U Weber WE A systematic review of prevalence studies of depression in Parkinson's disease Mov Disord 2008 23 183 189 17987654 \n31 Nazem S Siderowf AD Duda JE Suicide and death ideation in Parkinson's disease Mov Disord 23 1573 1579 18618660 \n32 Blomberg J Lagergren J Martin L Mattsson F Lagergren P Complications after percutaneous endoscopic gastrostomy in a prospective study Scand J Gastroenterol 2012 47 737 742 22471958 \n33 Itkin M DeLegge MH Fang JC McClave SA Kundu S d'Othee BJ Multidisciplinary practical guidelines for gastrointestinal access for enteral nutrition and decompression from the Society of Interventional Radiology and American Gastroenterological Association (AGA) Institute, with endorsement by Canadian Interventional Radiological Association (CIRA) and Cardiovascular and Interventional Radiological Society of Europe (CIRSE) Gastroenterol 2011 141 742 765 \n34 Epstein M Johnson D Hawes R Gastrointestinal safety of the levodopa-carbidopa intestinal gel delivery system in treating advanced Parkinson's patients [abstract] Mov Disord 2013 28 Suppl 1 402 23389864 \n35 Rajabally YA Martey J Neuropathy in Parkinson disease: prevalence and determinants Neurology 2011 77 1947 1950 22049200 \n36 Toth C Brown MS Furtado S Suchowersky O Zochodne D Neuropathy as a potential complication of levodopa use in Parkinson's disease Mov Disord 2008 23 1850 1859 18785232 \n37 Freeman R Cornblath D Anand P Incidence of peripheral neuropathy in advanced Parkinson's subjects treated with levodopa-carbidopa intestinal gel [abstract] Mov Disord 2013 28 Suppl 1 403 \n38 Müller T van Laar T Cornblath DR Peripheral neuropathy in Parkinson's disease: levodopa exposure and implications for duodenal delivery Parkinsonism Relat Disord 2013 19 501 507 23453891 \n39 Duodopa intestinal gel Summary of product characteristics 2013 Maidenhead, UK AbbVie Limited \n40 Nyholm D Klangemo K Johansson A Levodopa/carbidopa intestinal gel infusion long-term therapy in advanced Parkinson's disease Eur J Neurol 2012 19 1079 1085 22360705 \n41 Nyholm D Duodopa® treatment for advanced Parkinson's disease: a review of efficacy and safety Parkinsonism Relat Disord 2012 18 916 929 22824056 \n42 Deuschl G Schade-Brittinger C Krack P A randomized trial of deep-brain stimulation for Parkinson's disease N Engl J Med 2006 355 896 908 16943402 \n43 Williams A Gill S Varma T Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson's disease (PD SURG trial): a randomised, open-label trial Lancet Neurol 2010 9 581 591 20434403 \n44 Weaver FM Follett K Stern M Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial JAMA 2009 301 63 73 19126811 \n45 Martinez-Martin P Reddy P Antonini A Chronic subcutaneous infusion therapy with apomorphine in advanced Parkinson's disease compared to conventional therapy: a real life study of non motor effect J Parkinsons Dis 2011 1 197 203 23934921 \n46 Nyholm D Constantinescu R Holmberg B Dizdar N Askmark H Comparison of apomorphine and levodopa infusions in four patients with Parkinson's disease with symptom fluctuations Acta Neurol Scand 2009 119 345 348 18822087 \n47 De Gaspari D Siri C Landi A Clinical and neuropsychological follow up at 12 months in patients with complicated Parkinson's disease treated with subcutaneous apomorphine infusion or deep brain stimulation of the subthalamic nucleus J Neurol Neurosurg Psychiatry 2006 77 450 453 16543520 \n48 García Ruiz PJ Sesar Ignacio A Ares Pensado B Efficacy of long-term continuous subcutaneous apomorphine infusion in advanced Parkinson's disease with motor fluctuations: a multicenter study Mov Disord 2008 23 1130 1136 18442107 \n49 Manson AJ Hanagasi H Turner K Intravenous apomorphine therapy in Parkinson's disease: clinical and pharmacokinetic observations Brain 2001 124 331 340 11157560 \n50 Merola A Zibetti M Angrisano S Rizzi L Lanotte M Lopiano L Comparison of subthalamic nucleus deep brain stimulation and Duodopa in the treatment of advanced Parkinson's disease Mov Disord 2011 26 664 670 21469197\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0885-3185",
"issue": "30(4)",
"journal": "Movement disorders : official journal of the Movement Disorder Society",
"keywords": "dyskinesia; infusion; levodopa-carbidopa intestinal gel; percutaneous endoscopic gastrojejunostomy; “off” time",
"medline_ta": "Mov Disord",
"mesh_terms": "D000328:Adult; D000368:Aged; D000978:Antiparkinson Agents; D002230:Carbidopa; D004338:Drug Combinations; D005260:Female; D005782:Gels; D006801:Humans; D007422:Intestines; D007980:Levodopa; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease; D011446:Prospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "8610688",
"other_id": null,
"pages": "500-9",
"pmc": null,
"pmid": "25545465",
"pubdate": "2015-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21370258;18822087;19300565;20123567;11978145;21437987;11157560;19737673;23287001;17987654;19407449;2774496;16857573;24361112;22049200;18618660;21469197;9483164;23456290;20434403;18442107;10109801;16943402;21080185;18322402;23453891;19253412;17661426;12782919;23402675;22471958;19126811;23934921;22824056;18785232;16543520;18520982;10803796;20088619;10864606;19762271;21820533;15668416;19425079;22360705",
"title": "Levodopa-carbidopa intestinal gel in advanced Parkinson's disease: final 12-month, open-label results.",
"title_normalized": "levodopa carbidopa intestinal gel in advanced parkinson s disease final 12 month open label results"
} | [
{
"companynumb": "US-IMPAX LABORATORIES, LLC-2018-IPXL-04184",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBIDOPA\\LEVODOPA"
},
"dru... |
{
"abstract": "To evaluate the clinical efficacy and safety of quinidine in patients with KCNT1-related epilepsy of infancy with migrating focal seizures (EIMFS) in the infantile period and to compare with the effect of quinidine on mutant channels in vitro.\n\n\n\nWe identified 4 patients with EIMFS with onset in the neonatal period, pathogenic variants in the KCNT1 gene, and lack of response to AEDs. Patients were prospectively enrolled, treated with quinidine, and monitored according to a predefined protocol. Electroclinical, neuroimaging, and genetic data were reviewed. Two patients had novel variants in the KCNT1 gene that were modeled in Xenopus oocytes with channel properties characterized using electrophysiology recordings.\n\n\n\nThree of four patients were treated with quinidine early in their disease course, prior to 6 months of age. No significant side effects were noted with quinidine therapy. In addition, there were no significant changes in electroencephalography (EEG)-confirmed seizure burden during therapy, and patients had near hourly seizures before, during, and after treatment. Two patients had previously reported gain-of-function mutations, which demonstrated sensitivity to high levels of quinidine in the oocyte assay. Two patients with novel variants, showed characteristic gain-of-function and were thus predicted to be pathogenic. Of interest, these variants were essentially insensitive to high levels of quinidine.\n\n\n\nPatients had no reported benefit to quinidine therapy despite age at treatment initiation. Pharmacogenetic results in oocytes were consistent with clinical treatment failure in 2 patients, suggesting that single-dose pharmacologic assessment may be helpful in predicting which patients are exceedingly unlikely to achieve benefit with quinidine. In the 2 patients who had a lack of therapeutic benefit despite sensitivity to high concentrations of quinidine with in vitro oocyte assay, it is likely that the achievable exposure levels in the brain were too low to cause significant in vivo channel blockade.",
"affiliations": "Department of Neurology, University of California San Francisco, San Francisco, California.;The Florey Institute of Neuroscience & Mental Health, Parkville, Victoria, Australia.;Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.;Department of Neurology, Columbia University, New York, New York.;Department of Neurology, University of California San Francisco, San Francisco, California.;Department of Pediatrics, University of California San Francisco, San Francisco, California.;The Florey Institute of Neuroscience & Mental Health, Parkville, Victoria, Australia.;The Florey Institute of Neuroscience & Mental Health, Parkville, Victoria, Australia.;The Florey Institute of Neuroscience & Mental Health, Parkville, Victoria, Australia.;Department of Neurology, University of California San Francisco, San Francisco, California.",
"authors": "Numis|Adam L|AL|;Nair|Umesh|U|;Datta|Anita N|AN|;Sands|Tristan T|TT|;Oldham|Michael S|MS|;Patel|Akash|A|;Li|Melody|M|;Gazina|Elena|E|;Petrou|Steven|S|;Cilio|Maria Roberta|MR|",
"chemical_list": "D000927:Anticonvulsants; C496946:KCNA1 protein, human; D051662:Kv1.1 Potassium Channel; D011802:Quinidine",
"country": "United States",
"delete": false,
"doi": "10.1111/epi.14551",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-9580",
"issue": "59(10)",
"journal": "Epilepsia",
"keywords": "KCNT1; electrophysiology; epilepsy of infancy with migrating focal seizures; epileptic encephalopathy; precision medicine",
"medline_ta": "Epilepsia",
"mesh_terms": "D000818:Animals; D000927:Anticonvulsants; D002675:Child, Preschool; D004569:Electroencephalography; D004827:Epilepsy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D051662:Kv1.1 Potassium Channel; D008279:Magnetic Resonance Imaging; D008297:Male; D008564:Membrane Potentials; D016296:Mutagenesis; D009154:Mutation; D033661:Oocysts; D018408:Patch-Clamp Techniques; D010597:Pharmacogenetics; D011802:Quinidine; D014161:Transduction, Genetic; D016896:Treatment Outcome; D014981:Xenopus",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "1889-1898",
"pmc": null,
"pmid": "30182418",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Lack of response to quinidine in KCNT1-related neonatal epilepsy.",
"title_normalized": "lack of response to quinidine in kcnt1 related neonatal epilepsy"
} | [
{
"companynumb": "US-UCBSA-2018056067",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOBAZAM"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Fractional bipolar radiofrequency technology is associated with minimal downtime and rare side effects and become an increasingly popular tool in aesthetic dermatology practices. There is limited damage to the epidermis, and side effects such as post-inflammatory hypo/hyperpigmentation are rare. Transient erythema, edema, crusting, and persistent inflammatory papules have been previously reported. We report a rare case of sterile follicular pustulosis following treatment with bipolar fractional radiofrequency (eTwo technology). To the best of our knowledge, this unusual side effect has never been reported.",
"affiliations": "a Department of Dermatology , Tufts Medical Center , Boston , MA , USA.;a Department of Dermatology , Tufts Medical Center , Boston , MA , USA.",
"authors": "Deverapalli|Sandhya|S|;Konnikov|Nellie|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/14764172.2018.1525747",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1476-4172",
"issue": "21(5)",
"journal": "Journal of cosmetic and laser therapy : official publication of the European Society for Laser Dermatology",
"keywords": null,
"medline_ta": "J Cosmet Laser Ther",
"mesh_terms": "D005148:Facial Dermatoses; D005260:Female; D006801:Humans; D008875:Middle Aged; D011846:Radio Waves; D000078702:Radiofrequency Therapy; D012872:Skin Diseases, Vesiculobullous",
"nlm_unique_id": "101136419",
"other_id": null,
"pages": "262-263",
"pmc": null,
"pmid": "30321072",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sterile pustulosis as a rare side effect of fractional bipolar radiofrequency device: a case report.",
"title_normalized": "sterile pustulosis as a rare side effect of fractional bipolar radiofrequency device a case report"
} | [
{
"companynumb": "US-CELLTRION INC.-2019US023907",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe significance of HBV reactivation during immunosuppressive therapy was evaluated in three nationwide cohorts including patients with previously resolved HBV (prHBV) infection.\n\n\nMETHODS\nThe clinical features of 1061 patients with acute liver failure (ALF) or late-onset hepatic failure (LOHF) were retrospectively examined, focusing on those who experienced HBV reactivation. Additionally, 420 patients with prHBV infection were prospectively enrolled: 203 received immunosuppressive therapies immediately after enrollment, while the remaining 217 were enrolled after having received immunosuppressive therapies without the occurrence of HBV reactivation. The serum HBV-DNA levels were prospectively monitored every month, and the incidences of HBV reactivation, defined as a serum HBV-DNA level of 1.3 log IU/ml or more, were evaluated.\n\n\nRESULTS\nIn the retrospective study, persistent HBV infection was found in 90 patients, and HBV reactivation was responsible for liver injuries in 50 patients including 23 receiving immunosuppressive therapies (26 with HBs-antigen positivity, 7 with prHBV infection). None of seven patients with prHBV infection were rescued. In the prospective studies, HBV reactivation occurred in ten patients, but preemptive entecavir administration prevented liver injury. The cumulative reactivation rate was 3.2 % at 6 months, and the increase of the rate compared to that at 6 months was +1.5 % at 48 months.\n\n\nCONCLUSIONS\nHBV reactivation during immunosuppression was responsible for liver injuries in a quarter of the ALF/LOHF patients with persistent HBV infection. Early serum HBV-DNA monitoring may improve patient prognosis, since HBV reactivation typically occurs within 6 months of the start of immunosuppressive therapies in patients with prHBV infection.",
"affiliations": "Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan. smochida@saitama-med.ac.jp.;Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan.;Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan.;Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan.;Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan.;Department of Digestive and Lifestyle Related Diseases, Human and Enviromental Sciences, Health Research, Kagoshima University Graduate School of Medicine and Dental Sciences, Kagoshima, Japan.;Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan.;Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.;Division of Rheumatic Diseases, National Center for Global Health and Medicine, Tokyo, Japan.;Department of Gastroenterology and Rheumatology, School of Medicine, Fukushima Medical University, Fukushima, Japan.;Department of Dermatology, Saitama Medical University, Saitama, Japan.;Department of Nephrology, Saitama Medical University, Saitama, Japan.;Department of Nephrology, Teine Keijinkai Hospital, Sapporo, Japan.;Department of Hematology, Saitama Medical University, Saitama, Japan.;Department of Hematology, Saitama Medical University, Saitama, Japan.;Department of Hematology, Nippon Medical School, Tokyo, Japan.;Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Science, Nagoya, Japan.;Department of Medical Oncology, International Medical Cnter/Comprehensive Cancer Center, Saitama Medical University, Saitama, Japan.;Department of Clinical Oncology, Jichi Medical University, Shimotsuke, Japan.;Department of Hepatology, Toranomon Hospital, Tokyo, Japan.;Department of Hepatology, Toranomon Hospital, Tokyo, Japan.;Department of Allergy and Pheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.;Department of Medicine, Teikyo University of School of Medicine, Tokyo, Japan.;Department of Digestive and Lifestyle Related Diseases, Human and Enviromental Sciences, Health Research, Kagoshima University Graduate School of Medicine and Dental Sciences, Kagoshima, Japan.;The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.",
"authors": "Mochida|Satoshi|S|;Nakao|Masamitsu|M|;Nakayama|Nobuaki|N|;Uchida|Yoshihito|Y|;Nagoshi|Sumiko|S|;Ido|Akio|A|;Mimura|Toshihide|T|;Harigai|Masayoshi|M|;Kaneko|Hiroshi|H|;Kobayashi|Hiroko|H|;Tsuchida|Tetsuya|T|;Suzuki|Hiromichi|H|;Ura|Nobuyuki|N|;Nakamura|Yuichi|Y|;Bessho|Masami|M|;Dan|Kazuo|K|;Kusumoto|Shigeru|S|;Sasaki|Yasutsuna|Y|;Fujii|Hirofumi|H|;Suzuki|Fumitaka|F|;Ikeda|Kenji|K|;Yamamoto|Kazuhiko|K|;Takikawa|Hajime|H|;Tsubouchi|Hirohito|H|;Mizokami|Masashi|M|",
"chemical_list": "D000970:Antineoplastic Agents; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D007166:Immunosuppressive Agents",
"country": "Japan",
"delete": false,
"doi": "10.1007/s00535-016-1168-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0944-1174",
"issue": "51(10)",
"journal": "Journal of gastroenterology",
"keywords": "Acute liver failure; De novo hepatitis B; HBV reactivation; Immunosuppressive therapy",
"medline_ta": "J Gastroenterol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D002648:Child; D002675:Child, Preschool; D004279:DNA, Viral; D005260:Female; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007223:Infant; D007564:Japan; D017114:Liver Failure, Acute; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012189:Retrospective Studies; D014775:Virus Activation; D055815:Young Adult",
"nlm_unique_id": "9430794",
"other_id": null,
"pages": "999-1010",
"pmc": null,
"pmid": "26831356",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": "24528608;23409848;1983820;20668905;21528424;25935551;15044834;22825549;19544079;18328067;24397839;21246383;21884340;25447850;17229858;19714720;22633836;16382463;17576389;16879891;1054319;22686858;11187122;9500622;25421241;25613809",
"title": "Nationwide prospective and retrospective surveys for hepatitis B virus reactivation during immunosuppressive therapies.",
"title_normalized": "nationwide prospective and retrospective surveys for hepatitis b virus reactivation during immunosuppressive therapies"
} | [
{
"companynumb": "JP-PFIZER INC-2017117619",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nNivolumab is a human immunoglobulin G4 monoclonal antibody that inhibits programmed cell death-1 activity by binding to the programmed cell death-1 receptors. Cancer cells express increased number of programmed cell death-1 ligands and this allows them to escape the cytotoxic effects of the T cells. Therefore, the negative programmed cell death-1 receptor signal regulates T-cell proliferation and activation is disrupted. However, this change in the activity of the T cells can cause them to lose their ability to recognize host cells. The immune response enabled by these agents has led to side effects, commonly known as \"immune-related adverse events.\"\n\n\nMETHODS\nWe report a case of a 66-year-old male patient who was treated with nivolumab for recurrent renal cell carcinoma presented with hepatitis and adrenalitis. Three weeks after starting nivolumab, the patient had abdominal pain and weakness, and then aspartate and alanine transaminase levels were found to be elevated.\nHepatitis was predicted to be due to nivolumab, because other causes were excluded. He started using oral methylprednisolone and then, hepatitis improved. However, while receiving methylprednisolone treatment, fludrocortisone was started with the pre-diagnosis of adrenalitis due to the persistence of fatigue, weakness, and hyponatremia and hyperkalemia. With both treatments, the patient's symptoms and sodium and potassium level returned to normal.\n\n\nCONCLUSIONS\nThis case emphasizes the need for patient's education and awareness of immune-related adverse events, and the importance of understanding the management of life-threatening complications of the checkpoint inhibitors, because these side effects require prompt recognition and treatment.",
"affiliations": "Department of Endocrinology and Metabolism, 147015University of Health Sciences Kartal Dr Lütfi Kırdar Training and Research Hospital, Turkey.;Department of Endocrinology and Metabolism, 147015University of Health Sciences Kartal Dr Lütfi Kırdar Training and Research Hospital, Turkey.;Department of Medical Oncology, Kartal Dr. Lütfi Kirdar City Hospital, Health Science University, İstanbul, Turkey.;Department of Endocrinology and Metabolism, 70774Trakya University Faculty of Medicine, Turkey.;Department of Medical Oncology, Kartal Dr. Lütfi Kirdar City Hospital, Health Science University, İstanbul, Turkey.;Department of Medical Oncology, 147021University of Health Sciences Ümraniye Training and Research Hospital, Turkey.",
"authors": "Özyurt|Esra|E|;Özçelik|Serhat|S|https://orcid.org/0000-0002-0521-5866;Sürmeli|Heves|H|;Çelik|Mehmet|M|;Ayhan|Murat|M|https://orcid.org/0000-0002-0631-4006;Özçelik|Melike|M|https://orcid.org/0000-0003-0406-715X",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/10781552211038136",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": null,
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Nivolumab; adrenalitis; immune checkpoint inhibitor",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "10781552211038136",
"pmc": null,
"pmid": "34558355",
"pubdate": "2021-09-24",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Side effects of immune-checkpoint inhibitors: Can multiple side effects be seen in a patient?",
"title_normalized": "side effects of immune checkpoint inhibitors can multiple side effects be seen in a patient"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-329590",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
"d... |
{
"abstract": "5-Fluorouracil (5-FU) is commonly administered as a therapeutic agent for the treatment of various aggressive cancers. Severe toxic reactions to 5-FU have been associated with decreased levels of dihydropyrimidine dehydrogenase (DPD) enzyme activity. Manifestations of 5-FU toxicity typically include cytopenia, diarrhea, stomatitis, mucositis, neurotoxicity, and, in extreme cases, death. A variety of genetic variations in DPYD, the gene encoding DPD, are known to result in decreased DPD enzyme activity and to contribute to 5-FU toxic effects. Recently, it was reported that healthy African American individuals carrying the Y186C DPYD variant (rs115232898) had significantly reduced DPD enzyme activity compared with noncarriers of Y186C. Herein, we describe for the first time, to our knowledge, an African American patient with cancer with the Y186C variant who had severe toxic effects after administration of the standard dose of 5-FU chemotherapy. The patient lacked any additional toxic effect-associated variations in the DPYD gene or the thymidylate synthase (TYMS) promoter. This case suggests that Y186C may have contributed to 5-FU toxicity in this patient and supports the use of Y186C as a predictive marker for 5-FU toxic effects in individuals of African ancestry.",
"affiliations": "Division of Hematology/Oncology and Experimental Therapeutics; Tufts Medical Center, Boston, MA, USA.;Department of Molecular Pharmacology and Experimental Therapeutics; Mayo Clinic, Rochester, MN USA.;Department of Molecular Pharmacology and Experimental Therapeutics; Mayo Clinic, Rochester, MN USA.;Division of Hematology/Oncology and Experimental Therapeutics; Tufts Medical Center, Boston, MA, USA.;Division of Hematology/Oncology and Experimental Therapeutics; Tufts Medical Center, Boston, MA, USA.;Department of Molecular Pharmacology and Experimental Therapeutics; Mayo Clinic, Rochester, MN USA.",
"authors": "Saif|M Wasif|MW|;Lee|Adam M|AM|;Offer|Steven M|SM|;McConnell|Kathleen|K|;Relias|Valerie|V|;Diasio|Robert B|RB|",
"chemical_list": "D005819:Genetic Markers; D006360:Heat-Shock Proteins; D009944:Organoplatinum Compounds; D010446:Peptide Fragments; C063820:SNP nonapeptide; D042943:Dihydrouracil Dehydrogenase (NADP); D002955:Leucovorin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1016/j.mayocp.2013.09.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-6196",
"issue": "89(1)",
"journal": "Mayo Clinic proceedings",
"keywords": "5-FU; 5-fluorouracil; 5-fluorouracil, leucovorin, oxaliplatin; DPD; FOLFOX; INR; PCR; base pair; bp; dihydropyrimidine dehydrogenase; international normalized ratio; polymerase chain reaction",
"medline_ta": "Mayo Clin Proc",
"mesh_terms": "D000230:Adenocarcinoma; D001741:African Americans; D000971:Antineoplastic Combined Chemotherapy Protocols; D003110:Colonic Neoplasms; D003967:Diarrhea; D042943:Dihydrouracil Dehydrogenase (NADP); D017809:Fatal Outcome; D005260:Female; D005472:Fluorouracil; D005819:Genetic Markers; D006360:Heat-Shock Proteins; D006801:Humans; D002955:Leucovorin; D008875:Middle Aged; D052016:Mucositis; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D010446:Peptide Fragments; D011110:Polymorphism, Genetic; D057285:Precision Medicine; D013280:Stomatitis",
"nlm_unique_id": "0405543",
"other_id": null,
"pages": "131-136",
"pmc": null,
"pmid": "24388031",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "11913730;18299612;11895907;2293556;8698850;17121937;23588312;17716232;15494134;9817272;2293239;15539918;10971312;11988088;19922504;17064846;7964939;1648430;19858398;23328581;15355920;12069415;17000684;23604281;20385995;20530282;2656050",
"title": "A DPYD variant (Y186C) specific to individuals of African descent in a patient with life-threatening 5-FU toxic effects: potential for an individualized medicine approach.",
"title_normalized": "a dpyd variant y186c specific to individuals of african descent in a patient with life threatening 5 fu toxic effects potential for an individualized medicine approach"
} | [
{
"companynumb": "US-MYLANLABS-US2014011338",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "The potential of repetitive transcranial magnetic stimulation (rTMS) to treat numerous neurological and psychiatric disorders has been thoroughly studied for the last two decades. Here, we report for the first time, the case of a 65-year-old woman suffering from treatment-resistant depression who developed an acute frontal lobe syndrome following eight sessions of low-frequency rTMS (LF-rTMS) to the right dorsolateral prefrontal cortex while also treated with sertraline and mianserin. The pathophysiological mechanisms underlying such an unexpected acute frontal lobe dysfunction are discussed in relation to the therapeutic use of LF-rTMS in combination with pharmacotherapy in depressed patients.",
"affiliations": "AP-HP, Hôpital Saint-Antoine, Department of Psychiatry, Paris, France.;AP-HP, Hôpital Saint-Antoine, Department of Neurology, Paris, France.;AP-HP, Hôpital Saint-Antoine, Department of Psychiatry, Paris, France.;Sorbonne Universitas Pierre et Marie Curie (UPMC) University, Paris, France.;AP-HP, Hôpital Saint-Antoine, Department of Psychiatry, Paris, France.;FrontLab, INSERM U1127, CNRS UMR7225, IHU Translational Neurosciences, Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France.;FrontLab, INSERM U1127, CNRS UMR7225, IHU Translational Neurosciences, Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France.;FrontLab, INSERM U1127, CNRS UMR7225, IHU Translational Neurosciences, Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France.",
"authors": "Carle|Guilhem|G|;Touat|Mehdi|M|;Bruno|Nicolas|N|;Galanaud|Damien|D|;Peretti|Charles-Siegfried|CS|;Valero-Cabré|Antoni|A|;Levy|Richard|R|;Azuar|Carole|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fpsyt.2017.00096",
"fulltext": "\n==== Front\nFront PsychiatryFront PsychiatryFront. PsychiatryFrontiers in Psychiatry1664-0640Frontiers Media S.A. 10.3389/fpsyt.2017.00096PsychiatryCase ReportAcute Frontal Lobe Dysfunction Following Prefrontal Low-Frequency Repetitive Transcranial Magnetic Stimulation in a Patient with Treatment-Resistant Depression Carle Guilhem 123*Touat Mehdi 45Bruno Nicolas 13Galanaud Damien 36Peretti Charles-Siegfried 13Valero-Cabré Antoni 2378Levy Richard 234Azuar Carole 2391AP-HP, Hôpital Saint-Antoine, Department of Psychiatry, Paris, France2FrontLab, INSERM U1127, CNRS UMR7225, IHU Translational Neurosciences, Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France3Sorbonne Universitas Pierre et Marie Curie (UPMC) University, Paris, France4AP-HP, Hôpital Saint-Antoine, Department of Neurology, Paris, France5Paris Sud University, Gustave Roussy, INSERM U981, Villejuif, France6AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Neuroradiology, Paris, France7Laboratory for Cerebral Dynamics Plasticity and Rehabilitation, School of Medicine, Boston University, Boston, MA, USA8Cognitive Neuroscience and Information Technology Research Program, Open University of Catalonia (UOC), Barcelona, Spain9AP-HP, Groupe Hospitalier Pitié-Salpêtrière, National Reference Centre on Rare Dementias, Paris, FranceEdited by: Martin J. Herrmann, University of Würzburg, Germany\n\nReviewed by: Andreas J. Fallgatter, University of Tübingen, Germany; René Hurlemann, University of Bonn, Germany\n\n*Correspondence: Guilhem Carle, guilhem.carle@aphp.frSpecialty section: This article was submitted to Neuroimaging and Stimulation, a section of the journal Frontiers in Psychiatry\n\n30 5 2017 2017 8 9606 3 2017 11 5 2017 Copyright © 2017 Carle, Touat, Bruno, Galanaud, Peretti, Valero-Cabré, Levy and Azuar.2017Carle, Touat, Bruno, Galanaud, Peretti, Valero-Cabré, Levy and AzuarThis 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.The potential of repetitive transcranial magnetic stimulation (rTMS) to treat numerous neurological and psychiatric disorders has been thoroughly studied for the last two decades. Here, we report for the first time, the case of a 65-year-old woman suffering from treatment-resistant depression who developed an acute frontal lobe syndrome following eight sessions of low-frequency rTMS (LF-rTMS) to the right dorsolateral prefrontal cortex while also treated with sertraline and mianserin. The pathophysiological mechanisms underlying such an unexpected acute frontal lobe dysfunction are discussed in relation to the therapeutic use of LF-rTMS in combination with pharmacotherapy in depressed patients.\n\ndepressiontranscranial magnetic stimulationfrontal syndromeantidepressantstate-dependencyexecutive dysfunction\n==== Body\nBackground\nOver the past two decades, repetitive transcranial magnetic stimulation (rTMS) has shown promise in the treatment of a myriad of neurological and psychiatric conditions such as Parkinson’s disease, neuropathic pain, stroke, depression, and auditory hallucinations (1, 2). rTMS involves the use of a magnetic field to induce an electric current in cortical regions, in order to modulate their activity levels and those of their associated networks. Different stimulation parameters are combined in order to induce lasting increases or decreases of neuronal activity. rTMS was approved in 2008 by the Food and Drug Administration as a treatment for major depressive disorder (MDD) in patients who did not respond to at least one antidepressant medication (1–3). In a recent meta-analysis of MDD and treatment-resistant depression [TRD (4)], the administration of low-frequency rTMS (LF-rTMS) to the right dorsolateral prefrontal cortex (rDLPFC) proved efficacy in 30–40% of patients. Despite some rare adverse effects [including seizures, local pain, transient hypomanic or manic episode, and delusion (1, 5–8)], rTMS is then considered a well-tolerated method to treat depression. Herein, we report the first case of acute frontal lobe dysfunction induced by a concurrent administration of LF-rTMS and antidepressant treatment in a TRD patient. Neuropsychological and neuroimagery investigations revealed a temporal association between transient clinical symptoms and reversible brain alterations. We further discuss the pathophysiological hypothesis of such acute frontal lobe dysfunction, and the specificity of the delivery of rTMS concurrently with the administration of psychotropic medication. Our patient gave written consent to publish this case report.\n\nCase Presentation\nHistory and Symptoms at Presentation\nA 65-year-old right-handed retired woman presented with a depressive relapse. Her medical history revealed hypertension, hyperlipidemia, and rheumatoid arthritis in clinical remission for 6 years (DAS 28 score: 1.74), treated weekly with methotrexate [15 mg once daily (od)]. She reported neither a history of addictive behavior nor any neurological medical condition. She suffered from a TRD of 25 years (recurrent resistant episodes, with resistance to several types of antidepressant treatment, including resistance to electroconvulsive therapy), without any event of suicidal behavior or hypomanic/manic episode. She was treated with fluoxetine (40 mg od) and clomipramine (75 mg od) before relapsing. At presentation, she reported sadness, loss of interest, psychomotor retardation, thoughts of worthlessness, hyporexia, and difficulty concentrating. No agitation, irritability, insomnia, confusional state, or suicidal thoughts were reported. She was diagnosed with a severe TRD according to the Diagnostic and Statistical Manual of Mental Disorders IV-TR.\n\nClinical Course and Management\nConsidering her TRD and clomipramine-induced orthostatic hypotension, treatment was progressively switched to mianserin, sertraline, and diazepam. LF-rTMS was initiated 2 weeks after the onset of the new pharmacological treatment [at an intermediary dosage, mianserin (10 mg od), sertraline (50 mg od), and diazepam (2 mg od)], over the rDLPFC [Magstim Rapid2 stimulator (Whitland, UK, www.magstim.com), using a 70-mm diameter figure-of-eight coil, at 110% of resting motor threshold, with continuous patterns at 1 Hz (1,000 pulses/day) which followed international guidelines for clinical rTMS uses (1)].\n\nThe cortical target was defined as the scalp location 6 cm rostral and in a parasagittal plane from the hotspot of the abductor pollicis brevis muscle in the primary motor cortex (M1). Pretreatment assessments including standard blood tests, brain computerized tomography scanner, and electroencephalography (EEG) were normal.\n\nAfter the eighth rTMS session, the patient presented significant behavioral changes, including disinhibition, loss of manners, decrease in personal grooming, perseverative behaviors, hyperorality with sweet cravings, and impulsive actions (the patient ran away from the hospital to buy large amounts of chocolate at the supermarket). Aspontaneity and economy of speech without aphasia were also observed. She did not exhibit elevated mood, tachypsychia, logorrhea, or insomnia, excluding a diagnosis of hypomanic/manic episode. Moreover, the patient did not report any delusion or hallucination. On a neurological evaluation, the patient was alert and oriented, without any motor or sensitive deficit. However, the patient exhibited signs of right frontal lobe dysfunction including distractibility, environmental dependency, and left-sided visuospatial neglect (9).\n\nConsidering this acute frontal syndrome, we conducted an extensive checkup in order to rule out any acute neurological etiology. Epilepsy was ruled out with an EEG conducted during the acute symptomatic phase, revealing no ictal activity, notably in the frontal and temporal areas (even after provocation with hyperventilation test and flicker-fusion test). A second control EEG was conducted 7 days after the first EEG, revealing no abnormalities. Viral and bacterial encephalitis were ruled out by normal blood tests and cerebral spinal fluid (CSF) analysis [normal cell counts including no pleocytosis (0 cells), normal CSF protein level (0.33 g/L), normal CSF glucose level (3.5 mmol/L), negative HSV1/2-PCR, negative 14-3-3 protein]. General metabolic disturbances were ruled out by normal laboratory tests (normal glycemia, calcemia, and natremia). In order to rule out the hypothesis of an acute ischemic stroke, a 1.5 T brain magnetic resonance imaging (MRI) was performed on day 1. Right DLPFC hyperintensity on diffusion-weighted imaging was reported with a significant decreased apparent diffusion coefficient (ADC) as compared to the homotopic region [difference of 0.039 × 10−3 mm2/s, showing 0.723 in the rDLPFC versus 0.762 in the left DLPFC (×10−3 mm2/s), see Figure 1]. Nonetheless, these findings lacked an association with a high signal in FLAIR sequence more than 24 h after the onset of symptoms, and ADC level in our patient was higher than ADC level seen in patients suffering from an acute ischemic stroke (ADC mean in acute ischemic stroke = 0.533 × 10−3 mm2/s, SD = 0.157, 95% confidence intervals: 0.501–0.563) (10). The hypothesis of an acute ischemic stroke was then ruled out. In the context of rheumatoid arthritis, it was important to rule out the hypothesis of a cerebral vasculitis. First, considering rheumatoid arthritis, our patient had been in clinical remission for 6 years. There was no systemic sign of inflammatory activity, on a clinical and paraclinical level (including fever, fatigue, arthralgia, edema, cardiopulmonary function, renal and hepatic function, peripheral neuropathy, ophthalmic abnormalities). Second, blood tests were unremarkable {no inflammatory syndrome [normal C-reactive protein, normal white blood cell count, normal albuminemia (38 g/L)], normal serum protein electrophoresis}, and there was no inflammatory process revealed by CSF analysis (as already described). Furthermore, ADC level was not consistent with ADC level seen in acute ischemic stroke of any kind, including acute stroke induced by cerebral vasculitis (10). As the patient was treated with methotrexate, we aimed to address its imputability in the occurrence of such acute frontal syndrome. Methotrexate intake has always been well tolerated in our patient for 6 years. Our patient did not show any hypersensitivity reaction to methotrexate. She was supplemented with B vitamins, and laboratory tests revealed no vitamin deficiency. Finally, the period of time between the last intake of methotrexate and the acute phase had to be taken into account. Nonetheless, the reversibility of frontal symptoms was not correlated with a modification of this specific treatment. All put together, there was no argument in favor of a methotrexate-induced encephalitis.\n\nFigure 1 (A) 1.5 T brain magnetic resonance imaging (MRI) performed on day 1 showing a right dorsolateral prefrontal cortex (rDLPFC) hyperintensity on diffusion-weighted imaging with a significant decreased apparent diffusion coefficient (ADC) as compared to the homotopic region in the left hemisphere [difference of 0.039 × 10−3 mm2/s, showing 0.723 in the rDLPFC versus 0.762 in the left DLPFC (×10−3 mm2/s)]; (B) control brain MRI performed on day 9 after the onset of symptoms using the same MRI scanner and identical acquisition parameters revealing normal ADC levels on both DLPFC areas [no significant difference, showing 0.803 in the rDLPFC versus 0.785 in the left DLPFC (×10−3 mm2/s)].\n\nAfter having ruled out these hypotheses, we tried to specify the frontal lobe dysfunction by conducting a neuropsychological evaluation in combination with other brain imaging techniques. Neuropsychological evaluation revealed deficits in executive and working memory tasks, without any instrumental impairment (see Table S1 in Supplementary Material). A brain 99mTc-hexamethylpropyleneamine oxime single-photon emission computerized tomography (99mTc-HMPAO SPECT) performed 13 days after the onset of symptoms revealed a significant decrease in regional cerebral blood flow (rCBF) within the rDLPFC (see Figure 2).\n\nFigure 2 (A) Brain 99mTc-hexamethylpropyleneamine oxime single-photon emission computerized tomography (99mTc-HMPAO SPECT) performed 13 days after the onset of symptoms revealing a significant decrease in regional cerebral blood flow (rCBF) within the right dorsolateral prefrontal cortex (see white arrows); (B) a 10-month control 99mTc-HMPAO SPECT showing a complete cancelation of the right frontal rCBF decrease present during the symptoms.\n\nRepetitive TMS and sertraline were discontinued and the patient’s frontal lobe syndrome started to decline after 10 days off treatment. A control MRI performed on day 9 showed normal ADC levels in the rDLPFC [no significant difference, showing 0.803 in the rDLPFC versus 0.785 in the left DLPFC (×10−3 mm2/s), see Figure 1]. At the 3-month follow-up examination, the patient was stabilized on a regimen of mianserin 30 mg od in a complete recovery state, with a regression of the frontal dysfunction and a normalization of all neuropsychological functions. A 10-month control 99mTc-HMPAO SPECT revealed a complete cancelation of the rDLPFC rCBF decrease (see Figure 2).\n\nDiscussion\nSafety and potential side effects of LF-rTMS have been monitored clinically in thousands of depression patients and healthy controls to date (1, 2). Occasionally, studies have reported mild cognitive changes associated with the use of rTMS (improvement in number processing, memory recall, and creativity, or excessive tiredness, difficulty concentrating, and memory impairment), but these rare effects were subtle and lasted no more than several minutes (11–13). The current case report highlights the potential induction of an acute frontal lobe syndrome lasting up to a week, on a regime of LF-rTMS/antidepressant association.\n\nWe first placed particular emphasis on differential diagnosis. Psychiatric evaluation ruled out hypomania and mania, as described above. Moreover, the incidence of treatment-emergent mania is very low with rTMS and remains controversial (7). Nevertheless, we cannot exclude similar rTMS-induced cognitive dysfunctions as the one observed in our patient might have passed unnoticed. Indeed, some of the side effects of rTMS, such as agitation, hypomania, or mixed depressive episode, share core symptoms with a frontal lobe syndrome, and thus could easily be misdiagnosed (7, 8, 14, 15). Interestingly, all neurologic symptoms observed resolved shortly after the discontinuation of LF-rTMS and sertraline, without the use of specific therapeutics such as mood stabilizers.\n\nGiven the previous antidepressant switch in our patient, the risk for an antidepressant discontinuation syndrome (ADS) also needs to be considered. However, considering the 2-week latency between the antidepressant switch and the occurrence of symptoms, this possibility seems unlikely. Moreover, transient frontal lobe syndrome has never been reported in the context of an ADS (16).\n\nFinally, as described above, behavioral changes, dysexecutive syndrome, and left-sided visual neglect exhibited by the patient strongly suggest a focal dysfunction associated with rDLPFC (9, 17). Remarkably, brain MRI and 99mTc-HMPAO SPECT revealed, respectively, transient diffusion and rDLPFC rCBF abnormalities overlapping with the area of LF-rTMS stimulation. These results raise the question of the correlation between clinical and abnormal imaging findings reported above. Previous TMS studies have also found a decrease in rDLPFC rCBF after LF-rTMS (18), and even a correlation between rDLPFC rCBF decreases and the efficacy of LF-rTMS (19). In addition, some studies outlined how LF-rTMS has the ability to modulate rCBF and brain diffusion and that such effects might scale with the clinical outcome (20, 21).\n\nConsidering the clinical presentation, what remains unclear here is the mechanism linking the LF-TMS-antidepressant treatment association to such acute behavioral degradation. SSRIs are preferentially known to induce indifference and apathy (22). Though, medication might have interfered with rTMS treatment. Mianserin and sertraline, alone or in combination, form a relative hazard for application of rTMS due to their significant seizure threshold lowering potential (1). Furthermore, recent research has demonstrated the strong state-dependency of the rTMS effects (23). The magnitude and even the net sign of the stimulation may depend on the state of activity of the targeted area. Thus, a brain region kept in a high state of activity may be more responsive to rTMS-mediated suppression than one with either normal or suppressed levels of activity (23). We therefore suggest that rTMS inhibitory effect might have been strongly potentiated through pharmacological preconditioning in our patient, lowering the excitability threshold of the rDLPFC and its associated network, hence inducing a transient change in the functioning of this neuronal network. Such widespread effect induced from a focal stimulation has been well described in animals and humans with positron emission tomography studies (24).\n\nConcluding Remarks\nRepetitive transcranial magnetic stimulation/antidepressant treat-ment association is a very promising approach in the treatment of TRD. However, little is known on the neurophysiological mechanisms involved in such potentiation. To our knowledge, this is the first report of an acute frontal dysexecutive syndrome potentially mediated by rTMS/antidepressant treatment association in a TRD patient. Nonetheless, this report has to be considered with caution as this phenomenon occurred in a single case. Further rTMS/antidepressant studies are needed to explore such interaction and the mechanisms encountered in our patient. Moreover, our clinical observation provides support to adequately titrate rTMS/antidepressant treatment associations to boost the effects of rTMS for the therapy of TRD.\n\nAuthor Contributions\nGC and MT contributed in drafting and revising the manuscript. All authors contributed in revising the manuscript and collecting the clinical data.\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\nWe wish to sincerely thank Caroline Decaix (neuropsychologist) for her help and contribution in the monitoring and the neuropsychological assessment of our patient.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at http://journal.frontiersin.org/article/10.3389/fpsyt.2017.00096/full#supplementary-material.\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Rossi S Hallett M Rossini PM Pascual-Leone A Safety of TMS Consensus Group \nSafety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research . Clin Neurophysiol (2009 ) 120 :2008 –39 .10.1016/j.clinph.2009.08.016 19833552 \n2 Rossini PM Burke D Chen R Cohen LG Daskalakis Z Di lorio R \nNon-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee . Clin Neurophysiol (2015 ) 126 :1071 –107 .10.1016/j.clinph.2015.02.001 25797650 \n3 Lefaucheur JP André-Obadia N Poulet E Devanne H Haffen E Londero A \nFrench guidelines on the use of repetitive transcranial magnetic stimulation (rTMS): safety and therapeutic indications . Clin Neurophysiol (2011 ) 41 :221 –95 .10.1016/j.neucli.2011.10.062 \n4 Berlim MT Van den Eynde F Jeff Daskalakis Z . Clinically meaningful efficacy and acceptability of low-frequency repetitive transcranial magnetic stimulation (rTMS) for treating primary major depression: a meta-analysis of randomized, double-blind and sham-controlled trials . Neuropsychopharmacology (2013 ) 38 :543 –51 .10.1038/npp.2012.237 23249815 \n5 Hu SH Wang SS Zhang MM Wang JW Hu JB Huang ML \nRepetitive transcranial magnetic stimulation-induced seizure of a patient with adolescent-onset depression: a case report and literature review . J Int Med Res (2011 ) 39 :2039 –44 .10.1177/147323001103900552 22118010 \n6 Arul-Anandam AP Loo C Mitchell P . Induction of hypomanic episode with transcranial direct current stimulation . J ECT (2010 ) 26 :68 –9 .10.1097/YCT.0b013e3181a744bf 19483641 \n7 Xia G Gajwani P Muzina DJ Kemp DE Gao K Ganocy SJ \nTreatment-emergent mania in unipolar and bipolar depression: focus on repetitive transcranial magnetic stimulation . Int J Neuropsychopharmacol (2008 ) 11 :119 –30 .10.1017/S1461145707007699 17335643 \n8 Zwanzger P Ella R Keck ME Rupprecht R Padberg F \nOccurrence of delusions during repetitive transcranial magnetic stimulation (rTMS) in major depression . Biol Psychiatry (2002 ) 51 :602 –3 .10.1016/S0006-3223(01)01369-5 11950462 \n9 Ptak R . The frontoparietal attention network of the human brain: action, saliency, and a priority map of the environment . Neuroscientist (2012 ) 18 :502 –15 .10.1177/1073858411409051 21636849 \n10 Lopez-Mejia M Roldan-Valadez E \nComparisons of apparent diffusion coefficient values in penumbra, infarct, and normal brain regions in acute ischemic stroke: confirmatory data using bootstrap confidence intervals, analysis of variance, and analysis of variance, and analysis of means . J Stroke Cerebrovasc Dis (2016 ) 25 :515 –22 .10.1016/j.jstrokecerebrovasdis.2015.10.033 26654670 \n11 Sandrini M Rusconi E \nA brain for numbers . Cortex J Devoted Study Nerv Syst Behav (2009 ) 45 :796 –803 .10.1016/j.cortex.2008.09.002 \n12 Pascual-Leone A Houser CM Reese K Shotland LI Grafman J Sato S \nSafety of rapid-rate transcranial magnetic stimulation in normal volunteers . Electroencephalogr Clin Neurophysiol (1993 ) 89 :120 –30 .10.1016/0168-5597(93)90094-6 7683602 \n13 Snyder A Bossomaier T Mitchell DJ \nConcept formation: “object” attributes dynamically inhibited from conscious awareness . J Integr Neurosci (2004 ) 3 :31 –46 .10.1142/S0219635204000361 15139077 \n14 Janicak PG O’Reardon JP Sampson SM Husain MM Lisanby SH Rado JT \nTranscranial magnetic stimulation in the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure, and during reintroduction treatment . J Clin Psychiatry (2008 ) 69 :222 –32 .10.4088/JCP.v69n0208 18232722 \n15 Rachid F Golaz J Bondolfi G Bertschy G . Induction of a mixed depressive episode during rTMS treatment in a patient with refractory major depression . World J Biol Psychiatry (2006 ) 7 :261 –4 .10.1080/15622970600671002 17071547 \n16 Harvey BH Slabbert FN . New insights on the antidepressant discontinuation syndrome . Hum Psychopharmacol (2014 ) 29 :503 –16 .10.1002/hup.2429 25111000 \n17 Vossel S Weiss PH Eschenbeck P Fink GR \nAnosognosia, neglect, extinction and lesion site predict impairment of daily living after right hemispheric stroke . Cortex (2013 ) 49 :1782 –9 .10.1016/j.cortex.2012.12.011 23321249 \n18 Kito S Fujita K Koga Y . Regional cerebral blood flow changes after low-frequency transcranial magnetic stimulation of the right dorsolateral prefrontal cortex in treatment-resistant depression . Neuropsychobiology (2008 ) 58 :29 –36 .10.1159/000154477 18781088 \n19 Kito S Hasegawa T Koga Y . Neuroanatomical correlates of therapeutic efficacy of low-frequency right prefrontal transcranial magnetic stimulation in treatment-resistant depression . Psychiatry Clin Neurosci (2011 ) 65 :175 –82 .10.1111/j.1440-1819.2010.02183.x 21414091 \n20 Li X Nahas Z Lomarev M Denslow S Shastri A Bohning DE \nPrefrontal cortex transcranial magnetic stimulation does not change local diffusion: a magnetic resonance imaging study in patients with depression . Cogn Behav Neurol (2003 ) 16 :128 –35 .10.1097/00146965-200306000-00006 12799599 \n21 Mottaghy F Gangitano M Horkan C Chen Y Pascual-Leone A Schlaug G . Repetitive TMS temporarily alters brain diffusion . Neurology (2003 ) 60 (9 ):1539 –41 .10.1212/01.WNL.0000058903.15205.46 12743250 \n22 Sansone RA Sansone LA . SSRI-induced indifference . Psychiatry (Edgmont) (2010 ) 7 :14 –8 .21103140 \n23 Silvanto J Muggleton NG Cowey A Walsh V . Neural adaptation reveals state-dependent effects of transcranial magnetic stimulation . Eur J Neurosci (2007 ) 25 :1874 –81 .10.1111/j.1460-9568.2007.05440.x 17408427 \n24 Hayashi T Ohnishi T Okabe S Teramoto N Nonaka Y Watabe H \nLong-term effect of motor cortical repetitive transcranial magnetic stimulation . Ann Neurol (2004 ) 56 :77 –85 .10.1002/ana.20151 15236404\n\n",
