article dict | reports listlengths 1 3.97k |
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{
"abstract": "Dabigatran etexilate is an oral direct thrombin inhibitor approved for prevention of stroke and systemic embolization in patients with nonvalvular atrial fibrillation and for the treatment of venous thromboembolism. Although dabigatran has a favorable safety profile, predictable pharmacokinetics, fewer drug interactions than warfarin, and does not require monitoring, clinical data regarding dabigatran reversal are limited. In addition, currently available laboratory assays allow measurement of the presence, but not extent, of dabigatran-associated anticoagulation. Patient age, renal function, weight, concurrent drug therapy, adherence, and concomitant disease states can affect dabigatran's efficacy and safety. Management of dabigatran-related intracranial hemorrhage must be approached on a case-by-case basis and include assessment of degree of anticoagulation, severity of hemorrhage, renal function, timing of last dabigatran dose, and risk of thromboembolic events. Initial management includes dabigatran discontinuation and general supportive measures. Oral activated charcoal should be administered in those who ingested dabigatran within 2 hours. Four-factor prothrombin complex concentrates (4PCCs), activated PCC, or recombinant activated factor VII use may be reasonable but is not evidence based. Reserve fresh frozen plasma for patients with dilutional coagulopathy. If readily available, hemodialysis should be considered, particularly in patients with advanced kidney injury or excessive risk of thromboembolic events. More clinical studies are needed to determine a standardized approach to treating dabigatran-associated intracranial hemorrhage. Institutional protocol development will facilitate safe, efficacious, and timely use of the limited management options.",
"affiliations": "Department of Pharmacy Practice, Thomas Jefferson University, Jefferson School of Pharmacy, Philadelphia, PA, USA.;Department of Pharmacy, Jefferson Hospital for Neuroscience, Philadelphia, PA, USA.;Department of Neurological Surgery, Thomas Jefferson University and Jefferson College of Medicine, Philadelphia, PA, USA ; Division of Critical Care and Neurotrauma, Jefferson Hospital for Neuroscience, Philadelphia, PA, USA.",
"authors": "King|Amber E|AE|;Szarlej|Dorota K|DK|;Rincon|Fred|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1941874415569069",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-8744",
"issue": "5(4)",
"journal": "The Neurohospitalist",
"keywords": "dabigatran; intracerebral hemorrhage; intracranial hemorrhage; subarachnoid hemorrhage; thrombin inhibitors",
"medline_ta": "Neurohospitalist",
"mesh_terms": null,
"nlm_unique_id": "101558199",
"other_id": null,
"pages": "234-44",
"pmc": null,
"pmid": "26425251",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "22315257;21998060;23271794;20651276;24081972;22343277;23855420;22314599;23219111;24685669;23625942;23389759;24841749;22315271;20214409;19966341;24076487;22709744;23670031;21762464;20352166;23474679;21576658;23666496;22438031;17764540;24920984;23562920;24075284;18076218;24406026;22817470;24562061;19717844;24029592;23634926;23704302;22117051;23484796;19376304;23221509;23991661;22215856;22812619;23718677;24786913;24891030;21059484;23634730;24259602;18534438;23370205;24994722;22627883;22394293;17869635;24323795",
"title": "Dabigatran-Associated Intracranial Hemorrhage: Literature Review and Institutional Experience.",
"title_normalized": "dabigatran associated intracranial hemorrhage literature review and institutional experience"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-55445BI",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METOPROLOL"
},
... |
{
"abstract": "A 25-year-old woman sought medical attention because of iliocaval manifestations of retroperitoneal fibrosis while she was taking methysergide. Laboratory studies yielded substantially increased serum procollagen III levels and anticardiolipin antibodies accompanied with anti-beta(2) glycoprotein I, findings not previously described with this disorder. Clinical and laboratory manifestations resolved after cessation of methysergide therapy.",
"affiliations": "Department of Clinical Haematology, St. George Hospital, Sydney, NSW, Australia.",
"authors": "Bucci|J A|JA|;Manoharan|A|A|",
"chemical_list": "D014662:Vasoconstrictor Agents; D008784:Methysergide",
"country": "England",
"delete": false,
"doi": "10.4065/72.12.1148",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-6196",
"issue": "72(12)",
"journal": "Mayo Clinic proceedings",
"keywords": null,
"medline_ta": "Mayo Clin Proc",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D008784:Methysergide; D008881:Migraine Disorders; D012185:Retroperitoneal Fibrosis; D014662:Vasoconstrictor Agents",
"nlm_unique_id": "0405543",
"other_id": null,
"pages": "1148-50",
"pmc": null,
"pmid": "9413296",
"pubdate": "1997-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Methysergide-induced retroperitoneal fibrosis: successful outcome and two new laboratory features.",
"title_normalized": "methysergide induced retroperitoneal fibrosis successful outcome and two new laboratory features"
} | [
{
"companynumb": "PHBS1998AU11431",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYSERGIDE MALEATE"
},
"drugadditional": null,
... |
{
"abstract": "We report the case of a 47-year-old man with chronic obstructive pulmonary disease who was referred to our hospital for acute dyspnea. The radiologic findings revealed consolidation with a cavity in the left upper lobe of the lung. Blood/sputum cultures detected Pseudomonas aeruginosa. Despite intensive care, the patient died from respiratory failure. Autopsy revealed multiple small necrotizing cavities that had coalesced. Although P. aeruginosa is a known causative pathogen of community-acquired pneumonia in patients with structural lung disease, the radiologic findings were non-specific. Irrespective of imaging findings, P. aeruginosa should be considered a cause of community-acquired pneumonia.",
"affiliations": "Department of Infectious Diseases, Tokyo Metropolitan Bokutoh General Hospital, Tokyo, Japan. Electronic address: naoya_sakamoto@tmhp.jp.;Department of Infectious Diseases, Tokyo Metropolitan Bokutoh General Hospital, Tokyo, Japan.;Department of Infectious Diseases, Tokyo Metropolitan Bokutoh General Hospital, Tokyo, Japan.",
"authors": "Sakamoto|Naoya|N|;Tsuchiya|Kyohei|K|;Hikone|Mayu|M|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.resinv.2017.12.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2212-5345",
"issue": "56(2)",
"journal": "Respiratory investigation",
"keywords": "Autopsy; Cavitary lesion; Community-acquired pneumonia; Pseudomonas aeruginosa",
"medline_ta": "Respir Investig",
"mesh_terms": "D000208:Acute Disease; D001344:Autopsy; D016470:Bacteremia; D001769:Blood; D017714:Community-Acquired Infections; D004417:Dyspnea; D004646:Emphysema; D017809:Fatal Outcome; D006801:Humans; D008168:Lung; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D018410:Pneumonia, Bacterial; D011550:Pseudomonas aeruginosa; D029424:Pulmonary Disease, Chronic Obstructive; D012131:Respiratory Insufficiency; D013183:Sputum",
"nlm_unique_id": "101581124",
"other_id": null,
"pages": "189-194",
"pmc": null,
"pmid": "29548659",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Community-acquired necrotizing pneumonia with bacteremia caused by Pseudomonas aeruginosa in a patient with emphysema: An autopsy case report.",
"title_normalized": "community acquired necrotizing pneumonia with bacteremia caused by pseudomonas aeruginosa in a patient with emphysema an autopsy case report"
} | [
{
"companynumb": "JP-BAUSCH-BL-2018-022421",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "THEOPHYLLINE ANHYDROUS"
},
"drugadditional": ... |
{
"abstract": "Skilled clinical decision making in the diagnosis and treatment of chronic pain can create unique clinical and ethical challenges, particularly when opioid medications are involved. This report presents the case of a pregnant woman who sought treatment for an illicit opioid dependence, initiated by opioid analgesic treatment of chronic pain. While recognizing opioids' high level of effectiveness for pain relief, the case demonstrates the potential harms of opioid medications for particular patients. Using a framework informed by medical ethics, the report discusses how clinicians might assess the benefits and risks of opioid treatment by careful data gathering, knowledge of the evidence base and patient-centered, shared decision making.",
"affiliations": "Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine. Electronic address: jacob.taylor@jhmi.edu.;Johns Hopkins University School of Medicine.;Berman Institute of Bioethics, Johns Hopkins University, and Division of General Internal Medicine, Johns Hopkins University School of Medicine.;Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine.",
"authors": "Taylor|Jacob L|JL|;McKibben|Rebeccah A|RA|;DeCamp|Matthew|M|;Chisolm|Margaret S|MS|",
"chemical_list": "D000701:Analgesics, Opioid; D010098:Oxycodone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-8343",
"issue": "36(4)",
"journal": "General hospital psychiatry",
"keywords": "Ethics; Opioid dependence; Prescription drug dependence",
"medline_ta": "Gen Hosp Psychiatry",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D059350:Chronic Pain; D011307:Drug Prescriptions; D005260:Female; D006801:Humans; D009293:Opioid-Related Disorders; D010098:Oxycodone; D011247:Pregnancy; D011248:Pregnancy Complications; D063487:Prescription Drug Misuse; D055815:Young Adult",
"nlm_unique_id": "7905527",
"other_id": null,
"pages": "449.e1-2",
"pmc": null,
"pmid": "24745324",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Putting a face on the prescription opioid epidemic: a case report.",
"title_normalized": "putting a face on the prescription opioid epidemic a case report"
} | [
{
"companynumb": "US-ACTAVIS-2015-07656",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": null,
... |
{
"abstract": "Transient esophageal motor dysfunction with dysphagia was observed in a 62-year-old man receiving vincristine-containing chemotherapy for non-Hodgkin's lymphoma. Neurological examinations, including muscle strength of extremities, deep tendon reflexes and cranial nerves, were normal. However, the patient complained of severe numbness in the fingertips and toes. The results of esophagogram and esophagoscopy were unremarkable. However, a significantly prolonged esophageal transit time was observed. Vincristine was considered as the causative agent. Empirical vitamin and metoclopramide were prescribed for his neurological symptoms but there was no improvement. The symptoms of dysphagia subsided spontaneously 2 weeks later. However, prompt recurrence of severe dysphagia was observed again after administration of the second and third courses of treatment, which again disappeared upon discontinuation of the drug. Peripheral nerves and the gastrointestinal tract are often affected by vincristine. Common gastrointestinal tract symptoms of vincristine neuropathy may be colicky abdominal pain and constipation. However, vincristine-induced esophageal motor dysfunction with dysphagia is uncommon but generally reversible. The oncologist and chemotherapist should be aware of this complication.",
"affiliations": "Department of Medicine, Veterans General Hospital-Taipei and National Yang-Ming University School of Medicine, Taiwan.",
"authors": "Wang|W S|WS|;Chiou|T J|TJ|;Liu|J H|JH|;Fan|F S|FS|;Yen|C C|CC|;Chen|P M|PM|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hyd132",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0368-2811",
"issue": "30(11)",
"journal": "Japanese journal of clinical oncology",
"keywords": null,
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000972:Antineoplastic Agents, Phytogenic; D003680:Deglutition Disorders; D015154:Esophageal Motility Disorders; D006801:Humans; D016393:Lymphoma, B-Cell; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D012026:Reflex, Stretch; D014750:Vincristine",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "515-8",
"pmc": null,
"pmid": "11155923",
"pubdate": "2000-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vincristine-induced dysphagia suggesting esophageal motor dysfunction: a case report.",
"title_normalized": "vincristine induced dysphagia suggesting esophageal motor dysfunction a case report"
} | [
{
"companynumb": "JP-PFIZER INC-2001043339JP",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
"drugadditional": nu... |
{
"abstract": "Introduction: Lurasidone has been approved in the United States as a monotherapy and adjunct for acute bipolar I depression, as well as an antipsychotic for patients with schizophrenia.Areas covered: Herein, the authors review the pharmacodynamics and pharmacokinetics of lurasidone as well and the major randomized clinical trials. The authors also provide their expert opinion.Expert opinion: Lurasidone has not been studied in patients with mania or bipolar psychosis. It has been studied, both as a monotherapy and adjunctive treatment to lithium or valproate, in acute depression and in prevention of recurrence of any mood episode in patients with bipolar disorder initially treated for bipolar depression or mania. It is approved in the United States for acute bipolar I depression. It has clinically meaningful treatment effect sizes for improvement in depression compared to placebo (0.51 monotherapy, 0.34 adjunct). The number needed to treat (NNT) for response with monotherapy was 5 (for both lower and higher dose groups), and for remission was 6 and 7 (for lower dose and higher dose groups, respectively); the NNT for adjunctive therapy was 7. It has not demonstrated efficacy in relapse prevention when added to a mood stabilizer but is safe in combination with other medications.",
"affiliations": "Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, KY, USA.;Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, KY, USA.;Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, KY, USA.",
"authors": "Ali|Ziad|Z|;Tegin|Cunyet|C|;El-Mallakh|Rif S|RS|",
"chemical_list": "D014150:Antipsychotic Agents; D014635:Valproic Acid; D000069056:Lurasidone Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1080/14656566.2019.1695777",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1465-6566",
"issue": "21(3)",
"journal": "Expert opinion on pharmacotherapy",
"keywords": "Lurasidone; bipolar depression; bipolar disorder; serotonin 7 (5HT7) receptor",
"medline_ta": "Expert Opin Pharmacother",
"mesh_terms": "D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D006801:Humans; D000069056:Lurasidone Hydrochloride; D016032:Randomized Controlled Trials as Topic; D012008:Recurrence; D014635:Valproic Acid",
"nlm_unique_id": "100897346",
"other_id": null,
"pages": "253-260",
"pmc": null,
"pmid": "31957501",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Evaluating lurasidone as a treatment option for bipolar disorder.",
"title_normalized": "evaluating lurasidone as a treatment option for bipolar disorder"
} | [
{
"companynumb": "US-OTSUKA-2020_007474",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND Unequivocal brain radiation-induced parkinsonism has so far been reported in only in two pediatric patients. However, with the rising incidence rates for brain tumors in industrialized countries and the consequential increased exposure to cranial radiotherapy, clinicians might become more exposed to this entity. CASE REPORT Three patients were treated for intraparenchymal brain tumor with resection, chemotherapy, and whole brain radiation. One patient developed leukoencephalopathy and parkinsonism within one year of treatment, one developed it seven years after treatment completion, and one developed dementia, parkinsonism and cerebral infracts 40 years after whole brain radiation. Brain MRIs and a DaTscan were obtained. All patients failed a trial of carbidopa/levodopa. We suggest that the brain radiation exposure was responsible for levodopa resistant parkinsonism, cognitive decline, and diffuse leukoencephalopathy. CONCLUSIONS Although rare, radiation therapy-induced parkinsonism might be responsible for levodopa-resistant parkinsonism.",
"affiliations": "Department of Neurology, University of Texas Health Science Center, Houston, TX, USA;Department of Neurology, Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, TX, USA;Department of Neurology, Center for Neurological Restoration, Cleveland Clinic Foundation, Cleveland, OH, USA",
"authors": "Mehanna|Raja|R|;Jimenez-Shahed|Joohi|J|;Itin|Ilia|I|",
"chemical_list": "D000978:Antiparkinson Agents; D007980:Levodopa",
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.900537",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5923",
