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"abstract": "BACKGROUND\nPrior studies have shown that most patients with mild traumatic brain injury or negative computed tomography (CT) scans of the head rarely decline or require neurosurgical interventions. One common reason for a delayed decline is an intracranial hemorrhage that presents within 24-48 hours. This is typically seen in elderly patients and/or patients on antiplatelet or anticoagulation agents. We describe a case of a delayed subdural hemorrhage presenting in a young adult not on any antiplatelet or anticoagulation therapy.\n\n\nMETHODS\nA 19-year-old male presented to the emergency department after being involved in a motor vehicle accident. He had a Glasgow Coma Scale of 15, and an initial CT was negative for any intracranial hemorrhage or pathology, so he was then admitted to the intensive care unit for further care. The patient received 1 dose of aspirin 325 mg the following day for treatment of blunt cerebrovascular injury. Six hours later he reported a severe headache and had an episode of emesis with a subsequent rapid neurologic decline. Repeat CT showed an acute right subdural hematoma, and he underwent an emergent right decompressive hemicraniectomy.\n\n\nCONCLUSIONS\nIn rare cases, patients with negative initial head CT scans neurologically deteriorate as a result of a delayed acute subdural hematoma. We present an unusual case of a young patient on no medications with no CT findings of an intracranial injury who neurologically declined due to a delayed acute subdural hematoma.",
"affiliations": "New York Medical College, Valhalla, New York, USA. Electronic address: irybkin@nymc.edu.;Department of Neurosurgery, Westchester Medical Center, Valhalla, New York, USA.;Department of Neurosurgery, Westchester Medical Center, Valhalla, New York, USA.;Department of Neurosurgery, Westchester Medical Center, Valhalla, New York, USA.",
"authors": "Rybkin|Ilya|I|;Kim|Michael|M|;Amin|Anubhav|A|;Tobias|Michael|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2018.06.135",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "117()",
"journal": "World neurosurgery",
"keywords": "Glasgow Coma Scale; Subdural hematoma; Trauma; Traumatic brain injury",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000063:Accidents, Traffic; D001921:Brain; D001924:Brain Concussion; D020199:Hematoma, Subdural, Acute; D006801:Humans; D008297:Male; D013997:Time Factors; D055815:Young Adult",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "353-356",
"pmc": null,
"pmid": "29959076",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Development of Delayed Posttraumatic Acute Subdural Hematoma.",
"title_normalized": "development of delayed posttraumatic acute subdural hematoma"
} | [
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"companynumb": "US-BAYER-2018-146832",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "ASPIRIN"
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"abstract": "Hafnia alvei is a rare, poorly understood commensal bacterium which has, on occasion, been shown to infect humans. We present two cases. The first patient presented with a 1-week history of dyspnoea, pleurisy and a productive cough, and the second with a prodrome of fatigue and night sweats. The former had a history of severe chronic obstructive pulmonary disease and the latter had a history of Crohn's disease. Both patients had underlying comorbidities and immunosuppression, but differed in presentation, radiological findings and recovery. This case series aims to remind readers of the broad differential of pathogens that can lead to disease in the immunocompromised and that one should not dismiss atypical cultured bacteria as commensal too hastily.",
"affiliations": "Respiratory Medicine, Tunbridge Wells Hospital, Tunbridge Wells, UK.;Respiratory Medicine, Tunbridge Wells Hospital, Tunbridge Wells, UK joseph.guppy1@nhs.net.;Respiratory Medicine, Tunbridge Wells Hospital, Tunbridge Wells, UK.;Respiratory Medicine, Tunbridge Wells Hospital, Tunbridge Wells, UK.",
"authors": "Begbey|Austin|A|;Guppy|Joseph Henry|JH|http://orcid.org/0000-0002-8295-1138;Mohan|Chithra|C|;Webster|Simon|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin; D019980:Amoxicillin-Potassium Clavulanate Combination; D017291:Clarithromycin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-237061",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(12)",
"journal": "BMJ case reports",
"keywords": "infections; pneumonia (infectious disease); pneumonia (respiratory medicine); respiratory system",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000368:Aged; D019980:Amoxicillin-Potassium Clavulanate Combination; D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin; D017291:Clarithromycin; D015897:Comorbidity; D003424:Crohn Disease; D004756:Enterobacteriaceae Infections; D005260:Female; D020611:Hafnia alvei; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D018410:Pneumonia, Bacterial; D029424:Pulmonary Disease, Chronic Obstructive; D035583:Rare Diseases; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33384344",
"pubdate": "2020-12-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hafnia alvei pneumonia: a rare cause of infection in the multimorbid or immunocompromised.",
"title_normalized": "hafnia alvei pneumonia a rare cause of infection in the multimorbid or immunocompromised"
} | [
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"companynumb": "GB-TEVA-2021-GB-1898171",
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"activesubstancename": "BUDESONIDE\\FORMOTEROL"
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"drugadditional": "3... |
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"abstract": "Ruxolitinib is a targeted agent that inhibits Janus 2 Kinase and is approved for use in Polycythemia Vera and Primary Myelofibrosis. Its mechanism of action involves inhibition of cellular proliferation via the Janus kinase/signal transducer and activator of transcription proteins pathway. Ruxolitinib has different immune modulating effects that result in functional immunosuppression, leading to an increased susceptibility to certain infections. Klebsiella pneumoniae infections, in particular, were common among the reported pathogens contracted by ruxolitinib users. We report a 75-year-old male patient who had recurrent K. pneumoniae urinary tract infections while on ruxolitinib for Polycythemia Vera. This case is reported to add to the literature describing an increased susceptibility of patients to this often-resistant bacteria and to raise awareness about the immune modulating effects of JAK inhibitors.",
"affiliations": "Division of Nephrology, Department of Medicine UCLA, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. rhannamd81@yahoo.com.;Division of Nephrology, Department of Medicine, UCI School of Medicine, Irvine, CA 92868, USA. maham.khalid@yahoo.com.;Division of Nephrology, Department of Medicine UCLA, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. labdelnour@mednet.ucla.edu.;Division of Nephrology, Department of Medicine UCLA, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. uselamet@hotmail.com.",
"authors": "Hanna|Ramy M|RM|;Khalid|Maham|M|;El-Nour|Lama Abd|LA|;Selamet|Umut|U|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/antibiotics8030150",
"fulltext": "\n==== Front\nAntibiotics (Basel)Antibiotics (Basel)antibioticsAntibiotics2079-6382MDPI 10.3390/antibiotics8030150antibiotics-08-00150Case ReportFrequent Klebsiella pneumoniae Urinary Tract Infections in a Patient Treated with Ruxolitinib Hanna Ramy M. 12*Khalid Maham 2El-Nour Lama Abd 1Selamet Umut 131 Division of Nephrology, Department of Medicine UCLA, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; labdelnour@mednet.ucla.edu (L.A.E.-N.); uselamet@hotmail.com (U.S.)2 Division of Nephrology, Department of Medicine, UCI School of Medicine, Irvine, CA 92868, USA; maham.khalid@yahoo.com3 Division of Nephrology, Department of Medicine, Brigham Women’s and Children’s Hospital, Boston, MA 02101, USA* Correspondence: rhannamd81@yahoo.com or ramyh1@uci.edu; Tel.: +1-310-206-674116 9 2019 9 2019 8 3 15012 8 2019 11 9 2019 © 2019 by the authors.2019Licensee 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/).Ruxolitinib is a targeted agent that inhibits Janus 2 Kinase and is approved for use in Polycythemia Vera and Primary Myelofibrosis. Its mechanism of action involves inhibition of cellular proliferation via the Janus kinase/signal transducer and activator of transcription proteins pathway. Ruxolitinib has different immune modulating effects that result in functional immunosuppression, leading to an increased susceptibility to certain infections. Klebsiella pneumoniae infections, in particular, were common among the reported pathogens contracted by ruxolitinib users. We report a 75-year-old male patient who had recurrent K. pneumoniae urinary tract infections while on ruxolitinib for Polycythemia Vera. This case is reported to add to the literature describing an increased susceptibility of patients to this often-resistant bacteria and to raise awareness about the immune modulating effects of JAK inhibitors.\n\nRuxolitinibKlebsiella pneumoniaImmunemodulationJAK kinase (Janus Kinase)STAT (Signal Transducer and Activator of Transcription proteins) kinase\n==== Body\n1. Introduction\nRuxolitinib is an oral Janus Kinase (JAK) 1 and 2 inhibitor that is part of the family of tyrosine kinase inhibitors (TKI) [1]. This agent is approved by the US Food and Drug administration for the treatment of Polycythemia Vera (PCV) and Primary Myelofibrosis (PMF) [2]. While a rare condition, (2.8/100,000 in males, 1.3/100,000 in females), PCV had few modern therapy options with phlebotomy still being used as an option [3]. The efficacy of Ruxolitinib has been established in the Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera (RESPONSE) for PCV [2,4], and Controlled MyeloFibrosis Study with ORal JAK inhibitor Treatment I and II (COMFORT I and II) for myelofibrosis [2]. It is also being used in hemophagocytic lymphohistiocytosis [5].\n\nThe JAK/STAT (Signal Transducer and Activator of Transcription proteins) pathway is intimately involved with cellular division in hematopetic progenitor cell division and proliferation of adaptive immunity T cells [6]. Given its role in many dividing cells of the immune system, it can be expected to have an immune modulatory effect [7].\n\nEvidence of this effect emerged when many patients using ruxolitinib were reported to have an increased susceptibility to bacterial infections. This was first reported in myelofibrosis patients [6], but later was also found to be true in PCV patients [8]. In addition to increased susceptibility to bacterial infections, increased risk of fungal [9] and viral infections were subsequently reported [9]. The cells affected by ruxolitinib include T cells, natural killer cells, and dendritic cells [10]. One particular bacterial pathogen that has been reported in association with Ruxolitinib use has been K. pneumoniae, with the best-known reported patient developing a hepatic abscess [11,12]. We report another patient on ruxolitinib who developed frequent K. Pneumoinae urinary tract infections, given these reports, this case is documented to show the clinical link between ruxolitinib use and infection with an often resistant and virulently pathogenic organism.\n\nCase Report\nOur patient is a 75-year-old Caucasian male who was diagnosed with PCV that transitioned to myelofibrosis. He also had a history of non-ischemic cardiomyopathy with an ejection fraction of 30%, who was treated with ruxolitinib 20 mg by mouth twice a day. He presented to nephrology care for monitoring for myelofibrosis related nephropathy, which was suppressed due to angiotensin converting enzyme (ACE) inhibitor use. The patient’s serum creatinine improved when he was instructed to avoid non-steroidal anti-inflammatory agents. His serum potassium rose despite an improving serum creatinine and he had to be taken off his ACE inhibitors. His serum creatinine ranged between 1.3–1.7 mg/dL on ACE inhibitor and afterwards dropped to 1.2–1.3 mg/dL. The estimated glomerular filtration rate of 40 mL/min improved to 54 mL/min after ACE inhibitor discontinuation.\n\nHe had some proteinuria at 0.6 grams protein/gram creatinine but further investigation of his urine with a urinary culture being sent revealed a urinary tract infection and the patient noted frequency symptoms. His first infection was noted 12/2018 he was treated with a course of ciprofloxacin. His urinary culture returned with only one organism: >100,000 colony forming units (cfus) of K. pneumoniae. This isolate was resistant to ampicillin, susceptible with a minimum inhibitory concentration (MIC) of ≤1 µg/mL ceftriaxone, ≤0.25 µg/mL for ciprofloxacin, ≤1 µg/mL for gentamicin, ≤16 µg/mL for nitrofurantoin, susceptible to oral cephalosporins, ≤4 µg/mL for piperacillin/tazobactam, and ≤20 µg/mL for trimethoprim/sulfamethoxazole. Despite a week long course of ciprofloxacin 250 mg orally twice a day for a week, the patient reported ongoing symptoms. In 2/2019, a repeat urinary culture was drawn. This culture showed one organism, again >100,000 cfu of K. pneumoniae, with the same sensitivity pattern as the 12/2018 isolate except for ≤32 µg/mL MIC for nitrofurantoin. This time the patient was treated with cephalexin 500 mg by mouth for 1 week, and experienced some relief from symptoms. One month later, 3/2019, the patient reported urinary symptoms again and a similar isolate of K. pneumoniae was found with the same sensitivity pattern except now it was resistant to ampicillin and nitrofurantoin. This final time the patient was treated with cefuroxime 250 mg orally twice for 10 days. He finally reported resolution of urinary frequency, but is being monitored for recurrent symptoms and infection. The patient had no indwelling catheters, instrumentalization, kidney stones, or any other reason for a complicated urinary tract infection. It was felt clinically the patient may be having trouble clearing his K. pneumoniae infection, and the literature discussed earlier regarding ruxolitinib was discussed as a possible explanation for these recurrent urinary tract infections (UTIs).\n\n2. Discussion\nThe nearly ubiquitous role of tyrosine kinase inhibitors in cell division across red cell and immune cell progenitors provide a clear context for the classification of ruxolitinib as an immune modulating or even immunosuppressing agent [6,7,8,9,10,11,12]. Figure 1 shows the JAK/STAT kinase pathway as a schematic drawing. It is noted that ruxolitinib was postulated as a main etiology for why the reported patient could not clear his underlying K. Pneumoinae. urinary tract infections in this case. It is important in PCV, PMF, and other patients receiving this agent that the potential for viral, fungal, and bacterial infections [6,7,8,9,10] be appreciated and the patients should be monitored accordingly.\n\nWhile most infections associated with ruxolitinib are mild and treated successfully with antibiotics [1,2], the potential for rare [9], fungal [9], viral [8], and bacterial [6,7,8,10,11,12] infections that may present with abscesses, non-clearing infections, or even life threatening ways must be recognized and anticipated [10,11,12,13]. Please see Table 1 for the three reported cases of K. pneumoniae infections in patients receiving ruxolitinib.\n\nIt is important for oncologists, onconephrologists, and infectious disease specialists to recognize the immune suppressing effects of ruxolitinib, and the predilection for various atypical organisms [6,7,8,10,11,12,13], including the risk for the often resistant K. pneumoniae species. Given immunomodulatory/immune suppression risk of JAK 1,2 inhibitors, the risk of atypical and clinically silent infections must also be kept in mind when evaluating the patient on ruxolitinib. The beneficial effects of ruxolitinib on patients with myelofibrosis and PCV also warrant continued use of this agent, but with a vigilant eye for increased infection risks [14].\n\n3. Conclusions \nThis report is to increase awareness of ruxolitinib as an immunomodulatory/immuno-suppressive agent. Klebsiella pneumoniae infection can be seen with JAK kinase agents like ruxolitinib. Reported cases include recurrent urinary tract infections and one case of a hepatic abscess with K. pneumoniae in users of ruxolitinib.\n\nAuthor Contributions\nR.M.H. was the primary author of the manuscript; M.K. assisted with table construction, writing text, editing text; L.A.E.-N. assisted with writing and editing manuscript, and the figure. U.S. oversaw writing of this case report as the ranking onconephrology specialist at UCLA.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Schematic of Janus kinase 2 pathway (JAK/STAT pathway). CytR, cytokine receptor; DNA, deoxyribonucleic acid; Grb, Growth factor receptor-bound protein 2; JAK-Janus Kinase 1, 2; MAPK, a mitogen-activated protein kinase; P, phosphorous; Ras, rat sarcoma protein; Raf, serine/threonine kinase/cellular homolog of viral RAF gene; SoS, son of sevenless; STAT, signal transducer and activator of transcription.\n\nantibiotics-08-00150-t001_Table 1Table 1 Cases of K. Pneumoniae infections associated with ruxolitinib use.\n\nReference\tAge\tGender\tRace\tIndication\tInfection Location\t\n12\t78\tM\tNR\tPMF\tLiver abscess\t\n13\tNR\tNR\tNR\tNR\tUTI\t\nCC\t75\tM\tCaucasian\tPCV\tUTI\t\nCC, current case; M, male; NR, not reported; PCV, polycythemia vera, PMF, primary myelofibrosis; UTI; urinary tract infection.\n==== Refs\nReferences\n1. Becker H. Engelhardt M. von Bubnoff N. Wäsch R. Ruxolitinib Recent Results Cancer Res. 2014 201 249 257 24756798 \n2. Raedler L.A. Jakafi (Ruxolitinib): First FDA-Approved Medication for the Treatment of Patients with Polycythemia Vera Am. Health Drug Benefits 2015 8 75 79 26629270 \n3. Assi T. Baz E. Current applications of therapeutic phlebotomy Blood Transfus. 2014 12 Suppl. 1 s75 s83 24120605 \n4. Vannucchi A.M. Kiladjian J.J. Griesshammer M. Masszi T. Durrant S. Passamonti F. Harrison C.N. Pane F. Zachee P. Mesa R. Ruxolitinib versus Standrad Therapy for the Treatment of Polycythemia Vera N. Engl. J. Med. 2015 372 426 435 10.1056/NEJMoa1409002 25629741 \n5. Zandvakili I. Conboy C. Ayed A. Ruxolitinib as first-line treatment in secondary hemophagocytic lymphohistiocytosis: A second experience Am. J. Hematol. 2018 93 E123 E125 10.1002/ajh.25063 29417621 \n6. Seif F. Khoshmirsafa M. Aazami H. Mohsenzadegan M. Sedighi G. Bahar M. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells Cell Commun. Signal. 2017 15 23 10.1186/s12964-017-0177-y 28637459 \n7. Zarzour A. Tabarroki A. Taftaf R. Visconte V. Ai J. Hamilton B.K. Papadantonakis N. Lichtin A.E. Horwitz L.J. Advani A.S. Rates of Infection in Myelofibrosis PatientsTreated with Ruxolitinib Blood 2014 124 1835 \n8. Lussana F. Cattaneo M. Rambaldi A. Ruxolitinib-associated infections: A systematic review and meta-analysis Am. J. Hematol. 2018 93 339 347 10.1002/ajh.24976 29150886 \n9. Prakash K. Richman D. A case report of disseminated histoplasmosis and concurrent cryptococcal meningitis in a patient treated with ruxolitinib BMC Infect. Dis. 2019 19 287 10.1186/s12879-019-3922-6 30917797 \n10. Heine A. Bossart P. Wolf D. Ruxolitinib is a potent immunosuppressive compound: Is it time for anti-infective prophylaxis? Blood 2013 122 3843 3844 10.1182/blood-2013-10-531103 24288410 \n11. Manduzio P. Ruxolitinib in myelofibrosis: To be or not to be an immune disruptor Ther. Clin. Risk Manag. 2017 13 169 177 10.2147/TCRM.S121683 28243106 \n12. Kusano Y. Terui Y. Ueda K. Klebsiella pneumoniae primary liver abscess associated with ruxolitinib Ann. Hematol. 2016 95 1561 1562 10.1007/s00277-016-2718-7 27259987 \n13. Sylvine P. Thomas S. Pirayaeh E. Infections associated with ruxolitinib: Study in the French Pharmacovigilance database Ann. Hematol. 2018 97 913 914 10.1007/s00277-018-3242-8 29340760 \n14. Mascarenhas J. Hoffman R. A comprehensive review and analysis of the effect of ruxolitinib therapy on the survival of patients with myelofibrosis Blood 2013 121 4832 4837 10.1182/blood-2013-02-482232 23570800\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2079-6382",
"issue": "8(3)",
"journal": "Antibiotics (Basel, Switzerland)",
"keywords": "Immunemodulation; JAK kinase (Janus Kinase); Klebsiella pneumonia; Ruxolitinib; STAT (Signal Transducer and Activator of Transcription proteins) kinase",
"medline_ta": "Antibiotics (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101637404",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31527456",
"pubdate": "2019-09-16",
"publication_types": "D002363:Case Reports",
"references": "24120605;24756798;28637459;29340760;24288410;29150886;29417621;27259987;30917797;26629270;25629741;28243106;23570800",
"title": "Frequent Klebsiella pneumoniae Urinary Tract Infections in a Patient Treated with Ruxolitinib.",
"title_normalized": "frequent klebsiella pneumoniae urinary tract infections in a patient treated with ruxolitinib"
} | [
{
"companynumb": "US-BAYER-2020-073666",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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"actiondrug": null,
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"activesubstancename": "CIPROFLOXACIN HYDROCHLORIDE"
},
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{
"abstract": "BACKGROUND\nSome trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer.\n\n\nMETHODS\nPatients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m(2) day 1, LV 100 mg/m(2) as 2 h infusion and 5-FU 400 mg/m(2) as bolus, days 1 and 2 followed by 600 mg/m(2)/day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm).\n\n\nRESULTS\nFrom February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85-1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82-1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively.\n\n\nCONCLUSIONS\nA more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy.\n\n\nBACKGROUND\nClinicalTrials.gov Identifier: NCT01640782.",
"affiliations": "Istituto di Oncologia, Policlinico di Monza, Monza.;Laboratory of Clinical Research, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milano. Electronic address: irene.floriani@marionegri.it.;Struttura Complessa di Medicina Oncologica 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano.;Unità di Oncologia Medica, Ospedale Papa Giovanni XXIII, Bergamo.;Dipartimento di Ricerca Traslazionale, Università di Pisa, Istituto Toscano Tumori, Pisa.;S.C. Oncologia Medica, Azienda Ospedaliero-Universitaria Careggi, Firenze.;Oncologia Medica A, Fondazione Pascale, Istituto Nazionale dei Tumori, Napoli.;I.R.C.C.S. Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Meldola.;U.O. di Oncologia Medica, Policlinico S.Orsola Malpighi, Bologna.;Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Napoli.;Clinica Chiurgica 1, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche, Padova.;Dipartimento di Oncologia, A.O.G. Rummo, Benevento.;Dipartimento di Scienze Della Salute, Sezione di Farmacologia Clinica e Oncologia, Università degli Studi di Firenze, Firenze.;Laboratory of Clinical Research, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milano.;U.O. Oncologia e Ematologia, Humanitas Cancer Center, Istituto Clinico Humanitas-I.R.C.C.S., Rozzano.;Unità di Oncologia Medica, Ospedale Papa Giovanni XXIII, Bergamo.;S.C. di Oncologia Medica Addominale, dell'Istituto Tumori di Napoli, Napoli.;Oncologia, Arcispedale Santa Maria Nuova-I.R.C.C.S., Reggio Emilia, Reggio Emilia.;Divisione di Oncologia Medica, A.O. Ospedale di Circolo, Varese.;S.C. Oncologia Medica, A.O.S. Gerardo, Monza.;U.O. Oncologia Medica, Azienda USL6 di Livorno, Istituto Toscano Tumori, Livorno.;Unità Oncologia Medica, Ospedale S. Carlo, Potenza.;U.O. di Oncologia, Ospedale Infermi Rimini, Ospedale Cervesi, Azienda USL di Rimini, Rimini, Cattolica.;Oncologia Medica, USL 1, Massa Carrara.;U.O. di Oncologia Medica, Policlinico S.Orsola Malpighi, Bologna.;Ospedale Carlo Poma, Mantova, Italy.;Clinica Chiurgica 1, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche, Padova.",
"authors": "Bajetta|E|E|;Floriani|I|I|;Di Bartolomeo|M|M|;Labianca|R|R|;Falcone|A|A|;Di Costanzo|F|F|;Comella|G|G|;Amadori|D|D|;Pinto|C|C|;Carlomagno|C|C|;Nitti|D|D|;Daniele|B|B|;Mini|E|E|;Poli|D|D|;Santoro|A|A|;Mosconi|S|S|;Casaretti|R|R|;Boni|C|C|;Pinotti|G|G|;Bidoli|P|P|;Landi|L|L|;Rosati|G|G|;Ravaioli|A|A|;Cantore|M|M|;Di Fabio|F|F|;Aitini|E|E|;Marchet|A|A|;|||",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdu146",
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"issn_linking": "0923-7534",
"issue": "25(7)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "adjuvant chemotherapy; adjuvant treatment; gastric cancer; randomized clinical trial",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D003131:Combined Modality Therapy; D000077143:Docetaxel; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D013274:Stomach Neoplasms; D043823:Taxoids",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "1373-1378",
"pmc": null,
"pmid": "24728035",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer.",
"title_normalized": "randomized trial on adjuvant treatment with folfiri followed by docetaxel and cisplatin versus 5 fluorouracil and folinic acid for radically resected gastric cancer"
} | [
{
"companynumb": "IT-SA-2014SA098943",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
"dru... |
{
"abstract": "A 66-year-old woman with chronic myeloid leukaemia in nilotinib-induced remission was diagnosed with amaurosis fugax, caused by carotid stenosis. Serum cholesterol was 316 mg/dL (Low-Density Lipoprotein (LDL) cholesterol 213 mg/dL). Nilotinib was discontinued and replaced by interferon. Antiplatelet therapy and atorvastatin 40 mg/day were prescribed. Muscle pain and elevation of serum creatine kinase (CK) occurred; thus, atorvastatin was replaced by ezetimibe. Afterwards, muscle pain subsided and CK reverted to normal, but 2 years later serum cholesterol was still elevated at 218 mg/dL with LDL cholesterol 126 mg/dL. Simvastatin 5 mg/day was then started, but again muscle pain occurred and CK rose to 267 U/L. Simvastatin was stopped and serum cholesterol climbed to 252 mg/dL. Creatine was prescribed and simvastatin was reintroduced. Two months later, cholesterol was 171 mg/dL, CK was 72 U/L and there was no muscle pain. This case supports the view that creatine may prevent statin-induced myopathy.",
"affiliations": "Clinica Neurologica, Università degli Studi di Genova, Dipartimento di Neuroscienze Riabilitazione Oftalmologia Genetica e Scienze Materno-Infantili (DINOGMI), Genova, Italy.;Clinica Neurologica, Università degli Studi di Genova, Dipartimento di Neuroscienze Riabilitazione Oftalmologia Genetica e Scienze Materno-Infantili (DINOGMI), Genova, Italy.",
"authors": "Balestrino|Maurizio|M|http://orcid.org/0000-0002-5971-2200;Adriano|Enrico|E|",
"chemical_list": "C498826:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D011743:Pyrimidines; D019821:Simvastatin; D000069438:Ezetimibe; D003401:Creatine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-225395",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "cardiovascular system; lipid disorders; muscle disease; stroke; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D020757:Amaurosis Fugax; D000924:Anticholesteremic Agents; D016893:Carotid Stenosis; D008078:Cholesterol, LDL; D003401:Creatine; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D063806:Myalgia; D011743:Pyrimidines; D019821:Simvastatin; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30150340",
"pubdate": "2018-08-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20934984;2406992;26748651;17436778;28738130;21840598;27616593;27838722;23680457;16453090;28803825;19375663;25694464;21079234",
"title": "Statin-induced myopathy prevented by creatine administration.",
"title_normalized": "statin induced myopathy prevented by creatine administration"
} | [
{
"companynumb": "IT-LUPIN PHARMACEUTICALS INC.-2017-02949",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drugaddition... |
{
"abstract": "The patient was a man in his 70s with bone metastasis from renal cell carcinoma who had received immune checkpoint inhibitors(ICI)therapy. After 2 courses of chemotherapy, he was admitted to our hospital with diverticulitis. His diverticulitis could be treated with antibiotics, but he presented with severe hyponatremia and consciousness disorder during hospitalization. Brain MRI showed pituitary swelling, and his serum TSH, ACTH, cortisol levels decreased. We therefore diagnosed him with hypopituitarism due to ICIs. Hydrocortisone improved his hyponatremia and consciousness disorder. Endocrine stimulation tests revealed no reaction of ACTH, and low-level reactions of TSH, LH and FSH, ICIs cause many types of immune- related adverse events(irAEs). The indications for ICI therapy are expanding; thus, we can expect to experience more cases of serious irAEs in association with ICI treatment. Further studies should be performed to improve our understanding of irAEs.",
"affiliations": "Dept. of Surgery, Sumitomo Hospital.",
"authors": "Natsuki|Seiji|S|;Noda|Eiji|E|;Iimori|Nozomi|N|;Okuno|Tomohisa|T|;Kametani|Naoki|N|;Tokumoto|Mao|M|;Kato|Yukihiro|Y|;Yamada|Nobuya|N|;Nishimura|Shigehiko|S|;Taenaka|Naoyuki|N|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "47(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D002292:Carcinoma, Renal Cell; D006801:Humans; D000072659:Hypophysitis; D007680:Kidney Neoplasms; D008297:Male",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2095-2097",
"pmc": null,
"pmid": "33468812",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Hypophysitis Due to Immune Check Point Inhibitor Treatment.",
"title_normalized": "a case of hypophysitis due to immune check point inhibitor treatment"
} | [
{
"companynumb": "JP-B.BRAUN MEDICAL INC.-2107706",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": ... |
{
"abstract": "Myocarditis is an inflammatory disease of myocardium, associated with nonischemic necrosis and degeneration of myocytes. Although the clinical course is rapid, myocarditis can lead to dilated cardiomyopathy with chambers dilatation and ventricular dysfunction. The pathophysiology of myocarditis in humans is not completely understood. There are several etiological agents implicated, mainly viral agents. The clinical presentation is extremely various, with nonspecific systemic symptoms until sudden death. The great variability of symptoms makes the diagnosis, therefore, extremely difficult. We report the case of a 40-year-old woman who developed, after childbirth, hyperthermia associated with neck and left arm pain; initially treated with acetaminophen, without any benefit, the young woman, after few days, died suddenly. The autopsy documented the presence of edematous lungs and enlarged and congested liver. The microbiological tests performed 4 days after death were negative. The heart was normal in shape and volume; a section of the left ventricle wall showed subendocardial discromic areas histologically characterized by multifocal perivascular and interstitial inflammatory infiltrates. These infiltrates consisted mainly of neutrophils with eosinophil component associated with myocyte necrosis and hemorrhagic interstitial infiltration.",
"affiliations": "Cardiovascular Diseases Section, Department of Emergency and Organ Transplantation (DETO), University of Bari, P.zza G. Cesare, 11, 70124 Bari, Italy.;Cardiovascular Diseases Section, Department of Emergency and Organ Transplantation (DETO), University of Bari, P.zza G. Cesare, 11, 70124 Bari, Italy. Electronic address: ilaria.dentamaro@hotmail.it.;Cardiovascular Diseases Section, Department of Emergency and Organ Transplantation (DETO), University of Bari, P.zza G. Cesare, 11, 70124 Bari, Italy.;Cardiovascular Diseases Section, Department of Emergency and Organ Transplantation (DETO), University of Bari, P.zza G. Cesare, 11, 70124 Bari, Italy.;Cardiovascular Diseases Section, Department of Emergency and Organ Transplantation (DETO), University of Bari, P.zza G. Cesare, 11, 70124 Bari, Italy.;Department of Emergency and Organ Transplantation, Pathology Division, University of Bari, P.zza G. Cesare, 11, 70124 Bari, Italy.;Cardiovascular Diseases Section, Department of Emergency and Organ Transplantation (DETO), University of Bari, P.zza G. Cesare, 11, 70124 Bari, Italy.;Department of Interdisciplinary Medicine, Section of Legal Medicine, University of Bari, P.zza G. Cesare, 11, 70124 Bari, Italy.",
"authors": "Ciccone|Marco Matteo|MM|;Dentamaro|Ilaria|I|;Carbonara|Santa|S|;Ricci|Gabriella|G|;Vestito|Domenico|D|;Marzullo|Andrea|A|;Tunzi|Francesco|F|;Solarino|Biagio|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1054-8807",
"issue": "25(2)",
"journal": "Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology",
"keywords": "Forensic pathology; Peripartum myocarditis; Pregnant complications; Sudden death",
"medline_ta": "Cardiovasc Pathol",
"mesh_terms": "D000328:Adult; D001344:Autopsy; D016757:Death, Sudden, Cardiac; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D009205:Myocarditis; D058725:Peripartum Period; D011247:Pregnancy",
"nlm_unique_id": "9212060",
"other_id": null,
"pages": "87-9",
"pmc": null,
"pmid": "26764139",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fulminant Peripartum myocarditis associated with sudden cardiac death: a case report.",
"title_normalized": "fulminant peripartum myocarditis associated with sudden cardiac death a case report"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-110243",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"... |
{
"abstract": "Out-of-Hospital Cardiac Arrest (OHCA) and mild therapeutic hypothermia (MTH) have been linked to increased risk of Stent Thrombosis (ST) in comatose survivors who undergo percutaneous coronary intervention (PCI). In this sense, there is no formal recommendation about which antiplatelet regimen should be used in patients with acute coronary syndromes (ACS) after OHCA.\n\n\n\nTo compare the incidence of probable/definite ST and bleeding events between ticagrelor and clopidogrel, in patients with ACS under MTH after an OHCA.\n\n\n\nFrom January 2010 to August 2016, 144 patients underwent MTH after an OHCA. Overall, 114 had an ACS (79%) and 98 (67,3%) were treated with primary PCI and stent implantation. Among them, 61 (62,2%) were treated with clopidogrel, and 32 (32,6%) with ticagrelor. During hospitalization, the incidence of probable or definite ST was significantly higher in patients receiving clopidogrel compared to ticagrelor (11,4% vs. 0%; p: 0.04), and no significant differences in any (28,6% vs. 25%; p: 0.645) or major bleeding (BARC 3 or 5) (11,4% vs. 12,5%; p: 0.685) were found. Hospital mortality did not differ between groups (26,2% vs. 25%; p: 0.862).\n\n\n\nIn this study, as compared to clopidogrel, ticagrelor was associated with a lower rate of ST, without differences in haemorrhagic events in patients with OHCA for an ACS under MTH. Similarly to other settings, ticagrelor might be a valid alternative to clopidogrel in these patients.",
"affiliations": "Cardiology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Cardiology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain. Electronic address: freixa@clinic.ub.es.;Cardiology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Cardiology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Cardiology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Cardiology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Cardiology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Cardiology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Cardiology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Cardiology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Cardiology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Cardiology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Cardiology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.",
"authors": "Jiménez-Brítez|Gustavo|G|;Freixa|Xavier|X|;Flores-Umanzor|Eduardo|E|;San Antonio|Rodolfo|R|;Caixal|Gala|G|;Garcia|John|J|;Hernandez-Enriquez|Marco|M|;Andrea|Rut|R|;Regueiro|Ander|A|;Masotti|Mónica|M|;Brugaletta|Salvatore|S|;Martin|Victoria|V|;Sabaté|Manel|M|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.resuscitation.2017.02.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-9572",
"issue": "114()",
"journal": "Resuscitation",
"keywords": "Mild therapeutic hypothermia; Out-of-hospital cardiac arrest; Stent thrombosis; Ticagrelor",
"medline_ta": "Resuscitation",
"mesh_terms": "D000241:Adenosine; D000368:Aged; D000077144:Clopidogrel; D003328:Coronary Thrombosis; D006801:Humans; D007036:Hypothermia, Induced; D008297:Male; D008875:Middle Aged; D058687:Out-of-Hospital Cardiac Arrest; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors; D012189:Retrospective Studies; D012307:Risk Factors; D015607:Stents; D000077486:Ticagrelor; D013988:Ticlopidine",
"nlm_unique_id": "0332173",
"other_id": null,
"pages": "141-145",
"pmc": null,
"pmid": "28242212",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Out-of-hospital cardiac arrest and stent thrombosis: Ticagrelor versus clopidogrel in patients with primary percutaneous coronary intervention under mild therapeutic hypothermia.",
"title_normalized": "out of hospital cardiac arrest and stent thrombosis ticagrelor versus clopidogrel in patients with primary percutaneous coronary intervention under mild therapeutic hypothermia"
} | [
{
"companynumb": "ES-ACCORD-061852",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo examine postoperative bleeding in patients taking antiplatelet and anticoagulant medications after invasive periodontal procedures.\n\n\nMETHODS\nThis 6-year retrospective study collected data from the electronic health records of patients who underwent invasive periodontal procedures at the College of Dentistry, University of Kentucky Lexington, from January 1, 2011 through April 1, 2017. Records were included when the medical history was current, an invasive periodontal procedure was performed, an antiplatelet or anticoagulant medication was taken, and a postoperative visit was documented.\n\n\nRESULTS\nFour hundred and fifty-six patients (age range 22-89 years; mean age 66.1 years; 58% male) met the inclusion criteria and underwent 867 invasive periodontal procedures. Antiplatelet medications, warfarin, a direct oral anticoagulant, or a combination of these drugs were taken during 484 scaling and root planing procedures, 218 implant placements, 53 open flap debridements, 16 gingival grafts, 15 lateral windows, and 71 other. Medications were continued in 99.6% of patients during the procedure. Postoperative bleeding occurred after three procedures (0.35%) and resolved with local hemostatic measures. Medications were temporarily discontinued in four instances (range 1-5 days); none of these patients experienced postoperative bleeding.\n\n\nCONCLUSIONS\nPostoperative bleeding was infrequent in patients who underwent an invasive periodontal procedure while taking an antiplatelet or anticoagulant drug.",
"affiliations": "Department of Oral Health Practice, College of Dentistry, University of Kentucky, Lexington, KY, USA.;Department of Oral Health Practice, College of Dentistry, University of Kentucky, Lexington, KY, USA.;Department of Statistics, College of Arts & Sciences, University of Kentucky, Lexington, KY, USA.;Department of Oral Health Practice, College of Dentistry, University of Kentucky, Lexington, KY, USA.;Department of Oral Health Practice, College of Dentistry, University of Kentucky, Lexington, KY, USA. Electronic address: cmiller@uky.edu.",
"authors": "Rubino|Ryan T|RT|;Dawson|Dolph R|DR|;Kryscio|Richard J|RJ|;Al-Sabbagh|Mohanad|M|;Miller|Craig S|CS|",
"chemical_list": "D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.oooo.2019.04.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "128(3)",
"journal": "Oral surgery, oral medicine, oral pathology and oral radiology",
"keywords": null,
"medline_ta": "Oral Surg Oral Med Oral Pathol Oral Radiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D019106:Postoperative Hemorrhage; D012189:Retrospective Studies; D014859:Warfarin; D055815:Young Adult",
"nlm_unique_id": "101576782",
"other_id": null,
"pages": "243-249",
"pmc": null,
"pmid": "31103527",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Postoperative bleeding associated with antiplatelet and anticoagulant drugs: A retrospective study.",
"title_normalized": "postoperative bleeding associated with antiplatelet and anticoagulant drugs a retrospective study"
} | [
{
"companynumb": "US-BAYER-2020-045465",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Chronic myeloid leukaemia (CML) is a clonal haematological disease which is characterized by a diagnostic karyotypic abnormality t (9;22)(q34;q11) called as Philadelphia (Ph) chromosome. Occurrence of additional chromosomal abnormalities besides the Ph chromosome is defined as clonal evolution (CE) and considered to be a marker of disease progression. A 67-year-old male who was initially evaluated at a private hospital where a diagnosis of acute promyelocytic leukaemia was made on bone marrow aspirate with ambiguous RT-PCR report referred to our centre for further evaluation and treatment. On conventional karyotyping, Ph chromosome along with translocations t(5;13)(q12;p13), t(15;20)(q22;p13) and monosomy 13 was observed in all 20 metaphases. A final diagnosis of CML-myeloid blast crisis with complex cytogenetics was made. Patient succumbed to death within one month of initiation of imatinib therapy.",
"affiliations": "Senior Resident, Department of Laboratory Medicine, AIIMS , New Delhi, India .;Attending Consultant, Department of Hematology, Medanta, The Medicity , Gurgaon, Haryana, India .;Additional Professor, Department of Laboratory Oncology, AIIMS , New Delhi, India .;Professor, Department of Medical Oncology, AIIMS , New Delhi, India .",
"authors": "Shah|Bhoumik|B|;Gajendra|Smeeta|S|;Gupta|Ritu|R|;Sharma|Atul|A|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2015/12284.5940",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "9(5)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Complex cytogenetics; Monosomy 13; t(15;20)(q22;p13); t(5;13)(q12;p13)",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "XD05-XD06",
"pmc": null,
"pmid": "26155548",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports",
"references": "8558198;1386342;12176881;18469801;19050065;22133358;18024655;22039253;16056248;18072628;16772117;1065618",
"title": "Novel Cytogenetic Aberrations in a Patient of Chronic Myeloid Leukemia with Blast Crisis.",
"title_normalized": "novel cytogenetic aberrations in a patient of chronic myeloid leukemia with blast crisis"
} | [
{
"companynumb": "PHHY2015IN064746",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugadditional": null,
"druga... |
{
"abstract": "TAFRO syndrome is a systemic inflammatory disorder. TAFRO is an acronym that stands for thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, lymphadenopathy and hepatosplenomegaly. There are no reports of TAFRO syndrome describing cholangitis on liver biopsy. Herein, we report the first case of TAFRO syndrome with cholangitis. The patient was a 56-year-old man who presented with sudden onset abdominal pain and fever. His symptoms progressed to generalized edema, thrombocytopenia, hepatomegaly, and acute renal failure. Biopsies taken from the mediastinal lymph nodes and bone marrow showed the mixed type of multicentric Castleman's disease and mild reticulin fibrosis, respectively, compatible with TAFRO syndrome. His symptoms were temporarily relieved by steroid pulse therapy and tocilizumab. Fever and anasarca relapsed in a few weeks, however. He was then administered rituximab which resolved his symptoms almost completely.",
"affiliations": "Department of Hematology, Teine Keijinkai Hospital.",
"authors": "Nagai|Yuki|Y|;Ando|Sachiko|S|;Honda|Nanase|N|;Noguchi|Hiroko|H|;Maemori|Masayo|M|;Hayashi|Toshiaki|T|;Sakai|Hajime|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.57.2490",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "57(12)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": null,
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D001706:Biopsy; D002761:Cholangitis; D004487:Edema; D005334:Fever; D005355:Fibrosis; D006801:Humans; D008099:Liver; D008107:Liver Diseases; D008297:Male; D008875:Middle Aged; D013158:Splenic Diseases; D013577:Syndrome; D013921:Thrombocytopenia",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "2490-2495",
"pmc": null,
"pmid": "28090015",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "TAFRO syndrome showing cholangitis on liver biopsy.",
"title_normalized": "tafro syndrome showing cholangitis on liver biopsy"
} | [
{
"companynumb": "JP-ROCHE-1480527",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"drug... |
{
"abstract": "Myocardial stunning, known as stress cardiomyopathy, broken-heart syndrome, transient left ventricular apical ballooning, and Takotsubo cardiomyopathy, has been reported after many extracardiac stressors, but not following chemotherapy. We report 2 cases with characteristic electrocardiographic and echocardiographic features following combined modality therapy with combretastatin, a vascular-disrupting agent being studied for treatment of anaplastic thyroid cancer. In 1 patient, an ECG performed per protocol 18 hours after drug initiation showed deep, symmetric T-wave inversions in limb leads I and aVL and precordial leads V(2) through V(6). Echocardiography showed mildly reduced overall left ventricular systolic function with akinesis of the entire apex. The patient had mild elevations of troponin I. Coronary angiography revealed no epicardial coronary artery disease. The electrocardiographic and echocardiographic abnormalities resolved after several weeks. The patient remains stable from a cardiovascular standpoint and has not had a recurrence during follow-up. An electrocardiogram performed per protocol in a second patient showed deep, symmetric T-wave inversions throughout the precordial leads and a prolonged QT interval. Echocardiography showed mildly reduced left ventricular function with hypokinesis of the apical-septal wall. Acute coronary syndrome was ruled out, and both the electrocardiographic and echocardiographic changes resolved at follow-up. Although the patient remained pain-free without recurrence of anginal symptoms during long-term follow-up, the patient developed progressive malignancy and died.",
"affiliations": "Harrington-McLaughlin Heart and Vascular Institute, Ireland Cancer Center, and Department of Radiology, University Hospitals-Case Medical Center, Cleveland, Ohio 44106, USA.",
"authors": "Bhakta|Shyam|S|;Flick|Susan M|SM|;Cooney|Matthey M|MM|;Greskovich|John F|JF|;Gilkeson|Robert C|RC|;Remick|Scot C|SC|;Ortiz|Jose|J|",
"chemical_list": "D001632:Bibenzyls; D019210:Troponin I; C040105:combretastatin",
"country": "United States",
"delete": false,
"doi": "10.1002/clc.20685",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-9289",
"issue": "32(12)",
"journal": "Clinical cardiology",
"keywords": null,
"medline_ta": "Clin Cardiol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001632:Bibenzyls; D002277:Carcinoma; D003952:Diagnostic Imaging; D004562:Electrocardiography; D005260:Female; D006801:Humans; D017682:Myocardial Stunning; D013964:Thyroid Neoplasms; D019210:Troponin I",
"nlm_unique_id": "7903272",
"other_id": null,
"pages": "E80-4",
"pmc": null,
"pmid": "20014213",
"pubdate": "2009-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Myocardial stunning following combined modality combretastatin-based chemotherapy: two case reports and review of the literature.",
"title_normalized": "myocardial stunning following combined modality combretastatin based chemotherapy two case reports and review of the literature"
} | [
{
"companynumb": "US-PFIZER INC-202101414100",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditiona... |
{
"abstract": "Interventional pain management involves diagnosis and treatment of chronic pain. This specialty utilizes minimally invasive procedures to target therapeutics to the central nervous system and the spinal column. A subset of patients encountered in interventional pain are medicated using anticoagulant or antithrombotic drugs to mitigate thrombosis risk. Since these drugs target the clotting system, bleeding risk is a consideration accompanying interventional procedures. Importantly, discontinuation of anticoagulant or antithrombotic drugs exposes underlying thrombosis risk, which can lead to significant morbidity and mortality especially in those with coronary artery or cerebrovascular disease. This review summarizes the literature and provides guidelines based on best evidence for patients receiving anti-clotting therapy during interventional pain procedures.\n\n\n\nBest evidence synthesis.\n\n\n\nTo provide a current and concise appraisal of the literature regarding an assessment of the bleeding risk during interventional techniques for patients taking anticoagulant and/or antithrombotic medications.\n\n\n\nA review of the available literature published on bleeding risk during interventional pain procedures, practice patterns and perioperative management of anticoagulant and antithrombotic therapy was conducted. Data sources included relevant literature identified through searches of EMBASE and PubMed from 1966 through August 2018 and manual searches of the bibliographies of known primary and review articles.\n\n\n\n1. There is good evidence for risk stratification by categorizing multiple interventional techniques into low-risk, moderate-risk, and high-risk. Also, their risk should be upgraded based on other risk factors.2. There is good evidence for the risk of thromboembolic events in patients who interrupt antithrombotic therapy. 3. There is good evidence supporting discontinuation of low dose aspirin for high risk and moderate risk procedures for at least 3 days, and there is moderate evidence that these may be continued for low risk or some intermediate risk procedures.4. There is good evidence that discontinuation of anticoagulant therapy with warfarin, heparin, dabigatran (Pradaxa®), argatroban (Acova®), bivalirudin (Angiomax®), lepirudin (Refludan®), desirudin (Iprivask®), hirudin, apixaban (Eliquis®), rivaroxaban (Xarelto®), edoxaban (Savaysa®, Lixiana®), Betrixaban(Bevyxxa®), fondaparinux (Arixtra®) prior to interventional techniques with individual consideration of pharmacokinetics and pharmacodynamics of the drugs and individual risk factors increases safety.5. There is good evidence that diagnosis of epidural hematoma is based on severe pain at the site of the injection, rapid neurological deterioration, and MRI with surgical decompression with progressive neurological dysfunction to avoid neurological sequelae.6. There is good evidence that if thromboembolic risk is high, low molecular weight heparin bridge therapy can be instituted during cessation of the anticoagulant, and the low molecular weight heparin can be discontinued 24 hours before the pain procedure.7. There is fair evidence that the risk of thromboembolic events is higher than that of epidural hematoma formation with the interruption of antiplatelet therapy preceding interventional techniques, though both risks are significant.8. There is fair evidence that multiple variables including anatomic pathology with spinal stenosis and ankylosing spondylitis; high risk procedures and moderate risk procedures combined with anatomic risk factors; bleeding observed during the procedure, and multiple attempts during the procedures increase the risk for bleeding complications and epidural hematoma.9. There is fair evidence that discontinuation of phosphodiesterase inhibitors is optional (dipyridamole [Persantine], cilostazol [Pletal]. However, there is also fair evidence to discontinue Aggrenox [dipyridamole plus aspirin]) 3 days prior to undergoing interventional techniques of moderate and high risk. 10. There is fair evidence to make shared decision making between the patient and the treating physicians with the treating physician and to consider all the appropriate risks associated with continuation or discontinuation of antithrombotic or anticoagulant therapy.11. There is fair evidence that if thromboembolic risk is high antithrombotic therapy may be resumed 12 hours after the interventional procedure is performed.12. There is limited evidence that discontinuation of antiplatelet therapy (clopidogrel [Plavix®], ticlopidine [Ticlid®], Ticagrelor [Brilinta®] and prasugrel [Effient®]) avoids complications of significant bleeding and epidural hematomas.13. There is very limited evidence supporting the continuation or discontinuation of most NSAIDs, excluding aspirin, for 1 to 2 days and some 4 to 10 days, since these are utilized for pain management without cardiac or cerebral protective effect.\n\n\n\nThe continued paucity of the literature with discordant recommendations.\n\n\n\nBased on the survey of current literature, and published clinical guidelines, recommendations for patients presenting with ongoing antithrombotic therapy prior to interventional techniques are variable, and are based on comprehensive analysis of each patient and the risk-benefit analysis of intervention.\n\n\n\nPerioperative bleeding, bleeding risk, practice patterns, anticoagulant therapy, antithrombotic therapy, interventional techniques, safety precautions, pain.",
"affiliations": "LSU Health Science Center, New Orleans.;Pain Management Center of Paducah, Paducah, KY, and University of Louisville, Louisville, KY.;Medical College of Wisconsin, Wausau, WI.;Department of Pharmacology & Experimental Therapeutics, Louisiana State University- Health Sciences Center-New Orleans, LA.;Department of Anesthesiology, Tulane Medical Center Center-New Orleans, LA.;Department of Anesthesiology, Louisiana State University Health New Orleans.;Department of Anesthesiology, LSU School of Medicine, New Orleans, LA.;Assistant Professor, Departments of Anesthesiology and Pharmacology, Toxicology and Neuroscience, Director of Research, Department of Anesthesiology, Assistant Professor of Research, Department of Anesthesiology, Louisiana State University-Health Sciences Center-New Orleans, LA and Shreveport, LA.;Department of Anesthesiology, Louisiana State University-Health Sciences Center-New Orleans, LA.;Departments of Anesthesiology, University of Kentucky, Chandler Medical Center, Lexington, KY.;Departments of Anesthesiology, University of Kentucky, Chandler Medical Center, Lexington, KY.;Millennium Pain Center, Bloomington, IN.;Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.;University of Texas, MD Anderson Cancer Center, Houston, TX.;Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital/Harvard, Boston, MA; Department of Anesthesiology, LSU School of Medicine, New Orleans, LA.;Pain Management Center of Paducah, Paducah, KY.;Global Scientific Innovations, Evansville, IN.;Tri State Spine Care Institute.;Ohio Pain Clinic.;Millennium Pain Center, Bloomington, IN.;Vice Chair for Research and Education, Department of Anesthesiology and Pain Management, Advocate Illinois Masonic Medical Center, Clinical Associate Professor of Anesthesiology and Surgery at University of Illinois, Chicago, IL.;Clinical Radiology of Oklahoma, Edmond, OK.;MGH Center for Pain Medicine, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA.;Massachusetts General Hospital and Harvard Medical School, Boston, MA.",
"authors": "Kaye|Alan D|AD|;Manchikanti|Laxmaiah|L|;Novitch|Matthew B|MB|;Mungrue|Imran N|IN|;Anwar|Muhammad|M|;Jones|Mark R|MR|;Helander|Erik M|EM|;Cornett|Elyse M|EM|;Eng|Matthew R|MR|;Grider|Jay S|JS|;Harned|Michael E|ME|;Benyamin|Ramsin M|RM|;Swicegood|John R|JR|;Simopoulos|Thomas T|TT|;Abdi|Salahadin|S|;Urman|Richard D|RD|;Deer|Timothy R|TR|;Bakhit|Cyrus|C|;Sanapati|Mahendra|M|;Atluri|Sairam|S|;Pasupuleti|Ramarao|R|;Soin|Amol|A|;Diwan|Sudhir|S|;Vallejo|Ricardo|R|;Candido|Kenneth D|KD|;Knezevic|Nebojsa Nick|NN|;Beall|Douglas|D|;Albers|Sheri L|SL|;Latchaw|Richard E|RE|;Prabhakar|Hari|H|;Hirsch|Joshua A|JA|",
"chemical_list": "D000925:Anticoagulants; D005343:Fibrinolytic Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1533-3159",
"issue": "22(1S)",
"journal": "Pain physician",
"keywords": null,
"medline_ta": "Pain Physician",
"mesh_terms": "D000925:Anticoagulants; D059350:Chronic Pain; D005343:Fibrinolytic Agents; D006470:Hemorrhage; D006801:Humans; D059408:Pain Management",
"nlm_unique_id": "100954394",
"other_id": null,
"pages": "S75-S128",
"pmc": null,
"pmid": "30717501",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article; D017065:Practice Guideline",
"references": null,
"title": "Responsible, Safe, and Effective Use of Antithrombotics and Anticoagulants in Patients Undergoing Interventional Techniques: American Society of Interventional Pain Physicians (ASIPP) Guidelines.",
"title_normalized": "responsible safe and effective use of antithrombotics and anticoagulants in patients undergoing interventional techniques american society of interventional pain physicians asipp guidelines"
} | [
{
"companynumb": "US-ALLERGAN-2006708US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "KETOROLAC TROMETHAMINE"
},
"drugadditional": null... |
{
"abstract": "Pulmonary complications following allogeneic hematopoietic stem-cell transplantation (HSCT) are a significant source of morbidity and complications may arise from a myriad of infectious and noninfectious sources. These complications may occur soon or many months post-transplantation and can have a broad range of outcomes. Surveillance for pulmonary involvement in the pediatric HSCT population can be challenging due to poor compliance with clinical pulmonary function testing, primarily spirometry, and there may be a role for clinical imaging to provide an additional means of monitoring, particularly in the era of clinical low-dose computed tomography (CT) protocols. In this single-site, retrospective study, a review of our institution's radiological and HSCT databases was conducted to assess the utility of a quantitative CT algorithm to describe ventilation abnormalities on high-resolution chest CT scans of pediatric HSCT patients. Thirteen non-contrast enhanced chest CT examinations acquired both in inspiration and expiration, from 12 deceased HSCT patients (median age at HSCT 10.4 years, median days of CT 162) were selected for the analysis. Also, seven age-matched healthy controls (median age 15.5) with non-contrast-enhanced inspiration-expiration chest CT were selected for comparison. We report that, compared to healthy age-matched controls, HSCT patients had larger percentages of poorly ventilated (median, 13.5% vs. 2.3%, p < .001) and air trapped (median 12.3% vs. 0%, p < .001) regions of lung tissue, suggesting its utility as a potential screening tool. Furthermore, there was wide variation within individual HSCT patients, supporting the use of multivolume CT and quantitative analysis to describe and phenotype post-transplantation lung involvement.",
"affiliations": "Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Milano, Italy.;Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.;College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.;Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.;Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.;Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Milano, Italy.;Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.",
"authors": "Pennati|Francesca|F|;Walkup|Laura L|LL|;Chhabra|Anuj|A|;Towe|Christopher|C|0000-0002-1129-5671;Myers|Kasiani|K|;Aliverti|Andrea|A|;Woods|Jason C|JC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/ppul.25223",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1099-0496",
"issue": "56(5)",
"journal": "Pediatric pulmonology",
"keywords": "hematopoietic stem-cell transplantation; imaging; quantitative CT",
"medline_ta": "Pediatr Pulmonol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D012189:Retrospective Studies; D013909:Thorax; D014057:Tomography, X-Ray Computed; D014184:Transplantation, Homologous",
"nlm_unique_id": "8510590",
"other_id": null,
"pages": "1026-1035",
"pmc": null,
"pmid": "33314762",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Quantitative inspiratory-expiratory chest CT to evaluate pulmonary involvement in pediatric hematopoietic stem-cell transplantation patients.",
"title_normalized": "quantitative inspiratory expiratory chest ct to evaluate pulmonary involvement in pediatric hematopoietic stem cell transplantation patients"
} | [
{
"companynumb": "IT-OTSUKA-2021_033774",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nWe sought to define the disease characteristics and outcomes of those patients presenting with urothelial carcinoma and a persistently elevated white blood cell (WBC) count.\n\n\nMETHODS\nWe queried a prospectively maintained institutional database. Patients were included if they had had a histologic diagnosis of urothelial carcinoma and a WBC count of > 20,000 cells/μL on ≥ 2 occasions separated by 30 days. The patients' medical records were reviewed and were excluded from the analysis if an underlying cause for the leukocytosis could be identified. The clinical, histologic, and laboratory data were then collected from the remaining patient cohort.\n\n\nRESULTS\nWe identified a total of 1410 patients with a histologic diagnosis of urothelial carcinoma, 9 (0.6%) of whom met our inclusion criteria. These 9 patients had a median age of 63 years. At their presentation with leukocytosis, all 9 had muscle-invasive disease and 5 had evidence of metastatic disease. Leukocytosis was frequently associated with hypercalcemia (n = 6), thrombocytosis (n = 5), and anemia (n = 9). Chemotherapy was able to achieve a WBC response in 3 of 5 patients, although only 1 patient demonstrated a substantial reduction in tumor volume radiographically. Extirpative surgery was able to provide a response in the laboratory parameters in 2 of 4 patients. However, all studied patients ultimately developed leukocytosis recurrence after systemic or local therapy and experienced rapid disease progression, with a median interval from leukocytosis until death of 71 days.\n\n\nCONCLUSIONS\nParaneoplastic leukocytosis in the setting of urothelial carcinoma is a rare phenomenon but confers a poor prognosis, with a rapid progression to death.",
"affiliations": "Department of Urology, Queen's University, Kingston, ON, Canada. Electronic address: izardj@kgh.kari.net.;Department of Urology, University of Washington, Seattle, WA.;Division of Oncology, Department of Medicine, University of Washington, Seattle, WA.;Department of Urology, University of Washington, Seattle, WA.;Division of Oncology, Department of Medicine, University of Washington, Seattle, WA.",
"authors": "Izard|Jason P|JP|;Gore|John L|JL|;Mostaghel|Elahe A|EA|;Wright|Jonathan L|JL|;Yu|Evan Y|EY|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clgc.2015.02.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1558-7673",
"issue": "13(4)",
"journal": "Clinical genitourinary cancer",
"keywords": "Bladder cancer; Laboratory markers; Prognostic markers; White blood cell count",
"medline_ta": "Clin Genitourin Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002295:Carcinoma, Transitional Cell; D005260:Female; D006801:Humans; D007964:Leukocytosis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010257:Paraneoplastic Syndromes; D011379:Prognosis; D011446:Prospective Studies; D047368:Tumor Burden; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "101260955",
"other_id": null,
"pages": "e253-e258",
"pmc": null,
"pmid": "25882979",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Persistent, Unexplained Leukocytosis Is a Paraneoplastic Syndrome Associated With a Poor Prognosis in Patients With Urothelial Carcinoma.",
"title_normalized": "persistent unexplained leukocytosis is a paraneoplastic syndrome associated with a poor prognosis in patients with urothelial carcinoma"
} | [
{
"companynumb": "CA-JNJFOC-20150720660",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND\nTuberculous paradoxical reactions (PRs) are excessive immune reactions occurring after antituberculosis (TB) treatment and are commonly observed in immunocompromised hosts such as patients infected with the human immunodeficiency virus.\n\n\nMETHODS\nWe recently encountered a 63-year-old male heart transplant recipient who developed tuberculous PR after treatment for miliary TB. The patient had been receiving immunosuppressive therapy with cyclosporine and mycophenolate mofetil for over 15 years. The diagnosis of miliary TB was made based on the presence of intermittent fever and fatigue; thus, anti-TB treatments (isoniazid, levofloxacin, ethambutol, and pyrazinamide) were started, which led to rapid defervescence and regression of the granular shadow and pleural effusion. However, a new persistent fever and confused state developed 1 month after the anti-TB therapy was started. After excluding possible etiologies of the patient's symptom, a PR was suspected, and anti-TB drugs were continued; corticosteroids were added as anti-inflammatory agents. After that, he has shown a favorable course with long-term anti-TB chemotherapy.\n\n\nCONCLUSIONS\nA PR should always be considered when the patients' symptoms of tuberculosis re-exacerbate after an appropriate anti-TB therapy. A PR commonly occurs in patients with various immunologic conditions including heart transplant recipients.",
"affiliations": "Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Transplantation, National Cerebral and Cardiovascular Center, Osaka, Japan. Electronic address: oseguchi@ncvc.go.jp.;Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Transplantation, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Transplantation, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Transplantation, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Transplantation, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Pharmacy, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Pharmacy, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Cardiovascular Surgery, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Cardiovascular Surgery, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Cardiovascular Surgery, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Cardiovascular Surgery, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Transplantation, National Cerebral and Cardiovascular Center, Osaka, Japan. Electronic address: nori@ncvc.go.jp.",
"authors": "Wakamiya|A|A|;Seguchi|O|O|;Shionoiri|A|A|;Kumai|Y|Y|;Kuroda|K|K|;Nakajima|S|S|;Yanase|M|M|;Matsuda|S|S|;Wada|K|K|;Matsumoto|Y|Y|;Fukushima|S|S|;Fujita|T|T|;Kobayashi|J|J|;Fukushima|N|N|",
"chemical_list": "D000995:Antitubercular Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D007538:Isoniazid",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2018.01.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "50(3)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000995:Antitubercular Agents; D016572:Cyclosporine; D016027:Heart Transplantation; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007538:Isoniazid; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D014391:Tuberculosis, Miliary",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "947-949",
"pmc": null,
"pmid": "29661467",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paradoxical Reaction of Tuberculosis in a Heart Transplant Recipient During Antituberculosis Therapy: A Case Report.",
"title_normalized": "paradoxical reaction of tuberculosis in a heart transplant recipient during antituberculosis therapy a case report"
} | [
{
"companynumb": "JP-CMP PHARMA-2018CMP00014",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": nul... |
{
"abstract": "Multi-kinase inhibitor sorafenib showed dramatic effects in acute myeloid leukemia (AML) cells harboring fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation. However, FLT3-ITD mutation only occurs in 25% of AML cases. The therapeutic effects of sorafenib in AML patients without FLT3-ITD are still in need of further investigation.\n\n\n\nA young AML patient with central nervous system (CNS) relapse was treated with sorafenib combined with chemotherapy. Another patient with refractory AML arising form chronic myelomonocytic leukemia (CMML) was treated with sorafenib monotherapy. Spinal and cranial magnetic resonance imaging (MRI), minimal residual disease (MRD) and peripheral blood cell count were monitored to evaluate disease status.\n\n\n\nThe patient with CNS relapse exhibited significant shrink of tumor volume. The other patient with refractory AML achieved hematological improvements.\n\n\n\nThese two cases suggested that sorafenib might be utilized as a potent salvage therapy for some refractory/relapsed AML patients without the FLT3-ITD mutation.",
"affiliations": "Department of Hematology, Chinese People's Liberation Army General Hospital, Beijing, China.;Department of Hematology, Chinese People's Liberation Army General Hospital, Beijing, China.;Department of Hematology, Chinese People's Liberation Army General Hospital, Beijing, China.;Department of Hematology, Chinese People's Liberation Army General Hospital, Beijing, China.;Department of Hematology, Chinese People's Liberation Army General Hospital, Beijing, China.;Department of Hematology, Chinese People's Liberation Army General Hospital, Beijing, China.;Department of Hematology, Chinese People's Liberation Army General Hospital, Beijing, China.",
"authors": "Yang|Nan|N|;Gu|Zhenyang|Z|;Liu|Zhanxiang|Z|;Huang|Wenrong|W|;Wang|Shuhong|S|;Wang|Lili|L|;Gao|Chunji|C|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000077157:Sorafenib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3",
"country": "Netherlands",
"delete": false,
"doi": "10.2174/1871520618666180307125544",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1871-5206",
"issue": "18(10)",
"journal": "Anti-cancer agents in medicinal chemistry",
"keywords": "AML; CNS myeloid tumor; FLT3-ITD; Sorafenib; refractory; relapse.",
"medline_ta": "Anticancer Agents Med Chem",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D018365:Neoplasm, Residual; D047428:Protein Kinase Inhibitors; D016879:Salvage Therapy; D000077157:Sorafenib; D013329:Structure-Activity Relationship; D051941:fms-Like Tyrosine Kinase 3",
"nlm_unique_id": "101265649",
"other_id": null,
"pages": "1489-1494",
"pmc": null,
"pmid": "29521250",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Sorafenib as a Salvage Therapy in FLT3-ITD Negative Relapse/ Refractory Acute Myeloid Leukemia.",
"title_normalized": "sorafenib as a salvage therapy in flt3 itd negative relapse refractory acute myeloid leukemia"
} | [
{
"companynumb": "CN-ACCORD-120943",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DECITABINE"
},
"drugadditional": null,
"drug... |
{
"abstract": "The presentation of both Cotard and Capgras syndromes is uncommon in schizophrenia. We present a case of a 23-year-old male with the diagnosis of schizophrenia with Cotard syndrome who later developed Capgras syndrome. By persisting significant symptoms despite the use of two antipsychotics, he was given the diagnosis of treatment-resistant schizophrenia, and his symptoms improved with clozapine. This is one of the few cases of Cotard and Capgras syndromes in a patient with schizophrenia.",
"affiliations": "Psychiatry Section, Department of Medical Sciences, Universidad Peruana Cayetano Heredia, Lima, Peru.;Psychiatry Section, Department of Medical Sciences, Universidad Peruana Cayetano Heredia, Lima, Peru.;Psychiatry Section, Department of Medical Sciences, Universidad Peruana Cayetano Heredia, Lima, Peru.",
"authors": "Revilla|Joshep|J|https://orcid.org/0000-0003-3224-3763;Aliaga|Stephanie|S|https://orcid.org/0000-0003-1288-6331;Lozano-Vargas|Antonio|A|https://orcid.org/0000-0002-5615-2076",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/6652336",
"fulltext": "\n==== Front\nCase Rep Psychiatry\nCase Rep Psychiatry\nCRIPS\nCase Reports in Psychiatry\n2090-682X 2090-6838 Hindawi \n\n10.1155/2021/6652336\nCase Report\nCotard and Capgras Syndrome in a Patient with Treatment-Resistant Schizophrenia\nhttps://orcid.org/0000-0003-3224-3763Revilla Joshep joshep.revilla.z@upch.pe https://orcid.org/0000-0003-1288-6331Aliaga Stephanie https://orcid.org/0000-0002-5615-2076Lozano-Vargas Antonio Psychiatry Section, Department of Medical Sciences, Universidad Peruana Cayetano Heredia, Lima, Peru\nAcademic Editor: Michael Kluge\n\n\n2021 \n23 1 2021 \n2021 66523368 11 2020 12 1 2021 15 1 2021 Copyright © 2021 Joshep Revilla et al.2021This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The presentation of both Cotard and Capgras syndromes is uncommon in schizophrenia. We present a case of a 23-year-old male with the diagnosis of schizophrenia with Cotard syndrome who later developed Capgras syndrome. By persisting significant symptoms despite the use of two antipsychotics, he was given the diagnosis of treatment-resistant schizophrenia, and his symptoms improved with clozapine. This is one of the few cases of Cotard and Capgras syndromes in a patient with schizophrenia.\n==== Body\n1. Introduction\nThe presentation of both Cotard and Capgras syndromes is uncommon in schizophrenia, and a few cases have been reported. Cotard syndrome was first described by Jules Cotard in 1880, and one of the characteristics is the nihilistic delusions that are related to denying the existence of oneself or the world. Capgras syndrome was described in 1923 by Capgras and Reboul-Lachaux and is characterized by the delusion that the individual or family members have been replaced by substitutes [1]. We report the case of a patient with treatment-resistant schizophrenia who had symptoms of both syndromes.\n\n2. Case Presentation\nR. is a 23-year-old, male, with a family psychiatric history of psychotic disorder and whose symptoms started at 13 with social isolation and poor hygiene. At 15, he became aggressive and suspicious, and risperidone 3 mg was prescribed daily; then, auditory hallucinations developed, so the antipsychotic was increased to 4 mg daily. However, he subsequently presented on numerous occasions to the emergency room (ER) with aggressive behavior and persecutory delusions. When he was 18, disorganized behavior and delusions of prejudice were added; for this reason, sulpiride 400 mg and olanzapine 10 mg daily were prescribed but without good response. Then, he presented with nihilistic delusions concerning his existence “I am dead, I died in 2012,” nihilistic delusions related to his body “I do not have a heart,” hypochondriacal delusions “my organs are not working,” delusions of guilt “I am taking the blame,” and suicidal ideation. For these reasons, he was again taken for his dad to the ER. In the mental examination, he was agitated, asking people to kill him. The PANSS upon admission of the patient was 125. During the hospitalization, he continued with the suicidal ideation, and the initiation of electroconvulsive therapy was recommended. The patient received 25 sessions of electroconvulsive therapy with partial improvement in the psychotic symptoms. His previous medication was changed to quetiapine 900 mg daily, without improvement. He was given a diagnosis of treatment-resistant schizophrenia, and clozapine was started. During hospitalization, the patient started refusing food, and a nasogastric tube was inserted. On one occasion, he became unwell, developing aspiration pneumonia (Figure 1) and spent 15 days in intensive care. As his medical condition subsequently improved, he said “I don't have parents, the people who raised me are impostors, they look like my parents, they will be angels, my parents buried me and I never knew about them.” In the neurological physical exam, the patient was alert, oriented to person and time. He mentioned he was in purgatory. The speech was normal. The muscle strength was 5/5 bilaterally, with no motor deficits. The sensation was intact bilaterally. Reflexes are 2+ bilaterally. Brain computerized tomography scan showed no intra- or extra-axial fluid, hemorrhage, or mass; the ventricular size was normal, and the grey-white differentiation was preserved (Figure 2). The complete blood count, liver function test, creatinine, and glucose levels were within normal values. He later transferred back to the mental health hospital. The clozapine dose was gradually increased to 650 mg daily with an improvement of the auditory hallucinations, the suicidal ideation, and the symptoms of Cotard and Capgras syndrome. PANSS at the discharge was 51. A weekly normal absolute neutrophil count was obtained. The last WBC was 6500 cells/mcL and the ANC 4290 cells/mcL.\n\n3. Discussion\nIn this case report, we present a patient with schizophrenia with Cotard syndrome who later developed Capgras syndrome. The association of Cotard and Capgras delusions in the same patient is extremely rare [2].\n\nCotard and Capgras delusions can also be understood as the one-stage or the two-stage model [3]. In the first one, the experiential, delusions are elucidated as a normal rationalization of the unusual perceptual experience. In the second one, the inferential, delusions are considered as an abnormal rationalization of the unusual perceptual experience. In this case, they may represent the way a person tries to attribute negative events to external causes (as in the case of Capgras that is accompanied by delusions of persecution) or internal causes (as in the case of Cotard in the setting of a depressive disorder) [4].\n\nIn our case, the Cotard syndrome did not improve with the electroconvulsive therapy (ECT), successful treatment in cases of melancholia, or psychotic depression [5]. The reasons for this could include that the Cotard syndrome appeared in the psychotic setting, the early onset of the disorder alongside his strong genetic load (both parents having features of schizophrenia). Our patient had persisting significant symptoms despite the use of two antipsychotics suggesting treatment-resistant schizophrenia, so the treatment was progressively changed to clozapine.\n\nThrough the observation of this case, we conclude that the recognition of symptoms of Cotard and Capgras syndrome in schizophrenia is important for the assessment of appropriate treatment.\n\nConflicts of Interest\nNone of the authors have any conflicts of interest to declare.\n\nFigure 1 Frontal chest radiograph showing consolidation of both lungs with increasing density towards the lung bases, predominantly the left lung base.\n\nFigure 2 Noncontrast computed tomography of the head.\n==== Refs\n1 Debruyne H. Portzky M. Van den Eynde F. Audenaert K. Cotard’s syndrome: A review Current Psychiatry Reports 2009 11 3 197 202 10.1007/s11920-009-0031-z 2-s2.0-65749106719 19470281 \n2 Wright S. Young A. W. Hellawell D. J. Sequential Cotard and Capgras delusions The British Journal of Clinical Psychology 1993 32 3 345 349 10.1111/j.2044-8260.1993.tb01065.x 2-s2.0-0027378320 8251965 \n3 Graux J. Lemoine M. El Hage W. Camus V. From depersonalization to hallucination Psychopathology 2012 45 1 42 52 10.1159/000325911 2-s2.0-82455198791 22123515 \n4 Young A. W. Leafhead K. M. Szulecka K. The Capgras and Cotard delusions Psychopathology 1994 27 3–5 226 231 10.1159/000284874 2-s2.0-0028097250 7846242 \n5 Dieguez S. Cotard syndrome Neurologic-Psychiatric Syndromes in Focus Part II - From Psychiatry to Neurology 2018 42 23 34 10.1159/000475679 2-s2.0-85035105225\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6838",
"issue": "2021()",
"journal": "Case reports in psychiatry",
"keywords": null,
"medline_ta": "Case Rep Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101583308",
"other_id": null,
"pages": "6652336",
"pmc": null,
"pmid": "33552609",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "8251965;19470281;22123515;7846242;29151088",
"title": "Cotard and Capgras Syndrome in a Patient with Treatment-Resistant Schizophrenia.",
"title_normalized": "cotard and capgras syndrome in a patient with treatment resistant schizophrenia"
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"abstract": "In nephrotic syndrome there is an increased tendency for bacterial infections due to immunological changes secondary to proteinuria, treatment (including steroids), and other as yet unknown causes. However, necrotizing fasciitis (NF) is an uncommon complication of the disease and has rarely been reported in nephrotic children. We report a 14-month-old boy with nephrotic syndrome who developed sepsis and NF as a complication. He was treated successfully with intensive medical and surgical treatment.",
"affiliations": "Department of Pediatric Nephrology, Dr. Sami Ulus Children's Hospital, Ankara, Turkey.",
"authors": "Delibaş|Ali|A|;Bek|Kenan|K|;Bülbül|Mehmet|M|;Demircin|Gülay|G|;Baysun|Sahika|S|;Oner|Ayşe|A|",
"chemical_list": "D005938:Glucocorticoids; D011239:Prednisolone",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-004-1669-8",
"fulltext": null,
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"issn_linking": "0931-041X",
"issue": "20(1)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": null,
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D019115:Fasciitis, Necrotizing; D005938:Glucocorticoids; D006801:Humans; D007223:Infant; D008297:Male; D009404:Nephrotic Syndrome; D011239:Prednisolone; D018805:Sepsis",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "99-101",
"pmc": null,
"pmid": "15549409",
"pubdate": "2005-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "58203;2206878;10321948;241048;10583105;11275629;12016811;407543;12107805;13862397;11979121",
"title": "Necrotizing fasciitis in a child: a rare complication of idiopathic nephrotic syndrome.",
"title_normalized": "necrotizing fasciitis in a child a rare complication of idiopathic nephrotic syndrome"
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"activesubstancename": "PREDNISOLONE"
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"abstract": "OBJECTIVE\nIn typical arrest-related death (ARD) scenarios, the victims often show signs of excited delirium syndrome (ExDS), intoxication, exhaustion and/or suffered from a preexisting physical or psychiatrical condition, all of which could have caused or at least triggered the person's death. Since autopsy findings are very rare in such cases, a clear clinicopathologic diagnosis and thus mechanism of death is rarely found.\n\n\nMETHODS\nWe present a case of a 25-year old woman, who died while being arrested by the police. Based on the patient's medical history, autopsy findings, contradicting witness testimonies, and reliable clinical and toxicological blood parameters, the most probable diagnosis is discussed.\n\n\nRESULTS\nThe cause of death was determined as cardiac arrest subsequent to a combination of excited delirium syndrome, physical exhaustion and respiratory impairment. The manner of death was unnatural and juridically, the charges were dropped.\n\n\nCONCLUSIONS\nIn cases, where the cause and mechanism of death can only be diagnosed by exclusion, police collaboration, detailed clinical history (past and present) as well as clinical blood parameter analyses are necessary to help evaluating possible contributing factors and the most probable cause of death in ARD.",
"affiliations": "Institute of Forensic Medicine, Ulm University Hospital, Germany; Ulm University, Germany. Electronic address: sebastian.kunz@uniklinik-ulm.de.;Department of Pharmacology and Toxicology, University of Iceland, Reykjavik, Iceland.;Department of Pathology, Landspítali University Hospital Reykjavik, Iceland.",
"authors": "Kunz|S N|SN|;Þórðardóttir|S|S|;Jónasson|J G|JG|",
"chemical_list": "D000697:Central Nervous System Stimulants",
"country": "England",
"delete": false,
"doi": "10.1016/j.jflm.2020.102091",
"fulltext": null,
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"issn_linking": "1752-928X",
"issue": "77()",
"journal": "Journal of forensic and legal medicine",
"keywords": "Amphetamine; Arrest-related death; Asphyxia; Excited delirium syndrome; Forensic medicine; Restraint",
"medline_ta": "J Forensic Leg Med",
"mesh_terms": "D000328:Adult; D000697:Central Nervous System Stimulants; D003693:Delirium; D055030:Drug Users; D005260:Female; D006323:Heart Arrest; D006801:Humans; D005082:Physical Exertion; D016495:Police; D016684:Prone Position; D011595:Psychomotor Agitation; D012149:Restraint, Physical; D019966:Substance-Related Disorders",
"nlm_unique_id": "101300022",
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"pages": "102091",
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"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Arrest-related death on the basis of a drug-induced excited delirium syndrome.",
"title_normalized": "arrest related death on the basis of a drug induced excited delirium syndrome"
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"abstract": "Herpes simplex viruses are endemic worldwide, with an estimated seroprevalence of approximately 70% in developed countries. However, it is less well known that they are one of the viral causes of fulminant hepatitis (<2%) and constitute <1% of all causes of acute liver failure. We describe the case of an 89-year-old man who developed sepsis caused by a urinary tract infection due to drug-sensitive Escherichia coli. After empirical treatment with piperacillin-tazobactam was initiated, the patient's condition worsened with shock, acute liver and renal failure, encephalopathy and persistent fever, that led to admission to the intensive care unit. The emergence of an acute abdomen prompted exploratory laparotomy but the patient died soon after surgery from abdominal haemorrhage. Immunohistochemical analysis of a liver biopsy specimen identified herpes simplex virus (HSV) hepatitis. The authors emphasize the need for better understanding of this rare condition in order to more precisely identify patients at risk who need more aggressive evaluation and empirical treatment, especially patients presenting with marked hepatic cytolysis with a rapidly worsening clinical evolution.\nHerpes simplex virus hepatitis should be considered in patients with acute liver failure.This condition can occur even in immunocompetent individuals.Empirical treatment with aciclovir should be initiated in case of clinical suspicion.",
"affiliations": "Internal Medicine Department, Iris South Hospitals, Brussels, Belgium.;Internal Medicine Department, Iris South Hospitals, Brussels, Belgium.;Internal Medicine Department, Iris South Hospitals, Brussels, Belgium.;Internal Medicine Department, Iris South Hospitals, Brussels, Belgium.;Anatomical Pathology Department Institut Jules Bordet, Brussels, Belgium.;Intensive Care Unit, Iris South Hospitals, Brussels, Belgium.",
"authors": "Inthasot|Valentine|V|;Goushchi|Adonis|A|;Lazzaroni|Silvia|S|;Papaleo|Alberto|A|;Galdon|Maria Gomez|MG|;Chochrad|Didier|D|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2018_000982",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2018_000982982-1-6357-1-10-20181126ArticlesFatal Septic Shock Associated with Herpes Simplex Virus Hepatitis: A Case Report Inthasot Valentine 1§Goushchi Adonis 1§Lazzaroni Silvia 1Papaleo Alberto 1Galdon Maria Gomez 2Chochrad Didier 3\n1 Internal Medicine Department, Iris South Hospitals, Brussels, Belgium\n2 Anatomical Pathology Department Institut Jules Bordet, Brussels, Belgium\n3 Intensive Care Unit, Iris South Hospitals, Brussels, Belgium§ Both authors contributed equally to this work.\n\n2018 27 12 2018 5 12 00098203 11 2018 09 11 2018 © EFIM 20182018This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseHerpes simplex viruses are endemic worldwide, with an estimated seroprevalence of approximately 70% in developed countries. However, it is less well known that they are one of the viral causes of fulminant hepatitis (<2%) and constitute <1% of all causes of acute liver failure. We describe the case of an 89-year-old man who developed sepsis caused by a urinary tract infection due to drug-sensitive Escherichia coli. After empirical treatment with piperacillin-tazobactam was initiated, the patient’s condition worsened with shock, acute liver and renal failure, encephalopathy and persistent fever, that led to admission to the intensive care unit. The emergence of an acute abdomen prompted exploratory laparotomy but the patient died soon after surgery from abdominal haemorrhage. Immunohistochemical analysis of a liver biopsy specimen identified herpes simplex virus (HSV) hepatitis. The authors emphasize the need for better understanding of this rare condition in order to more precisely identify patients at risk who need more aggressive evaluation and empirical treatment, especially patients presenting with marked hepatic cytolysis with a rapidly worsening clinical evolution.\n\nLEARNING POINTS\nHerpes simplex virus hepatitis should be considered in patients with acute liver failure.\n\nThis condition can occur even in immunocompetent individuals.\n\nEmpirical treatment with aciclovir should be initiated in case of clinical suspicion.\n\nAcute liver failurehepatitisherpes simplex virusseptic shock\n==== Body\nCASE DESCRIPTION\nAn 89-year-old man was admitted to the emergency room after a fall. His medical history included hypertension, hypercholesterolaemia, mild chronic kidney disease and a suspicion of frontotemporal dementia with a vascular component. He lived alone with help from a property manager due to his cognitive disorders. He had undergone several orthopaedic procedures including osteosynthesis for a fracture of the right tibia after a car accident, a hip replacement for coxarthrosis, and osteosynthesis of a left humeral fracture after a fall 3 months previously. He had last stayed in hospital 1 week earlier when he had been treated with amoxicillin-clavulanic acid for bronchitis. He only took aspirin and a proton pump inhibitor as daily medication at home. No alcohol use or smoking was noted. On admission, the patient complained of parietal left thoracic pain. His vital signs were normal. The physical examination was unremarkable except for a graze in the left thoracic area which the patient had sustained in a fall.\n\nDuring his stay, the patient presented fever with mild blood inflammatory markers (white blood cells 5,920/mm3 with a high neutrophil count and a C-reactive protein which remained at 22–81 mg/l during his entire hospital stay) without any other clinical signs. However, his clinical condition deteriorated with severe hypotension. Empirical antibiotic treatment with piperacillin-tazobactam was initiated to combat infection. The bacteriological investigation showed the presence of drug-sensitive Escherichia coli in the blood culture and the urine. Despite treatment, the patient’s status worsened with fever and haemodynamic instability. Laboratory studies showed early signs of multiple organ failure with high liver enzymes (with AST increasing from 138 IU/l to 7,109 IU/l and ALT increasing from 103 IU/l to 2,108 IU/l during his stay in the emergency department and intensive care unit) without cholestasis or hyperbilirubinemia, coagulopathy, acute kidney injury, thrombopenia, leucopenia (white blood cells 3,200/mm3) and lymphopenia (lowest value 160/mm3). The patient was transferred to the intensive care unit for the management of shock, and haemodialysis for acute renal failure with metabolic acidosis and encephalopathy was initiated.\n\nAn aetiological investigation was conducted to look for another infection with a hepatotropic virus, a disseminated intravascular coagulopathy or a haemophagocytic lymphohistiocytosis. The thoraco-abdominal contrast-enhanced computed tomography examination was normal. The results of serological tests for parvovirus B19, CMV, EBV, hepatitis A, B, C, D, E and HIV showed no current infection. No antinuclear antibodies or anti-neutrophil cytoplasmic antibodies were found. Other laboratory tests revealed hyperferritinaemia (>10,000 μg/l), hypertriglyceridaemia (308 mg/dl), high D-dimer levels (>10,000 ng/ml) and high serum lactate dehydrogenase. Plasma fibrinogen was low (86 mg/dl). The factor VIII plasma concentration was within normal range (83%). Two days after admission to the intensive care unit, the patient deteriorated with an acute abdomen and acute anaemia which prompted an exploratory emergency laparotomy. During the procedure, the liver surface was seen to be covered with numerous white ‘rice’ spots and a biopsy was taken. No active bleeding was seen. The patient died soon after surgery from abdominal haemorrhage. Immunohistochemical analysis identified the infection as herpes simplex virus (HSV) hepatitis (Figs. 1–4).\n\nDISCUSSION\nHerpes simplex viruses are endemic worldwide, with an estimated seroprevalence of approximately 70% in developed countries[1]. However, it is less well known that they are one of the viral causes of fulminant hepatitis (<2%) and constitute <1% of all causes of acute liver failure[2].\n\nHSV hepatitis has been mainly described in immunocompromised patients and pregnant women in the late second and third trimesters[3], but also in immunocompetent hosts[4]. The clinical-biological presentation is not specific, but the triad of fever, markedly elevated liver enzymes and leucopenia can suggest this condition[5].\n\nThe difficulty in diagnosing HSV hepatitis leads to frequent post-mortem diagnoses (57.6%)[4]. In our case, the differential diagnosis remained a challenge, especially as urosepsis caused by E. coli was also present and the patient was not immunocompromised. The parsimony principle suggests that the evolution was secondary to this infection rather than a co-infection.\n\nAnte-mortem diagnostic tools include the detection and quantification[6] of blood viral HSV DNA, liver biopsy and serological testing for HSV[7]. In rare cases, some lesions can be seen on computed tomography imaging[8]. Treatment includes aciclovir, which is effective in 51% of cases[4]. Timing may be decisive[9]. The unfortunate outcome in our patient thus may have been be related to delays in diagnosis and treatment, despite the identification of some variables associated with death[4]. HSV hepatitis may mimic septic shock or hepatic failure itself[3]; our patient did indeed have septic shock complicated by a disseminated intravascular coagulopathy and a possible haemophagocytic lymphohistiocytosis.\n\nIn conclusion, there is a need for better understanding of this rare disease in order to more precisely identify patients at risk who need more aggressive evaluation and empirical treatment, especially patients presenting with marked hepatic cytolysis with a rapidly worsening clinical evolution.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 Right: submassive coagulative necrosis involving centrilobular zone 3. The necrotic zone is surrounded by hepatocytes with typical viral inclusions. There is minimal inflammation around the necrosis. Left: the centrolobular vein is spared\n\nFigure 2 Viral nuclear inclusions\n\nFigure 3 Immunostaining for herpes simplex shows infected cells in randomly distributed areas of coagulative necrosis\n\nFigure 4 Immunostaining for herpes simplex (high magnification)\n==== Refs\nREFERENCES\n1 Roizman B Knipe DM Whitley RJ Herpes simplex virus Knipe DM Howley PM Fields virology 5th edn Baltimore Lippincott Williams & Wilkins 2007 2502 2557 \n2 Schiødt FV Davern TJ Shakil AO McGuire B Samuel G Lee WM Viral hepatitis-related acute liver failure Am J Gastroenterol 2003 98 448 453 12591067 \n3 Kaufman B Gandhi SA Louie E Rizzi R Illei P Herpes simplex virus hepatitis: case report and review Clin Infect Dis 1997 24 334 338 9114181 \n4 Norvell JP Blei AT Jovanovic BD Levitsky J Herpes simplex virus hepatitis: an analysis of the published literature and institutional cases Liver Transpl 2007 13 1428 1434 17902129 \n5 Ichai P Roque Afonso AM Sebagh M Gonzalez ME Codés L Azoulay D Herpes simplex virus-associated acute liver failure: a difficult diagnosis with a poor prognosis Liver Transpl 2005 11 1550 1555 16315311 \n6 Beersma MF Verjans GM Metselaar HJ Osterhaus AD Berrington WR van Doornum GJ Quantification of viral DNA and liver enzymes in plasma improves early diagnosis and management of herpes simplex virus hepatitis J Viral Hepat 2011 18 e160 e166 20704650 \n7 Levitsky J Duddempudi AT Lakeman FD Whitley RJ Luby JP Lee WM Detection and diagnosis of herpes simplex virus infection in adults with acute liver failure Liver Transpl 2008 14 1498 1504 18825709 \n8 Tripuraneni V Patel K Brennan TV Ho LM Fulminant herpes simplex viral hepatitis: ultrasound and CT imaging appearance and a review of the imaging literature Clin Imaging 2014 38 191 194 24387920 \n9 Navaneethan U Lancaster E Venkatesh PG Wang J Neff GW Herpes simplex virus hepatitis - it’s high time we consider empiric treatment J Gastrointestin Liver Dis 2011 20 93 96 21451806\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2284-2594",
"issue": "5(12)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Acute liver failure; hepatitis; herpes simplex virus; septic shock",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "000982",
"pmc": null,
"pmid": "30755997",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "12591067;16315311;17902129;18825709;20704650;21451806;24387920;9114181",
"title": "Fatal Septic Shock Associated with Herpes Simplex Virus Hepatitis: A Case Report.",
"title_normalized": "fatal septic shock associated with herpes simplex virus hepatitis a case report"
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"companynumb": "BE-PFIZER INC-2019016675",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
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"abstract": "BACKGROUND Clopidogrel is an antiplatelet medication that plays an important role in primary management and secondary prevention of thrombotic vascular events in patients with acute coronary syndrome. It is generally well tolerated by most patients, but rare adverse effects such as inflammatory arthritis has been noted. A very few cases of migratory polyarthritis secondary to clopidogrel have been reported in the literature. CASE REPORT We describe 2 cases of acute migratory polyarthritis associated with clopidogrel that resolved with discontinuation of clopidogrel and did not recur after prasugrel initiation. In the first case, the patient presented with migratory polyarthritis approximately 2-3 days after initiating clopidogrel, and the symptoms lasted in each joint for 1-2 days. In the second case, the migratory polyarthritis started 1 week after initiating clopidogrel, and the symptoms lasted in each joint for approximately 2-3 days. The symptoms completely resolved after discontinuing clopidogrel in both the cases, which is typical of an immune-mediated drug reaction. A diagnosis of acute migratory inflammatory polyarthritis related to clopidogrel was determined in both cases by excluding other conditions causing inflammatory arthritis. In both cases, the eosinophil count was within normal limits, thereby differentiating the disease process from an acute allergic reaction. CONCLUSIONS Identifying the etiology of inflammatory arthritis in a patient on clopidogrel needs extensive evaluation. The diagnosis of clopidogrel-related inflammatory arthritis is often missed due to lack of awareness. Early diagnosis and timely intervention are essential, as the symptoms completely resolve after discontinuing clopidogrel.",
"affiliations": "Department of Internal Medicine, Division of Rheumatology, Montefiore Medical Center, Bronx, NY, USA.;Division of Immunology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.;Division of Immunology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.",
"authors": "Ayesha|Bibi|B|;Varghese|Jimmy|J|;Stafford|Haraldine|H|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel",
"country": "United States",
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"doi": "10.12659/AJCR.911598",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3096752310.12659/AJCR.911598911598ArticlesClopidogrel-Associated Migratory Inflammatory Polyarthritis Ayesha Bibi E1Varghese Jimmy EF2Stafford Haraldine F2\n1 Department of Internal Medicine, Division of Rheumatology, Montefiore Medical Center, Bronx, NY, U.S.A.\n2 Division of Immunology, University of Iowa Hospitals and Clinics, Iowa City, IA, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Bibi Ayesha, e-mail: drayesha25@gmail.com2019 10 4 2019 20 489 492 10 6 2018 29 12 2018 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Case series\n\nPatients: Male, 54 • Male, 77\n\nFinal Diagnosis: Clopidogrel associated migratory inflammatory arthritis\n\nSymptoms: Joint pain • joint swelling\n\nMedication: Clopidogrel\n\nClinical Procedure: —\n\nSpecialty: Rheumatology\n\nObjective:\nChallenging differential diagnosis\n\nBackground:\nClopidogrel is an antiplatelet medication that plays an important role in primary management and secondary prevention of thrombotic vascular events in patients with acute coronary syndrome. It is generally well tolerated by most patients, but rare adverse effects such as inflammatory arthritis has been noted. A very few cases of migratory polyarthritis secondary to clopidogrel have been reported in the literature.\n\nCase Report:\nWe describe 2 cases of acute migratory polyarthritis associated with clopidogrel that resolved with discontinuation of clopidogrel and did not recur after prasugrel initiation. In the first case, the patient presented with migratory polyarthritis approximately 2–3 days after initiating clopidogrel, and the symptoms lasted in each joint for 1–2 days. In the second case, the migratory polyarthritis started 1 week after initiating clopidogrel, and the symptoms lasted in each joint for approximately 2–3 days. The symptoms completely resolved after discontinuing clopidogrel in both the cases, which is typical of an immune-mediated drug reaction. A diagnosis of acute migratory inflammatory polyarthritis related to clopidogrel was determined in both cases by excluding other conditions causing inflammatory arthritis. In both cases, the eosinophil count was within normal limits, thereby differentiating the disease process from an acute allergic reaction.\n\nConclusions:\nIdentifying the etiology of inflammatory arthritis in a patient on clopidogrel needs extensive evaluation. The diagnosis of clopidogrel-related inflammatory arthritis is often missed due to lack of awareness. Early diagnosis and timely intervention are essential, as the symptoms completely resolve after discontinuing clopidogrel.\n\nMeSH Keywords:\nArthritisPlatelet Aggregation InhibitorsThienopyridines\n==== Body\nBackground\nClopidogrel is a thienopyridine, selective, irreversible ADP receptor/P2Y12 inhibitor. As clopidogrel has antiplatelet activity, it plays an important role in primary management and secondary prevention of thrombotic vascular events in patients with acute coronary syndrome [1,2]. The most common adverse effect of clopidogrel is increased risk of gastrointestinal bleeding [3]. Clopidogrel is well tolerated by most patients, but rare adverse effects such as inflammatory arthritis have been noted. A review of the literature found that very few cases of inflammatory arthritis due to clopidogrel have been reported [4–13]. We describe 2 cases of acute polyarthritis associated with clopidogrel that resolved with discontinuation of clopidogrel and did not recur after prasugrel initiation.\n\nCase report\nCase 1\nA 54-year-old white man with history of ST elevation myocardial infarction requiring percutaneous intervention (PCI) and drug-eluting stent placement (DES) presented 2 weeks later to a local emergency room with complaints of bilateral shoulder pain, left hand pain, and swelling. He was started with a loading dose of clopidogrel, and was later continued on clopidogrel and aspirin as dual-antiplatelet therapy in the view of his acute myocardial infarction. The other medications initiated were coumadin, atorvastatin, carvedilol, and furosemide for acute myocardial infarction complicated by left ventricular thrombus. Approximately 2–3 days after initiating the medications, he complained of bilateral shoulder pain and right hand pain with diffuse swelling. The initial impression was statin-induced myalgias; therefore, atorvastatin was discontinued. The furosemide dose was adjusted for acute renal insufficiency. A week later, he was re-evaluated in our emergency room for worsening bilateral shoulder pain associated with tingling and numbness of both hands, new-onset left hand pain, and right hip pain.\n\nOn examination, the patient was sitting comfortably; his heart rate was 88 bpm, blood pressure was 156/57 mmHg, and temperature was 100°F (37.8°C). The cardiovascular system, abdomen, lungs, and skin examinations were within normal limits. A neurology examination showed normal sensory examination, normal deep-tendon reflexes, and normal strength in all extremities except for 4/5 power in both proximal and distal muscles of the left upper extremity. On joint examination, Heberden’s nodes and Bouchard’s nodes on the 2nd through 5th fingers were present bilaterally. He had swelling and tenderness involving the dorsum of the left hand and wrist, associated with decreased range of motion. A bilateral shoulder joint examination showed restricted active and passive range of motion. The right knee had very minimal effusion, no tenderness on palpation, and normal range of motion.\n\nLaboratory testing showed a white blood cell count of 13.5 K/mm3 (normal 3.7–10.5 K/mm3) with 78% neutrophils, 8.1% lymphocytes, and 0.9% normal eosinophils. He had elevated blood urea nitrogen (38 mg/dL; normal, 10–20 mg/dL) and serum creatinine (1.3 mg/dL (normal, 0.7–1.3 mg/dL). His erythrocyte sedimentation rate (ESR) was 101 mm/h (normal, 0–15 mm/h) and C-reactive protein (CRP) was 29.7 mg/dL (normal, 0–0.5 mg/dL). The serum uric acid level was 10.9 mg/dl (normal, 2–7.8 mg/dl) with normal liver function tests and normal serum creatine kinase 44 IU/L (normal, 39–308 IU/L).\n\nHe was evaluated by neurosurgery and orthopedic surgery for the bilateral upper-extremity tingling and numbness and the left upper-extremity weakness. An MRI of the cervical spine demonstrated severe stenosis at C5–C6. The cervical spine was stabilized with a soft cervical collar as the patient was on coumadin and dual-antiplatelet therapy. Elective surgery was planned once the patient was stable enough to tolerate anticoagulation and dual-antiplatelet agents prior to surgery.\n\nOn day 3 of hospitalization, the inflammatory markers were still elevated, with ESR of 116 mm/h and CRP of 26.6 mg/dL. On evaluation, the left hand pain and swelling had resolved, but he had developed similar pain and diffuse swelling involving the soft tissues of the right hand. An infectious disease work-up was negative.\n\nOn day 4 of hospitalization, clopidogrel was discontinued and the patient was started on prasugrel 10 mg orally daily and continued on aspirin for post-PCI thrombosis prophylaxis. The next day, the right hand pain and swelling had completely resolved and the inflammatory markers were improved, with ESR of 11 mm/h and CRP of 5.1 mg/dL. There was no reoccurrence of symptoms. However, the bilateral upper-extremity tingling and numbness, as well as the left upper-extremity weakness, persisted due to the severe stenosis at C5–C6, and there was no progression of those symptoms.\n\nThe diagnosis of clopidogrel-induced acute polyarticular inflammatory arthritis was determined by excluding other causes of this condition, including statin-induced myalgia, infectious, crystal arthropathy, rheumatoid arthritis, and immune-mediated reaction to other medications.\n\nCase 2\nA 77-year-old white man with a history of hypertension, lymphoma, and recently-diagnosed crescendo angina requiring PCI 2 weeks prior presented with complaints of left shoulder and left hip pain. He was started on a loading dose of clopidogrel, and was later continued on clopidogrel and aspirin as dual-antiplatelet therapy, along with isosorbide nitrate for an-gina after his PCI. He was continued on his home medications, which included atorvastatin, carvedilol, lisinopril, and multi-vitamins. Approximately 1 week after starting dual-antiplatelet therapy, he developed acute nocturnal onset of severe left hand pain and swelling extending from his lower forearm to the distal fingers. The pain was associated with erythema, stiffness, and warmth. He was evaluated in his local emergency room and discharged home with hydromorphone. His symptoms resolved gradually. The following week he developed similar symptoms in the right forearm and hand and he was evaluated by his primary care physician. The initial impression was gout, and he was started on colchicine. A week later, these symptoms resolved and he then developed pain and stiffness of the right shoulder despite continuing colchicine therapy. He was evaluated in the rheumatology clinic 6 days later. His right shoulder pain had resolved but he then had severe pain and restriction of mobility of his left shoulder and left hip joints. He also complained of subjective fever, chills, weight loss, and asthenia for the last 3 weeks.\n\nOn examination, the patient was sitting comfortably; his heart rate was 62 bpm, blood pressure was 183/78 mmHg, and temperature 98.1°F (36,7°C). The cardiovascular system, abdomen, neurology exam, and skin examination were within normal limits. The lungs exams revealed bilateral basilar crackles. On joint examination, there was tenderness on palpation and restricted range of motion of the left shoulder joint and left hip joint.\n\nOn review of labs obtained at the local emergency room, the cell counts, renal function, liver function test, ESR and CRP, and uric acid were reported within normal limits. The rheumatoid factor and anti-cyclic citrullinated were negative. Repeat laboratories at the primary care physician’s office showed an ESR of 62 mm/h and CRP of 13.9 mg/dL. Repeat ESR and CRP at the rheumatology clinic were 92 mm/h and 15.3 mg/dL, respectively. An infectious disease work-up was negative. Arthrocentesis was negative for crystals and infection. The radiology images of the bilateral shoulder joints, hip joints, and hand were reported to be within normal limits.\n\nSince common causes of inflammatory polyarthritis were excluded, including rheumatoid arthritis, crystalline arthritis, infectious, and post-infectious etiologies, our impression was clopidogrel-induced polyarthritis. After discussion with his interventional cardiologist, clopidogrel was discontinued and the patient was started on prasugrel 10 mg orally daily and continued on aspirin for post-myocardial infarction thrombosis prophylaxis. The symptoms completely resolved and the inflammatory markers returned to baseline, with ESR of 31 mm/h and CRP of 0.5 mg/dL. There was no recurrence of symptoms.\n\nDiscussion\nPlatelets play an important role in the pathogenesis of atherothrombotic coronary artery disease. Antiplatelet therapy has been an important pharmacotherapy for the management of coronary artery disease for several decades [14]. The known antiplatelet medications are ticlopidine, clopidogrel, ticagrelor, and prasugrel. These medications play an important role in preventing thrombotic vascular events in patients with acute coronary syndrome. The dual-platelet therapy after myocardial infarction reduces the risk of stent thrombosis, myocardial infarction, and, possibly, cardiovascular death [1,2].\n\nAlthough ticlopidine, ticagrelor, clopidogrel, and prasugrel are in the antiplatelet class of medications, inflammatory arthritis has been noted with clopidogrel [4–13] and ticlopidine [15]. There currently are no reported cases of polyarticular arthritis associated with ticagrelor or prasugrel. The exact mechanism of inflammatory polyarthritis associated with clopidogrel and ticlopidine is unknown. Studies done on rat models suggest that proinflammatory effect of clopidogrel may be due to an unknown effect on cells, rather than on platelets, via an increase in proinflamma-tory cytokines such as IFN-γ, IL-6, and IL-1β [16]. Further studies are required to elucidate this mechanism and may be the key to understanding how to better treat this condition.\n\nMigratory polyarthritis secondary to clopidogrel is a diagnosis of exclusion. In our first case, the patient presented with migratory polyarthritis approximately 2–3 days after initiating clopidogrel, and the symptoms lasted in each joint for 1–2 days. He had elevated serum uric acid, most likely due to acute renal insufficiency. Polyarticular gout was a possible diagnosis; however, in gouty arthritis, symptoms in each joint typically persist for approximately 3–10 days without any active intervention [17] and the serum uric acid levels are often normal to low during the acute gout attack [18]. In this patient, the elevated serum uric acid levels were most likely due to acute renal insufficiency. After discontinuing clopidogrel, the joints pain and the very minimal left knee effusion completely resolved, so arthrocentesis was deferred. The inflammatory markers returned to baseline, which is typical of an immune-mediated drug reaction. Prasugrel was the selected alternative antiplatelet therapy [19].\n\nIn our second case, the migratory polyarthritis started 1 week after initiating clopidogrel, and the symptoms lasted in each joint for approximately 2–3 days. Clinical examination and laboratory findings ruled out other possible causes of acute inflammatory polyarthritis. The symptoms completely resolved after discontinuing clopidogrel.\n\nIn both cases, the loading dose of clopidogrel was similar, but in the first case symptoms started after a few days, and in the second case the patient became symptomatic 1 week after initiating the clopidogrel therapy. A diagnosis of acute migratory inflammatory polyarthritis related to clopidogrel was determined in both the cases by excluding other causes of this condition, including statin-induced myalgia, infectious or post-infectious process, crystal arthropathy, rheumatoid arthritis, and immune-mediated medication reaction to other medications. In both cases the eosinophil count was within normal limits, thereby differentiating the disease process from an acute allergic reaction [20–22]. The symptoms completely resolved after discontinuing clopidogrel, and the inflammatory markers returned to baseline. There was no reoccurrence of symptoms in either case after starting prasugrel.\n\nA review of the literature showed very few cases of clopidogrel-related inflammatory arthritis [4–13]. All these cases developed symptoms with elevated inflammatory markers within 1–3 weeks after initiating clopidogrel. In all these cases, the inflammatory markers returned to baseline and the symptoms resolved after discontinuing the clopidogrel and changing the therapy to either ticagrelor or prasugrel. Such cases need to be reported in the literature, as early diagnosis and timely intervention can completely resolve the symptoms.\n\nConclusions\nIdentifying the etiology of inflammatory arthritis in a patient on clopidogrel needs extensive evaluation. Rare conditions like clopidogrel-related inflammatory arthritis should not be missed in these patients. Clopidogrel-related inflammatory arthritis is challenging to diagnose and requires a high level of suspicion. Early diagnosis and timely intervention are essential, as the symptoms completely resolve after discontinuing clopidogrel, and the inflammatory markers return to baseline. There was no recurrence of symptoms in our 2 cases after starting prasugrel.\n==== Refs\nReferences:\n1. Dalby AJ Gottlieb S Cyr DD Dual antiplatelet therapy in patients with diabetes and acute coronary syndromes managed without revascularization Am Heart J 2017 188 156 66 28577671 \n2. Lettino M Leonardi S De Maria E Halvorsen S Antiplatelet and antithrombotic treatment for secondary prevention in ischaemic heart disease Eur J Prev Cardiol 2017 24 3 Suppl. 61 70 28618904 \n3. Nathan AS Sen S Yeh RW The risk of bleeding with the use of antiplatelet agents for the treatment of cardiovascular disease Expert Opin Drug Saf 2017 16 5 561 72 28387542 \n4. Agrawal S Harburger J Stallings G Clopidogrel-induced recurrent polyarthritis J Investig Med High Impact Case Rep 2013 1 3 2324709613500239 \n5. Williams MF Maloof JA Resolution of clopidogrel-associated polyarthritis after conversion to prasugrel Am J Health Syst Pharm 2014 71 13 1097 100 24939499 \n6. Coulter CJ Montandon SV Prasugrel as a safe alternative for clopidogrel-induced polyarthralgias Pharmacotherapy 2012 32 2 e24 26 22392428 \n7. Kanadiya MK Singhal S Koshal VB Prasugrel as a safe alternative for clopidogrel-associated arthritis J Invasive Cardiol 2011 23 6 E137 38 21646658 \n8. Boulman N Rozenbaum M Slobodin G Rosner I Acute polyarthritis associated with clopidogrel treatment Isr Med Assoc J 2005 7 10 670 71 16259352 \n9. Chen KK Ginges I Manolios N Clopidogrel-associated acute arthritis Intern Med J 2003 33 12 618 19 14656241 \n10. Garg A Radvan J Hopkinson N Clopidogrel associated with acute arthritis BMJ 2000 320 7233 483 \n11. Khan EA Blake JW Stamp LK Ticlopidine as a safe alternative for clopidogrel-associated arthritis J Rheumatol 2009 36 4 855 56 \n12. Muthusamy AS Vaidya A Friend PJ Clopidogrel-associated acute migratory arthritis following kidney-pancreas transplantation Int J Immunopathol Pharmacol 2006 19 2 443 44 16831311 \n13. Blauwet L Matteson E Acute inflammatory arthritis: an adverse effect of clopidogrel? J Clin Rheumatol 2003 9 2 128 29 17041444 \n14. Muller KA Chatterjee M Rath D Geisler T Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD Thromb Haemost 2015 114 3 498 518 26224127 \n15. Dakik HA Salti I Haidar R Uthman IW Drug points: Ticlopidine associated with acute arthritis BMJ 2002 324 7328 27 11777802 \n16. Garcia AE Mada SR Rico MC Clopidogrel, a P2Y12 receptor antagonist, potentiates the inflammatory response in a rat model of peptidoglycan polysaccharide-induced arthritis PLoS One 2011 6 10 e26035 22028806 \n17. Schlee S Bollheimer LC Bertsch T Crystal arthritides – gout and calcium pyrophosphate arthritis: Part 2: Clinical features, diagnosis and differential diagnostics Z Gerontol Geriatr 2018 51 5 579 84 28233118 \n18. Badulescu M Macovei L Rezus E Acute gout attack with normal serum uric acid levels Rev Med Chir Soc Med Nat Iasi 2014 118 4 942 45 25581951 \n19. Bergmeijer TO Janssen PWA van Oevelen M Incidence and causes for early ticagrelor discontinuation: A “real-world” Dutch registry experience Cardiology 2017 138 3 164 68 28697492 \n20. Calogiuri GF Al-Sowaidi S Nettis E A joint allergist/cardiologist classification for thienopyridines hypersensitivity reactions based on their symptomatic patterns and its impact on the management strategies Int J Cardiol 2016 222 509 14 27505343 \n21. Dong P Yang X Bian S Genetic polymorphism of CYP2C19 and inhibitory effects of ticagrelor and clopidogrel towards post-percutaneous coronary intervention (PCI) platelet aggregation in patients with acute coronary syndromes Med Sci Monit 2016 22 4929 36 27977637 \n22. Jia M Li Z Chu H Novel oral P2Y12 inhibitor prasugrel vs . clopidogrel in patients with acute coronary syndrome: Evidence based on 6 studies Med Sci Monit 2015 21 1131 37 25893318\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "20()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000368:Aged; D001168:Arthritis; D000077144:Clopidogrel; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors",
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"pubdate": "2019-04-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Clopidogrel-Associated Migratory Inflammatory Polyarthritis.",
"title_normalized": "clopidogrel associated migratory inflammatory polyarthritis"
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"abstract": "BACKGROUND\nSorafenib is an oral multiple tyrosine kinase inhibitor and is currently the only evidence-based treatment recommended for advanced hepatocellular carcinoma. We report a case of osteonecrosis of the jaw that occurred during sorafenib therapy in a patient with advanced hepatocellular carcinoma not treated with bisphosphonates or other antiangiogenic drugs.\n\n\nMETHODS\nA systematic search in PubMed yielded some cases of osteonecrosis of the jaw in patients treated with antiangiogenic agents, alone or in combination with bisphosphonates, for metastatic renal cell carcinoma. The only case of osteonecrosis observed during sorafenib therapy not combined with other predisposing agents was described by Guillet et al.\n\n\nRESULTS\nA 74-year-old man diagnosed with hepatocellular carcinoma ensuing in hepatitis C virus infection, who was treated with sorafenib at a daily dose of 400 mg, developed osteonecrosis of the right mandibular body. The lesion was documented by a dental CT scan and surgical evaluation did not lead to an indication for curettage treatment. Sorafenib was discontinued because of the radiological and laboratory features of hepatocellular carcinoma progression and the high risk of jaw fracture.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first description of osteonecrosis of the jaw detected in a cirrhotic patient on sorafenib therapy not combined with bisphosphonates.",
"affiliations": "Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna - Italy.;Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna - Italy.;Department of Head and Neck and Sense Organs, Neuroradiology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna - Italy.;Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna - Italy.;Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna - Italy.",
"authors": "Garuti|Francesca|F|;Camelli|Vittoria|V|;Spinardi|Luca|L|;Bucci|Laura|L|;Trevisani|Franco|F|",
"chemical_list": "D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib",
"country": "United States",
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"issn_linking": "0300-8916",
"issue": "102(Suppl. 2)",
"journal": "Tumori",
"keywords": null,
"medline_ta": "Tumori",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D006528:Carcinoma, Hepatocellular; D003131:Combined Modality Therapy; D018450:Disease Progression; D017809:Fatal Outcome; D006801:Humans; D007568:Jaw; D008113:Liver Neoplasms; D008297:Male; D009536:Niacinamide; D010020:Osteonecrosis; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D000077157:Sorafenib; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0111356",
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"pmid": "27079903",
"pubdate": "2016-11-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Osteonecrosis of the jaw during sorafenib therapy for hepatocellular carcinoma.",
"title_normalized": "osteonecrosis of the jaw during sorafenib therapy for hepatocellular carcinoma"
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"companynumb": "IT-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-087803",
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"abstract": "In patients with early-stage hepatocellular carcinoma, awaiting liver transplantation, current guidelines by AASLD and ESMO recommend a bridging therapy with a loco-regional treatment to prevent progression outside transplantation criteria. The standard of care in delaying disease progression has been recognized to be the transarterial chemoembolization. Permanent occlusion of tumor feeding vessels has effects on tumour stromal microenvironment by inducing intra- and intercellular signaling processes counteracting hypoxia, such as the release of vascular endothelial growth factor, a promoter of neoangiogenesis, tumour proliferation and metastatic growth. Among chemoembolization interventions, TACE with degradable starch microspheres represents an alternative to conventional cTACE and DEB-TACE and it minimizes detrimental effects on tumour stromal microenvironment, guaranteeing a transient occlusion of tumour feeding arteries and avoiding VEGF overexpression.Between January 2015 and September 2020, 54 consecutive patients with early-stage hepatocellular carcinoma and Child-Pugh stage B, who had undergone DSM-TACE as a bridging therapy while awaiting liver transplantation, were eligible for the study. A total of 154 DSM-TACE was performed, with a mean number of 2.85 procedures per patient. 18 patients (33.3%) succeeded in achieving liver transplantation, with a mean waiting time-to-transplantation of 11.7 months. The cumulative rates of patients still active on the WL at 6 months were about 91 and 93% when considering overall drop-out and tumour-specific drop-out respectively. Overall survival was about 96% at 6 months and 92% at 12 months. 17 patients experienced adverse events after the chemoembolizations. For patients with HCC in the transplant waiting list and within the Child-Pugh B stage, life expectancy may be dominated by the liver dysfunction, rather than by the tumour progression itself. In this population subset, the choice of LRT is critical because LRT itself could become a dangerous tool that is likely to precipitate liver dysfunction to an extent that survival is shortened rather than prolonged. Hence, the current study demonstrates that DSM-TACE is not far from being an ideal LRT, because it has an excellent safety profile, maintaining an efficacy that guarantees a clear advantage on the dropout rate with respect to the non-operative strategy, thus justifying its use.",
"affiliations": "Radiology Unit, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.;Digestive Surgery Unit, Science of Health Department, Magna Graecia University, Catanzaro, Italy.;Radiology Unit, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.;Medical Oncology Unit, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.;Medical Oncology Unit, University Hospital-Marche Polytechnic University, Ancona, Italy.;National Research Council (Cnr), Institute for High Performance Computing and Networking (ICAR), Rende, Italy.;Department of Medical and Surgical Sciences, Sant'Orsola Malpighi Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy.;General Surgery Unit, Science of Health Department, Magna Graecia University, Catanzaro, Italy.;Radiology Unit, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.",
"authors": "Minici|Roberto|R|;Ammendola|Michele|M|;Manti|Francesco|F|;Siciliano|Maria Anna|MA|;Giglio|Enrica|E|;Minici|Marco|M|;Melina|Marica|M|;Currò|Giuseppe|G|;Laganà|Domenico|D|",
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"doi": "10.3389/fphar.2021.634084",