"fulltext_license": "CC BY",
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"journal": "Frontiers in psychiatry",
"keywords": "antidepressant; depression; executive dysfunction; frontal syndrome; state-dependency; transcranial magnetic stimulation",
"medline_ta": "Front Psychiatry",
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"title": "Acute Frontal Lobe Dysfunction Following Prefrontal Low-Frequency Repetitive Transcranial Magnetic Stimulation in a Patient with Treatment-Resistant Depression.",
"title_normalized": "acute frontal lobe dysfunction following prefrontal low frequency repetitive transcranial magnetic stimulation in a patient with treatment resistant depression"
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"abstract": "Colchicine is the mainstay of treatment for familial Mediterranean fever. We investigated the frequency of leukopenia in 213 patients with familial Mediterranean fever treated with standard doses of colchicine (0.5-2.0 mg/day). We found that 23 patients (10.8%) had reversible leukopenia, 3 moderate, and none severe and that their rate of infections was not increased.",
"affiliations": "Division of Pediatric Rheumatology, Department of Pediatrics, Ankara, Turkey.;Division of Pediatric Rheumatology, Department of Pediatrics, Ankara, Turkey.;Division of Pediatric Rheumatology, Department of Pediatrics, Ankara, Turkey.;Division of Pediatric Rheumatology, Department of Pediatrics, Ankara, Turkey.;Division of Pediatric Rheumatology, Department of Pediatrics, Ankara, Turkey.;Division of Pediatric Hematology, Department of Pediatrics, Hacettepe University, Ankara, Turkey.;Division of Pediatric Rheumatology, Department of Pediatrics, Ankara, Turkey. Electronic address: sezaozen@gmail.com.",
"authors": "Sag|Erdal|E|;Bayindir|Yagmur|Y|;Adiguzel|Aydin|A|;Demir|Selcan|S|;Bilginer|Yelda|Y|;Aytac|Selin|S|;Ozen|Seza|S|",
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"mesh_terms": "D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003078:Colchicine; D004305:Dose-Response Relationship, Drug; D010505:Familial Mediterranean Fever; D005260:Female; D006801:Humans; D007970:Leukopenia; D008137:Longitudinal Studies; D008297:Male; D050257:Tubulin Modulators",
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"title": "Colchicine and Leukopenia: Clinical Implications.",
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"abstract": "Postoperative intracranial hypotension-associated venous congestion (PIHV) is an uncommon cause of clinical deterioration after a neurosurgical procedure that is often unrecognized until late in its course. Functional outcomes range from remarkable neurological recovery to death. Little is understood about the reason for deterioration in certain patients compared with improvement in others. A 68-year-old man with a progressive cervical myelopathy underwent an uncomplicated cervical decompression and alignment restoration at our hospital and suffered violent generalized tonic-clonic seizures intraoperatively and postoperatively. A postoperative head CT showed a right parietal hematoma, but no other cranial findings. A subsequent MRI demonstrated what we describe as early PIHV with symmetric T2 signal changes in the bilateral deep gray structures. No diffusion restriction corresponded to these areas. A CT myelogram revealed a considerable CSF collection within the operative bed. Upon returning to the operating room to localize the source of the leak, a large dural tear was identified off of midline with a bone chip alongside the defect. The defect was repaired, and the patient remained comatose for over a week postoperatively. He made a remarkable gradual recovery, and after a month in the hospital and rehabilitation, he returned home with relatively minimal neurological deficits.\n\n\n\nWe postulate that if caught early and treated aggressively, neurologic injury resulting from PIHV may be reversible despite initially ominous imaging. Neurosurgeons and neurointensivists should therefore be compelled to search for dural defects and return to the operating room for immediate repair.",
"affiliations": "Department of Neurosurgery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. snyder.kendall@mayo.edu.;Department of Neurosurgery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Critical Care Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.",
"authors": "Snyder|Kendall A|KA|;Clarke|Michelle J|MJ|;Gilbertson|Julie R|JR|;Hocker|Sara E|SE|",
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"mesh_terms": "D000368:Aged; D019299:Decompression, Surgical; D006801:Humans; D006940:Hyperemia; D019585:Intracranial Hypotension; D008297:Male; D011183:Postoperative Complications; D013117:Spinal Cord Compression",
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"title": "Prompt Recognition and Management of Postoperative Intracranial Hypotension-Associated Venous Congestion: A Case Report.",
"title_normalized": "prompt recognition and management of postoperative intracranial hypotension associated venous congestion a case report"
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"abstract": "Primary central nervous system lymphoma remission after steroid treatment is a well-known phenomenon, but remission without any type of treatment is extremely rare. We present a rare case of spontaneous remission of a diffuse large B-cell lymphoma of the central nervous system as well as its subsequent reappearance in another location. The atypical presentation misled the neurosurgeons and neurologists, delaying diagnosis and treatment. The patient underwent brain biopsy after the relapse and started radiotherapy and chemotherapy with cytarabine + methotrexate + rituximab. As of 32 months after the diagnosis, the patient remained asymptomatic, with no focal neurological deficits and the disease in complete remission. A PubMed search of the literature up to June 2017 regarding spontaneous remission central nervous system lymphoma was also carried out.",
"affiliations": "Departamento de Neurocirurgia. Hospital de Braga. Braga. Portugal.;Departamento de Neurorradiologia. Hospital de Braga. Braga. Portugal.;Departamento de Oncologia. Hospital de Braga. Braga. Portugal.;Departamento de Neurocirurgia. Hospital de Braga. Braga. Portugal.",
"authors": "Ramos|Rui|R|;Fernandes|João Soares|JS|;Almeida|Marta|M|;Almeida|Rui|R|",
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"keywords": "Central Nervous System Neoplasms/drug therapy; Central Nervous System Neoplasms/radiotherapy; Lymphoma/drug therapy; Lymphoma/radiotherapy",
"medline_ta": "Acta Med Port",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001921:Brain; D001932:Brain Neoplasms; D016543:Central Nervous System Neoplasms; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009365:Neoplasm Regression, Spontaneous; D012074:Remission Induction",
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"title": "A Rare Case of Spontaneous Remission and Relapse of a Primary Central Nervous System Lymphoma.",
"title_normalized": "a rare case of spontaneous remission and relapse of a primary central nervous system lymphoma"
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"abstract": "BACKGROUND\nCervical transforaminal epidural steroid injection (TFESI), can be an effective tool to improve pain associated with cervical radiculopathy. However, complications related to the procedure have been reported.\nA 50-year-old woman who experienced acute cervical myelopathy with quadriparesis after cervical TFESI under fluoroscopic guidance.\nThe initial post-procedure cervical MRI revealed acute cervical myelopathy INTERVENTIONS:: She received 1000 mg of methylprednisolone was injected intravenously daily for 3 days OUTCOMES:: Improvement in pain, with the only remaining complaints consisting of lingering mild pain in the left hand and occasional hypoesthesia LESSONS:: Cervical TFESI, despite careful fluoroscopic localization, resulted in spinal cord injury. A spinal cord injury may be treated with conservative treatments, such as medication and rehabilitation.",
"affiliations": "Department of Anesthesiology and Pain Medicine, College of Medicine, Inha University, Incheon, South Korea.",
"authors": "Yang|Chunwoo|C|;Kim|Na Eun|NE|;Beak|Jee Sun|JS|;Tae|Na-Young|NY|;Eom|Byeong Hun|BH|;Kim|Byung-Gun|BG|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health MD-D-19-0244810.1097/MD.0000000000018299182993300Research ArticleClinical Case ReportAcute cervical myelopathy with quadriparesis after cervical transforaminal epidural steroid injection A case reportYang Chunwoo MDKim Na Eun MDBeak Jee Sun MDTae Na-Young MDEom Byeong Hun MDKim Byung-Gun MD∗NA. Department of Anesthesiology and Pain Medicine, College of Medicine, Inha University, Incheon, South Korea.∗ Correspondence: Byung-Gun Kim, Department of Anesthesiology and Pain Medicine, Inha University School of Medicine, Inha University Hospital, Sinheung-dong 3-ga, Jung-gu, Incheon 400-711, South Korea (e-mail: wangunlove@gmail.com).12 2019 16 12 2019 98 50 e1829926 3 2019 21 10 2019 7 11 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nCervical transforaminal epidural steroid injection (TFESI), can be an effective tool to improve pain associated with cervical radiculopathy. However, complications related to the procedure have been reported.\n\nPatient concerns:\nA 50-year-old woman who experienced acute cervical myelopathy with quadriparesis after cervical TFESI under fluoroscopic guidance.\n\nDiagnoses:\nThe initial post-procedure cervical MRI revealed acute cervical myelopathy\n\nInterventions:\nShe received 1000 mg of methylprednisolone was injected intravenously daily for 3 days\n\nOutcomes:\nImprovement in pain, with the only remaining complaints consisting of lingering mild pain in the left hand and occasional hypoesthesia\n\nLessons:\nCervical TFESI, despite careful fluoroscopic localization, resulted in spinal cord injury. A spinal cord injury may be treated with conservative treatments, such as medication and rehabilitation.\n\nKeywords\ncase reportcomplicationscord injuryepiduralinjectionspinal cordOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nCervical radiculopathy is not a rare disease, with a prevalence of 83.2 cases per 100,000 individuals. It is commonly caused by compression of the cervical spinal nerve, which usually results from foraminal stenosis associated with cervical spondylosis (70%–75%) and herniated nucleus pulposus.[1] With respect to treatment, a cervical transforaminal epidural steroid injection (TFESI) can be an effective tool to improve the pain associated with cervical radiculopathy.[2] As conservative treatment for radiculopathy due to disc herniation and spinal stenosis in the cervical region, fluoroscopy-guided cervical TFESI is a useful technique to alleviate symptoms. TFESI has been performed in a large number of patients and its effects have been demonstrated in many studies.[3] However, complications related to the procedure have been reported, including paralysis around the lips, tinnitus, vertigo, temporal limb paralysis, convulsions, cardiovascular toxicity, and even coma and death in serious cases. Studies suggest that more serious complications are caused by ischemia of the central nervous system due to vascular injury, vasospasm, and embolism associated with intravascular injections.[4,5] Cervical TFESI requires special attention given the possibility of serious complications described in previous reports, including vertebral artery puncture despite close adherence to standardized procedures.\n\nIn the present report, we describe a case of spinal cord injury and left quadriparesis during a fluoroscopy-guided cervical TFESI for cervical spinal stenosis. We also discuss management options associated with this complication.\n\n2 Consent\nWritten informed consent for treatment and publication of anonymized case details was obtained from the patient.\n\n3 Case presentation\nA 50-year-old woman visited the outpatient clinic of the authors’ hospital with complaints of radiating pain and a prickling feeling from the left cervical vertebra to the scapula and one arm that began 10 days before the visit. Her body weight, height, and body mass index were 62.1 kg, 151.3 cm, and 27.1 kg/m2, respectively; she had no history of trauma or underlying disease. Physical examination revealed that the neck pain worsened when the neck was tilted backward, and especially when extended to the left. The patient also complained of a bursting sensation of pain toward the left upper limb and tingling in the finger tips. There was no hypoesthesia, and the pain was distributed from vertebrae C4 to T1. Her numerical rating scale (NRS) score for pain (0 = no pain, 10 = most severe pain imaginable) was 7 to 8 points. Magnetic resonance imaging (MRI) revealed central canal stenosis at C3-4, C4-5, C5-6, and C6-7, and neural foraminal stenosis at C3-4, C4-5, C5-6, and C6-7. MRI results strongly suggested an indication for surgery. However, based on the absence of sensory or motor impairment and short symptom manifestation, the authors elected to use an epidural steroid injection technique and oral medication for treatment in the outpatient clinic with subsequent follow-up. Laboratory investigations performed before the procedure were normal.\n\nFluoroscopy-guided cervical interlaminar epidural steroid injection was administered at the level of C7-T1 on her first visit, and then ≥2 injections were administered at an interval of one week. Although her NRS score decreased to 3 to 4 points, she still complained of a tingling sensation ranging from the left shoulder to the fingers. Thus, the authors decided to perform a left C6 cervical TFESI to deliver the drug to the anterior part of the epidural space and nerve root. The procedure was explained to the patient, and written informed consent was obtained. Electrocardiogram, oxygen saturation (SpO2), blood pressure, and consciousness of the patient were monitored throughout the procedure. The patient was placed supine on a table with the head slightly extended and turned away from the left side to be blocked. The overlying skin was prepared and draped in a sterile fashion, and 1% lidocaine was infiltrated at the needle insertion site. After the image intensifier (OEC series 9800, GE Heatlhcare, USA) was tilted and aligned perpendicular to the vertebral end plates in an anterior-posterior (AP) projection, it was rotated obliquely to the ipsilateral side by approximately 45° to provide the best view of the left C6 neural foramen. The procedure site was aseptically sterilized with chlorohexidine, followed by local anesthesia using 1% lidocaine. A 23-gauge spinal needle (B. Braun Medical, Germany) was carefully brought close to the anterior region of the facet joint with the assistance of the C-arm fluoroscope. As the tip of the needle touched the superior articular process, the block needle was moved approximately 1 mm forward to the front of the joint while keeping it adjacent to the bone. The depth of the needle was then verified in the AP view of the fluoroscope. The AP view ensured that the block needle was placed on the lower lateral side of the cervical pedicle and advanced no more than the medial one-third of the articular pillar. Once the ideal position of the block needle was determined, a total volume of 0.2 to 0.3 mL of contrast dye (Omnipaque, GE Healthcare, Dublin, Ireland) was injected under real-time fluoroscopic guidance to confirm needle placement and the absence of flow of the contrast agent into the vasculature (Fig. 1). After confirmation, a 4 ml mixture of 1% mepivacaine, dexamethasone 5 mg, and 1500 IU hyaluronidase was injected.\n\nFigure 1 Fluoroscopy-guided left C6 cervical transforaminal epidural steroid injection. (A) Anterior-posterior view and (B) Oblique view showing proper needle location and spread of contrast media.\n\nWhen approximately 1 ml of the medication was injected, the patient reported a shock-like pain radiating to the left hand. Considering she voiced no additional complaints of pain in response to inquiry, the authors believed that the pain was due to dural irritation. As the rest of the medication was injected, the patient complained of sudden pain in the posterior neck and the lateral part of the left upper limb, which spread to the fingers and lower limbs. The procedure was immediately discontinued and the block needle was removed. The patient reported hypoesthesia and motor weakness in the left upper limb. Approximately 10 minutes post-procedure, the patient noted weakness in the left arm and bilateral lower limbs, and temporarily lost consciousness. She was immediately placed on a bed and administered auxiliary breathing through an oxygen mask. Her heart rate was 100 beats/minute and blood pressure was 75/42 mmHg. After securing a venous route, 10 mg of ephedrine was administered intravenously along with fluid; blood pressure was restored and spontaneous breathing started. The authors initially believed the incident was a reaction to total spinal anesthesia with epidural puncture. However, paralysis of the upper left limb persisted, even after 4 hours when the patient had regained consciousness and the effect of the local anesthetic had dissipated. It was then decided to admit the patient for monitoring. Four to five hours after the procedure, her lower limb motor capacity had recovered to normal. However, hypoesthesia of the cortical sensory segment of C6 and the reduced motor capacity of the left shoulder joint and the finger muscles persisted. Physical examination during hospitalization revealed no abnormality in strength of the lower limbs. A strength test of the left upper arm revealed grade IV/V flexion in the left elbow and grade IV/V extension of left wrist, with grade III+/V extension of left elbow, abduction of the left fifth finger, and the pinching force of left fingers. The pinprick test revealed reduced tactile and vibrational sensations, and a 50% reduction in the left upper limb at C6 and lower levels. The pathological reflex test was positive for Hoffman's sign in the left upper limb, but no other pathological reflex was found. The results of the Spurling test, Lhermitte's sign, neck compression test, neck distraction test, and the shoulder abduction relief sign were negative. Thus, emergent cervical MRI was performed, which revealed intramedullary high-signal intensity at the left sided spinal cord from C4 to T4, with an ill-defined edema (Fig. 2). After consulting with the neurosurgeons, 1000 mg of methylprednisolone was injected intravenously daily for 3 days, but this injection was discontinued out of concern for adverse effects. The patient complained of sporadic bursting sensations of pain in the left upper limb and the posterior region of the neck. Pain management, including 150 mg pregabalin twice daily (Lyrica, Pfizer, Groton, CT), 75 mg extended-release tramadol HCl, and 650 mg acetaminophen fixed-combination tablets, was administered. The patient has been treated with continuous medication, rehabilitation therapy, and other conservative treatments.\n\nFigure 2 (A) Sagittal T2-weighted image of the cervical spine, intramedullary high signal intensity is seen at left sided spinal cord from C4 to T4 with ill-defined edema. (B) axial T2-weighted image of the cervical spine, showing intramedullary high signal intensity.\n\nAt the 6-month follow-up, the patient's complaints consisted of only intermittent mild pain and hypoesthesia in the left upper limb, and mild dysfunction of fine motor skills in the left hand. Thus, left-sided stellate ganglion block was performed once per week, and medication, rehabilitation, and other conservative treatments were provided. Cervical MR images captured 7 months since the procedure revealed the interval much decreased in the axial extent of the intramedullary high signal intensity at the left side spinal cord from C4 to T3, with decreased edema (Fig. 3). In outpatient follow-up, the patient reported improvement in pain, with the only remaining complaints consisting of lingering mild pain in the left hand and occasional hypoesthesia. The patient recovered motor function sufficient to enable casual activity, but still experienced some difficulties with grasping, and first and second finger abduction due to reduced muscle force in the fingers. The patient is currently being monitored without particular treatment.\n\nFigure 3 (A) Sagittal T2-weighted image of the cervical spine, the interval much decreased in the axial extent of the intramedullary high signal intensity at the left side spinal cord from C4 to T3, with decreased edema. (B) axial T2-weighted image of the cervical spine, showing decreased in the axial extent of the intramedullary high signal intensity.\n\n4 Discussion\nCervical TFESI is generally considered to be safe and is commonly recommended by physicians for the treatment of cervical radiculopathic pain.[1] For radiculopathy due to cervical disc herniation and foraminal stenosis resistant to medication and other conservative treatments, the interlaminar approach with epidural steroid injection was the choice of treatment. Cervical TFESI was later introduced to gain close access to the lesion and the procedure has been guided using fluoroscopy. Cervical TFESI is useful in patients with pain from radiculopathy, and effective in symptom improvement with smaller amounts of drug compared with the amount required for epidural block based on the posterior interlaminar approach. This is because the drug can more easily reach the anterior part of the epidural space and the target nerve root. In recent years, a large number of cervical TFESIs have been performed, with reports of unanticipated serious complications, including limb paralysis and even death.[6] There is also a case report describing complex regional pain syndrome type II after cervical TFESI.[7]\n\nDespite the controversy regarding its safety, cervical TFESI has distinctive merit in conservative treatment. Risks for complication are always present with the procedure because it is exceedingly difficult to identify all major structures of the neck—even under fluoroscopic guidance—and the needle may invade the internal jugular vein, or carotid and vertebral arteries.[8] There is also the possibility of serious complications including cerebral or spinal cord infarction, epidural hematoma, transient limb paralysis, and spinal cord injury. These complications have been reported since 2 cases of direct spinal cord injury in a C-arm-guided cervical epidural steroid injection were reported by Hodges in 1998.[9] It was suspected that the spinal cord injuries in those cases occurred because the patients were sedated using anesthetics, including midazolam or propofol, and could not react to the needle touching the spinal cord. However, in contrast to the belief that patients would feel the painful sensation when the needle goes into the spinal cord, they do not because the brain and spinal cord do not have their own sensory nerves. It has been reported that even conscious patients do not feel pain during injection, and do not experience a tingling sensation or reduced motor function with a test dose of epidural anesthesia, even though the needle penetrates the spinal cord.[10] Similarly, in our case, the patient did not experience a painful sensation when the cervical spinal cord was punctured, even though she was not sedated and was capable of communication. As a result, the medication was administered to the intramedullary space and caused acute spinal cord injury.\n\nSpinal cord injury can be treated in the early stages using high-dose steroid therapy. An initial administration of 30 mg/kg of methylprednisolone slowly for ≥15 minutes, and additional administration of 5.4 mg/kg/hour of methylprednisolone for 24 hours, can prevent symptom deterioration and promote neurological recovery.[11] However, in the present case, due to concerns for potential pulmonary complications[12] and various other side effects of high-dose steroid injection, administration of steroid was limited. Judging from previous case reports and our own experiences, cervical TFESI requires preventive efforts because spinal cord injury is a complication with potentially serious consequences. Some have suggested the use of computed tomography (CT) guidance to avoid vital vessels[13] and even argue to monitor the flow of contrast agent using digital subtraction angiography.[14] However, spinal cord injury has also been reported to occur during CT-guided C7 TFESI,[13] suggesting that it is not a completely safe method.\n\nSome suggestions to minimize the risk for spinal cord injury during cervical TFESI have been offered. First, the correct needle position should be confirmed in the AP, lateral, and oblique planes using real-time fluoroscopy.[15] Second, any complaint of lancinating pain during needle insertion should be considered a clear signal to immediately discontinue needle advancement.[15] When the patient complains of upper limb pain or paralysis, physicians must consider the possibility of spinal cord penetration rather than radicular stimulation. Third, electrocardiogram, SpO2, blood pressure, and consciousness of the patient should be closely monitored throughout the procedure. Furthermore, it is better to perform the procedure on conscious patients.\n\nIn summary, we describe a serious complication of cervical TFESI, which, despite careful fluoroscopic localization and guidance, can result in spinal cord injury. A spinal cord injury may be treated with conservative treatment, including medication and rehabilitation therapy, in addition to natural healing for functional restoration. Moreover, they should be accompanied with continuous close monitoring of patient symptoms.\n\nAuthor contributions\nConceptualization: Byung-Gun Kim.\n\nWriting – original draft: Chunwoo Yang, Jee Sun Beak.\n\nWriting – review & editing: Byung-Gun Kim, Na Eun Kim, Byeong Hun Eom, Na-Young Tae.\n\nConceptualization: Byung-Gun Kim.\n\nWriting, original draft: Chunwoo Yang, Na Eun Kim, Beak Jee Sun.\n\nWriting – review & editing: Byung-Gun Kim, Na-Young Tae, Eom Byeong Hun.\n\nByung-Gun Kim orcid: 0000-0002-0036-0765.\n\nAbbreviations: MRI = magnetic resonance imaging, NRS = numerical rating scale, TFESI = transforaminal epidural steroid injection.\n\nHow to cite this article: Yang C, Kim NE, Beak JS, Tae NY, Eom BH, Kim BG. Acute cervical myelopathy with quadriparesis after cervical transforaminal epidural steroid injection: A case report. Medicine. 2019;98:50(e18299).\n\nWritten informed consent for publication was obtained from the patient.\n\nThis work was supported by Inha University Research Grant (number 57848-01).\n\nThe authors have no conflicts of interests to disclose.\n==== Refs\nReferences\n[1] Sun Y Muheremu A Tian W \nAtypical symptoms in patients with cervical spondylosis: comparison of the treatment effect of different surgical approaches . Medicine (Baltimore) \n2018 ;97 :e10731 .29768345 \n[2] Choi JW Lim HW Lee JY \nEffect of cervical interlaminar epidural steroid injection: analysis according to the neck pain patterns and MRI findings . Korean J Pain \n2016 ;29 :96 –102 .27103964 \n[3] Bush K Hillier S \nOutcome of cervical radiculopathy treated with peridural/epidural corticosteroid injections: A prospective study with independent clinical review . Eur Spine J \n1996 ;5 :319 –25 .8915637 \n[4] Furman MB Giovanniello MT O’Brien EM \nIncidence of intravascular penetration in transforaminal cervical epidural steroid injections . Spine \n2003 ;28 :21 –5 .12544950 \n[5] Hoeft MA Rathmell JP Monsey RD \nCervical transforaminal injection and the radicular artery: variation in anatomical location within the cervical intervertebral foramina . Reg Anesth Pain Med \n2006 ;31 :270 –4 .16701194 \n[6] Tiso RL Cutler T Catania JA \nAdverse central nervous system sequelae after selective transforaminal block: the role of corticosteroids . Spine \n2004 ;4 :468 –74 .\n[7] Park GY Kwon DR Kwon DG \nComplex regional pain syndrome type II after cervical transforaminal epidural injection: a case report . Medicine (Baltimore) \n2018 ;97 :e10784 .29768371 \n[8] Hwang SJ Han KR Kim SY \nAnalysis of intravascular flow patterns following cervical transforaminal epidural injection . Korean J Pain \n2009 ;22 :52 –7 .\n[9] Hodges SD Casleberg RL Miller T \nCervical epidural steroid injection with intrinsic spinal cord damage: two case reports . Spine \n1998 ;23 :2137 –40 .9794061 \n[10] Tripathi M Nath SS Gupta RK \nParaplegia after intracord injection during attempted epidural steroid injection in an awake-patient . Anesth Analg \n2005 ;101 :1209 –11 .16192546 \n[11] Matsumoto T Tamaki T Kawakami M \nEarly complications of high-dose methylprednisolone sodium succinate treatment in the follow-up of acute cervical spinal cord injury . Spine \n2001 ;26 :426 –30 .11224891 \n[12] Cyteval C Thomas E Decoux E \nCervical radiculopathy: open study on percutaneous periradicular foraminal steroid infiltration performed under CT control in 30 patients . Am J Neuroradiol \n2004 ;25 :441 –5 .15037470 \n[13] Baker R Dreyfuss P Mercer S \nCervical transforaminal injection of corticosteroids into a radicular artery: a possible mechanism for spinal cord injury . Pain \n2003 ;103 :211 –5 .12749976 \n[14] Chang MC \nSpinal cord injury by direct damage during CT-guided C7 transforaminal epidural steroid injection . Am J Phys Med Rehabil \n2018 ;97 :e62 –4 .29116946 \n[15] Lee JH Lee JK Seo BR \nSpinal cord injury produced by direct damage during cervical transforaminal epidural injection . Reg Anesth Pain Med \n2008 ;33 :377 –9 .18675752\n\n",
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"mesh_terms": "D000208:Acute Disease; D002574:Cervical Vertebrae; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007268:Injections, Epidural; D008279:Magnetic Resonance Imaging; D008775:Methylprednisolone; D008875:Middle Aged; D011782:Quadriplegia; D011843:Radiculopathy",
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"title": "Acute cervical myelopathy with quadriparesis after cervical transforaminal epidural steroid injection: A case report.",
"title_normalized": "acute cervical myelopathy with quadriparesis after cervical transforaminal epidural steroid injection a case report"
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"abstract": "BACKGROUND\nHere we report the first case of postoperative endophthalmitis due to Candida pelliculosa after cataract surgery. We describe the clinical management of this type of candida infection in the eye.\n\n\nMETHODS\nA 57-year-old Turk man was seen at our clinic at the end of the first postoperative month after cataract surgery. He presented with eye redness, pain and decreased visual acuity. His ophthalmologic examination revealed moderate tyndall and a mild flare in the anterior chamber. Hypopyon in the capsular bag posterior to the intraocular lens was seen in the second postoperative month. Despite topical and subconjunctival bacterial endophthalmitis treatment, there was no improvement in the clinical situation. Candida pelliculosa was isolated from a sample culture obtained from the anterior chamber. Oral fluconazole could not be administered because of increased liver enzyme levels and intravenous amphotericin B could not be administered because of an allergic reaction. Intraocular lens explantation, pars plana vitrectomy and anterior chamber lavage by rupturing the posterior wall of the microabscesses were performed. Intravitreal and intracameral amphotericin B injections were given four times in addition to surgical interventions. The patient has been followed for 2 years and his best-corrected visual acuity was 0.4 at the last visit.\n\n\nCONCLUSIONS\nNearly 1 month after cataract surgery, a patient presented with eye redness and blurred vision, with corneal endothelial deposits, hypopyon in the capsular bag and microabscesses on the incision sites and corneal endothelium. Candida pelliculosa should be considered in patients showing these symptoms. Multiple intraocular amphotericin B (5 μg) administrations can be used safely even in cases with high sensitivity to systemic use. Rupturing the posterior wall of the abscesses on the corneal endothelium surgically with intraocular lens explantation and pars plana vitrectomy are recommended.",
"affiliations": "Department of Ophthalmology, Faculty of Medicine, Trakya University, Edirne, Turkey. halukesgin@trakya.edu.tr.",
"authors": "Esgin|Haluk|H|;Bulut|Erkan|E|;Orüm|Caglar|C|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B; D015725:Fluconazole",
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"doi": "10.1186/1756-0500-7-169",
"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central 1756-0500-7-1692465605310.1186/1756-0500-7-169Case ReportCandida pelliculosa endophthalmitis after cataract surgery: a case report Esgin Haluk 1halukesgin@trakya.edu.trBulut Erkan 1erkanbulut@hotmail.comÖrüm Çaglar 1caglarorum@hotmail.com1 Department of Ophthalmology, Faculty of Medicine, Trakya University, Edirne, Turkey2014 21 3 2014 7 169 169 25 6 2013 19 3 2014 Copyright © 2014 Esgin et al.; licensee BioMed Central Ltd.2014Esgin et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Background\nHere we report the first case of postoperative endophthalmitis due to Candida pelliculosa after cataract surgery. We describe the clinical management of this type of candida infection in the eye.\n\nCase presentation\nA 57-year-old Turk man was seen at our clinic at the end of the first postoperative month after cataract surgery. He presented with eye redness, pain and decreased visual acuity. His ophthalmologic examination revealed moderate tyndall and a mild flare in the anterior chamber. Hypopyon in the capsular bag posterior to the intraocular lens was seen in the second postoperative month. Despite topical and subconjunctival bacterial endophthalmitis treatment, there was no improvement in the clinical situation. Candida pelliculosa was isolated from a sample culture obtained from the anterior chamber. Oral fluconazole could not be administered because of increased liver enzyme levels and intravenous amphotericin B could not be administered because of an allergic reaction. Intraocular lens explantation, pars plana vitrectomy and anterior chamber lavage by rupturing the posterior wall of the microabscesses were performed. Intravitreal and intracameral amphotericin B injections were given four times in addition to surgical interventions. The patient has been followed for 2 years and his best-corrected visual acuity was 0.4 at the last visit.\n\nConclusion\nNearly 1 month after cataract surgery, a patient presented with eye redness and blurred vision, with corneal endothelial deposits, hypopyon in the capsular bag and microabscesses on the incision sites and corneal endothelium. Candida pelliculosa should be considered in patients showing these symptoms. Multiple intraocular amphotericin B (5 μg) administrations can be used safely even in cases with high sensitivity to systemic use. Rupturing the posterior wall of the abscesses on the corneal endothelium surgically with intraocular lens explantation and pars plana vitrectomy are recommended.\n==== Body\nBackground\nEndophthalmitis is a serious intraocular inflammatory disease and the most common form is postoperative endophthalmitis. The incidence of post-surgical endophthalmitis is nearly 0.093% and the organisms responsible are generally bacteria. Three percent of all cases with endophthalmitis after cataract surgery are due to fungi [1,2]. Fungi have been isolated from 21.8% of all culture positive postoperative endophthalmitis cases, and mostly Aspergillus spp. and Candida spp. were determined to be the cause of fungal endophthalmitis [3,4]. This is the first reported case with endophthalmitis due to Candida pelliculosa.\n\nCase presentation\nA 57-year-old Turk male was seen in our clinic with complaints of blurred vision in his left eye. His visual acuity was 2/20 and he had a nucleocortical and posterior subcapsular cataract. A history of systemic hypertension and past coronary by-pass surgery was present. Uncomplicated phacoemulsification surgery and foldable posterior chamber intraocular lens (IOL) implantation was performed. 1 mg/0.1 ml intracameral cefuroxime sodium (Cefurol® 1.5 g/15 ml flacon, I.E. Ulagay) was given for prophylaxis. The eye was closed with tobramycin ophthalmic ointment 3 mg/g and dexamethasone ophthalmic ointment 1 mg/g. Postoperative best-corrected visual acuity (BCVA) was 16/20 with minimal corneal edema after the first week.\n\nThe patient complained of pain and eye redness for 4 days on the 27th day after surgery. His BCVA was also decreased to 10/20. Ophthalmic examination revealed ++++ Tyndall, no hypopyon and ++ flare in the anterior chamber. Intraocular pressure was 14 mmHg OD; 17 mmHg OS. Fundus examination results were normal and the patient had no pain. Late onset toxic anterior segment syndrome (TASS) was suspected. Dexamethasone sodium phosphate eye drops 0.1% (Onadron® collyrium 1 ml, I.E. Ulagay) were given hourly, netilmicin sulfate eye drops 0.38% (Netira® collyrium, SIFI) were given 4 times a day and cyclopentolate HCl eye drops 1% (Sikloplejin® collyrium, Abdi Ibrahim) were given 3 times a day as a topical treatment.\n\nInitially, the patient’s symptoms were under control, however, 3 weeks later, some deposits on the corneal endothelium and dense exudate in the inferior capsular bag were observed despite topical treatment (Figure 1A). Even after treatment, endothelial precipitates and exudates increased and the patient was hospitalized (Figure 1B). Visual acuity was not at the worst level (6/20) and the patient felt no pain. A fundus evaluation showed ++ tyndall and + flare. Because the endophthalmitis was not as severe, we decided to add subconjunctival vancomycin 25 mg/0.5 ml injection (Vancomycin® Hcl 1 g flacon, ORNA) twice a day. Ceftazidime 100 mg/0.5 ml injection (Fortum® 1 g flacon, GlaxoSmithKline) and dexamethasone 2 mg/0.5 ml injection (Dekort® 2 ml, 8 mg, Deva) were added to the topical treatment. gatifloxacin 0.3% eye drop hourly (Zymar® collyrium, Abdi Ibrahim), dexamethasone eye drop hourly (Maxidex® collyrium, Abdi Ibrahim) and cyclopentolate eye drop 3 times a day (Sikloplejin® collyrium, Abdi Ibrahim). On the 5th day of hospitalization, a sample was taken via paracentesis. Purulent material was aspirated from the capsular bag and anterior chamber while ceftazidime was injected. C. pelliculosa was isolated from the sample culture. Systemic antifungal therapy (fluconazole Tab 100 mg × 4 daily) was initiated but increased levels of liver enzymes (alanine aminotransferase: 461, aspartate aminotrasferase: 197) developed on the 4th day after starting fluconazole. The drug was stopped and intravenous infusion therapy with liposomal amphotericin B (L-amB; 5 mg/kg/day) was started. One minute following L-amB infusion, the patient began to feel pain and fever, with hyperemia in his neck region. The liposomal amB was then stopped because of this allergic reaction. The patient refused any other systemic therapy. We were reticent to initiate intravitreous administration because of the high sensitivity to antifungal agents and the side effects of intraocular amB. Then a topical treatment with fluconazole that was prepared using fluconazole flacon 100 mg/50 ml was started. Despite medical treatment, the inflammation persisted. An intraocular lens explantation was performed. Two weeks later, the BCVA decreased to 2/20 and the patient had 2 mm hypopyon and deposits on the anterior hyaloid with a blurred fundus (++++tyndall, +++flare; Figure 1C). A pars plana vitrectomy (PPV) and an intraocular amB injection (5 μg) were performed. Hypopyon was resolved and the deposits were decreased in number. Topical treatment with fluconazole, dexamethasone and cyclopentolate were continued. The BCVA increased to 8/20 and the fundus was blurry but normal.\n\nFigure 1 Dense exudate (white arrow) in the inferior capsular bag. (A), endothelial precipitates and increased exudate in the capsular bag (B), hypopyon and deposits on the anterior hyaloids (C), corneal endothelial microabscesses (D), increased corneal endothelial microabscesses (white arrows) (E), sub endothelial encapsulated abscesses (black arrows) (F).\n\nOne month after the PPV, the patient was observed to have ciliary flush, an increased anterior chamber reaction, corneal endothelial microabscesses and minimal optic nerve head swelling (Figure 1D). A second intravitreal amB ( 5 μg) dose was injected on that day. Even with topical fluconazole treatment, the patient had pain, decreased visual acuity and increased corneal endothelial microabscesses 1.5 months after the second intravitreal injection (Figure 1E). Therefore, anterior chamber lavage, aspiration of the abscesses on the endothelium and a third intracameral intravitreal amB (5 μg) dose with triamcinolone acetonide 4 mg were given. An increase in corneal endothelial microabscesses and pain occurred again after 1 month (Figure 1F). Then, anterior chamber lavage and aspiration of abscesses by rupturing the posterior wall were performed and intracameral amB was injected for the 4th time. In the fundus, there was a ++ vitreous cellular reaction and a pale optic nerve head. Thereafter, no relapse was observed. The Infection management took place for 8 months. Moreover, there was no recurrence of endophthalmitis during 3 years of follow-up. The BCVA of the patient remained at 8/20.\n\nConclusions\nFungus is the cause of 7–13% of culture positive cases of postoperative endophthalmitis and the common fungal species that are isolated are Aspergillus spp., Cephalosporium spp. and Candida spp [2,3].\n\nPossible sources of exogenous fungal infection are contaminated intraocular irrigation solutions [5], intraocular lenses [6], ventilation systems or hospital construction activities [7]. We could not find any predisposing factor to account for the fungal endophthalmitis in this case. Colonization at the time of cataract surgery or postoperative self-inoculation by the patient may have occurred.\n\nThe mean time interval between cataract surgery and the development of symptoms in exogenous fungal endophthalmitis is 19.5 days [3]. In candida endophthalmitis, it ranges from 3 days to 50 days [5,7]. The interval was 23 days in our C. pelliculosa case.\n\nCorneal involvement, anterior chamber exudates, hypopyon and fibrinous reaction localized around the IOL have been seen in fungal endophthalmitis cases [7].\n\nParental antifungal treatment is recommended for 4–6 weeks in candida endophthalmitis. We were unable to manage allergic reactions due to L-AmB because of the hepatotoxicity of fluconazole and patient refusal. Increased liver enzymes due to fluconazole, such as in our case, have been seen in 2 of 27 cases [7].\n\nIntraocular AmB injections might be needed several times in fungal endophthalmitis. In one case with exogenous fungal endophthalmitis, three intravitreal AmB injections were needed [8]. In another case with candida endophthalmitis, 67 mg amB was injected 11 times in total [9]. In a case series, two or more injections were performed in 2 of 27 eyes [7]. In our case, despite topical treatment, inflammation recurred and we performed intravitreal amB injections 4 times.\n\nA combination of PPV and antifungal agents appears to be the best therapy for exogenous fungal endophthalmitis. The role of corticosteroids is controversial. Our aim in using corticosteroids was to diminish tissue destruction due to damage by fungal toxins.\n\nIt has been reported that visual outcomes were unfavorable in fungal postoperative endophthalmitis cases following PPV [3]. The final BCVA was better than 6/18 in only in 5 of 27 eyes [7]. Our final BCVA was 8/20 and we consider this a favorable outcome.\n\nIn summary, 23 days after cataract surgery, the patient presented with eye redness, pain and blurred vision. Corneal endothelial deposits, hypopyon in the capsular bag and microabscesses on the incision sites and corneal endothelium were thought to be caused by C. pelliculosa. PPV with IOL explantation and multiple amB (5 μg) injections into the anterior chamber and vitreous cavity with rupturing of the posterior wall of the abscesses on the endothelium are recommended.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nHE carried out the diagnosis, surgery and follow-up and suggested this case report, which he developed and coordinated. EB was the main physician responsible for caring for the patient and was involved in manuscript writing. ÇÖ performed retinal examinations and helped in reviewing the literature for this manuscript. All authors read and approved the final manuscript.\n==== Refs\nKresloff MS Castellarin AA Zarbin MA Endophthalmitis Surv Ophthalmol 1998 43 193 224 10.1016/S0039-6257(98)00036-8 9862309 \nHughes DS Hill RJ Infectious endophthalmitis after cataract surgery Br J Ophthalmol 1994 78 227 232 10.1136/bjo.78.3.227 8148340 \nChakrabarti A Shivaprakash MR Singh R Tarai B George VK Fomda BA Gupta A Fungal endophthalmitis: fourteen years' experience from a center in India Retina 2008 28 1400 1407 10.1097/IAE.0b013e318185e943 19009680 \nAnand AR Therese KL Madhavan HN Spectrum of etiological agents of postoperative endophthalmitis and antibiotic susceptibility of bacterial isolates Indian J Ophthalmol 2000 48 123 128 11116508 \nStern WH Tamura E Jacobs RA Pons VG Stone RD O’Day DM Irvine AR Epidemic postsurgical candida prapsilosis endophthalmitis: Clinical findings and management of 15 consecutive cases Ophthalmology 1985 92 1701 1709 10.1016/S0161-6420(85)34095-2 4088622 \nPettit TH Olson RJ Foos RY Martin WJ Fungal endophthalmitis following intraocular lens implantation. A surgical epidemic Arch Ophthalmol 1980 98 1025 1039 10.1001/archopht.1980.01020031015002 7190003 \nNarang S Gupta A Gupta V Dogra MR Ram J Pandav SS Chakrabarti A A fungal endophthalmitis following cataract surgery: clinical presentation, microbiological spectrum, and outcome Am J Ophthalmol 2001 132 609 617 10.1016/S0002-9394(01)01180-1 11704021 \nYang YS Results of extensive surgical treatment of seven consecutive cases of postoperative fungal endophthalmitis Korean J Ophthalmol 2009 23 159 163 10.3341/kjo.2009.23.3.159 19794941 \nLagnodo R Gupta R Osborne A Dua HS A case of postoperative candida endophthalmitis Eye 2005 19 703 705 10.1038/sj.eye.6701599 15359249\n\n",
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"mesh_terms": "D000666:Amphotericin B; D000867:Anterior Chamber; D000935:Antifungal Agents; D002175:Candida; D002386:Cataract; D002387:Cataract Extraction; D000075202:Contraindications; D009877:Endophthalmitis; D015725:Fluconazole; D006801:Humans; D056965:Injections, Intraocular; D019654:Lens Implantation, Intraocular; D007910:Lenses, Intraocular; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D014821:Vitrectomy",
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"title": "Candida pelliculosa endophthalmitis after cataract surgery: a case report.",
"title_normalized": "candida pelliculosa endophthalmitis after cataract surgery a case report"
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"abstract": "Angina bullosa hemorrhagica (ABH) is an infrequent dermatosis characterized by acute onset of hemorrhagic bulla in the oral cavity. Clinical presentation of ABH may be quite worrisome, and clinicians often feel skeptical regarding their clinical diagnosis and lack confidence in managing this distinct entity. Indeed, ABH is a completely benign and self-limited disorder. The exact etiopathogenesis of ABH is still unknown. There have been reports in the literature addressing a central role for mechanical instability of the epithelial-connective tissue connection in the pathogenesis of ABH. Moreover, it has been claimed that long-term usage of inhaled glucocorticoids (GCs) is involved in the development of ABH, since most of the reported cases are asthmatic patients, who were treated with inhaled GCs, and GCs are well known for their degradative activities on collagen formation. Here, we describe a case with ABH, who had a drug history of inhaled GCs and nonsteroidal anti-inflammatory drugs (NSAIDs). We assume that our case not only supports the association of inhaled GCs with ABH but also suggests a possible role for NSAIDs in the pathogenesis of ABH.",
"affiliations": "Department of Dermatology, Ankara Numune Research and Education Hospital, Ankara, Turkey.;Department of Dermatology, Ankara Numune Research and Education Hospital, Ankara, Turkey.",
"authors": "Yorulmaz|Ahu|A|;Yalcin|Basak|B|",