"issue": "17()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D000368:Aged; D000978:Antiparkinson Agents; D001932:Brain Neoplasms; D002648:Child; D004351:Drug Resistance; D005260:Female; D006801:Humans; D056784:Leukoencephalopathies; D007980:Levodopa; D008297:Male; D020734:Parkinsonian Disorders; D018714:Radiotherapy, Adjuvant; D017211:Treatment Failure",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "916-920",
"pmc": null,
"pmid": "27909286",
"pubdate": "2016-12-02",
"publication_types": "D016428:Journal Article",
"references": "12849888;16765832;12461804;11032946;8024661",
"title": "Three Cases of Levodopa-Resistant Parkinsonism After Radiation Therapy.",
"title_normalized": "three cases of levodopa resistant parkinsonism after radiation therapy"
} | [
{
"companynumb": "US-APOTEX-2017AP018788",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBIDOPA\\LEVODOPA"
},
"drugadditional": null,
... |
{
"abstract": "Purple glove syndrome (PGS) often begins with discoloration and progresses to a petechial rash with induration or evidence of infiltration. The etiology of PGS is unknown, although various theories center around i.v. extravasation. We report a case of PGS in a child's foot associated with administration of Dilantin (phenytoin).",
"affiliations": "Division of Pediatric Anesthesiology and Pediatric Intensive Care, Children's Medical and Surgical Center, Johns Hopkins University, Baltimore, Maryland 21287-3711.",
"authors": "Helfaer|M A|MA|;Ware|C|C|",
"chemical_list": "D010672:Phenytoin",
"country": "United States",
"delete": false,
"doi": "10.1097/00008506-199401000-00008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0898-4921",
"issue": "6(1)",
"journal": "Journal of neurosurgical anesthesiology",
"keywords": null,
"medline_ta": "J Neurosurg Anesthesiol",
"mesh_terms": "D003116:Color; D005528:Foot; D006801:Humans; D007223:Infant; D007275:Injections, Intravenous; D008297:Male; D010672:Phenytoin; D013577:Syndrome",
"nlm_unique_id": "8910749",
"other_id": null,
"pages": "48-9",
"pmc": null,
"pmid": "8298266",
"pubdate": "1994-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Purple glove syndrome.",
"title_normalized": "purple glove syndrome"
} | [
{
"companynumb": "IN-IMPAX LABORATORIES, INC-2016-IPXL-00138",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"drugadditiona... |
{
"abstract": "Twenty patients with haematological malignancies who developed Clostridium difficile bowel infection or colonisation are described. All isolates of C difficile were toxigenic in vitro and faecal cytotoxin (toxin B) was detected in 20/26 episodes. Ten of 20 episodes with detectable faecal cytotoxin were associated with typical antibiotic associated diarrhoea. In the other 10 episodes (nine patients), there was a severe unusual illness which was associated with detection of C difficile. The unusual features of the illness were pronounced jaundice (total bilirubin greater than or equal to 44 mumol/l), abdominal pain and distension, and initial constipation followed either by diarrhoea or by large bowel stasis. Four of these patients died within seven days. Bacteraemia was often a presenting feature in neutropenic patients subsequently shown to have C difficile. This was not the case in non-neutropenic patients. Bacteraemia was commonly polymicrobial and in two cases C difficile was isolated from blood culture. The clinical implications of recognition of this atypical C difficile associated syndrome are discussed.",
"affiliations": null,
"authors": "Rampling|A|A|;Warren|R E|RE|;Bevan|P C|PC|;Hoggarth|C E|CE|;Swirsky|D|D|;Hayhoe|F G|FG|",
"chemical_list": "D003603:Cytotoxins",
"country": "England",
"delete": false,
"doi": "10.1136/jcp.38.4.445",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-9746",
"issue": "38(4)",
"journal": "Journal of clinical pathology",
"keywords": null,
"medline_ta": "J Clin Pathol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D003013:Clostridium; D003015:Clostridium Infections; D003603:Cytotoxins; D003967:Diarrhea; D005243:Feces; D005260:Female; D006801:Humans; D007938:Leukemia; D007945:Leukemia, Lymphoid; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D018805:Sepsis",
"nlm_unique_id": "0376601",
"other_id": null,
"pages": "445-51",
"pmc": null,
"pmid": "3857233",
"pubdate": "1985-04",
"publication_types": "D016428:Journal Article",
"references": "79761;495635;536461;7387278;399365;7430017;7216943;7036924;6957419;6874905;6699196;6143871",
"title": "Clostridium difficile in haematological malignancy.",
"title_normalized": "clostridium difficile in haematological malignancy"
} | [
{
"companynumb": "GB-PFIZER INC-2017190002",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditi... |
{
"abstract": "Drug rash with eosinophilia and systemic symptoms (DRESS) is a serious adverse drug reaction with a high mortality rate. Discontinuation of the causative agent is the primary treatment. History of DRESS may put patients at higher risk of future episodes; however, cross-reactivity between various medications is not well established. An 18-year-old African American male with a history of bipolar I disorder with psychotic features was admitted for mania on his home dose of divalproex. After 1 week, olanzapine was added for refractory symptoms, but due to elevated creatinine phosphokinase (CPK), it was subsequently discontinued, and he was started on lorazepam and lithium. One week later, the patient was transferred to the intensive care unit with elevated CPK, fever, thrombocytopenia, elevated serum creatinine, hypotension, diarrhea, mild rigidity, bilateral inducible ankle clonus, and a rash. All medications were discontinued except for lorazepam. The skin pathology report was consistent with a drug eruption, and he was started on prednisone. Given continued symptoms of mania, carbamazepine was initiated. After clinical and laboratory improvement, the patient was discharged on hospital day 59 with instructions to continue carbamazepine and lorazepam. A MEDLINE search revealed no published case reports of the successful use of carbamazepine in a patient with a history of DRESS. Information regarding cross-reactivity between medications is limited primarily to aromatic antiepileptics. In our case report, carbamazepine was successfully used in a patient with a recent episode of DRESS during olanzapine, lithium, and valproate use.",
"affiliations": "Psychiatry Clinical Pharmacist Specialist, Department of Pharmacy, Beaumont Health, Southfield, Michigan.;Psychiatry Clinical Pharmacist Specialist, Department of Pharmacy, Beaumont Health, Southfield, Michigan.;House Officer, Department of Psychiatry, Michigan Medicine, Ann Arbor, Michigan.;Resident, Department of Psychiatry, Michigan Medicine, Ann Arbor, Michigan.;Clinical Assistant Processor, Department of Psychiatry, Michigan Medicine, Ann Arbor, Michigan.;Clinical Specialist, Psychiatry & Neurology, Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan.",
"authors": "Bixby|Alexandra L|AL|https://orcid.org/0000-0003-1869-5202;Goldsborough|Sarah|S|https://orcid.org/0000-0002-3356-0106;Iuppa|Aaron|A|https://orcid.org/0000-0003-0928-8939;LeBlanc|Andrew|A|https://orcid.org/0000-0002-5289-5788;Schultz|Heather E|HE|https://orcid.org/0000-0001-5000-8834;VandenBerg|Amy|A|https://orcid.org/0000-0002-2294-2694",
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"country": "United States",
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"doi": "10.9740/mhc.2019.09.331",
"fulltext": "\n==== Front\nMent Health ClinMent Health ClinmhclMent Health ClinThe Mental Health Clinician2168-9709College of Psychiatric & Neurologic Pharmacists 10.9740/mhc.2019.09.331mhcl-09-05-06MHC-D-19-00008Case ReportsSuccessful use of carbamazepine in a patient with drug rash with eosinophilia and systemic symptoms Bixby Alexandra L. PharmDhttps://orcid.org/0000-0003-1869-5202Goldsborough Sarah PharmD, BCPP2https://orcid.org/0000-0002-3356-0106Iuppa Aaron MD, MPH3https://orcid.org/0000-0003-0928-8939LeBlanc Andrew MD4https://orcid.org/0000-0002-5289-5788Schultz Heather E. MD5https://orcid.org/0000-0001-5000-8834VandenBerg Amy PharmD, BCPP6https://orcid.org/0000-0002-2294-2694\n2 Psychiatry Clinical Pharmacist Specialist, Department of Pharmacy, Beaumont Health, Southfield, Michigan\n\n3 House Officer, Department of Psychiatry, Michigan Medicine, Ann Arbor, Michigan\n\n4 Resident, Department of Psychiatry, Michigan Medicine, Ann Arbor, Michigan\n\n5 Clinical Assistant Processor, Department of Psychiatry, Michigan Medicine, Ann Arbor, Michigan\n\n6 Clinical Specialist, Psychiatry & Neurology, Department of Pharmacy, Michigan Medicine, Ann Arbor, Michigan\n1 Clinical Pharmacist Specialist, University Hospitals Cleveland Medical Center, Cleveland, Ohio, albixby17@gmail.comDisclosures: The authors have no potential conflicts of interest to disclose with respect to the research, authorship, or publication of this article.\n\n9 2019 4 9 2019 9 5 331 335 © 2019 CPNP. The Mental Health Clinician is a publication of the College of Psychiatric and Neurologic Pharmacists.2019This 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.Drug rash with eosinophilia and systemic symptoms (DRESS) is a serious adverse drug reaction with a high mortality rate. Discontinuation of the causative agent is the primary treatment. History of DRESS may put patients at higher risk of future episodes; however, cross-reactivity between various medications is not well established. An 18-year-old African American male with a history of bipolar I disorder with psychotic features was admitted for mania on his home dose of divalproex. After 1 week, olanzapine was added for refractory symptoms, but due to elevated creatinine phosphokinase (CPK), it was subsequently discontinued, and he was started on lorazepam and lithium. One week later, the patient was transferred to the intensive care unit with elevated CPK, fever, thrombocytopenia, elevated serum creatinine, hypotension, diarrhea, mild rigidity, bilateral inducible ankle clonus, and a rash. All medications were discontinued except for lorazepam. The skin pathology report was consistent with a drug eruption, and he was started on prednisone. Given continued symptoms of mania, carbamazepine was initiated. After clinical and laboratory improvement, the patient was discharged on hospital day 59 with instructions to continue carbamazepine and lorazepam. A MEDLINE search revealed no published case reports of the successful use of carbamazepine in a patient with a history of DRESS. Information regarding cross-reactivity between medications is limited primarily to aromatic antiepileptics. In our case report, carbamazepine was successfully used in a patient with a recent episode of DRESS during olanzapine, lithium, and valproate use.\n\nDRESScarbamazepineolanzapinelithiumvalproateCitationHow to cite: Bixby AL, Goldsborough S, Iuppa A, LeBlanc A, Schultz HE, VandenBerg A. Successful use of carbamazepine in a patient with drug rash with eosinophilia and systemic symptoms. Ment Health Clin [Internet].\n==== Body\nBackground\nDrug rash with eosinophilia and systemic symptoms (DRESS) is a rare but serious idiosyncratic drug reaction with an incidence of 0.1 to 1 per 1000 individuals taking high-risk medications and an associated mortality rate of 10% to 20%.1,2 Medications most commonly implicated with DRESS include allopurinol (18%); sulfonamides (12%); antibiotics (11%); and aromatic antiepileptics (35%), such as carbamazepine (20%), phenytoin (7%), lamotrigine (7%), and phenobarbital (1.7%).1 The diagnosis of DRESS is difficult due to the overlapping symptoms between DRESS and other serious conditions, such as serotonin syndrome and neuroleptic malignant syndrome (NMS).1,3,4 The clinical presentation of DRESS is characterized by fever, rash, lymphadenopathy, internal organ involvement (eg, liver), and hematologic abnormalities (eg, eosinophilia).1,2 A biopsy can help confirm the diagnosis; however, the histopathologic features of the rash often show variable inflammatory patterns.5 Drug rash with eosinophilia and systemic symptoms typically occurs 2 to 8 weeks following initiation of the culprit medication.1 The pathogenesis is not well understood but thought to be related to one of the following mechanisms: a delayed immunologic reaction, a transient state of immune suppression, and/ or reactivation of latent herpes virus infections. Discontinuation of the causative agent is the primary treatment.2 Following an episode of DRESS, choosing alternative pharmacological therapies must be done cautiously as there are limited data available regarding cross-reactivity between various medications. In this case report, we discuss a patient who was initiated on carbamazepine after the development of DRESS following recent exposure to divalproex sodium, lithium, and olanzapine.\n\nCase Report\nInitial Presentation\nAn 18-year-old African American male with a history of bipolar I disorder with psychotic features was admitted to inpatient psychiatry for mania. Three days prior to presenting, he restarted divalproex sodium delayed release (1000 mg at bedtime). He presented disorganized, distractible, sexually preoccupied, and hyperverbal. Urine toxicology was negative.\n\nPertinent Past Medical/Psychiatric History\nThe patient had no known drug allergies. However, during a psychiatric admission 4 years prior, he experienced creatinine phosphatase kinase (CPK) elevations on risperidone (CPK up to 3674 IU/L). Following the discontinuation of risperidone, he was initiated on olanzapine and chlorpromazine, but this resulted in repeat CPK elevations leading to the discontinuation of all antipsychotics and requiring combination therapy with lithium, lorazepam, and divalproex. Again, CPK concentrations increased, and he developed a fever and tachycardia in the presence of a transient macular rash. All medications aside from lorazepam were stopped, and electroconvulsive therapy (ECT) was initiated. With continued ECT, taper of lorazepam, and reinitiation of divalproex, his disorganization, agitation, and psychotic features improved, and his labs normalized.\n\nHospital Course\nOn admission, the patient's home dose of divalproex was continued (Table 1). From hospital day (HD) 1 to HD 10, he received as needed oral doses of olanzapine every other day and received one dose of intramuscular olanzapine for acute agitation. On HD 10, olanzapine 5 mg oral daily was scheduled and increased to 10 mg by HD 12. On HD 15, CPK was elevated, and his olanzapine was decreased to 2.5 mg daily. Creatinine phosphatase kinase continued to rise (3642 IU/L on HD 22), and olanzapine was discontinued as a precaution based on history of possible NMS with antipsychotics despite absence of other symptoms of NMS. This elevation in CPK was attributed to an episode of agitation requiring physical restraints and a dose of intramuscular olanzapine. He continued to appear manic and was subsequently started on lithium and lorazepam. He remained clinically stable, and his CPK down-trended to 718 IU/L. On HD 28, he developed a fever, lymphadenopathy, diarrhea, diffuse abdominal pain, and an episode of dark emesis, and his CPK increased to 1435 IU/mL. Additionally, liver function enzymes, white blood count, and serum creatinine were significantly elevated from baseline. He became increasingly tired and confused, and all psychotropic medications aside from lorazepam were discontinued due to concern for NMS. He was transferred to general medicine where he developed a morbilliform rash on his chest, trunk, arms, and legs. Because serotonin syndrome was not able to be ruled out, he was started on cyproheptadine and continued until the punch biopsy results returned consistent with drug eruption (perivascular lymphocytic inflammation with mild dermal hemorrhage). Dermatology, psychiatry, and hematology consult services agreed on a suspected diagnosis of DRESS, and he was initiated on a prednisone taper. Given the anticipated prolonged corticosteroid taper, sulfamethoxazole-trimethoprim was added for prophylaxis against Pneumocystis pneumonia based on a statement by the American Thoracic Society.6 His workup was negative for infection, hepatitis virus, and antinuclear antibody. As he improved medically, he began to exhibit grandiosity and mood lability concerning for reemergence of manic symptoms. Following initiation of carbamazepine on HD 34, the medication was slowly titrated, and his mood returned to baseline by discharge on HD 59. He was briefly rehospitalized 2 days after discharge due to residual symptoms in the context of psychosocial stressors, but no medication changes were made. During an outpatient follow-up, he continued to appear euthymic and all DRESS-related symptoms were resolved.