"fulltext": "\n==== Front\nFront Pharmacol\nFront Pharmacol\nFront. Pharmacol.\nFrontiers in Pharmacology\n1663-9812\nFrontiers Media S.A.\n\n634084\n10.3389/fphar.2021.634084\nPharmacology\nOriginal Research\nSafety and Efficacy of Degradable Starch Microspheres Transcatheter Arterial Chemoembolization as a Bridging Therapy in Patients with Early Stage Hepatocellular Carcinoma and Child-Pugh Stage B Eligible for Liver Transplant\nMinici et al.\nDSM-TACE in early-stage HCC\nMinici Roberto 1\n\nAmmendola Michele 2\nManti Francesco 1\n\nSiciliano Maria Anna 3\n\nGiglio Enrica 4\nMinici Marco 5\n\nMelina Marica 6\n\nCurrò Giuseppe 7\nLaganà Domenico 1 *\n1 Radiology Unit, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy\n2 Digestive Surgery Unit, Science of Health Department, Magna Graecia University, Catanzaro, Italy\n3 Medical Oncology Unit, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy\n4 Medical Oncology Unit, University Hospital-Marche Polytechnic University, Ancona, Italy\n5 National Research Council (Cnr), Institute for High Performance Computing and Networking (ICAR), Rende, Italy\n6 Department of Medical and Surgical Sciences, Sant’Orsola Malpighi Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy\n7 General Surgery Unit, Science of Health Department, Magna Graecia University, Catanzaro, Italy\nEdited by: Domenico Criscuolo, Italian Society of Pharmaceutical Medicine, Italy\n\nReviewed by: Roberto Massimo Carlesi, Independent researcher, Bellagio, Italy\n\nVito Barbieri, Azienda Ospedaliera Pugliese Ciaccio, Italy\n\n*Correspondence: Domenico Laganà, radiologyumg@gmail.com\nThis article was submitted to Pharmaceutical Medicine and Outcomes Research, a section of the journal Frontiers in Pharmacology\n\n09 4 2021\n2021\n12 63408427 11 2020\n19 2 2021\nCopyright © 2021 Minici, Ammendola, Manti, Siciliano, Giglio, Minici, Melina, Currò and Laganà.\n2021\nMinici, Ammendola, Manti, Siciliano, Giglio, Minici, Melina, Currò and Laganà\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nIn patients with early-stage hepatocellular carcinoma, awaiting liver transplantation, current guidelines by AASLD and ESMO recommend a bridging therapy with a loco-regional treatment to prevent progression outside transplantation criteria. The standard of care in delaying disease progression has been recognized to be the transarterial chemoembolization. Permanent occlusion of tumor feeding vessels has effects on tumour stromal microenvironment by inducing intra- and intercellular signaling processes counteracting hypoxia, such as the release of vascular endothelial growth factor, a promoter of neoangiogenesis, tumour proliferation and metastatic growth. Among chemoembolization interventions, TACE with degradable starch microspheres represents an alternative to conventional cTACE and DEB-TACE and it minimizes detrimental effects on tumour stromal microenvironment, guaranteeing a transient occlusion of tumour feeding arteries and avoiding VEGF overexpression.Between January 2015 and September 2020, 54 consecutive patients with early-stage hepatocellular carcinoma and Child-Pugh stage B, who had undergone DSM-TACE as a bridging therapy while awaiting liver transplantation, were eligible for the study. A total of 154 DSM-TACE was performed, with a mean number of 2.85 procedures per patient. 18 patients (33.3%) succeeded in achieving liver transplantation, with a mean waiting time-to-transplantation of 11.7 months. The cumulative rates of patients still active on the WL at 6 months were about 91 and 93% when considering overall drop-out and tumour-specific drop-out respectively. Overall survival was about 96% at 6 months and 92% at 12 months. 17 patients experienced adverse events after the chemoembolizations. For patients with HCC in the transplant waiting list and within the Child-Pugh B stage, life expectancy may be dominated by the liver dysfunction, rather than by the tumour progression itself. In this population subset, the choice of LRT is critical because LRT itself could become a dangerous tool that is likely to precipitate liver dysfunction to an extent that survival is shortened rather than prolonged. Hence, the current study demonstrates that DSM-TACE is not far from being an ideal LRT, because it has an excellent safety profile, maintaining an efficacy that guarantees a clear advantage on the dropout rate with respect to the non-operative strategy, thus justifying its use.\n\nbridging\ntranscatheter arterial chemoembolizalion\nhepatocellar carcinoma\ndegradable starch microspheres\ntransarterial\ndoxorubicin\nstromal microenvironment\ntumoral angiogenesis\n==== Body\nIntroduction\n\nIn patients with very early and early-stage hepatocellular carcinoma (HCC), awaiting liver transplantation (LT), the disease may progress beyond transplantation criteria while on the waiting list. A transplant offers the benefit of cancer removal as well as the exclusion of the cirrhotic environment, which could have led to the emergence of new malignant lesions (Majno et al., 2011). Patients who develop tumour progression beyond the Milan criteria while awaiting liver transplantation become ineligible for an HCC MELD (Model for End-Stage Liver Disease) upgrade, which equates to waitlist drop out and subsequent death due to progression of HCC (Kulik et al., 2018). MELD exception points were introduced to alleviate dropouts due to tumour progression (Wiesner et al., 2004). Furthermore, locoregional treatments (LRTs) may prevent progression outside transplantation criteria (Harnois et al., 1999; Fontana et al., 2002; Lee et al., 2017) and EASL Guideline for the management of hepatocellular carcinoma defines bridging therapy as the treatment of accepted transplant candidates within Milan criteria while on the waiting list (Galle et al., 2018). Confirm that all author affiliations are correctly listed. Note that affiliations are listed sequentially as per journal style and requests for non-sequential listing will not be applied. Note that affiliations should reflect those at the time during which the work was undertaken). Current guidelines recommend a bridging therapy with LRT for patients within Milan criteria who are expected to remain on the transplant waitlist for more than 6 months, according to American guideline by AASLD (Heimbach et al., 2018), or for more than 3 months, according to European guideline by ESMO (Vogel et al., 2018). However, due to unpredictable waiting times and risk of tumour progression, most patients receive some form of LRT while awaiting transplant (Kulik et al., 2018).\n\nThe standard of care in delaying disease progression has been recognized to be the transarterial chemoembolization (TACE) (Llovet et al., 2002; Lo et al., 2002; Cescon et al., 2013). Despite several studies have shown controversial results (Hayashi et al., 2004; Tan et al., 2018), others have demonstrated advantages with a drop-out rate of 3–9.3% (Millonig et al., 2007; Alba et al., 2008), lower than those recorded without bridging therapies (7–11% at 6 months and ∼38% at 12 months) (Llovet et al., 1999a; Yao et al., 2002). Besides, TACE goes beyond its role of bridging therapy, as scientific evidence shows that patients who received TACE before LT had lower recurrence rates and improved overall survival (OS) (Millonig et al., 2007; Alba et al., 2008; Oligane et al., 2017). More thoroughly, TACE is beneficial when a complete or partial response can be achieved (Pompili et al., 2013), suggesting that response to LRT is a surrogate marker of tumour aggressive biology that may be used as a predictive factor to select patients in transplant waiting list (Mazzaferro et al., 1996; Yao et al., 2005; Sandow et al., 2018; Mazzaferro et al., 2016). This is supported by intention-to-treat studies who enlighten that downstaged patients have similar survival to patients inside criteria from the beginning (Ravaioli et al., 2008; Yao et al., 2015). However, stimulation of the immune system response may also explain the improved prognosis (Ayaru et al., 2007; Zerbini et al., 2010; Mizukoshi et al., 2011).\n\nLRTs are an effective tool to minimize waitlist drop out but the selection of appropriate candidates is a non-negligible need to diminish the risk of exacerbating underlying liver disease and hence the development of worsening liver function and complications. A careful evaluation of advantages and disadvantages related to LRTs as bridging therapies is further necessary for patients with Child-Pugh stage B.\n\nAmong transarterial chemoembolization techniques, TACE with degradable starch microspheres (DSM) represents an alternative to conventional TACE (cTACE) with Lipiodol and chemotherapeutic agent or TACE with drug-eluting beads (DEB-TACE) (Gross and Albrecht, 2020). Carrying out a selective or super-selective catheterization with a complete embolization of Tumor Feeding Vessels (TFV) correlates with the efficacy of these treatments (Mauri et al., 2016). Permanent occlusion of TFV or an incomplete embolization has effects on tumour stromal microenvironment and induces intra- and intercellular signaling processes counteracting and reversing hypoxia (Carmeliet, 2005; Orlacchio et al., 2020), such as the activation of HIFs (hypoxia-inducible factors) and the subsequent release of vascular endothelial growth factor (VEGF), a promoter of neoangiogenesis, tumour proliferation and metastatic growth (Lencioni et al., 2013). To avoid VEGF overexpression and minimize detrimental effects on liver function, both induced by post-embolization ischemia, the idea of the transient occlusion of tumour feeding arteries (a half-life in vitro of 35–50 min) using DSM was born (Pieper et al., 2015; Schicho et al., 2016).\n\nDespite the aforementioned rationale, data on the safety of DSM-TACE, in terms of tolerability and toxicity, are scarce but encouraging, showing a favourable trend in comparison with cTACE and DEB-TACE (Kirchhoff et al., 2006; Lammer et al., 2010; Niessen et al., 2014; Brown et al., 2016; Iezzi et al., 2016; Lencioni et al., 2016; Schicho et al., 2017; Gruber-Rouh et al., 2018; Orlacchio et al., 2018; Gross and Albrecht, 2020).\n\nHence, DSM-TACE is a powerful tool among transarterial chemoembolization techniques and it acts on the tumour-stromal microenvironment in combination with classic chemotherapeutic agents. Despite the absence of prospective comparative multicenter study, it shows a good safety profile in comparison with cTACE and DEB-TACE, that makes it an interestingly resource among LRT usable as bridge therapies in patients with HCC in transplant list, particularly in the population subset within Child-Pugh stage B, in which a huge focus to not worsening liver function should be paid and balance the evaluation of other parameters, such as the efficacy.\n\nThis study aims to define the safety and efficacy of DSM-TACE as a bridging therapy in patients with HCC and Child-Pugh stage B eligible for a liver transplant, attempting to cover a current lack of data regarding this technique applied to the aforementioned population subset.\n\nMaterials and Methods\n\nStudy Design\n\nThis study is a single-centre, retrospective analysis of prospectively collected data of consecutive patients with early stage hepatocellular carcinoma (HCC) and Child-Pugh stage B, who had undergone, from January 2015 to September 2020, DSM-TACE as a bridging therapy while awaiting liver transplantation (LT).\n\nInclusion criteria were: I) early stage (A) - according to the Barcelona-Clínic Liver Cancer (BCLC) staging system (Llovet et al., 1999b; Forner et al., 2010) - hepatocellular carcinoma, diagnosed with histological assessment or non-invasive imaging-based criteria used by European Association for the Study of the Liver (Galle et al., 2018); II) Child-Pugh stage B; III) age between 18 and 75 years; IV) no previous treatment for HCC; V) Eastern Cooperative Oncology Group performance status (Oken et al., 1982) grade 0; VI) registration on the transplant waiting list, fulfilling the Milan criteria (Mazzaferro et al., 1996); VII) evaluation by a multidisciplinary team of hepatologist, oncologist, liver surgeon and interventional radiologist. The exclusion criteria were: I) concomitant diseases not compatible with the transplantation; II) missed radiological evaluations at the follow-up; III) execution of liver resection or ablation during the follow-up; IV) serum creatinine levels >2.0 mg/dl; V) platelet count <50000/μL and/or international normalized ratio >1.5; VI) serum bilirubin level ≥3 mg/dl; VII) doxorubicin administration contraindications. The Institutional Review Board approval and informed written consent from each patient have been obtained.\n\nIntervention\n\nAt baseline condition, within 3 weeks before the first treatment, all patients underwent a clinical, biochemical and imaging examination. Imaging evaluation was performed with contrast-enhanced computed tomography (CT) and/or gadolinium-enhanced magnetic resonance imaging (MRI), using a multiphase liver imaging protocol.\n\nDSM-TACE was performed within 2 weeks after the registration on the transplant waiting list, according to the evaluation made by a multidisciplinary team. DSM-TACE was performed in a dedicated angiography suite monitoring vital signs during anesthesia, by the same experienced interventional radiologists (30 and 2 years of experience, respectively). All patients were pre-medicated with a proton-pump inhibitor (Omeprazole 40 mg i.v.), a prokinetic drug (Metoclopramide 10 mg i.v.) and an analgesic drug (Ketorolac-Tromethamine 20 mg i.v.); if requested, conscious sedation was performed during the procedure. The treatment was performed through a femoral or radial approach, with a Seldinger needle, by using a 5-Fr arterial introducer sheath (Terumo, Tokyo, Japan). The selective celiac trunk catheterization and the cannulation of the common hepatic artery were performed with a 5-Fr diagnostic catheter (Cobra, Simmons; Terumo). The appropriate anatomy of the hepatic artery and any possible branches related to non-target structures and any possible arteriovenous fistulae were identified through a hepatic artery angiography. After diagnostic angiography, a selective lobar catheterization was performed with a coaxial technique, placing a 2.7-Fr microcatheter (Progreat; Terumo) in the right or left hepatic artery that was feeding the involved lobe. A selective lobar angiography was then performed to confirm the correct position of microcatheter, to identify non-hepatic arteries and limit any possible extrahepatic diffusion of the microspheres. In particular, the identification of the cystic artery was recommended to ensure that the catheter tip would bypass this anatomical point to avoid non-target embolization. When possible, a super-selective (segmental or sub-segmental) approach was obtained using the aforementioned microcatheter. However, when the selective catheterization of the feeding artery was not technically feasible, a lobar embolization, paying particular attention to prevent non-target embolization, was performed. DSMs were mixed with non-ionic iodinated contrast medium: 6 ml of nonionic iodinated contrast was used per 4 ml of DSMs before injection. Doxorubicin at a dose of 50 mg was diluted in 5 ml of normal saline. No dose adjustment was made for bilirubin concentration or body surface area. An appropriate suspension of DSMs, contrast medium and Doxorubicin was obtained before delivery. The mixture in the syringes was constantly shaken to avoid sedimentation and disaggregation of the microspheres, then slowly injected under fluoroscopic guidance at the proper site, until stasis was observed. Stasis was defined as the absence of antegrade flow within a vessel such that contrast filling the target vessel persisted, without washout, 5 cardiac beats after the injection of contrast (Brown et al., 2016). When stasis has been reached, a mixture of starch microspheres (4 ml) with contrast medium (6 ml) was slowly injected until a complete embolization was obtained.\n\nAll patients underwent physical examination, laboratory tests and imaging follow-up at 1 month after each treatment and every 3 months thereafter if no additional treatment was required. For each patient, the imaging modality (an abdominal contrast-enhanced CT or MRI examination) remained the same throughout the entire study period.\n\nDSM-TACE treatments were repeated on-demand upon the demonstration of progressive or stable disease in patients who continued to meet the inclusion criteria until 1 of the following endpoints was reached: 1) CR or PR (OR); 2) technical impossibility to embolize the residual tumour, for example, in a tumour only supplied by extrahepatic collateral arteries; 3) development of contraindications to DSM-TACE; 4) total resection or ablation of the tumour by subsequent surgery or local ablation; 5) competing event for transplant list drop-out (liver transplantation or non-cancer-related death or refusing of LT); 6) PD after each of two consecutive DSM-TACE treatments; 7) worsening of at least 2 points of the Child-Pugh score. Causes of drop-out from transplant list were cancer-related death or cancer progression beyond the Milan Criteria.\n\nOutcomes\n\nThe primary efficacy endpoint was the time-to-event analysis (listing to drop-out), to examine the efficacy of DSM-TACE as bridging therapy in preventing drop-out from the waiting list (WL). Analyses were performed for both drop-outs as a result of all causes (HCC-specific and medical aetiologies) as well as tumour-specific drop-out (caused by cancer progression or cancer-related death), taking into account the competing events such as non-HCC-related mortality, liver transplantation and refusal of LT. Wait time was calculated from the date of listing until either transplant or delisting. For patients who developed HCC while on the list, wait time was adjusted to begin at the date of the diagnosis of HCC. Patients were censored at the end of the follow-up (September 30, 2020) or at the time of LT or at the time they refused transplant or at the time a noncancer-related death has occurred. A sub-group time to event analysis, to verify the relationships between lymphocyte-to-monocyte ratio (LMR)/neutrophil-to-Lymphocyte Ratio (NLR) and tumour-specific drop-out from WL, was performed. The secondary efficacy endpoints included the radiological response to treatment, the waiting time for LT, the overall survival, the progression-free survival and the proportion of patients transplanted. The overall survival (OS) was calculated as the time from the listing date until death or the last follow-up. The progression-free survival (PFS) was measured from the listing date to disease progression.\n\nThe primary safety endpoint was the incidence of serious adverse events (SAEs), in accordance with the classification set out in the next paragraph. The secondary safety endpoints were the incidence and severity of adverse events (AEs), including liver function parameters and laboratory abnormalities.\n\nDefinitions\n\nTechnical success is defined as the ability to deliver the full planned dose of Doxorubicin and to obtain stop flow (Basile et al., 2012). Treatment response was assessed using mRECIST guidelines (Lencioni and Llovet, 2010). Complete response (CR) was defined as the disappearance of any intra-tumoral arterial enhancement in all target lesions. Partial response (PR) was defined as at least a 30% decrease in the sum of the diameters of viable (contrast-enhancing) target lesions. Progressive disease (PD) was defined as an increase of at least 20% in the sum of the diameters of the viable (enhancing) target lesions, and stable disease included all cases that did not qualify as either partial response or progressive disease. Patients developing new lesions, vascular invasion, and/or metastases were categorized as having PD. As previously reported (Lammer et al., 2010; Zhang et al., 2018), disease control (DC) was defined and calculated as CR + PR + SD. Responders referred to objective response (OR), namely the sum of patients who experienced CR or PR. Non-responders referred to the sum of patients who had stable disease (SD) and progressive disease (PD). The initial response was defined as the radiological response after the first DSM-TACE. The best response was defined as the best radiological response across repeated DSM-TACE sessions. Patients who achieved an objective response after the first treatment or after the following ones were considered as initial or best responders, respectively. Sustained response duration (SRD) was defined as the time between the date when CR, PR, or stable disease is achieved and the date progressive disease occurs.\n\nAll adverse events were graded using the National Cancer Institute Common Terminology Criteria for adverse events (CTCAE), version 4.0 (National Institute of Cancer, 2010), except for clinical complications associated with chemoembolization recorded using the CIRSE Classification System for Complications (Filippiadis et al., 2017). In reference to the CTCAE, toxicity was further graded using binary variables (mild: grades 1–2; serious: grades 3–4), adapted and modified from Kang et al., 2020.\n\nStatistical Analysis\n\nData were maintained in an Excel spreadsheet (Microsoft Inc., Redmond, Wash) and the statistical analyses were performed using SPSS software (SPSS, version 22 for Windows; SPSS Inc., Chicago IL, United States) and R/R Studio software. The analysis of efficacy was based on the Modified Intention-To-Treat (MITT) population, defined as all included patients who received at least one chemoembolization; this also defined the safety population. Kolmogorov-Smirnov test and Shapiro-Wilk test were used to verify the normality assumption of data. Categorical data are presented as frequency (percentage value). Continuous normally distributed data are presented as mean ± standard deviation. Continuous not normally distributed data are presented as median (interquartile range: 25th and 75th percentiles-IQR). The unpaired Student t-test was used to assess statistical differences for continuous normally distributed data, while categorical and continuous not normally distributed data were assessed using the Chi-squared test and the Mann-Whitney test, respectively. The incidence curves of tumour-specific drop-out were constructed and compared using the Gray method, taking into account the competing events (non-HCC-related mortality, liver transplantation and refusal of LT). Kaplan-Meier survival analysis was performed to assess time-dependent outcomes, and comparisons were made with the log-rank test. The independence between censored data and the tested events was assessed by clinical evaluation and telephone contacts in the cases of withdrawal. Hence, the assumption of independent censoring was met, avoiding bias regarding the observed time-dependent data. Among all survivors (with and without dropout from transplant list), follow-up was censored September 30, 2020. Univariate and multivariate analyses, using Cox proportional hazards and logistic regression models, were performed to identify individual predictors (patient/lesion characteristics) associated with drop-out while controlling for all other predictors in the model. A p-value of <0.05 was considered statistically significant for the aforementioned tests.\n\nResults\n\nPatient and Pathology Data\n\nBetween January 2015 and September 2020, 54 consecutive patients with early stage hepatocellular carcinoma (HCC) and Child-Pugh stage B, who had undergone DSM-TACE as a bridging therapy while awaiting liver transplantation (LT), were eligible for the study. All patients have received at least one chemoembolization treatment, meeting the criteria to be included in the Modified Intention-To-Treat (MITT) population. No patients were lost to follow-up. The mean age was 41.3 years and 77.8% of the patients were male. Among liver comorbidities, 11.1% of the patients had the hepatitis B virus, 40.7% the hepatitis C virus, 11.1% non-alcoholic fatty liver disease and 40.7% alcoholic liver disease. The median alpha-fetoprotein and Carbohydrate antigen 19–9 levels at the time of listing were 347 ng/ml and 9.7 U/ml, respectively. 38 patients (70.4%) were affected by cirrhosis; Child-Pugh score was B7 (88.9%) or B8 (11.1%). 59.3% of the patients had encephalopathy, while none had ascites. The median values of neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) were 3.7 and 8.4, respectively. One-third of patients had one nodule, one-third of patients had two nodules and the other one third had three; the median (IQR) maximum tumour size was 2.5 cm (2.4–2.8 cm). A total of 18 patients (33.3%) had bilobar disease, while 36 patients (66.7%) have shown capsulated tumours.\n\nDemographics and tumour data of the study population are reported in Table 1.\n\nTABLE 1 Population data.\n\nVariables\t\tAll patients (n = 54)\t\nAge (years)–mean\t\t41.3 (±16.6)\t\nSex (M/F)\t\t42 (77.8%)/12 (22.2%)\t\nHepatitis B virus\t\t6 (11.1%)\t\nHepatitis C virus\t\t22 (40.7%)\t\nNon-alcoholic fatty liver disease\t\t6 (11.1%)\t\nAlcoholic liver disease\t\t22 (40.7%)\t\nα-Fetoprotein (ng/ml)–median\t\t347 (0–1370.8)\t\nCarbohydrate antigen 19–9 (U/ml)–median\t\t9.7 (0.7–24.7)\t\nγ-Glutamyltransferase (U/L)–median\t\t89 (2–176)\t\nAlkaline phosphatase (U/L)–median\t\t34 (9.8–58.2)\t\nAspartate transaminase (U/L)–median\t\t30 (16–59.2)\t\nAlanine transaminase (U/L)–median\t\t43 (34.2–51.8)\t\nAlbumin (g/L)–median\t\t27 (24–31)\t\nTotal bilirubin (mg/dl)–median\t\t1.0 (0.8–1.4)\t\nProthrombin time (seconds prolonged)–median\t\t8 (7–9)\t\nAscites, no/yes\t\t54 (100%)/0 (0%)\t\nEncephalopathy, no/yes\t\t32 (59.3%)/22 (40.7%)\t\nChild-Pugh score, B7/B8\t\t48 (88.9%)/6 (11.1%)\t\nCirrhosis, no/yes\t\t16 (29.6%)/38 (70.4%)\t\nPlatelet count (no. x103/μl)–median\t\t96 (62.2–129.8)\t\nCreatinine (mg/dl)–median\t\t1.2 (1.1–1.3)\t\nHemoglobin (g/dl)–median\t\t13.5 (13.1–14.1)\t\nWhite blood cell count (per μL)–median\t\t4009 (4001–4230)\t\n\tNeutrophil count (per μL)\t3009 (2989–3202)\t\n\tLymphocyte count (per μL)\t809 (698–898)\t\n\tMonocyte count (per μL)\t108 (81–199)\t\n\tNeutrophil-to-lymphocyte ratio (NLR)\t3.7 (3.3–7.3)\t\n\tLymphocyte-to-monocyte ratio (LMR)\t8.4 (3.5–9.9)\t\nNumber of Tumors, 1/2/3\t\t18 (33.3%)/18 (33.3%)/18 (33.3%)\t\nMaximum tumour size (cm)–median\t\t2.5 (2.4–2.8)\t\nBilobar disease, no/yes\t\t36 (66.7%)/18 (33.3%)\t\nCapsule, absent/present\t\t18 (33.3%)/36 (66.7%)\t\n\nProcedure Data\n\nA total of 154 DSM-TACE was performed, with a mean number of 2.85 procedures per patient. The chemoembolization pattern was selective in 119 procedures (77.2%) and lobar in 35 procedures (22.8%); no procedure was performed with the catheter placed in the common hepatic artery.\n\nProcedure data are reported in Table 2.\n\nTABLE 2 Procedure and Outcomes data.\n\nVariables\t\tAll patients (n = 54)\t\nTotal number of DSM-TACEs\t\t154\t\nMean number of DSM-TACEs per patient\t\t2.85\t\nMean follow-up (months)\t\t23.7\t\nChemoembolization pattern\t\t\t\n\tSelective/Superselective\t119 (77.2%)\t\n\tLobar\t35 (22.8%)\t\n\tGlobal\t0\t\n Technical success, no/yes\t\t0 (0%)/154 (100%)\t\n Tumour response to first DSM-TACE (no.)\t\t54\t\n\tCR\t4 (7.4%)\t\n\tPR\t12 (22.2%)\t\n\tSD\t30 (55.6%)\t\n\tPD\t8 (14.8%)\t\n\tNon-responders (SD + PD)\t38 (70.4%)\t\n\tResponders or OR (CR + PR)\t16 (29.6%)\t\n\tDC (CR + PR + SD)\t46 (85.1%)\t\n Tumour response to second DSM-TACE (no.)\t\t42\t\n\tCR\t2 (4.8%)\t\n\tPR\t10 (23.8%)\t\n\tSD\t16 (38.1%)\t\n\tPD\t14 (33.3%)\t\n\tNon-responders (SD + PD)\t30 (71.4%)\t\n\tResponders or OR (CR + PR)\t12 (28.6%)\t\n\tDC (CR + PR + SD)\t28 (66.7%)\t\n Tumour response to third DSM-TACE (no.)\t\t38\t\n\tCR\t0 (0%)\t\n\tPR\t14 (36.8%)\t\n\tSD\t10 (26.3%)\t\n\tPD\t14 (36.9%)\t\n\tNon-responders (SD + PD)\t24 (63.2%)\t\n\tResponders or OR (CR + PR)\t14 (36.8%)\t\n\tDC (CR + PR + SD)\t24 (63.2%)\t\n Tumour response to fourth DSM-TACE (no.)\t\t20\t\n\tCR\t0 (0%)\t\n\tPR\t0 (0%)\t\n\tSD\t6 (30%)\t\n\tPD\t14 (70%)\t\n\tNon-responders (SD + PD)\t20 (100%)\t\n\tResponders or OR (CR + PR)\t0 (0%)\t\n\tDC (CR + PR + SD)\t6 (30%)\t\n Best Response (no.)\t\t54\t\n\tCR\t6 (11.1%)\t\n\tPR\t32 (59.3%)\t\n\tSD\t12 (22.2%)\t\n\tPD\t4 (7.4%)\t\n\tNon-responders (SD + PD)\t16 (29.6%)\t\n\tResponders or OR (CR + PR)\t38 (70.4%)\t\n\tDC (CR + PR + SD)\t50 (92.6%)\t\n Sustained Response duration (SRD), <6 months/≥6 months\t\t28 (51.8%)/26 (48.2%)\t\n Time-to-dropout from transplant list (months) - mean\t\t14.7 (±7.6)\t\n Event, censoring/death\t\t26 (48.1%)/28 (51.9%)\t\n Event, censoring/Hcc-related dropout\t\t38 (70.4%)/16 (29.6%)\t\n Event, censoring/Overall dropout\t\t29 (53.7%)/25 (46.3%)\t\n Liver Transplantation, no/yes\t\t36 (66.7%)/18 (33.3%)\t\n Waiting time-to-transplantation (months) - mean\t\t11.7 (±4.6)\t\n Post-procedural clinical complications (CIRSE class.), absent/present\t\t38 (70.4%)/16 (29.6%)\t\n\tGrade 1\t14 (25.9%)\t\n\tGrade 2\t0 (0%)\t\n\tGrade 3\t2 (3.7%)\t\n Adverse Events (CTCAE), absent/present\t\t37 (68.5%)/17 (31.5%)\t\n\tGrade 1\t9 (16.7%)\t\n\tGrade 2\t6 (11.1%)\t\n\tGrade 3\t2 (3.7%)\t\n\tGrade 4\t0 (0%)\t\n\tSerious Adverse Events\t2 (3.7%)\t\n\nEfficacy Outcomes\n\nTechnical success was achieved in 154 procedures (100%). The average follow-up was 23.7 months. After the first DSM-TACE, CR was achieved in 4 of 54 patients (7.4%), PR in 12 (22.2%), SD in 30 (55.6%) and PD in 8 (14.8%), with 38 (70.4%) non-responders, 16 (29.6%) responders (OR) and disease control (DC) achieved after 46 (85.1%) procedures. A second DSM-TACE was performed in 42 cases, after which CR was achieved in 2 patients (4.8%), PR in 10 (23.8%), SD in 16 (38.1%) and PD in 14 (33.3%). A third DSM-TACE was performed in 38 cases, after which no CR was achieved, PR was achieved in 14 patients (36.8%), SD in 10 (26.3%) and PD in 14 (36.9%). A fourth DSM-TACE was performed in 20 cases, after which no CR and PR were achieved, SD was achieved in 6 patients (30%) and PD in 14 (70%). Considering the best response across repeated DSM-TACE sessions for each patient, CR was achieved in 6 of 54 patients (11.1%), PR in 32 (59.3%), SD in 12 (22.2%) and PD in 4 (7.4%), with 16 (29.6%) non-responders, 38 (70.4%) responders (OR) and disease control (DC) achieved in 50 patients (92.6%). 26 (48.2%) patients achieved a Sustained Response Duration (SRD) of 6 months or more; the rest of the patients (51.8%) achieved an SRD of fewer than 6 months. Overall drop-out from WL was observed in 25 (46.3%) cases, while tumour-specific drop-out was observed only in 16 (29.6%) cases. The mean time-to-dropout from transplant waiting list was 14.7 (±7.6) months, considering Hcc-related drop-out. 18 patients (33.3%) succeeded in achieving liver transplantation, with a mean waiting time-to-transplantation of 11.7 (±4.6) months. When considering overall drop-out, the cumulative rates of patients still active on the WL were about 91% (±0.04) at 6 months, 72% (±0.07) at 12 months and 33% (±0.09) at 24 months. When considering tumour-specific drop-out, the cumulative rates of patients still active on the WL were about 93% (±0.04) at 6 months, 78% (±0.06) at 12 months and 52% (±0.10) at 24 months. For patients with lymphocyte-to-monocyte ratio (LMR) ≥ 4 and neutrophil-to-lymphocyte ratio (NLR) < 7.2, the median (range) time-to-dropout from WL was 23 (21-NA) months, which was better than that of patients with lymphocyte-to-monocyte ratio (LMR) < 4 and neutrophil-to-lymphocyte ratio (NLR) ≥ 7.2 (median [range] time-to-dropout from WL, 12 [9–19] months) (p = 0.00013, calculated by mean of Log-Rank test). The death occurred in 28 cases (51.9%) along the follow-up period. OS was about 96% (±0.03) at 6 months, 92% (±0.04) at 12 months and 48% (±0.07) at 24 months. For patients with SRD of more than 6 months, the median (range) OS was not applicable but still greater than 36 months (21-NA) months, which was better than that of patients with SRD of less than 6 months (median [range] OS, 21 [17-NA] months), although not statistically significant (p = 0.086, calculated by mean of Log-Rank test). Progression-free survival (PFS) was about 70% (±0.06) at 6 months, 51% (±0.07) at 12 months and 14% (±0.06) at 24 months with only 4 residual patients at risk.\n\nThe efficacy outcomes are shown in Tables 2, 3, 4; Figures 1, 2.\n\nTABLE 3 Time-to-event outcomes (listing to drop-out) as indicated in the related survival plot (Figure 1).\n\n\tCumulative rates of patients active on the WL\tAt 6 months rate (±SE)-numbers at risk\tAt 12 months rate (±SE)-numbers at risk\tAt 24 months rate (±SE)-numbers at risk\t\n\tHcc-related dropout\t93% (±0.04)–48\t78% (±0.06)–32\t52% (±0.10)–6\t\n\tOverall dropout\t91% (±0.04)–48\t72% (±0.07)–32\t33% (±0.09)–6\t\n\tLMR >4/NLR <7.2\t94% (±0.04)–30\t94% (±0.04)–24\t45% (±0.13)–6\t\n\tLMR <4/NLR >7.2\t85% (±0.08)–18\t38% (±0.12)–8\tNA\t\n\nTABLE 4 Time-to-event outcomes (listing to death/disease progression) as partly indicated in the related survival plot (Figure 2).\n\n\tCumulative rates\tAt 6 months rate (±SE) -numbers at risk\tAt 12 months rate (±SE)-numbers at risk\tAt 24 months rate (±SE)-numbers at risk\t\n\tOverall Survival (OS)\t96% (±0.03)–52\t92% (±0.04)–48\t48% (±0.07)–24\t\n\tOS according to SRD < 6 m\t100% (±0.00)–23\t91% (±0.06)–23\t30% (±0.10)–7\t\n\tOS according to SRD > 6 m\t93% (CT±0.05)–29\t93% (±0.05)–25\t63% (±0.09)–17\t\n\tProgression-free Survival (PFS)\t70% (±0.06)–42\t51% (±0.07)–24\t14% (±0.06)–4\t\n\nFIGURE 1 (A–B) Time-to-event analysis (listing to drop-out), according to the causes of drop-out (tumour-specific or all-causes) (A) and to the neutrophil-to-lymphocyte/lymphocyte-to-monocyte ratios in case of tumour-specific drop-out (B).\n\nFIGURE 2 Time-to-event analysis (listing to death), according to the Sustained Response Duration (SRD).\n\nDetails of the predictors of drop-out are listed in Table 5. Based upon the intention to treat on both univariate and multivariate analysis, aspartate transaminase more than 40 U/L (HR, 1.3; 95% CI, 1.2–1.6; p 0.04), number of tumors equal or less than two (HR, 0.6; 95% CI, 0.4–1.1; p 0.01), presence of tumor capsule (HR, 0.6; 95% CI, 0.3–1.0; p 0.01), objective response as the best response across repeated DSM-TACE sessions for each patient (HR, 0.6; 95% CI, 0.4–1.2; p 0.01), objective response as the initial response (HR, 0.5; 95% CI, 0.4–0.9; p 0.01), SRD of 6 months or more (HR, 0.3; 95% CI, 0.2–0.9; p 0.01) and lymphocyte-to-monocyte ratio (LMR) ≥ 4/neutrophil-to-lymphocyte ratio (NLR) < 7.2 (HR, 0.4; 95% CI, 0.3–0.7; p 0.01) were found to be the independent prognostic factors for drop-out from waiting list.\n\nTABLE 5 Factors predicting drop-out from the waiting list.\n\nVariable\tUnivariate HR (95%CI)–p value\tMultivariate HR (95%CI)–p value\t\nAge\t1.2 (0.9–1.3)–0.59\tNA\t\nAge ≥60 years\t1.3 (1.0–1.5)–0.53\tNA\t\nSex (Male)\t0.9 (0.7–1.3)–0.81\tNA\t\nHepatitis B virus\t1.1 (0.9–1.5)–0.79\tNA\t\nHepatitis C virus\t1.3 (1.0–1.5)–0.53\tNA\t\nNon-alcoholic fatty liver disease\t1.2 (0.8–1.3)–0.61\tNA\t\nAlcoholic liver disease\t1.2 (1.1–2.1)–0.39\tNA\t\nα-Fetoprotein (ng/ml) > 300\t0.9 (0.7–1.3)–0.80\tNA\t\nAspartate transaminase (>40 U/L vs ≤ 40)\t1.4 (1.3–1.6)–0.04\t1.3 (1.2–1.6)–0.04\t\nAlanine transaminase (>40 U/L vs ≤ 40)\t1.1 (1.0–1.3)–0.45\tNA\t\nCirrhosis (yes vs no)\t0.8 (0.7–1.1)– 0.08\tNA\t\nTumour no. (≤2 vs 3)\t0.6 (0.4–1.2)–0.01\t0.6 (0.4–1.1)–0.01\t\nCapsule (present vs absent)\t0.6 (0.5–1.1)–0.01\t0.6 (0.3–1.0)–0.01\t\nObjective response as the best response\t0.6 (0.4–1.2)–0.01\t0.6 (0.4–1.2)–0.01\t\nObjective response as the initial response\t0.5 (0.3–0.9)–0.01\t0.5 (0.4–0.9)–0.01\t\nSRD (≥6 months vs < 6 months)\t0.5 (0.3–1.0) –0.01\t0.3 (0.2–0.9)–0.01\t\nLMR/NLR (≥4/< 7.2 vs. < 4/≥ 7.2)\t0.4 (0.3–0.8)–0.01\t0.4 (0.3–0.7)–0.01\t\n\nSafety Outcomes\n\nAccording to the CIRSE Classification System for Complications, 16 patients (29.6%) experienced postprocedural clinical complications associated with chemoembolization. Apart from two treatment-related grade 3 events (non-surgical cholecystitis), only grade 1 events occurred (14 cases, 25.9%). These were pain responsive to analgesics (8 DSM-TACEs, 14.9%), post-embolization syndrome (4 DSM-TACEs, 7.4%), transient nausea (1 DSM-TACEs, 1.8%) and vomiting (1 DSM-TACEs, 1.8%). The aforementioned adverse events were transient and easily solved with standard analgesic or antiemetic medication during interventions.\n\nAccording to the CTCAE classification, 17 patients (31.5%) experienced adverse events after the chemoembolizations. Grade 1 events were observed in 9 of 54 patients (16.7%), grade 2 events in 6 (11.1%) and grade 3 in 2 (3.7%); no grade 4 adverse events were observed. Hence, only two (3.7%) serious adverse events (SAE) occurred, namely, grade 3 or 4 adverse events according to the Common Terminology Criteria for adverse events (CTCAE).\n\nDetails are given in Table 2.\n\nDiscussion\n\nCurrent guidelines recommend a bridging therapy with LRT for patients with HCC within Milan criteria who are expected to remain on the transplant waitlist for more than 6 months, according to American guideline by AASLD (Heimbach et al., 2018), or for more than 3 months, according to European guideline by ESMO (Vogel et al., 2018). The standard of care in delaying disease progression has been recognized to be the transarterial chemoembolization (TACE) (Llovet et al., 2002; Lo et al., 2002; Cescon et al., 2013). Among chemoembolization interventions, despite the absence of prospective comparative multicenter study, DSM-TACE shows an excellent safety profile in comparison with cTACE and DEB-TACE and a non-inferior efficacy (Kirchhoff et al., 2006; Lammer et al., 2010; Niessen et al., 2014; Brown et al., 2016; Iezzi et al., 2016; Lencioni et al., 2016; Schicho et al., 2017; Gruber-Rouh et al., 2018; Orlacchio et al., 2018; Gross and Albrecht, 2020). For patients with HCC in the transplant waiting list and within Child-Pugh B stage, life expectancy may be dominated by the liver dysfunction, rather than by the tumour progression itself (Bolondi et al., 2012). In this population subset, the choice of LRT is critical because LRT itself could become a dangerous tool that is likely to precipitate liver dysfunction to an extent that survival is shortened rather than prolonged. Hence, the ideal LRT used as bridging therapy in patients with hepatocellular carcinoma within Child-Pugh stage B awaiting liver transplantation should have an excellent safety profile, maintaining an efficacy that guarantees a clear advantage on the dropout rate, thus justifying its use. Based on the aforementioned rationale, DSM-TACE could prove to be an interesting tool. The primary efficacy endpoint was the time-to-event analysis (listing to drop-out) and the cumulative rates of patients still active on the WL at 6 months were about 91% (±0.04) and 93% (±0.04), when considering overall drop-out and tumour-specific drop-out respectively. These results seem to be at least comparable with those reported by Kulik in his meta-analysis on LRTs used as bridging therapies (Kulik et al., 2018), in which dropout rates due to all causes and due to progression were 0.19 (95% CI 0.15–0.24) and 0.11 (95% CI 0.07–0.17) respectively. For patients with lymphocyte-to-monocyte ratio (LMR) ≥ 4 and neutrophil-to-lymphocyte ratio (NLR) < 7.2, the median time-to-dropout from WL was significantly better than that of patients with lymphocyte-to-monocyte ratio (LMR) < 4 and neutrophil-to-lymphocyte ratio (NLR) ≥ 7.2. The prognostic role of neutrophil-to-lymphocyte ratio (NLR) in certain cancer populations have already been investigated, also in the HCC (Dan et al., 2013), but, at the best of our knowledge, no data on the lymphocyte-to-monocyte ratio (LMR) in HCC patients have been published so far. Therefore, NLR and LMR together could act as a marker that reflects the balance between host inflammatory response, which gives a major contribution to tumour-related angiogenesis, and immune response, which has a pivotal role in cytotoxic cancer cells death. Patients with elevated preoperative NLR and low preoperative LMR have poorer dropout rates, therefore these ratios could be used as surrogate markers of tumour aggressiveness, suggesting a more aggressive bridging strategy while on the waiting list for liver transplantation. The mean waiting time-to-transplantation (11.7 months) was similar to that reported for radiofrequency ablation (RFA) used as bridging therapy (9.5 months) (DuBay et al., 2010), with one-third of patients enrolled (18 patients, 33%) successfully transplanted at the end of the follow-up (mean follow-up time of 23.7 months). Response to loco-regional therapy may be a surrogate of tumour aggressiveness and has been reported to correlate with post LT outcomes. Furthermore, a period of at least 6 months of sustained response duration (SRD) after a successful downstaging was found to be an independent prognostic factor for OS, even after liver transplantation (Zhang et al., 2018). In our study, patients with SRD of more than 6 months have shown a favourable trend in OS, although not statistically significant (p = 0.086, calculated by means of Log-Rank test), compared to patients with SRD of less than 6 months. Besides, multivariate analysis showed that the dropout risk of patients with SRD of 6 months or more was reduced by 70%, more than that of initial responders (50%) and best responders (40%). Interestingly, these data demonstrate that among patients with an objective response, such as CR or PR, some factors other than radiological response, such as tumour biology and tumour microenvironment, may alter the efficacy of TACE. This implies that the maintenance of response, rather than achieving the radiological Objective Response (OR) itself, maybe more clinically important for long-term outcomes because more related to histological tumour necrosis. Hence, SRD reflects the result of the interactions between tumour cells, liver disease biology, and tumour microenvironment, and can be used in clinical practice as an excellent and reliable predictor of outcomes, similar to that shown by Zhang (Zhang et al., 2018). To date, no studies have previously explored the role of sustained response duration (SRD) in predicting clinical prognosis of early stage HCC after TACE in a bridging therapy setting. Moreover, the overall survival was equivalent, if not with a favourable trend (92% at 12 months), to that published in the literature for RFA performed as bridging therapy (Dubay et al., 2011). Therefore, DSM-TACE, when used as bridging therapy in preventing drop-out from the waiting list (WL), has shown comparable efficacy outcomes to those recorded with other LRTs. Safety of DSM-TACE in the present study is comparable to previous data on cTACE, DEB-TACE, DSM-TACE and RFA (DuBay et al., 2011; Gross and Albrecht, 2020; Iezzi et al., 2016; Lammer et al., 2010; Brown et al., 2016; Lencioni et al., 2016). The incidence of adverse events (31.5%) and serious adverse events (3.7%) after the chemoembolization procedures was very low, resulting in an excellent safety profile despite the high-risk population subset of Child-Pugh B patients.\n\nLimitations of the study are the lack of a control group, the single-centre setting, the retrospectivity of the analysis and the scarcity of data in the literature, necessary to evaluate the congruence and the consistency of the data presented. Besides, patients with SRD of more than 6 months have shown a favourable trend in OS, although not statistically significant (p = 0.086, calculated by means of Log-Rank test), compared to patients with SRD of less than 6 months; the absence of statistical significance may be due to a lack of statistical power, therefore a type II statistical error cannot be excluded. Good response to locoregional treatments in patients awaiting LT is a surrogate marker of favourable tumour biology and correlates with long-term OS after LT (Millonig et al., 2007). Hence, making a per-protocol analysis could lead to an unintentional selection bias, selecting a priori a population subset with less aggressive disease biology and favourable drop-out percentage and long-term post-LT OS. The modified-intention-to-treat analysis performed in this study should have minimized the aforementioned risk.\n\nConclusion\n\nAt the best of our knowledge, no observational studies have so far verified the efficacy and safety profile of DSM-TACE as bridging therapy in the population subset of patients with HCC and Child-Pugh stage B, eligible for liver transplantation. Hence, the results of the current study demonstrate that DSM-TACE could be an ideal LRT, because it has an excellent safety profile, maintaining an efficacy that guarantees a clear advantage on the dropout rate with respect to the non-operative strategy, thus justifying its use.\n\nFurthermore, sustained response duration (SRD) has a pivotal role in predicting clinical prognosis of early stage HCC after TACE in a bridging therapy setting and neutrophil-to-lymphocyte/lymphocyte-to-monocyte ratios (NLR and LMR) could be used as surrogate markers of tumour aggressiveness; how they will practically guide the bridging strategy needs to be furtherly investigated.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nEthical approval was not provided for this study on human participants because of the retrospective setting of the investigation. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nRM and DL conceived the study concepts and design. RM, FM, MA and GC performed literature research and assisted in data collection. RM, EG, MAS and MMe were in charge of manuscript editing. MMi performed the statistical analysis using the provided database. All authors read and approved the final manuscript.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nThe reviewer VB declared a past co-authorship with one of the authors MAS to the handling editor.\n\nAbbreviations\n\nAASLD, American association for the study of liver diseases; AEs, adverse events; BCLC, Barcelona-clínic liver cancer; CT, computed tomography; cTACE, conventional transarterial chemoembolization; DC, disease control; DEB, drug-eluting beads; DSM, degradable starch microspheres; ESMO, European society for medical oncology; HCC, hepatocellular carcinoma; HIFs, hypoxia-inducible factors; LMR, lymphocyte-to-monocyte ratio; LRTs, locoregional treatments; LT, liver transplantation; MELD, model for end-stage liver disease; MITT, modified intention-to-treat; NLR, neutrophil-to-lymphocyte ratio; OR, objective response; OS, overall survival; PFS, progression-free survival; RFA, radiofrequency ablation; SAEs, serious adverse events; SRD, sustained response duration; TACE, transarterial chemoembolization; TFV, tumor feeding vessel; VEGF, vascular endothelial growth factor; WL, waiting list\n==== Refs\nReferences\n\nAlba E. 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Percutaneous radiofrequency thermal ablation of hepatocellular carcinoma: a safe and effective bridge to liver transplantation. Liver Transplant. 8 , 1165–1174. 10.1053/jlts.2002.36394\nForner A. Reig M. E. Rodriguez de Lope C. Bruix J. (2010). Current strategy for staging and treatment: the BCLC update and future prospects. Semin. Liver Dis. 30 (1 ), 061–074. 10.1055/s-0030-1247133\nGalle P. R. Forner A. Llovet J. M. Mazzaferro V. Piscaglia F. Raoul J. L. (2018). EASL clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 69 , 182–236. 10.1016/j.jhep.2018.03.019 29628281\nGross A. Albrecht T. (2020). Transarterial chemoembolisation (TACE) with degradable starch microspheres (DSM) and anthracycline in patients with locally extensive hepatocellular carcinoma (HCC): safety and efficacyficacy. Cardiovasc. Intervent. Radiol. 43 , 402–410. 10.1007/s00270-019-02364-w 31705244\nGruber-Rouh T. Schmitt C. Naguib N. N. N. Nour-Eldin N. A. Eichler K. Beeres M. (2018). Transarterial chemoembolization (TACE) using mitomycin and lipiodol with or without degradable starch microspheres for hepatocellular carcinoma: comparative study. BMC Cancer 18 (1 ), 188. 10.1186/s12885-018-4099-x 29444653\nHarnois D. M. Steers J. Andrews J. C. Rubin J. C. Pitot H. C. Burgart L. (1999). Preoperative hepatic artery chemoembolization followed by orthotopic liver transplantation for hepatocellular carcinoma. Liver Transpl. 5 , 192–199. 10.1002/lt.500050307\nHayashi P. H. Ludkowski M. Forman L. M. Osgood M. Johnson S. Kugelmas M. (2004). Hepatic artery chemoembolization for hepatocellular carcinoma in patients listed for liver transplantation. Am. J. Transpl. 4 , 782–787. 10.1111/j.1600-6143.2004.00413.x\nHeimbach J. K. Kulik L. M. Finn R. S. Sirlin C. B. Abecassis M. M. Roberts L. R. (2018). AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 67 , 358–380. 10.1002/hep.29086 28130846\nIezzi R. Pompili M. Nestola M. Siciliano M. Annicchiarico E. Zocco M. A. (2016). Transarterial chemoembolization with degradable starch microspheres (DSM-TACE): an alternative option for advanced HCC patients? Preliminary results. Eur. Rev. Med. Pharmacol. Sci. 20 (13 ), 2872–2877. 27424988\nKang Y. J. Lee B. C. Kim J. K. Yim N. Y. Kim H. O. Cho S. B. (2020). Conventional versus small doxorubicin-eluting bead transcatheter arterial chemoembolization for treating Barcelona clinic liver cancer stage 0/A hepatocellular carcinoma. Cardiovasc. Intervent. Radiol. 43 (1 ), 55–64. 10.1007/s00270-019-02349-9 31646378\nKirchhoff T. D. Rudolph K. L. Layer G. Chavan A. Greten T. F. Rosenthal H. (2006). Chemoocclusion vs chemoperfusion for treatment of advanced hepatocellular carcinoma: a randomised trial. Eur. J. Surg. Oncol. (Ejso) 32 (2 ), 201–207. 10.1016/j.ejso.2005.11.003 16373084\nKulik L. Heimbach J. K. Zaiem F. Almasri J. Prokop L. J. Wang Z. (2018). Therapies for patients with hepatocellular carcinoma awaiting liver transplantation: a systematic review and meta-analysis. Hepatology 67 (1 ), 381–400. 10.1002/hep.29485 28859222\nLammer J. Malagari K. Malagari K. Vogl T. Pilleul F. Denys A. (2010). Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc. Intervent. Radiol. 33 (1 ), 41–52. 10.1007/s00270-009-9711-7 19908093\nLee M. W. Raman S. S. Asvadi N. H. Siripongsakun S. Hicks R. M. Chen J. (2017). Radiofrequency ablation of hepatocellular carcinoma as bridge therapy to liver transplantation: a 10-year intention-to-treat analysis. Hepatology 65 , 1979–1990. 10.1002/hep.29098 28170115\nLencioni R. Petruzzi P. Crocetti L. (2013). Chemoembolization of hepatocellular carcinoma. Semin. Intervent. Radiol. 30 , 3–11. 10.1055/s-0033-1333648 24436512\nLencioni R. de Baere T. Soulen M. C. Rilling W. S. Geschwind J.-F. H. (2016). Lipiodol transarterial chemoembolization for hepatocellular carcinoma: a systematic review of efficacy and safety dataficacy and safety data. Hepatology 64 (1 ), 106–116. 10.1002/hep.28453 26765068\nLencioni R. Llovet J. (2010). Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin. Liver Dis. 30 (1 ), 052–060. 10.1055/s-0030-1247132\nLlovet J. Brú C. Bruix J. (1999a). Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin. Liver Dis. 19 (3 ), 329–338. 10.1055/s-2007-1007122 10518312\nLlovet J. Fuster J. Bruix J. (1999b). Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 30 , 1424–1440. 10.1002/hep.510300629\nLlovet J. M. Real M. I. Montaña X. Planas R. Coll S. Aponte J. (2002). Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. The Lancet 359 (9319 ), 1734–1739. 10.1016/s0140-6736(02)08649-x\nLo C. M. Ngan H. Tso W. K. Liu C. L. Lam C.-M. Poon R. T. P. (2002). Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 35 , 1164–1171. 10.1053/jhep.2002.33156 11981766\nMajno P. Lencioni R. Mornex F. Girard N. Poon R. T. Cherqui D. (2011). Is the treatment of hepatocellular carcinoma on the waiting list necessary? Liver Transpl. 17 (2 ), S98–S108. 10.1002/lt.22391 21954097\nMauri G. Varano G. M. Orsi F. (2016). TAE for HCC: when the old way is better than the new ones!!!. Cardiovasc. Intervent. Radiol. 39 , 799–800. 10.1007/s00270-016-1340-3 27076176\nMazzaferro, V. (2016). Squaring the circle of selection and allocation in liver transplantation for HCC: An adaptive approach. Hepatology 63 (5 ), 1707 -1717.26703761\nMazzaferro V. Regalia E. Doci R. Andreola S. Pulvirenti A. Bozzetti F. (1996). Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N. Engl. J. Med. 334 , 693. 10.1056/nejm199603143341104 8594428\nMillonig G. Graziadei I. W. Freund M. C. Jaschke W. Stadlmann S. Ladurner R. (2007). Response to preoperative chemoembolization correlates with outcome after liver transplantation in patients with hepatocellular carcinoma. Liver Transpl. 13 , 272–279. 10.1002/lt.21033 17256758\nMizukoshi E. Nakamoto Y. Arai K. Yamashita T. Sakai A. Sakai Y. (2011). Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular carcinomafic t-cell responses in patients with hepatocellular carcinoma. Hepatology 53 , 1206. 10.1002/hep.24149 21480325\nNational Institute of Cancer (2010). Common Terminology criteria for adverse events (CTCAE) version 4.0. Available at: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.\nNiessen C. Unterpaintner E. Goessmann H. Schlitt H. J. Mueller-Schilling M. Wohlgemuth W. A. (2014). Degradable starch microspheres versus ethiodol and doxorubicin in transarterial chemoembolization of hepatocellular carcinoma. J. Vasc. Interv. Radiol. 25 (2 ), 240–247. 10.1016/j.jvir.2013.10.007 24291001\nOken M. M. Creech R. H. Tormey D. C. Horton J. Davis T. E. McFadden E. T. (1982). Toxicity and response criteria of the eastern cooperative Oncology group. Am. J. Clin. Oncol. 5 , 649–656. 10.1097/00000421-198212000-00014 7165009\nOligane H. C. Xing M. Kim H. S. (2017). Effect of bridging local-regional therapy on recurrence of hepatocellular carcinoma and survival after orthotopic liver transplantation. Radiology 282 , 869–879. 10.1148/radiol.2016160288 27673508\nOrlacchio A. Chegai F. Francioso S. Merolla S. Monti S. Angelico M. (2018). Repeated transarterial chemoembolization with degradable starch microspheres (DSMs-TACE) of unresectable hepatocellular carcinoma: a prospective pilot study. Cmir 14 (4 ), 637–645. 10.2174/1573405613666170616123657\nOrlacchio A. Chegai F. Roma S. Merolla S. Bosa A. Francioso S. (2020). Degradable starch microspheres transarterial chemoembolization (DSMs-TACE) in patients with unresectable hepatocellular carcinoma (HCC): long-term results from a single-center 137-patient cohort prospective study. Radiol. Med. 125 , 98–106. 10.1007/s11547-019-01093-x 31583558\nPieper C. C. Meyer C. Vollmar B. Hauenstein K. Schild H. H. Wilhelm K. E. (2015). Temporary arterial embolization of liver parenchyma with degradable starch microspheres (EmboCeptS) in a swine model. Cardiovasc. Intervent. Radiol. 38 , 435–441. 10.1007/s00270-014-0966-2 25138140\nPompili M. Francica G. Ponziani F. Iezzi R. Avolio A. (2013). Bridging and downstaging treatments for hepatocellular carcinoma in patients on the waiting list for liver transplantation. Wjg 19 , 7515–7530. 10.3748/wjg.v19.i43.7515 24282343\nRavaioli M. Grazi G. L. Piscaglia F. Trevisani F. Cescon M. Ercolani G. (2008). Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria. Am. J. Transpl. 8 , 2547–2557. 10.1111/j.1600-6143.2008.02409.x\nSandow T. A. Arndt S. E. Albar A. A. DeVun D. A. Kirsch D. S. Gimenez J. M. (2018). Assessment of response to transcatheter arterial chemoembolization with doxorubicin-eluting microspheres: tumor biology and hepatocellular carcinoma recurrence in a 5-year transplant cohort. Radiology 286 , 1072–1083. 10.1148/radiol.2017170731 29206595\nSchicho A. Hellerbrand C. Krüger K. Beyer L. P. Wohlgemuth W. Niessen C. (2016). Impact of different embolic agents for transarterial chemoembolization (TACE) procedures on systemic vascular endothelial growth factor (VEGF) levels. J. Clin. Transl. Hepatol. 4 , 288–292. 10.14218/JCTH.2016.00058 28097096\nSchicho A. Pereira P. L. Haimerl M. Niessen C. Michalik K. Beyer L. P. (2017). Transarterial chemoembolization (TACE) with degradable starch microspheres (DSM) in hepatocellular carcinoma (HCC): multi-center results on safety and efficacyficacy. Oncotarget 8 (42 ), 72613–72620. 10.18632/oncotarget.19997 29069813\nTan C. H. N. Yu Y. Tan Y. R. N. Lim B. L. K. Iyer S. G. Madhavan K. (2018). Bridging therapies to liver transplantation for hepatocellular carcinoma: a bridge to nowhere? Ann. Hepatobiliary Pancreat. Surg. 22 , 27–35. 10.14701/ahbps.2018.22.1.27 29536053\nVogel A. Cervantes A. Chau I. Daniele B. Llovet J. M. Meyer T. (2018). Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 29 (4 ), iv238–iv255. 10.1093/annonc/mdy308 30285213\nWiesner R. H. Freeman R. B. Mulligan D. C. (2004). Liver transplantation for hepatocellular cancer: the impact of the MELD allocation policy. Gastroenterology 127 , S261–S267. 10.1053/j.gastro.2004.09.040 15508092\nYao F. Y. Bass N. M. Nikolai B. Davern T. J. Kerlan R. Wu V. (2002). Liver transplantation for hepatocellular carcinoma: analysis of survival according to the intention-to-treat principle and dropout from the waiting list. Liver Transpl. 8 , 873–883. 10.1053/jlts.2002.34923 12360427\nYao F. Y. Hirose R. LaBerge J. M. Davern T. J. Bass N. M. Kerlan R. K. (2005). A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation. Liver Transpl. 11 , 1505–1514. 10.1002/lt.20526 16315294\nYao F. Y. Mehta N. Flemming J. Dodge J. Hameed B. Fix O. (2015). Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors within Milan criteria. Hepatology 61 , 1968–1977. 10.1002/hep.27752 25689978\nZerbini A. Pilli M. Laccabue D. Pelosi G. Molinari A. Negri E. (2010). Radiofrequency thermal ablation for hepatocellular carcinoma stimulates autologous NK-cell response. Gastroenterology 138 , 1931–1942. 10.1053/j.gastro.2009.12.051 20060829\nZhang Y. Zhang M. Chen M. Mei J. Xu L. Guo R. (2018). Association of sustained response duration with survival after conventional transarterial chemoembolization in patients with hepatocellular carcinoma. JAMA Netw. Open 1 (6 ), e183213. 10.1001/jamanetworkopen.2018.3213 30646226\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1663-9812",
"issue": "12()",
"journal": "Frontiers in pharmacology",
"keywords": "bridging; degradable starch microspheres; doxorubicin; hepatocellar carcinoma; stromal microenvironment; transarterial; transcatheter arterial chemoembolizalion; tumoral angiogenesis",
"medline_ta": "Front Pharmacol",
"mesh_terms": null,
"nlm_unique_id": "101548923",
"other_id": null,
"pages": "634084",
"pmc": null,
"pmid": "33897421",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "10573522;30197583;21159100;17237442;20060829;22648700;20175033;29536053;29628281;28097096;12049862;25689978;25138140;12474157;27424988;26834067;7165009;17256758;31583558;30285213;24436512;16315294;26703761;12360427;11981766;28584945;27076176;29444653;30646226;10518312;20175034;27673508;29206595;23041304;26765068;15084175;21954097;23516447;18430853;24282343;29069813;28859222;10226109;8594428;16355210;21480325;19032223;31705244;28130846;15508092;19908093;16373084;28170115;31646378;24291001;23397536",
"title": "Safety and Efficacy of Degradable Starch Microspheres Transcatheter Arterial Chemoembolization as a Bridging Therapy in Patients with Early Stage Hepatocellular Carcinoma and Child-Pugh Stage B Eligible for Liver Transplant.",
"title_normalized": "safety and efficacy of degradable starch microspheres transcatheter arterial chemoembolization as a bridging therapy in patients with early stage hepatocellular carcinoma and child pugh stage b eligible for liver transplant"
} | [
{
"companynumb": "IT-PFIZER INC-2021616065",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "KETOROLAC TROMETHAMINE"
},
"drugadditional": ... |
{
"abstract": "Catecholaminergic Polymorphic Ventricular Tachycardia is a rare but often lethal genetic disorder that affects approximately 1 in 10,000 people. It often first manifests as stress or exercise-related syncope or sudden unexplained cardiac death, primarily in the pediatric and young adult population. We present a case of a 6-year-old male who had a sudden unexplained prehospital cardiac arrest after being scared by a domestic animal and who presented in ventricular fibrillation. The patient was subsequently defibrillated with a return of spontaneous circulation. During the course of care, medications with beta-1 and -2 agonist properties were administered, followed by multiple further episodes of polymorphic ventricular tachycardia (PVT)/ventricular fibrillation (VF). Once these medications were discontinued and beta blockers were administered, the patient had no further episodes of PVT/VF and was subsequently discharged from hospital 7 days later, completely neurologically intact. This case suggests the need for caution when considering administering beta agonists in a pediatric cardiac arrest patient with no known history of heart disease who presents in VF or PVT after an incident of extreme stress or strenuous physical activity.",
"affiliations": null,
"authors": "Wilson|Michael|M|;Schwartz|Steven|S|;Verbeek|P Richard|PR|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/10903127.2019.1612972",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1090-3127",
"issue": "24(1)",
"journal": "Prehospital emergency care : official journal of the National Association of EMS Physicians and the National Association of State EMS Directors",
"keywords": "cardiac arrest; emergency medical services; pediatric resuscitation; polymorphic ventricular tachycardia; prehospital",
"medline_ta": "Prehosp Emerg Care",
"mesh_terms": "D002648:Child; D004554:Electric Countershock; D004632:Emergency Medical Services; D005239:Fear; D006323:Heart Arrest; D006801:Humans; D008297:Male; D017180:Tachycardia, Ventricular",
"nlm_unique_id": "9703530",
"other_id": null,
"pages": "94-99",
"pmc": null,
"pmid": "31038375",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Catecholaminergic Polymorphic Ventricular Tachycardia: An Unusual Case of Fright-Induced Prehospital Cardiac Arrest in a Healthy 6-Year-Old Child.",
"title_normalized": "catecholaminergic polymorphic ventricular tachycardia an unusual case of fright induced prehospital cardiac arrest in a healthy 6 year old child"
} | [
{
"companynumb": "CA-TEVA-2020-CA-1856285",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALBUTEROL"
},
"drugadditional": "3",
... |
{
"abstract": "Perioperative anticoagulation management for patients with heparin-induced thrombocytopenia requiring cardiopulmonary bypass and deep hypothermic circulatory arrest presents a clinical challenge. Alternative anticoagulants have been used but can cause significant postoperative bleeding. We report the successful use of cangrelor and heparin in a 30-year-old patient with severe heparin-induced thrombocytopenia undergoing urgent pulmonary thromboendarterectomy.",
"affiliations": "Department of Anesthesiology, Temple University Hospital, Philadelphia, Pennsylvania. Electronic address: jackie.ta@tuhs.temple.edu.;Department of Cardiology, Temple University Hospital, Philadelphia, Pennsylvania.;Department of Cardiology, Temple University Hospital, Philadelphia, Pennsylvania.;Department of Cardiology, Temple University Hospital, Philadelphia, Pennsylvania.;Department of Cardiothoracic Surgery, Temple University Hospital, Philadelphia, Pennsylvania.;Department of Cardiology, Temple University Hospital, Philadelphia, Pennsylvania.;Department of Anesthesiology, Temple University Hospital, Philadelphia, Pennsylvania.;Department of Anesthesiology, Temple University Hospital, Philadelphia, Pennsylvania.",
"authors": "Ta|Jackie|J|;Mishra|Suraj|S|;Vaidya|Anjali|A|;Forfia|Paul R|PR|;Toyoda|Yoshiya|Y|;Auger|William R|WR|;Salamanca-Padilla|Y Yuliana|YY|;Morewood|Gordon H|GH|",
"chemical_list": "D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D000249:Adenosine Monophosphate; C117446:cangrelor; D006493:Heparin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.athoracsur.2020.01.051",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "110(3)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D000249:Adenosine Monophosphate; D000328:Adult; D004691:Endarterectomy; D005343:Fibrinolytic Agents; D006493:Heparin; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors; D011655:Pulmonary Embolism; D013921:Thrombocytopenia",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "e161-e163",
"pmc": null,
"pmid": "32142813",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cangrelor and Heparin for Pulmonary Thromboendarterectomy in Heparin-Induced Thrombocytopenia.",
"title_normalized": "cangrelor and heparin for pulmonary thromboendarterectomy in heparin induced thrombocytopenia"
} | [
{
"companynumb": "US-MYLANLABS-2020M1077870",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SILDENAFIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nKidney transplantation (KTx) is the treatment of choice in patients with end-stage renal failure. Among various medical issues in female graft recipients, the need for maternity can become an overriding one. Gonadal dysfunction usually resolves within 6 months after transplantation; however, the prevalence of infertility is similar to this in the general population.\n\n\nMETHODS\nThis case series describes the experience in infertility treatment and following perinatal care among KTx women who underwent successful in vitro fertilization (IVF). We followed three patients who previously received KTx and underwent IVF between 2014 and 2015. The 34-year-old (patient A) and 39-year-old (patient B) women received single KTx, and the 31-year-old (patient C) woman had received three previous transplantations. Patients A and C were diagnosed with primary tubal factor infertility, while patient B suffered from secondary idiopathic infertility. The stimulation protocols had no influence on their general condition nor graft function. Viable singleton pregnancies were confirmed in all cases. All newborns were born preterm, via cesarean section, as a consequence of severe preeclampsia. Patients A and C gave birth at 34th week of gestation (WG) (A: 1810 g and C: 2295 g), while patient B gave birth at 36th WG (2655 g). Other pregnancy complications were intrauterine growth restriction (patient A) and gestational diabetes mellitus (patient B). Although mild graft dysfunction was observed prior to delivery, all clinical measures and hypertension resolved during the puerperium.\n\n\nCONCLUSIONS\nIn these cases, pregnancy after KTx did not implicate persistent graft dysfunction. Regardless of the method of conception, pregnancy following KTx is associated with an increased incidence of complications, therefore it requires a multidisciplinary approach. IVF itself seems to be a safe procedure in KTx recipients if the pregnancy is advisable.",
"affiliations": "1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.;1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland. Electronic address: iwona.szymusik@gmail.com.;1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.;1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.;1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.;1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.;1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.;Department of Transplantation Medicine, Nephrology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.;1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.;1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.",
"authors": "Warzecha|D|D|;Szymusik|I|I|;Grzechocińska|B|B|;Cyganek|A|A|;Kociszewska-Najman|B|B|;Mazanowska|N|N|;Madej|A|A|;Pazik|J|J|;Wielgoś|M|M|;Pietrzak|B|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2018.02.144",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "50(6)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D005260:Female; D005307:Fertilization in Vitro; D006801:Humans; D007231:Infant, Newborn; D007247:Infertility, Female; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D066027:Transplant Recipients",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1892-1895",
"pmc": null,
"pmid": "30056923",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "In Vitro Fertilization and Pregnancy Outcomes Among Patients After Kidney Transplantation: Case Series and Single-Center Experience.",
"title_normalized": "in vitro fertilization and pregnancy outcomes among patients after kidney transplantation case series and single center experience"
} | [
{
"companynumb": "PL-BAUSCH-BL-2018-023124",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Philadelphia (Ph) chromosome is a cytogenetic hallmark of chronic myeloid leukemia (CML). Most patients with CML harbor either the e13a2 or e14a2 BCR-ABL fusion product, while a small subset of the cases expresses e1a2 or e19a2 transcripts. We report a patient with chronic myelomonocytic leukemia (CMML), initially Ph chromosome negative at presentation, with rapid disease progression to acute myeloid leukemia (AML) and appearance of Ph chromosome and BCR-ABL e6a2, a very uncommon fusion transcript. The AML was refractory to treatment with subsequent emergence and dominance of a Ph negative leukemic clone. The patient expired shortly after disease progression.",
"affiliations": "Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.;Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.;Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.;Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.;Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.;Department of Laboratory Medicine and Pathology Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.",
"authors": "Yao|Jinjuan|J|;Douer|Dan|D|;Wang|Lu|L|;Arcila|Maria E|ME|;Nafa|Khedoudja|K|;Chiu|April|A|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.lrr.2017.01.003",
"fulltext": "\n==== Front\nLeuk Res RepLeuk Res RepLeukemia Research Reports2213-0489Elsevier S2213-0489(15)30018-210.1016/j.lrr.2017.01.003ArticleA case of acute myeloid leukemia with e6a2 BCR-ABL fusion transcript acquired after progressing from chronic myelomonocytic leukemia Yao Jinjuan yaoj1@mskcc.orga⁎Douer Dan aWang Lu aArcila Maria E. aNafa Khedoudja aChiu April Chiu.April@mayo.eduba Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USAb Department of Laboratory Medicine and Pathology Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA⁎ Corresponding author. yaoj1@mskcc.org31 1 2017 2017 31 1 2017 7 17 19 4 8 2015 15 1 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Philadelphia (Ph) chromosome is a cytogenetic hallmark of chronic myeloid leukemia (CML). Most patients with CML harbor either the e13a2 or e14a2 BCR-ABL fusion product, while a small subset of the cases expresses e1a2 or e19a2 transcripts. We report a patient with chronic myelomonocytic leukemia (CMML), initially Ph chromosome negative at presentation, with rapid disease progression to acute myeloid leukemia (AML) and appearance of Ph chromosome and BCR-ABL e6a2, a very uncommon fusion transcript. The AML was refractory to treatment with subsequent emergence and dominance of a Ph negative leukemic clone. The patient expired shortly after disease progression.\n\nKeywords\nCMMLBCR-ABL e6a2AML transformation\n==== Body\nPhiladelphia (Ph) chromosome results from the reciprocal translocation t(9;22)(q34.1;q11.2), and is a diagnostic feature for chronic myeloid leukemia (CML). In most cases, the breakpoint in BCR occurs in M-bcr region, leading to production of e13a2 and/or e14a2 fusion transcripts. The breakpoints infrequently occur in either m-bcr or μ-bcr, producing e1a2 or long e19a2 fusion transcripts. Several other variant transcripts, such as e8a2, e13a3, e14a3, and e6a2 have also been identified and account for <1% of CML cases. Late appearing Ph chromosome may be acquired over the course of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) or MDS, representing disease progression and often signifying poor prognosis. In this report we describe a patient with chronic myelomonocytic leukemia (CMML), a subtype of MDS/MPN, which progressed to AML with gain of the rare BCR-ABL1 fusion transcript e6a2 and died shortly of tumor lysis syndrome.\n\nFig. 1 A; larger BCR-ABL1 fusion product is amplified by multiplex PCR, which is confirmed to be e6a2 by Sanger sequencing. B; Sanger sequencing (reverse read) showed the fusion is between BCR exon 6 and ABL1 exon 2 (corresponding forward read is illustrated under the sequence graph).\n\nFig. 1.\n\nThis report illustrates an unusual case of CMML which transformed to AML rapidly with emergence of the rare BCR-ABL1 e6a2 fusion transcript. The possibility CML in blasts crisis was excluded as the CMML biopsy showed dysgranulopoiesis and lacked Ph chromosome and BCR-ABL1 fusion transcript.\n\nTable 1 Clinicopathologic features of reported chronic myeloid neoplasm cases harboring e6a2 fusion transcript.\n\nTable 1Case No.\tReference (year)\tAge/Sex\tDiagnosis\tBCR/ABL Transcript(s)\tTreatmenta\tResponse to TKI\tClinical course/outcome\tSurvival\t\n1\tHochhaus [3]\t41/M\tCML-CP\te6a2\tHU, allo-BMT\tNA\tAP after 19 months Death from sepsis 16 days after BMT\t33 mo.\t\n2\tDupont [4]\t50/M\tCML-CP\te6a2\tASCT, αIFN+ara-C\tNA\tNR\tNR\t\n3\tSchultheis [5]\t65/M\tCML-BP\te6a2\tHU, Imatinib\tReduction of WBC after 30 days\tDeath from pneumonia\t42 d\t\n4\tColla [2]\t76/M\tCML-CP\te6a2\tHU, αIFN\tNA\tRelapsed and death from cerebral ictus\t64 d\t\n5\tPopovici [6]\t67/M\tCML-CP\te6a2\tImatinib\tComplete hematologic and cytogenetic response\tHematologic remission\tAlive at 18 mo.\t\n6\tRoti [10]\t37/M\tCML-CP\te6a2, e1a2\tImatinib\tPartial molecular response\tDisease stabilized on imatinib\tAlive at 21 mo.\t\n7\tSchnittger [1]\t48/M\tCML-CP\te6a2\tImatinib, HU, dasatinib\tImatinib: disease progression with clonal evolution and resistence mutations\tDeath from blast crisis\t10 mo.\t\nDasatinib: Initial hematologic and cytogenetic remission followed by blast crisis and new resistance mutation\t\n8\tVefring [7]\t42/M\tCML-AP\te6a2\tImatinib, ASCT, dasatinib\tImatinib: persistent disease\tDeveloped myeloid sarcoma (CML-BP) after ASCT\t45 mo.\t\nDasatinib: effective on subsequent myeloid sarcoma\tDeath from hematemesis\t\n9\tVefring [7]\t48/M\tCML-CP\te6a2\tImatinib, CDA, αIFN, ASCT\tDisease progression\tHematologic remission after ASCT\tAlive at 62 mo.\t\n10\tLangabeer [8]\t36/M\tCML-CP\te6a2, e1a2\tImatinib, nilotinib, ASCT\tImatinib: progression to AP with clonal evolution\tComplete molecular remission\tAlive at 28 mo.\t\nNilotinib: complete cytogenetic remission\t\n11\tHayette [9]\t64/F\tCMML\te6a2 (acquired)\tImatinib\tReduction of BCR/ABL transcript after 3 months\tNR\tAlive at 3 mo.\t\n12\tPresent case\t58/M\tCMML\te6a2 (acquired)\tInduction chemotherapy, dasatinib, nilotinib\tDasatinib: received only 3 doses due to pneumonitis\tDisease progression to AML after one month\t15 mo.\t\nNilotinib: disease progression despite drastic reduction of Ph+ clone\tDeath due to rapid disease progression and tumor lysis syndrome\t\na Listed temporally. M, male; F, female; CML, chronic myelogenous leukemia; CP, chronic phase; AP, accelerated phase; BP, blast phase; AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; HU, hydroxyurea; allo, allogenic; BMT, bone marrow transplant; ASCT, allogenic stem cell transplant; SCT, stem cell transplant; αIFN, alpha interferon; ara-C, cytarabine; CDA, chlorodeoxyadenosine; TKI, tyrosine kinase inhibitor; mo., months; d, days; NR, not.\n\n\n\nCML with BCR-ABL1 e6a2 fusion transcript appears to be associated with more aggressive clinical features, including accelerated/blastic phase on presentation [5], [7], rapid disease progression [1], [3], [8], and imatinib treatment failure [1], [7], [8]. Their response to TKI treatment is variable (Table 1). Briefly, 3 of 7 patients who received a TKI (#5, #6, #10) responded to imatinib, nilotinib, or dasatinib; with disease stabilization or hematologic/molecular remission. Three patients (#7–9) showed persistent/progressive disease, while one died early from infection (#3). The other reported CMML case (#11) showed molecular response to imatinib after 3 months, although long term followup is not available. Our patient is unique since although his Ph+ clone drastically diminished in response to nilotinib (95% to 3.4%), his blast burden remained high (80%) with dominance of the Ph negative clone. Although it is tempting to speculate that the Ph negative clone may have been selected from suppression of the Ph+ clone by nilotinib, the patient’s rapidly progressive disease may be due to an inherently aggressive biological behavior of his antecedent CMML and unrelated to TKI therapy, a notion that appears to be supported by the presence of RUNX1 and TP53 mutations in the CMML specimen.\n\nIt was hypothesized that shorter BCR-ABL transcripts are associated with a more aggressive clinical course due to lack of important regulatory bcr sequences within the fusion proteins [2]. Specifically in e6a2 transcript, the breakpoint in bcr intron 6 may result in partial loss of GEF/dbl-like domain that mediates interaction with several Ras-like G proteins involved in cell proliferation and signal transduction, which leads to enhanced tyrosine kinase activity of the BCR-ABL1 fusion protein.\n\nIn summary, our case illustrates the importance of combining conventional karyotype/FISH and appropriate molecular studies to detect rare BCR-ABL fusion transcripts such as e6a2. As a late appearing secondary Ph chromosome is usually considered a poor prognostic factor in hematopoietic malignancies, individualized therapeutic strategies such as newer TKIs and allogeneic stem cell transplantation may be warranted.\n==== Refs\nReferences\n1 Schnittger S. Bacher U. Kern W. Haferlach T. Hertenstein B. Haferlach C. A new case with rare e6a2 BCR-ABL fusion transcript developing two new resistance mutations during imatinib mesylate, which were replaced by T315I after subsequent dasatinib treatment Leukemia 22 2008 856 858 17851552 \n2 Colla S. Sammarelli G. Voltolini S. Crugnola M. Sebastio P. Giuliani N. e6a2 BCR-ABL transcript in chronic myeloid leukemia: is it associated with aggressive disease? Haematologica 89 2004 611 613 15136228 \n3 Hochhaus A. Reiter A. Skladny H. A novel BCR-ABL fusion gene (e6a2) in a patient with Philadelphia chromosome-negative chronic myelogenous leukemia Blood 88 1996 2236 2240 8822944 \n4 Dupont M. Jourdan E. Chiesa J. Identification of E6A2 BCR-ABL fusion in a Philadelphia-positive CML Leukemia 14 2000 2011 2012 11069039 \n5 Schultheis B. Wang L. Clark R.E. Melo J.V. BCR-ABL with an e6a2 fusion in a CML patient diagnosed in blast crisis Leukemia 17 2003 2054 2055 14513059 \n6 Popovici C. Cailleres S. David M. Lafage-Pochitaloff M. Sainty D. Mozziconacci M.J. E6a2 BCR-ABL fusion with BCR exon 5-deleted transcript in a Philadelphia positive CML responsive to Imatinib Leuk Lymphoma 46 2005 1375 1377 16109618 \n7 Vefring H.K. Gruber F.X. Wee L. Chronic myelogenous leukemia with the e6a2 BCR-ABL and lacking imatinib response: presentation of two cases Acta Haematol 122 2009 11 16 19641300 \n8 Langabeer S.E. Crampe M. Kelly J. Fadalla K. Connaghan G. Conneally E. Nilotinib and allogeneic stem cell transplantation in a chronic myeloid leukemia patient with e6a2 and e1a2 BCR-ABL transcripts Leuk. Res. 34 2010 e204 205 20346507 \n9 Hayette S. Tigaud I. Thomas X. Identification of a rare e6a2 BCR-ABL fusion gene during the disease progression of chronic myelomonocytic leukemia: a case report Leukemia 18 2004 1735 1736 15356652 \n10 Roti G. La Starza R. Gorello P. e6a2 BCR/ABL1 fusion with cryptic der(9)t(9;22) deletions in a patient with chronic myeloid leukemia Haematologica 90 2005 1139 1141 16079118\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "7()",
"journal": "Leukemia research reports",
"keywords": "AML transformation; BCR-ABL e6a2; CMML",
"medline_ta": "Leuk Res Rep",
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"nlm_unique_id": "101608906",
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"pages": "17-19",
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"pmid": "28275539",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "19641300;16079118;11069039;20346507;16109618;15136228;15356652;14513059;8822944;17851552",
"title": "A case of acute myeloid leukemia with e6a2 BCR-ABL fusion transcript acquired after progressing from chronic myelomonocytic leukemia.",
"title_normalized": "a case of acute myeloid leukemia with e6a2 bcr abl fusion transcript acquired after progressing from chronic myelomonocytic leukemia"
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"abstract": "Skull base osteomyelitis (SBO) secondary to endoscopic surgery for chronic sinusitis and post-operative sphenopalatine artery electrocautery has not been previously reported. This case report details an instance of Central SBO with an unusual microbiology profile and highlights the need to readily consider SBO should patients present with persistent headache and cranial nerve palsies following sinus surgery. Laryngoscope, 131:E1086-E1087, 2021.",
"affiliations": "ENT Department, Darlington Memorial Hospital, Darlington, UK.;ENT Department, Darlington Memorial Hospital, Darlington, UK.;ENT Department, Darlington Memorial Hospital, Darlington, UK.",
"authors": "Shellman|Zachary|Z|0000-0003-3732-2524;Coates|Matthew|M|;Kara|Naveed|N|",
"chemical_list": "D000900:Anti-Bacterial Agents",
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"journal": "The Laryngoscope",
"keywords": "Central skull base osteomyelitis; chronic sphenoid rhinosinusitis; sinogenic skull base osteomyelitis; sphenoid bone; sphenopalatine artery",
"medline_ta": "Laryngoscope",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D004724:Endoscopy; D006801:Humans; D008297:Male; D010019:Osteomyelitis; D011183:Postoperative Complications; D012852:Sinusitis; D019291:Skull Base",
"nlm_unique_id": "8607378",
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"pmid": "32990341",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports",
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"title": "Polymicrobial Skull Base Osteomyelitis Related to Chronic Sphenoiditis and Endoscopic Sinus Surgery.",
"title_normalized": "polymicrobial skull base osteomyelitis related to chronic sphenoiditis and endoscopic sinus surgery"
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"abstract": "OBJECTIVE\nTo evaluate the clinical and cost benefits of the administration of aprepitant for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV) during high-dose chemotherapy (HDCT).\n\n\nMETHODS\nWe retrospectively reviewed the charts of patients who received HDCT at our institution between January 2009 and December 2013. Cost-effectiveness was analyzed using direct medical costs.\n\n\nRESULTS\nWe identified a total of 38 patients (27 with non-Hodgkin lymphoma and 11 with multiple myeloma). Thirteen patients received aprepitant and granisetron (aprepitant group) for CINV prophylaxis, whereas 25 patients received granisetron only (non-aprepitant group). The incidence of severe nausea (≥grade 3) was significantly lower in the aprepitant group than in the non-aprepitant group (p = 0.039). The total mean cost per patient during hospitalization, excluding the cost of HDCT and transplantation, was USD 10,941.8 in the aprepitant group and USD 14,577.2 in the non-aprepitant group (p = 0.041). This cost benefit reflected reductions in the costs of hospitalization, transfusion, and infection treatment.\n\n\nCONCLUSIONS\nOur data indicated that the addition of aprepitant for CINV prophylaxis during HDCT reduced the incidence of severe nausea and might also provide economic benefit in the overall management of HDCT prior to autologous peripheral blood stem cell transplantation.",
"affiliations": "Department of Pharmacy, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.",
"authors": "Nakamura|Ayumi|A|;Kojima|Yuki|Y|;Miyazawa|Kenji|K|;Matsumoto|Syuichi|S|;Iida|Hiroatsu|H|;Nagai|Hirokazu|H|",
"chemical_list": "D000970:Antineoplastic Agents; D009025:Morpholines; D000077608:Aprepitant; D017829:Granisetron",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000479032",
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"issue": "93(5)",
"journal": "Oncology",
"keywords": "Aprepitant; Autologous peripheral blood stem cell transplantation; Chemotherapy-induced nausea and vomiting; Cost-effectiveness; High-dose chemotherapy",
"medline_ta": "Oncology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000077608:Aprepitant; D003362:Cost-Benefit Analysis; D005260:Female; D017829:Granisetron; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D009025:Morpholines; D009101:Multiple Myeloma; D009325:Nausea; D036102:Peripheral Blood Stem Cell Transplantation; D012189:Retrospective Studies; D014839:Vomiting",
"nlm_unique_id": "0135054",
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"publication_types": "D016428:Journal Article",
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"title": "Clinical Impact of Aprepitant in Patients Receiving High-Dose Chemotherapy prior to Autologous Peripheral Blood Stem Cell Transplantation: A Cost-Effectiveness Analysis.",
"title_normalized": "clinical impact of aprepitant in patients receiving high dose chemotherapy prior to autologous peripheral blood stem cell transplantation a cost effectiveness analysis"
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"abstract": "This retrospective chart review aims to address gaps in the literature regarding the efficacy and interaction of gonadotropin-releasing hormone agonists (GnRHa) and gender-affirming hormone therapies in medical transition regimens in transgender adolescents. We abstracted and reviewed data from 83 patients at our pediatric gender clinic, and found that patients who initiated treatment with GnRHa before gender-affirming hormones (estrogen, testosterone) required lower doses of those hormones than those who did not use GnRHa. The results of this preliminary research provide a foundation for future long-term prospective studies aimed to better understand these relationships.",
"affiliations": "Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.;Division of Adolescent Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.;Division of Adolescent Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.;Division of Adolescent Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.;Division of Urology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.;Division of Endocrinology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.",
"authors": "Jensen|Rachel K|RK|;Jensen|Jennifer K|JK|;Simons|Lisa K|LK|;Chen|Diane|D|;Rosoklija|Ilina|I|;Finlayson|Courtney A|CA|",
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"doi": "10.1089/trgh.2018.0061",
"fulltext": "\n==== Front\nTransgend HealthTransgend HealthtrghTransgender Health2380-193XMary Ann Liebert, Inc., publishers 140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA 3166303710.1089/trgh.2018.006110.1089/trgh.2018.0061Short ReportEffect of Concurrent Gonadotropin-Releasing Hormone Agonist Treatment on Dose and Side Effects of Gender-Affirming Hormone Therapy in Adolescent Transgender Patients Jensen Rachel K. 1,*Jensen Jennifer K. 2Simons Lisa K. 2Chen Diane 2,3Rosoklija Ilina 4Finlayson Courtney A. 51 Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.2 Division of Adolescent Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.3 Division of Psychiatry, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.4 Division of Urology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.5 Division of Endocrinology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.* Address correspondence to: Rachel K. Jensen, MD, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, 420 E. Superior Street, Chicago, IL 60611 rachel.jensen@umm.edu29 10 2019 2019 29 10 2019 4 1 300 303 © Rachel K. Jensen et al. 2019; Published by Mary Ann Liebert, Inc.2019This Open Access article is distributed under the terms of the Creative Commons 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\nThis retrospective chart review aims to address gaps in the literature regarding the efficacy and interaction of gonadotropin-releasing hormone agonists (GnRHa) and gender-affirming hormone therapies in medical transition regimens in transgender adolescents. We abstracted and reviewed data from 83 patients at our pediatric gender clinic, and found that patients who initiated treatment with GnRHa before gender-affirming hormones (estrogen, testosterone) required lower doses of those hormones than those who did not use GnRHa. The results of this preliminary research provide a foundation for future long-term prospective studies aimed to better understand these relationships.\n\nKeywords\ngender-affirming hormone dosegender-affirming hormone side effectpuberty blockertransgender youth\n==== Body\nBackground/Literature Review\nCurrent clinical guidelines recommend the use of puberty suppressing hormones (gonadotropin-releasing hormone agonists [GnRHa]) in peri-pubertal patients diagnosed with gender dysphoria.1,2 GnRHa block the release of gonadotropins, inhibiting the production of endogenous sex hormones responsible for pubertal development.3 Pubertal suppression via GnRHa is reversible, with commencement of normal puberty upon cessation of their use.4 When initiated at onset of puberty in transgender youth, GnRHa can prevent irreversible physiologic changes known to exacerbate gender dysphoria and complicate future transition to the desired gender.5 Additionally, GnRHa administration has been associated with improved behavioral and psychological functioning and greater satisfaction with physical outcomes of gender-affirming hormones (testosterone, estrogen).6–8 Despite the accepted use of GnRHa among health care providers for this population, significant gaps exist in the literature regarding efficacy, side effects, and interactions of medical transition regimens for adolescent transgender patients, particularly of combined GnRHa and gender-affirming hormone regimens. Barriers to such research include lack of Food and Drug Administration approval and reliable insurance coverage for GnRHa for this indication, as well as variations in prescribed hormone regimens. Our study attempts to address some of these unknowns by isolating descriptive statistics that may provide basis for further research. Specifically, we aimed to (1) determine whether dosages of gender-affirming hormones in those taking GnRHa differ from those not taking GnRHa; and (2) identify the frequency of associated side effects in both groups. It is posited that suppression of endogenous sex hormones via GnRHa may reduce necessary doses and associated side effects of gender-affirming hormones.\n\nMethods\nInstitutional Review Board approval was granted based on the study design described below. Data from patients who began and were currently receiving gender-affirming hormone therapy at a pediatric gender clinic at a tertiary medical center before March 2016 were abstracted by a retrospective review of outpatient electronic medical records (EMR). Eighty-six patients were included in initial review, with one subject excluded due to nonbinary gender identification, as hormone doses for this individual differed from standard protocols so as to better address their specific transition goals. Data were extrapolated through January 2018 and included demographic information, health conditions and medications, GnRHa and gender-affirming hormone regimens, and reported side effects. Comorbid conditions were identified based on EMR Problem List as of the end of data collection, and recorded medications were limited to current prescriptions as of that date. Data regarding GnRHa and gender-affirming hormone dosing regimens were extrapolated from narrative and medication portions of the chart. Side effects were identified based on those recorded by care team physicians in narrative portions of EMR notes. In analyzing data regarding specific hormone regimens, we excluded two patients (one female-affirmed, one male-affirmed) who began GnRHa concurrently with gender-affirming hormones, to better distinguish between effects of GnRHa versus gender affirming hormones. Data from these subjects were included in demographic and health conditions/medication analyses. Statistical analysis included use of medians, ranges, and unpaired T-tests, which are reported in the tables below.\n\nResults\nOf the 85 subjects included, 62 (73%) were male-identified, and 23 (27%) were female-identified.\n\nThe majority of subjects (72%) had subjectively reported medical comorbidities as recorded in the problem list in the EMR. The severity or chronicity of these is unknown, but common conditions included depression and anxiety, asthma, and obesity.\n\nPrescriptions for psychiatric and nonpsychiatric medications were common, with 58/85 (68%) taking one or more medications aside from GnRHa or gender affirming medications.\n\nOf the 17 subjects taking GnRHa, 16 were taking leuprolide, and 1 patient had a histrelin implant (replaced yearly). Among these subjects, 11 (65%) experienced noted side effects, with hot flashes, mood swings, weight gain, and fatigue being most common. During the period of data collection, 10 (59%) patients discontinued use of GnRHa, most commonly due to loss of insurance coverage. Other subjects on GnRHa experienced lapses in insurance coverage for these medications, disrupting continuity of treatment. Female-affirmed subjects had a median duration of GnRHa use of 20.6 months, with a median 14.7 month overlap in GnRHa and hormone therapy treatment (Table 1). Male-affirmed subjects had a median duration of GnRHa use of 29.3 months, with a median 23.3 month overlap in GnRHa and hormone therapy treatment (Table 2). One patient (female-affirmed) ceased GnRHa use at the time of gender-affirming hormone therapy; all other subjects on GnRHa continued to use GnRHa for at least 6 months into gender-affirming hormone treatment.\n\nTable 1. Treatment characteristics in female-identified subjects\n\n \t+GnRHa\t−GnRHa\t\nN\t6\t16\t\nMedian age at initiation GnRHa\t14.5 (11.4–15.7)\tNA\t\nMedian duration GnRHa use (months)\t20.6 (8.6–44.1)\tNA\t\nMedian duration simultaneous GnRHa and hormone therapy (months)\t14.7 (0.0–38.8)\tNA\t\nMedian age at initiation gender-affirming hormone\t14.9 (14.1–15.7)\t16.7 (14.4–18.2)\t\nMedian duration follow-up after beginning gender-affirming hormones (months)\t24.1 (6.4–26.9)\t29.3 (7.2–53.0)\t\nTaking spironolactone and estrogen together\t0\t13\t\nExperienced side effects on estrogen\t4/6 (67%)\t9/16 (56%)\t\nMost commonly reported side effectsa\tBreast tenderness (2)\tBreast tenderness (7)\t\nIncreased liver enzymes (1)\tEstradiol>normal limit (2)\t\nIncreased liver enzymes (1)\t\nAverage ending dose estradiol tablets\t1.9 mg/day (SD=0.8, N=6)\t4.6 mg/day (SD 1.5, N=13b)\t\nEnding estradiol dose range (mg/day)\t0.5–3\t4–8\t\na Based on number of times side effects noted in all charts. (Excluded from this chart are side effects experienced by only one person on estrogen.)\n\nb Three patients not included were not taking oral estradiol—were on transdermal estrogens, estradiol valerate, and no form of estrogen (discontinued).\n\nGnRHa, gonadotropin-releasing hormone agonists.\n\nTable 2. Gender-affirming hormone characteristics in male-identified subjects\n\n \t+GnRHa\t−GnRHa\t\nN\t11\t50\t\nMedian age at initiation GnRHa\t13.9 (12.9–15.6)\tNA\t\nMedian duration GnRHa use (months)\t29.3 (13.6–51.1)\tNA\t\nMedian duration simultaneous GnRHa and hormone therapy (months)\t23.3 (12.3–27.3)\tNA\t\nMedian age at initiation gender-affirming hormone\t15.0 (13.7–16.5)\t16.9 (13.4–22.1)\t\nMedian duration follow-up after beginning gender-affirming hormones (months)\t26.6 (22.6–39.3)\t30.4 (10.6–59.3)\t\nExperienced side effects at any point during testosterone use\t6/11 (55%)\t38/50 (76%)\t\nMost commonly reported side effectsa\tAcne (3)\tAcne (26)\t\nMood changes (5)\tMood changes (23)\t\nIncreased appetite (2)\tIncreased appetite (12)\t\nHeadache (1)\tHeadache (2)\t\nHot flashes (3)\tHot flashes (1)\t\nInjection site rash (1)\tElevated red blood cell markers (9)\t\nFatigue (3)\t\nHair loss (3)\t\nSpotting (2)\t\nAverage ending dose subcutaneous testosterone cypionate\t37.9 mg/week (SD 15.0, n=11)\t51.7 mg/week (SD 8.4, n=48b)\t\nEnding subcutaneous testosterone cypionate dose range (mg/week)\t13.5–60\t40–80\t\na Based on number of times side effects noted in all charts. (Excluded from this chart are side effects experienced by only one person on testosterone.)\n\nb Two excluded from total because one on intramuscular (vs. subcutaneous) form, one stopped taking hormones.\n\nIn the female-affirmed population, GnRHa use beginning before estrogen was associated with a significantly lower average dose of oral estradiol at the end of the data collection period, p=0.0007 (Table 1). Rates of side effects of gender-affirming hormones were similar regardless of concurrent GnRHa use, with the majority in either condition reporting side effects, identified in the subjective portion of provider notes. Most commonly reported were breast tenderness, excessively elevated estradiol levels (>50 ng/dL, in accordance with Endocrine Society Guidelines), and elevated liver enzyme levels.2 Thirteen patients, all of whom were not taking GnRHa, were taking both spironolactone and estrogen at some point during the period of data collection.\n\nSimilarly, among male-affirmed subjects, GnRHa use correlated with lower doses of subcutaneous testosterone cypionate at the last data collection point, p=0.0001 (Table 2). The majority in both conditions experienced side effects, as recorded in the subjective sections of provider notes, the most common being acne, mood changes, increased appetite, and elevated red blood cell markers.\n\nConclusions\nGnRHa use was correlated with lower doses of gender-affirming hormones at the final point of data collection, suggesting that concurrent GnRHa may decrease doses of hormones needed to achieve desired physiologic changes. Frequency and type of side effects of gender-affirming hormones were similar regardless of whether GnRHa were prescribed, though severity of these effects was not assessed. In fact, the majority of subjects in all conditions experienced side effects of gender-affirming hormones, which appear to largely reflect changes commonly experienced in puberty, when these hormones are produced endogenously. As such, though uncomfortable, these “side effects” do not typically pose risk to the patient. More concerning are alterations in laboratory values, such as elevated liver enzymes or hematocrit, which if unaddressed can lead to organ damage.2 This reiterates the importance of patient monitoring in gender-affirming hormone treatment, as is currently recommended by the Endocrine Society Guidelines. Lower doses of these hormones, as appears to be reasonable with concurrent GnRHa use, may lessen the frequency and severity of these laboratory changes. Furthermore, for female-affirmed patients, those not taking GnRHa were often placed on spironolactone in addition to estrogen, which reflects the need for adjunctive therapies to achieve suppression of testosterone levels to the female range.9 That those on GnRHa were not placed on spironolactone may reflect diminished need for supplemental medications due to endogenous testosterone suppression by GnRHa.\n\nThough these data support the use of GnRHa in adjunct to gender-affirming hormones, GnRHa are not without their own side effects, as noted in our findings. Side effects such as hot flashes, mood swings, and weight gain reflect the induction of hormone suppression in subjects.2 Though not inherently dangerous to the patient, such side effects can cause substantial discomfort and should be included in risk-benefit discussions with patients. Additionally, GnRHa have been postulated to have potential adverse effects on bone mineral density, though studies have largely been inconclusive on the true extent of this theoretical risk, and risks associated with prolonged use of GnRHa have not been examined.2,10 Though our chart review does not address this particular concern, we reiterate the importance of reviewing this possible risk with patients and of regular monitoring during treatment.\n\nThe aim of this retrospective chart review was to assess whether the use of GnRHa was associated with altered dosing and associated side effects of gender-affirming hormones; however, data review was notable for several additional findings that may impact care of this population.\n\nIn this cohort, high rates of subjectively reported medical and psychiatric concerns and additional medication prescriptions indicate that care of these patients often requires coordination of multiple care teams, which may influence gender-affirming treatment decisions. Additionally, many patients taking GnRHa were noted to have lapses in insurance coverage of these medications, which prevented sustained use or resulted in discontinuation entirely. Without reliable insurance coverage, patients are often unable to access GnRHa in the first place, or are subject to suboptimal treatment due to early discontinuation or inconsistent use.\n\nLimitations and Future Directions\nLack of standardized documentation, including specifically documented provider rationale for gender-affirming hormone prescription doses, combined with the already highly individualized nature of gender-affirming hormone regimens present a significant challenge to data collection and analysis in this study. Likewise, variation in timing of serum hormone level monitoring prevents precise correlation of serum hormones with dosage requirements. In addition, irregular patient follow-up and uncertainty of medication adherence complicate our discussion. Difficulties in acquisition and maintenance of consistent insurance coverage for GnRHa were an obstacle to our study and should be considered in the design of future research. Finally, given the retrospective nature of this study, it is impossible to isolate the effects of GnRHa therapy before versus concurrent with gender-affirming hormone therapies.\n\nData from this study suggest the importance of conducting large, prospective studies with more standardized methods of data collection and clearly delineated hormone protocols. Such research may better elucidate the associations suggested by this research and establish causal relationships between use of GnRHa and doses and side effects of gender-affirming hormones. Additionally, such research may provide critical evidence necessary for Food and Drug Administration approval of GnRHa for this indication, as current lack thereof poses a significant obstacle to insurance coverage of these medications for many patients.\n\nAcknowledgments\nWe would like to acknowledge Dr. Robert Garofalo for his assistance in article structuring. Institutional Review Board approval was granted for this retrospective chart review.\n\nAuthor Disclosure Statement\nDr. Chen served on an advisory for Endo Pharmaceuticals. This was not related to the formatting or design of this study.\n\n\nCite this article as: Jensen RK, Jensen JK, Simons LK, Chen D, Rosoklija I, Finlayson CA (2019) Effect of concurrent gonadotropin-releasing hormone agonist treatment on dose and side effects of gender-affirming hormone therapy in adolescent transgender patients, Transgender Health 4:1, 300–303, DOI: 10.1089/trgh.2018.0061.\n\nAbbreviations Used\nEMRelectronic medical records\n\nGnRHagonadotropin-releasing hormone agonists\n==== Refs\nReferences\n1. \nWorld Professional Association for Transgender Health . Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People, 7th ed. Report of the World Professional Association for Transgender Health . Minneapolis, MN : World Professional Association for Transgender Health , 2011 \n2. \nHembree WC , Cohen-Kettenis PT , Gooren L , et al. \nEndocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society Clinical Practice Guideline . J Clin Endocrinol Metab . 2017 ;102 :3869 –3903 28945902 \n3. \nDe Vries AL , Steensma TD , Doreleijers TA , Cohen-Kettenis PT \nPuberty suppression in adolescents with gender identity disorder: a prospective follow-up study . J Sex Med . 2011 ;8 :2276 –2283 20646177 \n4. \nManasco PK , Pescovitz OH , Feuillan PP , et al. \nResumption of puberty after long term luteinizing hormone-releasing hormone agonist treatment of central precocious puberty . J Clin Endocrinol Metab . 1988 ;67 :368 –372 3292562 \n5. \nDelemarre-van de Waal HA , Cohen-Kettenis PT \nClinical management of gender identity disorder in adolescents: a protocol on psychological and paediatric endocrinology aspects . Eur J Endocrinol . 2006 ;155 :S131 –S137 \n6. \nCohen-Kettenis PT , Delemarre-van de Waal HA , Gooren LJG \nThe treatment of adolescent transsexuals: changing insights . J Sex Med . 2008 ;5 :1892 –1897 18564158 \n7. \nde Vries ALC , McGuire JK , Steensma TD , et al. \nYoung adult psychological outcome after puberty suppression and gender reassignment . Pediatrics . 2014 ;134 :696 –704 25201798 \n8. \nSmith YLS , Van Goozen SHM , Kuiper AJ , Cohen-Kettenis PT \nSex reassignment: outcomes and predictors of treatment for adolescent and adult transsexuals . Psychol Med . 2005 ;35 :89 –99 15842032 \n9. \nRosenthal SM \nApproach to the patient: transgender youth: endocrine considerations . J Clin Endocrinol Metab . 2014 ;99 :4379 –4389 25140398 \n10. \nKlink D , Caris M , Heijboer A , et al. \nBone mass in young adulthood following gonadotropin-releasing hormone analog treatment and cross-sex hormone treatment in adolescents with gender dysphoria . J Clin Endocrinol Metab . 2015 ;100 :E270 –E275 25427144\n\n",
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"keywords": "gender-affirming hormone dose; gender-affirming hormone side effect; puberty blocker; transgender youth",
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"title": "Effect of Concurrent Gonadotropin-Releasing Hormone Agonist Treatment on Dose and Side Effects of Gender-Affirming Hormone Therapy in Adolescent Transgender Patients.",
"title_normalized": "effect of concurrent gonadotropin releasing hormone agonist treatment on dose and side effects of gender affirming hormone therapy in adolescent transgender patients"
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"abstract": "Systemic lupus erythematosus (SLE) is a multisystemic disease which potentially involves various organs including the skin, joints, kidneys, liver, hematopoetic system, and serous membranes. It is rarely seen in elderly males. The most common cardiovascular involvement type is pericarditis. Anti-Ro antibodies may be associated with neonatal lupus which causes heart blocks. Recent literature indicates that anti-Ro antibodies may be associated with various rhythm and conduction disturbances in the adulthood. The most common finding associated with anti-Ro antibodies is prolonged corrected QT (QTc) interval. Herein, we present an elderly male patient with anti-Ro-positive SLE associated with prolonged QTc interval and AV blocks that significantly improved after corticosteroid treatment.",
"affiliations": "Department of Internal Medicine, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey.",
"authors": "Saribayev|Maksat|M|;Tufan|Fatih|F|;Oz|Fahrettin|F|;Erer|Burak|B|;Ozpolat|Tahsin|T|;Ozturk|Gulistan Bahat|GB|;Akin|Sibel|S|;Saka|Bulent|B|;Erten|Nilgun|N|;Tascioglu|Cemil|C|;Karan|Akif|A|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000974:Antibodies, Antinuclear; D007166:Immunosuppressive Agents; C035356:SS-A antibodies",
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"journal": "Aging clinical and experimental research",
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"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D000974:Antibodies, Antinuclear; D003428:Cross Infection; D004562:Electrocardiography; D017809:Fatal Outcome; D006327:Heart Block; D006801:Humans; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D008297:Male",
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"title": "Corticosteroid treatment normalizes QTc prolongation and improves heart block in an elderly patient with anti-Ro-positive systemic lupus erythematosus.",
"title_normalized": "corticosteroid treatment normalizes qtc prolongation and improves heart block in an elderly patient with anti ro positive systemic lupus erythematosus"
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"abstract": "Herein is described the case of a 64-year-old patient affected by metastatic clear-cell carcinoma, with exclusive bone disease, subjected after the initial cytoreductive nephrectomy to 3 successive lines of medical treatment (sunitinib, everolimus, and sorafenib) and multiple locoregional treatments (spinal surgery, radiation therapy, and selective arterial embolization), resulting in a surprisingly long survival of over 75 months. In the era of target therapy, integration strategies, including additional locoregional treatment to medical therapy, are essential to optimize the clinical benefit, to maximize treatment duration overcoming focal progressive disease, and to improve the quality of life. In this context, we would highlight that selective transcatheter embolization of bone metastases from renal cell carcinoma should be considered as an effective and safe option in the palliative setting for patients with bone metastasis, especially for pain relief.",
"affiliations": "Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, Unifversiti of Bologna, via Massarenti n. 9, 40138 Bologna, Italy.;Department of Interventional Angiographic Radiology, Istituto Ortopedico Rizzoli, Bologna, Italy.;Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, Unifversiti of Bologna, via Massarenti n. 9, 40138 Bologna, Italy.;Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, Unifversiti of Bologna, via Massarenti n. 9, 40138 Bologna, Italy.;Department of Interventional Angiographic Radiology, Istituto Ortopedico Rizzoli, Bologna, Italy.;Radiology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, Unifversiti of Bologna, via Massarenti n. 9, 40138 Bologna, Italy.;Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, Unifversiti of Bologna, via Massarenti n. 9, 40138 Bologna, Italy.",
"authors": "Gatto|L|L|;Facchini|G|G|;Saponara|M|M|;Nannini|M|M|;Rossi|G|G|;Di Scioscio|V|V|;Biasco|G|G|;Pantaleo|M A|MA|",
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"doi": "10.1016/j.radcr.2017.07.008",
"fulltext": "\n==== Front\nRadiol Case RepRadiol Case RepRadiology Case Reports1930-0433Elsevier S1930-0433(17)30201-710.1016/j.radcr.2017.07.008Interventional RadiologySuccessful selective arterial embolizations for bone metastases in renal cell carcinoma integrated with systemic therapies: A case report Gatto L. MDlidia.gatto83@gmail.coma*Facchini G. MDbSaponara M. MDaNannini M. MDaRossi G. MDbDi Scioscio V. MDcBiasco G. PROFaPantaleo M.A. PROFaa Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, Unifversiti of Bologna, via Massarenti n. 9, 40138 Bologna, Italyb Department of Interventional Angiographic Radiology, Istituto Ortopedico Rizzoli, Bologna, Italyc Radiology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy* Corresponding author. lidia.gatto83@gmail.com16 8 2017 12 2017 16 8 2017 12 4 775 779 4 5 2017 16 6 2017 3 7 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Herein is described the case of a 64-year-old patient affected by metastatic clear-cell carcinoma, with exclusive bone disease, subjected after the initial cytoreductive nephrectomy to 3 successive lines of medical treatment (sunitinib, everolimus, and sorafenib) and multiple locoregional treatments (spinal surgery, radiation therapy, and selective arterial embolization), resulting in a surprisingly long survival of over 75 months. In the era of target therapy, integration strategies, including additional locoregional treatment to medical therapy, are essential to optimize the clinical benefit, to maximize treatment duration overcoming focal progressive disease, and to improve the quality of life. In this context, we would highlight that selective transcatheter embolization of bone metastases from renal cell carcinoma should be considered as an effective and safe option in the palliative setting for patients with bone metastasis, especially for pain relief.\n\nKeywords\nRenal cell carcinomaArterial embolizationBone metastasesLocoregional therapyIntegration strategy\n==== Body\nIntroduction\nRenal cell carcinoma (RCC) represents 3% of all cancers, with the highest incidence occurring in western countries and representing the seventh most common cancer in men and the ninth most common cancer in women [1]. Approximately 30% of all patients with RCC have metastatic disease at presentation, and distant metastases occur most often in the lungs, the lymph nodes, the liver, the bones, and the brain. In particular, lung metastases affect 45%-50% of patients with advanced disease, followed by bone (30%) and liver (20%) metastases [2]. The estimated average 5-year survival in metastatic renal cancer is approximately 20% [3].\n\nBone metastases represent a crucial point in patient management because of the significant morbidity related to skeletal complications, such as pathologic fracture, spinal cord compression, and hypercalcemia, and correlate with a poor prognosis and a reduced overall survival [3], [4].\n\nThe recent advances in our understanding of the pathogenesis and the molecular landscape of renal cancer, and in particular of clear-cell carcinoma, have led to the development of molecular therapies targeting the vascular endothelial growth factor and the mammalian target of rapamycin (mTOR) pathways, and of immunotherapy resulting in a significant improvement of treatment options, rates of survival, and quality of life [5]. The introduction of these new drugs revolutionized the clinical management of patients affected by RCC with more attention to the early clinical and imaging predictive factors of treatment efficacy, with a more accurate management of the side effects, and with a systematic and critical attitude on the treatment sequence [5], [6], [7], [8].\n\nIn addition to these varied scenarios of systemic approach, the locoregional treatments should be placed, with the aim of controlling disease symptoms and optimizing systemic therapies, expanding the duration of each therapeutic line and improving the quality of life.\n\nPreoperative and palliative transarterial selective embolization is a safe and effective minimally invasive, interventional treatment for pain relief and devascularization of primary and metastatic bone tumors by various primary cancers [9], [10], [11], [12], [13], [14], [15]. This treatment can also be repeated during the course of disease and can be combined with other treatment modalities such as radiotherapy and chemotherapy.\n\nHere we present the case of a patient affected by metastatic RCC managed with a multimodality approach, consecutively treated, for over 6 years, with 3 tyrosine kinase inhibitors and several local treatments, including surgery, radiotherapy, and, in particular, with two superselective arterial embolizations of bone metastases, one in the right femur bone and one in the right pubic region.\n\nCase presentation\nIn April 2008, a 63-year-old man with a smoking habit and hypertension, and overweight in personal medical history presented with cruralgia and an intermittent pain in the left lumbar region. The subject underwent a contrast-enhanced computed tomography (CT) scan study, which demonstrated a large infiltrative mass in the lower pole of the left kidney measuring 5.7 × 5.6 × 6.0 cm, with vertebral metastasis (D9-L3) and with D12 and L1 cord compression and a right iliac crest metastasis. Admission laboratory tests revealed a normocytic anemia, a mildly elevated white cell count, and an elevated platelet count (Hg of 8.9 g/dL, MCV 87 fL, white blood cell count 12,000/µL, platelet count 573,000/µL). Chemistry laboratories revealed an elevated lactate dehydrogenase (584 U/L) with normal kidney and liver functions. A bone biopsy was performed, and the pathologic examination revealed a metastasis by clear-cell RCC.\n\nThe patient underwent, in the first instance, a left cytoreductive nephrectomy, followed by a surgical spinal decompression (D12 and L1) and stabilization (D9-L3) to avoid bone complications and a radiation treatment of the back-lumbar spine (D9-L3) with 20 Gy in 5 fractions for pain control.\n\nAfter surgery, a first-line treatment with sunitinib as the first-line therapy at a dose of 50 mg/day in a 4/2 schedule and zoledronic acid was started. Under sunitinib treatment, which was well tolerated, the patient had a progression-free survival of approximately 41 months, higher than the median progression-free survival observed in clinical trials [16], [17], [18]. A CT scan performed after the sixth cycle of sunitinib documented an increase in the diameter of the metastatic lesion localized in the right iliac crest associated with osteolytic aspects and the new appearance of a right femoral osteolytic metastasis.\n\nRadiotherapy of the right iliac crest (30 Gy in 10 fractions) was performed for pain control, and an mTOR inhibitor was started as a second-line therapy. Between April 2012 and November 2013, the patient was administered everolimus at a dose of 10 mg/day, obtaining a surprisingly stable disease for about 19 months. After 6 months of everolimus treatment, the patient experienced an interstitial pneumonitis, which required drug discontinuation for 20 days, therapy with supplemental oxygen, b-agonists, and prednisone 0.5 mg/kg.\n\nIn July 2013, during everolimus treatment, there was a significant clinical progression of the disease with worsening of the painful symptomatology in the right femur, with poor response to opioid analgesics. A fluorine-18 fluorodeoxyglucose-positron emission tomography scan showed hypermetabolic lesions in the right femoral neck (SUVmax = 4.5) and the omolateral pubic bone (SUVmax = 9) (Fig. 1).Fig. 1 Pre-embolization axial computed tomography (A, C) and positron emission tomography (B, D) images showing metastatic lesions and a pathologic fluorine-18 fluorodeoxyglucose uptake in the right pubic bone (SUVmax = 9) (A, B) and in the right femoral neck (SUVmax = 4.5) (C, D). The red arrows in A and B indicate the pubic metastatic lesion, whereas the red arrows in C and D indicate the right femoral neck metastatic lesion. SUV, stands for standardized uptake value.\n\nFig. 1\n\nWith the aim of improving pain control and delaying the occurrence of local complications, such as pathologic fractures, an arterial embolization treatment was proposed. The angiography, realized by microcatheter insertion into the common femoral artery, showed the presence of 2 hypervascular metastases in these 2 regions. The femoral and pubic lesions, characterized by a rich and pathologic neovascularization (Fig. 2), were embolized using N-butyl-cyanoacrylate with palliative intent, obtaining a complete devascularization, with the postembolization angiography showing a complete occlusion of the pathologic feeding vessels (Fig. 3). Moreover, a significant reduction in the pain score and the need for analgesics were observed.Fig. 2 Pre-embolization angiography. Two hypervascularized lesions: one in the proximal femur and one in the pubic bone.\n\nFig. 2Fig. 3 Postembolization angiography. Disappearance of the vasculature of the lesions.\n\nFig. 3\n\nIn June 2014, because of a further skeletal disease progression, a third-line therapy with sorafenib was started, at a standard dose of 800 mg/day. After a 2-cycle occurrence of G2 anemia, G2 thrombocytopenia, fatigue, and G2 hand-foot syndrome required a dose reduction to 400 mg/day. In December 2014, because of a severe deterioration of the performance status and disease progression, the cancer treatment was suspended, directing the patient only to supportive care.\n\nDiscussion\nBefore 2005, kidney cancer was considered a malignancy orphan of effective therapies, but in the past 10 years, the treatment options have been greatly expanded. The discovery of the crucial role of angiogenesis and the approval of sorafenib and sunitinib, respectively, in 2005 and 2006 dramatically changed the clinical outcome in these patients. In the following years, several other therapeutic options, characterized by a high rate of disease control, were approved, including vascular endothelial growth factor and vascular endothelial growth factor receptor multikinase inhibitors (bevacizumab, pazopanib, axitinib, cabozantinib, and lenvatinib), 2 mTOR inhibitors (everolimus and temsirolimus), and, more recently, the immune checkpoint inhibitor nivolumab [5]. Together with systemic therapies, a multimodality approach integrating locoregional treatments (surgery, radiotherapy, and arterial embolization) also repeated over the patient's history, is currently increasing.\n\nWe report a case of a patient with bone metastases from renal cancer locally treated with superselective arterial embolizations of 2 hypervascular bone lesions for pain management. The patient experienced a clinical benefit with pain control for 6 months and continued the same systemic therapy, thus avoiding to replace a treatment still potentially effective against the highest portion of disease.\n\nAll literature data regarding the use of the arterial embolization for the treatment of bone metastasis are retrospective; further prospective studies are needed to better define the real effectiveness of this treatment and the ideal setting to use. The current main indications for arterial embolization are (1) a first-line treatment of aneurysmal bone cyst as an alternative to traditional surgery [19]; (2) a definitive treatment of benign lesions such as hemangiomas or arteriovenous malformations; (3) a primary or an adjuvant treatment such as surgery, radiation therapy, or chemotherapy of both benign and malignant lesions to reduce bleeding before surgery and to facilitate other therapies; and (4) a palliative treatment of skeletal metastases [11], [12], [13], [14], [15].\n\nThe procedure, performed under local anesthesia, consists of a hyperselective catheterization through femoral artery and embolization of the pathologic vessels feeding the lesion, and is preceded by a diagnostic angiography to determine the vascular mapping of the tumor [13].\n\nMultiple embolic agents are currently available (polyvinyl alcohol particles, gelatin sponge, N-butyl-cyanoacrylate, etc.). Many factors determine the best choice of embolic material, such as the duration of occlusive effect and the preservation of normal tissue, but the most important is operator experience [14], [20].\n\nThe main effects of the procedure are devascularization and pain palliation. Vessel occlusion decreases the blood flow, the edema, and the volume of the tumor, with a consequent reduction of periosteum distention and of pressure effects on adjacent structures and nerves, resulting in pain relief, which may last between 1 and 9 months; at this time, re-embolization is safe and may be necessary. Complications of embolization include dissection of the femoral artery, accidental embolization of adjacent nontargeted vessels, subcutaneous or muscle necrosis, infection caused by tissue ischemia, and postembolization syndrome, characterized by fever and pain caused by tumor necrosis [21].\n\nThe effectiveness of the procedure also depends on the specific histologic type, with a higher rate of successful treatment in hypervascular metastases, such as in renal or thyroid lesions [11], [12], [15].\n\nIn RCC, bone metastases are present in 30%-40% of the patients and are a major cause of morbidity, resulting in pain, decreased mobility, and pathologic fracture. Palliative treatment options for patients with bone metastases are limited, such as standard radiation therapy, if possible, and analgesic medical treatments for pain control starting (nonsteroidal anti-inflammatory drugs or opioids); the lead role is played by radiation therapy, which, however, has limitations related to the cumulative regional dose delivered and the consequentinability to reradiate the same area. In one of the firstpublished experiences on arterial embolization of bone metastasis from RCC, a retrospective review of 21 patients was performed [22]. Thirty separate embolizations to treat 39 metastatic lesions obtained a clinical response (pain relief) in 36 treated sites; the mean duration of the response was 5.5 months.\n\nMore recently, a larger retrospective analysis was conducted on 107 patients with bone metastases from RCC [15]. One hundred sixty-three embolizations using N-2-butyl cyanoacrylate were performed from December 2002 to January 2011. The mean tumor diameter before embolization was 8.8 cm. After a mean follow-up of 4 years, a clinical response was achieved in 157 (96%) embolizations of sacroiliac metastases, and the mean maximal tumor diameter after embolization was 4.0 cm. The mean duration of the clinical response was 10 months (range 1-12). Moreover, hypoattenuating areas on the CT scan, resembling tumor necrosis, were observed in all patients (mean 75%). The most common complications (25% of the cases) were transient paresthesias in the lower extremities after embolizations of the pelvis and sacrum metastatic lesions; all patients completely recovered within a week. These data suggest that embolization may represent a rational therapeutic approach for pain relief as an important and efficacious adjunct in managing patients with hypervascular RCC bone metastases.\n\nThe case herein described surprisingly achieved a long survival (75 months after diagnosis, despite a bone metastasis generally correlated with a poor prognosis), thanks to the long disease control obtained by systemic therapies (41 months with sunitinib and 19 months with everolimus, respectively; practically a “super-responder” to everolimus) and the multiplicity of locoregional approaches carried out, including arterial embolization, which is a nonconventional procedure not currently indicated in the international guidelines of RCC. Therefore, this procedure should be considered in selected cases for the significant clinical benefit that it can bring to patients.\n\nThe progressively better survival of patients with metastatic RCC requires clinicians to use an increasing number of therapeutic tools aimed at symptom control and improvement of quality of life also in patients with a generalized metastatic disease with multiple metastases in several sites. Selective transcatheter embolization of bone metastases from renal cancer represents a reasonable tool for symptom palliation.\n\nIn conclusion, transcatheter arterial embolization does not represent a standard treatment in bone metastasis management but, in our case, brought significant clinical benefits, especially in terms of a long-lasting pain relief in both treated lesions and in the absence of embolization-related complications.\n\nCompeting Interests: The authors have declared that no competing interests exist.\n==== Refs\nReferences\n1 Ljungberg B. Campbell S.C. Choi H.Y. Jacqmin D. Lee J.E. Weikert S. The epidemiology of renal cell carcinoma Eur Urol 60 2011 615 621 21741761 \n2 Bianchi M. Sun M. Jeldres C. Shariat S.F. Trinh Q.D. Briganti A. Distribution of metastatic sites in renal cell carcinoma: a population-based analysis Ann Oncol 23 2012 973 980 21890909 \n3 McKay R.R. Kroeger N. Xie W. Lee J.L. Knox J.J. Bjarnason G.A. Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy Eur Urol 65 2014 577 584 23962746 \n4 Woodward E. Jagdev S. McParland L. Clark K. Gregory W. Newsham A. Skeletal complications and survival in renal cancer patients with bone metastases Bone 48 2011 160 166 20854942 \n5 Choueiri T.K. Motzer R.J. Systemic therapy for metastatic renal-cell carcinoma N Engl J Med 376 2017 354 366 28121507 \n6 Donskov F. Michaelson M.D. Puzanov I. Davis M.P. Bjarnason G.A. Motzer R.J. Sunitinib-associated hypertension and neutropenia as efficacy biomarkers in metastatic renal cell carcinoma patients Br J Cancer 113 2015 1571 1580 26492223 \n7 Maleddu A. Pantaleo M.A. Castellucci P. Astorino M. Nanni C. Nannini M. 11C-acetate PET for early prediction of sunitinib response in metastatic renal cell carcinoma Tumori 95 2009 382 384 19688982 \n8 Arakawa-Todo M. Yoshizawa T. Zennami K. Nishikawa G. Kato Y. Kobayashi I. Management of adverse events in patients with metastatic renal cell carcinoma treated with sunitinib and clinical outcomes Anticancer Res 33 2013 5043 5050 24222148 \n9 Rossi G. Mavrogenis A.F. Rimondi E. Ciccarese F. Tranfaglia C. Angelelli B. Selective arterial embolization for bone tumours: experience of 454 cases Radiol Med 116 2011 793 808 21424560 \n10 Mavrogenis A.F. Rossi G. Rimondi E. Calabrò T. Papagelopoulos P.J. Ruggieri P. Palliative embolization for osteosarcoma Eur J Orthop Surg Traumatol 24 2014 1351 1356 24062055 \n11 Rossi G. Mavrogenis A.F. Rimondi E. Braccaioli L. Calabrò T. Ruggieri P. Selective embolization with N-butyl cyanoacrylate for metastatic bone disease J Vascol Interv Radiol 22 2011 462 470 \n12 Barton P.P. Waneck R.E. Karnel F.J. Ritschl P. Kramer J. Lechner G.L. Embolization of bone metastases J Vasc Interv Radiol 7 1996 81 88 8773979 \n13 Mavrogenis A.F. Rossi G. Rimondi E. Papagelopoulos P.J. Ruggieri P. Embolization of bone tumors Orthopedics 34 2011 303 310 21469619 \n14 Munk P.L. Legiehn G.M. Musculoskeletal interventional radiology: applications to oncology Semin Roentgenol 42 2007 164 174 17599550 \n15 Rossi G. Mavrogenis A.F. Casadei R. Bianchi G. Romagnoli C. Rimondi E. Embolisation of bone metastases from renal cancer Radiol Med 118 2013 291 302 22430676 \n16 Motzer R.J. Hutson T.E. Tomczak P. Michaelson M.D. Bukowski R.M. Rixe O. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma N Engl J Med 356 2007 115 124 17215529 \n17 Motzer R.J. Hutson T.E. Tomczak P. Michaelson M.D. Bukowski R.M. Oudard S. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma J Clin Oncol 27 2009 3584 3590 19487381 \n18 Gore M.E. Szczylik C. Porta C. Bracarda S. Bjarnason G.A. Oudard S. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial Lancet Oncol 10 2009 757 763 19615940 \n19 Mavrogenis A.F. Angelini A. Rossi G. Rimondi E. Guerra G. Ruggieri P. Successful NBCA embolization of a T2 aneurysmal bone cyst Acta Orthop Belg 80 2014 126 131 24873097 \n20 Basile A. Rand T. Lomoschitz F. Toma C. Lupattelli T. Kettenbach J. Trisacryl gelatin microspheres versus polyvinyl alcohol particles in the preoperative embolization of bone neoplasms Cardiovasc Intervent Radiol 27 2004 495 502 15383854 \n21 Wirbel R.J. Roth R. Schulte M. Kramann B. Mutschler W. Preoperative embolization in spinal and pelvic metastases J Orthop Sci 10 2005 253 257 15928886 \n22 Forauer A.R. Kent E. Cwikiel W. Esper P. Redman B. Selective palliative transcatheter embolization of bony metastases from renal cell carcinoma Acta Oncol 46 2007 1012 1018 17851849\n\n",
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"keywords": "Arterial embolization; Bone metastases; Integration strategy; Locoregional therapy; Renal cell carcinoma",
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"title": "Successful selective arterial embolizations for bone metastases in renal cell carcinoma integrated with systemic therapies: A case report.",
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"abstract": "Some of the clinical characteristics of Crohn disease of the head and neck overlap those of squamous cell carcinoma of the head and neck. We describe the diagnostic and therapeutic complexities we encountered in an unusual case of piriform sinus cancer that had arisen in a field of pharyngeal Crohn disease. Based on our initial failure to recognize the predominant inflammatory component of the lesion, we discuss the special considerations that must be made for the detection, staging, and management of head and neck cancer in Crohn disease patients. We further describe the multiple potential interactions among smoking, inflammation, and immunosuppression therapy in the colocalized pathogenesis of the two disease states.",
"affiliations": "Department of Otolaryngology-Head and Neck Surgery, Hospital of the University of Pennsylvania, 3400 Spruce St., 5 Ravdin/Silverstein, Philadelphia, PA 19104, USA. devraj.basu@uphs.upenn.edu.",
"authors": "Yver|Christina|C|;Jhala|Darshana|D|;Muir|Amanda|A|;Basu|Devraj|D|",
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"issue": "96(10-11)",
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"mesh_terms": "D000368:Aged; D003424:Crohn Disease; D006801:Humans; D008297:Male; D010608:Pharyngeal Diseases; D010610:Pharyngeal Neoplasms; D056144:Pyriform Sinus",
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"title": "Managing head and neck malignancy arising in a field of Crohn disease inflammation: Report of a case.",
"title_normalized": "managing head and neck malignancy arising in a field of crohn disease inflammation report of a case"
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"abstract": "Data regarding coronavirus disease 2019 (COVID-19) description are still limited in pediatric oncology. The French society of pediatric oncology (SFCE) initiated a study to better describe COVID-19 in patients followed in French pediatric oncology and hematology wards. All patients diagnosed with COVID-19 and followed in a SFCE center were enrolled. Data from medical records were analyzed for all patients enrolled up to the end of May 2020. Data were available for 37 patients. Thirty-one were children under 18 years of age. Nineteen patients were female. Seventeen patients had a solid tumor, 16 had a hematological malignancy and four recently underwent hematopoietic stem cell transplantation (HSCT) for non-oncological conditions. Twenty-eight patients presented symptoms, most often with fever, cough, rhinorrhea and asthenia. Ground-glass opacities were the most frequent radiological finding with abnormalities mostly bilateral and peripherally distributed. Twenty-four patients received chemotherapy a month prior to COVID-19 diagnosis. Most patients did not require hospitalization. Three patients required oxygen at the time of diagnosis. In total, five patients were admitted in an intensive care unit because of COVID-19 and one died from the disease. Children and young adults treated for a cancer and/or with a HSCT may be at risk for severe COVID-19 and should be closely monitored.",
"affiliations": "Department of Pediatric Oncology and Hematology, University Hospital of Caen (CHU Caen), 14000 Caen, France.;Department of Oncology for Child and Adolescent, Gustave Roussy, 94800 Villejuif, France.;Department of Oncology for Child and Adolescent, Gustave Roussy, 94800 Villejuif, France.;Department of Pediatric Oncology and Hematology, University Hospital of Nancy (CHRU Nancy), 54000 Nancy, France.;Department of Pediatric Hematology and Oncology, Hôpital Hautepierre, 67200 Strasbourg, France.;Department of Pediatric, Adolescent, Young Adult, Institut Curie, CEDEX 05, 75248 Paris, France.;Department of Pediatric Hematology, Robert Debre Hospital, APHP, 75019 Paris, France.;Department of Pediatric Hemato-Oncology, Hospital Armand Trousseau, 75012 Paris, France.;Pediatric Oncology Unit, Centre Oscar Lambret, 59000 Lille, France.;Department of Pediatric Hematology, University Hospital of Lille (CHU Lille), 59000 Lille, France.;Department of Pediatric Oncology and Hematology, University Hospital of Nice, 06000 Nice, France.;Institute of Pediatric Hematology and Oncology IHOPE, Centre Leon Berard, Hospices Civils de Lyon, 69002 Lyon, France.;Department of Pediatric Hematology and Oncology, Hôpital pour enfant de La Timone, AP-HM, 13005 Marseille, France.;Department of Paediatric Hemato-Oncology, University Hospital of Rennes, University Rennes 1, 35000 Rennes, France.",