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"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-50-9110.4103/ijp.IJP_19_17Drug WatchIs inhaled glucocorticoids the only culprit in angina bullosa hemorrhagica? Yorulmaz Ahu Yalcin Basak Department of Dermatology, Ankara Numune Research and Education Hospital, Ankara, TurkeyAddress for correspondence: Dr. Ahu Yorulmaz, Department of Dermatology, Ankara Numune Research and Training Hospital, Samanpazari, Altindag, Ankara, Turkey. E-mail: ahuyor@gmail.comMar-Apr 2018 50 2 91 93 10 1 2017 27 5 2018 Copyright: © 2018 Indian Journal of Pharmacology2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Angina bullosa hemorrhagica (ABH) is an infrequent dermatosis characterized by acute onset of hemorrhagic bulla in the oral cavity. Clinical presentation of ABH may be quite worrisome, and clinicians often feel skeptical regarding their clinical diagnosis and lack confidence in managing this distinct entity. Indeed, ABH is a completely benign and self-limited disorder. The exact etiopathogenesis of ABH is still unknown. There have been reports in the literature addressing a central role for mechanical instability of the epithelial-connective tissue connection in the pathogenesis of ABH. Moreover, it has been claimed that long-term usage of inhaled glucocorticoids (GCs) is involved in the development of ABH, since most of the reported cases are asthmatic patients, who were treated with inhaled GCs, and GCs are well known for their degradative activities on collagen formation. Here, we describe a case with ABH, who had a drug history of inhaled GCs and nonsteroidal anti-inflammatory drugs (NSAIDs). We assume that our case not only supports the association of inhaled GCs with ABH but also suggests a possible role for NSAIDs in the pathogenesis of ABH.\n\nKeywords:\nAngina bullosa hemorrhagicahemorrhagic bullainhaled glucocorticoidsnonsteroidal anti-inflammatory drugs\n==== Body\nIntroduction\nAngina bullosa hemorrhagica (ABH), which is also known as localized oral purpura stomatopompholyx haemorrhagica and recurrent oral hemophlyctenosis, is a self-limited, benign oral mucosal disorder.[12345678910] It goes back to 1960s when Badram first described clinical features of this condition and coined the term “angina bullosa hemorrhagica.”[11] ABH is a rare dermatosis with limited available data in the literature.[1234567891011] Here, we report a case with ABH, who presents typical clinical characteristics of this entity. We not only highlight distinctive clinical features but also discuss the possible roles of inhaled glucocorticoids (GCs) and nonsteroidal anti-inflammatory drugs (NSAIDs) in the pathogenesis of ABH.\n\nCase Report\nA 57-year-old female came to our outpatient department with a sudden onset blood-filled blister on her tongue. She had a medical history of gastritis and asthma, for which she was receiving inhaled GCs and proton-pump inhibitors. However, a detailed query revealed that she used to take NSAIDs for headache prevention and she had taken naproxen 550 mg twice daily on the previous day of admission. She told that identical lesions had developed almost exactly on the same localization three or four times before, all of which spontaneously ruptured after a short period of time and completely disappeared around a week. However, she did not recall whether she had taken NSAIDs before the eruption of these similar lesions. Oral mucosal examination of the patient revealed a hemorrhagic bulla on the right lateral border of the tongue [Figure 1]. Laboratory investigations including complete blood count and differential, prothrombin time, and activated partial thromboplastin time were within normal limits. Based on typical history, clinical and laboratory findings, we made a diagnosis of ABH. Due to benign nature of the disease, we did not consider to perform a lesional biopsy; in addition, the patient did not want any invasive procedure. The patient reassured about the nature of the disorder and taken under follow-up. At the 2-week appointment, it was discovered that the lesion was completely recovered.\n\nFigure 1 A hemorrhagic bull about 1.5 cm × 1 cm in diameter on the right lateral border of the tongue\n\nDiscussion\nABH is characterized by acute onset hemorrhagic bulla in the oral cavity. The bulla is almost always solitary and the main localization is the junction of the hard and soft palate. On the other hand, the buccal mucosa, the lateral and ventral border of the tongue may be also affected. Typically blood-filled bulla bursts spontaneously in 24–48 h leaving superficial erosions that heal without scarring within 1 or 2 weeks. Initially, the intact bulla can be painful; however, after the rupture, the pain wanes. ABH has been reported to be seen more commonly in women with a peak incidence over the fifth decade. A unique feature of ABH is that the history of each occurrence is special and specific and identical for each patient.[12345678910]\n\nThe precise etiopathogenesis of ABH still needs to be elucidated. There have been factors implicated in the development of ABH. Among them, local factors (trauma, dental procedures, and endoscopy) and long-term usage of inhaled GCs for asthma are mostly appreciated ones. It has been suggested that a mechanical instability of the epithelial-connective tissue connection, which may induce a susceptibleness of the nonkeratinized mucosa to damage, is the primary pathogenetic mechanism in this disorder.[12345678910] We also agree on these presumed etiological factors and suggest that an explanation lies in understanding the morphology and cellular dynamics of the human skin.\n\nIt is well known that cutaneous atrophy is one of the utmost primary adverse effects of topical GC therapy. On the skin, long-term usage of topical GCs is associated with atrophic changes, characterized by an extensive increase in transparency of skin, rupturing, and bruising.[12] The physiopathology of skin atrophy induced by topical GCs involves the synthesis of lipocortin protein that suppresses the activity of phospholipase A2 (PLA2). As a result of the inhibition of PLA2, because of reduced release of arachidonic acid (AA), the inflammatory process is inhibited, but also mitotic activity and protein synthesis are impaired.[13] AA is also involved in the coagulation cascade. Free AA is a precursor for thromboxane A2, which is a dominant vasoconstrictor and inducer of platelet aggregation. Therefore, reduced release of AA leads to inactivation of the coagulation cascade.[14] Considering all these data, we suggest that long-term inhaled GC therapy is the main triggering factor in our patient. However, we appreciate the possible additive etiologic potential of NSAIDs, since NSAIDS are inhibitors of cyclooxygenase, the enzyme which mediates the bioconversion of AA to prostaglandins and thromboxanes. It is well known that NSAIDs have antiplatelet properties.[1516]\n\nThe most essential differential diagnosis of ABH comprises vesiculobullous diseases including pemphigus vulgaris, bullous pemphigoid, oral bullous lichen planus, and acquired epidermolysis bullosa, also blood dyscrasias.[17] The laboratory investigations of our patient were completely normal, and we did not detect any clinical signs of hematological diseases; thus, we ruled out blood dyscrasias. The characteristic solitary oral lesion without any other cutaneous finding apparently pointed to the diagnosis of ABH. Our patient did not have any other dermatological manifestation that suggests diseases included in the differential diagnosis.\n\nThe diagnosis of a ABH is essentially clinical. Symptomatic treatment is sufficient in these patients, and indeed no further evaluation and treatment are necessary. The most important responsibility is the reassurance of the patient. Awareness of this entity is very important to avoid misdiagnosis and unnecessary diagnostic procedures.[12345678910] In our opinion, ABH is one of the most peculiar diseases of dermatology practice. This case report highlights the underlying pathophysiology and clinical presentation of ABH. We assume that ABH is a multifactorial phenomenon and concomitant usage of inhaled GCs, and NSAIDs are the causative factor in our patient. On the other hand, causality assessment based on Naranjo Algorithm probability scale [18] showed that the drug-induced effect of NSAIDs in ABH is possible (score 2). We suggest that the reason for the low score is that the patient could not recall any association of NSAIDs intake with previous occurrences of ABH. As far as we know, there is not any other report in the literature describing a causal relationship of NSAIDs with ABH. Further case reports are needed to demonstrate typical clinical features of this uncommon disorder and to elucidate possible roles of inhaled GCs and NSAIDs in the pathogenesis of ABH.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Rai S Kaur M Goel S Angina bullosa hemorrhagica: Report of two cases Indian J Dermatol 2012 57 503 \n2 Shashikumar B Reddy RR Harish M Oral hemorrhagic blister: An enigma Indian J Dermatol 2013 58 407 \n3 Giuliani M Favia GF Lajolo C Miani CM Angina bullosa haemorrhagica: Presentation of eight new cases and a review of the literature Oral Dis 2002 8 54 8 11936457 \n4 Yip HK Angina bullosa haemorrhagica: A case report and a concise review Gen Dent 2004 52 162 4 15101312 \n5 Beguerie JR Gonzalez S Angina bullosa hemorrhagica: Report of 11 cases Dermatol Reports 2014 6 5282 25386327 \n6 Shoor H Mutalik S Pai KM Angina bullosa haemorrhagica BMJ Case Rep 2013 2013 pii: bcr2013200352 \n7 Singh D Misra N Agrawal S Misra P Angina bullosa haemorrhagica BMJ Case Rep 2013 2013 pii: bcr2012008505 \n8 Horie N Kawano R Inaba J Numa T Kato T Nasu D Angina bullosa hemorrhagica of the soft palate: A clinical study of 16 cases J Oral Sci 2008 50 33 6 18403881 \n9 Martini MZ Lemos CA Jr Shinohara EH Angina bullosa hemorrhagica: Report of 4 cases Minerva Stomatol 2010 59 139 42 20357740 \n10 Alberdi-Navarro J Gainza-Cirauqui ML Prieto-Elías M Aguirre-Urizar JM Angina bullosa hemorrhagica an enigmatic oral disease World J Stomatol 2015 4 1 7 \n11 Badham NJ Blood blisters and the oesophageal cast J Laryngol Otol 1967 81 791 803 6029172 \n12 Schoepe S Schäcke H May E Asadullah K Glucocorticoid therapy-induced skin atrophy Exp Dermatol 2006 15 406 20 16689857 \n13 Lemos MC Correr WR da Silva de Avó LR Germano CM Kurachi C Polikarpov I Fluorescence spectroscopy as a tool to detect and evaluate glucocorticoid-induced skin atrophy Lasers Med Sci 2012 27 1059 65 22249456 \n14 Sangkuhl K Shuldiner AR Klein TE Altman RB Platelet aggregation pathway Pharmacogenet Genomics 2011 21 516 21 20938371 \n15 Ricciotti E FitzGerald GA Prostaglandins and inflammation Arterioscler Thromb Vasc Biol 2011 31 986 1000 21508345 \n16 Cairns JA The coxibs and traditional nonsteroidal anti-inflammatory drugs: A current perspective on cardiovascular risks Can J Cardiol 2007 23 125 31 17311118 \n17 Cinar SL Kartal D Canöz Ö Borlu M Ferahbas A Case report: A rare cause of oral bullae: Angina bullosa hemorrhagica F1000Res 2017 6 1974 29259770 \n18 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508\n\n",
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"abstract": "McArdle disease is a metabolic myopathy that can may lead to severe perioperative problems. A case is reported of a woman with a history of McArdle disease, who was scheduled for a mastectomy. An understanding of the physiology and pathology, and the application of appropriate preventive measures can avoid complications. A overview of the complications and the management are described.",
"affiliations": "Servicio de Anestesiología, Reanimación y Terapéutica del dolor, Hospital San Pedro de Logroño, Logroño, España. Electronic address: veronica_ayerza@hotmail.com.;Servicio de Anestesiología, Reanimación y Terapéutica del dolor, Hospital San Pedro de Logroño, Logroño, España.;Servicio de Anestesiología, Reanimación y Terapéutica del dolor, Hospital San Pedro de Logroño, Logroño, España.;Servicio de Anestesiología, Reanimación y Terapéutica del dolor, Hospital San Pedro de Logroño, Logroño, España.",
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"title": "McArdle disease or glycogen storage disease type v: Should it affect anaesthetic management?.",
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"abstract": "Osteoporosis affects one in three women. There has been some confusion among women and health professionals about the management of osteoporosis since the publication of the Women's Health Initiative and Million Women studies. This guidance regarding estrogen-based and non-estrogen-based treatments for osteoporosis responds to the controversies about the benefits and risks of individual agents. Treatment choice should be based on up-to-date evidence and targeted to individual women's needs.",
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"abstract": "Calciphylaxis is a rare life-threatening condition that is characterized by calcification of small blood vessels and soft tissues. This condition is classically described in uraemic patients with end-stage renal failure who are on dialysis or had previous renal transplant. It has also been reported in non-uraemic patients and those who are on warfarin therapy. It is typically associated with high calcium/phosphorus product. Patients classically present with painful skin lesion that evolve into painful ulcers. There are multiple risk factors that were reported to trigger or worsen calciphylaxis. Treatment is a multidisciplinary approach that involves elimination of risk factors, wound management, pain control, and optimization of calcium/phosphorus metabolism. Reported mortality rates are very high especially in the uraemic group.\nHere we present a case of a patient, who is on chronic renal dialysis for stage renal failure, who underwent mechanical mitral valve replacement and tricuspid valve repair. In the perioperative period, she was exposed to multiple risk factors that are known to potentially trigger prophylaxis. In the early postoperative period, she developed new-onset rapidly deteriorating skin lesions and the histopathological diagnosis confirmed calciphylaxis. Her treatment plan included pain control, frequent wound care, and optimization of nutritional and metabolic status.\nCalciphylaxis is a very serious condition that is usually associated with poor outcome. In this case, we discuss the unusual presentation of this condition with particular emphasis on the multiple perioperative risk factors that can potentially trigger the onset of calciphylaxis in postoperative cardiac patients. We also discuss the epidemiology, pathogenesis, diagnosis, histopathological findings, and different lines of treatment of this serious condition and the potential preventative strategies.",
"affiliations": "Cardiac Surgery Department, Kingston Health Science Centre, 76 Stuart Street, Kingston, ON K7L 2V7, Canada.;Cardiac Surgery Department, Hospital San Rafael, Ls Jubias, 82, 15009 A Coruna, Spain.",
"authors": "Diasty|Mohammad El|ME|;Cuenca|Jose|J|https://orcid.org/0000-0002-1480-6027",
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"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n10.1093/ehjcr/ytab060\nytab060\nCase Report\nAcademicSubjects/MED00200\nNew-onset acute rapidly deteriorating case of calciphylaxis after open heart surgery: a case report\nDiasty Mohammad El 1\nhttps://orcid.org/0000-0002-1480-6027\nCuenca Jose 2\n1 Cardiac Surgery Department, Kingston Health Science Centre, 76 Stuart Street, Kingston, ON K7L 2V7, Canada\n2 Cardiac Surgery Department, Hospital San Rafael, Ls Jubias, 82, 15009 A Coruna, Spain\nSá Michel Pompeu Handling Editor\nTahlawi Mohammad El Editor\nMiglioranza Marcelo Haertel Editor\nTardo Daniel Editor\nSunjaya Anthony Paulo Editor\nCorresponding author. Tel: +13433637122, Email: doctordiasty@gmail.com\n3 2021\n14 3 2021\n14 3 2021\n5 3 ytab06025 1 2021\n26 11 2020\n23 12 2020\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nBackground \n\nCalciphylaxis is a rare life-threatening condition that is characterized by calcification of small blood vessels and soft tissues. This condition is classically described in uraemic patients with end-stage renal failure who are on dialysis or had previous renal transplant. It has also been reported in non-uraemic patients and those who are on warfarin therapy. It is typically associated with high calcium/phosphorus product. Patients classically present with painful skin lesion that evolve into painful ulcers. There are multiple risk factors that were reported to trigger or worsen calciphylaxis. Treatment is a multidisciplinary approach that involves elimination of risk factors, wound management, pain control, and optimization of calcium/phosphorus metabolism. Reported mortality rates are very high especially in the uraemic group.\n\nCase summary \n\nHere we present a case of a patient, who is on chronic renal dialysis for stage renal failure, who underwent mechanical mitral valve replacement and tricuspid valve repair. In the perioperative period, she was exposed to multiple risk factors that are known to potentially trigger prophylaxis. In the early postoperative period, she developed new-onset rapidly deteriorating skin lesions and the histopathological diagnosis confirmed calciphylaxis. Her treatment plan included pain control, frequent wound care, and optimization of nutritional and metabolic status.\n\nDiscussion \n\nCalciphylaxis is a very serious condition that is usually associated with poor outcome. In this case, we discuss the unusual presentation of this condition with particular emphasis on the multiple perioperative risk factors that can potentially trigger the onset of calciphylaxis in postoperative cardiac patients. We also discuss the epidemiology, pathogenesis, diagnosis, histopathological findings, and different lines of treatment of this serious condition and the potential preventative strategies.\n\nCalciphylaxis\nPostoperative complications\nCardiac surgery\nKidney disease\nCase report\n==== Body\nLearning points\n\nCalciphylaxis is a life-threatening condition that mainly affects patients with chronic end-stage renal disease, and it has poor prognosis.\n\nMultiple risk factors can trigger or worsen prophylaxis in this group of patients.\n\nDuring the perioperative period of cardiac surgery, these patients may be exposed to many of these risk factors which can potentially trigger calciphylaxis.\n\nPerioperative elimination of these risk factors and optimization of patients’ metabolic and nutritional status can potentially prevent the occurrence of this dire condition.\n\nIntroduction\n\nCalciphylaxis, also known as calcific uraemic arteriopathy,1 is a rare condition that is characterized by calcification and subsequent thrombosis of the micro-vessels of the subcutaneous fatty tissue and dermis.1 This results in the development of a wide spectrum of ischaemic skin lesions (ranging from erythema and tenderness to necrotic ulcers) which are characteristically very painful.2\n\nSerum levels of calcium and phosphate are typically elevated in calciphylaxis that can affect up to 35 per 10 000 patient-years among the patients with end-stage renal dysfunction (ESRD) on chronic haemodialysis in the USA.1 It can also affect, to lesser extent, non-uraemic patients.2 This condition can be triggered by multiple factors such as systemic corticosteroids, blood transfusions, low serum albumin, warfarin use, malnutrition, and weight loss.2\n\nTreatment of calciphylaxis is largely supportive and includes wound care, control of risk factors, and the use of pharmacological agents that interfere with the process of calcium deposition in tissues.3 Prognosis of calciphylaxis is usually very poor especially in the uraemic group of patients.1\n\nUraemic patients who undergo cardiac surgery under cardiopulmonary bypass (CPB) are frequently exposed to some of the risk factors that can trigger or worsen calciphylaxis during the immediate perioperative period. Perioperative optimization of this vulnerable group of patients and control of these risk factors is important to minimize the risk of occurrence of this dire condition.\n\nTimeline\n\nTen years\tCadaveric renal transplant.\t\nEight years\tRenal transplant failed.\t\nDay −1\tPatient was admitted for elective cardiac surgery\t\nDay 0\tPatient underwent cardiac surgery under cardiopulmonary bypass.\n\nShe received multiple blood transfusions.\n\n\t\nDay 0\tPatient was admitted to intensive care unit.\n\nMore blood units were given.\n\nRenal replacement therapy was started.\n\n\t\nDay 2\tPatient was extubated.\t\nDay 3\tWarfarin therapy was started.\t\nDay 4\tPatient was transferred to the floor.\t\nDay 7\tPatient started to develop skin lesions.\t\nDays 7–18\tDiagnosis of calciphylaxis was established and patient was treated conservatively.\t\nDay 19\tPatient was transferred to local district hospital for ongoing management of skin lesions.\t\nDay 45\tPatient deceased\t\n\nCase presentation\n\nWe present the case of a 39-year-old female patient with past medical history of long-term ESRD and on chronic renal dialysis. She suffered from chronic vesicoureteral reflux and she had received a cadaveric renal transplant 10 years before the date of admission. Unfortunately, her renal transplant failed after 2 years from implantation due to graft rejection. She has remained dependent on renal dialysis for the last 8 years. She also had secondary hyperparathyroidism, secondary arterial hypertension, and chronic anaemia. Her regular medications included iron supplements, atorvastatin, aspirin, amlodipine, erythropoietin, and vitamin D supplements. She presented with worsening dyspnoea over a period of 6–12 months. On admission, physical examination showed a malnourished and cachectic patient. She had a very faint diastolic murmur and bibasal lung crepitations. Echocardiogram showed severe mitral stenosis with severely calcified mitral annulus and sub-valvular apparatus with mean gradient of 10 mmHg and mitral valve area of 0.8 cm2. She also had severe tricuspid regurgitation with preserved biventricular ejection fraction. Coronary angiography did not show any flow-limiting coronary lesions. Her preoperative blood works showed levels of urea 111 (7–30 mg/dL), creatinine 4.7 (0.7–1.2 mg/dL), phosphorus 10 (2.8–4.5 mg/dL), calcium 8.6 (8.4–10.2 mg/dL), and parathormone hormone (PTH) 725 (50–330 pg/dL).\n\nThe patient underwent mitral valve replacement with mechanical prosthesis and tricuspid valve repair with annuloplasty ring. Intraoperatively, the mitral valve was found to be very severely calcified and required extensive tissue debridement and decalcification. She required the transfusion of multiple blood products (including red blood cells, plasma concentrates, platelets, and fibrinogen) for significant coagulopathy and bleeding both during surgery and in the intensive care unit (ICU). Postoperatively, she was immediately started on continuous renal replacement therapy for optimization of her metabolic parameters and for fluid off-loading. She was extubated on postoperative Day 2 and warfarin was started on postoperative Day 3 after her chest drains were removed. She was transferred from the ICU to the floor on Day 4 and she remained haemodynamically stable. After 3 days, she started to develop multiple rapidly worsening ulcerative lesions in the inner aspects of her thighs and calves (Figure 1). Ulcers were painful with necrotic base and erythematous borders and the widest lesion measured about 10 × 7 cm. She also developed rapidly deteriorating necrotic ulcers of her fingertips (Figure 1). Tissue biopsies from these lesions showed abundant deposition of calcium in walls of small vessels and surrounding tissues associated with necrotic changes. Histopathological diagnosis was confirmed to be compatible with calciphylaxis.\n\nFigure 1 Necrotic lesions of fingertips (left) and thigh (right).\n\nPatient wounds were treated conservatively with regular enzymatic debridement with collagenase-based ointment and frequent dressings. She was also started on empirical prophylactic antibiotics to minimize the risk of spreading any potential skin infection to her new mechanical mitral valve prosthesis. Repeated swab cultures from her ulcerative lesions remained negative for bacterial growth and her inflammatory markers remained within normal range. Based on risk and benefit, it was decided not to discontinue warfarin at any time due to the very high risk of prosthetic thrombosis. After a period of clinical stability, on Day 19, the patient was transferred to her local hospital for continued wound care and convalescence. Unfortunately, the patient’s condition started to deteriorate with worsening wound infection and sepsis. She eventually passed away 45 days after her surgery.\n\nDiscussion\n\nCalciphylaxis is a rare condition characterized by progressive microvascular calcification and occlusion of cutaneous blood vessels.4 It was first reported by Bryant and White5 in 1898, who described the combination of skin gangrene and vascular calcification, but it was not until 1962 when the term ‘calciphylaxis’ was used by Selye6 to describe the metastatic calcifications in various organs. It usually appears during the 5th decade of life, but it has also been described in younger patients and children as well.7 It is classically described in uraemic patients with end-stage renal failure and also in those who had previous renal transplants.3 Reported incidence varies in literature and in a recent major study from the Fresenius Medical Care North America (FMCNA), dialysis units reported calciphylaxis annual incidence rate of 35 per 10 000 ESRD patients who are on chronic haemodialysis.1 Calciphylaxis was also reported in non-uraemic patients with lesser degrees of renal dysfunction especially those who have other risk factors such as obesity and diabetes mellitus.2,7 In the German Calciphylaxis Registry, 10% of patients with calciphylaxis had either normal kidney function or had chronic kidney disease not requiring renal dialysis.1,8\n\nThe pathogenesis of this process is complex and the exact mechanism and sequence of events that lead to calcium deposition in vascular wall and thrombosis are not entirely clear.1,2,9 One common feature in these patients is the imbalance in calcium/phosphate metabolism which lead to elevated calcium/phosphorus product usually in the context of chronic renal failure and secondary hyperparathyroidism.2,9\n\nAlso, matrix Gla protein (MGP), a potent inhibitor of vascular calcification that requires the activity of a vitamin K-dependent carboxylase, has been described to play a role in this complex vascular calcification process.9\n\nIn addition to ESRD, many other risk factors have been reported to trigger or aggravate calciphylaxis such as diabetes mellitus, obesity, autoimmune diseases, hypoalbuminaemia, hypercalcaemia, hyperphosphataemia, hyperparathyrodism, and corticosteroids.1,2,7 Warfarin was also described as an important trigger for calciphylaxis including in non-uraemic patients. In some reports, it was found to increase the incidence of calciphylaxis by up to 10 folds.10 This may be attributed to promoting vascular calcification by inhibiting the vitamin K-dependent MGP with subsequent calcium deposition in arteries.11 Warfarin can also trigger thrombosis by reducing proteins C and S, both are essential for endothelial cells response to calcification and stress.10,12 Also, the initiation of renal dialysis was reported as a triggering factor due to the abrupt influx of calcium from the dialysate into the patient's blood and the correction of acidosis that can lead to abundant substrate that can promote the formation of Ca-P complex.13\n\nPatients classically present with a wide variety of painful skin lesions that usually start as erythema, induration, or nodule that eventually progress to necrotic painful skin ulcers.2,7,9 Patients may also present with widespread calcifications of skeletal muscles, cerebral, and pulmonary vessels.3,7 Cardiac lesions are variable and may include calcification of the aorta, heart valves, and the conduction system (bony heart).14\n\nTypical laboratory findings in these patients include hyperparathyroidism, hypercalcaemia, hyperphosphataemia, and high calcium-phosphorus product. Also, elevated serum levels of alkaline phosphatase, urea, and creatinine are common findings.2\n\nOnce there is a clinical high suspicion for calciphylaxis, skin biopsy is usually indicated to establish the diagnosis. Histopathological findings may include medial and intimal calcium deposition, intimal hyperplasia, and thrombosis of the micro-vessels in the dermal and subcutaneous layers with subsequent epidermal ulceration and necrosis.1,4 The most typical diagnostic histopathologic finding is calcification of small- to medium-size vessels with fat necrosis combined with proximal vascular thrombosis.10\n\nTreatment of calciphylaxis should take a multidisciplinary approach and should involve different specialties including renal physicians, nutritionists, pain specialists, and wound care teams.9 Initial efforts should be directed towards controlling and/or eliminating the triggering risk factors to prevent or slow down the progress of the disease.3 Wound care is an essential part of the management plan and it is largely conservative and may include proper debridement of necrotic tissues and frequent dressings. Surgical reconstruction may be considered to reduce pain and improve healing.15 Multiple pharmacological agents have been used to optimize calcium and phosphate levels such as sodium thiosulphate and bisphosphonates with variable reported degrees of success.3 Also, optimizing PTH levels have also been suggested to slow the disease progress.3\n\nFinally, prognosis of calciphylaxis is generally poor especially in the uraemic patients and mortality rates are high and can reach up to 60–80%. Death usually results from severe sepsis and malnutrition.1,2\n\nIn this case report, a patient with ESRD on long-term dialysis presented with new-onset acutely worsening necrotic skin lesions very early after her mitral and tricuspid valve surgery. Currently, there is not enough evidence to support the link between heart surgery under CPB per se and the occurrence of calciphylaxis. To the best of our knowledge, there are no similar reported cases in literature. However, during the perioperative period of cardiac surgery, patients with ESRD are potentially exposed to a multitude of the risk factors that were previously reported to trigger calciphylaxis. Regarding the CPB itself, it is well known that CPB can trigger a cascade of systemic inflammatory reactions that can result in transient compromise in the immune system especially by interfering with cell-mediated immunity.16 Previous studies reported the administration of immuno-suppressant drugs as a potential trigger for calciphylaxis.2 Whether the immune-suppressive effect of is comparable to the effect of these drugs remains unknown. Also, transfusion of blood products, which is very common after cardiac surgery, has also been reported to potentially trigger calciphylaxis.2 Also, many of the cardiac surgical patients who present with worsening symptoms of heart failure may have varying degrees of malnutrition and hypoalbuminaemia.17 Both of which have been described as risk factors for calciphylaxis.2,3 Also, renal dialysis patients who undergo cardiac surgery will have some degree of worsening kidney parameters and electrolyte imbalance which again, may be a risk factor for calciphylaxis.18 One more major factor that has been strongly associated with calciphylaxis is warfarin therapy.10 Our patient was started on warfarin for her mechanical mitral valve shortly before the appearance of skin lesions, however, in literature, the reported timeframe between the commencement of warfarin therapy and the appearance of calciphylaxis is usually longer and ranges from 1 to 168 months (mean, 32 months).10\n\nFinally, special care should be taken when managing patients with ESRD or patients on chronic renal dialysis who will undergo cardiac surgery. This group of high-risk patients may be exposed to multiple risk factors during their perioperative journey. Rigorous control of renal function, optimization of serum electrolytes, and avoidance of unnecessary blood transfusions should be considered. Patient nutritional status should also be optimized to avoid malnutrition and hypoalbuminaemia. The decision to use warfarin in this group of patients should be based on the benefit/cost balance and should be tailored on individual basis.\n\nConclusions\n\nCalciphylaxis is a rare but major condition associated with poor outcome especially in uraemic patients. These patients are likely to be exposed to multiple risk factors during the perioperative period of cardiac surgery which may result in triggering this dire complication. All care should be taken to eliminate or control these factors to avoid the occurrence or worsening of this condition.\n\nLead author biography\n\nDr Mohammad El Diasty is currently working as a Clinical Fellow in Cardiac Surgery Department in Queen's University, Kingston, ON, Canada. He has received intensive training in adult cardiac and thoracic surgery in Spain, the UK, the USA, and Canada. He is particularly interested in analysing postoperative outcomes and he has been involved in multiple quality improvement projects that focused mainly on improving the standards of patient care.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\nConsent: The patient reported in this case is deceased. Despite the best efforts of the authors, they have been unable to contact the patient's next-of-kin to obtain consent for publication. Every effort has been made to anonymize the case. This situation has been discussed with the editors.\n\nConflict of interest: None declared.\n\nFunding: None declared.\n\nSupplementary Material\n\nytab060_Supplementary_Data Click here for additional data file.\n\n \n\nFor the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast\n==== Refs\nReferences\n\n1 Nigwekar SU , ZhaoS, WengerJ, HymesJL, MadduxFW, ThadhaniRI et al A nationally representative study of calcific uremic arteriolopathy risk factors. J Am Soc Nephrol 2016;27 :3421–3429.27080977\n2 Daudén E , OñateMJ. Calciphylaxis. Dermatol Clin 2008;26 :557–568.18793990\n3 Nigwekar SU , ThadhaniR, BrandenburgVM. Calciphylaxis. N Engl J Med 2018;378 :1704–1714.29719190\n4 Essary LR , WickMR. Cutaneous calciphylaxis. An underrecognized clinicopathologic entity. Am J Clin Pathol 2000;113 :280–287.10664631\n5 Bryant JH , WhiteWH. A case of calcification of the arteries and obliterative endarteritis associated with hydronephrosis in a child aged six months. Guys Hosp Rep 1898;55 :17–28.\n6 Selye H. The dermatologic implications of stress and calciphylaxis. J Invest Dermatol 1962;39 :259–275.13987858\n7 Nigwekar SU , KroshinskyD, NazarianRM, GovermanJ, MalhotraR, JacksonVA et al Calciphylaxis: risk factors, diagnosis, and treatment. Am J Kidney Dis 2015;66 :133–146.25960299\n8 Brandenburg VM , KramannR, RotheH, KaeslerN, KorbielJ, SpechtP et al Calcific uraemic arteriolopathy (calciphylaxis): data from a large nationwide registry. Nephrol Dial Transplant 2017;32 :126–132.26908770\n9 Nigwekar SU. Calciphylaxis. Curr Opin Nephrol Hypertens 2017;26 :276–281.28375870\n10 Yu WY , BhutaniT, KornikR, PincusLB, MauroT, RosenblumMD et al Warfarin-associated nonuremic calciphylaxis. JAMA Dermatol 2017;153 :309–314.28099971\n11 Schurgers LJ , CranenburgEC, VermeerC. Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb Haemost 2008;100 :593–603.18841280\n12 Rosenberg RD , AirdWC. Vascular-bed–specific hemostasis and hypercoagulable states. N Engl J Med 1999;340 :1555–1564.10332019\n13 Sandhu G , CasaresP, RanadeA, JonesJ, AmarLI, GuisadoD et al Acute calciphylaxis precipitated by the initiation of hemodialysis. Clin Nephrol 2013;80 :301–305.22762780\n14 Kloeppel R , LuebkeP, MittagM, AchenbachH, StephanS, KlugeR et al Acute hypercalcemia of the heart (\"bony heart\"). J Comput Assist Tomogr 2001;25 :407–411.11351191\n15 Baldwin C , FarahM, LeungM, TaylorP, WerbR, KiaiiM et al Multi-intervention management of calciphylaxis: a report of 7 cases. Am J Kidney Dis 2011;58 :988–991.21872378\n16 Hall RI , SmithMS, RockerG. The systemic inflammatory response to cardiopulmonary bypass: pathophysiological, therapeutic, and pharmacological considerations. Anesth Analg 1997;85 :766–782.9322454\n17 Rahman A , JafryS, JeejeebhoyK, NagpalAD, PisaniB, AgarwalaR. Malnutrition and cachexia in heart failure. J Parenter Enteral Nutr 2016;40 :475–486.\n18 Hoste EA , CruzDN, DavenportA, MehtaRL, PiccinniP, TettaC et al The epidemiology of cardiac surgery-associated acute kidney injury. Int J Artif Organs 2008;31 :158–165.18311732\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "5(3)",
"journal": "European heart journal. Case reports",
"keywords": "Calciphylaxis; Cardiac surgery; Case report; Kidney disease; Postoperative complications",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": "ytab060",
"pmc": null,
"pmid": "33748662",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports",
"references": "26908770;28099971;22762780;13987858;29719190;28375870;21872378;25960299;18793990;18841280;27080977;10664631;9322454;18311732;11351191;10332019;25634161",
"title": "New-onset acute rapidly deteriorating case of calciphylaxis after open heart surgery: a case report.",
"title_normalized": "new onset acute rapidly deteriorating case of calciphylaxis after open heart surgery a case report"
} | [
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"companynumb": "US-TARO-2021TAR00744",
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"occurcountry": "CA",
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"activesubstance": {
"activesubstancename": "WARFARIN"
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"abstract": "This is a case of a 70-year-old man. Two courses of docetaxel/cisplatin/S-1 combination therapy were administered after clinical trial registration with diagnosis of Stage Ⅳ gastric cancer(ypT3N3aM1). In June 2014, gastrectomy and splenectomy were performed. Postoperative S-1 adjuvant chemotherapy was administered; however, in September 2014, aorticl ymph node metastasis was diagnosed as recurrent. After recurrence, irinotecan/cisplatin therapy was administered. In February 2015, recurrent lymph node metastasis increased, and chemotherapy was changed to paclitaxel. In May 2015, numbness (Grade 2)of the fingers was observed, and treatment was changed to oxaliplatin/S-1. In February 2016, storage of ascites became remarkable; therefore, chemotherapy was discontinued as per policy. After that, we continued outpatient visit and observed increased recurrent lymph node metastasis on image evaluation; however, as the patient's general condition was good, chemotherapy was restarted. Ramucirumab/paclitaxel therapy started in February 2017. During the course of treatment, neutropenia(Grade 2)was observed as an adverse event, but therapy continuation was possible without loss of ramucirumab only with loss of paclitaxel. Thereafter, the recurrence of lymph node metastasis was reduced, and the ascites accumulation decreased. Until now, 1 year after the start of ramucirumab/paclitaxel therapy, the patient still visits the outpa- tient clinic.",
"affiliations": "Dept. of Surgery, Yokohama City University.",
"authors": "Ono|Yukari|Y|;Aoyama|Toru|T|;Morita|Junya|J|;Maezawa|Yukio|Y|;Amano|Shinya|S|;Sawazaki|Sho|S|;Numata|Masakatsu|M|;Tamagawa|Hiroshi|H|;Sato|Tsutomu|T|;Oshima|Takashi|T|;Yoshikawa|Takaki|T|;Ozawa|Yukihiro|Y|;Yukawa|Norio|N|;Masuda|Munetaka|M|;Rino|Yasushi|Y|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C543333:ramucirumab; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "45(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D005743:Gastrectomy; D006801:Humans; D008297:Male; D017239:Paclitaxel; D013274:Stomach Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2156-2158",
"pmc": null,
"pmid": "30692316",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Advanced Gastric Cancer with Long-Term Survival Due to Successful Ramucirumab and Paclitaxel Therapy.",
"title_normalized": "a case of advanced gastric cancer with long term survival due to successful ramucirumab and paclitaxel therapy"
} | [
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"companynumb": "JP-SA-2019SA047227",
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"activesubstancename": "PACLITAXEL"
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"abstract": "Histiocytic sarcoma is considered an extremely rare condition. We herein report on a case of histiocytic sarcoma following combination chemotherapy for a primary mediastinal germ cell tumor in a 26-year-old Asian man who visited the General Medicine Department of a hospital with complaints of cough and high fever. Chest computed tomography (CT) imaging revealed a tumor (diameter 10.5 cm) in the anterior mediastinum, with no signs of metastasis, and CT-guided biopsy of the mediastinal tumor revealed the presence of some necrotic cartilages. The patient's serum α-fetoprotein (AFP) level was determined to be high at 160.4 ng/mL and a primary mediastinal non-seminomatous germ cell tumor was suspected, so the patient was referred to the Department of Urology. Despite the presence of severe thrombocytopenia, the patient was treated using a combination of chemotherapy and intermittent transfusion, which was able to normalize his serum AFP level. However, resection of the mediastinal tumor was unsuccessful due to persistent thrombocytopenia and the patient was subsequently transferred to our hospital for further examination and treatment. Despite management by hematologists, the condition of the patient did not improve; although his AFP level remained normal, the tumor increased in size and then metastasized to the liver and spleen. The general condition of the patient deteriorated and he died 9 months after his first visit. The patient was diagnosed with histiocytic sarcoma following a pathological autopsy. Due to the extremely rare incidence of histiocytic sarcoma, this condition should be a differential diagnosis and the appropriate tests must be conducted to give an exact treatment.",
"affiliations": "Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;Department of Urology, Ishikawa Prefectural Central Hospital, 2-1 Kuratsukihigashi, Kanazawa, Ishikawa 920-8530 Japan.;Department of Urology, Kanazawa Nishi Hospital, 6-15-41 Ekinishihonmachi, Kanazawa, Ishikawa 920-0025 Japan.;Department of Human Pathology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;Department of Human Pathology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;Department of Human Pathology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.",
"authors": "Yaegashi|Hiroshi|H|0000-0003-3188-8834;Kato|Yuki|Y|;Nohara|Takahiro|T|;Izumi|Kouji|K|;Kadono|Yoshifumi|Y|;Miyagi|Tohru|T|;Nakashima|Takao|T|;Yoshimura|Kaori|K|;Sato|Yasunori|Y|;Harada|Kenichi|K|;Mizokami|Atsushi|A|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1007/s13691-020-00467-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-3183",
"issue": "10(2)",
"journal": "International cancer conference journal",
"keywords": "Cisplatin-based chemotherapy; Histiocytic sarcoma; Non-seminomatous germ cell tumor; Primary mediastinal germ cell tumor; Thrombocytopenia",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "144-148",
"pmc": null,
"pmid": "33786289",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": "23801128;26765473;20119590;12121233;18987551;25209580;30971575;24720374;16086090;24567436;31376203;29188284",
"title": "Histiocytic sarcoma following combination chemotherapy for primary mediastinal germ cell tumor: a diagnostic dilemma.",
"title_normalized": "histiocytic sarcoma following combination chemotherapy for primary mediastinal germ cell tumor a diagnostic dilemma"
} | [
{
"companynumb": "JP-PFIZER INC-2021542791",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"abstract": "Infantile myofibromatosis (IM) is most commonly limited to cutaneous lesions that resolve spontaneously. However, generalized IM with visceral involvement, which has a reported mortality rate as high as 73%, has been successfully treated with a combination of methotrexate and vinblastine. Here we report the further efficacy of low-dose methotrexate and vinblastine in 2 pediatric patients with IM and visceral involvement and review the literature describing chemotherapy for these patients.",
"affiliations": "*University of Texas Southwestern Medical School †Department of Pediatrics, Division of Hematology-Oncology Departments of §Radiology ¶Pathology ∥Molecular Biology, University of Texas Southwestern Medical Center at Dallas ‡The Center for Cancer and Blood Disorders and Children's Medical Center Dallas, Dallas, TX.",
"authors": "Wu|Susan Y|SY|;McCavit|Timothy L|TL|;Cederberg|Kevin|K|;Galindo|Rene L|RL|;Leavey|Patrick J|PJ|",
"chemical_list": "D000970:Antineoplastic Agents; D014750:Vincristine; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000132",
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"issn_linking": "1077-4114",
"issue": "37(5)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008727:Methotrexate; D018224:Myofibromatosis; D014750:Vincristine; D014781:Viscera",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "402-5",
"pmc": null,
"pmid": "24608078",
"pubdate": "2015-07",
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"abstract": "We report three precautionary cases of perioperative anaphylaxis to chlorhexidine isopropyl alcohol antiseptic wipes (CAW). In two cases, the patients were inadvertently re-exposed to CAW despite known chlorhexidine hypersensitivity. Chlorhexidine has been described as 'the hidden allergen'. As a result, patients may suffer multiple reactions before chlorhexidine is confirmed as the cause. Healthcare workers may not recognize that products they use for common clinical steps contain chlorhexidine. These cases highlight the need for constant vigilance to facilitate the safe management of patients with a history of chlorhexidine anaphylaxis.",
"affiliations": "Tweed Hospital Perioperative Allergy Service, Australia.;Tweed Hospital Perioperative Allergy Service, Australia.",
"authors": "Doolan|Brigid T|BT|;Crilly|Helen M|HM|",
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"keywords": "allergen; anaphylaxis; chlorhexidine; disinfectants; drug hypersensitivity",
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"abstract": "We report the case of a subcutaneous abscess due to Nocardia spp. mimicking a spontaneous hematoma or an aneurysm of the temporal artery branch, in a giant cell arteritis patient treated with methylprednisolone and azathioprine. Ultrasonography, incision and drainage with cultures helped in the diagnosis. This case highlights the importance of considering rare pathogens in immunosuppressed patients, besides the more frequent disease complications.",
"affiliations": "Infectious Diseases Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.;Clinical Laboratory, Clinical Hospital of Infectious Diseases, Cluj-Napoca, Romania.;Infectious Diseases Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.;Rheumatology Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.",
"authors": "Briciu|Violeta Tincuta|VT|;Flonta|Mirela|M|;Lupse|Mihaela|M|;Damian|Laura|L|",