\n\nTABLE 1 Patient summary\n\nDay\tEvent\t\n0\tContinued home dose of divalproex sodium delayed release 1000 mg at bedtime\t\nWeight: 72 kg\t\nSCr: 0.9 mg/dL\t\nAST: 28 IU/L\t\nWBC: 12 000/μL\t\nPlatelets: 186 000/μL\t\n10\tOlanzapine 5 mg intramuscular given for acute agitation\t\nOlanzapine 5 mg orally once daily scheduled\t\nCPK: 844 IU/L\t\n12\tOlanzapine oral increased to 10 mg daily\t\nCPK: 740 IU/L\t\nValproic acid: 74.6 μg/mL\t\n15\tOlanzapine oral reduced to 2.5 mg daily\t\nCPK: 1374 IU/L\t\n17\tHaloperidol 5 mg intramuscular given once for agitation\t\nCPK: 631 IU/L\t\n20\tValproic acid: 106.7 μg/mL\t\nCPK: 1319 IU/L\t\n21\tOlanzapine 5 mg intramuscular given for acute agitation\t\nLorazepam 1 mg oral twice daily and lithium 300 mg oral twice daily initiated\t\nCPK: 1415 IU/L\t\n22\tOlanzapine discontinued\t\nCPK: 3642 IU/L\t\nTmax: 36.7°C\t\n26\tCPK: 718 IU/L\t\nValproic acid: 88 μg/mL\t\n27\tTmax: 39.5°C\t\nBP: 89/51 mmHg\t\nPulse: 125 BPM\t\nSCr: 1.3 mg/dL\t\nPlatelets: 80 000/μL\t\nCPK: 1435 IU/L\t\nValproic acid: 32.8 μg/mL\t\nLithium: 0.38 mmol/L\t\nDiarrhea, abdominal pain, mild rigidity, bilateral inducible ankle clonus\t\nMorbiliform rash on trunk and legs\t\nDivalproex sodium and lithium were discontinued\t\n29\tPunch biopsy obtained\t\nCPK: 4618 IU/L\t\nAbsolute lymphocyte count: 600/μL\t\nCyproheptadine 12 mg once, followed by 6 mg every 6 h started\t\n31\tPunch biopsy results consistent with drug eruption/reactive erythema\t\nCyprohepatadine stopped\t\nPrednisone 1 mg/kg/d oral and SMX/TMP 800-160 mg 3 times weekly initiated\t\nAST: 525 IU/L\t\n33\tWBC: 33 200/μL (peak)\t\nAbsolute eosinophils: 2700/μL (peak)\t\n34\tCarbamazepine 200 mg twice daily initiated\t\nAbsolute lymphocyte count: 8000/μL (peak)\t\nRash documented to be resolving\t\nCPK: 1499 IU/L\t\n59\tDischarged on carbamazepine 800 mg twice daily\t\nCPK: 161 IU/L\t\n61-68\tReadmitted to inpatient psychiatry\t\nWBC: 10 900/μL\t\nAbsolute lymphocyte count: 3300/μL\t\nAbsolute eosinophils: 0/μL\t\nPlatelets: 187 000/μL\t\nSCr: 0.83 mg/dL\t\nAST: 27 IU/L\t\nCPK: 386 IU/L\t\nCarbamazepine concentration: 9.0 mg/L\t\n84\tOutpatient follow-up visit\t\nMood appeared euthymic\t\nAll DRESS-related symptoms resolved\t\nNo labs obtained\t\nAST = aspartate aminotransferase; BP = blood pressure; CPK = creatinine phosphokinase; DRESS = drug rash with eosinophilia and systemic symptoms; SCr = serum creatinine; SMX/TMP = sulfamethoxazole-trimethoprim; Tmax = maximum temperature; WBC = white blood count.\n\nDiscussion\nThe differential diagnosis in this case included DRESS, serotonin syndrome, sepsis, and NMS. Based on the punch biopsy results, eosinophilia, and improvement following corticosteroid administration, it was determined that DRESS was the most definitive explanation for this presentation. Additionally, he scored a 6 of 9 on the DRESS scoring system developed by Karduan et al,1 which indicates a definite case of DRESS. However, the patient also met the diagnostic criteria for serotonin syndrome and NMS (Table 2). Divalproex, lithium, and olanzapine were subsequently discontinued. The patient was treated with corticosteroids based on treatment success in prior reports.1,2\n\nTABLE 2 Differential diagnosisa\n\nCategory\tDRESS1\tSerotonin Syndrome3\tNeuroleptic Malignant Syndrome4\t\nExposure\tReaction suspected to be drug-related\tRecent exposure to a serotonergic agent\nNo recent addition of a neuroleptic agent\tRecent exposure to dopamine antagonist\t\nHematologic\tHypereosinophilia\nBlood count abnormalities\nLymphocytosis\t…\tLeukocytosis\t\nOrgan involvement\tInvolvement of at least one internal organ\t…\t…\t\nNeurologic function\t…\tAltered mental status\nAgitation\tAltered mental status\t\nMusculoskeletal\t…\tMyoclonus\nHyperreflexia\nTremor\tElevated CPK\nSevere muscle rigidity\nTremor\t\nDermatologic\tAcute rash\t…\t…\t\nOther\tLymphadenopathy\nFever (>38°C)\tDiaphoresis\nFever (>38°C)\nDiarrhea\nShivering\tFever (>38°C)\nTachycardia\nDiaphoresis\nElevated or labile blood pressure\nMutism\t\nCPK = creatinine phosphokinase; DRESS = drug rash with eosinophilia and systemic symptoms.\n\na Bold indicates signs and symptoms the patient exhibited during hospital admission.\n\nDetermining the causative agent was challenging as all 3 medications have been associated with DRESS. Divalproex has been implicated as a cause of DRESS and has the most published reports of DRESS among the medications that the patient was taking.2 However, he previously tolerated divalproex monotherapy and historically only had adverse reactions when it was combined with antipsychotics or lithium. Lithium has been associated with DRESS in a limited number of case reports.7,8 However, the patient was only taking lithium for 6 days prior to the onset of DRESS, making it an unlikely culprit. Symptoms began roughly 21 days after the first dose of olanzapine, which is consistent with the onset of DRESS reported in the literature.1,2 Olanzapine is not an agent that has traditionally been associated with DRESS. However, in 2016, the US Food and Drug Administration9 published a warning regarding the risk of DRESS associated with olanzapine following 23 cases of olanzapine-induced DRESS.\n\nIn addition to discontinuing the agent(s) that may have induced DRESS, it is recommended to avoid agents with similar structures because cross-reactivity between aromatic anticonvulsants may be as high as 80%.2,10,11 Although less common, there are case reports of DRESS caused by nonaromatic psychotropic medications.2 As valproate and lithium are not aromatic and structurally dissimilar to the aromatic anticonvulsant carbamazepine, cross-reactivity was unlikely.12 There are some structural similarities between carbamazepine and olanzapine. In fact, 1 case report exists describing the cross-reactivity between these agents in a patient who developed DRESS.13 Case reports10,14-16 also describe secondary neosensitization to certain medications following DRESS induced by structurally different agents. Neosensitization is thought to be caused by a transient state of immunosuppression induced during the first episode of DRESS that may trigger a nonspecific immune system response leading to the inability to tolerate other drugs present at the time. In several reports of neosensitization, the agent that was related to the second hypersensitivity episode was initiated during the first episode of DRESS,15,16 but this was not consistent in every case.10,14,16 Although a positive history of DRESS is a major risk factor for future episodes, our patient was left with limited treatment options for his bipolar mania.2\n\nThe American Psychiatric Association (APA)17 recommends lithium, valproate, or a second-generation antipsychotic as the first-line treatment of acute mania. Because the patient was receiving all of these medications prior to the development of DRESS and none could be excluded as the causative agent, it was difficult to determine the most appropriate agent for the treatment of his bipolar disorder. Alternative treatment options recommended by the American Psychiatric Association include carbamazepine and ECT. Based on the patient's preference, ECT was not considered at this time. A MEDLINE search revealed no published case reports of the successful use of carbamazepine in a patient with a history of DRESS from a nonaromatic medication. Although carbamazepine carries a relatively high risk of DRESS, it was determined to be the safest option. Additionally, sulfamethoxazole-trimethoprim (which has a relatively high rate of DRESS) was successfully used.\n\nConclusion\nWhen patients have severe drug reactions, it is important to minimize risk of recurrence. Previous reports have demonstrated the cross-reactivity of certain psychotropic medications in causing DRESS. Ideally, alternative medications following an episode of DRESS should be structurally dissimilar and associated with a low risk of reaction. In this case, we were successfully able to use both carbamazepine and sulfamethoxazole-trimethoprim even though both have a relatively high rate of DRESS.\n==== Refs\nReferences\n1 Kardaun SH Sekula P Valeyrie-Allanore L Liss Y Chu CY Creamer D Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study Br J Dermatol 2013 169 5 1071 80 DOI: 10.1111/bjd.12501 PubMed PMID: 23855313 23855313 \n2 Bommersbach TJ Lapid MI Leung JG Cunningham JL Rummans TA Kung S Management of psychotropic drug-induced DRESS syndrome: a systematic review Mayo Clin Proc 2016 91 6 787 801 DOI: 10.1016/j.mayocp.2016.03.006 PubMed PMID: 27126302 27126302 \n3 Sternbach H The serotonin syndrome Am J Psychiatry 1991 148 6 705 13 DOI: 10.1176/ajp.148.6.705 PubMed PMID: 2035713 2035713 \n4 American Psychiatric Association Diagnostic and statistical manual of mental disorders. 5th ed Washington American Psychiatric Association; 2013 \n5 Ortonne N Valeyrie-Allanore L Bastuji-Garin S Wechsler J de Feraudy S Duong T-A Histopathology of drug rash with eosinophilia and systemic symptoms syndrome: a morphological and phenotypical study Br J Dermatol 2015 173 1 50 8 DOI: 10.1111/bjd.13683 PubMed PMID: 25630796 25630796 \n6 Limper AH Knox KS Sarosi GA Ampel NM Bennett JE Catanzaro A An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients Am J Respir Crit Care Med 2011 183 1 96 128 DOI: 10.1164/rccm.2008-740ST PubMed PMID: 21193785 21193785 \n7 Bains A Lithium-induced drug reaction with eosinophilia and systemic symptom syndrome Indian J Dermatol 2017 62 5 532 3 DOI: 10.4103/ijd.IJD_248_16 PubMed PMID: 28979021 28979021 \n8 Jeung Y-J Lee J-Y Oh M-J Choi D-C Lee B-J Comparison of the causes and clinical features of drug rash with eosinophilia and systemic symptoms and Stevens-Johnson syndrome Allergy Asthma Immunol Res 2010 2 2 123 6 DOI: 10.4168/aair.2010.2.2.123 PubMed PMID: 20358026 PubMed Central PMCID: PMC2846735 20358026 \n9 US Food and Drug Administration (FDA) FDA drug safety communication: FDA warns about rare but serious skin reactions with mental health drug olanzapine (Zyprexa, Zyprexa Zydis, Zyprexa Relprevv, and Symbyax) [Internet] Silver Spring (MD) FDA 2016 [cited 2018 Apr 1]. Available from: https://www.fda.gov/Drugs/DrugSafety/ucm499441.htm \n10 Seitz CS Pfeuffer P Raith P Bröcker EB Trautmann A Anticonvulsant hypersensitivity syndrome: cross-reactivity with tricyclic antidepressant agents Ann Allergy Asthma Immunol 2006 97 5 698 702 DOI: 10.1016/S1081-1206(10)61103-9 PubMed PMID: 17165282 17165282 \n11 Alvestad S Lydersen S Brodtkorb E Cross-reactivity pattern of rash from current aromatic antiepileptic drugs Epilepsy Res 2008 80 2-3 194 200 DOI: 10.1016/j.eplepsyres.2008.04.003 PubMed PMID: 18490142 18490142 \n12 Le Louarn E Barbaud A Trechot P Marcou G Lepoittevin J-P The use of three-dimensional similarity in assessing the risk of cross-reactivity between carbamazepine and psychotropic drugs Eur J Clin Pharmacol 2014 70 4 495 8 DOI: 10.1007/s00228-013-1627-0 PubMed PMID: 24408579 24408579 \n13 Brajon D Trechot P Waton J Cuny JF Schmutz JL Barbaud A Suspicion of a new cross-reaction between carbamazepine and olanzapine J Investig Allergol Clin Immunol 2014 24 1 60 1 PubMed PMID: 24765884 \n14 Song JM Jung YE Park JH Kim MD Cheon MS Lee CI Neosensitization to multiple drugs following valproate-induced drug reaction with eosinophilia and systemic symptoms syndrome Psychiatry Investig 2017 14 4 518 20 DOI: 10.4306/pi.2017.14.4.518 PubMed PMID: 28845181 PubMed Central PMCID: PMC5561412 \n15 Gaig P García-Ortega P Baltasar M Bartra J Drug neosensitization during anticonvulsant hypersensitivity syndrome J Investig Allergol Clin Immunol 2006 16 5 321 6 PubMed PMID: 17039674 \n16 Ben Fredj N Aouam K Chaabane A Toumi A Ben Rhomdhane F Boughattas N Hypersensitivity to amoxicillin after drug rash with eosinophilia and systemic symptoms (DRESS) to carbamazepine and allopurinol: a possible co-sensitization Br J Clin Pharmacol 2010 70 2 273 6 DOI: 10.1111/j.1365-2125.2010.03685.x PubMed PMID: 20653681 PubMed Central PMCID: PMC2911558 20653681 \n17 American Psychiatric Association Practice guideline for the treatment of patients with bipolar disorder (revision) Am J Psychiatry 2002 159 4 Suppl 1 50 PubMed PMID 11958165\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2168-9709",
"issue": "9(5)",
"journal": "The mental health clinician",
"keywords": "DRESS; carbamazepine; lithium; olanzapine; valproate",
"medline_ta": "Ment Health Clin",
"mesh_terms": null,
"nlm_unique_id": "101728585",
"other_id": null,
"pages": "331-335",
"pmc": null,
"pmid": "31534877",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": "11958165;17039674;17165282;18490142;2035713;20358026;20653681;21193785;23855313;24408579;24765884;25630796;27126302;28845181;28979021",
"title": "Successful use of carbamazepine in a patient with drug rash with eosinophilia and systemic symptoms.",
"title_normalized": "successful use of carbamazepine in a patient with drug rash with eosinophilia and systemic symptoms"
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"companynumb": "US-JUBILANT CADISTA PHARMACEUTICALS-2021JUB00263",
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"activesubstancename": "OLANZAPINE"
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"abstract": "Splenic rupture secondary to colonoscopy is a rare but potentially fatal complication. Given the disparity between the small number of case reports with the incidence reported by some investigators, we contend that the former is not representative of the true extent of this sequela. We present a case report of postcolonoscopy splenic rupture, where the patient had a bizarre initial presentation of chest pain and collapse; and only developed haemodynamic instability and abdominal pain on day 2 postprocedure. Diagnosis was made with a CT scan, and resolution of symptoms was achieved with a splenectomy.",
"affiliations": "General Surgery, Belford Hospital, Fort William, Highland, UK.;General Surgery, Belford Hospital, Fort William, Highland, UK.",
"authors": "Chow|Bing Lun|BL|http://orcid.org/0000-0002-8989-5343;Zia|Khawaja|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-231047",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(9)",
"journal": "BMJ case reports",
"keywords": "endoscopy; gastroenterology; general surgery",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D003113:Colonoscopy; D006801:Humans; D015994:Incidence; D008297:Male; D013154:Spleen; D014947:Wounds and Injuries",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31511266",
"pubdate": "2019-09-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21960762;22520377;23477750;23737576;21951473;19638324;22889306;16120923;23262476;19528563;25298862;26971282;19542830;19850154;27479605;18058621;26354835;29363661;19749393;28562115;30651952;28003318;20202406;20217421",
"title": "Postcolonoscopy splenic rupture: the under-reporting of an unpropitious phenomena?",
"title_normalized": "postcolonoscopy splenic rupture the under reporting of an unpropitious phenomena"
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"companynumb": "GB-MYLANLABS-2019M1102769",
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"abstract": "BACKGROUND\nThe utilization of bolus-dose phenylephrine (PHE) has transitioned to the emergency department (ED) for the treatment of acutely hypotensive patients, despite a paucity of literature in this setting.\n\n\nMETHODS\nThis was a single center retrospective chart review of the utilization of bolus-dosed PHE for acute hypotension in the ED at an academic non-forprofit hospital. The primary objective of this study is to report the frequency of patients that were initiated on a continuous vasopressor infusion (CVI) within 30 minutes after the first administration of bolus-dose PHE. Secondary objectives included an observational description of the impact of early preload expansion (fluids) on the initiation of CVIs in the setting of bolus-dose PHE in the ED.\n\n\nRESULTS\nSeventy-three patients met inclusion criteria for analysis. The primary outcome, 46.5% (n = 34) of patients were initiated on a CVI within 30 minutes following bolus-dose PHE. Initial preload expansion (30 mL/kg of IV fluids) was found to be significantly disproportionate with 34.2% appropriately fluid challenged vs 65.8% (P = .0048). In addition, a significant decrease in the number of PHE bolus doses were required [1.5 vs 2.3 (P = .01)] in the adequately IVF challenged group. For secondary endpoints, PHE was most commonly indicated for peri-intubation hypotension (n = 52, 71.2%). Significant adverse events were documented for 15 (20.5%) patients, with bradycardia (n = 7; 9.6%) as the most common adverse event.\n\n\nCONCLUSIONS\nInitial preload IVF expansion was found to be significantly disproportionate, and appears to be associated with an increase number of phenylephrine bolus doses in our study population.",
"affiliations": "University of Florida College of Pharmacy, 580 West 8th Street, Box T-5, Jacksonville, FL 32209. Electronic address: mbschwartz@ufl.edu.;Medical ICU, Department of Pharmacy UF Health - Jacksonville, 655 West 8th Street, Box C-89, Jacksonville, FL 32209. Electronic address: Jason.Ferreira@Jax.ufl.edu.;Emergency Medicine, Department of Pharmacy UF Health - Jacksonville, 655 West 8th Street, Box C-89, Jacksonville, FL 32209. Electronic address: aaronson@poison.ufl.edu.",