"authors": "Rouger-Gaudichon|Jérémie|J|0000-0001-6448-8832;Thébault|Eric|E|;Félix|Arthur|A|0000-0002-6034-6869;Phulpin|Aurélie|A|;Paillard|Catherine|C|;Alimi|Aurélia|A|;Brethon|Benoît|B|;Gouache|Elodie|E|;Raimbault|Sandra|S|;de Berranger|Eva|E|;Poirée|Marilyne|M|;Bouttefroy|Séverine|S|;André|Nicolas|N|0000-0002-6786-4968;Gandemer|Virginie|V|;On Behalf Of Société Française de Lutte Contre Les Cancers Et Leucémies de l'Enfant Et de L'adolescent Sfce|||",
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"fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694 MDPI \n\n33212828\n10.3390/cancers12113398\ncancers-12-03398\nArticle\nImpact of the First Wave of COVID-19 on Pediatric Oncology and Hematology: A Report from the French Society of Pediatric Oncology\nhttps://orcid.org/0000-0001-6448-8832Rouger-Gaudichon Jérémie 1* Thébault Eric 2 https://orcid.org/0000-0002-6034-6869Félix Arthur 2 Phulpin Aurélie 3 Paillard Catherine 4 Alimi Aurélia 5 Brethon Benoît 6 Gouache Elodie 7 Raimbault Sandra 8 de Berranger Eva 9 Poirée Marilyne 10 Bouttefroy Séverine 11 https://orcid.org/0000-0002-6786-4968André Nicolas 12 Gandemer Virginie 13 on behalf of Société Française de lutte contre les Cancers et leucémies de l’Enfant et de l’adolescent (SFCE) † 1 Department of Pediatric Oncology and Hematology, University Hospital of Caen (CHU Caen), 14000 Caen, France\n2 Department of Oncology for Child and Adolescent, Gustave Roussy, 94800 Villejuif, France; Eric.THEBAULT@gustaveroussy.fr (E.T.); Arthur.FELIX@gustaveroussy.fr (A.F.)\n3 Department of Pediatric Oncology and Hematology, University Hospital of Nancy (CHRU Nancy), 54000 Nancy, France; a.phulpin@chru-nancy.fr\n4 Department of Pediatric Hematology and Oncology, Hôpital Hautepierre, 67200 Strasbourg, France; catherine.paillard@chru-strasbourg.fr\n5 Department of Pediatric, Adolescent, Young Adult, Institut Curie, CEDEX 05, 75248 Paris, France; aurelia.alimi@curie.fr\n6 Department of Pediatric Hematology, Robert Debre Hospital, APHP, 75019 Paris, France; benoit.brethon@aphp.fr\n7 Department of Pediatric Hemato-Oncology, Hospital Armand Trousseau, 75012 Paris, France; elodie.gouache@aphp.fr\n8 Pediatric Oncology Unit, Centre Oscar Lambret, 59000 Lille, France; sandra.raimbault@gmail.com\n9 Department of Pediatric Hematology, University Hospital of Lille (CHU Lille), 59000 Lille, France; Eva.DEBERRANGER@chru-lille.fr\n10 Department of Pediatric Oncology and Hematology, University Hospital of Nice, 06000 Nice, France; poiree.m@chu-nice.fr\n11 Institute of Pediatric Hematology and Oncology IHOPE, Centre Leon Berard, Hospices Civils de Lyon, 69002 Lyon, France; Severine.BOUTTEFROY@lyon.unicancer.fr\n12 Department of Pediatric Hematology and Oncology, Hôpital pour enfant de La Timone, AP-HM, 13005 Marseille, France; nicolas.andre@ap-hm.fr\n13 Department of Paediatric Hemato-Oncology, University Hospital of Rennes, University Rennes 1, 35000 Rennes, France; virginie.gandemer@chu-rennes.fr\n* Correspondence: rouger-j@chu-caen.fr; Tel.: +33-(0)2-31-06-44-88; Fax: +33-(0)2-31-06-49-30† All authors are the members of Société Française de lutte contre les Cancers et leucémies de l’Enfant et de l’adolescent (SFCE). Members of SFCE are listed in the acknowledgments.\n\n\n17 11 2020 \n11 2020 \n12 11 339829 9 2020 09 11 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/).Simple Summary\nData regarding coronavirus disease 2019 (COVID-19) description are still limited in pediatric oncology. The French society of pediatric oncology (SFCE) initiated a study to better describe COVID-19 presentation and evolution in patients followed in French pediatric oncology and hematology wards. By describing COVID-19 in this specific population, we aimed to identify the patients who may be the most at risk of severe COVID-19 and establish specific recommendations.\n\nAbstract\nData regarding coronavirus disease 2019 (COVID-19) description are still limited in pediatric oncology. The French society of pediatric oncology (SFCE) initiated a study to better describe COVID-19 in patients followed in French pediatric oncology and hematology wards. All patients diagnosed with COVID-19 and followed in a SFCE center were enrolled. Data from medical records were analyzed for all patients enrolled up to the end of May 2020. Data were available for 37 patients. Thirty-one were children under 18 years of age. Nineteen patients were female. Seventeen patients had a solid tumor, 16 had a hematological malignancy and four recently underwent hematopoietic stem cell transplantation (HSCT) for non-oncological conditions. Twenty-eight patients presented symptoms, most often with fever, cough, rhinorrhea and asthenia. Ground-glass opacities were the most frequent radiological finding with abnormalities mostly bilateral and peripherally distributed. Twenty-four patients received chemotherapy a month prior to COVID-19 diagnosis. Most patients did not require hospitalization. Three patients required oxygen at the time of diagnosis. In total, five patients were admitted in an intensive care unit because of COVID-19 and one died from the disease. Children and young adults treated for a cancer and/or with a HSCT may be at risk for severe COVID-19 and should be closely monitored.\n\nSARS-CoV-2COVID-19childneoplasm\n==== Body\n1. Introduction\nCoronavirus disease 2019 (COVID-19), resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to affect children less severely than adults, with majority of benign forms and asymptomatic cases [1]. High mortality rates have been recently reported in adult patients with cancer [2,3]. Data are still limited in children with cancer while some reports suggested that they may be quite safe regarding the infection [4,5,6]. Although recommendations were initially made by the major child cancer organizations, new challenges have emerged [7,8]. A better description of the disease and its associated clinical and logistical challenges is available. As a result, pediatric oncology departments around the world can develop appropriate strategies [9].\n\nTo characterize clinical presentation and outcomes of children, adolescent and young adults with cancer and infected by SARS-CoV-2, the French society of pediatric oncology (Société Française de lutte contre les Cancers et leucémies de l’Enfant et de l’adolescent—SFCE) initiated a study (PEDONCOVID) to retrospectively and prospectively collect data regarding COVID-19 in this specific population. France has been so far one of the most affected countries with currently a total of 188,450 cases and 28,943 deaths [10]. We describe here the detailed data of 37 patients enrolled in French pediatric oncology centers from the SFCE.\n\n2. Results\nAs of the 28th of May 2020, 41 patients with COVID-19 have been declared in SFCE centers. Most of patients were from Eastern France and the region around Paris, consistent with the distribution of the epidemic in whole population (Figure 1). Thirty-seven patients were included in the study. The main characteristics of patients are shown in Table 1.\n\nOf the 37 patients, 31 were children under the age of 18 (mean: 11.2 years (1–25)). Nineteen patients (51%) were female. Seventeen patients had a solid tumor, 16 had a hematological malignancy and four recently underwent HSCT for non-oncological conditions. Nine patients were treated for a cancer relapse. Contact with an infected person was reported for 19 patients, with a median estimated incubation period of 9.5 days (data available for 10 patients). Twenty-eight patients presented symptoms (Table 2).\n\nAll patients were tested for SARS CoV-2 infection by PCR on a nasopharyngeal swab, which was positive in 34 patients (92%). Two patients were diagnosed with positive specific IgM serology and one patient was diagnosed upon typical clinical and radiological findings. Thoracic computed tomography-scan was performed in fifteen patients and was abnormal in all but one case. Ground-glass opacities were the most frequent abnormality (9 cases). Abnormalities were mostly bilateral and peripherally distributed. Blood count results were available for 31 patients. Lymphopenia below 0.5 G/L was found in thirteen patients. Neutropenia below 0.5 G/L was found in thirteen patients. Six patients presented concomitant neutropenia and lymphopenia. C-reactive protein (CRP) dosage results were available for 24 patients. Fifteen patients had an elevated CRP, with a CRP mean level of 41.6 mg/L (15–280). Four patients had a CRP above 50 mg/L. Liver enzymes were measured in seventeen patients, nine of whom had elevations greater than twice the upper limit of normal. A co-pathogen was found in blood samples of two patients (one with Staphyloccocus Epidermidis, and one with Epstein-Barr virus). Twenty-four patients received chemotherapy, on average 12.6 days (0–35) prior to COVID-19 diagnosis, with a mean number of drugs of 2.1 (1–5). Nine patients were currently (or recently) treated with less than 1 mg/kg/day of corticosteroids, five with cyclosporin A and one with tacrolimus. Overall, 20 patients were hospitalized at diagnosis but most of them did not require hospitalization specifically to manage COVID-19. There were significant discrepancies among pediatric oncology and hematology wards regarding schedule triage, rules of admission to hospital and SARS-CoV-2 testing. Seventeen patients received antibiotics, with ten patients presenting febrile neutropenia. Only one patient received remdesivir and two received hydroxychloroquine outside of a clinical trial.\n\nIn total, five patients were admitted into an ICU because of COVID-19 and one died from the disease. Their main characteristics are described in Table 3. Three patients required oxygen at the time of diagnosis and two of them were transferred into an ICU. The patient who received remdesivir had a long stay in ICU with neurological complications and SARS-CoV-2 was still detectable in nasopharyngeal swab and stool 20 and 28 days after COVID-19 diagnosis, respectively. Two injections of tocilizumab were performed as well. One patient who received hydroxychloroquine was discharged from ICU after a 10 days-long stay and was free of symptoms. SARS-CoV-2 test was not repeated for this patient. The other patient who received hydroxychloroquine presented COVID-related complications did not eliminate the virus and died from the infection despite the injection of two doses of tocilizumab.\n\nNotably, four patients had been heavily treated for their cancer and/or recently underwent HSCT. Except for these patients, there were only asymptomatic to moderate forms of infection, with a median follow-up of 21 days (0–58). For the 13 patients for whom PCR had been repeated and these data were available, the mean time to a negative PCR was 16.5 days (7–28). COVID-19 delayed oncology treatment in 16 patients for an average of 14 days.\n\n3. Discussion\nThe objective of this study was to describe the clinical presentation of COVID-19 in the pediatric oncology and hematology population, not to determine the incidence of COVID-19. Indeed, each center may have different screening strategies and the data collected in this study do not allow for the calculation of the incidence of COVID-19. Our data show that clinical and radiological descriptions of COVID-19 are quite similar to those reported in adults, and that incubation period or virus clearance appear to be the same in this population as what has been described before. Most of patients developed a mild or even an asymptomatic form of the disease. However, as we previously stated, [11] and in contrast with other reports [4,5,6], we found that patients may be at a higher risk of developing a severe form of COVID-19. Indeed, five patients (15%) required admission into an intensive care unit (ICU) and one patient died from COVID-19 complications. Among patients with a cancer history, one had high-grade glioma, the others had a relapsed acute lymphoblastic leukemia (ALL) and were highly immunocompromised. The deceased patient was a four-year-old boy undergoing induction chemotherapy for relapsed ALL. His respiratory state worsened, and he was admitted in an ICU, where he developed intense macrophage activation syndrome and subsequent complications that led to his death. In the study from Boulad et al., only one patient required a noncritical care hospitalization and the COVID-19 manifestations were mild for most patients [4]. This is concordant with the data from Spain where no severe case was reported [5]. In contrast, in New York, the joint experience form the memorial Sloan Kettering Cancer Center and New York Presbyterian Hospital shows that among 19 patients infected with SARS-CoV-2, five (20%) required intensive care including mechanical ventilation and a 12-year-old boy with hemoglobinopathy developed acute chest syndrome and died from COVID-19 complications. In Lombardia, Ferrari and al. reported COVID-19 complications in 2/21 patients [12]. We have no clear explanation for such differences between our work and these reports and it may be only due to happenstance. Indeed, ICU admission criteria are likely similar in France and other Western countries and there is no reason that French patients may be more immunocompromised or vulnerable than their US, Spanish or Italian counterparts. In adults, recent reports suggest that patients currently treated for a cancer or with a history of cancer more frequently develop severe COVID-19 compared to the general population [2,13,14]. Only three patients received an anti-SARS-CoV-2 treatment. Because of this small number of patients, outcomes are difficult to appreciate. Tolerance of the administrated treatments was not specifically evaluated in this study, but no complications were reported. Twenty patients were hospitalized, but the rules of admission were not uniform among centers and the reasons for hospitalization were not always specified. Thus, any interpretation of this high number of hospitalizations must be taken very carefully.\n\nOncologic treatment was delayed in almost half of cases, which indicates that COVID-19 impacted the care of patients even if most cases were mild. Notably, some patients had their treatment as planned and did not develop any complications. However, every situation is unique and clinicians who followed these patients made their decision regarding the patients’ own history and potent risk factors, so that no general recommendation to pursue oncologic treatment may be stated from this study. On the contrary, delaying a non-urgent oncologic treatment appears to be wise in the context of suspected or proven infection, as suggested by most clinicians [15]. Conversely, delaying the initial management of children with cancer may be dramatic. Thus, in Phildelphia, Ding et al. reported five patients who became critically hill because of delay in diagnosis illustrating indirect impact on morbidity of COVID-19 [7].\n\nA striking difference between our data and the first published reports is the sex ratio [4,5]. Though there were slightly more females than males in our study, our cohort is equilibrated regarding sex distribution. In some reports concerning pediatric oncology populations, there was a strong proportion of males with 5 to 15 times more male than female [4,5]. Similarly, Gampel and al. reported that among the five patients requiring intensive care, all were males [16]. Other studies in pediatric general population [17] or adult oncology population [2] did not find this high proportion of males. More recently, Bisogno et al. described COVID-19 management in 29 children treated by chemotherapy and/or immunotherapy. The sex ratio was comparable to those from our study, with 16 females and 13 males [18]. Thus, we cannot explain the difference between our study and the work from Boulad et al. and de Rojas et al. but there is currently no clue for a specific sex distribution among children and/or oncology patients.\n\nBiological findings are difficult to interpret since a high proportion of patients recently received drugs that could alter blood tests. However, profound neutropenia and profound lymphopenia were found in almost one third of patients. Even if that can be explained by the oncologic treatment received, the infection likely participated and increased the cytopenias. Lymphopenia is common with SARS-CoV-2 infection, and it appears that the deeper the lymphopenia, the more severe the disease [19,20]. Our cohort is too small to address this question even if two of the five patients admitted into an ICU had profound lymphopenia. For the same reason, it is not possible to draw a conclusion on the association between PCR level and disease severity. However, it should be noted that CRP level was quite low in our cohort and that of the four patients with elevated CRP level above 50 mg/L, two were admitted to an ICU.\n\nClinicians should pay attention to lung lesions caused by COVID-19 for patients who may receive treatments that could themselves damage lung tissue. Indeed, delaying lung irradiation or administration of drugs with known lung toxicity may be considered for infected patients. However, this delay should not be too long to avoid the risk of progression. In our cohort, the mean delay in treatment administration was 14 days, which appears reasonable regarding both this risk of disease progression and the risk of complications related to COVID-19. Of course, making the decision of delaying treatment and the length of this delay should be considered carefully and should depend on the situation.\n\nUntil we get more data, we advocate not reassuring parents regarding the mild forms of COVID-19 in patients treated for malignancies. We recommend that patients with severe hematological malignancies and/or receiving heavily immunosuppressive treatments should be carefully watched and protected from the COVID-19 risk. This shall be of interest for patients in South Asia and Latin America who are now facing the COVID-19 pandemic and countries facing the second wave.\n\n4. Materials and Methods\nAll patients followed in a SFCE center and diagnosed with a SARS-CoV-2 infection who had undergone anti-cancer treatment in the past 6 months were enrolled in the study. We also included all patients from SFCE centers who underwent a hematopoietic stem-cell transplantation (HSCT) for any reason and with immunosuppressive therapy either ongoing or interrupted less than 6 months prior. Since SFCE centers may provide care to children and adolescents as well as in young adults, there was no limit of age to enroll patients in the study.\n\nDiagnosis criteria for SARS-CoV-2 infection were as follows: (1) biologically proven infection with positive polymerase chain reaction (PCR) or positive specific positive IgM SARS-CoV-2 serology, (2) clinical and radiological diagnosis with at least two (if any contact with a suspected or confirmed COVID-19 case) or three (if no notion of contact) clinical signs (comprising fever, cough, loss of smell, loss of taste, myalgia, chest pain, dyspnea, respiratory distress syndrome, rhinorrhea, diarrhea, headaches, asthenia and skin rash) and computed-tomography (CT)-scan signs (ground glass opacities, crazy-paving, linear condensations with a peripheral and/or bilateral distribution) compatible with SARS-CoV-2 infection. All patients and their families were informed of this study. The study was approved by the ethics committee of the coordinating center (N04/2020/ROU). This study is registered in clinicaltrial (NCT04433871).\n\n5. Conclusions\nWe deliver here the first description of the French pediatric oncology and hematology cohort of patients diagnosed with SARS-CoV-2 infection, which to our knowledge is the largest ever published to date. Consistent with previous reports [4,5], relatively few pediatric cancer patients had clinical signs of COVID-19 or tested positive for the virus. Nevertheless, as previously noted [11], some highly immunocompromised patients are at risk of developing severe forms of COVID-19, notably those with hematological malignancies, who have been heavily pretreated and/or with a history of HSCT, which justifies social distancing and specific triage before admission in oncology units.\n\nAcknowledgments\nThe authors thank Alison Johnson for English proofreading. The authors are grateful to all collaborators from the SFCE that participate to the elaboration of this cohort: Coralie Mallebranche (CHU Angers), Liana Carausu (CHU Brest), Mathilde Dubrasquet (CHU Tours), Estelle Thébaud (CHU Nantes), Chrystelle Dupraz (CHU Poitiers), Stéphane Ducassou (CHU Bordeaux), Marion Gambart (CHU Toulouse), Christophe Piguet (CHU Limoges), Stéphanie Haouy (CHU Montepellier), Sandrine Thouvenin (CHU Saint-Etienne), Dominique Plantaz (CHU Grenoble), Justyna Kanold (CHU Clermont-Ferrand), Véronique Laithier (CHU Besançon), Claire Briandet (CHU Dijon), Claire Pluchart (CHU Reims), Pascale Schneider (CHU Rouen), Catherine Devoldere (CHU Amiens), Yves Réguerre (CHU La Réunion), Virginie Gandemer (CHU Rennes), Séverine Bouttefroy (institut d’hématologie et oncologie pédiatrique, Lyon), Marilyne Poirée (CHU Nice), Catherine Paillard (CHU Strasbourg), Eric Thébault (Institut Gustave Roussy, Villejuif), Arthur Félix (Institut Gustave Roussy, Villejuif), Benoît Brethon (Hôpital Robert Debré, Paris), Aurélie Phulpin (CHU Nancy), Elodie Gouache (Hôpital Trousseau, Paris), Eva de Berranger (CHU Lille), Sandra Raimbault (Centre Oscart Lambret, Lille), Aurélia Alimi (Institut Curie, Paris), Nicolas André (Assistance publique, hôpitaux de Marseille), Jérémie Rouger (CHU Caen).\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthor Contributions\nJ.R.-G., conceptualization; formal analysis; writing—original draft; project administration; funding acquisition. E.T., A.F., A.P., C.P., A.A., B.B., E.G., S.R., E.d.B., M.P., S.B.; resources; writing—review and editing. N.A., V.G.; conceptualization; resources; writing—review and editing; supervision. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research was funded by the French Agence Nationale de la Recherche (ANR).\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Reported COVID-19 cases in French pediatric oncology and hematology wards up to the 28th of May.\n\ncancers-12-03398-t001_Table 1Table 1 Main characteristics of enrolled patients.\n\nCharacteristics\tNumber of Patients\tPercentage\t\nSex\t\n\t\n\t\n- Male\t18\t49\t\n- Female\t19\t51\t\nAge\t\n\t\n\t\n- 0–2 years\t3\t8\t\n- 2–6 years\t8\t22\t\n- 6–12 years\t9\t24\t\n- 12–18 years \t11\t30\t\n- Above 18 years\t6\t16\t\nPathological condition\t\n\t\n\t\nHematological malignancy\t16\t43\t\n- ALL\t10\t27\t\n○ t (9;22) negative\t9\t24\t\n○ t (9;22) positive \t1\t3\t\n- AML\t1\t3\t\n- CML\t1\t3\t\n- NHL\t4\t11\t\nSolid tumor\t17\t46\t\n- Localized\t11\t30\t\n- Metastatic\t6\t16\t\n- CNS tumor\t7\t19\t\n- Medulloblastoma\t2\t5\t\n- CNS NB-FOXR2\t1\t3\t\n- Pinealoblastoma\t1\t3\t\n- High-grade glioma\t1\t3\t\n- Low-grade glioma\t1\t3\t\n- Cerebral ATRT\t1\t3\t\n- Bone tumor\t4\t11\t\n- Osteosarcoma\t2\t5\t\n- Ewing sarcoma\t2\t5\t\n- MPNST\t1\t3\t\n- Wilms’ tumor\t1\t3\t\n- Neuroblastoma\t1\t3\t\n- ATRT of the kidney\t1\t3\t\nNon-oncologic condition\t4\t11\t\n- Aplastic anemia\t1\t3\t\n- Sickle cell disease\t1\t3\t\n- EBV-induced macrophage activation syndrome\t1\t3\t\n- Familial septic granulomatosis\t1\t3\t\nCOVID-19 diagnosis method\t\n\t\n\t\n- Positive SARS-CoV-2 PCR\t34\t92\t\n- Positive serology\t2\t5\t\n- Clinical and radiological diagnosis\t1\t3\t\nSymptoms\t\n\t\n\t\n- Yes\t28\t76\t\n- No\t9\t24\t\nTreatments one month prior to COVID-19 diagnosis\t\n\t\n\t\n- Chemotherapy\t24\t65\t\n- Corticosteroids\t9\t24\t\n- G-CSF\t7\t19\t\n- Immunosupressive agents\t6\t16\t\n- Targeted therapy or moncolonal antibody\t5\t14\t\n- Radiotherapy\t2\t5\t\n- Surgery\t2\t5\t\n- None\t1\t3\t\nAbbreviations: ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; ATRT: atypical teratoid rhabdoid tumor; CML: chronic myeloid leukemia; CNS: central nervous system; CNS NB-FOXR2: CNS neuroblastoma with FOXR2 activation; COVID-19: coronavirus disease 2019; EBV: Epstein-Barr virus; G-CSF: granulocyte-colony stimulating factor; MPNST: malignant peripheral nerve sheath tumor; NHL: non-Hodgkin lymphoma; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.\n\ncancers-12-03398-t002_Table 2Table 2 Clinical signs of COVID-19 among the 28 symptomatic cases.\n\nSymptoms\tNumber of Patients\tPercentage of Symptomatic Cases\t\nFever\t20\t71%\t\n>38.5 °C\t14\t50%\t\nBetween 38 °C and 38.5 °C\t6\t21%\t\nCough\t14\t50%\t\nRhinorrhea\t12\t43%\t\nAsthenia\t12\t43%\t\nLoss of smell/taste\t8\t29%\t\nDiarrhea\t7\t25%\t\nChest pain\t6\t21%\t\nMyalgia\t5\t18%\t\nRespiratory distress signs\t5\t18%\t\nTachycardia\t4\t14%\t\nHeadaches\t3\t11%\t\nSkin rash\t2\t7%\t\nNeurological signs\t2\t7%\t\ncancers-12-03398-t003_Table 3Table 3 Clinical characteristics of patients admitted in an intensive care unit for COVID-19.\n\nAge (Years)\tSex\tPathology\tTime to ICU Admission (days)\tType of Respiratory Support\tSpecific Treatment Against SARS-CoV-2\tEvolution\tICU Stay (Days)\tBiology\tComments\t\n12\tM\tRelapsed B-ALL, HSCT 2 months prior SARS-CoV-2 infection, aGVHD\t1\tNon-invasive ventilation\tNo\tFavorable\t5\tNeutro:3.2 G/L\nLy: 0.07\nCRP 39 mg/L\tDeveloped cerebral toxoplasmosis after ICU stay \t\n5\tF\tSS sickle cell disease with cerebral vasculopathy, HSCT 1 month prior to SARS-CoV-2 infection\t2\tMechanic ventilation for 5 days\tRemdesivir\nTocilizumab (2 injections)\tFavorable\t29\tNeutro:5.12 G/L\nLy: 1.28\nCRP <10 mg/L\nFerritin 4400 µg/L\tNeurological complications (bilateral facial palsy, progressive acute polyneuropathy)\nSARS-CoV-2 still detectable in stool at day 28 of infection\t\n8\tF\tRelapsed high-grade astrocytoma\t10\tNon-invasive ventilation\tNo\tFavorable\tUnknown\tWBC: 2.7 G/L\nNeutro: 0.5 G/L\nCRP max: 251 mg/L\tRepeat PCR negative at day 8\t\n18\tF\tRelapsed B-ALL (2nd relapse), treated with vincristine only\t4\tNon-invasive ventilation\tHydroxychloroquine\tFavorable\t10\tNeutro: 0.7 G/L\nLy: 0.48 G/L\nCRP max: 267 mg/L\tCAR-T cell treatment delayed because of SARS-CoV-2 infection\t\n4\tM\tRelapsed B-ALL\t5\tMechanic ventilation for 2 days\tHydroxychloroquine\nTocilizumab (2 injections)\tDeceased (19 days after COVID-19 diagnosis)\t14\tWBC: 0.12 G/L\nCRP <10 mg/L\nFerritin > 300,000 µg/L\tSevere macrophage activation syndrome\t\nAbbreviations: aGVHD: acute graft versus host disease; ALL: acute lymphoblastic leukemia; CAR: chimeric antigen receptor; COVID-19: coronavirus disease 2019; HSCT: hematopoietic stem cell transplantation; ICU; intensive care unit; PCR: polymerase chain reaction; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.\n==== Refs\nReferences\n1. Jiatong S. Lanqin L. Wenjun L. COVID-19 epidemic: Disease characteristics in children J. Med. Virol. 2020 10.1002/jmv.25807 32232980 \n2. Assaad S. Avrillon V. Fournier M.-L. Mastroianni B. Russias B. Swalduz A. Cassier P. Eberst L. Steineur M.-P. Kazes M. High mortality rate in cancer patients with symptoms of COVID-19 with or without detectable SARS-COV-2 on RT-PCR Eur. J. Cancer 2020 10.1016/j.ejca.2020.05.028 32540204 \n3. Zhang L. Zhu F. Xie L. Wang C. Wang J. Chen R. Jia P. Guan H.Q. Peng L. Chen Y. Clinical characteristics of COVID-19-infected cancer patients: A retrospective case study in three hospitals within Wuhan, China Ann. Oncol. 2020 31 894 901 10.1016/j.annonc.2020.03.296 32224151 \n4. Boulad F. Kamboj M. Bouvier N. Mauguen A. Kung A.L. COVID-19 in Children with Cancer in New York City JAMA Oncol. 2020 6 1459 1460 10.1001/jamaoncol.2020.2028 32401276 \n5. De Rojas T. Pérez-Martínez A. Cela E. Baragaño M. Galán V. Mata C. Peretó A. Madero L. COVID-19 infection in children and adolescents with cancer in Madrid Pediatr. Blood Cancer 2020 67 e28397 10.1002/pbc.28397 32383819 \n6. Terenziani M. Massimino M. Biassoni V. Casanova M. Chiaravalli S. Ferrari A. Luksch R. Meazza C. Podda M. Schiavello E. SARS-CoV-2 disease and children under treatment for cancer Pediatr. Blood Cancer 2020 67 e28346 10.1002/pbc.28346 32374054 \n7. Ding Y.-Y. Ramakrishna S. Long A.H. Phillips C.A. Montiel-Esparza R. Diorio C.J. Bailey L.C. Maude S.L. Aplenc R. Batra V. Delayed cancer diagnoses and high mortality in children during the COVID-19 pandemic Pediatr. Blood Cancer 2020 67 e28427 10.1002/pbc.28427 32588960 \n8. André N. Covid-19: Breaking bad news with social distancing in pediatric oncology Pediatr. Blood Cancer 2020 67 e28524 10.1002/pbc.28524 32618416 \n9. Sullivan M. Bouffet E. Rodriguez-Galindo C. Luna-Fineman S. Khan M.S. Kearns P. Hawkins D.S. Challinor J. Morrissey L. Fuchs J. The COVID-19 pandemic: A rapid global response for children with cancer from SIOP, COG, SIOP-E, SIOP-PODC, IPSO, PROS, CCI, and St Jude Global Pediatr. Blood Cancer 2020 67 e28409 10.1002/pbc.28409 32400924 \n10. Johns Hopkins Coronavirus Resource Center COVID-19 Map Available online: https://coronavirus.jhu.edu/map.html (accessed on 14 April 2020) \n11. André N. Rouger-Gaudichon J. Brethon B. Phulpin A. Thébault É. Pertuisel S. Gandemer V. COVID-19 in pediatric oncology from French pediatric oncology and hematology centers: High risk of severe forms? Pediatr. Blood Cancer 2020 67 e28392 10.1002/pbc.28392 32383827 \n12. Ferrari A. Zecca M. Rizzari C. Porta F. Provenzi M. Marinoni M. Schumacher R.F. Luksch R. Terenziani M. Casanova M. Children with cancer in the time of COVID-19: An 8-week report from the six pediatric onco-hematology centers in Lombardia, Italy Pediatr. Blood Cancer 2020 67 e28410 10.1002/pbc.28410 32452123 \n13. Tang L.V. Hu Y. Poor clinical outcomes for patients with cancer during the COVID-19 pandemic Lancet Oncol. 2020 21 862 864 10.1016/S1470-2045(20)30311-9 32479788 \n14. Liang W. Guan W. Chen R. Wang W. Li J. Xu K. Li C. Ai Q. Lu W. Liang H. Cancer patients in SARS-CoV-2 infection: A nationwide analysis in China Lancet Oncol. 2020 21 335 337 10.1016/S1470-2045(20)30096-6 32066541 \n15. Rouger-Gaudichon J. Gariazzo L. Thébault E. Brethon B. Fenwarth L. Gambart M. Alimi A. Réguerre Y. Piguet C. Jubert C. Impact of COVID-19 on cancer care: A survey from the French Society of Pediatric Oncology (SFCE) Pediatr. Blood Cancer 2020 e28554 10.1002/pbc.28554 32893961 \n16. Gampel B. Lucas A.G.T. Broglie L. Gartrell-Corrado R.D. Lee M.T. Levine J. Orjuela-Grimm M. Satwani P. Glade-Bender J. Roberts S.S. COVID-19 disease in New York City pediatric hematology and oncology patients Pediatr. Blood Cancer 2020 67 e28420 10.1002/pbc.28420 32588957 \n17. Dong Y. Mo X. Hu Y. Qi X. Jiang F. Jiang Z. Tong S. Epidemiological Characteristics of 2143 Pediatric Patients with 2019 Coronavirus Disease in China Pediatrics 2020 58 712 713 10.1542/peds.2020-0702 32179660 \n18. Bisogno G. Provenzi M. Zama D. Tondo A. Meazza C. Colombini A. Galaverna F. Compagno F. Carraro F. De Santis R. Clinical Characteristics and Outcome of Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Italian Pediatric Oncology Patients: A Study from the Infectious Diseases Working Group of the Associazione Italiana di Oncologia e Ematologia Pediatrica J. Pediatr. Infect. Dis. Soc. 2020 10.1093/jpids/piaa088 32652521 \n19. Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. Xiang J. Wang Y. Song B. Gu X. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study Lancet 2020 395 1054 1062 10.1016/S0140-6736(20)30566-3 32171076 \n20. Suleyman G. Fadel R.A. Malette K.M. Hammond C. Abdulla H. Entz A. Demertzis Z. Hanna Z. Failla A. Dagher C. Clinical Characteristics and Morbidity Associated with Coronavirus Disease 2019 in a Series of Patients in Metropolitan Detroit JAMA Netw. Open 2020 3 e2012270 10.1001/jamanetworkopen.2020.12270 32543702\n\n",
"fulltext_license": "CC BY",
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"issue": "12(11)",
"journal": "Cancers",
"keywords": "COVID-19; SARS-CoV-2; child; neoplasm",
"medline_ta": "Cancers (Basel)",
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"pubdate": "2020-11-17",
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"title": "Impact of the First Wave of COVID-19 on Pediatric Oncology and Hematology: A Report from the French Society of Pediatric Oncology.",
"title_normalized": "impact of the first wave of covid 19 on pediatric oncology and hematology a report from the french society of pediatric oncology"
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"abstract": "Autoimmune polyglandular syndrome type 1 (APS1) is a rare autosomal recessive disorder, and large granular lymphocytic leukemia (LGLL) may, even more rarely, complicate APS1. LGLL may be subtle in presentation, but it is imperative to recognize LGLL in APS1 promptly, as outcome may otherwise be fatal, as described herein.",
"affiliations": "Department of Medicine and the Carole and Ray Neag Cancer Center University of Connecticut School of Medicine Farmington Connecticut.;Department of Medicine and the Carole and Ray Neag Cancer Center University of Connecticut School of Medicine Farmington Connecticut.;Department of Medicine Rutgers - Robert Wood Johnson Medical School New Brunswick New Jersey.",
"authors": "Harrison|Jonathan S|JS|0000-0002-5815-709X;Parmar|Harsh|H|;Wang|Xiangbing D|XD|",
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"doi": "10.1002/ccr3.1454",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1454CCR31454Case ReportCase ReportsLarge granular lymphocytic leukemia complicating autoimmune polyglandular syndrome type 1 in siblings J. S. Harrison et al.Harrison Jonathan S. http://orcid.org/0000-0002-5815-709Xjoharrison@uchc.edu \n1\nParmar Harsh \n1\nWang Xiangbing D. \n2\n\n1 \nDepartment of Medicine and the Carole and Ray Neag Cancer Center\nUniversity of Connecticut School of Medicine\nFarmington\nConnecticut\n\n2 \nDepartment of Medicine\nRutgers ‐ Robert Wood Johnson Medical School\nNew Brunswick\nNew Jersey\n* Correspondence\n\nJonathan S. Harrison, The University of Connecticut, 263 Farmington Avenue, Farmington 06030, CT.\n\nTel: 860‐679‐2282; Fax: 860‐679‐4451;\n\nE‐mail: joharrison@uchc.edu\n11 3 2018 5 2018 6 5 10.1111/ccr3.2018.6.issue-5847 850 22 11 2017 17 1 2018 02 2 2018 © 2018 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nAutoimmune polyglandular syndrome type 1 (APS1) is a rare autosomal recessive disorder, and large granular lymphocytic leukemia (LGLL) may, even more rarely, complicate APS1. LGLL may be subtle in presentation, but it is imperative to recognize LGLL in APS1 promptly, as outcome may otherwise be fatal, as described herein.\n\nAutoimmune polyglandular syndromelarge granular lymphocytic leukemiapure red cell aplasia source-schema-version-number2.0component-idccr31454cover-dateMay 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.7.2 mode:remove_FC converted:02.05.2018\n\nClinical Case Reports \n2018 ; 6 (5 ): 847 –850\n==== Body\nIntroduction\nLarge granular lymphocytic leukemia (LGLL), also known as T‐gamma lymphoproliferative disorder, is a clonal disorder of CD8‐positive T cells frequently complicated by cytopenias of a specific hematopoietic lineage. The cytopenias seen in LGLL may be isolated neutropenia, isolated thrombocytopenia, or pure red cell aplasia. Autoimmune polyglandular syndrome type 1 (APS type 1) is a rare, autosomal recessive disorder linked to mutations in the gene AIRE located on human chromosome 21. This disorder, also called autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), most often presents with three major clinical components: recurrent mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. AIRE encodes a 545 amino acid transcription factor, mutations in which are associated with loss of the normal deletion of T‐cell clones that, when persistent in an individual, mediate self‐immunity 1. Over one hundred mutations in the AIRE gene have been reported to date, and there is heterogeneity among patients with respect to frequent additional abnormalities seen in APS type 1. Minor components of the disease reported to date include recurrent fever with rash, retinal pigmentation, autoimmune hepatitis, alopecia, or vitiligo, among others 2. We encountered a woman with APS type 1 who, at age 23, developed pure red cell aplasia, and diagnostic evaluation documented LGLL with a clonal T‐cell population. One year after the proband patient developed pure red cell aplasia and LGLL, the proband's younger sister – who had then reached age 23 and who also had APS type 1 – developed clinically significant anemia. Diagnostic evaluation then documented LGLL with red cell hypoplasia in this younger sister. These observations suggest that the mutation in AIRE was causally related to development of LGLL and the consequent anemia with erythroid hypoplasia, in these two individuals.\n\nCase 1\nA 23‐year‐old woman presented to our medical center in August 2008 with complaints of progressive fatigue and exertional dyspnea of one‐month duration. At time of admission, hemoglobin was 6.5 gm/dL with normal leukocyte and platelet count. The patient's medical history was significant for autoimmune polyglandular syndrome type 1, identified during her teenage years. The patient had growth retardation noted by age 6, and developed clinically overt hypoparathyroidism at age 10. At age 14, adrenal insufficiency was documented; in addition, there was a history of recurrent oral candidiasis. Physical examination at initial presentation revealed a petite woman, awake, alert, and fully oriented in no acute distress, but reporting fatigue. Vital signs were normal aside from a resting tachycardia; the remainder of the examination was remarkable only for short stature and pale conjunctiva. Laboratory results at the time of hematology consultation included a total white blood cell count of 30.9 × 109/L, hemoglobin of 6.6 g/dL (4.09 mmol/L), and platelet count of 181 × 109/L. The mean corpuscular volume was 107.4 × 10−15L with reticulocyte count of 1.83%. Review of the peripheral blood film showed 87% segmented neutrophils, 5% lymphocytes, 3% monocytes, 2% eosinophils, 1% basophils, and 2% myelocytes. No further immature white blood cell forms were noted. The patient had received a “stress dose” of hydrocortisone on admission by the medical house staff, due to chronic corticosteroid replacement therapy and presumed acute illness. Total leukocyte counts fell toward normal range following reduction in corticosteroid dose (See Table 1). Schistocytosis was not observed in the peripheral blood. However, there were macrocytes, and occasional large granular lymphocytes were noted (Fig. 1A). Marrow examination showed pure red cell aplasia (Fig. 1B). Immunophenotyping of the blood and the marrow documented a clonal population of suppressor T cells, expressing CD2, CD3, CD5 (dim), CD7, CD8, and CD57. Molecular diagnostics by polymerase chain reaction amplification of the T‐cell receptor gamma chain (performed at the University of Washington Hematopathology Laboratory, Seattle, Washington) further documented a clonal T‐cell population in the blood and marrow. The patient was treated sequentially using high‐dose corticosteroids, followed by methotrexate, and subsequently cyclosporine A, all without significant improvement in erythropoiesis. She subsequently was admitted to hospital for further therapy, but died in November 2008, from what appeared to be infectious complications of immunosuppression. Autopsy documented intracranial hemorrhage, with a purulent infiltrate in the brain, and blood vessel findings are consistent with a vasculitis, but no bacterial or fungal organisms are identified.\n\nTable 1 Clinical Parameters at times of diagnosis\n\nPatient\tCase 1 (Proband–older sister)\tCase 2 (Younger sister)\t\nDate of laboratory evaluation\t12 August 2008\t10 September 2009\t\nWhite blood cell count (SI units: 109/L)\t17.5\t9.8\t\nAbsolute lymphocyte count (SI units: 109/L)\t12.3\t3.9\t\nHemoglobin (SI units: mmol/L)\t4.03 (6.5 gm/dL)\t6.14 (9.3 gm/dL)\t\nHematocrit (%)\t19\t28\t\nMean corpuscular volume (10−15L)\t113\t106\t\nReticulocyte count (%)\t1.5\t1.0\t\nPlatelet count (SI units: 109/L)\t181\t226\t\nTable of hematologic parameters for the two cases described. Data for Case 1 taken from the day of initial hospitalization; blood counts in the text of the manuscript are from the date of hematology consultation. Date for Case 2 is from the date of her outpatient bone marrow examination.\n\nJohn Wiley & Sons, LtdFigure 1 Blood count data from each case. (A) Large granular lymphocyte in the peripheral blood of proband (case 1). (B) Marrow biopsy showing red cell aplasia in proband (case 1). (C) Marrow biopsy showing red cell hypoplasia in sister of proband (case 2).\n\nCase 2\nA 23‐year‐old woman, a younger sister of the proband, initially presented to an outside medical center with complaint of progressive fatigue of two‐month duration in September 2009. At that time, hemoglobin was 10.3 gm/dL with normal leukocyte and platelet count. The patient's medical history was significant for autoimmune polyglandular syndrome type 1; a diagnosis was made during her teenage years. The patient had growth retardation noted by age 6, and developed clinically overt hypoparathyroidism at age 12. At age 13, adrenal insufficiency was documented; in addition, there was a history of recurrent oral candidiasis in this younger sister. Upon identification of anemia in the year 2009 (see Table 1 for blood counts), given the history of her older sister having died the previous year, diagnostic evaluation was undertaken promptly. Review of the peripheral blood smear revealed large granular lymphocytes, and immunophenotyping of the blood confirmed the presence of a clonal population of T cells, expressing CD2, CD3 (dim), CD5 (dim), CD7, CD8, and CD57 (performed at Genoptix Medical Laboratory, Carlsbad, CA). Molecular diagnostic study of the marrow for the T‐cell receptor beta chain gene was rearranged from germ line (also performed at Genoptix Medical Laboratory), further confirming the presence of a clonal population of suppressor T cells. Marrow aspirate and biopsy demonstrated erythroid hypoplasia; interestingly, a small amount of reticulin fibrosis was also noted.\n\nDiscussion\nSpecimens of blood and marrow from both the proband with APS type 1 and her similarly affected younger sister each demonstrated a clonal population of CD8‐positive suppressor lymphocytes by immunophenotyping. The microscopic appearance of these cells was, as noted, classic for large granular lymphocytes (Fig. 1A). In both patients, the abnormal T cells marked positive for CD2, CD3, CD5 (dim), CD7 (dim) in one sibling and bright in the other, CD8 and CD57. The appearance of these cells was classic for large granular lymphocytes (Fig. 1). In both patients, analysis of the T‐cell receptor gene complex showed a clonal pattern, indicating a monoclonal population of T cells in each of the patients (Fig. 2). The T‐cell receptor gamma‐chain gene was analyzed in the proband by PCR, and the T‐cell receptor beta chain gene was analyzed by polymerase chain reaction in the second case, due to logistical constraints in the clinical care of the two patients at different centers. Taken together, these results establish that both siblings had, at discordant times, T‐gamma large granular lymphocytic leukemia complicating APS type 1. Marrow examination of the proband in the year 2008 documented pure red cell aplasia. Marrow examination of the second patient, the younger sister of the proband, documented erythroid hypoplasia that progressively worsened over subsequent months. This younger sister of the proband has been treated using oral methotrexate and recombinant erythropoietin, and remains alive but under active medical care approximately 8 years after diagnosis.\n\nFigure 2 T‐cell clonality by polymerase chain reaction. Polymerase chain reaction amplification study documenting a clonal T‐cell population in the blood from the proband (see text).\n\nLarge granular lymphocytic leukemia is an uncommon, clonal disorder of CD8‐positive suppressor T cells, which is typically an indolent disease. One prominent hypothesis regarding the etiology of this disorder is that chronic antigenic stimulation results in the polyclonal expansion of T cells, which includes a clone that eventually becomes dominant, leading to a monoclonal population. If this clone recognizes a self‐antigen, then, due to regulatory failure and lack of deletion of that T cell clone, the disorder results in clinical symptomatology on an autoimmune basis. In the case of this particular family, the consequence of autoimmune polyglandular syndrome was not simply autoimmune polyendocrine failure, but the development of CD8‐positive large granular lymphocytic leukemia, also termed T‐gamma disease, and categorized by the World Health Organization as a form of mature T‐cell lymphoma. In both of these cases, the patient's clone of large granular lymphocytes appears to have targeted an erythroid antigen, resulting in erythroid hypoplasia and clinically significant anemia, suggesting that a similar T‐cell receptor rearrangement may have been present in both siblings. Unfortunately, sequencing of the T‐cell receptor genes in these patients was not logistically possible, and thus, the sequences could not be compared.\n\nThere are a small number of case reports and small series of patients with APS1 developing large granular lymphocytic leukemia complicated, in turn, by pure red cell aplasia. A review of the literature reveals six cases of APS1 associated with pure red cell aplasia prior to the present report. Orlova and colleagues recently reviewed this literature, following their experience with a 26‐year‐old woman with APS1 who developed pure red cell aplasia responsive to mycophenolic acid 3. Prior reports of pure red cell aplasia in the setting of APS1 have not described siblings with pure red cell aplasia complicating the course of more than one family member 4, 5, 6. Of the cases reported to date, no siblings have been described previously. Familial LGLL has been reported, but only in a father and son without evidence of APS1 7.\n\nConclusion\nIt may not be surprising that LGLL and pure red cell aplasia developed in both of the sisters described herein, as these siblings must, of course, have shared the same mutation in the AIRE gene. The diagnosis of LGLL complicated by pure red cell aplasia in the proband accelerated the recognition of the disease in the younger sister and may thus have improved the outcome for the second patient. Thus, it is important that, in patients with APS1, these individuals be closely monitored for the development of cytopenias. If cytopenias do occur, then the possibility of LGLL in the differential diagnosis should be considered early, as this may result in an improved outcome for the patient 8.\n\nAuthorship\nJSH: participated in care of both patients. JSH and XDW: participated in care of the proband patient. JSH and XDW: authored the manuscript. JSH, HP and XDW: critically reviewed and edited the manuscript and approved the final manuscript.\n\nConflict of Interest\nNone of the authors has existing conflict of interests to report.\n==== Refs\nReferences\n1 \n\nMichels , A. W. \n, and \nP. A. \nGottlieb \n. 2010 \nAutoimmune polyglandular syndromes. Nature Rev Endocrinol \n6 :270 –277 .20309000 \n2 \n\nOrlova , E. M. \n, \nL. S. \nSozaeva \n, \nM. A. \nKareva \n, \nB. E. \nOftedal \n, \nA. S. B. \nWolff \n, \nL. \nBreivik \n, et al. 2017 \nExpanding the phenotype and genotypic landscape of autoimmune polyendocrine syndrome type 1 . J. Clin. Endocrinol. Metab. \n102 :3546 –3556 .28911151 \n3 \n\nOrlova , E. M. \n, \nM. A. \nKareva \n, \nM. A. \nMelikyan \n, \nE. \nBoyakova \n, \nV. A. \nPeterkova \n, and \nA. A. \nMaschan \n. 2013 \nResponse of Pure Red cell Aplasia to cyclophosphamide after failure of mycofenolate mofetil in a patient with Polyglandular Syndrome Type 1 . J Ped Hematol Oncol \n35 :338 –340 .\n4 \n\nGrossi , A. \n, \nC. \nNozzoli \n, \nR. \nGheri \n, \nV. \nSantini \n, \nC. \nMarrani \n, \nA. \nZoccolante \n, et al. 1998 \nPure red cell aplasia in autoimmune polyglandular syndrome with T lymphocytosis . Haematologica \n83 :1043 –1045 .9864928 \n5 \n\nHervier , B. \n, \nM. \nRimbert \n, \nH. \nMaisonneuve \n, and \nM. A. \nHamidou \n. 2010 \nLarge granular lymphocyte leukemia with pure red cell aplasia associated with autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy: an unfortuitous association? \nInt J Immunopathol Pharmacol \n23 :947 –949 .20943067 \n6 \n\nBakrac , M. \n, \nV. \nJurisic \n, \nT. \nKostic \n, \nV. \nPopovic \n, \nS. \nPekic \n, \nN. \nKraguljac \n, et al. 2007 \nPure red cell aplasia associated with type 1 autoimmune polyglandular syndrome successful response to treatment with mycophenolate mofetil: case report and review of the literature . J Clinical Pathol \n60 :717 –720 .17220208 \n7 \n\nStalika , E. \n, \nA. \nPapalexandri \n, \nM. \nIskas \n, \nN. \nStavroyianni \n, \nG. \nKanellis \n, \nK. \nKotta \n, et al. 2014 \nFamilial CD3 + T large granular lymphocyte leukemia: evidence that genetic predisposition and antigen selection promote clonal cytotoxic T‐cell responses . Leukemia & Lymphoma \n55 :1781 –1787 .24180333 \n8 \n\nSanikommu , S. R. \n, \nM. J. \nClemente \n, \nP. \nChomczynski \n, \nM. G. \nAfable \n, \nA. \nJerez \n, \nS. \nThota \n, et al. 2017 \nClinical features and treatment outcomes in large granular lymphocytic leukemia . Leuk. Lymphoma \n20 :1 –7 .\n\n",
"fulltext_license": "CC BY",
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"issue": "6(5)",
"journal": "Clinical case reports",
"keywords": "Autoimmune polyglandular syndrome; large granular lymphocytic leukemia; pure red cell aplasia",
"medline_ta": "Clin Case Rep",
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"publication_types": "D002363:Case Reports",
"references": "24180333;28911151;20309000;17220208;20943067;9864928;28633612;23128333",
"title": "Large granular lymphocytic leukemia complicating autoimmune polyglandular syndrome type 1 in siblings.",
"title_normalized": "large granular lymphocytic leukemia complicating autoimmune polyglandular syndrome type 1 in siblings"
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"abstract": "Keratitis due to Nocardia infection is not commonly encountered in clinical practice and may therefore be mistaken for fungal or viral keratitis leading to delayed treatment and increased risk of permanent visual impairment.\n\n\n\nAn otherwise healthy 27 years old Caucasian Active Duty military member presented to the clinic with three days of light sensitivity and irritation of his right eye. He carried a history of PRK in both eyes six years prior and admitted to recent contact lens overuse. With empiric treatment for typical bacterial keratitis including corticosteroids, his condition worsened on close follow-up. While awaiting cultures, a shift to fortified topical antibiotics tobramycin, moxifloxacin and ciprofloxacin showed improvement with closure of the epithelial defect. Ulcerative relapse occurred with withdrawal of therapy. Culture proven Nocardia arthritidis prompted successful treatment with topical antibiotic amikacin. On follow-up at three months, the patient was doing well with a small peripheral anterior stromal scar without permanent visual sequelae. Visual acuity returned to baseline of 20/20 in the affected eye.\n\n\n\nKeratitis caused by Nocardia species, including arthritidis, responds well to amikacin. Late diagnosis and early treatment withdrawal may lead to a prolonged recovery. Current literature indicates that corticosteroids may be harmful in the treatment of Nocardia keratitis. Increased awareness of Nocardia as an ocular pathogen has the potential to reduce unnecessary morbidity related to delayed diagnosis, inadequate therapy and inappropriate use of corticosteroids.",
"affiliations": null,
"authors": "Gieger|Andrew|A|;Waller|Stephen|S|;Pasternak|Joseph|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial",
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"issue": "9(18)",
"journal": "Nepalese journal of ophthalmology : a biannual peer-reviewed academic journal of the Nepal Ophthalmic Society : NEPJOPH",
"keywords": null,
"medline_ta": "Nepal J Ophthalmol",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D003261:Contact Lenses; D004269:DNA, Bacterial; D015818:Eye Infections, Bacterial; D006801:Humans; D007634:Keratitis; D008297:Male; D009617:Nocardia Infections; D009616:Nocardia asteroides; D014792:Visual Acuity",
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"pages": "91-94",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Nocardia Arthritidis Keratitis: Case Report and Review of the Literature.",
"title_normalized": "nocardia arthritidis keratitis case report and review of the literature"
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"abstract": "Clinical trials are critical to informing cancer care but often are hampered by slow accrual and lack of generalizability because of poor geographic accessibility. We tested the feasibility of replacing onsite study visits with telemedicine visits in a prospective clinical trial.\n\n\n\nCastration-naïve patients with prostate cancer and a rising serum prostate-specific antigen after definitive local therapy were eligible. Patients were required to have a single onsite visit for enrollment. Study treatment consisted of oral metformin 850 mg daily for 1 month followed by 850 mg twice daily for 5 months. Telehealth video visits (televisits) were conducted monthly by using a Health Insurance Portability and Accountability Act-compliant smartphone application. The primary objective was to determine the feasibility of telemedicine-enabled study visits. Secondary objectives were defining safety, anticancer activity, quality of life, and patient satisfaction.\n\n\n\nFifteen patients with a median age of 68 years (range, 57 to 83 years) and median one-way driving time to the study center of 71 minutes (range, 12 to 147 minutes) were enrolled. The patients completed 84 eligible televisits (completion rate, 100%; 95% CI, 0.80 to 1). Diarrhea was the most common adverse event but was limited to grade 1 in severity; a single patient experienced grade ≥ 3 adverse events. Seven patients (46.7%; 95% CI, 24.8% to 69.9%) had a ≤ 20% increase in prostate-specific antigen relative to baseline. Patients agreed or strongly agreed that they would participate in a telemedicine-enabled clinical trial in the future.\n\n\n\nTo our knowledge, this interventional oncology clinical trial is the first to be conducted through telemedicine. Telemedicine-enabled trials are feasible and may overcome geographic barriers to trial participation. Metformin was generally well tolerated but associated with modest anticancer activity.",
"affiliations": "Matthew D. Galsky, Mohamed Shahin, Rachel Jia, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker, Amanda Leiter, Reza Mehrazin, John P. Sfakianos, Patricia Acon, and William K. Oh, Icahn School of Medicine at Mount Sinai; John Holland, AMC Health; Tomasz Sablinski, Transparency Life Sciences, New York; and David R. Shaffer, Albany Medical Center, Albany, NY.;Matthew D. Galsky, Mohamed Shahin, Rachel Jia, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker, Amanda Leiter, Reza Mehrazin, John P. Sfakianos, Patricia Acon, and William K. Oh, Icahn School of Medicine at Mount Sinai; John Holland, AMC Health; Tomasz Sablinski, Transparency Life Sciences, New York; and David R. Shaffer, Albany Medical Center, Albany, NY.;Matthew D. Galsky, Mohamed Shahin, Rachel Jia, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker, Amanda Leiter, Reza Mehrazin, John P. Sfakianos, Patricia Acon, and William K. Oh, Icahn School of Medicine at Mount Sinai; John Holland, AMC Health; Tomasz Sablinski, Transparency Life Sciences, New York; and David R. Shaffer, Albany Medical Center, Albany, NY.;Matthew D. Galsky, Mohamed Shahin, Rachel Jia, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker, Amanda Leiter, Reza Mehrazin, John P. Sfakianos, Patricia Acon, and William K. Oh, Icahn School of Medicine at Mount Sinai; John Holland, AMC Health; Tomasz Sablinski, Transparency Life Sciences, New York; and David R. Shaffer, Albany Medical Center, Albany, NY.;Matthew D. Galsky, Mohamed Shahin, Rachel Jia, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker, Amanda Leiter, Reza Mehrazin, John P. Sfakianos, Patricia Acon, and William K. Oh, Icahn School of Medicine at Mount Sinai; John Holland, AMC Health; Tomasz Sablinski, Transparency Life Sciences, New York; and David R. Shaffer, Albany Medical Center, Albany, NY.;Matthew D. Galsky, Mohamed Shahin, Rachel Jia, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker, Amanda Leiter, Reza Mehrazin, John P. Sfakianos, Patricia Acon, and William K. Oh, Icahn School of Medicine at Mount Sinai; John Holland, AMC Health; Tomasz Sablinski, Transparency Life Sciences, New York; and David R. Shaffer, Albany Medical Center, Albany, NY.;Matthew D. Galsky, Mohamed Shahin, Rachel Jia, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker, Amanda Leiter, Reza Mehrazin, John P. Sfakianos, Patricia Acon, and William K. Oh, Icahn School of Medicine at Mount Sinai; John Holland, AMC Health; Tomasz Sablinski, Transparency Life Sciences, New York; and David R. Shaffer, Albany Medical Center, Albany, NY.;Matthew D. Galsky, Mohamed Shahin, Rachel Jia, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker, Amanda Leiter, Reza Mehrazin, John P. Sfakianos, Patricia Acon, and William K. Oh, Icahn School of Medicine at Mount Sinai; John Holland, AMC Health; Tomasz Sablinski, Transparency Life Sciences, New York; and David R. Shaffer, Albany Medical Center, Albany, NY.;Matthew D. Galsky, Mohamed Shahin, Rachel Jia, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker, Amanda Leiter, Reza Mehrazin, John P. Sfakianos, Patricia Acon, and William K. Oh, Icahn School of Medicine at Mount Sinai; John Holland, AMC Health; Tomasz Sablinski, Transparency Life Sciences, New York; and David R. Shaffer, Albany Medical Center, Albany, NY.;Matthew D. Galsky, Mohamed Shahin, Rachel Jia, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker, Amanda Leiter, Reza Mehrazin, John P. Sfakianos, Patricia Acon, and William K. Oh, Icahn School of Medicine at Mount Sinai; John Holland, AMC Health; Tomasz Sablinski, Transparency Life Sciences, New York; and David R. Shaffer, Albany Medical Center, Albany, NY.;Matthew D. Galsky, Mohamed Shahin, Rachel Jia, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker, Amanda Leiter, Reza Mehrazin, John P. Sfakianos, Patricia Acon, and William K. Oh, Icahn School of Medicine at Mount Sinai; John Holland, AMC Health; Tomasz Sablinski, Transparency Life Sciences, New York; and David R. Shaffer, Albany Medical Center, Albany, NY.;Matthew D. Galsky, Mohamed Shahin, Rachel Jia, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker, Amanda Leiter, Reza Mehrazin, John P. Sfakianos, Patricia Acon, and William K. Oh, Icahn School of Medicine at Mount Sinai; John Holland, AMC Health; Tomasz Sablinski, Transparency Life Sciences, New York; and David R. Shaffer, Albany Medical Center, Albany, NY.;Matthew D. Galsky, Mohamed Shahin, Rachel Jia, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker, Amanda Leiter, Reza Mehrazin, John P. Sfakianos, Patricia Acon, and William K. Oh, Icahn School of Medicine at Mount Sinai; John Holland, AMC Health; Tomasz Sablinski, Transparency Life Sciences, New York; and David R. Shaffer, Albany Medical Center, Albany, NY.;Matthew D. Galsky, Mohamed Shahin, Rachel Jia, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker, Amanda Leiter, Reza Mehrazin, John P. Sfakianos, Patricia Acon, and William K. Oh, Icahn School of Medicine at Mount Sinai; John Holland, AMC Health; Tomasz Sablinski, Transparency Life Sciences, New York; and David R. Shaffer, Albany Medical Center, Albany, NY.",
"authors": "Galsky|Matthew D|MD|;Shahin|Mohamed|M|;Jia|Rachel|R|;Shaffer|David R|DR|;Gimpel-Tetra|Kiev|K|;Tsao|Che-Kai|CK|;Baker|Charles|C|;Leiter|Amanda|A|;Holland|John|J|;Sablinski|Tomasz|T|;Mehrazin|Reza|R|;Sfakianos|John P|JP|;Acon|Patricia|P|;Oh|William K|WK|",
"chemical_list": "D015415:Biomarkers; D014408:Biomarkers, Tumor; D008687:Metformin; D017430:Prostate-Specific Antigen",
"country": "United States",
"delete": false,
"doi": "10.1200/CCI.17.00044",
"fulltext": null,
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"issn_linking": "2473-4276",
"issue": "1()",
"journal": "JCO clinical cancer informatics",
"keywords": null,
"medline_ta": "JCO Clin Cancer Inform",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D014408:Biomarkers, Tumor; D003131:Combined Modality Therapy; D006801:Humans; D008297:Male; D008687:Metformin; D008875:Middle Aged; D000071066:Patient Reported Outcome Measures; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms; D011788:Quality of Life; D017216:Telemedicine; D016896:Treatment Outcome",
"nlm_unique_id": "101708809",
"other_id": null,
"pages": "1-10",
"pmc": null,
"pmid": "30657386",
"pubdate": "2017-11",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Telemedicine-Enabled Clinical Trial of Metformin in Patients With Prostate Cancer.",
"title_normalized": "telemedicine enabled clinical trial of metformin in patients with prostate cancer"
} | [
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"activesubstancename": "METFORMIN HYDROCHLORIDE"
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"abstract": "The presentation of an upper gastrointestinal bleed secondary to an accessory splenic artery is a rare circumstance described only in 2 previous case reports. This report is the first to describe an upper gastrointestinal bleed consequent of a submucosal accessory splenic artery arising from the left phrenic artery, requiring multiple endoscopies and endovascular embolization. Vascular anatomic variants can pose a challenge to treatment, especially when they are unknown. This case adds to the limited number of case reports involving accessory splenic arteries.",
"affiliations": "Imaging Institute, Department of Vascular and Interventional Radiology, Cleveland Clinic Foundation, Cleveland, OH.;Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH.;Department of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH.;Imaging Institute, Department of Vascular and Interventional Radiology, Cleveland Clinic Foundation, Cleveland, OH.;Department of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH.",
"authors": "Patel|Priyesh|P|0000-0003-0596-8830;Chadalavada|Pravallika|P|;Singh|Amandeep|A|;Gurajala|Ram Kishore|RK|;Achkar|Jean-Paul|JP|",
"chemical_list": null,
"country": "United States",
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"doi": "10.14309/crj.0000000000000550",
"fulltext": "\n==== Front\nACG Case Rep J\nACG Case Rep J\nACGCRJ\nACGCRJ\nAC9\nACG Case Reports Journal\n2326-3253\nWolters Kluwer Maryland, MD\n\n33718509\nACGCR-20-0790\n10.14309/crj.0000000000000550\n00004\nCase Report\nStomach\nAccessory Splenic Artery Causing Massive Gastrointestinal Bleed\nhttp://orcid.org/0000-0003-0596-8830\nPatel Priyesh MD 1\nChadalavada Pravallika MD 2chadalp@ccf.org\n\nSingh Amandeep MD 3singha4@ccf.org\n\nGurajala Ram Kishore MD 1gurajar@ccf.org\n\nAchkar Jean-Paul MD 3Achkarj@ccf.org\n\n1 Imaging Institute, Department of Vascular and Interventional Radiology, Cleveland Clinic Foundation, Cleveland, OH\n2 Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH\n3 Department of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH\nCorrespondence: Priyesh Patel, MD (patelp18@ccf.org).\n3 2021\n10 3 2021\n8 3 e0055029 6 2020\n04 10 2020\n© 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.\n2021\nThis is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nABSTRACT\n\nThe presentation of an upper gastrointestinal bleed secondary to an accessory splenic artery is a rare circumstance described only in 2 previous case reports. This report is the first to describe an upper gastrointestinal bleed consequent of a submucosal accessory splenic artery arising from the left phrenic artery, requiring multiple endoscopies and endovascular embolization. Vascular anatomic variants can pose a challenge to treatment, especially when they are unknown. This case adds to the limited number of case reports involving accessory splenic arteries.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\n\nUpper gastrointestinal (GI) bleeds are defined as intraluminal bleeding originating above the ligament of Treitz. There can be significant variation in the presentation of the bleed depending on the etiology. Upper GI bleeding has been reported to have an incidence of approximately 0.08%–0.16% and is a potentially life-threatening condition with a mortality rate of approximately 10%.1,2 Endoscopy and multiphase computed tomography (CT) are the 2 most common modalities initially used to identify the source of GI bleeding. Arterial phase CT can help identify arterial bleeds, while portal-venous phase CT is more beneficial to identify venous or variceal bleeds. Accessory splenic arteries are an uncommon anatomic variant described in few previous reports. There are many theories on the origin of the accessory arteries, including failure of regression or fusion of primitive vitelline arteries during embryological development.3 The presentation of an upper GI bleed secondary to an accessory splenic artery is a rare circumstance, described in only 2 previous case reports.4,5 Our report is the first to describe a massive upper GI bleed consequent of a submucosal accessory splenic artery arising from the left phrenic artery.\n\nCASE REPORT\n\nA 69-year-old man with a medical history significant for chronic neck pain requiring daily ibuprofen use along with the addition of aspirin and methylprednisolone for 1 week before admission presented with a complaint of black tarry stool. On arrival, he was slightly tachycardic and had a hemoglobin of 12 g/dL. However, he subsequently had an episode of large-volume hematemesis and a drop in hemoglobin to 8.6 g/dL. Urgent esophagogastroduodenoscopy (EGD) demonstrated old blood and clots in the gastric fundus without active bleeding. Attempts to clear the clots with suction and Roth Net were unsuccessful.\n\nA repeat EGD the following morning allowed for better visualization of the gastric fundus. A prominent tortuous vessel was identified within the submucosa of the gastric fundus initially believed to be a varix, but no active bleed or stigmata of recent bleeding was identified. Abdominal computed tomography was reviewed, and a prominent artery was identified arising from the left phrenic artery and coursing through the gastric fundus (Figure 1). No gastric varices were identified.\n\nFigure 1. Axial (left) and coronal (right) abdominal computed tomography (CT) showing a prominent artery arising from the left phrenic artery and coursing through the gastric fundus (arrows).\n\nOvernight the patient began to display evidence of a recurrent bleed and underwent visceral angiography, which demonstrated an accessory splenic artery arising from the left phrenic artery and supplying the superior third of the spleen (Figure 2). A conventional splenic artery was also demonstrated in the expected position, supplying the inferior two-thirds of the spleen. Angiography of the remaining mesenteric vessels did not show any active bleeding, and therefore, no intervention was performed.\n\nFigure 2. Digital subtraction angiography image (left) demonstrates the right and left (red arrows) phrenic arteries. The accessory splenic artery is identified (blue arrows), branching off of the left phrenic. Delayed digital subtraction angiography image (right) demonstrates accessory splenic artery supplying the upper third of the spleen.\n\nA few days later, the patient had recurrent bleeding with a drop in hemoglobin level to 5.9 g/dL. The patient was transfused and underwent a third EGD which revealed a serpiginous vessel with a fibrin plug in the gastric fundus. This abnormal artery was believed to be the source of the patient's melena, and 3 hemoclips were placed on the vessel (Figure 3). Although the bleeding initially stopped, the patient had another episode of bleeding the following day. The patient was brought to interventional radiology, and a second angiogram was performed which demonstrated the accessory splenic artery as the clipped culprit vessel (Figure 4). Although no active extravasation was identified, glue embolization of the accessory splenic artery was performed, given it was the likely source of the recurrent bleed.\n\nFigure 3. The third esophagogastroduodenoscopy demonstrating the tortuous submucosal vessel with fibrin clot (left). Endoscopic clipping of the suspected source of bleed (right).\n\nFigure 4. Accessory splenic artery (left) demonstrated coursing adjacent to the endoscopic clips. Digitally subtracted angiogram of the conventional splenic artery (right) confirming course.\n\nAfter the procedure, the patient did well clinically with no further bleeding. Considering the lack of data, the risk of recurrent bleeding with this anomaly remains largely unknown. As such, he was advised permanent cessation of nonsteroidal anti-inflammatory drugs and steroids. The patient continues to do well, without evidence of recurrent GI bleed.\n\nDISCUSSION\n\nMultiple variants in the origin and course of the splenic artery have been described in the literature, including aberrant origin from the aorta, common hepatic, left gastric, and superior mesenteric arteries. An intrahepatic and intrapancreatic courses, as well as congenital absence or total duplication of the splenic artery, have also been described.5–7 There is, however, a paucity of data regarding accessory splenic arteries.\n\nThe presence of an accessory splenic artery is rare, and its presentation as an upper GI bleed has only been described twice previously in the literature. Our case describes a GI bleed consequent of a submucosal accessory splenic artery arising as a branch of the left phrenic artery. This large caliber artery does not meet the criteria to be classified as a Dieulafoy lesion, which is defined as a prominent arteriole measuring 1-3 mm, without tapering and coursing through the submucosa.8 Previous case reports by Kervancioglu et al and Patel and Lowe have both described an accessory splenic artery arising from the left gastric artery and presenting as a gastric bleed.4,5 Cadaveric dissections have also demonstrated the presence of accessory splenic arteries. Padmalath et al reported an accessory splenic artery in a cadaver, arising from the left gastroepiploic artery.9 From our literature review, accessory splenic arteries have not been described as part of congenital syndromes or known to exist specifically with other anomalies.\n\nOur patient ultimately underwent angiographic embolization of the accessory splenic artery due to recurrent bleeding. The available surgical option was more complicated and cumbersome because it involves splenectomy with partial gastrectomy. As such, the lesser invasive option, endovascular embolization, was the preferred modality. After the procedure, the patient was discharged on day 3. The patient continues to do well and remains asymptomatic. Vascular anatomic variants can pose a challenge to treatment, especially when they are unknown. This case adds to the currently limited number of case reports involving accessory splenic arteries.\n\nDISCLOSURES\n\nAuthor contributions: P. Patel and P. Chadalavada wrote this manuscript. A. Singh provided the endoscopy images. RK Gurajala approved the final manuscript. J-P Achkar revised the manuscript for intellectual content. P. Patel is the article guarantor.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n\n1. Kurien M Lobo AJ . Acute upper gastrointestinal bleeding. Clin Med (Lond). 2015;15 (5 ):481–5.26430191\n2. Kichler A Jang S . Endoscopic hemostasis for non-variceal upper gastrointestinal bleeding: New frontiers. Clin Endosc. 2019;52 (5 ):401–6.31309768\n3. Kumar N Patil J Swamy RS Guru A Nayak SB . Atypical arterial supply to the spleen by polar branches of splenic artery and accessory splenic artery—A case report. J Clin Diagn Res. 2014;8 (8 ):AD03–4.\n4. Kervancioglu S Yilmaz FG Gulsen M Kervancioglu P Kervancioglu R . Massive upper gastrointestinal bleeding from an accessory splenic artery mimicking isolated gastric varices. Folia Morphol (Warsz). 2013;72 (4 ):366–70.24402761\n5. Patel SR Lowe S . Accessory splenic artery: A rare cause of upper gastrointestinal bleeding. Cardiovasc Intervent Radiol. 2017;40 :1115–7.28154918\n6. Pandey SK Bhattacharya S Mishra RN Shukla VK . Anatomical variations of the splenic artery and its clinical implications. Clin Anat. 2004;17 (6 ):497–502.15300870\n7. Sverdén E Markar SR Agreus L Lagergren J . Acute upper gastrointestinal bleeding. BMJ. 2018;363 :k4023.30361444\n8. Baxter M Aly EH . Dieulafoy's lesion: Current trends in diagnosis and management. Ann R Coll Surg Engl. 2010;92 (7 ):548–54.20883603\n9. Padmalath K Ramesh BR Prakash BS Balachandra N Mamatha Y . Accessory splenic artery from left gastroepiploic artery. Intern J Anatomic Variat. 2010;3 :106–7.\n\n",
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"title": "Accessory Splenic Artery Causing Massive Gastrointestinal Bleed.",
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"abstract": "The introduction of immune checkpoint inhibitors has demonstrated significant improvements in survival for subsets of cancer patients. However, they carry significant and sometimes life-threatening toxicities. Prompt prediction and monitoring of immune toxicities have the potential to maximise the benefits of immune checkpoint therapy. Herein, we develop a digital nanopillar SERS platform that achieves real-time single cytokine counting and enables dynamic tracking of immune toxicities in cancer patients receiving immune checkpoint inhibitor treatment - broader applications are anticipated in other disease indications. By analysing four prospective cytokine biomarkers that initiate inflammatory responses, the digital nanopillar SERS assay achieves both highly specific and highly sensitive cytokine detection down to attomolar level. Significantly, we report the capability of the assay to longitudinally monitor 10 melanoma patients during immune inhibitor blockade treatment. Here, we show that elevated cytokine concentrations predict for higher risk of developing severe immune toxicities in our pilot cohort of patients.",
"affiliations": "Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD, Australia.;Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD, Australia. a.wuethrich@uq.edu.au.;Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD, Australia.;Centre for Microscopy and Microanalysis, The University of Queensland, Brisbane, QLD, Australia.;Department of Molecular Sciences, ARC Centre of Excellence for Nanoscale BioPhotonics, Faculty of Science and Engineering, Macquarie University, Sydney, NSW, Australia. yuling.wang@mq.edu.au.;Oliva Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia.;Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD, Australia.;Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD, Australia. m.trau@uq.edu.au.",
"authors": "Li|Junrong|J|0000-0002-3777-2245;Wuethrich|Alain|A|0000-0001-9569-0478;Sina|Abu A I|AAI|0000-0001-8099-3863;Cheng|Han-Hao|HH|0000-0002-4663-5111;Wang|Yuling|Y|0000-0003-3627-7397;Behren|Andreas|A|0000-0001-5329-280X;Mainwaring|Paul N|PN|;Trau|Matt|M|0000-0001-5516-1280",
"chemical_list": "D054428:Chemokine CX3CL1; D016207:Cytokines; D000082082:Immune Checkpoint Inhibitors; D000074324:Ipilimumab; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor",
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"doi": "10.1038/s41467-021-21431-w",
"fulltext": "\n==== Front\nNat Commun\nNat Commun\nNature Communications\n2041-1723 Nature Publishing Group UK London \n\n21431\n10.1038/s41467-021-21431-w\nArticle\nA digital single-molecule nanopillar SERS platform for predicting and monitoring immune toxicities in immunotherapy\nhttp://orcid.org/0000-0002-3777-2245Li Junrong 1 http://orcid.org/0000-0001-9569-0478Wuethrich Alain a.wuethrich@uq.edu.au 1 http://orcid.org/0000-0001-8099-3863Sina Abu A. I. 1 http://orcid.org/0000-0002-4663-5111Cheng Han-Hao 2 http://orcid.org/0000-0003-3627-7397Wang Yuling yuling.wang@mq.edu.au 3 http://orcid.org/0000-0001-5329-280XBehren Andreas 45 Mainwaring Paul N. 1 http://orcid.org/0000-0001-5516-1280Trau Matt m.trau@uq.edu.au 16 1 grid.1003.20000 0000 9320 7537Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD Australia \n2 grid.1003.20000 0000 9320 7537Centre for Microscopy and Microanalysis, The University of Queensland, Brisbane, QLD Australia \n3 grid.1004.50000 0001 2158 5405Department of Molecular Sciences, ARC Centre of Excellence for Nanoscale BioPhotonics, Faculty of Science and Engineering, Macquarie University, Sydney, NSW Australia \n4 grid.1018.80000 0001 2342 0938Oliva Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Heidelberg, VIC Australia \n5 grid.1008.90000 0001 2179 088XDepartment of Medicine, University of Melbourne, Heidelberg, VIC Australia \n6 grid.1003.20000 0000 9320 7537School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD Australia \n17 2 2021 \n17 2 2021 \n2021 \n12 108727 5 2020 15 1 2021 © The Author(s) 2021Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.The introduction of immune checkpoint inhibitors has demonstrated significant improvements in survival for subsets of cancer patients. However, they carry significant and sometimes life-threatening toxicities. Prompt prediction and monitoring of immune toxicities have the potential to maximise the benefits of immune checkpoint therapy. Herein, we develop a digital nanopillar SERS platform that achieves real-time single cytokine counting and enables dynamic tracking of immune toxicities in cancer patients receiving immune checkpoint inhibitor treatment - broader applications are anticipated in other disease indications. By analysing four prospective cytokine biomarkers that initiate inflammatory responses, the digital nanopillar SERS assay achieves both highly specific and highly sensitive cytokine detection down to attomolar level. Significantly, we report the capability of the assay to longitudinally monitor 10 melanoma patients during immune inhibitor blockade treatment. Here, we show that elevated cytokine concentrations predict for higher risk of developing severe immune toxicities in our pilot cohort of patients.\n\nThere is a clinical need to monitor immune-related toxicities of immune checkpoint blockade therapy. Here, the authors develop a digital SERS platform for multiplexed single cytokine counting to track immune-toxicities and demonstrate the ability to use pre-screening to identify patients at higher risk.\n\nSubject terms\nNanobiotechnologyCancer immunotherapyStructural propertiesRaman spectroscopyhttps://doi.org/10.13039/501100000925Department of Health | National Health and Medical Research Council (NHMRC)APP1173669Wuethrich Alain issue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\nThe advent of immune checkpoint therapy has revolutionised the landscape of traditional cancer treatment and is believed to constitute the backbone of managing certain malignancies1–3. By capitalising on the blockade of immune checkpoint inhibitors to take the brakes off parts of the immune system, this emerging therapy has achieved great success producing long-lasting responses (e.g., 10 years or more) in a small but significant fraction of patients3–6. Nevertheless, upon the blockade of immune checkpoint molecules, the activated and potentiated immune reaction predisposes patients to a significant risk of immune-related adverse events (irAEs), which can occur in up to 80% of patients receiving immune checkpoint therapy7–9. The high incidence of irAEs, which may manifest at any time during treatment, can offset the clinical benefits, lead to premature therapy cessation, and even be life-threatening for certain patients10–12. To assist the successful implementation of immune checkpoint therapy, the use of predictive biomarkers for early identification and vigilant monitoring of irAEs is thus critical and a pressing need in avoiding or ameliorating detrimental effects and adjusting therapeutic options.\n\nCytokines, small signalling proteins, are promising candidates to indicate the occurrence of irAEs due to their prominent role in modulating the anti-cancer immune responses, including enhancing antigen priming, recruiting immune cells into the tumour microenvironment, and upregulating certain immune checkpoint molecules9,13,14. Particularly, excessive cytokine secretion has been implicated in severe inflammation as a major constituent leading to irAEs. For example, the overproduction of fibroblast growth factor 2 (FGF-2)15–18, granulocyte colony-stimulating factor (G-CSF)19, granulocyte-macrophage colony-stimulating factor (GM-CSF)20, and fractalkine (CX3CL1)21 have been found to participate in immune-related inflammatory disease (e.g., rheumatoid arthritis, autoimmune gastritis, and Crohn’s disease). These inflammatory cytokines have recently been reported to indicate irAEs for melanoma patients who underwent immune checkpoint therapy9. The clinical deployment of cytokine analysis for irAE monitoring is challenging and requires a technology that can (i) determine the selected cytokines with great sensitivity9, especially at the onset of irAE development, where the cytokine concentrations are likely to be the lowest; as well as (ii) simultaneously detect a panel of cytokines to reflect the complex interplay of cytokine signalling pathways22 and the variable irAE symptoms among patients.\n\nConventional cytokine analyses such as immunosorbent assays have limited clinical applicability for irAE assessment due to their limited capacity to detect low cytokine concentrations in blood as well as for assessing a panel of cytokines in a single sample simultaneously. Recently, advances in micro/nanomaterial-based systems have provided a promising suite of technologies that improve the conventional assays by overcoming the above limitations23,24. Encouragingly, the unique advantages of micro/nanomaterial-based systems convey an attractive option for cytokine analysis with the desired results of high sensitivity and multiplexing. The high specific surface area of these miniaturised materials increases mass transfer subsequently enhancing the interaction with target molecules and thus improving the detection sensitivity25. The capabilities of micro/nanomaterial fabrication techniques permit individually separated compartments sufficiently discrete to hold single molecules and hence encompasses a promising strategy for counting assays that can further push the sensitivity of the traditional assays24,26,27. Moreover, the physicochemical properties of nanostructured materials can be exploited to simultaneously label multiple targets (e.g., various spectral signatures) for high-throughput parallel measurements28–30. Therefore, by combining the potential of micro/nanomaterial systems with the need for sensitive irAE monitoring, we have developed a platform for sensitive and multiplex cytokine counting analysis.\n\nCombining the use of (a) discrete single cytokine nanopillar array chip with discretely separated compartments, (b) control of target concentrations to follow a Poisson distribution, and (c) the recognition of target by single-particle active surface-enhanced Raman scattering (SERS) nanotags with a confocal Raman microscope allows accurate and in situ counting of a multi-cytokine panel (FGF-2, G-CSF, GM-CSF, and CX3CL1). Different from the fluorescence-based digital counting strategies24,26, the strikingly narrow spectral peaks of SERS (~1–2 nm) in comparison to fluorescence (~50 nm) makes this platform intrinsically ideal for multiplexed cytokine analysis28.\n\nIn this work, we present a digital nanopillar SERS platform that enables the specific cytokine quantification down to attomolar levels and the application in melanoma patients receiving immune checkpoint blockade therapy. Beyond the capability to predict irAEs in melanoma patients receiving therapy, the digital nanopillar SERS assay could potentially be extended to other cytokine-associated immune responses such as excessive immune activation due to viral or bacterial infections (such as COVID-19).\n\nResults\nDigital nanopillar SERS platform for parallel profiling of single cytokine\nOur concept of digital nanopillar SERS platform for cytokine analysis relies on Rayleigh criterion separation, probability-driven Poisson distribution, single-particle active SERS nanotags, and confocal SERS mapping (Fig. 1). To precisely fabricate the pillar array, we opted to use an electron beam lithographic approach to write the array into a photon-sensitive material followed by physical vapour deposition of gold to create the gold-topped pillars, and selectively reactive ion etching to reveal the pillar structure (Supplementary Fig. 1). The nanopillar array chip consisted of 250,000 individual pillars. As shown in the scanning electron microscope (SEM) image of Fig. 1a, the cubic nanopillars have an edge-to-edge width of 1000 nm and are evenly distributed at 1000 nm intervals to suit the lateral Raman microscope resolution (~1000 nm) that fulfils the Rayleigh criterion separation required to acquire a single SERS spectrum from each pillar without spectral overlap from adjacent pillars.Fig. 1 Digital single-molecule nanopillar surface-enhanced Raman scattering (SERS) platform for parallel counting of four types of cytokines.\nSEM images of a pillar array side view, b nanoboxes, and c a single nanobox on the top of a pillar; d SERS spectra of nanoboxes conjugated with 5,5-dithiobis (2-nitrobenzoic acid) (DTNB), 4-mercaptobenzoic acid (MBA), 2,3,5,6-tetrafluoro-4-mercaptobenzoic acid (TFMBA), or 2‐mercapto‐4‐methyl‐5‐thiazoleacetic acid (MMTAA) Raman reporters; e workflow for multiplex counting of cytokines, including fibroblast growth factor 2 (FGF-2), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and fractalkine (CX3CL1). Data from one independent experiment.\n\n\n\nBy using specific gold-thiol chemistry with the linker molecule dithiobis (succinimidyl propionate) (DSP), the gold-topped pillars were selectively functionalised with target recognition antibodies (anti-FGF-2, anti-G-CSF, anti-GM-CSF, and anti-CX3CL1) and acted as the small compartments to capture and confine the individual cytokine. Upon DSP binding on the gold-topped pillars through gold-thiol bond, DSP uses N-hydroxysuccimide (NHS) ester to react with the amine groups of the antibodies31,32. The successful antibody conjugation on gold-topped pillar surfaces was confirmed by matrix-assisted laser desorption ionisation-time of flight mass spectrometry (MALDI-TOF MS) (Supplementary Fig. 2), which showed high molecular weight fragments derived from antibodies. Furthermore, spectroscopic ellipsometry was utilised to estimate the antibody density on pillar surfaces. Based on the obtained film thickness of 18.5 nm, the calculated antibody surface density was 5.5 mg/m2 using the Cuypers model33, which was in agreement with the reported antibody density on substrate surfaces34. Though these characterisations indicated the presence of antibodies on the pillar array, it was not possible to assess the exact distribution of the four structurally related (same immunoglobulin G family) antibodies on a single pillar with an area of 1 µm2. As an advantage of the digital read-out with a large redundancy of pillars, it is not essential to have all four types of antibodies equally distributed on a single pillar for the assay to work. The combined surface area of all antibody-conjugated pillars provides an excess of cytokine binding sites, which maximises successful cytokine capture within the pillar array. Supplementary Fig. 3 shows the SERS mapping images of an equimolar cytokine solution (1031 aM) that provided a similar signal count for the FGF-2, GM-CSF, G-CSF, and CX3CL1 SERS nanotags, indicating a required distribution of four kinds of antibodies conjugated to the array of pillars. Instrumental to the digital counting of cytokines, we controlled the target concentration based on the principle of Poisson distribution where the ratio of cytokine molecules to pillar number was <1:10, ensuring a 99% probability that there was either one cytokine molecule or zero per pillar24. At a ratio of 1:10, 10% of all pillars were occupied or activated with the cytokine molecules.\n\nFollowing the capture of cytokines on nanopillars, SERS nanotags were applied to recognise the captured cytokines. The preparation of SERS nanotags was performed by the co-conjugating of Raman reporter and target antibody onto gold–silver alloy nanoboxes. Specifically, an average size of 80 nm gold–silver alloy nanoboxes were firstly synthesised using a rapid and aqueous phase approach35 as indicated in the SEM image in Fig. 1b. Supplementary Fig. 4a, b shows the transmission electron microscope (TEM) image of the nanoboxes with the hollow inner structure and a wall thickness of around 15 nm. Nanoparticle tracking analysis (NTA), which allows the tracking and detection of single particles, shows the nanoboxes have a mode size of 77 nm (D10 = 67.6 nm and D90 = 110.6 nm) (Supplementary Fig. 4c). UV-vis extinction spectroscopy demonstrates the nanoboxes possess a surface plasmon resonance (SPR) peak at 610 nm (Supplementary Fig. 4d). The resonance frequency of the nanoboxes enables a more sensitive signal readout with 632.8 nm laser excitation29, which also has a higher Raman scattering efficiency than 785 nm laser. Thereafter, four types of Raman reporters (5,5-dithiobis (2-nitrobenzoic acid) (DTNB), 4-mercaptobenzoic acid (MBA), 2,3,5,6-tetrafluoro-4-mercaptobenzoic acid (TFMBA), and 2‐mercapto‐4‐methyl‐5‐thiazoleacetic acid (MMTAA)) that generate unique Raman signals (1330 cm−1, 1080 cm−1, 1380 cm−1, and 1288 cm−1) were coupled with their corresponding detection antibodies onto nanoboxes as specific SERS nanotags for identification of FGF-2, G-CSF, GM-CSF, and CX3CL1, respectively. As shown in Fig. 1d, the four SERS nanotags provide the strong and non-overlapping Raman signals, which facilitates the multiplexing analysis of four cytokines. The assignment of the major Raman peaks from the four Raman reporters was summarised into Supplementary Table 1. To evaluate the SERS enhancement property of the nanoboxes, we calculated the enhancement factor (EF) of the four Raman reporters on the nanoboxes. Based on the labelled characteristic peaks in Supplementary Fig. 5, the calculated EFs of DTNB, MBA, TFMBA, and MMTAA were 8.14 × 106, 1.46 × 107, 4.01 × 107, and 3.26 × 107, respectively. The obtained EFs were higher than the reported spherical gold nanoparticles and pure silver nanocubes36 and comparable to the reported hollow nanocubes37, illustrating the high SERS property of the nanoboxes. To investigate the SERS nanotag stability, we monitored the Raman signal intensity over 7 days. As shown in Supplementary Fig. 6, Raman signal intensity variations are less than 5% in the SERS spectra, suggesting the good stability of the prepared SERS nanotags.\n\nThe following SERS mapping generated false-colour images for counting single cytokine molecules. Under the Raman microscope, the pillar array was visualised as a blue and black grid by representing the specific Raman shifts corresponding to the silicon signals (520 cm−1), in which the blue colour was assigned to silicon signals showing silicon substrates and the black colour indicated the gold-topped pillars because of the lack of silicon signals. The representation of the four colours of the SERS nanotags (red, green, purple, and cyan) on the gold-topped pillars (i.e., black) reflected cytokine molecule occupation (FGF-2, G-CSF, GM-CSF, and CX3CL1). Elevating the sensing area (or gold-topped pillars) from the silicon substrate was selected as a strategy to minimise the false-positive events. By using the confocal function of the Raman microscope, the laser was selectively focused on the gold-topped pillars, thus largely removing the background signals from potentially non-specifically adsorbed SERS nanotags on the silicon substrate. Finally, the specific SERS nanotag signals present or absent on the gold-topped pillars were counted and represented as percentage of active pillars used for total cytokine quantification. For statistical calculations, SERS mapping was applied for scanning 6480 pillars. This digital counting mode, therefore, has the potential to reach the ultimate sensitivity of single molecule cytokine detection.\n\nDemonstration of the single-particle SERS activity of gold–silver alloy nanoboxes\nThe successful implementation of digital nanopillar SERS assay necessitates the use of single-particle active plasmonic nanostructures that give a clearly detectable signal for each of the single cytokine binding event. The single-particle SERS detection sensitivity is essential to this assay development as the single-particle inactive plasmonic nanoparticles (e.g., spherical gold nanoparticles)38 would unavoidably result in an underestimate of cytokine concentration.\n\nWe evaluated the single-particle SERS activity of the prepared anisotropic nanoboxes by acquiring the signals from the individual nanoboxes that were labelled with DTNB reporters. The use of DTNB, a non-resonant Raman reporter, guaranteed the Raman signal enhancement was solely contributed from the nanobox-generated electromagnetic field. As seen in the SEM image (Fig. 2a), two clearly separated DTNB-labelled nanoboxes were deposited on the silicon wafer (highlighted in red circles). The corresponding Raman image (Fig. 2b) displayed several bright Raman spots originating from these individual nanoboxes. The elongated bright Raman spots in the SERS mapping image were probably caused by the slight aggregation of several nanoboxes during sample preparation processes (e.g., centrifugation)38, which was difficult to visually resolve in the SEM image (Fig. 2a). However, unlike the intensity-based assay, the aggregated nanoboxes as SERS nanotags to target cytokine will not skew the digital readout result, because each cytokine will occupy a single pillar following Poisson distribution and both aggregated and individual nanoparticles are regarded as a single binding event that truly reflects the target number39. We then acquired the SERS spectra from two individual SERS nanoboxes (Fig. 2c, (1) and (2)) and two separate spots of bare silicon (Fig. 2c, (3) and (4)). The presence of nanoboxes showed the characteristic Raman signal at 1330 cm−1 from DTNB, whereas the silicon spectra (3) and (4) lacked the specific peak. This observation demonstrated the single-particle SERS activity of nanoboxes, which was largely attributed to the enhanced electromagnetic fields of nanoboxes on specific regions (e.g., tips and corners)40,41 and thereby facilitated the sensitive and accurate counting of cytokines. Based on the acquired SERS mapping image, the median (interquartile range) of the DTNB peak intensity (1330 cm−1) in the presence and absence of nanoboxes were 183.03 a.u. (149.48–243.35 a.u.) and 18.07 a.u. (15.51–23.12 a.u.), respectively. Furthermore, the mean ± standard deviation of the DTNB peak intensity with nanoboxes (213.41 ± 85.03 a.u.) distinguished clearly from the position without nanoboxes (18.79 ± 6.01 a.u.), which demonstrated the feasibility of correctly identifying the presence of nanoboxes.Fig. 2 Demonstration of the single-particle SERS activity of DTNB-labelled nanoboxes.\na SEM image and b corresponding SERS mapping image of DTNB-labelled nanoboxes on a silicon substrate; c representative SERS spectra of numbered locations indicated in a and b. The red dotted line shows the characteristic peak at 1330 cm−1 from DTNB. Data from one independent experiment. Source data are provided in the Source Data file.\n\nFig. 3 Study of confocal height on Raman signal intensity.\nSERS mapping of FGF-2 SERS nanotags on the silicon substrate with changing confocal height of a 0 nm, b 500 nm, c 1000 nm, and d 1500 nm; selected Raman spectra obtained from e red circles and f blue circles of SERS images. Red dotted lines in e and f indicate peak signal at 1330 cm−1 from DTNB. Data from one independent experiment. Source data are provided in the Source Data file.\n\nFig. 4 Specificity of digital nanopillar SERS platform for FGF-2 cytokine detection.\nRepresentative confocal SERS images in the presence of a target FGF-2 (1031 aM), and negative controls with non-target controls b G-CSF (1031 aM), c GM-CSF (1031 aM), d CX3CL1 (1031 aM), and e PBS. The median (interquartile range) of active pillars per scanning image for FGF-2, G-CSF, GM-CSF, CX3CL1, and PBS was 72 (63.5–76.75), 1.5 (1.5–2), 2 (1–4), 0.5 (0–1.25), and 1 (1–1.75), respectively. Data from one independent experiment.\n\n\n\nOptimisation of digital nanopillar SERS platform for cytokine detection\nThe reliable detection of single cytokine molecules by the digital nanopillar SERS platform depends on the geometric features of the pillar array (i.e., pillar height, cross-section area of pillar) and assay conditions (i.e., incubation time for sample and SERS nanotags).\n\nWe first sought to investigate the effect of pillar height on Raman signal intensity to differentiate signals from non-specifically bound SERS nanotags on the silicon substrate and specifically bound SERS nanotags on the gold-topped pillars. FGF-2 SERS nanotags were randomly deposited on the silicon substrate to mimic the non-specific binding scenario and the Raman mappings were perfomed by moving the objective along the z-axis direction with different heights (0 nm, 500 nm, 1000 nm, and 1500 nm) to compare the signal intensity. In Fig. 3, a–d show the false-colour SERS images and e, f the corresponding SERS spectra with characteristic DTNB reporter peak at 1330 cm−1 acquired from the circled spots in a–d. At the height of 0 nm where the SERS nanotags were in focus, we noticed bright Raman spots (Fig. 3a) and strong Raman signals (black line in Fig. 3e, f). With increasing z heights to 500 nm and 1000 nm, the Raman spots decreased (Fig. 3b, c) and the signal intensity weakened/disappeared (red and blue lines in Fig. 3e, f) as the nanoboxes became increasingly out of focus. A further increase to 1500 nm did not remarkably weaken Raman signals compared to the height of 1000 nm (Fig. 3d). Hence, for the fabrication of the pillar array chip, we selected a pillar height of 1000 nm to greatly reduce the potential interference from non-specific signals.\n\nThe cross-section area of the pillars provides the space for cytokine binding and labelling with SERS nanotags. To study the effect of pillar cross-section area, we fabricated array chips with pillars of various widths (250 nm, 500 nm, and 1000 nm) (Supplementary Fig. 7a–c) and functionalised with anti-FGF-2 antibody. Each chip consisted of 250,000 individual pillars. We then analysed a sample that contained ~25,000 molecules of FGF-2 (40 µL, 1031 aM), which should result in 10% active pillars (ratio FGF-2: pillars of 0.1). As seen in Supplementary Fig. 7d–f, an increasing pillar cross-section area results in a higher fraction of active pillars. In reference to the expected active pillar percentage (10%), the 250 nm and 500 nm pillar arrays produced lower active pillars (2% and 6%), which suggested a significant loss of target recognition by SERS nanotags. For the 1000 nm wide pillars, the active pillar percentage was 11%, close to the nominal value of 10%. We further tested a sample with 260 aM FGF-2 (i.e., 2.5% active pillars) on the pillar array chips with 250, 500, and 1000 nm pillar widths. The capture efficiency of these three chips was summarised in Supplementary Table 2. In comparison to the pillar array of 250 nm and 500 nm sizes, the 1000 nm provided an improved capture efficiency. As the accessible target recognition surface area per pillar increases, it can possibly promote the thermodynamics and kinetics for higher surface binding and capture efficiency25. Consequently, the 1000 nm pillar array was adopted in the subsequent experiments.\n\nAn optimal incubation time of cytokine and SERS nanotags on the pillar array can shorten the operation time and reduce the potential risk of nonspecific binding that could lead to false-positive counting. We thus studied the effect of incubation time of cytokine with SERS nanotags for 30 to 90 min in a solution of 1031 aM FGF-2 and FGF-2 SERS nanotags. As suggested by Supplementary Fig. 8, the increase in incubation time gives rise to a higher proportion of active pillars. In comparison with the theoretical active pillar percentage (10%), both 30 min and 60 min incubation time were able to provide a desirable active pillar percentage (11% and 13%, respectively). A longer incubation time (90 min), however, reported an active pillar percentage (20%) two times higher than the theoretical, indicating the occurrence of nonspecific absorption of SERS nanotags on the pillar array chip. Thus, we selected 30 min incubation time for further digital nanopillar SERS measurements.\n\nSpecificity of the digital nanopillar SERS platform for cytokine detection\nAccurate and reliable recognition of the specific target is essential for cytokine quantification in clinical samples. To demonstrate the detection specificity of the digital nanopillar SERS assay, we prepared an anti-FGF-2 antibody functionalised pillar array and measured samples containing target FGF-2 cytokine and controls (G-CSF, GM-CSF, CX3CL1, and PBS). It was observed that only the presence of FGF-2 activated significant amounts of pillars whereas the negative controls only generated negligible active pillars (Fig. 4), indicating the high specificity for FGF-2 detection. Similarly, we studied the specific detection of G-CSF, GM-CSF, and CX3CL1, as shown in Supplementary Figs. 9–11, in which the typical Raman images displayed high proportions of active pillars in the presence of specific targets but not for the negative controls.\n\nTo further investigate the specificity of binding between SERS nanotag and antibody-functionalised pillar, we performed SEM analysis to “closely” inspect the pillar array for the presence or absence of SERS nanotags. As a representative model, we selected to image FGF-2 SERS nanotags on the anti-FGF-2-functionalised pillar array after sample incubation with FGF-2 cytokine and non-target controls (Fig. 5). As expected, we observed the cubic nanoparticles on the top of pillars in the presence of FGF-2 due to the successful recognition of SERS nanotags. On the contrary, pillar arrays did not display a significant number of FGF-2 SERS nanotags with non-target controls. Consequently, the consistent Raman and SEM data demonstrate the capability of the assay for specific target cytokine counting. The ability to selectively identify these four cytokines in the designed assay is critically important for their usage in clinical samples.Fig. 5 Specificity of the digital nanopillar SERS platform for FGF-2 cytokine detection.\nRepresentative SEM images of pillar array incubated with FGF-2 SERS nanotags in the presence of a, b FGF-2 (1031 aM), c G-CSF (1031 aM), d GM-CSF (1031 aM), e CX3CL1 (1031 aM), and f PBS. The red circles highlight the existence of SERS nanotags. Panel b is the magnified SEM image of the red-highlighted section in a. It is noted that nanofabrication debris on the sidewall of the pillars can also be seen. Data from one independent experiment.\n\n\n\nSensitivity of the digital nanopillar SERS platform for cytokine detection\nAs there is typically low abundance of cytokines in clinical samples, the technique based on cytokine detection is expected to possess sufficient sensitivity to reliably assess irAEs9. To investigate the sensitivity and dynamic detection range of the digital nanopillar SERS assay, we firstly titrated the designated concentration of one target cytokine (FGF-2) on the pillar array chip with 250,000 pillars. To comply with the Poisson distribution, the upper number of cytokine molecules in the sample is 25,000 which should result in 10% activated pillars. Based on this upper molecule number, we were motivated to challenge the assay by serially diluting the number of cytokine molecule in the sample from 25,000 (1031 aM), 6305 (260 aM), 631 (26 aM), and 63 (2.6 aM). As suggested by the Raman images in Supplementary Fig. 12 and with the decrease in FGF-2 molecules, the percentage of active pillars decreased correspondingly from 9.39% for 1031 aM, 6.59% for 260 aM, 1.12% for 26 aM, and 0.62% for 2.6 aM, showing a strong correlation that facilitates quantitative cytokine analysis.\n\nSubsequently, we were interested in exploring the multiplexing capability of SERS to investigate the digital nanopillar SERS assay’s dynamic range for the simultaneous quantification of all studied cytokines. As the targets independently follow Poisson distribution, each of the cytokine was separately controlled to activate less than 10% pillars. The specific SERS nanotags provided unique signals for each cytokine that was visualised in the false-colour SERS images by a different colour, thereby enabling in situ and simultaneous cytokine detection. As suggested by the confocal SERS images in Fig. 6, an increase in cytokine concentration corresponded with a higher percentage of active pillars. To facilitate quantitative measurements of the cytokines, we calculated the logarithmic transformation of the percentage of active pillars versus cytokine concentration (Supplementary Fig. 13) confirming the strong statistical and potentially clinically relevant correlation (coefficient of determination (R2) >0.97) observed in the SERS images.Fig. 6 Sensitivity for the simultaneous detection of four cytokines.\nRepresentative confocal SERS images of fibroblast growth factor 2 (FGF-2), granulocyte colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and fractalkine (CX3CL1) with the concentration of a 2.6 aM, b 26 aM, c 260 aM, d 1031 aM. Colour scale bars indicate Raman intensities from 5,5-dithiobis (2-nitrobenzoic acid) (DTNB), 4-mercaptobenzoic acid (MBA), 2,3,5,6-tetrafluoro-4-mercaptobenzoic acid (TFMBA), or 2‐mercapto‐4‐methyl‐5‐thiazoleacetic acid (MMTAA). The median (interquartile range) of active pillars per scanning image of FGF-2, G-CSF, GM-CSF, CX3CL1 for 2.6 aM: 3 (1.5–3), 1 (1–2), 2 (1–3), 2 (1–3); 26 aM: 8 (5.5–10), 10 (9–13), 7 (6–10), 8 (6–10); 260 aM: 40 (36–48), 40 (35–52), 39 (35–50), 37 (36–49); and 1031 aM: 79 (61.5–97), 78 (72–87.5), 88 (68.5–97), 79 (64–95), respectively. Data represents one experiment from three independent tests.\n\n\n\nTo further investigate the multiplexing quantification performance of the digital nanopillar SERS assay in human serum, we spiked standard cytokines in human serum and tested the dynamic range. Supplementary Fig. 14 shows the linear relationship curves for the four targets. Because of the more complicated sample matrix composition in human samples, the lowest detectable cytokine concentration (5.2 aM) was higher than the PBS solution (2.6 aM).\n\nAt a cytokine to pillar ratio of 1:10, we studied the probability of each pillar being occupied by different molecule numbers. To experimentally investigate the number of molecules on a single pillar, we analysed a cytokine mixture that contained all four target cytokines at equal concentration (i.e., ~6250 molecules per cytokine). To visualise and count molecule binding events on a single pillar, we labelled the captured cytokines with the four SERS nanotags that provide clearly distinguishable signals. Under Poisson distribution, the likelihood of having two or more molecules on a single pillar is <0.45% (Supplementary Table 3), which underlies the digital counting principle24. Compared to the theoretical Poisson distribution, the experiment data reported a close but slightly higher value, which was probably due to minor non-specific binding of SERS nanotags on the pillars.\n\nThe high sensitivity (attomolar level) of the digital nanopillar SERS assay can be ascribed to the following factors: the digital counting strategy, the single-particle SERS activity of the nanoboxes, and the use of pillars to suit confocal Raman mapping that efficiently excludes false-positive signals. Commercially available methods with potential for trace analysis of cytokines include the single-molecule ELISA Simona by Quanterix and electrochemical luminescence assay42,43 by Meso Scale Discovery. Compared to these two methods, the developed digital nanopillar SERS platform enabled in situ multiplexed detection of four cytokines with comparable sensitivity. Unlike the issues of photo bleaching and poor multiplexing analysis often encountered in fluorescence44 and luminescence assays45, SERS provides the advantage of high multiplexing (e.g., 31-plex)46–48 with the narrow Raman linewidth and high photo stability of the Raman reporters. In addition, this digital nanopillar SERS platform can provide more accurate quantification of cytokines by reducing the false-positive signals with the confocal setting, thus eventually help clinicians to monitor irAEs during immune checkpoint therapy. The highly sensitive readout for multiple targets also indicated the capability of this assay for cytokine detection to assess irAEs in clinically relevant samples.\n\nEvaluation of digital nanopillar SERS platform on simulated patient samples\nThe detection of trace concentrations of cytokines in serum samples is difficult because plasma samples contain a high abundance of non-target molecules (e.g., serum albumin and other proteins) that can potentially interfere with cytokine detection and lead to inaccurate clinical results. To evaluate the capability of the digital nanopillar SERS assay in accurately counting single cytokine molecules, we opted to perform a recovery test in simulated patient plasma samples (i.e., healthy human serum spiked with 1 fM of FGF-2, G-CSF, GM-CSF, and CX3CL1). The rapid scan rate (i.e., 0.05 s for Raman signal integration) facilitated the detection of Raman signals from FGF-2, G-CSF, GM-CSF, and CX3CL1 SERS nanotags rather than the non-target molecules present in human serum due to their low Raman cross-section. As a representative example, Supplementary Fig. 15 shows the Raman signal distribution of the FGF-2 SERS nanotags on five different spots on the pillar array obtained from the recovery test without noticeable Raman signals from other molecules. It is worth noting that unlike the solution-based DTNB labelled SERS nanotag spectra in Fig. 1d, some of the peaks at 1556 cm−1 and 1330 cm−1 in Supplementary Fig. 15 had a similar intensity, which was probably because of the different orientation of the anisotropic nanoboxes on the substrate relative to the polarisation of excitation laser49. Supplementary Tables 4 and 5 show the cytokine concentrations in healthy human serum and human serum spiked with 1 fM cytokine standards determined by digital nanopillar SERS platform, respectively. On five independent pillar arrays, the measured concentrations had the relative standard deviation (RSD) below 9.0% and the Kruskal–Wallis test showed no statistical differences among these results (p » 0.05). Overall, the observed inter-chip variation should enable accurate identification of disease progression to severe irAEs (e.g., grade 3 or 4), but may encounter some challenges in discriminating mild progressing to moderate irAEs (e.g., grade 1 or 2). The assay enabled trace determination of the four targets in simulated human serum as suggested by the target recovery rates of 80.00% to 137.00% with RSD from 16.02% to 21.80% (Supplementary Table 6). Importantly, the ability to measure reliably cytokines at attomolar levels in simulated human serum samples holds promise for detecting early changes in cytokine concentrations as predictors for the emergence of irAEs in immune checkpoint blockade treated patients.\n\nTo validate the accuracy of the digital nanopillar SERS assay, we compared the assay with commercially available ELISA kits (one kit for each cytokine tested) for cytokine quantification. To represent a potential clinical scenario of a patient developing irAEs during immune checkpoint blockade therapy, we prepared three samples with increasing concentrations of cytokines (spike in experiments into fetal bovine serum (FBS)) and subsequently analysed these samples with our digital nanopillar SERS assay and the commercial ELISA kits. FBS was used as complex sample matrix devoid of human cytokines. As the limits of detection for the ELISA kits (FGF-2 = 0.95 pM, G-CSF = 1.66 pM, GM-CSF = 1.11 pM, and CX3CL1 = 17.86 pM) were above the attomolar level, the simulated samples were prepared to suit the detection range of these kits. For the digital nanopillar SERS assay, the samples were diluted correspondingly and generated consistent results with the ELISA kits as shown in Supplementary Table 7. No statistical differences were found between ELISA and digital nanopillar SERS results based on Mann–Whitney test. Furthermore, we compared the detection of four cytokines in human serum with digital nanopillar assay and ELISA kits (Supplementary Table 8). The cytokine levels in human serum were below the limit of detection for the conventional ELISA kits, whereas their concentration was quantified by digital nanopillar SERS platform. For the human serum spiked with standard cytokines, the digital SERS platform generated similar results to ELISA without significant differences by Mann–Whitney test. Collectively, the digital nanopillar SERS platform showcased the ability to robustly and accurately quantify cytokines in complicated samples, which is significant for the prospect of dynamic correlation monitoring of irAEs in clinical samples.\n\nFollowing the demonstration of the accuracy of digital nanopillar SERS platform, we tested the four cytokine levels in ten healthy people (Supplementary Table 9). These ten healthy people showed cytokine concentrations beyond the conventional ELISA capability to accurately quantify, which was consistent with previous reports9,50,51.\n\nDynamic correlation monitoring of irAEs in melanoma patients receiving immune checkpoint blockade treatment\nHaving established the feasibility of digital nanopillar SERS in simulated clinical samples, we applied the platform for longitudinally monitoring irAEs in ten melanoma patients (2–3 time points per patient, 26 samples in total) who underwent immune checkpoint blockade therapy (Supplementary Table 10). By diluting the patient samples to follow Poisson distribution, we quantified the cytokine concentration using digital nanopillar SERS platform. Based on the clinical assessments, the patients were classified into two categories: (i) developed severe irAEs (grades 3 and 4) and needed hospitalisation and dedicated treatment (Patients 1, 2, 3, 4, 5); and (ii) developed minor irAEs (grades 1 and 2) that could be managed with immunosuppressants (e.g., corticosteroids) or exhibited no symptom of irAEs (Patients 6, 7, 8, 9, 10).\n\nAs a representative case, Fig. 7 shows two cytokine profiles of a patient with severe irAEs (Patient 1) and a patient with mild irAEs (Patient 1). For Patient 1 who received ipilimumab (cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor) and was checked on days 7, 21, and 42, the confocal SERS images showed an increase in active pillars with the continuation of treatment (Fig. 7a–c), suggesting an elevation of the cytokine levels that could potentially trigger the severe irAEs. In agreement with the Raman images, the quantitative counting results for the four cytokines also corroborated the increase of cytokine concentrations peaking in sub-fM levels (Fig. 7d). These cytokine levels were below the limit of detection of conventional ELISA kits (pM level). Importantly, we observed significantly elevated cytokine concentrations in Patient 1 serum on day 42 compared to days 7 and 21. This patient showed the onset of grade 4 irAEs (i.e., colitis) 13 days later (day 55), consistent with the concept that higher cytokine levels correlate with increased risk of developing irAEs9. To further evaluate the utility of these four biomarkers as a signature in identifying and characterising irAEs, we analysed all the counting data from Patient 1 by applying linear discriminant analysis (LDA). As seen in Fig. 7e, the LDA successfully distinguished the data on day 42 into a separate zone from days 7 and 21, which may indicate the potential value of biomarkers in monitoring irAEs development. We further demonstrated Patient 1 LDA with the use of all combinations of two (Supplementary Fig. 16) and three cytokines (Supplementary Fig. 17). Overall, the LDA with four cytokines showed improved classification over using three or less cytokines. Interestingly, considering FGF-2/G-CSF, G-CSF/GM-CSF, and G-CSF/CX3CL1, the LDA generated similar performance to the LDA with four cytokines. To further compare the classification power of FGF-2/G-CSF, G-CSF/GM-CSF, and G-CSF/CX3CL1, and four cytokines, we performed LDA of Patient 2 (Supplementary Fig. 18), which suggested a better differentiation with the use of four cytokines. Therefore, the inclusion of all four cytokines in LDA facilitated a wider and more accurate patient sample analysis. Similarly, Patients 2, 3, 4, and 5, who manifested severe irAEs were connected with higher cytokine levels (Supplementary Fig. 19) and amelioration of irAEs symptom was witnessed with a decrease of cytokine concentrations. For these severe irAEs patients, the LDA model showed a clear discrimination in cytokine profile and this could help to identify patients at risk of irAEs (Supplementary Fig. 19).Fig. 7 Digital nanopillar SERS assay for monitoring melanoma patients during immune checkpoint therapy.\nFor Patient 1 who developed severe irAEs, SERS images for cytokine detection on a day 7, b day 21, c day 42, d cytokine concentration graph for fibroblast growth factor 2 (FGF-2), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and fractalkine (CX3CL1). The two shorter horizontal lines denote the interquartile ranges (25th and 75th percentile) and the longer horizontal lines in between denote the median (50th percentile), and e LDA analysis, respectively. For Patient 6 who developed mild irAEs, SERS images for cytokine detection on f day 0, g day 21, h day 42, i four cytokine concentration graph, the two shorter horizontal lines denote the interquartile ranges (25th and 75th percentile) and the longer horizontal lines in between denote the median (50th percentile), and j LDA analysis, respectively. IPI ipilimumab, PEMBRO pembrolizumab; G3 grade 3, G2 grade 2; SD stable disease, PR partial response. For Patient 1, the median (interquartile range) of active pillars per scanning image of FGF-2, G-CSF, GM-CSF, CX3CL1 on day 7: 14 (11–22.5), 23 (21, 29), 12 (7.5–18), 17 (9–25.5); day 21: 30 (19–37.5), 33 (19–41), 26 (17.5–36.5), 29 (21–43); and day 42: 33 (16.5–58.5), 76 (64–128.5), 25 (14–39.5), 48 (26.5–73.5), respectively. For Patient 6, the median (interquartile range) of active pillars per scanning image of FGF-2, G-CSF, GM-CSF, CX3CL1 on day 0: 18 (16–23), 49 (31.5–56), 23 (17.5–28), 20 (14.5–27); day 21: 29 (24–33.5), 53 (46.5–70), 35 (25–46), 22 (19–29.5); and day 42: 13 (8–16.5), 44 (23.5–55.5), 10 (6.5–12.5), 30 (24–34.5), respectively. The data represented three technical replicates obtained from three chips. Nine images were acquired from each chip for cytokine counting. Statistical analysis was based on Kruskal–Wallis test followed by Dunn’s test to correct multiple comparisons (two-sided). Source data are provided in the Source Data file.\n\n\n\nAs for Patient 6 who exhibited mild grade 2 irAEs on the skin during combined ipilimumab and pembrolizumab (programmed death-1 (PD-1) inhibitor) or single ipilimumab treatments, the dynamic monitoring displayed relatively stable cytokine levels on different follow-up visits (Fig. 7). Specifically, the confocal Raman images (Fig. 7f–h) and the molecular counting (Fig. 7i) in this patient serum consistently showed no significant cytokine level alterations on the three time points (days 0, 21, 42). Under this circumstance, LDA failed to clearly classify the data into separate sections (Fig. 7j). Likewise, Patients 7, 9, and 10 possessed stable cytokine levels and were diagnosed with low grade irAEs. Meanwhile, Patient 8 who showed decreasing cytokine levels did not display signs of irAEs. LDA was not able to classify Patients 7 and 8 who had mild irAEs and did not show irAEs, but it recognised the minor difference in Patients 9 and 10 who showed grade 1 irAEs (Supplementary Fig. 20).\n\nOverall, we found the preliminary evidence to suggest that significantly elevated cytokine levels have a strong correlation with the development and manifestation of severe irAEs, whereas stabile, low baseline, and decreasing cytokine concentration indicate mild and manageable irAEs. The relatively low concentrations of these four cytokines were below the detection sensitivities of commercially available ELISA kits (pM level), which limits their use in clinical studies. Importantly, the measurement at fM cytokine levels in clinical samples is consistent with the median concentrations of cytokine measured by using digital ELISA51. The successful demonstration of the digital nanopillar SERS platform in dynamic detection of cytokines in patient serum provides a potential approach for the future accurate early detection, characterisation, and monitoring of irAEs in clinical settings. However, it is important to note that the cytokine concentration changes are not directly correlated with the treatment response according to response evaluation criteria in solid tumours (RECIST). In our pilot study, some melanoma patients showed higher levels of cytokines compared to the healthy controls. The power of our digital nanopillar SERS platform lies in the capability to longitudinally monitor cytokines in individual patients over time.\n\nDiscussion\nDespite the frequent occurrence of irAEs in immune checkpoint therapy, particularly for the combination treatment, the prediction of the emergence of irAEs remains elusive. Mounting data suggest a potential role of cytokines as predictive markers for irAE monitoring in immune checkpoint therapy9,11,13,52. Although promising, accurate quantification of these biomarkers was often not possible due to the dearth in technologies with sufficient detection sensitivity. Typically, either cytokines above the detection limit of immunosorbent assay were selected11, or relative cytokine quantification9 was performed for investigating irAEs. The former approach has the drawback of potentially excluding the low abundance cytokines of significance in irAEs. As for relative quantification9,53, the cytokine concentrations are determined by relating to a standard that had the observed median fluorescence value closest to the median of the test sample. The relative concentration, however, may fail to represent accurate cytokine levels and thus needs further exploration. Our developed digital nanopillar SERS assay offers early data suggestive of a potential approach to the above-mentioned challenges and provides the possibility to study trace amounts of a panel of cytokines in an accurate quantification manner as well as concomitantly providing attomolar level sensitivity. The current proof-of-principle approach has measured four of the potential inflammatory and/or immune toxicity-related cytokines for the prediction of emergence, characterisation, and/or quantifiable correlation with irAEs in melanoma patients.\n\nBy leveraging the narrow line width of Raman spectra, the developed digital SERS counting assay shows the ability to sensitively and simultaneously detect multiple cytokines. The adoption of the novel digital quantification mode in SERS using gold–silver alloy nanoboxes further improves the high sensitivity of SERS technology. Notably, the digital counting strategy offers an option for reproducible SERS quantification by avoiding the common Raman signal fluctuations induced by ensemble measurements. The ensemble measurement in SERS relies on the enhancement of Raman signals of molecules located in or near the “hot spots” (i.e., strong electromagnetic fields)30. Due to the random distribution and various efficiencies of “hot spots”, it can result in the discrepancies in acquired SERS intensities for inter-laboratory and even intra-laboratory tests29. To circumvent the impact of Raman intensity fluctuation on accurate quantification, we employed the digital SERS signals from the single-SERS-active nanoboxes on discrete pillar arrays to enumerate the targets and only count the “yes” or “no” signal for a robust and reproducible SERS analysis. Furthermore, the digital readout model, which regards both aggregated and single nanoparticle as a single binding event to reflect the true target number, can have a better accuracy and robustness than the intensity-based assay39.\n\nWe believe that the proposed digital nanopillar SERS assay could be used to monitor other cytokine-induced immune responses. For instance, with the outbreak of 2019 novel coronavirus (2019-nCoV), it is yet difficult to predict which infected patient will develop a strong immune response that requires hospitalisation. However, cytokines have been indicated to play a major role in the severity of immune response for critically ill patients infected with 2019-nCoV54. The specific detection of multiple cytokines at early stages of viral infection could thus potentially address this issue and help to provide the clinical care for people at the highest risk. For patients with high cytokine concentrations, the digital nanopillar SERS platform will require the sample dilution to suit Poisson distribution.\n\nIn summary, we propose a digital nanopillar SERS platform for the parallel counting of single cytokines and dynamic monitoring in the clinical context of irAE development during immune checkpoint blockade therapy. The platform achieved attomolar level sensitivity by utilising discrete pillar array compartments to hold the single cytokine and subsequently applied single-particle active nanobox-based SERS nanotags for cytokine identification and counting. The confocal Raman mapping on the pillar array offered the highest possible clinical specificity by reducing nonspecific signals and provided a “yes/no” type counting approach for reproducible Raman signal readout. The designed platform was rigorously optimised and tested in simulated clinical samples prior to the evaluation for irAE monitoring in stage IV melanoma patients receiving immune checkpoint blockade therapy. We envisaged this platform possessing the advantages of highly sensitive and multiplexing analysis capability can transit into future irAE detection methodologies after extensive validation in a large cohort of clinical samples over different time courses.\n\nMethods\nMaterials\nSilver nitrate (AgNO3), hydrogen tetrachloroaurate (III) trihydrate (HAuCl4·3H2O), MBA, DTNB, TFMBA, MMTAA, DSP were obtained from Sigma Aldrich. Ascorbic acid (AA) of analytical grade was purchased from MP Biomedicals. FGF-2 (223-FB), G-CSF (214-CS), GM-CSF (215-GM), CX3CL1 (365-FR) cytokines; monoclonal anti-FGF-2 (MAB233), anti-G-CSF (MAB214), anti-GM-CSF (MAB615), anti-CX3CL1 (MAB3652) antibodies; polyclonal anti-FGF-2 (AF-233), anti-G-CSF (AF-214), anti-GM-CSF (AF-215), anti-CX3CL1 (AF-365) antibodies; and FGF-2 (DY233-05), G-CSF (DY214-05), GM-CSF (DY215-05), and CX3CL1 (DY365) ELISA kits were bought from R&D Systems.\n\nAll the patient serum or plasma samples were collected at the Austin Hospital (Melbourne) under approved human ethic protocols and written informed consents were obtained from all patients before sample collection. Ethics approval was obtained from The University of Queensland Institutional Human Research Ethics Committee (approval nos. 2011001315 and 2016000876) and the following clinical assay was carried out according to the approved guidelines.\n\nPreparation of single-particle active SERS nanotags\nThe preparation of SERS nanotags involved the synthesis of nanoboxes and the subsequent functionalisation with Raman reporters and antibodies. For nanobox synthesis, 45 µL of HAuCl4 (1 wt%) was added into 10 mL of ultrapure H2O (18.2 Ω cm) under magnetic stirring (800 r.p.m.) for 1 min, followed by simultaneously introducing 170 µL of AgNO3 (6 mM) and 30 µL of AA (0.1 M) into the stirring solution. Then, the formation of nanoboxes was indicated by the appearance of an apparent blue colour within 6 s and the samples were collected 1 min later by centrifuging at 600 g for 15 min.\n\nTo functionalise nanoboxes with Raman reporters and antibodies, 300 µL of nanoboxes centrifuged from 1 mL of as-prepared solution were co-incubated with one type of Raman reporters (i.e., 10 µL of DTNB, 8 µL of MBA, 10 µL of TFMBA, or 10 µL of MMTAA) and 2 µL of DSP linker for 6 h. After that, the Raman reporter and DSP functionalised nanoboxes were separated by centrifuging at 600 g for 15 min, and resuspended into 300 µL of PBS (0.1 mM). Then, 2 µg of anti-FGF-2, anti-G-CSF, anti-GM-CSF, anti-CX3CL1 antibodies were added to MBA, DTNB, TFMBA, and MMTAA labelled nanoboxes, respectively. After overnight incubation at 4 oC, the functionalised nanoboxes were purified by centrifuging at 600×g for 15 min to separate free antibodies and the final products were resuspended into 200 µL of 0.1% BSA for future use.\n\nFabrication of pillar arrays\nThe chip was made of a sensing array measuring 1 mm × 1 mm (Supplementary Fig. 1a) and consisted of 250,000 individual pillars. Each pillar was 1 µm wide, 1 µm long, and 1 µm high. The pillars were evenly spaced by 1 µm from one pillar to the next (Supplementary Fig. 1b). The pillar array was designed using Nanosuite 6.0 (Raith GmbH) and Beamer 5.9.1 (GenISys GmbH) and fabricated on a 4-inch p-type <100> silicon wafer (Bonda Technology Pte Ltd, Singapore) using electron beam lithography (EBL). The wafer accommodated 76 separate pillar arrays. Silicon wafer was first cleaned in acetone, isopropanol with sonication for 2 min each, followed by rising with deionised H2O and dehydration bake at 180 °C for 2 min. Prior to the resist coating, the wafer had undergone a further O2 plasma cleaning at 200 W for 5 min (Diener Atto, Diener Electronic GmbH). The cleaned wafer was spin-coated with two layers of polymethyl methacrylate (bottom: 495K A4 PMMA, top: 950k A4 PMMA, from MicroChemicals GmbH) using the CEE Apogee Coater (Cost Effective Equipment, LLC) at 1500 r.p.m. for 60 s each. After the coating of each layer, the wafer was baked immediately on a hot plate to prevent from intermixing of the two layers of resist. The baking time was 10 and 3 min for the bottom and top layer, respectively, at 180 °C. The thickness of the photoresist was found to be ~450 nm (top PMMA: ~250 nm, bottom PMMA: ~200 nm), characterised by white light reflectometry (FilmTek 2000M, Scientific Computing International). EBL was performed in the Raith EBPG5150 system. The patterns were exposed in EBL with an accelerated voltage of 100 kV, 150 nA of beam current (spot size ~80 nm), with step sizes of 40 nm and an electron dose of 1200 µC/cm2. The exposure time per 4-inch wafer was ~35 min, each containing 76 individual chips. After exposure, the wafer was developed in a mixture of isopropanol and methyl isobutyl ketone (3:1) for 60 s and rinsed immediately with isopropanol, followed by drying with N2. An oxygen plasma descum process, at 100 W, 60 s (Diener Atto, Diener Electronic GmbH) was carried out to remove resist residues prior to the deposition. Next, 10 nm titanium and 200 nm gold were deposited by physical vapour deposition using a Temescal FC-2000 electron beam evaporator (Ferrotec, U.S.A.). After overnight lift-off at room temperature in Remover PG (MicroChemicals GmbH, Germany), the excess material was washed off and the pillar array structure was revealed (Supplementary Fig. 1c). To create the pillar height (i.e., 1 µm), reactive ion etching (Oxford Instruments, UK) was applied for anisotropic etching of the silicon. Hereby, the deposited gold served as mask to protect the underlying silicon while the un-masked silicon was removed. Next, the wafer was coated with a protective layer of cured AZnLOF 2020 prior to wafer dicing into 76 individual sensing chips consisting of a single pillar array. Prior to use, the protective layer was washed off by consecutive washes with isopropanol and acetone and dried under a stream of nitrogen.\n\nPillar array functionalization\nAntibody functionalisation of the gold-topped pillar array was conducted by crosslinking the antibodies to the gold surface using DSP. A solution of 5 mM DSP in dimethyl sulfoxide was pipetted onto the pillar array and incubated at room temperature for 2 h. After rinsing the pillar array with ethanol and PBS, a solution of 5 µg/mL anti-cytokine monoclonal antibody solution (100 fold dilution of antibody stock solution) in PBS was incubated overnight at 4 °C. Subsequently, the pillar array was rinsed with PBS and blocked using 1% bovine serum albumin in PBS for 1 h. Prior to use, the pillar array was rinsed with PBS. All PBS solutions were filtered through a sterile 0.22 µm syringe filter (Millex-GP, Merck, U.S.A.).\n\nDigital nanopillar SERS profiling of cytokines\nCytokines (FGF-2, G-CSF, GM-CSF, and CX3CL1) with different concentrations in PBS (2.6 aM, 26 aM, 260 aM, and 1031 aM) were incubated with antibody functionalised pillar arrays at room temperature for 30 min, followed by washing the pillar array three times with washing buffer (0.1% BSA and 0.01% Tween 20 in PBS). SERS nanotags were then added into the pillar array for another 30 min incubation under room temperature to identify the targets. Finally, the pillar arrays were washed to remove the free SERS nanotags and were subject to confocal Raman microscope for quantification. For each sample, nine SERS images with each image has the dimension of 60 µm × 48 µm were taken on the pillar array to calculate the overall cytokine concentration.\n\nSimulated clinical sample detection\nFor the recovery experiment, standard cytokines (FGF-2, G-CSF, GM-CSF, and CX3CL1) with the concentration of 1 fM were added into healthy human serum and then diluted ten times with PBS to quantify.\n\nFor the quantification of cytokines in FBS, three simulated clinical samples were prepared by titrating various concentrations of standard cytokines into 10% FBS: Sample 1 (FGF-2 = 3.64 pM, G-CSF = 3.19 pM, GM-CSF = 4.29 pM, and CX3CL1 = 28.57 fM); Sample 2 (FGF-2 = 7.28 pM, G-CSF = 6.38 pM, GM-CSF = 8.58 pM, and CX3CL1 = 571.4 fM); and Sample 3 (FGF-2 = 14.56 pM, G-CSF = 12.76 pM, GM-CSF = 17.16 pM, and CX3CL1 = 1142.8 fM). These three samples were then detected directly using the commercial ELISA kits or digital nanopillar SERS assay with a further dilution of 105, 2 × 105, and 4 × 105, respectively.\n\nSpectroscopic ellipsometry\nThe antibody film thickness was measured by in-solution spectroscopic ellipsometry (M2000V JA Woollam Co., Inc. USA) using gold-coated substrates and flow cell (QSense® Ellipsometry, Biolin Scientific, Sweden). Measurements were performed at an angle of 65°. Data analysis was performed by CompleteEASE® software using a B-Spline data fit and Cauchy model to calculate the antibody film thickness.\n\nMALDI-TOF MS\nThe antibody-functionalised nanopillar array chip was subjected to tryptic digest prior to analysis. Sequencing-grade trypsin was made to 50 ng/µL in 25 mM ammonium bicarbonate, and sprayed over the chip using a Bruker Imageprep instrument (Bruker, USA). After trypsin deposition, the chip was incubated in a humid environment at 40 °C for 3 h. Subsequently, the chip was sprayed with a matrix solution, 10 g/L α-cyano-4-hydroxycinnamic acid in 50% acetonitrile with 0.2% trifluoroacetic acid. Next, the chip was analysed with a Bruker Ultraflex III MALDI-TOF mass spectrometer (Bruker, USA) in positive linear mode using Flex Imaging 4.0 (Bruker, USA) with a pixel size of 60 µm. Data were collected from 2 k–30 k m/z, at a laser repetition rate of 200 Hz. Data were normalised using the root mean square approach and visualised using Flex Imaging 4.0 (Bruker, USA) and SCILS LAB 2017a software. For the SCILS LAB analysis, the data were imported using a convolution baseline subtraction, and displayed using root mean squared normalisation.\n\nInstrumentations\nSEM images of pillar arrays and nanoboxes were taken on a JEOL-7100 field emission (FE)-SEM (20 kV voltage). TEM images of nanoboxes were taken on a JEOL-2100 microscope (200 kV voltage). NTA of nanobox size distribution was performed with Malvern NanoSight NS300. UV-vis extinction spectrum of nanoboxes was performed with a Shimadzu UV-2450 spectrophotometer. Confocal Raman mapping was conducted on a WITec alpha 300 R spectrometer using 632.8 nm He–Ne laser with the power of 35 mW, a grating of 600 g/mm used with EMCCD camera, spectral resolution of 1.390 cm−1 to 2.114 cm−1, confocal pinhole size of 100 µm, 100× air objective with NA of 0.90, and 0.05 s integration time. The theoretical spot size was 857.80 nm based on the Abbe diffraction limit (i.e., d = 1.22λ/NA). The scanning area was set to have 60 µm × 48 µm with 86 points per line and 69 lines per image. For each pillar array, nine separate scanning areas were taken in total and the total active pillars were used for quantification. The SERS mapping images for counting were taken by focusing the laser on the top of the pillar surfaces. Specifically, the laser was firstly focused on the silicon substrates by obtaining the strongest silicon signals (520 cm−1) and then the 100× objective was moved up in z-axis direction of 1 µm for SERS scanning. The system was calibrated with the first-order photo peak of silicon at 520 cm−1.\n\nData analysis\nTo assign the SERS nanotag membership for DTNB, MBA, TFMBA, and MMTAA, Project Five 5.0 software from WITec was utilised to create four filters, which summed a spectral range of 40 cm−1 with the centre position at the characteristic Raman peak of each reporter and subtracted the background with a polynomial algorithm. Specifically, the filter ranges of four Raman reporters DTNB-, MBA-, TFMBA-, and MMTAA-coated SERS nanotags were (1310–1350 cm−1), (1060–1100 cm−1), (1360–1400 cm−1), and (1268–1308 cm−1), respectively. All the SERS images were analysed by using threshold intensity to determine the successful binding events. Specifically, the threshold intensity of FGF-2, G-CSF, GM-CSF, and CX3CL1 was set at 5000, 4000, 5000, and 5000, respectively. For each image, the threshold intensity was doubled-checked and adjusted based on the true Raman peaks in the spectra. Statistical analysis assuming unequal variances was conducted with Kruskal–Wallis test among three groups or Mann–Whitney test between two groups with GraphPad Prism 8.4. To control the error appropriately, we performed multiple comparisons using Dunn’s test. LDA of clinical samples was performed in R software (3.6.2) with the MASS package (7.3-52). The active pillars in SERS images were counted with Image J software.\n\nSupplementary information\nSupplementary Information\n\n Peer Review File\n\n Source data\nSource Data\n\n\n\nPeer review information\nNature Communications thanks Chongwen Wang and Isaac Pence for their contribution to the peer review of this work. Peer reviewer reports are available.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nThe online version contains supplementary material available at 10.1038/s41467-021-21431-w.\n\nAcknowledgements\nThe authors acknowledge grants received by our laboratory from the National Breast Cancer Foundation of Australia (CG-12-07) and the ARC DP (160102836 and 210103151). These grants have significantly contributed to the environment to stimulate the research described here. J.L. acknowledges support from the Australian Government Research Training Program Scholarship. A.W. and A.A.I.S. thank the National Health and Medical Research Council for funding (APP1173669 and APP1175047). A.B. is the recipient of a Fellowship from the Victorian Government Department of Health and Human Services acting through the Victorian Cancer Agency. We acknowledge the facilities, and the scientific and technical assistance, of the Australian Microscopy & Microanalysis Research Facility at the Centre for Microscopy and Microanalysis, The University of Queensland. We appreciate to receive the technical and scientific guidance from Queensland node of the Australian National Fabrication Facility (Q-ANFF) in confocal Raman mapping and spectroscopic ellipsometry measurement.\n\nAuthor contributions\nJ.L., A.W., A.I.S., H-H.C., Y.W., A.B., P.M., and M.T. contributed to the design of the experiments and analysing the data. J.L. and A.W. performed the experiments and prepared the manuscript. All authors read, commented, and edited the manuscript, and assisted during the revision process.\n\nData availability\nData supporting the findings of this work are available within this paper and the supporting information files. A reporting summary of this work is available as a Supplementary file. Source data are provided with this paper.\n\nCompeting interests\nThe authors declare no competing interests.\n==== Refs\nReferences\n1. Sharma P Allison JamesP Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential Cell 2015 161 205 214 10.1016/j.cell.2015.03.030 25860605 \n2. Sharma P Allison JP Dissecting the mechanisms of immune checkpoint therapy Nat. Rev. Immunol. 2020 20 75 76 10.1038/s41577-020-0275-8 31925406 \n3. Sharma P Allison JP The future of immune checkpoint therapy Science 2015 348 56 61 10.1126/science.aaa8172 25838373 \n4. Darvin P Toor SM Sasidharan Nair V Elkord E Immune checkpoint inhibitors: recent progress and potential biomarkers Exp. Mol. Med. 2018 50 1 11 10.1038/s12276-018-0191-1 30546008 \n5. Topalian SL Taube JM Anders RA Pardoll DM Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy Nat. Rev. Cancer 2016 16 275 287 10.1038/nrc.2016.36 27079802 \n6. 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Schlücker S SERS microscopy: nanoparticle probes and biomedical applications ChemPhysChem 2009 10 1344 1354 10.1002/cphc.200900119 19565576 \n48. Tsao SC-H Characterising the phenotypic evolution of circulating tumour cells during treatment Nat. Commun. 2018 9 1482 10.1038/s41467-018-03725-8 29662054 \n49. McLellan JM Li Z-Y Siekkinen AR Xia Y The sers activity of a supported ag nanocube strongly depends on its orientation relative to laser polarization Nano Lett. 2007 7 1013 1017 10.1021/nl070157q 17375965 \n50. Yelleswarapu V Mobile platform for rapid sub–picogram-per-milliliter, multiplexed, digital droplet detection of proteins Proc. Natl Acad. Sci. USA 2019 116 4489 4495 10.1073/pnas.1814110116 30765530 \n51. Wu D Milutinovic MD Walt DR Single molecule array (simoa) assay with optimal antibody pairs for cytokine detection in human serum samples Analyst 2015 140 6277 6282 10.1039/C5AN01238D 26270328 \n52. Kennedy LB Salama AKS A review of cancer immunotherapy toxicity CA Cancer J. Clin. 2020 70 86 104 10.3322/caac.21596 31944278 \n53. Masi A Cytokine levels and associations with symptom severity in male and female children with autism spectrum disorder Mol. Austism 2017 8 63 10.1186/s13229-017-0176-2 \n54. Huang C Clinical features of patients infected with 2019 novel coronavirus in wuhan, china Lancet 2020 395 497 506 10.1016/S0140-6736(20)30183-5 31986264\n\n",