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"fulltext": "\n==== Front\nClujul MedClujul MedCMClujul Medical1222-21192066-8872Iuliu Hatieganu University of Medicine and Pharmacy 10.15386/cjmed-726cm-90-231Case ReportCutaneous nocardiosis manifesting as a frontal mass in a patient with giant cell arteritis BRICIU VIOLETA TINCUTA 1FLONTA MIRELA 2LUPSE MIHAELA 1DAMIAN LAURA 31 Infectious Diseases Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania2 Clinical Laboratory, Clinical Hospital of Infectious Diseases, Cluj-Napoca, Romania3 Rheumatology Department, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaAddress for correspondence: briciu.tincuta@umfcluj.ro2017 25 4 2017 90 2 231 234 24 9 2016 30 11 2016 14 12 2016 2017This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International LicenseWe report the case of a subcutaneous abscess due to Nocardia spp. mimicking a spontaneous hematoma or an aneurysm of the temporal artery branch, in a giant cell arteritis patient treated with methylprednisolone and azathioprine. Ultrasonography, incision and drainage with cultures helped in the diagnosis.\n\nThis case highlights the importance of considering rare pathogens in immunosuppressed patients, besides the more frequent disease complications.\n\nnocardiosisgiant cell arteritissubcutaneous abscess\n==== Body\nIntroduction\nNocardiosis is an infection due to Nocardia aerobic actinomycete responsible for localized or disseminated infections. Nocardia species are ubiquitous environmental saprophytes, occurring in soil, organic matter and water. Human infection usually arises by inhalation or from direct inoculation of the skin or soft tissues. Nocardiosis is not common in clinical practice and most cases occur as an opportunistic infection in immunocompromised patients.\n\nGiant cell arteritis (GCA) is a systemic large-vessel vasculitis of the elderly that affects extracranial arteries, mainly temporal arteries, but also the aorta and peripheral arteries. Amongst the various serious systemic complications, the most dreaded is visual loss, due to ophthalmic artery involvement, and large dose corticosteroids are administered in the attempt to prevent it. GCA may co-exist with polymyalgia rheumatica, a more common inflammatory disease of the elderly that requires lower doses of prednisone [1].\n\nCase report\nA 74 years old patient, diagnosed one month prior with giant cells arteritis (GCA), treated with methylprednisolone and azathioprine, presented with a superficial, soft, painless mass on the right frontal scalp region, noticed by the patient to have grown slowly in the previous week. From the medical history we report pulmonary tuberculosis (treated in 1975), Lyme borreliosis treated with intravenous ceftriaxone in March 2013, followed by moderate Clostridium difficile infection. The laboratory tests revealed increased erythrocyte sedimentation rate (ESR=120 mm/hour) and C-reactive protein (CRP=2.05 mg/dl), hyper-potassemia (5.9 mEq/l) and hypo-sodemia (132 mEq/l).\n\nOne week before, physical examination had shown an enlarged painful left temporal artery and a previously absent right frontal scar, most probably a cutaneous superficial atrophy due to vasculitis (Figure 1a, b). Therefore, the new frontal mass suggested a hematoma from a vasculitis-injured vessel effraction, or a superficial arterial aneurysm. Ultrasonography, performed with an Esaote MyLab ™Five machine with a 10–13 MHz multifrequence linear transducer, showed an aspect compatible with an abscess (Figure 2). A puncture from the scalp collection reveled pus; a drainage tube was inserted for complete evacuation. The microscopic examination revealed Gram-positive long thin branching roads and culture on Colombia blood agar was indicative of Nocardia spp. with white chalky colonies after 3 days of incubation (Figure 3). Because direct inoculation of Nocardia was less probable (no skin lesion was visible and the patient did not recall any injury), disseminated infection was suspected. The cerebral MRI and abdominal CT did not find any abscesses. The pulmonary radiography detected left apical and subclavicular nodules recalling previous healed pulmonary tuberculosis, but also multiple bilateral subclavicular nodular opacities, the latter not present on the x-ray performed one month before, suggestive of possible tuberculosis reactivation or pulmonary nocardiosis. A bronchoscopy with bronchoalveolar aspiration showed the aspect of suppurative bronchitis; culture identified Acinetobacter calcoaceticus, interpreted as colonization and not as infection, as no pneumonia was detected on X-ray findings. Pulmonary CT scan showed the image of a subcarinal mediastinal mass with polycyclic shape, 6 cm in diameter, other mediastinal adenopathies and minimal bilateral pleural effusion. The transbronchial biopsy was not successful, while diagnostic thoracotomy could not be performed, due to the altered status of the patient.\n\nThe patient underwent therapy with intravenous imipenem-cilastatin 2g/day for 21 days and Amikacin 1g/day for 14 days for Nocardia infection, associated with tuberculostatic therapy (rifampicin, izoniazide, ethambutol and pyrazinamide). Tuberculostatic therapy was initiated due to the presence of radiologic subclavicular nodular opacities in a patient with immunosuppressive therapy and history of pulmonary tuberculosis and was stopped when cultures for Mycobacterium tuberculosis were reported as negative.\n\nThe scalp collection completely resolved after surgical drainage and antibiotic therapy. Therapy for nocardiosis was recommended after discharge with long term trimethoprim-sulfamethoxazole (TMP 10 mg/kg/day), justified by the immunocompromised status and immunosuppressive therapy. However, after 2 months the patient developed drug-induced myelosuppression and a severe and complicated recurrent Clostridium difficile infection that led to multiorgan dysfunction and exitus.\n\nDiscussion\nNocardia are ubiquitous, soil-borne organisms that are most commonly introduced into the body via inhalation or through a cut or abraded skin. In humans nocardiosis presents as pulmonary, systemic, cutaneous or central nervous system disease. It usually occurs in immunodepressed individuals suffering from diabetes, malignancies, HIV/AIDS, lung disorders, connective tissue disorders, chronic alcoholism, transplant patients, and patients on corticosteroid therapy [2].\n\nCutaneous nocardiosis is an uncommon infectious disease that presents as primary cutaneous infection or as a part of disseminated pulmonary nocardiosis.\n\nDue to the frontal localization of the subcutaneous abscess in our patient and the signs of active vasculitis, an arterial aneurysm or a hematoma from a vasculitis-injured vessel effraction were first suspected. Aneurysms involving the aorta or other vessels are found in 18% of GCA cases, particularly of the thoracic aorta [3]. However, in peripheral arteries GCA evolves rather with occlusions due to smooth, long segments of wall thickening [4].\n\nUltrasonography was useful for the differential diagnosis (Figure 2). In GCA, the arteries involved have a hypoechoic wall thickening (the hallo sign) [5]. Blood pulsations are seen in an enlarging aneurysm, while in pseudoaneurysms resulting from a vessel wall rupture contained by the adventitia or surrounding tissue, the turbulent forward and backward flow realize the yin-yang sign [6]. No link with the vessel was found in our case.\n\nIn abscesses, ultrasonography identifies spherical complex fluid collections, with irregular borders, and content ranging from anechoic to hyperechoic, depending on its age, sometimes with mass effect. The pus may be compressed with the transducer. Wall hyperemia and gas as acoustic shadowing or reverberation artifacts may be seen [7].\n\nSuccessful treatment of the subcutaneous abscess included surgical drainage and antibiotic treatment.\n\nImaging manifestations of pulmonary nocardiosis include irregular nodules (usually cavitating when large) and pleural effusions [8]. The X-ray findings are nonspecific and differential diagnosis with Mycobacterium tuberculosis infection was difficult in a patient with history of pulmonary tuberculosis, as culture time for Mycobacterium species is long. Regarding the Nocardia culture from bronchoalveolar aspiration, Nocardial colonies are easily obscured by more rapidly growing bacteria in specimens containing mixed flora (e.g., respiratory secretions) [9]. Though Acinetobacter calcoaceticus pneumonia is increasingly described in critically ill patients, the CT scan did not support the diagnosis of pneumonia and Acinetobacter calcoaceticus was interpreted as a colonizing bacteria. Nocardiosis may manifest on pulmonary CT as a solitary or multiple lung nodules of various sizes [10], not found on the pulmonary CT. The subcarinal mediastinal mass with polycyclic shape, absent two months earlier, was interpreted as a lymph node mass, although a tumour or ganglionary tuberculosis could not be completely ruled out, as the family did not approve the biopsy or post-mortem autopsy.\n\nNocardiosis occurs in immunocompromized hosts, but it was reported in only few GCA patients (Table I). Héron et al. (2006) reported a choroidal abscess due to Nocardia infection mimicking GCA disease-related ophthalmic manifestations [11]. Borget et al. (1992) reported a Nocardia deltoid abscess in a patient with GCA [12] and Sherber et al. (2006) reported an ulcerated skin lesion due to Nocardia infection in a patient with GCA, also on less than a month of immunosuppressive therapy [13]. To our knowledge, primary Nocardia subcutaneous abscess has not been previously reported associated to GCA, and its frontal localization was initially deceiving. It may be speculated that the abscess site could have been related to our patient’s local cutaneous ischemia, a recognized GCA complication associated with an increased mortality [14]. Interestingly, in a previous report, the temporal artery biopsy revealed an infectious Nocardial arteritis [11]. In our patient a further biopsy was not performed after the abscess finding and drainage.\n\nSteroid use is an independent risk factor for Nocardia infection, the risk being lowered by steroid-sparing therapy [15]. Moreover, Nocardia infections have been reported also in polymyalgia rheumatica, where lower corticosteroid doses are required [16]. The symptoms and laboratory may mimic a disease relapse or complication, leading to intensification of therapy.\n\nThis case emphasizes that in patients with giant cell arteritis rare immunosuppression-related infections have to be taken in account, besides the more frequent disease complications. The symptoms and laboratory analyses may suggest a disease relapse, leading to unnecessary intensification of immunosuppressive therapy. Ultrasonography may be helpful in these instances, differentiating an active giant cell arteritis disease from other associated complications.\n\nFigure 1a Left temporal artery enlargement with local tenderness.\n\nFigure 1b Right frontal scar, occurred spontaneous, likely due to vasculitis-related skin atrophy. There are also small areas of cutaneous necrosis.\n\nFigure 2 Hypoechogenyc heterogeneous lesion located in soft parts of the frontal region, extending dermo-epidermal and possible tendency to fistulization.\n\nFigure 3 Colonies of Nocardia species after 72 hours of growth on Colombia blood agar.\n\nTable I Nocardiosis in giant cell arteritis.\n\nReport\tObservations\tReferences\t\nPrimary deltoid abscess\tNocardia asteroides\t[12]\t\nLung abscess\tNocardia asteroides (coexisting with Cryptococcus neoformans)\t[17]\t\nGlabellar non-healing ulcer after inoculation\tNocardia spp.\t[13]\t\nOcular and systemic nocardiosis\tNocardia asteroides\t[11]\t\nEndogenous endophtalmitis\tNocardia farcinica\t[18]\n==== Refs\nReferences\n1 Salvarani C Pipitone N Versari A Hunder GG Clinical features of polymyalgia rheumatica and giant cell arteritis Nat Rev Rheumatol 2012 8 509 521 22825731 \n2 Minero MV Marín M Cercenado E Rabadán PM Bouza E Muñoz P Nocardiosis at the turn of the century Medicine (Baltimore) 2009 88 4 250 261 19593231 \n3 Nuenninghoff DM Hunder GG Christianson TJ McClelland RL Matteson EL Incidence and predictors of large-artery complications (aortic aneurysm, aortic dissection, and/or large artery stenosis) in patients with giant cell arteritis: a population-based study over 50 years Arthritis Rheum 2003 48 12 3522 3531 14674004 \n4 Kermani TA Warrington KJ Lower extremity vasculitis in polymyalgia rheumatica and giant cell arteritis Curr Opin Rheumatol 2011 23 1 38 42 21037479 \n5 Schmidt WA Natusch A Moller DE Vorpahl K Gromnica-Ihle E Involvement of peripheral arteries in giant cell arteritis: a color Doppler sonography study Clin Exp Rheumatol 2002 20 309 318 12102466 \n6 Weerakody Y D’Souza D False aneurysm Radiopedia.org rID: 1326. Available from: https://radiopaedia.org/articles/false-aneurysm \n7 Adhikari S Blaivas M Sonography first for subcutaneous abscess and cellulitis evaluation J Ultrasound Med 2012 31 10 1509 1512 23011612 \n8 Shariff M Gunasekaran J Pulmonary Nocardiosis: Review of Cases and an Update Can Respir J 2016 2016 7494202 10.1155/2016/7494202 27445562 \n9 Sorrell TC Mitchell DH Iredell JR Chen SC-A Nocardia species Mandell GL Bennett JE Dolin R Principles and Practice of Infectious Diseases, seventh edition Philadelphia Churchill Livingstone Elsevier 2010 3199 3208 \n10 Kanne JP Yandow DR Mohammed TL Meyer CA CT Findings of pulmonary nocardiosis AJR Am J Roentgenol 2011 197 W266 W272 21785052 \n11 Héron E Augustin P Cervera P Girmens JF Généreau T Lortholary O Systemic nocardiosis mimicking an ocular relapse of giant-cell arteritis Rheumatology (Oxford) 2006 45 5 641 643 16531438 \n12 Borget C Gepner P Piette AM Chapman A Primary Nocardia asteroides deltoid abscess in treated Horton disease Rev Rhum Mal Osteoartic 1992 59 2 149 151 1604228 \n13 Sherber NS Olivere JW Martins CR An 80-year-old man with a nonhealing glabellar lesion. Primary cutaneous nocardiosis Arch Pathol Lab Med 2006 130 10 e100 e101 17090207 \n14 Tsianakas A Ehrchen JM Presser D Fischer T Kruse-Loesler B Luger TA Scalp necrosis in giant cell arteritis: case report and review of the relevance of this cutaneous sign of large-vessel vasculitis J Am Acad Dermatol 2009 61 4 701 706 19577329 \n15 Arduino RC Johnson PC Miranda AG Nocardiosis in renal transplant recipients undergoing immunosuppression with cyclosporine Clin Infect Dis 1993 16 505 512 8513056 \n16 Cargill JS Boyd GJ Weightman NC Nocardia cyriacigeorgica: a case of endocarditis with disseminated soft-tissue infection J Med Microbiol 2010 59 Pt 2 224 230 19797466 \n17 Shafiq M Schoch PE Cunha BA Iliescu MD Nocardia asteroides and Cryptococcus neoformans lung abscess Am J Med 2000 109 1 70 71 10991741 \n18 Chen LY Kesen MR Ghafourian A Nguyen QD Eberhart CG Do DV Isolated endogenous Nocardia endophthalmitis after immunosuppression J Ophthalmic Inflamm Infect 2012 2 3 141 143 22278699\n\n",
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"keywords": "giant cell arteritis; nocardiosis; subcutaneous abscess",
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"title": "Cutaneous nocardiosis manifesting as a frontal mass in a patient with giant cell arteritis.",
"title_normalized": "cutaneous nocardiosis manifesting as a frontal mass in a patient with giant cell arteritis"
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"abstract": "Disseminated nocardiosis is a rare but growing concern in immunocompromised patients. Typical localizations include the lung, brain and/or soft tissues, but laboratory confirmation of nocardiosis usually requires sampling of infected organs by invasive procedures such as bronchoalveolar lavage or brain biopsy. We report a case of disseminated nocardiosis occurring in a hematopoietic stem-cell transplant recipient, with clinical lung and brain localizations. Examination of the thyroid gland was suggestive of a unilateral abscess. A culture of thyroid pus sampled by fine-needle aspiration was positive for Nocardia farcinica and therefore avoided a more invasive procedure. The patient recovered after a six-month antibiotic therapy without thyroid surgery. We reviewed other ten cases of thyroid nocardiosis published in the medical literature. Among the ten cases of disseminated nocardiosis established during the patient's lifetime including ours, six (60%) were asymptomatic and seven (70%) were confirmed by culture of the aspiration of thyroid pus. When disseminated nocardiosis is suspected, systematic examination for a thyroid abscess may help establish a microbiological diagnosis and prevent further invasive procedures.",
"affiliations": "AP-HP, Service de maladies infectieuses et tropicales, CHU Bicêtre, Le Kremlin-Bicêtre, France.;Département d'hématologie, Gustave Roussy, Villejuif, France.;AP-HP, Service de maladies infectieuses et tropicales, CHU Bicêtre, Le Kremlin-Bicêtre, France.;AP-HP, Service de maladies infectieuses et tropicales, CHU Bicêtre, Le Kremlin-Bicêtre, France.;AP-HP, Service de maladies infectieuses et tropicales, CHU Bicêtre, Le Kremlin-Bicêtre, France.;Gustave Roussy, service de microbiologie, Villejuif, France.;Département de médecine, Gustave Roussy, Villejuif, France.;AP-HP, Service de maladies infectieuses et tropicales, CHU Bicêtre, Le Kremlin-Bicêtre, France.",
"authors": "Esnault|Violaine|V|https://orcid.org/0000-0002-6960-6700;Wittnebel|Sebastian|S|;Pouillon|Mathias|M|;Collarino|Rocco|R|;Jauréguiberry|Stephane|S|;Chachaty|Elisabeth|E|;Gachot|Bertrand|B|;Wyplosz|Benjamin|B|https://orcid.org/0000-0002-9779-9044",
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"keywords": "hematopoietic stem cell transplantation; immunocompromised patients; infection; nocardia; thyroid",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D006801:Humans; D016867:Immunocompromised Host; D009615:Nocardia; D009617:Nocardia Infections; D013961:Thyroid Gland",
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"abstract": "FDG PET-CT is a useful imaging tool in the diagnosis and response assessment of neurolymphomatosis, especially in cases of otherwise unexplained neuropathy following conventional diagnostic work-up including lumbar puncture, CT, and MRI. The use of a novel PET reconstruction algorithm improves image quality and lesion detection through increased signal-to-noise ratio.",
"affiliations": "Department of Haematology Oxford University Hospitals NHS Foundation Trust Oxford UK.;Department of Haematology Buckinghamshire Healthcare NHS Trust Aylesbury UK.;Department of Nuclear Medicine Oxford University Hospitals NHS Foundation Trust Oxford UK.",
"authors": "Bruce|David|D|;Eagleton|Helen|H|;Subesinghe|Manil|M|0000-0002-5688-0153",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.734CCR3734Case ReportCase ReportsDiagnostic and response assessment FDG PET‐CT in neurolymphomatosis D. Bruce et al.Bruce David \n1\nEagleton Helen \n2\nSubesinghe Manil http://orcid.org/0000-0002-5688-0153manil.subesinghe@ouh.nhs.uk \n3\n1 Department of HaematologyOxford University Hospitals NHS Foundation TrustOxfordUK2 Department of HaematologyBuckinghamshire Healthcare NHS TrustAylesburyUK3 Department of Nuclear MedicineOxford University Hospitals NHS Foundation TrustOxfordUK* Correspondence\n\nManil Subesinghe, Department of Nuclear Medicine, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Old Road, Oxford OX3 7LE, UK. Tel: +44 1865 235733; Fax: +44 1865 235007; E‐mail: manil.subesinghe@ouh.nhs.uk\n28 10 2016 12 2016 4 12 10.1002/ccr3.2016.4.issue-121172 1174 24 11 2015 21 8 2016 06 10 2016 © 2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Key Clinical Message\n\nFDG PET‐CT is a useful imaging tool in the diagnosis and response assessment of neurolymphomatosis, especially in cases of otherwise unexplained neuropathy following conventional diagnostic work‐up including lumbar puncture, CT, and MRI. The use of a novel PET reconstruction algorithm improves image quality and lesion detection through increased signal‐to‐noise ratio.\n\nBayesian penalized likelihoodDLBCLimage reconstructionneurolymphomatosisPET‐CT source-schema-version-number2.0component-idccr3734cover-dateDecember 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.8 mode:remove_FC converted:01.12.2016\n==== Body\nA 66‐year‐old woman with stage IVB diffuse large B‐cell lymphoma (DLBCL) with bone marrow involvement but no other sites of extranodal disease, as confirmed on a contrast‐enhanced CT of the neck, chest, abdomen and pelvis and lumbar puncture, was treated to a complete response with six cycles of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), two additional rituximab infusions, and four cycles of intrathecal methotrexate for central nervous system prophylaxis. One month following completion of treatment, the patient developed a painful progressive sensorimotor neuropathy in both arms and legs. Biochemical tests including serum B12, folate, and thyroid function tests were normal. Myeloid‐associated glycoprotein antibody and paraneoplastic antibody assays including anti‐Hu, Yo, Ri, and Ma were negative. A repeat staging CT was normal as was a MRI of her brain and whole spine. CSF analysis showed no evidence of lymphoma and only a mildly elevated CSF protein of 0.52 g/L (normal range 0.15–0.45 g/L) with normal CSF glucose. A trial of high‐dose steroids had no effect. Nerve conduction studies showed severe multifocal sensory and motor axonal loss with lymphomatous nerve infiltration or paraneoplastic vasculitis as possible causes (rather than demyelination or vincristine‐related neuropathy).\n\nA baseline FDG PET‐CT scan prior to commencing chemotherapy (Fig. 1) was acquired using a three‐dimensional mode time‐of‐flight (ToF) Discovery 690 PET‐CT system (GE Healthcare) with PET images reconstructed using a novel Bayesian penalized likelihood PET reconstruction algorithm, an iterative technique recently introduced by GE Healthcare (Q.Clear, GE Healthcare, Milwaukee, WI, USA); the previous standard PET reconstruction was a ToF‐ordered subset expectation maximization (OSEM) with two iterations, 24 subsets, and a 6.4‐mm Gaussian filter (VPFX, GE Healthcare). PET‐CT imaging revealed extensive intensely FDG avid (peri)neural linear uptake along both arms (left > right) without corresponding structural abnormality, in addition to further linear FDG uptake along the left fifth intercostal nerve (Q.clear = SUVmax 20.3, ToF OSEM = SUVmax 8.3), both L3 nerves (left L3; Q.clear = SUVmax 28.5, ToF OSEM = SUVmax 16.0), and left sciatic nerve (Q.clear = SUVmax 13.6, ToF OSEM = SUVmax 5.4). There was new bulky intensely FDG avid nodal disease above and beneath the diaphragm. Overall appearances were consistent with widespread FDG avid neurolymphomatosis and recurrent nodal disease above and beneath the diaphragm.\n\nFigure 1 Three‐dimensional (3D) maximum intensity projection (MIP) PET image prior to commencing chemotherapy demonstrating extensive intensely FDG avid (peri)neural linear uptake most apparent along both arms (left > right), in addition to further linear FDG uptake along the left fifth intercostal nerve (black arrow), both L3 nerves (left L3; gray arrow), and left sciatic nerve (white arrow) with bulky intensely FDG avid nodal disease above and beneath the diaphragm.\n\nShe was commenced on salvage treatment with rituximab, ifosfamide, carboplatin, and etoposide (R‐ICE) chemotherapy. Response assessment FDG PET‐CT imaging after two cycles of chemotherapy (Fig. 2) revealed an excellent response to treatment with complete resolution of the widespread (peri)neural FDG uptake. There was some clinical improvement, with the patient being able to walk with assistance having been previously bed bound, but she continued to be troubled by neuropathic pain at the time of discharge.\n\nFigure 2 3D MIP PET image following two cycles of R‐ICE chemotherapy demonstrating complete resolution of the widespread (peri)neural FDG uptake.\n\nNeurolymphomatosis (NL) is defined as peripheral or cranial nerve, nerve root, or plexus infiltration by malignant lymphocytes, usually of B‐cell non‐Hodgkin's lymphoma origin 1; the most common subtype is DLBCL 1, 2. NL is a rare and potentially devastating manifestation of NHL that can occur at diagnosis or relapse; it should be considered in any patient with NHL presenting with unexplained neuropathy. Rarely T‐cell NHL 3 or acute leukemia 4 can give rise to NL. Presentation is variable and depends on the neural structures involved. A painful sensorimotor neuropathy is most common. However, pure motor, pure sensory, or any combination of mono or polyneuropathy has been described 1.\n\nFDG PET‐CT has proven efficacy in high‐grade lymphoma for the detection of FDG avid nodal and extranodal disease with superior sensitivity to MRI in the detection of NL 5, 6. Standard iterative techniques, for example, OSEM, are commonly used for reconstruction of PET data. Multiple iterations are performed with each iteration producing an image closer to the true image. However, the number of iterations is limited by the increasing level of noise associated with each iteration. The novel Bayesian penalized likelihood PET reconstruction algorithm is an iterative technique using a penalty function to act as a noise suppressor. This permits an increased number of iterations without an accompanying increase in noise, thereby resulting in improved image quality through increased signal‐to‐noise ratio and affording improved lesion detection particularly of small lesions (Fig. 3) when compared with standard reconstruction techniques (Fig. 3) 7, 8. FDG PET‐CT also permits accurate assessment of response to treatment, especially of extranodal disease. CSF analysis and bone marrow examination are often unhelpful in these circumstances, and if diagnostic uncertainty remains, FDG PET‐CT can help guide biopsy of potentially accessible affected nerves.\n\nFigure 3 Coronal PET images prior to chemotherapy, using a novel Bayesian penalized likelihood PET reconstruction algorithm (A) compared with the standard ToF OSEM reconstruction (B), demonstrating improved image quality through increased signal‐to‐noise ratio in a couple of sub‐cm right neck nodes, for example, superior node (Q.clear = SUVmax 6.8, ToF OSEM = SUVmax 2.7) and right axillary nerve (black arrows).\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\n1 \n\nGrisariu , S. \n, \nB. \nAvni \n, \nT. T. \nBatchelor \n, \nM. J. \nvan den Bent \n, \nF. \nBokstein \n, \nD. \nSchiff \n, et al. 2010 \nNeurolymphomatosis: an International Primary CNS Lymphoma Collaborative Group report . Blood \n115 :5005 –5011 .20368468 \n2 \n\nBaehring , J. M. \n, \nD. \nDamek \n, \nE. C. \nMartin \n, \nR. A. \nBetensky \n, and \nF. H. \nHockberg \n. 2003 \nNeurolymphomatosis . Neuro. Oncol. \n5 :104 –115 .12672282 \n3 \n\nMatano , S. \n, \nH. \nShirasaki \n, \nS. \nTerahata \n, \nK. \nNobata \n, and \nT. \nSugimoto .\n2006 \nThickening of multiple cranial nerves in a patient with extranodal peripheral T‐cell lymphoma . J. Neuroimaging \n16 :167 –169 .16629741 \n4 \n\nAregawi , D. G. \n, \nJ. H. \nSherman \n, \nM. G. \nDouvas \n, \nT. M. \nBurns \n, and \nD. \nSchiff .\n2008 \nNeuroleukemiosis: case report of leukemic nerve infiltration in acute lymphoblastic leukemia . Muscle Nerve \n38 :1196 –1200 .18642385 \n5 \n\nSalm , L. P. \n, \nB. \nVan der Hiel \n, and \nM. P. \nStokkel \n. 2012 \nIncreasing importance of 18F‐FDG PET in the diagnosis of neurolymphomatosis . Nucl. Med. Commun. \n33 :907 –916 .22714006 \n6 \n\nRosso , S. M. \n, \nH. G. \nde Bruin \n, \nK. L. \nWu \n, and \nM. J. \nvan den Bent .\n2006 \nDiagnosis of neurolymphomatosis with FDG PET . Neurology \n67 :722 –723 .16924037 \n7 \n\nTeoh , E. J. \n, \nD. R. \nMcGowan \n, \nR. E. \nMacpherson \n, \nK. M. \nBradley \n, and \nF. V. \nGleeson \n. 2015 \nPhantom and clinical evaluation of the Bayesian penalized likelihood reconstruction algorithm Q.Clear on an LYSO PET/CT system . J. Nucl. Med. \n56 :1447 –1452 .26159585 \n8 \n\nTeoh , E. J. \n, \nD. R. \nMcGowan \n, \nK. M. \nBradley \n, \nE. \nBelcher \n, \nE. \nBlack \n, and \nF. V. \nGleeson \n. 2016 \nNovel penalised likelihood reconstruction of PET in the assessment of histologically verified small pulmonary nodules . Eur. Radiol. \n26 :576 –584 .25991490\n\n",
"fulltext_license": "CC BY-NC-ND",
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"keywords": "Bayesian penalized likelihood; DLBCL; PET‐CT; image reconstruction; neurolymphomatosis",
"medline_ta": "Clin Case Rep",
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"title": "Diagnostic and response assessment FDG PET-CT in neurolymphomatosis.",
"title_normalized": "diagnostic and response assessment fdg pet ct in neurolymphomatosis"
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"abstract": "Osteonecrosis is a devastating complication of systemic steroid use. Prolonged steroid use produces a hyperlipidemic state in most patients and puts them at risk for osteoporosis and osteonecrosis. The fat content within the femoral head increases, resulting in increased intracortical pressure that may lead to sinusoidal collapse and osteonecrosis. Statins are lipid-clearing agents that dramatically reduce lipid levels in blood and tissues. Statins are widely used to prevent cardiovascular disease and have been shown to reduce the adverse effects of steroids on lipid metabolism. The purpose of this study was to determine whether the use of statin drugs affects later development of osteonecrosis in patients receiving steroids. The records of 284 patients who were taking statin drugs at the time they were started on high dose steroids were examined to determine whether osteonecrosis had developed. The patients remained on statin drugs during the entire time of steroid exposure. Magnetic resonance imaging scans were used to verify the osteonecrosis unless it was visible by radiograph. After an average of 7.5 years (minimum followup, 5 years), only three patients (1%) from the group had osteonecrosis develop. This 1% incidence is much less than the 3% to 20% incidence usually reported for patients receiving high-dose steroids. Statins may offer some protection against having osteonecrosis develop when steroid treatment is necessary.",
"affiliations": "Department of Orthopaedic Surgery, University of Washington, Seattle 98104, USA.",
"authors": "Pritchett|J W|JW|",
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"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005271:Femur Head Necrosis; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006949:Hyperlipidemias; D000960:Hypolipidemic Agents; D008297:Male; D008875:Middle Aged; D010020:Osteonecrosis; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D012680:Sensitivity and Specificity",
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"title": "Statin therapy decreases the risk of osteonecrosis in patients receiving steroids.",
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"abstract": "Calcium channel blockers (CCBs) are a potent class of medications that exert its action by blocking 'L-type' calcium channels. CCB overdose can be fatal even with appropriate and aggressive therapy. Death ensues from heart block, myocardial suppression, vasoplegia, and shock. Early use of methylene blue (MB) might provide additional means to improve outcomes.\nA 25-year-old female presented after an attempted suicide. The patient ingested a substantial amount of diltiazem, promethazine, and trazodone. Seven hours following the ingestion, she became profoundly vasoplegic and hypotensive. Despite guideline-based therapy and high doses of vasopressors, she suffered from worsening lactic acidosis and multiorgan failure. Administration of an intravenous bolus dose of MB resulted in a rapid and sustained improvement of vasoplegia, and the patient subsequently went on to make a complete recovery.\nIn addition to calcium channel blockade, CCBs cause vascular smooth muscle relaxation by the production of nitric oxide (NO). In cases of overdose, NO production can be significant. MB is a safe and inexpensive medication with the potential to reverse NO-mediated vasoplegia that is responsible for CCB induced shock state. In parts of the world where access to advanced medical care is not readily available, early use of MB might have a significant role in the management of CCB overdose.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, Ozarks Medical Center, West Plains, MO, USA.;Division of Critical Care Nursing, Albany Medical College, Albany, NY, USA.;Division of Pulmonary and Critical Care Medicine, Albany Medical College, Albany, NY, USA.",
"authors": "Saha|Biplab K|BK|;Bonnier|Alyssa|A|;Chong|Woon|W|",
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"fulltext": "\n==== Front\nAfr J Emerg Med\nAfr J Emerg Med\nAfrican Journal of Emergency Medicine\n2211-419X 2211-4203 African Federation for Emergency Medicine \n\nS2211-419X(20)30067-7\n10.1016/j.afjem.2020.06.014\nCase Report\nRapid reversal of vasoplegia with methylene blue in calcium channel blocker poisoning\nSaha Biplab K. spanophiliac@yahoo.coma⁎ Bonnier Alyssa b Chong Woon c a Division of Pulmonary and Critical Care Medicine, Ozarks Medical Center, West Plains, MO, USA\nb Division of Critical Care Nursing, Albany Medical College, Albany, NY, USA\nc Division of Pulmonary and Critical Care Medicine, Albany Medical College, Albany, NY, USA\n⁎ Corresponding author. spanophiliac@yahoo.com\n10 7 2020 \n12 2020 \n10 7 2020 \n10 4 284 287\n30 4 2020 17 6 2020 30 6 2020 © 2020 African Federation for Emergency Medicine. Publishing services provided by Elsevier.2020African Federation for Emergency MedicineThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nCalcium channel blockers (CCBs) are a potent class of medications that exert its action by blocking ‘L-type’ calcium channels. CCB overdose can be fatal even with appropriate and aggressive therapy. Death ensues from heart block, myocardial suppression, vasoplegia, and shock. Early use of methylene blue (MB) might provide additional means to improve outcomes.\n\nCase presentation\nA 25-year-old female presented after an attempted suicide. The patient ingested a substantial amount of diltiazem, promethazine, and trazodone. Seven hours following the ingestion, she became profoundly vasoplegic and hypotensive. Despite guideline-based therapy and high doses of vasopressors, she suffered from worsening lactic acidosis and multiorgan failure. Administration of an intravenous bolus dose of MB resulted in a rapid and sustained improvement of vasoplegia, and the patient subsequently went on to make a complete recovery.\n\nDiscussion\nIn addition to calcium channel blockade, CCBs cause vascular smooth muscle relaxation by the production of nitric oxide (NO). In cases of overdose, NO production can be significant. MB is a safe and inexpensive medication with the potential to reverse NO-mediated vasoplegia that is responsible for CCB induced shock state. In parts of the world where access to advanced medical care is not readily available, early use of MB might have a significant role in the management of CCB overdose.\n\nKeywords\nCalcium channel blockerOverdoseVasoplegiaMethylene blueReversal\n==== Body\nAfrican relevance\n• Methylene blue is an inexpensive, safe, and widely available medication that can help in the reversal of NO-mediated vasoplegia from calcium channel blocker overdose.\n\n• Methylene blue might have a significant role in parts of the world where access to advanced life support might not be readily available.\n\n• Methylene blue remains stable in aqueous solution indefinitely, even when exposed to sunlight. This property makes methylene blue extremely cost-effective.\n\n\n\nIntroduction\nCalcium channel blockers (CCBs) are commonly used as antihypertensive, antianginal and antiarrhythmic medications. They have been used in clinical practice since the 1960s, and unfortunately, intentional or accidental overdose is not rare. Based on their molecular structure, CCBs are divided into two groups, 1) Dihydropyridine (DHP) and 2) Non dihydropyridine (NDP). DHP CCBs include nifedipine, amlodipine, nimodipine and felodipine among others. NDP group consists of verapamil; a phenylalkylamine, and diltiazem; a benzothiazepine. CCBs exert their action by blocking ‘L type’ calcium channel. DHPs primarily cause vasodilation and reduced peripheral vascular resistance, whereas NDPs are associated with negative chronotropic, inotropic and dromotropic effects. When ingested in massive doses, the tissue selectivity of the CCBs might be lost. Profound vasoplegic shock in the absence of bradyarrhythmia from NDP CCBs is rare [1]. We present a case of diltiazem overdose induced vasoplegic shock in the absence of bradyarrhythmia and successful treatment of the patient with methylene blue (MB).\n\nCase presentation\nA 25-year-old female was brought to the hospital following an attempted suicide. She reported ingesting ninety sustained release tablets of diltiazem180 mg, a total of 16.2 g (186 mg/kg), trazodone (3 g, 35 mg/kg), and promethazine (1.5 g, 17 mg/kg) 1 h before presenting to the ER. Her past medical history was notable for supraventricular tachycardia requiring cardiac ablation therapy and severe depression. Her vital signs on arrival were, blood pressure-136/66 mmHg, pulse-116 beats per minute, temperature-36.1 °C, respiratory rate-21 breaths per minute and oxygen saturation of 96% on room air. Physical examination revealed a drowsy but arousable woman with tachycardia. Within a period of thirty minutes, her mental status worsened rapidly. The patient underwent rapid sequence intubation with 20 mg of etomidate and 100 mg of succinylcholine. Optimal sedation post-intubation was achieved with propofol and fentanyl infusion. Blood work was unremarkable (shown in annexure). Urine toxicologic screening and toxic alcohol panel were negative. EKG showed sinus tachycardia with prolonged QTc (Fig. 1).Fig. 1 EKG showing sinus tachycardia and prolonged QTc.\n\nFig. 1\n\nTherapy with activated charcoal and whole bowel irrigation was initiated. An echocardiogram demonstrated normal ejection fraction (Fig. 2). As the patient ingested extended-release preparation of diltiazem, it was thought to be too early to see any effect from the CCB overdose. The encephalopathy and tachycardia were attributed to the promethazine and trazodone overdose. The patient was emergently brought to the ICU with the expectation of worsening hemodynamic status.Fig. 2 Echocardiogram with parasternal long axis (A) and apical four chamber (B) views demonstrated normal right and left ventricular architecture, wall thickness and function.\n\nFig. 2\n\nSeven hours post overdose, she developed hypotension that quickly became refractory to multiple pressors. She received treatment with intravenous calcium gluconate, glucagon, and high dose insulin. Incrementing doses of vasopressors (phenylephrine and norepinephrine) and low dose vasopressin were simultaneously administered to maintain acceptable hemodynamic parameters (dosing regimen is shown in Table 1).Table 1 Admission electrocardiogram.\n\nTable 1Medication\tDose used\t\nCalcium gluconate (10%)\tBolus: 30 ml intravenous over 10 min × 3 (20 min apart), followed by\nInfusion: 1 ml/kg/h\t\nGlucagon\tBolus: 5 mg intravenous, followed by\nInfusion: 5 mg/h\t\nHigh dose regular insulin\tBolus: 1 unit/kg intravenous\nInfusion: initiated at 0.5 units/kg/h, titrated up to 5 units/kg/h\nDextrose (10%) infusion and dextrose (50%) intravenous push to maintain blood glucose >150 mg/dL\nPotassium chloride (KCl) infusion to maintain serum potassium > 3 meq/L\t\nNorepinephrine\tInfusion: initiated at 2 mcg/min and was titrated up to 180 mcg/min\t\nPhenylephrine\tInfusion: initiated at 20 mcg/min and was titrated up to 180 mcg/min\t\nVasopressin\tInfusion: 0.03 units/min\t\nMethylene blue\tBolus: 2 mg/kg intravenous over 30 min\nInfusion: none\t\nMedication dosing regimen.\n\n\n\nThe patient, however, suffered from worsening lactic acidosis and multiorgan dysfunction syndrome. Intravenous MB bolus (2 mg/kg over 30 min) was administered as the last resort before initiating veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Following the administration of MB, the patient experienced rapid and sustained improvement in her hemodynamics as well as a reduction of the vasopressor requirement by more than 75% (Fig. 3). Thirty-six hours post overdose, the patient required minimal pressor support and went on to make a full recovery with supportive therapy.Fig. 3 Trend in hemodynamic parameters and lactic acid following diltiazem overdose and interventions. There was a significant reduction in pressor requirements (both norepinephrine and phenylephrine) following the administration of intravenous bolus dose of methylene blue (red arrow). The maximum vasoconstrictor effect lasted about 4 h. The vasopressor requirements went up subsequently but to a much lesser extent. SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)\n\nFig. 3\n\nDiscussion\nWe have reported a case of severe vasoplegic shock from diltiazem overdose that was rapidly and almost entirely reversed with MB. A cause and effect is established by the observed temporal relationship between the administration of MB and reduction of pressor requirements as well as the necessity to up titrate vasopressors after 4 h, which would be the expected duration of peak effect following a bolus dose of MB. Amlodipine was the most common DHP CCB that caused vasoplegic shock in the previously reported cases where MB was used as rescue therapy. In contrast, our patient suffered from profound vasoplegia with an NDP CCB in the absence of any bradyarrhythmia. We believe that the tachycardia observed in this patient stemmed from the co-ingestion of promethazine and trazodone, medications known to have anticholinergic and serotonergic effects, respectively. The other possibility could be compensatory tachycardia in the setting of profound vasodilation.\n\nA diagnosis of CCB poisoning can usually be attained by history alone. Identification of the correct formulation (immediate release versus sustained release) and quantification of the ingested medication is important. An extensive effort should be made to find potential evidence suggestive of other prescription or nonprescription substance abuse. The onset of symptoms is variable based on the medication formulation. Sustained release preparation of diltiazem takes 6-11 h to reach its peak action [2]. Patients usually suffer from hypotension, bradycardia, heart block, vasodilatory shock, and multiorgan failure. Cardiogenic and sometimes non-cardiogenic pulmonary edema secondary to pulmonary arterial vasodilation can result in respiratory failure. Complete atrioventricular block refractory to chronotropic agents or intravenous pacing can ensue. Laboratory data is usually normal when obtained early, except hyperglycemia which may develop due to calcium channel blockade in pancreatic islet cells and relative hypoinsulinemia.\n\nThe treatment of CCB poisoning starts with the administration of activated charcoal and bowel decontamination in a time-dependent fashion. Intravenous fluid is used for volume expansion in patients with hypotension. Intravenous calcium is used in an attempt to overcome competitive antagonism [3]. Intravenous glucagon has been used to reverse both bradycardia and hypotension from CCB poisoning [4]. Vasopressors and ionotropic agents are used as necessary, with norepinephrine being the preferred agent. The norepinephrine requirements in CCB overdose might be higher compared to septic shock. Hyperinsulinemia-euglycemia therapy, which involves the use of large doses of IV insulin therapy (1–10 unit/kg), and glucose to prevent hypoglycemia, have been shown to be beneficial and safe [5]. Hyperinsulinemia-euglycemia therapy has been recommended as a single therapy when there is evidence of myocardial depression or in combination with vasopressors and intravenous calcium, even in the absence of myocardial dysfunction. There are also cases of successful use of IV lipid emulsion. A guideline based on expert opinion recommends the use of lipid emulsion in cases of refractory shock or cardiac arrest [6]. It is important to emphasize that no randomized control trial has prospectively evaluated these interventions, and most data come from case series, observational, and small animal studies. The level of evidence for these recommendations is fair to poor [6].\n\nMB is a novel therapy for CCB overdose. MB does not affect the calcium channels or bypass it to increase intracellular cyclic adenosine mono phosphate (cAMP), rather, represents a clinical approach directed towards one of the underlying pathobiologies of vasoplegia in CCB overdose. Successful therapy with rapid improvement of hemodynamic status has been reported in a few cases [7]. CCBs upregulate endothelial nitric oxide synthase activity (eNOS) and increase the production of nitric oxide (NO) [[8], [9]]. Thus, a significant quantity of NO production is expected with massive CCB overdose. This NO activates cytosolic guanylate cyclase (GC) and results in the generation of cyclic guanosine monophosphate (cGMP) that culminates in smooth muscle relaxation and vasoplegia. MB is a potent inhibitor of GC; it prevents the generation of cGMP and causes vasoconstriction [9]. MB also improves catecholamine sensitivity. MB has been effective in all shock states that are mediated by NO overproduction, e.g., septic, anaphylactic and circulatory shock following coronary artery bypass graft surgery [10].\n\nThe recently published expert opinion did not recommend the use of MB for CCB overdose. This is likely due to the scarcity of definitive evidence, as only a few case reports exist in the literature where MB was utilized in CCB overdose refractory to traditional therapy [6]. We postulate that in cases of vasoplegic shock from CCB poisoning, it would be beneficial to use MB early rather than using it as a last resort. It addition, MB is inexpensive, safe and associated with rare side effects [10]. A bolus dose of MB followed by prolonged low dose infusion has proven to be safe in a patient with CCB overdose [11]. Minimal toxicity occurs when MB is used at low doses. The common and expected side effect is the blue discoloration of body fluids, and sometimes the skin. Methemoglobinemia is insignificant, even with a cumulative dose up to 7 mg/kg. The other potential side effects include hemolytic anemia (especially with glucose 6-phosphate dehydrogenase deficiency), coronary vasoconstriction, cardiac arrhythmia, serotonin syndrome and anaphylaxis [10]. These more serious side effects are uncommon when the medication is used cautiously and judiciously. A false reading on pulse oximetry may also occur [12].\n\nCCB poisoning can be fatal despite aggressive and appropriate therapy. Vasoplegic shock and complete heart block are terminal events that result in circulatory failure. Vasoplegia in CCB overdose is usually managed by high dose of vasopressor therapy. As NO precipitates profound vasodilatation in CCB poisoning, we believe that early use of MB will likely result in a reduction of vasopressor requirement and minimize overall complications. MB is easily available, inexpensive, and has a long history of being safe. In parts of the world where access to advanced medical care is not readily available, MB might have a significant role in the management of CCB overdose. Prospective studies are necessary to establish the utility of MB in CCB overdose definitively.\n\nDissemination of results\nResults from this report were shared with the house staff members of emergency medicine, internal medicine, and pulmonary and critical care medicine at the data collection site through formal presentation.\n\nAuthors' contribution\nAuthors' contributed as follow to the conception or design of the work; the acquisition, analysis, or interpretation of data for the work; and drafting the work or revising it critically for important intellectual content. BKS contributed 65%; AB 25%; and WC contributed 10%. All authors approved the version to be published and agreed to be accountable for all aspects of the work.\n\nDeclaration of competing interest\nThe authors declared no conflict of interest.\n\nAppendix A Supplementary data\nSupplementary material\n\nImage 1 \n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.afjem.2020.06.014.\n==== Refs\nReferences\n1 Hofer C.A. Smith J.K. Tenholder M.F. Verapamil intoxication: a literature review of overdoses and discussion of therapeutic options Am J Med 95 4 1993 431 438 Oct 8213877 \n2 Abernethy D.R. Schwartz J.B. Calcium-antagonist drugs N Engl J Med 341 19 1999 1447 1457 Nov 4 10547409 \n3 Hung Y.-M. Olson K.R. Acute amlodipine overdose treated by high dose intravenous calcium in a patient with severe renal insufficiency Clin Toxicol Phila Pa 45 3 2007 301 303 \n4 Mahr N.C. Valdes A. Lamas G. Use of glucagon for acute intravenous diltiazem toxicity Am J Cardiol 79 11 1997 1570 1571 Jun 1 9185662 \n5 Greene S.L. Gawarammana I. Wood D.M. Jones A.L. Dargan P.I. Relative safety of hyperinsulinaemia/euglycaemia therapy in the management of calcium channel blocker overdose: a prospective observational study Intensive Care Med 33 11 2007 2019 2024 Nov 17622512 \n6 St-Onge M. Anseeuw K. Cantrell F.L. Gilchrist I.C. Hantson P. Bailey B. Experts consensus recommendations for the management of calcium channel blocker poisoning in adults Crit Care Med 45 3 2017 e306 e315 Mar 27749343 \n7 Ahmed S. Barnes S. Hemodynamic improvement using methylene blue after calcium channel blocker overdose World J Emerg Med 10 1 2019 55 58 30598720 \n8 Ding Y. Vaziri N.D. Calcium channel blockade enhances nitric oxide synthase expression by cultured endothelial cells Hypertension 32 4 1998 718 723 Oct 9774369 \n9 Fan L. Yang Q. Xiao X.-Q. Grove K.L. Huang Y. Chen Z.-W. Dual actions of cilnidipine in human internal thoracic artery: inhibition of calcium channels and enhancement of endothelial nitric oxide synthase J Thorac Cardiovasc Surg 141 4 2011 1063 1069 Apr 20599230 \n10 Ginimuge P.R. Jyothi S.D. Methylene blue: revisited J Anaesthesiol Clin Pharmacol 26 4 2010 517 520 21547182 \n11 Aggarwal N. Kupfer Y. Seneviratne C. Tessler S. Methylene blue reverses recalcitrant shock in β-blocker and calcium channel blocker overdose Case Reports 2013 2013 Jan 18. bcr2012007402 \n12 Clifton J. Leikin J.B. Methylene blue Am J Ther 10 4 2003 289 291 Aug 12845393\n\n",
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"issue": "10(4)",
"journal": "African journal of emergency medicine : Revue africaine de la medecine d'urgence",
"keywords": "Calcium channel blocker; Methylene blue; Overdose; Reversal; Vasoplegia",
"medline_ta": "Afr J Emerg Med",
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"title": "Rapid reversal of vasoplegia with methylene blue in calcium channel blocker poisoning.",
"title_normalized": "rapid reversal of vasoplegia with methylene blue in calcium channel blocker poisoning"
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"abstract": "Thrombotic thrombocytopenic purpura (TTP) is a rare, serious, life-threatening disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and hypercoagulability. The etiology is a deficiency of ADAMTS13 which is usually caused by acquired antibodies. Plasma exchange and steroids is the standard of care in the treatment of TTP. However, there are refractory cases of TTP which require further management. Rituximab appears to be a safe and effective therapy for refractory and relapsing TTP. Here we report a challenging case of TTP that responded to treatment with rituximab twice weekly. According to our knowledge, rituximab twice weekly has never been used for TTP before.",
"affiliations": "Department of Medical Education, Hamad Medical Corporation, Doha, Qatar.;Department of Medical Education, Hamad Medical Corporation, Doha, Qatar.;Department of Medical Education, Hamad Medical Corporation, Doha, Qatar.;Department of Medical Education, Hamad Medical Corporation, Doha, Qatar.;Department of Medical Education, Hamad Medical Corporation, Doha, Qatar.;National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.;National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.;National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.;National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.;National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.",
"authors": "Azrieh|Bahjat|B|;Alsaud|Arwa|A|;Obeidat|Khaldun|K|;Ashour|Amr|A|;Elebbi|Seham|S|;Mohamed|Shehab F|SF|;Abdelaty|Mohamed Adel|MA|;Akkari|Abdelraouf|A|;Elbuzidi|Abdurrahman Ali|AA|;Yassin|Mohamed A|MA|",
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"doi": "10.1159/000505236",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1662-6575",
"issue": "13(1)",
"journal": "Case reports in oncology",
"keywords": "Platelet disorder; Refractory disease; Relapse; Rituximab; Thrombocytopenia; Thrombotic thrombocytopenic purpura",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "153-157",
"pmc": null,
"pmid": "32231537",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "30808221;9886798;15774620;12033285;24523598;11217814;31588978;26052230",
"title": "Rituximab Twice Weekly for Refractory Thrombotic Thrombocytopenic Purpura in a Critically Ill Patient with Acute Respiratory Distress Syndrome.",
"title_normalized": "rituximab twice weekly for refractory thrombotic thrombocytopenic purpura in a critically ill patient with acute respiratory distress syndrome"
} | [
{
"companynumb": "QA-ROCHE-2580745",
"fulfillexpeditecriteria": "1",
"occurcountry": "QA",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"d... |
{
"abstract": "Cetuximab (Erbitux) is a targeted therapy that used to treat metastatic colorectal cancer. It is classified as a \"monoclonal antibody\" and \"signal transduction inhibitor\" by binding to epidermal growth factor receptors (EGFR). We report 6 patients who responded well to cetuximab out of 8 patients with recurrent/advanced colorectal cancer who have received the drug at our hospital since November 2008. Four patients were men and 2 were women, with their ages ranging from 48 to 77 years. The primary cancers were located in the rectum (n=1), sigmoid colon (n=4), and ascending colon (n=1). Performance status (PS) was 0-1. These patients were treated with cetuximab as second-line (n=1), third-line (n=3), fifth-line (n=1), or seventh-line (n=1) therapy. Three patients received cetuximab monotherapy, while the other 3 were given CPT-11 (150 mg/m2, every 2 weeks) as concomitant therapy. Among the 3 patients receiving combination therapy, 2 patients had already received treatment with FOLFIRI. Even in the cetuximab monotherapy group, a partial response (PR) was observed in 2 patients, demonstrating a strong cytoreductive effect. Tumor markers also showed large decreases, with the percent decrease at 1 month being 31.7% and 60.8% in the monotherapy and combination therapy groups, respectively, while it was respectively 14.1% and 29.5% at 2 months. The mean progression-free survival (PFS) time and the time to treatment failure (TTF) were respectively 3.0 months and 4.5 months in the monotherapy group versus 7.3 months and 9.3 months in the combination therapy group. Acneiform rash and paronychia occurred in all 6 patients.",
"affiliations": "Dept. of Surgery, Veritas Hospital.",
"authors": "Katsumoto|Yoshihiro|Y|;Aritake|Noriko|N|;Endoh|Akira|A|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "37(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D000068818:Cetuximab; D015179:Colorectal Neoplasms; D005260:Female; D005472:Fluorouracil; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D012004:Rectal Neoplasms; D012811:Sigmoid Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2523-5",
"pmc": null,
"pmid": "21224627",
"pubdate": "2010-11",