"authors": "Schwartz|Madison B|MB|;Ferreira|Jason A|JA|;Aaronson|Patrick M|PM|",
"chemical_list": "D058646:Adrenergic alpha-1 Receptor Agonists; D010656:Phenylephrine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2016.09.041",
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"issn_linking": "0735-6757",
"issue": "34(12)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D058646:Adrenergic alpha-1 Receptor Agonists; D000368:Aged; D001794:Blood Pressure; D001919:Bradycardia; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D007022:Hypotension; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010656:Phenylephrine; D012189:Retrospective Studies",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "2419-2422",
"pmc": null,
"pmid": "27720568",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "The impact of push-dose phenylephrine use on subsequent preload expansion in the ED setting.",
"title_normalized": "the impact of push dose phenylephrine use on subsequent preload expansion in the ed setting"
} | [
{
"companynumb": "US-ECLAT PHARMACEUTICALS-2016ECL00071",
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... |
{
"abstract": "BACKGROUND\nVoriconazole is extensively metabolized by the CYP450 isoenzymes 2C19 and 3A4 and to a lesser extent by CYP2C9; therefore, any medication that affects this pathway can alter its plasma concentration. Treatment failure can probably occur if subtherapeutic levels are achieved.\n\n\nMETHODS\nA 32-year-old woman who suffered from acute lymphoblastic leukemia was admitted and received treatment with vincristine and dexamethasone. After several days, to control her fever, based on two consecutive positive serum galactomannan test results, voriconazole as an antifungal agent was added to Aspergillus infection treatment. Through the first week after voriconazole initiation, its plasma concentrations were subtherapeutic. The most suspicious medication for interaction was dexamethasone, which can induce CYP450 isoenzymes and reduce plasma concentration.\n\n\nCONCLUSIONS\nAs a result of the narrow therapeutic window of voriconazole and the relationship between efficacy and plasma concentration of azoles, therapeutic drug monitoring of voriconazole in patients receiving a high dose of glucocorticoids is recommended, in order to achieve optimal response to treatment and toxicity reduction. Further studies regarding the interaction between voriconazole and dexamethasone to prevent clinically relevant interactions should be considered.",
"affiliations": "1 Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.;1 Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.;1 Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.;3 Hematology-Oncology Research Center and Stem Cell Transplantation, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.;3 Hematology-Oncology Research Center and Stem Cell Transplantation, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Taghvaye Masoumi|Hamidreza|H|;Hadjibabaie|Molouk|M|;Gholami|Kheirollah|K|;Zarif-Yeganeh|Morvarid|M|https://orcid.org/0000-0003-2196-4119;Ghavamzadeh|Ardeshir|A|",
"chemical_list": "D014750:Vincristine; D003907:Dexamethasone; D065819:Voriconazole",
"country": "England",
"delete": false,
"doi": "10.1177/1078155218783248",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(5)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Voriconazole; acute lymphoblastic leukemia; dexamethasone; drug interaction; therapeutic drug monitoring",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000328:Adult; D003907:Dexamethasone; D004347:Drug Interactions; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014750:Vincristine; D065819:Voriconazole",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1239-1242",
"pmc": null,
"pmid": "29945531",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Significant drug interaction between voriconazole and dexamethasone: A case report.",
"title_normalized": "significant drug interaction between voriconazole and dexamethasone a case report"
} | [
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"companynumb": "PHHY2018IR074191",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
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"activesubstancename": "VANCOMYCIN"
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"drugadditional": "3",
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{
"abstract": "BACKGROUND\nJuvenile idiopathic arthritis (JIA) is the most common chronic rheumatologic disease of childhood. The various subtypes of JIA differ in clinical features and treatments. The aim of this study was to analyze the frequency of JIA subtypes, patient demographic and clinical features, as well as the rates of macrophage activation syndrome, uveitis, and remission in Turkish JIA patients treated at a single center, and to compare the findings to those in the literature.\n\n\nMETHODS\nThe files of all JIA patients treated at our pediatric rheumatology department between January 2017 and January 2019 were retrospectively reviewed. Patient demographic, clinical, and laboratory data were obtained from the patients' files and the hospital database.\n\n\nRESULTS\nThe study included 305 patients (180 females) with a mean age at onset of 7.83 ± 4.62 years. Among all the JIA subtypes, the most frequent was oligoarthritis (41.6%), followed by enthesitis-related arthritis (29.2%), rheumatoid factor (RF)-negative polyarthritis (13.4%), systemic arthritis (9.5%), RF-positive polyarthritis (2.6%), psoriatic arthritis (2.0%), and undifferentiated arthritis (1.6%). At the time of data collection, 278 patients (91.0%) were in remission, whereas 27 patients (9.0%) had active disease. Macrophage activation syndrome developed in 12 of the 29 (41.0%) systemic arthritis. Uveitis was noted in 32 (10.0%) patients. Biological agents were administered in 142 of the patients.\n\n\nCONCLUSIONS\nThe available data indicate that JIA as a whole is a heterogeneous disease with significant variability in course and long-term outcome. As such, each patient should be evaluated according to his / her disease subtype.",
"affiliations": "Departments of, Department of, Pediatric Rheumatology, Dr Sami Ulus Maternity and Child Health and Diseases Training and Research Hospital, Ankara, Turkey.;Departments of, Department of, Pediatric Rheumatology, Dr Sami Ulus Maternity and Child Health and Diseases Training and Research Hospital, Ankara, Turkey.;Departments of, Department of, Pediatric Rheumatology, Dr Sami Ulus Maternity and Child Health and Diseases Training and Research Hospital, Ankara, Turkey.;Departments of, Department of, Pediatric Rheumatology, Dr Sami Ulus Maternity and Child Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of, Pediatrics, Dr Sami Ulus Maternity and Child Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of, Pediatrics, Dr Sami Ulus Maternity and Child Health and Diseases Training and Research Hospital, Ankara, Turkey.;Departments of, Department of, Pediatric Rheumatology, Dr Sami Ulus Maternity and Child Health and Diseases Training and Research Hospital, Ankara, Turkey.",
"authors": "Ozdel|Semanur|S|https://orcid.org/0000-0001-5602-4595;Baglan|Esra|E|https://orcid.org/0000-0001-5637-8553;Cakıcı|Evrim Kargın|EK|https://orcid.org/0000-0002-1697-6206;Yazılıtas|Fatma|F|https://orcid.org/0000-0001-6483-8978;Yücel|Hüsniye|H|https://orcid.org/0000-0002-7477-0302;Senel|Saliha|S|;Bulbul|Mehmet|M|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/ped.14481",
"fulltext": null,
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"issn_linking": "1328-8067",
"issue": "63(6)",
"journal": "Pediatrics international : official journal of the Japan Pediatric Society",
"keywords": "arthritis; idiopathic; juvenile; remission",
"medline_ta": "Pediatr Int",
"mesh_terms": "D001171:Arthritis, Juvenile; D002648:Child; D005260:Female; D006801:Humans; D055501:Macrophage Activation Syndrome; D012189:Retrospective Studies; D012219:Rheumatology; D014605:Uveitis",
"nlm_unique_id": "100886002",
"other_id": null,
"pages": "636-642",
"pmc": null,
"pmid": "32969552",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical features in 305 patients with juvenile idiopathic arthritis: A single center Turkish Study.",
"title_normalized": "clinical features in 305 patients with juvenile idiopathic arthritis a single center turkish study"
} | [
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"activesubstancename": "INFLIXIMAB"
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... |
{
"abstract": "In the present report, we describe a man with type 2 progressive squamous cell carcinoma (cT3N1M0, cStage Ⅲ) that was detected in the esophago-gastric junction during follow-up after ESD for early gastric cancer. We performed a middle inferior part esophagectomy, a 2-region dissection, and a posterior mediastinum gastric tube reconstruction after preoperative chemotherapy (docetaxel plus cisplatin plus 5-FU). The patient only received 1 course of preoperative chemotherapy because of neutropenia. The pathology results were pT3N2M0, pStage Ⅲ. Six months later, we started chemotherapy (nedaplatin plus adriamycin plus 5-FU) owing to an abdominal lymph node recurrence. We administered 3 courses, but then switched to radiotherapy because of AEs. After receiving a radiation dose of 50.4 Gy, the patient experienced a para-aortic lymph node recurrence and was administered 50.4 Gy for the new lesion, resulting in a CR. Six months later, we identified lymph node recurrences under the left superficialis neck muscle and performed left cervical lymph node resection. All 3 of the enlarged lymph nodes that we resected were found to contain a metastasis of esophageal cancer. Currently (after 6 months), there are no signs of recurrence.",
"affiliations": "Dept. of Surgery, National Hospital Organization Osaka National Hospital.",
"authors": "Murakami|Hirotomo|H|;Nishikawa|Kazuhiro|K|;Hirao|Motohiro|M|;Yamamoto|Kazuyoshi|K|;Maeda|Sakae|S|;Uemura|Mamoru|M|;Miyake|Masakazu|M|;Hama|Naoki|N|;Ohmiya|Hideyasu|H|;Miyamoto|Atsushi|A|;Miyazaki|Michihiko|M|;Ikeda|Masataka|M|;Takami|Koji|K|;Nakamori|Shoji|S|;Sekimoto|Mitsugu|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "42(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D003131:Combined Modality Therapy; D004938:Esophageal Neoplasms; D006801:Humans; D008197:Lymph Node Excision; D008207:Lymphatic Metastasis; D008297:Male",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1626-8",
"pmc": null,
"pmid": "26805118",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A Case of Combined Modality Therapy for a Cervical Lymph Node Recurrence after Surgery for Esophageal Cancer.",
"title_normalized": "a case of combined modality therapy for a cervical lymph node recurrence after surgery for esophageal cancer"
} | [
{
"companynumb": "JP-BAUSCH-BL-2017-005874",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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"activesubstance": {
"activesubstancename": "DOXORUBICIN"
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"drugadditional": null,
... |
{
"abstract": "Idiopathic intracranial hypertension (IIH), also known as pseudotumour cerebri syndrome (PTCS), is characterized by the presence of signs and symptoms of raised intracranial pressure without evidence of any intracranial structural cause and with normal cerebrospinal fluid microscopy and biochemistry. Obesity, various systemic diseases and endocrine conditions, and a number of medications are known to be risk factors for PTCS. The medications commonly associated with PTCS are amiodarone, antibiotics, corticosteroids, cyclosporine, growth hormone, oral contraceptives, vitamin A analogues, lithium, phenytoin, NSAIDs, leuprolide acetate, and some neuroleptic drugs. In relation to antibiotics, quinolones may cause intracranial hypertension, and most reported cases of quinolone-induced intracranial hypertension were associated with nalidixic acid, ciprofloxacin, ofloxacin, or pefloxacin. Literature reports of levofloxacin-induced PTCS are rare. Some authors recently hypothesized that Mycoplasma pneumoniae may trigger PTCS.\n\n\n\nWe report on a 14-year-old overweight White Italian boy who suffered headache, diplopia, and severe bilateral papilloedema after a Mycoplasma pneumoniae infection, exacerbated on levofloxacin intake. A spontaneous improvement in headache and a reduction in diplopia was seen during hospitalisation. Oral acetazolamide therapy led to the regression of papilloedema in about five months. No permanent eye damage has been observed in our patient to date.\n\n\n\nPTCS pathophysiology may be multifactorial and its specific features and severity may be a consequence of both constitutional and acquired factors interacting synergistically. It may be useful for paediatricians to know that some antibiotics may have the potential to precipitate PTCS in patients who already have an increased CSF pressure due to a transitory imbalanced CSF circulation caused by infections such as Mycoplasma pneumoniae, with headache being the first and most sensitive, but also the least specific, symptom.",
"affiliations": "Pediatric Highly Intensive Care Unit, Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. laura.maffeis@gmail.com.;Service of Pediatric Neurophysiology , Unit of Clinical Neurophysiology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.;Pediatric Highly Intensive Care Unit, Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Pediatric Highly Intensive Care Unit, Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Service of Pediatric Neurophysiology , Unit of Clinical Neurophysiology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.;Department of Ophthalmology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Division of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Pediatric Highly Intensive Care Unit, Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, and a Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.",
"authors": "Maffeis|Laura|L|0000-0002-5422-7927;Dilena|Robertino|R|;Guez|Sophie|S|;Menni|Francesca|F|;Bana|Cristina|C|;Osnaghi|Silvia|S|;Carrabba|Giorgio|G|;Marchisio|Paola|P|",
"chemical_list": "D000900:Anti-Bacterial Agents; D064704:Levofloxacin",
"country": "England",
"delete": false,
"doi": "10.1186/s12887-018-1371-9",
"fulltext": "\n==== Front\nBMC PediatrBMC PediatrBMC Pediatrics1471-2431BioMed Central London 137110.1186/s12887-018-1371-9Case ReportPseudotumour cerebri associated with mycoplasma pneumoniae infection and treatment with levofloxacin: a case report http://orcid.org/0000-0002-5422-7927Maffeis Laura laura.maffeis@gmail.com 1Dilena Robertino robertino.dilena@policlinico.mi.it 2Guez Sophie sophie.guez@policlinico.mi.it 1Menni Francesca francesca.menni@policlinico.mi.it 1Bana Cristina cristina.bana@policlinico.mi.it 2Osnaghi Silvia silvia.osnaghi@policlinico.mi.it 3Carrabba Giorgio giorgio.carrabba@policlinico.mi.it 4Marchisio Paola paola.marchisio@unimi.it 51 0000 0004 1757 8749grid.414818.0Pediatric Highly Intensive Care Unit, Fondazione IRCSS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy 2 0000 0004 1757 8749grid.414818.0Service of Pediatric Neurophysiology , Unit of Clinical Neurophysiology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy 3 0000 0004 1757 8749grid.414818.0Department of Ophthalmology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy 4 0000 0004 1757 8749grid.414818.0Division of Neurosurgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy 5 0000 0004 1757 2822grid.4708.bPediatric Highly Intensive Care Unit, Fondazione IRCSS Ca’ Granda Ospedale Maggiore Policlinico, and a Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy 5 1 2019 5 1 2019 2019 19 44 5 2018 13 12 2018 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nIdiopathic intracranial hypertension (IIH), also known as pseudotumour cerebri syndrome (PTCS), is characterized by the presence of signs and symptoms of raised intracranial pressure without evidence of any intracranial structural cause and with normal cerebrospinal fluid microscopy and biochemistry.\n\nObesity, various systemic diseases and endocrine conditions, and a number of medications are known to be risk factors for PTCS. The medications commonly associated with PTCS are amiodarone, antibiotics, corticosteroids, cyclosporine, growth hormone, oral contraceptives, vitamin A analogues, lithium, phenytoin, NSAIDs, leuprolide acetate, and some neuroleptic drugs. In relation to antibiotics, quinolones may cause intracranial hypertension, and most reported cases of quinolone-induced intracranial hypertension were associated with nalidixic acid, ciprofloxacin, ofloxacin, or pefloxacin. Literature reports of levofloxacin-induced PTCS are rare. Some authors recently hypothesized that Mycoplasma pneumoniae may trigger PTCS.