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"title": "A digital single-molecule nanopillar SERS platform for predicting and monitoring immune toxicities in immunotherapy.",
"title_normalized": "a digital single molecule nanopillar sers platform for predicting and monitoring immune toxicities in immunotherapy"
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"abstract": "Polycythemia vera (PV) is a myeloproliferative disorder usually characterized by an increase tendency toward thromboembolic events. Spontaneous hemorrhage/bleeding in PV patients is seldom reported in neurosurgical literature.\n\n\n\nWe report the case of a 76-year-old male with PV who developed a spontaneous subdural hematoma requiring surgical evacuation. He improved significantly after the resolution of brain compression and mass effect caused by the hematoma.\n\n\n\nSporadic reports of hemorrhage within the central nervous system in the setting of PV exist and are attributed to microvascular thrombotic events with hemorrhagic conversion. Though rare, spontaneous central nervous system hemorrhage in the absence of vascular malformation or an inciting event such as trauma can occur in the setting of myeloproliferative disorders like PV.",
"affiliations": "Department of Neurosurgery, Albany Medical Center, Albany, New York, USA. Electronic address: entezap@amc.edu.;Department of Medicine, Albany Medical Center, Albany, New York, USA; New York Oncology and Hematology, Albany, New York, USA.;Department of Neurosurgery, Albany Medical Center, Albany, New York, USA.;Department of Neurosurgery, Albany Medical Center, Albany, New York, USA.;Department of Neurosurgery, Albany Medical Center, Albany, New York, USA.",
"authors": "Entezami|Pouya|P|;Raval|Mihir Pradipkumar|MP|;Sanders|Laura Nicole|LN|;Adepoju|Adedamola|A|;Yamamoto|Junichi|J|",
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"title": "Spontaneous Subdural Hematoma in Patient with Polycythemia Vera.",
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"abstract": "Bone marrow failure syndromes can be associated with abnormalities of the forearms. We observed a neonate with congenital thrombocytopenia who had bilateral radio-ulnar synostosis and fifth finger clinodactly. We performed an evaluation of the mechanism causing the thrombocytopenia using a combination of direct and indirect measures of thrombopoiesis. These tests indicated decreased platelet production. This entity of congenital hyporegenerative thrombocytopenia with bilateral radio-ulnar synostosis and fifth-finger clinodactly is an uncommon but easily recognizable form of congenital amegakaryocytic thrombocytopenia (CAMT). This entity can be distinguished from the TAR syndrome (thrombocytopenia and absent radii) by the distinctive orthopedic issues, different underlying genetic mutations, and a more worrisome prognosis for CAMT than for TAR.",
"affiliations": "Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA.",
"authors": "Sola|Martha C|MC|;Slayton|William B|WB|;Rimsza|Lisa M|LM|;Perez|Jose A|JA|;Fuchs|Deborah|D|;Fuch|Deborah|D|;Calhoun|Darlene A|DA|;Christensen|Robert D|RD|",
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"abstract": "We report the case of an 88-year old woman referred for evaluation of increased INR. Surprisingly supratherapeutic levels of rivaroxaban was detected. Upon scrutiny of the patient's medical history, a drug-drug interaction between amiodarone and rivaroxaban persisting 3 weeks after cessation of amiodaron remains the prime suspect causing the clinical picture. Both INR and rivaroxaban levels returned to normal within 3 days of cessation of rivaroxaban. The case highlights that rivaroxaban, although highly variably, does affect INR. Furthermore, it highlights that the potential for DDIs involving amiodarone may persists for weeks or months after discontinuation. Amiodarone is predicted to increase rivaroxaban exposure, through inhibition of rivaroxaban elimination via CYP3A4 and P-gp. Elderly patients and patients with declining renal function are especially at risk of increased rivaroxaban exposure when a DDI with amiodarone occurs.",
"affiliations": "Clinical Pharmacology Unit, Zealand University Hospital, Roskilde, Denmark.;Department of Cardiology, Zealand University Hospital, Roskilde, Denmark.;Department of Clinical Biochemistry, Slagelse and Ringsted Hospitals, Naestved, Denmark.;Department of Haematology, Zealand University Hospital, Roskilde, Denmark.",
"authors": "Skov|Kenneth|K|https://orcid.org/0000-0003-3612-5828;Falskov|Britt|B|;Jensen|Esther Agnete|EA|;Dorff|Mikkel Helleberg|MH|",
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"keywords": "amiodarone; cardiovascular pharmacology; clinical toxicology; cytochrome P450 (CYP); drug-drug interactions; pglycoprotein; pharmacokinetics; rivaroxaban",
"medline_ta": "Basic Clin Pharmacol Toxicol",
"mesh_terms": "D000369:Aged, 80 and over; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D000925:Anticoagulants; D051544:Cytochrome P-450 CYP3A; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D000069552:Rivaroxaban",
"nlm_unique_id": "101208422",
"other_id": null,
"pages": "351-353",
"pmc": null,
"pmid": "32336024",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Supratheraputic rivaroxaban levels: A persistent drug-drug interaction after discontinuation of amiodarone.",
"title_normalized": "supratheraputic rivaroxaban levels a persistent drug drug interaction after discontinuation of amiodarone"
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"activesubstancename": "RIVAROXABAN"
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"drugadditional": "1",
... |
{
"abstract": "Minoxidil hair formulation is commonly used for the treatment of male or female androgenic alopecia. This over-the-counter product is wrongly considered safe. The ingestion of a few milliliters by a child can lead to significant intoxication. We report a case of significant intoxication after the ingestion of topical minoxidil (Alopexy; Pierre Fabre Laboratoires, SA, Switzerland). A 7-year-old girl, who accidentally ingested a teaspoon of minoxidil hair solution, presented to the pediatric emergency department for emesis. At admission, she had a blood pressure of 86/56 mm Hg and a pulse of 149 beats per minute. Hypotension lasted 40 hours with the lowest value 24 hours after ingestion (79/33 mm Hg). She presented electrocardiogram changes (sinus tachycardia and flattening T-waves) but normal cardiac enzymes. Infusion of 20 mL/kg of normal saline fluid had no hemodynamic effect. Her blood pressure normalized on day 2. Minoxidil topical solution is an unsafe product for children. This formulation should be strictly kept out of reach of children and manufacturers should enhance child-resistance security of packaging. The over-the-counter availability must be questioned.",
"affiliations": "From the *Pediatric Emergency Department, Children University Hospital and †Regional Poison Center, Purpan University Hospital, Toulouse, France.",
"authors": "Claudet|Isabelle|I|;Cortey|Caroline|C|;Honorat|Raphaele|R|;Franchitto|Nicolas|N|",
"chemical_list": "D000959:Antihypertensive Agents; D012965:Sodium Chloride; D008914:Minoxidil",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000000301",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "31(1)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000287:Administration, Topical; D000959:Antihypertensive Agents; D001794:Blood Pressure; D002648:Child; D004562:Electrocardiography; D005260:Female; D006339:Heart Rate; D006801:Humans; D007022:Hypotension; D008914:Minoxidil; D012965:Sodium Chloride",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "44-6",
"pmc": null,
"pmid": "25426682",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Minoxidil topical solution: an unsafe product for children.",
"title_normalized": "minoxidil topical solution an unsafe product for children"
} | [
{
"companynumb": "FR-BAXTER-2015BAX008628",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "We developed a new high-dose combination of infusional gemcitabine with busulfan and melphalan for lymphoid tumors. Gemcitabine dose was escalated by extending infusions at a fixed rate of 10 mg/m(2)/min in sequential cohorts, in daily, 3-dose or 2-dose schedules. Each gemcitabine dose immediately preceded busulfan (adjusted targeting area under the curve 4,000 μM/min(-1)/day × 4 days) or melphalan (60 mg/m(2)/day × 2 days). We enrolled 133 patients (80 Hodgkin lymphoma [HL], 46 non-Hodgkin lymphoma [NHL], 7 myeloma), median 3 prior regimens; primary refractory disease in 63% HL/45% NHL and positron emission tomography positive tumors at transplantation in 50% patients. Two patients died from early posttransplantation infections. The major toxicity was mucositis. The daily and 3-dose schedules caused substantial cutaneous toxicity. In contrast, the 2-dose schedule was better tolerated, which allowed us to extend the infusions from 15 to 270 minutes. Pretransplantation values of C-reactive protein, B-type natriuretic peptide, ferritin, or haptoglobin did not correlate with toxicity. Overall response and complete response rates were 87%/62% (HL), 100%/69% B large-cell lymphoma (B-LCL), 66%/66% (T-NHL), and 71%/57% (myeloma). At median follow-up of 24 months (range, 3-63 months), the event-free/overall survival rates were 54%/72% (HL), 60%/89% (B-LCL), 70%/70% (T-NHL), and 43%/43% (myeloma). In conclusion, gemcitabine/busulfan/melphalan is a feasible regimen with substantial activity against a range of lymphoid malignancies. This regimen merits further evaluation in phase II and III trials.",
"affiliations": "Department of Stem-Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030. ynieto@mdanderson.org",
"authors": "Nieto|Yago|Y|;Thall|Peter|P|;Valdez|Ben|B|;Andersson|Borje|B|;Popat|Uday|U|;Anderlini|Paolo|P|;Shpall|Elizabeth J|EJ|;Bassett|Roland|R|;Alousi|Amin|A|;Hosing|Chitra|C|;Kebriaei|Partow|P|;Qazilbash|Muzaffar|M|;Frazier|Erin|E|;Gulbis|Alison|A|;Chancoco|Christina|C|;Bashir|Qaiser|Q|;Ciurea|Stefan|S|;Khouri|Issa|I|;Parmar|Simrit|S|;Shah|Nina|N|;Worth|Laura|L|;Rondon|Gabriela|G|;Champlin|Richard|R|;Jones|Roy B|RB|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D002066:Busulfan; D008558:Melphalan",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "18(11)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": null,
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002066:Busulfan; D003841:Deoxycytidine; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007262:Infusions, Intravenous; D008223:Lymphoma; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D052016:Mucositis; D012008:Recurrence; D015996:Survival Rate; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1677-86",
"pmc": null,
"pmid": "22643322",
"pubdate": "2012-11",
"publication_types": "D016428:Journal Article",
"references": "12885837;17279415;1740680;11208832;20981156;20674757;22023523;17242397;12488306;8096958;11313668;7481842;11821447;14965358;19944463;11821446;12089230;15133625;8724701;1525392;6606682;16670205;7718326;8893877;12576433;19289617;15073038;17242396;11939604;17166848;20080663;18022574;18940674;16702182;7477169;10893294;7746977;20577834;21292775;15812553;9779700;20173786;12374451;18794340;1998982;12003187;15386331;17222753;7481845;17950919;8893876;7481844;17426059;2350571",
"title": "High-dose infusional gemcitabine combined with busulfan and melphalan with autologous stem-cell transplantation in patients with refractory lymphoid malignancies.",
"title_normalized": "high dose infusional gemcitabine combined with busulfan and melphalan with autologous stem cell transplantation in patients with refractory lymphoid malignancies"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-B0821216A",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
... |
{
"abstract": "Almost half of all cases of invasive aspergillosis (IA) occur in the intensive care unit (ICU), with mortality rates of 70-80% for probable or proven cases. IA has become a major concern among non-neutropenic patients in the ICU with chronic obstructive pulmonary disease (COPD) but although prompt, appropriate antifungal therapy is crucial, diagnosis in this situation is challenging. Criteria for a probable diagnosis in critically ill patients have been proposed to help to expedite therapy.\n\n\n\nA case of probable invasive pulmonary aspergillosis (IPA) in a non-neutropenic patient admitted to the ICU was used to illustrate potential issues in the diagnostic work-up and management of patients in this setting.\n\n\n\nA non-neutropenic 69-year-old man with COPD receiving clomipramine was diagnosed in the ICU with probable invasive aspergillosis based on the presence of severe chronic obstructive pulmonary disease, suspected X-linked granulomatous disease, nodular infiltrates and galactogamman positivity on bronchoalveolar lavage (BAL) fluid. Voriconazole was unsuitable due to the patient's prolonged QT interval and risk of a drug-drug interaction with clomipramine. Isavuconazole was initiated and the patient's condition improved. The three-month course of isavuconazole treatment was well-tolerated and resulted in compete recovery of the patient.\n\n\n\nVoriconazole is a standard first-line treatment for IA but intravenous therapy is associated with toxicity and the potential for drug-drug interactions. Isavuconazole is another first-line therapy which was effective and safe in the management of this critically ill non-neutropenic patient with baseline QT prolongation and potential drug-drug interactions with voriconazole.",
"affiliations": "Infectious Diseases Division, Department of Medicine, University of Udine and Santa Maria Misericordia University Hospital, Udine, Italy.;Infectious Diseases Division, Department of Medicine, University of Udine and Santa Maria Misericordia University Hospital, Udine, Italy.;Infectious Diseases Division, Department of Medicine, University of Udine and Santa Maria Misericordia University Hospital, Udine, Italy.",
"authors": "Bassetti|Matteo|M|;Carnelutti|Alessia|A|;Righi|Elda|E|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2018.02.011",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(18)30019-210.1016/j.idcr.2018.02.011ArticleIssues in the management of invasive pulmonary aspergillosis in non-neutropenic patients in the intensive care unit: A role for isavuconazole Bassetti Matteo mattba@tin.it⁎Carnelutti Alessia Righi Elda Infectious Diseases Division, Department of Medicine, University of Udine and Santa Maria Misericordia University Hospital, Udine, Italy⁎ Corresponding author at: Clinica Malattie Infettive, Azienda Ospedaliera Universitaria Santa Maria della Misericordia, Piazzale Santa Maria della Misericordia 15, 33100, Udine, Italy. mattba@tin.it01 3 2018 2018 01 3 2018 12 7 9 31 1 2018 27 2 2018 27 2 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nAlmost half of all cases of invasive aspergillosis (IA) occur in the intensive care unit (ICU), with mortality rates of 70–80% for probable or proven cases. IA has become a major concern among non-neutropenic patients in the ICU with chronic obstructive pulmonary disease (COPD) but although prompt, appropriate antifungal therapy is crucial, diagnosis in this situation is challenging. Criteria for a probable diagnosis in critically ill patients have been proposed to help to expedite therapy.\n\nMethods\nA case of probable invasive pulmonary aspergillosis (IPA) in a non-neutropenic patient admitted to the ICU was used to illustrate potential issues in the diagnostic work-up and management of patients in this setting.\n\nResults\nA non-neutropenic 69-year-old man with COPD receiving clomipramine was diagnosed in the ICU with probable invasive aspergillosis based on the presence of severe chronic obstructive pulmonary disease, suspected X-linked granulomatous disease, nodular infiltrates and galactogamman positivity on bronchoalveolar lavage (BAL) fluid. Voriconazole was unsuitable due to the patient's prolonged QT interval and risk of a drug–drug interaction with clomipramine. Isavuconazole was initiated and the patient's condition improved. The three-month course of isavuconazole treatment was well-tolerated and resulted in compete recovery of the patient.\n\nConclusions\nVoriconazole is a standard first-line treatment for IA but intravenous therapy is associated with toxicity and the potential for drug–drug interactions. Isavuconazole is another first-line therapy which was effective and safe in the management of this critically ill non-neutropenic patient with baseline QT prolongation and potential drug–drug interactions with voriconazole.\n\nKeywords\nAspergillosisNon-neutropenicIsavuconazoleQT prolongationDrug interactions\n==== Body\nIntroduction\nInvasive fungal infections in the intensive care unit (ICU) are often missed or diagnosed late due to non-specific signs and symptoms, a low index of suspicion, and the difficulty of differentiating between colonization and infection [1]. However, invasive infections caused by filamentous fungi are potentially devastating.\n\nAlmost half of all cases of invasive aspergillosis (IA), the most frequent invasive fungal infection [1], occur in the ICU [2]. Estimates of the incidence of IA in critical care units range from 0.3% to 19% [3]. Patients with IA in the ICU are often referred with pre-existing infection, for example after developing respiratory failure in the bone marrow transplant unit due to IA. Alternatively, patients who acquire IA in the community or as a nosocomial infection may be admitted directly to the ICU while, less often, patients may acquire IA while in the ICU due to airborne spores in contaminated air. Reported mortality rates following diagnosis of proven or probable IA are extremely high: proven or probable IA in the ICU can lead to death in over 70–80% of cases, largely due to delayed diagnosis [4].\n\nIn recent years, IA has become a major concern among non-neutropenic patients with a mild degree of immunosuppression and without classic predisposing risk factors [4]. The most common underlying comorbidities in non-neutropenic patients are chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome, chronic corticosteroid therapy, liver cirrhosis, congenital or acquired immunodeficiency, and recent thoracic or valvular surgery. Prompt, appropriate antifungal therapy in IA is crucial to improve clinical outcomes and reduce mortality. However, achieving a proven diagnosis of IA in non-neutropenic patients is challenging, since clinical manifestations (e.g. fever, cough and purulent sputum) are non-specific, and the conventional radiologic features of “halo sign” and “air crescent sign” are present in only a minority of non-neutropenic patients.\n\nStarting therapy at the stage of possible infection, as opposed to proven or probable infection, might improve survival rates [5]. Voriconazole is a first-line treatment for IA according to current guidelines [6] and is widely used. However, voriconazole has been associated with an increased risk for adverse events, including renal impairment in patients given intravenous therapy, hepatotoxicity, reversible ocular disturbances, photosensitivity, exfoliative dermatitis, cutaneous reactions, neurotoxicity and QT prolongation [[7], [8]]. Moreover, since voriconazole is metabolized by human P450 cytochromes, it has the potential for drug–drug interactions in patients receiving other P450-CYP3A4 substrates [9].\n\nIsavuconazole is a novel triazole agent with a wide spectrum of antifungal activity. It is recommended as a first-line therapy for IA in recent guidelines from the European Conference on Infections in Leukemia (ECIL) [10] and the Infectious Diseases Society of America (IDSA) [11] based on the results of the phase III SECURE study which demonstrated non-inferiority to voriconazole [12]. The main advantages of isavuconazole compared to voriconazole are: (1) reduced nephrotoxicity in patients given intravenous therapy; (2) it does not contribute to a prolonged QT interval; (3) fewer drug–drug interactions; and (4) no requirement for dose adjustments in patients with renal or hepatic impairment [[12], [13]].\n\nThe following case report illustrates some potential issues in the diagnostic work-up and management of patients admitted to the ICU with probable invasive pulmonary aspergillosis (IPA).\n\nCase report\nClinical presentation\nA 69-year-old man with severe COPD requiring chronic oxygen supplementation (1 L/min) and suspected underlying X-linked granulomatous disease was admitted to the ICU with acute-on-chronic respiratory failure. He had a progressively worsening cough, shortness of breath, increased sputum production and had experienced a 10 kg weight loss with muscle depletion in the preceding three months. The patient had been treated for pulmonary tuberculosis at the age of 23 years, with no subsequent recurrence of infection. Chronic treatment with clomipramine (75 mg/day) was ongoing for a major depressive syndrome which had been diagnosed five years earlier. He was being monitored with monthly seriated electrocardiograms for QT prolongation attributable to clomipramine therapy.\n\nDiagnosis of invasive pulmonary aspergillosis\nAt ICU admission, the patient presented with severe dyspnea. Arterial blood-gas analysis showed mixed respiratory failure (pH 7.22, PaO2 58 mmHg, PaCO2 80 mmHg, HCO3− 35 mMol/L) requiring non-invasive ventilation. Chest examination revealed bilateral crackles, with no signs of chronic heart failure. Blood tests showed the white blood cell count to be in the normal range (8000/mm3), with no neutropenia (neutrophil count 1846/mm3), but mild lymphopenia was present (lymphocytes 810/mm3). The patient was anemic (Hb 10.9 g/dL). Platelet count was high (438,000/μL) and C-reactive protein (CRP) was markedly increased (35 mg/L; normal level <5 mg/L). Renal function was normal (serum creatinine 0.9 mg/dL), as were liver function tests (aspartate transaminase [AST] 11 IU/L, alanine transaminase [ALT] 14 IU/L, gamma-glutamyl transpeptidase [GGT] 30 IU/L, total bilirubin 0.15 mg/dL). Baseline electrocardiogram showed a sinus rhythm with a right bundle branch block and prolonged QT interval (453 ms).\n\nChest x-ray showed multiple bilateral lung opacities. CT and [18F] fluorodeoxyglucose (FDG)-PET/CT scans revealed bilateral nodular infiltrates.\n\nDue to the patient’s critical condition and the multiple potential etiologies for the pulmonary infection, a bronchoscopy was performed, which demonstrated purulent secretions. Broncho-alveolar lavage (BAL) fluid was negative for bacteria, fungi, mycobacteria, Actinomyces spp. and Nocardia, but tested positive for galactomannan (GM; ODI 2.6).\n\nAccording to the European Organisation for Research and Treatment of Cancer (EORTC) criteria for non-neutropenic patients [6], the diagnosis of probable IPA was made based on the presence of baseline predisposing comorbidities (severe COPD and suspected X-linked granulomatous disease), the presence of bilateral nodular infiltrates, and GM positivity on BAL.\n\nTreatment\nVoriconazole was considered unsuitable due to the patient’s baseline QT prolongation and the risk of a drug–drug interaction with clomipramine, potentially leading to further QT prolongation and severe cardiac arrhythmias. Isavuconazole therapy was selected, and started with a loading dose of 200 mg every 8 h for six doses, following by 200 mg daily.\n\nOutcome\nAfter starting antifungal treatment with isavuconazole, the patient showed a progressive improvement in his clinical condition. At week 2, the arterial blood-gas analysis showed resolution of the decompensated respiratory acidosis, with normalization of pH (pH 7.40, PaO2 62 mmHg, PaCO2 50 mmHg, HCO3− 30 mMol/L). There was no further need of non-invasive ventilation. On day 17, the patient was moved from the ICU to the infectious diseases ward, and required only low flow oxygen supplementation (1 L/min). He was discharged on day 42. CT scanning and FDG-PET/TC after eight weeks of antifungal treatment confirmed the improvement of pulmonary infiltrates. In total, a three-month course of isavuconazole treatment was completed, and there were no clinical or radiologic signs of infection after six months’ follow-up. Isavuconazole was well-tolerated, with no adverse events and no change in liver enzymes. Serial ECG monitoring showed no prolongation of the QT interval.\n\nDiscussion\nInvasive fungal diseases have been categorized as proven, probable or possible by the EORTC/MSG Consensus Group [6]. Proven diagnosis of IA requires confirmation by histopathologic, cytopathologic, or direct microscopic examination of a specimen obtained by needle aspiration or biopsy [6], which inevitably involves a delay. Criteria for a probable diagnosis in critically ill patients have been proposed [14] that can help to expedite therapy. These require a lower respiratory tract specimen culture positive for Aspergillus, compatible signs and symptoms, abnormal medical images of the lungs by X-ray or CT scan, with either host risk factors or a semi-quantitative Aspergillus-positive culture of BAL fluid and detection of branching hyphae on cytological smear [14]. GM positivity on BAL fluid, in particular, has high sensitivity (87%) and specificity (87%) for the diagnosis of IA [15]. In our patient, these criteria were met and the findings were also consistent with probable IPA according to EORTC/MSG criteria [6].\n\nVoriconazole is a standard first-line treatment for proven or probable IA and is widely prescribed [6]. However, our patient was receiving the tricyclic antidepressant clomipramine which can increase the QT interval (likely accounting for the prolonged QT interval in this patient), and addition of voriconazole could compound this risk. A recent retrospective study by Gueta et al. analyzed risk factors associated with QT prolongation in a cohort of hemato-oncologic patients treated with voriconazole [16]. Baseline QT prolongation (≥450 ms) and low serum potassium levels were found to be independent risk factors for a prolonged QT interval [16]. Moreover, an increased risk has been observed when voriconazole is administered in combination with other drugs which can induce QT prolongation (e.g. fluoroquinolones and methadone), potentially resulting in life-threatening arrhythmias such as “torsade de pointes” [[17], [18]]. Contrasting results were found in a post-hoc analysis of data from patients receiving isavuconazole in the SECURE trial [12]. The analysis demonstrated that the 50% inhibitory concentrations for L-type Ca2+ channels were higher than the maximum serum concentrations of non-protein-bound isavuconazole in vivo. As a result, isavuconazole does not prolong the QT interval. Indeed, isavuconazole is associated with a shortened QT interval, which leads to its contraindication in patients with familial short QT syndrome [[13], [19]], a rare (100 reports in the literature to date) genetic disorder characterized by accelerated repolarization and a predisposition for cardiac arrest [20]. Here, another option might have been to change clomipramine to an alternative agent with a lower risk for QT prolongation.\n\nVoriconazole inhibits multiple enzymatic pathways and is a substrate and inhibitor of multiple cytochromes including CYP2C19, CYP2C9, CYP3A4 and CYP2B6 [21], increasing its potential for drug–drug interactions with CYP inhibitors and inducers. Clomipramine is metabolized by CYP2C19, and a possible interaction could not be ruled out. The effect of different triazoles on the cytochrome P450 system varies; isavuconazole shows less extensive drug–drug interactions than voriconazole and only interactions with CYP3A4 inducers or inhibitors are of concern [19].\n\nMortality from IA in the critical care setting exceeds 70%, and this patient had a particularly poor prognosis due to his comorbid COPD and X-linked chronic granulomatous disease. Prompt initiation of antifungal treatment was essential due to the patient’s critical condition, but voriconzole was contraindicated due to the increased risk of QT interval prolongation. The case described here shows that isavuconazole is effective and safe in the management of a critically ill non-neutropenic patient with baseline QT prolongation and potential drug–drug interactions with voriconazole.\n\nCompeting interests\nMatteo Bassetti has received research grants from Astellas, Pfizer, MSD and Gilead, has acted as an advisor/consultant to Angelini, Astellas, AstraZeneca, Bayer, Basilea, Gilead, Menarini, MSD, Pfizer, Novartis, Shionogi, Vifor, The Medicines company, Tetraphase, Achaogen and Paratek, and has received speaker's honoraria from Angelini, Astellas, AstraZeneca, Bayer, Pfizer, MSD, Gilead, Vifor, Novartis, Bayer and Tetraphase.\n\nFunding\nEditorial support was provided by a medical writer funded by Basilea Pharmaceutica International Ltd., Basel, Switzerland.\n==== Refs\nReferences\n1 Bassetti M. Bouza E. Invasive mould infections in the ICU setting: complexities and solutions J Antimicrob Chemother 72 suppl. 1 2017 39 i47 \n2 Cornillet A. Camus C. Nimubona S. Gandemer V. Tattevin P. Belleguic C. Comparison of epidemiological, clinical, and biological features of invasive aspergillosis in neutropenic and nonneutropenic patients: a 6-year survey Clin Infect Dis 43 5 2006 577 584 16886149 \n3 Dimopoulos G. Frantzeskaki F. Poulakou G. Armaganidis A. Invasive aspergillosis in the intensive care unit Ann NY Acad Sci 1272 2012 31 39 23231712 \n4 Meersseman W. Vandecasteele S.J. Wilmer A. Verbeken E. Peetermans W.E. Van Wijngaerden E. Invasive aspergillosis in critically ill patients without malignancy Am J Respir Crit Care Med 170 6 2004 621 625 15229094 \n5 Nivoix Y. Velten M. Letscher-Bru V. Moghaddam A. Natarajan-Amé S. Fohrer C. Factors associated with overall and attributable mortality in invasive aspergillosis Clin Infect Dis 47 9 2008 1176 1184 18808352 \n6 De Pauw B. Walsh T.J. Donnelly J.P. Stevens D.A. Edwards J.E. Calandra T. European organization for research and treatment of Cancer/Invasive fungal infections cooperative group. 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 (EORT/MSG) consensus group Clin Infect Dis 46 12 2008 1813 1821 18462102 \n7 Dolton M.J. McLachlan A.J. Voriconazole pharmacokinetics and exposure-response relationships: assessing the links between exposure, efficacy and toxicity Int J Antimicrob Agents 44 3 2014 183 193 25106074 \n8 Epaulard O. Leccia M.T. Blanche S. Chosidow O. Mamzer-Bruneel M.F. Ravaud P. Phototoxicity and photocarcinogenesis associated with voriconazole Med Mal Infect 41 12 2011 639 645 22055586 \n9 Groll A.H. Townsend R. Desai A. Azie N. Jones M. Engelhardt M. Drug-drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P 450 3A4 Transpl Infect Dis July 2017 19. Epublication ahead of print \n10 Herbrecht R. Tissot F. Agrawal S. Update of the ECIL guidelines for antifungal treatment in leukemia and HSCT patients 2013 http://www.kobe.fr/ecil/telechargements2013/ECIL5%20Antifungal%20Therapy.pdf \n11 Patterson T.F. Thompson 3rd G.R. Denning D.W. Fishman J.A. Hadley S. Herbrecht R. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America Clin Infect Dis 63 4 2016 e1 e60 27365388 \n12 Maertens J.A. Raad I.I. Marr K.A. Patterson T.F. Kontoyiannis D.P. Cornely O.A. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial Lancet 387 10020 2016 760 769 26684607 \n13 Keirns J. Desai A. Kowalski D. Lademacher C. Mujais S. Parker B. QT interval shortening with isavuconazole: in vitro and in vivo effects on cardiac repolarization Clin Pharmacol Ther 101 6 2017 782 790 28074556 \n14 Blot S.I. Taccone F.S. Van den Abeele A.M. Bulpa P. Meersseman W. Brusselaers N. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients Am J Respir Crit Care Med 186 1 2012 56 64 22517788 \n15 Meersseman W. Lagrou K. Maertens J. Galactomannan in bronchoalveolar lavage fluid: a tool for diagnosing aspergillosis in intensive care unit patients Am J Respir Crit Care Med 177 1 2008 27 34 17885264 \n16 Gueta I. Loebstein R. Markovits N. Kamari Y. Halkin H. Livni G. Voriconazole-induced QT prolongation among hemato-oncologic patients: clinical characteristics and risk factors Eur J Clin Pharmacol 73 9 2017 1181 1185 28624887 \n17 Zeuli J.D. Wilson J.W. Estes L.L. Effect of combined fluoroquinolone and azole use on QT prolongation in hematology patients Antimicrob Agents Chemother 57 3 2013 1121 1127 23229485 \n18 Prosser J.M. Mills A. Rhim E.S. Perrone J. Torsade de pointes caused by polypharmacy and substance abuse in a patient with human immunodeficiency virus Int J Emerg Med 1 3 2008 217 220 19384521 \n19 Cresemba Prescribing Information, Basilea Pharmaceutica International Ltd (June 2015).\n20 Mazzanti A. Kanthan A. Monteforte N. Novel insight into the natural history of short QT syndrome J Am Coll Cardiol 63 13 2014 1300 1308 24291113 \n21 Jeong S. Nguyen P.D. Desta Z. Comprehensive in vitro analysis of voriconazole inhibition of eight cytochrome P450 (CYP) enzymes: major effect on CYPs 2B6, 2C9, 2C19, and 3A Antimicrob Agents Chemother 53 2 2009 541 551 19029318\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "12()",
"journal": "IDCases",
"keywords": "Aspergillosis; Drug interactions; Isavuconazole; Non-neutropenic; QT prolongation",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "7-9",
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"pmid": "29850401",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D002363:Case Reports",
"references": "18462102;24291113;22517788;18808352;16886149;28074556;19029318;28722255;25106074;28355466;17885264;23229485;19384521;23231712;15229094;26684607;27365388;28624887;22055586",
"title": "Issues in the management of invasive pulmonary aspergillosis in non-neutropenic patients in the intensive care unit: A role for isavuconazole.",
"title_normalized": "issues in the management of invasive pulmonary aspergillosis in non neutropenic patients in the intensive care unit a role for isavuconazole"
} | [
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"abstract": "Drug-induced methemoglobinemia can be caused due to topical anesthetics, dapsone, nitrates (e.g., nitroglycerin), and metoclopramide. Cyanosis in the setting of topical anesthetic use, along with the arterial blood gas results indicating hypoxemia, points towards the diagnosis of methemoglobinemia. We highlight the potential complication with the use of topical pharyngeal benzocaine through this case presentation.",
"affiliations": "Internal Medicine, State University of New York (SUNY) Upstate Medical University, Syracuse, USA.;Internal Medicine, State University of New York (SUNY) Upstate Medical University, Syracuse, USA.;Gastroenterology, State University of New York (SUNY) Upstate Medical University, Syracuse, USA.;Gastroenterology, State University of New York (SUNY) Upstate Medical University, Syracuse, USA.",
"authors": "Riaz|Sana|S|;Kudaravalli|Pujitha|P|;Saleem|Sheikh A|SA|;Heisig|David|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.7900",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.7900\nAnesthesiology\nGastroenterology\nMethemoglobinemia: A Life-threatening Complication of Topical Pharyngeal Anesthetics\nMuacevic Alexander Adler John R Riaz Sana 1 Kudaravalli Pujitha 1 Saleem Sheikh A 2 Heisig David 2 \n1 \nInternal Medicine, State University of New York (SUNY) Upstate Medical University, Syracuse, USA \n\n2 \nGastroenterology, State University of New York (SUNY) Upstate Medical University, Syracuse, USA \n\nSana Riaz riazs@upstate.edu\n30 4 2020 \n4 2020 \n12 4 e790031 3 2020 30 4 2020 Copyright © 2020, Riaz et al.2020Riaz et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/30006-methemoglobinemia-a-life-threatening-complication-of-topical-pharyngeal-anestheticsDrug-induced methemoglobinemia can be caused due to topical anesthetics, dapsone, nitrates (e.g., nitroglycerin), and metoclopramide. Cyanosis in the setting of topical anesthetic use, along with the arterial blood gas results indicating hypoxemia, points towards the diagnosis of methemoglobinemia. We highlight the potential complication with the use of topical pharyngeal benzocaine through this case presentation.\n\nmethemoglobinemialidocainetopical anesthesiaThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nTopical pharyngeal anesthetics such as benzocaine are used in conjunction with moderate sedation to increase patient comfort during esophagogastroduodenoscopy (EGD). Topical pharyngeal anesthetics can cause methemoglobinemia, which is a rare and life-threatening complication [1]. We present a case of a 22-year-old healthy female with no known co-morbidities who developed symptoms of shortness of breath following the use of topical anesthesia for EGD and was subsequently diagnosed with methemoglobinemia based on her arterial blood gas and methemoglobin levels. Through this case, we want to highlight the possible complication of methemoglobinemia with the use of benzocaine.\n\nCase presentation\nA 22-year-old female with no prior medical history presented with odynophagia after swallowing a piece of meat. She underwent inpatient EGD and received topical pharyngeal benzocaine spray along with moderate sedation. EGD was unremarkable, but during recovery, the patient became dyspneic, cyanotic, and her oxygen saturation (SaO2) dropped to 85% on room air. On chest examination, she had no wheezing, rhonchi, or crackles. Arterial blood gas showed pH 7.50, partial pressure of carbon dioxide 21 mmHg, partial pressure of oxygen 409 mmHg, and SaO2 99%. Blood work showed a methemoglobin level of 27.8%. She was transferred to the intensive care unit (ICU) and was given supplemental oxygen through facemask and IV ascorbic acid, which resolved her cyanosis and hypoxemia. Repeat methemoglobin level was 8.3% with normal oxygen saturation on room air. Upon stabilization, she was discharged home 48 hours after her initial presentation.\n\nDiscussion\nMethemoglobinemia is the oxidation of ferrous to ferric iron within hemoglobin, impairing its ability to transport oxygen, leading to tissue hypoxemia and death [2]. The etiologies of methemoglobinemia are hemoglobinopathy (hemoglobin M), hereditary nicotinamide adenine dinucleotide reductase (NADH) enzyme deficiency, and drug induced [3]. The diagnosis of clinical methemoglobinemia depends on the co-oximeter measurement of an elevated methemoglobin level (>1% or 2%) [4]. Treatments include the use of methylene blue and other agents such as ascorbic acid and riboflavin. \n\nDrug-induced methemoglobinemia is commonly seen in patients undergoing endoscopic procedures such as EGDs, laryngoscopies, and bronchoscopies. It should be considered in patients presenting with cyanosis and hypoxemia following topical pharyngeal anesthetic use. Despite the rare incidence, most cases of topical-anesthesia-induced methemoglobinemia are secondary to benzocaine. Benzocaine is considered to be a more powerful oxidizing agent compared to lidocaine, and a dose-response relationship has been observed between benzocaine and methemoglobin [5]. There is insufficient evidence for methemoglobinemia caused by topical pharyngeal lidocaine alone and reported cases of lidocaine associated methemoglobinemia occurred in patients with either cardiorespiratory diseases or with the use of other anesthetic agents [5]. In a review of 242 cases of methemoglobinemia by Guay et al., benzocaine was implicated in 66% of all cases, while lidocaine accounted for only about 5% [4]. More recently, in a retrospective study by Vallurupalli et al. to determine the incidence of methemoglobinemia with the use of different local anesthetics, it was noted that all cases resulted from the use of 20% benzocaine spray. No cases were reported with lidocaine spray [6].\nThis case has been presented as an abstract to the American Journal of Gastroenterology [7]. (Abstract: Riaz S, Kudaravalli P, Saleem SA, Heisig D. Methemoglobinemia: A Life-Threatening Complication of Topical Pharyngeal Anesthetics. American Journal of Gastroenterology; October 2019).\n\nConclusions\nMethemoglobinemia is a rare complication in clinical practice; however, it is commonly seen in patients undergoing endoscopic procedures. Methemoglobinemia is believed to be seen in patients with genetic predispositions; however, the increasing use of topical anesthetics during procedures has made methemoglobinemia a disease entity that every clinical provider should be able to recognize. Drug-induced methemoglobinemia is more commonly seen with benzocaine than lidocaine. Therefore, if the use of topical pharyngeal anesthetics is deemed necessary during an endoscopic procedure, topical viscous lidocaine should be preferred over benzocaine to avoid this potentially life-threatening complication.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 The influence of lidocaine topical anesthesia during transesophageal echocardiography on blood methemoglobin level and risk of methemoglobinemia Int J Cardiovasc Imaging Filipiak-Strzecka D Kasprzak JD Wiszniewska M Walusiak-Skorupa J Lipiec P 727 731 31 2015 25663608 \n2 Methemoglobinemia: etiology, pharmacology, and clinical management Ann Emerg Med Wright RO Lewander WJ Woolf AD 646 656 34 1999 10533013 \n3 Methemoglobin levels following intravenous lidocaine administration Ann Emerg Med Weiss LD Generalovich T Heller MB Paris PM Stewart RD Kaplan RM Thompson DR 323 325 16 1987 3813168 \n4 Methemoglobinemia related to local anesthetics: a summary of 242 episodes Anesth Analg Guay J 837 845 108 2009 19224791 \n5 Methemoglobinemia complicating topical lidocaine used during endoscopic procedures Am J Med Karim A Ahmed S Siddiqui R Mattana J 150 153 111 2001 11498069 \n6 Risk of acquired methemoglobinemia with different topical anesthetics during endoscopic procedures Local Reg Anesth Vallurupalli S Manchanda S 25 28 4 2011 22915889 \n7 Methemoglobinemia: a life-threatening complication of topical pharyngeal anesthetics Am J Gastroenterol Riaz S Kudaravalli P Saleem SA Heisig D 0 114 2019\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(4)",
"journal": "Cureus",
"keywords": "lidocaine; methemoglobinemia; topical anesthesia",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e7900",
"pmc": null,
"pmid": "32494515",
"pubdate": "2020-04-30",
"publication_types": "D002363:Case Reports",
"references": "11498069;3813168;19224791;25663608;10533013;22915889",
"title": "Methemoglobinemia: A Life-threatening Complication of Topical Pharyngeal Anesthetics.",
"title_normalized": "methemoglobinemia a life threatening complication of topical pharyngeal anesthetics"
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"abstract": "Gorham-Stout disease is a life-threatening disorder often manifested by lymphatic malformation and osteolysis. Unfortunately, available therapies are not uniformly effective and often carry substantial morbidity. We report an 18-year-old male with Gorham-Stout disease manifested by lytic rib lesions and an intractable pleural effusion that responded dramatically to the combination of the mammalian target of rapamycin (mTOR) inhibitor sirolimus and the aminobisphosphonate zoledronic acid after failing interferon therapy. This tolerable therapeutic combination has demonstrated synergism in preclinical cancer models and merits further study in vascular anomalies.",
"affiliations": "Departments of *Pediatrics, Division of Hematology and Oncology, Children's of Alabama †Pathology, University of Alabama at Birmingham, Birmingham, AL ‡Department of Radiology §Cancer and Blood Disorders Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.",
"authors": "Cramer|Stuart L|SL|;Wei|Shi|S|;Merrow|Arnold C|AC|;Pressey|Joseph G|JG|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D007166:Immunosuppressive Agents; D000077211:Zoledronic Acid; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000514",
"fulltext": null,
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"issn_linking": "1077-4114",
"issue": "38(3)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004359:Drug Therapy, Combination; D006801:Humans; D007093:Imidazoles; D007166:Immunosuppressive Agents; D008297:Male; D010015:Osteolysis, Essential; D020123:Sirolimus; D000077211:Zoledronic Acid",
"nlm_unique_id": "9505928",
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"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gorham-Stout Disease Successfully Treated With Sirolimus and Zoledronic Acid Therapy.",
"title_normalized": "gorham stout disease successfully treated with sirolimus and zoledronic acid therapy"
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"companynumb": "US-DRREDDYS-USA/USA/16/0080280",
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"abstract": "OBJECTIVE\nTo estimate the effects of using depot medroxyprogesterone acetate (DMPA) or oral contraceptives (OCs) containing 20 micrograms ethinyl estradiol and 0.15 mg desogestrel on serum lipid levels.\n\n\nMETHODS\nSerum lipids were measured at baseline and every 6 months thereafter for 3 years in 703 white, African-American, and Hispanic women using DMPA, OC, or nonhormonal birth control. Those who discontinued DMPA were followed for up to 2 additional years. Participants completed questionnaires containing demographic and behavioral measures every 6 months and underwent 24-hour dietary recalls annually. Mixed-model regression analyses and general-estimating-equations procedures were used to estimate changes over time in lipids by method along with their predictors.\n\n\nRESULTS\nUsers of OCs experienced significantly greater increases in levels of triglycerides, total cholesterol, very-low-density lipoprotein (VLDL) cholesterol, and high-density lipoprotein (HDL) cholesterol than did nonhormonal-contraceptive users (P<.001). However, no difference was noted in the low-density lipoprotein (LDL) cholesterol:HDL ratio between OC users and nonhormonal-contraceptive users. Among DMPA users, HDL levels initially decreased for 6 months but then returned to baseline. The LDL:HDL ratio rose in the first 6 months of DMPA use but then dropped back to baseline over the next 24 months. After DMPA was discontinued, triglyceride, VLDL, and HDL levels were significantly higher in women who used OCs than in those who chose nonhormonal (P<.05) methods.\n\n\nCONCLUSIONS\nUse of very-low-dose OCs containing desogestrel can elevate lipid levels. Users of DMPA were at increased risk of developing an abnormally low HDL level as well as an abnormally high LDL level and an increase in the LDL:HDL cholesterol ratio, although these effects appeared to be temporary.\n\n\nMETHODS\nII.",
"affiliations": "From the Department of Obstetrics and Gynecology, the Center for Interdisciplinary Research in Women's Health, and the Department of Preventive Medicine and Community Health, the University of Texas Medical Branch, Galveston, Texas.",
"authors": "Berenson|Abbey B|AB|;Rahman|Mahbubur|M|;Wilkinson|Gregg|G|",
"chemical_list": "D003276:Contraceptives, Oral; D014280:Triglycerides; D004997:Ethinyl Estradiol; D017135:Desogestrel; D002784:Cholesterol; D017258:Medroxyprogesterone Acetate",
"country": "United States",
"delete": false,
"doi": "10.1097/AOG.0b013e3181b76bea",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-7844",
"issue": "114(4)",
"journal": "Obstetrics and gynecology",
"keywords": null,
"medline_ta": "Obstet Gynecol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001741:African Americans; D002784:Cholesterol; D003276:Contraceptives, Oral; D017135:Desogestrel; D004997:Ethinyl Estradiol; D005260:Female; D006630:Hispanic or Latino; D006801:Humans; D006937:Hypercholesterolemia; D015228:Hypertriglyceridemia; D008137:Longitudinal Studies; D017258:Medroxyprogesterone Acetate; D014280:Triglycerides; D044465:Whites; D055815:Young Adult",
"nlm_unique_id": "0401101",
"other_id": null,
"pages": "786-794",
"pmc": null,
"pmid": "19888036",
"pubdate": "2009-10",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "19041439;9704813;161523;9225641;3157546;8513671;19135567;15914128;1836088;2878838;8520092;6221882;8574257;9757954;9673838;3287934;8449018;7639106;8419671;1832626;8497347;16860045;15695947;12270857;18599013;6446443;18827121;18342648;18460475;1436906;3171020;19254592;949896;1836755",
"title": "Effect of injectable and oral contraceptives on serum lipids.",
"title_normalized": "effect of injectable and oral contraceptives on serum lipids"
} | [
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"companynumb": "US-JNJFOC-20130706841",
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"actiondrug": "5",
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"activesubstancename": "UNSPECIFIED INGREDIENT"
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{
"abstract": "BACKGROUND\nGranuloma annulare (GA) and the related annular elastolytic giant cell granuloma (AEGCG) and interstitial granulomatous dermatitis (IGD) are idiopathic histiocytic inflammatory disorders, which are frequently recalcitrant to treatment.\n\n\nOBJECTIVE\nEvaluate the efficacy of sulphasalazine in treating GA, AEGCG and IGD.\n\n\nMETHODS\nSixteen patients were identified with granulomatous disease who were treated with sulphasalazine between September 2015 and September 2019. Outcomes were based on patients' and providers' subjective evaluations.\n\n\nRESULTS\nSixteen patients were included in the study (ages 56-89, four male and twelve female). Previous treatments were attempted in fifteen patients. Clinical improvement was seen in fourteen patients (87.5%). Initial improvement was noted within a mean (SD) of 66.4 (35.1) days after starting therapy, with increasing benefits over time. Ten patients (62.5%) reported complete or near-complete clearance, three patients (18.8%) reported significant improvement, and one (6.3%) reported partial improvement. Twelve patients elected to stop or reduce therapy, resulting in relapse or worsening in five patients.\n\n\nCONCLUSIONS\nSulphasalazine may be considered as treatment for GA and GA-related conditions.",
"affiliations": "Mayo Clinic, Scottsdale, AZ, USA.;Mayo Clinic, Scottsdale, AZ, USA.;Mayo Clinic, Scottsdale, AZ, USA.;Mayo Clinic, Scottsdale, AZ, USA.;Mayo Clinic, Scottsdale, AZ, USA.;Mayo Clinic, Scottsdale, AZ, USA.",
"authors": "Yang|Y W|YW|https://orcid.org/0000-0001-5465-0357;Lehrer|M D|MD|;Mangold|A R|AR|;Yiannias|J A|JA|;Nelson|S A|SA|;Pittelkow|M R|MR|",
"chemical_list": "D012460:Sulfasalazine",
"country": "England",
"delete": false,
"doi": "10.1111/jdv.16356",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0926-9959",
"issue": "35(1)",
"journal": "Journal of the European Academy of Dermatology and Venereology : JEADV",
"keywords": null,
"medline_ta": "J Eur Acad Dermatol Venereol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D003872:Dermatitis; D005260:Female; D006099:Granuloma; D016460:Granuloma Annulare; D006101:Granuloma, Giant Cell; D006801:Humans; D008297:Male; D008875:Middle Aged; D012460:Sulfasalazine",
"nlm_unique_id": "9216037",
"other_id": null,
"pages": "211-215",
"pmc": null,
"pmid": "32216136",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of granuloma annulare and related granulomatous diseases with sulphasalazine: a series of 16 cases.",
"title_normalized": "treatment of granuloma annulare and related granulomatous diseases with sulphasalazine a series of 16 cases"
} | [
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"actiondrug": "5",
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"abstract": "Tocilizumab (TCZ), an IL-6 receptor blocker, is approved for relapsing, refractory giant cell arteritis (GCA). We report real-life clinical experience with TCZ in GCA including assessment of responses on imaging (ultrasound (US) and 18F-Fluorodeoxyglucose Positron Emission Tomography-computed Tomography (18FDG-PET-CT)) during the first year of treatment. We included 22 consecutive patients with GCA treated with TCZ where EULAR core data set on disease activity, quality of life (QoL) and treatment-related complications were collected. Pre-TCZ US and 18FDG-PET/CT findings were available for 21 and 4 patients, respectively, where we determined the effect on US halo thickness, temporal and axillary artery Southend Halo Score and Total Vascular Score on 18FDG-PET-CT. The 22 patients with GCA (10 cranial, 10 large vessel, 2 both) had a median disease duration of 58.5 (range, 1-370) weeks prior to initiation of TCZ. Half had used prior conventional synthetic disease-modifying antirheumatic drug (csDMARDs). TCZ was initiated for refractory (50%), ischaemic (36%) or relapsing (14%) disease. Median follow-up was 43 (12-52) weeks. TCZ was discontinued due to serious adverse events (SAEs) in two patients. On treatment with TCZ, 4 discontinued prednisolone, 11 required doses ≤2.5 mg, 2 required daily dose of 2.5-5 mg and 5 needed prednisolones ≥5 mg daily. QoL improved by 50%. Total US halo thickness decreased in 38 arterial segments, median temporal artery Halo Score decreased from 11 to 0, axillary artery Halo Score remained stable. Median Total Vascular Score on FDG-PET/CT reduced from 11.5 to 6.5. In our experience, TCZ showed an excellent response with acceptable safety in GCA, with improvement on US and FDG-PET/CT imaging.",
"affiliations": "Rheumatology, Southend University Hospital NHS Foundation Trust, Westcliff-on-Sea,UK.;Rheumatology, Southend University Hospital NHS Foundation Trust, Westcliff-on-Sea,UK.;Rheumatology, Southend University Hospital NHS Foundation Trust, Westcliff-on-Sea,UK.;Rheumatology, Southend University Hospital NHS Foundation Trust, Westcliff-on-Sea,UK.;Rheumatology, Southend University Hospital NHS Foundation Trust, Westcliff-on-Sea,UK.;Radiology, Southend Hospital NHS Trust, Westcliff-on-sea,UK.;Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.;Rheumatology, Southend University Hospital NHS Foundation Trust, Westcliff-on-Sea,UK bhaskar.dasgupta@southend.nhs.uk.",
"authors": "Sebastian|Alwin|A|0000-0002-9562-6748;Kayani|Abdul|A|;Prieto-Pena|Diana|D|;Tomelleri|Alessandro|A|0000-0002-5440-2078;Whitlock|Madeline|M|;Mo|Jonathan|J|;van der Geest|Niels|N|;Dasgupta|Bhaskar|B|0000-0002-5523-6534",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.1136/rmdopen-2020-001417",
"fulltext": "\n==== Front\nRMD Open\nRMD Open\nrmdopen\nrmdopen\nRMD Open\n2056-5933 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\n33161376\nrmdopen-2020-001417\n10.1136/rmdopen-2020-001417\nVasculitis\nClinical caseEfficacy and safety of tocilizumab in giant cell arteritis: a single centre NHS experience using imaging (ultrasound and PET-CT) as a diagnostic and monitoring tool\nhttp://orcid.org/0000-0002-9562-6748Sebastian Alwin 12 Kayani Abdul 1 Prieto-Pena Diana 13 http://orcid.org/0000-0002-5440-2078Tomelleri Alessandro 14 Whitlock Madeline 1 Mo Jonathan 5 van der Geest Niels 6 http://orcid.org/0000-0002-5523-6534Dasgupta Bhaskar 12 \n1 \nRheumatology, Southend University Hospital NHS Foundation Trust, Westcliff-on-Sea,UK\n\n\n2 \nSchool of Sport, Rehabilitation and Exercise Science, University of Essex, Colchester, UK\n\n\n3 \nRheumatology, Marques De Valdecilla University Hospital, Santander, Spain\n\n\n4 \nUnit of Immunology, Rheumatology, Allergy and Rare Diseases, San Raffaele Scientific Institute, Milan, Italy\n\n\n5 \nRadiology, Southend Hospital NHS Trust, Westcliff-on-sea,UK\n\n\n6 \nRheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands\n\nCorrespondence to Bhaskar Dasgupta; bhaskar.dasgupta@southend.nhs.uk\n2020 \n9 11 2020 \n6 3 e00141705 8 2020 03 10 2020 21 10 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.Abstract\nTocilizumab (TCZ), an IL-6 receptor blocker, is approved for relapsing, refractory giant cell arteritis (GCA). We report real-life clinical experience with TCZ in GCA including assessment of responses on imaging (ultrasound (US) and 18F-Fluorodeoxyglucose Positron Emission Tomography-computed Tomography (18FDG-PET-CT)) during the first year of treatment. We included 22 consecutive patients with GCA treated with TCZ where EULAR core data set on disease activity, quality of life (QoL) and treatment-related complications were collected. Pre-TCZ US and 18FDG-PET/CT findings were available for 21 and 4 patients, respectively, where we determined the effect on US halo thickness, temporal and axillary artery Southend Halo Score and Total Vascular Score on 18FDG-PET-CT. The 22 patients with GCA (10 cranial, 10 large vessel, 2 both) had a median disease duration of 58.5 (range, 1–370) weeks prior to initiation of TCZ. Half had used prior conventional synthetic disease-modifying antirheumatic drug (csDMARDs). TCZ was initiated for refractory (50%), ischaemic (36%) or relapsing (14%) disease. Median follow-up was 43 (12–52) weeks. TCZ was discontinued due to serious adverse events (SAEs) in two patients. On treatment with TCZ, 4 discontinued prednisolone, 11 required doses ≤2.5 mg, 2 required daily dose of 2.5–5 mg and 5 needed prednisolones ≥5 mg daily. QoL improved by 50%. Total US halo thickness decreased in 38 arterial segments, median temporal artery Halo Score decreased from 11 to 0, axillary artery Halo Score remained stable. Median Total Vascular Score on FDG-PET/CT reduced from 11.5 to 6.5. In our experience, TCZ showed an excellent response with acceptable safety in GCA, with improvement on US and FDG-PET/CT imaging.\n\nGiant Cell ArteritisUltrasonographySystemic vasculitisGlucocorticoidsRoyal College of Physicians IrelandBresnihan-Molloy Fellowship\n==== Body\nINTRODUCTION\nINTRODUCTION\nGiant cell arteritis (GCA) is a vasculitis associated with sight loss, jaw and limb claudication, headaches, polymyalgia rheumatica and vascular damage.1 Glucocorticoids (GC) are the mainstay of long-term therapy. GiACTA study showed that tocilizumab (TCZ), an interleukin-6 receptor (IL-6R) antagonist, is more effective than placebo plus blinded prednisone taper for inducing sustained remission at 52 weeks. The European medicines agency (EMA) and the Food and Drug Administration (FDA) approved TCZ for the GCA. National Institute for Health and Care Excellence (NICE) approved its use in relapsing and refractory GCA from July 2018 for a maximum of 1 year.2\n\n\nAssessing real-life efficacy and safety of TCZ is difficult due to its cost, limited availability and absence of a GCA registry. It is also challenging to identify groups with highest unmet need. This involves disease stratification (severity, extent and damage) into subgroups according to response to GC: remitting, relapsing, refractory disease and patients with adverse effects/GC-intolerance.3 Large vessel GCA (LV-GCA) has a more relapsing course and requires higher cumulative doses of GC.4\n\n\nOur experience from a NHS Hospital emphasises several aspects of GCA disease management. It underlines the role of imaging (ultrasound (US) and 18F-Fluorodeoxyglucose Position Emission Tomography-computed Tomography (18FDG PET-CT)) and histology for providing secure diagnosis and stratifying disease type (cranial, large vessel (LV) or combined), pre-approval of TCZ. Disease assessment is problematic due to TCZ suppression of inflammatory markers. US (including the quantitative Southend Halo score) and 18PET-CT imaging during the follow-up of some TCZ-treated patients were included here. We also emphasise the need for nursing support to monitor adverse events, patient safety and logistic issues.\n\nWe hope that this case series enables improved standards of care, monitoring and use of other agents in GCA.\n\nKey messages\nWhat is already known about the study?\nTocilizumab (TCZ) is approved to treat refractory and relapsing giant cell arteritis (GCA); vascular ultrasound and FDG-PET/CT are recommended imaging tools to recognise GCA.\n\nWhat does the study add?\nThis real-life study shows Tocilizumab has an excellent response with acceptable safety and improves quality of life in GCA.\n\nUltrasound Halo Score may be a promising marker in addition to halo thickness and PET-CT total vascular score in assessing the GCA activity.\n\nHow might this impact on clinical practice or future developments?\nThese findings indicate that TCZ treatment is efficacious and safe outside the clinical trial setting; our real-life data indicate that vascular abnormalities on ultrasound (Halo Score) and FDG-PET/CT imaging improve during treatment and may be used to monitor response.\n\nMETHODS\nPatients\nWe included 22 consecutive patients with GCA treated with TCZ at Southend University Hospital from July 2018 to February 2020. Our academic centre is a tertiary referral centre in the East of England for GCA.\n\nThe diagnosis was based on clinical, laboratory and imaging findings5 with a confirmatory imaging test or temporal artery (TA) biopsy required. Diagnosis was confirmed by at least 6 months follow-up in all patients.\n\nEULAR core data items6 were prospectively collected (online supplemental table S1) including demographics, clinical symptoms and signs, ophthalmology report, GC use, disease-modifying antirheumatic drugs (DMARDs) therapy, comorbidities, clinical outcomes, imaging findings and laboratory results (online supplemental table S2).\n\n10.1136/rmdopen-2020-001417.supp2Supplementary data \n\n\n\n 10.1136/rmdopen-2020-001417.supp1Supplementary data \n\n\n\n GCA disease activity and adverse events were assessed by an expert rheumatologist (BD). ‘Remission’ was defined as the absence of signs and symptoms.7 For ‘refractory’ and ‘relapsing’ disease, we used the NHSE Blueteq form, a web-based approval system which notifies a person starting TCZ.8 ‘Refractory disease’ is inability to induce remission in a patient who has (i) confirmatory diagnosis of GCA with (ii) ischaemic signs or symptoms with a significant risk of end organ or vascular damage, despite optimal standard care (ie, GC safe doses in compliance with accepted Guidelines). ‘Relapsing disease’ is a patient previously responded to treatment with confirmatory evidence of currently active or progressive GCA with (a) definite ischaemic complications and/or (b) clear recurrence of symptoms with/without increased inflammatory markers without another explanation.\n\nStart of TCZ was not always associated with an increment of GC and remission was not always obtained by GC prior to initiate TCZ.\n\n‘Cranial GCA’ was defined as a disease limited to TAs and their branches. ‘LV-GCA’ was defined as a disease involving extra-cranial large vessels (thoracic and abdominal aorta; carotid, subclavian, axillary arteries (AAs)).\n\nImaging of temporal and axillary arteries\nUS scans were performed or supervised by an experienced ultrasonographer (BD) with an Esaote MyLabTwice, Esaote US machine using a linear probe LA435 (frequency 18 MHz or 22 MHz), colour Doppler frequency 9 MHz and a pulse repetition frequency of 2–3 kHz.9 The common superficial TA, its frontal and parietal branches and/or the AA were examined bilaterally in the long and short axis. Halo was measured at the point of maximum thickness in the longitudinal plane. A halo sign was morphologically defined as a US finding of a dark hypoechoic, non-compressible area around the vessel lumen.10–13 An abnormal vessel wall thickness was defined as >0.29–0.42 mm in TA segments and >1.0 mm in AA.14 The Southend Halo Score was determined as described.15 In addition, a provisional AA Halo Score was assessed.5 Baseline US scans were performed within 4 weeks of TCZ start.\n\nPET-CT: modified total vascular score\nPET scans were all combined with low-dose CT. Interval between FDG injection and image acquisition was 60 min. Vascular FDG uptake was visually graded compared to liver uptake (0: no uptake; 1: less than liver; 2: equal to liver; 3: greater than liver).16 For each patient, a modified total vascular score (TVS) was calculated including the AAs compared to previously published TVS.17 In total, 11 vascular regions (ascending aorta, aortic arch, descending thoracic aorta, abdominal aorta, innominate artery and bilateral carotid, subclavian and AAs) were assessed. Modified TVS ranged from 0 to 33 (previous TVS ranges 0–27), with higher scores indicating more intense and extensive vascular inflammation. Baseline PET scans were performed within 4 weeks of TCZ start. All 18PET-CT scans were reviewed and TVS was calculated by an experienced radiologist (JM).\n\nStatistical analysis\nStatistical analysis was performed using SPSS Statistics for Windows, version 18.0 (SPSS Inc. Chicago, IL, USA). All continuous variables were tested for normality, and results were expressed as means±SD/SEM or as the median and range as appropriate. The comparison of continuous variables among time periods was performed using the Wilcoxon signed-rank test. A two-sided p value <0.05 was considered statistically significant.\n\nRESULTS\nPatients’ characteristics\nAmong 22 patients treated with TCZ, 10 had cranial GCA, 10 LV-GCA and 2 with both. Indications for TCZ treatment were refractory (50%), ischaemic (36%) and relapsing (14%) disease. The median age of patients was 71 (range, 54–88) years, with 64% of them being females (table 1). Median duration after GCA diagnosis to initiate TCZ was 58.5 (range, 1–370) weeks. Temporal headache (73%), scalp tenderness (41%), jaw claudication (46%), constitutional symptoms (82%), polymyalgic symptoms (55%) and visual disturbance (59%) were the main clinical symptoms at the initial presentation (table 2). With visual symptoms, the patients complained of blurred vision (69%), diplopia (23%) and amaurosis (8%). Six (27%) patients had prior permanent sight loss due to ischaemic optic neuropathy, central retinal artery occlusion or both at presentation. Half had used a conventional synthetic disease-modifying antirheumatic drug (csDMARD) prior to initiation of TCZ, including methotrexate, leflunomide, azathioprine or mycophenolate mofetil (mean duration, 23 weeks). In all cases, DMARD was continued after TCZ start.\n\nTable 1 Main features at diagnosis of 22 patients with giant cell arteritis treated with tocilizumab\n\n\tGCA patients treated with TCZ (n=22)\t\n\nDemographic data\n\t\t\nAge, years (mean±SD)\t72.1±7.0\t\nFemale sex, n (%)\t14 (63.6)\t\nWeeks from GCA diagnosis to TCZ start, median (range)\t58.5 (1–370)\t\n\nGCA subset\n\t\t\nCranial, n (%)\t10 (45.5)\t\nLVV, n (%)\t10 (45.5)\t\nBoth, n (%)\t2 (9)\t\n\nCranial manifestations\n\t\t\nTemporal headache, n (%)\t16 (72.7)\t\nScalp tenderness, n (%)\t9 (40.9)\t\nJaw claudication, n (%)\t10 (45.5)\t\nVisual disturbances, n (%)\t13 (59.0)\t\n\nAmaurosis.\n\n\n\t1/13 (7.7)\t\n\nBlurred vision.\n\n\n\t9/13 (69.2)\t\n\nDiplopia.\n\n\n\t3/13 (23.1)\t\nVision loss, n (%)\t6 (27.3)\t\n\nAION.\n\n\n\t3/6 (50.0)\t\n\nCRAO.\n\n\n\t2/6 (33.3)\t\n\nAION+CRAO.\n\n\n\t1/6 (16.7)\t\n\nSystemic manifestations\n\t\t\nPMR symptoms, n (%)\t12 (54.5)\t\nConstitutional symptoms, n (%)\t18 (81.8)\t\n\nFever.\n\n\n\t4/18 (22.2)\t\n\nNight sweats.\n\n\n\t14/18 (77.8)\t\n\nWeight loss.\n\n\n\t13/18 (72.2)\t\n\nDiagnosis confirmatory test\n\t\t\nUltrasound, n (%)\t21 (95.4)\t\n\nUltrasound alone, n/N (%).\n\n\n\t7/21 (33.3)\t\n\nUltrasound + PET, n/N (%).\n\n\n\t8/21 (38.1)\t\n\nUltrasound+TAB, n/N (%).\n\n\n\t5/21 (23.8)\t\n\nUltrasound+PET+TAB, n/N (%).\n\n\n\t1/21 (4.8)\t\nPET/CT alone, n (%)\t1 (4.5)\t\n\nComorbidities\n\t\t\nHypertension, n (%)\t9 (40.9)\t\nDiabetes mellitus, n (%)\t5 (22.7)\t\nOsteoporosis, n (%)\t3 (13.6)\t\n\nPatients treated with DMARDs, n (%)\n\t11 (50.0)\t\nLeflunomide, n (%)\t6 (27.3)\t\nMycophenolate mofetil, n (%)\t2 (9.1)\t\nMethotrexate, n (%)\t4 (18.2)\t\nAzathioprine, n (%)\t1 (4.5)\t\nAION, anterior ischaemic optic neuritis; CRAO, central retinal artery occlusion; CT, computed tomography; GCA, giant cell arteritis; LVV, large vessel vasculitis; PET, position emission tomography; PMR, polymyalgia rheumatica; TCZ, tocilizumab.\n\nTable 2 Demographics, clinical, imaging and treatment details of 22 patients with giant cell arteritis treated with tocilizumab\n\nNo.\tAge\tSex\tGCA type\tConfirmatory test\tPrior\ncsDMARD\tDisease duration prior TCZ (months)\tTCZ indication\tTCZ treatment\tOutcome\tPrednisolone, dose at TCZ start\tPrednisolone, lowest dose during TCZ\t\n1\t66\tF\tLVV\tUS+PET\tMMF\t19\tRefractory\tContinuous\tRemission\t40 mg\t2.5 mg\t\n2\t73\tF\tLVV\tUS+PET\tMTX +AZA\t39\tRelapse\tContinuous\tRemission\t20 mg\t3.75 mg\t\n3\t70\tF\tLVV\tUS+PET\tLEF\t14\tRelapse\tContinuous\tRemission\t15 mg\t2.5 mg\t\n4\t84\tM\tCranial\tUS\t\t2\tIschaemia\tContinuous\tRemission\t20 mg\t6 mg\t\n5\t72\tF\tBoth\tUS+TAB\t\t1\tIschaemia\tContinuous\tRemission\t20 mg\t2.5 mg\t\n6\t70\tF\tLVV\tUS+PET\tLEF\t28\tRefractory\tDiscontinued\tRemission\t20 mg\t1 mg\t\n7\t75\tM\tCranial\tUS\t\t4\tIschaemia\tContinuous\tRemission\t60 mg\t2.5 mg\t\n8\t70\tM\tCranial\tUS\t\t3\tIschaemia\tInterrupted\tRemission\t60 mg\t15 mg\t\n9\t71\tF\tLVV\tUS+PET\tMTX\t35\tRefractory\tCompleted\tActive\t60 mg\t2.5 mg\t\n10\t77\tF\tCranial\tUS\t\t2\tRefractory\tContinuous\tRemission\t50 mg\t2.5 mg\t\n11\t59\tF\tCranial\tUS\t\t2\tIschaemia\tCompleted\tRemission\t60 mg\t2.5 mg\t\n12\t60\tM\tLVV\tUS+PET\tLEF\t15\tRefractory\tContinuous\tRemission\t10 mg\t0 mg\t\n13\t75\tF\tBoth\tUS+TAB\tMTX\t16\tRefractory\tDiscontinued\tActive\t60 mg\t8.75 mg\t\n14\t84\tF\tCranial\tUS+TAB\t\t0\tIschaemia\tCompleted\tRemission\t40 mg\t5 mg\t\n15\t69\tM\tLVV\tUS+TAB+PET\tMMF\t42\tRefractory\tCompleted\tRemission\t30 mg\t0 mg\t\n16\t68\tF\tCranial\tUS+TAB\tMTX+LEF\t92\tRelapse\tContinuous\tRemission\t20 mg\t2 mg\t\n17\t66\tM\tLVV\tUS+PET\tLEF\t20\tRefractory\tContinuous\tRemission\t20 mg\t15 mg\t\n18\t76\tF\tCranial\tUS\t\t4\tIschaemia\tContinuous\tRemission\t60 mg\t0 mg\t\n19\t71\tM\tCranial\tUS\t\t37\tIschaemia\tContinuous\tRemission\t20 mg\t2.5 mg\t\n20\t88\tM\tCranial\tUS+TAB\t\t12\tRefractory\tContinuous\tRemission\t30 mg\t12.5 mg\t\n21\t71\tF\tLVV\tUS+PET\tLEF\t21\tRefractory\tContinuous\tRemission\t7.5 mg\t7.5 mg\t\n22\t70\tF\tLVV\tPET\t\t3\tRefractory\tContinuous\tRemission\t30 mg\t0 mg\t\nAZA, azathioprine; csDMARD, conventional synthetic disease-modifying antirheumatic drug; GCA, giant cell arteritis; LEF, leflunomide; LVV: large vessel vasculitis; MTX, methotrexate; MMF, mycophenolate mofetil; PET: position emission tomography; TCZ: tocilizumab; US: ultrasound.\n\nEfficacy and safety of tocilizumab in real-life practice\nAll patients received TCZ subcutaneously (162 mg weekly); it was initiated intravenously (8 mg/kg) in four patients (18%) with critical ischaemic presentation.\n\nFour patients (18%) have completed 12 months of treatment. Three patients were in remission at this time point, with a maximum daily dose of 5 mg (range 0–5) prednisolone. One had an acute LV-GCA flare (confirmed by 18FDG-PET) within a month of stopping TCZ.\n\nFifteen patients (68%) are on TCZ (median duration of TCZ—43 weeks) and all remain in remission at their most recent follow-up evaluation with a median daily dose of 2.5 mg (range, 0–12.5) prednisolone.\n\nIn one patient, TCZ is currently withheld due to a leg ulcer. He is in remission with 15 mg of prednisolone (table 3). Six patients developed adverse events leading to a brief discontinuation of TCZ (2–8 weeks). In two patients (9%), TCZ had to be permanently discontinued. The first patient had a severe allergic reaction to TCZ, and the disease was in remission with 1 mg of prednisolone. In the second patient, TCZ was discontinued after six injections due to detection of new bladder cancer. At the last review, she was on prednisolone 8.75 mg daily.\n\nTable 3 Adverse events on TCZ\n\nPatient\tAdverse event\tTCZ outcome\tDuration of TCZ suspension\t\nPatient 1\tVaricella Zoster infection\tRestarted\t6 weeks\t\nPatient 3\tChicken pox\tRestarted\t4 weeks\t\nPatient 4\tDental abscess\tRestarted\t8 weeks\t\nPatient 5\tMyocardial infarction\tRestarted\t2 weeks\t\nPatient 6\tSevere allergic reaction\tDiscontinued\t–\t\nPatient 8\tLeg ulcer\tOn Hold\t3 weeks\t\nPatient 10\tInjection site reaction\tRestarted\t7 weeks\t\nPatient 13\tBladder cancer\tDiscontinued\t–\t\nPatient 16\tUrinary tract infection\tRestarted\t2 weeks\t\nTCZ: tocilizumab.\n\nThere were no new reports of vision loss on any patient after TCZ was started.\n\nEffect of tocilizumab on patient-reported outcomes\nSubjective measures of Quality of life (QoL), specifically mood level, sleep hygiene and fatigue, were evaluated by a questionnaire at the most recent follow-up visit (online supplemental table S3). Patients were asked whether these parameters had improved, remained similar or worsened since TCZ treatment was started. Eight (36%) patients reported that all three measures had improved, one (5%) patient reported that two had improved, three (14%) patients reported that one had improved and nine (41%) patients reported that all three remained similar. Only one patient reported worsening in two measures.\n\n10.1136/rmdopen-2020-001417.supp3Supplementary data \n\n\n\n Fifteen out of 22 patients contacted the Rheumatology advice line during their treatment, for a total of 28 calls (online supplemental table S4). Queries were mainly related to drug administration and possible adverse effects.\n\n10.1136/rmdopen-2020-001417.supp4Supplementary data \n\n\n\n Effect of tocilizumab on imaging findings (online supplemental table S5)\nChange in halo thickness on US was assessed in 21 patients. Halo thickness in a total of 92 and 66 arterial segments was recorded pre and post TCZ, respectively. Among the 54 segments with a positive halo before TCZ start, 38 showed a reduction during follow-up (range 3–12 months) of treatment (figure 1).\n\nFigure 1 Halo thickness in individual patients at TA branches and AA. AA, axillary artery; TA, temporal artery.\n\n10.1136/rmdopen-2020-001417.supp5Supplementary data \n\n\n\n The effect of TCZ on the TA and AA Halo Score was evaluated in five and eight patients, respectively. TA Halo Score showed a marked improvement on follow-up (range 3–12 months). The AA Halo Score remained stable during the follow-up period (range 3–12 months) (figure 2).\n\nFigure 2 (A) TA and AA Halo Score pre and post TCZ. (B) PET-CT TVS before and after TCZ. AA, axillary artery; TA, temporal artery; TCZ, tocilizumab; TVS, total vascular score.\n\nBaseline and follow-up 18FDG-PET/CT scans were available for four patients. The modified TVS decreased after 8 months (range 2–8 months) of TCZ treatment.\n\n\nOnline supplemental table S5 gives more information regarding US and PET-CT results with timelines of assessments.\n\nDISCUSSION\nOur real-life experience shows that TCZ is efficacious and safe outside the clinical trial setting in the treatment of relapsing and refractory GCA. It leads to a significant reduction in GC dose and improves QoL. Imaging abnormalities on US and FDG-PET/CT scan improve during treatment and may be used to monitor response and assess GCA disease activity.\n\nOur study results indicate that TCZ has an effective steroid sparing effect in GCA patients, and this supports evidence from GiACTA.2 Our data showed a remission rate of 91% on TCZ with a significant reduction in GC from a median daily dose of 30 mg to 2.5 mg. The cumulative GC dose reduction is noted here, as in published data.18 Daily maintenance dose of GC (IQR 1–5 mg) was achieved within a shorter period as compared to EULAR and British Society for Rheumatology (BSR) recommendations.19–21 Clinical remission was defined as the absence of signs and symptoms of GCA. In addition, we included objective measures such as stability or improvement of US halo thickness or PET-CT uptake. Inflammatory parameters such as C-Reactive Protein (CRP) were not considered in our study to assess the disease activity as CRP level normalises with TCZ due to IL-6 blockade.22\n\n\nNICE approval of TCZ in the UK is limited to 12 months. Among the four patients (18%) who completed the 12 months TCZ to date, one had an acute LV-GCA flare (confirmed by FDG-PET) within a month of stopping TCZ. A similar aortic flare after 12 months led to a death with a ruptured aortic aneurysm.23 Valvular heart diseases, aortic aneurysm and dissection are well-known complications of LV-GCA.24\n\n\nCurrent NICE TA highlights the unmet need for effective GC sparing agents beyond 12 months of therapy in relapsing and refractory GCA. There is lack of quality evidence for maintenance of cDMARDs in GCA. A meta-analysis suggests a modest effect for methotrexate and there are case series and an open non-randomised study of leflunomide.25–27 We feel that TCZ retreatment should be permitted and even continued long term with aortic/large vessel disease. There is also a need to recruit TCZ unresponsive or post-TCZ flares to further clinical trials in GCA.\n\nPermanent visual loss is a significant complication of GCA.28 Our study found six (27%) had lost sight before referral to our service. This data is higher than previously published data of GCA-related blindness of 15–20%29 30 but it is expected since NHSE guidelines include ischaemic vascular complications as refractory disease and hence as an eligibility criterion for TCZ.8\n\n\nDiverticulitis and bowel perforation have been reported in TCZ-treated rheumatoid arthritis patients.31 In our study, two had to permanently discontinue TCZ due to severe adverse events. However, our findings suggest that overall TCZ is well tolerated.\n\nNinety-five per cent of patients had US as first imaging investigation to diagnose GCA. This complies with the EULAR recommendation of GCA.9 Halo thickness reduced in most TA and AA segments, with statistically significant reduction seen in two. The Southend Halo Score,15 particularly the TA Halo Score, showed considerable improvement in follow-up scans. A single patient with persisting AA halo has completed 12 months treatment and remains clinical remission. Our ongoing HAS GCA (HAlo Score GCA) study5 should provide definitive answers for the role of quantitative Southend Halo Score in the prognosis and monitoring of GCA.\n\nThe study demonstrated a good correlation between the PET-CT TVS and the disease activity. Four in clinical remission (18%) had a PET-CT before and after TCZ treatment with significant reduction in TVS at follow-up. Grading of vascular uptake against the liver uptake16 32 previously did not include the AAs.7 We feel that AA inclusion in a modified TVS is essential in LV-GCA. A limitation of PET-CT is decreased FDG uptake after high-dose GC treatment.33 In our patients 1, 12, 17 and 21 who had a follow-up PET-CT, the daily dose of prednisolone was 2.5, 0, 1.5 and 7.5 mg, respectively, which was withheld 2 weeks before the scan.\n\nNursing support played a major role in initiating and monitoring TCZ drug therapy. Nearly half of the patients’ queries could be resolved by specialist nursing staff. Patients were comfortable sharing their subjective measures and queries through the telephone helpline. Minor adverse events, blood monitoring abnormalities or logistic problems were identified promptly and brought to immediate attention of the treating clinician.\n\nAmong our strengths, this is the first case series with data collection based on the EULAR core dataset, towards a GCA registry. The use of US and PET-CT to diagnose and monitor our cohort along with nursing input seems a requirement for using biologic agents in GCA.\n\nAmong limitations is the retrospective real-life study design with small sample size. Not all the patients had completed the 12 months of follow-up. Follow-up US results were not available in all the segments. However, the available Halo Score results bear promise. Follow-up PET-CT and TVS were available in four patients but showed significant improvement and suggest PET-CT as an effective monitoring modality for LV-GCA.\n\nIn conclusion, our data suggests that TCZ is efficacious and safe in GCA. US is a valuable imaging tool for diagnosis and follow-up of GCA disease activity. Quantitative Southend Halo Score may be superior to halo thickness in assessment of GCA. PET-CT is a useful investigation, particularly in LV-GCA. Nursing support is vital and plays a pivotal role in GCA services.\n\nTwitter: Bhaskar Dasgupta @profbdasgupta.\n\nAcknowledgements: All authors would like to thank the Research and Development department at Southend University hospital and the East of England ENRAD MDT led by Dr Frances Hall.\n\nContributors: AS, DPP, MW and BD contributed to the conception or design of the work. DPP, AK, AT and BD contributed to acquisition of data. All US scans were done or supervised by BD. All PET-CT scans were reported and TVS calculated by JM. AS, DPP, KSMvdG and BD contributed to the analysis or the interpretation of data. All authors were involved in drafting the work or revising it critically for relevant intellectual content. All authors provided final approval of the version published.\n\nFunding: AS received an international educational (Bresnihan-Molloy) fellowship grant from the Royal College of Physicians of Ireland.\n\nCompeting interests: BD reports grants and personal fees from Roche, personal fees from GSK, BMS, Sanofi and Abbie, outside the submitted work. KSMvdG reports grants from the Mandema Stipend and the Dutch Society for Rheumatology, and personal fees from Roche, outside the submitted work. All other authors have nothing to declare.\n\nPatient consent for publication: Not required.\n\nEthics approval: This is a retrospective study where Research Ethics Committee approval is not required according to the local ethics guidelines.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData availability statement: All data relevant to the study are included in the article or available as supplemental material.\n\nSupplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.\n==== Refs\nREFERENCES\n1 \n\nDejaco \nC \n, \nDuftner \nC \n, \nButtgereit \nF \n , et al.\nThe spectrum of giant cell arteritis and polymyalgia rheumatica: revisiting the concept of the disease\n. Rheumatology (UK) \n2017 \n10.1093/rheumatology/kew273 \n\n2 \n\nCoath \nF \n, \nGillbert \nK \n, \nGriffiths \nB \n , et al.\nGiant cell arteritis: new concepts, treatments and the unmet need that remains\n. Rheumatology (United Kingdom) \n2019 ;58 :1123 –5\n. 10.1093/rheumatology/key326 \n\n3 \n\nKermani \nTA \n, \nDasgupta \nB \n \nCurrent and emerging therapies in large-vessel vasculitis\n. 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N Engl J Med \n2017 ;377 :317 –28\n. 10.1056/NEJMoa1613849 \n28745999 \n8 \nNHS England \nSpecialised services circular_SSC1894. Blueteq form. Technology appraisal 518: tocilizumab for treating giant cell arteritis\n. Issued July 2018 [Internet ]. Available \nhttp://www.moz-extension://aa362167-b248-4b0b-904d-52bbf5bafc6d/enhanced-reader.html?openApp&pdf=https%3A%2F%2Fwww.nice.org.uk%2Fguidance%2Fta518%2Fresources%2Ftocilizumab-for-treating-giant-cell-arteritis-pdf-82606786726597\n(accessed 17 Jul 2020) \n\n9 \n\nDejaco \nC \n, \nRamiro \nS \n, \nDuftner \nC \n , et al.\nEULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice\n. Ann Rheum Dis \n2018 ;77 :636 –43\n. 10.1136/annrheumdis-2017-212649 \n29358285 \n10 \n\nSchmidt \nWA \n, \nKraft \nHE \n, \nVorpahl \nK \n , et al.\nColor duplex ultrasonography in the diagnosis of temporal arteritis\n. N Engl J Med \n1997 ;337 :1336 –42\n. 10.1056/NEJM199711063371902 \n9358127 \n11 \n\nChrysidis \nS \n, \nDuftner \nC \n, \nDejaco \nC \n , et al.\nDefinitions and reliability assessment of elementary ultrasound lesions in giant cell arteritis: a study from the OMERACT large vessel vasculitis ultrasound working group\n. RMD Open \n2018 ;4 :e000598\n10.1136/rmdopen-2017-000598 \n29862043 \n12 \n\nAschwanden \nM \n, \nDaikeler \nT \n, \nKesten \nF \n , et al.\nTemporal artery compression sign - a novel ultrasound finding for the diagnosis of giant cell arteritis\n. Ultraschall Der Medizin \n2013 \n10.1055/s-0032-1312821 \n\n13 \n\nAschwanden \nM \n, \nImfeld \nS \n, \nStaub \nD \n , et al.\nThe ultrasound compression sign to diagnose temporal giant cell arteritis shows an excellent interobserver agreement\n. Clin Exp Rheumatol \n2015 .\n14 \n\nSchäfer \nVS \n, \nJuche \nA \n, \nRamiro \nS \n , et al.\nUltrasound cut-off values for intima-media thickness of temporal, facial and axillary arteries in giant cell arteritis\n. Rheumatol (UK) \n2017 \n10.1093/rheumatology/kex143 \n\n15 \n\nVan Der Geest \nKSM \n, \nBorg \nF \n, \nKayani \nA \n , et al.\nNovel ultrasonographic halo score for giant cell arteritis: assessment of diagnostic accuracy and association with ocular ischaemia\n. Ann Rheum Dis \n2019 \n10.1136/annrheumdis-2019-216343 \n\n16 \n\nSlart \nRHJA \n, \nGlaudemans \nAWJM \n, \nChareonthaitawee \nP \n , et al.\nFDG-PET/CT(A) imaging in large vessel vasculitis and polymyalgia rheumatica: Joint procedural recommendation of the EANM, SNMMI, and the PET Interest Group (PIG), and endorsed by the ASNC\n. Eur J Nucl Med Mol Imaging \n2018 \n10.1007/s00259-018-3973-8 \n\n17 \n\nGrayson \nPC \n, \nAlehashemi \nS \n, \nBagheri \nAA \n , et al.\n18F-fluorodeoxyglucose: positron emission tomography as an imaging biomarker in a prospective, longitudinal cohort of patients with large vessel vasculitis\n. Arthritis Rheumatol \n2018 \n10.1002/art.40379 \n\n18 \n\nCalderón-Goercke \nM \n, \nLoricera \nJ \n, \nAldasoro \nV \n , et al.\nTocilizumab in giant cell arteritis. Observational, open-label multicenter study of 134 patients in clinical practice\n. Semin Arthritis Rheum \n2019 \n10.1016/j.semarthrit.2019.01.003 \n\n19 \n\nStrehl \nC \n, \nBijlsma \nJWJ \n, \nDe Wit \nM \n , et al.\nDefining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations: viewpoints from an EULAR task force\n. Ann Rheum Dis \n2016 ;75 :952 –7\n. 10.1136/annrheumdis-2015-208916 \n26933146 \n20 \n\nHellmich \nB \n, \nAgueda \nA \n, \nMonti \nS \n , et al.\nUpdate of the EULAR recommendations for the management of large vessel vasculitis\n. Ann Rheum Dis \n2018 ;2020 \n10.1136/annrheumdis-2019-215672 \n\n21 \n\nMackie \nSL \n, \nDejaco \nC \n, \nAppenzeller \nS \n , et al.\nBritish society for rheumatology guideline on diagnosis and treatment of giant cell arteritis\n. Rheumatology \n2020 \n10.1093/rheumatology/kez664 \n\n22 \n\nVilliger \nPM \n, \nAdler \nS \n, \nKuchen \nS \n , et al.\nTocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial\n. Lancet \n2016 \n10.1016/S0140-6736(16)00560-2 \n\n23 \n\nM \nC \n, \nS \nJ \n \nA case for continuing tocilizumab beyond 12 months in giant cell arteritis?\n\nRheumatol Adv Pract \n2019 \n10.1093/rap/rkz028.024 \n\n24 \n\nRobson \nJC \n, \nKiran \nA \n, \nMaskell \nJ \n , et al.\nThe relative risk of aortic aneurysm in patients with giant cell arteritis compared with the general population of the UK\n. Ann Rheum Dis \n2015 \n10.1136/annrheumdis-2013-204113 \n\n25 \n\nAdizie \nT \n, \nChristidis \nD \n, \nDharmapaliah \nC \n , et al.\nEfficacy and tolerability of leflunomide in difficult-to-treat polymyalgia rheumatica and giant cell arteritis: a case series\n. Int J Clin Pract \n2012 \n10.1111/j.1742-1241.2012.02981.x \n\n26 \n\nDiamantopoulos \nAP \n, \nHetland \nH \n, \nMyklebust \nG \n \nLeflunomide as a corticosteroid-sparing agent in giant cell arteritis and polymyalgia rheumatica: a case series\n. Biomed Res Int \n2013 \n10.1155/2013/120638 \n\n27 \n\nHočevar \nA \n, \nJeše \nR \n, \nŽ \nR \n , et al.\nDoes leflunomide have a role in giant cell arteritis? An open-label study\n. Clin Rheumatol \n2019 \n10.1007/s10067-018-4232-x \n\n28 \n\nPatil \nP \n, \nWilliams \nM \n, \nMaw \nWW \n , et al.\nFast track pathway reduces sight loss in giant cell arteritis: results of a longitudinal observational cohort study\n. Clin Exp Rheumatol \n2015 .\n29 \n\nSalvarani \nC \n, \nCimino \nL \n, \nMacchioni \nP \n , et al.\nRisk factors for visual loss in an Italian population-based cohort of patients with giant cell arteritis\n. Arthritis Care Res \n2005 \n10.1002/art.21075 \n\n30 \n\nGonzález-Gay \nMA \n, \nGarcía-Porrúa \nC \n, \nLlorca \nJ \n , et al.\nVisual manifestations of giant cell arteritis: trends and clinical spectrum in 161 patients\n. Medicine (Baltimore) \n2000 \n10.1097/00005792-200009000-00001 \n\n31 \n\nStrangfeld \nA \n, \nRichter \nA \n, \nSiegmund \nB \n , et al.\nRisk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs\n. Ann Rheum Dis \n2017 \n10.1136/annrheumdis-2016-209773 \n\n32 \n\nSoussan \nM \n, \nNicolas \nP \n, \nSchramm \nC \n , et al.\nManagement of large-vessel vasculitis with FDG-PET\n. Medicine (United States) \n2015 \n10.1097/MD.0000000000000622 \n\n33 \n\nNielsen \nBD \n, \nGormsen \nLC \n, \nHansen \nIT \n , et al.\nThree days of high-dose glucocorticoid treatment attenuates large-vessel 18F-FDG uptake in large-vessel giant cell arteritis but with a limited impact on diagnostic accuracy\n. Eur J Nucl Med Mol Imaging \n2018 \n10.1007/s00259-018-4021-4\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2056-5933",
"issue": "6(3)",
"journal": "RMD open",
"keywords": "Giant Cell Arteritis; Glucocorticoids; Systemic vasculitis; Ultrasonography",
"medline_ta": "RMD Open",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D013700:Giant Cell Arteritis; D006801:Humans; D008297:Male; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography; D011788:Quality of Life; D013222:State Medicine",
"nlm_unique_id": "101662038",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33161376",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "24106691;29069518;32332274;25193809;24095936;27405509;30898837;28431106;29637252;26016760;31900304;9358127;29145713;25860208;27481272;26952547;28745999;30655091;29671039;26016758;31970410;22897467;22693039;29862043;26933146;11039076;31270110;30423174;30084049;29358285;15818722",
"title": "Efficacy and safety of tocilizumab in giant cell arteritis: a single centre NHS experience using imaging (ultrasound and PET-CT) as a diagnostic and monitoring tool.",
"title_normalized": "efficacy and safety of tocilizumab in giant cell arteritis a single centre nhs experience using imaging ultrasound and pet ct as a diagnostic and monitoring tool"
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"abstract": "OBJECTIVE\nDiabetes mellitus is recognized as a risk factor for mortality and morbidity after coronary bypass grafting. We aimed to determine the association between preoperative hemoglobin HbA1c and AF after isolated off-pump coronary bypass grafting (OPCAB).\n\n\nMETHODS\nThe seventy-two diabetic patients undergoing isolated off-pump coronary bypass grafting were retrospectively analyzed for AF. They were divided into; Low (4.8-5.4%), Medium (5.5-8%) and High (8.1-11.5%) groups. The three groups were compared with respect to demographic, echocardiographic, intraoperative and postoperative clinical characteristics correlation.\n\n\nRESULTS\nThree patients died during postoperative period. AF occurred in 12 patients (16.6%) after surgery. The incidence of postoperative AF was 15.3% in the lower, 4.4% middle and 57.1% upper group. There was statistically significant correlation between preoperative HbA1C and preoperative stroke, preoperative MI history, Left atrial (LA) size, preoperative levosimendan, preoperative clopidogrel, postoperative AF, postoperative dopamine and dobutamine use, IABP, duration of extubation time, 24-hour chest tube drainage, duration of ICU and hospital mortality. Univariate logistic regression analysis showed significant correlation between postoperative AF and variables like preoperative HbA1c levels, LVEF<30%, history of preoperative MI, preoperative use of levosimendan, preoperative use of clopidogrel, postoperative dopamine, dobutamine adrenaline use, left atrium size, 24-hour chest tube drainage and length of stay in the intensive care unit.\n\n\nCONCLUSIONS\nPreoperative HbA1c levels could predict the occurrence of postoperative AF in diabetic patients and may entail to administer protective strategies.",
"affiliations": "Suleyman Surer, Chief Resident, Diskapi Yildirim Beyazit Training & Research Hospital, Department of Cardiovascular Surgery, Diskapi-Altindag/Ankara, Turkey.;Mustafa Seren, Chief Resident, Diskapi Yildirim Beyazit Training & Research Hospital, Department of Cardiovascular Surgery, Diskapi-Altindag/Ankara, Turkey.;Onur Saydam, Chief Resident, Diskapi Yildirim Beyazit Training & Research Hospital, Department of Cardiovascular Surgery, Diskapi-Altindag/Ankara, Turkey.;Ali Bulut, Chief Resident, Diskapi Yildirim Beyazit Training & Research Hospital, Department of Cardiovascular Surgery, Diskapi-Altindag/Ankara, Turkey.;Ugursay Kiziltepe, Professor of Cardiovascular Surgery, Diskapi Yildirim Beyazit Training & Research Hospital, Department of Cardiovascular Surgery, Diskapi-Altindag/Ankara, Turkey.",
"authors": "Surer|Suleyman|S|;Seren|Mustafa|M|;Saydam|Onur|O|;Bulut|Ali|A|;Kiziltepe|Ugursay|U|",
"chemical_list": null,
"country": "Pakistan",
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"doi": "10.12669/pjms.321.8588",
"fulltext": "\n==== Front\nPak J Med SciPak J Med SciPJMSPakistan Journal of Medical Sciences1682-024X1681-715XProfessional Medical Publications Pakistan PJMS-32-5910.12669/pjms.321.8588Original ArticleThe relationship between HbA1c & atrial fibrillation after off-pump coronary artery bypass surgery in diabetic patients Surer Suleyman 1Seren Mustafa 2Saydam Onur 3Bulut Ali 4Kiziltepe Ugursay 51 Suleyman Surer, Chief Resident, Diskapi Yildirim Beyazit Training & Research Hospital, Department of Cardiovascular Surgery, Diskapi-Altindag/Ankara, Turkey2 Mustafa Seren, Chief Resident, Diskapi Yildirim Beyazit Training & Research Hospital, Department of Cardiovascular Surgery, Diskapi-Altindag/Ankara, Turkey3 Onur Saydam, Chief Resident, Diskapi Yildirim Beyazit Training & Research Hospital, Department of Cardiovascular Surgery, Diskapi-Altindag/Ankara, Turkey4 Ali Bulut, Chief Resident, Diskapi Yildirim Beyazit Training & Research Hospital, Department of Cardiovascular Surgery, Diskapi-Altindag/Ankara, Turkey5 Ugursay Kiziltepe, Professor of Cardiovascular Surgery, Diskapi Yildirim Beyazit Training & Research Hospital, Department of Cardiovascular Surgery, Diskapi-Altindag/Ankara, Turkey\nCorrespondence: Dr. Suleyman Surer, MD. Chief Resident, Diskapi Yildirim Beyazit Training & Research Hospital, Department of Cardiovascular Surgery, Diskapi - Altindag / Ankara, Turkey. E-mail: drsuleyman1@hotmail.comJan-Feb 2016 32 1 59 64 17 7 2015 27 10 2015 05 11 2015 Copyright: © Pakistan Journal of Medical Sciences2016This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Objective:\nDiabetes mellitus is recognized as a risk factor for mortality and morbidity after coronary bypass grafting. We aimed to determine the association between preoperative hemoglobin HbA1c and AF after isolated off-pump coronary bypass grafting (OPCAB).\n\nMethods:\nThe seventy-two diabetic patients undergoing isolated off-pump coronary bypass grafting were retrospectively analyzed for AF. They were divided into; Low (4.8–5.4%), Medium (5.5–8%) and High (8.1–11.5%) groups. The three groups were compared with respect to demographic, echocardiographic, intraoperative and postoperative clinical characteristics correlation.\n\nResults:\nThree patients died during postoperative period. AF occurred in 12 patients (16.6%) after surgery. The incidence of postoperative AF was 15.3% in the lower, 4.4% middle and 57.1% upper group. There was statistically significant correlation between preoperative HbA1C and preoperative stroke, preoperative MI history, Left atrial (LA) size, preoperative levosimendan, preoperative clopidogrel, postoperative AF, postoperative dopamine and dobutamine use, IABP, duration of extubation time, 24-hour chest tube drainage, duration of ICU and hospital mortality. Univariate logistic regression analysis showed significant correlation between postoperative AF and variables like preoperative HbA1c levels, LVEF<30%, history of preoperative MI, preoperative use of levosimendan, preoperative use of clopidogrel, postoperative dopamine, dobutamine adrenaline use, left atrium size, 24-hour chest tube drainage and length of stay in the intensive care unit.\n\nConclusion:\nPreoperative HbA1c levels could predict the occurrence of postoperative AF in diabetic patients and may entail to administer protective strategies.\n\nKEY WORDS\nHbA1cOff-pump coronary surgeryAtrial fibrillation\n==== Body\nINTRODUCTION\nAtrial fibrillation (AF) is the most common arrhythmic complication of coronary artery bypass grafting surgery (CABG). Depending on the type of cardiac surgery, its incidence varies between 30% and 50%.1 The exact factors affecting its incidence are largely unknown. Postoperative AF has been showed to increase both postoperative and 10-year mortality rates, with the latter being increased by 29%.2 Some studies have reported that elevated HbA1c levels preceding surgery are linked to the severity of adverse outcomes after CABG.3 An elevated HbA1c level is reportedly related to a greater incidence of cardiovascular events.4 We aimed to determine the association between preoperative hemoglobin A1c and AF after isolated off-pump coronary bypass grafting (OPCAB).\n\nMETHODS\nSeventy-two diabetic patients undergoing OPCAB at our hospital from January 2012 to June 2014 were retrospectively analyzed for AF. The study was approved by the hospital ethic committee. OPCAB was performed in all patients and a shift to cardiopulmonary bypass was not necessary for any patients. Baseline demographic and clinical data were available for all patients, and medical records were accessed for the initial medical data. We divided these patients into three groups (control of diabetic regulation was very good, good and bad) according to the preoperative HbA1c levels. The cutoff points for the groups were selected as follows: Low group; 4.5–5.4% (n =13), Medium group; 5.5–8% (n = 45), and high group: 8.1–11.5% (n =14). Continuous electrocardiographic monitoring via a bedside monitor at the intensive care unit and a telemetry unit at the hospital ward were carried out in all patients after completion of the surgery.\n\nA 12-lead electrocardiogram was taken and evaluated by an experienced physician when the automatic alarm function detected an arrhythmic episode. HbA1c levels were measured before surgery by liquid chromatography. During the bypass surgery, multiple and complete coronary revascularization were attempted at all times, using a composite or sequential grafting in all cases. Arterial grafts in general, and in situ arterial grafts in particular, were used whenever possible. Continuous infusion of diltiazem (0.5-1. 0 µg/kg) was utilized to prevent arterial spasm during and within 24 hours after the operation, followed by oral diltiazem (90 mg/day), acetylsalicylic acid(100 mgr/day) and clopidogrel (75 mg/day) commenced at the next morning.\n\nAnesthetic & surgical technique\nIntravenous fentanyl citrate, midazolam, and vecuronium bromide were employed for anesthesia induction while intravenously administered remifentanyl, vecuronium bromide and low concentrations of inhaled sevoflurane as necessary served for anesthesia maintenance. Heparin was administered to anticoagulated patients after harvesting bypass conduits. The activated clotting time was maintained at more than 250s. The off-pump technique was used for all patients. Intravenous administration of Magnesium (Mg levels were kept over 2 mgr/dl) and potassium were given (K levels were kept over 4 mgr/dl) before pericardiotomy was done for all patients.\n\nStatistical Analysis\nStatistical analysis was performed on SPSS 15.0 for Windows software package with 95% confidence. Independent Sample t-test was used for the parametric features like age, BMI and HbA1c in the men and women. Kruskal Wallis H statistical analysis was used for the comparison between the non-parametric features in continuous variables of more than two groups. Relationships between variables were assessed by Pearson and Spearman correlation analysis. The effects of variables on postoperative AF occurrence were examined using logistic regression analysis. P <0.05 was considered statistically significant.\n\nRESULTS\nDemographic findings of the patient groups can be seen in Table-I. Fig.1 shows the distribution of HbA1c and the median value of HbA1c (25th–75th percentile) was 6.0 (5–7.5). AF occurred in 12 of 72 patients (16.6%) after surgery, most often on postoperative day 2 (75%), with 24.9% of occurrences on postoperative day 3. The incidences of postoperative AF were 15.3% (2/13) in the Low group, 4.4% (2/45) in the Median group, and 57.1% (8/14) in the High group. Three patients died at postoperative period in the High group (hospital mortality, P = 0.000) (Table-I).\n\nTable-I Baseline characteristics & operative variables.\n\n\t\tPreoperative HbA1C\tP value\t\n\t\n\t\tLow (n=13)\tMedian (n=45)\tHigh (n=14)\t\nSex\tMale/Female\t7/6\t26/19\t7/7\t0,831*\t\nAge\t62,85±7,84\t62,4±10,27\t66,21±10,21\t0,302*\t\nLVEF\t(<30)\t0 (0)\t2 (4,4)\t4 (28,6)\t0,910*\t\n(30-50)\t10 (76,9)\t20 (44,4)\t3 (21,4)\t\t\n(>50)\t3 (23,1)\t23 (51,1)\t7 (50)\t\nChronic renal failure\t1 (7,7)\t5 (11,1)\t1 (7,1)\t0,950\t\nHypertension\t10 (76,9)\t36 (80)\t11 (78,6)\t0,922\t\nPrevious cerebrovascular disease\t3 (23,1)\t1 (2,2)\t0 (0)\t0,011\t\nChronic pulmonary disease\t3 (23,1)\t3 (6,7)\t2 (14,3)\t0,499\t\nPeripheral vascular disease\t1 (7,7)\t2 (4,4)\t0 (0)\t0,319\t\nPrevious Myocardial infaction\t1 (7,7)\t12 (26,7)\t4 (28,6)\t0,213\t\nLeft atrial dimension (cm)\t3,64±0,4\t3,82±0,41\t3,99±0,44\t0,144\t\nNumber of anastomoses\t2,92±1,26\t2,62±1,3\t3,14±1,23\t0,245\t\nNumber of arterial anastomoses\t1,15±0,55\t1,27±0,5\t1,5±0,52\t0,066\t\nNumber of vein grafts\t2±0,82\t1,66±0,55\t1,7±0,95\t0,462\t\nPreoperative used of Beta- Blockers\t1 (7,7)\t15 (33,3)\t3 (21,4)\t0,451\t\nUse of Levosimendan\t1 (7,7)\t3 (6,7)\t5 (35,7)\t0,025\t\nAngiotensin converting inhibitors use\t4 (30,8)\t16 (35,6)\t8 (57,1)\t0,157\t\nUse of Angiotensin receptor blockers\t2 (15,4)\t8 (17,8)\t1 (7,1)\t0,540\t\nUse of Statins\t3 (23,1)\t14 (31,1)\t5 (35,7)\t0,482\t\nUse of Oral antidiabetics\t11 (84,6)\t24 (53,3)\t10 (71,4)\t0,521\t\nUse of Insulin\t1 (7,7)\t15 (33,3)\t2 (14,3)\t0,741\t\nUse of Clopidogrel\t2 (15,4)\t8 (17,8)\t5 (35,7)\t0,189\t\nEndartterectomy\t2 (15,4)\t4 (8,9)\t0 (0)\t0,150\t\nUse of Intra-aortic balloon pump\t0 (0)\t0 (0)\t4 (28,6)\t0,001\t\nUse of insulin during intensive care\t7 (53,8)\t18 (40)\t10 (76,9)\t0,243\t\nPostoperative use of Dopamin\t4 (30,8)\t20 (44,4)\t9 (64,3)\t0,081*\t\nPostoperative use of Dobutamin\t2 (15,4)\t2 (4,4)\t7 (50)\t0,010*\t\nPostoperative use of Adrenalin\t1 (7,7)\t0 (0)\t4 (28,6)\t0,028*\t\nPostoperative use of Diltizem\t1 (7,7)\t8 (17,8)\t5 (35,7)\t0,066*\t\nPostoperative AF occurrence\t0 (0)\t4 (8,9)\t8 (57,1)\t0,000\t\nPost-discharge AF\t0 (0)\t1 (2,2)\t4 (28,6)\t0,003\t\nMortality\t0 (0)\t0 (0)\t3 (21,4)\t0,005\t\nIntubation time(hr)\t9,08±3,73\t7,54±2,56\t17,68±29,8\t0,072\t\nChest tube drainage (ml)\t457,69±181,25\t432,22±183,76\t539,29±301,39\t0,658\t\nIntensive care unit stay time(hr)\t46,15±23,42\t39,33±10,97\t63,43±31,02\t0,006\t\nMean time to AF occurrence (day)\t-\t1,5±1\t1,38±0,74\t0,911\t\nData are number (percent), mean ± standard deviation, or median [25th–75th percentile]. Low 4.5-5.4%; Median, 5.5-8%; High, >8.%.\n\nFig.1 Distribution of Preoperative HbA1c.\n\nIn univariate logistic regression analysis between the presence of postoperative AF and variables like LVEF <30 (p=0.015), preoperative MI history (p = 0.004), preoperative use of levosimendan (p = 0.003) and clopidogrel (p = 0.011), postoperative dopamine (P = 0.036), dobutamine (p = 0.000) and adrenaline use (p = 0.004), LA size (P = 0.002), 24-hour chest tube drainage (p = 0.029), length of stay in the ICU (p = 0.003) and preoperative HbA1c (p = 0.000) showed values were statistically significant (p <0.05) (Table-III). Higher HbA1c levels were correlated with intraaortic balloon counter pulsation use (IABP) (p=0.01), preoperative cerebrovascular disease rate (p=0.011), use of preoperative levosimendan usage (p=0.025), use of postoperative dobutamine (p=0.01) and adrenalin (p=0.028) and longer intensive care unit stay (p=0.006). Correlation analysis showed that there is statistically significant correlation between preoperative HbA1C and occurrences of SVO (p = 0.020), postoperative AF with preoperative MI history (p = 0.002), Left atrial (LA) size (p = 0.000), preoperative use of levosimendan (p = 0.001), preoperative use of clopidogrel (p = 0.006), postoperative dopamine (p = 0.000) and dobutamine use (p = 0.000), IABP usage (p = 0.011), duration of extubation (p = 0.011), 24 hour chest tube drainage (p = 0.011), duration of ICU (p = 0.01) and hospital mortality (p = 0.000) (p <0.05) (Table-II).\n\nTable-II Correlation analysis of preoperative & postoperative variables with HbA1c values associated with AF.\n\n\tPreoperative HbA1C\tPostoperative AF\t\n\t\nr\tp\tr\tp\t\nPrevious cerebrovascular disease\t-0,273\t0,020\t-0,108\t0,364\t\nPrevious Myocardial infaction\t0,057\t0,632\t0,366\t0,002\t\nLeft atrial dimension (cm)\t0,151\t0,204\t0,441\t0,000\t\nLevosimendan\t0,201\t0,090\t0,394\t0,001\t\nClopidogrel\t0,089\t0,458\t0,321\t0,006\t\nPostoperative used of Dopamin\t0,081\t0,501\t0,262\t0,026\t\nPostoperative used of Dobutamin\t0,232\t0,049\t0,535\t0,000\t\nPostoperative used of Adrenalin\t0,253\t0,032\t0,464\t0,000\t\nUse of Intra-aortic balloon pump\t0,361\t0,002\t0,542\t0,000\t\nIntubation time(hr)\t0,167\t0,161\t0,300\t0,011\t\nChest tube drainage (ml)\t0,113\t0,346\t0,276\t0,019\t\nIntensive care unit stay time(hr)\t0,349\t0,003\t0,472\t0,000\t\nMortality\t0,303\t0,010\t0,466\t0,000\t\nTable-III All variables with the presence of postoperative AF in univariate logistic regression analysis.\n\n\tAF+ (n=12)\tAF – (n=60)\tOdds Ratio (95% C.I.)\tp\t\nSex\tM/F\t4/8\t28/32\t1,75 (0,48-6,44)\t0,400\t\nAge\t65,92±11,1\t62,68±9,6\t1,04 (0,97-1,11)\t0,299\t\nLVEF\t(>50)\t5 (41,7)\t28 (46,7)\tReferance\t0,015\t\n(30-50)\t3 (25)\t30 (50)\t0,56 (0,12-2,56)\t0,455\t\n(<30)\t4 (33,3)\t2 (3,3)\t11,2 (1,6-78,4)\t0,015\t\nChronic renal failure\t1 (8,3)\t6 (10)\t0,82 (0,09-7,49)\t0,859\t\nHypertension\t11 (91,7)\t46 (76,7)\t3,35 (0,4-28,25)\t0,267\t\nPrevious cerebrovascular disease\t- (-)\t4 (6,7)\t0 (0-)\t0,999\t\nChronic pulmonary disease\t3 (25)\t5 (8,3)\t3,67 (0,74-18,08)\t0,110\t\nPeripheral vascular disease\t- (-)\t3 (5)\t0 (0-)\t0,999\t\nPrevious Myocardial infaction\t7 (58,3)\t10 (16,7)\t7 (1,84-26,56)\t0,004\t\nPreoperative used of Beta- Blockers\t5 (41,7)\t14 (23,3)\t2,35 (0,64-8,56)\t0,196\t\nLevosimendan\t5 (41,7)\t4 (6,7)\t10 (2,16-46,26)\t0,003\t\nAngiotensin converting inhibitors\t6 (50)\t22 (36,7)\t1,73 (0,5-6,01)\t0,391\t\nAngiotensin receptor blockers\t1 (8,3)\t10 (16,7)\t0,45 (0,05-3,93)\t0,474\t\nStatins\t4 (33,3)\t18 (30)\t1,17 (0,31-4,37)\t0,819\t\nOral antidiabetics\t7 (58,3)\t38 (63,3)\t0,81 (0,23-2,86)\t0,744\t\nInsulin\t3 (25)\t15 (25)\t1 (0,24-4,18)\t1,000\t\nClopidogrel\t6 (50)\t9 (15)\t5,67 (1,49-21,54)\t0,011\t\nEndartterectomy\t- (-)\t6 (10)\t0 (0-.)\t0,999\t\nPostoperative use of Dopamin\t9 (75)\t24 (40)\t4,5 (1,1-18,34)\t0,036\t\nPostoperative use of Dobutamin\t7 (58,3)\t4 (6,7)\t19,6 (4,24-90,67)\t0,000\t\nPostoperative use of Adrenalin\t4 (33,3)\t1 (1,7)\t29,5 (2,92-297,9)\t0,004\t\nPostoperative use of Diltizem\t1 (8,3)\t13 (21,7)\t0,33 (0,04-2,79)\t0,308\t\nUse of Intra-aortic balloon pump\t4 (33,3)\t- (-)\t\t0,999\t\nUse of insulin during intensive care\t9 (75)\t26 (44,1)\t3,81 (0,94-15,5)\t0,062\t\nPost-discharge AF\t5 (41,7)\t- (-)\t\t0,999\t\nHospital Mortality\t3 (25)\t- (-)\t\t0,999\t\nLeft atrial dimension (cm)\t4,23±0,38\t3,73±0,39\t21,84 (3,25-146,71)\t0,002\t\nNumber of anastomoses\t2,92±1,24\t2,75±1,3\t1,1 (0,69-1,77)\t0,679\t\nNumber of arterial anastomoses\t1,25±0,45\t1,3±0,53\t0,82 (0,23-2,94)\t0,758\t\nNumber of vein grafts\t2±0,93\t1,68±0,65\t1,9 (0,64-5,64)\t0,245\t\nIntubation time(hr)\t18,83±32,25\t7,98±2,86\t1,13 (0,96-1,34)\t0,153\t\nChest tube drainage (ml)\t587,5±296,28\t431,67±182,95\t1 (1-1,01)\t0,029\t\nIntensive care unit stay time(hr)\t67±32,14\t40,9±14,51\t1,05 (1,02-1,09)\t0,003\t\nPreoperative HbA1C\t8,58±1,38\t6,31±1,06\t3,92 (1,92-7,99)\t0,000\t\nValues are odds ratio (95% confidence interval), LV, left ventricle; EF, Ejection fraction.\n\nCorrected Bonferroni Mann Whitney U test was used to find out the correlation of HbA1c level and several clinical conditions like the use of dopamine and ICU durations between medial and high groups (p = 0.008, p=0.001 p<0.016 respectively) (Table-I). The mortality was significantly higher in High group (n=3, 100%) compared to low and median groups.\n\nWhen examined all variables of preoperative HbA1c groups, statistically significant differences were found between groups of postoperative AF, AF after discharge and hospital mortality (p<0, 05) (Table-I).\n\nDISCUSSION\nAssociation of OPCAB surgery with decreased incidence of AF was shown in a meta analysis and provided evidence that OPCAB surgery may be associated with a reduced incidence of postoperative AF than on-pump CPB techniques in a generalized population. The off-pump and on-pump groups had postoperative AF incidences of 19% (1612/8265) and 24% (1976/8240).5 Our study revealed that AF complicated 16.6% of off-pump operations. Limited number of patients in our study can be shown to be the main reason of this low rates. In a prospective cohort study of 3089 patients with and without diabetes, Halkos et al.6 showed a significant correlation between HbA1c and in-hospital mortality and postoperative morbidity. The rates of postoperative complications, e.g. renal failure and cerebrovascular accident, were higher in patients with HbA1c ≥ 8.6%. AF occurred in 20.9% of patients having an HbA1c of less than 7.0% vs. 15.1% in those with an HbA1c level equal to or greater than 7.0%. Patients with a poor glycemic control evidenced by an HbA1c ≥7% had more complications than those with an HbA1c of less than 7%. Similarly, in 101 diabetic subjects operated with off-pump CABG, Matsuura et al.7 found a postoperative AF rate of 29.7% for an HbA1c of less than 6.5% and 22.2% for an HbA1c that was greater than 6.5%. In our study 72 diabetic patients undergoing OPCAB were retrospectively analyzed. We divided these patients into three groups according to the preoperative HbA1c levels (Low group; 4.5–5.4%, Medium group; 5.5–8%, and high group: 8.1–11.5%). Corrected Bonferroni Mann Whitney U test was used to find out the correlation of HbA1c level and several clinical conditions like the use of dopamine, ICU durations and mortality rates between medial and high groups. As a reason for this result, all of the patients in a low group LVEF values greater than 30%. However, Matsuura et al the two groups did not differ significantly with regard to early and late postoperative mortality, wound dehiscence, number of anastomosis, use of bilateral internal thoracic arteries, and patency rates. On the other hand, in 805 diabetic subjects operated with OPCAB surgery, Kinoshita et al.8 reported that the lower group, the middle group, and the upper group had postoperative AF rates of 28.3%, 17.4%, and 12.5%, respectively. Postoperative AF was less likely when an elevated preoperative HbA1c was present. Our study demonstrated that the lower group, the middle group, and the upper group had postoperative AF incidences of 15.3%, 4.4%, and 57.1%, respectively. The risk of postoperative AF was greater with an elevated preoperative HbA1c. Dublin et al.9 demonstrated an elevated risk in parallel with HbA1c level in a population-based case control study conducted in 1410 patients with newly-diagnosed AF. Another population-based study in 75-year-old subjects similarly showed higher HbA1c levels in patients who developed AF.10 Diabetics with higher HbA1c levels also suffer a higher rate of perioperative myocardial infarction.6,11. Our study also showed similar results in that higher HbA1c levels significantly associated with risk of death. Faritous et al.12 demonstrated that a higher incidence of IABP, massive bleeding, and multi-organ failure result from higher HbA1c levels. Morbidity, but not mortality, is increased by elevated HbA1c levels following CABG. We showed that elevated HbA1c level increased the likelihood of IABP use (p=0.01), rate of preoperative cerebrovascular disease (P=0.011), use of preoperative levosimendan (P=0.025), use of postoperative dobutamine (p=0.01) in conjunction with adrenaline (p=0.028), longer intensive care unit stay (p=0.006), postoperative and post-discharge AF, and mortality rate (p<0, 05). Goksedef et al.13 reported that in 150 diabetic and non-diabetic patients enrolled in a prospective fashion the rates of postoperative mediastinitis and local sternal infection (P = 0.8) were not significantly altered by an HbA1c level of >7%. On the other hand, Sato et al.14 in a prospective study of 273 diabetic and non-diabetic patients, demonstrated that diabetics with a HbA1c greater than 6.5% suffered significantly more postoperative complications (minor infections and a more labor-intensive hospital stay). Alserius et al.15 Prospectively investigated the relationship between HbA1c level and infection and mortality rates in 605 subjects. HbA1c level greater than 6% was associated with significantly increased incidence of superficial sternal wound infections and mortality.\n\nLimitations of the study\nFirst, off-pump technique was performed at a single center. Second, it was not a randomized controlled study. Third, it solely used preoperative laboratory data including HbA1c level but not assessed postoperative HbA1c alterations.\n\nCONCLUSION\nOur study showed that preoperative HbA1c level was associated with AF in diabetic patients undergoing OPCAB. In conclusion, preoperative HbA1c could be predicts the occurrence of postoperative AF after isolated off-pump CABG.\n\nDisclosure Statement: The authors declare no conflict of interest in this study.\n\n\nAuthors’ Contribution\nSuleyman Surer, Mustafa Seren and Ali Bulut conceived, designed and did statistical analysis & editing of manuscript.\n\nOnur Saydam did data collection and manuscripwof manuscript.\n==== Refs\nREFERENCES\n1 Crystal E Garfinkle MS Connolly SS Ginger TT Sleik K Yusuf SS Interventions for preventing post-operative AF in patients undergoing heart surgery Cochrane Database Syst Rev 2004 18 4 CD003611 doi:10.1002/14651858.CD003611 15495059 \n2 Benussi S Galanti A Alfieri O Restoring sinus rhythm in patients at a high risk for postoperative atrial fibrillation Arch Med Sci 2008 4 2 108 115 \n3 Filardo G Hamilton C Hebeler RF Hamman BL Grayburn PA New-onset postoperative atrial fibrillation after isolated coronary artery bypass graft surgery & long-term survival Circ Cardiovasc Qual Outcomes 2009 2 3 164 169 doi:10.1161/CIRCOUTCOMES.108.816843 20031833 \n4 Elley CR Kenealy T Robinson E Drury PL Glycated haemoglobin & cardiovascular outcomes in people with Type 2 diabetes: a large prospective cohort study Diabet Med 2008 25 11 1295 1301 doi:10.1111/j.1464-5491.2008.02581 19046219 \n5 Athanasiou T Aziz O Manqoush O Al-Ruzzeh S Nair S Malinovski V Does off-pump coronary artery bypass reduce the incidence of post-operative atrial fibrillation?A question revisited European J Cardio-thoracic Surg 2004 26 4 701 710 doi:10.16/j.ejcts.2004.05.053 \n6 Halkos ME Puskas JD Lattouf OM Kilgo P Kerendi F Song HK Elevated preoperative HbA1c level is predictive of adverse events after coronary artery bypass surgery J Thorac Cardiovasc Surg 2008 136 3 631 640 doi:10.1016/j.jtcvs.2008.02.091 18805264 \n7 Matsuura K Imamaki M Ishida A Shimura H Niitsuma Y Miyazaki M Off-pump coronary artery bypass grafting for poorly controlled diabetic patients Ann Thorac Cardiovasc Surg 2009 15 1 18 22 19262445 \n8 Kinoshita T Asai T Suzuki T Kambara A Matsubayashi K Preoperative hemoglobin A1C predicts atrial fibrillation after off-pump coronary bypass surgery Euro J Cardio-Thoracic Surg 2012 41 1 102 107 doi:10.1016/j.ejcts.2011.04.011 \n9 Dublin S Glazer NL Smith NL Psaty BM Lumley T Wiggins KL Diabetes mellitus, glycemic control, and risk of atrial fibrillation J Gen Intern Med 2010 25 8 853 858 doi:10.1007/s11606-010-1340 20405332 \n10 Johansen OE Brustad E Enger S Tveit A Prevalence of abnormal glucose metabolism in atrial fibrillation: A case control study in 75 year-old subjects Cardio-vascular Diabetol 2008 7 28 doi:10.1186/1475-2840-7-28 \n11 Knapik P Ciesla D Filipiak K Knapik M Zembala M Prevalence & clinical significance of elevated preoperative glycosylated hemoglobin in diabetic patients scheduled for coronary artery surgery Eur J Cardiothorac Surg 2011 39 4 484 489 doi:10.1016/j.ejcts.2010.07.037 21087870 \n12 Faritous Z Ardeshiri M Yazdanian F Jalali A Totonchi Z Azarfarin R Hyperglycemia or high hemoglobin A1C: Which one is more associated with morbidity & mortality after coronary artery bypass graft surgery?Ann Thorac Cardiovasc Surg 2014 20 3 223 228 doi:10.5761/atcs.oa.13.02282 \n13 Goksedef D Ömerolu S Yalvac E Bitargil M Ipek G Is elevated HbA1c a risk factor for infection after coronary artery bypass grafting surgery Turk J Thorac Cardiovasc Surg 2010 18 4 252 258 \n14 Sato H Carvalho G Sato T Lattermann R Matsukawa T Schricker T The association of preoperative glycaemic control, intraoperative insulin sensitivity & outcomes after cardiac surgery J Clin Endocrinol Metab 2010 95 9 4338 4344 doi:10.1210/jc.2010-0135 20631016 \n15 Alserius T Anderson RE Hammar N Nordqvist T Ivert T Elevated glycosylated hemoglobin (HbA1c) is a risk marker in coronary artery bypass surgery Scand Cardiovasc J 2008 42 6 392 398 doi:10.1080/14017430801942393 18609043\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1681-715X",
"issue": "32(1)",
"journal": "Pakistan journal of medical sciences",
"keywords": "Atrial fibrillation; HbA1c; Off-pump coronary surgery",
"medline_ta": "Pak J Med Sci",
"mesh_terms": null,
"nlm_unique_id": "100913117",
"other_id": null,
"pages": "59-64",
"pmc": null,
"pmid": "27022346",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "18822173;15495059;15450560;19262445;20405332;21087870;20631016;20031833;21612941;23666248;19046219;18609043;18805264",
"title": "The relationship between HbA1c & atrial fibrillation after off-pump coronary artery bypass surgery in diabetic patients.",
"title_normalized": "the relationship between hba1c atrial fibrillation after off pump coronary artery bypass surgery in diabetic patients"
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"abstract": "Cephalexin is a cephalosporin antibiotic that is commonly used in the treatment of infectious diseases. We report a patient exhibiting a rare adverse effect of cephalexin: drug-induced Acute Generalized Exanthematous Pustulosis (AGEP). We present this case because of the scarcity of reports associating cephalexin with AGEP in hopes that clinicians will consider AGEP in their differential diagnosis in the appropriate clinical setting.",
"affiliations": "University of Kansas Medical Center, Kansas City, Kansas, USA.;University of Kansas Medical Center, Kansas City, Kansas, USA.;University of Kansas Medical Center, Kansas City, Kansas, USA.",
"authors": "DaCunha|Matthew|M|;Moore|Sarah|S|;Kaplan|David|D|",
"chemical_list": null,
"country": "Italy",
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"doi": "10.4081/dr.2018.7686",