"publication_types": "D002363:Case Reports; D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "The efficacy of cetuximab for metastatic colorectal cancer.",
"title_normalized": "the efficacy of cetuximab for metastatic colorectal cancer"
} | [
{
"companynumb": "JP-FRESENIUS KABI-FK201601845",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "CETUXIMAB"
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{
"abstract": "Heterotopic liver tissue in the umbilical cord is rare, and the outcome is quite unpredictable based on the few reported cases. We present a case of heterotopic liver nodule in the umbilical cord of a midtrimester fetus who died in utero. Although such association has only been reported once, heterotopic nodular tissue in the umbilical cord must be regarded as a potential cause of fetal demise by a mechanism analogous to the more common umbilical cord abnormalities resulting in umbilical vessel compromise.",
"affiliations": "Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.;Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.;Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.",
"authors": "Carreon|Chrystalle Katte|CK|;Putra|Juan|J|;Vargas|Sara O|SO|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1093526621993330",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1093-5266",
"issue": "24(3)",
"journal": "Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society",
"keywords": "ectopic liver; heterotopia; intrauterine fetal demise; single umbilical artery; umbilical cord; umbilical cord mass",
"medline_ta": "Pediatr Dev Pathol",
"mesh_terms": "D002828:Choristoma; D005260:Female; D005313:Fetal Death; D006801:Humans; D008099:Liver; D011247:Pregnancy; D058529:Single Umbilical Artery; D014470:Umbilical Cord",
"nlm_unique_id": "9809673",
"other_id": null,
"pages": "241-245",
"pmc": null,
"pmid": "33593145",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Heterotopic Liver Nodule Compressing a Two-Vessel Umbilical Cord: An Unusual Cause of Intrauterine Fetal Demise.",
"title_normalized": "heterotopic liver nodule compressing a two vessel umbilical cord an unusual cause of intrauterine fetal demise"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-US2021GSK125645",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RANITIDINE HYDROCHLORIDE"
},
"drugad... |
{
"abstract": "Carbapenemases-producing Enterobacteriaceae (CPE) are a worldwide public health emergency. In Mexico, reports of CPE are limited, particularly in the pediatric population. Here, we describe the clinical, epidemiological, and molecular characteristics of seven consecutive cases in a third-level pediatric hospital in Mexico City over a four-month period during 2016.\n\n\n\nThe Enterobacteriaceae identified were three Escherichia coli strains (producing OXA-232, NDM-1 and KPC-2), two Klebsiella pneumoniae strains (producing KPC-2 and NDM-1), one Klebsiella oxytoca strain producing OXA-48 and one Enterobacter cloacae strain producing NDM-1. The majority of patients had underlying disesases, three were immunocompromised, and three had infections involved the skin and soft tissues. Half patients died as a result of CPE infection.\n\n\n\nThis study represents the first report of E. coli ST131-O25b clone producing NDM-1 in Latin America. In addition, this study is the first finding of K. oxytoca producing OXA-48 and E. coli producing OXA-232 in Mexican pediatric patients.",
"affiliations": "Molecular Microbiology Laboratory, Instituto Nacional de Pediatría, Insurgentes Sur 3700-C, Insurgentes Cuicuilco, ZC, 04530, Coyoacán Mexico City, Mexico.;Molecular Microbiology Laboratory, Instituto Nacional de Pediatría, Insurgentes Sur 3700-C, Insurgentes Cuicuilco, ZC, 04530, Coyoacán Mexico City, Mexico.;Pediatric Infectious Disease Department, Instituto Nacional de Pediatria, Mexico City, Mexico.;Clinical Bacteriology Laboratory, Instituto Nacional de Pediatria, Mexico City, Mexico.;Molecular Microbiology Laboratory, Instituto Nacional de Pediatría, Insurgentes Sur 3700-C, Insurgentes Cuicuilco, ZC, 04530, Coyoacán Mexico City, Mexico. agustin.decolsa@infecto.mx.",
"authors": "Aquino-Andrade|Alejandra|A|;Merida-Vieyra|Jocelin|J|;Arias de la Garza|Eduardo|E|;Arzate-Barbosa|Patricia|P|;De Colsa Ranero|Agustín|A|0000-0001-6323-6668",
"chemical_list": "C491478:beta-lactamase KPC-2; D001618:beta-Lactamases; C547585:beta-lactamase KPC-2, Klebsiella pneumoniae; C552864:beta-lactamase NDM-1; C108449:oxacillinase",
"country": "England",
"delete": false,
"doi": "10.1186/s12866-018-1166-z",
"fulltext": "\n==== Front\nBMC MicrobiolBMC MicrobiolBMC Microbiology1471-2180BioMed Central London 116610.1186/s12866-018-1166-zResearch ArticleCarbapenemase-producing Enterobacteriaceae in Mexico: report of seven non-clonal cases in a pediatric hospital Aquino-Andrade Alejandra alejandra.aquino@infecto.mx 1Merida-Vieyra Jocelin jmerida18@yahoo.com.mx 1Arias de la Garza Eduardo lalo_arias@hotmail.com 2Arzate-Barbosa Patricia patyarzateinp@hotmail.com 3http://orcid.org/0000-0001-6323-6668De Colsa Ranero Agustín (52-55) 1084-0900agustin.decolsa@infecto.mx 121 0000 0004 1773 4473grid.419216.9Molecular Microbiology Laboratory, Instituto Nacional de Pediatría, Insurgentes Sur 3700-C, Insurgentes Cuicuilco, ZC, 04530 Coyoacán Mexico City, Mexico 2 0000 0004 1773 4473grid.419216.9Pediatric Infectious Disease Department, Instituto Nacional de Pediatria, Mexico City, Mexico 3 0000 0004 1773 4473grid.419216.9Clinical Bacteriology Laboratory, Instituto Nacional de Pediatria, Mexico City, Mexico 19 4 2018 19 4 2018 2018 18 3821 7 2017 15 3 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nCarbapenemases-producing Enterobacteriaceae (CPE) are a worldwide public health emergency. In Mexico, reports of CPE are limited, particularly in the pediatric population. Here, we describe the clinical, epidemiological, and molecular characteristics of seven consecutive cases in a third-level pediatric hospital in Mexico City over a four-month period during 2016.\n\nResults\nThe Enterobacteriaceae identified were three Escherichia coli strains (producing OXA-232, NDM-1 and KPC-2), two Klebsiella pneumoniae strains (producing KPC-2 and NDM-1), one Klebsiella oxytoca strain producing OXA-48 and one Enterobacter cloacae strain producing NDM-1. The majority of patients had underlying disesases, three were immunocompromised, and three had infections involved the skin and soft tissues. Half patients died as a result of CPE infection.\n\nConclusions\nThis study represents the first report of E. coli ST131-O25b clone producing NDM-1 in Latin America. In addition, this study is the first finding of K. oxytoca producing OXA-48 and E. coli producing OXA-232 in Mexican pediatric patients.\n\nKeywords\nCarbapenemase-producing EnterobacteriaceaePediatricsMexicoNDM-1KPC-2OXA-48OXA-232http://dx.doi.org/10.13039/501100003141Consejo Nacional de Ciencia y Tecnología181041issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nCurrently, antimicrobial resistance is considered a global public health problem of highest priority, and the emergence of CPE is increasing. This situation is especially alarming due to the ease of dispersion of these resistance mechanisms, the difficulty in choosing adequate antimicrobial therapy, and the increase in mortality and hospital stay lengths caused by infections with these pathogens [1]. The mortality of patients infected with CPE varies from 26% to 44% [2] and can reach as high as 85% in patients with CPE bloodstream infections [3].\n\nCarbapenem resistance in Enterobacteriaceae is largely mediated by the presence of enzymes known as carbapenemases, which have the capacity to inactivate beta-lactam antibiotics, including third- and fourth-generation cephalosporins and carbapenems. The most common carbapenemases in Enterobacteriaceae are the VIM, IMP, KPC, NDM and OXA types [4].\n\nThe frequency of CPE isolation varies among regions of the world. In the U.S., the CPE frequency from 1999 to 2012 was 0.08%, and species of Enterobacter were the most common isolates (0.57%) [5]. The Antimicrobial Surveillance Program SENTRY, carried out in 18 European countries from 2010 to 2013, evaluated 14,286 Enterobacteriaceae isolates and found that 2% were CPE, with a frequency varying from 0.1% (Ireland) to 17.3% (Poland). The most common CPE species were K. pneumoniae (86.4%) and E. cloacae (7.9%), and the most frequent carbapenemases found in this study were KPC 2/3 (85.4%), VIM (12.5%), and IMP-19 (2.1%) [6]. The equivalent program in Latin America, which included 11 countries during 2011–2014, revealed that 4.3% of isolates of Enterobacteriaceae were CPE, with the highest frequencies reported in Brazil (9%) and Argentina (6.3%). In Mexico, the reported frequencies of CPE were 0.7% [7].\n\nIn the National Institute of Pediatrics (INP) we performed a retrospective analysis of Enterobacteriaceae isolates collected during February 2013–January 2015, based on antimicrobial susceptibility testing and molecular tests, and we only identified four E. cloacae isolates producing VIM-2.\n\nIn April 2016, the Pediatric Infectious Diseases Department detected a CPE in a patient with sepsis and neutropenic colitis. In the next months, six additional CPE were reported in the INP.\n\nIn this study, we describe the clinical, epidemiological and molecular data from a series of consecutive infection cases caused by seven CPE during a four-month period.\n\nMethods\nStudy site\nThe INP is a public teaching-hospital with 243 beds, and is one of the largest pediatric reference centers in Mexico.\n\nClinical aspects\nOver a four-month period (April–July 2016), seven non-clonal Enterobacteriaceae isolates causing different clinical infections were obtained. The resistance profiles of these bacteria suggested that they were carbapenemases producers.\n\nWe reviewed the medical file from each patient to collect clinical and epidemiological data such as: demographic characteristics, underlying medical condition, previous antibiotic treatment, surgical procedure, mechanical ventilation, stay in pediatric intensive care unit (PICU), and number of clinical departments during hospitalization, among others. Acquisition of the different infections was determined to be healthcare-associated infections according to the definitions of the Centers for Disease Control and Prevention [8]. For this study, a case was defined as the appearance of at least one infection by a CPE that was clinically and microbiologically documented.\n\nMicrobiological methods\nThe identification and susceptibility profiles of the isolates were performed using the Phoenix® BD system (Becton Dickinson, Sparks, MD, U.S.). The production of extended spectrum beta-lactamases (ESBL) and carbapenemases was confirmed phenotypically using the combined disk method and the CarbaNP test, respectively. We determined the minimum inhibitory concentration to colistin according to the Clinical Laboratory Standards Institute (CLSI) [9].\n\nBeta-lactamase typing\nWe extracted DNA from each isolate using the QIAamp® DNA Mini kit (QIAGEN, Hilden, Germany). We detected beta-lactamases by PCR amplification of blaCTX-M-1,\nblaCTX-M-2,\nblaCTX-M-9,\nblaSHV,\nblaTEM,\nblaLAT,\nblaDHA,\nblaVIM, blaIMP, blaNDM, blaKPC and blaOXA-48 genes using a GenAmp PCR System 9700 thermal cycler (Applied Biosystems Foster City, CA, USA). AmpliTaq Gold® 360 MasterMix (Applied Biosystems) was used for all reactions; the primers and amplification conditions were described previously [10–12]. The amplified fragments were purified using the QIAquick PCR purification kit (QIAGEN), and each product obtained was sequenced using a 3500 XL System (Applied Biosystems). We determined the beta-lactamase subtype using the BLAST bioinformatic tool.\n\nMultilocus sequence typing\nMultilocus sequence typing (MLST) was performed on the E. coli, K. pneumoniae, and E. cloacae isolates [13–15]. We amplified trpA, pabB and rfb genes using conditions previously described, to detect the O25b-ST131 clone for all E. coli isolates [16].\n\nResults\nBacterial isolates and detection of beta-lactamases\nWe identified three strains of E. coli, two of K. pneumoniae, one of Klebsiella oxytoca, and one of E. cloacae. All isolates were carbapenem resistant but showed differences in their susceptibility profiles to other antibiotic families, no resistance to colistin was observed in any isolate (Table 1). The confirmatory test for ESBL detection was positive for two isolates (C1 and C2). Coexistence of other beta-lactamases, including TEM-1, SHV-1 (non-ESBL), SHV-12, and CTX-M-15 (ESBL), was found in five isolates, two isolates with CTX-M-15 and NDM-1 were negative for ESBL test (Table 2). None isolate possessed genes encoding enzymes of the CTX-M-2, CTX-M-9, DHA, or LAT type.Table 1 Resistance profile of carbapenemase-producing Enterobacteriaceae\n\nCase\tSpecies\tMIC (mg/L)\t\nIMP\tMEM\tERT\tAMP\tAMP/SULB\tCFZ\tCXM\tFOX\tCAZ\tCRO\tFEP\tPTZ\tAZT\tCIP\tLEV\tGE\tAK\tTOB\tSXT\tTE\tCOL\t\n1\t\nE. coli\n\t> 8\t> 32\t≥1\t> 16\t> 16/8\t> 16\t> 16\t> 16\t> 16\t> 32\t> 16\t> 64/4\t> 16\t> 2\t> 4\t> 8\t≤8\t> 8\t> 2/38\t> 8\t0.5\t\n2\t\nK. pneumoniae\n\t8\t8\t≥1\tIR\t> 16/8\t> 16\t> 16\t> 16\t> 16\t> 32\t> 16\t> 64/4\t> 16\t≤0.5\t≤1\t≤2\t> 32\t≤2\t> 2/38\t> 8\t1.0\t\n3\t\nE. coli\n\t4\t4\t≥1\t> 16\t> 16/8\t> 16\t> 16\t> 16\t> 16\t> 32\t> 16\t> 64/4\t> 16\t≤0.5\t≤1\t> 8\t≤8\t8\t≤0.5/9.5\t> 8\t0.5\t\n\nK. pneumoniae\n\t≥8\t32\t≥1\tIR\t> 16/8\t> 16\t> 16\t> 16\t> 16\t> 32\t> 16\t> 64/4\t> 16\t2\t≤1\t> 8\t≤8\t8\t> 2/38\t> 8\t0.5\t\n4\t\nK. oxytoca\n\t4\t2\t≥1\t> 16\t> 16/8\t> 16\t8\t≤4\t≤0.5\t≤2\t≤1\t> 64/4\t≤2\t2\t≤1\t≤2\t≤8\t≤2\t≤0.5/9.5\t≤2\t0.5\t\n5\t\nE. coli\n\t> 8\t16\t≥1\t> 16\t> 16/8\t> 16\t> 16\t> 16\t> 16\t> 32\t> 16\t> 64/4\t> 16\t> 2\t> 4\t> 8\t≤8\t> 8\t> 2/38\t> 8\t0.5\t\n6\t\nE. cloacae\n\t> 8\t32\t≥1\tIR\tIR\tIR\tIR\tIR\t> 16\t> 32\t> 16\t> 64/4\t> 16\t> 2\t> 4\t> 8\t> 32\t> 8\t> 2/38\t> 8\t0.5\t\nMIC minimum inhibitory concentration, IMP imipenem, MEM meropenem, ERT ertapenem, AMP/SULB ampicillin/sulbactam, CFZ cefazolin, CXM cefuroxime, FOX cefoxitin, CAZ ceftazidime, CTX cefotaxime, CRO ceftriaxone, FEP cefepime, PTZ piperacillin/tazobactam, AZT Aztreonam, CIP ciprofloxacin, LEV levofloxacin, GE gentamicin, TOB tobramycin, AK amikacin, SXT trimethoprim sulfamethoxazole, TE tetracycline, NIT nitrofurantoin, COL colistin, IR intrinsic resistance\n\nTable 2 Genotype characteristics of carbapenemase-producing Enterobacteriaceae\n\nCase\tSpecies\tESBL\tCo-existing beta-lactamases\tCarbaNP test\tCBP\tMLST\t\n1\t\nE. coli\n\t+\tCXT-M-15\t–\tOXA-232\tST2003\t\n2\t\nK. pneumoniae\n\t+\tSHV-12\t+\tNDM-1\tST76\t\n3\t\nE. coli\n\t–\t–\t+\tKPC-2\tST457\t\n\t\nK. pneumoniae\n\t–\tSHV-1*\t+\tKPC-2\tST5\t\n4\t\nK. oxytoca\n\t–\t–\t–\tOXA-48\tND\t\n5\t\nE. coli\n\t–\tCXT-M-15\t+\tNDM-1\tST131-O25b\t\n6\t\nE. cloacae\n\t–\tCXT-M-15, TEM-1 *\t+\tNDM-1\tST182\t\nESBL phenotype test for the detection of extended-spectrum beta-lactamases, CBP carbapenemases, −: negative, +: positive, *: non-ESBL, ND: not determined\n\n\n\nPhenotypic tests, carbapenemases detection and MLST\nFive isolates were positive for the CarbaNP test. However, carbapenemase production was not detected using this technique in isolates producing OXA-type enzymes. Four carbapenemase types were detected: NDM-1, KPC-2, OXA-48 and OXA-232 in the seven isolates studied (Table 1). The sequence types (ST) of the E. coli isolates were ST2003 (C1), ST457 (C3), and ST131 (C5); K. pneumoniae isolates were ST5 (C3) and ST76 (C2), and E. cloacae ST182 (C6) (Table 2).\n\nClinical and epidemiological characteristics\nThese isolates were obtained from six patients, one of whom had an infection with two isolates (C3), both producing KPC-2. With the exception of one female, all patients were male. The average age was 6.7 years (range 4 months - 16 years). Five patients had an underlying disease and three, were immunocompromised (C1, C4 and C5). Three patients presented skin and soft tissue infections (C2, C3 and C6). All deaths occurred in patients who CPE was isolated in blood. All of them had an intra-abdominal source of infection and secondary sepsis (Table 3).Table 3 Characteristics of patients with carbapenemase-producing Enterobacteriaceae\n\nData\tCases\t\n1\t2\t3\t4\t5\t6\t\n\nE. coli\n\t\nK. pneumoniae\n\t\nE. coli\n\n\nK. pneumoniae\n\t\nK. oxytoca\n\t\nE. coli\n\t\nE. cloacae\n\t\nOXA-232\tNDM-1\tKPC-2\tOXA-48\tNDM-1\tNDM-1\t\nBase diagnosis\tAML-M2\tIntestinal malrotation\tKTWS\tpreB-ALL\tTrisomy 21, Fallot Tetralogy\tComplicated varicella\t\nImmuno-compromised\tYes\tNo\tNo\tYes\tYes\tNo\t\nInfection\tSepsis, Neutropenic colitis\tNecrotizing fasciitis, SSI\tCellulitis, SSI\tAbdominal sepsis\tUTI\tNecrotizing fasciitis\t\nSample\tBlood, peritoneal liquid\tBlood, wound drainage\tSurgical wound drainage\tBlood\tUrine\tWound drainage\t\nID timea\t10\t8\t22\t39\t157\t9\t\nOther hospital\tNo\tYes\tNo\tNo\tNo\tYes\t\nPICU\tYes\tYes\tYes\tYes\tYes\tNo\t\nMV\tYes\tYes\tYes\tYes\tYes\tNo\t\nSurgery\tNo\tYes\tYes\tYes\tYes\tYes\t\nCVC\tYes\tYes\tYes\tYes\tYes\tNo\t\nTPN\tNo\tYes\tYes\tYes\tYes\tNo\t\nPrevious AB\t\t\t\t\t\t\t\n 3GC (days)\tNo\tYes (2)\tYes (23)\tYes (3)c\tYes (7)\tYes (3)\t\n 4CG (days)\tYes (1)\tNo\tNo\tYes (8)c\tNo\tNo\t\n Carbapenems\tYes (8)\tYes (18)\tYes (42)b\tYes (26)b\tYes (37)\tYes (29)b\t\n Colistin\tNo\tNo\tNo\tNo\tYes\tNo\t\n Definitive Tx\tCOL+MEM\tMEM + LEV\tMEM + AK\tMEM + PTZ\tNIT\tCOL+MEM\t\n LOS (days)\t11\t20\t44\t40\t197\t35\t\n ND\t2\t2\t3\t3\t3\t2\t\n DI\tPICU\tSurgery\tPIDD\tPIDD\tPIDD\tPIDD\t\n Evolution\tDeceased\tDeceased\tAlive\tDeceased\tAlive\tAlive\t\nDx diagnosis, AML-M2 acute myeloid leukemia M2, KTWS Klippel-Trenaunay-Weber syndrome, preB-ALL pre-B acute lymphoblastic leukemia, SSI surgical site infection, UTI urinary tract infection, PICU pediatric intensive care unit, MV mechanical ventilation, CVC central venous catheter, TPN total parenteral nutrition, AB antibiotics, 3GC third generation cephalosporins, Tx treatment, LOS length of in-hospital stay, COL colistin, MEM meropenem, AK amikacin, PTZ piperacillin/tazobactam, NIT nitrofurantoin, ND number of clinical departments during hospitalization, DI Clinical department in which the isolate was obtained, PIDD Pediatric Infectious Diseases Department, aDays since admission to identification of the organism, bIsolation during meropenem treatment, cEscalating regimen\n\n\n\nBefore sampling for CPE screening, all patients had been hospitalized with an average of 41 days (range 8 to 157 days); therefore, all infections were considered to be healthcare-associated. Only two patients were admitted to an institution other than INP in the 30 days prior to infection (C2 and C6). Five patients required admission to the pediatric intensive care unit (PICU), mechanical ventilation, and central venous catheter placement, whereas four patients received total parenteral nutrition. Five patients had surgery prior to CPE isolation (Table 3).\n\nRegarding prior use of antimicrobials, all patients received third or fourth generation cephalosporins, whereas all patients were treated with carbapenems. CPE were isolated in one patient (C6) while receiving meropenem.\n\nOnly two patients (C1 and C6) received treatment with colistin days prior to the isolation of CPE (Table 3).\n\nDiscussion\nIn this report, we describe the consecutive emergence of seven CPE isolates in a third-level pediatric hospital: three E. coli producing NDM-1, KPC-2 and OXA-232, two K. pneumoniae producing KPC-2 and NDM-1, one K. oxytoca producing OXA-48, and one E. cloacae producing NDM-1. These pathogens with these carbapenemases appear for the first time in our institution. Previous to this report, we did not have an active screening to detect colonizing patients. In this study, all infections were considered primary cases. None patient had secondary cases due to the control measures that were taken, such as strictly supervised hand washing, staff training, restriction of personnel in contact with the patients, isolation of the patients in private rooms, exhaustive cleaning and decontamination of physical areas, and alerts on their conditions in the medical records of the discharged patients for future admissions.\n\nWorldwide, K. pneumoniae, E. coli and Enterobacter spp. are the most frequent species of Enterobacteriaceae producing carbapenemases [6, 7]. To date, K. oxytoca has rarely been associated with carbapenemase production [17]. In Mexico, K. oxytoca has been related to VIM-2 production [18]; in other Latin American countries, production of other carbapenemases, including KPC-2 [19], IMP-4 [20], and VIM-4, have also been reported [21].\n\nDescriptions of CPE with KPC-2 in Mexico are limited. From 2010 to 2014, KPC-2 and KPC-3-producing isolates of K. pneumoniae were reported [22, 23]. In one patient, we found two isolates that produce KPC-2, one K. pneumoniae strain and another E. coli strain (C3). This study is the first report of KPC-2-producing E. coli in pediatric patients in Mexico; this isolate belongs to ST457. In Australia, E. coli ST457 has been described with CMY-1 and CTX-M-15, isolated from dog feces and extra-intestinal infections [24] and in Korea with OXA-232 in healthy individuals colonized [25].\n\nThe first report of NDM-1 in Mexico was registered in 2012, and the first cases were associated with an outbreak of a Providencia rettgeri clone [26]. In Mexico, E. coli (ST617), E. cloacae (ST182), and K. pneumoniae (ST22) isolates from adult patients [27] and K. pneumoniae (ST22) isolates from pediatric patients [28] have also been found to produce NDM-1. In the present series, NDM-1 was the enzyme most commonly found. This study is the first report of E. coli (C5) and E. cloacae (C6) producing NDM-1 in pediatric patients in Mexico.\n\nFor C5, the isolation of NDM-1-producing E. coli belonging to clone ST131-O25b was obtained from a urinary tract infection (UTI). The ST131 clone is considered the most predominant pathogenic lineage of this species in extra-intestinal infections and is associated with resistance to fluoroquinolones and dissemination of the beta-lactamase CTX-M [29]. There are reports in Mexico of E. coli ST131-O25b causing UTI healthcare-associated and community acquired; these infections have been associated with CTX-M-15, but not NDM-1 [30]. NDM production by E. coli ST131 is rare but has been reported in clinical and environmental isolations in countries such as India, Vietnam, Serbia, Philippines [31] and U.S. [32, 33]. This is the first report of NDM-1-producing E. coli ST131-O25b in Latin America.\n\nPatient C6, who was infected with NDM-1-producing E. cloacae, received colistin for the treatment of fasciitis and presented a favorable therapeutic outcome. This isolate belonged to ST182, this clone has been described in our country recently involved in a hospital outbreak during 2014–2015 [34].\n\nWe identified an OXA-48-producing K. oxytoca isolate with susceptibility to third- and fourth-generation cephalosporins but resistance to carbapenems. This pattern is characteristic of isolates producing this enzyme. Moreover, the coexistence of ESBL in the same isolate may lead to the suspicion of another type of carbapenemase [35]. Using the CarbaNP test, we did not detect carbapenemase activity in this isolate, as was previously described; therefore, this test is not recommended for the detection of the OXA-type enzyme phenotype [36]. Five isolates of OXA-48-producing K. oxytoca were reported in 2010 in Turkey [37]; however, in contrast to the strain isolated from C4, these strains produce other ESBL, including SHV, TEM, CTX-M, and VEB. One OXA-48-producing K. oxytoca isolate was reported in Israel with susceptibility to ceftazidime, ceftriaxone, gentamicin and meropenem but resistance to imipenem and ertapenem [38].\n\nThe first report of OXA-48 enzymes produced by E. coli in our country was described in a cohort of patients at risk of being CPE fecal carriers, and three K. pneumoniae and 13 E. coli isolates producing OXA-232 alone or in combination with other SHV and CTX-M-15 type beta-lactamases were obtained from this cohort [39]. Later, the same group reported that the most common carbapenemase in their hospital was OXA-232, mainly in E. coli and K. pneumoniae; infections by these microorganisms were associated with prior use of beta-lactams with beta-lactamase inhibitors and third-generation cephalosporins [40]. The E. coli with OXA-232 isolate (C1) belongs to ST2003 and additionally produces CTX-M-15. Although this ST has been associated with the production of other enzymes, such as KPC-2 and CTX-M-55 [41], there are no reports of OXA-232 production. The OXA-232 enzyme has also been found in E. coli ST457 and ST131 [25] and coexists in E. coli and K. pneumoniae isolates that produce other carbapenemases, such as NDM-1 [42, 43].\n\nThe two patients who suffered from CPE infections with OXA-type enzymes had leukemia as an underlying illness, the origin of these infections was abdominal, and both patients died (Table 3). The mortality reported by Enterobacteriaceae producing OXA-48-like enzymes reaches 50% [44]. This study represents the first report of OXA-48-producing K. oxytoca and OXA-232-producing E. coli in Mexican pediatric patients. Performing MLST for K. oxytoca was not possible.\n\nThe presence of other beta-lactamase enzymes was commonly reported in CPE, notably non-ESBL TEM and SHV, CTX-M-15, SHV-12, CMY and DHA subtypes, and sometimes other carbapenemases, such as VIM and IMP [16, 45–47]. We detected non-ESBL enzymes (TEM-1 and SHV-1) as well as ESBL (CTX-M-15 and SHV-12) in four isolates, but none produced enzymes of the CMY and DHA types or the other CTX-M subtypes. CTX-M-15 has also been found in CPE that produce NMD-1 [27]. However, CTX-M-15 and SHV-12 are the most commonly detected ESBL in other third-level hospitals in Mexico [30]. In two isolates, E. coli and E. cloacae with NDM-1 (case 5 and 6, respectively) we found CTX-M-15, but we could not phenotypically detect the production of ESBL, according to the literature this can be explained because the NDM type enzymes are not inhibited by clavulanic acid, which can intervene in the interpretation of the ESBL test, when NDM and CTX-M-15 co-exist in the same isolate [48]. A variety of risk factors have been considered in the acquisition of CPE, such as prior, recurrent, or prolonged hospitalization, the use of antimicrobials, immunosuppression, the presence of central venous catheters, intensive care unit (ICU) admission and recent surgery [49]. The majority of patients in this series had these risk factors.\n\nThe mortality in this study was high, because half patients died. This finding is similar to other reports in the literature; the mortality of patients with CPE infection reached 44% [2]. In our series, all patients with documented CPE with bloodstream infection died. Mortality can reach 85% in cases of bloodstream infection [3]. All cases were controlled, and no secondary cases appeared. The emergence of these CPE isolates was an institutional alarm because all cases were healthcare-associated infections; because we do not have a surveillance program for the detection of CPE carriers in the INP. Four patients among six had recurrent or prolonged hospitalization in our hospital, considered a risk factor. However, two cases (C2 and C6) were patients who came from other hospitals and in whom an infection was detected earlier (8 and 9 days, respectively). Therefore, these patients may have been colonized prior to admission at our institution. The role of CPE colonization at the intestinal level is well documented and allows cross-transmission and dissemination in healthcare institutions [49, 50]. CPE as the cause of outbreaks is a growing problem that is reported at a global level. Therefore, establishing screening programs for the early identification of these pathogens through rectal swabs of these patients is important [50], as is the implementation of prevention and control measures to avoid dissemination of these pathogens [49, 50].\n\nConclusions\nThis study reports the clinical, epidemiological and molecular characteristics of seven consecutive CPE cases. We report the finding of Enterobacteriaceae isolates producing carbapenemases not previously detected in Mexican pediatric patients. Finally, this is the first report of an NDM-1-producing E. coli ST131-O25b clone in Latin America.\n\nThe monitoring, surveillance, and control of CPE should be reinforced due to the ease of resistance cross-transmission among these pathogens, the possibility of dissemination, and the limited therapeutic possibilities.\n\nAbbreviations\n3GCthird generation cephalosporins\n\nABantibiotics\n\nAKamikacin\n\nAML-M2acute myeloid leukemia M2\n\nAMP/SULBampicillin/sulbactam\n\nAZTaztreonam\n\nBLASTBasic Local Alignment Serach Tool\n\nCAZceftazidime\n\nCBPcarbapenemases\n\nCFZcefazolin\n\nCIPciprofloxacin\n\nCLSIClinical Laboratory Standards Institute\n\nCMY-1cephamycin AmpC beta-lactamase\n\nCOLcolistin\n\nCPECarbapenemase-producing Enterobacteriaceae\n\nCROceftriaxone\n\nCTXcefotaxime\n\nCTX-MCefotaximase–München\n\nCVCcentral venous catheter\n\nCXMcefuroxime\n\nDHADhahran Hospital, Saudi Arabia AmpC beta-lactamase\n\nDIClinical department in which the isolate was obtained\n\nDxdiagnosis\n\nERTertapenem\n\nESBLextended spectrum beta-lactamases\n\nFEPcefepime\n\nFOXcefoxitin\n\nGEgentamicin\n\nICUintensive care unit\n\nIMPimipenem\n\nIMPimipenemase\n\nINPNational Institute of Pediatrics\n\nIRintrinsic resistance\n\nKPC-2Klebsiella pneumoniae carbapenemase\n\nKTWSKlippel-Trenaunay-Weber syndrome\n\nLATlatamoxef AmpC beta-lactamase\n\nLEVlevofloxacin\n\nLOSlength of in-hospital stay\n\nMEMmeropenem\n\nMICminimum inhibitory concentration\n\nMLSTMultilocus Sequence Typing\n\nMVmechanical ventilation\n\nNDnot determined\n\nNDnumber of clinical departments during hospitalization\n\nNDM-1New Delhi metallo-β-lactamase\n\nNITnitrofurantoin\n\nOXA-232oxacillinase-232\n\nOXA-48oxacillinase-48\n\nPICUpediatric intensive care unit\n\nPIDDPediatric Infectious Diseases Department\n\npreB-ALLpre-B acute lymphoblastic leukemia\n\nPTZpiperacillin/tazobactam\n\nSHVSulfhydryl variable beta-lactamaase\n\nSSIsurgical site infection\n\nSTsequence types\n\nSXTtrimethoprim sulfamethoxazole\n\nTEtetracycline\n\nTEMTemoneira beta-lactamase\n\nTOBtobramycin\n\nTPNtotal parenteral nutrition\n\nTxtreatment\n\nUTIurinary tract infection\n\nVEBVietnamese extended-spectrum beta-lactamases\n\nVIMVerona integron-encoded metallo-β-lactamase\n\nAcknowledgements\nWe thank to MsC Silvestre Ortega Peña for support in microbiological methods.\n\nFunding\nWe appreciate the support provided by the National Council for Science and Technology (Consejo Nacional de Ciencia y Tecnología) through the Health Sector Fund (Fondo Sectorial de Salud FOSSIS) in project 2012–1-181041 and the Federal Budget Research Funds (Fondos de Presupuesto Federal para Investigación) 2016 of the INP. They had none role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.\n\nAvailability of data and materials\nAll the data supporting our findings is contained within the manuscript.\n\nAuthors’ contributions\nAAA, JMV and ADC designed the study; AAA and JMV performed the experiments; ADC and EAG collected the epidemiological data; AAA, JMV and PAB collected the microbiological data; AAA and ADC analyzed the data; AAA and ADC wrote the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThis descriptive study was approved by the ethics and research committees of the INP (IRB:00008064, reference number of protocol 066/2013). In this study, informed consent was not necessary because the isolates included in the study were obtained as part of standard care. Patient identity and all the personal information were confidential. 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"fulltext_license": "CC BY",
"issn_linking": "1471-2180",
"issue": "18(1)",
"journal": "BMC microbiology",
"keywords": "Carbapenemase-producing Enterobacteriaceae; KPC-2; Mexico; NDM-1; OXA-232; OXA-48; Pediatrics",
"medline_ta": "BMC Microbiol",
"mesh_terms": "D000293:Adolescent; D000073182:Carbapenem-Resistant Enterobacteriaceae; D002648:Child; D002675:Child, Preschool; D016972:Enterobacter cloacae; D004756:Enterobacteriaceae Infections; D004926:Escherichia coli; D005260:Female; D005838:Genotype; D006776:Hospitals, Pediatric; D006801:Humans; D007223:Infant; D041121:Klebsiella oxytoca; D007711:Klebsiella pneumoniae; D007843:Latin America; D008297:Male; D008800:Mexico; D008826:Microbial Sensitivity Tests; D017720:Molecular Epidemiology; D001618:beta-Lactamases",
"nlm_unique_id": "100966981",
"other_id": null,
"pages": "38",
"pmc": null,
"pmid": "29673319",
"pubdate": "2018-04-19",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Carbapenemase-producing Enterobacteriaceae in Mexico: report of seven non-clonal cases in a pediatric hospital.",
"title_normalized": "carbapenemase producing enterobacteriaceae in mexico report of seven non clonal cases in a pediatric hospital"
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"abstract": "In recent solid organ transplant recipients, acute febrile illness is usually a source of grave concern and a diagnostic dilemma, especially if no response is noted after initiation of broad antimicrobial therapy. Human Monocytic Ehrlichiosis (HME) is a tick-borne illness caused by Ehrlichia chaffeensis and is not considered an opportunistic infection in immunocompromised patients such as solid organ transplant patients. Ehrlichiosis in immunocompromised patients can be life-threatening, and a strong index of suspicion is needed, especially in patients who live in endemic areas, for proper treatment initiation with doxycycline. We report a case of a 40-year-old male who received an orthotopic liver transplant six months earlier secondary to primary sclerosing cholangitis, on chronic immunosuppressive medication, who presented with complaints of sudden onset fever associated with nausea, vomiting, and diarrhea. Initial extensive infectious workup was negative and no response to empiric antimicrobials. There was suspicion for ehrlichiosis prompting empiric doxycycline use. Subsequently, E. chaffeensis polymerase chain reaction (PCR) was positive, and the antibiotic regimen was de-escalated to only doxycycline with complete resolution of his symptoms and progressive improvement in previously abnormal biochemical indices.",
"affiliations": "Internal Medicine and Pediatrics Residency Program, University of Tennessee Health Science Center, Memphis, USA.;College of Medicine, University of Tennessee Health Science Center, Memphis, USA.;College of Medicine, University of Tennessee Health Science Center, Memphis, USA.;Division of Infectious Diseases, University of Tennessee Health Science Center, Memphis, USA.",
"authors": "Parkinson|Melissa|M|https://orcid.org/0000-0002-5165-0578;Vuyyuru|Spandana|S|;Patel|Jay|J|;Animalu|Chinelo|C|",
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"doi": "10.1155/2021/8285326",
"fulltext": "\n==== Front\nCase Rep Transplant\nCase Rep Transplant\nCRIT\nCase Reports in Transplantation\n2090-6943\n2090-6951\nHindawi\n\n10.1155/2021/8285326\nCase Report\nChallenges of Diagnosing Severe Ehrlichiosis in Orthotopic Liver Transplant Recipients\nhttps://orcid.org/0000-0002-5165-0578\nParkinson Melissa mparkin1@uthsc.edu\n1\nVuyyuru Spandana 2\nPatel Jay 2\nAnimalu Chinelo 3\n1Internal Medicine and Pediatrics Residency Program, University of Tennessee Health Science Center, Memphis, USA\n2College of Medicine, University of Tennessee Health Science Center, Memphis, USA\n3Division of Infectious Diseases, University of Tennessee Health Science Center, Memphis, USA\nAcademic Editor: Ryszard Grenda\n\n2021\n17 11 2021\n2021 828532628 5 2021\n15 10 2021\nCopyright © 2021 Melissa Parkinson et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nIn recent solid organ transplant recipients, acute febrile illness is usually a source of grave concern and a diagnostic dilemma, especially if no response is noted after initiation of broad antimicrobial therapy. Human Monocytic Ehrlichiosis (HME) is a tick-borne illness caused by Ehrlichia chaffeensis and is not considered an opportunistic infection in immunocompromised patients such as solid organ transplant patients. Ehrlichiosis in immunocompromised patients can be life-threatening, and a strong index of suspicion is needed, especially in patients who live in endemic areas, for proper treatment initiation with doxycycline. We report a case of a 40-year-old male who received an orthotopic liver transplant six months earlier secondary to primary sclerosing cholangitis, on chronic immunosuppressive medication, who presented with complaints of sudden onset fever associated with nausea, vomiting, and diarrhea. Initial extensive infectious workup was negative and no response to empiric antimicrobials. There was suspicion for ehrlichiosis prompting empiric doxycycline use. Subsequently, E. chaffeensis polymerase chain reaction (PCR) was positive, and the antibiotic regimen was de-escalated to only doxycycline with complete resolution of his symptoms and progressive improvement in previously abnormal biochemical indices.\n\nUniversity of TennesseeMethodist University Hospital\n==== Body\npmc1. Background and Introduction\n\nSolid organ transplant is a life-saving treatment for many patients with end-stage organ disease. However, the immunosuppressive regimens these patients require leave them susceptible to severe infections from both opportunistic and common organisms. The wide range of potential infectious agents and blunted immune response in these patients can make prompt diagnosis and treatment difficult.\n\nEhrlichiosis is a disease caused by obligate intracellular bacteria from the genus Ehrlichia transmitted via tick bite that infects human and animal leukocytes. E. chaffeensis is the most common species to infect humans and causes Human Monocytic Ehrlichiosis (HME). Rates of reported HME rose from just 200 in 2000 to 1,799 in 2018 and continue to rise, making it an increasingly important illness [1]. E. chaffeensis is transmitted primarily through the lone star tick and is endemic (Figure 1 [1]) to the southeastern, south-central, and mid-Atlantic United States [1]. Contact with the ticks and subsequent transmission can occur in areas where humans are with natural tick reservoirs (e.g., cats and deer) (Figure 2 [2]).\n\nManifestation of HME can range from asymptomatic to severe, with severe illness being more likely in the elderly, those with comorbid conditions, and immunocompromised patients. Many of the common early symptoms are nonspecific, including fever, chills, malaise, myalgia, headache, nausea, vomiting, diarrhea, and loss of appetite. Rash and neurological symptoms like confusion may also be present [1]. Delays in treatment and immunocompromised states can lead to more severe late disease with meningoencephalitis, respiratory failure, uncontrolled bleeding, organ failure, and death [1]. Definitive diagnosis can be made with several laboratory techniques, including serology, polymerase chain reaction (PCR), and buffy coat examination. Treatment with doxycycline is usually initiated based on a presumptive diagnosis when clinical suspicion is high. However, when tick-borne illness is not suspected early on, definitive treatment can be critically delayed due to the initial empiric antibiotic regimen's exclusion of E. chaffeensis coverage.\n\n2. Case Report\n\nWe present the case of a 40-year-old male who six months prior underwent an orthotopic liver transplant secondary to primary sclerosing cholangitis on chronic immunosuppressive therapy. He presented to the emergency room with complaints of sudden onset fever ongoing for three days associated with nausea, vomiting, and diarrhea (about five to six watery bowel movements per day). He also endorsed fatigue. He denied chest pain, shortness of breath, headache, confusion, or vision changes. His immunosuppressive medications consisted of prednisone, mycophenolate mofetil, tacrolimus, and valganciclovir. He previously had cytomegalovirus (CMV) viremia, for which he was treated with valganciclovir. Serial CMV PCR was negative, and the valganciclovir dose was decreased to a maintenance dose.\n\nAt the time of initial presentation, he was febrile with a maximum temperature of 38.9°C, blood pressure 93/55 mmHg, pulse 101 beats/min, and oxygen saturation 98% on room air. He was alert, oriented, cooperative, and in no apparent distress. The physical exam was unremarkable, with no rashes or lesions noted.\n\nInitial labs revealed sodium of 130 mEq/L, potassium 5.6 mEq/L, chloride 105 mEq/L, creatinine 1.60 mg/dL, albumin 4.6 g/dL, total bilirubin 1.2 mg/dL, AST 44 U/L, ALT 51 U/L, WBC 1.70 thou/mcL with absolute neutrophil count of 0.6 thou/mcL, platelets 40 thou/mcL, and hemoglobin 8.7 g/dL. CMV PCR was negative. Blood cultures were sent and were subsequently negative. A chest X-ray did not reveal any acute abnormalities. Abdominal ultrasound showed findings consistent with medical renal disease only. Gastrointestinal PCR panel was negative for enterotoxigenic E. coli, Giardia, Norovirus, Salmonella, Shiga-like Toxin producing E. coli, Plesiomonas shigelloides, Vibrio, Yersinia enterocolitica, enteroaggregative E. coli, Cyclospora cayetanensis, Entamoeba histolytica, Adenovirus F 40/41, Astrovirus, Sapovirus, Enteropathogenic E. coli, and Shigella/Enteroinvasive E. coli. Clostridium difficile and SARS-CoV-2 PCR were negative. Serum Cryptococcus neoformans and histoplasmosis antigens were negative. Acute hepatitis A, B, and C panel was negative. Rocky Mountain spotted fever IgM titer and Rickettsia typhi IgM and IgG antibodies were negative. Urinalysis was unremarkable.\n\nHe was started on empiric vancomycin, meropenem, and micafungin (doses adjusted for renal function) without any clinical improvement in 48 hours. His immunosuppressive medication doses were reduced appropriately. His fever persisted, and renal function, as well as liver functions, declined rapidly (Figure 3), prompting an infectious disease consult. On further questioning, the patient revealed he worked as a resource manager in a state park and is exposed regularly to ticks; he did not recall any obvious tick bites and had never had to pluck out a tick from his skin. He denied eating unpasteurized goods and did not consume uncooked meat or fish. He had not been swimming in public pools.\n\nGiven this history, intravenous doxycycline for presumptive ehrlichiosis was initiated on hospital day 3 while awaiting studies. Subsequently, E. chaffeensis PCR returned positive. He required a short ICU stay for vasopressor support due to septic shock. Given his severe acute kidney injury and creatinine clearance decline to <15 mL/min, hemodialysis was initiated on hospital day 4. His immunosuppressive medication regimen was initially held on admission and later changed to prednisone and tacrolimus, while mycophenolate was discontinued.\n\nAfter initiation of doxycycline, clinical improvement was noted both in symptoms and laboratory indices (Figure 3). He completed a 10-day course of doxycycline and was taken off hemodialysis on hospital day 10. The patient was discharged home in a stable condition and, since his discharge, has continued to do well.\n\n3. Discussion\n\nSince its first recognition in the late 1980s, cases of HME have been rising, with over 1000 cases reported by the CDC annually since 2012, occurring in both immunocompromised and immunocompetent patients [1]. Case numbers in 2018 were over eight times higher than in 2000, making HME important to consider when a patient presents with nonspecific findings, particularly in an endemic area [1]. While many studies examine HME in the context of the United States, there has been an increasing incidence of HME internationally on continents such as Asia and Africa [3]. Various studies are emerging that have shown Ehrlichia species found in different animal vectors that were thought not to host them, suggesting that there could be more unknown reservoirs of this bacterium and that overall distribution and disease of this bacterium may be more widespread than previously thought [4–6].\n\nThe number of HME cases occurring in solid-organ transplant (SOT) recipients makes up a small but significant portion of overall cases. It is important to recognize this as a potential cause of infection in SOT patients, particularly in endemic areas. A literature search was done, and all known cases of Ehrlichia complicating various SOT are tabulated in Table 1. There were 143 found in the literature, and, interestingly, doxycycline was used in the vast majority of these patients, and most patients survived as well.\n\nDiagnosis of ehrlichiosis in transplant recipients can often be challenging due to the low prevalence of solid-organ transplant (SOT) HME, nonspecific symptoms, which can be seen in a wide range of infection as well as organ rejection, and blunting of the immune response [3, 4]. Common symptoms reported from Ehrlichia infections in transplant patients from one review of cases include a history of fatigue (30%), subjective fevers (95-100%), headache (55-60%), and GI symptoms (40-60%), which were similar across other reports [7–11]. Our patient presented with fever, diarrhea, nausea, vomiting, and fatigue—similar symptoms to those reported in other SOT patients; however, he had no headache or other neurologic symptoms. Less commonly, HME can present with cutaneous manifestations, pulmonary embolism, severe disease leading to hemophagocytic lymphohistiocytosis, and fulminant organ failure [12].\n\nPreemptive treatment is usually initiated for suspected ehrlichiosis while workup for definitive diagnosis is in progress. Several current diagnostic methods include serologies, peripheral blood smear (buffy-coat preparation) examination, PCR, immunohistochemical (IHC) staining, and culture. Serologic studies can be done via an indirect fluorescent antibody test (IFA) or enzyme-linked immunosorbent assay (ELISA). IFA is the standard reference test for ehrlichiosis; it is widely available and can be obtained through state health departments [13]. This assay requires comparing antibody titers of acute and convalescent serum samples collected 2–4 weeks apart to demonstrate evidence of a fourfold seroconversion. While the test is 94-100% sensitive, antibody titers are usually low during the first week of illness, decreasing utility in detecting HME in the early phase [13–15]. Thus, IFA is infrequently due to minimal early clinical utility and time-consuming nature [16]. In addition, ELISA also measures antibody titers and is excellent for confirming findings from IFA, but it is not very good at evaluating variations in antibody titers with time [13, 16]. Thus, similar to IFA, ELISA's clinical utility is low and better suited for clinical trials [16]. Peripheral blood smear examination using a buffy-coat preparation is usually useful within the first week of illness, where microscopic examination may reveal a collection of microcolonies of Ehrlichia in the cytoplasm of white blood cells [13]. The utility of examining peripheral blood depends on the patient population [17]. Sensitivity of doing a peripheral blood smear in immunocompetent people is 17%; however, immunocompromised patients can have a sensitivity as high as 100%, increasing utility in the transplant population [17, 18]. This is likely due to the immunocompromised state enabling a more considerable morula burden, increasing the chance of seeing morula on slides. PCR is a rapid diagnostic test that is becoming more widely available, and it has good sensitivity (85%) and specificity (100%) [14, 19]. It is most sensitive within the first week of symptom onset, and a positive result is considered diagnostic; however, a negative result does not rule out ehrlichiosis, especially if antibiotics have begun [20]. IHC staining of ehrlichial antigens in tissue can be done, but this is not widely available and not routinely used for acute diagnosis, limiting clinical utility [20]. These can be performed in bone marrow, live tissue specimens, or postmortem specimens [20]. Lastly, culture is slow, not widely available, and is not very useful [16, 20].\n\nThis case highlights the importance of taking a thorough history to identify potential exposures. Treatment for HME was only initiated after a thorough exposure history revealed that the patient worked outside and had significant tick exposure. Doxycycline is the drug of choice for the treatment of HME [21]. However, in some patients with a severe allergy to doxycycline, alternative therapy such as rifampin and chloramphenicol has been used even though there are no robust studies available at this time supporting the routine use of these agents [22]. There are case reports where successful use of these agents has been documented; chloramphenicol is not readily available in the United States and is associated with hematological side effects [22]. Travel history to endemic areas, work and hobby history, and a thorough skin exam should all be performed when concerned for possible HME infection. While a definitive diagnosis of HME can be made using a variety of methods, including PCR and serology, there are diagnostic clues that can be identified in an initial lab workup that is typical of HME, including leukopenia, thrombocytopenia, elevated liver enzymes, elevated creatinine, and less commonly hyponatremia, pancytopenia, and decreased serum albumin levels [7–11]. In this case, the patient had lab findings consistent with HME, including hyponatremia, pancytopenia, elevated creatinine, and elevated liver enzymes (Figure 3).\n\nEarly detection of disease is crucial to prevent disease progression and end-organ damage. In one study, delayed time to treatment was associated with the need for ICU admission [8]. In this case, delays in the patient's diagnosis led to renal failure requiring hemodialysis and septic shock requiring vasopressor support. Immunosuppression has often been suggested as a possible risk factor for worse prognosis and ICU admission, but the data are mixed. One study found that immunosuppression was associated with decreased need for ICU admission, while others showed that it was associated with more severe disease [8, 10, 23]. Transplant type has been associated with worse outcomes and more prolonged ICU admissions, with lung transplant being associated with a poorer prognosis compared with other solid organ transplants [10, 24]. The case fatality rate has been reported between 0% and 26% for transplant patients, which is similar to the case fatality rate in all HME cases [8–10]. Case fatality has decreased since its discovery despite the number of cases increasing [1].\n\nThis case report adds to the body of literature on ehrlichiosis in transplant patients, serves as an example of clinical patterns of infection, and stresses the importance of early identification of disease to enable prompt treatment within the vulnerable population of transplant recipients.\n\nAcknowledgments\n\nWe would like to show appreciation to the Methodist University Hospital and the University of Tennessee Health Science Center.\n\nData Availability\n\nThe data used to support the findings of this study are included within the article.\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Annual incidence (per million population) of HME in the United States in 2019. This graph shows the general distribution and incidence of HME in the United States, with most cases occurring in the south-central and southeastern United States. Courtesy of the Centers for Disease Control and Prevention [1].\n\nFigure 2 Tick-borne pathogen transmission. This image shows the life cycle of Ehrlichia species and which animal different tick-borne pathogens can inhabit. This also shows the different ways humans can come in contact with ticks. Image courtesy of the open access article by Rojero-Vázquez et al. [2].\n\nFigure 3 Trends of key lab findings throughout hospital stay. Doxycycline was started on hospital day 3 for suspected ehrlichiosis. The patient had been started on hemodialysis due to acute renal failure on hospital day 4 and was taken off on day 10 due to marked clinical improvement. The progression of creatinine (mg/dL), WBC count (thou/mcL), and total bilirubin (mg/dL) over his hospital stay is seen in (a). The progression of AST (U/L) and ALT (U/L) over his hospital stay is seen in (b).\n\nTable 1 All cases of ehrlichiosis complicating solid organ transplants.\n\nTotal cases\tAge median\n(Yr, range)\tSex\tTransplant type\tDiagnosis method\tManagement\tOutcome\tReferences\t\n25\t54 (26-68)\t68% M\tH (2), Li (5), Lu (5), R (13)\tPCR\tDox\tS\tLawrence et al. [10]\t\n51\t57 (9-72)\t75% M\tH (12), Li (7), Lu (12), R (18), R/P (2)\tPCR\tNA\tS\tOtrock et al. [11]\t\n1\t69\tF\tLu\tPCR, PBS\tDox\tS\tRegunath et al. [18]\t\n15\t50 (15-73)\t87% M\tH (6), Li (1), Lu (1), R (7)\tPCR (93%), Ser (7%)\tDox\tS\tThomas et al.[9]\t\n2\t56, 57\t50% M\tR (2)\tPCR (50%), Ser (50%)\tDox, Tigecycline\tS\tSachdev et al. [25]\t\n1\t38\tM\tLu\tPCR, PBS\tDox\tS\tSafdar et al. [23]\t\n1\t57\tM\tLi\tPCR, Ser\tDox\tS\tLiddell et al. [24]\t\n1\t63\tM\tR\tPCR, PBS\tDox\tS\tKumar et al. [26]\t\n1\t60\tM\tR\tPCR, PBS, Ser\tDox\tS\tCotant et al. [27]\t\n1\t11\tM\tR\tPCR\tDox\tS\tBuller et al. [28]\t\n1\tNA\tM\tR\tPCR\tDox\tS\tSadikot et al. [29]\t\n1\t35\tM\tR\tSer, PCR\tDox\tS\tSchutze et al. [30]\t\n1\t47\tM\tLi\tPCR\tDox\tS\tTan et al. [14]\t\n1\t27\tM\tR\tPBS, Ser\tDox\tS\tDorn et al. [31]\t\n1\t35\tF\tR\tPCR\tDox\tS\tMasterson et al. [7]\t\n27\tNA\tNA\tNA\tPCR\tDox\tNA\tKuriakose et al. [8]\t\n1\t51\tM\tLi\tSer\tDox\tS\tAntony et al. [32]\t\n3\t38, 41, 50\t66% M\tP/R, P/R, P\tPBS\tDox\t66% S\tTrofe et al. [33]\t\n1\t67\tM\tR\tPBS, PCR\tDox\tS\tAdachi et al. [34]\t\n1\t66\tF\tR\tPBS, PCR\tDox\tS\tVannorsdall et al. [35]\t\n1\t57\tM\tR\tPCR\tDox\tS\tHassan et al. [36]\t\n5\t43 (5-70)\tM\tLu (1), R (4)\tPCR (80%); PBS (20%)\tDox\t60% S\tSaha et al. [15]\t\nD: death; Dox: doxycycline; F: female; H: heart; Li: liver; Lu: lung; M: male; NA: not available; P: pancreas; PBS: peripheral blood smear; PCR: polymerase chain reaction; R: renal; Ser: serology; S: survived; Yr: year. This table helps demonstrate that, while HME can occur in a wide range of ages, it is most often seen in older patients. Interestingly, PCR was most often used to help diagnose HME. Notably, most patients received doxycycline and had a good outcome.\n==== Refs\n1 CDC Ehrlichiosis 2021 Available from: https://www.cdc.gov/ehrlichiosis/index.html\n2 Rojero-Vázquez E. Gordillo-Pérez G. Weber M. Infection of Anaplasma phagocytophilum and Ehrlichia spp. in opossums and dogs in Campeche, Mexico: the role of tick infestation Frontiers in Ecology and Evolution 2017 5 161 10.3389/fevo.2017.00161 2-s2.0-85043707786\n3 Rochlin I. Toledo A. Emerging tick-borne pathogens of public health importance: a mini-review Journal of Medical Microbiology 2020 69 6 p. 781\n4 Doudier B. Olano J. Parola P. Brouqui P. 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Reinfection with Ehrlichia chaffeensis in a liver transplant recipient Clinical Infectious Diseases 2002 34 12 1644 1647 10.1086/340523 2-s2.0-0037097644 12032902\n25 Sachdev S. H. Joshi V. Cox E. R. Amoroso A. Palekar S. Severe life-threateningEhrlichia chaffeensisinfections transmitted through solid organ transplantation Transplant Infectious Disease 2014 16 1 119 124 10.1111/tid.12172 2-s2.0-84893856095 24330198\n26 Kumar N. Goyal J. Goel A. Shakoory B. Chatham W. Macrophage activation syndrome secondary to human monocytic ehrlichiosis Indian Journal of Hematology and Blood Transfusion 2014 30 Supplement 1 145 147 10.1007/s12288-013-0299-3 2-s2.0-84924812282\n27 Cotant C. Okulicz J. F. Brezina B. Riley D. J. Conger N. G. Human monocytic ehrlichiosis in a renal transplant patient Scandinavian Journal of Infectious Diseases 2006 38 8 699 702 10.1080/00365540500444694 2-s2.0-33746618761 16857619\n28 Buller R. S. Arens M. Hmiel S. P. Ehrlichia ewingii, a newly recognized agent of human ehrlichiosis The New England Journal of Medicine 1999 341 3 148 155 10.1056/NEJM199907153410303 2-s2.0-0033565959 10403852\n29 Sadikot R. Shaver M. J. Reeves W. B. Ehrlichia chaffeensis in a renal transplant recipient American Journal of Nephrology 1999 19 6 674 676 10.1159/000013540 2-s2.0-0032708213 10592362\n30 Schutze G. E. Jacobs R. F. Human monocytic ehrlichiosis in children Pediatrics 1997 100 1 p. e10 10.1542/peds.100.1.e10\n31 Dorn H. Dickinson B. Agarwal A. Brayman K. L. Human ehrlichiosis after treatment of acute cellular rejection in a kidney transplant Patient Transplantation 2012 94 10S p. 531 10.1097/00007890-201211271-01022\n32 Antony S. J. Dummer J. S. Hunter E. Human ehrlichiosis in a liver transplant recipient Transplantation 1995 60 8 879 880 10.1097/00007890-199510270-00021 7482752\n33 Trofe J. Reddy K. S. Stratta R. J. Human granulocytic ehrlichiosis in pancreas transplant recipients Transplant Infectious Disease 2001 3 1 34 39 10.1034/j.1399-3062.2001.003001034.x 2-s2.0-0035125980 11429038\n34 Adachi J. A. Grimm E. M. Johnson P. Uthman M. Kaplan B. Rakita R. M. Human granulocytic ehrlichiosis in a renal transplant PATIENT Transplantation 1997 64 8 1139 1142 10.1097/00007890-199710270-00010 2-s2.0-0030671041 9355830\n35 Vannorsdall M. D. Thomas S. Smith R. P. Human granulocytic ehrlichiosis in a renal allograft recipient: review of the clinical spectrum of disease in solid organ transplant patients Transplant Infectious Disease 2002 4 2 97 101 10.1034/j.1399-3062.2002.01015.x 2-s2.0-0036618979 12220247\n36 Hassan W. Talwar M. Balaraman V. Molnar M. Z. Ehrlichiosis infection mimicking thrombotic microangiopathy syndrome early after kidney transplantation Transplant Infectious Disease 2020 22 5 10.1111/tid.13305\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6951",