\n\nCase presentation\nWe report on a 14-year-old overweight White Italian boy who suffered headache, diplopia, and severe bilateral papilloedema after a Mycoplasma pneumoniae infection, exacerbated on levofloxacin intake. A spontaneous improvement in headache and a reduction in diplopia was seen during hospitalisation. Oral acetazolamide therapy led to the regression of papilloedema in about five months. No permanent eye damage has been observed in our patient to date.\n\nConclusions\nPTCS pathophysiology may be multifactorial and its specific features and severity may be a consequence of both constitutional and acquired factors interacting synergistically. It may be useful for paediatricians to know that some antibiotics may have the potential to precipitate PTCS in patients who already have an increased CSF pressure due to a transitory imbalanced CSF circulation caused by infections such as Mycoplasma pneumoniae, with headache being the first and most sensitive, but also the least specific, symptom.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12887-018-1371-9) contains supplementary material, which is available to authorized users.\n\nKeywords\nIntracranial hypertensionPseudotumour cerebri syndromeMycoplasma pneumoniaeLevofloxacinPaediatrichttp://dx.doi.org/10.13039/501100009702Fondazione IRCCS Ca' Granda Ospedale Maggiore PoliclinicoRicerca Corrente Grant 2018 850/02Marchisio Paola issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nIdiopathic intracranial hypertension (IIH), also known as pseudotumour cerebri syndrome (PTCS), is defined as raised intracranial pressure in the absence of underlying causes such as intracranial mass lesions, cerebral malformations, CNS infections, cerebral venous sinus thrombosis, or hydrocephalus [1, 2].\n\nThe incidence of PTCS in children has been estimated as 0.5–0.9 per 100,000 children per year [1, 3], although this estimate is based on small or retrospective studies. Recently, Matthews et al. published a national prospective population-based cohort study that is a prospective survey of all cases of paediatric PTCS in the United Kingdom and establishes, for the first time, reliable estimates of age-specific, sex-specific and weight-specific annual incidence rates [4].\n\nThe classic symptoms of PTCS are headache, nausea, tinnitus, blurring of vision and diplopia. In 1937 Dandy defined the diagnostic criteria for PTCS [5], and in 2013 Friedman et al. published revised criteria which categorise PTCS as “definitive”, “probable”, or “suggestive of PTCS” [6].\n\nThe severity of papilloedema may be variable and the eyes may be asymmetrically involved. Currently, there is no diagnostic-therapeutic consensus algorithm, since there are no randomised studies that allow evidence-based treatment. The management of PTCS remains controversial. The current trend is close clinical monitoring of signs and symptoms. The therapeutic approach is based on clinical severity, with particular attention to the degree of eye involvement [1–3, 7].\n\nThe prognosis of PTCS is generally good. With early diagnosis and treatment, most children have complete resolution of symptoms. Nevertheless, complications of persistent papilloedema may lead to loss of visual acuity or even blindness. Ophthalmological assessment and monitoring is therefore strongly recommended by all authors.\n\nThe exact pathogenesis of PTCS is unknown and many associated aetiologies are reported in literature. Mosquera Gorostidi et al. analysed a total of 12 children with PTCS and described a possible association with Mycoplasma pneumoniae [3]. These authors hypothesized that M. pneumoniae may trigger intracranial hypertension and cause recurrences at later stages.\n\nAn iatrogenic hypothesis for PTCS has also been proposed in the literature and several medications have been associated with PTCS. The oldest known association is with vitamin A and retinoids. Other described associations are with lithium, steroids, reproductive hormones (progestins, oestrogens, testosterone, contraception or hormone supplementation therapy), thyroid replacement therapy, recombinant human growth hormone, non-steroidal anti-inflammatory drugs and Nonan and Neem extract, used as a supplement for infants in southern India [8]. Antibiotics (tetracyclines (tetracycline, minocycline and doxycycline), sulfamethoxazole, gentamicin, cephalexin and quinolones) are also reported as a possible cause of PTCS. Most reported cases of quinolone-induced intracranial hypertension were associated with nalidixic acid [9–12], ciprofloxacin [13], ofloxacin [14], or pefloxacin [15]. Literature reports of levofloxacin-induced PTCS intracranial hypertension are rare [16, 17].\n\nCase presentation\nA 14-year-old White Italian boy came to our Emergency Unit with a headache that had worsened over 20 days together with blurred vision and diplopia over the previous 10 days. His past history was negative for significant morbidities. He reported a recent episode of fever associated with cough, which coincided with the onset of headache. For this respiratory infection he had started taking levofloxacin 500 mg once a day one week before coming to our attention but had stopped taking it after three days due to worsening headache. This headache was initially associated with daytime somnolence, myalgia and arthralgia. The somnolence and arthralgia underwent rapid and spontaneous regression, with subsequent appearance of blurred vision.\n\nThe physical examination revealed an alert adolescent with weight of 66 kg (75th -90th percentile) [18], height of 169 cm (50th–75th percentile) [19] and body mass (BMI) of 23.1 kg/m2 (85th–95th percentile) [19]. The general examination was normal. The neurological examination was normal except for a right eye abduction deficit. Eye examination showed a normal visual acuity (10/10) in both eyes with normal colour vision and pupillary light responses, but a fundus examination revealed severe bilateral papilloedema with elevated disc, hyperaemia, blurred margins and vessel tortuosity in both eyes (Fig. 1a-b). Lancaster red-green test confirmed a right abducens nerve palsy, and campimetry showed a restricted visual field with external right muscle deficiency on the right side. Cranial neuroimaging (CT and MRI) showed a normal brain parenchyma with no evidence of hydrocephalus, mass, structural lesion, or abnormal meningeal enhancement. MRI neuroimaging showed oedema of both optic nerves with a tapered appearance of the right optic nerve. Venography was not performed, but an angio-MRI of the cerebral circulation was normal. Visual evoked cortical potentials were normal. A 24-h Ambulatory Blood Pressure Monitoring was negative.Fig. 1 a-b IR fundus photography. Elevated disc, blurred margins and vessel tortuosity was found at the first ophthalmological visit in both eyes (A-right eye, B-left eye)\n\n\n\nBlood tests showed high M. pneumoniae IgM (15.00 AU/ml, normal range 0–9) and normal M. pneumoniae IgG levels (3.89 AU/ml, normal range 0–9) suggesting a recent infection, with normal white blood cell indices and negative C-reactive protein. Clarithromycin was then prescribed for 14 days without any adverse effects.\n\nSerological screening for Coxsackie, Parvovirus, ECHO virus, Adenovirus, Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Herpes Simplex Virus 1 (HSV1), and Herpes Simplex Virus 2 (HSV2) excluded recent infections. Thyroid function was normal. Antinuclear antibodies (ANA), anti-double stranded DNA (dsDNA), ENA screening and rheumatoid factor were negative.\n\nDuring hospitalisation we observed a complete and spontaneous regression of headache and an initial spontaneous reduction in diplopia within a few days. Oral prednisone 50 mg/day (0.75 mg/kg/day) was administered for a week and ocular fundus was monitored.\n\nSince severe bilateral papilloedema persisted one week after the first assessment, lumbar puncture was performed with the patient sedated and relaxed in lateral recumbent position. Opening cerebrospinal fluid (CSF) pressure measured with a standard manometer was 20 cm H2O and closing pressure was 19 cm H2O. These CSF pressure values have traditionally been considered borderline, but are within normal range according to a recent study in children [20].\n\nCSF biochemical tests and cultures were negative. HSV1, HSV2, VZV, HHV6, CMV, Neisseria, Haemophilus, Streptococcus pneumoniae, Streptococcus B group, Escherichia coli, Listeria and Cryptococcus neoformans, Parvovirus, Adenovirus, EBV DNA and Enterovirus and Parechovirus RNA PCR were negative. CSF oligoclonal bands were absent on CSF and blood tests.\n\nOral acetazolamide (1 g divided twice daily) was introduced to accelerate recovery. A gradual further improvement in diplopia was seen during hospitalisation (Fig. 2a-b). Ophthalmological, neurological and neurosurgical follow up was continued after discharge. The patient gradually improved, with complete resolution of the right abducens nerve palsy in one month and resolution of papilloedema in three months (Figs. 3 and 4). For this reason, acetazolamide was gradually reduced and stopped on resolution of the papilloedema (see Additional file 1).Fig. 2 a-b IR fundus photography. Reduction in the papilloedema was found after one month of acetazolamide: the margins of the disc appear sharper but the vessel tortuosity persists (A-right eye, B-left eye)\n\nFig. 3 OCT performed at the first visit. An abnormal increase in RNFL thickness was observed\n\nFig. 4 OCT performed after three months of acetazolamide. A dramatic reduction in average RNFL thickness was documented\n\n\n\nDiscussion and conclusions\nThis case involved a Mycoplasma pneumoniae infection, probably occurring before the onset of headache and disturbed vision. Headache, diplopia and blurred vision were preceded by respiratory symptoms (cough) and systemic symptoms (such as fever, myalgia and arthralgia), which may be related to M. pneumoniae infection. As previously described [3], our case suggests that M. pneumoniae may trigger PTCS. Furthermore, in our case the already present headache dramatically worsened after administration of levofloxacin. In fact, the patient decided to stop taking levofloxacin after just three days.\n\nQuinolone-induced intracranial hypertension is well described in the literature. The onset of pseudotumour cerebri with quinolones is variable, and can occur after a few days or several weeks of treatment. In this case, the clinical course suggests that M. pneumoniae infection and levofloxacin therapy have a synergic role in precipitating the most severe symptoms of raised intracranial pressure.\n\nThe delay of lumbar puncture was due to the fact that during the first days of hospitalization the symptoms (headache and diplopia) were dramatically and spontaneously reduced. For the same reason, a short therapy with oral prednisone was attempted with the aim of promoting the reduction of the symptoms which had already spontaneously started.\n\nA 24-h Ambulatory Blood Pressure Monitoring was performed because a positive family history for essential hypertension at a young age was reported.\n\nCSF oligoclonal bands were absent on CSF and blood tests. It supported the absence of a neurological inflammatory disease.\n\nAlthough lumbar puncture was performed later, when the symptoms had already improved, we hypothesize that the CSF pressure must have been higher when the symptoms peaked and the papilloedema probably developed.\n\nA CSF opening pressure (OP) of ≥28 cm H2O [21] is considered a diagnostic criterion for PTCS in children. However, it has been proposed that a diagnosis of “probable” PTCS can be made with an OP < 28 cm H2O, if the other diagnostic criteria are met [22]; OP values must always be interpreted within the clinical context as a whole. In our patient OP was 20 cm H2O, but the presence of 1) clinical signs and symptoms of raised intracranial pressure (headache, diplopia, papilloedema and abducent nerve palsy) without additional abnormal neurological signs 2) normal magnetic resonance imaging and 3) unremarkable examination of CSF constituents are supportive for a diagnosis of “probable” PTCS, according to the definition of probable PTCS given by Tibussek et al. [22].\n\nTreatment principles for “probable” PTCS should be similar to those used for demonstrated PTCS [22].\n\nFinally, our case suggests that PTCS pathophysiology may be multifactorial and its specific features and severity may be a consequence of different factors interacting synergistically. This observation needs to be verified in larger studies, but it may be useful for paediatricians to know that some antibiotics may have the potential to precipitate PTCS in patients who already have an increased CSF pressure due to a transient imbalanced CSF circulation caused by infections such as M. pneumoniae, with headache being the first and most sensitive, but also least specific, symptom.\n\nThis case also confirmed the importance of a multidisciplinary team including paediatricians, paediatric neurologists, ophthalmologists and neurosurgeons to ensure the good management of PTCS and its complications. Although the prognosis is good in most cases, serial ophthalmological evaluation is required in order to monitor the evolution of papilloedema and preserve visual function.\n\nAdditional file\n\nAdditional file 1: Timeline Table. (DOCX 15 kb)\n\n \n\n\nAbbreviations\nCNSCentral nervous system\n\nCSFCerebrospinal fluid\n\nCTComputerized tomography\n\nIIHIdiopathic intracranial hypertension\n\nMRIMagnetic resonance imaging\n\nNSAIDsNonsteroidal anti-inflammatory drugs\n\nPTCSPseudotumour cerebri syndrome\n\nAcknowledgements\nNot applicable.\n\nFunding\nThis study was funded by the Italian Ministry of Health (Ricerca Corrente grant 2018 850/02). The funder had no role in the study design, data collection and analysis, the decision to publish, or the preparation of the manuscript.\n\nAvailability of data and materials\nThe datasets used and/or analysed are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nAll authors made substantive intellectual contributions to the manuscript. LM, RD, SG, FM, CB, SO, GB equally contributed to the patient’s management and drafting and revising the manuscript including literature search and references. PM coordinated the group. LM and SO selected and commented the Figs. RD and PM critically revised the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s parents for publication of this Case report and any accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Aylward SC Reem RE Pediatric intracranial hypertension Pediatr Neurol 2017 66 32 43 10.1016/j.pediatrneurol.2016.08.010 27940011 \n2. Albakr A Hamad MH Alwadei AH Idiopathic intracranial hypertension in children: diagnostic Anda management approach Sudan J Paediatr 2016 16 67 76 28096561 \n3. Mosquera Gorostidi A, Iridoy Zulet M, Azcona Ganuza G, Gembero Esarte E, Yoldi Petri ME, Aguilera Albesa S. Seudotumor cerebri en ninos: etiologia, caracteristicas clinicas y evolucion. Neurologia. 2016. 10.1016/j.nrl.2016.11.003.\n4. Matthews Y-Y, Dean F, Lim MY, Mclachlan K, Rigby AS, Solanski GA, et al. Pseudotumor cerebri syndrome in childhood:incidence,clinical profile and risk factors in a national prospective population-based cohort study. Arch Dis Child. 2017. 10.1136/archdischild-2016-312238.\n5. Dandy WE Intracranial pressure without brain tumor: diagnosis and treatment Ann Surg 1937 106 492 513 10.1097/00000658-193710000-00002 17857053 \n6. Friedman DI Liu GT Digre KB Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children Neurology 2013 81 1159 1165 10.1212/WNL.0b013e3182a55f17 23966248 \n7. Monge Galindo L, Fernando Martínez R, Fuertes Rodrigo C. Hipertensión intracraneal idiopática: experiencia en 25 an ~os y protocolo de actuación. An Pediatr (Barc). 2016. 10.1016/j.anpedi.2016.09.001.\n8. Thon O Gittinger JJ Medication-related Pseudotumor Cerebri syndrome Semin Ophthalmol 2017 32 134 143 10.1080/08820538.2016.1228415 27786584 \n9. Cohen DN Intracranial hypertension and papilledema associated with nalidixic acid therapy Am J Ophthalmol 1973 76 680 682 10.1016/0002-9394(73)90562-X 4583929 \n10. Guran P Moriette G Blanc A Acute and transitory intracranial hypertension in a 9-year-old child treated by nalidixic acid Arch Fr Pediatr 1972 29 1107 1111 4662282 \n11. Comelli A Gasparetto P Mourelle BO A case of pseudotumor cerebri during treatment with nalidixic acid Minerva Pediatr 1973 25 969 971 4745023 \n12. Banzas TM Clegg P Balerio A Intracranial hypertension during treatment with nalidixic acid Arch Argent Pediatr Child 1970 68 121 126 \n13. Winrow AP Supramaniam G Benign intracranial hypertension after ciprofloxacin administration Arch Dis Child 1990 65 1165 1166 10.1136/adc.65.10.1165 2248512 \n14. Getenet JC Croisile B Vighetto A Grochowicki M Goudable B Aimard G Trillet M Idiopathic intracranial hypertension after ofloxacin treatment Acta Neurol Scand 1993 87 503 504 10.1111/j.1600-0404.1993.tb04145.x 8356883 \n15. Blanc P Paupe A Carbajal R Lenclen R Olivier-Martin M Benign intracranial hypertension after treatment with pefloxacin Arch Pediatr 1998 5 930 931 10.1016/S0929-693X(98)80205-4 9759304 \n16. Lardizabal DV Intracranial hypertension and levofloxacin: a case report Headache 2009 49 300 310 10.1111/j.1526-4610.2008.01212.x 18647180 \n17. Van der Laan LE Schaaf HS Solomons R Willemse M Mohamed N Baboolal SO Probable levofloxacin-associated secondary intracranial hypertension in a child with multidrug-resistant tuberculosis Ped Infect Disease J 2016 35 706 708 10.1097/INF.0000000000001137 \n18. Cacciari E Milani S Balsamo A Directive Councils of SIEDP/ISPED for 1996–97 and 2002–03 J Endocrinol Invest 2006 29 581 593 10.1007/BF03344156 16957405 \n19. The WHO Child growth standards: growth reference, from 5 to 19 years, height-for-age, weight-for-age and body mass index-for-age (weight-for-age) 2006 \n20. Avery RA Shah SS Licht DJ Seiden JA Huh JW Boswinkel J Reference range for cerebrospinal fluid opening pressure in children N Engl J Med 2010 363 891 893 10.1056/NEJMc1004957 20818852 \n21. Avery RA Reference range of cerebrospinal fluid opening pressure in children: historical overview and current data Neuropediatrics 2014 45 206 211 10.1055/s-0034-1376202 24867260 \n22. Tibussek D Distelmaier F Karenfort M Harmsen S Klee D Mayatepek E Probable pseudotumor cerebri complex in 25 children. Further support of a concept Eur J Paediatr Neurol 2017 21 280 285 10.1016/j.ejpn.2016.10.004 27825557\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2431",