"fulltext": "\n==== Front\nDermatol ReportsDRDermatology Reports2036-73922036-7406PAGEPress Publications, Pavia, Italy 10.4081/dr.2018.7686Case ReportCephalexin-induced acute generalized exanthematous pustulosis DaCunha Matthew Moore Sarah Kaplan David University of Kansas Medical Center, Kansas City, Kansas, USAUniversity of Kansas Medical Center, 4601 W 109th St., Suite 116, Overland Park, KS 66211, USA. dookdoc@gmail.comContributions:the authors contributed equally.\n\nConflict of interest: the authors declare no potential conflict of interest.\n\n01 10 2018 01 10 2018 10 2 768618 3 2018 12 8 2018 19 7 2018 ©Copyright M. DaCunha et al., 20182018Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Cephalexin is a cephalosporin antibiotic that is commonly used in the treatment of infectious diseases. We report a patient exhibiting a rare adverse effect of cephalexin: drug-induced Acute Generalized Exanthematous Pustulosis (AGEP). We present this case because of the scarcity of reports associating cephalexin with AGEP in hopes that clinicians will consider AGEP in their differential diagnosis in the appropriate clinical setting.\n\nKey words\nTenderErythematousPustular eruptionDrug reactionAntibioticFunding: none.\n==== Body\nCase Report\nA 35-year-old female presented with a 10-day history of rash, starting on her left forearm, clinically diagnosed as a staphylococcal infection. The patient was started on cephalexin 500 mg three times a day by her primary care physician. She now presents with flat 2.0 cm superficially eroded plaques on her left forearm, which was the initial presenting lesion, as well as new erythematous eroding papules on the antecubital and popliteal fossa (Figure 1).\n\nShe describes the new lesions as both itchy and tender. She has stopped the antibiotics two days prior to this presentation. An initial bacterial culture taken by her primary care physician showed no growth. A repeat bacterial culture was obtained during this visit while starting a one-week course of trimethoprim/sulfamethoxazole. Mupirocin was also added to all affected areas. She returned four days later with more lesions appearing on the extremities (Figure 2).\n\nA skin biopsy was obtained along with a CBC and chemistry panel as culture results again showed no growth. The histology was non-diagnostic, showing a neutrophilic inflammation within the epidermis and areas of confluent parakeratosis. She was again seen three days later as the rash continued to spread on the extremities. She complained of flu like symptoms including fever, sweats, and malaise. Her bloodwork was unremarkable. Skin biopsy was repeated since the previous was non-diagnostic. Histology now showed intracorneal neutrophils and neutrophilic spongiosis along with pustule formation (Figure 3) consistent with Acute Generalized Exanthematous Pustulosis (AGEP), which correlated clinically. She was started on prednisone and resolved uneventfully over the next 2 weeks.\n\nDiscussion\nAGEP is a rare adverse reaction with only 3-5 cases per million per year.1-3 Though AGEP is rare, more than 90% of AGEP cases are drug-induced with the most common offenders being beta-lactam antibiotics.1-4 Cephalexin-induced AGEP, however, has only been reported in 3 case reports to our knowledge, making this case a probable 4th case supporting the connection between cephalexin and AGEP.5 Cephalexin is an oral 1st-generation cephalosporin beta-lactam antibiotic that has been shown to have bactericidal activity via the inhibition penicillin-binding proteins. 6 In comparison to 2nd and 3rd generation cephalosporins, cephalexin has more activity against gram-positive organisms, with less activity against gramnegatives. 1,2,7 Common side effects of cephalexin include dyspepsia, gastritis, diarrhea, abdominal pain, and urticarial,1,2,7,8 with AGEP being much rarer. Despite these adverse effects, cephalexin is a well-tolerated and effective bactericidal antibiotic used to treat gram-positive infections, making it a reasonable option in the treatment of common streptococcal and staphylococcal conditions including otitis media and pharyngitis. 8\n\nAGEP is a severe cutaneous reaction which is part of a group of pustular drug eruptions that commonly has a delayed diagnosis due to mimicking other rashes. Typically, the rash starts locally on flexor surfaces such as the groin and axilla, as in this case, before spreading into a more generalized distribution. AGEP presents as erythematous eruptions of pustules and papules. Although extremely uncommon, AGEP can present with signs of fever or malaise. Onset of rash usually occurs within 2 days of exposure to the offending agent, and typically resolves over the course of 1-2 weeks after discontinuation of the causative drug as the skin sheds and regenerates itself.1,9,10\n\nAlthough biopsy can be used as a supportive measure in diagnosis, AGEP is often diagnosed clinically.1 Treatment includes the discontinuation of the offending agent and infection prevention with topical antibiotics. Additionally, topical corticosteroids are beneficial in the treatment of AGEP.9\n\nConclusions\nWe present the challenges of diagnosing AGEP as its presentation can mimic other pustular eruptions. It can be difficult for the clinician to make an accurate and timely diagnosis. Clinical clues to diagnosis include flexural involvement of the rash, negative bacterial cultures, a recent exacerbation of symptoms while on appropriate antibiotic therapy. Clinical assessment diagnosis can be supported by histology with a skin biopsy.10 We present this particular case because of the paucity of reports associating cephalexin with AGEP in hopes of having clinicians consider AGEP in their differential diagnosis in the appropriate clinical setting. To our knowledge, cephalexin-induced AGEP has only been reported in 3 previous case reports.5 Although this case cannot conclusively say that AGEP was directly caused by cephalexin due to the delay in diagnosis, AGEP is the most likely diagnosis with cephalexin being the most probable cause. This would be the 4th probable case of cephalexin-induced AGEP. It is imperative for dermatologists to recognize the signs and symptoms of AGEP, as it may require the discontinuation of antibiotics such as cephalexin and prompt the use of alternative medications.1,9 It is also important to communicate to the patient and interdisciplinary team members that the condition may be resolved more rapidly with the use of topical corticosteroids in addition to discontinuation of the offending agent.9,10\n\nAcknowledgements\nThe authors would like to acknowledge Dr. Allison Lisle Cargnel for the histology image.\n\nFigure 1. Tender erythematous eroding papules on the antecubital fossa.\n\nFigure 2. Tender erythematous papulopustular eruption of the proximal lower extremity.\n\nFigure 3. Intracorneal neutrophils and neutrophilic spongiosis with subcorneal neutrophils forming pustule.\n==== Refs\nReferences\n1. Sidoroff A \nAcute generalized exanthematous pustulosis . Hautarzt \n2014 ;65 :430 -5 .24820800 \n2. Sidoroff A Halevy S Bavinck JN \nAcute generalized exanthematous pustulosis (AGEP)-a clinical reaction pattern . J Cutan Pathol \n2001 ;28 :113 -9 .11168761 \n3. Cranga TA Simpson MA Featherstone P. \nAcute generalised exanthematous pustulosis (AGEP)-a potential pitfall for the acute physician . Acute Med \n2016 ;15 :140 -4 .27759749 \n4. Roujeau JC Bioulac-Sage P Bourseau C \nAcute generalized exanthematous pustulosis. Analysis of 63 cases . Arch Dermatol \n1991 ;127 :1333 -8 .1832534 \n5. Holscher CM Mauck SK Armstrong L Buchanan JA \nMan with rash and nausea. Acute generalized exanthematous pustulosis after cephalexin use . Ann Emerg Med \n2011 ;58 :508 -16 .22098993 \n6. Williamson R Collatz E Gutmann L. \nMechanisms of action of beta-lactam antibiotics and mechanisms of nonenzymatic resistance . Presse Med \n1986 ;15 :2282 -9 .2949269 \n7. Gerald R Donowitz MD Gerald L Mandell MD \nBeta-Lactam Antibiotics . N Engl J Med \n1988 ;318 :490 -500 .3277054 \n8. Thienvibul C Vachiramon V Chanprapaph K. \nFive-year retrospective review of acute generalized exanthematous pustulosis . Dermatol Res Pract \n2015 ;2015 :260928 .26783390 \n9. Kley C Murer C Maul JT \nRapid involution of pustules during topical steroid treatment of acute generalized exanthematous pustulosis . Case Rep Dermatol \n2017 ;9 :135 -9 .28559812 \n10. Speeckaert MM Speeckaert R Lambert J Brochez L. \nAcute generalized exanthematous pustulosis: an overview of the clinical, immunological and diagnostic concepts . Eur J Dermatol \n2010 ;20 :425 -33 .20542841\n\n",
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"issue": "10(2)",
"journal": "Dermatology reports",
"keywords": "Antibiotic; Drug reaction; Erythematous; Pustular eruption; Tender",
"medline_ta": "Dermatol Reports",
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"title": "Cephalexin-induced acute generalized exanthematous pustulosis.",
"title_normalized": "cephalexin induced acute generalized exanthematous pustulosis"
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"abstract": "The authors present a case of a 66-year-old male who was diagnosed with human immunodeficiency virus, and his medical course of highly active antiretroviral therapy was complicated with the development of immune reconstitution inflammatory syndrome, which led to development of movement disorder consisting of right-sided resting tremor, neck dystonia, and jaw clenching.\n\n\n\nThe patient's symptoms resembled that of rubral tremor, and he underwent placement of a deep brain stimulation electrode into the left ventral intermediate nucleus of the thalamus with significant improvement of symptoms.\n\n\n\nThis is the first reported case in the literature of a human immunodeficiency virus-positive patient's treatment course complicated with immune reconstitution inflammatory syndrome with neurologic manifestation, which was refractory to medical therapy and thus treated with deep brain stimulation.",
"affiliations": "Riverside University Health System, Department of Neurosurgery, Riverside, California, USA. Electronic address: h.ghanchi@ruhealth.org.;Western University of Health Science, College of Osteopathic Medicine, Pomona, California, USA.;Riverside University Health System, Department of Neurosurgery, Riverside, California, USA.;Kaiser Permanente Los Angeles Medical Center, Department of Neurosurgery, Los Angeles, California, USA.",
"authors": "Ghanchi|Hammad|H|;Siddiqi|Imran|I|;Patchana|Tye|T|;Ananda|Ajay|A|",
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"issue": "141()",
"journal": "World neurosurgery",
"keywords": "Deep brain stimulation; HIV; Holmes; IRIS; Tremor",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000368:Aged; D001259:Ataxia; D046690:Deep Brain Stimulation; D006678:HIV; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D008297:Male; D013788:Thalamus; D014202:Tremor",
"nlm_unique_id": "101528275",
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"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Acquired Holmes Tremor in a Human Immunodeficiency Virus Immune Reconstitution Inflammatory Syndrome Patient Treated with Deep Brain Stimulation.",
"title_normalized": "acquired holmes tremor in a human immunodeficiency virus immune reconstitution inflammatory syndrome patient treated with deep brain stimulation"
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"abstract": "We report on a 17-year-old girl who developed steatohepatitis and marked weight gain during risperidone treatment for paranoid psychosis. Viral, metabolic, and other causes of liver disease were excluded. Although the exact mechanism of antipsychotic associated weight gain is unclear, the impact of risperidone on the serotonergic system and on neuropeptide Y, a stimulator of food intake, might be implicated in the development of obesity. Additionally, weight gain-related hyperleptinemia could be a link between overweight and hepatotoxicity via cytokines. Physicians should routinely monitor body weight, liver function, fasting blood glucose, and lipid profiles in children and adolescents at the beginning of risperidone therapy. Additionally, patients complaining about weight gain should be monitored more carefully during the maintenance phase.",
"affiliations": null,
"authors": "Holtmann|M|M|;Kopf|D|D|;Mayer|M|M|;Bechtinger|E|E|;Schmidt|M H|MH|",
"chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone",
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"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D005234:Fatty Liver; D005260:Female; D006801:Humans; D010259:Paranoid Disorders; D018967:Risperidone; D015430:Weight Gain",
"nlm_unique_id": "8402938",
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"publication_types": "D016430:Clinical Trial; D016422:Letter",
"references": null,
"title": "Risperidone-associated steatohepatitis and excessive weight-gain.",
"title_normalized": "risperidone associated steatohepatitis and excessive weight gain"
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"abstract": "Minoxidil is a potent antihypertensive used as an adjunctive agent in refractory hypertension. It exerts an antihypertensive effect through two mechanisms: selective arterial vasodilation by activation of potassium channels in the vascular smooth muscle and stimulation of carotid and aortic baroreceptors, leading to downstream release of renin and norepinephrine. Although frequently cited in reviews of antihypertensive agents, limited data about the use of minoxidil in neonates are available. We describe an infant girl, born at 35 weeks of gestation, who was diagnosed with idiopathic hypertension after extensive diagnostic evaluation. Adequate blood pressure control was not achieved with captopril, amlodipine, and clonidine. Oliguria secondary to captopril and rapid-onset congestive heart failure due to persistent hypertension led to the introduction of intravenous agents labetalol and nitroprusside. Although adequate blood pressure control was achieved, attempts to transition back to oral agents were unsuccessful, prompting the use of minoxidil as an alternative agent. Although good blood pressure control was achieved, the infant's oral intake plummeted from 210 to 63 ml/kg/day. The anorexia quickly resolved after stopping minoxidil, and she was discharged home at 5 months of age receiving propranolol, amlodipine, and doxazosin. Use of the Naranjo adverse drug reaction probability scale indicated a definite relationship (score of 10) between the patient's development of anorexia and minoxidil therapy. To our knowledge, there have been no previous reports of minoxidil-associated anorexia in preterm or term infants. Clinicians should be aware that anorexia is a possible adverse effect of minoxidil in this patient population when initiating the drug in similar patients.",
"affiliations": "Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.",
"authors": "Vesoulis|Zachary A|ZA|;Attarian|Stephanie J|SJ|;Zeller|Brandy|B|;Cole|Francis Sessions|FS|",
"chemical_list": "D000959:Antihypertensive Agents; D008914:Minoxidil",
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"keywords": "adverse effect; anorexia; antihypertensive; idiopathic hypertension; minoxidil; neonatal; oliguria",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000855:Anorexia; D000959:Antihypertensive Agents; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D006974:Hypertension, Malignant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases; D008914:Minoxidil",
"nlm_unique_id": "8111305",
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"title": "Minoxidil-associated anorexia in an infant with refractory hypertension.",
"title_normalized": "minoxidil associated anorexia in an infant with refractory hypertension"
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"abstract": "We report the clinical features and outcome af a patient who presented Kaposi's sarcoma following immunosuppressive therapy for FGS; Cyclophosphamide and steroids were administered; the patient recovered after three months treatment with i.v. vinblastine.",
"affiliations": "Division of Nephrology and Dialysis, Desio Hospital, Milan, Italy. simona.zerbi@tiscalinet.it",
"authors": "Zerbi|S|S|;Saruggia|M|M|;Brambilla|L|L|;Lodeville|D|D|;Buccianti|G|G|",
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"mesh_terms": "D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D008297:Male; D008875:Middle Aged; D012514:Sarcoma, Kaposi; D012878:Skin Neoplasms",
"nlm_unique_id": "9012268",
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"references": null,
"title": "Kaposi's sarcoma in a patient with focal glomerulosclerosis.",
"title_normalized": "kaposi s sarcoma in a patient with focal glomerulosclerosis"
} | [
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"abstract": "We herein report the successful treatment of a 4-year-old girl with left ventricular noncompaction (LVNC) who presented with incessant ventricular fibrillation at 5 months of age. An implantable cardioverter defibrillator (ICD) was implanted, and dual chamber (DDD) pacing was initiated at 7 months of age. At her 10-month follow-up, her left ventricular ejection fraction (LVEF) had decreased from 45% to 20% with mechanical dyssynchrony. After upgrading to cardiac resynchronization therapy (CRT), the LVEF improved to 50%. The usefulness of CRT in pediatric LVNC has not been fully elucidated. However, our case suggests that CRT therapy may be an effective option for LVNC-induced cardiac dysfunction.",
"affiliations": "Department of Pediatrics, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.;Department of Pediatrics, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.;Department of Pediatrics, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.;Department of Pediatrics, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.",
"authors": "Kimura|Masato|M|0000-0002-9933-1402;Kawano|Kengo|K|0000-0002-6495-7325;Yaoita|Hisao|H|;Kure|Shigeo|S|",
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"doi": "10.1155/2018/9562326",
"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi 10.1155/2018/9562326Case ReportSuccessful Treatment of an Infant with Left Ventricular Noncompaction Presenting with Fatal Ventricular Arrhythmia Treated with Cardiac Resynchronization Therapy and an Implantable Cardioverter Defibrillator http://orcid.org/0000-0002-9933-1402Kimura Masato mkimura774@med.tohoku.ac.jphttp://orcid.org/0000-0002-6495-7325Kawano Kengo Yaoita Hisao Kure Shigeo Department of Pediatrics, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, JapanAcademic Editor: Tayfun Sahin\n\n2018 1 4 2018 2018 95623264 1 2018 1 3 2018 11 3 2018 Copyright © 2018 Masato Kimura et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We herein report the successful treatment of a 4-year-old girl with left ventricular noncompaction (LVNC) who presented with incessant ventricular fibrillation at 5 months of age. An implantable cardioverter defibrillator (ICD) was implanted, and dual chamber (DDD) pacing was initiated at 7 months of age. At her 10-month follow-up, her left ventricular ejection fraction (LVEF) had decreased from 45% to 20% with mechanical dyssynchrony. After upgrading to cardiac resynchronization therapy (CRT), the LVEF improved to 50%. The usefulness of CRT in pediatric LVNC has not been fully elucidated. However, our case suggests that CRT therapy may be an effective option for LVNC-induced cardiac dysfunction.\n==== Body\n1. Introduction\nLeft ventricular noncompaction (LVNC) is a rare congenital cardiomyopathy with a clinical presentation that ranges from no symptoms to sudden cardiac death due to fatal arrhythmia or heart failure. The onset of fatal ventricular arrhythmia under 1 year of age is a risk factor for cardiac death and an indication for heart transplantation [1]. LVNC is characterized by prominent left ventricular (LV) trabeculations and deep intertrabecular recesses, which are assumed to be the result of failure or abnormality of the myocardial compaction process during the prenatal period [2]. However, Jensen et al. recently hypothesized that hypertrabeculation may not be a failure of myocardial compaction, but rather an aberration of mammalian cardiogenesis [3]. Cardiac resynchronization therapy (CRT) for heart failure in pediatric congenital heart disease is an emerging option [4, 5]; however, few reports on CRT in pediatric LVNC patients are available [6].\n\n2. Case Report\nA 6-month-old girl was transferred to our university hospital presenting with incessant ventricular fibrillation (VF) after rewarming therapy for cerebral hypothermia. There was no family history of cardiovascular or neurologic disease. Her development until the event was normal, and at 5 months after birth, she went into cardiopulmonary arrest. During cardiopulmonary resuscitation by emergency medical services, VF was detected using an automated external defibrillator. Sinus rhythm was restored by defibrillation shock. Cerebral hypothermia treatment for 4 days was initiated at a tertiary emergency city hospital. After rewarming, VF occurred again and incessantly repeated without stimulation. She was moved to our university hospital, and her electrocardiogram (ECG) showed polymorphic ventricular tachycardia and VF (Figure 1(a)). After administration of various antiarrhythmic drugs and sedatives, the fatal arrhythmia finally stopped (Figure 1(b)). Laboratory blood tests did not indicate myocarditis or metabolic disease. A chest X-ray revealed no cardiomegaly with a cardiothoracic ratio (CTR) of 52% (Figure 1(c)). Transthoracic echocardiography confirmed global LV hypokinesis with an ejection fraction (EF) of 30%. B-mode analysis revealed a two-layer structure with a compacted thin epicardial band and a thick, noncompacted endocardial layer with prominent trabeculae and deep intertrabecular recesses at the LV apical and lateral walls. In the end-systolic phase, the ratio of noncompacted to compacted layers was 2.8. Color Doppler imaging revealed blood filling the recesses from the ventricular cavity (Figures 1(d) and 1).\n\nFor secondary prevention, an implantable cardioverter defibrillator (ICD) (Protecta™ XT DR; Medtronic, Minneapolis, MN, USA) was implanted in the patient's left upper abdominal quadrant, and dual chamber (DDD) pacing was started due to 2 : 1 atrioventricular (AV) block (Figure 1(f)), which might have been induced by administration of amiodarone and beta-blocker (at 7 months of age; height 68 cm, weight 5.6 kg) (Figure 2(a)). The shock lead was run outside of the epicardium and fixed at the level of the superior vena cava. At discharge, the left ventricular ejection fraction (LVEF) was 45% and the brain natriuretic peptide (BNP) level was 96 pg/ml. At her 10-month follow-up, the LVEF decreased to 20% and the patient's mitral regurgitation had deteriorated severely. Moreover, mechanical dyssynchrony was observed on strain echocardiography (Figure 2(e)), and the patient's BNP levels increased to 1,300 pg/ml. After ICD implantation, appropriate discharge of the ICD occurred only once when she had developed acute gastroenteritis with ventricular tachycardia. ICD right ventricular (RV) pacing was upgraded to biventricular pacing with a cardiac resynchronization therapy defibrillator (CRTD) (Viva™ XT; Medtronic, NJ, USA) (height 72 cm, weight 8.5 kg). After this upgrade, her LV function gradually improved, with an LVEF of 50% without mechanical dyssynchrony and mild mitral regurgitation (Figure 2(f)). The BNP level decreased to 26 pg/ml, and the CTR was 53% (Figure 2(b)). Over a 3-year follow-up period, the patient's course was uneventful and she was maintained on bisoprolol (0.3 mg/kg), enalapril (0.25 mg/kg), aspirin, and diuretics. The extent and location of abnormal LV trabeculation did not change during this period. Her developmental delays improved, with exercise, social, and vocal capacities being at the 2-, 3-, and 3-year-old levels, respectively.\n\nWhole exome sequencing revealed a nonsense mutation in exon 7 of the DTNA gene (C601T). While the patient's mother also had the same mutation in the DTNA gene, echocardiogram revealed that the mother's heart was morphologically and functionally normal. The patient's father did not have a mutation of the DTNA gene. The DTNA gene of the patient's older sister was not investigated because of her normal echocardiogram with no medical history.\n\n3. Discussion\nWe herein report the successful treatment of a 4-year-old girl who presented with incessant VF and LVNC at 5 months of age. After RV pacing, her cardiac function deteriorated and LVEF decreased; however, CRT corrected her mechanical dyssynchrony, which subsequently improved cardiac function.\n\nLVNC was first described pathologically by Grant in 1926 [7] and has been defined as a genetic cardiomyopathy by the American Heart Association since 2006 [8]. It is a rare disorder that is believed to develop due to cessation of the refinement of ventricular muscles between the 5th and 8th week of gestational age [2]. However, Jansen et al. recently hypothesized that hypertrabeculation is not a failure of myocardial compaction, but rather an aberration of mammalian cardiogenesis [3]. They proposed that the evolutionary and developmental models of normal and hypertrabeculated hearts and trabeculations in LVNC are not similar to the trabeculations of embryos or ectotherms, viewed in the light of histological and magnetic resonance imaging (MRI) findings.\n\nThe clinical presentation of LVNC ranges from no symptoms to sudden cardiac death due to fatal arrhythmia or heart failure. Brescia et al. investigated the long-term prognosis of 242 pediatric LVNC patients and reported that the mortality rate was 12.8%, the sudden cardiac death rate was 6.2%, and 5.4% of patients received a heart transplant [1]. The risk of death was strongly associated with cardiac dysfunction and ventricular arrhythmias for <1 year. LVNC is a genetically heterogeneous disorder, and gene mutations, which encode sarcomeric, cytoskeletal, and nuclear membrane proteins, are identified in only half of all reported cases [2]. In 2001, Ichida et al. reported a family with LVNC and a DTNA missense mutation in exon 4 (C362T) [9]. Whole exome sequencing in our patient revealed a nonsense mutation in exon 7 of the DTNA gene (C601T). Interestingly, our patient's mother also had the same mutation; however, her heart was morphologically normal. These differences may be due to incomplete penetrance of the DTNA gene in our case and/or the dominant negative effects of the missense mutation in exon 4. To the best of our knowledge, a DTNA gene mutation associated with LVNC was observed in only one family, and the function of the DTNA gene in LVNC has not been fully elucidated. No specific treatment has been established for LVNC, and ICD implantation is performed as a preventive measure for lethal ventricular arrhythmia. In a previous study, Kobza et al. reported that ICD implantation was effective as a primary and secondary preventive measure for sudden cardiac death in LVNC patients (30 patients; mean age 48 ± 14 years) [10]. Moreover, ICD with cardiac resynchronization improved LVEF from 22 ± 5% before implantation to 37 ± 15% after implantation, with a mean follow-up of 18 ± 11 months (six patients; mean age 58 ± 17 years). These studies were conducted in adult populations. However, implantation of ICD in pediatric patients is associated with several limitations. Indeed, the size of the devices and lead implantation result in placement difficulties of these therapeutic devices in pediatric patients. In our case, it seems that RV (DDD) pacing using an ICD caused LV function deterioration due to mechanical dyssynchrony. Cardiac function dramatically improved after introducing biventricular pacing using CRTD. It is known that in a certain proportion of pediatric patients with RV pacing, LV failure may develop. Indeed, Roman et al. demonstrated that epicardial RV free wall pacing is a risk factor for pacing-induced heart failure [11]. Moreover, due to their small heart size, selecting pacing lead positions is very difficult in infants. RV pacing-induced LV dysfunction responds well to biventricular pacing therapy [4]. Currently, there are no prospective randomized controlled trials evaluating pediatric CRT, and device therapy has become an emerging option for treating heart failure in pediatric heart disease [5]. Most reports in the medical literature concerning the use of CRT in pediatric patients are case reports that focus on the efficacy of CRT in treating severe heart failure. Only two large studies on the use of CRT in pediatric patients with dilated cardiomyopathy (DCM) have been published. Dubin et al. [12] reported their findings in 16 patients, while Cecchin et al. [13] included 10 patients with DCM in their study. No mortality was reported in these studies; however, additional reports of similar cases are needed to determine standard guidelines concerning the use of CRT in pediatric patients. The usefulness of CRT in pediatric LVNC remains to be fully elucidated. Our case suggests that CRT therapy could be an effective option for LVNC-induced cardiac dysfunction.\n\nThe present case provides important insights into the midterm effects of biventricular pacing and CRTD implantation for infantile LVNC. It is necessary to consider pediatric body size with respect to device and lead implantation. CRTD treatment is useful for the management of infantile LVNC with mechanical dyssynchrony and may improve prognosis.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Electrocardiogram (ECG) and arterial blood pressure monitoring on admission (a). (Top panel) ECG shows polymorphic ventricular tachycardia, with a rate of approximately 300 bpm. (Bottom panel) arterial blood pressure monitoring. (b) Lead II of the ECG after polymorphic ventricular tachycardia was stopped. The heart rate (HR) was 79 bpm, PR interval was 160 msec, and QTc interval was 510 msec with alternate T waves. (c) Chest X-ray on admission showing a cardiothoracic ratio of 52%. Transthoracic echocardiography on admission. (d) Transthoracic echocardiography shows left ventricular noncompaction on the parasternal short axis view, with a ratio of noncompacted to compacted area at end-systole > 2. (e) Color Doppler imaging reveals communication between myocardial recesses and the left ventricular cavity. (f) The 12-lead ECG before implantable cardioverter defibrillator (ICD) implantation, showing 2 : 1 atrioventricular block. The HR was 76 bpm, PR interval was 170 msec, and QTc interval was 462 msec. P indicates the P wave in lead II.\n\nFigure 2 Chest X-rays pre- and postcardiac resynchronization therapy (CRT). (a) The defibrillator was placed into the left upper abdomen, and the shock lead was fixed at the level of the superior vena cava. The right ventricular (RV) epicardial lead was placed at the RV free wall. (b) The left ventricular (LV) lead was placed at the LV lateral wall. The 12-lead ECG pre- and post-CRT. Before CRT (c), the QRS duration was 114 msec. After CRT (d), the QRS duration was shortened to 80 msec. Speckle-tracking radial dyssynchrony pre- and post-CRT (Artida™; Toshiba Medical Systems, Tokyo, Japan). Pre-CRT (e), dyssynchrony is shown as a time difference (arrow) between time to peak strain in the anterior wall (yellow) and septum peak strain (purple) (dual chamber (DDD) 90–150 bpm with an atrioventricular (AV) delay of 130 msec). Post-CRT (C-II), dyssynchrony disappeared (DDD 80–160 bpm, with an AV delay of 120 msec and a LV-RV delay of 0 msec).\n==== Refs\n1 Brescia S. T. Rossano J. W. Pignatelli R. Mortality and sudden death in pediatric left ventricular noncompaction in a tertiary referral center Circulation 2013 127 22 2202 2208 10.1161/circulationaha.113.002511 2-s2.0-84878602090 23633270 \n2 Oechslin E. Jenni R. Left ventricular non-compaction revisited: a distinct phenotype with genetic heterogeneity? European Heart Journal 2011 32 12 1446 1456 10.1093/eurheartj/ehq508 2-s2.0-79959422575 21285074 \n3 Jansen B. Agger P. de Boer B. A. The hypertrabeclated (noncompacted) left ventricle is different from the ventricle of embryos and ectothermic vertebrates Biochimica et Biophysica Acta 2016 1863 7 1696 1706 10.1016/j.bbamcr.2015.10.018 2-s2.0-84949024112 26516055 \n4 Janousek J. Gebauer R. A. Cardiac resynchronization therapy in pediatric and congenital heart disease PACE 2008 31 S21 S23 10.1111/j.1540-8159.2008.00949.x 2-s2.0-38449091239 18226029 \n5 Motonaga K. S. Dubin A. M. Cardiac resynchronization therapy for pediatric patients with heart failure and congenital heart disease: a reappraisal of results Circulation 2014 129 18 1879 1891 10.1161/circulationaha.113.001383 2-s2.0-84900415168 24799504 \n6 Saito K. Ibuki K. Yoshimura N. Successful cardiac resynchronization therapy in a 3-year-old girl with isolated left ventricular non-compaction and narrow QRS complex: a case report Circulation Journal 2009 73 2173 2177 10.1253/circj.cj-08-0806 2-s2.0-58549118184 19352045 \n7 Grant R. T. An unusual anomaly of the coronary vessels in the malformed heart of a child Heart 1926 13 273 283 \n8 Maron B. J. Towbin J. A. Thiene G. Contemporary definitions and classification of the cardiomyopathies Circulation 2006 113 14 1807 1816 10.1161/circulationaha.106.174287 2-s2.0-33646693410 16567565 \n9 Ichida F. Tsubata S. Bowles K. R. Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome Circulation 2001 103 9 1256 1263 10.1161/01.cir.103.9.1256 2-s2.0-0035814967 11238270 \n10 Kobza R. Steffel J. Erne P. Implantable cardioverter-defibrillator and cardiac resynchronization therapy in patients with left ventricular noncompaction Heart Rhythm 2010 7 11 1545 1549 10.1016/j.hrthm.2010.05.025 2-s2.0-77957324892 20493963 \n11 Gebauer R. A. Tomek V. Salameh A. Predictors of left ventricular remodelling and failure in right ventricular pacing in the young European Heart Journal 2009 30 9 1097 1104 10.1093/eurheartj/ehp060 2-s2.0-65949108587 19286675 \n12 Dubin A. M. Janousek J. Rhee E. Resynchronization therapy in pediatric and congenital heart disease patients. An international multicenter study Journal of the American College of Cardiology 2005 46 2277 2283 10.1016/j.jacc.2005.05.096 2-s2.0-26444442157 16360058 \n13 Cecchin F. Frangini P. A. Brown D. W. Cardiac resynchronization therapy (and multisite pacing) in pediatrics and congenital heart disease: five years experience in a single institution Journal of Cardiovascular Electrophysiology 2009 20 1 58 65 10.1111/j.1540-8167.2008.01274.x 2-s2.0-58149117952 18775051\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6404",
"issue": "2018()",
"journal": "Case reports in cardiology",
"keywords": null,
"medline_ta": "Case Rep Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101576452",
"other_id": null,
"pages": "9562326",
"pmc": null,
"pmid": "29808126",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "16567565;21285074;16360058;18226029;18775051;19286675;11238270;26516055;23633270;20493963;24799504;19352045",
"title": "Successful Treatment of an Infant with Left Ventricular Noncompaction Presenting with Fatal Ventricular Arrhythmia Treated with Cardiac Resynchronization Therapy and an Implantable Cardioverter Defibrillator.",
"title_normalized": "successful treatment of an infant with left ventricular noncompaction presenting with fatal ventricular arrhythmia treated with cardiac resynchronization therapy and an implantable cardioverter defibrillator"
} | [
{
"companynumb": "JP-PFIZER INC-2018518327",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMIODARONE HYDROCHLORIDE"
},
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{
"abstract": "OBJECTIVE\nTo evaluate a simplification strategy for HIV-1-infected patients virologically suppressed on antiretroviral therapy (ART) by switching to a single-tablet regimen consisting of efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF).\n\n\nMETHODS\n: Prospective, randomized, controlled, open-label, multicenter study.\n\n\nMETHODS\nPatients on stable ART with HIV-1 RNA <200 copies per milliliter for > or = 3 months were stratified by prior nonnucleoside reverse transcriptase inhibitor-based or protease inhibitor-based therapy and randomized (2:1) to simplify treatment to EFV/FTC/TDF or to stay on their baseline regimen (SBR). Efficacy and safety assessments were performed at baseline and at weeks 4, 12, 24, 36, and 48. Additional patient-reported outcomes included the following: adherence by visual analog scale, quality of life by SF-36 (v2) survey, HIV Symptom Index, and the Preference of Medication and Perceived Ease of the Regimen for Condition questionnaires.\n\n\nRESULTS\nThree hundred patients (EFV/FTC/TDF 203, SBR 97) were evaluated (prior protease inhibitor-based ART, 53%; nonnucleoside reverse transcriptase inhibitor-based ART, 47%). The arms were well balanced at baseline with 88% males, 29% blacks, and a mean age of 43 years; CD4 was 540 cells per cubic millimeter, 96% had HIV-1 RNA <50 copies per milliliter, and 88% were on their first ART regimen. Through 48 weeks, 89% vs. 88% in the EFV/FTC/TDF vs. SBR arms, respectively, maintained HIV-1 RNA <200 copies per milliliter by time to loss of virologic response algorithm (intent to treat, noncompleters = failures) with the difference (95% confidence interval) between arms of 1.1% (-6.7% to 8.8%), indicating noninferiority of EFV/FTC/TDF vs. SBR. Similarly, maintenance of HIV-1 RNA <50 copies per milliliter by time to loss of virologic response algorithm was 87% vs. 85% for EFV/FTC/TDF vs. SBR, respectively [difference (95% confidence interval) 2.6% (-5.9% to 11.1%)]. Discontinuation rates were similar (EFV/FTC/TDF 11%, SBR 12%); more discontinuations for adverse events occurred in the EFV/FTC/TDF arm vs. SBR (5% vs. 1%), most commonly for nervous system symptoms. More patients withdrew consent in the SBR arm vs. EFV/FTC/TDF (7% vs. 2%). Estimated glomerular filtration rate (by Modification of Diet in Renal Disease) remained unchanged over 48 weeks in both arms (median change < 1 mL.min.1.73 m). A decrease in fasting triglycerides was observed at 48 weeks in the EFV/FTC/TDF vs. SBR arm (-20 vs. -3.0 mg/dL; P = 0.035). Adherence of > or = 96% was reported by visual analog scale in both arms at baseline and at all study visits.\n\n\nCONCLUSIONS\nSimplification to EFV/FTC/TDF maintained high and comparable rates of virologic suppression vs. SBR through 48 weeks.",
"affiliations": "Orlando Immunology Center, Orlando, FL 32803, USA. edejesus@oicorlando.com",
"authors": "Dejesus|Edwin|E|;Young|Benjamin|B|;Morales-Ramirez|Javier O|JO|;Sloan|Louis|L|;Ward|Douglas J|DJ|;Flaherty|John F|JF|;Ebrahimi|Ramin|R|;Maa|Jen-Fue|JF|;Reilly|Karen|K|;Ecker|Janet|J|;McColl|Damian|D|;Seekins|Daniel|D|;Farajallah|Awny|A|;|||",
"chemical_list": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D004338:Drug Combinations; D063065:Organophosphonates; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine; C098320:efavirenz",
"country": "United States",
"delete": false,
"doi": "10.1097/QAI.0b013e3181a572cf",
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"issue": "51(2)",
"journal": "Journal of acquired immune deficiency syndromes (1999)",
"keywords": null,
"medline_ta": "J Acquir Immune Defic Syndr",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D003841:Deoxycytidine; D004338:Drug Combinations; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates; D010349:Patient Compliance; D000068698:Tenofovir",
"nlm_unique_id": "100892005",
"other_id": null,
"pages": "163-74",
"pmc": null,
"pmid": "19357529",
"pubdate": "2009-06-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Simplification of antiretroviral therapy to a single-tablet regimen consisting of efavirenz, emtricitabine, and tenofovir disoproxil fumarate versus unmodified antiretroviral therapy in virologically suppressed HIV-1-infected patients.",
"title_normalized": "simplification of antiretroviral therapy to a single tablet regimen consisting of efavirenz emtricitabine and tenofovir disoproxil fumarate versus unmodified antiretroviral therapy in virologically suppressed hiv 1 infected patients"
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"companynumb": "US-CIPLA LTD.-2015US05114",
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"activesubstance": {
"activesubstancename": "EFAVIRENZ"
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"abstract": "Febrile illness is a common clinical problem and frequently caused by bacterial and viral infections. When blood cultures are negative and symptoms persist despite empirical antibiotic treatment, clinicians must consider other differential diagnoses including malignancy, rheumatologic disease and parasitic infections.\n\n\n\nA Norwegian male in his eighties experienced febrile illness during a stay in Southern Spain. Upon return to Norway, he was hospitalized with fever, weight-loss, enlarged spleen, pancytopenia and hypergammaglobulinemia. After failing to respond to broad-spectrum antibiotics and antifungals, he was diagnosed with visceral leishmaniasis and Leishmania infantum was confirmed by PCR and sequencing of spleen biopsy and blood.\n\n\n\nWith increasing migration and tourism, doctors in non-endemic countries should be familiar with visceral leishmaniasis.",
"affiliations": null,
"authors": "Blomberg|Bjørn|B|;Müller|Karl Erik|KE|;Helgeland|Lars|L|;Fladeby|Cathrine|C|;Mørch|Kristine|K|",
"chemical_list": "D000981:Antiprotozoal Agents; D000666:Amphotericin B",
"country": "Norway",
"delete": false,
"doi": "10.4045/tidsskr.18.0546",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-2001",
"issue": "139(13)",
"journal": "Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke",
"keywords": null,
"medline_ta": "Tidsskr Nor Laegeforen",
"mesh_terms": "D000369:Aged, 80 and over; D000666:Amphotericin B; D000981:Antiprotozoal Agents; D001168:Arthritis; D005334:Fever; D006801:Humans; D018314:Leishmania infantum; D007898:Leishmaniasis, Visceral; D008297:Male; D010198:Pancytopenia; D013030:Spain; D013163:Splenomegaly; D014057:Tomography, X-Ray Computed; D000076082:Travel-Related Illness",
"nlm_unique_id": "0413423",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31556531",
"pubdate": "2019-09-24",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A man in his 80s with arthritis and persistent fever.",
"title_normalized": "a man in his 80s with arthritis and persistent fever"
} | [
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"companynumb": "NO-ACCORD-184366",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
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"activesubstancename": "PREDNISOLONE"
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"abstract": "Oncogenic osteomalacia is a rare paraneoplastic metabolic syndrome that is characterised by severe hypophosphataemia, hyperphosphaturia and osteomalacia secondary to renal loss of phosphate. It is commonly caused by overproduction of fibroblast growth factor-23 (FGF23) from benign tumours of mesenchymal origin. Currently, there is no clear evidence on the management of oncogenic osteomalacia in patients with metastatic solid tumours.\nWe report a case of breast cancer-induced oncogenic osteomalacia and discuss its diagnosis and management.\nA 71-year-old woman with advanced breast cancer developed symptomatic oncogenic osteomalacia with raised FGF23, severe hypophosphataemia and hypocalcaemia. The electrolytic disturbances were exacerbated after the administration of bisphosphonates in the context of her oncological treatment. Systemic chemotherapy and maintenance endocrine treatment along with phosphate and calcium supplementation reduced the activity of oncogenic osteomalacia and resolved the electrolytic imbalances.\nTo our knowledge, this is the first reported case of oncogenic osteomalacia in a patient with breast cancer. Oncogenic osteomalacia constitutes a diagnostic and therapeutic challenge. Pre-clinical and clinical evidence suggest that a possible underlying mechanism is the presence of molecular alterations in the FGF/FGFR signalling pathway leading to overexpression of FGF23. In metastatic setting, anticancer treatment can potentially lead to the normalisation of the electrolytic disturbances and reduction of the activity of oncogenic osteomalacia. The use of antiresorptive therapy in patients with bone metastases can potentially trigger FGF23 overexpression. Its use should be guided by the patients' risk of skeletal-related events and electrolytic disturbances as well as the degree of activity of oncogenic osteomalacia.",
"affiliations": "1Cancer Sciences Unit, Centre for Cancer Immunology, Faculty of Medicine, University Of Southampton, Tremona Road, Southampton, SO16 6YD UK.;2Translational Oncology, Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, NG51 PB UK.;2Translational Oncology, Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, NG51 PB UK.;4Department of Endocrinology and Metabolic Medicine, Nottingham University Hospitals NHS Trust, Nottingham, NG5 1PB UK.",
"authors": "Savva|Constantinos|C|0000-0003-0805-4719;Adhikaree|Jason|J|;Madhusudan|Srinivasan|S|;Chokkalingam|Kamal|K|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40200-019-00398-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2251-6581",
"issue": "18(1)",
"journal": "Journal of diabetes and metabolic disorders",
"keywords": "Breast cancer; Hypocalcaemia; Hypophosphataemia; Tumour-induced osteomalacia",
"medline_ta": "J Diabetes Metab Disord",
"mesh_terms": null,
"nlm_unique_id": "101590741",
"other_id": null,
"pages": "267-272",
"pmc": null,
"pmid": "31275898",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": "14988389;15040831;15998839;18230836;19933269;20356849;21030580;21490240;21712446;22069563;22298654;22532501;22552356;22893628;23000897;23393166;25155552;25655009;25682388;26078430;26093811;26273497;26463732;26612848;26718193;27034530;27118742;28326350;28571152;28703220;29021995;29632597;29696242",
"title": "Oncogenic osteomalacia and metastatic breast cancer: a case report and review of the literature.",
"title_normalized": "oncogenic osteomalacia and metastatic breast cancer a case report and review of the literature"
} | [
{
"companynumb": "PHHY2019GB164720",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
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"activesubstancename": "AMITRIPTYLINE"
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"drugadditional": "3",
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{
"abstract": "BACKGROUND\nFibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder marked by painful, recurrent flare-ups and heterotopic ossification (HO) in soft and connective tissues, which can be idiopathic or provoked by trauma, illness, inflammation, or surgery. There are currently no effective treatments for FOP, or for patients with FOP who must undergo surgery. Palovarotene, an investigational retinoic acid receptor-γ agonist, offers a potential avenue to prevent HO formation.\n\n\nMETHODS\nThe patient is a 32 year-old male, who at age 29 enrolled in a study evaluating palovarotene to prevent HO formation in FOP. One year after starting palovarotene, he fell resulting in a left intertrochanteric fracture. He underwent intramedullary nailing of the femur shaft with screw placement at the distal femur. After surgery, he received palovarotene at 20 mg/day for 4 weeks, then 10 mg/day for 8 weeks. Imaging 12 weeks after surgery showed new bridging HO at the site of intramedullary rod insertion and distal screw. Nine months after the left hip fracture, the patient had a second fall resulting in a subdural hematoma, left parietal bone fracture, and right intertrochanteric fracture. He underwent intramedullary nailing of the right hip, in a modified procedure which did not require distal screw placement. Palovarotene 20 mg/day was started at fracture occurrence and continued for 4 weeks, then reduced to 10 mg/day for 8 weeks. HO also formed near the insertion site of the intramedullary rod. No HO developed at the right distal intramedullary rod. After each fracture, the patient had prolonged recurrent flare-ups around the hips.\n\n\nCONCLUSIONS\nSurgery is only rarely considered in FOP due to the high risks of procedural complications and potential for inducing HO. This case emphasizes the risks of increased flare activity and HO formation from injury and surgery in patients with FOP. The efficacy of HO prevention by palovarotene could not be assessed; however, our observation that palovarotene can be administered in an individual with FOP following surgery with no negative impact on clinical fracture healing, osteointegration, or skin healing will help facilitate future trials testing the role of palovarotene as a therapy for HO.",
"affiliations": "Division of Endocrinology and Metabolism, Department of Medicine, the Institute for Human Genetics; and the Program in Craniofacial Biology - University of California, San Francisco, 513 Parnassus Ave., HSE901, San Francisco, CA, 94143-0794, USA.;Department of Medicine, University of California, San Francisco, 533 Parnassus Ave, San Francisco, CA, 94143, USA.;Division of Endocrinology and Metabolism, Department of Medicine, the Institute for Human Genetics; and the Program in Craniofacial Biology - University of California, San Francisco, 513 Parnassus Ave., HSE901, San Francisco, CA, 94143-0794, USA.;Department of Radiology, University of California, San Francisco, 505 Parnassus Ave, San Francisco, CA, 94143, USA.;Department of Orthopedic Surgery, University of California, San Francisco, and the Orthopedic Trauma Institute, 2550 23rd Street, Building 9, 2nd Floor, San Francisco, CA, 94110, USA.;Department of Anesthesiology, University of California, San Francisco, 521 Parnassus Ave, San Francisco, CA, 94131, USA.;Division of Endocrinology and Metabolism, Department of Medicine, the Institute for Human Genetics; and the Program in Craniofacial Biology - University of California, San Francisco, 513 Parnassus Ave., HSE901, San Francisco, CA, 94143-0794, USA. Edward.hsiao@ucsf.edu.",
"authors": "Singh|Sukhmani|S|;Kidane|Joseph|J|;Wentworth|Kelly L|KL|;Motamedi|Daria|D|;Morshed|Saam|S|;Schober|Andrew E|AE|;Hsiao|Edward C|EC|",
"chemical_list": "D011720:Pyrazoles; D013267:Stilbenes; C546535:Palovarotene",
"country": "England",
"delete": false,
"doi": "10.1186/s12891-020-03240-2",
"fulltext": "\n==== Front\nBMC Musculoskelet Disord\nBMC Musculoskelet Disord\nBMC Musculoskeletal Disorders\n1471-2474 BioMed Central London \n\n3240\n10.1186/s12891-020-03240-2\nCase Report\nSurgical management of bilateral hip fractures in a patient with fibrodysplasia ossificans progressiva treated with the RAR-γ agonist palovarotene: a case report\nSingh Sukhmani 1 Kidane Joseph 2 Wentworth Kelly L. 1 Motamedi Daria 3 Morshed Saam 4 Schober Andrew E. 5 Hsiao Edward C. Edward.hsiao@ucsf.edu 1 1 grid.266102.10000 0001 2297 6811Division of Endocrinology and Metabolism, Department of Medicine, the Institute for Human Genetics; and the Program in Craniofacial Biology - University of California, San Francisco, 513 Parnassus Ave., HSE901, San Francisco, CA 94143-0794 USA \n2 grid.266102.10000 0001 2297 6811Department of Medicine, University of California, San Francisco, 533 Parnassus Ave, San Francisco, CA 94143 USA \n3 grid.266102.10000 0001 2297 6811Department of Radiology, University of California, San Francisco, 505 Parnassus Ave, San Francisco, CA 94143 USA \n4 grid.266102.10000 0001 2297 6811Department of Orthopedic Surgery, University of California, San Francisco, and the Orthopedic Trauma Institute, 2550 23rd Street, Building 9, 2nd Floor, San Francisco, CA 94110 USA \n5 grid.266102.10000 0001 2297 6811Department of Anesthesiology, University of California, San Francisco, 521 Parnassus Ave, San Francisco, CA 94131 USA \n3 4 2020 \n3 4 2020 \n2020 \n21 2047 2 2020 25 3 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nFibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder marked by painful, recurrent flare-ups and heterotopic ossification (HO) in soft and connective tissues, which can be idiopathic or provoked by trauma, illness, inflammation, or surgery. There are currently no effective treatments for FOP, or for patients with FOP who must undergo surgery. Palovarotene, an investigational retinoic acid receptor-γ agonist, offers a potential avenue to prevent HO formation.\n\nCase presentation\nThe patient is a 32 year-old male, who at age 29 enrolled in a study evaluating palovarotene to prevent HO formation in FOP. One year after starting palovarotene, he fell resulting in a left intertrochanteric fracture. He underwent intramedullary nailing of the femur shaft with screw placement at the distal femur. After surgery, he received palovarotene at 20 mg/day for 4 weeks, then 10 mg/day for 8 weeks. Imaging 12 weeks after surgery showed new bridging HO at the site of intramedullary rod insertion and distal screw.\n\nNine months after the left hip fracture, the patient had a second fall resulting in a subdural hematoma, left parietal bone fracture, and right intertrochanteric fracture. He underwent intramedullary nailing of the right hip, in a modified procedure which did not require distal screw placement. Palovarotene 20 mg/day was started at fracture occurrence and continued for 4 weeks, then reduced to 10 mg/day for 8 weeks. HO also formed near the insertion site of the intramedullary rod. No HO developed at the right distal intramedullary rod. After each fracture, the patient had prolonged recurrent flare-ups around the hips.\n\nConclusion\nSurgery is only rarely considered in FOP due to the high risks of procedural complications and potential for inducing HO. This case emphasizes the risks of increased flare activity and HO formation from injury and surgery in patients with FOP. The efficacy of HO prevention by palovarotene could not be assessed; however, our observation that palovarotene can be administered in an individual with FOP following surgery with no negative impact on clinical fracture healing, osteointegration, or skin healing will help facilitate future trials testing the role of palovarotene as a therapy for HO.\n\nKeywords\nFibrodysplasia ossificans progressiva (FOP)PalovaroteneRetinoic acid receptor (RAR) agonistsHeterotopic ossification (HO)ProphylaxisHip fractureRepair surgeryCase reporthttp://dx.doi.org/10.13039/100000002National Institutes of HealthNIH R01AR073015T32DK007418F32HD91025K08DE028946Singh Sukhmani Wentworth Kelly L. http://dx.doi.org/10.13039/100008070Department of Medicine, University of California, San FranciscoREAC Summer Explore fellowshipKidane Joseph issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nHeterotopic ossification (HO) is a severe condition of bone formation in an inappropriate anatomic location, often triggered by trauma or other inflammatory processes [1]. One genetic condition that leads to massive and progressive HO is fibrodysplasia ossificans progressiva (FOP), a rare debilitating disease resulting from mutations in the Activin A Receptor Type 1 (ACVR1)/Activin-like Kinase 2 (ALK2) gene encoding for a type 1 membrane receptor for bone morphogenetic proteins (BMPs) [2]. This mutation leads to over-activation of downstream SMAD pathways which trigger the formation of excessive heterotopic endochondral bone [3].\n\nFOP may be diagnosed in childhood by findings of malformations of the great toes combined with unusual indurated masses that eventually form bone. Patients with FOP develop painful soft tissue swellings (“flare-ups”), which can be precipitated by trauma, injury, illness, or other inflammatory processes. These flare-ups can progress to HO and progressive loss of mobility [4, 5]. For this reason, any type of injury, including iatrogenic injury from medical or surgical procedures, must be minimized. Current therapies to reduce disease flare-ups are limited, with steroids and non-steroidal anti-inflammatory agents (NSAIDs) currently being used for symptom management though they may not alter disease course [5].\n\nPalovarotene is a retinoic acid receptor (RAR) γ agonist that can reduce heterotopic bone formation in mouse models of FOP [6]. Studies in mice have also suggested that retinoids may be associated with a transient delay in fracture healing which may have implications for patients on treatment [7]. Ongoing clinical trials suggest that palovarotene may be administered as episodic treatments for flare-ups (NCT02190747, NCT03312634). Here we present a case study showing that routine fracture healing after surgical repair of two hip fractures in an individual with FOP on palovarotene treatment showed no clinically significant delay in fracture healing and that the medication was not associated with any unexpected adverse events.\n\nCase presentation\nThe patient is a 32 year-old male at the time of this case report with a history of asthma, Gilbert’s disease, and hypertension who was diagnosed with FOP at age 9 after presenting with a limp. At presentation, he had calcification in his left sartorius muscle on imaging. He subsequently had FOP bone formation flare-ups with increasing frequency leading to reduced mobility, though he remained independent for activities of daily living and ambulated without assistive devices. The major joints affected were his spine, jaw, shoulders, right hip, and bilateral ankles. From his teens to his mid-twenties flare-ups were treated with a prednisone taper following standard-of-care guidelines [8]. Between ages 13 to 28 years he also received 4-week courses of thalidomide for flare-ups as part of a clinical study, for its anti-angiogenic effect, but without major clinical changes in his disease course [9]. He received his first dose of zoledronic acid, in an effort to reduce flare-ups through possible anti-inflammatory effects [10], at approximately age 19 years, then received 8 doses between the ages of 25 to 29 years and yearly thereafter.\n\nAt age 29 years, he enrolled in the phase 2 randomized control trial of palovarotene for the treatment of preosseous flare-ups in FOP (NCT02190747). He was having approximately 4 flares per year at the time of enrollment. He completed 6 weeks on the study protocol and subsequently enrolled in an open-label extension trial for the use of palovarotene (episodic dosing of 20 mg/day for 4 weeks, then 10 mg/day for 8 weeks) for flare-ups (NCT02279095). He then transitioned to a chronic treatment arm with palovarotene (5 mg/day) along with the episodic treatment with palovarotene for flare-ups. In addition to palovarotene, he received prednisone 110 mg/day for 4 days followed by a taper for his flare-up treatments. His treatment course and flare-up activity in the open-label extension trial is depicted in Fig. 1. During this time, the patient received topical prophylaxis with Aquaphor barrier ointment, triamcinolone 0.1% for retinoid skin reactions such as rash and dry skin, and artificial tears, for managing the most common potential mucocutaneous side effects of palovarotene.\nFig. 1 Timeline of palovarotene dosing in the open label phase of the PVO-1A-202B trial. Flare-up dosing, flare site, and fracture events are noted\n\n\n\nOne year after starting chronic palovarotene treatment, the patient had a fall resulting in a left inter-trochanteric fracture (Fig. 2). He was on palovarotene 5 mg/day, and had just completed a palovarotene/prednisone treatment cycle two weeks prior. Palovarotene 5 mg/day treatment was interrupted for one day after the fall then resumed at 5 mg/day until his surgery. Immediately after the fall, he was started on high-dose prednisone (110 mg/day) to reduce inflammation at the surgical site [5]. High-dose prednisone was continued until 3 days post-op and then tapered by 10 mg/day until completely stopped. To minimize the risk of flare-ups, intravenous (IV) treatments were discontinued as early as possible and aspirin (81 mg twice daily) was used for deep vein thrombosis prophylaxis. Celecoxib 100 mg twice daily was started based on prior studies indicating that NSAIDs may reduce HO formation after hip surgery [11].\nFig. 2 X-Ray imaging of the left hip: (a) X-Ray of the left pelvis at the time of the subtrochanteric fracture [arrow]. (b) X-Ray of the knee 4 months after surgery with HO at the site of distal screw insertion [arrow]. (c) Brooker class D HO at the rod insertion site 4 months after surgery [arrows] and after 9 months (d). (e) X-ray showing matured HO formation at 12 months [arrow]\n\n\n\nSurgery was pursued to stabilize the fracture, reduce pain, and preserve potential mobility. The surgical approach was designed to minimize soft tissue trauma but provide adequate access to safely stabilize the fracture in a way that would allow immediate weight-bearing. The patient underwent intramedullary nailing of the femur shaft with screw placement at the distal femur 9 days after the fall, after transfer to University of California, San Francisco (UCSF). Asleep nasal fiberoptic intubation with a small tube was carefully performed after induction of general anesthesia. This approach was used to minimize trauma which could trigger an obstructing neck flare leading to cervical spine fusions, ankyloses of the temporomandibular joint, or airway compromise. Methylprednisolone 50 mg IV was administered at the time of surgery to decrease the risk of airway edema and 2 g cefazolin was administered prior to incision for antibiotic prophylaxis. Bony prominences were carefully padded to prevent pressure-induced flare-ups. The jaw was also propped closed with foam tucked under the chin to prevent stretching and injury to the masseter muscles. After surgery, he was started on prednisone 50 mg twice daily for 1 day and then tapered by 10 mg/day until completion.\n\nManual traction was employed to position the hip to restore length; however, as varus was still noted, a pin was placed through the planned skin incision for nail insertion from the top of the greater trochanter across the base of the femoral neck fracture into the calcar in order to anatomically reduce the displaced fracture. Afterward, a threaded tip guidewire was placed to guide trochanteric entry of the nail. A 4 cm incision was made for passage of the trocar and entry reamer and a ball-tipped guidewire was placed across the fracture and to the level of the superior pole of the patella within the medullary cavity of the femur. This was followed by passage of serial reamers starting at 10 mm and advancing in 1 mm increments up until endosteal chatter was obtained at 15 mm. The final reaming diameter was 15.5 mm. A 13 mm trochanteric entry cephalomedullary nail was attached to the insertion jig and inserted (Trochanteric Fixation Nail, DePuy Synthes, West Chester, Pennsylvania). Using fluoroscopic imaging, the nail was positioned to allow for passage of a spiral blade in a central position within the femoral head and neck. A guidewire was passed using imaging guidance into the subchondral bone of the femoral head and the spiral blade was inserted over the guidewire through the proximal aspect of the nail via a second lateral proximal thigh incision. A single distal interlocking screw was placed using freehand technique via a 2 cm incision on the distal lateral thigh. The position was confirmed on fluoroscopic imaging. Care was taken to irrigate any bone from the soft tissues at the nail, spiral blade, and distal interlocking screw site in order to minimize the risk of HO.\n\nAfter surgery, flare-up based palovarotene dosing was started at 20 mg daily for 4 weeks and then decreased to 10 mg/day for an additional 8 weeks per the study protocol. Due to repeated flare-ups he was not able to decrease his palovarotene to the 5 mg/day chronic dosing. Post-operative celecoxib was continued.\n\nRadiologic and clinical assessments did not show any delay in fracture healing. Over the subsequent 2 months, the patient showed progressive clinical loss in the range of motion of the left hip and required the use of a cane for ambulation. A review of X-ray images at the time of the fracture showed no evidence of HO at the left hip (Fig. 2a). Radiologically, HO and a callus were evident around the distal screw by the left knee after 4 months (Fig. 2b). In addition, HO at the left hip was evident by 9 weeks and fully matured by 14 weeks (Fig. 2c). Brooker class D HO was clearly present on imaging at 9 months after surgery and matured at 12 months after surgery [12] (Fig. 2d-e).\n\nNine months after the left femoral fracture, the patient was on palovarotene 10 mg/day after a separate series of flare-ups. Four days after tapering to palovarotene 10 mg/day dose, he had an intercurrent flare in his chest that was treated with palovarotene 20 mg/day. The patient had a second fall 4 days later, where he lost his balance and fell backwards resulting in a subdural hematoma, left parietal bone fracture, and a displaced right sub-trochanteric femoral fracture. Palovarotene was continued at 20 mg/day per a study modification allowing for prophylactic treatment of a physical injury, and the patient received prednisone 100 mg/day for 4 days followed by a taper by 20 mg every 2 days, starting on the day of the injury.\n\nThe risks and benefits of non-operative management versus surgery were discussed again with the patient. Adequate pain control was difficult during the non-operative treatment. After transfer to UCSF and stabilization of his other injuries, he underwent intramedullary nailing of the right hip 10 days after sustaining the fracture.\n\nDespite straightforward asleep nasal fiberoptic intubation during the prior surgery, repeat attempt at nasal intubation for this procedure was difficult, requiring multiple attempts and eventual oral intubation with a video laryngoscope. Once his airway was stabilized, the identical long cephalomedullary nail was used. Antibiotic prophylaxis with 2 g cefazolin at the time of incision was again used. However, on the right side we avoided the use of a distal interlocking screw as its use is not required for successful fixation and stabilization of such injuries and may have contributed to the HO around the knee after his prior surgery. The intertrochanteric fracture was noted to be in some degree of varus and the femur minimally shortened, but in order to minimize soft tissue injury, an open reduction was not performed. No traction pins or additional bony manipulation was performed. Under fluoroscopic imaging, the appropriate incision was mapped out proximal to the greater trochanter and in line with the femur in the sagittal plane. A threaded tip guidewire was once again positioned to direct nail entry using fluoroscopic imaging. An entry reamer was inserted with as little trauma as possible through the soft tissues and passed into the proximal femur. This was followed by placement of a ball-tipped guidewire into the distal aspect of the femur. A 15.5 mm reamer was attached to the reaming drive and passed in a single pass without any evidence of compromise to the surrounding endosteal surfaces of the femur. A 13 mm trochanteric fixation nail was inserted in an antegrade fashion. A lateral cortical drill and reamer was used to open up the canal for passage of the spiral blade. Fluoroscopy was used to confirm restoration of alignment and correct positioning of all implant components. He remained intubated after the procedure and was extubated without incident on post-operative day 1. Fortunately, he suffered no significant complications from a longer duration of intubation or HO formation in the temporomandibular joint or surrounding tissues.\n\nFracture healing was not delayed based on clinical imaging; however, the patient showed continued loss of mobility, requiring the use of a walker and wheelchair. Again, the patient showed multiple and prolonged FOP flare-up activity, resulting in a significant increase in the number of flares/year. The right hip showed new development of Brooker class B HO at the greater trochanter, near the insertion site of the intramedullary rod, by 3 months after surgery (Fig. 3).\nFig. 3 X-Ray imaging of the right hip: (a) Intertrochanteric fracture noted by arrow. There is longstanding osteochondromatosis at the right femoral head [arrowheads]. (b) X-ray of the femur 13 weeks after surgery show post-surgical hardware and demonstrate Grade B HO at the left femoral head [arrow]\n\n\n\nDiscussion and conclusions\nHere, we describe the first case using the RAR-γ agonist, palovarotene, in a patient with FOP undergoing hip fracture repair surgery. It has been shown that chondrogenesis requires transcriptional repression of RARs and that retinoic acid receptor activation blocks chondrogenesis. Activation of RAR-γ, expressed in chondrogenic cells and chondrocytes, can selectively inhibit HO [7, 13, 14]. Initial studies by Shimono et al. with RAR agonists in mouse mesenchymal stem cells showed decreased phosphorylation of SMAD1, SMAD5, and SMAD8 and overall SMAD levels, suggesting a reduction in BMP signaling [7]. This led to studies of the use of palovarotene in trauma-induced mouse models of FOP. Chakkalakal et al. demonstrated a significant reduction in HO formation and fibroproliferative responses in knock-in Acvr1R206H mice when palovarotene was administered after cardiotoxin induced injury [6]. Joint and limb mobility was preserved in these palovarotene-treated mice.\n\nPhase 2 (NCT02279095) and 3 clinical trials (NCT03312634) to test palovarotene in patients with FOP are currently on-going. A prior study of palovarotene for treatment of emphysema showed that the drug was well tolerated with skin, gastrointestinal, eye, and respiratory mucocutaneous side effects being most common at the dosing regimen used in that patient population [15].\n\nDespite the known link between retinoids and skin adverse events, the patient described here had normal wound healing and showed no unexpected or major skin adverse events. The patient received topical prophylaxis with Aquaphor barrier ointment, triamcinolone 0.1% for retinoid skin reactions such as rash and dry skin, and artificial tears, for managing the most common potential mucocutaneous side effects. Notably, the patient showed no delayed healing of his skin wound or tissue after either surgery. Thus, the high-dose retinoid was well tolerated by this patient in the setting of two surgeries. Palovarotene did not have a significant or negative impact on clinical fracture healing or osteointegration with the repair hardware.\n\nThe bilateral fragility fractures were likely multifactorial in origin. The patient had a history of prolonged and high dose prednisone throughout childhood and adulthood. CT bone densitometry performed after the first fracture showed a lumbar spine T-score 3.8 standard deviations below the reference population, consistent with a diagnosis of severe osteoporosis. This likely arose from both decreased weight bearing as well as steroid-induced osteoporosis despite having received IV zoledronate on a regular basis. Osteoporosis may be a major clinical feature of advanced FOP since severe bone thinning is clearly evident in the two FOP skeletons housed in the Mutter Museum. Shifts in calcium from the native skeleton to inappropriate sites have also been reported in patients with severe atherosclerosis [16, 17], suggesting that shifts in calcium stores may be a contributor to FOP related degeneration of the native skeleton. In addition, the frequent and long-term use of bisphosphonates in this patient raised the possibility that the patient was predisposed to atypical-like femur fractures. In our patient, he reported no prodrome symptoms, and the fractures occurred in the setting of clear trauma.\n\nIn general, patients with FOP should avoid surgery unless absolutely necessary because of the high risks of complications from intubation, the surgical procedure, and triggering of FOP flares. Although the patient was successfully intubated, the second intubation was extremely difficult and emphasizes the high risks of surgery on FOP patients. It is unclear whether this was due to the presence of skull fractures, residual facial soft tissue swelling, HO from the prior intubation, or some combination thereof. Fortunately, he suffered no significant complications from a longer duration of intubation or HO formation in the temporomandibular joint or surrounding tissues as a result. In addition, HO formed in areas near surgical interventions such as the hardware insertion tract through the soft tissues and around the locking screw above the left knee. The prolific formation of HO after surgeries in FOP has been described before [18].\n\nThe formation of HO at the hardware insertion sites raises the concern that the reaming process may have contributed to HO formation. The physiologic effects of canal reaming can disrupt cortical blood flow but appears to be offset by increased circulation to the periosteum and surrounding skeletal muscle with subsequent revascularization that ultimately promotes healing [19, 20]. Investigations into reaming debris have showed elevated levels of FGF, PDGF, IGF-1, TGF-B and BMP-2 [21]. While these factors might usual induce recruitment and migration of progenitor cells into the fracture, stimulating osteogenesis and angiogenesis, in a patient with FOP this may lead to further activation of the ACVR1/Smad cascade. This stimulation could, in theory, contribute to HO formation in patients with FOP; however, as there was a concern for nonunion, stabilization of the fracture sites was the highest priority which led to the decision to proceed with reaming. To minimize trauma, biopsies were not obtained from the fracture sites.\n\nNotably, the patient developed a significant increase in flare activity after each fall. The occurrence of multiple flares after the trauma likely resulted in further HO formation, and makes it difficult to assess whether palovarotene reduced HO formation since the inflammatory stimuli were persistently present. In addition, the second fall involved multiple injuries consistent with poly-trauma, which in and of itself is associated with increased risks of heterotopic ossification [22] such as in survivors of high-energy trauma. Although it is difficult to compare the left and right fracture events, there was significantly less heterotopic ossification on the right side (second fracture) as compared to the left side (which involved more surgical manipulation). It is worth noting that minor clinically evident HO formation was eventually detectable after the extensive manipulation of the temporomandibular joint and upper airways during the difficult intubation for the second surgery. Whether administration of palovarotene played a role in avoidance of facial and airway HO formation is unknown. These observations, as well as the finding of multiple subsequent “after-shock” flares after the primary injury, further reinforces the importance of judicious surgical management for patients with FOP and the likely correlation between the degree of injury and the severity of the subsequent HO. These observations also suggest that future therapeutic strategies to control the inflammatory response after the inciting injury may be useful considerations for breaking the prolonged cycles of flares reported by FOP patients, and that these cycles may increase the risk of heterotopic bone formation.\n\nThough this case involves a patient with a genetic form of HO, testing of RAR-γ agonists in non-genetic forms of HO may still be beneficial. Non-genetic HO has been demonstrated to occur in adults, typically in their second and third decades, after a history of trauma or repetitive mechanical stress and can range from being clinically unnoticeable to resulting in chronic pain and high morbidity [23]. HO has been noted particularly in the setting of combat related injury such as post-blast injury or extremity amputation, where the prevalence of HO formation can approach 65% of patients [22]. Orthopedic surgery, including hip arthroplasty, fracture, traumatic brain or spinal cord injury, and severe burns are risk factors in the development of heterotopic ossification. The pathogenesis is thought to be similar to HO development in FOP, where inflammation leads to recruitment of progenitor cells and ultimately endochondral or intramembranous ossification but there are multiple pathways involved [24]. Studies in non-genetic HO models are limited. A selective RAR-α agonist was tested in an rhBMP-2 mouse model and reduced heterotopic cartilage, bone and expression of chondrogenic genes [25]. A study of palovarotene in a blast-related traumatic injury mouse model decreased HO formation by 50–60% and decreased ectopic chondrogenesis, osteogenesis and angiogenesis at the injury site [26]. Palovarotene showed slight inhibitory effects on wound healing, but this was not statistically significant. Thus, RAR-γ agonism may still be beneficial for non-genetic forms of HO.\n\nCurrent treatment for FOP [5] is largely limited to avoidance of trauma and supportive measures such as glucocorticoids for flare management, COX-2 inhibitors, non-steroidal anti-inflammatory, bisphosphonates, mast cell inhibitors, and potentially imatinib [27] or IL-1 inhibitors [28]. Surgery should still be avoided in FOP patients whenever possible; however, if surgical intervention is needed, the most minimally invasive approach should be used.\n\nOur patient demonstrates that careful treatment of a patient with FOP undergoing surgery with a retinoic acid receptor agonist such as palovarotene can be well tolerated with minimal side effects. However, major trauma may increase FOP flare activity that would complicate end-point assessments for clinical trials of medications for surgical treatment in FOP. Thus, fracture healing, flare activity, and HO formation are key endpoints that should be assessed in clinical trials involving surgical outcomes in novel FOP therapies [29]. Finally, it remains to be seen if palovarotene or other blockers of chondrogenic ossification may be useful for the treatment of non-genetic HO in more common conditions such as hip arthroplasty.\n\nAbbreviations\nFOPFibrodysplasia ossificans progressiva\n\nHOHeterotopic ossification\n\nNSAIDsNon-steroidal anti-inflammatory agents\n\nRARRetinoic acid receptor\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nECH is the corresponding and senior author who cared for the patient, and oversaw all aspects of manuscript preparation, writing, and editing. KLW helped care for the patient. SS, KLW, and JK analyzed and interpreted patient data and contributed to writing the manuscript. DM reviewed all of the radiologic imaging and interpretation. SM performed both orthopedic surgeries and cared for the patient. AES managed the general anesthesia and cared for the patient. All authors read and approved the final manuscript.\n\nFunding\nThe salaries of ECH, SS, and KLW for this study was supported by NIH R01AR073015 to ECH; T32DK007418 to SS; and K08DE028946 to KLW. JK received a stipend from UCSF Summer Explore fellowship. The phase 2 clinical study was funded by Clementia, an Ipsen company. ECH and KW receive clinical trials research support through their institution from Clementia, an Ipsen company. The funders had no role in the analysis of the data or writing of the manuscript.\n\nAvailability of data and materials\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n\nEthics approval and consent to participate\nThe phase 2 palovarotene study was sponsored by Clementia, an Ipsen company, and approved by the Institutional Review Board at the University of California, San Francisco. The participant involved in the study gave informed consent and signed an informed consent form.\n\nConsent for publication\nWritten consent to publish this information was obtained from the patient.\n\nCompeting interests\nECH serves in a volunteer capacity on the registry advisory board of the International Fibrodysplasia Ossificans Progressiva Association; on the International Clinical Council on FOP, and on the Fibrous Dysplasia Foundation Medical Advisory Board. ECH received prior research support through his institution from Regeneron Pharmaceuticals. ECH and KW receive clinical trials research support through their institution from Clementia, an Ipsen company. These pose no conflicts for this study.\n==== Refs\nReferences\n1. Matsuo K, Dalton CR, Barruet E, Hsiao EC. Inflammation in Fibrodysplasia Ossificans Progressiva and other forms of heterotopic ossification. Curr Osteoporosis Rep. 2019:17(6):387–94.\n2. 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Di Rocco A Uchibe K Larmour C Berger R Liu M Barton ER Selective retinoic acid receptor γ agonists promote repair of injured skeletal muscle in mouse Am J Pathol 2015 185 9 2495 2504 10.1016/j.ajpath.2015.05.007 26205250 \n15. Stolk J Stockley RA Stoel BC Cooper BG Piitulainen E Seersholm N Randomised controlled trial for emphysema with a selective agonist of the γ-type retinoic acid receptor Eur Respir J 2012 40 2 306 312 10.1183/09031936.00161911 22282548 \n16. Demer LL Tintut Y Mechanisms linking osteoporosis with cardiovascular calcification Curr Osteoporosis Rep 2009 7 2 42 46 10.1007/s11914-009-0008-1 \n17. Khosla S A shift in calcium Nat Med 2011 17 4 430 431 10.1038/nm0411-430 21475237 \n18. Eekhoff EMW Netelenbos JC de Graaf P Hoebink M Bravenboer N Micha D Flare-up after maxillofacial surgery in a patient with fibrodysplasia ossificans progressiva: an [18F]-NaF PET/CT study and a systematic review JBMR Plus 2018 2 1 55 58 10.1002/jbm4.10008 30283890 \n19. Hupel TM Aksenov SA Schemitsch EH Muscle perfusion after intramedullary nailing of the canine tibia J Trauma Acute Care Surg 1998 45 2 256 262 10.1097/00005373-199808000-00009 \n20. McCarthy I The Physiology of Bone Blood Flow: A Review J Bone Joint Surg 2006 88 Supplement 1 4 9 17079361 \n21. Pfeifer R Sellei R Pape H The biology of intramedullary reaming Injury 2010 41 2 S4 S8 10.1016/S0020-1383(10)70002-4 21144926 \n22. Dey D Wheatley BM Cholok D Agarwal S Yu PB Levi B The traumatic bone: trauma-induced heterotopic ossification Transl Res 2017 186 95 111 10.1016/j.trsl.2017.06.004 28668522 \n23. Meyers C Lisiecki J Miller S Levin A Fayad L Ding C Heterotopic ossification: a comprehensive review JBMR Plus 2019 3 4 e10172 10.1002/jbm4.10172 31044187 \n24. Pacifici M Acquired and congenital forms of heterotopic ossification: new pathogenic insights and therapeutic opportunities Curr Opin Pharmacol 2018 40 51 58 10.1016/j.coph.2018.03.007 29614433 \n25. Shimono K Morrison TN Tung W Chandraratna RA Williams JA Iwamoto M Inhibition of ectopic bone formation by a selective retinoic acid receptor α-agonist: a new therapy for heterotopic ossification? J Orthop Res 2010 28 2 271 277 19725108 \n26. Pavey GJ Qureshi AT Tomasino AM Honnold CL Bishop DK Agarwal S Targeted stimulation of retinoic acid receptor-γ mitigates the formation of heterotopic ossification in an established blast-related traumatic injury model Bone 2016 90 159 167 10.1016/j.bone.2016.06.014 27368930 \n27. Kaplan FS Andolina JR Adamson PC Teachey DT Finklestein JZ Ebb DH Early clinical observations on the use of imatinib mesylate in FOP: a report of seven cases Bone 2018 109 276 280 10.1016/j.bone.2017.07.019 28736245 \n28. Haviv R Moshe V De Benedetti F Prencipe G Rabinowicz N Uziel Y Is fibrodysplasia ossificans progressiva an interleukin-1 driven auto-inflammatory syndrome? Pediatr Rheumatol Online J 2019 17 1 84 10.1186/s12969-019-0386-6 31864380 \n29. Wentworth KL Masharani U Hsiao EC Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva Br J Clin Pharmacol 2019 85 6 1180 1187 10.1111/bcp.13823 30501012\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2474",
"issue": "21(1)",
"journal": "BMC musculoskeletal disorders",
"keywords": "Case report; Fibrodysplasia ossificans progressiva (FOP); Heterotopic ossification (HO); Hip fracture; Palovarotene; Prophylaxis; Repair surgery; Retinoic acid receptor (RAR) agonists",
"medline_ta": "BMC Musculoskelet Disord",
"mesh_terms": "D000058:Accidental Falls; D000328:Adult; D001858:Bone Nails; D004334:Drug Administration Schedule; D006620:Hip Fractures; D006801:Humans; D008297:Male; D009221:Myositis Ossificans; D009999:Ossification, Heterotopic; D011720:Pyrazoles; D013267:Stilbenes; D016896:Treatment Outcome; D014965:X-Rays",
"nlm_unique_id": "100968565",
"other_id": null,
"pages": "204",
"pmc": null,
"pmid": "32245464",
"pubdate": "2020-04-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21460849;28668522;28629737;31864380;26896819;22282548;21144926;9715181;25427427;29954195;26205250;27368930;21475237;31044187;30281842;29614433;19631027;30283890;30501012;19725108;28736245;17079361;12183663;16642017;31721068;12105181",
"title": "Surgical management of bilateral hip fractures in a patient with fibrodysplasia ossificans progressiva treated with the RAR-γ agonist palovarotene: a case report.",
"title_normalized": "surgical management of bilateral hip fractures in a patient with fibrodysplasia ossificans progressiva treated with the rar agonist palovarotene a case report"
} | [
{
"companynumb": "US-BAYER-2020-084462",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Glycopeptides have an established role in the management of infective endocarditis, and feature in current treatment guidelines. Newer lipoglycopeptide agents (dalbavancin, telavancin and oritavancin), which are analogues of glycopeptides with structural modifications giving rise to added novel mechanisms of antimicrobial activity, are approved for the treatment of Gram-positive skin and skin structure infections, and also for nosocomial pneumonia (only telavancin has approval for the latter indication). Recent evidence has also emerged to support their use in the treatment of bone and joint infections. This article reviews the current literature on dalbavancin and telavancin in the treatment of infective endocarditis, a condition for which the role of these agents is yet to be established.",
"affiliations": "Department of Infectious Diseases, Northwick Park Hospital, London North West University Healthcare NHS Trust, London, UK. Electronic address: temi.lampejo@nhs.net.",
"authors": "Lampejo|Temi|T|",
"chemical_list": "D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000077427:Lipoglycopeptides; C100708:oritavancin; C487637:telavancin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijantimicag.2020.106072",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0924-8579",
"issue": "56(3)",
"journal": "International journal of antimicrobial agents",
"keywords": "Dalbavancin; Infective endocarditis; Lipoglycopeptide; Telavancin",
"medline_ta": "Int J Antimicrob Agents",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D004697:Endocarditis, Bacterial; D005260:Female; D006094:Gram-Positive Bacteria; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D000077427:Lipoglycopeptides; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged",
"nlm_unique_id": "9111860",
"other_id": null,
"pages": "106072",
"pmc": null,
"pmid": "32629114",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Dalbavancin and telavancin in the treatment of infective endocarditis: a literature review.",
"title_normalized": "dalbavancin and telavancin in the treatment of infective endocarditis a literature review"
} | [
{
"companynumb": "AT-ALLERGAN-1823550US",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DALBAVANCIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "France has recently witnessed a nationwide outbreak of measles. Data on severe forms of measles in adults are lacking. We sought to describe the epidemiologic, clinical, treatment, and prognostic aspects of the disease in adult patients who required admission to an intensive care unit (ICU). We performed a retrospective analysis of a cohort of 36 adults admitted to a total of 64 ICUs throughout France for complications of measles from January 1, 2009, to December 31, 2011. All cases of measles were confirmed by serologic testing and/or reverse transcription polymerase chain reaction.The cohort consisted of 21 male and 15 female patients, with a median age of 29.2 years (25th-75th interquartile range [IQR], 27.2-34.2 yr) and a median Simplified Acute Physiology Score (SAPS II) of 13 (IQR, 9-18). Among the 26 patients whose measles vaccination status was documented, none had received 2 injections. One patient had developed measles during childhood. Underlying comorbid conditions included chronic respiratory disease in 9 patients, immunosuppression in 7 patients, and obesity in 3 patients, while measles affected 5 pregnant women.Respiratory complications induced by measles infection led to ICU admission in 32 cases, and measles-related neurologic complications led to ICU admission in 2 cases. Two patients were admitted due to concurrent respiratory and neurologic complications.Bacterial superinfection of measles-related airway infection was suspected in 28 patients and was documented in 8. Four cases of community-acquired pneumonia, 6 cases of ventilator-associated pneumonia, 1 case of tracheobronchitis, and 2 cases of sinusitis were microbiologically substantiated.Of 11 patients who required mechanical ventilation, 9 developed acute respiratory distress syndrome (ARDS). Among the patients with ARDS, extraalveolar air leak complications occurred in 4 cases. Five patients died, all of whom were severely immunocompromised.On follow-up, 1 patient had severe chronic respiratory failure related to lung fibrosis, and 2 patients had mild lower limb paraparesis along with bladder dysfunction, both of which were ascribable to measles-induced encephalitis and myelitis. Among the 5 pregnant patients, the course of measles infection was uneventful, albeit 1 patient underwent emergent cesarean delivery because of fetal growth restriction.Measles is a disease with protean and potentially deceptive clinical manifestations, especially in the immunocompromised patient. Measles-associated pneumonitis and its complications, and less commonly postinfectious encephalomyelitis, are the main source of morbidity and mortality. In contrast with the usually benign course of the disease in immunocompetent patients, measles occurring in immunocompromised patients gives rise to lethal complications including ARDS, with or without bacterial superinfection. Other patients potentially at high risk for severe measles are young adults and pregnant women. Measles pneumonitis may predispose to air leak disease in patients using mechanical ventilation. To date, vaccination remains the most potent tool to control measles infection.",
"affiliations": "From AP-HP, Service de Réanimation Médico-Chirurgicale, Université Paris Diderot, Sorbonne Paris Cité Hôpital Louis Mourier, Colombes (CR, JDR, JM, DD, SG); Department of Intensive Care Medicine, Lapeyronie University Hospital, Montpellier (KK, SM); Institut National de la Santé et de la Recherche Médicale, INSERM U722, Paris (JDR, JM, DD, SG); Université Paris Diderot, Sorbonne Paris Cité, UMR 722, Paris (JDR, JM, DD, SG); AP-HP, Service de Pneumologie et Réanimation, Hôpital Tenon, Université Pierre-et-Marie-Curie, Paris (JM); Aix-Marseille Université, Faculté de Médecine, URMITE UMR CNRS 7278, Marseille, and APHM, Hôpital Nord, Réanimation des Détresses Respiratoires et des Infections Sévères, Marseille (AR); AP-HP, Service de Réanimation Médicale et des Maladies Infectieuses, Université Paris Diderot, Sorbonne Paris Cité, Hôpital Bichat-Claude-Bernard, Paris (RS); Service de Réanimation Médicale, Hôpital Saint-André, CHU Bordeaux, Bordeaux (OG); Service d'Anesthésie et Réanimation, Polyclinique Bordeaux Nord Aquitaine, Bordeaux (WP); Hospices Civils de Lyon, Service de Réanimation Médicale, Hôpital de la Croix Rousse, Lyon (CG); AP-HP, Hôpital de Bicêtre, Service de Réanimation Médicale, Le Kremlin-Bicêtre (JLT); CHU Clermont-Ferrand, Unité de Réanimation Médicale, Pôle REUNNIRH, Hôpital G Montpied, Clermont-Ferrand (NM); Medical-Surgical Intensive Care Unit, Saint-Etienne University Hospital, and Jean Monnet University, Saint-Etienne (MD); Medico-Surgical Intensive Care Unit, Avicenne Teaching Hospital, Bobigny (FC); AP-HP, Service de Pneumologie et Réanimation Médicale, Groupe Hospitalier Pitié-Salpêtrière, Paris (MS); and Medical Intensive Care Unit, Tours University Hospital, Tours (EM); France.",
"authors": "Rafat|Cédric|C|;Klouche|Kada|K|;Ricard|Jean-Damien|JD|;Messika|Jonathan|J|;Roch|Antoine|A|;Machado|Sonia|S|;Sonneville|Romain|R|;Guisset|Olivier|O|;Pujol|Wilfried|W|;Guérin|Claude|C|;Teboul|Jean-Louis|JL|;Mrozek|Natacha|N|;Darmon|Michaël|M|;Chemouni|Frank|F|;Schmidt|Matthieu|M|;Mercier|Emmanuelle|E|;Dreyfuss|Didier|D|;Gaudry|Stéphane|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0b013e3182a713c2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-7974",
"issue": "92(5)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": null,
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "257-272",
"pmc": null,
"pmid": "23982057",
"pubdate": "2013-09",
"publication_types": "D016428:Journal Article",
"references": "9681739;13820247;11934711;22797452;11448026;7811865;20684816;20390298;8900387;21172172;1605607;8709770;19536;18761924;20843472;19428862;12707855;19131097;17992509;8272926;6204579;15189961;16133728;12620751;17499339;10881678;1696863;21855993;9493801;7581755;12087526;16362981;6197651;9191837;8213869;12850161;7429429;8648708;22277189;18566565;21682798;20032319;15106083;6402654;7008941;8414327;14506633;7282741;8440043;3372286;17334722;10866602;11385511;19967134;20012881;11170977;9323433;22571199;16686771;19683347;18646073;19264619;16603610;21666185;804571;20419819;22534001;16157422;3187632;16752670;3486248;12631938;10065681;8323578;8254858;11993533;17395344;1862285;11234459;12781536;20214870;17088933;10382817;1538561;5947548;19822121",
"title": "Severe Measles Infection: The Spectrum of Disease in 36 Critically Ill Adult Patients.",
"title_normalized": "severe measles infection the spectrum of disease in 36 critically ill adult patients"
} | [
{
"companynumb": "FR-TEVA-547851ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Light chain deposition disease (LCDD) is a rare systemic disorder in which monoclonal light chains are abnormally secreted due to clonal proliferation of plasma cells and get deposited in various organs; the kidneys being the common one to be affected leading to renal failure. Advocated therapeutic options include chemotherapy with alkylating agents and steroids, High-Dose Melphalan (HDM) with Autologous Stem Cell Transplantation. Recently, Bortezomib has proven to be a novel therapeutic option in these patients when combined with dexamethasone. Here, we report a patient who presented with acute renal failure, was diagnosed to have LCDD and treated with bortezomib and dexamethasone.",
"affiliations": "Assistant Professor, Department of Medical Oncology.;Final Year MBBS Student.;Professor, Department of General Medicine, PSG Institute of Medical Sciences & Research, Coimbatore, Tamil Nadu.",
"authors": "Kandakumar|Vignesh|V|;Nagalapuram|Vishnu|V|;Menon|Sujaya|S|",
"chemical_list": "D000970:Antineoplastic Agents; D000069286:Bortezomib",
"country": "India",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-5772",
"issue": "64(8)",
"journal": "The Journal of the Association of Physicians of India",
"keywords": null,
"medline_ta": "J Assoc Physicians India",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D000069286:Bortezomib; D005260:Female; D006801:Humans; D009101:Multiple Myeloma",
"nlm_unique_id": "7505585",
"other_id": null,
"pages": "97-98",
"pmc": null,
"pmid": "27762125",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bortezomib Based Chemotherapy for Light Chain Deposition Disease.",
"title_normalized": "bortezomib based chemotherapy for light chain deposition disease"
} | [
{
"companynumb": "IN-MYLANLABS-2019M1050317",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugaddit... |
{
"abstract": "Autism spectrum disorder (ASD) is a debilitating neurodevelopmental disorder with high heterogeneity and no clear common cause. Several drugs, in particular risperidone and aripiprazole, are used to treat comorbid challenging behaviors in children with ASD. Treatment with risperidone and aripiprazole is currently recommended by the Food and Drug Administration (FDA) in the USA for children aged 5 and 6 years and older, respectively. Here, we investigated the use of these medications in younger patients aged 4 years and older.\nThis retrospective case series included 18 children (mean age, 5.7 years) with ASD treated at the Kids Neuro Clinic and Rehab Center in Dubai. These patients began treatment with risperidone or aripiprazole at the age of 4 years and older, and all patients presented with comorbid challenging behaviors that warranted pharmacological intervention with either risperidone or aripiprazole.\nAll 18 children showed objective improvement in their ASD core signs and symptoms. Significant improvement was observed in 44% of the cases, and complete resolution (minimal-to-no-symptoms) was observed in 56% of the cases as per the Childhood Autism Rating Scale 2-Standard Test (CARS2-ST) and the Clinical Global Impression (CGI) scales.\nOur findings indicate that the chronic administration of antipsychotic medications with or without ADHD medications is well tolerated and efficacious in the treatment of ASD core and comorbid symptoms in younger children when combined with standard supportive therapies. This is the first report to suggest a treatment approach that may completely resolve the core signs and symptoms of ASD. While the reported outcomes indicate significant improvement to complete resolution of ASD, pharmacological intervention should continue to be considered as part of a multi-component intervention in combination with standard supportive therapies. Furthermore, the findings support the critical need for double-blind, placebo-controlled studies to validate the outcomes.",
"affiliations": "Kids Neuro Clinic and Rehab Center, Dubai, United Arab Emirates.;Kids Neuro Clinic and Rehab Center, Dubai, United Arab Emirates.;Kids Neuro Clinic and Rehab Center, Dubai, United Arab Emirates.;Pediatric Neurology, Dent Neurological Institute, Amherst, NY, USA.;Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY, USA.;Pediatric Neurology, Nationwide Children's Hospital and Ohio State University, Columbus, OH, USA.",
"authors": "Alsayouf|Hamza A|HA|0000-0002-3646-7599;Talo|Haitham|H|;Biddappa|Marisa L|ML|0000-0001-5086-012X;Qasaymeh|Mohammad|M|0000-0003-0559-3944;Qasem|Shadi|S|0000-0001-6724-7057;De Los Reyes|Emily|E|0000-0002-1123-6903",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/NDT.S277294",
"fulltext": "\n==== Front\nNeuropsychiatr Dis Treat\nNeuropsychiatr Dis Treat\nndt\nneurodist\nNeuropsychiatric Disease and Treatment\n1176-6328 1178-2021 Dove \n\n277294\n10.2147/NDT.S277294\nCase Series\nPharmacological Intervention in Children with Autism Spectrum Disorder with Standard Supportive Therapies Significantly Improves Core Signs and Symptoms: A Single-Center, Retrospective Case Series\nAlsayouf et alAlsayouf et alhttp://orcid.org/0000-0002-3646-7599Alsayouf Hamza A 1 Talo Haitham 1 http://orcid.org/0000-0001-5086-012XBiddappa Marisa L 1 http://orcid.org/0000-0003-0559-3944Qasaymeh Mohammad 2 http://orcid.org/0000-0001-6724-7057Qasem Shadi 3 http://orcid.org/0000-0002-1123-6903De Los Reyes Emily 4 1 Kids Neuro Clinic and Rehab Center, Dubai, United Arab Emirates\n2 Pediatric Neurology, Dent Neurological Institute, Amherst, NY, USA\n3 Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY, USA\n4 Pediatric Neurology, Nationwide Children’s Hospital and Ohio State University, Columbus, OH, USA\nCorrespondence: Hamza A Alsayouf Kids Neuro Clinic and Rehab Center, Dubai Healthcare City, Dubai, United Arab EmiratesTel +97 145570326 Email leeamra1000@gmail.com\n16 11 2020 \n2020 \n16 2779 2794\n16 8 2020 27 10 2020 © 2020 Alsayouf et al.2020Alsayouf et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Purpose\nAutism spectrum disorder (ASD) is a debilitating neurodevelopmental disorder with high heterogeneity and no clear common cause. Several drugs, in particular risperidone and aripiprazole, are used to treat comorbid challenging behaviors in children with ASD. Treatment with risperidone and aripiprazole is currently recommended by the Food and Drug Administration (FDA) in the USA for children aged 5 and 6 years and older, respectively. Here, we investigated the use of these medications in younger patients aged 4 years and older.\n\nPatients and Methods\nThis retrospective case series included 18 children (mean age, 5.7 years) with ASD treated at the Kids Neuro Clinic and Rehab Center in Dubai. These patients began treatment with risperidone or aripiprazole at the age of 4 years and older, and all patients presented with comorbid challenging behaviors that warranted pharmacological intervention with either risperidone or aripiprazole.\n\nResults\nAll 18 children showed objective improvement in their ASD core signs and symptoms. Significant improvement was observed in 44% of the cases, and complete resolution (minimal-to-no-symptoms) was observed in 56% of the cases as per the Childhood Autism Rating Scale 2-Standard Test (CARS2-ST) and the Clinical Global Impression (CGI) scales.\n\nConclusion\nOur findings indicate that the chronic administration of antipsychotic medications with or without ADHD medications is well tolerated and efficacious in the treatment of ASD core and comorbid symptoms in younger children when combined with standard supportive therapies. This is the first report to suggest a treatment approach that may completely resolve the core signs and symptoms of ASD. While the reported outcomes indicate significant improvement to complete resolution of ASD, pharmacological intervention should continue to be considered as part of a multi-component intervention in combination with standard supportive therapies. Furthermore, the findings support the critical need for double-blind, placebo-controlled studies to validate the outcomes.\n\nKeywords\nrisperidonearipiprazoleantipsychoticcomorbid challenging behaviorsThere is no funding to reportThere is no funding to report.\n==== Body\nPlain Language Summary\nASD is a chronic neurodevelopmental disorder that is increasing in prevalence worldwide.\n\nThere are no FDA-approved medications to treat the core symptoms even though ASD shares many signs and symptoms with other neuropsychiatric diseases.\n\nFDA-approved pharmacological therapies are currently only indicated for the treatment of comorbid irritability and severe behavioral issues in children with ASD aged 5 years and older.\n\nIn this study, antipsychotic medications, with or without ADHD medications, were found to significantly improve ASD core symptoms when used in combination with standard supportive therapies.\n\nWe observed complete resolution of core ASD symptoms in 56% of our patient cohort, which is unprecedented in the medical literature.\n\nDose optimization for each patient and chronic use are key to resolving core signs and symptoms.\n\nThe potential benefits and risks must be weighed on a case-by-case basis when considering further optimization of medications to target core symptoms in children with ASD and comorbid behavioral issues.\n\nIntroduction\nAutism spectrum disorder (ASD) is a complex neurodevelopmental disorder with high heterogeneity.1 In 2013, the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), consolidated the four previously separate categories of autism under the single umbrella of “autism spectrum disorder.”1 These categories were autistic disorder, Asperger’s syndrome, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified.1,2 While the symptoms of ASD can manifest before 2 years of age, they usually become more apparent between 2 and 3 years of age.1,3 Patients with ASD are all unique in their presentation; however, the disorder is characterized by core symptoms that include impairments in social interaction and communication, as well as the presence of restricted and repetitive behaviors.1 These symptoms are universal regardless of culture, race, ethnicity, or socioeconomic group.1 All children with ASD experience difficulty in developing social, speech, and behavioral skills. Therefore, early intervention with behavioral therapy affords these children with the best opportunity to support healthy development and to deliver benefits across their life span.2 Pharmacological interventions, where needed, are used as an adjunct to support patients’ function in their daily activities and to treat comorbid irritability and difficult behaviors.4,5\n\nASD impairs social skills and autonomy to a variable and sometimes severe extent. A longitudinal study over 40 years has shown general improvement in symptoms in young adulthood but poor outcomes in later adulthood.6 Although core domains may improve across the life span, some symptom subdomains, such as limited interests or facial expressions, may remain unchanged over time.7,8 The impact of these long-term deficits on functioning is severe, with manifestations that can become increasingly complex later in life.9 In 2018, the Centers for Disease Control and Prevention (CDC) in the USA determined that approximately 1 in 59 children is diagnosed with ASD (1 in 37 boys and 1 in 151 girls), with increasing prevalence year after year.10\n\nUnfortunately, the current evidence-based pharmacological treatment approach for ASD is limited to the treatment and control of comorbid challenging behaviors only.11 Risperidone and aripiprazole were approved by the FDA in 2006 and 2009, respectively, to treat irritability associated with ASD.12,13 The recommended age to initiate treatment with these medications is 5 years and above for risperidone and 6 years and above for aripiprazole. In randomized controlled trials, risperidone and aripiprazole have been found to improve irritability and agitation in children with ASD.14,15 The majority of children with ASD show improvements in challenging comorbid behaviors such as irritability, agitation, aggression, self-injury, and disruptive behaviors when using these medications.16 Both drugs are classified as atypical antipsychotics, and this class of medication can potentially cause significant side effects such as sedation, weight gain, and metabolic disturbances; therefore, close follow-up and monitoring by a physician with special expertise are required when using these medications.17 To mitigate medication-induced weight gain, metformin can be prescribed if needed.17,18 Several medications typically used to treat children with attention-deficit hyperactivity disorder (ADHD), including methylphenidate, atomoxetine, guanfacine, and bupropion, have been reported to also improve hyperactivity and attention symptoms in children with ASD.19–22\n\nIn this retrospective report, we present our single-center experience in treating 18 children with ASD and comorbid behavioral issues. These children were treated from the age of 4 years and older with risperidone or aripiprazole, either with or without atomoxetine or methylphenidate, combined with standard supportive therapies. A significant clinical and statistical improvement in the patients’ core signs and symptoms, in addition to improvements in their behavioral issues, was observed as per the Childhood Autism Rating Scale 2-Standard Test (CARS2-ST) and the Clinical Global Impression (CGI) scales.23,24 The Clinical Global Impression-Severity (CGI-S) and CARS2-ST scale were performed at baseline, and serial Clinical Global Impression-Improvement (CGI-I) scores were obtained to monitor improvement. Once a patient attained a CGI-I score of 1 or 2 we repeated the CGI-S and CARS2-ST to further confirm improvement, in addition to serial clinical evaluations and follow-up.\n\nPatients and Methods\nPatients\nThis is a retrospective case series report of all patients, aged 4 years or older, who were diagnosed with autism spectrum disorder and comorbid behavioral issues and treated at our center (Kids Neuro Clinic and Rehab Center, Dubai) from 2017 to 2020, and for whom informed consent was obtained from the parents or legal guardians to participate in this study. The cohort comprised 18 children in total. The children’s parents and legal guardians were duly notified of the off-label use and potential side effects of the antipsychotic medications used in this study. The data collected for each patient included: age at presentation, age of initiation of the first medication, medications used, starting dose, time to reach the maximum dose, current medications, medication side effects, analyses performed, initial signs and symptoms, initial formal diagnosis as per the DSM-5 criteria and CARS2-ST, baseline CGI-S score before starting medications, Clinical Global Impression-Improvement (CGI-I) score, and their repeat CARS2-ST as per their last visit to our clinic.\n\nTo supplement the CGI-I scale, we also used the CGI-S score in addition to CARS2-ST at baseline against which we marked each patient’s severity prior to starting medications. Condition severity was scored on the following seven-point CGI-S scale: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill patients.23\n\nCGI-I is scored on a seven-point scale that compares the patient’s current condition to their baseline condition before treatment initiation: 1 = very much improved since the initiation of treatment; 2 = much improved; 3 = minimally improved; 4 = no change from baseline (the initiation of treatment); 5 = minimally worse; 6 = much worse; 7 = very much worse since the initiation of treatment.23\n\nCARS2-ST can be used for children aged 2 years and older and classifies patients into three ASD severity groups based on a 15-category scoring system: minimal-to-no symptoms of ASD, mild-to-moderate symptoms of ASD, and severe symptoms of ASD.5,24,25\n\nThis retrospective observational case series was approved by an independent Institutional Review Board (IRB), the Pearl IRB Committee, which is fully accredited by the Association for the Accreditation of Human Research Protection Program (AAHRPP; approval no. 20-KNRC-101). This study was also approved locally by the Dubai Healthcare City Regulatory Ethics Committee (DHCR; approval no. KNCRC-01)\n\nDiagnosis\nWhen a patient with signs and symptoms suggestive of ASD presented at our clinic, we performed a thorough history and physical examination. In addition, we performed an electroencephalogram (EEG) with a sleep sample to evaluate for electrical status epilepticus in sleep or epileptic encephalopathy, as well as an auditory brainstem response (ABR) test to assess for hearing loss. These tests were conducted to exclude potentially treatable conditions requiring different treatment approaches.26–29 Pharmacological treatment was recommended if the individual had a normal ABR, normal EEG, no findings suggestive of a genetic disorder (such as dysmorphic features, a family history of genetic disorders, or an abnormal genetic test), no global developmental delay, and a confirmed ASD diagnosis as per the DSM-5 criteria and CARS2-ST, and a CGI-S score ≥ 4 with comorbid behavioral issues. In each case, the diagnosis was obtained by both a pediatric neurologist and a clinical psychologist following a multidisciplinary assessment and diagnostic approach. A flowchart of the diagnosis and medication schedule is depicted in Figure 1.Figure 1 Flowchart of the diagnosis and medication schedule.\n\n\n\nTreatment\nBased on previous safety and efficacy studies recommending atypical antipsychotics for the treatment of the comorbid behavioral symptoms of ASD, patients were prescribed either risperidone or aripiprazole.12,13 Risperidone treatment was usually initiated with 0.25 mg orally at night, and this dose was increased gradually every 1 to 2 weeks until reaching either a maximum dose of 2 mg in the morning and 0.5 mg at night or the maximum dose tolerated by each patient within these limits (see Table 1 for each patient’s dosing schedule). This regimen was adhered to as long as the patient showed improvement with each dose increment and no side effects. This approach was followed for 8/18 (44%) cases (cases 1, 6, 7, 9, 10, 14, 17, and 18). Aripiprazole was started at 1 mg at night, and this dose was increased gradually every 1 to 2 weeks until reaching a maximum dose of 15 mg at night or the maximum tolerated dose for the patient (Table 1). This regimen was adhered to as long as an improvement was observed with no side effects. This approach was followed for 10/18 (56%) cases (cases 2, 3, 4, 5, 8, 11, 12, 13, 15, and 16). The clinical data for all of the patients are provided in Table 1.Table 1 Clinical Characteristics of All Patients in the Case Series\n\nCase\tSex\tAge (Years); Date Medication Started (mm/yy)\tMedication Starting Dose\tMaximum Dose;a Time to Reach this Dose\tCurrent Dose;a Total Duration\tLaboratory Findingsb\tCardiac\nEvaluation\tNotes on Medications and Side Effects\t\n1\tM\t4; 01/19\tRisperidone 0.25 mg at night.\nAtomoxetine 10 mg was added at night after 11 months.\tRisperidone 0.75 mg twice a day; 11 months.\nAtomoxetine 40 mg at night; 2.5 months.\tRisperidone 0.75 mg twice a day; 19 months.\nAtomoxetine 40 mg at night; 8 months.\tNormal\tNormal\t\t\n2\tM\t7; 05/19\tAripiprazole 1 mg at night.\nAtomoxetine 10 mg was added at night after 2 months.\tAripiprazole 10 mg at night; 2 months.\nAtomoxetine 60 mg at night; 7 months.\tAripiprazole 10 mg at night; 16 months.\nAtomoxetine 60 mg at night; 13 months.\tNormal\tNormal\tWeight gain on aripiprazole; therefore, atomoxetine was added.\t\n3\tM\t4; 02/20\tAripiprazole 1 mg at night.\tAripiprazole 3 mg at night; 2 months.\tAripiprazole 3 mg at night; 6 months.\tNot done\tNot done\t\t\n4\tM\t5; 07/18\tAripiprazole 2.5 mg at night.\nAtomoxetine 18 mg was added at night after 2 months.\nLong-acting methylphenidate 18 mg was added in the morning after 17 months.\tAripiprazole 15 mg at night; 2 months.\nAtomoxetine 40 mg at night; 7 months.\nLong-acting methylphenidate 36 mg in the morning; 1 month.\tAripiprazole 15 mg at night; 26 months.\nAtomoxetine 40 mg at night; 24 months.\nLong-acting methylphenidate 36 mg in the morning; 8 months.\tNormal\tNot done\tAtomoxetine was added for hyperactivity and inability to focus.\nLong-acting methylphenidate was added as he continued to be inattentive.\t\n5\tF\t7; 01/17\tMethylphenidate 5 mg in the morning and 2.5 mg at 2 pm.\nAripiprazole 2.5 mg was added at night after 1 month.\tMethylphenidate 10 mg in the morning and 2.5 mg at 2 pm; 1 month. It was then stopped.\nAripiprazole 5 mg; 8 months.\tAripiprazole 5 mg at night; 43 months.\tNormal\tNot done\tMethylphenidate made her irritable.\nTried to switch her to risperidone at 24 months as aripiprazole was out of stock; she completely regressed. This was continued for 2 weeks only then she was put back on aripiprazole.\nTrial wean of aripiprazole made her anxious and she started to self-talk with poor attention.\t\n6\tM\t6; 11/19\tRisperidone 0.5 mg at night.\nMethylphenidate 5 mg in the morning and 2.5 mg at 2 pm was added after 1 month.\nAtomoxetine 10 mg was added at night after another 2 months.\tRisperidone 0.5 mg twice a day; 1 month.\nRisperidone 2 mg in the morning and 0.5 mg at night; another 2 months.\nAtomoxetine 18 mg at night; 1 month.\tRisperidone 2 mg in the morning and 0.5 mg at night; 10 months.\nAtomoxetine 18 mg at night; 6 months.\tNot done\tNot done\tRisperidone was making him sleepy; therefore, methylphenidate was added.\nMethylphenidate made him very irritable and angry; therefore. it was stopped after 1 week.\nAtomoxetine was added to augment attention.\t\n7\tM\t4; 01/20\tRisperidone 0.25 mg at night.\nAtomoxetine 10 mg was added at night after 2 months.\tRisperidone 2 mg in the morning and 0.5 mg at night; 3 months.\nAtomoxetine 10 mg at night; from start.\tRisperidone 2 mg in the morning and 0.5 mg at night; 8 months.\nAtomoxetine 10 mg at night, 5 months.\tNot done\tNormal\t\t\n8\tM\t7; 06/19\tAripiprazole 1 mg at night.\nAtomoxetine 10 mg was added at night after 5 months.\nMethylphenidate 5 mg was added in the morning after 7 months.\tAripiprazole 10 mg at night, 5 months.\nAtomoxetine 40 mg at night; 5 months.\nMethylphenidate 20 mg in the morning; 5 months.\tAripiprazole 10 mg at night; 15 months.\nMethylphenidate 20 mg in the morning; 9 months.\tNormal\tNot done\tMethylphenidate was added as patient got irritated on atomoxetine 40 mg. He was on atomoxetine for a total of 5 months, then stopped.\t\n9\tM\t5; 12/18\tRisperidone 0.25 mg at night.\nRisperidone 0.5 mg was started at night after 7 months.\tRisperidone 1.5 mg at night; 5 months.\nRisperidone 1.25 mg twice a day; 8 months.\tRisperidone 1.25 mg twice a day, 22 months.\tProlactin was mildly elevated with no clinical signs or symptoms of hyperprolactinemia.\tNormal\tRisperidone was stopped for 2 months by the patient’s mother after reaching a dose of 1.5 mg at night as she was concerned about medication side effects.\t\n10\tM\t10; 06/19\tRisperidone 0.75 mg in the morning and 0.5 mg at night.\nAtomoxetine 10 mg was added at night after 8 months.\tRisperidone 2 mg in the morning and 0.5 mg at night; 8 months.\nAtomoxetine 60 mg at night; 2 months.\tRisperidone 2 mg in the morning and 0.5 mg at night; 13 months.\nAtomoxetine 60 mg at night; 7 months.\tProlactin was elevated 10-fold with no clinical signs or symptoms of hyperprolactinemia.\tNot done\tHe was already using risperidone for 6 months, 0.75 mg in the morning and 0.5 mg at night, when first visiting our clinic.\t\n11\tF\t7; 05/19\tAripiprazole 1 mg at night.\nAtomoxetine 10 mg was added at night after 7 months.\nMethylphenidate 5 mg was added in the morning after another 3 months.\tAripiprazole 10 mg at night; 7 months.\nMethylphenidate 10 mg in the morning; 1 month.\tAripiprazole 10 mg at night; 15 months.\nMethylphenidate 10 mg in the morning; 6 months.\tNormal\tNormal\tShe was prescribed risperidone 2 years prior to visiting our clinic but used it only for 1 month as her family was not willing to use medications.\nAtomoxetine was stopped after 1 week as it made her irritable.\t\n12\tM\t7; 12/19\tAripiprazole 0.5 mg at night.\tAripiprazole 10 mg at night; 4 months.\tAripiprazole 10 mg at night; 9 months.\tNot done\tNormal\t\t\n13\tM\t4; 03/19\tAripiprazole 1 mg at night.\tAripiprazole 9 mg at night; 10 months.\tAripiprazole 9 mg at night; 17 months.\tNormal\tNormal\t\t\n14\tM\t4; 03/17\tAlready on risperidone 0.1 mg twice a day for 3 months prior to his first visit.\tRisperidone 2 mg in the morning and 0.5 mg at night; 16 months.\nFour months after reaching full dose the family ran out of medication, so he was restarted at risperidone 1 mg in the morning.\tRisperidone 0.75 mg in the morning; 37 months.\tNormal\tNormal\tCurrently off medication\t\n15\tM\t5; 02/19\tMethylphenidate 2.5 mg in the morning.\nAripiprazole 1 mg was added at night after 2 months.\nAtomoxetine 10 mg was added at night after another 5 months.\tMethylphenidate 10 mg in the morning; 2 months.\nAripiprazole 10 mg at night; 6 months.\nAtomoxetine 40 mg at night; 4 months.\tAripiprazole 10 mg at night; 19 months.\nAtomoxetine 40 mg at night; 15 months.\tNormal\tNormal\tMethylphenidate made him hyperactive, so this was stopped and replaced with aripiprazole.\nAtomoxetine was added because he continued to be hyperactive.\t\n16\tM\t4; 04/18\tRisperidone 0.25 mg at night.\nAtomoxetine 10 mg was added at night after 5 months.\nAripiprazole 2 mg was added at night after 16 months and risperidone was stopped.\tRisperidone 0.5 mg twice a day; 13 months.\nAtomoxetine 60 mg at night; 14 months.\nAripiprazole 6 mg at night; 5 months.\tAtomoxetine 60 mg at night; 23 months.\nAripiprazole 6 mg at night; 12 months.\tNormal\tNot done\tPatient was switched to aripiprazole as he continued to gain weight on risperidone and we were not able to increase the dose to the target of 2 mg in the morning and 0.5 mg at night.\nAtomoxetine was added to control appetite and augment attention.\t\n17\tF\t4; 11/19\tRisperidone 0.25 mg at night.\nMethylphenidate 2.5 mg was added in the morning after 3 months.\nAtomoxetine 10 mg was added at night after 3 months.\tRisperidone 1 mg in the morning and 0.5 mg at night; 3 months.\nMethylphenidate 5 mg in the morning; 1 week then stopped as it made her irritable.\nAtomoxetine 18 mg at night; 2 months.\tRisperidone 1 mg in the morning and 0.5 mg at night; 10 months.\nAtomoxetine 18 mg at night; 6 months.\tNormal\tNot done\tEthosuximide was given before visiting us. This was stopped after her first consultation with us.\nMethylphenidate was later added because of weight gain on risperidone and to augment attention. Tried for one week then stopped as it made her irritable.\t\n18\tF\t8; 09/19\tAlready on risperidone 0.75 mg twice a day and atomoxetine 18 mg at night prior to her first visit.\tRisperidone 1.75 mg in the morning and 0.75 mg at night, 7 months.\nAtomoxetine 25 mg at night, 2 months.\tRisperidone 1.75 mg in the morning and 0.75 mg at night.\nAtomoxetine 25 mg at night, 16 months.\tNormal\tNot done\t\t\nNotes:\naAll medications were given orally. bComplete blood count, electrolytes, liver enzymes, kidney function test, lipid panel, hemoglobin A1c, and prolactin.\n\nAbbreviations: ASD, autism spectrum disorder; CGI-I, Clinical Global Impression-Improvement scale; F, female; M, male.\n\n\n\n\nWhen a patient tolerated risperidone or aripiprazole with no side effects and showed progressive improvement to a CGI-I score of 1 or 2, the child was continued on that medication. If the CGI-I score plateaued at 2 or higher, or the patient started to gain excessive weight and still exhibited hyperactivity or an inadequate attention span, methylphenidate or atomoxetine was added in an effort to augment improvement to a CGI-I score of 1, improve their attention span, and control excessive weight gain (these classes of medication are known to suppress appetite). All children with progressive weight gain were also referred to a nutritionist since progressive weight gain can cause serious health issues and may affect compliance with therapy and lead to the premature tapering of the medication.\n\nMethylphenidate was usually added at 2.5 mg in the morning and increased gradually to a maximum dose of 20 mg in the morning or less as tolerated. Atomoxetine was usually added at 10 mg at night and increased gradually to a maximum dose of 60 mg at night or less as tolerated, as long as no side effects were observed and an improvement was seen with each dose increment (Table 1). Once a patient reached a CGI-I score of 1 and a repeat CARS2-ST score of minimal-to-no symptoms of ASD, we continued the medications for an additional 6 months before trying to wean the child very slowly off the medications (Figure 1 describes the process used for weaning).\n\nBefore the initiation of therapy, a complete blood count, kidney function test, and lipid panel were performed, and the levels of electrolytes, liver enzymes, hemoglobin A1c, and prolactin were determined to provide a baseline for monitoring any metabolic side effects of the antipsychotic medications.30–34 The tests were repeated 3 to 6 months after initiating medication, followed by subsequent yearly checkups. Similarly, cardiac evaluations to monitor for any adverse medication effects, including an echocardiogram and electrocardiogram, were obtained by a fully trained pediatric cardiologist for half of the patients 9/18 (50%) when the maximum dose was reached or earlier if clinically indicated.35–37 Serial measurements of weight, body mass index (BMI), height, and vital signs were obtained for each patient at every office visit.\n\nThe initial presenting and current signs and symptoms of each patient, initial and current CARS2-ST scores, initial diagnosis as per the DSM-5 criteria, baseline CGI-S score, and current CGI-S and CGI-I scores are described in Supplementary Table S1.\n\nAll patients were strongly advised to continue the standard supportive therapies, such as applied behavior analysis (ABA) therapy, speech therapy, and occupational therapy. Where a family could not afford these therapies, the parents and caregivers were provided practical support and guidance as per our center’s practice. All parents and caregivers were strongly encouraged to maximize their child’s opportunity for social interactions by attending a daycare, nursery, or playgroups, as well as strongly advised to limit their child’s screen time where applicable.\n\nStatistical Analysis\nThe statistical significance of the differences between the mean pre- and post-treatment CGI-S and CARS2-ST scores was determined with the Wilcoxon signed-rank test. A P-value < 0.05 was considered statistically significant. Data were analyzed using the VassarStats online suite of statistical tools (www.vassarstats.net).\n\nResults\nIn total, 18 cases of ASD were included in this study, comprising 14 males and 4 females with a 3.5:1 male-to-female ratio. The age of the patients at presentation ranged from 4 to 10 years (mean age 5.7 years). The duration of treatment ranged from 6 to 43 months (mean 18.3 months). Eight patients (44%) were started on risperidone and 10 patients (56%) were started on aripiprazole. Efficacy of treatment was based on the changes in the CGI-I score from baseline, the repeat CARS2-ST score, family reports, and clinical observations of the treating physician.\n\nIn total, 10/18 (56%) patients attained a CGI-I score of 1 and had minimal-to-no symptoms of ASD (ie, complete resolution of ASD symptoms) when reassessed with the CARS2-ST, while the remaining 8/18 (44%) patients attained a CGI-I of 2 and a reassessment using CARS2-ST showed significant improvement from their baseline score. The differences in the mean CGI-S and CARS2-ST scores pre- and post-treatment in our cohort were statistically significant (Z = 3.71, P < 0.001 for both) using the Wilcoxon signed-ranked test, with pre- and post-treatment median values of 5 and 1 for CGI-S, respectively, and 35 and 22 for CARS2-ST, respectively.\n\nAmong the eight patients who were treated with risperidone with or without methylphenidate or atomoxetine in this case series, 5/8 patients (62%) achieved a CGI-I score of 1 and minimal-to-no-symptoms of ASD when reassessed on the CARS2-ST (cases 1, 9, 10, 14, and 18). The other 3/8 patients (38%) achieved a CGI-I score of 2 and their repeat CARS2-ST showed significant improvement from baseline (cases 6, 7, and 17). Two of the eight patients (25%) continued with risperidone only and did not require any adjunct therapy for attention issues (cases 9 and 14).\n\nAmong the 10 patients who were treated with aripiprazole with or without atomoxetine or methylphenidate in this case series, 6/10 patients (60%) achieved a CGI-I score of 1 with a normal repeat CARS2-ST (cases 2, 3, 4, 5, 8, and 13), and 4/10 patients (40%) achieved a CGI-I score of 2 and their repeat CARS2-ST showed significant improvement from baseline (cases 11, 12, 15, and 16). The remaining 3/10 patients (30%) did not require any adjunct therapy to aid attention (cases 3, 12, and 13).\n\nThree patients (cases 2, 16, and 17) showed clear improvement on monotherapy with risperidone or aripiprazole to a CGI-I score of 1 or 2 but started to exhibit excessive weight gain (BMI > 25) with attention deficit; therefore, atomoxetine or methylphenidate was added. One patient (case 4) continued to be inattentive on aripiprazole 15 mg and atomoxetine 40 mg at night; therefore, long-acting methylphenidate was added in the morning and the dose was increased to 36 mg. This combination improved his attention greatly and further improved his CGI-I score from 2 to 1 with minimal-to-no symptoms of ASD on his repeat CARS2-ST. One patient (case 16) started to gain excessive weight with no clear improvement with risperidone dose increments; therefore, he was switched to aripiprazole with clear improvement. Two patients (cases 1 and 11) did not tolerate or did not show clear clinical improvement with atomoxetine as an adjunct therapy and were switched to methylphenidate with superior results. Three patients (cases 6, 15, and 17) who did not show clear improvement on methylphenidate as an adjunct therapy or who started to be irritable were switched to atomoxetine with clear improvement. One patient attained a CGI-I score of 1 and had minimal-to-no-symptoms of ASD when reassessed on the CARS2-ST, and he is currently off all medications after being on risperidone for a total of 37 months (case 14). One patient is on a maintenance dose only to control symptoms of anxiety and self-talking, currently attends regular school, and had minimal-to-no-symptoms of ASD when reassessed on the CARS2-ST (case 5). All medication regimens are presented in Table 1.\n\nOne family stopped risperidone prematurely due to concerns about medication side effects, and this resulted in a clear regression of the patient (case 9) to his original status. Risperidone was then restarted. The parents of one patient (case 14) ran out of medication 20 months after starting risperidone and 4 months after reaching the full dose of 2 mg in the morning and 0.5 mg at night. The family noted that during the 4 weeks that he was off medication, the child became hyperactive again and inattentive but did not relapse to his initial ASD symptoms. That he did not completely relapse may be explained by the fact that he had already been on risperidone for 20 months, in comparison with case 13, who had only been on risperidone for 5 months. Of note, one patient (case 5) completely regressed when she was switched to risperidone from aripiprazole when aripiprazole was out of stock, and she was, therefore, placed back on aripiprazole as soon as it became available again. Another patient (case 18) was already on risperidone and atomoxetine for almost a year when she presented to us but was still showing signs and symptoms of ASD. Once the doses were optimized, she attained a CGI-I score of 1 and had minimal-to-no-symptoms of ASD when reassessed on the CARS2-ST.\n\nLaboratory results for our patients (complete blood count, electrolytes, liver enzymes, kidney function test, lipid panel, and hemoglobin A1c) were all within normal limits for their age. Three patients (17%; cases 9, 10, and 14) developed asymptomatically elevated prolactin levels and were treated conservatively as per the recommendations of a pediatric endocrinologist. Cardiac monitoring did not reveal any adverse effects. Some families were unable to afford cardiac evaluation or unwilling to undergo it, in which case the patients were monitored clinically for any signs or symptoms of cardiac issues, but none showed any adverse cardiac effects.\n\nDiscussion\nAltered neuronal connectivity and plasticity in the brain cortex are reported to be the underlying cause for the signs and symptoms observed in ASD patients.38–41 In mice with ASD, the prefrontal cortex appears to be the main site of brain pathology.42–45 Aman et al reported a considerable improvement in irritability and maladaptive behavior in comparison to the baseline, including core symptoms associated with ASD, in ASD patients who had been treated with risperidone for an average of 21 months.46 Recent studies in mice have shown that the chronic administration of risperidone or aripiprazole improves valproic acid-induced social interaction deficits and recognition memory impairment, with reductions observed in dendritic spine density in the prefrontal cortex and hippocampus.47 In addition, methylphenidate and atomoxetine were both found to improve valproic acid-induced social deficits and recognition memory impairment in mice.48\n\nThe financial and social burden of ASD is huge and expected to rise substantially in the coming years.10 For example, intensive behavioral interventions for children with ASD cost from $40,000 to $60,000 per child in the USA in 2011.49 The lifelong cost of supporting an individual with ASD and intellectual disability is estimated to be $2.4 million in the USA and £1.5 million ($2.2 million) in the UK.50 Residential care or supportive living accommodation during adulthood and individual productivity loss both contribute to these high costs.50 Caring for Americans with ASD cost society a staggering $268 billion in 2015, a number that has increased more than six-fold since 2006 and is expected to rise to $461 billion by 2025 in the absence of more effective interventions and support across patients’ life spans.10,51 Therefore, finding a successful treatment for ASD is a global necessity.\n\nFor this case series, children who presented with ASD and comorbid challenging behaviors at our center were started on the antipsychotics risperidone or aripiprazole provided their parents or legal guardians agreed with the treatment plan and understood the off-label use of such medications. We titrated medication doses to also target core symptoms and not just control challenging behaviors. We combined two proven therapeutic approaches, namely non-biological (eg, ABA therapy) and biological therapies (risperidone and aripiprazole), to treat children with ASD in a region where the vast majority cannot afford full supportive therapies. We added ADHD medications as needed to further augment attention as attention is crucial in the learning process. This intervention approach is based on our initial observations that these medications improved many aspects of ASD symptoms when used to control comorbid behavior as indicated by the FDA. We noted that treating difficult comorbid behavior, anxiety, poor attention, and hyperactivity made ASD patients a lot more responsive and receptive to supportive therapies. In addition, many previous studies and reports support the use of these medications in young children with ASD.14–17,19,20 Several studies have shown improvements in the core symptoms of children with ASD when using risperidone or aripiprazole, including language impairment, maladaptive behaviors, social withdrawal, stereotypy, sensory motor issues, inappropriate speech, and ADHD.52–58 Troost et al, in their placebo discontinuation study, reported that risperidone helped prevent relapses in problem behaviors in children with ASD when used for 6 months, and the authors concluded that these results provide a rationale for the continued use of risperidone beyond 6 months with close observation for weight gain.59\n\nHere, the medication doses were slowly increased to the maximum dose tolerated and this regimen was maintained as long as the patient continued to show improvement and the maximum allowed dose had not been reached. If the patient did not respond to risperidone, the patient was shifted to aripiprazole or vice versa. Patients who responded initially but then plateaued over subsequent dose increments were supplemented with atomoxetine or methylphenidate to help increase attention, control hyperactivity, and attain further improvement. Patients who continued to improve with risperidone or aripiprazole increments but started to experience side effects, such as excessive weight gain along with attention deficit and/or hyperactivity, were also supplemented with atomoxetine or methylphenidate to control their weight and further improve their attention span. Our goal was to achieve a low CGI-I score with minimal-to-no-symptoms of ASD as per the CARS2-ST and clinical evaluation.\n\nWe used the DSM-5 criteria and CARS2-ST to confirm the diagnosis of ASD. The CGI scale and CARS2-ST were used to measure baseline severity and to monitor improvement. The American Academy of Child and Adolescent Psychiatry (AACAP), in its 2014 ASD practice parameters, emphasized that the most important diagnostic step is clinical diagnosis based on careful consideration of the DSM-5 criteria.4 These guidelines further emphasize that while there are many assessment instruments for ASD, including the childhood autism rating scale (CARS) and the autism diagnostic observation scale (ADOS) among others, these instruments, if needed, should only supplement and not replace informed clinical judgment based on the DSM-5 criteria. The American Academy of Pediatrics (AAP), in its latest ASD clinical report published in 2020, emphasized the importance of using the DSM-5 criteria and definitions for the clinical diagnosis of ASD.5 Severity ratings of DSM-5 criteria do not provide a quantifiable score and are based on the extent of the patient’s social communication impairments, their restricted and repetitive patterns of behavior, and the resultant level of care the individual requires; thus, these ratings often reflect the impact of cognitive limitations.5,60 In contrast, the CGI-I scale offers an objective, readily understood, and practical measurement tool that can be easily applied even in a very busy clinical setting. It has two main features that make it suitable for ASD patients and treatment trials: there is scope for cross-comparison with the many other trials in which the CGI-I rating scale has been used in psychiatry, and it reflects general severity and clinical improvement even in small ASD studies, especially when combined with a standard ASD test like CARS2-ST.60,61 Therefore, in addition to clinical diagnosis based on the DSM-5 criteria, which also provides a severity scale, we included CARS2-ST and the CGI scales to try to maximize sensitivity and specificity in diagnosis and when monitoring for improvement among our patients.5,7,60 Diagnosis in each case was made by a team comprising both a pediatric neurologist and clinical psychologist.\n\nIn this case series, while risperidone or aripiprazole was started at an earlier age than that recommended by the FDA to primarily control behavioral issues, the off-label use of risperidone, aripiprazole, and other psychotropic medications is well described in common practice with a trend of increasing use in recent years, especially in preschool children with ASD.62–68 Treating our patients with early and chronic administration of risperidone or aripiprazole along with standard supportive therapies, supplemented with methylphenidate or atomoxetine as needed to augment attention, resulted in marked and statistically significant clinical improvement with minimal-to-no-symptoms (resolution of symptoms) of ASD in 56% of these patients as per the CGI-S scale, CARS2-ST, and clinical evaluation.\n\nThis is a single-center case series of children with ASD who were treated successfully with the antipsychotic drugs risperidone and aripiprazole in combination with atomoxetine or methylphenidate along with standard supportive therapies. These medications have been available on the market for over a decade and have been used to treat psychiatric disorders that share many features with ASD.69,70 Recent meta-analyses concluded that patients with ASD have a high burden of comorbid neuropsychiatric disorders such as anxiety disorders, depressive disorders, bipolar and mood disorders, schizophrenia spectrum, suicidal behavior disorders, attention-deficit/hyperactivity disorder, as well as disruptive, impulse-control, and conduct disorders and may share underlying brain circuit disruption or pathology.69,70 The improvements in symptoms in our patient cohort are likely due to the following: initiating risperidone or aripiprazole as soon as a diagnosis was made and as young as 4 years to control challenging behavior that can be a major barrier for learning, prescribing medications to control challenging behavior and target the core symptoms under the assumption that all ASD core symptoms are neuropsychiatric in nature and need to be treated the same way, and slowly increasing the medication doses to the maximum tolerated or highest dose allowed to achieve significant clinical improvement with an individualized treatment plan. These medications need to be used for many months to result in minimal-to-no-symptoms of ASD signs and symptoms, and treatment requires combining antipsychotic drugs with medications used for attention deficit hyperactivity as needed, to augment attention and control hyperactivity. This must be performed in a manner that is tailored to each patient’s response, as attention plays a critical role in the learning process. Unfortunately, all double-blind, placebo-controlled studies performed to date on ASD were of short duration, used medications to primarily control challenging behaviors in children with ASD, did not combine antipsychotic medications with ADHD medications, and did not include cross-over design for non-responders.14,15,56,71–78\n\nThe main side effects noted were weight gain, sedation, drooling, and irritability. Sedation and drooling were noted mainly when first initiating the medications, were mild in nature, and disappeared with continuation of the medications. This could be related to the very slow titration schedule we used for our patients. Weight gain was excessive, uncontrollable (BMI > 25), and required further intervention in only five patients (17%).\n\nA major challenge we faced in our approach was to convince the families to start or continue using the medications once they were duly informed about the side effects of the medications and their FDA-approved uses.\n\nThe findings of this case series are limited because of the small sample size and retrospective nature of the data collection. These factors might have caused an inherent bias in the results. Cardiac evaluations were not performed for all patients, mainly because of affordability issues or the families being unwilling.\n\nConclusions\nOur study showed clinically and statistically significant improvement of ASD patients’ core signs and symptoms as per the CGI scales and CARS2-ST with early and chronic administration of risperidone or aripiprazole, with or without ADHD medications, and combined with standard supportive therapy. Our findings suggest that a notable proportion of patients with ASD can be successfully treated and potentially cured this way. Early intervention with behavioral therapy and pharmacological medications provide the best opportunity to support normal development in children with ASD. No one medication works for all children, and a trial of other antipsychotic medications should be used if a patient fails to respond to the first medication tried. While reported outcomes indicate significant improvement in the core signs and symptoms of ASD, pharmacological intervention should continue to be considered as part of a multi-component intervention in combination with standard supportive therapies. The potential benefits and risks must be weighed on a case-by-case basis when considering the use of medications to target core symptoms in children with ASD. Double-blind, placebo-controlled studies should be conducted to verify the findings of our study. Finding an effective treatment for ASD is of utmost importance because of its increasing prevalence, its poorly understood causes and pathology, and its devastating consequences.\n\nData Sharing Statement\nThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\n\nEthics Approval and Informed Consent\nThis retrospective observational case series was deemed by an independent Institutional Review Board (IRB), the Pearl IRB Committee, which is fully accredited by the Association for the Accreditation of Human Research Protection Program (AAHRPP), as exempt according to FDA 21 CFR 56.104 and 45CFR46.104(b)(4): (4) Secondary Research Uses of Data or Specimens on 06/01/2020 (approval no. 20-KNRC-101). This study was also approved locally by the Dubai Healthcare City Regulatory Ethics Committee (DHCR; approval no. KNCRC-01). Informed consent to participate in this study and publish the case details was obtained from the parents or legal guardians of all patients.\n\nAuthor Contributions\nAll authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.\n\nDisclosure\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. American Psychiatric Association . DSM-5 Task Force. Diagnostic and Statistical Manual of Mental Disorders: DSM-5 . 5th ed. Washington, DC : American Psychiatric Association ; 2013 .\n2. Zwaigenbaum \nL , Bauman \nML , Choueiri \nR , et al. 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Child Psychiatry Hum Dev . 2017 ;48 (5 ):796 –806\n. doi:10.1007/s10578-016-0704-x 28004215 \n77. Marcus \nRN , Owen \nR , Kamen \nL , et al. A placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder\n. J Am Acad Child Adolesc Psychiatry . 2009 ;48 (11 ):1110 –1119\n. doi:10.1097/CHI.0b013e3181b76658 19797985 \n78. Finding \nRL , Mankoski \nR , Timko \nK , et al. A randomized controlled trial investigating the safety and efficacy of aripiprazole in the long-term maintenance treatment of pediatric patients with irritability associated with autistic disorder\n. J Clin Psychiatry . 2014 ;75 (1 ):22 –30\n. doi:10.4088/JCP.13m08500 24502859\n\n",