"issue": "2021()",
"journal": "Case reports in transplantation",
"keywords": null,
"medline_ta": "Case Rep Transplant",
"mesh_terms": null,
"nlm_unique_id": "101591863",
"other_id": null,
"pages": "8285326",
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"pmid": "34840851",
"pubdate": "2021",
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"references": "11435982;19836890;25332563;9355830;24330198;32306509;11927032;30274412;15606643;16263231;16857619;17511689;10403852;14976527;28036138;19819631;33201233;10592362;12032902;26227842;9200384;30913447;7482752;34329411;33711942;32478654;19228344;11429038;26918212;32358827;12220247;33669023",
"title": "Challenges of Diagnosing Severe Ehrlichiosis in Orthotopic Liver Transplant Recipients.",
"title_normalized": "challenges of diagnosing severe ehrlichiosis in orthotopic liver transplant recipients"
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"abstract": "Women presenting to the cardiac catheterization laboratory with normal coronary arteries without significant atherosclerotic disease is a common presentation. In such patients, it is important to maintain a wide differential and consider alternate diagnoses. We present two cases of women presenting with chest pain found to have severe coronary vasospasm in the setting of recent initiation of phentermine. Phentermine may have vasospastic proprieties which are important to consider when prescribing to patients.",
"affiliations": "Department of Cardiology, Mayo Clinic, Rochester, MN.;Department of Cardiology, Mayo Clinic, Rochester, MN.;Department of Cardiology, Mayo Clinic, Rochester, MN.;Department of Cardiology, Mayo Clinic, Rochester, MN. Electronic address: lerman.amir@mayo.edu.",
"authors": "Prasad|Megha|M|;El Sabbagh|Abdallah|A|;Rihal|Charanjit|C|;Lerman|Amir|A|",
"chemical_list": "D000697:Central Nervous System Stimulants; D014665:Vasodilator Agents; D010645:Phentermine; D005996:Nitroglycerin",
"country": "England",
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"issue": "94(7)",
"journal": "Mayo Clinic proceedings",
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"medline_ta": "Mayo Clin Proc",
"mesh_terms": "D000697:Central Nervous System Stimulants; D002637:Chest Pain; D003329:Coronary Vasospasm; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008875:Middle Aged; D009203:Myocardial Infarction; D005996:Nitroglycerin; D010645:Phentermine; D014665:Vasodilator Agents",
"nlm_unique_id": "0405543",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Phentermine and Coronary Vasospasm-Induced Myocardial Infarction.",
"title_normalized": "phentermine and coronary vasospasm induced myocardial infarction"
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"abstract": "Colonoscopy is considered a gold standard tool for the diagnostic evaluation of colorectal diseases. Bowel preparation, a pre-requisite for colonoscopy, usually involves ingestion of purgatives for the cleansing of the bowel so that visualization is not obscured during the procedure. Commonly used preparations are sodium phosphate-based solutions, sodium picosulphate and polyethylene glycol. The use of such preparations is associated with electrolyte disturbances, commonly hyponatremia. Hyponatremia is usually seen with sodium phosphate based solutions and is rare with polyethylene glycol. Symptomatic hyponatremia, however, is rare following bowel preparation and is attributable to other factors as well, such as the age of patient, non-osmotic release of antidiuretic hormone and the procedure itself. In this report, we discuss a case of severe symptomatic hyponatremia observed in a 71-year-old gentleman who underwent polyethylene glycol based bowel preparation for colonoscopy.",
"affiliations": "Department of Anaesthesiology, Maharajgunj Medical Campus, Maharjgunj, Kathmandu, Nepal.;Department of Anaesthesiology, Maharajgunj Medical Campus, Maharjgunj, Kathmandu, Nepal.;Department of Critical Care Medicine, Om Hospital and Research Centre, Chabahil, Kathmandu, Nepal.;Department of Gastroenterology, Maharajgunj Medical Campus, Maharjgunj, Kathmandu, Nepal.;Department of Anaesthesiology, Maharajgunj Medical Campus, Maharjgunj, Kathmandu, Nepal.",
"authors": "Sunder Shrestha|Pramesh|P|;Acharya|Utsav|U|;Karki|Bipin|B|;Pathak|Rahul|R|;Acharya|Subhash Prasad|SP|",
"chemical_list": "D002400:Cathartics; D010710:Phosphates; D011092:Polyethylene Glycols",
"country": "Nepal",
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"doi": "10.31729/jnma.5039",
"fulltext": "\n==== Front\nJNMA J Nepal Med Assoc\nJNMA J Nepal Med Assoc\nJ Nepal Med Assoc\nJNMA\nJNMA: Journal of the Nepal Medical Association\n0028-2715 1815-672X Journal of the Nepal Medical Association \n\n10.31729/jnma.5039\nCase Report\nSymptomatic Hyponatremia following Bowel Preparation for Colonoscopy: A Case Report\nShrestha Pramesh Sunder 1 Acharya Utsav 1 Karki Bipin 2 Pathak Rahul 3 Acharya Subhash Prasad 3 1 Department of Anaesthesiology, Maharajgunj Medical Campus, Maharjgunj, Kathmandu, Nepal\n2 Department of Critical Care Medicine, Om Hospital and Research Centre, Chabahil, Kathmandu, Nepal\n3 Department of Gastroenterology, Maharajgunj Medical Campus, Maharjgunj, Kathmandu, Nepal\nCorrespondence: Dr. Pramesh Sunder Shrestha, Department of Anesthesiology, Institute of Medicine, Maharajgunj, Kathmandu, Nepal. Email: drpramesh@outlook.com, Phone: +977-9841298710.\n11 2020 \n30 11 2020 \n58 231 938 940\n© The Author(s) 2018.2018This is an Open-Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.ABSTRACT\nColonoscopy is considered a gold standard tool for the diagnostic evaluation of colorectal diseases. Bowel preparation, a pre-requisite for a colonoscopy, usually involves the ingestion of purgatives for the cleansing of the bowel so that visualization is not obscured during the procedure. Commonly used preparations are sodium phosphate-based solutions, sodium picosulphate, and polyethylene glycol. The use of such preparations is associated with electrolyte disturbances, commonly hyponatremia. Hyponatremia is usually seen with sodium phosphate-based solutions and is rare with polyethylene glycol. Symptomatic hyponatremia, however, is rare following bowel preparation and is attributable to other factors as well, such as the age of the patient, non-osmotic release of anti-diuretic hormone, and the procedure itself. In this report, we discuss a case of severe symptomatic hyponatremia observed in a 71-year-old gentleman who underwent polyethylene glycol-based bowel preparation for colonoscopy.\n\nKeywords\ncolonoscopycolorectal diseasehyponatremiapolyethylene glycol\n==== Body\nINTRODUCTION\nColonoscopy is still a gold standard tool for the diagnosis of diseases of the colorectal mucosa.1 Cleansing of the bowel is a prerequisite for colonoscopy and is usually done by oral administration of purgatives, commonly sodium-phosphate (NaP) based solutions or polyethylene glycol (PEG) based solutions. Electrolyte abnormalities following bowel preparation is a possibility, especially with NaP based solutions.2 As PEG-based solutions are usually reserved for those at risk of developing electrolyte imbalance, PEG is considered relatively safe.3 Although electrolyte abnormalities have been reported with PEG-based solutions as well, symptomatic hyponatremia is rare.\n\nCASE REPORT\nA 71-year-old gentleman was transferred to our intensive care unit (ICU) from surgical ward after he was found to be drowsy for the last few hours. He was admitted to the surgical ward the day before, with complaints of loss of appetite for the last six months and passage of blood in stool for one month. There was also a history of significant weight loss for the last six months. He was a known diabetic under the medication and was being managed in the ward with suspicion of malignancy of the large bowel.\n\nOn arrival in the ICU, his Glasgow Coma Scale (GCS) score was 10/15 (E3V2M5). Pupils were bilateral equal in size and reactive to light. He was afebrile and there were no signs of meningeal irritation. Reflexes and jerks were normal. There was no history of recent administration of any sedatives. A colonoscopy was performed about four hours back, during which sedated with midazolam. However, the patient had regained full consciousness before he was transferred to the ward. An examination of other systems revealed no abnormalities. Arterial blood gas (ABG) analysis and serum electrolytes were sent among which Magnesium, Phosphate, and Calcium were normal. The ABG was normal. The report of serum electrolytes revealed hyponatremia, with the sodium (Na+) level of 111mmol/L. The blood glucose level was normal. On further evaluation of the history, it was revealed that the patient had ingested around 7-8 liters of overzealous free water overnight with the PEG solution for bowel preparation for colonoscopy. He had presumed extra water would cleanse the bowel and make the procedure easy and more diagnostic. In the ICU patient developed generalized tonic-clonic seizure which was treated with intravenous midazolam and leverecietam was added as anticonvulsant. Optic Nerve Sheath Diameter was recorded which was 6.1mm in Right Eye and 5.1mm in Left Eye (Figures 1a and b).\n\nFigure 1 A ONSD Right Eye. B. ONSD Left Eye.\nAn urgent computed tomography (CT) scan of the head was done which revealed a normal scan with cerebral atrophy (Figure 2).\n\nFigure 2 CT scan of the head showing a normal scan with cerebral atrophy.\nThe patient was started on injection of 3% NaCl for treatment of hyponatremia. Electroencephalogram (EEG) was done which recorded seizure activity (Figure 3).\n\nFigure 3 EEG showing seizure activity.\nSo, levericetam 1g intravenous was reloaded and the dose increased. Sodium gradually increased to 117mmol/L on next but there was no neurological improvement. After 2 days, the sodium increased to 132mmol/L, there was a gradual improvement in neurological status with GCS of E4V5M6. The patient was discharged home after 3 days of hospital stay with normal electrolytes report. Follow up histopathology report was normal.\n\nDISCUSSION\nHyponatremia is seen in 15-30% of in-patients in a hospital, especially in intensive care units. The etiology is multifactorial but the basic abnormality lies in the body not being able to excrete free water or an excessive intake of free water.4 The features range from asymptomatic to severe neurologic manifestations such as seizures, permanent brain damage, coma, and death.1\n\nHyponatremia has been reported in 7.5% of patients undergoing colonoscopy.5 The factor most commonly attributable to this is the osmotic shift resulting from the use of osmotically active solutions for bowel preparation. However, studies have shown that although contributory, bowel preparation alone is not the lone factor responsible for electrolyte abnormality. More recently, the role of a non-osmotic release of antidiuretic hormone (ADH), low dietary solute intake, and excessive and rapid free fluid intake have also been considered as contributing factors for hyponatremia associated with colonoscopy.1 Non-osmotic release of ADH is usually associated with vomiting, pain, anxiety, stress, and hypoglycemia.6 Our patient had an excessive intake of free water the day before a colonoscopy. This, coupled with the age-related reduction in the ability of the kidneys to excrete free water load could have contributed to hyponatremia. As our patient developed features after the procedure, the anxiety and discomfort during the procedure could have triggered a non-osmotic release of ADH.\n\nWhatever the reason, it is very important to keep in mind the possibility of electrolyte imbalance during the preparation of elderly patients for colonoscopy. Preparedness and anticipation will help physicians identify the problem sooner and act promptly so that the neurologic sequelae of hyponatremia can be checked before it progresses to irreversible neurological damage.\n\nConsent:\nJNMA Case Report Consent Form was signed by the patient and the original article is attached with the patient's chart.\n\nConfict of Interest:\nNone.\n==== Refs\nREFERENCES\n1. Windpessl M Schwarz C Wallner M \"Bowel prep hyponatremia\" - a state of acute water intoxication facilitated by low dietary solute intake: case report and literature review BMC Nephrol 2017 18 1 54 10.1186/s12882-017-0464-2 28173768 \n2. Frizelle FA Colls BM Hyponatremia and Seizures After Bowel Preparation: Report of Three Cases Dis Colon Rectum 2005 45 393 6 10.1007/s10350-004-0778-6 15812590 \n3. Weir MA Fleet JL Vinden C Shariff SZ Liu K Hyponatremia and Sodium Picosulfate Bowel Preparations in Older Adults Am J Gastroenterol 2014 109 5 686 94 10.1038/ajg.2014.20 24589671 \n4. Sahay M Sahay R Hyponatremia: A practical approach Indian J Endocrinol Metab 2014 18 6 760 71 10.4103/2230-8210.141320 25364669 \n5. Gabriel JCM Muñoz SR Bertolo JDC et al Electrolytic disturbances and colonoscopy : bowel lavage solutions, age and procedure Spanish J Gastroenterol 2003 95 12 863 75 \n6. Saradna A Shankar S Soni P et al Hyponatremic Seizures after Polyethylene Glycol Bowel Preparation: The Elderly at Risk Am J Ther 2018 25 6 e779 e80 10.1097/MJT.0000000000000789 30398996\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0028-2715",
"issue": "58(231)",
"journal": "JNMA; journal of the Nepal Medical Association",
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"mesh_terms": "D000368:Aged; D002400:Cathartics; D003113:Colonoscopy; D006801:Humans; D007010:Hyponatremia; D008297:Male; D010710:Phosphates; D011092:Polyethylene Glycols",
"nlm_unique_id": "0045233",
"other_id": null,
"pages": "938-940",
"pmc": null,
"pmid": "34506430",
"pubdate": "2020-11-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24589671;25364669;15812590;28173768;30398996;14972007",
"title": "Symptomatic Hyponatremia following Bowel Preparation for Colonoscopy: A Case Report.",
"title_normalized": "symptomatic hyponatremia following bowel preparation for colonoscopy a case report"
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"abstract": "BACKGROUND\nFunctional pancreatic neuroendocrine tumors (pNETs) rarely produce vasopressin. Here, we reported a case of pNET producing vasopressin in a 78-year-old man with hyponatremia.\nThe patient presented with anorexia approximately 4 years ago, and the laboratory test results indicated hyponatremia. He was hospitalized 3 times subsequently due to anorexia in the past 4 years, during which laboratory tests consistently indicated severe hyponatremia.\n\n\nMETHODS\nUpon admission, his serum osmolarity, urine osmolarity, urine sodium level, and 24-hour urine sodium level was 277 mOsm/kg H2O, 465 mOsm/kg H2O, 82.5 mmol/L, and 140.25 mmol, respectively. Gallium-68-labeled tetraazacyclododecanetetraacetic acid-Dphel-Tyr3-octreotate positron emission tomography-computed tomography showed a high uptake lesion measuring approximately 1 cm in diameter in the pancreatic body, and the possibility of pNET was considered. Besides, laboratory tests showed that adrenocorticotropic hormone, follicle-stimulating hormone, and luteinizing hormone released by the pituitary was insufficient in the case of low levels of cortisol, estradiol, progesterone, and testosterone. Thus, the diagnosis of the syndrome of inappropriate antidiuresis (SIAD) was considered along with hypopituitarism.\n\n\nMETHODS\nThe patient underwent surgery, and pNET was confirmed by pathology examination. The immunohistochemical study showed that the tumor cells were positive for somatostatin receptors 2 and vasopressin.\n\n\nRESULTS\nIn the last follow-up 17 months after surgery, the patient was in good condition, taking methylprednisolone 4 mg every other day, and had been free of anorexia or hyponatremia episodes.\n\n\nCONCLUSIONS\nThis case illustrated the potential ectopic production of vasopressin resulting in SIAD in pNETs, highlighting the adoption of gallium-68-labeled tetraazacyclododecanetetraacetic acid-Dphel-Tyr3-octreotate positron emission tomography-computed tomography and vasopressin immunohistochemical staining in the evaluation of the etiology of SIAD.",
"affiliations": "Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China.;Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China.;Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China.;Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China.;Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China.;Department of Cardiovascular Disease, Tianjin Medical University General Hospital, Tianjin, China.;Department of PET-CT, Tianjin Medical University General Hospital, Tianjin, China.;Department of PET-CT, Tianjin Medical University General Hospital, Tianjin, China.;Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.;Department of Pathology, Tianjin Medical University General Hospital, Tianjin, China.;Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China.",
"authors": "Li|Jingyan|J|;Zhang|Xinxin|X|;He|Qing|Q|;Feng|Wenli|W|;Ding|Li|L|;Wang|Zhuoqun|Z|;Yu|Haonan|H|;Chen|Qiusong|Q|;Lu|Ning|N|;Xu|Dongbo|D|;Cui|Jingqiu|J|0000-0002-7568-3622",
"chemical_list": "D000305:Adrenal Cortex Hormones; D014667:Vasopressins",
"country": "United States",
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"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\nMD-D-21-04999\n10.1097/MD.0000000000027453\n27453\n4300\nResearch Article\nClinical Case Report\nPancreatic neuroendocrine tumor producing vasopressin\nA case report\nLi Jingyan MD a\nZhang Xinxin MD a\nHe Qing MD a\nFeng Wenli MD a\nDing Li MD a\nWang Zhuoqun MM b\nYu Haonan MM c\nChen Qiusong MD c\nLu Ning MD d\nXu Dongbo MD e\nhttp://orcid.org/0000-0002-7568-3622\nCui Jingqiu MD a ∗\nSaranathan. Maya\na Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China\nb Department of Cardiovascular Disease, Tianjin Medical University General Hospital, Tianjin, China\nc Department of PET-CT, Tianjin Medical University General Hospital, Tianjin, China\nd Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China\ne Department of Pathology, Tianjin Medical University General Hospital, Tianjin, China.\n∗ Correspondence: Jingqiu Cui, Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, No. 154, AnShan Road, HePing District, Tianjin 300052, China (e-mail: cuijingqiu2020@163.com).\n08 10 2021\n08 10 2021\n100 40 e2745315 7 2021\n6 9 2021\n20 9 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nRationale:\n\nFunctional pancreatic neuroendocrine tumors (pNETs) rarely produce vasopressin. Here, we reported a case of pNET producing vasopressin in a 78-year-old man with hyponatremia.\n\nPatient concerns:\n\nThe patient presented with anorexia approximately 4 years ago, and the laboratory test results indicated hyponatremia. He was hospitalized 3 times subsequently due to anorexia in the past 4 years, during which laboratory tests consistently indicated severe hyponatremia.\n\nDiagnosis:\n\nUpon admission, his serum osmolarity, urine osmolarity, urine sodium level, and 24-hour urine sodium level was 277 mOsm/kg H2O, 465 mOsm/kg H2O, 82.5 mmol/L, and 140.25 mmol, respectively. Gallium-68-labeled tetraazacyclododecanetetraacetic acid-Dphel-Tyr3-octreotate positron emission tomography-computed tomography showed a high uptake lesion measuring approximately 1 cm in diameter in the pancreatic body, and the possibility of pNET was considered. Besides, laboratory tests showed that adrenocorticotropic hormone, follicle-stimulating hormone, and luteinizing hormone released by the pituitary was insufficient in the case of low levels of cortisol, estradiol, progesterone, and testosterone. Thus, the diagnosis of the syndrome of inappropriate antidiuresis (SIAD) was considered along with hypopituitarism.\n\nInterventions:\n\nThe patient underwent surgery, and pNET was confirmed by pathology examination. The immunohistochemical study showed that the tumor cells were positive for somatostatin receptors 2 and vasopressin.\n\nOutcomes:\n\nIn the last follow-up 17 months after surgery, the patient was in good condition, taking methylprednisolone 4 mg every other day, and had been free of anorexia or hyponatremia episodes.\n\nLessons:\n\nThis case illustrated the potential ectopic production of vasopressin resulting in SIAD in pNETs, highlighting the adoption of gallium-68-labeled tetraazacyclododecanetetraacetic acid-Dphel-Tyr3-octreotate positron emission tomography-computed tomography and vasopressin immunohistochemical staining in the evaluation of the etiology of SIAD.\n\nKeywords\n\nhyponatremia\npancreatic neuroendocrine tumors\nrelative adrenal insufficiency\nsyndrome of inappropriate antidiuresis\nvasopressin\nnational natural science foundation of china82070854 Jingqiu Cuinational natural science foundation of china81900720 Wenli FengOPEN-ACCESSTRUE\n==== Body\npmc1 Introduction\n\nPancreatic neuroendocrine tumor (pNET) is a neuroendocrine tumor (NET) that originates from the pancreas. Although pNETs are rare neoplasms, the incidence and prevalence have been steadily increasing.[1] pNETs include both functional pNETs with clinical syndromes caused by substances produced by the tumors and nonfunctional pNETs with no distinct clinical manifestations.[2] Functional pNETs may produce a variety of hormones, including insulin, gastrin, vasoactive intestinal polypeptide, glucagon, somatostatin, growth hormone-releasing hormone, and adrenocorticotropic hormone (ACTH).[3,4]\n\nVasopressin, also known as antidiuretic hormone (ADH), is synthesized in the hypothalamus and stored in the neurohypophysis, which keeps plasma osmolality within a narrow range by regulating the reabsorption of water in the kidneys.[5] It has been hypothesized that an inappropriate release of ADH or an increased renal response to ADH results in the syndrome of inappropriate antidiuresis (SIAD),[6] which manifests as excessive reabsorption of water and dilutional hyponatremia. Conditions that may cause SIAD include: ectopic ADH secretion by malignant tumor cells, for example, small cell lung cancer; increased production of ADH-like substances by the hypothalamus, secondary to trauma, infection, or tumors; infectious lung disease, including tuberculosis, pneumonia, and fungal infection, etc; and secretion of ADH stimulated by drugs, including cytotoxic drugs, anesthetics, and interferons.[7] However, few cases of vasopressin-producing pNETs leading to SIAD have been reported so far.[8]\n\nHerein, we reported an unusual case of a pNET ectopically producing vasopressin that resulted in SIAD, which was confirmed by pathological examination and immunohistochemical staining for vasopressin.\n\n2 Case presentation\n\nA 78-year-old man was referred to the Department of Endocrinology and Metabolism of our hospital for recurrent episodes of hyponatremia on July 5, 2019. The patient presented with anorexia approximately 4 years ago, and the laboratory test results from the local hospital indicated hyponatremia, which was resolved by symptomatic treatment. The patient was hospitalized 3 times subsequently due to anorexia in the past 4 years, during which laboratory tests consistently indicated severe hyponatremia. The lowest serum sodium level was 121 mmol/L. He was not on any medication known to induce hyponatremia. He did not have a familial history of NET. Upon admission, his blood pressure, pulse rate, respiratory rate, and temperature was 144/74 mm Hg, 60 beats per minute, 20 breaths per minute, and 36.4 °C, respectively. He was alert and had normal skin elasticity. Physical examinations of his heart and lungs were unremarkable. The abdomen was soft, without tenderness, and with normal bowel sounds. There was mild edema in the lower limbs.\n\nLaboratory findings on admission showed hyponatremia (128 mmol/L; normal, 136-145), glucose 5.5 (normal 3.6-5.8) mmol/L, blood urea nitrogen 1.4 (normal, 2.5-7.1) mmol/L, uric acid 141 (normal, 140-414) μmol/L, and creatinine 58 (normal, 62-133) μmol/L. Serum osmolarity, urine osmolarity, urine sodium, and 24-hour urine sodium was 277 (normal 275-305) mOsm/kg·H2O, 465 (normal 600-1000) mOsm/kg·H2O, 82.5 mmol/L, and 140.25 (normal 130.00-260.00) mmol/24 hour, respectively. Other laboratory findings are presented in Table 1. The levels of renin and aldosterone were low. Moreover, the ACTH, follicle-stimulating hormone, and luteinizing hormone released by the pituitary were insufficient in the case of low levels of cortisol, estradiol, progesterone, and testosterone. SIAD was suspected along with possible hypopituitarism. The patient underwent positron emission tomography-computed tomography (PET-CT) to exclude the possibility of a tumor. PET-CT using 18F-fluorodexyglucose was unremarkable. However, gallium-68-labeled tetraazacyclododecanetetraacetic acid-Dphel-Tyr3-octreotate (68Ga-DOTATATE) PET-CT displayed a lesion with high DOTATATE uptake, measuring approximately 1 cm in diameter in the pancreatic body (Fig. 1), which was indicative of the pNET. Furthermore, non-enhanced and enhanced magnetic resonance imaging of the upper abdomen revealed a small nodule in the body of the pancreas, which was consistent with the pNET (Fig. 2). Head magnetic resonance imaging did not show any signs of central nervous system disease. There were no signs and symptoms of heart failure, and left ventricular ejection fraction was normal as assessed by echocardiography. Adrenal computed tomography findings were normal. A diagnosis of SIAD was made on the basis of laboratory and clinical findings. Normal serum sodium levels were maintained for a week after the oral administration of 7.5 mg tolvaptan. Besides, ultrasound of lower extremity vein indicated deep venous thrombosis, which caused pain in the left lower limbs, and diclofenac sodium, a nonsteroidal anti-inflammatory drug, was given.\n\nTable 1 Laboratory tests during hospitalization of the patient.\n\nCategory\tDate\tReference range\tValues\t\nTP (g/L)\tJuly 5, 2019\t63–82\t62\t\nAlb (g/L)\tJuly 5, 2019\t35–50\t31\t\nGlo (g/L)\tJuly 5, 2019\t20–40\t31\t\nTC (mmol/L)\tJuly 6, 2019\t3.59–5.17\t5.23\t\nTG (mmol/L)\tJuly 6, 2019\t0.57–1.71\t1.76\t\nHDL-C (mmol/L)\tJuly 6, 2019\t0.80–2.20\t0.52\t\nLDL-C (mmol/L)\tJuly 6, 2019\t1.33–3.36\t3.95\t\nFT3 (pmol/L)\tJuly 6, 2019\t2.63–5.70\t2.48\t\nFT4 (pmol/L)\tJuly 6, 2019\t9.01–19.05\t11.78\t\nTSH (μIU/mL)\tJuly 6, 2019\t0.35–4.94\t2.914\t\nFSH (IU/L)\tJuly 6, 2019\t0.95–11.95\t6.34\t\nLH (IU/L)\tJuly 6, 2019\t0.57–12.07\t3.34\t\nPRL (ng/mL)\tJuly 6, 2019\t3.46–19.40\t5.87\t\nE2 (pg/mL)\tJuly 6, 2019\t11.00–44.00\t<10\t\nP (ng/mL)\tJuly 6, 2019\t0.00–0.20\t<0.10\t\nT (ng/dL)\tJuly 6, 2019\t142.39–923.14\t19.37\t\n8:00 am cortisol (μg/dL)\tJuly 6, 2019\t5.00–25.00\t5.71\t\nACTH (pg/mL)\tJuly 6, 2019\t0.00–46.00\t27.60\t\n8:00 am cortisol (μg/dL)\tJuly 10, 2019\t5.00–25.00\t14.90\t\nACTH (pg/mL)\tJuly 10, 2019\t0.00–46.00\t33.90\t\nUrinary cortisol (μg/24 h)\tJuly 10, 2019\t33.00–110.00\t35.02\t\nRenin (recumbent position, uIU/mL)\tJuly 8, 2019\t2.8–39.9\t1.7\t\nAldosterone (recumbent, ng/dL)\tJuly 8, 2019\t3.0–23.6\t<0.97\t\nRenin (recumbent, uIU/mL)\tJuly 15, 2019\t2.8–39.9\t0.6\t\nAldosterone (recumbent, ng/dL)\tJuly 15, 2019\t3.0–23.6\t<0.97\t\nRenin (standing, uIU/mL)\tJuly 17, 2019\t4.4–46.1\t<0.5\t\nAldosterone (standing, ng/dL)\tJuly 17, 2019\t3.0–35.3\t2.1\t\nACTH = adrenocorticotropic hormone, E2 = estradiol, FSH = follicle-stimulating hormone, FT3 = free triiodothyronine, FT4 = free thyroxine, HDL-C = high density lipoprotein cholesterol, LDL-C = low density lipoprotein cholesterol, LH = luteinizing hormone, P = progesterone, PRL = prolactin, T = testosterone, TC = total cholesterol, TG = triglycerides, TSH = thyroid-stimulating hormone.\n\nFigure 1 A lesion with high DOTATATE uptake approximately 1 cm in diameter in the pancreatic body showed by the 68Ga-DOTATATE PET-CT. 68Ga-DOTATATE = Gallium-68-labeled tetraazacyclododecanetetraacetic acid-Dphel-Tyr3-octreotate, PET-CT = Positron emission tomography-CT.\n\nFigure 2 A small nodule (arrows) in the body of the pancreas consistent with the feature of pNET in the non-enhanced and enhanced magnetic resonance (MR) imaging of the upper abdomen. pNET = pancreatic neuroendocrine tumor.\n\nThe patient underwent laparoscopic-assisted middle segment pancreatectomy and pancreatic-gastric anastomosis on July 31, 2019. A diagnosis of pNETs was confirmed by pathology examination (G2, Fig. 3). Karyokinesis was rare. The Ki-67 index was greater than 3%. Immunohistochemistry showed positivity for CgA, Syn, CD56, CK, somatostatin receptors 2 (SSTR2, Fig. 4A), and vasopressin (NB110-65214, Neurophysin II/Arg-vasopressin Antibody, Novus Biologicals, Fig. 4B) in the tumor cells, indicating a vasopressin-producing pNET.\n\nFigure 3 Pathology of the pancreatic neuroendocrine tumor (pNET) (A, H&E stain, ×40; B, H&E stain, ×100). pNET = pancreatic neuroendocrine tumor.\n\nFigure 4 Positivity for SSTR2 (A, immunohistochemical stain, ×40) and vasopressin (B, immunohistochemical stain, ×40) in surgical specimens of the tumor. SSTR2 = somatostatin receptors 2.\n\nThe patient developed heart failure in the postoperative period. He suffered from hyponatremia again, with a serum sodium level of 134 mmol/L. Because of suspected relative hypopituitarism, intravenous and oral corticosteroids were initiated. The serum sodium level was normalized (142 mmol/L) 5 days after 50 to 100 mg of hydrocortisone treatment daily. The dosage of corticosteroid was gradually tapered. In the last follow-up 17 months after surgery, the patient was in good condition, taking methylprednisolone 4 mg every other day, and had been free of anorexia or hyponatremia episodes. Owing to the outbreak of coronavirus disease 2019 (COVID-19), the patient did not visit our hospital for the recent follow-up.\n\n3 Discussion\n\nIn this case, the pNET ectopically producing vasopressin was clinically suspected and confirmed in pathology, highlighting the adoption of 68Ga-DOTATATE PET-CT and immunohistochemical staining for vasopressin in evaluating the etiology of SIAD.\n\nHyponatremia is mainly an abnormality of water balance with a relative excess of body water compared to the total sodium content in the body.[9] Sodium ions are the main component of osmotic pressure in the extracellular fluid. The main physiological mechanisms of regulating serum osmolarity are thirst, as well as vasopressin released by the pituitary.[9] Vasopressin is a polypeptide synthesized by the supraventricular nucleus and paraventricular nucleus of the hypothalamus and secreted by the posterior pituitary gland. The main reaction to vasopressin is the increased water reabsorption in the collecting tubules of the kidneys. Hyponatremia is usually related to a disorder of vasopressin that governs water balance.[9]\n\nHyponatremia is the most common electrolyte abnormality observed in clinical practice.[10] The diagnosis of hyponatremia is complex due to its complicated etiology and nonspecific clinical feature. The etiology of hyponatremia is thought to be multifactorial. A prospective study recruiting ambulatory patients indicated approximately half of the patients had a multifactorial etiology of hyponatremia.[11] In our patient, multiple factors contributed to his hyponatremia. Firstly, owing to insufficient ACTH, follicle-stimulating hormone, and luteinizing hormone released by the pituitary in the case of low levels of cortisol, estradiol, progesterone, and testosterone, as well as the effect of methylprednisolone, hypopituitarism was considered in our patient, which could be a possible etiology of his hyponatremia. Secondly, there was vasopressin ectopically produced by pNET in this patient, which was confirmed by pathological examination and immunohistochemical staining for vasopressin. Furthermore, laboratory findings showed that the levels of renin and aldosterone were low. After hospitalization, the patient was prescribed diclofenac sodium to relieve pain in the left lower limbs caused by deep venous thrombosis. It has been demonstrated that the use of nonsteroidal anti-inflammatory drugs will decrease the levels of renin and aldosterone.[12] Thus, the low level of the renin-angiotensin-aldosterone system was an aggravating factor of hyponatremia. Therefore, in this patient, low level of the renin-angiotensin-aldosterone system, hypopituitarism, and the inappropriate production of vasopressin by the pNET jointly resulted in hyponatremia.\n\nPrevious studies have indicated that inappropriate ADH secretion may occur as follows: ADH synthesized by the supraventricular nucleus and paraventricular nucleus of the hypothalamus and released by the posterior pituitary gland; ectopic ADH secretion; missense mutation of the V2 vasopressin receptor causing constitutive activation of V2 vasopressin receptor and SIAD-like clinical manifestation of patients.[13] In our patient, we found an inappropriate release of vasopressin by the pNET, which was an unusual cause of SIAD.\n\nAs far as we know, there has been only 1 case of vasopressin-producing pNET reported so far. Alshaikh et al[8] reported on a 52-year-old man presenting with intermittent abdominal pain. Core biopsy confirmed a NET originating from the pancreas. The pathology of the NET was positive for pancreatic polypeptide and insulin. At that point, the blood glucose level was 6.5 mmol/L and serum sodium level was 132 mmol/L. Four years later, he developed hypoglycemia accompanied by inappropriately elevated proinsulin and insulin levels. Laboratory findings showed that serum osmolality was 250 mOsm/kg and urine osmolality was 140 mOsm/kg, which were consistent with those of SIAD. The autopsy was diffusely positive for vasopressin, which was not observed in the original biopsy. In this patient, the vasopressin-producing feature of the pNET was confirmed by autopsy when he died of the disease nearly 9 years after the initial diagnosis. This suggests that early diagnosis of the cause of hyponatremia is difficult in clinical practice.\n\nAs shown above, the 68Ga-DOTATATE PET-CT and immunohistochemistry of vasopressin provided key information in our case. Therefore, it is essential to conduct immunohistochemical staining for vasopressin in patients who could have vasopressin-producing NETs. 68Ga-DOTATATE PET-CT is a functional imaging modality used to assess well-differentiated NETs[14] and an effective tool for locating primary tumors in patients with an unknown type of NET.[15] Ga-DOTATATE has the highest affinity for SSTR2, which tends to be most overexpressed in NETs.[16] It has become the preferred imaging method for initial diagnosis, patients inclined to receive peptide receptor radionuclide therapy, and localization of unknown primary tumors.[14] Moreover, a prospective study showed that 68Ga-DOTATATE PET-CT changed the treatment of 33 (66%) among 50 patients who underwent this imaging procedure.[17] Thus, for staging and monitoring of NETs, 68Ga-DOTATATE PET-CT should be considered as it is usually related to changes in treatment.[17]\n\nThere are several limitations to our case report. First, we did not measure the ADH level due to the lack of routine analysis of serum ADH in clinical practice. Second, due to the critical condition of our patient and the difficulty in obtaining ACTH, assessment of adrenal function, such as the circadian adrenocortical rhythm and the ACTH stimulation, was insufficient before surgery. Third, we did not receive data on the patient's detailed serum sodium levels after discharge. Due to the influence of COVID-19 on the hospital environments as well as his advanced age, he was unable to visit our department, making follow-up visits difficult. However, we learned that he was in good condition through telephone interviews.\n\n4 Conclusion\n\nIn conclusion, we reported an unusual case of a pNET ectopically producing vasopressin. The pNET was suggested by 68Ga-DOTATATE PET-CT and confirmed by immunohistochemistry of vasopressin. Early diagnosis of the cause of hyponatremia is difficult, so the vasopressin-producing features of pNETs may be undetected in clinical practice. Our case highlights pNETs are possibly 1 of the causes of hyponatremia. A systematic prospective study of SIAD should be conducted to clarify the true prevalence of this phenomenon.\n\nAuthor contributions\n\nJL obtained the clinical findings, reviewed the literature, and prepared the figures. XZ wrote the initial manuscript and prepared the figures. QH obtained the clinical findings, reviewed and approved the manuscript. WF performed the immunohistochemical study of SSTR2 and vasopressin. LD reviewed and approved the manuscript. ZW got the patient's history and built the timeline. HY performed the 18F-fluorodexyglucose PET-CT and 68Ga-DOTATATE PET-CT for the patients. QC was responsible for the diagnosis of the PET-CT. NL operated on the patient. DX made the pathological diagnosis for the patients. JC obtained the clinical findings, reviewed and approved the manuscript, the figures, the diagnosis, and supervised the manuscript.\n\nConceptualization: Jingyan Li, Xinxin Zhang, Qing He, Wenli Feng, Li Ding, Zhuoqun Wang, Haonan Yu, Qiusong Chen, Ning Lu, Dongbo Xu, Jingqiu Cui.\n\nData curation: Jingyan Li, Xinxin Zhang, Qing He, Wenli Feng, Li Ding, Zhuoqun Wang, Haonan Yu, Qiusong Chen, Ning Lu, Dongbo Xu, Jingqiu Cui.\n\nFormal analysis: Jingyan Li, Xinxin Zhang, Qing He, Wenli Feng, Li Ding, Zhuoqun Wang, Haonan Yu, Qiusong Chen, Ning Lu, Dongbo Xu, Jingqiu Cui.\n\nFunding acquisition: Wenli Feng, Jingqiu Cui.\n\nInvestigation: Jingyan Li, Xinxin Zhang, Qing He, Wenli Feng, Li Ding, Zhuoqun Wang, Haonan Yu, Qiusong Chen, Ning Lu, Dongbo Xu, Jingqiu Cui.\n\nMethodology: Jingyan Li, Xinxin Zhang, Qing He, Wenli Feng, Li Ding, Zhuoqun Wang, Haonan Yu, Qiusong Chen, Ning Lu, Dongbo Xu, Jingqiu Cui.\n\nProject administration: Jingyan Li, Xinxin Zhang, Qing He, Wenli Feng, Li Ding, Zhuoqun Wang, Haonan Yu, Qiusong Chen, Ning Lu, Dongbo Xu, Jingqiu Cui.\n\nResources: Jingyan Li, Xinxin Zhang, Qing He, Wenli Feng, Li Ding, Zhuoqun Wang, Haonan Yu, Qiusong Chen, Ning Lu, Dongbo Xu, Jingqiu Cui.\n\nSupervision: Jingyan Li, Xinxin Zhang, Qing He, Wenli Feng, Li Ding, Zhuoqun Wang, Haonan Yu, Qiusong Chen, Ning Lu, Dongbo Xu, Jingqiu Cui.\n\nValidation: Jingyan Li, Xinxin Zhang, Qing He, Wenli Feng, Li Ding, Zhuoqun Wang, Haonan Yu, Qiusong Chen, Ning Lu, Dongbo Xu, Jingqiu Cui.\n\nVisualization: Jingyan Li, Xinxin Zhang, Qing He, Wenli Feng, Li Ding, Zhuoqun Wang, Haonan Yu, Qiusong Chen, Ning Lu, Dongbo Xu, Jingqiu Cui.\n\nWriting – original draft: Jingyan Li, Xinxin Zhang.\n\nWriting – review & editing: Jingyan Li, Xinxin Zhang, Qing He, Wenli Feng, Li Ding, Zhuoqun Wang, Haonan Yu, Qiusong Chen, Ning Lu, Dongbo Xu, Jingqiu Cui.\n\nAbbreviations: ACTH = adrenocorticotropic hormone, ADH = antidiuretic hormone, DOTATATE = tetraazacyclododecanetetraacetic acid–DPhe1-Tyr3-octreotate, PET-CT = positron emission tomography-computed tomography, pNET = pancreatic neuroendocrine tumor, SIAD = syndrome of inappropriate antidiuresis, SSTR2 = somatostatin receptors 2.\n\nHow to cite this article: Li J, Zhang X, He Q, Feng W, Ding L, Wang Z, Yu H, Chen Q, Lu N, Xu D, Cui J. Pancreatic neuroendocrine tumor producing vasopressin: a case report. Medicine. 2021;100:40(e27453).\n\nJL and XZ contributed equally to this work.\n\nThis work was supported by the National Natural Science Foundation of China (NSFC) (82070854 and 81900720).\n\nThis study was approved by the medical research ethics committee of Tianjin Medical University General Hospital before study participation.\n\nWritten informed consent was obtained from the participant's son for publication purposes due to the advanced age of the patients.\n\nThis manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal.\n\nThe authors have no conflicts of interest to disclose.\n\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n==== Refs\nReferences\n\n[1] Dasari A Shen C Halperin D . Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol 2017;3 :1335–42.28448665\n[2] Oberg K . Pancreatic endocrine tumors. Semin Oncol 2010;37 :594–618.21167379\n[3] Falconi M Eriksson B Kaltsas G . ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology 2016;103 :153–71.26742109\n[4] de Mestier L Hentic O Cros J . Metachronous hormonal syndromes in patients with pancreatic neuroendocrine tumors: a case-series study. Ann Intern Med 2015;162 :682–9.25984844\n[5] Bankir L Bichet DG Morgenthaler NG . Vasopressin: physiology, assessment and osmosensation. J Intern Med 2017;282 :284–97.28649750\n[6] Ellison DH Berl T . Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med 2007;356 :2064–72.17507705\n[7] Yarmohammadi H Erinjeri JP Brown KT . Embolization of metastatic neuroendocrine tumor resulting in clinical manifestations of syndrome of inappropriate secretion of antidiuretic hormone. J Vasc Interv Radiol 2015;26 :533–7.25805538\n[8] Alshaikh OM Yoon JY Chan BA . Pancreatic neuroendocrine tumor producing insulin and vasopressin. Endocr Pathol 2018;29 :15–20.28718084\n[9] Spasovski G Vanholder R Allolio B . Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant 2014;29 : Suppl 2 : i1–39.\n[10] Upadhyay A Jaber BL Madias NE . Incidence and prevalence of hyponatremia. Am J Med 2006;119 : 7 Suppl 1 : S30–5.16843082\n[11] Tasdemir V Oguz AK Sayin I Ergun I . Hyponatremia in the outpatient setting: clinical characteristics, risk factors, and outcome. Int Urol Nephrol 2015;47 :1977–83.26490555\n[12] Funder JW Carey RM Mantero F . The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2016;101 :1889–916.26934393\n[13] Feldman BJ Rosenthal SM Vargas GA . Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med 2005;352 :1884–90.15872203\n[14] Sanli Y Garg I Kandathil A . Neuroendocrine tumor diagnosis and management: (68)Ga-DOTATATE PET/CT. Am J Roentgenol 2018;211 :267–77.29975116\n[15] Hofman MS Lau WF Hicks RJ . Somatostatin receptor imaging with 68Ga DOTATATE PET/CT: clinical utility, normal patterns, pearls, and pitfalls in interpretation. Radiographics 2015;35 :500–16.25763733\n[16] Jaïs P Terris B Ruszniewski P . Somatostatin receptor subtype gene expression in human endocrine gastroentero-pancreatic tumours. Eur J Clin Invest 1997;27 :639–44.9279525\n[17] Tierney JF Kosche C Schadde E . (68)Gallium-DOTATATE positron emission tomography-computed tomography (PET CT) changes management in a majority of patients with neuroendocrine tumors. Surgery 2019;165 :178–85.30415869\n\n",
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"issn_linking": "0025-7974",
"issue": "100(40)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D000855:Anorexia; D006801:Humans; D007010:Hyponatremia; D007177:Inappropriate ADH Syndrome; D008297:Male; D018358:Neuroendocrine Tumors; D010190:Pancreatic Neoplasms; D014667:Vasopressins",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e27453",
"pmc": null,
"pmid": "34622867",
"pubdate": "2021-10-08",
"publication_types": "D016428:Journal Article",
"references": "29975116;26742109;16843082;15872203;26934393;21167379;9279525;17507705;28718084;28649750;25763733;30415869;25805538;26490555;28448665;24569496;25984844",
"title": "Pancreatic neuroendocrine tumor producing vasopressin: A case report.",
"title_normalized": "pancreatic neuroendocrine tumor producing vasopressin a case report"
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"companynumb": "CN-NOVARTISPH-NVSC2021CN262504",
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"activesubstancename": "DICLOFENAC SODIUM"