"issue": "19(1)",
"journal": "BMC pediatrics",
"keywords": "Intracranial hypertension; Levofloxacin; Mycoplasma pneumoniae; Paediatric; Pseudotumour cerebri syndrome",
"medline_ta": "BMC Pediatr",
"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D006801:Humans; D064704:Levofloxacin; D008297:Male; D011019:Pneumonia, Mycoplasma; D011559:Pseudotumor Cerebri",
"nlm_unique_id": "100967804",
"other_id": null,
"pages": "4",
"pmc": null,
"pmid": "30611233",
"pubdate": "2019-01-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "2248512;23966248;8356883;18647180;4662282;28096561;20818852;27786584;27940011;24867260;16957405;27825557;28356250;5476695;4583929;9759304;4745023;17857053;26974890",
"title": "Pseudotumour cerebri associated with mycoplasma pneumoniae infection and treatment with levofloxacin: a case report.",
"title_normalized": "pseudotumour cerebri associated with mycoplasma pneumoniae infection and treatment with levofloxacin a case report"
} | [
{
"companynumb": "IT-JUBILANT CADISTA PHARMACEUTICALS-2019JUB00022",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drug... |
{
"abstract": "OBJECTIVE\nBevacizumab is an active anti-angiogenic agent in the treatment of recurrent glioblastoma. Temozolomide can prolong survival in patients with newly diagnosed glioblastoma. At recurrence, alternate dosing of temozolomide has shown to further deplete methyl-guanine-methyltransferase (MGMT) conferring added activity for patients who have progressed on the standard dosing regimen. In this study, bevacizumab plus biweekly temozolomide was evaluated for efficacy in adult patients with recurrent glioblastoma.\n\n\nMETHODS\nThirty patients with recurrent glioblastoma were treated with bevacizumab on (10 mg/kg i.v.) days 1 and 15 of a 28-day cycle combined with temozolomide (100 mg/m2) on days 1-5 and 15-19 on a 28-day cycle. Responses were assessed at week 4 and then every 8 weeks. MGMT status and quality of life measures were also assessed.\n\n\nRESULTS\nOverall response rate from diagnosis was 51 weeks, the 6-month progression-free survival was 52%, and median time to tumor progression was 5.5 months.\n\n\nCONCLUSIONS\nBevacizumab plus bi-weekly temozolomide was well tolerated and may be a salvage regimen to be considered in a subset of patients with recurrent glioblastoma.",
"affiliations": "Center for Neurosciences, 2450 E River Rd, Tucson, AZ, 85718, USA. badru001@neurotucson.com.;Center for Neurosciences, 2450 E River Rd, Tucson, AZ, 85718, USA.;Center for Neurosciences, 2450 E River Rd, Tucson, AZ, 85718, USA.;Center for Neurosciences, 2450 E River Rd, Tucson, AZ, 85718, USA.;Genentech, Inc., DNA Way, South San Francisco, CA, 94080, USA.;Center for Neurosciences, 2450 E River Rd, Tucson, AZ, 85718, USA.;Center for Neurosciences, 2450 E River Rd, Tucson, AZ, 85718, USA.;University of Arizona Cancer Center, 1515 N. Campbell Avenue, Tucson, AZ, 85724, USA. dmahadevan@uacc.arizona.edu.;Center for Neurosciences, 2450 E River Rd, Tucson, AZ, 85718, USA.",
"authors": "Badruddoja|Michael A|MA|;Pazzi|Marjorie|M|;Sanan|Abhay|A|;Schroeder|Kurt|K|;Kuzma|Kevin|K|;Norton|Thomas|T|;Scully|Thomas|T|http://orcid.org/0000-0003-1752-2713;Mahadevan|Daruka|D|http://orcid.org/0000-0002-2991-0361;Ahmadi|Michael Malek|MM|http://orcid.org/0000-0001-9901-3650",
"chemical_list": "D000068258:Bevacizumab; D003606:Dacarbazine; D000077204:Temozolomide",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-017-3405-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "80(4)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Bevacizumab; Glioblastoma; Methyl-guanine; Methyltransferase; Temozolomide",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001932:Brain Neoplasms; D003606:Dacarbazine; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011788:Quality of Life; D000077204:Temozolomide; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "715-721",
"pmc": null,
"pmid": "28808777",
"pubdate": "2017-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "Phase II study of bi-weekly temozolomide plus bevacizumab for adult patients with recurrent glioblastoma.",
"title_normalized": "phase ii study of bi weekly temozolomide plus bevacizumab for adult patients with recurrent glioblastoma"
} | [
{
"companynumb": "US-009507513-1708USA010346",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe objective of this study was to determine the efficacy and safety of valproic acid versus risperidone in children, 3-7 years of age, with bipolar I disorder (BPD), during a mixed or manic episode.\n\n\nMETHODS\nForty-six children with Diagnostic and Statistical Manual of Mental Disorders. 4th ed., Text Revision (DSM-IV-TR) diagnosis of bipolar disorder, manic, hypomanic, or mixed episode, were recruited over a 6 year period from two academic outpatient programs for a double-blinded, placebo-controlled trial in which subjects were randomized in a 2:2:1 ratio to risperidone solution, valproic acid, or placebo.\n\n\nRESULTS\nAfter 6 weeks of treatment, the least-mean Young Mania Rating Scale (YMRS) total scores change, adjusted for baseline YMRS scores, from baseline by treatment group was: Valproic acid 10.0±2.46 (p=0.50); risperidone 18.82±1.55 (p=0.008); and placebo 4.29±3.56 (F=3.93, p=0.02). The mixed models for repeated measure (MMRM) analysis found a significant difference for risperidone-treated subjects versus placebo treated subjects (p=0.008) but not for valproic acid-treated subjects versus placebo-treated subjects (p=0.50). Treatment with risperidone over 6 weeks led to increased prolactin levels, liver functions, metabolic measures, and weight/body mass index (BMI). Treatment with valproic acid led to increases in weight/BMI and decreases in total red blood cells (RBC), hemoglobin, and hematocrit.\n\n\nCONCLUSIONS\nIn this small sample of preschool children with BPD, risperidone demonstrated clear efficacy versus placebo, whereas valproic acid did not. The laboratory and weight findings suggest that younger children with BPD are more sensitive to the effects of both of these psychotropics, and that, therefore, frequent laboratory and weight monitoring are warranted.",
"affiliations": "1 The Ohio State University Wexner Medical Center/Nationwide Children's Hospital , Columbus, Ohio.",
"authors": "Kowatch|Robert A|RA|;Scheffer|Russell E|RE|;Monroe|Erin|E|;Delgado|Sergio|S|;Altaye|Mekibib|M|;Lagory|Denise|D|",
"chemical_list": "D018692:Antimanic Agents; D014150:Antipsychotic Agents; D014635:Valproic Acid; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": "10.1089/cap.2014.0166",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1044-5463",
"issue": "25(4)",
"journal": "Journal of child and adolescent psychopharmacology",
"keywords": null,
"medline_ta": "J Child Adolesc Psychopharmacol",
"mesh_terms": "D018692:Antimanic Agents; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D018967:Risperidone; D014635:Valproic Acid",
"nlm_unique_id": "9105358",
"other_id": null,
"pages": "306-13",
"pmc": null,
"pmid": "25978742",
"pubdate": "2015-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "4917967;10852092;2574607;1564026;8084982;9481807;15571788;16832314;16958564;17606652;18258348;19192470;19264269;11314571;11869768;14977459;20868458;21711253;21784295;22213771;10638066;10846305;728692",
"title": "Placebo-controlled trial of valproic Acid versus risperidone in children 3-7 years of age with bipolar I disorder.",
"title_normalized": "placebo controlled trial of valproic acid versus risperidone in children 3 7 years of age with bipolar i disorder"
} | [
{
"companynumb": "US-JNJFOC-20150519724",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo describe an atypical presentation of intraoperative anaphylaxis due to fentanyl.\n\n\nMETHODS\nA 40-yr-old otherwise healthy woman was admitted for abdominal hysterectomy. She denied any drug allergies or past adverse anesthetic reactions. Physical examination, vital signs, and laboratory findings were all within normal limits. Twenty minutes after induction of general anesthesia with propofol, lidocaine, fentanyl, and rocuronium, she developed sudden onset of hypotension and bronchospasm. She was treated with fluids and epinephrine, but nonetheless required mechanical ventilation for 48 hr. Chest x-ray revealed pulmonary edema which resolved over two days. She recovered completely and was discharged home. Subsequent skin testing showed reactions to fentanyl and succinylcholine. Because the patient had not received succinylcholine, the cause of her anaphylaxis was attributed to fentanyl. The patient later returned for her hysterectomy and tolerated spinal anesthesia with bupivacaine and morphine.\n\n\nCONCLUSIONS\nAnaphylaxis is a fulminant, unexpected, IgE-mediated allergic reaction which can be triggered by multiple agents. Common causative agents include neuromuscular blocking drugs, latex, antibiotics, colloids, hypnotics, and opioids. Fentanyl, however, is an extremely unusual cause of anaphylaxis. Pulmonary edema, although uncommon in anaphylaxis, can be a prominent feature, as was the case with this patient.",
"affiliations": "Department of Regional Practice Anesthesiology, The Cleveland Clinic, Ohio, USA. cummink2@ccf.org",
"authors": "Cummings|Kenneth C|KC|;Arnaut|Katherina|K|",
"chemical_list": "D000701:Analgesics, Opioid; D001993:Bronchodilator Agents; D005283:Fentanyl; D004837:Epinephrine",
"country": "United States",
"delete": false,
"doi": "10.1007/BF03022776",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0832-610X",
"issue": "54(4)",
"journal": "Canadian journal of anaesthesia = Journal canadien d'anesthesie",
"keywords": null,
"medline_ta": "Can J Anaesth",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D000707:Anaphylaxis; D000768:Anesthesia, General; D001993:Bronchodilator Agents; D004837:Epinephrine; D005260:Female; D005283:Fentanyl; D006801:Humans; D007022:Hypotension; D007044:Hysterectomy; D007431:Intraoperative Complications; D011654:Pulmonary Edema; D011859:Radiography",
"nlm_unique_id": "8701709",
"other_id": null,
"pages": "301-6",
"pmc": null,
"pmid": "17400983",
"pubdate": "2007-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case report: fentanyl-associated intraoperative anaphylaxis with pulmonary edema.",
"title_normalized": "case report fentanyl associated intraoperative anaphylaxis with pulmonary edema"
} | [
{
"companynumb": "US-PFIZER INC-2007035985",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nOur purpose was to describe the clinical course, and individualized management approaches, of patients with migration of a dexamethasone implant into the anterior chamber.\n\n\nMETHODS\nThis was a retrospective review of four patients with seven episodes of anterior chamber migration of a dexamethasone implant.\n\n\nRESULTS\nAfter 924 intravitreal dexamethasone injections, anterior migration of the implant occurred in four eyes of four patients (0.43%). All four eyes were pseudophakic: one eye had a posterior chamber intraocular lens in the capsular bag but in a post-laser posterior capsulotomy state, two eyes had a sulcus intraocular lens (IOL), and one eye had an iris-fixated retropupillary IOL. All eyes had a prior vitrectomy and no lens capsule. The time interval from injection to detection of the implant migration ranged from 2 to 6 weeks. Of the four eyes with corneal edema, only one eye required a corneal transplantation, although it was unclear whether the implant migration was the direct cause of the corneal decompensation because the patient had a history of bullous keratopathy resulting from an extended history of uveitis. All patients underwent surgical intervention: two patients with a repositioning procedure, and the other two patients with removal due to repeated episodes, although surgical removal was not always necessary to reverse the corneal complications.\n\n\nCONCLUSIONS\nIn our study, not all patients required surgical removal of the implants. Repositioning the implant back into the vitreous cavity may be considered as an option in cases involving the first episode with no significant corneal endothelial decompensation. Considering potential anterior segment complications and the loss of drug effectiveness together, an individualized approach is recommended to obtain the best treatment outcomes and to minimize the risk of corneal complications.",
"affiliations": "Department of Ophthalmology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211, Eonjuro, Gangnam-gu, Seoul, Republic of Korea.;Department of Ophthalmology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211, Eonjuro, Gangnam-gu, Seoul, Republic of Korea.;Department of Ophthalmology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211, Eonjuro, Gangnam-gu, Seoul, Republic of Korea.;Institute of Vision Research, Department of Ophthalmology, Severance Hospital, Yonsei University College of Medicine, 06273, 134 Shinchon-dong, Seodaemun-gu, Seoul, Republic of Korea, 135-270.;Institute of Vision Research, Department of Ophthalmology, Severance Hospital, Yonsei University College of Medicine, 06273, 134 Shinchon-dong, Seodaemun-gu, Seoul, Republic of Korea, 135-270.;Department of Ophthalmology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211, Eonjuro, Gangnam-gu, Seoul, Republic of Korea. minkim76@hotmail.com.",
"authors": "Kang|Hyunseung|H|;Lee|Min Woo|MW|;Byeon|Suk Ho|SH|;Koh|Hyoung Jun|HJ|;Lee|Sung Chul|SC|;Kim|Min|M|http://orcid.org/0000-0003-1873-6959",
"chemical_list": "D004343:Drug Implants; D005938:Glucocorticoids; D003907:Dexamethasone",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00417-017-3705-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0721-832X",
"issue": "255(9)",
"journal": "Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie",
"keywords": "Anterior chamber; Dexamethasone implant; Dislocation; Migration; Ozurdex®; Vitrectomy",
"medline_ta": "Graefes Arch Clin Exp Ophthalmol",
"mesh_terms": "D000368:Aged; D000867:Anterior Chamber; D015715:Corneal Edema; D003907:Dexamethasone; D004343:Drug Implants; D005260:Female; D005500:Follow-Up Studies; D005548:Foreign-Body Migration; D005938:Glucocorticoids; D006801:Humans; D058449:Intravitreal Injections; D007906:Lens Subluxation; D008269:Macular Edema; D008297:Male; D008875:Middle Aged; D013508:Ophthalmologic Surgical Procedures; D011379:Prognosis; D012189:Retrospective Studies; D000072776:Slit Lamp Microscopy; D041623:Tomography, Optical Coherence; D017211:Treatment Failure; D014821:Vitrectomy",
"nlm_unique_id": "8205248",
"other_id": null,
"pages": "1819-1825",
"pmc": null,
"pmid": "28601910",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "20417567;23323589;23890421;22801828;26405769;21487341;25425713;22763812;25389729;22005792;27124797;24907062;21861084;21960148;21220619;3878357;22801827;21845032;26615950",
"title": "The clinical outcomes of surgical management of anterior chamber migration of a dexamethasone implant (Ozurdex®).",
"title_normalized": "the clinical outcomes of surgical management of anterior chamber migration of a dexamethasone implant ozurdex"
} | [
{