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"issue": "16()",
"journal": "Neuropsychiatric disease and treatment",
"keywords": "antipsychotic; aripiprazole; comorbid challenging behaviors; risperidone",
"medline_ta": "Neuropsychiatr Dis Treat",
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"references": "28004215;18026891;26430170;16239862;24701014;27556593;27422400;24502859;9672054;24424351;26601124;23115501;23212807;19772883;27278054;26922658;24472258;29390871;18582177;21890117;31447415;18486823;19486849;23552907;15930063;32203749;19948625;19861668;18989389;26077193;25589889;14747245;27813651;25524787;30101492;30078460;29112191;17069546;16601648;20526405;12469238;26908468;26262903;28798977;23739917;15492353;16948927;19702492;22265360;24082002;24911948;23553574;31843864;19797985;17019624;29159857;26714434;18566881;18030077;31355670;29486137;25067827;32632024;21856714;31660042;15456328;25250061;26506581;26315981",
"title": "Pharmacological Intervention in Children with Autism Spectrum Disorder with Standard Supportive Therapies Significantly Improves Core Signs and Symptoms: A Single-Center, Retrospective Case Series.",
"title_normalized": "pharmacological intervention in children with autism spectrum disorder with standard supportive therapies significantly improves core signs and symptoms a single center retrospective case series"
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"abstract": "Penicillium species are rarely reported agents of infections in immunocompromised patients. We report 3 cases of invasive mycosis caused by voriconazole-resistant Penicillium oxalicum in patients with acute myeloid leukemia, diabetes mellitus, and chronic obstructive pulmonary disease, while on voriconazole therapy. Penicillium oxalicum has not been previously recognized as a cause of invasive mycoses.",
"affiliations": "Vallabhbhai Patel Chest Institute , University of Delhi , Delhi , India.;Vallabhbhai Patel Chest Institute , University of Delhi , Delhi , India.;Rajan Babu Institute of Pulmonary Medicine and Tuberculosis , Delhi , India.;Rajiv Gandhi Cancer Institute & Research Centre , Delhi , India.;Vallabhbhai Patel Chest Institute , University of Delhi , Delhi , India.;Rajiv Gandhi Cancer Institute & Research Centre , Delhi , India.;Canisius-Wilhelmina Hospital , Nijmegen , The Netherlands ; Radboud University Medical Centre , Nijmegen , The Netherlands.",
"authors": "Chowdhary|Anuradha|A|;Kathuria|Shallu|S|;Agarwal|Kshitij|K|;Sachdeva|Neelam|N|;Singh|Pradeep K|PK|;Jain|Sandeep|S|;Meis|Jacques F|JF|",
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"doi": "10.1093/ofid/ofu029",
"fulltext": "\n==== Front\nOpen Forum Infect DisOpen Forum Infect DisofidofidsOpen Forum Infectious Diseases2328-8957Oxford University Press 10.1093/ofid/ofu029ofu029Brief ReportsVoriconazole-Resistant Penicillium oxalicum: An Emerging Pathogen in Immunocompromised Hosts Chowdhary Anuradha 1Kathuria Shallu 1Agarwal Kshitij 2Sachdeva Neelam 3Singh Pradeep K. 1Jain Sandeep 3Meis Jacques F. 451 Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India2 Rajan Babu Institute of Pulmonary Medicine and Tuberculosis, Delhi, India3 Rajiv Gandhi Cancer Institute & Research Centre, Delhi, India4 Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands5 Radboud University Medical Centre, Nijmegen, The NetherlandsCorresponding Author: Anuradha Chowdhary, MD, PhD, Department of Medical Mycology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi 110 007, India (dranuradha@hotmail.com).9 2014 16 8 2014 1 2 ofu0291 4 2014 5 5 2014 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.2014This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.Penicillium species are rarely reported agents of infections in immunocompromised patients. We report 3 cases of invasive mycosis caused by voriconazole-resistant Penicillium oxalicum in patients with acute myeloid leukemia, diabetes mellitus, and chronic obstructive pulmonary disease, while on voriconazole therapy. Penicillium oxalicum has not been previously recognized as a cause of invasive mycoses.\n\nimmunocompromisedIndiainvasivePenicillium oxalicumposaconazolevoriconazole resistance cover-dateSummer 2014\n==== Body\nPenicillium species are ubiquitously present in the environment and are usually considered as laboratory contaminants or non-pathogenic. Among Penicillium species Penicillium marneffei is the only dimorphic member, which is an established agent of invasive mycoses in immunocompromised and immunocompetent patients [1, 2]. However, invasive fungal infections due to Penicillium species other than P marneffei such as Penicillium chrysogenum [3, 4], Penicillium citrinum [5], Penicillium decumbens [3, 6], Penicillium piceum [7, 8], Penicillium commune [9], and Penicillium purpurogenum [3] have also been rarely reported. The reduced susceptibility of these species to voriconazole, which is often the first-line therapy for invasive mold infections, is particularly worrisome [10, 11]. In this study, we report 3 rare cases of opportunistic fungal infection caused by voriconazole-resistant Penicillium oxalicum in patients with acute myeloid leukemia (AML), diabetes mellitus (DM), and chronic obstructive pulmonary disease (COPD), while on voriconazole therapy for 3–6 weeks.\n\nCASE REPORTS\nCase 1\nIn August 2013, a 12-year-old girl from Nepal presented to the Rajiv Gandhi Cancer Institute with fever and ecchymosis for 1 month and abdominal pain for 5 days. Her physical examination, chest x-ray, and ultrasound of the abdomen were unremarkable. The hemoglobin (9.2 gm/dL), white blood cell count (1200/µL), and platelet count (7000/µL) prompted a bone marrow biopsy, which revealed AML without maturation (AML-M1). Induction chemotherapy was initiated as per UK-AML12 protocol. Cefoperazone-sulbactam, metronidazole, and linezolid were administered empirically. As her fever persisted on day 4, imipenem/cilastatin was administered until day 15 but she remained febrile. On day 17, computed tomography (CT) of the thorax showed bilateral ill-defined nodules (Figure 1A). However, sputum and blood cultures were negative for bacteria and fungi. A probability of invasive pulmonary aspergillosis (IPA) was considered, and oral voriconazole (6 mg/kg twice daily) was given for 3 weeks. Meanwhile, she received another induction regimen in September 2013, during her fever defervescence of 4 days. On day 18 of induction, she developed right subcostal pain. An ultrasound of the abdomen revealed multiple rim-enhancing foci in both lobes of the liver and spleen. Fine-needle aspiration (FNA) of the hepatic lesion showed periodic acid-Schiff (PAS) positive septate hyphae (Figure 1B), which on culture yielded P. oxalicum (accession number VPCI979/P/13) with high minimum inhibitory concentrations (MICs) of voriconazole. The treatment was changed to posaconazole oral suspension (200 mg thrice a day) based on results of antifungal susceptibility testing (AFST). Her fever subsided after 4 days of posaconazole. A repeat abdominal ultrasound after 2 weeks of therapy showed reduction in size and number of lesions. Similarly, a CT chest scan showed complete resolution of lesions. Posaconazole was continued for 6 weeks during which she received 2 consolidation-chemotherapy cycles with high-dose cytarabine and is presently doing well.\nFigure 1. (A) Thoracic computed tomography (CT) of Case 1 showing an ill-defined nodule in the right upper lobe; (B) periodic acid-Schiff (PAS) stain of liver aspirate (Case 1) revealed septate hyphae, ×400; (C) thoracic CT of Case 2 showing an air-crescent within a cavitating nodule in the left upper lobe indicative of a mycetoma; (D) wet mount of KOH-digested fine-needle aspiration (FNA) of pulmonary lesion of Case 2 showed nondichotomously branching hyaline septate hyphae, ×400; (E) thoracic CT of Case 3 showing multiple thick-walled cavities along with bronchiectasis and pleural thickening in relation to the upper lobes bilaterally; (F) the FNA of a pulmonary nodule of Case 3 showed PAS-positive septate hyphae; (G) culture on Sabouraud's dextrose agar plates incubated at 28°C and 37°C showed bluish-green mold after 5 days of incubation; (H) lactophenol cotton blue mount of Czapek Yeast extract agar slide culture after 1 week of incubation revealed hyaline septate hyphae forming biverticillate conidiophores. The conidia were smooth to rough, globose to subglobose measuring 1.9 × 3.2 µm, ×1000.\n\n\n\nCase 2\nA 45-year-old female from Delhi, India was diagnosed with COPD, and she was treated with inhaled budesonide and formoterol and repeated systemic steroids for 3 years. She presented to the Vallabhbhai Patel Chest Institute, Delhi in October 2013 with complaints of productive cough, dyspnea, and intermittent fever. Her CT thorax revealed cavitating consolidation in the left upper lobe with mycetoma formation (Figure 1C), and sputum cultures yielded Aspergillus fumigatus. In addition, her serum was positive for precipitating antibodies against A. fumigatus [12]. A bronchoalveolar lavage (BAL) from the right upper lobe grew A. fumigatus, which was susceptible to azoles, but BAL galactomannan was negative. Chronic pulmonary aspergillosis (CPA) was diagnosed by compatible clinical symptoms, cavitating pulmonary lesions, precipitating antibodies, and the isolation of A. fumigatus from the BAL [13]. She received oral voriconazole (200 mg twice a day) for 59 days and showed initial symptomatic improvement which also corroborated with initial radiological and mycological clearance. However, on day 60 her complaints reoccurred. Thoracic CT revealed multiple cavitating nodules in the left upper lobe. A FNA from the pulmonary lesion showed nondichotomous septate hyphae in KOH mount (Figure 1D) and grew P. oxalicum (accession number VPCI533/P/12). No Aspergillus was isolated. Based on the results of AFST, oral posaconazole (200 mg thrice a day) was given for 6 weeks. She reported symptomatic relief, corroborated by replacement of the pulmonary nodules with fibrotic scars.\n\nCase 3\nA 54-year-old male from Delhi was being treated with oral prednisolone and inhaled corticosteroids for COPD for 6 years. He presented to the Vallabhbhai Patel Chest Institute in November 2013 with dyspnea, anorexia, weight loss, and intermittent fever. He had poorly controlled DM type 2, for 7 years. His thoracic CT showed bilateral upper lobe cavities with pleural thickening (Figure 1E). Sputum cultures were negative for bacterial pathogens, but microscopy showed septate hyaline hyphae. Fungal culture grew A. fumigatus, which had a voriconazole MIC of 0.06 μg/mL. Serum was positive for precipitating antibodies against A. fumigatus, but galactomannan was negative [12, 13]. Chronic pulmonary aspergillosis was diagnosed and oral voriconazole (200 mg twice daily) was prescribed. After an initial improvement, his condition deteriorated on day 40, when he developed hemoptysis. The thoracic CT showed fresh nodules in the right middle and left lingular lobes, in addition to the above findings. Computed tomography-guided FNA from a right middle lobe nodule on day 45 was positive for septate hyphae (Figure 1F) and grew a pure culture of P. oxalicum (accession number VPCI1136/13). Unfortunately, on day 49 the patient succumbed to massive hemoptysis. A diagnosis of invasive pulmonary P. oxalicum infection was also established by culture of a post mortem lung biopsy.\n\nDirect microscopy of KOH mounts of the liver (Case 1) and lung (Cases 2 and 3) aspirates showed hyaline, septate, nondichotomously branching hyphae, which were PAS positive. All of the specimens cultured on Sabouraud's dextrose agar plates, incubated at 28°C and 37°C, showed white cottony mold colonies after 2 days at both temperatures, which later turned bluish-green (Figure 1G). Lactophenol cotton blue mounts of Czapek Yeast extract agar (HiMedia Laboratories, Mumbai, India) slide culture after 1 week of incubation revealed hyaline septate hyphae forming symmetrical monoverticillate/biverticillate conidiophores with metulae in whorls of 3–5. Phialides were closely packed and ampulliform. The conidia were smooth to rough, globose to subglobose measuring 1.9 × 3.2 µm (Figure 1H). The identity of isolates was confirmed by partial sequencing of β-tubulin and calmodulin genes [14, 15]. The β-tubulin and calmodulin gene sequences exhibited 99% identity with P. oxalicum isolates from Korea, Malaysia, China, and the Netherlands (GenBank accession numbers KC344992, JF521520, AY678546, and JX141543, respectively). The β-tubulin and calmodulin gene sequences are submitted to GenBank under accession numbers KJ022632–KJ022634 and KJ022635–KJ022637, respectively. All of the isolates are deposited in the CBS-KNAW Fungal Biodiversity Centre (Utrecht, The Netherlands) under the accession numbers CBS 137558–CBS 137560. In vitro antifungal susceptibility was determined using the Clinical and Laboratory Standards Institute microbroth dilution method, following the M38-A2 guidelines [16]. The antifungals tested were amphotericin B (Sigma-Aldrich, St. Louis, MO), itraconazole (Lee Pharma, Hyderabad, India), voriconazole (Pfizer, Groton, CT), posaconazole (Merck, Whitehouse Station, NJ), isavuconazole (Basilea Pharmaceutica, Basel, Switzerland), and caspofungin (Merck). The isolates showed excellent activity to amphotericin B (MIC range, <0.03–0.5 μg/mL), posaconazole (MIC range, 0.125–0.5 μg/mL), itraconazole (MIC range, 0.5–2 μg/mL), and caspofungin (MIC range, 0.5–1 μg/mL). However, all 3 isolates had high MICs of voriconazole (MIC range, 2 – >16 μg/mL) and isavuconazole (8 μg/mL) (Table 1).\nTable 1. In Vitro Antifungal Susceptibility Profile of 3 Strains of Penicillium oxalicum Isolated From Patients Whose Clinical Characteristics Are Detailed Below\n\nCharacteristics\tCase 1, VPCI 979/P/13\tCase 2, VPCI 533/P/12\tCase 3, VPCI 1136/13\t\nAge/Sex\t12/F\t45/F\t54/M\t\nClinical summary\tAML, on induction chemotherapy\tCOPD, on steroids\tCOPD, on steroids, uncontrolled diabetes mellitus\t\nPresent clinical diagnosis\tSuspected pulmonary aspergillosis\tCPA\tCPA\t\nVRC: indication\tEmpirical therapy for IPA\tTherapy for CPA\tTherapy for CPA\t\nVRC: started after admission on day\t17\t12\t7\t\nSymptoms\tIntermittent fever\tIntermittent fever since 1.5 years, cough\tDyspnoea, anorexia, weight loss, intermittent fever since 4 years\t\nRadiology\tNodule, upper lobe of right lung; enhancing ring lesions in liver and spleen\tDiffuse, bilateral pulmonary infiltrates\tCavitating consolidation, middle lobe, lingual and bilateral upper lobes of the lung\t\nSite of Infection\tLiver, spleen and lung\tLung\tLung\t\nDuration of VRC therapy (days)\t38\t59\t49\t\nClinical specimen\tLiver aspirate\tFNAB, BAL, sputum\tFNAB, sputum\t\nIn vitro AFST (MIC/MEC μg/mL)\t\n VRC\t2\t>16\t2\t\n AMB\t≤0.03\t0.5\t0.5\t\n ITC\t0.5\t2\t1\t\n POS\t0.125\t0.5\t0.125\t\n ISA\t8\t8\t8\t\n CAS\t1\t0.5\t0.5\t\nTreatment (duration)\tPOS (6 weeks)\tPOS (6 weeks)\tDeath before start of the therapy\t\nOutcome\tSurvived\tSurvived\tDeath\t\nAbbreviations: AFST, antifungal susceptibility testing; AMB, amphotericin B; AML, acute myeloid leukemia; BAL, bronchoalveolar lavage; CAS, caspofungin; COPD, chronic obstructive pulmonary disease; CPA, chronic pulmonary aspergillosis; FNAB, fine-needle aspiration biopsy; IPA, invasive pulmonary aspergillosis; ITC, itraconazole; MEC, minimum effective concentration; MIC, minimum inhibitory concentration; POS, posaconazole; ISA, isavuconazole; VRC, voriconazole.\n\n\n\nThe phylogenetic tree of β-tubulin sequences using maximum-likelihood analyses with 2000 bootstrap simulations [17] revealed that our P. oxalicum isolates were genetically related to environmental isolates from South Africa (GenBank accession number JX091528), Korea (GenBank accession number JF521520), Japan (GenBank accession number AB849501), Malaysia (GenBank accession number KC344992), and the Netherlands (GenBank accession number KF499574, CBS301.97). The present isolates had 99.5%–100% similarity with each other and 97.9%–100% with those from other countries, thus indicating intraspecies genotypic variation amongst the P. oxalicum strains.\n\nDISCUSSION\nThe cases presented herein highlight the potential pathogenic role of voriconazole-resistant P. oxalicum in immunocompromised hosts. All patients reported were predisposed to invasive fungal infections due to the presence of blood dyscrasias, cancer chemotherapy, prolonged steroid use, uncontrolled DM, and preexisting anatomical lung damage, each of which has been reported as an independent risk factor for invasive fungal disease [18, 19]. The lung was the portal of entry for this pathogen. The patient with AML (Case 1) was a case of invasive pulmonary infection due to voriconazole-resistant P. oxalicum, and she was initially misdiagnosed as possible IPA. Thus, she was administered voriconazole, leading to dissemination pending appropriate therapy. Notably, Cases 2 and 3 developed P. oxalicum infection while on voriconazole therapy for CPA. The initial favorable response in Case 2 can be attributed to the activity of voriconazole against the voriconazole-sensitive A. fumigatus, resulting in breakthrough infection with voriconazole-resistant P. oxalicum. One may argue that the isolation of A. fumigatus from the subsequent samples could have been inhibited by previous use of voriconazole and that the isolation of P. oxalicum could be contamination. However, the clinico-radiologic worsening of patients while on voriconazole, isolation of P. oxalicum from otherwise sterile, deep-seated tissues with FNA, and the absence of other pathogens suggests a pathogenic role of this mold. In addition, it may be pointed out that, although therapeutic drug monitoring for azoles was not performed, the initial favorable response to voriconazole (Cases 2 and 3) and subsequently to posaconazole, suggests optimal dosing of the drug. Case 3 had a similar background to Case 2 but was more immunocompromised due to uncontrolled DM. The patient succumbed to autopsy-proven progressive fungal illness before appropriate therapy could be instituted. Therefore, the possibility of acquiring breakthrough infections while on voriconazole therapy was likely in both. In previous studies, breakthrough infections with voriconazole-resistant molds such as mucormycetes have been reported in patients with hematological malignancies on voriconazole treatment/prophylaxis [20].\n\nPenicillium oxalicum, a plant pathogen [21], has not been previously recognized as an agent of invasive mycoses. In a previous study, Lyratzopoulos et al [3] reported 3 cases of invasive mycoses due to Penicillium species and reviewed an additional 31 cases of invasive infections caused by Penicillium species other than P. marneffei from 1951 to 2000. We discuss 11 additional cases of invasive disease, reported subsequent to 2001 including the present report (Table 2) [3, 7, 8, 22–27]. Of the 45 cases reported globally, 16 occurred in immunocompromised patients and 29 occurred in immunocompetent patients. Among 16 immunocompromised patients, 6 had hematological malignancies, 3 were on immunosuppressive drugs, 2 were human immunodeficiency virus positive, and another 2 had chronic granulomatous disease. Other conditions included 1 case each of chronic liver disease, chronic kidney disease, and DM. Although Penicillium species are considered rare fungal pathogens in patients with hematological malignancies, 2 species of Penicillium, namely P. citrinum and P. purpurogenum, and the present case of P. oxalicum have been associated with leukemias [3, 5, 8]. It is likely that infections caused by Penicillium species are usually overlooked or misdiagnosed as aspergillosis due to nonspecific clinical and radiological findings. Moreover, direct microscopic examination of both the genera shows similar hyaline septate hyphae. The pathogenic species such as P. chrysogenum [3, 4], P. citrinum [5], P. decumbens [3, 6], P. piceum [7, 8], P. commune [9], and P. purpurogenum [3], previously reported as agents of invasive infections, grow at 37°C, whereas the majority of common laboratory aerial contaminants grow below this temperature.\nTable 2. Global Literature Review of Invasive Cases due to Penicillium Species Other Than Penicillium marneffei\n\nYear\tSex/Age (yrs)\tUnderlying Disease\tOrgan Involved\tOrganism and Identification\tDiagnosis\tSpecimen Positive\tTreatment and Outcome\tIn Vitro Susceptibility\t\n1951–2000 [3] N = 34\t22 M, 8 F, 4 unknown status\tImmunocompromised (n = 9; includes 2 HIV, 5 acute leukemia, 1 chronic hemolytic anemia, 1 CGD]; immunocompetent (n = 25);\tHeart, lung peritoneum, eye, brain, urinary tract, esophagus\tP. purpurogenum (n = 2), P. citrinum (n = 1), P. brevicompactum (n = 1), P. chrysogenum (n = 5), P. decumbens (n = 3), P. janthinellum (n = 1), P. lilanicum (n = 2), Penicillium species (n = 19)\tPulmonary infection (n = 13), prosthetic valve endocarditis (n = 4), CAPD peritonitis (n = 6), endophthalmitis (n = 5), fungemia (1), esophagitis (1), upper UTI (1) and intracranial infection (2), paravertebral infection (1)\tLung biopsy, biopsy of cysts in corpus callosum, paravertebral soft-tissue biopsya\tDeaths (9), cured (18)\tAMB, 0.25–4 μg/mL; FLU, 32–100 μg/mL; FC, 2–16 μg/mL; ITC, 0.03–0.5 μg/mL; KTC, 0.06 μg/mLa\t\n2001 [8]\tF/57\tCholangiocarcinoma\tDisseminated\tP. piceum, ITS sequencing\tFungemia\tBlood\tAMB for 2 weeks, but patient died of cardiovascular disorder\tND\t\n2004 [22]\tM/73\tTrauma to the head leading to probable intracranial fungal implantation\tBrain, spinal cord\tP. chrysogenum, ITS and β-tubulin gene sequencing\tCNS infection\tCSF\tFLU 400 mg/day and then 200 mg/day for 4 months\tAMB, 2 μg/mL; FLU, 8 μg/mL; ITC, 1 μg/mL; 5-FC, 0.125 μg/mL; TERB, 0.06 μg/mL\t\n2005 [23]\tM/41\tCLD\tBrain\tPenicillium species\tMultiple brain abscess\tBrain stereotactic biopsy\tAMB began, but patient died due to gastrointestinal bleeding\tND\t\n2005 [24]\tF/51\tIncarcerated peristomal hernia with perforated small bowel\tDisseminated\tP. chrysogenum identified by Southern Regional Research Centre (New Orleans, LA)\tDisseminated penicilliosis\tBlood\tAMB and ITC and cured\tAMB, 1.0 µg/mL; ITC, 0.25 µg/mL, VRC 1 µg/mL\t\n2006 [7]\tM/8\tCGD\tLung\tP. piceum, ITS sequencing\tPulmonary nodule and adjacent rib osteomyelitis\tCT-FNAC and surgically resected lung and rib lesions\tSurgical removal of lung nodule and rib lesion, AMB and VRC and cured after 1 year treatment\tND\t\n2007 [25]\tF/46\tCAPD\tPeritoneum\tPenicillium species\tPeritonitis\tPeritoneal fluid\tFLU and AMB, but patient died due to septicemia\tND\t\n2013 [26]\tM/78\tHistory of bronchial asthma and pulmonary emphysema\tLung\tP. digitatum, β-tubulin gene sequencing\tPneumonia with fungal ball\tSputum\tITC, MFG, VRC, AMB, and FLU, and patient died from renal failure\tND\t\n2013 [27]\tM/56\tLung transplant, immunosuppressive drugs received\tLung\tP. chrysogenum, ITS and β -tubulin gene sequencing\tIPM\tBAL and transbronchial biopsy\tVRC and CAS combination therapy; further AMB was added; patient died due to multiorgan failure and Penicillium infection\tAMB, 16 μg/mL; VRC, 0.25 μg/mL; CAS, 0.19 μg/mL; POS, 0.25 μg/mL\t\nAbbreviations: AMB, amphotericin B; BAL, bronchoalveolar lavage; CAPD, continuous ambulatory peritoneal dialysis; CAS, caspofungin; CGD, chronic granulomatous disease; CLD, chronic liver disease; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; FC, flucytosine; FLU, fluconazole; FNAC, fine-needle aspiration cytology; HIV, human immunodeficiency virus; IPM, invasive pulmonary mycosis; ITC, itraconazole; ITS, internal transcribed spacer; KTC, ketoconazole; MFG, micafungin; ND, ; POS, posaconazole; TERB, terbinafine; UTI, urinary tract infection; VRC, voriconazole; ND, no details available\n\na Details provided include 3 cases reported by Lyratzopoulos et al [3].\n\n\n\nFurthermore, resistance to voriconazole and other azoles have been well documented in A. fumigatus, and similarly species of Penicillum exhibit reduced susceptibility to voriconazole and itraconazole [11, 29]. Therefore, the role of accurate molecular identification and AFST of Penicillium isolates especially from invasive cases can hardly be overemphasized. In the present study, phenotypic characteristics, partial β-tubulin region, and calmodulin gene sequencing were used for identification of the isolates. The internal transcribed spacer (ITS) region, which is accepted as primary fungal barcode, could not be amplified for these isolates in spite of repeated attempts. Many species in the genus Penicillium may not be unambiguously identified by ITS sequencing alone, and (partial) β-tubulin or calmodulin sequences may be required to ensure correct species identification [14].\n\nIn addition, this mold has never been isolated before, either from CPA or allergic bronchopulmonary aspergillosis patients of our institute or from patients with hematological malignancies from the cancer hospital. The observation of voriconazole-resistant fungal infection developing during receipt of voriconazole therapy underscores the need for diagnostic vigilance in immunocompromised patients.\n\nNote\nPotential conflict of interests. J. F. M. received grants from Astellas, Basilea, and Merck. He has been a consultant to Astellas, Basilea, and Merck and received speaker's fees from Merck and Gilead.\n\nAll authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1 Duong TA Infection due to Penicillium marneffei , an emerging pathogen: review of 155 reported cases Clin Infect Dis 1996 23 125 30 8816141 \n2 Hu Y Zhang J Li X Penicillium marneffei infection: an emerging disease in mainland China Mycopathologia 2013 175 57 67 22983901 \n3 Lyratzopoulos G Ellis M Nerringer R Invasive infection due to Penicillium species other than Penicillium marneffei J Infect 2002 45 184 95 12387776 \n4 Hoffman M Bash E Berger SA Fatal necrotizing esophagitis due to Penicillium chrysogenum in a patient with acquired immunodeficiency syndrome Eur J Clin Microbiol Infect Dis 1992 11 1158 60 1291312 \n5 Mok T Koehler AP Yu MY Fatal Penicillium citrinum pneumonia with pericarditis in a patient with acute leukemia J Clin Microbiol 1997 35 2654 6 9316926 \n6 Alvarez S Systemic infection caused by Penicillium decumbens in a patient with acquired immunodeficiency syndrome J Infect Dis 1990 162 283 2355206 \n7 Santos PE Piontelli E Shea YR Penicillium piceum infection: diagnosis and successful treatment in chronic granulomatous disease Med Mycol 2006 44 749 53 17127632 \n8 Horré R Gilges S Breig P Case report. Fungaemia due to Penicillium piceum , a member of the Penicillium marneffei complex Mycoses 2001 44 502 4 11820265 \n9 Huang SN Acute disseminated penicilliosis: report of a case and review of the pertinent literature Am J Clin Pathol 1963 39 167 74 13955352 \n10 Diekema DJ Messer SA Hollis RJ Activities of caspofungin, itraconazole, posacoanzole, ravuconazole, voriconazole, and amphotericin B against 448 recent clinical isolates of filamentous fungi J Clin Microbiol 2003 41 3623 6 12904365 \n11 Cuenca-Estrella M Gomez-Lopez A Mellado E 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 50 917 21 16495251 \n12 Ouchterlony O Diffusion-in-gel methods for immunological analysis Prog Allergy 1958 5 1 78 13578996 \n13 Jhun BW Jeon K Eom JS Clinical characteristics and treatment outcomes of chronic pulmonary aspergillosis Med Mycol 2013 51 811 7 23834282 \n14 Samson RA Seifert KA Kuijpers AFA Phylogenetic analysis of Penicillium subgenus Penicillium using partial β-tubulin sequences Stud Mycol 2004 49 175 200 \n15 Hong SB Cho HS Shin HD Novel Neosartorya species isolated from soil in Korea Int J Syst Evol Microbiol 2006 56 477 86 16449461 \n16 Clinical Laboratory Standards Institute Reference Method for Broth Dilution Antifungal Susceptibility Testing Of Conidium-Forming Filamentous Fungi; Approved Standard, 2nd Edition, document M38-A2. Clinical Laboratory Standards Institute 2008 Wayne, PA \n17 Tamura K Peterson D Peterson N MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods Mol Biol Evol 2011 28 2731 9 21546353 \n18 Chowdhary A Sharma C Duggal S New clonal strain of Candida auris , Delhi, India Emerg Infect Dis 2013 19 1670 3 24048006 \n19 Singh PK Kathuria S Agarwal K Clinical significance and molecular characterization of nonsporulating molds isolated from the respiratory tracts of bronchopulmonary mycosis patients with special reference to basidiomycetes J Clin Microbiol 2013 51 3331 7 23903552 \n20 Vigouroux S Morin O Moreau P Zygomycosis after prolonged use of voriconazole in immunocompromised patients with hematologic disease: attention required Clin Infect Dis 2005 40 e35 7 15712069 \n21 Umemoto S Odake Y Takeuchi T Blue mold of tomato caused by Penicillium oxalicum in Japan J Gen Plant Pathol 2009 75 399 400 \n22 Kantarcioğlu AS Apaydin H Yücel A Central nervous system infection due to Penicillium chrysogenum Mycoses 2004 47 242 8 15189193 \n23 Noritomi DT Bub GL Beer I Multiple brain abscesses due to Penicillium spp infection Rev Inst Med Trop Sao Paulo 2005 47 167 70 16021292 \n24 Barcus AL Burdette SD Herchline TE Intestinal invasion and disseminated disease associated with Penicillium chrysogenum Ann Clin Microbiol Antimicrob 2005 4 21 16371150 \n25 Böhlke M Souza PA Menezes AM Peritonitis due to Penicillium and Enterobacter in a patient receiving continuous ambulatory peritoneal dialysis Braz J Infect Dis 2007 11 166 8 17625749 \n26 Oshikata C Tsurikisawa N Saito A Fatal pneumonia caused by Penicillium digitatum : a case report BMC Pulm Med 2013 13 16 23522080 \n27 Geltner C Lass-Flörl C Bonatti H Invasive pulmonary mycosis due to Penicillium chrysogenum : a new invasive pathogen Transplantation 2013 95 e21 3 23423272 \n28 Breton P Rare pulmonary mycoses in patients with hematologic diseases Rev Pneumol Clin 1998 54 253 7 9894280 \n29 Chowdhary A Kathuria S Xu J Emergence of azole resistant Aspergillus fumigatus strains due to agricultural azole use creates an increasing threat to human health PloS Pathog 2013 9 1003633.\n\n",
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"keywords": "India; Penicillium oxalicum; immunocompromised; invasive; posaconazole; voriconazole resistance",
"medline_ta": "Open Forum Infect Dis",
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"title": "Voriconazole-Resistant Penicillium oxalicum: An Emerging Pathogen in Immunocompromised Hosts.",
"title_normalized": "voriconazole resistant penicillium oxalicum an emerging pathogen in immunocompromised hosts"
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"abstract": "Pyridoxine is an important co-factor for many biochemical reactions in cellular metabolism related to the synthesis and catabolism of amino acids, fatty acids, neurotransmitters. Deficiency of pyridoxine results in impaired transcellular signaling between neurons and presents with muscular convulsions, hyperirritability, and peripheral neuropathy. Deficiency of pyridoxine is usually found in association with other vitamin B deficiencies such as folate (vitamin B9) and cobalamin (vitamin B12). Isolated pyridoxine deficiency is extremely rare. We present the case of a 59-year old female with type 2 diabetes who complained of painful muscle spasms. Her muscle spasms involved in both feet, which have spread proximally to her legs. She also experienced intermittent muscle spasms in her left arm, which is not alleviated by baclofen, cyclobenzaprine. Her plasma pyridoxal 5-phosphate confirmed pyridoxine deficiency. Vitamins B1, B3, B12, and folate were within normal limits. The patient received standard-dose intramuscular pyridoxine injections for three weeks followed by oral supplements for 3 months and her symptoms resolved. This case illustrates the rare instance of isolated pyridoxine deficiency in type 2 diabetes patient manifesting as myoclonic muscle spasms involving the legs and arms in the absence of objective polyneuropathy. Pyridoxine level should, therefore, be assessed in patients with type 2 diabetes, including newly diagnosed patients.",
"affiliations": "College of Medicine, Central Michigan University, Mount Pleasant, MI, USA. Electronic address: zhou1jy@cmich.edu.;College of Medicine, Central Michigan University, Mount Pleasant, MI, USA; MidMichigan Health, Midland, MI, USA.",
"authors": "Zhou|Joseph|J|;Effiong|Utibe|U|",
"chemical_list": "D011736:Pyridoxine",
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"keywords": "Muscle spasm; Pyridoxine; Type 2 diabetes",
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"mesh_terms": "D003924:Diabetes Mellitus, Type 2; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008875:Middle Aged; D011736:Pyridoxine; D013035:Spasm; D026681:Vitamin B 6 Deficiency",
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"title": "Isolated Pyridoxine Deficiency Presenting as Muscle Spasms in a Patient With Type 2 Diabetes: A Case Report and Literature Review.",
"title_normalized": "isolated pyridoxine deficiency presenting as muscle spasms in a patient with type 2 diabetes a case report and literature review"
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"abstract": "The aim of this study was to investigate and compare the incidence of suspected or definite cases of clozapine induced myocarditis (SDM) and clinical factors which could influence its onset in two different time periods, defined by pre- and post-cardiac monitoring at an inpatient setting, during the initiation phase of clozapine treatment. Hospital records of patients started on clozapine in the inpatient unit between 2011 and 2018 were investigated. Eight in 38 patients (11.3%) were classified as SDM after the initiation of the monitoring protocol, whereas only 1 in 33 patients (1.4%) was classified as SDM, before. Monitored and non-monitored patient groups were similar with regard to demographic and clinical variables. Diagnosis of schizoaffective disorder and use of concominant lithium, valproic acid and atypical antipsychotics were higher in patients with SDM, while clozapine dose titration was similar compared to the rest of the patients. Cardiac monitoring seems to be the main factor leading to the increase in the detection of clozapine induced myocarditis (CIM). If not monitored, the outcome of CIM can be fatal without any warning signs and symptoms. Concominant use of mood stabilizers including valproic acid and lithium, are important risk factors for the development of CIM.",
"affiliations": "Department of Psychiatry, Hacettepe University Faculty of Medicine, Ankara, Turkey. Electronic address: eanil@hacettepe.edu.tr.;Department of Psychiatry, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Psychiatry, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Psychiatry, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Psychiatry, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Biostatistics, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Department of Psychiatry, Hacettepe University Faculty of Medicine, Ankara, Turkey.",
"authors": "Anıl Yağcıoğlu|A Elif|AE|;Ertuğrul|Aygün|A|;Karakaşlı|Ahmet Alp|AA|;Ağaoğlu|Esen|E|;Ak|Sertaç|S|;Karahan|Sevilay|S|;Yazıcı|M Kâzım|MK|",
"chemical_list": "D014150:Antipsychotic Agents; D014635:Valproic Acid; D008094:Lithium; D003024:Clozapine",
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"keywords": "Adverse effects; Clozapine; Life threatening; Myocarditis; Risk factors",
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"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D015994:Incidence; D007297:Inpatients; D008094:Lithium; D008297:Male; D008875:Middle Aged; D008991:Monitoring, Physiologic; D009205:Myocarditis; D011618:Psychotic Disorders; D012307:Risk Factors; D014635:Valproic Acid; D055815:Young Adult",
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"title": "A comparative study of detection of myocarditis induced by clozapine: With and without cardiac monitoring.",
"title_normalized": "a comparative study of detection of myocarditis induced by clozapine with and without cardiac monitoring"
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"abstract": "Leprosy is a common skin disease in Sri Lanka which is being increasingly diagnosed due to the existing successful public health programme. Dapsone is a drug which holds unique pharmacological properties where it serves as both anti-inflammatory and antimicrobial agents. Of its main adverse effects, agranulocytosis is a serious consequence which is reported mainly in adults and elderly. We report a 7-year-old child who sustained life-threatening skin and subcutaneous tissue sepsis because of dapsone-induced agranulocytosis. Besides, this case highlights the importance of meticulous monitoring of cell counts due to the risk of neutropenia and the natural history of cell recovery following occurrence of neutropenia. Though high mortality rate has been described in most of the similar cases reported, the child we describe made a complete recovery following severe neutropenic sepsis.",
"affiliations": "University of Kelaniya, Colombo, Sri Lanka.;University of Ruhuna, Matara, Sri Lanka.;Lady Ridgeway Hospital for Children, Colombo, Sri Lanka.;Lady Ridgeway Hospital for Children, Colombo, Sri Lanka.;Lady Ridgeway Hospital for Children, Colombo, Sri Lanka.",
"authors": "Fernando|Meranthi|M|0000-0001-7162-3748;Kankananarachchi|Imalke|I|0000-0002-9351-2966;Navabalasooriyar|Pratheep|P|0000-0003-4319-8072;Herath|Bhagya|B|;Punchihewa|Pushpa|P|",
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"doi": "10.1155/2019/2314379",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2019/2314379Case ReportA Case of Dapsone-Induced Severe Agranulocytosis Causing Life-Threatening Skin Sepsis in a Sri Lankan Child with Borderline Leprosy: A Success Story! http://orcid.org/0000-0001-7162-3748Fernando Meranthi meranthif@gmail.com\n1\nhttp://orcid.org/0000-0002-9351-2966Kankananarachchi Imalke \n2\nhttp://orcid.org/0000-0003-4319-8072Navabalasooriyar Pratheep \n3\nHerath Bhagya \n3\nPunchihewa Pushpa \n3\n\n1University of Kelaniya, Colombo, Sri Lanka\n2University of Ruhuna, Matara, Sri Lanka\n3Lady Ridgeway Hospital for Children, Colombo, Sri LankaAcademic Editor: Pablo Fernandez-Peñas\n\n2019 6 5 2019 2019 231437910 1 2019 21 4 2019 Copyright © 2019 Meranthi Fernando et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Leprosy is a common skin disease in Sri Lanka which is being increasingly diagnosed due to the existing successful public health programme. Dapsone is a drug which holds unique pharmacological properties where it serves as both anti-inflammatory and antimicrobial agents. Of its main adverse effects, agranulocytosis is a serious consequence which is reported mainly in adults and elderly. We report a 7-year-old child who sustained life-threatening skin and subcutaneous tissue sepsis because of dapsone-induced agranulocytosis. Besides, this case highlights the importance of meticulous monitoring of cell counts due to the risk of neutropenia and the natural history of cell recovery following occurrence of neutropenia. Though high mortality rate has been described in most of the similar cases reported, the child we describe made a complete recovery following severe neutropenic sepsis.\n==== Body\n1. Introduction\nLeprosy is a common dermatological disorder among adults and in children in Sri Lanka. It is increasingly being detected due to raised awareness [1]. Dapsone (4,4′-diaminodiphenylsulfone) has been used as an antileprosy agent since the 1940s [2]. In addition, it is being used in multiple other dermatological conditions [3]. Though dapsone is a very effective drug, it carries a unique adverse effect profile [4]. Agranulocytosis is a rare, serious adverse effect following dapsone therapy which carries a high mortality rate [4]. There are no cases reported on dapsone-induced agranulocytosis in Sri Lankan paediatric population. Moreover, a limited number of cases have been reported in children internationally. Here, we report a 7-year-old girl who sustained life-threatening skin sepsis secondary to dapsone-induced agranulocytosis and recovered eventually [5].\n\n2. Case Report\nA 7-year-old girl presented with fever and swelling of the face and neck for 2 days. Symptoms were gradually progressive with dysphagia and difficulty in breathing.\n\nExamination revealed an ill, febrile child with swelling of the face and neck with associated cellulitis. Severe mucositis was noted with trismus and drooling of saliva (Figure 1). She had dental caries. Clinical condition deteriorated with severe cellulitis and formation of a deep-seated abscess in the submandibular region and resulted in stridor.\n\nThere were two hypopigmented skin lesions over the left arm with loss of thermal sensations which raised the suspicion of leprosy (Figure 2). No thickened palpable nerves were identified. The underlying diagnosis of leprosy was apparent with direct questioning, and it was revealed that the child had been on rifampicin and dapsone for 2 months. Unfortunately, no cell counts were monitored since commencement of antileprosy medications.\n\nInvestigations revealed a white blood cell (WBC) count of 1,000/mm3 with an absolute neutrophil count (ANC) of zero. Blood picture revealed dapsone-induced changes with numerous bite cells, blister cells, and agranulocytosis. Bone marrow examination was a bloody tap, and it was not repeated as the child improved with supportive care.\n\nInflammatory markers showed a CRP level of 220 with an ESR of 70 at the 1st hour. Blood culture was sterile. Liver and renal functions were normal. Serial USS showed deep-seated abscesses with overlying skin oedema in the submandibular region bilaterally.\n\nManagement included immediate cessation of dapsone with commencement of broad-spectrum antibiotics. Repeated incision and drainage were required to drain the abscesses. Nebulised adrenaline and IV dexamethasone were used to manage stridor and airway compression. Granulocyte colony-stimulating factor (GCSF) was used initially to manage neutropenia to which she had a poor response. Thus, buffy coat was transfused as per management of any other case of neutropenia [6].\n\nHer ANC rose up to 1500, following 5 days of admission, and she made a complete recovery (Table 1).\n\n3. Discussion\nDapsone has been widely used to treat many dermatological and autoimmune conditions due to its antibacterial and anti-inflammatory actions [7]. Inhibition of bacterial folate synthesis is the mechanism of its antibacterial property; however, there is no clear explanation for its anti-inflammatory action [6].\n\nThe prevalence of dapsone-induced agranulocytosis is 0.2–0.4% [8]. And it is possibly due to its idiosyncratic action. Other common haematological side effects such as haemolytic anaemia and methemoglobinemia are dose dependent [7].\n\nAgranulocytosis due to dapsone therapy was described among 16 US soldiers in Vietnam when they were treated for prophylaxis of malaria. Majority of them developed agranulocytosis within 1 to 3 months of the therapy [9]. Similarly, in this case, the onset of neutropenia was after 2 months of treatment. The common clinical manifestations were fever, lymphadenitis, tonsillitis, and septicaemia where the mortality rate was nearly 50%. Though this child made a quick recovery with complete normalisation of ANC, there had been cases where prolonged neutropenia was observed even after withdrawal of the drug. It could possibly be due to the extensive protein-binding property of the drug and might be related to enterohepatic circulation [4].\n\nManagement of dapsone-induced agranulocytosis includes prompt cessation of therapy and commencement of broad-spectrum antibiotics as per management of febrile neutropenia [4]. GCSF is indicated when ANC is less than 0.1 × 109/L.\n\nAgranulocytosis should actively be sought in patients on dapsone irrespective of the underlying diagnosis. Full blood count should be performed fortnightly during the first 3–6 months followed by once in 2-3 months subsequently [10]. Furthermore, repeated health education messages are prudent to make the primary health care workers and patients vigilant in detecting this important adverse effect as early presentation will be life-saving.\n\nAcknowledgments\nThanks are due to paediatric dermatology and intensive care team for their contribution in patient management.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Skin sepsis with severe mucositis.\n\nFigure 2 Two hypopigmented skin lesions over the left upper arm.\n\nTable 1 Serial blood counts.\n\nDay\t1\t2\t3\t5\t6\t\nWBC\t1000\t400\t600\t7.3\t24.7\t\nN (%)\t0\t3.5\t4.6\t22\t68\t\nL (%)\t80\t87\t71\t75\t17\t\nANC\t0\t14\t27\t1606\t16796\t\nHb\t9.5\t8.6\t7.2\t13.3\t14.2\t\nPLT\t289\t296\t192\t235\t289\n==== Refs\n1 Atukorala D. N. Leprosy and the child in Sri Lanka Sri Lanka Journal of Child Health 2009 32 4 p. 89 10.4038/sljch.v32i4.690 \n2 Sago J. Hall R. P. III Dapsone Dermatologic Therapy 2002 15 4 340 351 10.1046/j.1529-8019.2002.01543.x 2-s2.0-0036966716 \n3 Stendahl O. Molin L. Dahlgren C. The inhibition of polymorphonuclear leukocyte cytotoxicity by dapsone Journal of Clinical Investigation 1978 62 1 214 220 10.1172/jci109109 2-s2.0-0018139945 207742 \n4 Tesfa D. Keisu M. Palmblad J. Idiosyncratic drug-induced agranulocytosis: possible mechanisms and management American Journal of Hematology 2009 84 7 428 434 10.1002/ajh.21433 2-s2.0-67649742556 19459150 \n5 Fernando C. M. P. Navabalasooriyar P. Punchihewa P. M. G. Herath H. R. B. M. Dapsone induced severe agranulocytosis causing life threatening skin sepsis, in a child with borderline leprosy background Proceedings of the 6th Global Congress for Consensus for Paediatrics and Child Health November 2017 Colombo, Sri Lanka \n6 Zuidema J. Hilbers-Modderman E. S. M. Merkus F. W. H. M. Clinical pharmacokinetics of dapsone Clinical Pharmacokinetics 1986 11 4 299 315 10.2165/00003088-198611040-00003 2-s2.0-0022519155 3530584 \n7 Coleman M. Dapsone-mediated agranulocytosis: risks, possible mechanisms and prevention Toxicology 2001 162 1 53 60 10.1016/s0300-483x(01)00360-2 2-s2.0-0035848971 11311458 \n8 Ognibene A. J. Agranulocytosis due to dapsone Annals of Internal Medicine 1970 72 4 521 524 10.7326/0003-4819-72-4-521 2-s2.0-0014765305 5437633 \n9 Morton S. Mijovic A. Marks D. I. Use of granulocyte transfusions among haematology units in England and North Wales Transfusion Medicine 2018 28 3 243 248 10.1111/tme.12452 2-s2.0-85049021737 28833874 \n10 Wozel G. Blasum C. Dapsone in dermatology and beyond Archives of Dermatological Research 2014 306 2 103 124 10.1007/s00403-013-1409-7 2-s2.0-84896700466 24310318\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2019()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "2314379",
"pmc": null,
"pmid": "31198424",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "11311458;19459150;207742;24310318;28833874;3530584;5437633",
"title": "A Case of Dapsone-Induced Severe Agranulocytosis Causing Life-Threatening Skin Sepsis in a Sri Lankan Child with Borderline Leprosy: A Success Story!",
"title_normalized": "a case of dapsone induced severe agranulocytosis causing life threatening skin sepsis in a sri lankan child with borderline leprosy a success story"
} | [
{
"companynumb": "LK-ALVOGEN-2019-ALVOGEN-100307",
"fulfillexpeditecriteria": "1",
"occurcountry": "LK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report a case of amiodarone-induced vortex keratopathy-associated anatomical findings and subjective visual perception before and after treatment with topical heparin eye drops.\n\n\nMETHODS\nCase report.\n\n\nRESULTS\nA 76-year-old man complained of halos in his vision in both his eyes due to prominent bilateral cornea verticillata. For treatment of cornea verticillata, we prescribed unpreserved eye drops of a sterile, phosphate-free solution of 0.1% sodium hyaluronate with 1300 IU/mL heparin sodium 3 times daily to the left eye, whereas the other side served as the control. The area of corneal deposits was measured by 2 examiners before and at the 1- and 3-month examination. At last follow-up, cornea verticillata had been reduced from 6 to 2 mm in area by approximately 66% from grade-III to grade-II amiodarone keratopathy.\n\n\nCONCLUSIONS\nIn patients using amiodarone, clearing of cornea verticillata may be achieved by topical use of unpreserved eye drops of a sterile, phosphate-free solution of 0.1% sodium hyaluronate with 1300 IU/mL heparin sodium.",
"affiliations": "*Department of Ophthalmology, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany; and †Eye Clinic Gerolzhofen, Gerolzhofen, Germany.",
"authors": "Frings|Andreas|A|;Schargus|Marc|M|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D005343:Fibrinolytic Agents; D009883:Ophthalmic Solutions; D006493:Heparin; D000638:Amiodarone",
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000001306",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "36(11)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000287:Administration, Topical; D000368:Aged; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D003316:Corneal Diseases; D005343:Fibrinolytic Agents; D006493:Heparin; D006801:Humans; D008297:Male; D009883:Ophthalmic Solutions; D014792:Visual Acuity",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "1419-1422",
"pmc": null,
"pmid": "28834813",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recovery From Amiodarone-Induced Cornea Verticillata by Application of Topical Heparin.",
"title_normalized": "recovery from amiodarone induced cornea verticillata by application of topical heparin"
} | [
{
"companynumb": "PHHY2017DE172772",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METOPROLOL"
},
"drugadditional": "3",
"druga... |
{
"abstract": "OBJECTIVE: This report describes the case of a 76-year-old male who developed an upper gastrointestinal bleed shortly after beginning megestrol acetate (MGA) to treat geriatric failure to thrive (GFTT). He was also taking rivaroxaban for stroke prevention because of atrial fibrillation but had a low risk of bleeding. This article aims to provide the reader with an overview of MGA's impact on hemostasis, as well as a review of therapeutics on appetite stimulants and important transitions of care considerations for GFTT.<br/> SETTING: The primary setting was a community teaching hospital in Florida. The patient had many transitions of care, including hospital-to-skilled nursing facility and then a hospital readmission for the primary problem reported here. A skilled nursing facility medication administration record and outpatient community pharmacy were the primary sources of the patient's admission and discharge medication histories.<br/> PRACTICE CONSIDERATIONS: MGA's published labeling supports a prothrombotic mechanism; however, its pharmacology may also confer anticoagulant properties. This may lead to potential drug-drug interactions in patients on concomitant anticoagulant therapy. There is weak evidence supporting appetite stimulants in GFTT, and transitions of care in this population is especially important because of these patients' frequent care continuum contact.<br/> CONCLUSIONS: MGA, a synthetic derivative of endogenous progesterone used to treat GFTT, may exert either prothrombotic or anticoagulant effects, and as such potential for drug interactions with anticoagulants must be considered. Patients taking MGA should be closely monitored for coagulation changes throughout transitions of care.",
"affiliations": null,
"authors": "Boylan|Paul M|PM|;Santibañez|Melissa|M|",
"chemical_list": "D000069552:Rivaroxaban; D000069604:Dabigatran; D019290:Megestrol Acetate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2639-9636",
"issue": "34(8)",
"journal": "The Senior care pharmacist",
"keywords": null,
"medline_ta": "Sr Care Pharm",
"mesh_terms": "D000069604:Dabigatran; D005431:Florida; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D008297:Male; D019290:Megestrol Acetate; D000069552:Rivaroxaban",
"nlm_unique_id": "101737969",
"other_id": null,
"pages": "501-509",
"pmc": null,
"pmid": "31462353",
"pubdate": "2019-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Upper Gastrointestinal Bleeding in a Male Patient Taking Megestrol Acetate and Rivaroxaban: A Case Report.",
"title_normalized": "upper gastrointestinal bleeding in a male patient taking megestrol acetate and rivaroxaban a case report"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-19-04995",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MEGESTROL ACETATE"
},
... |
{
"abstract": "Nine episodes of drug associated acute interstitial nephritis, in seven patients, were treated between 1972 and 1980. The drugs implicated were cotrimoxazole (three times), ampicillin, Magnapen (ampicillin and flucloxacillin), penicillin, gentamicin, paracetamol and bendrofluazide. The time from exposure to the onset of symptoms ranged from one to 30 days. Presentation was with acute renal failure, which was non-oliguric in five cases, accompanied by rash (four), fever (four), and loin pain (two). Renal biopsy was carried out in all cases, and showed a characteristic interstitial infiltrate comprising substantial numbers of lymphocytes and plasma cells, with a variable number of neutrophils, eosinophils and histiocytes. Immunofluorescence was negative in all four cases studied in the acute phase, and showed scattered deposits of IgG, IgM, IgA and C3 on the tubular basement membrane in one patient during recovery. Significant proteinuria and an abnormal urine deposit were present in all cases, and seven of nine had radiological evidence of enlarged kidneys. Seven episodes were treated with high doses of methyl prednisolone and in all there was a response with a diuresis or spontaneous fall in serum creatinine within 72 hrs, and recovery of virtually normal renal function. Of two cases who did not initially receive steroids, one improved more slowly and one developed chronic renal impairment.",
"affiliations": null,
"authors": "Pusey|C D|CD|;Saltissi|D|D|;Bloodworth|L|L|;Rainford|D J|DJ|;Christie|J L|JL|",
"chemical_list": "D000892:Anti-Infective Agents, Urinary; D004338:Drug Combinations; D005839:Gentamicins; D010406:Penicillins; D000082:Acetaminophen; D005436:Floxacillin; D001539:Bendroflumethiazide; D000667:Ampicillin; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014295:Trimethoprim; D013420:Sulfamethoxazole; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-5622",
"issue": "52(206)",
"journal": "The Quarterly journal of medicine",
"keywords": null,
"medline_ta": "Q J Med",
"mesh_terms": "D000082:Acetaminophen; D000208:Acute Disease; D000328:Adult; D000667:Ampicillin; D000892:Anti-Infective Agents, Urinary; D001539:Bendroflumethiazide; D004338:Drug Combinations; D005260:Female; D005436:Floxacillin; D005839:Gentamicins; D006801:Humans; D007668:Kidney; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D009395:Nephritis, Interstitial; D010406:Penicillins; D013420:Sulfamethoxazole; D014295:Trimethoprim; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "0401027",
"other_id": null,
"pages": "194-211",
"pmc": null,
"pmid": "6604293",
"pubdate": "1983",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Drug associated acute interstitial nephritis: clinical and pathological features and the response to high dose steroid therapy.",
"title_normalized": "drug associated acute interstitial nephritis clinical and pathological features and the response to high dose steroid therapy"
} | [
{
"companynumb": "GB-PFIZER INC-2018166611",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GENTAMICIN SULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report our surgical experience with ocular surface stem cell transplantation (OSST) for limbal stem cell deficiency (LSCD) in the setting of keratitis-ichthyosis-deafness (KID) syndrome.\n\n\nMETHODS\nRetrospective interventional case series.\n\n\nRESULTS\nWe present 5 eyes of 3 patients with KID syndrome that developed LSCD and underwent OSST. Mean follow-up after OSST was 8.3 ± 4.3 years (range 3.4-11.4 years). Two eyes underwent living-related conjunctival limbal allograft (lr-CLAL), and 3 eyes were treated with keratolimbal allograft (KLAL). Four of the 5 eyes underwent subsequent keratoplasty. Both lr-CLAL eyes maintained a stable ocular surface at final follow-up. Conversely, all KLAL eyes developed a failed surface requiring repeat KLAL surgery. Because of multiple failed KLALs, 1 eye underwent placement of a keratoprosthesis.\n\n\nCONCLUSIONS\nKID syndrome is a rare cause of LSCD. Although OSST can stabilize the surface, long-term treatment of KID syndrome can be challenging. An lr-CLAL may offer further benefit over a KLAL in these eyes because it is HLA- and ABO-matched tissue; it also helps to treat keratoconjunctivitis sicca, often a prominent feature of KID syndrome.",
"affiliations": "Department of Ophthalmology, Cincinnati Eye Institute, University of Cincinnati, Cincinnati, OH.;University of Cincinnati College of Medicine, Cincinnati, OH.;Department of Ophthalmology, Cincinnati Eye Institute, University of Cincinnati, Cincinnati, OH.;Department of Ophthalmology, Cincinnati Eye Institute, University of Cincinnati, Cincinnati, OH.;Department of Ophthalmology, Cincinnati Eye Institute, University of Cincinnati, Cincinnati, OH.;Division of Nephrology and Hypertension, University of Cincinnati, Cincinnati, OH.;Department of Ophthalmology, Cincinnati Eye Institute, University of Cincinnati, Cincinnati, OH.",
"authors": "Cheung|Albert Y|AY|;Patel|Sunny|S|;Kurji|Khaliq H|KH|;Sarnicola|Enrica|E|;Eslani|Medi|M|;Govil|Amit|A|;Holland|Edward J|EJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000001802",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "38(1)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000328:Adult; D003228:Conjunctiva; D005500:Follow-Up Studies; D006801:Humans; D007634:Keratitis; D008297:Male; D012189:Retrospective Studies; D033581:Stem Cell Transplantation; D013997:Time Factors; D014184:Transplantation, Homologous; D014792:Visual Acuity",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "123-126",
"pmc": null,
"pmid": "30371567",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ocular Surface Stem Cell Transplantation for Treatment of Keratitis-Ichthyosis-Deafness Syndrome.",
"title_normalized": "ocular surface stem cell transplantation for treatment of keratitis ichthyosis deafness syndrome"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0110865",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditiona... |
{
"abstract": "Electrocardiogram (EKG) monitoring during methadone maintenance treatment (MMT) has been recommended to prevent potentially fatal prolonged computed QT intervals (QTc). However, risk indicators for obtaining EKGs do not exist. This study assessed 23 variables that might help identify prolonged QTc during MMT.\n\n\n\nEKGs concurrent with methadone serum levels were obtained from 69 veterans during a 5-year study, encompassing 302.8 person-years. Two cardiologists hand-measured QT intervals, selecting each patient's longest QTc. QTc categories included: normal duration <440 ms; borderline duration of 440-469 ms; and abnormal duration ≥470 ms. QTc's were compared with seven methadone parameters and 16 bio-psycho-social variables using two QTc cut-offs (440 and 470 ms).\n\n\n\nAmong the 69 patients, 19 had normal QTc's, 28 had borderline QTc's, and 22 had abnormal QTc's. Methadone dose/weight was moderately correlated with QTc, and independently associated with longer QTc at both 440 and 470 cut-offs.\n\n\n\nDose/weight ≥.49 is useful for screening EKGs for QTc's ≥440 cut-off. Dose/weight ≥.65 produces high-yield abnormal QTc's ≥470 cut-off.\n\n\n\nMethadone dose/weight provides moderately reliable thresholds for making routine screening decisions and urgent clinical decisions to obtain an EKG for prolonged QTc. (Am J Addict 2016;25:499-507).",
"affiliations": "Mental Health Service, Minneapolis VA Medical Center, Minneapolis, Minnesota.;Cardiology Service, Minneapolis VA Medical Center, Minneapolis, Minnesota.;Cardiology Service, Minneapolis VA Medical Center, Minneapolis, Minnesota.;Mental Health Service, Minneapolis VA Medical Center, Minneapolis, Minnesota.;Mental Health Service, West Haven VA Medical Center, West Haven, Connecticut.;Mental Health Service, Minneapolis VA Medical Center, Minneapolis, Minnesota.",
"authors": "Westermeyer|Joseph|J|;Adabag|Selcuk|S|;Anand|Vidhu|V|;Thuras|Paul|P|;Yoon|Gihyun|G|;Batres-Y-Carr|Tegan|T|",
"chemical_list": "D009294:Narcotics; D008691:Methadone",
"country": "England",
"delete": false,
"doi": "10.1111/ajad.12423",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1055-0496",
"issue": "25(6)",
"journal": "The American journal on addictions",
"keywords": null,
"medline_ta": "Am J Addict",
"mesh_terms": "D000328:Adult; D001835:Body Weight; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D008403:Mass Screening; D008691:Methadone; D008875:Middle Aged; D009294:Narcotics; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D012307:Risk Factors; D013223:Statistics as Topic; D058014:Veterans Health",
"nlm_unique_id": "9208821",
"other_id": null,
"pages": "499-507",
"pmc": null,
"pmid": "27548638",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Methadone maintenance dose/weight ratio, long QTc, and EKG screening.",
"title_normalized": "methadone maintenance dose weight ratio long qtc and ekg screening"
} | [
{
"companynumb": "US-MALLINCKRODT-T201804884",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Natural killer/T-cell lymphoma (NKTCL) and its presentation with extranodal orbital involvement as a single lesion are extremely rare. The aim of this article was to describe the presentation, diagnosis, and systemic treatment of a primary orbital NKTCL. A 67-year-old Caucasian woman presented with left exophthalmos, pain, periorbital swelling, and limited extrinsic ocular motility. Orbital cellulitis was suspected, but finally orbital biopsy was performed due to no response to initial antibiotic and anti-inflammatory standard treatment. The pathologic diagnosis was NKTCL. Systemic evaluations were negative. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy was initiated, but after 2 cycles of treatment, tumoral progression was observed. SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) rescue chemotherapy was then administered. Lymphoma progression was inevitable. She died 10 months later. Although more nasal NKTCL cases have been described, the nonnasal primary orbital NKTCL is an uncommon neoplasm with high mortality rate, despite the recent use of more potent chemotherapy regimens.",
"affiliations": "*Department of Ophthalmology, Santa Creu i Sant Pau Hospital; †Department of Orbital and Ophthalmic Plastic Surgery, Institut Català de Retina; ‡Department of Hematology and §Department of Pathology, Santa Creu i Sant Pau Hospital, Barcelona, Spain.",
"authors": "Marchino|Tizana|T|;Ibáñez|Núria|N|;Prieto|Sebastián|S|;Novelli|Silvana|S|;Szafranska|Justyna|J|;Mozos|Anna|A|;Graell|Xavier|X|;Buil|José A|JA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/IOP.0b013e3182a65026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0740-9303",
"issue": "30(5)",
"journal": "Ophthalmic plastic and reconstructive surgery",
"keywords": null,
"medline_ta": "Ophthalmic Plast Reconstr Surg",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D005094:Exophthalmos; D058447:Eye Pain; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008223:Lymphoma; D054391:Lymphoma, Extranodal NK-T-Cell; D009918:Orbital Neoplasms; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8508431",
"other_id": null,
"pages": "e131-4",
"pmc": null,
"pmid": "24317101",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An aggressive primary orbital natural killer/T-cell lymphoma case: poor response to chemotherapy.",
"title_normalized": "an aggressive primary orbital natural killer t cell lymphoma case poor response to chemotherapy"
} | [
{
"companynumb": "ES-BAXTER-2015BAX000568",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Chemo-refractory NHL has a very poor outcome; the addiction of RIT to salvage regiment pre ASCT had recently demonstrated promising results.We performed a retrospective sequential study to determine the feasibility of standard Zevalin with BEAM in high-risk relapse/refractory NHL. A matched cohort analysis with a group treated with standard BEAM without Zevalin was performed as secondary endpoint. Between October 2006 and January 2013, 37 NHL patients at high risk for progression or early (< 1 year) or multiple relapses were treated with Z-BEAM and ASCT after R-DHAP or R-ICE as salvage therapy. Clinical characteristics were 19 refractory and 18 early or multiple relapse; 16 patients received 1, and 21 had 2 or more previous rituximab-containing chemotherapy. At the end of treatment, response was CR 22 (59%), PR 10 (27%), PD 4 (11%), and toxic death (TD) 1 (3%). With a median follow up of 61 months, 3-year PFS was 61% and OS 61%. Fifteen patients died, 12 of lymphoma. Comparison with 21 treated with BEAM alone showed a numerical higher 3-yr PFS rate in favor of Z-BEAM but not statistically significant (57 vs 48%). With the limitation of the small sample subgroup analysis, a significant benefit was observed in relapsed patients for PFS (78% Z-BEAM vs 22% BEAM p = 0.016) and OS (83% Z-BEAM vs 22% BEAM p = 0.001). In relapsed/refractory high-risk NHL, Z-BEAM+ASCT is able to achieve a good ORR. Three-year PFS is promising for early relapsed patients but is not satisfactory for those with refractory disease.",
"affiliations": "Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy. ciochettochiara@gmail.com.;Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy.;Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy.;Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy.;Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy.;Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy.;Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy.;Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy.;Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy.;Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy.;Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy.;Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy.;Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy.;Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy.;Hematology Department, Città della Salute e della Scienza, Corso Bramante 88, 10126, Turin, Italy.",
"authors": "Ciochetto|Chiara|C|http://orcid.org/0000-0002-9415-4208;Botto|Barbara|B|;Passera|Roberto|R|;Bellò|Marilena|M|;Benevolo|Giulia|G|;Boccomini|Carola|C|;Castellino|Alessia|A|;Chiappella|Annalisa|A|;Freilone|Roberto|R|;Nicolosi|Maura|M|;Orsucci|Lorella|L|;Pecoraro|Clara|C|;Pregno|Patrizia|P|;Bisi|Gianni|G|;Vitolo|Umberto|U|",
"chemical_list": "D000911:Antibodies, Monoclonal; D015021:Yttrium Radioisotopes; D003561:Cytarabine; C000615496:Yttrium-90; C422802:ibritumomab tiuxetan; D011034:Podophyllotoxin; D008558:Melphalan; D002330:Carmustine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-018-3328-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "97(9)",
"journal": "Annals of hematology",
"keywords": "Aggressive refractory NHL; Autologous stem cell transplantation; Zevalin",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D002330:Carmustine; D003131:Combined Modality Therapy; D003561:Cytarabine; D019008:Drug Resistance, Neoplasm; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007558:Italy; D016393:Lymphoma, B-Cell; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011034:Podophyllotoxin; D012008:Recurrence; D012189:Retrospective Studies; D016879:Salvage Therapy; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult; D015021:Yttrium Radioisotopes",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1619-1626",
"pmc": null,
"pmid": "29663029",
"pubdate": "2018-09",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Yttrium-90 ibritumomab tiuxetan (Zevalin) followed by BEAM (Z-BEAM) conditioning regimen and autologous stem cell transplantation (ASCT) in relapsed or refractory high-risk B-cell non-Hodgkin lymphoma (NHL): a single institution Italian experience.",
"title_normalized": "yttrium 90 ibritumomab tiuxetan zevalin followed by beam z beam conditioning regimen and autologous stem cell transplantation asct in relapsed or refractory high risk b cell non hodgkin lymphoma nhl a single institution italian experience"
} | [
{
"companynumb": "IT-PFIZER INC-2018170452",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "A 49-year-old male with Ewing sarcoma and bone, pleural, lung and mediastinal lymph node metastasis was treated with cabozantinib after four lines of previous systemic treatments. He responded objectively and subjectively well for 8 months. In this heavily pretreated patient, the daily starting dose of 60 mg had to be reduced to 30 mg because of adverse events. We conclude that treatment with cabozantinib administered in further-line was active in this particular patient with metastatic Ewing sarcoma. The underlying mechanism of action remains unclear. Because of a stable disease on a long-term treatment with pazopanib targeting an anti-angiogenic pathway common to both drugs previously administered in this patient, it is hypothesized that the action of cabozantinib could be ascribed to its action on the non-common receptors AXL and c-Met. The potential of cabozantinib should be further investigated more upfront in this disease either alone or in combination with other systemic treatments.",
"affiliations": "Department of Medical Oncology UZ Brussel, Brussels, Belgium denis.schallier@uzbrussel.be.;Department of Pathology UZ Brussel, Brussels, Belgium.;Department of Nuclear Medicine UZ Brussel, Brussels, Belgium.",
"authors": "Schallier|Denis|D|;Lesfevre|Pierre|P|;Everaert|Hendrik|H|",
"chemical_list": "D000813:Anilides; D011725:Pyridines; C558660:cabozantinib",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.14190",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "40(4)",
"journal": "Anticancer research",
"keywords": "Ewing Sarcoma; cabozantinib; metastatic",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000813:Anilides; D001859:Bone Neoplasms; D017809:Fatal Outcome; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011725:Pyridines; D012512:Sarcoma, Ewing",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "2265-2269",
"pmc": null,
"pmid": "32234924",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Antitumor Activity of Cabozantinib in Metastatic Adult Ewing Sarcoma: A Case Report.",
"title_normalized": "antitumor activity of cabozantinib in metastatic adult ewing sarcoma a case report"
} | [
{
"companynumb": "BE-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-246869",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"druga... |
{
"abstract": "OBJECTIVE\nTo evaluate adaptive behavior outcomes of children prenatally exposed to lamotrigine, valproate, or carbamazepine, and to determine if these outcomes were dose-dependent.\n\n\nMETHODS\nData were collected from women enrolled in the North American Anti epileptic Drug (AED) Pregnancy Registry who had taken lamotrigine, valproate, or carbamazepine monotherapies throughout pregnancy to suppress seizures. The adaptive behavior of 252 exposed children (including 104 lamotrigine-exposed, 97 carbamazepine-exposed, and 51 valproate-exposed), ages 3- to 6-years-old, was measured using the Vineland-II Adaptive Behavior Scales, administered to each mother by telephone. Mean Adaptive Behavior Composite (ABC), domain standard scores for communication, daily living, socialization and motor skills, and adaptive levels were analyzed and correlated with first trimester drug dose.\n\n\nRESULTS\nAfter adjusting for maternal age, education, folate use, cigarette and alcohol exposure, gestational age, and birth weight by propensity score analysis, the mean ABC score for valproate-exposed children was 95.6 (95% CI [91, 101]), versus 100.8 (95% CI [98, 103]) and 103.5 (95% CI [101, 106]) for carbamazepine- and lamotrigine-exposed children, respectively (ANOVA; p=0.017). Significant differences were observed among the three drug groups in the ABC (p=0.017), socialization (p=0.026), and motor (p=0.018) domains, with a trend toward significance in the communication domain (p=0.053). Valproate-exposed children scored lowest and lamotrigine-exposed children scored highest in every category. Valproate-exposed children were most likely to perform at a low or moderately low adaptive level in each category. Higher valproate dose was associated with significantly lower ABC (p=0.020), socialization (p=0.009), and motor (p=0.041) scores before adjusting for confounders. After adjusting for the above variables, increasing VPA dose was associated with decreasing Vineland scores in all domains, but the relationships were not statistically significant. No dose effect was observed for carbamazepine or lamotrigine.\n\n\nCONCLUSIONS\nUnlike carbamazepine and lamotrigine, prenatal valproate exposure was associated with adaptive behavior impairments with specific deficits in socialization and motor function, along with a relative weakness in communication. Increasing valproate dose was associated with a decline in adaptive functioning. This finding of a linear dose-dependent teratogenic effect suggests that valproate should be avoided at any dose during pregnancy. However, some women with epilepsy controlled only by valproate will decide, in consultation with their provider, that the benefits of continuing valproate during pregnancy outweigh the fetal risks. Faced with difficult choices, clinicians should be supportive as these patients consider their options.",
"affiliations": "MassGeneral Hospital for Children, United States; Yale University School of Medicine, United States. Electronic address: uma.deshmukh@yale.edu.;University of Massachusetts, Boston, United States.;Harvard Medical School, United States; Massachusetts General Hospital Biostatistics Center, United States.;MassGeneral Hospital for Children, United States.;MassGeneral Hospital for Children, United States.;Harvard Medical School, United States; Brigham and Women's Hospital, United States.;Harvard Medical School, United States; Brigham and Women's Hospital, United States.;MassGeneral Hospital for Children, United States; University of Massachusetts, Boston, United States; Brigham and Women's Hospital, United States.",
"authors": "Deshmukh|Uma|U|;Adams|Jane|J|;Macklin|Eric A|EA|;Dhillon|Ruby|R|;McCarthy|Katherine D|KD|;Dworetzky|Barbara|B|;Klein|Autumn|A|;Holmes|Lewis B|LB|",
"chemical_list": "D000927:Anticonvulsants; D014227:Triazines; D002220:Carbamazepine; D014635:Valproic Acid; D000077213:Lamotrigine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0892-0362",
"issue": "54()",
"journal": "Neurotoxicology and teratology",
"keywords": "Antiepileptic; Behavior; Carbamazepine; Lamotrigine; Pregnancy; Valproate",
"medline_ta": "Neurotoxicol Teratol",
"mesh_terms": "D000704:Analysis of Variance; D000927:Anticonvulsants; D002220:Carbamazepine; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities; D004827:Epilepsy; D005260:Female; D005790:General Adaptation Syndrome; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects; D014227:Triazines; D014635:Valproic Acid",
"nlm_unique_id": "8709538",
"other_id": null,
"pages": "5-14",
"pmc": null,
"pmid": "26791321",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "24444855;16796590;18992367;23865818;15794725;11950853;23352199;21224309;21042872;16322174;21339499;21415043;21783425;16157661;15781808;10882750;17146708;16029946;18346940;11118242;18177411;16894099;15781806;23370617;21263139;15491979;17049311;19047565;10553991;9579936;24012508;16108456;1574165;19369666;7509419;12464511;14718692;21670385;25540307;23613074;15955936;15046269;25518975;25851171;3125743",
"title": "Behavioral outcomes in children exposed prenatally to lamotrigine, valproate, or carbamazepine.",
"title_normalized": "behavioral outcomes in children exposed prenatally to lamotrigine valproate or carbamazepine"
} | [
{
"companynumb": "US-ALEMBIC PHARMACUETICALS LIMITED-2016SCAL000157",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"dru... |
{
"abstract": "OBJECTIVE\nThe first non-vitamin K antagonist oral anticoagulant (NOAC) introduced to the market in Japan was dabigatran in March 2011, and three more NOACs, rivaroxaban, apixaban, and edoxaban, have since become available. Randomized controlled trials of NOACs have revealed that intracranial hemorrhage (ICH) occurs less frequently with NOACs compared with warfarin. However, the absolute incidence of ICH associated with NOACs has increased with greater use of these anticoagulants, and we wanted to explore the incidence, clinical characteristics, and treatment course of patients with NOACs-associated ICH.\n\n\nMETHODS\nWe retrospectively analyzed the characteristics of symptomatic ICH patients receiving NOACs between March 2011 and September 2014.\n\n\nRESULTS\nICH occurred in 6 patients (5 men, 1 woman; mean ± SD age, 72.8 ± 3.2 years). Mean time to onset was 146.2 ± 111.5 days after starting NOACs. Five patients received rivaroxaban and 1 patient received apixaban. None received dabigatran or edoxaban. Notably, no hematoma expansion was observed within 24 h of onset in the absence of infusion of fresh frozen plasma, activated prothrombin complex concentrate, recombinant activated factor VIIa or hemodialysis. When NOAC therapy was initiated, mean HAS-BLED and PANWARDS scores were 1.5 ± 0.5 and 39.5 ± 7.7, respectively. Mean systolic blood pressure was 137.8 ± 15.9 mmHg within 1 month before spontaneous ICH onset.\n\n\nCONCLUSIONS\nSix symptomatic ICHs occurred early in NOAC therapy but hematoma volume was small and did not expand in the absence of infusion of reversal agents or hemodialysis. The occurrence of ICH during NOAC therapy is possible even when there is acceptable mean systolic blood pressure control (137.8 ± 15.9 mmHg) and HAS-BLED score ≤ 2. Even stricter blood pressure lowering and control within the acceptable range may be advisable to prevent ICH during NOAC therapy.",
"affiliations": "Department of Neurology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.;Department of Neurology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.;Department of Neurology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.",
"authors": "Akiyama|Hisanao|H|;Uchino|Kenji|K|;Hasegawa|Yasuhiro|Y|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0132900",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2617186210.1371/journal.pone.0132900PONE-D-15-14194Research ArticleCharacteristics of Symptomatic Intracranial Hemorrhage in Patients Receiving Non-Vitamin K Antagonist Oral Anticoagulant Therapy Symptomatic Intracranial Hemorrhage during NOAC TherapyAkiyama Hisanao *Uchino Kenji Hasegawa Yasuhiro \nDepartment of Neurology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan\nGarcia de Frutos Pablo Editor\nIIBB-CSIC-IDIBAPS, SPAIN\nCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: HA. Performed the experiments: HA KU. Analyzed the data: HA. Wrote the paper: HA. Collected the clinical data: HA KU. Provided study supervision: YH.\n\n* E-mail: h2akiyama@marianna-u.ac.jp14 7 2015 2015 10 7 e01329002 4 2015 22 6 2015 © 2015 Akiyama et al2015Akiyama et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Objectives\nThe first non-vitamin K antagonist oral anticoagulant (NOAC) introduced to the market in Japan was dabigatran in March 2011, and three more NOACs, rivaroxaban, apixaban, and edoxaban, have since become available. Randomized controlled trials of NOACs have revealed that intracranial hemorrhage (ICH) occurs less frequently with NOACs compared with warfarin. However, the absolute incidence of ICH associated with NOACs has increased with greater use of these anticoagulants, and we wanted to explore the incidence, clinical characteristics, and treatment course of patients with NOACs-associated ICH.\n\nMethods\nWe retrospectively analyzed the characteristics of symptomatic ICH patients receiving NOACs between March 2011 and September 2014.\n\nResults\nICH occurred in 6 patients (5 men, 1 woman; mean ± SD age, 72.8 ± 3.2 years). Mean time to onset was 146.2 ± 111.5 days after starting NOACs. Five patients received rivaroxaban and 1 patient received apixaban. None received dabigatran or edoxaban. Notably, no hematoma expansion was observed within 24 h of onset in the absence of infusion of fresh frozen plasma, activated prothrombin complex concentrate, recombinant activated factor VIIa or hemodialysis. When NOAC therapy was initiated, mean HAS-BLED and PANWARDS scores were 1.5 ± 0.5 and 39.5 ± 7.7, respectively. Mean systolic blood pressure was 137.8 ± 15.9 mmHg within 1 month before spontaneous ICH onset.\n\nConclusion\nSix symptomatic ICHs occurred early in NOAC therapy but hematoma volume was small and did not expand in the absence of infusion of reversal agents or hemodialysis. The occurrence of ICH during NOAC therapy is possible even when there is acceptable mean systolic blood pressure control (137.8 ± 15.9 mmHg) and HAS-BLED score ≤ 2. Even stricter blood pressure lowering and control within the acceptable range may be advisable to prevent ICH during NOAC therapy.\n\nThe authors have no support or funding to report. Data AvailabilityAll relevant data are within the paper.Data Availability\nAll relevant data are within the paper.\n==== Body\nIntroduction\nPatients with cardiogenic embolism associated with nonvalvular atrial fibrillation often experience serious and recurrent embolic events. Anticoagulant therapy with warfarin has been used for a long time to prevent this condition, but warfarin also has various disadvantages, such as complexity of dosing, interaction with many foods and medications, and a high risk of hemorrhagic complications. To avoid these problems, dabigatran, indicated for “patients with nonvalvular atrial fibrillation for prevention of ischemic stroke and systemic embolism” [1], was first introduced to the Japanese market as a non-vitamin K antagonist oral anticoagulant (NOAC) in March 2011. Three more NOACs, rivaroxaban, apixaban, and edoxaban, have since become available. Although large-scale clinical studies showed advantages of NOACs over warfarin with regard to hemorrhagic complications [2–7], several cases of intracranial hemorrhage (ICH) associated with NOAC therapy have been reported with the increasingly widespread use of NOACs [8–22]. Nevertheless, the number of studies reporting such cases, especially cases of patients receiving rivaroxaban or apixaban, is still limited.\n\nTo date, we have treated 6 patients who developed symptomatic ICH while receiving NOAC therapy (rivaroxaban or apixaban). In this article, we discuss their clinical characteristics, focusing in particular on blood pressure control before ICH onset, and compare them with those of patients reported by other groups.\n\nSubjects and Methods\nEthic Statement\nThe study was conducted in accordance with the guiding principles of the Declaration of Helsinki and was approved by the local ethics committee of St. Marianna University Hospital (No. 2877). All patients or their next of kin gave written informed consent to participate in this study.\n\nPatients and demographic data\nSubjects were 6 consecutive patients admitted to our hospital between March 2011 (when dabigatran was launched in Japan) and September 2014 in whom symptomatic ICH occurred during NOAC therapy. Four NOACs are currently available in the Japanese market, but edoxaban, which was launched on 26 September 2014 at almost the end of this 3.5-year study, was not administered to any subject in this study.\n\nThe following clinical factors and outcome at the time of hospital discharge, as noted in the medical records and from reading brain computed tomography (CT) images, were examined retrospectively: age; sex; chief complaints and neurologic findings on hospital admission; underlying illness; type of NOAC; NOAC dose and duration of NOAC therapy; time between the last NOAC administration and ICH onset; concurrent anticoagulation; blood pressure on hospital admission and within 1 month before ICH onset; blood test results; predictive scores for the risk of cerebral infarction (CHADS2) and bleeding (HAS-BLED and PANWARDS); and ICH-related information (location, hematoma volume, hematoma expansion, and surgical treatment). Our findings were then compared with corresponding results in the recent literature.\n\nStatistical analysis\nWelch’s t-test was used to compare the means calculated in this retrospective study and those obtained from the results reported previously by other groups. Creatinine clearance rate was calculated using the Cockcroft-Gault equation. Hematoma volume was calculated with the following formula using measurements on a plain CT image of the brain: maximum length of an ellipsoid representing intraparenchymal hemorrhage × width perpendicular to maximum length × thickness of hematoma × 0.5. Hematoma expansion was defined as volume increasing by > 6 ml or > 33% [23–24]. Mean annual incidence rates of ICH were calculated by the person-years method. Results with p value less than 0.05 were considered statistically significant.\n\nResults\nClinical background (Table 1)\n10.1371/journal.pone.0132900.t001Table 1 Clinical characteristics of our 6 cases (1).\nNOAC, Non-vitamin K antagonist oral anticoagulant; mRS, Modified Rankin Scale; M, Male; F, Female; IC, Impaired consciousness; Ri, Rivaroxaban; Ap, Apixaban; ASA, Acetylsalicylic acid; Rt, Right; Lt, Left; Th, Thalamus; SAH, Subarachnoid hemorrhage; SDH, Subdural hemorrhage; Ca, Caudate head hemorrhage; Pu, Putamen; ICH, Intra cerebral hemorrhage.\n\nPresent study\tCase 1\tCase 2\tCase 3\tCase 4\tCase 5\tCase 6\t\nAge (years)\t69\t73\t73\t78\t75\t69\t\nGender\tM\tM\tF\tM\tM\tM\t\nChief complain\tIC\tIC\tIC\tMotor paresis in the right lower extremity\tSensory impairment in the right upper extremity\tDysarthria\t\nType of NOACs\tRi\tRi\tAp\tRi\tRi\tRi\t\nDaily dose of NOAC (mg)\t15\t10\t10\t10\t10\t10\t\nDuration of NOAC therapy (days)\t124\t54\t99\t51\t171\t378\t\nTime between the last NOAC administration and ICH onset (hours)\t12\tUnknown\t10\t12\t4\t10\t\nAntiplatelet therapy\t-\t+ (ASA 100mg)\t-\t-\t+ (ASA 100mg)\t-\t\nHypertension\t+\t-\t+\t+\t+\t+\t\nDiabetes mellitus\t-\t-\t-\t-\t+\t-\t\nDyslipidemia\t-\t-\t+\t+\t+\t+\t\nLocation of hematoma\tRt. Th\tSAH with bil. SDH\tRt. Ca\tLt. Th\tLt. Th\tRt. Pu\t\nVentricular rupture\t+\t-\t+\t-\t-\t-\t\nHydrocephalus\t+\t-\t+\t-\t-\t-\t\nHematoma volume (ml)\t13\t-\t-\t1.38\t1.8\t3.56\t\nHematoma expansion\t-\t-\t-\t-\t-\t+\t\nPre-morbid mRS\t0\t0\t0\t0\t0\t4\t\nHead injury\t-\t+\t-\t-\t-\t-\t\nOperation\t+\t-\t+\t-\t-\t-\t\nCHADS2 score\t1\t1\t3\t4\t3\t1\t\nWe encountered 6 patients (5 men [83.3%], 1 woman; mean age at onset, 72.8 ± 3.2 years; age range, 69–78 years) who developed symptomatic ICH while receiving NOAC therapy during the 3.5-year study period between March 2011 and September 2014. Three patients showed impaired consciousness. Five patients (83.3%) had the same underlying condition (hypertension) and were receiving antihypertensive therapy. In addition, 1 patient (16.7%) had diabetes mellitus and 4 (66.7%) had dyslipidemia.\n\nThe most common NOAC given to patients in this study was rivaroxaban, which was given to 5 patients (83.3%); the remaining patient received apixaban. None of the patients received dabigatran. Mean daily dose of rivaroxaban was 11.0 ± 2.0 mg (10 mg in 4 patients, 15 mg in 1 patient). In Japan, the recommended dose of rivaroxaban is 15 mg orally once daily, and if creatinine clearance rate is 15 to 50 ml/min, a dose reduction to 10 mg orally once daily is recommended. The daily dose of apixaban was 10 mg in the remaining patient. Mean interval between initiation of NOAC therapy and onset of symptomatic ICH was 146.2 ± 111.5 days (range, 51–378 days), and mean time between the last NOAC administration (known for 5 patients only) and ICH onset was 9.6 ± 2.9 h (range, 4–12 h). Two patients received concurrent antiplatelet therapy with 100 mg/day aspirin.\n\nICH-related information (Tables 1 and 2, Fig 1)\n10.1371/journal.pone.0132900.t002Table 2 Clinical characteristics of our 6 cases (2).\nBMI, Body mass index; BP, Blood pressure; ICH, Intra cerebral hemorrhage; APTT, Activated partial thromboplastin time; PT-INR, prothrombin time-international normalized ratio; Ccr, Creatinine clearance; NOAC, Non-vitamin K antagonist oral anticoagulant; mRS, Modified Rankin Scale; NIHSS, National Institute of Health Stroke Scale; NSAID, Non-steroidal anti-inflammatory drug; Ap, Apixaban; Wa, Warfarin; Tr, Transferred to the rehabilitation hospital; D, Death; Cd, Changed departments; NE, Not evaluated.\n\nPresent study\tCase 1\tCase 2\tCase 3\tCase 4\tCase 5\tCase 6\t\nBody weight (kg)\t50.7\t64.1\t66.5\t64.7\t70.5\t49\t\nBMI\t17.1\t23\t28.3\t27.1\t25.9\t20.9\t\nPlatelet on admission (×104/μl)\t28\t12.7\t22.4\t14.3\t26.6\t17.4\t\nBP on admission (mmHg)\t184/76\t147/101\t169/122\t148/82\t162/56\t131/78\t\nBP within 1 month of ICH onset (mmHg)\t147/92\t63/45\t118/67\t152/81\t153/66\t119/67\t\nAPTT (sec)\t28.9\t36.9\t37.2\t42.2\t35.5\t42.5\t\nPT-INR\t0.98\t1.51\t1.11\t1.61\t1.19\t1.52\t\nCcr on admission (ml/min)\t82\t31\t73\t58\t70\t48\t\nCcr on NOACs introduction (ml/min)\t80\t41\t51\t55\t63\t46\t\nNIHSS score on admission\t16\tNE\tNE\t1\t10\t5\t\nLiver abnormality\t-\t-\t-\t-\t-\t-\t\nNSAIDs\t-\t-\t-\t-\t-\t-\t\nHAS-BLED score\t1\t2\t1\t1\t2\t2\t\nPANWARDS score\t41\t30\t39\t55\t37\t35\t\nPost mRS\t4\t6\t3\t1\t1\t4\t\nHospital stay (days)\t90\t-\t35\t34\t18\t55\t\nFinal anti-thrombotic therapy\t-\t-\tAp\tWa\tAp\tAp\t\nOutcome\tTr\tD\tCd\tTr\tTr\tTr\t\n10.1371/journal.pone.0132900.g001Fig 1 Brain computed tomography (CT) on admission (left) and 24 h later (right) in Cases 1, 3–6, 1.5 h later (right) in Case 2 who had intracranial hemorrhage during NOAC therapy.\nNo hematoma expansion is evident in any of the cases.\n\nICHs were located in the parenchyma in most cases (5/6, 83.3%): 3 in the thalamus, 1 in the putamen, 1 in the caudate head, and 1 in the subarachnoid with bilateral subdural hematoma. The median modified Rankin scale (mRS) score was 0 (range, 0–4). Traumatic ICH was suspected in 1 patient, who developed subarachnoid hemorrhage with bilateral subdural hematoma while receiving rivaroxaban therapy (Case 2). Two patients (33.3%) underwent surgery (endoscopic hematoma evacuation) for obstructive hydrocephalus as a complication of hematoma but not for hematoma expansion.\n\nHematoma volume measured on head CT images was small in 4 patients (Cases 1, 4–6), with a mean estimated volume of 4.9 ± 4.7 ml. Cases 2 and 3 were excluded as the hematoma could not be measured because of its form. Hematoma expansion within a 24-h period was not observed in Cases 1, 3–6; Case 2 died before receiving inpatient treatment. None of the 6 patients received an infusion of fresh frozen plasma (FFP), activated prothrombin complex concentrate (PCC), recombinant activated factor VIIa (rFVIIa) or hemodialysis. Hematoma volume on hospital admission was very small (1.38 ml) in Case 4, even though oral rivaroxaban therapy was continued for 4 days after the onset of motor paresis possibly due to ICH.\n\nIn the 6 patients, mean age at initiation of NOAC therapy was 72.7 ± 3.4 years, mean body weight was 60.9 ± 8.1 kg (range, 49.0–70.5 kg), and mean BMI was 22.3 ± 3.9. There were no problems with initiation of NOAC therapy in any cases. In 2 of the 5 patients receiving rivaroxaban, the daily dose was appropriately reduced to 10 mg because of a creatinine clearance rate of 30–49 ml/min, while in the remaining 3 patients, the dose was inappropriately reduced for 2 patients whose creatinine clearance rate (≥ 50 ml/min) did not meet the dose reduction criteria. The dose of apixaban was 10 mg daily in the 1 patient that took it in this study, which was appropriate since his age, body weight, and serum creatinine clearance rate did not meet the dose reduction criteria.\n\nTests of blood specimens collected upon hospitalization (at ICH onset) showed a mean platelet count of 202,000 ± 59,000 cells, mean activated partial thromboplastin time (APTT) of 37.2 ± 4.6 s, prothrombin time-international normalized ratio (PT-INR) of 1.32 ± 0.24 and creatinine clearance rate of 60.3 ± 17.0 ml/min. The creatinine clearance rate was also favorable (56.0 ± 12.8 ml/min) at initiation of NOAC therapy. None of the patients abused alcohol or had hepatic damage. None received non-steroidal anti-inflammatory drugs (NSAIDs).\n\nMean systolic and diastolic blood pressure was high at admission (156.8 ± 17.1 mmHg and 85.8 ± 20.8 mmHg, respectively). Within 1 month before ICH onset, the former was 125.3 ± 31.4 mmHg (range, 63–153 mmHg) and the latter was 69.7 ± 14.5 mmHg (range, 45–92 mmHg), suggesting reasonable blood pressure control in all patients. However, in the 5 patients with spontaneous ICH (excluding Case 2, in which traumatic ICH occurred), mean systolic and diastolic blood pressure was moderately high (137.8 ± 15.9 and 74.6 ± 10.3 mmHg, respectively; range 118–153 / 66–92 mmHg) albeit within the acceptable range.\n\nHAS-BLED and PANWARDS scores, which predict the risk for intracranial bleeding, were 1.5 ± 0.5 (median 1.5) and 39.5 ± 7.7, respectively, at initiation of NOAC therapy, suggesting a low risk in all 6 patients.\n\nFive of the 6 patients received NOAC therapy at our hospital and the remaining patient received it initially at our hospital and then at the nearby clinic. The total number of prescriptions of each NOAC at our hospital was 171 dabigatran prescriptions in 43 months, 342 rivaroxaban prescriptions in 30 months, and 233 apixaban prescriptions in 20 months. Under the assumption that all prescriptions were provided by our hospital, the annual incidence rate of symptomatic ICH was found to be higher with rivaroxaban (0.58%) than with dabigatran (0%) or apixaban (0.26%). The overall annual incidence rate of NOACs-associated ICH was 0.22% (746 prescriptions in 43 months).\n\nOutcome at discharge (Table 2)\nThe mRS score at the time of discharge was 1 in 2 patients, 3 in 1 patient, and 4 in 2 patients. The median score in 5 patients was 3 (excluding deceased Case 2). Case 6 had the mRS score of 4 at discharge and also before ICH onset, suggesting that there were few cases of disease aggravation.\n\nOne patient was transferred to the hematology department after being diagnosed with diffuse large B-cell lymphoma. When the number of days of stay in our department was used for calculation, mean duration of hospital stay was 46.4 ± 24.8 days (range, 18–90 days). One patient required a long hospital stay (90 days) because of ventriculoperitoneal shunting for aqueduct stenosis and treatment for a complication (Methicillin-Resistant Staphylococcus Aureus pneumonia). Four patients were eventually transferred to rehabilitation clinics.\n\nAfter discharge, 1 patient did not receive anticoagulant therapy and 4 received anticoagulant therapy with a NOAC that was different from the one given before ICH onset. Previously used NOACs were changed to warfarin in 1 patient and apixaban in 3 patients.\n\nDiscussion\nWarfarin has been used worldwide for more than 50 years in anticoagulant therapy for the prevention of cardiogenic embolism associated with nonvalvular atrial fibrillation. However, NOACs are gradually replacing warfarin after several randomized controlled trials (RCTs) conducted in recent years (RE-LY, ROCKET AF, J-ROCKET AF, ARISTOTLE, AVERROES, and ENGAGE AF) showed that NOACs are clinically equivalent or superior to warfarin in reducing the risks of cerebral infarction and ICH [2–7]. In Japan, dabigatran was launched in March 2011, rivaroxaban in April 2012, and apixaban in February in 2013, and edoxaban was approved for additional indications in September 2014. NOACs are known to have a lower risk of ICH complications than warfarin, but recent studies, albeit with a limited number of cases, have demonstrated the occurrence of ICH associated with NOAC therapy as the use of NOACs has become widespread [8–22].\n\nThe clinical characteristics in these previous studies (Tables 3 and 4) were as follows [8–22]. Mean age at ICH onset while receiving NOAC therapy was 79.3 ± 6.6 years, which was significantly higher (p = 0.003) than in our study. The number of male patients was higher than that of female patients. Dabigatran tended to be given in cases of subdural hemorrhage, while rivaroxaban tended to be given in cases of intraparenchymal hemorrhage. None of the previously reported patients received apixaban. Mean duration of NOAC therapy was 102.2 ± 114.6 days. Some patients were also receiving concurrent antiplatelet therapy, and hypertension was observed in most cases. Hematoma volume was small and remained so. Using the blood test results and clinical data (e.g., blood pressure) available, we calculated that mean systolic and diastolic blood pressure at ICH onset was 159.8 ± 28.7 mmHg and 90.4 ± 16.5 mmHg, respectively. Blood pressure before ICH onset was not available in any of the previously reported cases.\n\n10.1371/journal.pone.0132900.t003Table 3 Characteristics of symptomatic ICH in patients receiving NOACs (1).\nmRS, Modified Rankin Scale; NOAC, Non-vitamin K antagonist oral anticoagulant; BP, Blood pressure; ICH, Intracerebral hemorrhage; Cr, Creatinine; eGFR, Estimate glomerular filtration rate; Ccr, Creatinine clearance; PT-INR, Prothrombin time-international normalized ratio; APTT, Activated partial thromboplastin time; M, Male; F, Female; Sub, Subcortical hemorrhage; SDH, Subdural hemorrhage; SAH, Subarachhnoid hemorrhage; Th, Thalamic hemorrhage; Bg, Basal ganglia hemorrhage; NR, Not reported; Da, Dabigatran; Ri, Rivaroxaban; S, small; L, Large; m, Month; w, Week; d, Day; MF, Mechanical fall; HT, Head trauma; BE, Burr-hole evacuation; D, Death; Dh, discharged to home; Tr, Transferred to the rehabilitation hospital.\n\nPast reports\t2012 Garber et al\t2012 Chen et al\t2013 Chang et al\t2013 Awad et al\t2013 Wassef et al\t2014 Faust et al\t2014 Simonsen et al\t2014 Kasliwal et al\t2014 Ross et al\t2014 Hana et al\t\nNumber of cases\t1\t1\t1\t1\t3\t1\t1\t2\t7\t4\t\nAge (years)\t83\t80\t94\t85\t79/72/72\t85\t75\t83/80\tNR/NR/NR/NR/NR/NR/NR\t77/73/78/NR\t\nGender\tM\tM\tM\tF\tF/M/M\tM\tM\tM/M\tNR/NR/NR/NR/NR/NR/NR\tM/F/M/M\t\nLocation of hematoma\tSub+SDH+SAH\tSDH\tSDH\tSDH\tTraumatic Sub/SDH/SAH\tBg+Th\tSub\tTh/SDH\tICH/ICH/ICH/ICH/ICH/ICH/ICH\tTh/Sub/Th/Sub\t\nHematoma volume (ml)\tNR\tS\tL\t2.2cm\tNR/NR/NR\t2.5cm in diameter\t15\t2×1cm/NR\tNR/NR/NR/NR/NR/NR/NR\tS/L/NR/S\t\nHematoma expansion\t+\t-\t-\t+\t+ / - /-\t+\t+\t- /-\tNR/NR/NR/NR/NR/NR/NR\t+ /NR/NR/ +\t\nPre—morbid mRS\tNR\tNR\tNR\tNR\tNR/NR/NR\tNR\tNR\tNR/NR\tNR/NR/NR/NR/NR/NR/NR\tNR/NR/NR/NR\t\nType of NOACs\tDa\tDa\tDa\tDa\tDa/Da/Da\tDa\tDa\tRi/Da\tDa/Da/Da/Da/Da/Da/Da\tRi/Ri/Da/Da\t\nDuration of NOAC therapy (days)\t1m\tNR\t7m\tNR\tNR/NR/NR\t2w\t54d\tNR/NR\tNR/NR/NR/NR/NR/NR/NR\tNR/2w/NR/NR\t\nDaily dose of total NOACs (mg)\t300\t300\t300\tNR\t300/300/NR\t300\t300\t20/300\tMost 300\tNR/NR/NR/NR\t\nAnti-thrombotic therapy\tNR\tNR\tNR\tNR\t- / + / -\tNR\tNR\tNR/NR\tNR/NR/NR/NR/NR/NR/NR\tNR/NR/NR/NR\t\nHypertension\tNR\tNR\tNR\tNR\t- / + / -\t+\t+\t+ /NR\tNR/NR/NR/NR/NR/NR/NR\t+ / + / + /NR\t\nHead injury\t+ (MF)\t+ (MF)\t+ (MF)\t+ (HT)\t+ (MF)/ - /+ (MF)\t-\tNR\tNR/NR\tNR/NR/NR/NR/NR/NR/NR\tNR/NR/NR/NR\t\nBP on admission (mmHg)\tNR\t149/64\tNR\tNR\tNR/NR/NR\t182/98\t138/76\tNR/NR\tNR/NR/NR/NR/NR/NR/NR\tNR/NR/NR/NR\t\nBP within 1 month of ICH onset (mmHg)\tNR\tNR\tNR\tNR\tNR/NR/NR\tNR\tNR\tNR/NR\tNR/NR/NR/NR/NR/NR/NR\tNR/NR/NR/NR\t\nCr on admission (mg/dl)\tNR\t1.31\t0.74\tNR\tNR/NR/NR\t0.9\tNR\tNormal/Normal\tNR/NR/NR/NR/NR/NR/NR\tNR/NR/NR/NR\t\neGFR on admission (ml/min/1.73m2)\tNR\tNR\t79\tNR\t>90/>90/46\tNR\tNR\tNR/NR\tNR/NR/NR/NR/NR/NR/NR\tNR/NR/NR/NR\t\nCCr on admission (ml/min)\tNR\t53.69\tNR\tNR\tNR/NR/NR\tNR\t71\tNR/NR\tNR/NR/NR/NR/NR/NR/NR\tNR/NR/NR/NR\t\nPT-INR on admission\t1.4\t1.2\t1.52\tNR\tNormal/1.2/2.0\tNR\t1.3\tNormal/1.48\tNR/NR/NR/NR/NR/NR/NR\t2.5/2.3/Normal/NR\t\nAPTT on admission (sec)\t43\t37.6\t39.8\tNR\tNormal/26/47\t45.7\t59\tNormal/45.8\tNR/NR/NR/NR/NR/NR/NR\tNR/NR/NR/NR\t\nPlatelet on admission (×104/μl)\t27.1\t24.7\tNR\tNR\tNR/18.3/11.9\tNR\tNR\tNR/NR\tNR/NR/NR/NR/NR/NR/NR\tNR/NR/NR/NR\t\nOperation\t-\t-\t+ (BE)\t+ (BE)\t- / + (BE)/-\t-\t-\t- / +\tTotal 3 cases\t+ / - / - /-\t\nOutcome\tD\tTr\tTr\tDh\tD/Dh/Dh\tTr\tD\tDh/Tr\tD/D/D/Dh/Dh/Dh/Tr\tTr/D/Tr/D\t\n10.1371/journal.pone.0132900.t004Table 4 Characteristics of symptomatic ICH in patients receiving NOACs (2).\nmRS, Modified Rankin Scale; NOAC, Non-vitamin K antagonist oral anticoagulant; BP, Blood pressure; ICH, Intracerebral hemorrhage; Cr, Creatinine; eGFR, Estimate glomerular filtration rate; Ccr, Creatinine clearance; PT-INR, Prothrombin time-international normalized ratio; APTT, Activated partial thromboplastin time; M, Male; F, Female; S, Small; Me, Medium; d, day; m, month; y, year; SDH, Subdural hemorrhage; SAH, Subarachhnoid hemorrhage; Th, Thalamic hemorrhage; Pu, Putaminal hemorrhage; Ce, Cerebellar hemorrhage; Bg, Basal ganglia hemorrhage; Ca, Caudate head hemorrhage; Sub, Subcortical hemorrhage; NR, Not reported; Da, Dabigatran; Ri, Rivaroxaban; MF, Mechanical fall; HT, Head trauma; BE, Burr-hole evacuation; VE, Ventricular drainage; D, Death; Dh, discharged to home; Tr, Transferred to the rehabilitation hospital.\n\nPast reports\t2013 Komori et al\t2014 Hagii et al\t2014 Shoji et al\t2015 Debata et al\tTotal\t\nNumber of cases\t8\t5\t5\t3\t43\t\nAge (years)\t79/87/80/86/74/87/92/82\t67/80/75/82/64\t83/76/69/82/87\t71/76/80\tMean 79.3 ± 6.6 (p = 0.003, compared to our 6 cases)\t\nGender\tM/F/F/M/M/F/F/M\tM/M/F/M/M\tM/M/M/F/M\tM/M/M\tM; 27 F; 9\t\nLocation of hematoma\tSDH/SDH/SDH/SDH/SDH/Traumatic SAH/Th/Pu\tTh/Th/Ce/Th/Bg\tSDH/Pu/Pu/Traumatic ICH/SDH\tTh/Ca/Th\tSDH; 13 SAH; 3 Sub; 5 Pu; 3 Th; 10 Bg; 2 Ce; 1\t\nHematoma volume (ml)\tS/Me/Me/Me/Me/S/Me(5ml)/S(1ml)\t10/4/5/1/2\tNR/NR/Max diameter 4cm/NR/NR\t2010/3/15\t \t\nHematoma expansion\t- / - / - / - / - / - / - /-\t- / - / - / - / -\tNR\t- / + / +\t+; 9\t\nPre- morbid mRS\t0/0/0/0/0/0/3/0\t0/4/1/3/0\t0/1/0/0/0\tNR\t \t\nType of NOACs\tDa/Da/Da/Da/Da/Da/Da/Da\tRi/Ri/Ri/Ri/Ri\tDa/Da/Da/Da/Da\tRi/Ri/Ri\tDa; 32 Ri; 11\t\nDuration of NOAC therapy\t1m/6m/3m/1m/8d/10m/9m/3m\t29d/77d/>1y/>1y/14d\t1m/2m/1m/1m/1m\tNR\tMean 102.2 ± 114.6\t\nDaily dose of total NOACs (mg)\t220/220/220/220/220/220/220/220\t15/10/15/10/15\t220/220/300/150/220\t15/15/10\tDa; Mean 251.0 ± 46.0 Ri; Mean 13.9 ± 3.3\t\nAntipletelet therapy\t- / - / - / - / - / - / - / +\t- / - / - / - / -\t- / - / + / - /-\t- / - /-\t+; 3\t\nHypertension\t+ / - / - / + / - / - / + / +\t+ / + / + / + / +\t+ / + / + / - /-\t+ / + / +\t+; 22\t\nHead injury\t- / + / + / + / + / + / - /-\tNR\t- / - / - / + /-\t- / - /-\t+; 12\t\nBP on admission (mmHg)\t100/75 120/60 156/89 123/69 130/79 149/84 164/85 154/90\t176/115 162/95 167/110 168/93 163/102\t158/82 215/126 201/92 148/88 221/123\t141/98 209/96 151/81\tMean 159.8 ± 28.7/90.4 ± 16.5\t\nBP within 1 month of ICH onset (mmHg)\t126/70 104/60 112/81 129/72 124/82 128/61 NR 140/86\tNR\tNR\tNR\tMean 123.3 ± 11.0/73.1 ± 9.5\t\nCr on admission (mg/dl)\tNR\tNR\t1.08/1.05/0.98/0.68/1.23\t- / - /1.19\tMean 1.02 ± 0.20\t\neGFR on admission (ml/min/1.73m2)\tNR\tNR\tNR\tNR\t \t\nCCr on admission (ml/min)\t72.9/46/32/43/53/35/38/55\t110/53/114/51/101\t51/57/73/50/40\t74/100.4/41.5\tMean 61.5 ± 23.7\t\nPT-INR on admission\tNR\t0.90/1.27/0.92/0.97/1.15\t1.31/NR/1.09/NR/1.11\t1.02/1.17/1.14\tMean 1.35 ± 0.43\t\nAPTT on admission (sec)\t31.6/47.2/46.9/37.5/38.2/45.8/44.7/72.4\t34.0/36.4/29.5/36.5/38.1\t39.2/45.8/36.9/38.0/34.4\t28.9/32.4/29.1\tMean 40.3 ± 9.3\t\nPlatelet on admission (×104/μl)\tNR\tNR\t15.6/18.4/13.3/13.0/21.5\tNormal/Normal/8.4\tMean 17.2 ± 5.6\t\nOperation\t- / + (BE) / + (BE) / + (BE) / + (BE) / - /-\t- / - / - / - / -\t+ (BE) / - / - / - /-\t- / + / +\t+; 15\t\nOutcome\tmRS 0/0/0/0/0/0/4/1\tmRS 2/4/3/4/1\tmRS 1(Dh)/3/4(Tr)/5/6\tTr/D/D\t \t\nIn our study, we examined the clinical characteristics, including blood pressure control before ICH onset, of 6 consecutive patients admitted to our hospital with symptomatic ICH that occurred during NOAC therapy. We found that hematoma volume was small, onset occurred relatively early after initiation of NOAC therapy (≤ 6 months), and none of the patients showed expansion of a small hematoma in the absence of infusion of FFP, PCC, rFVIIa or hemodialysis. Our study suggests that infusion of these reversal agents or hemodialysis is not necessary to prevent hematoma expansion, but there is still debate about whether these agents are useful for preventing hematoma expansion or improving outcome [8–18, 22].\n\nThe advantage of NOACs is probably that they do not inhibit the production of factor VII and prothrombin [18–19, 21–22, 25], the key factors in the blood coagulation cascade, and they inhibit the coagulation activities of factor Xa and thrombin in a reversible manner, unlike warfarin. Another suggested reason is the loss of anticoagulant action of NOACs at blood trough concentrations, so that the intracranial hemostatic mechanism becomes normal temporarily. Several reasons for the differences in incidence of ICH among NOACs have been suggested but not proven; for example, differences in their dose, differences in peak and trough concentrations attributed to the dosage (e.g., once a day or twice a day), involvement of the thrombin-thrombomodulin complex, differences in tissue distribution volumes, involvement of apixaban-specific intestinal excretion, and differences in inhibition of MMP-9 activity shown in an animal model [26]. In the present study, mean time between onset of ICH and last NOAC administration was 9.6 h, suggesting the occurrence of hemorrhage irrespective of the peak blood levels of NOACs. This observation supports Kaneko et al.’s finding that peak blood levels were comparable between the groups with and without hemorrhage [27], suggesting the importance of blood pressure management during NOAC therapy (see below).\n\nHAS-BLED proposed by Pisters et al. [28], PANWARDS by Hankey et al. [29], and Q-bleeds by Hippisley-Cox and Coupland [30] are commonly used scoring systems for prediction of hemorrhage during anticoagulant therapy. However, hemorrhage occurred in all patients in this study, despite the risk of hemorrhage being predicted as low by the above scores (HAS-BLED score ≤ 2, and PANWARDS score = 39.5 points, predicting the hemorrhage frequency of 2.5% within 2.5 years). It is well known that hypertension is the strongest risk factor for ICH, and indeed the HAS-BLED bleeding score was higher by 1 point in patients with poorly controlled blood pressure than in those with successful control (≤ 160 mmHg). We focused on blood pressure control before ICH onset during NOAC therapy in the present study because there was no strict target blood pressure level in previous studies. Blood pressure on admission was high in all the patients in our study, as expected at ICH onset (i.e., in the acute phase). However, we found that systolic blood pressure of 137.8 ± 15.9 mmHg within 1 month before spontaneous ICH onset when the case of traumatic subdural hematoma was excluded, suggesting a need for stricter blood pressure lowering and control. A few previous studies have investigated the target systolic blood pressure level during antithrombotic therapy, such as antiplatelet or warfarin therapy. In the BAT study [31], which was a prospective, multicenter, observational study, Toyoda et al. estimated that the optimal blood pressure level was < 130/81 mmHg among 4009 patients receiving oral antithrombotic therapy, not including NOACs (e.g., receiving single or dual antiplatelet therapy, warfarin therapy, or warfarin plus antiplatelet therapy). In the Perindopril Protection Against Recurrent Stroke (PROGRESS) study [32], Arima et al. found that blood pressure may need to be controlled at < 120 mmHg among 4876 patients receiving antithrombotic therapy for a mean duration of 3.9 years. In the SPS3 randomized trial [33], Benavente et al. found that the rate of ICH was significantly reduced (hazard ratio, 0.37; 95% confidence interval (95% CI), 0.15–0.95; p = 0.03) in the lower target blood pressure group (< 130 mmHg) among 3020 patients with recent lacunar stroke who took aspirin or aspirin with clopidogrel for a mean duration of 3.7 ± 2.0 years. In a subanalysis of the Cilostazol Stroke Prevention Study 2 (CSPS 2) [34], Uchiyama et al. found that cilostazol was associated with a significantly lower risk for hemorrhagic stroke compared with aspirin at all systolic blood pressure control levels (< 130, 130–140, ≥ 140 mmHg) and that the effect was particularly notable in the < 130 mmHg group (incidence, 0.18% person-year; 95% CI, 0.04–0.71) among 2627 patients with previous ischemic stroke taking either cilostazol or aspirin for a mean duration of 29 months. In sum, we suggest that stricter blood pressure control appears necessary for the prevention of hemorrhagic complications and that the systolic blood pressure criterion in the HAS-BLED scoring should ideally be changed from 160 mmHg to 130 mmHg.\n\nThe dose reduction criteria for NOACs (e.g., age, renal disorder, and body weight) were not met in any of our patients, indicating that the dose at initation of NOAC therapy was not excessive in any of our patients. It is possible that hemorrhage arises from pre-existing cerebral microbleeds (CMBs) [19]. However, magnetic resonance fast field echo imaging was not performed at the start of NOAC therapy and the presence of CMBs was therefore unclear in this study. Although concurrent antiplatelet and NOAC therapy is thought to induce hemorrhage, 2 of our patients who had received concurrent antiplatelet medication did not show hematoma expansion. None of the patients had hepatic and/or renal disorder or hemorrhage tendency and did not receive concurrent NSAIDs. Only 1 patient had a previous stroke.\n\nTaken together, the risk for symptomatic ICH remained in patients on NOAC therapy, even when mean systolic blood pressure before onset was controlled to around 137 mmHg and the HAS-BLED score was ≤ 2. It is likely that stricter blood pressure control is necessary and prospective studies are necessary to investigate this issue further.\n\nThe limitations of this study include its retrospective and single-center design, short observation period, small number of cases, lack of comparison with warfarin-associated ICH cases, lack of more data in 24 h blood pressure before ICH onset, and absence of edoxaban cases (due to its later launch).\n\nIn conclusion, symptomatic ICH occurred early in NOAC therapy, and hematoma volume was small and remained so despite the lack of infusion of FFP, PCC, rFVIIa or hemodialysis. Our findings suggest that even stricter blood pressure lowering and control within the acceptable range may be advisable to prevent ICH during NOAC therapy. Further prospective studies are warranted.\n==== Refs\nReferences\n1 \nEzekowitz MD , Reilly PA , Nehmiz G , Simmers TA , Nagarakanti R , Parcham-Azad K , et al\nDabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study) . Am J Cardiol . 2007 ;100 : 1419 –1426 .\n17950801 \n2 \nConnolly SJ , Ezekowitz MD , Yusuf S , Eikelboom J , Oldgren J , Parekh A , et al\nDabigatran versus warfarin in patients with atrial fibrillation . N Engl J Med . 2009 ;361 : 1139 –1151 . 10.1056/NEJMoa0905561 \n19717844 \n3 \nPatel MR , Mahaffey KW , Garg J , Pan G , Singer DE , Hacke W , et al\nRivaroxaban versus warfarin in nonvalvular atrial fibrillation . N Engl J Med . 2011 ;365 : 883 –891 . 10.1056/NEJMoa1009638 \n21830957 \n4 \nHori M , Matsumoto M , Tanahashi N , Momomura S , Uchiyama S , Goto S , et al\nRivaroxaban vs. warfarin in Japanese patients with atrial fibrillation-the J-ROCKET AF study- . Circ J . 2012 ;76 : 2104 –2111 .\n22664783 \n5 \nGranger CB , Alexander JH , McMurray JJ , Lopes RD , Hylek EM , Hanna M , et al\nApixaban versus warfarin in patients with atrial fibrillation . N Engl J Med . 2011 ;365 : 981 –992 . 10.1056/NEJMoa1107039 \n21870978 \n6 \nConnolly SJ , Eikelboom J , Joyner C , Diener HC , Hart R , Golitsyn S , et al\nApixaban in patients with atrial fibrillation . N Engl J Med . 2011 ;364 : 806 –817 . 10.1056/NEJMoa1007432 \n21309657 \n7 \nGiugliano RP , Ruff CT , Braunwald E , Murphy SA , Wiviott SD , Halperin JL , et al\nEdoxaban versus warfarin in patients with atrial fibrillation . N Engl J Med . 2013 ;369 : 2093 –2104 . 10.1056/NEJMoa1310907 \n24251359 \n8 \nGarber ST , Sivakumar W , Schmidt RH . Neurosurgical complications of direct thrombin inhibitors- catastrophic hemorrhage after mild traumatic brain injury in a patient receiving dabigatran . J Neurosurg . 2012 ;116 : 1093 –1096 . 10.3171/2012.2.JNS112132 \n22394293 \n9 \nChen BC , Viny AD , Garlich FM , Basciano P , Howland MA , Smith SW , et al\nHemorrhagic complications associated with dabigatran use . Clin Toxicol . 2012 ;50 : 854 –857 .\n10 \nChang DN , Dager WE , Chin AI . Removal of dabigatran by hemodialysis . Am J Kidney Dis . 2013 ;61 : 487 –489 . 10.1053/j.ajkd.2012.08.047 \n23219111 \n11 \nAwad AJ , Walcott BP , Stapleton CJ , Yanamadala V , Nahed BV , Coumans JV . Dabigatran, intracranial hemorrhage, and the neurosurgeon . Neurosurg Focus . 2013 ;34 : E7 .\n12 \nWassef SN , Abel TJ , Grossbach A , Viljoen SV , Jackson AW , Howard MA , et al\nTraumatic intracranial hemorrhage in patients taking dabigatran: report of 3 cases and review of the literature . Neurosurgery . 2013 ;73 : E368 –E374 . 10.1227/01.neu.0000430763.95349.5f \n23670031 \n13 \nFaust AC , Peterson EJ . Management of dabigatran-associated intracerebral and intraventricular hemorrhage: a case report . J Emerg Med . 2014 ;46 : 525 –529 . 10.1016/j.jemermed.2013.11.097 \n24508114 \n14 \nSimonsen CZ , Steiner T , Tietze A , Damgaard D . Dabigatran-related intracerebral hemorrhage resulting in hematoma expansion . J Stroke Cerebrovasc Dis . 2014 ;23 : e133 –e134 . 10.1016/j.jstrokecerebrovasdis.2013.08.011 \n24103671 \n15 \nKasliwal MK , Panos NG , Munoz LF , Moftakhar R , Lopes DK , Byrne RW . Outcome following intracranial hemorrhage associated with novel oral anticoagulants . J Clin Neurosci . 2014 ;22 : 212 –215 . 10.1016/j.jocn.2014.04.025 \n25065949 \n16 \nRoss B , Miller MA , Ditch K , Tran M . Clinical experience of life-threatening dabigatran-related bleeding at a large, tertiary care, academic medical center: a case series . J Med Toxicol . 2014 ;10 : 223 –228 . 10.1007/s13181-013-0364-1 \n24385325 \n17 \nHana A , Berthold C , Gunness VRN , Hana A , Dooms G , Standhardt H , et al\nNOAC and intracerebral bleeding—Presentation of four cases and review of literature . Bull Soc Sci Med Grand Duche Luxemb . 2014 ;1 : 57 –66 .\n25011204 \n18 \nKomori M , Yasaka M , Kokuba K , Matsuoka H , Fujimoto S , Yoshida M , et al\nIntracranial hemorrhage during dabigatran treatment . Circ J . 2014 ;78 : 1335 –1341 .\n24662438 \n19 \nHagii J , Tomita H , Metoki N , Saito S , Shiroto H , Hitomi H , et al\nCharacteristics of intracerebral hemorrhage during rivaroxaban treatment: Comparison with those during warfarin . Stroke . 2014 ;45 : 2805 –2807 . 10.1161/STROKEAHA.114.006661 \n25082810 \n20 \nShoji A , Satoh K , Nakano Y , Sumitomo H , Niki H , Kinouchi T , et al\nDabigatran related intracranial hemorrhage, five cases report . Jpn J Stroke . 2014 ;36 : 186 –190 .\n21 \nDebata A , Tateishi Y , Hamabe J , Horie N , Izumo T , Hayashi K , et al\nThree cases of spontaneous intracerebral hemorrhage on rivaroxaban . Jpn J Stroke . 2015 ;37 : 41 –46 .\n22 \nSaji N , Kimura K , Aoki J , Uemura J , Sakamoto Y . Intracranial hemorrhage caused by non-vitamin K antagonist oral anticoagulants (NOACs)–Multicenter retrospective cohort study in Japan– . Circ J . 2015 ;79 : 1018 –1023 . 10.1253/circj.CJ-14-1209 \n25739470 \n23 \nDemchuk AM , Dowlatshahi D , Rodriguez-Luna D , Molina CA , Blas YS , Dzialowski I , et al\nPrediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study . Lancet Neurol . 2012 ;11 : 307 –314 . 10.1016/S1474-4422(12)70038-8 \n22405630 \n24 \nCiura VA , Brouwers HB , Pizzolato R , Ortiz CJ , Rosand J , Goldstein JN , et al\nSpot sign on 90-second delayed computed tomography angiography improves sensitivity for hematoma expansion and mortality . Stroke . 2014 ;45 : 3293 –3297 . 10.1161/STROKEAHA.114.005570 \n25300974 \n25 \nChatterjee S , Sardar P , Biondi-Zoccai G , Kumbhani DJ . New oral anticoagulants and the risk of intracranial hemorrhage: Traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation . JAMA Neurol . 2013 ;70 : 1486 –1490 . 10.1001/jamaneurol.2013.4021 \n24166666 \n26 \nKono S , Yamashita T , Deguchi K , Omote Y , Yunoki T , Sato K , et al\nRivaroxaban and apixaban reduce hemorrhagic transformation after thrombolysis by protection of neurovascular unit in rat . Stroke . 2014 ;45 : 2404 –2410 . 10.1161/STROKEAHA.114.005316 \n24984746 \n27 \nKaneko M , Tanigawa T , Hashizume K , Kajikawa M , Tajiri M , Mueck W , et al\nConfirmation of model-based dose selection for Japanese phase III study of rivaroxaban in non-valvular atrial fibrillation patients . Drug Metab Pharmacokinet . 2013 ;28 : 321 –331 .\n23337693 \n28 \nPisters R , Lane DA , Nieuwlaat R , de Vos CB , Crijns HJ , Lip GY . A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation; the Euro Heart Survey . Chest . 2010 ;138 : 1093 –1100 . 10.1378/chest.10-0134 \n20299623 \n29 \nHankey GJ , Stevens SR , Piccini JP , Lokhnygina Y , Mahaffey KW , Halperin JL , et al\nIntracranial hemorrhage among patients with atrial fibrillation anticoagulated with warfarin or rivaroxaban . Stroke . 2014 ;45 : 1304 –1312 . 10.1161/STROKEAHA.113.004506 \n24743444 \n30 \nHippisley-Cox J and Coupland C . Predicting risk of upper gastrointestinal bleed and intracranial bleed with anticoagulants: cohort study to derive and validate the QBleed scores . BMJ . 2014 ;349 : g4606 \n10.1136/bmj.g4606 \n25069704 \n31 \nToyoda K , Yasaka M , Uchiyama S , Nagao T , Gotoh J , Nagata K , et al\nBleeding with Antithrombotic Therapy (BAT) Study Group. Blood pressure levels and bleeding events during antithrombotic therapy: the Bleeding with Antithrombotic Therapy (BAT) Study . Stroke . 2010 ;41 : 1440 –1444 . 10.1161/STROKEAHA.110.580506 \n20489173 \n32 \nArima H , Anderson C , Omae T , Woodward M , MacMahon S , Mancia G , et al\nEffects of blood pressure lowering on intracranial and extracranial bleeding in patients on antithrombotic therapy: The PROGRESS Trial . Stroke . 2012 ;43 : 1675 –1677 . 10.1161/STROKEAHA.112.651448 \n22535269 \n33 \nThe SPS3 Investigators. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial . Lancet . 2013 ;382 : 507 –515 . 10.1016/S0140-6736(13)60852-1 \n23726159 \n34 \nUchiyama S , Shinohara Y , Katayama Y , Yamaguchi T , Handa S , Matsuoka K , et al\nBenefit of cilostazol in patients with high risk of bleeding: subanalysis of cilostazol stroke prevention study 2 . Cerebrovasc Dis . 2014 ;37 : 296 –303 . 10.1159/000360811 \n24820203\n\n",