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"abstract": "BACKGROUND\nPatients with severe portopulmonary hypertension (PoPH) responsive to medical therapy may be considered for liver transplantation. We present a case of extracorporeal membrane oxygenation (ECMO) resuscitation for PoPH crisis in a child following liver transplantation (LT), and review the literature on management of this challenging setting.\n\n\nMETHODS\nA 7-year-old girl, with previous Kasai portoenterostomy and subsequent severe PoPH responsive to pulmonary vasodilator therapy, underwent orthotopic LT. Five days following surgery, she had an asystolic arrest with suprasystemic pulmonary hypertension, and was resuscitated with ECMO therapy. Multi-modal strategies included sildenafil, ambrisentan, nitric oxide, intravenous Epoprostenol infusion, levosimendan, and atrial septostomy. Ten days after her LT, exploration for bleeding was necessary following abdominal drain removal. By 10 days of ECMO support, she was reviewed and considered for lung transplantation. Unfortunately, she deteriorated precipitously with abdominal compartment syndrome and multi-organ failure; sadly, life support was withdrawn 23 days after transplantation.\n\n\nCONCLUSIONS\nPatients with severe PoPH may need combined thoracic organ and liver transplantation either at single or serial events. Case reports on ECMO use include resuscitation after massive pulmonary embolism during liver transplantation, bridge until the goal of vasodilatory therapy was reached in worsening PoPH following LT, and bridge to lung or repeat liver transplantation for severe pulmonary hypertension.\n\n\nCONCLUSIONS\nECMO resuscitation and support may be deployed as rescue therapy around the period of liver transplantation. We highlight the importance of patient selection and high risk of complications during ECMO therapy as a bridge to PoPH control.",
"affiliations": "1 Pediatric Intensive Care Unit, Royal Brompton Hospital, Royal Brompton & Harefield NHS Foundation Trust, London - UK.",
"authors": "Chan-Dominy|Amy C|AC|;Rahiman|Sarfaraz N|SN|;Anders|Marc|M|;Butt|Warwick|W|",
"chemical_list": null,
"country": "United States",
"delete": false,
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"issn_linking": "0391-3988",
"issue": "38(6)",
"journal": "The International journal of artificial organs",
"keywords": null,
"medline_ta": "Int J Artif Organs",
"mesh_terms": "D002648:Child; D015199:Extracorporeal Membrane Oxygenation; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D016031:Liver Transplantation",
"nlm_unique_id": "7802649",
"other_id": null,
"pages": "337-42",
"pmc": null,
"pmid": "26044656",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Extracorporeal membrane oxygenation and severe portopulmonary hypertension following liver transplantation: brief report.",
"title_normalized": "extracorporeal membrane oxygenation and severe portopulmonary hypertension following liver transplantation brief report"
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"companynumb": "GB-GILEAD-2016-0217237",
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"abstract": "HIV-positive patients are treated with various antiretroviral-containing drug combinations to control their underlying disease, which may also be combined with drugs aimed to manage independent or secondary comorbidities. This can expose patients to drug-drug interactions (DDIs) that may lead to suboptimal drug exposure, an increased risk of therapeutic failure or poor tolerability, and a need to adopt alternative therapeutic strategies. Although such undesired responses to pharmacological therapies can be appropriately managed in some situations, the fact that the available information is usually incomplete which makes it difficult (if not impossible) to assess DDIs and the consequent adjustments of polytherapies in clinical practice. For these reasons, we set up our ambulatory polytherapy management (Gestione Ambulatoriale Politerapie [GAP]) outpatient clinic in September 2016 to manage polypharmacy in HIV-infected patients. The main aims of the GAP clinic are to check whether patients are treated with drug combinations that are contraindicated due to known or predictable DDIs; assess the clinical and/or pharmacokinetic relevance of the DDIs; and provide written advice as to how the treatments should be modified if possible. We here describe the results of our 2-year experience in various clinical scenarios.",
"affiliations": "Gestione Ambulatoriale Politerapie Outpatient Clinic. ASST Fatebenefratelli Sacco University Hospital, Milan, Italy.;Department of Infectious Diseases. ASST Fatebenefratelli Sacco University Hospital, Milan, Italy.;Gestione Ambulatoriale Politerapie Outpatient Clinic. ASST Fatebenefratelli Sacco University Hospital, Milan, Italy.",
"authors": "Gervasoni|Cristina|C|;Formenti|Tiziana|T|;Cattaneo|Dario|D|",
"chemical_list": "D019380:Anti-HIV Agents; D019440:Anti-Obesity Agents; D002121:Calcium Channel Blockers",
"country": "Spain",
"delete": false,
"doi": "10.24875/AIDSRev.19000035",
"fulltext": null,
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"issn_linking": "1139-6121",
"issue": "21(1)",
"journal": "AIDS reviews",
"keywords": "Drug-drug interactions; HIV; Polypharmacy",
"medline_ta": "AIDS Rev",
"mesh_terms": "D000554:Ambulatory Care Facilities; D019380:Anti-HIV Agents; D019440:Anti-Obesity Agents; D002121:Calcium Channel Blockers; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D015658:HIV Infections; D006801:Humans; D007558:Italy; D019338:Polypharmacy",
"nlm_unique_id": "101134876",
"other_id": null,
"pages": "40-49",
"pmc": null,
"pmid": "30899119",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Management of Polypharmacy and Drug-Drug Interactions in HIV Patients: A 2-year Experience of a Multidisciplinary Outpatient Clinic",
"title_normalized": "management of polypharmacy and drug drug interactions in hiv patients a 2 year experience of a multidisciplinary outpatient clinic"
} | [
{
"companynumb": "IT-MYLANLABS-2019M1101326",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ORLISTAT"
},
"drugadditional": null,
... |
{
"abstract": "Borreliosis is a common affliction in northern countries and its neurological manifestations often mislead trained clinicians. We present three cases of Lyme neuroborreliosis, with intrathecal synthesis of specific antibodies, lymphocytic meningitis and magnetic-resonance imaging (MRI) findings. Our description aims at illustrating the natural history of the infection, highlighting persistent intrathecal synthesis of anti-Borrelia antibodies months after treatment completion, and its clinical significance. We then review the literature on MRI findings in neuroborreliosis and the kinetics of intrathecal synthesis of specific anti-Borrelia antibodies.",
"affiliations": "Service de médecine interne, institut mutualiste Montsouris, 42, boulevard Jourdan, 75014 Paris, France.;Service de radiologie, institut mutualiste Montsouris, 42, boulevard Jourdan, 75014 Paris, France.;Centre national de référence de la maladie de Lyme, 1, rue Koeberlé, 67000 Strasbourg, France; Laboratoire de biologie, centre hospitalier de Mende, 53, avenue du 8-mai-1945, 48000 Mende, France.;Service de médecine interne, institut mutualiste Montsouris, 42, boulevard Jourdan, 75014 Paris, France.;Service de médecine interne, institut mutualiste Montsouris, 42, boulevard Jourdan, 75014 Paris, France. Electronic address: julie.cosserat@gmail.com.",
"authors": "Jeantin|L|L|;Rodriguez-Regent|C|C|;De Martino|S|S|;Gayraud|M|M|;Cosserat|J|J|",
"chemical_list": "D000907:Antibodies, Bacterial; D007074:Immunoglobulin G",
"country": "France",
"delete": false,
"doi": "10.1016/j.idnow.2021.02.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2666-9919",
"issue": "51(7)",
"journal": "Infectious diseases now",
"keywords": "Borrelia; Immunoglobulin; Lyme neuroborreliosis; Magnetic resonance imaging; Meningitis",
"medline_ta": "Infect Dis Now",
"mesh_terms": "D000907:Antibodies, Bacterial; D001898:Borrelia; D006801:Humans; D007074:Immunoglobulin G; D007700:Kinetics; D020852:Lyme Neuroborreliosis",
"nlm_unique_id": "101775152",
"other_id": null,
"pages": "627-629",
"pmc": null,
"pmid": "33870892",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Intrathecal antibody kinetics in neuroborreliosis: A report on three cases and a literature review.",
"title_normalized": "intrathecal antibody kinetics in neuroborreliosis a report on three cases and a literature review"
} | [
{
"companynumb": "FR-MYLANLABS-2021M1073894",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nCytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) prolongs survival in selected patients with peritoneal metastases. Since this procedure is likely to be associated with increased morbidity and mortality, it remains controversial whether it is also suitable for patients older than 70 years.\n\n\nMETHODS\nConsecutive patients with radiographic evidence of peritoneal metastases (PM) were scheduled for CRS and HIPEC at the Comprehensive Cancer Center, University Hospital Tübingen, Germany. Clinical data were retrospectively analyzed categorizing patients with respect to age into elderly (age ≥ 70) and non-elderly patients (age < 70).\n\n\nRESULTS\nBetween June 2005 and March 2014, 381 patients with a median age of 55 [14-77] years could be enrolled with 29 patients (8 %) being at least 70 years old. Both groups were comparable for tumor-related parameters including PCI, CC-status, time in operating room, and visceral resections. However, there was a difference in patient-related factors such as cardio-pulmonary comorbidities and ASA score. We found no difference in overall and recurrence-free survival between the two groups. Surgery-related mortality was 0.9 % in patients younger than 70 years whereas no patient died in the elderly group. Overall morbidity was 47 % in the younger and 76 % in the elderly group (p = 0.048). There was no difference in Clavien-Dindo grade III-IV morbidity. Logistic regression analysis proved age as an independent risk factor for increased overall morbidity in elderly patients.\n\n\nCONCLUSIONS\nIn elderly patients, CRS and HIPEC are associated with increased overall morbidity but neither Dindo III-IV morbidity nor surgery-related mortality.",
"affiliations": "Comprehensive Cancer Center with the Department of General, Visceral and Transplant Surgery, University of Tübingen, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany.",
"authors": "Beckert|Stefan|S|;Struller|Florian|F|;Horvath|Philipp|P|;Falcke|Anya|A|;Königsrainer|Alfred|A|;Königsrainer|Ingmar|I|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00423-015-1325-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1435-2443",
"issue": "400(6)",
"journal": "Langenbeck's archives of surgery",
"keywords": null,
"medline_ta": "Langenbecks Arch Surg",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D010478:Chemotherapy, Cancer, Regional Perfusion; D065426:Cytoreduction Surgical Procedures; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010534:Peritoneal Neoplasms; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9808285",
"other_id": null,
"pages": "693-8",
"pmc": null,
"pmid": "26245705",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
"references": "14567022;19701772;20101645;19387742;21431408;21780124;15310771;15123461;14551293;8849954;19152648;19917862;19917863;17653801;25753048;15273542;1531739;23780382;16420934;12089832;17496308;8849962;24809147;6279229",
"title": "Overall morbidity but not mortality is increased in elderly patients following cytoreductive surgery and HIPEC.",
"title_normalized": "overall morbidity but not mortality is increased in elderly patients following cytoreductive surgery and hipec"
} | [
{
"companynumb": "DE-JNJFOC-20150902433",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND\nPhotosensitivity, which is a main feature of Jeavons syndrome, can be seen in other types of idiopathic or genetic epilepsies with focal or generalized seizures and tends to disappear spontaneously usually in the second decade. Although it responds well to antiepileptic treatment, especially to valproic acid, it may continue into adulthood in rare cases.\n\n\nMETHODS\nWe describe a 63-year-old male patient with eyelid myoclonia with absences, generalized tonic-clonic seizures, and severe photosensitivity accompanied by eyelid myoclonia. Seizures were treated with antiepileptic treatment, whereas photosensitivity still continued on electroencephalogram without clinical findings.\n\n\nCONCLUSIONS\nOur elderly patient with Jeavons syndrome with ongoing remarkable photosensitivity demonstrated that it may continue to older ages, although it is uncommon.",
"affiliations": "Department of Neurology, Cerrahpasa School of Medicine, İstanbul University.",
"authors": "Gülen Abanoz|Yeşim|Y|;Abanoz|Yasin|Y|;Özkara|Çiğdem|Ç|",
"chemical_list": "D000927:Anticonvulsants",
"country": "United States",
"delete": false,
"doi": "10.1097/NRL.0000000000000175",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1074-7931",
"issue": "23(3)",
"journal": "The neurologist",
"keywords": null,
"medline_ta": "Neurologist",
"mesh_terms": "D000927:Anticonvulsants; D004569:Electroencephalography; D004832:Epilepsy, Absence; D006801:Humans; D008297:Male; D008875:Middle Aged; D009207:Myoclonus; D010775:Photic Stimulation",
"nlm_unique_id": "9503763",
"other_id": null,
"pages": "94-97",
"pmc": null,
"pmid": "29722743",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ongoing Photosensitivity in An Elderly Patient With Jeavons Sydrome.",
"title_normalized": "ongoing photosensitivity in an elderly patient with jeavons sydrome"
} | [
{
"companynumb": "TR-VALIDUS PHARMACEUTICALS LLC-TR-2018VAL000859",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drug... |
{
"abstract": "Thrombotic thrombocytopenic purpura (TTP) is a microangiopatic thrombotic state associated with a deficiency on the cleavage function of the Von Willebrand factor polymers by a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13. We report a patient with relapsing TTP successfully treated with N-acetylcysteine (NAC) after failure of plasma exchange (PE) with steroids, rituximab, cyclophosphamide, vincristine, and azathioprine. A 51-year-old male who had an altered mental status while he was on rehabilitation for a previously treated TTP with a subsequent neurologic deficit. He was treated 7 days ago with PE plus steroids and subsequently discharged to our facility for rehabilitation. He was found to have a platelet level of 153,000/mm, hemoglobin decreased from 9.2 to 6.2 g/dL, creatinine raised from 1.0 to 2.4 mg/dL, and the peripheral smear showed schistocytes. A brain computed tomography showed a subacute infarction in the left frontal lobe and an abdominal-pelvic computed tomography disclosed a retroperitoneal hematoma. PE and steroids were started for 14 days. On day 15th, rituximab was added weekly for 10 cycles. A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 activity level was 95% without platelet count improvement. We started cyclophosphamide, then vincristine, and finally azathioprine. His platelet were maintained above 150,000/mm for a few days. He had several episodes of sepsis after every chemotherapeutic drug. On day 135th, NAC was commenced at 150 mg/kg for 10 days along with PE and low-dose steroids for 10 days. Complete recover of platelet count was achieved and the patient was successfully discharged. Relapsing TTP is often difficult to manage and may last longer than expected carrying several comorbidities and complications. PE plus steroids are the mainstay of TTP treatment and Rituximab is the drug of choice after they have failed. The patient had a complete remission after NAC therapy. Hence, NAC likely can be considered an earlier choice of treatment after rituximab, before the use of chemotherapeutic agents, considering its toxic and adverse effects.",
"affiliations": "Department of Medicine, New York Medical College Metropolitan Hospital Center, New York, NY.",
"authors": "Cabanillas|Gerardo|G|;Popescu-Martinez|Andrea|A|",
"chemical_list": "D013256:Steroids; D000069283:Rituximab; D000111:Acetylcysteine",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000386",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "23(5)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000111:Acetylcysteine; D003131:Combined Modality Therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D010951:Plasma Exchange; D010976:Platelet Count; D011697:Purpura, Thrombotic Thrombocytopenic; D012008:Recurrence; D012074:Remission Induction; D000069283:Rituximab; D013256:Steroids; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e1277-9",
"pmc": null,
"pmid": "26720166",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "N-Acetylcysteine for Relapsing Thrombotic Thrombocytopenic Purpura: More Evidence of a Promising Drug.",
"title_normalized": "n acetylcysteine for relapsing thrombotic thrombocytopenic purpura more evidence of a promising drug"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-16-02278",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"... |
{
"abstract": "OBJECTIVE\nTo describe a case of chronic pancreatic insufficiency related to antituberculous therapy.\n\n\nMETHODS\nA 57-year-old man developed rash, fever, and hepatitis (aspartate aminotransferase 369 IU/L, alanine aminotransferase 506 IU/L), 6 weeks after starting isoniazid, rifampin, ethambutol, and pyrazinamide. He also developed severe metabolic acidosis secondary to diabetic ketoacidosis and lactic acidosis (serum bicarbonate 7 mEq/L, glucose 1778 mg/dL, and lactate 4.0 mEq/L). Acute pancreatitis was diagnosed on the basis of a mildly elevated amylase concentration (392 U/L) and radiologic evidence of pancreatic inflammation. He developed pancreatic insufficiency with steatorrhea and an abnormal secretin test. He continues to require pancreatic enzyme replacement and insulin therapy. Rechallenge was not performed.\n\n\nCONCLUSIONS\nHypersensitivity syndromes have been reported for various drug therapies, including antituberculous agents. Hypersensitivity syndrome reactions are characterized by fever, rash, and internal organ involvement. Rifampin has been reported to cause acute pancreatitis in up to 2.7% of patients. Drug-induced chronic pancreatitis, however, is reported to be extremely rare. This is the first reported case of chronic pancreatic insufficiency occurring in the setting of a hypersensitivity syndrome reaction to antituberculous drugs.\n\n\nCONCLUSIONS\nChronic pancreatic insufficiency should be considered as a possible long-term sequelae of a hypersensitivity syndrome reaction to antituberculous therapy.",
"affiliations": "Department of Medicine, Sunnybrook Health Science Centre, Toronto, Ontario, Canada.",
"authors": "Liu|B A|BA|;Knowles|S R|SR|;Cohen|L B|LB|;Werb|M R|MR|;Shear|N H|NH|",
"chemical_list": "D000995:Antitubercular Agents; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin",
"country": "United States",
"delete": false,
"doi": "10.1177/106002809703100610",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "31(6)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000995:Antitubercular Agents; D002908:Chronic Disease; D004342:Drug Hypersensitivity; D004359:Drug Therapy, Combination; D004977:Ethambutol; D010188:Exocrine Pancreatic Insufficiency; D006801:Humans; D007538:Isoniazid; D008297:Male; D008875:Middle Aged; D011718:Pyrazinamide; D012293:Rifampin",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "724-6",
"pmc": null,
"pmid": "9184712",
"pubdate": "1997-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pancreatic insufficiency due to antituberculous therapy.",
"title_normalized": "pancreatic insufficiency due to antituberculous therapy"
} | [
{
"companynumb": "CA-SA-2018SA159925",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugadditional": "1",
"drug... |
{
"abstract": "A patient was treated for several years with high doses of opioids for malignant pain. During a recent hospitalization, the patient's pain remained uncontrolled despite escalating doses of various opioids. We suspected that this patient suffered from the clinical phenomenon of opioid-induced hyperalgesia (OIH). The patient was then rotated from her other opioids to methadone, and her pain was adequately controlled within several days. Methadone, because of its NMDA antagonist properties, offers an effective treatment for OIH. The use of methadone for analgesia is complex and should be undertaken only by practitioners who have appropriate experience.",
"affiliations": "Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA.",
"authors": "Axelrod|David J|DJ|;Reville|Barbara|B|",
"chemical_list": "D000701:Analgesics, Opioid; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.5055/jom.2007.0048",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1551-7489",
"issue": "3(2)",
"journal": "Journal of opioid management",
"keywords": null,
"medline_ta": "J Opioid Manag",
"mesh_terms": "D000701:Analgesics, Opioid; D001416:Back Pain; D016903:Drug Monitoring; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D006930:Hyperalgesia; D008691:Methadone; D008875:Middle Aged; D009101:Multiple Myeloma; D010147:Pain Measurement; D010148:Pain, Intractable; D016896:Treatment Outcome",
"nlm_unique_id": "101234523",
"other_id": null,
"pages": "113-4",
"pmc": null,
"pmid": "17520991",
"pubdate": "2007",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Using methadone to treat opioid-induced hyperalgesia and refractory pain.",
"title_normalized": "using methadone to treat opioid induced hyperalgesia and refractory pain"
} | [
{
"companynumb": "US-SPECGX-T202002182",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXYCODONE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "In the National Comprehensive Cancer Network (NCCN) guidelines, oxaliplatin (L-OHP)-based chemotherapeutic regimens, including 5-fluorouracil, Leucovorin (LV), and L-OHP (FOLFOX); capecitabine and L-OHP (CapeOX); and 5-fluorouracil, folinic acid, and L-OHP (FLOX) are designated as category 1 recommendations for postoperative adjuvant chemotherapy in Stage III colon cancer, followed by capecitabine and 5-fluorouracil plus LV as category 2A recommendations. We studied the selection of drugs for adjuvant chemotherapy and assessed the tolerability and safety of CapeOX and tegafur-uracil (UFT) plus LV (UFT/LV) in patients with Stage III colon cancer. The study group included 104 consecutive patients with Stage III colon cancer who underwent curative surgery. One patient changed hospitals immediately after surgery. Among the remaining 103 patients, 82 (80%) received adjuvant chemotherapy and 21 (20%) did not. CapeOX was administered to 32 patients (31%), UFT/LV to 49 patients (48%), and capecitabine to 1 patient (1%). In 59 patients, the treatment choice was determined according to the patient's preference; 32 patients (54%) selected CapeOX, 26 (44%) selected UFT/LV, and 1 (2%) selected no chemotherapy. The treatment completion rate was 80% for CapeOX and 84% for UFT/LV. Among patients who completed chemotherapy, dose reduction and drug withdrawal were not required in 22% of patients who received CapeOX and 80% of those who received UFT/LV. Neither CapeOX nor UFT/LV was associated with any serious adverse events. The tolerability and safety of CapeOX and UFT/LV were acceptable. However, CapeOX dose had to be carefully adjusted according to each patient's condition.",
"affiliations": "Dept. of Gastroenterological Surgery, Tokai University School of Medicine.",
"authors": "Okada|Kazutake|K|;Sadahiro|Sotaro|S|;Saito|Gota|G|;Tanaka|Akira|A|;Suzuki|Toshiyuki|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "43(5)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012189:Retrospective Studies",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "587-92",
"pmc": null,
"pmid": "27210088",
"pubdate": "2016-05",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Postoperative Adjuvant Chemotherapy for Stage III Colon Cancer--Drug Selection, Tolerability, and Safety in Clinical Practice.",
"title_normalized": "postoperative adjuvant chemotherapy for stage iii colon cancer drug selection tolerability and safety in clinical practice"
} | [
{
"companynumb": "JP-ROCHE-1834268",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "A 78-year-old man visited our hospital with a prolapsed hemorrhoid. He was referred to the dermatology unit due to the thickness and redness of the perianal skin. He was diagnosed as having extra mammary Paget's disease by skin biopsy. After a biopsy of the anal polyp was performed to investigate the primary site, he was diagnosed with early anal canal cancer with Pagetoid spread and underwent a radical operation. Abdominoperineal resection with skin(D2 prx D3 lymphadenectomy) was performed with perineal reconstruction using a gracilis muscle graft. Postoperative surveillance without adjuvant therapy was performed because the pathological stage was stage I. Two years and 2 months after surgery, multiple liver metastases were found, and the patient was diagnosed with multiple liver, bone, and lymph node metastases(K-ras and UGT1A1 wild type)on PET. XELOX plus bevacizumab was used as first-line treatment and the liver metastases showed remarkable shrinkage; however, disease progression occurred in the bone. IRIS plus bevacizumab was started as second-line therapy but grade 3 hematotoxicity was observed during the first course. After 4 courses, it was difficult to maintain the therapy due to toxicity and cancer-related pain. The liver metastases had almost disappeared but the patient died 11 months after the initiation of chemotherapy.",
"affiliations": "Dept. of Surgery, Tokyo Women's Medical University Medical Center East.",
"authors": "Yoshimatsu|Kazuhiko|K|;Osawa|Gakuji|G|;Yokomizo|Hajime|H|;Yano|Yuki|Y|;Okayama|Sachiyo|S|;Sakuma|Akiko|A|;Satake|Masaya|M|;Yamada|Yasufumi|Y|;Asaka|Shinichi|S|;Usui|Takebumi|T|;Yamaguchi|Kentaro|K|;Shiozawa|Shunichi|S|;Shimakawa|Takeshi|T|;Katsube|Takao|T|;Naritaka|Yoshihiko|Y|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "43(10)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001005:Anus Neoplasms; D001706:Biopsy; D001859:Bone Neoplasms; D017809:Fatal Outcome; D006801:Humans; D008113:Liver Neoplasms; D008207:Lymphatic Metastasis; D008297:Male",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1292-1294",
"pmc": null,
"pmid": "27760964",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Early Anal Canal Cancer with Pagetoid Spread with Different Antitumor Effects of Chemotherapy on Different Metastatic Sites.",
"title_normalized": "a case of early anal canal cancer with pagetoid spread with different antitumor effects of chemotherapy on different metastatic sites"
} | [
{
"companynumb": "JP-ACCORD-048627",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GIMERACIL\\OTERACIL\\TEGAFUR"
},
"drugadditional": nul... |
{
"abstract": "BACKGROUND\nErythema nodosum is often associated with a distressing symptomatology, including painful subcutaneous nodules, polyarthropathy, and significant fatigue. Whilst it is a well-documented side-effect of estrogen therapy in females, we describe what we believe to be the first report in the literature of erythema nodosum as a result of estrogen therapy in a male.\n\n\nMETHODS\nA 64-year-old Afro-Caribbean man with locally advanced carcinoma of the prostate agreed to participate in a randomized controlled trial comparing estrogen patches with luteinizing hormone-releasing hormone analogs to achieve androgen deprivation, and was allocated to the group receiving estrogen patches. One month later he presented with tender lesions on his shins and painful swelling of his ankles, wrists, and left shoulder. This was followed by progressive severe fatigue that required hospital admission, where he was diagnosed with erythema nodosum by a rheumatologist. Two months after discontinuing the estrogen patches the erythema nodosum, and associated symptoms, had fully resolved, and to date he remains well with no further recurrence.\n\n\nCONCLUSIONS\nTrial results may establish transdermal estrogen as an alternative to luteinizing hormone-releasing hormone analogs in the management of prostate cancer, and has already been established as a therapy for male to female transsexuals. It is essential to record the toxicity profile of transdermal estrogen in men to ensure accurate safety information. This case report highlights a previously undocumented toxicity of estrogen therapy in men, of which oncologists, urologists, and endocrinologists need to be aware. Rheumatologists and dermatologists should add estrogen therapy to their differential diagnosis of men presenting with erythema nodosum.",
"affiliations": "MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London, WC2B 6NH, UK. c.coyle@ucl.ac.uk.;Imperial College Healthcare NHS Trust, Charing Cross Hospital, Fulham Palace Road, London, W6 8RF, UK. s.mangar@imperial.ac.uk.;Department of Surgery, 'B' Block Hammersmith Campus, Imperial College Faculty of Medicine, DuCane Road, London, W12 0NN, UK. p.abel@imperial.ac.uk.;MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London, WC2B 6NH, UK. ruth.langley@ucl.ac.uk.",
"authors": "Coyle|Christopher|C|;Mangar|Stephen|S|;Abel|Paul|P|;Langley|Ruth E|RE|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D004967:Estrogens; D004958:Estradiol",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-015-0776-4",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 77610.1186/s13256-015-0776-4Case ReportErythema nodosum as a result of estrogen patch therapy for prostate cancer: a case report Coyle Christopher c.coyle@ucl.ac.uk Mangar Stephen s.mangar@imperial.ac.uk Abel Paul p.abel@imperial.ac.uk Langley Ruth E. ruth.langley@ucl.ac.uk MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London, WC2B 6NH UK Imperial College Healthcare NHS Trust, Charing Cross Hospital, Fulham Palace Road, London, W6 8RF UK Department of Surgery, ‘B’ Block Hammersmith Campus, Imperial College Faculty of Medicine, DuCane Road, London, W12 0NN UK Department of Urology (3N), Charing Cross Hospital, Imperial College Healthcare NHS Trust, Fulham Palace Road, London, W6 8RF UK 14 12 2015 14 12 2015 2015 9 28510 4 2015 25 11 2015 © Coyle et al. 2015\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.Introduction\nErythema nodosum is often associated with a distressing symptomatology, including painful subcutaneous nodules, polyarthropathy, and significant fatigue. Whilst it is a well-documented side-effect of estrogen therapy in females, we describe what we believe to be the first report in the literature of erythema nodosum as a result of estrogen therapy in a male.\n\nCase presentation\nA 64-year-old Afro-Caribbean man with locally advanced carcinoma of the prostate agreed to participate in a randomized controlled trial comparing estrogen patches with luteinizing hormone-releasing hormone analogs to achieve androgen deprivation, and was allocated to the group receiving estrogen patches. One month later he presented with tender lesions on his shins and painful swelling of his ankles, wrists, and left shoulder. This was followed by progressive severe fatigue that required hospital admission, where he was diagnosed with erythema nodosum by a rheumatologist. Two months after discontinuing the estrogen patches the erythema nodosum, and associated symptoms, had fully resolved, and to date he remains well with no further recurrence.\n\nConclusion\nTrial results may establish transdermal estrogen as an alternative to luteinizing hormone-releasing hormone analogs in the management of prostate cancer, and has already been established as a therapy for male to female transsexuals. It is essential to record the toxicity profile of transdermal estrogen in men to ensure accurate safety information. This case report highlights a previously undocumented toxicity of estrogen therapy in men, of which oncologists, urologists, and endocrinologists need to be aware. Rheumatologists and dermatologists should add estrogen therapy to their differential diagnosis of men presenting with erythema nodosum.\n\nKeywords\nErythema nodosumEstrogen patchPATCH TrialProstate cancerTransdermal estrogenissue-copyright-statement© The Author(s) 2015\n==== Body\nIntroduction\nErythema nodosum classically presents as raised tender nodules in the skin and subcutaneous tissue. These nodules are most commonly distributed on the lower extremities, particularly the pretibial surfaces, but may occur in other anatomical locations including the thighs and extensor aspects of the forearms. Other associated symptoms may include fever, arthralgia, and generalized weakness [1]. Whilst it is thought to represent a hypersensitivity reaction, determining the etiology of erythema nodosum is notoriously difficult, with the resulting uncertainty causing patients additional distress. The underlying causes include infections, (most commonly Group A streptococcus, but also hepatitis B and C, human immunodeficiency virus, tuberculosis, and mycoplasma pneumonia), disease processes (including inflammatory bowel disease, sarcoidosis, and Behçet’s disease), elevated hormonal states (pregnancy), malignancy (for example, Hodgkin’s lymphoma), and medications (estrogens, sulfonamides, penicillins), and up to 55 % of cases are thought to be idiopathic in origin [2].\n\nErythema nodosum most commonly occurs in young women. A recent Italian case series (n = 124) found that the ratio of females to males was 10:1 and the mean age of onset was 39.5 years old [3]. The propensity towards females is at least partially due to estrogen exposure; in this series, 6.5 % of cases occurred during pregnancy and 5.6 % were attributed to a combination of estrogen-based and progesterone-based medications [3].\n\nThe toxicity profile of estrogen is established mainly from its use in women. Toxicities specific to females include breast pain, endometrial hyperplasia, and an increased risk of breast and endometrial cancer [4]. Adverse effects unrelated to gender include venous and arterial thromboembolism, cardiovascular morbidity including cerebrovascular accident, and myocardial infarction [4]. The consequences of estrogen therapy in males may be attributed to either the resulting low testosterone levels (loss of libido, impotence, and hot flushes) or to the direct effects of estrogen (gynecomastia).\n\nMost established indications for estrogen therapy are in women, for example, as a treatment for the symptoms and sequelae of estrogen deficiency in post-menopausal women, and in combination with progesterone as a contraceptive. In males, estrogen therapy is currently used in the treatment of male to female transsexuals [5], and transdermal estrogen is currently being investigated as a potential therapy for men with prostate cancer.\n\nAndrogen deprivation therapy resulting in testosterone suppression is a key strategy in the management of prostate cancer. This is mainly achieved through the use of luteinizing hormone-releasing hormone (LHRH) analogs, and occasionally by surgical orchidectomy. Historically, oral estrogen (diethylstilboestrol) has been used for androgen deprivation therapy; however, it is not used routinely because of cardiovascular toxicity attributed to first-pass hepatic metabolism [6]. Transdermal administration of estrogen avoids the entero-hepatic circulation and so is expected to mitigate the risk of cardiovascular toxicity [7].\n\nPATCH (Prostate Adenocarcinoma: TransCutaneous Hormones Trial) is a randomized controlled trial of transcutaneous estrogen patches versus LHRH analogs. An early analysis of toxicity in PATCH (n = 138) revealed that men allocated estrogen patches experienced gynecomastia (75 %), impotence (57 %), loss of libido (56 %), and hot flushes (25 %) within the first 6 months of using the patches, though most effects were mild (mainly Common Terminology Criteria for Adverse Events [CTCAE] grade 1 or 2) [8]. In addition to these effects, the consequences of estrogen therapy in male to female transsexuals include redistribution of body fat, decreased muscle mass and strength, softening of skin, and decreased terminal hair growth [5]. To date, there have been no reports in the literature of erythema nodosum developing as a result of estrogen therapy in a man.\n\nCase presentation\nA 64-year-old Afro-Caribbean man with locally advanced adenocarcinoma of the prostate (T4 NO MO, Gleason score 4+5) was randomized to the transdermal estrogen arm (initially, three Merck Estrogen Femseven patches 100 μg/24 hours, changed twice a week) of the PATCH study (control arm was an LHRH analog). Four weeks later he developed tender lesions on his shins (Fig. 1) associated with painful swelling in his ankles, wrists, and left shoulder, which was followed by progressive severe fatigue. On review by an oncologist, there were initial concerns that the combination of swollen ankles and fatigue could be a result of heart failure secondary to estrogen-induced cardiovascular toxicity. His testosterone level had also fallen to castrate levels, and the number of estrogen patches administered was changed to twice weekly as mandated in the trial protocol. He was then seen by his general practitioner and on examination was found to have bilateral subconjunctival hematomas in addition to the tender nodules on his shins. He was treated with oral diclofenac and misoprostol, oral cephalexin, and chloramphenicol eye drops. His symptoms persisted despite these interventions and 1 week later the decision was made to discontinue the estrogen patches and switch his therapy to an LHRH analog (goserelin).Fig. 1 A photograph of bilateral shin lesions taken at the time of first presentation\n\n\n\nTwo weeks after switching to the LHRH analog, he was admitted to hospital with worsening fatigue and arthralgia. He was found to have sinus tachycardia (115 beats per minute) with no other abnormalities on electrocardiogram, elevated C-reactive protein (122 mg/L, normal <8 mg/L), and elevated alkaline phosphatase (265 u/L, normal range 30–130 u/L). He had recently had a chest X-ray with no abnormal findings, and tested negative for tuberculosis. Streptococcal infection was also excluded.\n\nOur patient was reviewed by a rheumatologist, who confirmed a diagnosis of erythema nodosum as a result of estrogen therapy. His symptoms resolved 8 weeks after discontinuing the estrogen patches (replaced with the LHRH analog), and to date he remains well with no further recurrence. A serious adverse event form was completed describing grade 2 arthralgia and grade 2 peripheral edema (CTCAE v3.0). As a serious and unexpected toxicity of estrogen patches in men, this was reported to the Medicines and Healthcare products Regulatory Agency as a “suspected unexpected serious adverse reaction.”\n\nDiscussion\nAttributing the underlying etiology of erythema nodosum relies on the exclusion of other potential causes that fit with the case history. Behçet’s disease may also present with a combination of erythema nodosum and ophthalmic signs, however Behçet’s disease is usually associated with redness and inflammation of the eyes rather than bilateral subconjunctival hematomas, and the absence of any of other features (recurrent mouth and genital ulcers) made this an unlikely diagnosis. Another etiology considered was infection, given the finding of raised C-reactive protein; however, no infective source was identified. Whilst an infectious etiology could not be excluded, given that the initiation and discontinuation of estrogen patches corresponded with the emergence and resolution of erythema nodosum, it seemed highly probable that estrogen was the underlying cause in this case.\n\nConclusions\nThis case report highlights a rare toxicity of estrogen therapy, with only one case recorded, at the time of submission, in 448 patients receiving transdermal estrogen in PATCH with an estimated total of 1120 patient-years of exposure, and no other cases reported in the literature to the best of our knowledge. Transdermal estrogen is already prescribed for male to female transsexuals, and, depending on the findings of PATCH, may be used as an alternative to LHRH analogs in the management of prostate cancer. Transdermal estrogen should be added to the differential diagnosis of men with erythema nodosum, and all health professionals prescribing transdermal estrogen need to be aware of this potential toxicity.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nCTCAE v3.0Common Terminology Criteria for Adverse Events Version 3.0\n\nLHRHluteinizing hormone-releasing hormone\n\nPATCHProstate Adenocarcinoma: TransCutaneous Hormones trial\n\nCompeting interests\n\nRL and PA are Co-Principal Investigators of PATCH. The authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nRL and PA conceived the manuscript. CC performed a literature search and wrote the manuscript. SM acquired patient information. SM, PA, and RL revised the manuscript critically for important intellectual content and all authors reviewed and approved the final version of the manuscript.\n\nAcknowledgements\nPATCH is supported by the Medical Research Council Clinical Trials Unit at University College London funded by Cancer Research UK.\n==== Refs\nReferences\n1. Cribier B Caille A Heid E Grosshans E Erythema nodosum and associated diseases. A study of 129 cases Int J Dermatol 1998 37 9 667 72 10.1046/j.1365-4362.1998.00316.x 9762816 \n2. Blake T Manahan M Rodins K Erythema nodosum - a review of an uncommon panniculitis Dermatol Online J 2014 20 4 22376 24746312 \n3. Papagrigoraki A Gisondi P Rosina P Cannone M Girolomoni G Erythema nodosum: etiological factors and relapses in a retrospective cohort study Eur J Dermatol 2010 20 6 773 7 21030339 \n4. MHRA. Summary of Product Characteristics (SmPC) FemSeven® 100, 100 micrograms/24 hours, transdermal patch. http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1437714884499.pdf Accessed 19 Mar 2015.\n5. Hembree WC Cohen-Kettenis P Delemarre-van de Waal HA Gooren LJ Meyer WJ III Spack NP Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline J Clin Endocrinol Metab 2009 94 9 3132 54 10.1210/jc.2009-0345 19509099 \n6. Phillips I Shah SI Duong T Abel P Langley RE Androgen deprivation therapy and the re-emergence of parenteral estrogen in prostate cancer Oncol Hematol Rev 2014 10 1 42 7 10.17925/OHR.2014.10.1.42 24932461 \n7. Ockrim JL el Lalani N Kakkar AK Abel PD Transdermal estradiol therapy for prostate cancer reduces thrombophilic activation and protects against thromboembolism J Urol 2005 174 2 527 33 10.1097/01.ju.0000165567.99142.1f 16006886 \n8. Langley RE Cafferty FH Alhasso AA Rosen SD Sundaram SK Freeman SC Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal estrogen: the randomised, phase 2 MRC PATCH trial (PR09) Lancet Oncol 2013 14 4 306 16 10.1016/S1470-2045(13)70025-1 23465742\n\n",
"fulltext_license": "CC BY",
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"mesh_terms": "D000279:Administration, Cutaneous; D018931:Antineoplastic Agents, Hormonal; D004893:Erythema Nodosum; D004958:Estradiol; D004967:Estrogens; D005221:Fatigue; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms; D016032:Randomized Controlled Trials as Topic; D017211:Treatment Failure",
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"pubdate": "2015-12-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Erythema nodosum as a result of estrogen patch therapy for prostate cancer: a case report.",
"title_normalized": "erythema nodosum as a result of estrogen patch therapy for prostate cancer a case report"
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"abstract": "Pneumatosis intestinalis (PI) can be classified into two groups. Primary PI is idiopathic, and patients can recover spontaneously. In contrast, secondary PI is considered fatal due to the high mortality rate associated with mesenteric ischemia. Herein, we describe two patients with PI and concurrent pneumoperitoneum. Both patients were receiving targeted anticancer therapy, yet neither developed abdominal pain nor fatal symptoms. One of the patients underwent surgery, while the other was managed conservatively. Even though there were no complications, the patient who underwent surgery was hospitalized for 34 days, whereas the one who was managed conservatively was hospitalized for only five days. Usually, patients with cancer receiving chemotherapy are immunosuppressed and susceptible to infections. Therefore, based on the patients' clinical features, surgical management of patients with cancer who develop PI after receiving anticancer chemotherapy should be done prudently.",
"affiliations": "Department of Emergency Medicine, Kyungpook National University School of Medicine, Daegu, Korea.;Department of Emergency Medicine, Kyungpook National University School of Medicine, Daegu, Korea.",
"authors": "Yeo|In Hwan|IH|;Kim|Yun Jeong|YJ|",
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"country": "Korea (South)",
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"doi": "10.15441/ceem.20.153",