"companynumb": "KR-ALLERGAN-1724715US",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nThe frequency with which atypical antipsychotics initiated in the intensive care unit (ICU) is unknown. While there is lack of evidence to support the exact duration of treatment, antipsychotics should not be continued chronically for agitation and psychosis related to critical illness. The objective of this study was to determine whether atypical antipsychotics initiated in the ICU at a large tertiary academic medical center were continued after hospital discharge. Safety outcomes were also assessed.\n\n\nMETHODS\nA total of 1023 patients who received atypical antipsychotics during ICU stay were identified. Patients were assessed in a pseudo-randomized fashion until a sample of 191 patients was reached. After review of the exclusion criteria, the final study population was 100 patients. When antipsychotics were discontinued, progress notes were reviewed to identify the reason for discontinuation. Safety outcomes were assessed based on physician documentation in the medical charts.\n\n\nRESULTS\nAtypical antipsychotics were continued in 23% of patients. Atypical antipsychotics were discontinued in 1 patient due to QTc prolongation.\n\n\nCONCLUSIONS\nAtypical antipsychotics initiated in the ICU are frequently continued after hospital discharge. Given the known risks associated with extended therapy, initiatives are needed to prevent inappropriate continuation.",
"affiliations": "1 Yale New Haven Hospital, New Haven, CT, USA.;1 Yale New Haven Hospital, New Haven, CT, USA.;1 Yale New Haven Hospital, New Haven, CT, USA.;1 Yale New Haven Hospital, New Haven, CT, USA.",
"authors": "Farrokh|Salia|S|;Castle|Amber C|AC|;Heavner|Mojdeh|M|;Pisani|Margaret A|MA|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190016645026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "30(3)",
"journal": "Journal of pharmacy practice",
"keywords": "atypical antipsychotics; inappropriate prescribing; intensive care unit; medication reconciliation; medication safety",
"medline_ta": "J Pharm Pract",
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"title": "Continuation Rate of Atypical Antipsychotics After Discharge When Initiated in the Intensive Care Unit.",
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"abstract": "A 55-year-old man with hypogammaglobulinemia due to previous rituximab treatment developed persistent coronavirus disease 2019 pneumonia. Treatment with REGN-COV2 (casirivimab and imdevimab) resulted in the clearance of the infection. Targeted antiviral antibodies may be an important weapon in the management of immunocompromised patients infected with severe acute respiratory syndrome coronavirus 2 who fail to mount an immune response.",
"affiliations": "Department of Internal Medicine, Amita Saint Francis Hospital Evanston, Evanston, Illinois, USA.;Department of Infectious Disease, Amita Saint Mary and Elizabeth Hospital Chicago, Chicago, Illinois, USA.;Department of Hematology-Oncology, Amita Saint Francis Hospital Evanston, Evanston, Illinois, USA.",
"authors": "Luitel|Pankaj|P|;Vais|Dana|D|;Gidron|Adi|A|https://orcid.org/0000-0002-5994-7288",
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"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957\nOxford University Press US\n\n10.1093/ofid/ofab335\nofab335\nBrief Reports\nAcademicSubjects/MED00290\nSuccessful Treatment of Persistent Coronavirus Disease 2019 Infection in a Patient With Hypogammaglobulinemia With REGN-COV2: A Case Report\nLuitel Pankaj 1\nVais Dana 2\nhttps://orcid.org/0000-0002-5994-7288\nGidron Adi 3\n1 Department of Internal Medicine, Amita Saint Francis Hospital Evanston, Evanston, Illinois, USA\n2 Department of Infectious Disease, Amita Saint Mary and Elizabeth Hospital Chicago, Chicago, Illinois, USA\n3 Department of Hematology-Oncology, Amita Saint Francis Hospital Evanston, Evanston, Illinois, USA\nCorrespondence: Adi Gidron, MD, Amita Saint Francis Hospital Evanston, 800 Austin St, East Tower, Suite 360, Evanston, IL 60202, USA (adi.gidron@amitahealth.org).\n8 2021\n24 6 2021\n24 6 2021\n8 8 ofab33505 4 2021\n21 6 2021\n22 6 2021\n14 8 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-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\n\nAbstract\n\nA 55-year-old man with hypogammaglobulinemia due to previous rituximab treatment developed persistent coronavirus disease 2019 pneumonia. Treatment with REGN-COV2 (casirivimab and imdevimab) resulted in the clearance of the infection. Targeted antiviral antibodies may be an important weapon in the management of immunocompromised patients infected with severe acute respiratory syndrome coronavirus 2 who fail to mount an immune response.\n\nCOVID-19\nhypogammaglobulinemia\nREGN-COV2\nrituximab\n==== Body\nCoronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic with significant morbidity and mortality. Although age, sex, comorbidities, and ethnicity are risk factors for adverse outcomes [1], various preexisting conditions, including hematological cancers, have also been reported to correlate with poor outcomes [2]. Anti-CD20 monoclonal antibodies such as rituximab represent the cornerstone of treatment of most patients with B-cell malignancies and, to a lesser extent, patients with autoimmune disease [3, 4]. Anti-CD20 treatment is associated with a risk of prolonged humoral immunodeficiency, which can last years and can hamper the ability to mount an antibody response to infection [5]. Nonsustained hypogammaglobulinemia after treatment with rituximab can persist for 42 months, while around 4% of patients had never recovered CD20 cell function [6]. A treatment standard for patients who fail to mount an antibody response to COVID-19 is yet to be defined. Convalescent plasma has been reported to be used in such patients with limited benefits [7]. We report a case of a 55-year-old man with severe hypogammaglobulinemia, following treatment for mantle cell lymphoma with a rituximab-containing regimen, who developed persistent SARS-CoV-2 infection and was treated successfully with REGN-COV2 antibody after failing to clear the infection.\n\nCASE REPORT\n\nOur patient is a 55-year-old man with a history of mantle cell lymphoma in remission after treatment with hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose cytarabine and high-dose methotrexate (Hyper-CVAD) and rituximab maintenance concluded in 2015. He subsequently developed hypogammaglobulinemia managed with monthly intravenous immunoglobulin (Gamunex-C 65 g). He developed fever, nausea, diarrhea, and generalized weakness in the first week of December 2020. On 12 December 2020, he tested positive for SARS-CoV-2 by high-sensitivity polymerase chain reaction (PCR) (nasal swab) and was subsequently admitted to hospital for COVID-19 pneumonia where he completed a course of remdesivir and dexamethasone. His hospital stay was uneventful, and he was discharged after 5 days.\n\nHowever, the patient continued to have fever, diarrhea, and weakness and lost 13.6 kg (30 lbs) over the next 4 weeks. He developed progressive dyspnea with exertion and his blood oxygen saturation decreased to 91% on room air. Empiric therapy with azithromycin and then amoxicillin-clavulanate did not improve his symptoms. A SARS-CoV-2 antibody test (Abbott anti-nucleocapsid immunoglobulin G) performed on 19 January 2021 was negative. Serum levels of immunoglobulins A, G, and M at that time were <10 mg/dL, 479 mg/dL, and <20 mg/dL, respectively. COVID-19 high-sensitivity reverse-transcription PCR tests from nasopharyngeal swabs done on 2 different platforms on 22 and 29 January 2021 were negative. Contrast-enhanced computed tomography of the chest, abdomen, and pelvis done on 3 February 2021 showed bilateral diffuse ground-glass appearance consistent with COVID-19 pneumonia and no evidence of recurrence of lymphoma. Clostridioides difficile was ruled out given persistent diarrhea. To rule out other pathogens, a bronchoscopy was done on 5 February 2021. Legionella, Pneumocystis jirovecii, fungal pathogens, acid-fast bacilli, influenza, parainfluenza, respiratory syncytial virus, Bordetella pertussis, Chlamydia pneumoniae, and Mycoplasma pneumoniae were ruled out. Other coronaviruses were excluded as well. The bronchoalveolar lavage sample was positive for SARS-CoV-2 by high-sensitivity PCR with cycle numbers of 29.9 of 40 cutoff, performed on Cepheid GeneXpert, thus confirming the diagnosis of COVID-19 pneumonia. At that time his oxygen saturation was 90% at rest and decreased to 85% with ambulation of 50 feet.\n\nGiven the deteriorating clinical picture, an emergency authorization was obtained from the US Food and Drug Administration (FDA) for the use of REGN-COV2, and the patient was given the infusion of casirivimab 1200 mg and imdevimab 1200 mg on 9 February 2021 and was under observation for 1 hour without any complications or adverse effects during or following the therapy. His fevers resolved within 12 hours of treatment. Within 36 hours he no longer had diarrhea. On 11 February 2021, his oxygen saturation was 99% at rest and dropped to 92% while ambulating 200 feet but returned to 99% within 2 minutes of rest. On 18 February 2021, he reported marked improvement in his stamina, appetite, and ability to ambulate. He was able to walk 200 feet and climb 2 flights of stairs without desaturation below 95%. On 1 March 2021, repeat bronchoscopy was negative for SARS-CoV-2 by high-sensitivity PCR. The patient reported complete recovery to preinfection baseline (Figure 1).\n\nFigure 1. Course of illness. Abbreviations: BAL, bronchoalveolar lavage; COVID, coronavirus disease 2019; CT, computed tomography; PCR, polymerase chain reaction; RGEN-COV2, casirivimab and imdevimab; SARS, severe acute respiratory syndrome coronavirus 2; SpO2, oxygen saturation.\n\nDISCUSSION\n\nAs the SARS-CoV-2 pandemic swept across the globe, there was an effort to find effective treatments for COVID-19. Although thousands of papers were published, the experience with managing severely immunocompromised patients is still scant. We report a case of successful treatment of persistent COVID-19 infection in a patient with acquired humoral immune deficiency due to treatment with anti-CD20 antibody rituximab for a diagnosis of mantle cell lymphoma, who failed to mount an antibody response to COVID-19 infection.\n\nAnti-CD20 monoclonal antibodies such as rituximab not only deplete malignant B lymphocytes but also their normal counterparts, and therefore impair humoral immunity [5]. Patients with prior rituximab exposure are known to be poor responders to various types of vaccinations including influenza viruses, Haemophilus influenzae, and Streptococcus pneumoniae [8, 9]. In general, these patients have a higher risk of infections, both bacterial and viral, as demonstrated previously [10]. While some individuals with COVID-19 have a mild prolonged course and eventually develop antibodies [11], others may develop a more ominous course. While the dynamics of T-cell and B-cell responses in successfully controlling this viral infection are not fully understood, there may be lack of coordination within the adaptive immune system with rituximab affecting the naive B cells in the blood (which seem to be the source of neutralizing antibodies in COVID-19), resulting in an ineffective response [12].\n\nThe impact of COVID-19 on immunodeficient individuals and the optimal treatment modality is still unclear. There have been reports of patients after B-cell depletion therapy or with hypogammaglobulinemia who cleared SARS-CoV-2 infection on their own; however, other patients undergoing recent rituximab therapy had severe and prolonged COVID-19 infections with persistent detectable virus [5].\n\nTreatment modalities such as remdesivir, dexamethasone, and convalescent plasma [13–15] have shown benefit in the general population. Convalescent plasma therapy has also been used in the general population of COVID-19 patients with a benefit when used with high antibody titer early (within 3 days of symptoms) [7], but did not show a mortality benefit when given late or as low titer [16, 17]. Since, in immunocompetent patients, higher antigen load would drive up the antibody titers to control infection, the monoclonal antibodies might provide a much-needed booster in immunocompromised patients.\n\nREGN-COV2, manufactured by Regeneron Pharmaceuticals, is a combination of 2 SARS-CoV-2 monoclonal antibodies, casirivimab and imdevimab. These antibodies target the receptor-binding domain of the SARS-CoV-2 spike protein, thereby preventing viral entry into human cells through the angiotensin-converting enzyme 2 receptor. REGN-COV2 is a synthetic drug, unlike convalescent plasma, which is obtained from a human donor, thus eliminates transfusion-related complications. REGN-COV2 is in phase 3 clinical trials and has been authorized by FDA for emergency use for patients with mild to moderate COVID who have a high risk of propagating to severe disease and hospitalization [18]. REGN-COV2 is not authorized for use in patients who are hospitalized, or in those who require oxygen therapy. REGN-COV2 is not approved yet for routine clinical use. Efficacy and safety are not yet fully established [18].\n\nThe pivotal study by Weinreich et al, which led to the approval of REGN-COV2, showed that REGN-COV2 enhanced clearance of virus, particularly in patients in whom an endogenous immune response had not yet been initiated or who had a high viral load at baseline [19]. REGN-COV2 has shown in a clinical trial to reduce COVID-19–related hospitalization of emergency room visits in patients at high risk for disease progression within 28 days after treatment when compared to placebo [18].\n\nOur patient showed persistent symptoms of fever, diarrhea, weight loss, and generalized weakness. His symptoms persisted for >2 months and worsened even after initial hospitalization and treatment with remdesivir and dexamethasone. His lung function deteriorated to the point of requiring oxygen therapy and he lost 15% of his bodyweight, leading to severe generalized weakness and inability to function. Treatment with REGN-COV2 led to an immediate resolution of most symptoms, rapid improvement in respiratory function and functional capacity, and ultimately clearance of the infection.\n\nThis case demonstrates the potential of REGN-COV2 to significantly alter the course of illness in immunocompromised patients. We believe REGN-COV2 is a promising treatment option for immunocompromised patients who are unable to mount a humoral immune response. It should be deployed early in the course of the illness or as soon as it is established that a patient is unable to develop antibodies against SARS-CoV-2. It is not yet known if this product would provide any long-term protection from reinfection. In this regard, it may be useful to evaluate the potential for REGN-COV2 to affect long-term passive immunity to SARS-CoV-2 in patients with humoral immunity defects.\n\nNotes\n\nAuthor contributions. All authors drafted the manuscript. P. L. produced the figure. D. V. and A. G. revised the manuscript, and A. G. submitted the manuscript for publication.\n\nPatient consent statement. The patient provided written consent. All information was anonymized as much as possible. The Amita Health institutional review board (IRB) approved the treatment plan. Local standards do not require IRB approval of case reports.\n\nPotential conflicts of interest. All authors: No reported conflicts of interest.\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\n\n1. HuangC, WangY, LiX, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395 :497–506.31986264\n2. AriesJA, DaviesJK, AueRL, et al. Clinical outcome of coronavirus disease 2019 in haemato-oncology patients. Br J Haematol 2020; 190 :e64–7.32420609\n3. SallesG, BarrettM, FoàR, et al. Rituximab in B-cell hematologic malignancies: a review of 20 years of clinical experience. Adv Ther 2017; 34 :2232–73.28983798\n4. HawkerK, O’ConnorP, FreedmanMS, et al ; OLYMPUS Trial Group. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 2009; 66 :460–71.19847908\n5. YasudaH, TsukuneY, WatanabeN, et al. Persistent COVID-19 pneumonia and failure to develop anti-SARS-CoV-2 antibodies during rituximab maintenance therapy for follicular lymphoma. Clin Lymphoma Myeloma Leuk 2020; 20 :774–6.32933879\n6. RobertsDM, JonesRB, SmithRM, et al. Rituximab-associated hypogammaglobulinemia: incidence, predictors and outcomes in patients with multi-system autoimmune disease. J Autoimmun 2015; 57 :60–5.25556904\n7. JoynerMJ, SenefeldJW, KlassenSA, et al. Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three-month experience. medRxiv [Preprint]. Posted online 12 August 2020 . doi:10.1101/2020.08.12.20169359.\n8. EisenbergRA, JawadAF, BoyerJ, et al. Rituximab-treated patients have a poor response to influenza vaccination. J Clin Immunol 2013; 33 :388–96.23064976\n9. NaziI, KeltonJG, LarchéM, et al. The effect of rituximab on vaccine responses in patients with immune thrombocytopenia. Blood 2013; 122 :1946–53.23851398\n10. SallesG, SeymourJF, OffnerF, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011; 377 :42–51.21176949\n11. FalletB, KyburzD, WalkerUA. Mild course of COVID-19 and spontaneous virus clearance in a patient with depleted peripheral blood B cells due to rituximab treatment. Arthritis Rheumatol 2020; 72 :1581–2.32458534\n12. SetteA, CrottyS. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell 2021; 184 :861–80.33497610\n13. RECOVERY Collaborative Group;HorbyP, LimWS, EmbersonJR, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med 2021; 384 :693–704.32678530\n14. BeigelJH, TomashekKM, DoddLE.et al. Remdesivir for the treatment of COVID-19—final report. N Engl J Med 2020; 383 :1813–26.32445440\n15. SimonovichVA, Burgos PratxLD, ScibonaP, et al ; PlasmAr Study Group. A randomized trial of convalescent plasma in Covid-19 severe pneumonia. N Engl J Med 2021; 384 :619–29.33232588\n16. HuesoT, PouderouxC, PéréH, et al. Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19. Blood 2020; 136 :2290–5.32959052\n17. Convalescent plasma in the management of moderate covid-19 in adults in India: open-label phase II multicentre randomized controlled trial (PLACID Trial) [erratum]. BMJ 2020; 371 :m3939. 33093056\n18. ClinicalTrials.gov. Safety, tolerability, and efficacy of anti-spike (S) SARS-CoV-2 monoclonal antibodies for the treatment of ambulatory adult and pediatric patients with COVID-19 (NCTo4426695). 2020. https://clinicaltrials.gov/ct2/show/NCT04426695. Accessed 24 June 2021.\n19. WeinreichDM, SivapalasingamS, NortonT, et al ; Trial Investigators. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N Engl J Med 2021; 384 :238–51.33332778\n\n",