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"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants; D001794:Blood Pressure; D005260:Female; D006406:Hematoma; D006801:Humans; D020300:Intracranial Hemorrhages; D008297:Male; D010351:Patient Discharge; D012189:Retrospective Studies; D016896:Treatment Outcome",
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"references": "19717844;17950801;20299623;21309657;21830957;21870978;22405630;22394293;22535269;22664783;22970730;23219111;23634926;23670031;23726159;23337693;24251359;24103671;24166666;24508114;24743444;24662438;24820203;24385325;25011204;25069704;24984746;25082810;25300974;25065949;25739470;20489173",
"title": "Characteristics of Symptomatic Intracranial Hemorrhage in Patients Receiving Non-Vitamin K Antagonist Oral Anticoagulant Therapy.",
"title_normalized": "characteristics of symptomatic intracranial hemorrhage in patients receiving non vitamin k antagonist oral anticoagulant therapy"
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"abstract": "BACKGROUND\nCastleman disease (CD) is a rare polyclonal lymphoproliferative disorder with unknown etiology. TAFRO syndrome is now regarded as a specific subtype of CD, and is still a huge challenge for clinicians.\n\n\nMETHODS\nTo clarify the clinical features and management of TAFRO syndrome in China, we retrospectively analyzed 96 patients with HIV-negative CD (52 with unicentric CD and 44 with multicentric CD), who were diagnosed and treated at our center between 2008 and 2017. Specially, we systematically reviewed the 7 TAFRO syndrome cases based on the 2015 criteria proposed by Masaki.\n\n\nRESULTS\nAmong the 7 cases, there were 3 men and 4 women, and the median age was 53 years. The main symptoms included thrombocytopenia (7/7), anasarca (7/7), fever (4/7), renal dysfunction (7/7), and organomegaly (6/7). One patient was treated with corticosteroid monotherapy, one received RD (Rituximab, dexamethasone), and 5 received CHOP/COP like chemotherapy as first-line treatment, 2 of the 5 combined with Rituximab. Four patients needed hemodialysis or CRRT because of progressive renal failure. The outcome for TAFRO syndrome was significantly worse compared to other types of CD. Although 3 patients improved after early treatment, 4 patients died due to disease progression, and only one patient achieved complete resolution of all the symptoms after changing to lenalidomide based regimen.\n\n\nCONCLUSIONS\nThis study reveals that TAFRO syndrome is more severe and has more systemic symptoms than other iMCD, most cases need active treatment, and their prognoses are poor. Lenalidomide based regimen may be as a promising new therapy for TAFRO syndrome.",
"affiliations": "Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, P. R. China.;Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, P. R. China.;Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, P. R. China.;Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, P. R. China.;Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, P. R. China.;Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, P. R. China.;Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, P. R. China. wangzhaoming1963@163.com.;Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, P. R. China. jiej0503@zju.edu.cn.",
"authors": "Zhang|Yi|Y|;Suo|Shan-Shan|SS|;Yang|Han-Jin|HJ|;Zhou|Xin-Ping|XP|;You|Liang-Shun|LS|;Yu|Wen-Juan|WJ|;Wang|Zhao-Ming|ZM|;Jin|Jie|J|http://orcid.org/0000-0002-8166-9915",
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"fulltext": "\n==== Front\nJ Cancer Res Clin OncolJ. Cancer Res. Clin. OncolJournal of Cancer Research and Clinical Oncology0171-52161432-1335Springer Berlin Heidelberg Berlin/Heidelberg 312010.1007/s00432-019-03120-wOriginal Article – Cancer ResearchClinical features and treatment of 7 Chinese TAFRO syndromes from 96 de novo Castleman diseases: a 10-year retrospective study Zhang Yi zhangyi19911227@163.com 123Suo Shan-Shan 123Yang Han-Jin 4Zhou Xin-Ping 123You Liang-Shun 123Yu Wen-Juan 123Wang Zhao-Ming wangzhaoming1963@163.com 4http://orcid.org/0000-0002-8166-9915Jin Jie jiej0503@zju.edu.cn 1231 grid.13402.340000 0004 1759 700XDepartment of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003 P. R. China 2 Zhejiang Province Key Laboratory of Hematology Oncology, Diagnosis and Treatment, Hangzhou, China 3 grid.13402.340000 0004 1759 700XInstitute of Hematology, Zhejiang University, Hangzhou, Zhejiang China 4 grid.13402.340000 0004 1759 700XDepartment of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003 P. R. China 14 1 2020 14 1 2020 2020 146 2 357 365 14 11 2019 24 12 2019 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Background\nCastleman disease (CD) is a rare polyclonal lymphoproliferative disorder with unknown etiology. TAFRO syndrome is now regarded as a specific subtype of CD, and is still a huge challenge for clinicians.\n\nMethods\nTo clarify the clinical features and management of TAFRO syndrome in China, we retrospectively analyzed 96 patients with HIV-negative CD (52 with unicentric CD and 44 with multicentric CD), who were diagnosed and treated at our center between 2008 and 2017. Specially, we systematically reviewed the 7 TAFRO syndrome cases based on the 2015 criteria proposed by Masaki.\n\nResults\nAmong the 7 cases, there were 3 men and 4 women, and the median age was 53 years. The main symptoms included thrombocytopenia (7/7), anasarca (7/7), fever (4/7), renal dysfunction (7/7), and organomegaly (6/7). One patient was treated with corticosteroid monotherapy, one received RD (Rituximab, dexamethasone), and 5 received CHOP/COP like chemotherapy as first-line treatment, 2 of the 5 combined with Rituximab. Four patients needed hemodialysis or CRRT because of progressive renal failure. The outcome for TAFRO syndrome was significantly worse compared to other types of CD. Although 3 patients improved after early treatment, 4 patients died due to disease progression, and only one patient achieved complete resolution of all the symptoms after changing to lenalidomide based regimen.\n\nConclusions\nThis study reveals that TAFRO syndrome is more severe and has more systemic symptoms than other iMCD, most cases need active treatment, and their prognoses are poor. Lenalidomide based regimen may be as a promising new therapy for TAFRO syndrome.\n\nKeywords\nGiant lymph node hyperplasiaCastleman diseaseTAFRO syndromeDiagnosisTherapeuticsthe National Natural Science Foundation of China81670124issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2020\n==== Body\nIntroduction\nCastleman disease (CD), also known as giant lymph node hyperplasia, is a rare polyclonal lymphoproliferative disorder that was first described by Dr. Benjanmin Castleman in 1954 (Castleman et al. 1956; Castleman and Towne 1954). According to the lesions involved, CD can be classified as unicentric CD (UCD) and multicentric CD (MCD). UCD only involves a single lymph node region, with minimal symptoms and is often treated with localized surgical removal (Wong 2018). In contrast, MCD manifests with widespread lymphadenopathy, has constitutional symptoms, and systemic therapy is always required. Histologically, CD can be divided into hyaline vascular (HV), plasma cell (PC), and mixed cellular (Mix) subtypes. The HV subtype is common in UCD, and the PC subtype in MCD (Astle et al. 2018; Dong et al. 2015). Compared with UCD, MCD has a significantly inferior prognosis (Zhang et al. 2018). In 2014, Fajgenbaum et al. proposed the concept of idiopathic multicentric Castleman disease (iMCD), which defines as MCD patients with negative human herpesvirus (HHV-8) and human immunodeficiency virus (HIV), which accounts for about 50% of MCD (Fajgenbaum et al. 2014, 2017). It is currently believed that iMCD can be classified into TAFRO syndrome and idiopathic multicentric Castleman disease-not otherwise specified (iMCD-NOS) based on clinical characteristics, pathological features, and laboratory results (Carbone and Pantanowitz 2016; Igawa and Sato 2018).\n\nTAFRO (or Castleman-Kojima) syndrome has been gradually recognized in recent years. It is a systemic inflammatory disease characterized by thrombocytopenia (T), anasarca (A), myelofibrosis/fever (F), renal dysfunction/reticulin fibrosis (R), and organomegaly (O). Kojima et al. (2008) described the clinical and pathological findings of the idiopathic plasmacytic lymphadenopathy (IPL) and non-IPL. TAFRO syndrome was first reported by Takai et al. (2010). Currently, we may regard TAFRO syndrome as a type of non-IPL-type MCD. In 2012, the Fukushima (6 June 2012) and Nagoya (22 September 2012) meetings in Japan defined TAFRO syndrome as a systemic inflammatory disease characterized by a series of clinical symptoms, and also discussed the diagnosis and treatment options for this disease (Kawabata et al. 2013). The optimal treatment for TAFRO syndrome is unknown, some patients are treated with corticosteroids and/or immunosuppressive agents, and some are treated with chemotherapy or combined with novel drugs such as monoclonal antibody of CD20 antigen (Rituximab), anti-human interleukin-6 (IL-6) receptor antibody (Tocilizumab), or immunomodulator (Thalidomide, Lenalidomide) (Fujiwara et al. 2016; Igawa and Sato 2018). Up to now, most of the understanding for TAFRO syndrome comes from rare case reports and smaller case series, and few of the cases were Chinese. Thus, the purpose of this study is to clarify the strategies for diagnosing and treating of Chinese TAFRO syndrome. Here, we described the clinical features, actual treatments, as well as the outcomes of 7 Chinese patients diagnosed with TAFRO syndrome among 96 HIV- negative CD in our center.\n\nMaterials and methods\nPatients\nWe identified 110 HIV-negative CD cases with the confirmed clinical and pathological diagnoses who were admitted to our hospital between March 2008 and December 2017. After review of the medical records, 12 MCD patients whose primary treatments were not in our center, and 2 UCD patients admitted because of disease relapses were excluded. The remaining 96 de novo CD patients were enrolled, Fig. 1. All data were collected through telephone and medical records. Latest follow-up was June 2019. Written informed consent was obtained from all patients in accordance with the Declaration of Helsinki, and the study was approved by the ethics committee of the First Affiliated Hospital of Zhejiang University.Fig. 1 Flow diagram of patient recruitment\n\n\n\nCriteria\nThe diagnosis and severity classification of TAFRO syndrome are based on the criteria proposed by Masaki. Thrombocytopenia was defined as platelet count < 100 × 109/L. Pleural effusion and/or ascites were diagnosed by computed tomography (CT) scans or B ultrasonography. The diagnosis of myelofibrosis depended on bone marrow biopsy. Fever was defined as a temperature > 37.5 °C, and renal dysfunction as elevated serum creatinine levels above the reference range or GFR < 60 mL/min/1.73 m2. Spleen and liver size was evaluated by CT scans. Survival time was defined as the period from diagnosis to either death or the last follow-up.\n\nStatistical analysis\nAll statistical analyses were performed using SPSS Version 25. Continuous variables were described as median (range) analyzed by Mann–Whitney U test, and categorical variables were described as frequency (percentage) compared by Pearson χ2 test. The Kaplan–Meier method was used for survival analysis, and the log-rank test was applied to compare the survival rate between groups. A two-tailed P < 0.05 was considered significant.\n\nResults\nPatient characteristics\nThe number of CD diagnosed and treated in our center was increasing year by year, Fig. 2a. In total we analyzed 96 patients, the median age was 46.5 (range 14–77) years old and 49 (51.0%) were male. Within this cohort, 52 (54.2%) cases were classified with UCD, while the remaining 44 (45.8%) cases were MCD. Sites of lymph node involvement in UCD included abdomen (34.6%), mediastinum (30.8%), neck (11.5%), pelvis (9.6%), axilla (5.4%), groin (1.9%) etc. Sites such as skin, bronchial bifurcation and parotid gland were also involved in our cases, Fig. 2b. In all CD, there were HV for 55 (57.3%), PC for 31 (32.3%), and Mix for 10 (10.4%). The patient’s first visit departments included oncology surgery, thoracic surgery, hepatobiliary surgery, hematology, infection, nephrology, etc. The main manifestations included painless swelling of lymph nodes and in some case spleen, liver or other organomegaly, followed by B symptoms (fever, weight loss and fatigue), and in several cases the initial clinical symptoms were shortness of breath caused by pleural effusion or bloating caused by ascites. Other patients were diagnosed accidentally by physical exam. Among the 96 CD cases some patients showed paraneoplastic pemphigus 1 (1.0%), POEMS syndrome 2 (2.1%), TAFRO syndrome 7 (7.3%), or 2 (2.1%) transformed to lymphoma. The detailed clinical data are analyzed in Table 1.Fig. 2 The comparison of characteristics and outcomes between unicentric and multicentric Castleman disease. a The annual onset of unicentric (UCD) and multicentric (MCD) Castleman disease; b the distribution of lymphadenopathy among patients with UCD; c overall survival of patients with UCD and MCD\n\nTable 1 Clinical characteristics of 96 patients with Castleman disease\n\nItem\tTotal\tUCD (n = 52)\tMCD (n = 44)\tP value\t\nAge\t46.5 (14–77)\t41 (14–77)\t53 (24–77)\t0.001\t\nGender\t\t\t\t\t\n Male\t49 (51.0%)\t24 (46.2%)\t25 (56.8%)\t0.298\t\n Female\t47 (49.0%)\t28 (53.8%)\t19 (43.2%)\t\t\nHistological subtype\t\t\t\t\t\n HV\t55 (57.3%)\t46 (88.5%)\t9 (20.5%)\t0.000\t\n PC\t31 (32.3%)\t5 (9.6%)\t26 (59.1%)\t\t\n Mix\t10 (10.4%)\t1 (1.9%)\t9 (20.5%)\t\t\nLeukocyte, 109/L\t5.6 (1.2–15.2)\t51 (2.8–14.3)\t6.5 (1.2–15.2)\t0.366\t\n Hemoglobin, g/L\t127 (48–174)\t137 (86–174)\t97 (48–151)\t0.000\t\nPlatelet, 109/L\t202 (23–592)\t211 (115–444)\t169.0 (23–592)\t0.024\t\nC-reactive protein, mg/L\t21.9 (0–335.0)\t5.4 (0–159)\t42.7 (0–335)\t0.012\t\nSerum albumin, g/L\t41.4 (13.3–59.1)\t46.9 (35.3–59.1)\t35.7 (13.3–51.2)\t0.000\t\nSerum globulin, g/L\t26.4 (15.6–82.0)\t25.0 (18.8–60.2)\t30.5 (15.6–82.0)\t0.000\t\nSerum creatinine, µmol/L\t65 (36–245)\t60.5 (36–220)\t74 (37–245)\t0.053\t\nLDH Ul/L\t194 (105–475)\t211 (128–231)\t184 (105–475)\t0.498\t\nFever (≥ 37.5 °C)\t16 (16.7%)\t1 (1.9%)\t15 (34.1%)\t\t\nPleural effusion and/or ascites\t18 (18.8%)\t1 (1.9%)\t17 (38.6%)\t\t\nHepatosplenomegaly\t22 (21.9%)\t1 (1.9%)\t21 (47.7%)\t\t\nThrombocytopenia\t14 (14.6%)\t0\t14 (31.8%)\t\t\nRenal dysfunction\t12 (12.5%)\t0\t12 (27.3%)\t\t\nMyelofibrosis\t5 (5.2%)\t0\t5 (11.4%)\t\t\nPNP\t1 (1.0%)\t1 (1.9%)\t0\t\t\nPOEMS syndrome\t2 (2.1%)\t0\t2 (4.5%)\t\t\nTAFRO syndrome\t7 (7.3%)\t0\t7 (15.9%)\t\t\nProgress to lymphoma\t2 (2.1%)\t0\t2 (4.5%)\t\t\nContinuous variables were described using median (range) analyzed by Mann–whitney U test and categorical variables were described using frequency (percentage) compared by Pearson χ2 test. Significant P values are in bold\n\nUCD unicentric Castleman disease, MCD multicentric Castleman disease, HV hyaline vascular, PC plasma cell, Mix mixed cellular, PNP paraneoplastic pemphigus, POEMS polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin abnormalities, TAFRO thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, organ enlargement\n\n\n\nWe also compared the 52(54.2%) UCD and 44(45.8%) MCD in Table 1. UCD patients were much younger than MCD cases, the median age was 41(14–77) years and 53 (24–77) years, respectively (P = 0.001). But there was no difference in the gender distribution, with male cases of 46.2% vs. 56.8%, respectively (P = 0.298). The major histological type was HV (88.5%) and PC (59.1%), respectively (P < 0.001). Compared with UCD, MCD had lower hemoglobin, platelet counts, and serum albumin, but higher serum globulin and C-reactive protein (all, P < 0.05).\n\nTreatments and survival\nAll UCD cases of our center had surgery for diagnosis and treatment, and 2 patients were treated with 3 months’ interferon after surgery. In all, 3 patients relapsed. One patient with paraneoplastic pemphigus (PNP) was treated with Rituximab for 4 cycles but died because of bronchiolitis obliterans organizing pneumonia (BOOP). The treatment strategies of MCD patients were heterogeneous. Lymph node biopsies were arranged only for pathological diagnoses. 33 (75.0%) cases underwent chemotherapy, 9 (20.5%) received prednisone only, and the remaining 2 (4.5%) cases had a watch and wait strategy. Among them 5 (11.4%) patients were cured, 23 (52.3%) were stable, 8 (18.2%) died, and the other 8(18.2%) had lost. Treatments and outcomes of MCD are summarized in Table 2. After a median follow-up of 41(range 1–138) months, the 5-year overall survival rate for all CD was 89.6%, and the 5-year overall survival rate for UCD and MCD was 98.1% and 77.7%, respectively (P = 0.003). The survival of UCD and MCD were compared in Fig. 2c.Table 2 Treatment and outcomes of 44 patients with multicentric Castleman disease (MCD)\n\nTreatment and status\tCase (n)\tProportion (%)\t\nTreatments\t\t\t\n Wait and watch\t2\t4.5\t\n Corticosteroid monotherapy\t9\t20.5\t\n Chemotherapya\t33\t75.0\t\n Chemotherapy only\t15\t34.1\t\n Chemotherapy with R\t16\t36.4\t\n Chemotherapy with L\t5\t11.4\t\n Chemotherapy with B\t4\t9.1\t\n Chemotherapy with T\t2\t4.5\t\nStatus\t\t\t\n ANED\t5\t11.4\t\n AWD\t23\t52.3\t\n DEAD\t8\t18.2\t\n LFU\t8\t18.2\t\naChemotherapy including: CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone, COP cyclophosphamide, vincristine, and prednisone, E-COP Etoposide, cyclophosphamide, vincristine, and prednisone, TCD Thalidomide, cyclophosphamide, and Dexamethasone, MP melphala plus prednisone, R Rituximab, L Lenalidomide, B Bortezomib, T Tocilizumab. Among them, 6 patients had combination of at least 2 of R, L, B, T; ANED alive, no evidence of disease, AWD alive with disease, DEAD dead, LFU lost follow-up\n\n\n\nTAFRO syndrome\nThe diagnosis of TAFRO syndrome is often delayed. In our groups, the interval between onset and diagnosis was about 12 (1.5–40) weeks. There were 3 men and 4 women with a median age of 53 (35–66) years, 3 patients with PC, 2 with HV, 2 with Mix, all patients were HHV-8 and HIV-negative. At disease onset, 3 out of 7 cases were accompanied by autoimmune diseases, which were rheumatoid arthritis, mixed connective tissue disease and hypothyroidism, respectively. Most MCD exhibits an indolent clinical course, but the 7 TAFRO syndromes in our center manifested with serious and life-threatening symptoms. The main symptoms included thrombocytopenia (7/7), anasarca (7/7), fever (4/7), renal dysfunction (7/7) and organomegaly (6/7). Among the 7 cases, 1 received prednisone monotherapy, 1 received RD (Rituximab, dexamethasone) and the other 5 cases received CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or COP (cyclophosphamide, vincristine, and prednisone) -like therapy as first-line treatment, 2 of the 5 patients combined with Rituximab. Four patients needed hemodialysis or CRRT (continuous renal replacement therapy) because of progressive renal failure. However, one patient failed to have hemodialysis because of low platelet count and rapid disease progression. According to the 2015 diagnostic criteria for TAFRO syndrome, the disease severity was regarded as 3 with ‘slightly severe’ and 4 with ‘severe’ risk. Overall, 3 patients improved by early treatment, 4 patients died from disease progression, only 1 patient (patient No. 4) achieved complete resolution of all the symptoms after the change to lenalidomide based regimen [the detail of this patient was listed in another article as case 3 (Zhou et al. 2017)]. The main clinical findings and outcomes of the 7 patients with TAFRO syndrome are shown in Table 3.Table 3 Clinical characteristics and outcomes of 7 patients with TAFRO\n\nPatient no\tAge/gender\tDuration (weeks)\tHistopathology\tPLT (109/L)\tAnasarca\tFever\tCr (µmol/L)\tOrgan enlargement\tCRP (mg/L)\tPrimary treatment\tAdditional treatment\tBest efficacy\tStatus\tOS (months)\tScoresa\tRisk stratification\t\n1\t66/F\t12\tMIX\t83 (24)\t1\t0\t171 (249)\t0\t85\tcorticosteroid\t\tSD\tLFU\t1.5\t3/2/1/2\tSlightly severe\t\n2\t50/M\t24\tHV\t47 (16)\t1\t0\t245 (770)\t1\t136\tR-COPa6\tHemodialysis\tPR\tLFU\t23.3\t1/2/2/3\tSlightly severe\t\n3\t44/F\t40\tHV\t28 (2)\t1\t0\t131 (373)\t1\t53.6\tE-COP\t\tPD\tDEAD\t0.7\t3/3/1/3\tSevere\t\n4\t53/M\t2\tPC\t23 (8)\t1\t1\t97 (126)\t1\t335.4\tRD\tL-based regimen\tCR\tANED\t50.8\t2/3/3/1\tSevere\t\n5\t35/F\t1.5\tPC\t42 (3)\t1\t1\t90 (780)\t1\t31.6\tCHOP\t\tPD\tDEAD\t1.0\t3/3/1/3\tSevere\t\n6\t65/M\t1.5\tPC\t56 (14)\t1\t1\t66 (506)\t1\t165\tCOP\themodialysis\tPR\tDEAD\t3.5\t3/2/2/3\tSevere\t\n7\t54/F\t20\tMIX\t44 (7)\t1\t1\t75 (233)\t1\t4.8\tR-CHOP\tCRRT\tPD\tDEAD\t0.6\t1/3/0/3\tSlightly severe\t\nPLT platelet (at diagnosis/the lowest result), Fever T > 37.5 °C, Cr serum creatinine (at diagnosis/the highest result), CRP C-reactive protein, COP cyclophosphamide, vincristine, and prednisone, RD rituximab, dexamethasone, CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone, R rituximab, E etoposide, L lenalidomide, CRRT continuous renal replacement therapy, LFU lost follow-up, DEAD dead, ANED alive, no evidence of disease\n\naScores, anasarca/thrombocytopenia/fever and/or inflammation / renal insufficiency. (1) anasarca: three points maximum, one point for pleural effusion on imaging, one point for ascites on imaging, one point for pitting edema on physical examination. (2) thrombocytopenia: three points maximum, one point for lowest platelet counts < 100,000/μL, two points for lowest platelet counts < 50,000/μL, three points for lowest platelet counts < 10,000/μL. (3) fever and/or inflammation: three points maximum, one point for fever ≥ 37.5 °C but < 38.0 °C or for CRP ≥ 2 mg/dL but < 10 mg/dL, two points for fever ≥ 38.0 °C but < 39.0 °C or for CRP ≥ 10 mg/dL but < 20 mg/dL, three points for fever ≥ 39.0 °C or for CRP ≥ 20 mg/dL. (4) renal insufficiency: three points maximum, one point for GFR < 60 mL/min/1.73 m2, two points for GFR < 30 mL/min/1.73 m2, three points for GFR < 15 mL/min/1.73 m2 or need for hemodialysis. Risk stratification, insufficient for diagnosis (0–2 points), mild (grade 1) (3–4 points), moderate (grade 2) (5–6 points), slightly severe (grade 3) (7–8 points), severe (grade 4) (9–10 points), very severe (grade 5) (11–12 points)\n\n\n\nDiscussion\nIn this study, we analyzed 7 patients with TAFRO syndrome from 96 de novo CDs, and compared the heterogeneity between UCD and MCD in detail. We conclude that UCD may occur in different parts of the body, patients are generally younger and in good condition. Complete resection of the involved lesion can cure these patients, but paraneoplastic pemphigus may be an unfavorable prognostic factor. However, MCD cases had more constitutional symptoms often associated with laboratory abnormalities. Most of them were treated with chemotherapy and the prognosis was significantly worse compared to patients with UCD. For the first time, we discuss 7 Chinese patients with TAFRO syndrome from a single institution. Their prognosis was poor and these patients had more systemic symptoms than classic MCD patients. Most cases received active treatment even with hemodialysis. Lenalidomide based regimen may be a promising new therapy for TAFRO syndrome.\n\nTAFRO syndrome can occur in any age and any race, but it is more common in East Asian populations, especially Japanese and mostly occurs in the middle-aged and elderly (Alhoulaiby et al. 2017; Coutier et al. 2017; Finocchietto et al. 2015; Kubokawa et al. 2014; Liu et al. 2016; Owattanapanich et al. 2018). 7.3% (7/96) of HIV-negative CD and 15.9% (7/44) of MCD patients in our center were diagnosed with TAFRO syndrome, the rate was higher than the reported rate by Oksenhendler et al. (2018) who described that 7% (2/27) of French iMCD consistent with TAFRO syndrome (Oksenhendler et al. (2018), but lower than the results of Owattanapanich et al. (2018) of 18.2% (6/33). In our study, 3 patients were diagnosed within 2 weeks, and most patients’ Eastern Cooperative Oncology Group (ECOG) performance status > 1, these patients appear to have more acute or subacute onset and in poor condition, which corresponded with the review of Igawa and Sato (2018). The clinical and laboratory characteristics of TAFRO syndrome are significantly different from iMCD-NOS. It is reported that TAFRO syndrome patients were often associated with an elevated VEGF level and a lower IL-6 level, with a normal level of immunoglobulin (Ig), also characteristic with small lymph nodes, obvious thrombocytopenia, pleural effusion and ascites (Nishimura et al. 2019; Srkalovic et al. 2017). All of the 7 cases in our study had thrombocytopenia, anasarca, and renal dysfunction, but none of them had myelofibrosis. The lowest platelet count downed to 2 × 109/L, and the highest serum creatinine reached 780 µmol/L. On histology patients with TAFRO syndrome tend to have a highly vascular lymph node architecture, most cases were Mix, less frequently HV histology. On the contrary, lymph nodes of iMCD-NOS patients often show the pathological features of the typical PC variant CD, including diffuse follicular zone plasma cell proliferation, germinal center protrusion, most were PC type.\n\nTo date, the diagnostic criteria for TAFRO syndrome were proposed by Masaki et al. (2016) and Iwaki et al. (2016), respectively. Masaki et al. (2016) also distinguished TAFRO syndrome into 5 risk grades according to systemic edema, platelet count, fever/inflammation, and glomerular filtration rate (GFR). In our study, 3 out of 7 cases were ‘slightly severe’, the other 4 reached the level of ‘severe’ risk. Nara et al. (2017) reported two cases of TAFRO syndrome in Japan, and the disease severity was regarded as “slightly severe” in case 1 and “severe” in case 2. Masaki et al. (2016) evaluated 18 TAFRO syndrome patients in Japan who were classified as having mild (5.5%), moderate (61.1%), slightly severe (22.2%), severe (11.1%), and very severe (0%) risk. This means that the incidence of high-risk TAFRO syndrome patients in China is higher.\n\nIn our study, 4 out of 7 patients died and TAFRO syndrome correlated with significantly poorer survival consistent with other reports (Iwaki et al. 2016; Kubokawa et al. 2014; Yu et al. 2017). The optimal treatment for TAFRO syndrome has not been well established. As reported by Iwaki, the clinical course of TAFRO syndrome is more aggressive and characterized by frequent steroid refractoriness requiring additional therapies (Igawa and Sato 2018). Based on the understanding of iMCD, the current treatment strategies for TAFRO syndrome are mainly divided into four categories, including corticosteroid anti-inflammatory therapy, immunosuppressive therapy, chemotherapy, and some novel drugs such as rituximab, anti-IL-6 receptor Ab, anti-angiogenic drugs, and immunomodulator (van Rhee et al. 2018). Corticosteroids are the first-line treatment options, which may be effective at the onset of the disease, but most patients are prone to recurrence during corticosteroid reduction or withdrawal. Patients who are resistant to corticosteroids or have contraindications, rituximab, and anti-IL-6 receptor Ab may be a choice (Fujiwara et al. 2016; Jain et al. 2015). The efficacy of rituximab in HHV-8-positive MCD patients has been well established (Hoffmann et al. 2011), but its effect on long-term survival of iMCD patients may be inferior to anti-IL-6 receptor Abs (Yu et al. 2017). For patients who have a more acute onset and more severe clinical manifestation, like our cases, lymphoma-related chemotherapy may be considered, but the adverse effect after chemotherapy are obvious, and recurrence may occur in some patients. Besides, novel therapeutic approaches such as Bortezomib, recombinant IL-1 receptor antagonist (Anakinra), especially lenalidomide also have achieved good results in selected patients. The use of thalidomide in MCD and TAFRO syndrome has been reported in several cases (Ramasamy et al. 2012; Tatekawa et al. 2015). Lenalidomide as a functional and structural analog of thalidomide, has greater potency but less peripheral neurotoxicity. Lenalidomide has been shown with anti-inflammatory, anti-angiogenic and immunomodulatory effects. This specific immunomodulation may be effective in malignant plasma diseases, inhibits production of interleukin-6, which is the key cytokine in the pathogenesis of CD. To date, 7 articles were obtained from PUBMED literature search using keyword Lenalidomide and Castleman disease (Adam et al. 2012, 2016; Cai et al. 2019; Szturz et al. 2012, 2013a, b; Zhou et al. 2017). Including one in which we summarized our experience with lenalidomide containing regimen as salvage therapy in 3 relapsed/refractory MCD (Zhou et al. 2017). From those data, we observed an excellent effect of lenalidomide in MCD. Since TAFRO is a subtype of MCD and strongly related to immunity, it is possible that lenalidomide can be a new treatment option for TAFRO syndrome.\n\nCastleman disease, especially TAFRO syndrome, is still a huge challenge for clinicians. At present, researchers still have insufficient understanding of TAFRO syndrome, and the analysis of patients with CD, especially TAFRO syndrome will deepen the understanding of the disease. For CD patients with renal dysfunction, thrombocytopenia, and multiple serous effusions, the possibility of TAFRO syndrome should be considered.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nYi Zhang and Shan-Shan Suo contributed equally to this study.\n\nAcknowledgements\nThe study was supported by the National Natural Science Foundation of China (Grant/Award Number: ‘No. 81670124’).\n\nCompliance with ethical standards\nConflict of interest\nThe authors have no conflict of interest.\n==== Refs\nReferences\nAdam Z The effect of lenalidomide on rare blood disorders: Langerhans cell histiocytosis, multicentric Castleman disease, POEMS syndrome, Erdheim-Chester disease and angiomatosis Vnitr Lek 2012 58 856 866 23256832 \nAdam Z Treatment of 14 cases of Castlemans disease: the experience of one centre and an overview of literature Vnitr Lek 2016 62 287 298 27250606 \nAlhoulaiby S Ahmad B 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"fulltext_license": "CC BY",
"issn_linking": "0171-5216",
"issue": "146(2)",
"journal": "Journal of cancer research and clinical oncology",
"keywords": "Castleman disease; Diagnosis; Giant lymph node hyperplasia; TAFRO syndrome; Therapeutics",
"medline_ta": "J Cancer Res Clin Oncol",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D005871:Castleman Disease; D003520:Cyclophosphamide; D003907:Dexamethasone; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D000069283:Rituximab; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "7902060",
"other_id": null,
"pages": "357-365",
"pmc": null,
"pmid": "31938902",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article",
"references": "28956126;26980221;24362880;31211492;29157612;22583139;21902577;23801135;13165944;27063975;30181172;29464312;29143319;21778341;27250606;24622327;28135567;27084250;24890946;18499694;28100459;23256832;13356266;28087540;26663467;28367597;25808231;26185651;20534952;28580156;26805758;23718671;25824806;29157620;31725610;29124835;28502946",
"title": "Clinical features and treatment of 7 Chinese TAFRO syndromes from 96 de novo Castleman diseases: a 10-year retrospective study.",
"title_normalized": "clinical features and treatment of 7 chinese tafro syndromes from 96 de novo castleman diseases a 10 year retrospective study"
} | [
{
"companynumb": "NVSC2020CN013213",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"druga... |
{
"abstract": "OBJECTIVE\nVisual impairment represents an infrequent form of cisplatin-induced neurotoxicity; however, visual deterioration has been reported in several studies. To evaluate potential morphological and functional retinal alterations in patients with germ cell cancer (GCC) treated with cisplatin-based chemotherapy (CBC).\n\n\nMETHODS\nMulti-disciplinary and multi-institutional study design. Examination of 28 eyes of 14 male GCC patients, who had received at least one cycle of CBC. A matched control group of healthy, untreated patients were included in this study. Subjects underwent a retinal nerve fiber thickness (RNFL) measurement, color vision, visual acuity testing, full-field electroretinograms (ff-ERG). To assess a correlation between cumulative cisplatin dose and measured RNFL and ff-ERG Pearson correlation coefficient analysis was performed.\n\n\nRESULTS\nBoth study groups (CBC recipients vs. healthy controls) consisted each of 14 participants with a median patient age of 30 years (interquartile range (IQR) 26-37 years). Tumor histology was seminoma in 6 of 14 patients (43%), and non-seminomatous GCC in 8 of 14 patients (57%). Median cumulative cisplatin dosis at examination was 627 mg/m2 (IQR 413-1013 mg/m2). Morphological assessment revealed reduced RNFL in 11 of 14 patients (78.6%). Reduction in RNFL was significantly correlated to the cumulative CBC dose received (rho = + 0.70; p = 0.004). ff-ERG showed significant differences between CBC recipients and the control group in 2 of 5 tested categories (all p values <0.001).\n\n\nCONCLUSIONS\nThis study represents first evidence of chronic subclinical retinal toxicity due to cisplatin-based chemotherapy in patients with GCC. The reduction of RNFL might become clinically relevant in upcoming age-related chronic degenerative disorders such as glaucoma.",
"affiliations": "Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Urology, Albertinen Medical Center, Hamburg, Germany.;Department of Urology, Military Army Medical Center, Hamburg, Germany.;Department of Urology, Military Army Medical Center, Hamburg, Germany.;Department of Medical Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Medical Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Medical Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Medical Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Medical Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.;Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.;Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.;Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.;Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.;Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.;Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.;Department of Urology, University Medical Center Goettingen, Goettingen, Germany.;Department of Medical Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Medical Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.;Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.;Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.;Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany. L.Kluth@uke.de.",
"authors": "Dulz|Simon|S|;Asselborn|Niels H|NH|;Dieckmann|Klaus-Peter|KP|;Matthies|Cord|C|;Wagner|Walter|W|;Weidmann|Jens|J|;Seidel|Christoph|C|;Oing|Christoph|C|;Berger|Lars A|LA|;Alsdorf|Winfried|W|;Mankichian|Blanche|B|;Meyer|Christian|C|;Vetterlein|Malte W|MW|;Gild|Philipp|P|;Ludwig|Tim A|TA|;Soave|Armin|A|;Schriefer|Philipp|P|;Becker|Andreas|A|;Ahyai|Sascha A|SA|;Oechsle|Karin|K|;Bokemeyer|Carsten|C|;Wagenfeld|Lars|L|;Fisch|Margit|M|;Hartmann|Michael|M|;Chun|Felix K-H|FK|;Kluth|Luis A|LA|",
"chemical_list": "D000970:Antineoplastic Agents; D002945:Cisplatin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00432-017-2384-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0171-5216",
"issue": "143(7)",
"journal": "Journal of cancer research and clinical oncology",
"keywords": "Chemotherapy; Cisplatin; Germ cell cancer; Late effects; Retinal toxicity; Testicular cancer",
"medline_ta": "J Cancer Res Clin Oncol",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D002945:Cisplatin; D004596:Electroretinography; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal; D010865:Pilot Projects; D012160:Retina; D013736:Testicular Neoplasms; D041623:Tomography, Optical Coherence",
"nlm_unique_id": "7902060",
"other_id": null,
"pages": "1319-1325",
"pmc": null,
"pmid": "28281024",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": "15738540;26992838;8213988;23008318;4067616;8119103;19030905;25024068;17060482;1558119;24623533;71004;17714993;12782925;9078334;3340295;10980655;24399786;26189086",
"title": "Retinal toxicity after cisplatin-based chemotherapy in patients with germ cell cancer.",
"title_normalized": "retinal toxicity after cisplatin based chemotherapy in patients with germ cell cancer"
} | [
{
"companynumb": "DE-TEVA-800724GER",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"druga... |
{
"abstract": "METHODS\nA 73 year-old woman with depression treated with escitalopram developed acute secondary angle closure glaucoma related to uveal effusion after duplicating the drug dose 3 days before. She evolved favorably once the antidepressant treatment was suspended and a new treatment with topical hypotensive therapy and oral prednisone was used.\n\n\nCONCLUSIONS\nThe uveal effusion syndrome associated to medicines is rare; it may be associated with acute myopic shift and acute angle closure glaucoma. The correct diagnosis and discontinuation of the drug lead to the resolution of this nosology.",
"affiliations": "Servicio de Oftalmología, Complejo Hospitalario Mancha Centro, Alcázar de San Juan, Ciudad Real, España.;Servicio de Oftalmología, Complejo Hospitalario Mancha Centro, Alcázar de San Juan, Ciudad Real, España. Electronic address: javierinmol@hotmail.com.;Servicio de Oftalmología, Complejo Hospitalario Mancha Centro, Alcázar de San Juan, Ciudad Real, España.;Servicio de Oftalmología, Complejo Hospitalario Mancha Centro, Alcázar de San Juan, Ciudad Real, España.;Servicio de Oftalmología, Complejo Hospitalario Mancha Centro, Alcázar de San Juan, Ciudad Real, España.;Servicio de Oftalmología, Complejo Hospitalario Mancha Centro, Alcázar de San Juan, Ciudad Real, España.",
"authors": "Arias Palomero|A|A|;Infantes Molina|E J|EJ|;López Arroquia|E|E|;Riveira Villalobos|L|L|;López Mondéjar|E|E|;González del Valle|F|F|",
"chemical_list": "D011985:Receptors, Serotonin; D017367:Serotonin Uptake Inhibitors; D015283:Citalopram; D000068438:Brimonidine Tartrate; D001285:Atropine; D013999:Timolol; D011241:Prednisone",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0365-6691",
"issue": "90(7)",
"journal": "Archivos de la Sociedad Espanola de Oftalmologia",
"keywords": "Acute glaucoma; Acute myopia; Antidepresivos; Antidepressants; Efusión uveal; Escitalopram; Glaucoma agudo; Miopía aguda; Uveal effusion",
"medline_ta": "Arch Soc Esp Oftalmol",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D001285:Atropine; D000068438:Brimonidine Tartrate; D015862:Choroid Diseases; D002924:Ciliary Body; D015283:Citalopram; D062787:Drug Overdose; D004630:Emergencies; D005260:Female; D015812:Glaucoma, Angle-Closure; D006801:Humans; D009216:Myopia; D011241:Prednisone; D011985:Receptors, Serotonin; D017367:Serotonin Uptake Inhibitors; D058471:Subretinal Fluid; D013999:Timolol; D014603:Uveal Diseases",
"nlm_unique_id": "1304603",
"other_id": null,
"pages": "327-30",
"pmc": null,
"pmid": "25817959",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Uveal effusion induced by escitalopram.",
"title_normalized": "uveal effusion induced by escitalopram"
} | [
{
"companynumb": "ES-TEVA-762375ROM",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ESCITALOPRAM OXALATE"
},
"drugadditional": "1",
... |
{
"abstract": "Generalized anxiety disorder (GAD) is characterized by persistent and excessive worry. Around half of the patients treated for GAD will fail to respond to initial treatment. Treatment-resistant (or refractory) GAD is defined as failure to respond to at least 1 trial of antidepressant therapy at adequate dose and duration. Review of the literature indicates several potential medication classes and individual agents that can be used as augmentation strategies to treat residual symptoms when recommended therapy per clinical practice guidelines fails. A thorough literature search revealed 2 medication classes with the largest amount of data to support their use in treatment-resistant GAD treatment: gamma-aminobutyric acid-related agents and atypical antipsychotics. This article focuses on evidence-based recommendations for the use of these agents as adjunctive therapies for patients with treatment-resistant GAD. Different pharmacologic approaches to use these agents are demonstrated through 2 patient cases in which patients have failed first-line treatment options.",
"affiliations": null,
"authors": "Ansara|Elayne D|ED|https://orcid.org/0000-0001-9835-0305",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.9740/mhc.2020.11.326",
"fulltext": "\n==== Front\nMent Health Clin\nMent Health Clin\nmhcl\nMent Health Clin\nThe Mental Health Clinician\n2168-9709 College of Psychiatric & Neurologic Pharmacists \n\n10.9740/mhc.2020.11.326\nMHC-D-20-00016\nPsychopharmacology Pearls\nManagement of treatment-resistant generalized anxiety disorder\nhttps://orcid.org/0000-0001-9835-0305Ansara Elayne D. PharmD, BCPS, BCPP 1 Clinical Pharmacy Specialist, Mental Health, Residency Program Director, PGY2 Psychiatric Pharmacy Residency, Veteran Health Indiana, Indianapolis, Indiana, elayne.ansara@va.govDisclosures: I have nothing personal to disclose. Psychopharmacology Pearls are review articles intended to highlight both the evidence base available and/or controversial areas of clinical care for psychiatric and neurologic conditions as well as strategies of clinical decision-making used by expert clinicians. As pearls, articles reflect the views and practice of each author as substantiated with evidence-based facts as well as opinion and experience. Articles are edited by members of the Psychopharmacology Pearls Editorial Board as well as peer reviewed by MHC reviewers. This article was developed as part of the 2020 Psychopharmacology Pearls product for BCPP recertification credit. The course information and testing center is at https://cpnp.org/415126.\n\n\n11 2020 \n5 11 2020 \n10 6 326 334\n© 2020 CPNP. The Mental Health Clinician is a publication of the College of Psychiatric and Neurologic Pharmacists.2020This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Generalized anxiety disorder (GAD) is characterized by persistent and excessive worry. Around half of the patients treated for GAD will fail to respond to initial treatment. Treatment-resistant (or refractory) GAD is defined as failure to respond to at least 1 trial of antidepressant therapy at adequate dose and duration. Review of the literature indicates several potential medication classes and individual agents that can be used as augmentation strategies to treat residual symptoms when recommended therapy per clinical practice guidelines fails. A thorough literature search revealed 2 medication classes with the largest amount of data to support their use in treatment-resistant GAD treatment: gamma-aminobutyric acid–related agents and atypical antipsychotics. This article focuses on evidence-based recommendations for the use of these agents as adjunctive therapies for patients with treatment-resistant GAD. Different pharmacologic approaches to use these agents are demonstrated through 2 patient cases in which patients have failed first-line treatment options.\n\ngeneralized anxiety disordertreatment-resistantpregabalintiagabineatypical antipsychotics\n==== Body\nIntroduction\nGeneralized anxiety disorder (GAD) is classified under the umbrella of anxiety disorders within the Diagnostic and Statistical Manual of Mental Disorders, 5th edition.1 All anxiety disorders share characteristics of excessive fear and anxiety and differ from developmentally normal fear and anxiety by being excessive beyond appropriate periods. Diagnostic features of GAD included persistent and excessive anxiety and worry about various domains that the patient finds difficult to control. Symptoms of GAD also include feeling keyed up or on edge, fatigue, difficulty with concentration, irritability, muscle tension, and sleep disturbances. Symptoms must be present most days for a period of at least 6 months and cause clinically significant distress or impairment in social, occupational, or other important areas of functioning (Table 1).1 Evidence points towards neurochemical abnormalities in the gamma-aminobutyric (GABA)/ benzodiazepine (BZD), norepinephrine, and serotonin systems.2\n\nTABLE 1 The Diagnostic and Statistical Manual of Mental Disorders, 5th edition,1 diagnostic criteria for generalized anxiety disorder\n\nCriterion\tDescription\t\nA\tExcessive anxiety and worry, occurring more days than not for at least 6 mo, about a number of events or activities.\t\nB\tThe individual finds it difficult to control the worry.\t\nC\tThe anxiety and worry are associated with 3 (or more) of the following 6 symptoms (with at least some symptoms having been present for more days than not for the past 6 mo): Restlessness or feeling keyed up or on edge.\n\nBeing easily fatigued.\n\nDifficulty concentrating or mind going blank.\n\nIrritability.\n\nMuscle tension.\n\nSleep disturbance.\n\n\t\nD\tThe anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.\t\nE\tThe disturbance is not attributable to the physiological effects of a substance or another medical condition.\t\nF\tThe disturbance is not better explained by another mental disorder.\t\nGeneralized anxiety disorder is the most common anxiety disorder seen in the primary care setting.3 The 12-month prevalence of GAD is 2.9% among adults in the United States. Prevalence of the diagnosis tends to peak in middle age and decline over the course of aging.4 Nonpharmacologic interventions for treatment of GAD include psychotherapies such as cognitive behavioral therapy or relaxation therapy. These psychotherapies can be used as first-line treatment choices or in combination with medication therapy.5 Goals of therapy include decreasing core symptoms of the disorder, such as worry and distress, and improving overall function. A decrease in somatic symptoms such as fatigue and musculoskeletal complaints should also be achieved. Achieving symptom remission should enhance the patient's overall satisfaction in life.6 First-line pharmacotherapy treatments approved by the Food and Drug Administration (FDA) for GAD include the selective serotonin reuptake inhibitors (SSRIs) escitalopram and paroxetine and the serotonin-norepinephrine reuptake inhibitors duloxetine and extended-release venlafaxine.6 Other SSRIs have been shown effective in treating GAD and include fluoxetine, sertraline, and citalopram. Other FDA-labeled antidepressants such as vilazodone, mirtazapine, vortioxetine, and bupropion all have demonstrated varying degrees of efficacy in the treatment of GAD.7 Other agents such as buspirone (FDA-approved for GAD) and antihistamines like hydroxyzine (FDA-approved for anxiety) have also demonstrated efficacy in the treatment of GAD and are considered reasonable second-line or third-line agents for management of the disorder.3 Agents such as imipramine, a tricyclic antidepressant, are also considered second-line or third-line treatments secondary to their side effect profile when compared to preferred agents.8\n\nTake Home Points:\nAround 50% of the patients treated for generalized anxiety disorder (GAD) will not respond to first-line treatment such as antidepressant therapy. Treatment-resistant GAD (TR-GAD) is usually considered when a patient does not respond to at least 1 antidepressant at an adequate dose for an adequate duration.\n\nWhile benzodiazepines have shown benefit in the short-term use of TR-GAD, long-term use is not recommended secondary to the potential for dependence, misuse, and correlation to cognitive decline.\n\nGamma-aminobutyric acid–related agents, such as the gabapentinoid pregabalin, have demonstrated efficacy in treating TR-GAD as adjunctive agents. Caution should be taken if using a gabapentinoid in a patient with respiratory compromise.\n\nAtypical antipsychotics, such as quetiapine, risperidone, aripiprazole and ziprasidone, have demonstrated efficacy in the management of TR-GAD as adjunctive agents. Lower doses than those used in schizophrenia and bipolar disorder are typically needed for symptom improvement.\n\nBZD Use in GAD\nOther agents historically used in the treatment of GAD include medications in the BZD class. Alprazolam, diazepam, and lorazepam all have demonstrated efficacy for the treatment of GAD, however their use is recommended as second-line therapy and for short duration use because of their known side effects, potential for dependence, and withdrawal issues.8 Maximal duration of BZD use in clinical practice guidelines ranges from 2 to 8 weeks, followed by a slow taper. Despite these recommendations for short-term use, studies have found chronic, long-term BZD prescribing in anxiety patients, with rates as high as 83%.9\n\nThe discrepancy between guideline recommendations and observed clinical practice warrants further examination. Researchers have investigated the long-term use of BZDs in the treatment of anxiety disorders, however interpretation of the evidence can be difficult given the variability in duration and design. A systematic review10 concluded that there was no significant differences in changes in Hamilton Anxiety Rating Scale (HAM-A), all-cause discontinuation, number of panic attacks, and side effects between BZDs and antidepressants after 8 weeks of acute treatment. The review also points out that, given the limited amount of evidence, further investigation of the long-term effectiveness and safety of BZDs is warranted. Some correlate low dropout rates in these studies to efficacy, despite results that showed that BZDs did not separate from placebo in effectiveness measures such as HAM-A.11 A 2014 review12 of clinical practice guidelines investigated the recommendation for short-term or long-term use of BZDs in GAD. In this review BZDs were recommended for short-term treatment of GAD, either until the effects of the concomitantly started antidepressant were apparent, or for use during an unexpected crisis or period of time where increased anxiety was identified. Long-term use of BZDs was only recommended for patients with a lack of treatment response or intolerance to first-line antidepressant and psychological intervention.\n\nOpposition of long-term use of BZDs is largely driven by safety concerns, namely discontinuation and withdrawal symptoms, misuse, and cognitive impairment.11 While the anxiolytic effect of BZDs is observed with short term use (ie, <4 weeks), use beyond that can cause rebound anxiety.13 Rebound symptoms appear after medication termination and are the opposite of the effects of the medication (ie, worsening anxiety, restlessness). These symptoms may be severe enough to cause the patient to return to using the medication, mistaking the rebound symptoms for symptoms of their anxiety disorder.14 When contemplating long-term BZD use, consideration should be given to their effects on cognition and development of cognitive impairment. Patient populations identified to be at high risk for cognitive changes are those who require high doses of BZDs, males, elderly, those with concurrent substance use disorders, or those taking medications with anticholinergic properties. Visuospatial impairments appear to have been most specifically linked to long-term use. Changes in psychomotor function, motor speed, sustained attention, and verbal memory appeared to be unassociated with long-term BZD use. After cessation of the BZD, patients have demonstrated recovery in cognitive domains, however some impairment can still persist when compared with control groups.15 Given the potential for cognitive effects to occur, along with other concerns such as dependence and withdrawal effects, a risk versus benefit analysis and conversation with the patient should occur when deciding if long-term BZD use is appropriate for treatment.\n\nWhile a host of pharmacologic agents are available to treat GAD, it is estimated that as many as half of the patients treated will not respond adequately to selected therapy. Although there is not one recognized definition, treatment-resistant GAD (TR-GAD) can be defined when a patient does not respond to at least one antidepressant at an adequate dose for an adequate duration.7 Given that anxiety disorders often take longer to observe a treatment response compared to the treatment of depression, an adequate duration of at least 8 weeks of treatment is warranted before considering the treatment a failure. If a first-line agent is not effective, another first-line agent can be tried. Clinical practice guidelines offer several second-line and third-line therapies to treat GAD (Table 2). However, because there is a high partial or nonresponse rate in GAD treatment, augmentation strategies have been studied to guide pharmacologic therapy to help achieve the goal of remission in these difficult-to-treat patients. The remainder of this review will focus on some of these augmentation strategies.\n\nTABLE 2 Summary of current generalized anxiety disorder treatment guidelines\n\nGuideline\tIntervention Level\t\nProcess\tFirst Line\tSecond Line\tThird Line\t\nBAP16\tSystematic review and expert opinion/ clinical experience\tPsy: CBT or applied relaxation SSRI: citalopram, escitalopram, paroxetine, sertraline SNRIa: duloxetine, venlafaxine Pregabalina Treatment period: 12 wk\tSwitch to another EBT (includes: agomelatine, quetiapine, BZD, imipramine, hydroxyzine, trazodone) Consider combination of EBTs Pregabalin augmentation Combination drug treatment and CBT\tBZD after non-response to SSRI, SNRI, pregabalin and buspirone\t\nCanadian Clinical Practice Guidelines8\tSystematic review and consensus process\tPsy: CBT SSRI: escitalopam, sertraline paroxetine; paroxetine CR SNRI: duloxetine, venlafaxine XR Agomelatine Pregabalin\tBZD (short-term): alprazolam, bromazepam, diazepam, lorazepam Bupropion XL Buspirone Hydroxyzine Imipramine Quetiapine XR Vortioxetine 2nd line adjunctive therapy: pregabaline\tSSRI: citalopram, fluoxetine Divalproex Mirtazapine Trazodone 3rd line adjunctive therapy: aripiprazole, olanzapine, quetiapine, quetiapine XR, risperidone\t\nNICE17\tSystematic review and expert testimony; considers costs\tPsy: CBT or applied relaxation SSRI: sertraline\tAlternative SSRI or SNRI Pregabalinb\t\t\nBAP = British Association of Psychopharmacology; BZD = benzodiazepine; CBT = cognitive behavior therapy; CR = extended release; EBT = evidence-based therapy; NICE = National Institute for Health and Care Excellence; Psy = psychotherapy; SNRI = serotonin norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; XL = extended release; XR = extended release.\n\na If SSRIs are not suitable.\n\nb If SSRI/SNRI not tolerated.\n\nCase 1\nA 63-year-old with a history significant for GAD presented to the psychiatrist for evaluation after failed treatment of anxiety symptoms by the primary care provider for the past 8 months. Chief complaints included excessive anxiety and worry most days of the week. The reported anxiety was accompanied by feelings of fatigue, irritability, muscle tension, and difficulty with sleep. Both monotherapy with paroxetine and extended-release venlafaxine, optimized to maximum dosage were tried and tolerated to help alleviate these symptoms. Residual symptoms were still reported with extended-release venlafaxine after 16 weeks of treatment. At that time buspirone was added and titrated to maximum tolerated dose, however prominent symptoms that interfere with daily functioning continued to be reported. Per review of records, cognitive behavioral therapy sessions were attended regularly, and all homework was completed thoroughly and in a timely manner. The physical exam and all laboratory values and vital signs were within normal limits. Other known medical conditions included hypertension and diabetes mellitus, both of which were controlled. There were no known allergies to medications.\n\nGABA-Related Agents\nPregabalin\nThe GABA analogue pregabalin has demonstrated efficacy as both monotherapy and as an adjunctive intervention for TR-GAD.7 Pregabalin exerts its anxiolytic effects by potently binding to the alpha2-delta subunit of the voltage-gated N-and P/Q-type calcium channels in central nervous system (CNS) tissue.18 This causes a decrease in presynaptic calcium currents which modulates the release of neurotransmitters, including glutamate, substance P, and calcitonin gene-related peptide from excited neurons. Unlike BZDs, pregabalin does not exacerbate GABA-mediated responses nor does it affect GABA reuptake or GABA transaminase inhibition.8,18\n\nThe efficacy of pregabalin as an adjunctive treatment in TR-GAD has been studied in randomized, double-blind, placebo-controlled trials.19,20 Studies were 8 weeks in length and used the HAM-A as the primary endpoint for measuring anxiety refractory to treatment with antidepressants. Results from these trials show clinical response compared to placebo19 or usual care20 by week 1 and the addition of pregabalin as an augmenting agent was associated with significantly higher benefit in anxiety outcomes. A potential benefit of using pregabalin may be this quick time to effect as demonstrated in these studies, compared to the delayed effect of trialing another antidepressant medication.7 Treatment with pregabalin was associated with significantly greater improvement compared to placebo in 3 out of 7 assessment timepoints (weeks 1, 3, and 4). Mean reduction in HAM-A total scores over the 8-week period were –7.6 for pregabalin versus –6.4 for placebo (P < .05).19 Doses varied between 150 and 600 mg/d. Treatment with pregabalin was generally well-tolerated within this dose range. Studies of pregabalin for use in GAD indicate that serious side effects are rare. Mild side effects include dizziness, somnolence, and dry mouth. Side effects were observed to be correlated to dose, as patients who discontinued secondary to adverse effects tended to be taking higher doses.21\n\nAlthough literature indicates a large number needed to harm for the use of pregabalin in TR-GAD, it should be noted that in December 2019 the FDA22 issued a drug safety communication regarding the use of gabapentinoids (gabapentin and pregabalin). Several data sources, including case reports (reported to the FDA or published in the medical literature), observational studies, clinical trials, and animal studies, were reviewed by the FDA and showed that serious breathing difficulties can occur when gabapentinoids, including pregabalin, are taken by patients with preexisting respiratory risk factors. The warning specifies preexisting risk factors as medical conditions such as chronic obstructive pulmonary disease, as well as in combination with medications such as opioid pain medication or other medications that depress the CNS. Other medications that can depress the CNS are antianxiety medications, such as BZDs, antidepressants, and antihistamines. Given that these medications can be used in the treatment of TR-GAD, caution should be used if pregabalin is selected as an augmenting agent. Prescribers should use caution if initiating a gabapentinoid in combination with a CNS depressant to start at the lowest possible dose and monitor for symptoms of respiratory depression.22 Additional caution should also be noted for rising concern of the abuse and misuse of gabapentinoids. A recent published analysis23 of the FDA Adverse Events Reporting System revealed more than 600 cases of gabapentinoid abuse over a 4-year time period.\n\nTiagabine\nTiagabine is a GABA-reuptake inhibitor and exerts its action on the presynaptic GABA transporter-1.7 Inhibition of the GABA reuptake pump allows for higher concentrations of GABA, which can potentiate GABA receptor activity. The pharmacodynamic effect of tiagabine is similar to BZDs, which can be used to treat GAD.24 While results from double-blind placebo-controlled trials have produced mixed results, open label studies have found tiagabine to be effective and well tolerated in the treatment of TR-GAD.7 Augmentation doses reported in open label studies range from 10 to 16 mg/d given in divided doses. Clinical improvement, if seen, was observed within 2 months of therapy.24 Tiagabine was generally well tolerated with common adverse effects reported to be similar to those of pregabalin, which include dizziness, headache, nausea, fatigue, and somnolence.7\n\nCase 1 is an example of a patient with GAD which is considered treatment-resistant, given failure of symptom remission after adequate trials of recommended first-line antidepressants, in this case paroxetine and extended-release venlafaxine, as well as augmentation with buspirone. Even though the patient notes some relief of symptoms, they still occur to a point of functional interference. While agents such as BZDs could be considered for treatment, there is limited data to support their long-term use and clinical efficacy in GAD. An argument could be made for short-term use of BZDs, however, given the partial response to current therapy with extended-release venlafaxine, long-term augmentation to control symptoms is likely needed for this patient. Known safety risks of long-term use of BZDs limit the feasibility for use in this patient. Additionally, given the age of this patient, additional concern is warranted when considering long-term use and the risk for cognitive impairment.\n\nThe GABA-related agents, such as pregabalin, could be considered for augmentation to help alleviate symptoms in this case. Although tiagabine has some evidence for use, the relative amount of data for use of pregabalin compared to tiagabine makes pregabalin the preferred choice. Although there are safety concerns for pregabalin as well, the patient does not have any known risk factors outside of the use of the prescribed antidepressant agent, as mentioned in the FDA drug safety communication, that would make pregabalin a less preferred agent. The FDA drug safety communication classifies antidepressants as CNS depressants, thus the rationale for extra precautions when combining them with pregabalin, or another gabapentinoid. The risk of combining an antidepressant (such as venlafaxine) could be argued as lower, compared to selecting an agent such as a BZD for reasons stated above. An additional benefit of selecting pregabalin in this case for augmentation is the relatively quick onset of symptom remission. As noted above, symptom remission was seen as quickly as within the first week. This quick response time is likely preferable compared to the time it may take to switch to another antidepressant agent and wait for an effect.\n\nCase 2\nAfter stabilization at an outside hospital, a 32-year-old with GAD was admitted to an inpatient psychiatric treatment facility after a suicide attempt via overdose on lorazepam. Despite multiple trials of recommended antidepressants as well as augmenting therapies including buspirone and long-term lorazepam, minimal remission of anxiety symptoms had been observed since starting treatment for GAD in the patient's mid-20s. Engagement with both cognitive behavioral therapy and relaxation therapy, in addition to pharmacologic treatment was noted in the medical record. Primary symptoms reported include excessive worry as well as somatic symptoms, primarily muscle tension and inability to sleep, which led to the suicide attempt. No other psychiatric diagnoses were noted. Physical exam, laboratory values, and vital signs were all within normal limits. Since the suicide attempt and subsequent stabilization, home doses of escitalopram 20 mg by mouth daily and buspirone 20 mg by mouth 3 times daily were restarted. Lorazepam was not restarted. There were no known allergies to medications.\n\nAtypical Antipsychotics\nThe exact mechanism of action of atypical antipsychotics in the treatment of GAD is unknown. Proposed mechanisms include antagonism at the 5-HT2A receptors, as well as partial agonism at the 5-HT1A receptors. Modulation of histamine receptors may also contribute to the efficacy of these agents in treating GAD. Additionally, the active metabolite of quetiapine, norquetiapine, is a norepinephrine reuptake inhibitor. The atypical antipsychotics aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone all have been examined as augmentation options in the treatment of TR-GAD.6\n\nAripiprazole\nAripiprazole is a partial dopamine type 2 (D2) and serotonin type 1A (5-HT1A) receptor agonist that binds to dopamine type 3 and serotonin type 2A (5-HT2A) receptors.7 One open-label study25 examined the use of aripiprazole as an augmenting agent in patients with GAD who had an inadequate response despite an adequate dose and duration of their SSRI. Doses ranged from 7.5 to 30 mg/d. Aripiprazole improved the mean (± SD) baseline Clinical Global Impression - Severity (CGI-S) score from 5.4 ± 0.5 to 3.8 ± 1.3 (P < .001). Fifty-nine percent of the patients (10/17) were rated as demonstrating a full response, defined as a significant mean change in CGI-S score from baseline to endpoint and Clinical Global Impression - Improvement (CGI-I) score of ≤2 (much improved or very much improved). Five of the 17 patients reported having no adverse effects. Adverse effects that were reported included lightheadedness and jaw clenching. Two patients reported weight gain as a primary adverse effect at the end of the 12-week trial.25 Another open-label study26 looked at aripiprazole as an augmenting agent over a 6-week period in 9 patients with TR-GAD. The mean dose of aripiprazole used at the end of the study was 13.9 mg/d. Addition of aripiprazole to current regimen in this study showed improvement in the HAM-A with the baseline mean of 26.2 to 14.2 (P < .0001). Five patients were deemed HAM-A responders (≥50% reduction) and 1 was a remitter (HAM-A <10). One patient terminated the study secondary to akathisia. Side effects reported as mild to moderate included headache, nausea, dizziness, tiredness, blurred vision, weight gain, and increased anxiety. An open-label study27 of adjunctive aripiprazole in 23 patients with either GAD or panic disorder found that augmentation was associated with a significant reduction in CGI-S scores. Similar to other augmentation studies, patients remained symptomatic despite treatment with an adequate dose of an anxiolytic agent for at least 8 weeks. Aripiprazole was initiated at 2.5 mg/d and flexibly titrated up to a maximum dose of 30 mg/d. Mean aripiprazole dose at endpoint was 10.5 ± 4.95 mg/d. In addition to the primary outcome of CGI-S score, a subgroup analysis of the GAD patients showed significant improvement in HAM-A scores (23.5 ± 3.5 to 16.8 ± 6.3; P ≤ .01). Augmentation with aripiprazole was generally well tolerated, common adverse effects were fatigue, insomnia, and jitteriness. Mean weight gain was 1.1 ± 1.9 kg in this 8-week study.\n\nOlanzapine\nOlanzapine has potent, mixed effects at serotonin type 2 (5-HT2) and D2 dopamine receptors. One randomized controlled trial28 of 24 patients with TR-GAD investigated olanzapine augmentation in patients treated with the SSRI fluoxetine. Treatment with olanzapine augmentation (n = 12) compared to placebo (n = 12) demonstrated a decrease in mean HAM-A scores (± SD) from 17.4 ± 6.5 to 10.4 ± 6.4 in the olanzapine treated group, compared to 22.6 ± 5.2 to 18.7 ± 9.2 in the placebo group (P = .4). Authors28 note that while reduction in HAM-A scores were not statistically different when compared to placebo, the change in score was in the expected direction and achieved an effect size of 0.58, indicating that a larger study may find greater reduction in HAM-A with olanzapine use. The mean dose of olanzapine used in augmentation of fluoxetine 20 mg/d was 8.7 ± 7.1 mg/d. Most adverse events reported were mild to moderate in severity, however 4 patients in the olanzapine arm did discontinue the study secondary to sedation. For those who completed the study, average weight gain on olanzapine was 5.0 ± 2.2 kg (range 0.9 to 7.2 kg) compared to –0.3 ± 1.1 kg with placebo after 6 weeks of olanzapine therapy.\n\nRisperidone\nRisperidone has potent effects at serotonergic, as well as dopaminergic, receptors with its modulation of the serotonin system being theorized as the mechanism by which it exerts its anxiolytic effects.29,30 In 1 open-label study,29 30 patients with panic disorder, social anxiety disorder, or GAD refractory to initial pharmacotherapy with adequate antidepressant trial of at least 8 weeks received risperidone augmentation. Doses of risperidone ranged from 0.25 to 3 mg/d and resulted in an average decrease in HAM-A of 6.75 points (P = .0005). Common adverse effects reported were sedation, increased appetite, and dizziness. Five patients discontinued risperidone because of adverse effects. An additional double-blind, placebo-controlled study30 evaluated the use of risperidone in patients who continued to experience GAD symptoms, despite anxiolytic or antidepressant treatment for at least 4 weeks. Patients were initiated on once daily risperidone or placebo. Doses started at 0.5 mg/d and were titrated to 1.5 mg/d based on tolerability and response. The primary outcome measure was change from baseline to endpoint on the HAM-A total score after 5 weeks of therapy. Thirty-nine patients were included in the study, 19 of which received at least 1 dose of risperidone. Adjunctive risperidone was found significantly more effective than placebo in reducing anxiety as evidence by change in total HAM-A score (–9.8 ± 5.5 vs –6.2 ± 4.9; P = .034). In this 5-week investigation, risperidone was reported as being well tolerated, but 3 patients did discontinue the study secondary to adverse effects. Mostly commonly reported events were dizziness, somnolence, and blurred vision. No patients required adjunctive treatment with anticholinergic agents. Mean changes in weight between the groups was not statistically significant.\n\nZiprasidone\nZiprasidone is an atypical antipsychotic whose mechanism is mediated through the combination of D2 and 5-HT2 antagonism. Additionally ziprasidone has moderate affinity for histamine 1 receptors.31 Its serotonergic properties are what may make it useful in the treatment of GAD.32 Ziprasidone's use in TR-GAD was investigated in an open-label pilot study32 of patients with GAD who had HAM-A scores ≥16 after 8 weeks of treatment with at least 1 first-line antianxiety agent. Patients were randomized to receive ziprasidone monotherapy for 7 weeks, starting at 20 mg/d and titrating based on response up to 80 mg/d. Thirteen patients were enrolled, and treatment with ziprasidone showed that 54% of the patients receiving ziprasidone responded (reduction in HAM-A ≥50%) and 38% of the patients receiving ziprasidone remitted (HAM-A <7). Although this was a small pilot study, results indicate that ziprasidone may be useful in the treatment of TR-GAD. Adverse effects included sedation, difficulty concentrating, dizziness, and insomnia. The QTc change from baseline to end point was 1.7 milliseconds. A placebo-controlled, double-blind 8-week study33 investigated the use of ziprasidone in 62 patients with TR-GAD. In this randomized study, 41 received ziprasidone as augmentation or monotherapy. Mean doses of ziprasidone ranged from 50.24 mg/d to 62.86 mg/d. HAM-A total scores in the intent to treat population (n = 57) did not show statistical significance (P = .22); however, in the medication augmented group a trend towards significance was noted. Common adverse effects reported with ziprasidone use included drowsiness, stimulation, insomnia, and dry mouth. Administration of ziprasidone with food is recommend as absorption is increased up to 2-fold in the presence of food.31 In both these studies32,33 it was not assessed if ziprasidone was administered with food.\n\nQuetiapine\nQuetiapine, and its active metabolite norquetiapine, have moderate to high affinity for D2 and 5-HT2 receptors. Norquetiapine is also a potent inhibitor of the norepinephrine transporter.34 Quetiapine exists in both immediate release and extended-release formulations. Efficacy and tolerability of the extended-release preparation as monotherapy in GAD has been demonstrated in randomized, double-blind, placebo-controlled and active comparator-controlled trials.34 In TR-GAD, safety and efficacy has been evaluated with immediate release quetiapine as an augmenting agent. In 1 randomized, placebo-controlled study,35 20 patients with GAD who had failed treatment with an adequate trial of an SSRI for 8 weeks were randomized to receive augmentation with quetiapine or placebo in addition to their current therapy. Individual doses of quetiapine were not reported, but patients were initiated at 25 mg/d and titrated weekly up to a maximum of 150 mg/d. At end point, the quetiapine group showed a statistically significant improvement over placebo on the HAM-A. Number of responders was higher in quetiapine group compared to placebo but did not reach statistical significance (60% vs 30%; P = .37). This was also true with regards to remitters (40% vs 20%; P = .63). As serotonergic effects of quetiapine appear to start at 150 mg/d, the maximum dose used (150 mg/d) may have limited the observed. No patient discontinued the trial because of side effects or lack of compliance. Another flexible-dose, open-label pilot trial36 investigated the use of quetiapine as an adjunctive pharmacology in patients with GAD who had not achieved remission following at least 8 weeks of an adequate and stable dose of traditional therapy. Forty patients received adjunctive doses of quetiapine immediate release, in addition to their current medication. The dose range of quetiapine for those who completed the study was 25 to 800 mg/d (mean dose 386 mg/d). Adjunctive quetiapine significantly reduced the HAM-A scores as early as week 1 and achieved statistical significance by week 12 with a mean decrease of –20.6 in the HAM-A score (P < .001). No serious adverse effects were reported during the course of the study, with the most commonly reported adverse effects of sedation and dry mouth. Seven patients withdrew because of adverse effects.\n\nOne limitation in the use of atypical antipsychotics for the use in the treatment of TR-GAD is the incomplete evaluation of these medications on metabolic adverse effects. Many trials did not evaluate lipid panels or fasting glucose measurements, therefore the metabolic effects of these agents on patients when used for the treatment of GAD is largely unknown.5 Many of these studies are short in duration (6-8 weeks) and therefore the long-term effect of these agents when used as adjunctive therapy in TR-GAD has still not been elucidated.\n\nCase 2 illustrates a patient who has failed many monotherapy and adjunctive therapy options in the treatment of GAD. Continuation of the BZDs as a treatment option would not be recommended given the inefficacy of the agent to treat anxiety symptoms, risk of long-term effects, and perhaps most importantly safety concerns given the patient's history of overdose requiring hospitalization. While augmentation options including the aforementioned GABA-related agents could be considered, atypical antipsychotics would also be a treatment option for this patient to help reduce symptoms. Several atypical antipsychotics have been investigated and found efficacious as augmentation to recommended antidepressant therapy to improve residual symptoms. An agent should be selected based on patient-specific factors including side effect profile and potential drug-drug interaction. Efficacy of these agents has been shown in short-term trials ranging from 5 to 8 weeks in duration. It is unknown if therapy for these agents should be continued indefinitely if symptom remission is achieved. Given the known adverse effects of these agents such as metabolic syndrome and their potential for extrapyramidal symptoms, usefulness should continually be evaluated and assessed for discontinuation or dose reduction. Although studies discussed did not demonstrate these effects to be significant, the short duration may be a limiting factor in observing their development. Given the lack of long-term data on the use of atypical antipsychotics in TR-GAD, their use should routinely be evaluated for continued inclusion in a patient's treatment regimen.\n\nDosing of these agents is also variable among studies. In general, doses of atypical antipsychotics seem to be less than those typically used in schizophrenia and bipolar disorder, and more in line with doses used for augmentation in the treatment of depression. If an atypical antipsychotic is selected as an augmenting agent, initiation at a low starting dose with titration based on clinical response is recommended. In instance of patient case 2, an agent such as quetiapine, initiated at 25 mg/d and titrated at weekly intervals to response could be considered for therapy in addition to the escitalopram. Choice of another atypical antipsychotic discussed above would also be appropriate. Additionally, the patient should be monitored for metabolic events such as weight gain and blood pressure, lipid, or blood glucose changes.\n\nConclusion\nTreatment-resistant GAD can be defined as the failure of 1 antidepressant at adequate dose and duration. Although there is an armamentarium of agents that have been studied in the treatment of GAD, and current published treatment guidelines provide substantial guidance on treatment pathways, about 50% of the patients with GAD still do not respond adequately to selected treatment. Given the high nonresponse or failure rate of treatment, alternative, off-label agents should be considered to help treat patients. Considerations to GABA-related agents such as pregabalin and tiagabine, as well as atypical antipsychotics such as aripiprazole, olanzapine, risperidone, ziprasidone, and quetiapine should be given. Although limited, data has been presented to support trials of these agents in this difficult-to-treat population.\n\nAcknowledgments\nThe contents do not represent the views of the US Department of Veterans Affairs or the US Government. This article is the result of work supported with resources and the use of facilities at Veteran Health Indiana in Indianapolis, Indiana.\n==== Refs\nReferences\n1 American Psychiatric Association Diagnostic and statistical manual of mental disorders 5th ed Arlington (VA) American Psychiatric Association; 2013 \n2 Nutt DJ Neurobiological mechanisms in generalized anxiety disorder J Clin Psychiatry 2001 62 Suppl 11 22 7 discussion 28. PubMed PMID: 11414547 \n3 Abejuela HR Osser DN The psychopharmacology algorithm project at the Harvard South Shore Program: an algorithm for generalized anxiety disorder Harv Rev Psychiatry 2016 24 4 243 56 DOI: 10.1097/HRP.0000000000000098 PubMed PMID: 27384395 27384395 \n4 Kessler RC Petukhova M Sampson NA Zaslavsky AM Wittchen H-U Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States Int J Methods Psychiatr Res 2012 21 3 169 84 DOI: 10.1002/mpr.1359 PubMed PMID: 22865617 22865617 \n5 Patterson B van Ameringen M Augmentation strategies for treatment-resistant anxiety disorders: a systematic review and meta-analysis Depress Anxiety 2016 33 8 728 36 DOI: 10.1002/da.22525 PubMed PMID: 27175543 27175543 \n6 Lorenz RA Jackson CW Saitz M Adjunctive use of atypical antipsychotics for treatment-resistant generalized anxiety disorder Pharmacotherapy 2010 30 9 942 51 DOI: 10.1592/phco.30.9.942 PubMed PMID: 20795849 20795849 \n7 Wright BM Eiland EH Lorenz R Augmentation with atypical antipsychotics for depression: a review of evidence-based support from the medical literature Pharmacotherapy 2013 33 3 344 59 DOI: 10.1002/phar.1204 PubMed PMID: 23456734 23456734 \n8 Katzman MA Bleau P Blier P Chokka P Kjernisted K van Ameringen M Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders BMC Psychiatry 2014 14 Suppl 1 S1 DOI: 10.1186/1471-244X-14-S1-S1 PubMed PMID: 25081580 PubMed Central PMCID: PMC4120194 25081580 \n9 Tanguay Bernard M-M Luc M Carrier J-D Fournier L Duhoux A Côté E Patterns of benzodiazepines use in primary care adults with anxiety disorders Heliyon 2018 4 7 e00688 DOI: 10.1016/j.heliyon.2018.e00688 PubMed PMID: 29998202 29998202 \n10 Shinfuku M Kishimoto T Uchida H Suzuki T Mimura M Kikuchi T Effectiveness and safety of long-term benzodiazepine use in anxiety disorders: a systematic review and meta-analysis Int Clin Psychopharmacol 2019 34 5 211 21 DOI: 10.1097/YIC.0000000000000276 PubMed PMID: 31274696 31274696 \n11 Donoghue J Lader M Usage of benzodiazepines: a review Int J Psychiatry Clin Pract 2010 14 2 78 87 DOI: 10.3109/13651500903447810 PubMed PMID: 24922466 24922466 \n12 Canadian Agency for Drugs and Technologies in Health Short- and long-term use of benzodiazepines in patients with generalized anxiety disorder: a review of guidelines [Internet] Ottawa (ON) Canadian Agency for Drugs and Technologies in Health c2014 [updated 2014 7 28 cited 2020 May 17] Available from: https://www.ncbi.nlm.nih.gov/books/NBK254091/ \n13 Rynn MA Brawman-Mintzer O Generalized anxiety disorder: acute and chronic treatment CNS Spectr 2004 9 10 716 23 DOI: 10.1017/S1092852900022367 PubMed PMID: 15448583 15448583 \n14 Salzman C The APA Task Force report on benzodiazepine dependence, toxicity, and abuse Am J Psychiatry 1991 148 2 151 2 DOI: 10.1176/ajp.148.2.151 PubMed PMID: 1987812 1987812 \n15 Stewart SA The effects of benzodiazepines on cognition J Clin Psychiatry 2005 66 Suppl 2 9 13 PubMed PMID: 15762814 \n16 Baldwin DS Anderson IM Nutt DJ Allgulander C Bandelow B den Boer JA Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology J Psychopharmacol 2014 28 5 403 39 DOI: 10.1177/0269881114525674 PubMed PMID: 24713617 24713617 \n17 National Institute for Health and Care Excellence [Internet] Generalised anxiety disorder and panic disorder in adults: management (NICE Quality Standard CG113) c2011 [updated 2018 7 26 cited 2020 May 18] Available from: https://www.nice.org.uk/guidance/cg113 \n18 Bandelow B Wedekind D Leon T Pregabalin for the treatment of generalized anxiety disorder: a novel pharmacologic intervention Expert Rev Neurother 2007 7 7 769 81 DOI: 10.1586/14737175.7.7.769 PubMed PMID: 17610384 17610384 \n19 Rickels K Shiovitz TM Ramey TS Weaver JJ Knapp LE Miceli JJ Adjunctive therapy with pregabalin in generalized anxiety disorder patients with partial response to SSRI or SNRI treatment Int Clin Psychopharmacol 2012 27 3 142 50 DOI: 10.1097/YIC.0b013e328350b133 PubMed PMID: 22302014 22302014 \n20 Álvarez E Olivares JM Carrasco JL López-Gómez V Rejas J Clinical and economic outcomes of adjunctive therapy with pregabalin or usual care in generalized anxiety disorder patients with partial response to selective serotonin reuptake inhibitors Ann Gen Psychiatry 2015 14 1 2 DOI: 10.1186/s12991-014-0040-0 PubMed PMID: 25632294 25632294 \n21 Baldwin DS den Boer JA Lyndon G Emir B Schweizer E Haswell H Efficacy and safety of pregabalin in generalised anxiety disorder: a critical review of the literature J Psychopharmacol 2015 29 10 1047 60 DOI: 10.1177/0269881115598411 PubMed PMID: 26259772 26259772 \n22 The Food and Drug Administration [Internet] FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR) [cited 2019 Dec 19]. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-serious-breathing-problems-seizure-and-nerve-pain-medicines-gabapentin-neurontin \n23 Evoy KE Covvey JR Peckham AM Ochs L Hultgren KE Reports of gabapentin and pregabalin abuse, misuse, dependence, or overdose: an analysis of the Food And Drug Administration Adverse Events Reporting System (FAERS) Res Social Adm Pharm 2019 15 8 953 958 DOI: 10.1016/j.sapharm.2018.06.018 PubMed PMID: 31303196 31303196 \n24 Schwartz TL The use of tiagabine augmentation for treatment-resistant anxiety disorders: a case series Psychopharmacol Bull 2002 36 2 53 7 PubMed PMID: 12397840 12397840 \n25 Worthington JJ Kinrys G Wygant LE Pollack MH Aripiprazole as an augmentor of selective serotonin reuptake inhibitors in depression and anxiety disorder patients Int Clin Psychopharmacol 2005 20 1 9 11 DOI: 10.1097/00004850-200501000-00002 PubMed PMID: 15602109 15602109 \n26 Menza MA Dobkin RD Marin H An open-label trial of aripiprazole augmentation for treatment-resistant generalized anxiety disorder J Clin Psychopharmacol 2007 27 2 207 10 DOI: 10.1097/01.jcp.0000248620.34541.bc PubMed PMID: 17414231 17414231 \n27 Hoge EA Worthington JJ Kaufman RE Delong HR Pollack MH Simon NM Aripiprazole as augmentation treatment of refractory generalized anxiety disorder and panic disorder CNS Spectr 2008 13 6 522 7 PubMed PMID: 18567977 18567977 \n28 Pollack MH Simon NM Zalta AK Worthington JJ Hoge EA Mick E Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study Biol Psychiatry 2006 59 3 211 5 DOI: 10.1016/j.biopsych.2005.07.005 PubMed PMID: 16139813 16139813 \n29 Simon NM Hoge EA Fischmann D Worthington JJ Christian KM Kinrys G An open-label trial of risperidone augmentation for refractory anxiety disorders J Clin Psychiatry 2006 67 3 381 5 DOI: 10.4088/jcp.v67n0307 PubMed PMID: 16649823 16649823 \n30 Brawman-Mintzer O Knapp RG Nietert PJ Adjunctive risperidone in generalized anxiety disorder: a double-blind, placebo-controlled study J Clin Psychiatry 2005 66 10 1321 5 PubMed PMID: 16259547 16259547 \n31 Geodon® [package insert] New York Roerig Division of Pfizer, Inc c 2020 \n32 Snyderman SH Rynn MA Rickels K Open-label pilot study of ziprasidone for refractory generalized anxiety disorder J Clin Psychopharmacol 2005 25 5 497 9 DOI: 10.1097/01.jcp.0000177853.15910.de PubMed PMID: 16160630 16160630 \n33 Lohoff FW Etemad B Mandos LA Gallop R Rickels K Ziprasidone treatment of refractory generalized anxiety disorder: a placebo-controlled, double-blind study J Clin Psychopharmacol 2010 30 2 185 9 DOI: 10.1097/JCP.0b013e3181d21951 PubMed PMID: 20520293 20520293 \n34 Bandelow B Chouinard G Bobes J Ahokas A Eggens I Liu S Extended-release quetiapine fumarate (quetiapine XR): a once-daily monotherapy effective in generalized anxiety disorder. Data from a randomized, double-blind, placebo- and active-controlled study Int J Neuropsychopharmacol 2010 13 3 305 20 DOI: 10.1017/S1461145709990423 PubMed PMID: 19691907 19691907 \n35 Altamura AC Serati M Buoli M Dell'Osso B Augmentative quetiapine in partial/nonresponders with generalized anxiety disorder: a randomized, placebo-controlled study Int Clin Psychopharmacol 2011 26 4 201 5 DOI: 10.1097/YIC.0b013e3283457d73 PubMed PMID: 21403524 21403524 \n36 Katzman MA Vermani M Jacobs L Marcus M Kong B Lessard S Quetiapine as an adjunctive pharmacotherapy for the treatment of non-remitting generalized anxiety disorder: a flexible-dose, open-label pilot trial J Anxiety Disord 2008 22 8 1480 6 DOI: 10.1016/j.janxdis.2008.03.002 PubMed PMID: 18455360 18455360\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2168-9709",
"issue": "10(6)",
"journal": "The mental health clinician",
"keywords": "atypical antipsychotics; generalized anxiety disorder; pregabalin; tiagabine; treatment-resistant",
"medline_ta": "Ment Health Clin",
"mesh_terms": null,
"nlm_unique_id": "101728585",
"other_id": null,
"pages": "326-334",
"pmc": null,
"pmid": "33224690",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": "15762814;18455360;16139813;24713617;17414231;21403524;19691907;11414547;27175543;15602109;25632294;25081580;15448583;29998202;24922466;18567977;26259772;31303196;20520293;22302014;16259547;16160630;31274696;12397840;1987812;27384395;20795849;17610384;16649823;22865617;23456734",
"title": "Management of treatment-resistant generalized anxiety disorder.",
"title_normalized": "management of treatment resistant generalized anxiety disorder"
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"abstract": "OBJECTIVE\nTo report a case of recurrent clozapine-induced fever that was associated with a rise in C-reactive protein (CRP).\n\n\nMETHODS\nA 73-year-old man with Lewy Body dementia was admitted for psychosis. He was treated with clozapine (initial dose 12.5 mg/day, titrated to 75 mg/day over 15 days). On day 15 of clozapine therapy, he developed a benign fever (maximum 38.4 degrees C) that was associated with a rise in the CRP level (3.96 mg/dL). The level normalized when clozapine was discontinued. However, when the patient was rechallenged with clozapine, the CRP level became elevated (4.36 mg/dL) after 3 days of therapy, with a subsequent recurrence of fever (38.7 degrees C).\n\n\nCONCLUSIONS\nWe postulate that the elevation in CRP levels and the subsequent fever were caused by the effects of clozapine on the cytokine system via interleukin-6 and tumor necrosis factor-alpha, resulting in an inflammatory response with an acute phase reaction. This case is unique, as it is the first reported in the literature associating a recurrence of clozapine-induced fever with the known immunomodulatory effects of clozapine on cytokines and CRP level. According to the Naranjo probability scale, this adverse effect is probably associated with clozapine.\n\n\nCONCLUSIONS\nClozapine-related fever is generally benign but difficult to assess and manage, as it can be confused with much more serious conditions. Further research is needed to study whether CRP is a useful tool in predicting and managing clozapine fever.",
"affiliations": "Geriatric Psychiatry Division, North Shore-Long Island Jewish Health System, The Zucker Hillside Hospital, Glen Oaks, NY 11004,USA. ikohen@nshs.edu",
"authors": "Kohen|Izchak|I|;Afzal|Noman|N|;Hussain|Saira|S|;Manu|Peter|P|",
"chemical_list": "D015415:Biomarkers; D002097:C-Reactive Protein; D003024:Clozapine",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1L467",
"fulltext": null,
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"issn_linking": "1060-0280",
"issue": "43(1)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000368:Aged; D015415:Biomarkers; D002097:C-Reactive Protein; D003024:Clozapine; D005334:Fever; D006801:Humans; D008297:Male; D011237:Predictive Value of Tests",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "143-6",
"pmc": null,
"pmid": "19126823",
"pubdate": "2009-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Increases in C-reactive protein may predict recurrence of clozapine-induced fever.",
"title_normalized": "increases in c reactive protein may predict recurrence of clozapine induced fever"
} | [
{
"companynumb": "US-JAZZ-2016-US-001621",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nFew case reports have described vaso-occlusive retinopathy in systemic lupus erythematosus (SLE) using optical coherence tomography (OCT) angiography. Here we report the clinical features of a patient with SLE, complicated by Kikuchi-Fujimoto disease, who developed vaso-occlusive retinopathy. We then describe the subsequent recovery of the macular capillaries as assessed by OCT angiography.\n\n\nMETHODS\nA 16-year-old male was referred to us with fever, a 1-month history of violaceous red papules and erythematous plaques on his face and a painful nodule in his right neck. We diagnosed him with SLE complicated by Kikuchi-Fujimoto disease through physiological assessment and histology from his neck lymph node and chin skin. Systemic steroids were prescribed as treatment. After remission, his fever and cervical lymph node swelling with pain recurred and he developed blurred inferior vision in his left eye. His best-corrected visual acuities were 1.0 and 0.1 in the right and left eyes, respectively. Extensive cotton wool spots were observed in the right fundus, and retinal capillary occlusions were detected by OCT angiography of the left eye. We diagnosed this case as vaso-occlusive retinopathy with SLE and increased immunosuppressive treatment together with anticoagulation therapy. Macular capillaries, observed by OCT angiography, gradually recovered function following assessment at 7 and 16 months post-onset of the vaso-occlusive retinopathy.\n\n\nCONCLUSIONS\nWe reported a 1½-year course of vaso-occlusive retinopathy in a patient with SLE complicated by Kikuchi-Fujimoto disease. Occlusion of the retinal vasculature and the subsequent recovery of circulation are clearly observed by OCT angiography.",
"affiliations": "Department of Ophthalmology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, Japan. rkino@asahikawa-med.ac.jp.;Asahikawa Red Cross Hospital, Akebono 1-1-1-1, Asahikawa, Hokkaido, Japan.;Department of Ophthalmology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, Japan.;Department of Ophthalmology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, Japan.",
"authors": "Kinouchi|Reiko|R|http://orcid.org/0000-0003-1344-1641;Kinouchi|Motoshi|M|;Ishibazawa|Akihiro|A|;Yoshida|Akitoshi|A|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10792-017-0650-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5701",
"issue": "38(4)",
"journal": "International ophthalmology",
"keywords": "Kikuchi–Fujimoto disease; OCT angiography; Systemic lupus erythematosus; Vaso-occlusive retinopathy",
"medline_ta": "Int Ophthalmol",
"mesh_terms": "D000293:Adolescent; D002196:Capillaries; D020042:Histiocytic Necrotizing Lymphadenitis; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008266:Macula Lutea; D008297:Male; D016491:Peripheral Vascular Diseases; D012164:Retinal Diseases; D012171:Retinal Vessels",
"nlm_unique_id": "7904294",
"other_id": null,
"pages": "1797-1801",
"pmc": null,
"pmid": "28695380",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27784073;18304938;16538388;12675765;27780174;25892939;18173424;25500707;27472076;14746601;25310212;19107085;27685676",
"title": "Macular capillary recovery in systemic lupus erythematosus complicated by Kikuchi-Fujimoto disease.",
"title_normalized": "macular capillary recovery in systemic lupus erythematosus complicated by kikuchi fujimoto disease"
} | [
{
"companynumb": "JP-BAUSCH-BL-2018-023114",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. The advent of immunobiologic therapy with TNF inhibitors agents, has been associated with a significant increase in incident cases of tuberculosis in this population.\n\n\n\nTo estimate the incidence of tuberculosis in patients receiving TNF inhibitors therapy for rheumatic diseases. As secondary objectives, we sought to evaluate mortality and the clinical impact of screening for latent tuberculosis infection.\n\n\n\nThis retrospective study included patients with rheumatic diseases of Public Health System from the Brazilian state, a high TB incidence area, who received prescriptions of TNF inhibitors agents between 2006 and 2016.\n\n\n\nA total of 5853 rheumatic disease patients were included. Patients were predominantly women (68.7%) aged 49.5 (± 14.7) years old. Forty-three cases of TB were found (2.86 cases per 1000 person-years; 18 times higher than in the general population). Adalimumab and certolizumab users presented a higher risk for TB development compared to etanercept users (RR: 3.11, 95%CI 1.16-8.35; 7.47, 95%CI 1.39-40.0, respectively). In a subgroup of patients, screening for latent tuberculosis infection was performed in 86% of patients, and 30.2% had a positive tuberculin skin test. Despite latent TB treatment, TB was diagnosed in 2 out of 74 (2.7%) patients. Overall, TB diagnosis did not increase mortality.\n\n\n\nIn this population-based study of rheumatic disease patients from a high incident area, TNF inhibitor exposure was associated with an 18-time increased TB incidence. Adalimumab and certolizumab were associated with greater and earlier TB diagnosis compared to etanercept.",
"affiliations": "Department of Rheumatology, Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.;Department of Internal Medicine, UFRGS, Porto Alegre, Brazil.;Department of Rheumatology, Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.;Planning and Evaluation Advisory Office, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil.;Department of Rheumatology, Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.",
"authors": "Sartori|Natália Sarzi|NS|0000-0002-4316-0771;Picon|Paulo|P|;Papke|Afonso|A|;Neyeloff|Jeruza Lavanholi|JL|;da Silva Chakr|Rafael Mendonça|RM|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0224963",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0224963PONE-D-19-21256Research ArticleMedicine and Health SciencesInfectious DiseasesBacterial DiseasesTuberculosisMedicine and Health SciencesTropical DiseasesTuberculosisBiology and Life SciencesPhysiologyImmune PhysiologyCytokinesMedicine and Health SciencesPhysiologyImmune PhysiologyCytokinesBiology and Life SciencesImmunologyImmune SystemInnate Immune SystemCytokinesMedicine and Health SciencesImmunologyImmune SystemInnate Immune SystemCytokinesBiology and Life SciencesDevelopmental BiologyMolecular DevelopmentCytokinesMedicine and Health SciencesRheumatologyPeople and placesGeographical locationsSouth AmericaBrazilMedicine and Health SciencesRheumatologyArthritisRheumatoid ArthritisMedicine and Health SciencesClinical MedicineClinical ImmunologyAutoimmune DiseasesRheumatoid ArthritisBiology and Life SciencesImmunologyClinical ImmunologyAutoimmune DiseasesRheumatoid ArthritisMedicine and Health SciencesImmunologyClinical ImmunologyAutoimmune DiseasesRheumatoid ArthritisMedicine and Health SciencesClinical MedicineClinical ImmunologyAutoimmune DiseasesAnkylosing SpondylitisBiology and Life SciencesImmunologyClinical ImmunologyAutoimmune DiseasesAnkylosing SpondylitisMedicine and Health SciencesImmunologyClinical ImmunologyAutoimmune DiseasesAnkylosing SpondylitisMedicine and Health SciencesRheumatologyArthritisPsoriatic ArthritisBiology and Life SciencesOrganismsBacteriaActinobacteriaMycobacterium TuberculosisA population-based study of tuberculosis incidence among rheumatic disease patients under anti-TNF treatment Tuberculosis incidence in patients exposed to anti-TNF therapyhttp://orcid.org/0000-0002-4316-0771Sartori Natália Sarzi ConceptualizationData curationInvestigationMethodologySupervisionValidationVisualizationWriting – original draft1*Picon Paulo MethodologyWriting – review & editing2Papke Afonso InvestigationMethodologyResourcesWriting – original draft1Neyeloff Jeruza Lavanholi Formal analysisMethodologySoftware3da Silva Chakr Rafael Mendonça ConceptualizationFormal analysisInvestigationMethodologyProject administrationSupervisionWriting – original draftWriting – review & editing121 \nDepartment of Rheumatology, Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil2 \nDepartment of Internal Medicine, UFRGS, Porto Alegre, Brazil3 \nPlanning and Evaluation Advisory Office, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, BrazilAbu-Shakra Mahmoud EditorSoroka University Medical Center, ISRAELCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: nataliasartori2007@yahoo.com.br2 12 2019 2019 14 12 e022496328 7 2019 26 10 2019 © 2019 Sartori et al2019Sartori et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Introduction\nTuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. The advent of immunobiologic therapy with TNF inhibitors agents, has been associated with a significant increase in incident cases of tuberculosis in this population.\n\nObjective\nTo estimate the incidence of tuberculosis in patients receiving TNF inhibitors therapy for rheumatic diseases. As secondary objectives, we sought to evaluate mortality and the clinical impact of screening for latent tuberculosis infection.\n\nMethods\nThis retrospective study included patients with rheumatic diseases of Public Health System from the Brazilian state, a high TB incidence area, who received prescriptions of TNF inhibitors agents between 2006 and 2016.\n\nResults\nA total of 5853 rheumatic disease patients were included. Patients were predominantly women (68.7%) aged 49.5 (± 14.7) years old. Forty-three cases of TB were found (2.86 cases per 1000 person-years; 18 times higher than in the general population). Adalimumab and certolizumab users presented a higher risk for TB development compared to etanercept users (RR: 3.11, 95%CI 1.16–8.35; 7.47, 95%CI 1.39–40.0, respectively). In a subgroup of patients, screening for latent tuberculosis infection was performed in 86% of patients, and 30.2% had a positive tuberculin skin test. Despite latent TB treatment, TB was diagnosed in 2 out of 74 (2.7%) patients. Overall, TB diagnosis did not increase mortality.\n\nConclusion\nIn this population-based study of rheumatic disease patients from a high incident area, TNF inhibitor exposure was associated with an 18-time increased TB incidence. Adalimumab and certolizumab were associated with greater and earlier TB diagnosis compared to etanercept.\n\nThis work was funded by the Graduate Program in Medical Sciences of the Federal University of Rio Grande do Sul, through the Research and Events Incentive Fund (FIPE) of the Hospital de Clínicas de Porto, which provided financial support for the publication of this study. The funder had no role in study design, data collection and analysis, publication decision, or manuscript preparation. Data AvailabilityAll relevant data are within the manuscript.Data Availability\nAll relevant data are within the manuscript.\n==== Body\nIntroduction\nTumor necrosis factor-alpha (TNF-α) is a cytokine involved in the pathogenesis of several systemic rheumatic diseases.[1,2] With the advent of TNF inhibitors therapy, treatment of these diseases has advanced markedly and clinical outcomes have improved, especially in patients refractory to conventional therapy.[3–7] The benefits of TNF inhibitors therapy have been well established in several studies that have demonstrated efficacy in controlling disease activity in rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA).[8–10] Five TNF inhibitors agents are currently available for use in Brazil: infliximab (IFX), etanercept (ETN), adalimumab (ADA), golimumab (GOL), and certolizumab pegol (CZP).\n\nTNF-α is known to play a role in the control of infectious diseases, particularly those caused by intracellular microorganisms such as Mycobacterium tuberculosis.[11] Its role is particularly important in organizing the activation and maintenance of granuloma.[12,13] Accordingly, despite its efficacy, TNF inhibitors therapy has been shown to increase the incidence of infections in general and of serious infections (such as tuberculosis) in particular.[14,15]\n\nIn 2016, an estimated 10.4 million incident cases of tuberculosis (TB) will have occurred worldwide.[16] Brazil ranks 20th among the 30 countries with the highest TB burden in the world, and accounts for approximately one-third of all incident cases of TB in the Americas.[17] In 2017, TB incidence rate of 33.5 cases per 100,000 population were reported in Brazil. Rates in the state of Rio Grande do Sul (RS) appear to be higher than the national average, with an incidence rate of 39.5 cases per 100,000 population; this makes RS one of the four states with the highest incidence of new-onset TB in Brazil.[18]\n\nThe risk of developing TB is higher in individuals with RA when compared to the general population.[19] This risk is fourfold higher in RA patients on TNF inhibitors therapy when compared to that of anti-TNF-naive RA patients. [15,20–22] In areas with a higher incidence of TB, such as in Asian countries, a nearly 26-fold greater risk of TB was found in those exposed to TNF inhibitors agents.[23] In patients given infliximab, risk could be up to 30 times greater than in the general population.[24,25]\n\nConsidering this increased risk, screening and treatment of latent tuberculosis infection (LTBI) has been recommended prior to initiation of TNF inhibitors therapy.[2,26–29] Screening for LTBI has been shown to reduce the risk of TB reactivation. According to the Spanish Society of Rheumatology registry of patients on immunobiologicals, BIOBADASER, this practice has managed to reduce the number of incident cases of TB in patients starting TNF inhibitors TNF therapy by 78% between 2002 and 2006, when it was implemented.[29,30]\n\nA previous study carried out in Brazil, based on records from the Brazilian Registry of Biologic Therapy Monitoring (BiobadaBrasil) maintained by the Brazilian Society of Rheumatology, found a TB incidence in RA patients with TNF inhibitors exposure of 2.8 cases per 1,000 exposed.[31] Given the higher-than-average incidence of TB in southern Brazil, it is believed that the rate of new TB cases in patients with rheumatic diseases exposed to TNF inhibitors therapy in Rio Grande do Sul may also be significantly higher than that of the general population.[18] Within this context, the primary objective of this study is to estimate the incidence of tuberculosis in patients receiving TNF inhibitors therapy for rheumatic diseases. As secondary objectives, we sought to evaluate mortality and the influence of screening for latent tuberculosis infection on clinical outcomes in this population.\n\nMethods\nStudy design and patients\nThis population-based retrospective cohort study included all Public Health System patients from the state of Rio Grande do Sul who were prescribed and dispensed TNF inhibitors therapy for rheumatic diseases from 2006 to 2016. Inclusion was based on the records of the statewide Exceptional Circumstance Drug Dispensing Program, considering those ICD-10 codes covered by the Brazilian Clinical Protocols and Therapeutic Guidelines for rheumatic diseases. Because TB is a notifiable disease in Brazil, definition of TB cases was based on TB reporting data, obtained from the Notifiable Diseases Information System. This system includes all patients with a confirmed diagnosis of tuberculosis, as well as the clinical presentation, treatment regimen and final follow-up outcome. Positive cases being defined by patients with clinical diagnosis associated with bacteriological diagnosis.\n\nMortality data were obtained from the Mortality Information System, provided by the state centralizing agency for all death certificates in this state. To unify information from these different databases, the linkage technique was used, whereby standardized information is used to find the same individual across several data sources. The variables used for linkage were patient’s name, mother’s name, and date of birth.\n\nScreening for latent tuberculosis prior to the initiation of TNF inhibitors is recommended for all patients who are candidates for therapy and drug release is required. In subgroup of patients being followed at the outpatient rheumatology clinic of Hospital de Clínicas de Porto Alegre (HCPA) underwent a tuberculin skin test prior to initiation of TNF inhibitors therapy; if LTBI was detected, positive tuberculin skin test or suggestive chest X-ray findings without history of previous tuberculosis treatment, isoniazid treatment was indicated. This information was obtained from a review of patients’ medical records. In addition, patients with and without a history of treatment for LTBI were evaluated for potential TB infection.\n\nStatistical analyses\nData were analyzed in SPSS version 18.03.\n\nNo sample calculation was performed since all samples were scheduled to be included in the study.\n\nDescriptive analyses of the incidence rate of tuberculosis, calculated per 1000 exposed patient-years and per 100,000 exposed patients, were carried out. Person- years were calculated from the first day of TNF inhibitor therapy to the date of tuberculosis infection, or death or discontinuation of TNF inhibitor use.\n\nFor incidence density analysis, we used the time of use related to the first exposure for calculation of incidence related to the first exposure, also the total time of use of any TNF inhibitor during follow-up to define cumulative incidence density over the course of the study.\n\nIn addition, descriptive analyses of all data related to age, sex, underlying disease, duration of anti-TNF exposure, and number of anti-TNF agents used were performed. Among TB cases, we evaluated demographic characteristics, underlying rheumatic disease, TNF inhibitors agent used, and time elapsed from initiation of TNF inhibitors therapy to onset of TB.\n\nFig 1 illustrates the model used to validate a TB case as related to TNF inhibitors TNF agent exposure. A case of TB was considered related to anti-TNF therapy if it occurred up to 90 days after ETN, ADA, GOL, or CZP were last dispensed to the patient, and up to 180 days after IFX was last dispensed. The 90-day period was defined based on a previous study to evaluate the incidence of tuberculosis, and time on drug influence was still considered.[32] Specifically, considering infliximab this time was extended to 180 days in view of some evidence pointing to the presence of drug circulating up to 28 weeks post exposure.[33]\n\n10.1371/journal.pone.0224963.g001Fig 1 Model for drug-related tuberculosis cases.\n Cases of TB during TNF inhibitors use. Cases of TB associated with recente use of TNF inhibitors. Cases of TB not related to TNF inhibitors use.\n\nTo compare the incidence of TB among different drugs, incidence was evaluated as percentage, with Fisher’s exact test for statistical significance. P-values <0.05 were considered statistically significant.\n\nDisease-free survival time was analyzed in all patients receiving TNF inhibitors therapy by the Kaplan–Meier method, with head-to-head comparison of drugs using the Mantel-Cox log-rank test for the event of interest.\n\nPatient survival was also evaluated using Kaplan–Meier analysis, which included all patients in the cohort. The last evaluation of mortality records was defined as the time point for censoring. The log-rank test was used to compare all-cause mortality versus deaths due to TB.\n\nIn the subgroup of patients who underwent screening for LTBI, categorical comparison was performed using Pearson’s chi-square test or Fisher’s exact test. Again, p-values <0.05 were considered significant for all analyses.\n\nThis study was approved by the Research Ethics Committees of Hospital de Clínicas de Porto Alegre and the School of Public Health/Rio Grande do Sul State Department of Health with opinion number 66184417.8.3001.5312.\n\nResults\nA total of 5853 patients and 6902 courses of TNF inhibitors therapy were included, from 2006 to 2016. The sample was predominantly female (68.7%), with a mean age of 49.1 years (Table 1). All five TNF inhibitors agents approved for use in Brazil by the Public Health System were covered: adalimumab accounted for 2980 courses of treatment (43.8%), etanercept for 2543 (37.4%), infliximab for 623 (9.1%), golimumab for 492 (7.2%), and certolizumab pegol for 164 (2.4%).\n\n10.1371/journal.pone.0224963.t001Table 1 Demographic and clinical features in patients in patients exposed to TNF inhibitors.\nPatients’ features\tRA\n(n = 3653)\tAS\n(n = 1150)\tPsA\n(n = 872)\tJIA\n(n = 124)\tOther spondyloarthritis\n(n = 54)\tTotal\n(n = 5853)\tp*\t\nFemale\t3004 (82.2)*\t467 (40.6)\t446 (51.1)\t76 (61.2)\t29 (53.7)\t4022 (68.7)\t<0,001\t\nAge (years)—mean (SD)\t52.7 (12.8)d\t42.8 (11.9)b\t47.7 (12.5)c\t13.1 (7.51)a\t44.0 (13.5)bc\t49.1 (14.1)\t<0,001\t\n≤65 years\t3039 (83.2)\t1112 (96.7)*\t798 (91.5)*\t124 (100)*\t51 (94.4)\t5124 (87.6)\t\t\n>65 years\t614 (16.8)*\t38 (3.3)\t74 (8.5)\t0\t3 (5.6)\t729 (12.4)\t\t\nTNF inhibitors agent\t4212\t1345\t1030\t151\t60\t6802\t\t\nIFX\t430 (10.2)*\t113 (8.4)\t69 (6.6)\t7 (4.6)\t4 (6.6)\t623 (9.1)\t0,001\t\nETN\t1441 (34.1)\t533 (39.2)*\t427 (41.4)*\t118 (78.1)*\t24 (40)\t2543 (37.3)\t<0,001\t\nADA\t1695 (40.2)\t696 (51.74)*\t529 (51.3)*\t28 (18.5)\t32 (53.3)\t2980 (43.8)\t<0,001\t\nGOL\t483 (11.4)*\t3 (0.2)\t4 (0.3)\t2 (1.3)\t0\t492 (7.2)\t<0,001\t\nCZP\t163 (3.8)*\t0\t1 (0.1)\t0\t0\t164 (2.4)\t<0,001\t\nNumber of patients per TNF inhibitors\t\t\t\t\t\t\t0,006\t\n1 TNF inhibitors\t3090 (84.6)*\t953 (83)\t713 (81.7)\t92 (74.2)\t48 (89)\t4896 (83.6)\t\t\n2 or more TNF inhibitors\t563 (15.4)\t197 (17)\t159 (18.3)\t32 (25.8)*\t6 (11)\t957 (16.4)\t\t\nDuration of TNF inhibitors therapy—mean years (SD)\t2.55 (2.03)b\t2.67 (1.71)b\t2.59 (1.85)b\t2.87 (2.27)b\t1.56(1.55)a\t2.58 (1.95)\t<0,001\t\nAbbreviations: RA, rheumatoid arthritis; AS, ankylosing spondylitis; PsA, psoriatic arthritis; JIA, juvenile idiopathic arthritis; TNF, tumor necrosis factor; IFX, infliximab; ETN, etanercept; ADA, adalimumab; GOL, golimumab; CZP, certolizumab pegol; SD, standard deviation;\n\n* p significant\n\nvariables with letters not repeated = p significant\n\nOf the patients included, 3653 (62.4%) had been diagnosed with rheumatoid arthritis, 1150 (19.7%) with ankylosing spondylitis, 872 (14.9%) with psoriatic arthritis, 124 (2.1%) with juvenile idiopathic arthritis, and 54 (0.9%) with other inflammatory spondyloarthropathies.\n\nIn this sample of TNF inhibitors users, 4896 (83.6%) used only one TNF inhibitor throughout the study period, while 957 (16.4%) were exposed to two or more drugs of this class. The average duration of follow-up, ie exposure to TNF inhibitors therapy was 2.58 ± 1.95 years.\n\nOf the 5853 patients included, 43 received a diagnosis of TB during follow-up; 28 of these occurred during the first exposure. The characteristics of these patients are described in Table 2. The mean age of these patients was 49.5 ± 14.7 years. No significant relationship was found with age >65 years (p = 0.298). Twenty-four (55.8%) were women, 28 (65.1%) had RA, 8 (18.6%) had AS, 6 (13.9%) had PsA, and 1 (2.3%) had JIA. Regarding anti-TNF agents, 27 (62.8%) cases were associated with ADA, 10 (23.2%) with ETN, 3 (7%) with IFX, 2 (4.6) with CZP and 1 (2.3%) with GOL.\n\n10.1371/journal.pone.0224963.t002Table 2 Demographic and clinical features in patients with tuberculosis.\nPatients with tuberculosis\tRA\n(n = 28)\tAS\n(n = 8)\tPsA\n(n = 6)\tJIA\n(n = 1)\tTotal\n(n = 43)\tp\t\nFemale\t19 (67.8)\t4 (50)\t1 (16.7)\t0)\t24 (55.8)\t0,080\t\nAge (years)—mean (SD)\t52 (14.1)\t43.5 (11.1)\t51.6 (14.3)\t13.4\t49.5 (14.7)\t0,298\t\n≤65 years\t21 (75)\t7 (100)\t5 (83.3)\t1 (100)\t35 (81.4)\t\t\n>65 years\t7 (25)\t0\t1 (16.7)\t0\t8 (18.6)\t\t\nTNF inhibitors agent\t\t\t\t\t\t\t\nIFX\t3 (10.7)\t0\t0\t0\t3 (7)\t0,501\t\nETN\t6 (21.4)\t2 (25)\t1 (16.7)\t1 (100)\t10 (23.2)\t0,344\t\nADA\t16 (57.1)\t6 (75)\t5 (83.3)\t0\t27 (62.8)\t0,344\t\nGOL\t1 (3.6)\t0\t0\t0\t1 (2.3)\t0,771\t\nCZP\t2 (7.1)\t0\t0\t0\t2 (4.6)\t0,771\t\nPatients with prior TNF inhibitors\t11 (37.4)\t0\t4 (66.7)*\t0\t15 (34.9)\t0,028\t\nTime to active TB§ (years)—mean (SD)\t0.5 (0.1)\t0.9 (0.7)\t1.3 (1.1)\t1.7\t0.9 (0.5)\t0,981\t\nSite of TB\t\t\t\t\t\t0,678\t\nPulmonary\t17 (60.7)\t5 (62.5)\t3 (50)\t1 (100)\t26 (60.5)\t\t\nExtrapulmonary\t7 (25)\t3 (37.5)\t3 (50)\t0\t13 (30.2)\t\t\nPulmonary and extrapulmonary\t4 (14.3)\t0\t0\t0\t4 (9.3)\t\t\nAbbreviations: RA, rheumatoid arthritis; AS, ankylosing spondylitis; PsA, psoriatic arthritis; JIA, juvenile idiopathic arthritis; TNF, tumor necrosis factor; IFX, infliximab; ETN, etanercept; ADA, adalimumab; GOL, golimumab; CZP, certolizumab pegol; SD, standard deviation.\n\n§Time from onset of TNF inhibitors to development of tuberculosis\n\n* p significant\n\nThe overall incidence rate of TB in the study population was 734.7 cases per 100,000 exposed. In patient-years, this incidence corresponds to 2.73 per 1000 patient-years exposed (considering first exposure to an TNF inhibitor agent), while the cumulative incidence of TB in the overall study population was 2.86 per 1000 patient-years. Disaggregated by rheumatic disease, the cumulative incidence was 3 per 1000 patient-years for RA (9305 patient-years exposed), 2.61 per 1000 patient-years for AS (3054 patient-years exposed), 2.66 per 1000 patient-years for PsA (2249 patient-years exposed), and 2.8 per 1000 patient-years for JIA (353 patient-years exposed), with no significant differences across groups.\n\nFig 2 shows the number of TB cases among the different TNF inhibitors agents in relation to the total number of cases, with 0.7% of cases occurring with ADA, 1.5% with CZP, 0.2% with ETN, 0.3% with GOL, and 0.4% with IFX. The proportion of cases of TB was significantly higher among ADA users than among ETN users (p = 0.043, Fisher’s exact test). Fifteen patients had prior exposure to another TNF inhibitor agent. The mean time elapsed from initiation of TNF inhibitors therapy to onset of TB was 0.9 ± 0.5 years overall (i.e., for all anti-TNF agents).\n\n10.1371/journal.pone.0224963.g002Fig 2 Tuberculosis—Proportion related to first exposure to TNF inhibitors in percentage.\n*Positive association with tuberculosis. **Negative association with tuberculosis. p = 0.043, Fisher’s exact test.\n\nThe time tuberculosis-free drug use (Fig 3) differed significantly across different TNF inhibitors agents, with a higher likelihood of developing TB at first exposure with ADA versus ETN (p = 0.01) and a shorter time to onset of TB with CZP therapy than with any other TNF inhibitors agent (p < 0.05).\n\n10.1371/journal.pone.0224963.g003Fig 3 A: Survival curves for patients on tumor necrosis factor antagonists as a function of whether they developed tuberculosis during follow-up (log-rank p < 0.05). B: Probability of tuberculosis considering disease-free drug use in years (* p< 0.02; § p<0.01 for all TNF by log rank test).\n\nThe variables gender, age, duration of exposure, number of exposures, rheumatic disease and exposure medication were evaluated in the regression model. When performing multivariate Poisson regression analysis, the number of exposures remained associated with the development of TB (RR = 1.17, 95% CI 1.01 to 1.37, p = 0.043) indicating that for each exposure the incidence increased of TB increased by 17%. The first exposure medication also remained after Poisson regression significantly associated with the risk of developing tuberculosis, among medications, ADA presented a 3.11-fold higher risk of TB when compared to ETN (RR = 3.11, 95% CI 1.16 to 8.35, p = 0.024), in addition to this medication, the use of CZP increased the risk of tuberculosis in 7.47-fold compared to ETN (RR = 7.47, 95% CI 1.39–40.0, p = 0.019). The other medications were not significantly different from the risk of ETN (p> 0.5).\n\nThe subsample designed to evaluate LTBI treatment enrolled patients from the assisted therapy center of the outpatient rheumatology clinic of Hospital de Clínicas de Porto Alegre. A total of 268 patients in this subgroup were on TNF inhibitors therapy, among these patients, 232 (86%) underwent a tuberculin (PPD) skin test before initiation of TNF inhibitors therapy; 70 (30.2%) tested positive (wheal >5mm). Ninety-three patients underwent repeat tuberculin skin test, of whom 3 ultimately converted to a reactive result. Of the 70 patients with a reactive PPD test, 43 (23.3%) had RA, 20 (50%) had AS, and 7 (24.1%) had PsA; patients with AS were significantly more likely to test positive than patients with RA or PsA (p = 0.004). Seventy-four patients completed treatment for latent TB. There were 5 cases of TB diagnosed during TNF inhibitors therapy. Of these patients, 2 had completed treatment for LTBI, 2 had been nonreactive on PPD skin test, and 1 had not undergone PPD testing (a PPD test had been performed more than 2 years before initiation of TNF inhibitors therapy). The number of cases of tuberculosis was compared between groups with treatment for latent tuberculosis, non-reactive PPD and PPD not known without significant difference between the groups (p = 0.379, p = 0.700 respectively by Fischer’s exact test). There was no significant difference in cases of tuberculosis across these different rheumatic diseases.\n\nRegarding all-cause mortality, there were 250 deaths in the overall sample (4.3%). Among patients with TB, 2 (both with RA) had a TB-related death. As shown in Fig 4, the mean 10-year overall survival rate of these patients by the Kaplan–Meier method was 95.7%, with no statistically significant difference on the log rank test (p = 0.2) among all-cause deaths and deaths from tuberculosis.\n\n10.1371/journal.pone.0224963.g004Fig 4 Survival in relation patients with TNF inhibitors use with deaths due to general causes and deaths due to tuberculosis.\n(p = 0,20 by log rank test). 0 = deaths from all causes. 1 = deaths due to tuberculosis.\n\nDiscussion\nBrazil is a country with high TB incidence, particularly so in Rio Grande do Sul.[18] Our study found a TB incidence at first anti-TNF exposure of 2.73 per 1000 patient-years exposed. This rate is similar to that found in a previous Brazilian study of RA patients (2.86 per 1000 patient-years)[31] and in studies conducted in the first years of TNF inhibitors prescribing in countries such as Italy and Canada, which reported incidence rates of 2.46 per 1000 and 2.57 per 1000 patient-years exposed, respectively. [14,34] These countries had a much lower incidence of TB in the general population than Brazil. However, as the studies were conducted at the very dawn of TNF inhibitors therapy for the treatment of rheumatic diseases, protocols for LTBI screening and treatment were not yet well established, and the risk of reactivation of granulomatous disease was consequently higher, with a greater number of cases in their populations. The implementation of LTBI therapy revealed a 7-fold higher likelihood of TB reactivation in those exposed to TNF inhibitors therapy who did not follow guidelines for latent TB treatment, and a 78% reduction in the rate of active TB cases among those who did [29,35].\n\nIn this sense, our subgroup analysis of patients from the HCPA outpatient rheumatology clinic evaluated LTBI screening and treatment prior to the start of TNF inhibitors therapy. The tuberculin test is recommended in our country for latent tuberculosis evaluation, although it is known that Interferon Gamma Release Assay has better reproducibility and specificity than the tuberculin test, but not yet defined protocol of use in areas with higher incidence of tuberculosis in the general population. [36,37]. A tuberculin test was performed in 86% of patients prior to initiation of immunobiologics, and approximately 30% tested positive, a rate similar to those described elsewhere in the literature.[29,38,39] Comparison across different rheumatic diseases revealed a significantly higher rate of PPD positivity among individuals with AS compared to those with RA or PsA; this finding is consistent with the well-known lower responsiveness of RA patients to tuberculin.[40] However, despite this greater anergy to the Mantoux reaction and consequent risk of false-negative results, this group of patients with RA did not have a higher risk of active TB. Ultimately, there was no significant difference in the rate of incident TB infection among patients with different rheumatic diseases.\n\nAs in previous investigations, our study showed a high incidence of TB in patients with rheumatic diseases exposed to TNF inhibitors therapy: 735.29 per 100,000 exposed, approximately 18 times higher than that of the general population of the state of Rio Grande do Sul (39.5 per 100,000).[24]\n\nConsidering the different TNF inhibitors agents in use, a higher incidence of TB at first exposure was associated with ADA and CZP therapy, while the lowest incidence was found among patients on ETN. It bears stressing that the only statistically significant difference found on head-to-head comparison was between ADA and ETN, with a positive association of TB cases with ADA therapy and a negative association between ETN therapy and onset of TB, with a risk about 3 times greater of TB development when compared to ETN. This differential risk of TB development in relation to ETN therapy has been reported in previous studies.[7] The lower risk of TB in ETN users has been associated with its mechanism of action. ETN tends to bind to TNF in a less stable manner, which could be associated with less structural damage to granuloma, especially when compared to ADA and IFX.[41–43] We found a trend toward higher incidence of TB among patients on CZP. However, the difference was not statistically significant, probably due to the small number of patients on this drug; however, an interesting—and statistically significant—finding regarding CZP therapy was that it was associated with the highest likelihood of TB development in the first year of exposure compared to the other TNF inhibitors agents. In addition to presenting about 7 times greater risk of developing TB when compared to ETN. Some studies have noted a trend toward frequent TB cases with CZP therapy, but real-life studies of this drug are scarce due to its more recent introduction in relation to other TNF inhibitors agents. Nevertheless, data from clinical trials also support an association with a high number of TB cases.[44] To date, studies with BiobadaBrasil registry data have not shown any incident cases of TB in users of GOL and CZP, unlike in our cohort.[31,45]\n\nIn addition to the risk associated with the type of TNF inhibitor, another feature that can be assessed due to the design of our study was the increased risk of developing tuberculosis related to the number of exposures to TNF inhibitors, with a 17% increase in risk each time. although exposure time was not at higher risk as in previous studies [46].\n\nConsidering the different rheumatologic diseases evaluated, in our study we found no statistically significant difference between the incidence of tuberculosis in the different rheumatologic pathologies that were under study. Despite the increased risk of developing tuberculosis in rheumatoid arthritis patients compared to the general population, when comparing the risk of tuberculosis with the use of TNF inhibitors among inflammatory arthropathies, our study and previous studies found no significant difference. [24,47]\n\nRegarding the mean time to TB development, active granulomatous disease was detected already in the first year of exposure to TNF inhibitors therapy (mean time elapsed, 0.9 ± 0.5 years). This is corroborated by several studies which have suggested a higher risk of TB development in the first months of TNF inhibitors therapy, a phenomenon attributable to reactivation of latent disease.[46,48–50] In addition, considering the disease-free survival time, there was a significantly higher likelihood of developing TB over the years in patients exposed to ADA than in those exposed to ETN, as well as a significantly higher likelihood of TB onset in the first year of exposure among CZP users in relation to all other TNF inhibitors agents.\n\nAnalysis of TB sites revealed a predominance of pulmonary tuberculosis (n = 26, 60.4%), as in previous studies.[34,51] Extrapulmonary TB was found in 13 cases (30.2%), a rate lower than that reported in previous studies of national registry data.[31,50]\n\nIn this cohort of TNF inhibitors users, the overall survival rate was 95.7%. All-cause mortality was thus 4.3% over the study period. Among cases of incident TB, there were 2 deaths attributable to TB infection (4.6%). These findings are similar to previous reports of mortality data among TB patients receiving TNF inhibitors therapy. TB-attributable mortality rates are consistently lower than in the general population, probably due to the presence of HIV-coinfected patients in the general population.[52,53]\n\nThe present study is the first large investigation to evaluate the incidence of TB in patients receiving TNF inhibitors therapy for rheumatic diseases in the state of Rio Grande do Sul, and one of the first in Brazil to evaluate the incidence of TB in such a large population (n = 5853) with different rheumatic conditions over such a long follow-up period, using real-life, population-based data.\n\nSome limitations of this study are inherent to retrospective designs. As our data were retrieved from existing records, no information could be obtained on LTBI screening and treatment prior to initiation of TNF inhibitors therapy, except in our subgroup analysis. In addition, exposure to TNF inhibitors agents was assessed solely by the proxy indicators of drug dispensing and discontinuation. We did not analyze data on concomitant use of other disease-modifying antirheumatic drugs, for instance, nor did we assess whether TNF inhibitors therapy was used in combination with glucocorticoids, which could constitute an additional risk factor for development of TB in this population. In addition to these limitations in our study we were unable to evaluate possible host-related risk factors for TB such as drug or alcohol use, associated comorbidities, and socioeconomic conditions. We also had fewer prescriptions of infliximab and golimumab, and their negative association with tuberculosis should be interpreted with caution. Nevertheless, this was the largest retrospective cohort study of patients receiving TNF inhibitors therapy for rheumatic diseases conducted to date in Brazil. Its retrospective design notwithstanding, the fact that TB and mortality records were obtained from SINAN and from the SUS mortality information system respectively ensures that these data were reliable, because TB is a notifiable disease in Brazil and the associated mortality data were fed into the mortality information system from official death certificates. Besides that, our study included only patients using the public health system, not including patients with TNF inhibitors prescription through health insurance or private acquisition, and may be a selection bias, however, a Brazilian study showed in the sample that the portion of patients with health insurance represented only about 15% of immunobiological prescriptions.[45]\n\nConclusions\nThe use of TNF inhibitors therapy by patients with systemic rheumatic diseases significantly increases the number of incident cases of tuberculosis in this population, with an 18-time increased TB incidence in these patients when compared to the general population. Considering the different TNF inhibitors agents used by our sample, our study demonstrated that a greater number of cases of TB were associated with ADA than with ETN, Finally, we found that newer drugs such as CZP, which have had a much shorter postmarketing surveillance period for assessment of their potential for infectious adverse events, appear to be associated with a higher frequency of incident TB. This highlights the need for proper screening and treatment of latent tuberculosis, as well as the surveillance of new contacts with individuals with tuberculosis, annual screening among people with initial negative screening as recent recommendations, and discussion of the use of interferon gamma release quantification tests more broadly in this population.