"fulltext": "\n==== Front\nClin Exp Emerg Med\nClin Exp Emerg Med\nCEEM\nClinical and Experimental Emergency Medicine\n2383-4625\nThe Korean Society of Emergency Medicine\n\n10.15441/ceem.20.153\nceem-20-153\nCase Report\nTwo case reports of pneumatosis intestinalis in patients with cancer: is surgical management mandatory?\nYeo In Hwan\nhttp://orcid.org/0000-0002-7906-9734\nKim Yun Jeong\nDepartment of Emergency Medicine, Kyungpook National University School of Medicine, Daegu, Korea\nCorrespondence to: Yun Jeong Kim Department of Emergency Medicine, Kyungpook National University School of Medicine, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Korea E-mail: kimyjem@knu.ac.kr\n9 2021\n30 9 2021\n8 3 237241\n17 12 2020\n17 2 2021\n1 3 2021\nCopyright © 2021 The Korean Society of Emergency Medicine\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/).\nPneumatosis intestinalis (PI) can be classified into two groups. Primary PI is idiopathic, and patients can recover spontaneously. In contrast, secondary PI is considered fatal due to the high mortality rate associated with mesenteric ischemia. Herein, we describe two patients with PI and concurrent pneumoperitoneum. Both patients were receiving targeted anticancer therapy, yet neither developed abdominal pain nor fatal symptoms. One of the patients underwent surgery, while the other was managed conservatively. Even though there were no complications, the patient who underwent surgery was hospitalized for 34 days, whereas the one who was managed conservatively was hospitalized for only five days. Usually, patients with cancer receiving chemotherapy are immunosuppressed and susceptible to infections. Therefore, based on the patients’ clinical features, surgical management of patients with cancer who develop PI after receiving anticancer chemotherapy should be done prudently.\n\nPneumoperitoneum\nConservative treatment\nNeoplasms\nPneumatosis cystoides intestinalis\nCapsule Summary\n\nWhat is already known\n\nPneumatosis intestinalis can be classified into two groups. Generally, symptomatic patients with mesenteric ischemia can be identified in the emergency department. However, especially in cancer patients, there are several patients with pneumatosis intestinalis who do not have severe symptoms.\n\nWhat is new in the current study\n\nWe introduce two cancer patients with pneumatosis intestinalis and pneumoperitoneum who had minor symptoms at emergency department presentation. The length of hospitalization was different based on the treatment. Therefore, unnecessary surgical management should be avoided in patients with pneumatosis intestinalis undergoing anticancer chemotherapy.\n==== Body\npmcINTRODUCTION\n\nPneumatosis intestinalis (PI) is the presence of gas within the wall of the gastrointestinal tract. It is not a clinical diagnosis, but a physical or radiological finding resulting from an underlying pathological process [1]. PI is classified as primary (idiopathic) or secondary. Generally, primary PI is managed conservatively. In contrast, secondary PI could be fatal and requires surgery.\n\nHerein, we present two patients diagnosed with PI and concurrent renal cell carcinoma (RCC), who presented with abdominal distension after anticancer chemotherapy. In addition, we discussed the treatment of PI in patients with cancer.\n\nCASE REPORT\n\nCase 1\n\nAn 81-year-old male presented to our emergency department (ED) with painless post-prandial epigastric discomfort for five days. He had a 12-year history of RCC, chronic obstructive pulmonary disease, hypertension, and chronic renal failure. The patient was receiving chemotherapy for RCC. A month ago, he has taken 40 mg of methylprednisolone for chronic obstructive pulmonary disease exacerbation for 3 days, and he was on 5 mg of axitinib (Inlyta; Pfizer, New York, NY, USA) daily for the past year. His vital signs were within the normal range. Apart from elevated blood urea nitrogen (55.5 mg/dL, 9.0–23.0 mg/L) and creatinine (1.7 mg/dL, 0.7–1.3 mg/dL) levels, his blood tests (complete blood count with differential count, liver function tests, coagulation tests, electrolytes, and lactate level, etc.) were within normal ranges. Plain abdominal radiography and abdominal computed tomography (CT) without contrast revealed diffuse PI, predominantly in the jejunum, with a large amount of intra-abdominal free air (Fig. 1). Following a suspicion of bowel perforation, an exploratory laparotomy was performed. However, during the operation, we only found PI, which occupied 20 cm of the bowel wall 1 m away from the ileocecal valve without ischemic changes or bowel perforation (Fig. 2). On postoperative day (POD) 4, the patient started eating soft foods and did not develop any complications. On POD 8, plain abdominal radiography was performed, which showed the absence of any free air. However, the patient developed diarrhea after resuming foods. On POD 17, abdominal CT was repeated, which showed the absence of PI or pneumoperitoneum. The patient was discharged on POD 34 without any complications.\n\nCase 2\n\nA 63-year-old male was referred to the ED by a radiologist who found PI and pneumoperitoneum incidentally on CT during his regular check-up. He complained of a migrating discomfort in both flanks and abdominal distension, which started a month prior to this consultation. He had a medical history of RCC and hypothyroidism. The patient was receiving chemotherapy for RCC. He had been taking 40 mg of cabozantinib (Cabometyx; Exelixis, Alameda, CA, USA) daily for the past year. His initial vital signs were within the normal range. He had elevated blood urea nitrogen (27.3 mg/dL) and creatinine (1.81 mg/dL) levels. However, other blood tests including lactate level were within normal ranges. Plain abdominal radiography and abdominal CT without contrast revealed diffuse PI, predominantly in the jejunum, with free air in the perihepatic space (Fig. 3). He was hospitalized and managed conservatively. He started eating soft foods on postadmission day 3. He was discharged on postadmission day 5 without complications.\n\nDISCUSSION\n\nPI is caused by several underlying gastrointestinal or extra-gastrointestinal diseases, such as autoimmune diseases (e.g., scleroderma), inflammatory diseases (e.g., inflammatory bowel disease), infectious diseases (e.g., Clostridium difficile infection or human immunodeficiency virus), pulmonary diseases (e.g., chronic obstructive pulmonary disease), drugs (e.g., corticosteroids and immunosuppressive agents), and trauma (e.g., blunt abdominal trauma) [1,2]. Studies suggest that PI occurs due to disruption of the mucosal integrity. There are two major theories to explain the cause of the intramural gas [3] : (1) the bacterial theory: gas-producing bacteria translocate from the gastrointestinal lumen to the submucosal space through mucosal gaps or areas of the enhanced permeability and (2) the mechanical theory: normal gas moves from the lumen into the non-inflamed bowel wall due to disruption of the mucosal integrity.\n\nPrimary PI (15%) is asymptomatic, rare, and usually located in the colon. Individuals who are at a high risk of primary PI are males aged from 40 to 60 years [4]. Secondary PI is more common and can be fatal; it is associated with several underlying conditions, such as coronary artery disease, peripheral vascular disease, and smoking, which could lead to acute mesenteric ischemia [5]. A case series of 919 patients with PI showed that PI had a peak incidence among people in their 40s, with a male predominance (male-to-female ratio 3:1). PI affected all parts of the gastrointestinal tract: small bowel (42%), large bowel (36%), and both (22%) [6]. Patients with cancer usually receive immunosuppressive therapies, which can reduce the number of lymphocytes in the gastrointestinal wall, particularly in Peyer’s patches, and thereby impairing the bowel defense barrier system [7]. In a case series of 84 cancer-related PI cases, the CT findings associated with clinically worrisome PI were portomesenteric venous gas (PVG), bowel dilatation, bowel wall thickening, ascites, and peri-intestinal mesenteric stranding, whereas PI confined in the colon was benign [3].\n\nIn a previous report of three PI cases, an association between PI and steroids or chemotherapeutic agents (e.g., lapatinib, capecitabine, zoledronic acid, docetaxel, etc.) was found, and all the cases were benign. Such cases can be resolved with supportive care alone and close observation [8]. The most common cause of nonsurgical pneumoperitoneum is PI [9,10]. When a cyst ruptures, it may result in a pneumoperitoneum with a spectrum of symptoms ranging from asymptomatic to acute abdominal pain. Even when it mimics secondary PI, patients with gross radiological evidence could follow a more benign clinical course [10,11]. Thus, when there are no abdominal signs of peritonitis and the patient is afebrile and has normal white blood cell counts, conservative management should be considered [11].\n\nIn case 1, the patient had received targeted anticancer therapy using axitinib. In this patient, PI was confined to the small intestines with pneumoperitoneum; he did not have abdominal pain or any evidence of bowel ischemia. Although he did not have potentially fatal symptoms, such as severe abdominal pain, acidosis, and fever, which are frequently seen in secondary PI, the general surgeon performed an exploratory laparotomy to rule out bowel perforation. After confirming the absence of bowel perforation, the surgeon concluded that the patient should be managed conservatively. Due to his immunosuppressive status, old age, and imaging results, the surgeon was skeptical of the patient’s condition; however, conservative management and follow-up observation were successful.\n\nCase 2 was similar to case 1. The patient was receiving targeted anticancer therapy. In case 2, the PI was confined to the small bowel with pneumoperitoneum, and the patient did not have pain. His symptoms were not worrisome. He was managed conservatively during his 5-day hospitalization.\n\nClinicians must carefully decide how to treat a patient with PI, especially those with cancer. In a case series of 88 patients with PI, the patients’ characteristics and treatments were reviewed, and a management algorithm was constructed [5]. Among the 84 patients, 70 patients were included in an exploratory series, while 14 were included in a confirmatory series. Among the 70 patients, 19 had benign disease, and six of them with PI received chemotherapy. Among them, ten patients were managed conservatively, and nine patients underwent exploratory laparoscopy. There were no signs of bowel injury, ischemia, or necrosis. A management algorithm was constructed using the results of the exploratory series. A 3-step algorithm consists of the patients’ stability (critically ill and unstable), radiologic findings (PI/PVG with mechanical disease or iatrogenic gastrointestinal trauma), and vascular disease score (determined by patients’ medical history, physical examination, lactate level, and radiologic findings; a score below 4 suggests benign PI). Seven of 14 patients in the confirmatory series had benign PI; all their vascular disease scores were below 4. One patient underwent non-therapeutic laparoscopy, and the postoperative period for all the patients was uneventful.\n\nFurthermore, based on the management algorithm for PI and/or PVG, we can classify the PI in our patients as benign. They were not critically ill or unstable, and they had no vascular obstructions or iatrogenic GI trauma. In addition, the vascular disease score was 2.5 and 1.5, respectively.\n\nThe management of patients with PI remains controversial. In patients with PI and concurrent pneumoperitoneum, clinicians cannot be certain of the presence of bowel perforation. In addition, surgical exploration is not a simple procedure wherein a patient can recover completely several hours after the operation. For this reason, clinicians should thoroughly review PI cases, apply a management algorithm to patients with PI, and then carefully select a treatment option. If the patient has benign PI, clinicians should observe their patients closely. If the patient has secondary PI, surgical management should be provided immediately. Non-surgical treatment of benign PI can improve patients’ health and shorten their hospitalization time. Physicians should consider primary PI associated with anticancer chemotherapy when a patient presents with vague symptoms at the emergency department. Careful consideration of the patient’s history, thorough examination, and assessment of diagnostic clues is mandatory.\n\nFig. 1. Initial plain abdominal X-ray and abdominal computed tomography images. (A) The simple abdominal erect image shows subphrenic free air and pneumatosis intestinalis in the left upper quadrant. (B) The coronal abdominal computed tomography image shows pneumoperitoneum and pneumatosis intestinalis in the left upper quadrant. Informed consent for publication of the clinical images was obtained from the patient.\n\nFig. 2. Gross photographs of pneumatosis intestinalis in the operation field. The arrows in the figure indicate pneumatosis intestinalis. (A) and (B) Ileum. Informed consent for publication of the clinical images was obtained from the patient.\n\nFig. 3. Initial abdominal computed tomography (CT) images of a 63-year-old male incidentally diagnosed with pneumatosis intestinalis (PI). (A) The coronal CT image shows pneumoperitoneum and PI in the small intestines. (B) The axial CT image shows pneumoperitoneum and PI in the small intestines. Informed consent for publication of the clinical images was obtained from the patient.\n\nNo potential conflict of interest relevant to this article was reported.\n==== Refs\nREFERENCES\n\n1 St Peter SD Abbas MA Kelly KA The spectrum of pneumatosis intestinalis Arch Surg 2003 138 68 75 12511155\n2 Vogel Y Buchner NJ Szpakowski M Tannapfel A Henning BF Pneumatosis cystoides intestinalis of the ascending colon related to acarbose treatment: a case report J Med Case Rep 2009 3 9216 19918292\n3 Lee KS Hwang S Hurtado Rua SM Janjigian YY Gollub MJ Distinguishing benign and life-threatening pneumatosis intestinalis in patients with cancer by CT imaging features AJR Am J Roentgenol 2013 200 1042 7 23617487\n4 Koss LG Abdominal gas cysts (pneumatosis cystoides intestinorum hominis); an analysis with a report of a case and a critical review of the literature AMA Arch Pathol 1952 53 523 49 14923068\n5 Wayne E Ough M Wu A Management algorithm for pneumatosis intestinalis and portal venous gas: treatment and outcome of 88 consecutive cases J Gastrointest Surg 2010 14 437 48 20077158\n6 Jamart J Pneumatosis cystoides intestinalis: a statistical study of 919 cases Acta Hepatogastroenterol (Stuttg) 1979 26 419 22 525221\n7 Ezuka A Kawana K Nagase H Takahashi H Nakajima A Improvement of pneumatosis cystoides intestinalis after steroid tapering in a patient with bronchial asthma: a case report J Med Case Rep 2013 7 163 23803391\n8 Sassi C Pasquali M Facchini G Bazzocchi A Battista G Pneumatosis intestinalis in oncologic patients: when should the radiologist not be afraid? BJR Case Rep 2016 3 20160017 30363314\n9 Mularski RA Ciccolo ML Rappaport WD Nonsurgical causes of pneumoperitoneum West J Med 1999 170 41 6 9926735\n10 Iflazoglu N Gokce ON Kıvrak MM Kocamer B Spontaneous idiopathic pneumoperitoneum with acute abdomen Ulus Cerrahi Derg 2013 31 110 2 26170747\n11 Williams NM Watkin DF Spontaneous pneumoperitoneum and other nonsurgical causes of intraperitoneal free gas Postgrad Med J 1997 73 531 7 9373590\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2383-4625",
"issue": "8(3)",
"journal": "Clinical and experimental emergency medicine",
"keywords": "Conservative treatment; Neoplasms; Pneumatosis cystoides intestinalis; Pneumoperitoneum",
"medline_ta": "Clin Exp Emerg Med",
"mesh_terms": null,
"nlm_unique_id": "101657493",
"other_id": null,
"pages": "237-241",
"pmc": null,
"pmid": "34649412",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": "23617487;525221;20077158;12511155;30363314;19918292;23803391;9926735;14923068;9373590;26170747",
"title": "Two case reports of pneumatosis intestinalis in patients with cancer: is surgical management mandatory?",
"title_normalized": "two case reports of pneumatosis intestinalis in patients with cancer is surgical management mandatory"
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"abstract": "Potassium is the most abundant cation in intracellular compartment. A deficiency or excess of its serum concentration can be deleterious to the one suffering from a cardiac ailment. Post cardiac surgery patients are often on multiple drugs like angiotensin receptor blockers (ARBs), angiotensin converting enzyme inhibitors (ACEI), diuretics including potassium sparing diuretics which are known to predispose for hyperkalemia. We report two postoperative cases who developed life threatening hyperkalemia despite normal renal function due to a combination of factors like treatment with ACEI, potassium sparing diuretics, high dietary intake of potassium and we also discuss renal handling of potassium in this review of literature.\n\n\n\nWe present a case series of two cases of cardiac surgery, who presented in the emergency department with hyperkalemia, managed conservatively and detailed history revealed that patient were also on very high nutritional potassium.\n\n\n\nBoth the patients responded to conservative management and there was no recurrence of such episodes once the dose of diuretics was adjusted and diet modification advised.\n\n\n\nIn India, many patients are from a low socioeconomic background and often resort to cheap and filling food items like bananas. This dietary factor should be kept in mind while prescribing patients with these medications and adequate counseling regarding diet should be done.",
"affiliations": "Department of Anaesthesiology, SGPGIMS, Lucknow, Uttar Pradesh, India.;Department of Cardiothoracic Vascular Surgery, SGPGIMS, Lucknow, Uttar Pradesh, India.;Department of Anaesthesiology, SGPGIMS, Lucknow, Uttar Pradesh, India.",
"authors": "Dixit|Aanchal|A|;Majumdar|Gauranga|G|;Tewari|Prabhat|P|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D004232:Diuretics; D007328:Insulin; D017419:Potassium, Dietary; D013148:Spironolactone; D017693:Sodium Bicarbonate; D005947:Glucose",
"country": "India",
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"doi": "10.4103/aca.ACA_65_18",
"fulltext": "\n==== Front\nAnn Card AnaesthAnn Card AnaesthACAAnnals of Cardiac Anaesthesia0971-97840974-5181Wolters Kluwer - Medknow India 30971598ACA-22-16210.4103/aca.ACA_65_18Original ArticleHyperkalemia in Ambulant Postcardiac Surgery Patients during Combined Therapy with Angiotensin-converting Enzyme Inhibitor, Spironolactone, and Diet Rich in Potassium: A Report of Two Cases and Review of Literature Dixit Aanchal Majumdar Gauranga 1Tewari Prabhat Department of Anaesthesiology, SGPGIMS, Lucknow, Uttar Pradesh, India1 Department of Cardiothoracic Vascular Surgery, SGPGIMS, Lucknow, Uttar Pradesh, IndiaAddress for correspondence: Dr. Aanchal Dixit, Department of Anaesthesiology, SGPGIMS, Lucknow - 226 014, Uttar Pradesh, India. E-mail: aanchal.dixit14@gmail.comApr-Jun 2019 22 2 162 168 Copyright: © 2019 Annals of Cardiac Anaesthesia2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Introduction:\nPotassium is the most abundant cation in intracellular compartment. A deficiency or excess of its serum concentration can be deleterious to the one suffering from a cardiac ailment. Post cardiac surgery patients are often on multiple drugs like angiotensin receptor blockers (ARBs), angiotensin converting enzyme inhibitors (ACEI), diuretics including potassium sparing diuretics which are known to predispose for hyperkalemia. We report two postoperative cases who developed life threatening hyperkalemia despite normal renal function due to a combination of factors like treatment with ACEI, potassium sparing diuretics, high dietary intake of potassium and we also discuss renal handling of potassium in this review of literature.\n\nMethodology:\nWe present a case series of two cases of cardiac surgery, who presented in the emergency department with hyperkalemia, managed conservatively and detailed history revealed that patient were also on very high nutritional potassium.\n\nResult:\nBoth the patients responded to conservative management and there was no recurrence of such episodes once the dose of diuretics was adjusted and diet modification advised.\n\nConclusion:\nIn India, many patients are from a low socioeconomic background and often resort to cheap and filling food items like bananas. This dietary factor should be kept in mind while prescribing patients with these medications and adequate counseling regarding diet should be done.\n\nAngiotensin-converting enzyme inhibitorsdietary potassiumhyperkalemiapotassium homeostasispotassium-sparing diuretics\n==== Body\nIntroduction\nHyperkalemia is a potentially life-threatening electrolyte abnormality. Hyperkalemia is a known complication of the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blocker (ARB). Incidence of hyperkalemia with ACEI or ARB therapy was found to be more among persons with lower estimated glomerular filtration rate (eGFR). It has been described previously that hyperkalemia develops in about 10% of outpatients with chronic kidney disease within a year of ACEIs being prescribed.[1] A recent large study found that among persons with eGFR <30 mL/min/1.73 m2, new users of ACE-I or ARB therapy had a 55% and 29% 1-year occurrence of potassium >5 and >5.5 mmol/L, respectively. In those with preserved renal function, potassium >5 mmol/L occurred in 5.6% and potassium >5.5 mmol/L occurred in 1.7% of patients.[2]\n\nAddition of spironolactone to long-term ACEI therapy results in clinical improvement among patients with refractory heart failure and has beneficial effects on the left ventricle remodeling.[3] The safety of the simultaneous administration of ACEI and spironolactone remains a source of concern due to the risk of hyperkalemia.[4] Main predictors of hyperkalemia in patients with combined therapy are renal insufficiency, diabetes mellitus (DM), congestive heart failure (CHF), and elderly population.[56]\n\nRole of high dietary intake of potassium for causing hyperkalemia in addition to these factors in patients with normal renal function has seldom been reported. Here, we are reporting two cases with severe hyperkalemia during combined therapy with ACEI and spironolactone who neither had compromised renal function nor were diabetic or in CHF at the time of discharge. Both were young patients who were taking large amount of bananas on a daily basis, a fruit rich in potassium.\n\nCase Report\nCase no 1\n36 year old female patient weighing 36 kgs, height 152 cm, admitted to our hospital with diagnosis of rheumatic heart disease, severe mitral stenosis (MS), severe aortic stenosis (AS), and severe tricuspid regurgitation (TR). The patient had dyspnea on exertion for the last 1½ years, with recent deterioration to dyspnea of New York Heart Association Class III. She was admitted with CHF 7 months back and managed conservatively. On examination, the patient had a pulse rate of 100 beats/min (bpm) in atrial fibrillation rhythm, mild pallor, and icterus, and pedal edema was present. Cardiovascular examination findings were suggestive of MS and AS. Hepatomegaly was present.\n\nShe was started on tablet furosemide 40 mg once daily (OD) along with tablet metoprolol 25 mg twice a day.\n\nShe was operated and mitral valve was replaced with size 27 St. Jude's mechanical valve and aortic valve with size 17 regent mechanical valve. Tricuspid commissurotomy was performed. Immediate postoperative period was uneventful and all predischarge investigations were within normal range. She was discharged on the postoperative day (POD) 9 with prescription of tablet furosemide 40 mg OD, tablet aldactone 100 mg OD, tablet ramipril 5 mg HS, and tablet amiodarone 200 mg OD, and ecosprin 150 mg OD. On discharge, the patient did not have pedal edema or hepatomegaly.\n\nOn POD 28, her medication was changed to furosemide with spironolactone 40/25 mg BD, tablet acenocoumarol, tablet aldactone 100 mg OD, and tablet digoxin 0.25 mg OD. High dose of diuretics was used for a short while as the patient still had features of fluid overload. Postoperative echocardiography showed normal prosthetic valve function with normal biventricular function and moderate TR.\n\nOn POD 33, she presented in the emergency department with complaints of loose stool and vomiting (3 episodes) with severe muscular weakness. On examination, pulse was 36 bpm, irregular, systolic BP 60 mmHg, extremities were cold and clammy, signs of dehydration present, peripheral pulses not palpable, valve click present, and tender hepatomegaly present. Serum electrolytes showed hyperkalemia with serum potassium of 7.87 meq/L, hyponatremia with serum sodium 129 mmol/L and hypocalcemia, hemoglobin 9.6 gm% and hematocrit 38%, pH 7.28, base deficit-11, serum osmolality 252 mmol/L, serum creatinine 1.1 mg%, and blood urea nitrogen (BUN) 17 mg/dl. Electrocardiograph (ECG) showed heart rate of 30 beats/min, broad QRS complex, tented T-wave, and impending sine wave pattern. When detailed history was elicited from her husband, he revealed that apart from her medication, she was taking 7–8 bananas every day as part of her regular diet for the last 3 weeks.\n\nShe was managed with aggressive antihyperkalemic treatment with intravenous (IV) calcium gluconate, glucose-insulin drip, soda-bicarbonate, loop diuretics, K+ binding resins, and IV fluids. Over 24 h, she was stabilized in the intensive care unit (ICU) with same treatment. Hemodialysis was not required, she recovered hemodynamically and maintained good urine output. Potassium levels were serially monitored and were on a decreasing trend and finally levels decreased to 4.5 meq/L. ECG showed normal sinus rhythm, rate of 80–90 bpm. She was discharged from ICU after 2 days. She was advised to eat 1–2 bananas every day and the dose of potassium-sparing diuretics was reduced. She remained in a regular follow-up and no such incidence recurred.\n\nCase no 2\n8 years old child weighing 21 kgs, height 130 cm, admitted to our hospital with diagnosis of tetralogy of Fallot physiology for intracardiac repair. Examination showed a cyanotic child with pulse rate of 78 bpm in sinus rhythm and blood pressure of 100/70 mmHg. Preoperatively, the patient was continued on tablet propranolol 10 mg 8th hourly.\n\nPerioperatively, dacron patch closure of ventricular septal defect, infundibular resection done, and transannular bovine pericardial patch placed. On POD 1, the patient developed complete heart block and was treated with temporary pacing, and injection dexamethasone was started, which was tapered off gradually and stopped on POD 10. Other medications included tablet furosemide 20 mg OD and tablet captopril 12.5 Mg 8th hourly. For nutrition, he was adviced to include banana in the diet. Gradually over next week, the patient developed hepatomegaly and weight gain of 4 kg and was started on tablet aldactone 25 mg BD. The patient was then discharged on POD 15 after features of CHF were relieved.\n\nOn POD 21, he presented in the emergency department with nausea and vomiting, electrolytes showed K+ of 7.12 meq/L, Na+ 121 meq/L, serum creatinine 1.2 mg%, and BUN 15 mg%. ECG showed hyperkalemic changes. He was shifted to ICU and antihyperkalemic treatment started that included IV calcium gluconate, sodium bicarbonate, glucose-insulin drip, and potassium-binding resin. He was maintaining good hemodynamics with adequate urine output. Potassium levels were serially monitored and after 24 h of aggressive management, his K+ level was 4 meq/l. Dialysis was not required. He was discharged from ICU after 2 days. Retrospectively on interrogating further his father said that the boy was eating at least 6–7 bananas every day for the last 15 days. He was advised to eat a single banana every day and he remained in regular follow-up and had no such episode again.\n\nDiscussion\nPotassium homeostasis\nPotassium is the most abundant intracellular cation. Only 2% of body K+ is extracellular. An average 70 kg man has about 3500 mEq of K+. Plasma K+ is freely filtered at the glomerulus and most of it reabsorbed in the proximal convoluted tubule (PCT) and loop of Henle (LOH). K+ is secreted in the distal convoluted tubule (DCT) and collecting duct. Figure 1 shows K+ handling by the kidney. K+ is freely filtered at the glomerulus. At PCT: 65% is reabsorbed here by solvent drag mechanism along with NaCl and water and also enters through the paracellular pathway. At thick ascending LOH: K+ enters the cell from the lumen along with Na+ and two Cl− ions through the Na+–K+–2Cl -cotransporter and through paracellular pathway. Some of the K+ is secreted into the lumen through the renal outer medullary potassium (ROMK) channels. This is promoted by increased intracellular K+ concentration from the 3Na+–2K+ ATPase channel that uses ATP and shifts two potassium ions inside cell and three sodium ions outside the cell across the basolateral membrane, keeps intracellular environment more electronegative, and promotes more Na+ reabsorption.\n\nFigure 1 Dietary K+ stimulates splanchnic receptors and causes aldosterone release which acts on principal cells of late distal convoluted tubule and cortical collecting duct that stimulates epithelial sodium channel which maintains electronegative environment by Na intake, favoring K+ secretion. It also stimulates 3Na+–2K+ ATPase, the renal outer medullary potassium and with-no-lysine kinase 4 channels that inhibit Na+–Cl− cotransporter in early distal convoluted tubule increasing delivery of Na, Cl in late distal convoluted tubule and cortical collecting duct hence providing substrate for epithelial sodium channel, increasing flow of urine that washes locally secreted K+ favoring more secretion. K+ directly increases expression of 3Na+–2K+ ATPase, the renal outer medullary potassium, epithelial sodium channel, and K+ maxi conductance channels\n\nEarly DCT: Here sodium and chloride continue to get reabsorbed by thiazide sensitive Na+–Cl− cotransporter. Potassium is secreted into the lumen through ROMK channel. Activity of both these channels is enhanced by the 3Na+–2K+ ATPase channel that increases intracellular potassium concentration and decreasing intracellular sodium ion concentration.\n\nLate DCT and cortical connecting tubule and cortical collecting duct: Two types of cells are present here: (1) Principal cells: here potassium secreted into the lumen majorly by ROMK channels and K+ maxi conductance channels. Minor pathway is K+–Cl− cotransporter that shifts both potassium and chloride ion from the intracellular compartment into the lumen. Here, epithelial sodium channels (ENaC) are also present that shift sodium from the lumen to inside the cell; this helps in maintaining electronegative environment in immediate vicinity of cell that favors potassium secretion. These channels are blocked by potassium-sparing diuretics (ENaC blocker, e.g.,: Amiloride). (2) Intercalated cells (IC); type A/acid/H+ secreting IC: here, potassium uptake inside the cell from the lumen is done with the help of K+–H+ exchanger where one potassium ion is exchanged for one hydrogen ion. Hydrogen ion is made available by break down of H2CO3 into H+ and HCO3 −. HCO3- is reabsorbed at basolateral membrane with a chloride exchanger and hydrogen ion is exchanged with potassium.\n\nDistal K+ secretion is regulated by aldosterone, acid–base status, the rate of urine flow in DCT, and membrane polarity [Figure 2].\n\nFigure 2 This figure shows K+ handling by the kidney. Proximal convoluted tubule: 65% K+ is reabsorbed. Thick ascending loop of Henle: K+ enters the cell via the Na+–K+–2Cl− cotransporter. Early distal convoluted tubule: Na+ and Cl− reabsorbed by Na+–Cl− cotransporter. K+ is secreted into the lumen via the renal outer medullary potassium channel. Late distal convoluted tubule, connecting tubule, and cortical collecting duct: (1) Principal cells: K+ secreted into the lumen by the renal outer medullary potassium channels and K+ maxi conductance channels. Epithelial Na channel shifts Na from the lumen to inside the cell. (2) Intercalated cells Type A: K+ taken up inside the cell from the lumen with the help of K+–H+ exchanger\n\nHigh circulating aldosterone levels lead to increased K+ secretion and kaliuresis. Deficiency or suppression of aldosterone decreases distal K+ secretion and results in renal K+ conservation. Increased delivery of sodium to DCT and high distal nephron urine flow rates favor potassium excretion. Reabsorption of sodium in DCT causes luminal electrical negativity further increases potassium secretion. Hence, loop diuretic therapy or high intake of sodium is associated with increased secretion of potassium.\n\nRabinowitz[7] in his classical article on aldosterone and potassium homeostasis, described four basic mechanisms of potassium secretion. First, aldosterone as a kaliuretic hormone, especially in the presence of hyperkalemia. Second, plasma potassium itself acts as homeostatic regulator of potassium excretion. It was further added by Young[8] in his paper in this regard that a very small change in potassium excretion occurred when plasma potassium concentration was changed over its normal physiologic range.\n\nRabinowitz also stated that potassium receptors exist in some regions of gut, liver, and the portal circulation, which respond to local increase in potassium concentration, thus initiate a reflex kaliuresis (involves brain and undetermined kaliuretic regulatory factors), third mechanism of potassium secretion. Fourth factor described is a physiologic circadian rhythm in K+ excretion driven by an oscillator in the brain. It is independent of cyclic K+ intake, adrenal hormones, changes in plasma K+, renal nerves, and sodium cyclic excretion. The efferent factors connecting brain and kidney are not known yet.\n\nAizman and Rabinowitz[9] in their review found evidence connecting certain receptors in the brain and renal potassium excretion.\n\nHomeostatic mechanisms to maintain normokalemia are highly effective in normal individuals and capacity of renal potassium excretion is very high. Hyperkalemia is practically always associated with impaired urinary potassium excretion[10] in patients with acute or chronic renal failure where high potassium intake can contribute to the development of hyperkalemia.\n\nCauses of hyperkalemia\n\nIncreased oral/IV potassium intake.\n\n\n\n\nIncreased release from cells\n\nPseudohyperkalemia\n\nMetabolic acidosis\n\nInsulin deficiency, hyperglycemia, and hyperosmolality\n\nBeta-adrenergic blockers\n\nIncreased tissue catabolism\n\nSevere exercise\n\nHyperkalemic periodic paralysis\n\nDrugs: Digitalis overdose, succinylcholine, arginine, heparin.\n\n\n\n\nReduced urinary potassium excretion\n\nRenal failure\n\nEffective circulating volume depletion\n\nSelective impairment of potassium excretion\n\nHypoaldosteronism.\n\n\n\n\nMechanisms of drug-induced hyperkalemia\n\nIncreased potassium release from cells:\n\n\nBeta-adrenergic blockers\n\nAlpha-adrenergic agonists\n\nInsulin antagonists (somatostatin, diazoxide)\n\nArginine hydrochloride\n\nSuccinylcholine\n\nDigitalis.\n\n\n\n\nDecreased activity of renin–angiotensin axis:\n\n\nACEI\n\nBeta-adrenergic blockers\n\nNonsteroidal anti-inflammatory drugs (NSAIDS)\n\nHeparin.\n\n\n\n\nInhibition of potassium secretion:\n\n\nSpironolactone\n\nAmiloride\n\nTrimethoprim\n\nTriamterene\n\nPentamidine\n\nCyclosporine A.\n\n\n\n\n\n\n\nCauses of hypoaldosteronism causing hyperkalemia\nAssociated with decreased activity of renin–angiotensin system and low aldosterone levels\n\nHyporeninemic hypoaldosteronism (DM most common)\n\nNSAIDS (possible exception sulindac)\n\nACEI\n\nCyclosporine\n\nHeparin (decreased adrenal aldosterone production)\n\nAcquired immunodeficiency syndrome.\n\n\n\n\nReduced adrenal synthesis\n\nLow cortisol levels: primary adrenal insufficiency and congenital adrenal hyperplasia\n\nNormal cortisol levels: heparin, postremoval of adrenal adenoma, and isolated hypoaldosteronism\n\n\n\n\nAldosterone resistance with normal or increased aldosterone levels\n\nPotassium-sparing diuretics\n\nTrimethoprim\n\nCyclosporine\n\nPseudohypoaldosteronism (hereditary or acquired resistance to aldosterone).\n\n\n\n\nRole of combined therapy with angiotensin-Converting enzyme inhibitor/angiotensin receptor blocker and spironolactone in causing hyperkalemia\nMost studies depicting the risks and benefits of the therapeutic combination of ACEI/ARB with spironolactone have reported a relatively low incidence of hyperkalemia. These studies involved younger patients and excluded those with serum creatinine >2.5 mg%.[11] After the publication of RALES trial, the prescription of spironolactone with ACEI increased several fold with median dose being 25 mg, but the rate of hyperkalemia-associated hospital admission also increased steadily. Therefore, this combination therapy should be used judiciously used, especially in patients at risk of hyperkalemia (concurrent use of NSAIDS, beta-blockers, or presence of diabetes or renal dysfunction).[1213]\n\nHans Schepkens et al.[14] studied 25 patients admitted with K+ >6, with combination therapy and on admission serum creatinine was found to be in the range of 3.8 ± 1.8 mg/dl with metabolic acidosis. Main cause of renal failure was dehydration and worsening heart failure. Daily dose of spironolactone was 57 ± 32 mg. Two patients died, 17 patients required hemodialysis. They concluded that combination of ACEI and spironolactone should be considered with caution and monitored closely in patients with renal insufficiency, diabetes, older age, worsening heart failure, risk of dehydration, and combination with other medication that may cause hyperkalemia and daily spironolactone dose should not be exceeded beyond 25 mg.\n\nAhuja et al.[15] found main predictors of hyperkalemia were the presence of diabetes and increasing renal insufficiency. Diabetics with renal failure usually have hyporeninemic hypoaldosteronism predisposing them to development of hyperkalemia with ACEI.[15] ACEI by blocking the production of angiotensin II and therefore aldosterone leads to retention of potassium and hyperkalemia more marked in patients with renal insufficiency. They also found CHF to be a predictor of hyperkalemia as it leads to decreased delivery of sodium to the distal tubule for exchange with potassium and hence causes K+ retention.\n\nIn a study population of 1818 patients with ACEI, 11% prevalence of hyperkalemia was found by Reardon and Macpherson.[16] An elevated BUN level (>18 mg%), creatinine level (>1.6 mg%), and CHF were strongly and independently associated with hyperkalemia. An additional increased risk of hyperkalemia was observed with use of long-acting ACEI. Reduced risk was observed with use of thiazide and loop diuretic agents.\n\nTherefore, conditions that may lead to the development of severe hyperkalemia in patients with heart failure who are taking spironolactone and ACE inhibitors or ARBs include: advanced age, dose of spironolactone >25 mg daily, reduced renal function, and DM Type 2.\n\nRole of dietary component in causing hyperkalemia\nDietary component can play a major role in causing hyperkalemia when it is combined with other factors such as potassium-sparing diuretics even in patients with normal renal functions. Food items with high potassium content include fruits such as kiwi, bananas, orange; vegetables such as potatoes, avocados, turnip, dried peas, dairy products, meat, nuts, and apricots; and certain herbal products (e.g., noni juice, Siberian ginseng, dandelion).[17]\n\nROMK and maxi-K channels are also localized in the cytoplasm, and their trafficking to apical membranes in distal tubules is regulated by dietary K+.[18]\n\nEric Williams and Fulop[19] reported a puzzling case of hyperkalemia in 2001 in a patient with a history of stable chronic kidney disease on tablet lisinopril who was admitted with recurrent hyperkalemia. He had a history of taking 2.5–4.5 L of apple juice per day that added about 60–120 mmol/day of potassium to his body. Other juices having higher potassium concentrations includes pineapple, grapes, and orange juice.\n\nPavletic reported a case of hyperkalemia induced by excessive consumption of dried fruits (figs) in an otherwise healthy female secondary to a psychiatric eating disorder.[20]\n\nIn a third world country like India where our patients can not afford to eat dry fruits or other expensive nutritious fruit and supplements, banana is available as good cheap option. About 100 g of figs would cost about 120–150 rupees in India while 100 gms of banana would cost around 8–10 rupees. Banana is a healthy and cheap fruit that is also good for maintaining regular bowel movements and satiety. It is rich in potassium, magnesium, iron, and Vitamin B6 and C. Hence, most of our population resorts to eating bananas on a daily basis, especially postoperative patients who are adviced to maintain a good, healthy diet enriched with fruits.\n\nIn both our cases, there was a history of intake of large amount of potassium-rich fruit, mainly banana about 6–8/day. Each banana (weighing about 150 g) consists of 15.2 mmol of potassium according to a food composition cart.[21] Eating 6–8 bananas will add about 91–121 mmol of potassium. The WHO recommends potassium intake of about 90 mmol of potassium per day for an adult. In our patients, probably the high intake of bananas along with other food items and potassium-sparing diuretics led to life-threatening hyperkalemia despite normal renal function.\n\nOur first patient was a young lady, nondiabetic with normal renal function; she was not in CHF at the time of discharge but developed severe hyperkalemia and presented with three episodes of vomiting and diarrhea. She was taking combination therapy of ACEI (ramipril 5 mg OD) along with furosemide and potassium-sparing diuretics (a slightly higher dose as patient had features of fluid overload). On taking dietary history, it was found she used to take 6–7 medium-sized bananas daily since her valve replacement (potassium-rich diet). ACEI causes hypoaldosteronism and decreased potassium secretion, along with potassium-sparing diuretics and rich potassium diet, all three factors culminated in hyperkalemia which causes decreased GFR and more potassium retention in the body.\n\nThe second patient was a child who underwent TOF repair, developed severe hyperkalemia following combined therapy with captopril, potassium-sparing diuretics, aldactone 100 mg OD, and dexamethasone (for complete heart block). Interestingly, he was very fond of banana and used to eat 5–6 medium-sized bananas daily. One medium-sized banana contains very rich amount of potassium, approximately 11% of daily requirement. 5–6 banana added ample amount of potassium in his diet (50% daily requirement). Transient adrenal suppression from dexamethasone withdrawal may cause decreased synthesis of cortisol, along with ACEI, marked hypoaldosteronism can occur. He also received potassium-sparing diuretics as well as very high potassium-rich diet; all these factors culminated to severe hyperkalemia despite normal renal function.\n\nConclusion\nHence, we conclude that life-threatening hyperkalemia can occur in postoperative cardiac surgical patients when the patients have a combination of predisposing factors like treatment with ACEI/ARB in combination with potassium-sparing diuretics and taking a diet rich in potassium in excess of the recommended dose, despite normal renal function. History of taking a potassium-rich diet (in excess of recommendation) may often be missed, and this article attempts to highlight the importance of all the contributing factors along with this lesser known and discussed entity.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Espinel E Joven J Gil I Suñé P Renedo B Fort J Risk of hyperkalemia in patients with moderate chronic kidney disease initiating angiotensin-converting enzyme inhibitors or angiotensin receptor blockers: A randomized study BMC Res Notes 2013 6 306 23915518 \n2 Bandak G Sang Y Gasparini A Chang AR Ballew SH Evans M Hyperkalemia after initiating renin-angiotensin system blockade: The Stockholm creatinine measurements (SCREAM) project J Am Heart Assoc 2017 6 pii: e005428 \n3 Wu CT Wang ZH Li ZQ Wang LF Effect of spironolactone on cardiac remodeling after acute myocardial infarction World J Emerg Med 2013 4 48 53 25215092 \n4 Abbas S Ihle P Harder S Schubert I Risk of hyperkalemia and combined use of spironolactone and long-term ACE inhibitor/angiotensin receptor blocker therapy in heart failure using real-life data: A population – And insurance-based cohort Pharmacoepidemiol Drug Saf 2015 24 406 13 25683504 \n5 Sato A Suzuki Y Saruta T Effects of spironolactone and angiotensin-converting enzyme inhibitor on left ventricular hypertrophy in patients with essential hypertension Hypertens Res 1999 22 17 22 10221346 \n6 Odwara M Asano M Yamashita K Life – Threatening hyperkalemia caused by angiotensin converting enzyme inhibitors and diuretics Diabet Med 1997 14 169 70 9047098 \n7 Rabinowitz L Aldosterone and potassium homeostasis Kidney Int 1996 49 1738 42 8743488 \n8 Young DB Relationship between plasma potassium concentration and renal potassium excretion Am J Physiol 1982 242 F599 603 7091315 \n9 Rabinowitz L Aizman RI The central nervous system in potassium homeostasis Front Neuroendocrinol 1993 14 1 26 8477870 \n10 Rabinowitz L Sarason RL Yamauchi H Sheep renal potassium excretion: Efferent kaliuretic regulatory factors Am J Physiol 1984 247 F520 6 6476127 \n11 Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the randomized aldactone evaluation study [RALES] Am J Cardiol 1996 78 902 7 8888663 \n12 Dolovich L Gavura S Pottie K Hyperkalemia associated with spironolactone therapy Can Fam Physician 2005 51 357 60 15794020 \n13 Jarman PR Kehely AM Mather HM Hyperkalaemia in diabetes: Prevalence and associations Postgrad Med J 1995 71 551 2 7479468 \n14 Schepkens H Vanholder R Billiouw JM Lameire N Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: An analysis of 25 cases Am J Med 2001 110 438 41 11331054 \n15 Ahuja TS Freeman D Jr Mahnken JD Agraharkar M Siddiqui M Memon A Predictors of the development of hyperkalemia in patients using angiotensin-converting enzyme inhibitors Am J Nephrol 2000 20 268 72 10970978 \n16 Reardon LC Macpherson DS Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors. How much should we worry? Arch Intern Med 1998 158 26 32 9437375 \n17 Raebel MA Hyperkalemia associated with use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers Cardiovasc Ther 2012 30 e156 66 21883995 \n18 Carrisoza-Gaytán R Salvador C Satlin LM Liu W Zavilowitz B Bobadilla NA Potassium secretion by voltage-gated potassium channel kv1. 3 in the rat kidney Am J Physiol Renal Physiol 2010 299 F255 64 20427469 \n19 Williams E Fulop M A puzzling case of hyperkalaemia Lancet 2001 357 1176 11323046 \n20 Pavletic AJ Hyperkalemia induced by excessive consumption of dried fruits – Manifestation of an undiagnosed eating disorder? Psychosomatics 2011 52 494 5 21907077 \n21 Miller KC Plasma potassium concentration and content changes after banana ingestion in exercised men J Athl Train 2012 47 648 54 23182013\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-9784",
"issue": "22(2)",
"journal": "Annals of cardiac anaesthesia",
"keywords": "Angiotensin-converting enzyme inhibitors; dietary potassium; hyperkalemia; potassium homeostasis; potassium-sparing diuretics",
"medline_ta": "Ann Card Anaesth",
"mesh_terms": "D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors; D006348:Cardiac Surgical Procedures; D002648:Child; D003131:Combined Modality Therapy; D004232:Diuretics; D005260:Female; D005440:Fluid Therapy; D005947:Glucose; D006801:Humans; D006947:Hyperkalemia; D007328:Insulin; D008297:Male; D011183:Postoperative Complications; D017419:Potassium, Dietary; D017693:Sodium Bicarbonate; D013148:Spironolactone; D016138:Walking",
"nlm_unique_id": "9815987",
"other_id": null,
"pages": "162-168",
"pmc": null,
"pmid": "30971598",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "8477870;10221346;20427469;8888663;21883995;25683504;8743488;11323046;10970978;28724651;11331054;15794020;21907077;23915518;9437375;9047098;23182013;25215092;7479468;7091315;6476127",
"title": "Hyperkalemia in ambulant postcardiac surgery patients during combined therapy with angiotensin-converting enzyme inhibitor, spironolactone, and diet rich in potassium: A report of two cases and review of literature.",
"title_normalized": "hyperkalemia in ambulant postcardiac surgery patients during combined therapy with angiotensin converting enzyme inhibitor spironolactone and diet rich in potassium a report of two cases and review of literature"
} | [
{
"companynumb": "IN-PFIZER INC-2019197085",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIGOXIN"
},
"drugadditional": "3",
"... |
{
"abstract": "Methotrexate (MTX) carries a risk of lymphoproliferative disorders (LPDs), but MTX-associated LPDs (MTX-LPDs) can resolve spontaneously after MTX withdrawal. However, the precise clinicopathologic features of MTX-LPD remain unclear. We aimed to investigate the clinicopathologic characteristics, outcomes, and prognostic factors for histologic types of MTX-LPD. Paraffin-embedded tissue samples of 219 patients with MTX-LPD were analyzed. In total, 30,33,106, and 26 had reactive lymphoid hyperplasia (RH), polymorphic-LPD (Poly-LPD), diffuse large B-cell lymphomas (DLBCLs), and classic Hodgkin lymphoma (CHL), respectively. The clinicopathologic features of RH, Poly-LPD, DLBCLs, and CHL were as follows: extranodal involvement: 13.8% (4/29), 36.4% (12/33), 69.5% (73/105), and 15.4% (4/26); Epstein-Barr virus encoded RNA positivity: 55.2% (16/29), 71.9% (23/32), 45.3% (48/106), and 76.9% (20/26); necrosis: 0% (0/29), 51.5% (17/33), 34.3% (36/105), and 12.0% (3/25); and Hodgkin Reed-Sternberg-like cells: 17.2% (5/29), 50% (14/28), and 19.8% (21/106). The median duration from MTX withdrawal to the time of disease regression was 10.4, 3.0, 4.2, and 2.7 months for RH, Poly-LPD, DLBCLs, and CHL. After MTX withdrawal, progression-free survival was the greatest for RH, followed by for Poly-LPD, DLBCL, and CHL (all P<0.05). Overall survival did not differ significantly between the groups. On univariate analysis, the predictive factors for progression-free survival included plasma cell infiltrate for CHL, eosinophil infiltrate, age above 70 years, and extensive necrosis for Poly-LPD, while they were Epstein-Barr virus encoded RNA positivity and International Prognostic Index risk for DLBCL on multivariate analysis. In conclusion, histologic categorization and histology-specific factors could be useful for predicting MTX-LPD progression after MTX withdrawal.",
"affiliations": "Departments of Pathology.;Departments of Pathology.;Departments of Pathology.;Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka.;Department of Hematology, Nagasaki University Hospital, Nagasaki.;Medicine, Division of Hematology and Oncology, Kurume University School of Medicine, Kurume.;Departments of Pathology.;Departments of Pathology.;Departments of Pathology.;Departments of Pathology.;Departments of Pathology.;Departments of Pathology.;Division of Hematology, Saitama Medical Center.;Medicine, Division of Hematology and Oncology, Kurume University School of Medicine, Kurume.;Department of Pathology, Saitama Medical Center, Saitama Medical University, Saitama, Japan.;Division of Hematology, Saitama Medical Center.;Departments of Pathology.",
"authors": "Kurita|Daisuke|D|;Miyoshi|Hiroaki|H|;Ichikawa|Ayako|A|;Kato|Koji|K|;Imaizumi|Yoshitaka|Y|;Seki|Ritsuko|R|;Sato|Kensaku|K|;Sasaki|Yuya|Y|;Kawamoto|Keisuke|K|;Shimono|Joji|J|;Yamada|Kyohei|K|;Muto|Reiji|R|;Kizaki|Masahiro|M|;Nagafuji|Koji|K|;Tamaru|Jun-Ichi|JI|;Tokuhira|Michihide|M|;Ohshima|Koichi|K|",
"chemical_list": "D018501:Antirheumatic Agents; D012367:RNA, Viral; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1097/PAS.0000000000001271",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-5185",
"issue": "43(7)",
"journal": "The American journal of surgical pathology",
"keywords": null,
"medline_ta": "Am J Surg Pathol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D016867:Immunocompromised Host; D008232:Lymphoproliferative Disorders; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009894:Opportunistic Infections; D000077982:Progression-Free Survival; D012367:RNA, Viral; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors",
"nlm_unique_id": "7707904",
"other_id": null,
"pages": "869-884",
"pmc": null,
"pmid": "31116708",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Methotrexate-associated Lymphoproliferative Disorders in Patients With Rheumatoid Arthritis: Clinicopathologic Features and Prognostic Factors.",
"title_normalized": "methotrexate associated lymphoproliferative disorders in patients with rheumatoid arthritis clinicopathologic features and prognostic factors"
} | [
{
"companynumb": "JP-SILVERGATE PHARMACEUTICALS, INC.-2019SIL00036",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drug... |
{
"abstract": "To describe clinical, laboratory, radiological and progression characteristics of myelopathy in systemic lupus erythematosus (SLE).\n\n\n\nA retrospective analysis was performed on a cohort of 1193 patients with SLE (ACR criteria) in order to identify patients with myelopathy (neuropsychiatric ACR). Disease activity was assessed by the SLE activity index (SLEDAI) on the date of the event and functional capacity was assessed by the Expanded Disability Status Scale (EDSS) at the last visit.\n\n\n\nWe identified 14 (1.2%) patients with myelopathy. All were women with a mean age of 30±11.5 years. Myelopathy occurred at the diagnosis of SLE in four (28%) patients; and nine (64%) patients had another type of neuropsychiatric manifestation associated. Neurological recurrence was observed in one (7%) patient. Disease activity was observed in 2 (14%) patients. Cerebrospinal fluid presented pleocytosis on 7 (53%) patients; antiphospholipid antibodies were positive in 5 (45%). Magnetic resonance imaging (MRI) showed T2 hyperintensity with a predominance of longitudinal involvement in 6 (86%) patients. Most were treated with intravenous corticosteroids and cyclophosphamide. No patient had full recovery and four (36%) had high EDSS scores. Three (21%) patients died from sepsis early in the course of their myelopathy, during or after immunosuppressive therapy.\n\n\n\nMyelopathy occurred in 14 (1.2%) of the patients in our cohort and this may be the first manifestation of the disease occurring independently of systemic disease activity. Although rare, myelopathy shows great morbidity and mortality, can be recurrent and MRI is critical for diagnosis.",
"affiliations": "Faculdade de Ciências Médicas (FCM), Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.;Hospital das Clínicas, Faculdade de Ciências Médicas (FCM), Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.;Faculdade de Ciências Médicas (FCM), Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.;Faculdade de Ciências Médicas (FCM), Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil. Electronic address: appenzellersimone@yahoo.com.",
"authors": "Costallat|Beatriz Lavras|BL|;Ferreira|Daniel Miranda|DM|;Costallat|Lilian Tereza Lavras|LT|;Appenzeller|Simone|S|",
"chemical_list": null,
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2255-5021",
"issue": "56(3)",
"journal": "Revista brasileira de reumatologia",
"keywords": "Lúpus eritematoso sistêmico; Magnetic resonance; Mielite transversa; Mielopatia; Myelopathy; Ressonância magnética; Systemic lupus erythematosus; Transverse myelitis",
"medline_ta": "Rev Bras Reumatol Engl Ed",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D018450:Disease Progression; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008279:Magnetic Resonance Imaging; D008297:Male; D012189:Retrospective Studies; D013118:Spinal Cord Diseases; D055815:Young Adult",
"nlm_unique_id": "101672232",
"other_id": null,
"pages": "240-51",
"pmc": null,
"pmid": "27267643",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Myelopathy in systemic lupus erythematosus: clinical, laboratory, radiological and progression findings in a cohort of 1,193 patients.",
"title_normalized": "myelopathy in systemic lupus erythematosus clinical laboratory radiological and progression findings in a cohort of 1 193 patients"
} | [
{
"companynumb": "BR-PFIZER INC-2016361360",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"druga... |
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