\n\nWe would like to thank all the individuals who participated in any way that this study has achieved its outcome. Special thanks to the teams of the state health department who worked to make all the data used in the research feasible.\n\n10.1371/journal.pone.0224963.r001Decision Letter 0 Abu-Shakra Mahmoud Academic Editor© 2019 Mahmoud Abu-Shakra2019Mahmoud Abu-ShakraThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Submission Version0\n2 Sep 2019\n\n\nPONE-D-19-21256\n\nA POPULATION-BASED STUDY OF TUBERCULOSIS INCIDENCE AMONG RHEUMATIC DISEASE PATIENTS UNDER ANTI-TNF TREATMENT\n\nPLOS ONE\n\nDear Mrs Sartori,\n\nThank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. 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You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)\n\nReviewer #1: General comment.\n\nThe paper confirm the increased risk of TB reactivation associated with anti-TNFs in and endemic TB Country. Apart from some English language imprecisions that should be corrected, the report is exhaustive and provides useful data for clinicians.\n\nSpecific comments.\n\nPage 3. Line 2. References 1 and 2 should be written in superscript.\n\nPage 4. First sentence. The Authors should correct this phrase by adding that RA itself increases the risk of TB (add the referencei.e. Yeh JJ, et al. PLoS One. 2014 Oct 22;9(10):e110922.\n\nPage 5. Line 3 and followings, The AA. should better address the notification system in Brazil. In some Countries also the suspected cases of TB should be notified. Is the same in Brazil, or are only definite TB diagnoses included? This issue is not negligible in terms of TB incidence calculation. Does the system include information from the patients' clinical chart?\n\nPage 5. Last paragraph. Apart from the cohort observed at the Hospital of Porto Alegre, did the patients undergo LTBI screening? The AA. should indicate this.\n\nPage 5. Last paragrafh, The AA. should indicate if LTBI diagnosis was done by TST only, or, at least in a percentage of patients, by Quantiferon, combined or not with TST.\n\nPage 10. Line 10. The AA. should insert a sentence on the better accuracy of Quantiferon TB Plus test for LTBI screening. (see. Baddley JW, et al. Clin Microbiol Infect. 2018 Jun;24 Suppl 2:S10-S20.\n\nPage 12. Discussion section. Last paragraph. Regarding the study limits, the AA, should add the absence of information on the host-related additional risk factors for TB, including drug or alcohol abuse, comorbidities, socio-economic conditons, etc.\n\nPage 13. Conclusions. The text is redundant and with some repetitions. I suggest to shorten this section by underlining the main results and emphasizing the need of accurate LTBI screening (adding Quantiferon-TB Plus test).\n\nReviewer #2: This was a cohort study of tuberculosis in rheumatic disease patients who have been treated with anti-TNF. It is useful to get estimates from other parts of the world, especially those with a higher incidence in the underlying population, to better understand what the risk is of this adverse outcome. The linkage of data across registers in Brazil was an excellent way to answer this study question. There are some basic methodological and epidemiological pieces of the study that were not described that need clarification.\n\nMajor comments\n\n- The TB cases were based on reporting data. Did these reports depend on TB being culture-verified? Could any TB be reported to the system or did it have to be reported through a lab that found a positive test?\n\n- The study design and patients does not describe person-time (start of follow-up, end of follow-up). Given that there are incidence rates and survival estimates in the paper, how person-time was calculated needs to be included.\n\n- Is this a new-user design? Are the exposures to TNFi all instances of the 1st use of TNFi? Or 1st use of the particular TNFi? This should be made more clear in the methods. In the results it states that the number of exposures was used as a variable in the model, so this indicates that people had previous exposures – of the same TNFi or another TNFi?\n\n- It is odd that incidence is “evaluated as a percentage” when incidence is a rate – the number of cases, per person per year. There is an aspect of time that is missing. It is hard to compare these results to those from other studies when percentages are given.\n\n- A summary of the follow-up time should be included in the results (see STROBE guidelines, if needed)\n\n- Are the survival curves adjusted for anything?\n\n- A table 1 in a cohort study usually has the exposure as the header of the table so that the reader can see how characteristics of the study differ by exposure. This is necessary for the reader to understand other factors, such as age and sex, which are potentially related to starting on a TNFi.\n\n- To have p values for every line of every table and every line in every graph is a lot of tests and does not seem necessary (for example, we can see clearly that the age is different across rheumatic diseases in Table 1, it’s not necessary to do a statistical test for it).\n\n- In Figure 2, it says there was a positive association, compared to what? These are unadjusted for age and sex, which is a major limitation. The reader is interested in rates (unadjusted are ok, sex- and age-standardized are even better) and then the adjusted rate ratios are helpful for comparing rates. Statistically comparing unadjusted rates is not very useful for inference.\n\n- There wasn’t much discussion about potential differences in TB risk in the different rheumatic diseases. This could be a limitation if all diseases are put together in this study.\n\nMinor comments\n\n- In the abstract results there is a typo, it should be “Forty-three cases”\n\n- In the discussion, one usually starts with a first sentence that summarizes the results. It would be a better start to the discussion if the first sentence (describing a recent study) is moved elsewhere and the results of the present study are summarized.\n\n**********\n\n6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.\n\nIf you choose “no”, your identity will remain anonymous but your review may still be made public.\n\nDo you want your identity to be public for this peer review? 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Please note that Supporting Information files do not need this step.\n\n10.1371/journal.pone.0224963.r002Author response to Decision Letter 0 Submission Version1\n17 Oct 2019\n\n\nDear Publishers,\n\nWe respectfully welcome and appreciate the valuable contributions of the reviewers, with their suggestions and correction requests that certainly qualify and give greater consistency to our study.\n\nThe following describes the treatment given to each of the changes proposed by the reviewers for resubmission of the manuscript PONE-D-19-21256 (A POPULATION-BASED STUDY OF TUBERCULOSIS INCIDENCE AMONG RHEUMATIC DISEASE PATIENTS UNDER ANTI-TNF TREATMENT).\n\nReviewer 1:\n\nIntroduction:\n\n#Page 3. Line 2. References 1 and 2 should be written in superscript.\n\nThank you for your observation, the correction in the body of the text (pages 3, lines 1 and 2).\n\n#Page 4. First sentence. The Authors should correct this phrase by adding that RA itself increases the risk of TB (add the referencei.e. Yeh JJ, et al. PLoS One. 2014 Oct\n\nWe thank and adjust information about the risks of tuberculosis in this patient population, adding reference suggested by relevance. (page 4, line 1 and 2).\n\nMethods:\n\n#Page 5. Line 3 and followings, The AA. should better address the notification system in Brazil. In some Countries also the suspected cases of TB should be notified. Is the same in Brazil, or are only definite TB diagnoses included? This issue is not negligible in terms of TB incidence calculation. Does the system include information from the patients' clinical chart?\n\nThis information has been added to the methods section to clarify the definition of tuberculosis cases in the Brazilian reporting system.\n\n“This system includes all patients with a confirmed diagnosis of tuberculosis, as well as the clinical presentation, treatment regimen and final follow-up outcome.” (Page 5, line 8)\n\n#Page 5. Last paragraph. Apart from the cohort observed at the Hospital of Porto Alegre, did the patients undergo LTBI screening? The AA. should indicate this.\n\n\nThe request has been fulfilled and included in an attempt to provide clarity.\n\n“Screening for latent tuberculosis prior to the initiation of TNF inhibitors is recommended for all patients who are candidates for therapy and drug release is required.” (page 5 – last paragraph)\n\n#Page 5. Last paragrafh, The AA. should indicate if LTBI diagnosis was done by TST only, or, at least in a percentage of patients, by Quantiferon, combined or not with TST.\n\n\nThank you for your observation, the correction in the body of the text.\n\n“positive tuberculin skin test or suggestive chest X-ray findings without history of previous tuberculosis treatment” (page 5 – last paragraph).\n\nDiscussion:\n\n#Page 10. Line 10. The AA. should insert a sentence on the better accuracy of Quantiferon TB Plus test for LTBI screening. (see. Baddley JW, et al. Clin Microbiol Infect. 2018 Jun;24 Suppl 2:S10-S20.\n\n\nRelevant information about the use of another method for identifying latent tuberculosis was added to the discussion.\n\n“The tuberculin test is recommended in our country for latent tuberculosis evaluation, although it is known that Interferon Gamma Release Assay has better reproducibility and specificity than the tuberculin test, but not yet defined protocol of use in areas with higher incidence of tuberculosis in the general population” (page 10 – last paragraph).\n\n#Page 12. Discussion section. Last paragraph. Regarding the study limits, the AA, should add the absence of information on the host-related additional risk factors for TB, including drug or alcohol abuse, comorbidities, socio-economic conditons, etc.\n\nInformation was mentioned in the discussion as limitations of our study.\n\n“In addition to these limitations in our study we were unable to evaluate possible host-related risk factors for TB such as drug or alcohol use, associated comorbidities, and socioeconomic conditions” (page 12 – last paragraph).\n\nConclusion:\n\n#Page 13. Conclusions. The text is redundant and with some repetitions. I suggest to shorten this section by underlining the main results and emphasizing the need of accurate LTBI screening (adding Quantiferon-TB Plus test).\n\nThe findings have been rewritten to meet the proposed objectives. (page 14 - last paragraph).\n\nReviewer 2:\n\nMajor comments\n\nMethods:\n\n# The TB cases were based on reporting data. Did these reports depend on TB being culture-verified? Could any TB be reported to the system or did it have to be reported through a lab that found a positive test?\n\nThis information has been added to the methods section to clarify the definition of tuberculosis cases in the Brazilian reporting system.\n\n“Positive cases being defined by patients with clinical diagnosis associated with bacteriological diagnosis.” (page5, line 10)\n\n# The study design and patients does not describe person-time (start of follow-up, end of follow-up). Given that there are incidence rates and survival estimates in the paper, how person-time was calculated needs to be included.\n\nThis information was added to the methods in order to provide more clarity in the definitions used.\n\n“Person- years were calculated from the first day of TNF inhibitor therapy to the date of tuberculosis infection, or death or discontinuation of TNF inhibitor use” (page 6, line 3)\n\n# Is this a new-user design? Are the exposures to TNFi all instances of the 1st use of TNFi? Or 1st use of the particular TNFi? This should be made more clear in the methods. In the results it states that the number of exposures was used as a variable in the model, so this indicates that people had previous exposures – of the same TNFi or another TNFi?\n\n\nThis information was added to the methods in order to provide more clarity in the definitions used. For TNF inhibitor exposure, this is a new-user design. \n\n“For incidence density analysis, we used the time of use related to the first exposure for calculation of incidence related to the first exposure, also the total time of use of any TNF inhibitor during follow-up to define cumulative incidence density over the course of the study.” (page 6, second paragraph)\n\nResults:\n\n# It is odd that incidence is “evaluated as a percentage” when incidence is a rate – the number of cases, per person per year. There is an aspect of time that is missing. It is hard to compare these results to those from other studies when percentages are given.\n\nThe incidence density is presented in person time for better comparison with studies as mentioned (page 8 - second paragraph).\n\nAs noted, we corrected information referring to figure 2 in the body of the text and in the figure itself, in which we had no intention of presenting incidence rates and density, but only presentation in the number of cases in proportion.\n\n“Figure 2 shows the number of TB cases among the different TNF inhibitors agents in relation to the total number of cases, with 0.7% of cases occurring with ADA, 1.5% with CZP, 0.2% with ETN, 0.3% with GOL, and 0.4% with IFX. The proportion of cases of TB was significantly higher among ADA users than among ETN users (p = 0.043, Fisher’s exact test)” (page 8 – third paragraph).\n\n#A summary of the follow-up time should be included in the results (see STROBE guidelines, if needed)\n\nAdjustment was performed in the body of the text as suggested and oriented guidelines STROBE.\n\n“The average duration of follow-up, ie exposure to TNF inhibitors therapy was 2.58 ± 1.95 years”. (page 7 – sixth paragraph).\n\n# Are the survival curves adjusted for anything?\n\n\nAs described in the body text adjustment was performed.\n\n“The variables gender, age, duration of exposure, number of exposures, rheumatic disease and exposure medication were evaluated in the regression model”. (page 8 – last paragraph).\n\n# A table 1 in a cohort study usually has the exposure as the header of the table so that the reader can see how characteristics of the study differ by exposure. This is necessary for the reader to understand other factors, such as age and sex, which are potentially related to starting on a TNFi.\n\n\"Thank you for your relevant comment on table 1. In the submitted version we tried to follow STROBE´s recommendation to give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders, but we are open to modify it, if necessary. In this population-based study, our primary goal was to estimate the incidence of tuberculosis in patients receiving TNF inhibitors (TNFi) therapy for rheumatic diseases. Considering that all participants were exposed to TNFi, we thought it would be more informative to report on how each disease subgroup could differ, as treatment protocols are unique and TNFi exposure could vary significantly among rheumatic diseases. As the number of TNFi exposures is expected to be a confounding factor, we included this variable in regression model and, ultimately, found it as an independent predictor of TB development, as reported in the results section. Nonetheless, if this is not the best way to present our participants, we would be pleased to change it accordingly.\" \n\n# To have p values for every line of every table and every line in every graph is a lot of tests and does not seem necessary (for example, we can see clearly that the age is different across rheumatic diseases in Table 1, it’s not necessary to do a statistical test for it).\n\nThanks for the comment, we are grateful for the observation, however, we understand that keeping the value of p shows the differences more clearly. Despite our understanding, if not necessary, we agree to their withdrawal.\n\n# In Figure 2, it says there was a positive association, compared to what? These are unadjusted for age and sex, which is a major limitation. The reader is interested in rates (unadjusted are ok, sex- and age-standardized are even better) and then the adjusted rate ratios are helpful for comparing rates. Statistically comparing unadjusted rates is not very useful for inference.\n\nA) The comparison was made between users of adalimumab and etanercept.\n\n“The proportion of cases of TB was significantly higher among ADA users than among ETN users (p = 0.043, Fisher’s exact test)” (page 8 – third paragraph).\n\nB) We did not perform adjustment in this case because it is not a rate but only the demonstration of the number of tuberculosis cases by each TNF inhibitor. number of exposures, exposure time, type of medication and rheumatologic disease taken to the regression model.\n\n#There wasn’t much discussion about potential differences in TB risk in the different rheumatic diseases. This could be a limitation if all diseases are put together in this study.\n\nAs suggested considering the design of our study we included assessment of the incidence density of tuberculosis due to rheumatologic disease separately.\n\n“Disaggregated by rheumatic disease, the cumulative incidence was 3 per 1000 patient-years for RA (9305 patient-years exposed), 2.61 per 1000 patient-years for AS (3054 patient-years exposed), 2.66 per 1000 patient-years for PsA (2249 patient-years exposed), and 2.8 per 1000 patient-years for JIA (353 patient-years exposed), with no significant differences across groups.” (page 8 – second paragraph).\n\nMinor comments\n\n\n# In the abstract results there is a typo, it should be “Forty-three cases”\n\nBug pointed out has been fixed. (abstract - page 2)\n\n# In the discussion, one usually starts with a first sentence that summarizes the results. It would be a better start to the discussion if the first sentence (describing a recent study) is moved elsewhere and the results of the present study are summarized.\n\nThe initial discussion session was rewritten and adjusted as suggested for a better presentation of our study findings.\n\n“Brazil is a country with high TB incidence, particularly so in Rio Grande do Sul.18 Our study found a TB incidence at first anti-TNF exposure of 2.73 per 1000 patient-years exposed. This rate is similar to that found in a previous Brazilian study of RA patients (2.86 per 1000 patient-years)31 and in studies conducted in the first years of TNF inhibitors prescribing in countries such as Italy and Canada, which reported incidence rates of 2.46 per 1000 and 2.57 per 1000 patient-years exposed, respectively.” (page 10 – second paragraph)\n\nWe are at your disposal for any necessary clarifications.\n\nSincerely,\n\nThe authors\n\nAttachment Submitted filename: Response to Reviewers.docx\n\nClick here for additional data file.\n\n 10.1371/journal.pone.0224963.r003Decision Letter 1 Abu-Shakra Mahmoud Academic Editor© 2019 Mahmoud Abu-Shakra2019Mahmoud Abu-ShakraThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Submission Version1\n28 Oct 2019\n\n\nA POPULATION-BASED STUDY OF TUBERCULOSIS INCIDENCE AMONG RHEUMATIC DISEASE PATIENTS UNDER ANTI-TNF TREATMENT\n\nPONE-D-19-21256R1\n\nDear Dr. Sartori,\n\nWe are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.\n\nWithin one week, you will receive an e-mail containing information on the amendments required prior to publication. 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(Please upload your review as an attachment if it exceeds 20,000 characters)\n\nReviewer #2: (No Response)\n\n**********\n\n7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.\n\nIf you choose “no”, your identity will remain anonymous but your review may still be made public.\n\nDo you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.\n\nReviewer #2: Yes: Elizabeth Arkema\n\n10.1371/journal.pone.0224963.r004Acceptance letter Abu-Shakra Mahmoud Academic Editor© 2019 Mahmoud Abu-Shakra2019Mahmoud Abu-ShakraThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\n12 Nov 2019\n\n\nPONE-D-19-21256R1 \n\nA population-based study of tuberculosis incidence among rheumatic disease patients under anti-TNF treatment \n\nDear Dr. Sartori:\n\nI am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. \n\nIf your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.\n\nFor any other questions or concerns, please email plosone@plos.org. \n\nThank you for submitting your work to PLOS ONE.\n\nWith kind regards,\n\nPLOS ONE Editorial Office Staff\n\non behalf of\n\nDr. Mahmoud Abu-Shakra \n\nAcademic Editor\n\nPLOS ONE\n==== Refs\nReferences\n1 Lee SK , Kim SY , Kim EY , Jung JY , Park MS , Kim YS , et al\nMycobacterial infections in patients treated with tumor necrosis factor antagonists in South Korea . 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Global Tuberculosis Report 2017. World Health Organization. 2017. 1–262 p.\n17 Ministério da Saúde. Secretaria de Vigilancia em Saúde. Departamento de Vigilancia Epidemiologica . Manual de Recomendações para o Controle da Tuberculose no Brasil . 2011 ;(61 ).\n18 BRASIL M da SS de V em S . Implantação do Plano Nacional pelo Fim da Tuberculose como Problema de Saúde Pública no Brasil: primeiros passos rumo ao alcance das metas . Bol Epidemiológico 11 [Internet]. 2018 ;49 (11 ):18 Available from: http://portalarquivos2.saude.gov.br/images/pdf/2018/marco/26/2018-009.pdf\n19 Yeh JJ , Wang YC , Sung FC , Kao CH . Rheumatoid arthritis increases the risk of nontuberculosis mycobacterial disease and active pulmonary tuberculosis . PLoS One . 2014 ;9 (10 )\n20 Askling J , Fored CM , Brandt L , Baecklund E , Bertilsson L , Cöster L , et al\nRisk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden . 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J Bras Pneumol . 2009 ;35 (10 ):1018 –48 .19918635 \n27 Maria L , Cruz BA , Brenol CV , Pereira IA , Rezende-fronza LS , Bertolo MB , et al\nReumatologia para o tratamento da artrite reumatoide . Rev Bras Reumatol [Internet]. 2012 ;52 (2 ):152 –74 . Available from: http://www.ncbi.nlm.nih.gov/pubmed/2246040722460407 \n28 Cantini F , Nannini C , Niccoli L , Iannone F , Delogu G , Garlaschi G , et al\nGuidance for the management of patients with latent tuberculosis infection requiring biologic therapy in rheumatology and dermatology clinical practice . Autoimmun Rev [Internet]. 2015 ;14 (6 ):503 –9 . Available from: 10.1016/j.autrev.2015.01.011 \n25617816 \n29 Gomez-Reino JJ , Carmona L , Angel Descalzo M . Risk of tuberculosis in patients treated with tumor necrosis factor antagonists due to incomplete prevention of reactivation of latent infection . Arthritis Rheum . 2007 ;57 (5 ):756 –61 . 10.1002/art.22768 \n17530674 \n30 Pérez-Sola MJ , Torre-Cisneros J , Pérez-Zafrilla B , Carmona L , Descalzo MA , Gómez-Reino JJ . Infections in patients treated with tumor necrosis factor antagonists: incidence, etiology and mortality in the BIOBADASER registry . Med Clin (Barc) . 2011 ;137 (12 ):533 –40 .21514606 \n31 Yonekura CL , Oliveira RDR , Titton DC , Ranza R , Ranzolin A , Hayata AL , et al\nIncidência de tuberculose em pacientes com artrite reumatoide em uso de bloqueadores do TNF no Brasil: dados do Registro Brasileiro de Monitoração de Terapias Biológicas BiobadaBrasil . Rev Bras Reumatol [Internet]. 2017 ;57 (S 2 ):477 –83 . Available from: 10.1016/j.rbr.2017.05.003 \n32 Dixon WG , Symmons DPM , Lunt M , Watson KD , Hyrich KL , Silman AJ . Serious infection following anti–tumor necrosis factor α therapy in patients with rheumatoid arthritis: Lessons from interpreting data from observational studies . 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Arthritis Rheum . 2005 ;52 (6 ):1766 –72 . 10.1002/art.21043 \n15934089 \n36 Baddley JW , Cantini F , Goletti D , Gómez-Reino JJ , Mylonakis E , San-Juan R , et al\nESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [I]: anti-tumor necrosis factor-α agents) . Clin Microbiol Infect . 2018 ;24 :S10 –20 . 10.1016/j.cmi.2017.12.025 \n29459143 \n37 Siqueira RC . The potential of the IGRA (Interferon Gamma Release Assay) test for the diagnosis of ocular . 2019 ;78 (3 ):202 –9 .\n38 Bonfiglioli KR , Ribeiro ACM , Moraes JCB , Saad CGS , Souza FHC , Calich AL , et al\nLTBI screening in rheumatoid arthritis patients prior to anti-TNF treatment in an endemic area . Int J Tuberc Lung Dis . 2014 ;18 (8 ):905 –11 . 10.5588/ijtld.13.0755 \n25199003 \n39 Garziera G , Morsch ALB , Otesbelgue F , Staub FL , Palominos PE , Brenol CV , et al\nLatent tuberculosis infection and tuberculosis in patients with rheumatic diseases treated with anti-tumor necrosis factor agents . Clin Rheumatol . 2017 ;36 (8 ):1891 –6 . 10.1007/s10067-017-3714-6 \n28589321 \n40 Marques CDL , Duarte ÂLBP , de Lorena VMB , de Souza JR , Souza W , de M Gomes Y , et al\nResposta atenuada ao PPD no diagnóstico de infecção tuberculosa latente em pacientes com artrite reumatoide . Rev Bras Reumatol [Internet]. 2009 ;49 (2 ). Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0482-50042009000200004&lng=pt&nrm=iso&tlng=pt\n41 Ehlers S . Role of tumour necrosis factor (TNF) in host defence against tuberculosis: Implications for immunotherapies targeting TNF . Ann Rheum Dis . 2003 ;62 (SUPPL. 2 ):37 –42 .12480667 \n42 Gardam MA , Keystone EC , Menzies R , Manners S , Skamene E , Long R , et al\nAnti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management . Lancet Infect Dis [Internet]. 2003 ;3 (3 ):148 –55 . Available from: http://linkinghub.elsevier.com/retrieve/pii/S1473309903005450\n12614731 \n43 Wallis RS , Broder MS , Wong JY , Hanson ME , Beenhouwer DO . Granulomatous Infectious Diseases Associated with Tumor Necrosis Factor Antagonists . Clin Infect Dis [Internet]. 2004 ;38 (9 ):1261 –5 . Available from: https://academic.oup.com/cid/article-lookup/doi/10.1086/383317\n15127338 \n44 Lahiri M , Dixon WG . Risk of infection with biologic antirheumatic therapies in patients with rheumatoid arthritis . Best Pract Res Clin Rheumatol [Internet]. 2015 ;29 (2 ):290 –305 . Available from: 10.1016/j.berh.2015.05.009 \n26362745 \n45 Titton DC , Silveira IG , Louzada-junior P , Hayata AL , Carvalho HMS , Ranza R , et al\nRegistro Brasileiro de Biológicos : preliminares do BiobadaBrasil . Rev Bras Reum . 2011 ;51 (2 ):145 –60 .\n46 Kisacik B , Pamuk ON , Onat AM , Erer SB , Hatemi G , Ozguler Y , et al\nCharacteristics predicting tuberculosis risk under tumor necrosis factor-α inhibitors: Report from a large multicenter cohort with high background prevalence . J Rheumatol . 2016 ;43 (3 ):524 –9 . 10.3899/jrheum.150177 \n26773107 \n47 Nisar MK , Rafiq A , Östör AJK . Biologic therapy for inflammatory arthritis and latent tuberculosis: real world experience from a high prevalence area in the United Kingdom . Clin Rheumatol [Internet]. 2015 ;34 (12 ):2141 –5 . Available from: http://link.springer.com/10.1007/s10067-015-3099-3\n26497501 \n48 Keane J . TNF-blocking agents and tuberculosis: New drugs illuminate an old topic . Rheumatology . 2005 ;44 (6 ):714 –20 . 10.1093/rheumatology/keh567 \n15741198 \n49 Sichletidis L , Settas L , Spyratos D , Chloros D , Patakas D . Tuberculosis in patients receiving anti-TNF agents despite chemoprophylaxis . Int J Tuberc Lung Dis . 2006 ;10 (10 ):1127 –32 . 17044206 \n50 Nobre CA , Callado MRM , Lima JRC , Gomes KWP . Tuberculosis infection in rheumatic patients with infliximab therapy: Experience with 157 patients . Rheumatol Int . 2012 ;32 (9 ):2769 –75 . 10.1007/s00296-011-2017-5 \n21822912 \n51 Dixon WG , Hyrich KL , Watson KD , Lunt M , Galloway J , Ustianowski A , et al\nDrug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: Results from the British Society for Rheumatology Biologics Register (BSRBR) . Ann Rheum Dis . 2010 ;69 (3 ):522 –8 . 10.1136/ard.2009.118935 \n19854715 \n52 Denis B , Lefort A , Flipo RM , Tubach F , Lemann M , Ravaud P , et al\nLong-term follow-up of patients with tuberculosis as a complication of tumour necrosis factor (TNF)-a antagonist therapy: safe re-initiation of TNF-a blockers after appropriate anti-tuberculous treatment . 2007 ;183 –6 .\n53 Rossato D. , Diego S. , De Tarso P. , and Dalcin R. , “Factors Associated with Mortality in Hospitalized Patients with Newly Diagnosed Tuberculosis ,” pp. 33 –41 , 2010 \n10.1007/s00408-009-9224-9 \n20131479\n\n",
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"issn_linking": "1932-6203",
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"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001938:Brazil; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D055985:Latent Tuberculosis; D008297:Male; D008403:Mass Screening; D008875:Middle Aged; D009169:Mycobacterium tuberculosis; D012189:Retrospective Studies; D012216:Rheumatic Diseases; D014374:Tuberculin Test; D014376:Tuberculosis; D014409:Tumor Necrosis Factor-alpha",
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"title": "A population-based study of tuberculosis incidence among rheumatic disease patients under anti-TNF treatment.",
"title_normalized": "a population based study of tuberculosis incidence among rheumatic disease patients under anti tnf treatment"
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"abstract": "BACKGROUND Angioedema is characterized by localized swelling of subcutaneous or submucosal tissue resulting from fluid extravasation due to the loss of vascular integrity. It most commonly occurs with exposure to allergens and certain medications, namely nonsteroidal anti-inflammatory agents and angiotensin-converting enzyme inhibitors. There have been few incidences of angioedema following the administration of tissue plasminogen activator. CASE REPORT We describe an 84-year-old woman with a history of hypertension managed with lisinopril who presented with an acute onset of right-sided hemiparesis, slurred speech, and right-sided hemianopsia. Urgent computed tomography of the head revealed subacute infarct of the left pons without hemorrhage. Intravenous alteplase was administered and within 30 min our patient developed severe orolingual edema requiring emergent intubation. Subsequent imaging revealed acute to subacute infarct of the left occipital lobe in the posterior cerebral artery region, consistent with her initial presenting symptoms. CONCLUSIONS Angioedema induced by tissue plasminogen activator occurs in approximately 1-5% of patients receiving thrombolysis for ischemic stroke and can be life-threatening. The risk is increased in patients taking angiotensin-converting enzyme inhibitors, in patients with ischemic strokes of the middle cerebral artery, and in the presence of C1 esterase inhibitor deficiency. This phenomenon is usually self-limited and treatment is supportive, although evidence supports the use of antihistamines, steroids, epinephrine, and complement inhibitors. Due to the severity of angioedema and the potential progression to airway compromise, it is crucial to closely monitor patients receiving tissue plasminogen activator.",
"affiliations": "Department of Medicine, Arnot Ogden Medical Center, Elmira, NY, USA.;Department of Medicine, Arnot Ogden Medical Center, Elmira, NY, USA.;Department of Medicine, Arnot Ogden Medical Center, Elmira, NY, USA.;Department of Medicine, Arnot Ogden Medical Center, Elmira, NY, USA.",
"authors": "Duymun|Shahnaz|S|;Reddy|Vidhya|V|;Bentley|Emma|E|;Bose-Kolanu|Anjali|A|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
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"doi": "10.12659/AJCR.927137",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n33441533\n10.12659/AJCR.927137\n927137\nArticles\nTissue Plasminogen Activator-Induced Angioedema Involving a Posterior Cerebral Artery Infarct: A Case Presentation\nDuymun Shahnaz EF Reddy Vidhya EF Bentley Emma EF Bose-Kolanu Anjali E Department of Medicine, Arnot Ogden Medical Center, Elmira, NY, U.S.A.\nCorresponding Author: Shahnaz Duymun, e-mail: sduymun23@gmail.comAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2021 \n14 1 2021 \n22 e927137-1 e927137-5\n29 6 2020 30 10 2020 21 11 2020 © Am J Case Rep, 20212021This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 84-year-old\n\nFinal Diagnosis: Angioedema\n\nSymptoms: Angioedema\n\nMedication:—\n\nClinical Procedure: —\n\nSpecialty: Critical Care Medicine • General and Internal Medicine\n\nObjective:\nUnusual clinical course\n\nBackground:\nAngioedema is characterized by localized swelling of subcutaneous or submucosal tissue resulting from fluid extravasation due to the loss of vascular integrity. It most commonly occurs with exposure to allergens and certain medications, namely nonsteroidal anti-inflammatory agents and angiotensin-converting enzyme inhibitors. There have been few incidences of angioedema following the administration of tissue plasminogen activator.\n\nCase Report:\nWe describe an 84-year-old woman with a history of hypertension managed with lisinopril who presented with an acute onset of right-sided hemiparesis, slurred speech, and right-sided hemianopsia. Urgent computed tomography of the head revealed subacute infarct of the left pons without hemorrhage. Intravenous alteplase was administered and within 30 min our patient developed severe orolingual edema requiring emergent intubation. Subsequent imaging revealed acute to subacute infarct of the left occipital lobe in the posterior cerebral artery region, consistent with her initial presenting symptoms.\n\nConclusions:\nAngioedema induced by tissue plasminogen activator occurs in approximately 1–5% of patients receiving thrombolysis for ischemic stroke and can be life-threatening. The risk is increased in patients taking angiotensin-converting enzyme inhibitors, in patients with ischemic strokes of the middle cerebral artery, and in the presence of C1 esterase inhibitor deficiency. This phenomenon is usually self-limited and treatment is supportive, although evidence supports the use of antihistamines, steroids, epinephrine, and complement inhibitors. Due to the severity of angioedema and the potential progression to airway compromise, it is crucial to closely monitor patients receiving tissue plasminogen activator.\n\nMeSH Keywords:\nAngioedemaDrug-Related Side Effects and Adverse ReactionsInfarction, Posterior Cerebral ArteryNeurologyThrombolytic TherapyTissue Plasminogen Activator\n==== Body\nBackground\nIt is becoming increasingly common to use tissue plasminogen activator (tPA) in the treatment of acute ischemic stroke, pulmonary embolism, and ST-elevation myocardial infarctions. Since tPA was approved in 1996, its utilization has illustrated marked improvement in stroke recovery and decreased hospital stay [1]. Major concerns with the administration of tPA are intracranial hemorrhage, edema, and possible brain herniation; however, other severe reactions such as hemopericardium, cardiac tamponade, angioedema, and anaphylaxis should not be forgotten.\n\nAngioedema induced by tPA is an infrequent, but potentially fatal outcome of thrombolysis. The mechanisms behind such reactions are presumed to involve mast cells, bradykinin release, histamine, and the complement cascade. It primarily occurs with infarction of the middle cerebral artery and is more likely to occur in patients with concomitant use of angiotensin-converting enzyme inhibitors and in carriers of C1 esterase inhibitor deficiency. It is mostly self-limited and treatment is usually supportive. Some cases may require antihistamines, steroids, and epinephrine, with refractory cases needing complement inhibitors and severe cases leading to intubation or cricothyroidotomy. In this report, we present a case of an elderly woman who developed angioedema following tPA administration for treatment of a posterior cerebral artery stroke, which has only been documented in 2 other cases, as per our literature review.\n\nCase Report\nAn 84-year-old woman presented to the Emergency Department for right-sided weakness, slurred speech, and right-sided hemianopsia after having collapsed onto the floor. She had a history of hypertension, which managed with lisinopril; chronic obstructive pulmonary disease; and lung cancer with subsequent left upper lobectomy. Her history also included atrial fibrillation, but she had not been on anticoagulation therapy for approximately 3 months due to gastrointestinal bleed. The patient did not experience loss of consciousness, convulsions, or any prodromal symptoms. Upon arrival to the Emergency Department, she was found to have 2/5 strength of her right-sided extremities and right-sided neglect. An urgent computed tomography (CT) scan of the head was performed and revealed a subacute infarct of the left pons with no acute hemorrhage (Figure 1). A CT angiography was obtained and confirmed these findings. She was given 0.9 mg/kg alteplase intravenously, 10% as a bolus followed by an intravenous infusion of the remaining dose. Within 30 min from the onset of infusion, she developed orolingual angioedema consisting of tongue swelling and bilateral lip swelling requiring emergent intubation for airway protection.\n\nThe infusion was stopped prematurely, and the patient was given intravenous methylprednisolone 125 mg, diphenhydramine 50 mg, and famotidine 20 mg to help treat her angioedema. The neurology and critical care teams aided in the management of her care. There was marked improvement of her angioedema within 24 h, and she was subsequently extubated the following morning. Repeat CT of the head revealed an acute to subacute infarct with encephalomalacia of the left occipital lobe, which was believed to be the cause of her initial deficits (Figure 2). Echocardiography did not reveal an atrial shunt or evidence of thrombi. Subsequent magnetic resonance imaging illustrated infarct involving the posterior cerebral artery circulation without hemorrhagic conversion (Figure 3). She was started on full-dose aspirin as well as fluoxetine 20 mg daily for stroke recovery. She began to work with physical therapy and had some improvement in her motor skills as well as her vision.\n\nDuring her hospitalization, she experienced persistent nausea and vomiting, ultimately controlled with promethazine. Her anticoagulation was restarted 10 days after the onset of her stroke. Her strength did not improve as she or her family had hoped. Family discussions were held, and it was decided the best course of action would be to receive hospice care at home. She was ultimately discharged to home with hospice on morphine sulfate, lorazepam, fluoxetine, and promethazine. She died a week later.\n\nDiscussion\nTissue plasminogen activator is commonly used to treat ischemic stroke, myocardial infarction, and pulmonary embolism. It is generally well tolerated and can be life-saving; however, there are concerning adverse reactions to be mindful of, one of which is angioedema. Angioedema induced by tPA is an uncommon but potentially fatal occurrence. It is typically observed within 1 h of completing the tPA infusion [2]. It is postulated to occur in approximately 1–5% of patients receiving thrombolysis after an ischemic stroke, and it usually presents with hemifacial edema contralateral to the infarct zone [3]. An extensive study done by Myslimi et al. [4] evaluated 923 patients who received thrombolysis for stroke treatment. Of these patients, only 20 developed angioedema. A retrospective chart review performed by Sczepanski and Bozyk [5] reviewed 147 cases, with only 4 developing edema.\n\nThe mechanism behind this phenomenon is still unclear; however, several hypotheses have been proposed to explain this occurrence. One hypothesis suggests a bradykinin-mediated pathway, in which tPA hydrolyzes plasminogen into plasmin, which in turn activates the kinin pathway augmenting the production of bradykinin [5]. Bradykinin is a potent pro-inflammatory and pro-edematous peptide that increases vascular permeability and vasodilation, leading to angioedema. In addition, tPA can augment histamine, causing vasodilation [3]. Other hypotheses propose that both tPA and plasmin activate the complement pathway, increasing complement levels and in turn activating mast cells, histamine, and basophil degranulation, which contribute to angioedema [5,6]. An additional hypothesis focuses on a mutation of the plasminogen gene, drawing on the remarkable clinical similarity between tPA-induced orolingual angioedema and a recently described new subtype of hereditary angioedema with normal C1 inhibitor. This subtype is caused by a highly specific missense mutation of the plasminogen gene and the resulting presence of the aberrant plasminogen protein is hypothesized to lead to angioedema [7].\n\nThe risk of developing angioedema following thrombolytic administration is amplified in patients who take angiotensin-converting enzyme (ACE) inhibitors because these drugs increase the concentration of circulating bradykinin [8]. Additionally, neurokinins such as substance P are increased with ACE inhibition and are mediators in inflammation and angioedema [9]. The combination of tPA-related increase in bradykinin, ACE inhibitor-mediated decrease in bradykinin metabolism, and ACE inhibitor-related increase in neurokinin levels amplify the risk of angioedema. For instance, in the study by Myslimi et al. [4], among the 20 patients who developed angioedema after thrombolysis, 45% concomitantly took ACE inhibitors.\n\nLesion-mapping studies have been performed that concluded infarctions of the middle cerebral artery, especially the branch that supplies the right insular cortex, have the highest propensity of causing angioedema. Ninety percent of patients who developed angioedema in the study completed by Myslimi et al. [4] and 75% of those in the study done by Sczepanski and Bozyk [5] had infarcts of the middle cerebral artery. The lesion-mapping study by Frohlich et al. [3] illustrated an association with right-sided insular infarcts and the development on tPA-related angioedema. The authors postulated that insular infarcts augment sympathetic hyperactivity due to impaired autonomic function, which in turn intensifies proinflammatory cytokine production and vascular permeability thus causing orolingual edema [3]. It is also believed that the tissue damage itself could be a trigger for angioedema via the generation of bradykinin, which increases inflammation and edema [4,8]. Our patient, however, had a posterior cerebral artery infarct, which is not consistent with this hypothesis, making our case unusual. In the retrospective institutional study done by Sczepanski and Bozyk [5], only 1 out of 147 patients had an infarct involving the posterior cerebral artery, and only 1 out of 42 patients in the analysis by Hurford et al. [10] had involvement of the posterior circulation. None were detected in the lesion-mapping study by Frohlich et al. [3] or in the meta-analysis by Yayan [1], and no alternate explanation could be found to support angioedema following tPA treatment of a posterior circulation stroke. The Table 1 summarizes findings from multiple studies including stroke location, development of angioedema after thrombolysis, and concomitant ACE inhibition [11–13].\n\nAngioedema mediated by tPA is a rare and potentially life-threatening occurrence. At the first signs of tPA-induced angioedema, hospital staff should be aware of the commonly used interventions and medications. It is critical to discontinue the tPA infusion when signs of angioedema occur. The 2018 guidelines for the management of tPA-induced angioedema recommend the administration of intravenous methylprednisolone 125 mg, oral diphenhydramine 50 mg, and oral ranitidine 50 mg or famotidine 20 mg with a class IIb recommendation and level C expert opinion [14,15]. If symptoms persist despite these measures, epinephrine can be administered; however, it should be administered cautiously because it may suddenly increase blood pressure and thus the risk of intracranial hemorrhage [14]. Epinephrine would have been a reasonable alternative in this case due to the extent of angioedema that developed. Other alternatives include fresh frozen plasma, ecallantide (a recombinant protein that inhibits kallikrein), and C1 esterase inhibitors, all of which have been primarily used in ACE inhibitor-triggered angioedema or C1 esterase inhibitor deficiency but could have a role in tPA-related angioedema given the role of bradykinin [2,14]. Pahs et al. [16] demonstrated the use of plasma-derived C1 esterase inhibitor in a case of tPA-mediated angioedema. They described a case of potential airway compromise following tPA administration refractory to steroids and H2 blockers that ultimately resolved with a C1 esterase inhibitor and avoided the need for an invasive airway maneuver [16]. One last alternate therapy involves icatibant, a selective bradykinin B2 receptor antagonist; however, this is contraindicated with concomitant use of ACE inhibitors because they exert their vasodilating effect via increased bradykinin concentrations [17]. In severe or refractory cases of angioedema, patients may require intubation or cricothyroidotomy.\n\nConclusions\nAngioedema induced by tPA is an infrequent but potentially fatal outcome of thrombolysis occurring in 1 of 50 patients, which increases to 1 of 10 in insular infarcts and 1 of 6 in individuals who are concomitantly using ACE inhibitors at the time of thrombolysis [4]. Angioedema typically presents within the hour of tPA administration and can quickly compromise the airway. Due to its severity, close monitoring of these individuals is imperative and prompt treatment is essential. Though exposed to ACE inhibitors, our patient was found to have an infarct of her posterior cerebral artery and developed angioedema after thrombolysis. This combination has rarely been documented, making this case unusual.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Computed tomography at initial presentation showing subacute infarct of the left pons indicated by the yellow arrow.\n\nFigure 2. Repeat computed tomography showing acute to subacute infarct with encephalomalacia involving the left occipital lobe indicated by the red arrow.\n\nFigure 3. Magnetic resonance imaging revealing an area of ischemia supplied by the posterior cerebral artery indicated by the green arrow.\n\nTable 1. Comparison of studies involving tissue plasminogen activator-associated angioedema, highlighting the location of stroke and concomitant angiotensin-converting enzyme (ACE) inhibition.\n\nStudy\tNumber of tPA-treated stroke patients\tAngioedema post-thrombolysis\tConcomitant ACE-inhibition*\tLocations of Infarct (n)\t\nMyslimi et al. [4]\t923\t20\t9\tMCA (18)\t\nLin et al. [11]\t559\t5\t2\tMCA (5)\t\nEngelter et al. [9]\t120\t2\t1\tInsular\t\nFrohlich et al. [3]\t136\t15\t10\tPrimarily MCA\t\nCorreia et al. [12]\t236\t8\t5\tMCA (3); Frontal (1); Basal Ganglia (1); Others (3)\t\nHill et al. [13]\t176\t9\t7\tMCA/Insula (7); Brainstem (1)\t\nYayan [1]\tn.s.\t41\t24\tMCA (18); Insular (3); Others (3); Not mentioned (17)\t\nSczepanski and Bozyk [5]\t147\t4\t3\tMCA (3); PCA (1)\t\nHurford et al. [10]\t530\t42\t24\tACA (38); Lacunar (3); PCA (1)\t\nACA – anterior cerebral artery; MCA – middle cerebral artery; n – number of infarcts in listed location correlating to number of patients with angioedema after thrombolysis in a given study; n.s. – not specified; PCA – posterior cerebral artery.\n\n* Number of patients using ACE inhibitors that developed angioedema after thrombolysis.\n==== Refs\nReferences:\n1. Yayan J Onset of orolingual angioedema after treatment of acute brain ischemia with alteplase depends on the site of brain ischemia: A meta-analysis North Am J Med Sci 2013 5 589 93 \n2. Rathbun K Angioedema after thrombolysis with tissue plasminogen activator: An airway emergency Oxf Med Case Reports 2019 2019 1 omy112 30697429 \n3. Frohlich K Macha K Gerner ST Angioedema in stroke patients with thrombolysis a lesion mapping Stroke 2019 50 1682 87 31182002 \n4. Myslimi F Capparos F Dequatre-Ponchelle N Orolingual angioedema during or after thrombolysis for cerebral ischemia Stroke 2016 47 1825 30 27197851 \n5. Sczepanski M Bozyk P Institutional incidence of severe tPA-induced angioedema in ischemic cerebral vascular accidents Crit Care Res Pract 2018 2018 9360918 30363665 \n6. Madden B Chebl R Hemi orolingual angioedema after tPA administration for acute ischemic stroke West J Emerg Med 2015 16 175 77 25671036 \n7. Dewald G A missense mutation in the plasminogen gene, within the plasminogen kringle 3 domain, in hereditary angioedema with normal C1 inhibitor Biochem Biophys Res Commun 2018 498 193 98 29548426 \n8. Gauberti M Potzeha F Vivien D Impact of bradykinin generation during thrombolysis in ischemic stroke Front Med 2018 5 195 \n9. Engelter ST Fluri F Buitrago-Tellez C Life-threatening orolingual angioedema during thrombolysis in acute ischemic stroke J Neurol 2005 252 1167 70 16184341 \n10. Hurford R Rezvani S Kreimei M Incidence, predictors and clinical characteristics of orolingual angio-oedema complicating thrombolysis with tissue plasminogen activator for ischaemic stroke J Neurol Neurosurg Psychiatry 2015 86 520 23 25016564 \n11. Lin SY Tang SC Tsai LK Orolingual angioedema after alteplase therapy of acute ischaemic stroke: Incidence and risk of prior angiotensin-converting enzyme inhibitor use Eur J Neurol 2014 21 1285 91 24909847 \n12. Correia AS Matias G Calado S Orolingual angioedema associated with alteplase treatment of acute stroke: A reappraisal J Stroke Cerebrovasc Dis 2015 24 1 31 40 25440357 \n13. Hill MD Lye T Moss H Hemi-orolingual angioedema and ACE inhibition after alteplase treatment of stroke Neurology 2003 60 1525 27 12743244 \n14. Burd M McPheeters C Scherrer LA Orolingual angioedema after tissue plasminogen activator administration in patients taking angiotensin-converting enzyme inhibitors Adv Emerg Nurs J 2019 41 3 204 14 31356244 \n15. Powers WJ Rabinstein AA Ackerson T 2018 Guidelines for the early management of patients with acute ischemic stroke: A guideline for health-care professionals from the American Heart Association/American Stroke Association Stroke 2018 49 46 99 29203686 \n16. Pahs L Droege C Kneale H Pancioli A A novel approach to the treatment of orolingual angioedema after tissue plasminogen activator administration Ann Emerg Med 2016 68 345 48 27174372 \n17. Dubois EA Cohen AF Icatibant Br J Clin Pharmacol 2010 69 425 26 20573077\n\n",
"fulltext_license": "CC BY-NC-ND",
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"journal": "The American journal of case reports",
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"mesh_terms": "D000369:Aged, 80 and over; D000799:Angioedema; D020520:Brain Infarction; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D020769:Posterior Cerebral Artery; D010959:Tissue Plasminogen Activator",
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"pages": "e927137",
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"pmid": "33441533",
"pubdate": "2021-01-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27174372;24909847;30018956;16184341;31182002;20573077;25671036;29367334;25016564;30363665;24350070;29548426;30697429;27197851;12743244;31356244;25440357",
"title": "Tissue Plasminogen Activator-Induced Angioedema Involving a Posterior Cerebral Artery Infarct: A Case Presentation.",
"title_normalized": "tissue plasminogen activator induced angioedema involving a posterior cerebral artery infarct a case presentation"
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"abstract": "Introduction: Intensive oncological treatment integrated with resection of metastases raised the clinical outcome of metastatic colorectal cancer (MCRC). In clinical practice, complex evaluation of clinical (age, performance status, comorbidities), and biological (tumoral genotype, pharmacogenomic) parameters addresses tailored, personalized multidisciplinary treatment strategies. Patients with MCRC unsuitable for first-line intensive medical treatments are prevalent and showed worse clinical outcome. After progression to oxaliplatin-based chemotherapy, aflibercept/FOLFIRI significantly improved clinical outcome, even if no survival benefit was reported in adjuvant fast relapsers by aflibercept addition. The case reported a young-elderly (yE) patient with KRAS mutant colorectal cancer rapidly progressing to adjuvant chemotherapy, unfit owing to comorbidities, with multiple pharmacogenomic alterations, who gained long-term survival in clinical practice by multidisciplinary treatment strategy consisting of first-line and re-introduction of aflibercept-containing chemotherapy and two-stage lung metastasectomies. Case presentation: A 71-years-old yE patient, unfit for intensive oncological treatments owing to Cumulative Illness Rating Scale (CIRS) stage secondary, affected by KRAS c.35 G>T mutant colorectal cancer, rapidly progressing with lung metastases after adjuvant XelOx chemotherapy, reached long-term survival 66 months with no evidence of disease after first-line and re-introduction of tailored, modulated aflibercept (4 mg/kg) d1,15-irinotecan (120 mg/m2) d1,15-5-fluorouracil (750 mg/m2/day) dd1-4, 15-18; and secondary radical bilateral two-stage lung metastasectomies. Safety profile was characterized by limiting toxicity syndrome at multiple sites (LTS-ms), requiring 5-fluorouracil discontinuation and aflibercept reduction (2 mg/kg), because of G2 hand-foot syndrome (HFS) for >2 weeks, and G3 hypertension. Pharmacogenomic analyses revealed multiple alterations of fluoropyrimidine and irinotecan metabolism: severe deficiency of fluorouracil degradation rate (FUDR), single nucleotide polymorphisms of UGT1A1 *28 variable number of tandem repeats (VNTR) 7R/7R homozygote, ABCB1 c.C3435T, c.C1236T, MTHFR c.C667T homozygote, DPYD c.A166G, TSER 28bp VNTR 2R/3R heterozygote. Conclusions: In clinical practice, a complex management evaluating clinical parameters and RAS/BRAF genotype characterizing an individual patient with MCRC, particularly elderly and/or unfit owing to comorbidities, is required to properly address tailored, multidisciplinary medical and surgical treatment strategies, integrated with careful monitoring of superimposing toxicity syndromes, also related to pharmacogenomic alterations, to gain optimal activity, and long-term efficacy.",
"affiliations": "Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy.;Thoracic Surgery, S. Andrea Hospital, Faculty of Medicine and Psychology, University La Sapienza, Rome, Italy.;Advanced Molecular Diagnostics, S. Andrea Hospital, Rome, Italy.;Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.;Thoracic Surgery, S. Andrea Hospital, Faculty of Medicine and Psychology, University La Sapienza, Rome, Italy.;Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy.",
"authors": "Bruera|Gemma|G|;D'Andrilli|Antonio|A|;Simmaco|Maurizio|M|;Guadagni|Stefano|S|;Rendina|Erino Angelo|EA|;Ricevuto|Enrico|E|",
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"doi": "10.3389/fonc.2020.01155",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.01155\nOncology\nCase Report\nRelevance of Pharmacogenomics and Multidisciplinary Management in a Young-Elderly Patient With KRAS Mutant Colorectal Cancer Treated With First-Line Aflibercept-Containing Chemotherapy\nBruera Gemma 12* D'Andrilli Antonio 3 Simmaco Maurizio 4 Guadagni Stefano 25 Rendina Erino Angelo 3 Ricevuto Enrico 12 Oncology Network ASL1 Abruzzo1Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy\n2Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy\n3Thoracic Surgery, S. Andrea Hospital, Faculty of Medicine and Psychology, University La Sapienza, Rome, Italy\n4Advanced Molecular Diagnostics, S. Andrea Hospital, Rome, Italy\n5Universitary General Surgery, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy\nEdited by: Pashtoon Murtaza Kasi, University of Iowa, United States\n\nReviewed by: Andrea Botticelli, Sapienza University of Rome, Italy; Nicola Silvestris, University of Bari Aldo Moro, Italy\n\n*Correspondence: Gemma Bruera gemma.gbb@gmail.comThis article was submitted to Gastrointestinal Cancers, a section of the journal Frontiers in Oncology\n\n\n04 8 2020 \n2020 \n10 115506 2 2020 08 6 2020 Copyright © 2020 Bruera, D'Andrilli, Simmaco, Guadagni, Rendina and Ricevuto.2020Bruera, D'Andrilli, Simmaco, Guadagni, Rendina and RicevutoThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Introduction: Intensive oncological treatment integrated with resection of metastases raised the clinical outcome of metastatic colorectal cancer (MCRC). In clinical practice, complex evaluation of clinical (age, performance status, comorbidities), and biological (tumoral genotype, pharmacogenomic) parameters addresses tailored, personalized multidisciplinary treatment strategies. Patients with MCRC unsuitable for first-line intensive medical treatments are prevalent and showed worse clinical outcome. After progression to oxaliplatin-based chemotherapy, aflibercept/FOLFIRI significantly improved clinical outcome, even if no survival benefit was reported in adjuvant fast relapsers by aflibercept addition. The case reported a young-elderly (yE) patient with KRAS mutant colorectal cancer rapidly progressing to adjuvant chemotherapy, unfit owing to comorbidities, with multiple pharmacogenomic alterations, who gained long-term survival in clinical practice by multidisciplinary treatment strategy consisting of first-line and re-introduction of aflibercept-containing chemotherapy and two-stage lung metastasectomies.\n\nCase presentation: A 71-years-old yE patient, unfit for intensive oncological treatments owing to Cumulative Illness Rating Scale (CIRS) stage secondary, affected by KRAS c.35 G>T mutant colorectal cancer, rapidly progressing with lung metastases after adjuvant XelOx chemotherapy, reached long-term survival 66 months with no evidence of disease after first-line and re-introduction of tailored, modulated aflibercept (4 mg/kg) d1,15-irinotecan (120 mg/m2) d1,15-5-fluorouracil (750 mg/m2/day) dd1–4, 15–18; and secondary radical bilateral two-stage lung metastasectomies. Safety profile was characterized by limiting toxicity syndrome at multiple sites (LTS-ms), requiring 5-fluorouracil discontinuation and aflibercept reduction (2 mg/kg), because of G2 hand-foot syndrome (HFS) for >2 weeks, and G3 hypertension. Pharmacogenomic analyses revealed multiple alterations of fluoropyrimidine and irinotecan metabolism: severe deficiency of fluorouracil degradation rate (FUDR), single nucleotide polymorphisms of UGT1A1*28 variable number of tandem repeats (VNTR) 7R/7R homozygote, ABCB1 c.C3435T, c.C1236T, MTHFR c.C667T homozygote, DPYD c.A166G, TSER 28bp VNTR 2R/3R heterozygote.\n\nConclusions: In clinical practice, a complex management evaluating clinical parameters and RAS/BRAF genotype characterizing an individual patient with MCRC, particularly elderly and/or unfit owing to comorbidities, is required to properly address tailored, multidisciplinary medical and surgical treatment strategies, integrated with careful monitoring of superimposing toxicity syndromes, also related to pharmacogenomic alterations, to gain optimal activity, and long-term efficacy.\n\naflibercept/chemotherapycase reportyoung-elderly unfit MCRCmultidisciplinary managementpharmacogenomic analyses\n==== Body\nIntroduction\nActivity of intensive medical treatment integrated with surgical resection of metastases raised the effectiveness of clinical outcome of patients with metastatic colorectal cancer (MCRC). We previously demonstrated that first-line intensive FIr-B/FOx triplet chemotherapy plus bevacizumab reached an objective response rate (ORR) of 82%, median progression-free survival (PFS) of 12 months, and overall survival (OS) of 28 months (1, 2). High activity correlated with 26% secondary liver resections and 15% pathologic complete response (CR) (3). Integrated multidisciplinary treatments significantly improved clinical outcome of liver-limited patients (PFS 17 months, OS 44 months), compared with other/multiple metastatic sites (O/MM) (3), not significantly affected by KRAS/NRAS/BRAF genotype (4). In non-elderly RAS wild-type patients, FIr-C/FOx-C triplet chemotherapy plus cetuximab was highly active and tolerable at recommended doses, with PFS 12 months, confirming that intensive first-line regimens increase efficacy, also by increasing secondary resection of liver metastases (5). In patients progressing after oxaliplatin-based first-line treatment, aflibercept addition to FOLFIRI significantly improved OS to 13.5 months, PFS to 6.9 months, and ORR to 19.8% (6). Patients fast relapsing to adjuvant chemotherapy showed poorer efficacy and no survival benefit by aflibercept addition (OS 10.4 vs. 9.6 months) (7, 8).\n\nIn clinical practice, a complex evaluation of clinical (age, performance status, comorbidity status) and biological (KRAS/NRAS/BRAF genotype) parameters addresses tailored, multidisciplinary treatment strategies (9). Patients unsuitable for first-line FIr-B/FOx regimen due to old-elderly status (≥75 years), performance status (PS) ≥2, and/or comorbidities were prevalent, mostly elderly, PS 1-2, CIRS stage intermediate/secondary (7), O/MM (9, 10); they were treated with tailored triplet or doublet first-line treatments, and showed worse clinical outcome (11). Thus, in unfit patients, it is challenging to select the proper, modulated treatment regimen, weighing expected efficacy with safety profile (9). To this aim, we recently added the evaluation of toxicity syndromes (TS), specifically limiting TS (LTS), evaluating the spectrum of limiting and non-limiting toxicities observed in the individual patient (12). Evaluation of LTS integrated with pharmacogenomic analysis of fluorouracil and irinotecan metabolism can be useful to personalize treatment schedule and doses (5).\n\nWe reported an experience in clinical practice of multidisciplinary management of a yE patient with KRAS mutant colorectal cancer rapidly progressing to adjuvant chemotherapy, unfit for intensive medical treatment, owing to yE and comorbidities, who reached long-term OS with no evidence of disease after first-line and re-introduction of aflibercept-containing chemotherapy integrated with secondary, bilateral, two-stage lung metastasectomies.\n\nClinical Case Presentation\nA 71-years-old man, with secondary CIRS stage (10), resulting from hypertensive cardiopathy, dyslipidemia, diabetes on treatment, and positive cancer family history (mother with unspecified cancer at 75 years, brother with unspecified bone tumor, son with fibrosarcoma diagnosed at 8 months, relapsed at 17 years and surgically treated), underwent right colectomy for an ulcerative, stenotic lesion of 3 × 2.5 cm, microscopically defined as moderately differentiated adenocarcinoma with 5% mucinous component, infiltrating colic wall and pericolic fat, infiltrating pattern, poor lymphocytic infiltration, mesenteric tumoral nodes, negative resection margins, four out of 30 metastatic regional lymph nodes, stage pT3 pN2a, KRAS mutant c. 35 G>T genotype. Preoperative CT scan and postoperative PET did not show metastatic disease. Because of the elderly status and secondary CIRS stage, the patient underwent adjuvant chemotherapy according to the following schedule: oxaliplatin (120 mg/m2) d1, capecitabine (825 mg/m2 bid) d1–14, cycles repeated every 21 days, for six cycles. Safety profile was characterized by LTS-ms, specifically G2 HFS associated with G2 anemia (1, 4, 12, 13). At disease-free survival (DFS) 10 months and disease-free interval (DFI) 4 months after completion of adjuvant chemotherapy, CT scan showed bilateral lung metastases at left antero-basal (8 mm), right inferior (7 mm), and posterior–superior lobe (3 mm), confirmed by PET. CEA, CA19.9 tumor markers were negative.\n\nThe yE patient with secondary CIRS stage, KRAS mutant c.35 G>T MCRC rapidly relapsing after adjuvant XelOx chemotherapy, previously experiencing LTS-ms, underwent first-line modulated treatment according to the following schedule: aflibercept (4 mg/kg) d1,15-irinotecan (120 mg/m2) d1,15-5-fluorouracil (750 mg/m2/day) dd1–4, 15–18, cycles repeated every 28 days (Figure 1), based on previously reported doublet fluorouracil/irinotecan schedule (14). Received dose intensities were 100% of planned. Safety profile was characterized by LTS-ms: G2 HFS for >2 weeks, G3 alopecia, G2 rhinitis, G1 hypertension, mucositis, epistaxis, asthenia, dysphonia, diarrhea, and bilirubin increase. Pharmacogenomic analyses showed multiple alterations involving fluoropyrimidine and irinotecan metabolism: severe deficiency of fluorouracil degradation rate (FUDR) 0.51 ng/min/mil.cell (severe deficiency cut-off <0.68 ng/min/mil.cell), single nucleotide polymorphisms (SNPs) of UGT1A1*28 homozygote VNTR 7R/7R, ABCB1 heterozygote c.C3435T, c.C1236T, MTHFR homozygote c.C667T, DPYD heterozygote c.A166G, TSER 28bp heterozygote VNTR 2R/3R. First evaluation of response by CT scan showed partial response (PR) of secondary lung metastases with intra-lesion necrosis (Figure 2). Because of limiting HFS at 5-FU dose intensity 1,500 mg/m2/week and pharmacogenomic alterations, specifically reduced FUDR, 5-fluorouracil was discontinued, and further aflibercept/irinotecan three cycles were planned. CT scan after six cycles confirmed PR. Patient underwent further three aflibercept/irinotecan cycles. Safety profile was characterized by G3 hypertension, G3 alopecia, G1 HFS, mucositis, rhinitis, epistaxis, asthenia, and dysphonia. After nine cycles, with persistent PR, treatment was discontinued owing to limiting G3 hypertension. At PFS 16 months and PFI 5 months off-treatment, CT scan showed progression of lung metastases. Re-challenge of the same regimen was proposed for three cycles, according to the following schedule, because of previous limiting G3 hypertension: aflibercept 2 mg/kg d1, 15-irinotecan 120 mg/m2 d1, 15, every 28 days. Received dose intensities were 100%. Safety profile was characterized by G3 alopecia, G2 hypertension, G1 mucositis, rhinitis, epistaxis, asthenia, and dysphonia. First evaluation of response by CT scan showed 50% PR of secondary lung nodules (Figure 3). Treatment was planned for further three cycles. Tolerability was characterized by G3 alopecia, G2 hypertension, G1 mucositis, rhinitis, epistaxis, asthenia, and dysphonia. PET scan confirmed metabolic PR at PFS 7 months.\n\nFigure 1 Planned treatment schedule.\n\nFigure 2 CT scan images showing bilateral lung metastases early relapsed after adjuvant chemotherapy (A) and re-evaluated after first-line aflibercept/chemotherapy (B).\n\nFigure 3 CT scan images showing bilateral lung metastases relapsed after first-line chemotherapy (A) and re-evaluated after aflibercept/chemotherapy re-introduction (B).\n\nBecause of long-term control of bilateral lung metastastes during aflibercept/irinotecan first-line and re-challenge treatments, low disease burden, even if bilateral lung metastases, multidisciplinary treatment strategy was shared with thoracic surgeons, and bilateral lung resections were planned. The patient underwent atypical resection of right dorsal segment of superior lobe and apical segment of inferior lobe; metastatic lesions of 1.4 cm and 0.8 cm of mucinous colon adenocarcinoma were diagnosed. Nine weeks after, the patient underwent second-stage atypical resection of inferior lobe. Histological examination confirmed a sub-pleural partially necrotic lesion of 2.4 cm, with mucinous features of colon adenocarcinoma. PET scan confirmed no evidence of disease, no further medical treatment was planned, and re-evaluation was performed 3 months after.\n\nTo date, clinical outcome shows PFS 50 months from aflibercept/irinotecan re-challenge, PFI 40 months after two-stage lung metastasectomies, and OS of metastatic disease 66 months, with no evidence of disease (Figure 4).\n\nFigure 4 Timeline.\n\nThe procedures followed were in accordance with the ethical standards. Written informed consent was provided by the patient for proposed medical and surgical treatments, and to represent his clinical case. Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article. Clinical management was shared with the patient, balancing oncological indication with patient's priorities, specifically regarding different available first-line treatment options, safety evaluation and implication on daily living, treatment modulation and interruptions caused by LTS, re-introduction, and integration with lung metastasectomies, followed by follow-up.\n\nDiscussion\nThe case reported a yE patient with KRAS c.35 G>T (G12V) mutant MCRC rapidly progressing to adjuvant chemotherapy with bilateral lung metastases, unfit for intensive medical treatment owing to comorbidities, who was treated by first-line and re-introduction of aflibercept-containing chemotherapy followed by two-stage lung metastasectomies and gained in clinical practice by multidisciplinary treatment strategy long-term OS 66 months of metastatic disease with no evidence of disease at PFI 40 months.\n\nPrimary right-sided colonic adenocarcinoma with 5% mucinous component, Dukes C stage, harbored the second most prevalent (22.5%) KRAS c.35 G>T (G12V) mutation (15) and showed DFS 10 months, DFI 4 months after XelOx adjuvant chemotherapy. Prevalently occurring codon 12 KRAS mutations confer worse clinical behavior of CRC, and KRAS c.35 G>T mutation was an independent factor related with increased risk of recurrence and death (16), with significantly unfavorable DFS and OS in patients affected by Dukes C stage CRC (17); the poorer prognosis was not confirmed in other studies (18, 19). KRAS codon 12 mutations, specifically c.35 G>T, were related with worse OS compared with KRAS/BRAF wild-type cancers (20).\n\nEffectiveness of intensive medical treatment integrated with radical resection of metastases raised clinical outcome of MCRC. In fit patients with MCRC, first-line FIr-B/FOx, developed from doublet and triplet schedules backbone (14, 21), reached ORR 82%, correlated with 26% secondary liver resections, PFS 12 months, OS 28 months (1); the prevalent codon 12 KRAS c.35 G>A mutant status was significantly associated with worse clinical outcomes of patients with MCRC treated with FIr-B/FOx compared with KRAS/BRAF wild-type and other KRAS mutant patients (22–24). FIr-B/FOx treatment integrated with metastasectomies significantly improved outcomes in liver-limited (PFS 17 months, OS 44 months) vs. O/MM patients (3, 22). Clinical outcome was not significantly affected by KRAS exon 2 (22), nor KRAS/NRAS/BRAF genotype, even if trendly favorable in triple wild-type (5). KRAS exon 2 wild-type liver-limited patients gained significantly favorable outcome because of secondary surgery, with respect to mutant (22). Increased efficacy of intensive first-line treatment and improved liver resection rate was confirmed in non-elderly RAS/BRAF wild-type patients treated with FIr-C/FOx-C triplet chemotherapy plus cetuximab, highly active and tolerable, reaching PFS 12 months (5).\n\nThe reported yE patient with secondary CIRS stage required tailored medical treatment (9, 11). Elderly status, PS ≥ 2, and/or comorbidities represent major parameters justifying treatment modulation to avoid limiting toxicities, preserve adequate quality of life, and to maintain proper dose intensities for expected activity. Elderly patients with MCRC are prevalent, and proper selection between intensive vs. tailored treatments is challenging, weighing expected tolerability and clinical outcome. Consecutive patients unsuitable for first-line intensive regimens, as a result of elderly (≥65 years) and/or comorbidity status, were 56%: elderly 76%, old-elderly 54%, PS 1–2 59%, intermediate/secondary CIRS stage 89%, with O/MM extension 79% (9). They were prevalently treated with modulated triplet or doublet regimens (49 and 40%, respectively). Patients treated with doublet regimens showed worse clinical outcomes (9). Unfit patients who underwent secondary liver surgery did not experience increased morbidity/mortality, reported to be significantly higher in elderly (8%) (25). Moreover, KRAS wild-type compared with mutant patients showed significantly favorable PFS, but not OS (22). KRAS c.35 G >A mutant genotype correlated with significantly worse PFS and OS vs. wild-type and/or other mutant (23, 24).\n\nIn patients with MCRC resistant to or progressing after oxaliplatin-based first-line chemotherapy, aflibercept addition to FOLFIRI significantly improved outcome (OS 13.5 months, PFS 6.9 months, ORR 19.8%) (6). Prolonged OS benefit was demonstrated: 38.5% at 18 months, 28.0% at 24 months, and 22.3 at 30 months (26), consistent across pre-specified randomization factors (27), only trendly favorable in RAS/BRAF wild-type and not according to sidedness (28). Adjuvant fast relapsers showed poorer efficacy and no survival benefit from addition of aflibercept (10.4 vs. 9.6 months) (7, 8); in Spanish real-life experience, PFS was 5.3–6.8 months (29, 30) and OS 12 months (30). Patients with metachronous vs. synchronous disease had significantly longer PFS 11 vs. 5 months, OS 17 vs. 10 months; left- vs. right-sided tumors had longer PFS 7 vs. 3 months, OS 12 vs. 8 months (30). Our clinical practice experience underlines the potential relevance of first-line aflibercept-based chemotherapy in a yE patient, unfit, KRAS mutant, with rapidly progressing MCRC achieving PFS 16 months, PFI 5 months. More re-challenge of the same schedule achieved a PR and PFS 7 months before lung metastasectomies, even at reduced aflibercept and irinotecan doses, and after fluorouracil discontinuation. Aflibercept vs. bevacizumab added to mFOLFOX6 reported equivalent median PFS 8.48 months and ORR 49.1 vs. 45.9%; RAS/BRAF mutations did not significantly correlate with PFS (31, 32). Aflibercept addition to mFOLFOX for six cycles, followed by maintenance and oxaliplatin reintroduction at progression, gained PFS 9.3 months (33). Aflibercept/FOLFIRI reached ORR 61.3% and PFS 8.4 months (34). Aflibercept/FOLFIRI for 12 cycles followed by aflibercept maintenance gained ORR 46.6%, PFS 8.4 months, and OS 20.9 months (35). At progression, first-line aflibercept-based chemotherapy was resumed, owing to long first-line PFS, consistent OR, and chemotherapy-free interval 5 months. After progression to first-line FIr-B/FOx, the outcome was significantly favorable in patients re-challenged with intensive regimen, unfavorable in c.35 G>A KRAS mutant (36). Triplet chemotherapy plus targeted agent re-challenge was offered to patients with previous OR, long PFS (≥10 months), off-treatment interval ≥3 months, no previous LT, and gained ORR 80%, related with 40% subsequent resections, PFS 13 months, and 2-years OS 80% (36).\n\nThen, because of long-term control of bilateral lung metastastes during first-line aflibercept/irinotecan and re-challenge, bilateral resections of lung metastases were performed. The diagnosis of mucinous lung metastases may justify such a long OS 66 months of metastatic disease without evidence of disease at PFS 50 months and PFI 40 months from second stage lung metastasectomies, thus realizing the effectiveness of the integrated lung metastasectomies. In a retrospective Spanish real-life analysis of 32 patients who underwent surgical resection after aflibercept/FOLFIRI (37), PR was 56.3%, CR 3.1%, and resection rates R0 75.0%, R1 15.6%, and R2 9.4%. Secondary resection of different metastatic sites was performed: liver, 46.9%; lung, 25.0%; cytoreductive surgery for carcinomatosis, 15.6%; supra-adrenalectomy, 3.1%; liver and peritoneal carcinomatosis, 9.4%. Median PFS from surgery was 8.0 months and OS 37.3 months; in 22% of patients, aflibercept was resumed after surgery.\n\nReported yE, unfit patient underwent first-line MCRC treatment with reduced doses of aflibercept, irinotecan, and fluorouracil. Nevertheless, safety profile was characterized by LTS-ms, particularly G2 HFS lasting >2 weeks with different other G2–G1 toxicities. Because of limiting HFS and multiple pharmacogenomic alterations, 5-fluorouracil was discontinued; then, LTS-ms was observed, characterized by G3 hypertension, and re-introduction was planned with further aflibercept dose reduction. Reported prevalent toxicities with FOLFIRI/aflibercept were diarrhea (19.3%), mucositis (13.7%), asthenia (16.9%), HFS (2.8%), hypertension (2.9%), arterial (1.8%) and venous (7.9%) thromboembolic events, neutropenia (36.7%), and thrombocytopenia (3.3%) (8), the majority occurring within the first four cycles (26). In Spanish real-life experience, prevalent LT were neutropenia (7.9–15%), diarrhea (4.5–6.4%), asthenia (6.8–10%), and hypertension (3.4–6.8%) (30, 38, 39). Hypertension on-treatment was reported as a potential surrogate efficacy marker, associated with increased PFS 10.6 months and OS 17 months (30). In real-world data, >50% of patients requiring modified FOLFIRI schedules and doses had slightly older median age (63 years, range 35–82), 44% <65 years; no significantly different outcomes were reported according to modified schedules and doses, nor in elderly patients (39); G3–4 adverse events (40) and serious toxicity-related hospitalization were more common in elderly patients (≥65 years) (39). In Aflibercept Safety and Quality of Life Programs (41, 42), including an Italian experience with 43% yE, 10% early relapsers, 13.5 and 12% receiving, respectively, 5-fluorouracil and irinotecan lower dose, prevalent G3–4 toxicities were hypertension 24.1–28%, neutropenia 23.1–27.5%, and diarrhea 15.3–17%; no QoL worsening was reported; in elderly patients, G3–4 toxicities were lower than in VELOUR trial (81.3 vs. 89.3%) (41). As first-line treatment, aflibercept added to mFOLFOX6 reported G3–4 neutropenia 36.1%, hypertension 35.3%, proteinuria 9.2%, deep vein thrombosis 5.9%, and pulmonary embolism 5.9% (31). As we have previously reported in patients with MCRC treated by intensive first-line FIr-B/FOx and confirmed in the reported patient, toxicity induced by cancer medical treatments relies on individual clinical scenario of toxicity syndromes (TS), eventually LTS, frequently including multiple sites (LTS-ms) with clinical signs and symptoms of different degrees, requiring proper clinical management and drug modulations (1, 2, 12, 43). We introduced the innovative concept of LTS and defined LTS single site (LTS-ss), characterized by the LT alone, and LTS-ms, characterized by ≥2 LTs or a LT plus other, at least G2, non-LTs (1, 12, 13). Thus, LTS depicts toxicity burden in the individual patients. Cumulative G3–4 toxicities reported with FIr-B/FOx were equivalent in yE patients (≥65– <75 years), carefully selected by favorable PS, functional, comorbidity status: 44% overall; 46% in yE, mainly including diarrhea (69.2%), with significantly higher rate of LTS-ms vs. LTS-ss, compared with non-elderly (1, 12, 13). Overall, FIr-C/FOx-C induced LTS 65.5%, significantly more represented by LTS-ms (59%) vs. LTS-ss, prevalently LT plus other at least G2 non-limiting toxicities (34%) or ≥2 LTs (24%) (5). We previously showed that LTS monitoring could enhance evaluation of individual safety profile also in other different cancer settings (44–46).\n\nFurthermore, the yE, unfit patient reported LTS-ms with XelOx adjuvant chemotherapy, confirmed all along with aflibercept-containing first-line chemotherapy and re-challenge. Fluorouracil and irinotecan doses were adjusted according to pharmacogenomic analyses, revealing multiple alterations of fluoropyrimidine and irinotecan metabolism, specifically severe 5-FUDR deficiency, SNPs of UGT1A1*28 homozygote 7 repeats, ABCB1 c.C3435T and C1236T heterozygote, MTHFR—c.C667T homozygote, DPYD c.A166G heterozygote, and TSER 28bp heterozygote VNTR 2R/3R. Dihydropyrimidine dehydrogenase gene (DPYD) and UGT1A1 SNPs variably influence fluoropyrimidines and irinotecan tolerability (47). In phase II trials evaluating triplet capecitabine, oxaliplatin, irinotecan, plus bevacizumab, or cetuximab, most relevant G3–4 toxicities were, respectively diarrhea (19 and 46%), neutropenia (3 and 7%), and asthenia (0 and 7%) (40). Limiting toxicity and treatment modulations were independently and significantly associated with DPYD c.496A > G (P = 0.022) and c.1896 T > C (P = 0.027), trendly with UGT1A1*28 SNPs (P = 0.054) (48). UGT1A1*28 allele determines decreased glucuronidation of SN-38 metabolite and enhances the risk of limiting irinotecan-related neutropenia (47–49). 5-FUDR was reported as a potential predictive biomarker of fluorophyrimidin toxicity in gastrointestinal cancers (50, 51). To further relate individual LTS occurrence, we performed specific companion analysis of pharmacogenomic biomarkers of fluorouracil and irinotecan safety profile 5-FUDR, ABCB1, UGT1A1, CYP3A4, and DYPD SNPs in 14 patients treated with FIr-C/FOx-C (5). Pharmacogenomic alterations involved 5-FUDR (43%), SNPs of UGT1A1 (50%), ABCB1 (71%), CYP3A4 (14%), and DYPD (15%), in the reported range (47, 49). Most patients (65%), specifically those who developed gastrointestinal LTS (78%), showed >1 pharmacogenomic alteration, including reduced FUDR, UGT1A1, or CYP3A4 SNPs (range 1–3), thus predicting occurrence of LTS-ms in patients at risk of gastrointestinal LT (5). Thus, apart from the primary evaluation of patient as unfit, owing to yE and comorbidities, LTS reported with different chemotherapy combinations and related to detected pharmacogenomic alterations further confirms how complex, careful, and rigorous it would be in clinical practice to monitor medical treatments of individual patients with cancer.\n\nConclusion\nIn clinical practice, a complex management evaluating patient-related clinical parameters and RAS/BRAF genotype of patients with MCRC, particularly the elderly and/or those who are unfit because of comorbidities, is required to properly tailor multidisciplinary medical and surgical treatment strategies to gain optimal activity and long-term efficacy, integrated with careful monitoring of toxicity syndromes, potentially related to pharmacogenomic alterations.\n\nEthics Statement\nWritten informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nGB and ER were the medical oncologists responsible for clinical and bioclinical management of patient. 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Kirsten ras mutations in patients with colorectal cancer: the multicenter ‘RASCAL' study\n. J Natl Cancer Inst. (1998 ) 90 :675 –84\n. 10.1093/jnci/90.9.675 9586664 \n17. Andreyev HJ Norman AR Cunningham D Oates J Dix BR Iacopetta BJ . Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II' study\n. Br J Cancer. (2001 ) 85 :692 –6\n. 10.1054/bjoc.2001.1964 11531254 \n18. Samowitz WS Curtin K Schaffer D Robertson M Leppert M Slattery ML . Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival: a population-based study\n. Cancer Epidemiol Biomarkers Prev. (2000 ) 9 :1193 –7\n.11097226 \n19. Westra JL Schaapveld M Hollema H de Boer JP Kraak MMJ de Jong D . Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients\n. J Clin Oncol. (2005 ) 23 :5635 –43\n. 10.1200/JCO.2005.04.096 16110022 \n20. Imamura Y Morikawa T Liao X Lochhead P Kuchiba A Yamauchi M . Specific mutations in KRAS codons 12 and 13, and patient prognosis in 1075 BRAF-wild-type colorectal cancers\n. Clin Cancer Res. (2012 ) 18 :4753 –63\n. 10.1158/1078-0432.CCR-11-3210 22753589 \n21. Morelli MF Santomaggio A Ricevuto E Cannita K De Galitiis F Tudini M \nTriplet schedule of weekly 5-Fluorouracil and alternating irinotecan or oxaliplatin in advanced colorectal cancer: a dose-finding and phase II study\n. Oncol Rep. (2010 ) 23 :1635 –40\n. 10.3892/or_00000805 20428819 \n22. Bruera G Cannita K Di Giacomo D Lamy A Troncone G Dal Mas A . Prognostic value of KRAS genotype in metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx) according to extension of metastatic disease\n. BMC Med. (2012 ) 10 :135 . 10.1186/1741-7015-10-135 23136868 \n23. Bruera G Cannita K Di Giacomo D Lamy A Frebourg T Sabourin JC \nWorse prognosis of KRAS c.35 G > A mutant metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx)\n. BMC Med. (2013 ) 11 :59 \n10.1186/1741-7015-11-59 23497191 \n24. Bruera G Cannita K Tessitore A Russo A Alesse E Ficorella C . The prevalent KRAS exon 2 c.35 G > A mutation in metastatic colorectal cancer patients: a biomarker of worse prognosis and potential benefit of bevacizumab-containing intensive regimens?\n\nCrit Rev Oncol Hematol. (2015 ) 93 :190 –202\n. 10.1016/j.critrevonc.2014.10.004 25459669 \n25. Figueras J Ramos E López-Ben S Torras J Albiol M Llado L \nSurgical treatment of liver metastases from colorectal carcinoma in elderly patients\n. When is it worthwhile? Clin Transl Oncol. (2007 ) 9 :392 –400\n. 10.1007/s12094-007-0072-x 17594954 \n26. Ruff P Ferry DR Lakomy R Prausova' J Van Hazel GA Hoff PM . Time course of safety and efficacy of aflibercept in combination with FOLFIRI in patients with metastatic colorectal cancer who progressed on previous oxaliplatin-based therapy\n. Eur J Cancer. (2015 ) 51 :18 –26\n. 10.1016/j.ejca.2014.10.019 25466509 \n27. Tabernero J Van Cutsem E Lakomy' R Prausova' J Ruff P van Hazel GA . Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial\n. Eur J Cancer. (2014 ) 50 :320 –31\n. 10.1016/j.ejca.2013.09.013 24140268 \n28. Wirapati P Pomella V Vandenbosch B Kerr P Maiello E Jeffery Grahame M \nVELOUR trial biomarkers update: impact of RAS, BRAF, and sidedness on aflibercept activity\n. Ann Oncol. (2017 ) 28 (suppl.3 ):LBA −005\n. 10.1093/annonc/mdx302.004 \n29. Feliu J Díez de Corcuera I Manzano JL Valladares-Ayerbes M Alcaide J García T . Effectiveness and safety of aflibercept for metastatic colorectal cancer: retrospective review within an early access program in Spain\n. Clin Transl Oncol. (2017 ) 19 :498 –507\n. 10.1007/s12094-016-1556-3 27718155 \n30. Fernandez Montes A Martinez Lago N Covela Rua M de la Camara Gomez J Gonzalez Villaroel P Mendez JC . Efficacy and safety of FOLFIRI/aflibercept in second-line treatment of metastatic colorectal cancer in a real-world population: prognostic and predictive markers\n. Cancer Med. (2019 ) 8 :882 –9\n. 10.1002/cam4.1903 30690930 \n31. Folprecht G Pericay C Saunders MP Thomas A Lopez R Roh JK \nOxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: the AFFIRM study\n. Ann Oncol. (2016 ) 27 :1273 –9\n. 10.1093/annonc/mdw176 27091810 \n32. Lambrechts D Thienpont B Thuillier V Sagaert X Moisse M Peuteman G . Evaluation of efficacy and safety markers in a phase II study of metastatic colorectal cancer treated with aflibercept in the first-line setting\n. Br J Cancer. (2015 ) 113 :1027 –34\n. 10.1038/bjc.2015.329 26355232 \n33. Chibaudel B Bachet JB André T Auby D Desramé J Deplanque G . Efficacy of aflibercept with FOLFOX and maintenance with fluoropyrimidine as first-line therapy for metastatic colorectal cancer: GERCOR VELVET phase II study\n. Int J Oncol. (2019 ) 54 :1433 –45\n. 10.3892/ijo.2019.4709 30720091 \n34. Matikas A Souglakos J Katsaounis P Kotsakis A Kouroupakis P Pantazopoulos N . MINOAS: a single-arm translational phase II trial of FOLFIRI plus aflibercept as first-line therapy in unresectable, metastatic colorectal cancer\n. Target Oncol. (2019 ) 14 :285 –93\n. 10.1007/s11523-019-00647-3 31203498 \n35. Pentheroudakis G Kotoula V Koliou GA Karavasilis V Samantas E Aravantinos G . AMALTHEA: prospective, single-arm study of the hellenic cooperative oncology group (HeCOG) evaluating efficacy and safety of first-line FOLFIRI + aflibercept for 6 months followed by aflibercept maintenance in patients with metastatic colorectal cancer\n. Clin Colorectal Cancer. (2018 ) 17 :e631 –7\n. 10.1016/j.clcc.2018.06.003 29980490 \n36. Bruera G Cannita K Giordano AV Vicentini R Ficorella C Ricevuto E . Differential prognosis of metastatic colorectal cancer patients post-progression to first line triplet chemotherapy plus bevacizumab, FIr-B/FOx, according to second line treatment and KRAS genotype\n. Int J Oncol. (2014 ) 44 :17 –26\n. 10.3892/ijo.2013.2179 24247407 \n37. Munoz Martin AJ Garcia Adrian S Pericay C Ruiz A Ibeas P Grandez R \nMetastases resection after FOLFIRI-aflibercept (FA) in oxaliplatin-refractory colorectal cancer patients (ORF-CRC)\n. J Clin Oncol. (2018 ) 36 :862 –2\n. 10.1200/JCO.2018.36.4_suppl.862 \n38. Salgado Fernández M Pérez Hoyos MT Díaz de Corcuera I Vidal Arbués A García de la Torre M . Aflibercept for metastatic colorectal cancer: safety data from the Spanish named patient program\n. Expert Opin Drug Saf. (2015 ) 14 :1171 –9\n. 10.1517/14740338.2015.1057495 26076885 \n39. Montes AF Lopez CL Martinez GA Lopez DP Munoz AML Paredas BG . Prognostic nomogram and patterns of use of FOLFIRI-aflibercept in advanced colorectal cancer: a real-world data analysis\n. Oncologist. (2019 ) 24 :e687 –95\n. 10.1634/theoncologist.2018-0824 31147489 \n40. Ruff P Van Cutsem E Lakomy R Prausova J van Hazel GA Moiseyenko VM . Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: an age-based analysis from the randomized placebo-controlled phase III VELOUR trial\n. J Geriatr Oncol. (2018 ) 9 :32 –39\n. 10.1016/j.jgo.2017.07.010 28807738 \n41. Riechelmann RP Srimuninnimit V Bordonaro R Kavan P Di Bartolomeo M Maiello E . Aflibercept plus FOLFIRI for second-line treatment of metastatic colorectal cancer: observations from the global aflibercept safety and health-related quality-of-life program (ASQoP)\n. Clinical Colorectal Cancer. (2018 ) 18 :183 –91\n. 10.1016/j.clcc.2019.05.003 31221542 \n42. Pastorino A Di Bartolomeo M Maiello E Iaffaioli V Ciuffreda L Fasola G . Aflibercept plus FOLFIRI in the real-life setting: safety and quality of life data from the Italian patient cohort of the aflibercept safety and quality-of-life program study\n. Clin Colorectal Cancer. (2018 ) 17 :e457 –70\n. 10.1016/j.clcc.2018.03.002 29605592 \n43. Ficorella C Bruera G Cannita K Porzio G Lanfiuti Baldi P Tinari N . Triplet chemotherapy in patients with metastatic colorectal cancer: toward the best way to safely administer a highly active regimen in clinical practice\n. Clin Colorectal Cancer. (2012 ) 11 :229 –37\n. 10.1016/j.clcc.2012.05.001 22694897 \n44. Bruera G Massacese S Candria S Galvano A Manetta R Giordano AV . Real life triplet FIr/FOx chemotherapy in first line metastatic pancreatic ductal adenocarcinoma patients: recommended schedule for expected activity and safety and phase II study\n. Oncotarget. (2018 ) 9 :31861 –76\n. 10.18632/oncotarget.25870 30159128 \n45. Bruera G Massacese S Galvano A Dal Mas A Guadagni S Ciacco E . Dose-finding study of intensive weekly alternating schedule of docetaxel, 5-fluorouracil, and oxaliplatin, FD/FOx regimen, in metastatic gastric cancer\n. Oncotarget. (2018 ) 9 :20339 –50\n. 10.18632/oncotarget.24861 29755655 \n46. Bruera G Giuliani A Romano L Chiominto A Di Sibio A Mastropietro S . Poorly differentiated neuroendocrine rectal carcinoma with uncommon immune-histochemical features and clinical presentation with a subcutaneous metastasis, treated with first line intensive triplet chemotherapy plus bevacizumab FIr-B/FOx regimen: an experience of multidisciplinary management in clinical practice\n. BMC Cancer. (2019 ) 19 :960 . 10.1186/s12885-019-6214-z 31619203 \n47. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group \nRecommendations from the EGAPP working group: can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan?\n\nGenet Med . (2009 ) 11 :15 –20\n. 10.1097/GIM.0b013e31818efd9d 19125128 \n48. Falvella FS Cheli S Martinetti A Mazzali C Iacovelli R Maggi C . DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan\n. Br J Clin Pharmacol. (2015 ) 80 :581 –8\n. 10.1111/bcp.12631 25782327 \n49. Dias MM McKinnon RA Sorich MJ . Impact of the UGT1A1*28 allele on response to irinotecan: a systematic review and meta-analysis\n. Pharmacogenomics. (2012 ) 13 :889 –99\n. 10.2217/pgs.12.68 22676194 \n50. Onesti CE Botticelli A La Torre M Borro M Gentile G Romiti A . 5-fluorouracil degradation rate could predict toxicity in stages II-III colorectal cancer patients undergoing adjuvant FOLFOX\n. Anticancer Drugs . (2017 ) 28 :322 –6\n. 10.1097/CAD.0000000000000453 27845948 \n51. Roberto M Romiti A Botticelli A Mazzuca F Lionetto L Gentile G . Evaluation of 5-fluorouracil degradation rate and pharmacogenetic profiling to predict toxicity following adjuvant capecitabine\n. Eur J Clin Pharmacol. (2017 ) 73 :157 –64\n. 10.1007/s00228-016-2160-8 27864592\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "aflibercept/chemotherapy; case report; multidisciplinary management; pharmacogenomic analyses; young-elderly unfit MCRC",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "1155",
"pmc": null,
"pmid": "32850329",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "27718155;24307987;9552069;22676194;31221542;22949147;27845948;29605592;22694897;29755655;30720091;25782327;21545334;31619203;30690930;24247407;22206922;25459669;16596209;29899858;26706237;28807738;20428819;25142418;23497191;11531254;31203498;28053287;20958992;31147489;24140268;19125128;16110022;9586664;26076885;27091810;26355232;11097226;27864592;22753589;32154172;2547513;31205502;30159128;23136868;24715238;29980490;25466509;17594954",
"title": "Relevance of Pharmacogenomics and Multidisciplinary Management in a Young-Elderly Patient With KRAS Mutant Colorectal Cancer Treated With First-Line Aflibercept-Containing Chemotherapy.",
"title_normalized": "relevance of pharmacogenomics and multidisciplinary management in a young elderly patient with kras mutant colorectal cancer treated with first line aflibercept containing chemotherapy"
} | [
{
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{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "IRINOTECAN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "We report a case of massive overdose of hydroxychloroquine treated with circulatory assistance by peripheral extracorporeal circulation (ECC). We expose the case of a 39-year-old woman who ingested 12 g of hydroxychloroquine with bromazepam, paroxetine, and zolpidem, in a suicide attempt. Patient has developed central nervous system depression, hemodynamic failure, life-threatening ventricular arrhythmias, and serious hypokalemia. Initially the patient has received conventional treatment with gastric lavage and activated charcoal for gastrointestinal decontamination, blood volume expansion and vasopressive drugs, intubation and mechanical ventilation, high dose of diazepam, and potassium replacement. A ventricular fibrillation was treated with external cardiac massage. In spite of this treatment, cardiogenic shock was uncontrolled, and imposed circulatory assistance. After extracorporeal circulation, we observed a spectacular improvement of hemodynamic parameters and electrocardiographic normalization at day one. Extracorporeal circulation could be used as a rescue treatment of cardiotrope and hydroxychloroquine overdoses.",
"affiliations": "Département d'anesthésie-réanimation cardiovasculaire et thoracique, hôpital Michallon, boulevard de la Chantourne, 38700 La Tronche, Grenoble, France. frederic.mongenot@gmail.com",
"authors": "Mongenot|F|F|;Gonthier|Y Tessier|YT|;Derderian|F|F|;Durand|M|M|;Blin|D|D|",
"chemical_list": "D000931:Antidotes; D010952:Plasma Substitutes; D011725:Pyridines; D026941:Sodium Channel Blockers; D014662:Vasoconstrictor Agents; D002606:Charcoal; D017374:Paroxetine; D006886:Hydroxychloroquine; D000077334:Zolpidem; D003975:Diazepam; D011188:Potassium; D001960:Bromazepam; D004837:Epinephrine",
"country": "France",
"delete": false,
"doi": "10.1016/j.annfar.2006.09.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0750-7658",
"issue": "26(2)",
"journal": "Annales francaises d'anesthesie et de reanimation",
"keywords": null,
"medline_ta": "Ann Fr Anesth Reanim",
"mesh_terms": "D000328:Adult; D000931:Antidotes; D001960:Bromazepam; D002606:Charcoal; D003128:Coma; D003131:Combined Modality Therapy; D003975:Diazepam; D062787:Drug Overdose; D004837:Epinephrine; D005112:Extracorporeal Circulation; D005260:Female; D005440:Fluid Therapy; D005751:Gastric Lavage; D006336:Heart Massage; D006801:Humans; D006886:Hydroxychloroquine; D007008:Hypokalemia; D017374:Paroxetine; D010952:Plasma Substitutes; D011188:Potassium; D011725:Pyridines; D012770:Shock, Cardiogenic; D026941:Sodium Channel Blockers; D013406:Suicide, Attempted; D014662:Vasoconstrictor Agents; D014693:Ventricular Fibrillation; D000077334:Zolpidem",
"nlm_unique_id": "8213275",
"other_id": null,
"pages": "164-7",
"pmc": null,
"pmid": "17092685",
"pubdate": "2007-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment of hydroxychloroquine poisoning with extracorporeal circulation.",
"title_normalized": "treatment of hydroxychloroquine poisoning with extracorporeal circulation"
} | [
{
"companynumb": "FR-SA-2019SA174472",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BROMAZEPAM"
},
"drugadditional": null,
"dr... |
{
"abstract": "Common variable immunodeficiency disorder is a primary immunodeficiency disorder characterized by reduced levels of serum immunoglobulins and impaired antibody response. This condition may be associated with development of noninfectious granulomatous dermatitis of the skin which may be disfiguring and destructive. There are no published guidelines for the treatment of cutaneous granulomas in this patient population. In recent studies, rubella virus-positive cells in granulomas were localized to M2 macrophages which have an important role in wound healing and the secretion of immunoregulatory cytokines. We present a case of treatment-refractory, disfiguring common variable immunodeficiency disorder-associated granulomatous dermatitis. Immunofluorescence microscopy of the biopsy specimen confirmed the presence of rubella vaccine capsid proteins in M2 macrophages within the granuloma, a newly recognized phenomenon in this patient population. This knowledge may serve to identify future therapeutic targets or preventative strategies for granulomatous dermatitis in patients with primary immunodeficiency disorder.",
"affiliations": "Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI; and.;Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI; and.;Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI; and.;Departments of Dermatology and Laboratory Medicine & Pathology, Mayo Clinic, Jacksonville, FL.",
"authors": "Bender|Nicole R|NR|;Cardwell|Leah A|LA|;Siegel|Dawn|D|;Sokumbi|Olayemi|O|",
"chemical_list": "D012411:Rubella Vaccine",
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000001598",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "42(6)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D017074:Common Variable Immunodeficiency; D003872:Dermatitis; D006099:Granuloma; D006801:Humans; D008264:Macrophages; D008297:Male; D012411:Rubella Vaccine; D055815:Young Adult",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "455-457",
"pmc": null,
"pmid": "31899704",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rubella Vaccine Persistence Within Cutaneous Granulomas in Common Variable Immunodeficiency Disorder.",
"title_normalized": "rubella vaccine persistence within cutaneous granulomas in common variable immunodeficiency disorder"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-296289",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drug... |
{
"abstract": "Myasthenia gravis is a neuromuscular autoimmune disease characterized by fatigable weakness of skeletal muscles that results from an antibody-mediated immunological attack directed at acetylcholine postsynaptic receptors. Autologous hematopoietic stem cell transplantation is considered as a treatment option in refractory cases of myasthenia gravis. A 56-year-old Colombian male presented with six months of progressive hoarseness and dysphagia, with a positive repetitive stimulation test suggestive of end plate neuromuscular disease. Myasthenia gravis was confirmed with serology testing that reported presence of circulating acetylcholine postsynaptic receptors antibodies. The patient received several lines of pharmacological treatment and thymectomy without control of symptoms, requiring admission to the intensive care unit and mechanical ventilation in two occasions. Patient underwent autologous hematopoietic stem cell transplantation and has been in complete clinical remission for 65 months. Hematopoietic stem cell transplantation is a well-tolerated treatment that should be considered over conventional therapy in selected patients with refractory myasthenia gravis.",
"affiliations": "Division of Hematology and Hematopoietic Stem Cell Transplantation, Department of Internal Medicine, School of Medicine, Universidad Autonoma de Bucaramanga, Bucaramanga, Colombia; Hematology and Stem Cell Transplantation Unit, Clinica FOSCAL, Bucaramanga, Colombia. Electronic address: csossa@unab.edu.co.;Division of Hematology and Hematopoietic Stem Cell Transplantation, Department of Internal Medicine, School of Medicine, Universidad Autonoma de Bucaramanga, Bucaramanga, Colombia; Hematology and Stem Cell Transplantation Unit, Clinica FOSCAL, Bucaramanga, Colombia.;Division of Hematology and Hematopoietic Stem Cell Transplantation, Department of Internal Medicine, School of Medicine, Universidad Autonoma de Bucaramanga, Bucaramanga, Colombia; Hematology and Stem Cell Transplantation Unit, Clinica FOSCAL, Bucaramanga, Colombia.;Division of Hematology and Hematopoietic Stem Cell Transplantation, Department of Internal Medicine, School of Medicine, Universidad Autonoma de Bucaramanga, Bucaramanga, Colombia; Hematology and Stem Cell Transplantation Unit, Clinica FOSCAL, Bucaramanga, Colombia.;Department of Internal Medicine, Clinica FOSCAL, Bucaramanga, Colombia.;Division of Hematology and Hematopoietic Stem Cell Transplantation, Department of Internal Medicine, School of Medicine, Universidad Autonoma de Bucaramanga, Bucaramanga, Colombia.;Department of Internal Medicine, Clinica FOSCAL, Bucaramanga, Colombia.;Department of Neurology, Clinica FOSCAL, Bucaramanga, Colombia; Division of Neurology, Department of Internal Medicine, School of Medicine, Universidad Autonoma de Bucaramanga, Bucaramanga, Colombia.",
"authors": "Sossa Melo|Claudia Lucía|CL|;Peña|Angela María|AM|;Salazar|Luis Antonio|LA|;Jiménez|Sara Inés|SI|;Gómez|Edgar David|ED|;Chalela|Claudia Marcela|CM|;Ayala-Castillo|Miguel|M|;Peña|Iván Mauricio|IM|",
"chemical_list": "D001323:Autoantibodies; D011950:Receptors, Cholinergic",
"country": "England",
"delete": false,
"doi": "10.1016/j.nmd.2018.11.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-8966",
"issue": "29(2)",
"journal": "Neuromuscular disorders : NMD",
"keywords": "Autologous hematopoietic stem cell transplantation; Miastenia gravis; Refractory; Treatment",
"medline_ta": "Neuromuscul Disord",
"mesh_terms": "D001323:Autoantibodies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis; D011950:Receptors, Cholinergic; D013934:Thymectomy; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "9111470",
"other_id": null,
"pages": "142-145",
"pmc": null,
"pmid": "30639064",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Autologous hematopoietic stem cell transplantation in a patient with refractory seropositive myasthenia gravis: A case report.",
"title_normalized": "autologous hematopoietic stem cell transplantation in a patient with refractory seropositive myasthenia gravis a case report"
} | [
{
"companynumb": "PHHY2019CO061022",
"fulfillexpeditecriteria": "1",
"occurcountry": "CO",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Here we describe clinicopathologic features of Ebola virus disease in pregnancy. One woman infected with Sudan virus in Gulu, Uganda, in 2000 had a stillbirth and survived, and another woman infected with Bundibugyo virus had a live birth with maternal and infant death in Isiro, the Democratic Republic of the Congo in 2012. Ebolavirus antigen was seen in the syncytiotrophoblast and placental maternal mononuclear cells by immunohistochemical analysis, and no antigen was seen in fetal placental stromal cells or fetal organs. In the Gulu case, ebolavirus antigen localized to malarial parasite pigment-laden macrophages. These data suggest that trophoblast infection may be a mechanism of transplacental ebolavirus transmission.",
"affiliations": "Infectious Diseases Pathology Branch.;Médecins Sans Frontières, Barcelona, Spain.;Viral Special Pathogens Branch.;Viral Special Pathogens Branch.;Rickettsial Zoonoses Branch, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.;Médecins Sans Frontières.;Médecins Sans Frontières.;Viral Special Pathogens Branch.;Poxvirus and Rabies Branch, Division of High-Consequence Pathogens and Pathology.;Infectious Diseases Pathology Branch.;Infectious Diseases Pathology Branch.;Médecins Sans Frontières, Barcelona, Spain.;Ministry of Health, Kinshasa, Democratic Republic of the Congo.;Ministry of Health, Kinshasa, Democratic Republic of the Congo.;Viral Special Pathogens Branch.;Infectious Diseases Pathology Branch.;Viral Special Pathogens Branch.;Viral Special Pathogens Branch.;Infectious Diseases Pathology Branch.",
"authors": "Muehlenbachs|Atis|A|;de la Rosa Vázquez|Olimpia|O|;Bausch|Daniel G|DG|;Schafer|Ilana J|IJ|;Paddock|Christopher D|CD|;Nyakio|Jean Paul|JP|;Lame|Papys|P|;Bergeron|Eric|E|;McCollum|Andrea M|AM|;Goldsmith|Cynthia S|CS|;Bollweg|Brigid C|BC|;Prieto|Miriam Alía|MA|;Lushima|Robert Shongo|RS|;Ilunga|Benoit Kebela|BK|;Nichol|Stuart T|ST|;Shieh|Wun-Ju|WJ|;Ströher|Ute|U|;Rollin|Pierre E|PE|;Zaki|Sherif R|SR|",
"chemical_list": "D000914:Antibodies, Viral; D000956:Antigens, Viral; D007074:Immunoglobulin G; D007075:Immunoglobulin M",
"country": "United States",
"delete": false,
"doi": "10.1093/infdis/jiw206",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1899",
"issue": "215(1)",
"journal": "The Journal of infectious diseases",
"keywords": "Bundibugyo virus; Ebola virus disease; Sudan virus; malaria; pathology; placenta; pregnancy",
"medline_ta": "J Infect Dis",
"mesh_terms": "D000328:Adult; D000914:Antibodies, Viral; D000956:Antigens, Viral; D015023:Democratic Republic of the Congo; D029043:Ebolavirus; D005260:Female; D019142:Hemorrhagic Fever, Ebola; D006801:Humans; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007150:Immunohistochemistry; D008264:Macrophages; D008288:Malaria; D046529:Microscopy, Electron, Transmission; D010920:Placenta; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D050497:Stillbirth; D017154:Stromal Cells; D014327:Trophoblasts",
"nlm_unique_id": "0413675",
"other_id": null,
"pages": "64-69",
"pmc": null,
"pmid": "27226206",
"pubdate": "2017-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ebola Virus Disease in Pregnancy: Clinical, Histopathologic, and Immunohistochemical Findings.",
"title_normalized": "ebola virus disease in pregnancy clinical histopathologic and immunohistochemical findings"
} | [
{
"companynumb": "PHHY2016US086346",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYTOCIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "OBJECTIVE\nBrain infarction is a critical complication after lung resection using video-assisted thoracoscopic surgery. Recent reports have described its association with thrombosis in the pulmonary vein (PV) stump. However, the optimal management of this complication remains controversial. We describe serial 3 cases of brain infarctions associated with thrombosis in the PV stumps, which were successfully treated with the oral Xa inhibitor rivaroxaban.\n\n\nRESULTS\nWe retrospectively reviewed medical records of 3 patients. The first case was a 72-year-old man who underwent left upper lobectomy for treatment of lung adenocarcinoma. The second case was a 55-year-old man who underwent right lower segmentectomy for treatment of metastatic tumor from Barrett's esophageal carcinoma. The third case was a 73-year-old man who underwent left upper lobectomy for treatment of metastatic tumor from colon adenocarcinoma. In the first case, a large cerebellar infarction was developed and a decompressive craniotomy was performed on postoperative day 4. In the second and the third case, cerebral infarctions in the territories of right middle cerebral arteries occurred on postoperative day 2. In all cases, contrast-enhanced computed tomography demonstrated the thrombi in the stumps of the PVs. They were treated with oral administration of rivaroxaban without adverse effect, and the thrombi in the PVs disappeared within 1 month.\n\n\nCONCLUSIONS\nBlood flow stasis in the long PV stump after lung resection might contribute to thrombosis development. Oral Xa inhibitor rivaroxaban appeared to be safe and useful for the management of ischemic stroke associated with PV thrombosis after lung resection.",
"affiliations": "Department of Neurosurgery, Harasanshin Hospital, Fukuoka, Japan. Electronic address: amemiya@ns.med.kyushu-u.ac.jp.;Department of Neurosurgery, Harasanshin Hospital, Fukuoka, Japan.;Department of Neurosurgery, Harasanshin Hospital, Fukuoka, Japan.;Department of Neurosurgery, Harasanshin Hospital, Fukuoka, Japan.;Department of Surgery, Harasanshin Hospital, Fukuoka, Japan.;Department of Surgery, Harasanshin Hospital, Fukuoka, Japan.;Department of Surgery, Harasanshin Hospital, Fukuoka, Japan.;Department of Surgery, Harasanshin Hospital, Fukuoka, Japan.",
"authors": "Amemiya|Takeo|T|;Shono|Tadahisa|T|;Yamagami|Keitaro|K|;Takagishi|Soh|S|;Toma|Hiroki|H|;Kobarai|Tomonari|T|;Eguchi|Toru|T|;Hirota|Ichio|I|",
"chemical_list": "D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2019.104321",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "28(11)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Anticoagulation therapy; cerebral infarction; lung resection; pulmonary-vein thrombosis; rivaroxaban",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D002545:Brain Ischemia; D056424:Decompressive Craniectomy; D065427:Factor Xa Inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D011013:Pneumonectomy; D011667:Pulmonary Veins; D012189:Retrospective Studies; D000069552:Rivaroxaban; D020521:Stroke; D016896:Treatment Outcome; D020246:Venous Thrombosis",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "104321",
"pmc": null,
"pmid": "31422005",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Usefulness of Oral Xa Inhibitor for Management of Ischemic Stroke Associated with Thrombosis in the Pulmonary Vein Stump after Lung Resection.",
"title_normalized": "usefulness of oral xa inhibitor for management of ischemic stroke associated with thrombosis in the pulmonary vein stump after lung resection"
} | [
{
"companynumb": "JP-TEVA-2019-JP-1146342",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "Guidance and evidence to support best practices in rotating between gabapentinoids is lacking. This retrospective cohort study was performed to describe and evaluate strategies for rotation. Patients rotated while admitted from June 1st, 2014 to April 25th, 2020 at a large, academic medical center were included. The primary outcome was the proportion of rotations using a direct switch strategy compared to a cross-taper strategy. Secondary outcomes were successful rotation, defined as stable or improved pain scores pre- to post-rotation, dose ratios, and adverse effects. A total of 67 patients were included. Median age was 50 years (35 - 59) and 58% (38) were male. The majority used a direct switch strategy (87%). Ninety-five percent of patients using the direct switch strategy and 78% of patients using the cross-taper strategy were successful. There was no difference in strategies between those who were successful and those who were not. Post hoc analysis of patients with normal renal function (eGFR ≥ 50 mL/min/1.73 m2) found that those who were successful were more likely to have used a direct switch strategy (p = 0.048). There were no differences in adverse effects. These findings suggest that either strategy is reasonable for gabapentinoid rotation in the inpatient setting.",
"affiliations": "Madison N. Irwin, PharmD is with Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA and College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. Kyle Quirk, PharmD is with Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA and Department of Pharmacy, Ohio State University James Cancer Hospital, Columbus, Ohio, USA. Andrea Banner, BS is in College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. Kevin Hosseini, PharmD Candidate is in College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. Michael A. Smith, PharmD, BCPS is with Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA and College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.;Madison N. Irwin, PharmD is with Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA and College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. Kyle Quirk, PharmD is with Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA and Department of Pharmacy, Ohio State University James Cancer Hospital, Columbus, Ohio, USA. Andrea Banner, BS is in College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. Kevin Hosseini, PharmD Candidate is in College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. Michael A. Smith, PharmD, BCPS is with Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA and College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.;Madison N. Irwin, PharmD is with Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA and College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. Kyle Quirk, PharmD is with Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA and Department of Pharmacy, Ohio State University James Cancer Hospital, Columbus, Ohio, USA. Andrea Banner, BS is in College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. Kevin Hosseini, PharmD Candidate is in College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. Michael A. Smith, PharmD, BCPS is with Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA and College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.;Madison N. Irwin, PharmD is with Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA and College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. Kyle Quirk, PharmD is with Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA and Department of Pharmacy, Ohio State University James Cancer Hospital, Columbus, Ohio, USA. Andrea Banner, BS is in College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. Kevin Hosseini, PharmD Candidate is in College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. Michael A. Smith, PharmD, BCPS is with Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA and College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.;Madison N. Irwin, PharmD is with Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA and College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. Kyle Quirk, PharmD is with Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA and Department of Pharmacy, Ohio State University James Cancer Hospital, Columbus, Ohio, USA. Andrea Banner, BS is in College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. Kevin Hosseini, PharmD Candidate is in College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA. Michael A. Smith, PharmD, BCPS is with Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA and College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.",
"authors": "Irwin|Madison N|MN|https://orcid.org/0000-0003-3769-7035;Quirk|Kyle|K|https://orcid.org/0000-0002-2232-399X;Banner|Andrea|A|;Hosseini|Kevin|K|;Smith|Michael A|MA|https://orcid.org/0000-0002-9762-0104",
"chemical_list": "D000069583:Pregabalin; D000077206:Gabapentin",
"country": "England",
"delete": false,
"doi": "10.1080/15360288.2020.1852358",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1536-0288",
"issue": "35(1)",
"journal": "Journal of pain & palliative care pharmacotherapy",
"keywords": "Gabapentin; gabapentinoid rotation; pregabalin",
"medline_ta": "J Pain Palliat Care Pharmacother",
"mesh_terms": "D000077206:Gabapentin; D006760:Hospitalization; D006801:Humans; D007297:Inpatients; D008297:Male; D008875:Middle Aged; D000069583:Pregabalin; D012189:Retrospective Studies",
"nlm_unique_id": "101125608",
"other_id": null,
"pages": "13-22",
"pmc": null,
"pmid": "33600265",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Strategies for Rotation between Gabapentinoids in the Inpatient Setting.",
"title_normalized": "strategies for rotation between gabapentinoids in the inpatient setting"
} | [
{
"companynumb": "US-APOTEX-2021AP042387",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPrurigo nodularis is a chronic disease characterized by a hard dome-like or wart-like nodule which is solitary and does not fuse. Prurigo nodularis presents as one of the symptoms of atopic Dermatitis (AD).\n\n\nMETHODS\nWe present three cases of AD children with intractable prurigo nodularis. 1) a 9-Year-Old Boy, 2) an 11-Year-Old Girl, and 3) an 8-Year-Old Boy. The Eczema Area and Severity Index (EASI) in the first visit was 27.7, 30.6, and 49.0, respectively. All patients had been treated with very strong or strongest potency topical steroids for 3-9 years. Quality of life (QOL) had declined due to severe pruritus, and they had striae and secondary adrenal suppression as side effects of steroids. Case 1 and 2 were treated with Cyclosporine A (CyA), case 3 was treated with Duplimab when he was 15 years old; all patients improved.\n\n\nCONCLUSIONS\nCyA and Duplimab are not indicated for children in Japan, however, it is necessary to consider not only topical medicine but also other additional treatments when faced with adrenal suppression as a side effect of steroids or loss of QOL.\n\n\nCONCLUSIONS\nCyA and Duplimab, that were effective in AD with intractable prurigo nodularis, are expected to become indications for AD children.",
"affiliations": "Department of Pediatrics, National Hospital Organization Fukuoka National Hospital.;Department of Dermatology, National Hospital Organization Fukuoka National Hospital.;Ide Allergy Respiratory Clinic.;Department of Pediatrics, National Hospital Organization Fukuoka National Hospital.;Department of Pediatrics, National Hospital Organization Fukuoka National Hospital.;Department of Dermatology, National Hospital Organization Fukuoka National Hospital.;Department of Pediatrics, National Hospital Organization Fukuoka National Hospital.",
"authors": "Murakami|Yoko|Y|;Sugiyama|Akiko|A|;Ideguchi|Hideharu|H|;Murakami|Yoshitaka|Y|;Amimoto|Yuko|Y|;Nishie|Haruko|H|;Odajima|Hiroshi|H|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C582203:dupilumab; D016572:Cyclosporine",
"country": "Japan",
"delete": false,
"doi": "10.15036/arerugi.69.213",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-4884",
"issue": "69(3)",
"journal": "Arerugi = [Allergy]",
"keywords": "atopic dermatitis; children; cyclosporine A; dupilumab; prurigo nodularis",
"medline_ta": "Arerugi",
"mesh_terms": "D000293:Adolescent; D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D016572:Cyclosporine; D003876:Dermatitis, Atopic; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D011536:Prurigo; D011788:Quality of Life",
"nlm_unique_id": "0241212",
"other_id": null,
"pages": "213-217",
"pmc": null,
"pmid": "32435023",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "THREE CASES OF ATOPIC DERMATITIS CHILDREN WITH INTRACTABLE PRURIGO NODULARIS.",
"title_normalized": "three cases of atopic dermatitis children with intractable prurigo nodularis"
} | [
{
"companynumb": "NVSC2020JP227055",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Graft-vs-host disease (GVHD) after liver transplantation is a rare complication with a high mortality rate. A complex interplay between donor and recipient immunity plays a role in the development of GVHD. Infection following liver transplantation is one of the most common complications in a recipient of an organ transplant who is immunosuppressed. On clinical signs of infection, the immune reaction of the recipient can be reconstituted by withdrawal of immunosuppression in order to help combat infection. However, the discontinuation of immunosuppression could restore the donor's immune activity rather than that of the recipient. There is little information available as to whether the discontinuation of immunosuppression for severe infection could contribute to the development of GVHD in a patient who underwent ABO-incompatible (ABO-I) living donor liver transplantation (LDLT). Herein, we present a unique case of GVHD following ABO-I LDLT, for which the cessation of immunosuppression could be responsible.",
"affiliations": "Department of Laboratory Medicine, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea.;Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea.;Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea.;Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea.;Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea.;Department of Laboratory Medicine, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea. Electronic address: hilhj1120@gmail.com.;Department of Laboratory Medicine, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea.;Department of Laboratory Medicine, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea.",
"authors": "Kim|Keun Ju|KJ|;Lee|Tae Beom|TB|;Yang|Kwang Ho|KH|;Ryu|Je Ho|JH|;Choi|Byung Hyun|BH|;Lee|Hyun-Ji|HJ|;Lee|Sun-Min|SM|;Kim|In-Suk|IS|",
"chemical_list": "D000017:ABO Blood-Group System",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2019.07.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "51(9)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000017:ABO Blood-Group System; D001787:Blood Group Incompatibility; D006086:Graft vs Host Disease; D006801:Humans; D007165:Immunosuppression Therapy; D007239:Infections; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "3136-3139",
"pmc": null,
"pmid": "31611115",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Temporary Cessation of Immunosuppression for Infection May Contribute to the Development of Graft-vs-Host Disease After ABO-Incompatible Living Donor Liver Transplantation: A Case Report.",
"title_normalized": "temporary cessation of immunosuppression for infection may contribute to the development of graft vs host disease after abo incompatible living donor liver transplantation a case report"
} | [
{
"companynumb": "KR-CELLTRION INC.-2019KR027505",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nTo determine whether 3 biomarkers, L-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA), can predict outcomes in patients with Kawasaki disease (KD).\n\n\nMETHODS\nPlasma levels of L-arginine, ADMA, and SDMA were measured in 39 patients with KD and 27 febrile control patients.\n\n\nRESULTS\nPlasma L-arginine, ADMA, and SDMA levels were lower in patients with KD than in control patients before treatment with intravenous immunoglobulin (IVIG; P=.027, P<.001, and P<.001, respectively). After treatment with IVIG, L-arginine, ADMA, L-arginine/ADMA ratios, and arginine methylation ([ADMA+SDMA]/L-arginine) increased significantly (P<.001, P=.001, P=.014, and P=.001, respectively). Compared with control patients, persistent lower SDMA and higher ADMA/SDMA ratios existed in patients with KD. Furthermore, a lesser magnitude of change in terms of L-arginine and ADMA/SDMA ratios after IVIG treatment was associated with the formation of coronary dilation (P=.025, and .029, respectively).\n\n\nCONCLUSIONS\nLevels of L-arginine, ADMA, and SDMA appear to be associated with KD. Lower L-arginine levels and ADMA/SDMA after treatment with IVIG was associated with coronary artery abnormalities patients with KD.",
"affiliations": "Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.;Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.;Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.;Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. Electronic address: erickuo48@yahoo.com.tw.",
"authors": "Huang|Ying-Hsien|YH|;Tain|You-Lin|YL|;Lee|Chiu-Ping|CP|;Kuo|Ho-Chang|HC|",
"chemical_list": "D015415:Biomarkers; D016756:Immunoglobulins, Intravenous; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D001120:Arginine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3476",
"issue": "165(2)",
"journal": "The Journal of pediatrics",
"keywords": null,
"medline_ta": "J Pediatr",
"mesh_terms": "D001120:Arginine; D015415:Biomarkers; D002675:Child, Preschool; D003324:Coronary Artery Disease; D003331:Coronary Vessels; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007223:Infant; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome",
"nlm_unique_id": "0375410",
"other_id": null,
"pages": "295-9",
"pmc": null,
"pmid": "24874168",
"pubdate": "2014-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Asymmetric and symmetric dimethylarginine are associated with coronary artery lesions in Kawasaki disease.",
"title_normalized": "asymmetric and symmetric dimethylarginine are associated with coronary artery lesions in kawasaki disease"
} | [
{
"companynumb": "TW-BAXTER-2014BAX052941",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
... |
{
"abstract": "Relapsing polychondritis (RP) is a rare systemic inflammatory disease primarily affecting the ears, nose and tracheobronchial tree cartilage, but also the cardiovascular system. Cardiovascular complications are the second cause of mortality in RP. We report the case of a woman with a corticosteroid-resistant RP-associated aortitis, who was successfully treated with tocilizumab (TCZ). The FDG-PET/CT was a useful tool for diagnosing aortitis and assessing the effect of biotherapy. We conducted a systematic literature review confirming this is the first case of rapid and sustained remission in a patient with corticosteroid-resistant RP-associated aortitis after TCZ treatment administered as a first-line immunotherapy. However, further studies are needed to confirm the beneficial effect of TCZ used in this life-threatening condition.",
"affiliations": "Assistance Publique- Hôpitaux de Paris (AP-HP), Hôpital Avicenne, Service de Médecine Interne, Université Paris 13, Sorbonne Paris Cité, Faculté de Médecine SMBH, 125 Route de Stalingrad, 93009, Bobigny Cedex 9, France.;AP-HP, Hôpital Avicenne, Service de Médecine Nucléaire, Université Paris 13, Sorbonne Paris Cité, Faculté de Médecine SMBH, Bobigny, France.;Assistance Publique- Hôpitaux de Paris (AP-HP), Hôpital Avicenne, Service de Médecine Interne, Université Paris 13, Sorbonne Paris Cité, Faculté de Médecine SMBH, 125 Route de Stalingrad, 93009, Bobigny Cedex 9, France.;Assistance Publique- Hôpitaux de Paris (AP-HP), Hôpital Avicenne, Service de Médecine Interne, Université Paris 13, Sorbonne Paris Cité, Faculté de Médecine SMBH, 125 Route de Stalingrad, 93009, Bobigny Cedex 9, France.;Assistance Publique- Hôpitaux de Paris (AP-HP), Hôpital Avicenne, Service de Médecine Interne, Université Paris 13, Sorbonne Paris Cité, Faculté de Médecine SMBH, 125 Route de Stalingrad, 93009, Bobigny Cedex 9, France.;Assistance Publique- Hôpitaux de Paris (AP-HP), Hôpital Avicenne, Service de Médecine Interne, Université Paris 13, Sorbonne Paris Cité, Faculté de Médecine SMBH, 125 Route de Stalingrad, 93009, Bobigny Cedex 9, France. sebastien.abad@aphp.fr.",
"authors": "Elourimi|Ghassan|G|;Soussan|Michael|M|;Warzocha|Ursula|U|;Bugaud|Hélène|H|;Dhôte|Robin|R|;Abad|Sébastien|S|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D019788:Fluorodeoxyglucose F18; C502936:tocilizumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-017-3832-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "37(11)",
"journal": "Rheumatology international",
"keywords": "Aortitis; FDG-PET/CT; Relapsing polychondritis; Tocilizumab; Vasculitis",
"medline_ta": "Rheumatol Int",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D001025:Aortitis; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008875:Middle Aged; D011081:Polychondritis, Relapsing; D000072078:Positron Emission Tomography Computed Tomography",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "1931-1935",
"pmc": null,
"pmid": "28965131",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": "11713914;24854377;23280172;21800117;27406844;24681839;19651886;11071587;28229816;9973170;11684729;12233932;26361883;27886803;26948271;15868636;28528280;24051104;22298790;24831688;26529231;21239745;24442581;26187053;15529362;9213383;24121046;19106169;24642923;3484422;16770977;17933796",
"title": "Efficacy of tocilizumab highlighted by FDG-PET/CT in a patient with relapsing polychondritis-associated aortitis.",
"title_normalized": "efficacy of tocilizumab highlighted by fdg pet ct in a patient with relapsing polychondritis associated aortitis"
} | [
{
"companynumb": "FR-MYLANLABS-2017M1077732",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "A fifty-one years-old patient with a history of rheumatoid arthritis of recent diagnosis is hospitalized for exploration of a rapidly progressive anasarca state. First analysis discovered an impure nephrotic syndrome (acute renal failure, hematuria) and massive glomerular proteinuria. Auto-medication by nonsteroidal anti-inflammatory drug was revealed. Renal biopsy showed minimal glomerular disease and acute tubular necrosis. Corticosteroid use permitted a normalization of proteinuria and renal recovery was obtained. Literature review showed renal impairment occurring in rheumatoid polyarthritis. Minimal glomerular disease is rare but can be associated with rheumatoid arthritis. This disease, associated with the use of nonsteroidal anti-inflammatory drug, may be responsible of the patient condition.",
"affiliations": "CHRU de Lille, rue Michel-Polonowski, 59000 Lille, France.;Centre de biologie pathologie, CHRU de Lille, 59000 Lille, France.;Service de néphrologie, centre hospitalier de Dunkerque, 130, avenue Louis-Herbaux, 59240 Dunkerque, France. Electronic address: raymond.azar@ch-dunkerque.fr.",
"authors": "Daniel|Adrien|A|;Gibier|Jean-Baptiste|JB|;Azar|Raymond|R|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D004232:Diuretics",
"country": "France",
"delete": false,
"doi": "10.1016/j.nephro.2019.04.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1769-7255",
"issue": "15(6)",
"journal": "Nephrologie & therapeutique",
"keywords": "Anti-inflammatoire non stéroïdien; Insuffisance rénale; Kidney failure; Lésion glomérulaire minime; Minimal glomerular disease; Nephrotic syndrome; Nonsteroidal anti-inflammatory drug; Polyarthrite rhumatoïde; Rheumatoid arthritis; Syndrome néphrotique",
"medline_ta": "Nephrol Ther",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D001172:Arthritis, Rheumatoid; D001706:Biopsy; D015897:Comorbidity; D004232:Diuretics; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D008875:Middle Aged; D009402:Nephrosis, Lipoid; D009404:Nephrotic Syndrome; D011507:Proteinuria; D012074:Remission Induction",
"nlm_unique_id": "101248950",
"other_id": null,
"pages": "461-464",
"pmc": null,
"pmid": "31636048",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A patient with rheumatoid arthritis presenting a nephrotic syndrome: A case report.",
"title_normalized": "a patient with rheumatoid arthritis presenting a nephrotic syndrome a case report"
} | [
{
"companynumb": "FR-DEXPHARM-20200069",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional": null,
... |
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