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"title": "Successful Treatment of Persistent Coronavirus Disease 2019 Infection in a Patient With Hypogammaglobulinemia With REGN-COV2: A Case Report.",
"title_normalized": "successful treatment of persistent coronavirus disease 2019 infection in a patient with hypogammaglobulinemia with regn cov2 a case report"
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"abstract": "Fatal agranulocytosis in an Indian male receiving 100mg of dapsone daily, hospitalized for mid-borderline leprosy in type I reaction with triple nerve paralysis is reported. Various case reports concerning dapsone-induced agranulocytosis are reviewed.",
"affiliations": "Department of Dermatology, Venereology & Leprosy, Fr. Muller Medical College, Kankanady, Mangalore, Karnataka 575 002, India. rameshderma@yahoo.com",
"authors": "Bhat|Ramesh M|RM|;Radhakrishnan|K|K|",
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"title": "A case report of fatal dapsone-induced agranulocytosis in an Indian mid-borderline leprosy patient.",
"title_normalized": "a case report of fatal dapsone induced agranulocytosis in an indian mid borderline leprosy patient"
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"abstract": "The association between seronegative spondyloarthro- pathies and IgA nephropathy is well documented, mainly in cases of ankylosing spondylitis (AS). However, although these diseases have been associated, the physiopathological links between each other appear unclear. Anti-TNFalpha agents have transformed the outcome of axial forms of AS resistant to conventional anti-inflammatory therapies. Infliximab, a monoclonal anti-TNFalpha antibody, has greatly improved the evolution of AS although several adverse events have been described. On the other hand, infliximab has been demonstrated to reduce renal symptoms associated with chronic inflammatory rheumatological diseases, such as amyloid A (AA) amyloidosis, but few data are available on its efficacy in controlling IgA nephropathy associated with AS [1,2]. We report here a case of IgA nephropathy associated with AS that became symptomatic, whereas infliximab therapy efficiently controlled the rheumatological disease. This suggests that even though infliximab therapy effectively controls rheumatological manifestations, it may not be able to prevent IgA nephropathy associated with AS. Thus, this case report illustrates the complexity of the physiopathology of both diseases.",
"affiliations": "Department of Nephrology, Kremlin Bicêtre Hospital, 94275 Le Kremlin Bicetre, France. antoine.jacquet@hotmail.fr",
"authors": "Jacquet|Antoine|A|;Francois|Helene|H|;Frangie|Carlos|C|;Yahiaoui|Yasmina|Y|;Ferlicot|Sophie|S|;Micelli|Corinne|C|;Mariette|Xavier|X|;Durrbach|Antoine|A|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
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"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D005922:Glomerulonephritis, IGA; D006801:Humans; D000069285:Infliximab; D008297:Male; D013167:Spondylitis, Ankylosing; D014409:Tumor Necrosis Factor-alpha",
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"title": "IgA nephropathy associated with ankylosing spondylitis is not controlled by infliximab therapy.",
"title_normalized": "iga nephropathy associated with ankylosing spondylitis is not controlled by infliximab therapy"
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"abstract": "Congenital hypomagnesemia is a rare disease, with an impact on cognitive and neurological development. We report on three familial cases of congenital hypomagnesemia, two boys and one girl who belong to the same consanguineous family. They all presented neonatal seizures and a psychomotor developmental delay. Cerebral computed tomography showed cerebral atrophy and calcifications in one case and magnetic resonance imaging found predominant cerebellar atrophy in the two other cases. All three patients also had hypocalcemia, hyperphosphoremia, and hypomagnesemia. The parathyroid hormone blood level was low in two cases and normal in the third. One 7-month old patient died. The others received a supplementation of calcium and magnesium, which normalized calcemia, phosphatemia but not magnesemia, which remained low despite high doses. They have both developed cognitive and behavioral impairments.",
"affiliations": "Service de neurologie, CHU Fann, BP 5035, Dakar, Sénégal; Hôpital d'enfants Albert-Royer, Sénégal. Electronic address: ngouille@hotmail.com.;Service de neurologie, CHU Fann, BP 5035, Dakar, Sénégal.;Service de neurologie, CHU Fann, BP 5035, Dakar, Sénégal.;Service de neurologie, CHU Fann, BP 5035, Dakar, Sénégal.;Service de neurologie, CHU Fann, BP 5035, Dakar, Sénégal.;Hôpital d'enfants Albert-Royer, Sénégal.;Service de neurologie, CHU Fann, BP 5035, Dakar, Sénégal.;Service de neurologie, CHU Fann, BP 5035, Dakar, Sénégal.;Service de neurologie, CHU Fann, BP 5035, Dakar, Sénégal.;Hôpital d'enfants Albert-Royer, Sénégal.;Service de neurologie, CHU Fann, BP 5035, Dakar, Sénégal.",
"authors": "Ndiaye|M|M|;Toffa|D H|DH|;Sow|A-D|AD|;Sène|M-S|MS|;Basse|A-M|AM|;Fall|A-L|AL|;Seck|L-B|LB|;Touré|K|K|;Diop|A-G|AG|;Sow|H-D|HD|;Ndiaye|M-M|MM|",
"chemical_list": "D010281:Parathyroid Hormone",
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"issue": "20(11)",
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"medline_ta": "Arch Pediatr",
"mesh_terms": "D001284:Atrophy; D001921:Brain; D002114:Calcinosis; D003241:Consanguinity; D005260:Female; D006801:Humans; D054559:Hyperphosphatemia; D006996:Hypocalcemia; D007223:Infant; D007231:Infant, Newborn; D008275:Magnesium Deficiency; D008297:Male; D010281:Parathyroid Hormone; D015499:Renal Tubular Transport, Inborn Errors; D012640:Seizures",
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"title": "Familial congenital hypomagnesemia revealed by neonatal convulsions.",
"title_normalized": "familial congenital hypomagnesemia revealed by neonatal convulsions"
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... |
{
"abstract": "This case considers underdosing of analgesics as a prime contributor to hypertension in diffuse axonal injury (DAI) patients who are being mechanically ventilated. In the air medical environment, obtunded patients' hemodynamic parameters are the primary tools available in diagnosing complex disorders such as an acute rise in intracranial pressure (ICP) when invasive ICP monitoring is not available. Therefore, differential diagnoses must follow a continuum, from most severe to least, in order to deal with sudden-onset hypertension rapidly. Not until all critical differentials have been eliminated is analgesia considered. Mimicking the signs of ICP, a compensatory rise in the mean arterial pressure (MAP) is displayed in an acute pain response for mechanically ventilated patients. Therefore, poor analgesic coverage should be considered early in DAI patients who are being ventilated, especially when an increased metabolic drive may be occurring, forcing the therapeutic dosing intervals to be increased. This patient was transferred from Europe back to North America via a fixed wing aircraft, a 16-hour transport time.",
"affiliations": "School of Medicine, St George's University, West Indies, Grenada. Electronic address: mcarvey@sgu.edu.",
"authors": "Carvey|Matthew|M|",
"chemical_list": "D000700:Analgesics",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amj.2018.11.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1067-991X",
"issue": "38(1)",
"journal": "Air medical journal",
"keywords": null,
"medline_ta": "Air Med J",
"mesh_terms": "D000328:Adult; D000700:Analgesics; D020833:Diffuse Axonal Injury; D004632:Emergency Medical Services; D005060:Europe; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D006973:Hypertension; D007427:Intracranial Pressure; D008991:Monitoring, Physiologic",
"nlm_unique_id": "9312325",
"other_id": null,
"pages": "55-57",
"pmc": null,
"pmid": "30711088",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case of a Hypertensive Crisis in Diffuse Axonal Injury.",
"title_normalized": "case of a hypertensive crisis in diffuse axonal injury"
} | [
{
"companynumb": "GD-PURDUE PHARMA-GBR-2019-0064457",
"fulfillexpeditecriteria": "1",
"occurcountry": "GD",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MORPHINE SULFATE"
},
"drugadditional"... |
{
"abstract": "We report on a 28-year-old female patient who had no history of diseases and who was brought to our intensive care unit in a comatose state by the ambulance service. The clinical picture corresponded to sepsis with a massively increased blood sugar concentration (> 2000 mg/dl) as well as a pronounced skin mycosis in the groin region of the very obese patient (body mass index [BMI]: 33.7 kg/m2) in the physical examination. The treatment of sepsis was initially supplemented by a calculated antifungal treatment. The blood culture diagnosis confirmed the presence of Candida albicans and Candida glabrata. Despite adequate anti-infective treatment, the patient developed a septic shock in the further course, so that the additional escalation of treatment was initiated by renal replacement therapy on the second day and venovenous extracorporeal membrane oxygenation because of an ARDS. Despite all of these measures and maximum intensive care treatment, the patient developed a progressive multiple organ failure. When the pupils became rigid to light, a cerebral computed tomography was carried out. This showed evidence of a severe cerebral edema without signs of cerebral bleeding. Multiple examinations of somatosensory evoked potentials and electroencephalograms showed signs of irreversible brain damage. In view of this poor prognosis the therapeutic measures were limited. The patient died on day 24 after admission to the intensive care unit. The case study shows that antifungal treatment should definitely be considered in the context of sepsis treatment if there is a clinically justified suspicion.The role of the severely altered metabolic situation with massive hyperglycemia and ketoacidosis cannot be finally assessed.",
"affiliations": "Klinik für Innere Medizin II, Lehrkrankenhaus der Universitätsmedizin Mainz, Gemeinschaftsklinikum Mittelrhein, Standort Kemperhof Koblenz, Koblenzer Straße 115-155, 56073, Koblenz, Deutschland. sebastian.niel@gk.de.;Klinik für Innere Medizin II, Lehrkrankenhaus der Universitätsmedizin Mainz, Gemeinschaftsklinikum Mittelrhein, Standort Kemperhof Koblenz, Koblenzer Straße 115-155, 56073, Koblenz, Deutschland.;Klinik für Intensivmedizin, Lehrkrankenhaus der Universitätsmedizin Mainz, Gemeinschaftsklinikum Mittelrhein, Standort Kemperhof Koblenz, Koblenzer Straße 115-155, 56073, Koblenz, Deutschland.",
"authors": "Niel|S|S|;Douwa|R|R|;Sakka|S G|SG|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00101-021-01062-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2417",
"issue": null,
"journal": "Der Anaesthesist",
"keywords": "Animycotics; Caspofungin; ECMO; Fluconazol; Mycosis",
"medline_ta": "Anaesthesist",
"mesh_terms": null,
"nlm_unique_id": "0370525",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34817633",
"pubdate": "2021-11-24",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": "19325481;27787406;24550327;12872348;8565541;15844093;16505659;26679628;18983417;16647248;30455229;17576324;21069271;21514797;26554775;33064220;8254858;23040766",
"title": "Severe Candida sepsis in a 28-year-old female patient with initial diagnosis of diabetes mellitus and marked hyperosmolar coma.",
"title_normalized": "severe candida sepsis in a 28 year old female patient with initial diagnosis of diabetes mellitus and marked hyperosmolar coma"
} | [
{
"companynumb": "DE-009507513-2112DEU009387",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUCLOXACILLIN"
},
"drugadditional": "3",
... |
{
"abstract": "Fifteen patients with refractory AML were treated in a phase 1 study with SU11248, an oral kinase inhibitor of fms-like tyrosine kinase 3 (Flt3), Kit, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) receptors. Separate cohorts of patients received SU11248 for 4-week cycles followed by either a 2- or a 1-week rest period. At the starting dose level of 50 mg (n = 13), no dose-limiting toxicities were observed. The most frequent grade 2 toxicities were edema, fatigue, and oral ulcerations. Two fatal bleedings possibly related to the disease, one from a concomitant lung cancer and one cerebral bleeding, were observed. At the 75 mg dose level (n = 2), one case each of grade 4 fatigue, hypertension, and cardiac failure was observed, and this dose level was abandoned. All patients with FLT3 mutations (n = 4) had morphologic or partial responses compared with 2 of 10 evaluable patients with wild-type FLT3. Responses, although longer in patients with mutated FLT3, were of short duration. Reductions of cellularity and numbers of Ki-67(+), phospho-Kit(+), phospho-kinase domain-containing receptor-positive (phospho-KDR(+)), phospho-signal transducer and activator of transcription 5-positive (phospho-STAT5(+)), and phospho-Akt(+) cells were detected in bone marrow histology analysis. In summary, monotherapy with SU11248 induced partial remissions of short duration in acute myeloid leukemia (AML) patients. Further evaluation of this compound, for example in combination with chemotherapy, is warranted.",
"affiliations": "Department of Oncology/Hematology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. fiedler@uke.uni-hamburg.de",
"authors": "Fiedler|Walter|W|;Serve|Hubert|H|;Döhner|Hartmut|H|;Schwittay|Michael|M|;Ottmann|Oliver G|OG|;O'Farrell|Anne-Marie|AM|;Bello|Carlo L|CL|;Allred|Randy|R|;Manning|William C|WC|;Cherrington|Julie M|JM|;Louie|Sharianne G|SG|;Hong|Weiru|W|;Brega|Nicoletta M|NM|;Massimini|Giorgio|G|;Scigalla|Paul|P|;Berdel|Wolfgang E|WE|;Hossfeld|Dieter K|DK|",
"chemical_list": "D007211:Indoles; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D051941:fms-Like Tyrosine Kinase 3; D000077210:Sunitinib",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2004-05-1846",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "105(3)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007211:Indoles; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib; D051941:fms-Like Tyrosine Kinase 3",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "986-93",
"pmc": null,
"pmid": "15459012",
"pubdate": "2005-02-01",
"publication_types": "D016430:Clinical Trial; D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease.",
"title_normalized": "a phase 1 study of su11248 in the treatment of patients with refractory or resistant acute myeloid leukemia aml or not amenable to conventional therapy for the disease"
} | [
{
"companynumb": "DE-PFIZER INC-2002132294DE",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": "048",
"drugau... |
{
"abstract": "Serotonin specific reuptake inhibitors (SSRI) are widely used antidepressants for variety of clinical conditions and have found popularity. They are sometimes associated with extrapyramidal side effects including Parkinsonism. We report a case of generalized anxiety disorder on treatment with SSRI (fluoxetine / sertraline) who developed irreversible Parkinsonism. SSRI are known to cause reversible or irreversible motor disturbances through pathophysiological changes in basal ganglion motor system by altering the dopamine receptors postsynaptically. Clinician should keep risk benefit ratio in mind and change of antidepressant of different class may be considered. Case is reported to alert physicians to possibility of motor system damage while treating with SSRI.",
"affiliations": "Classified Specialist, Department of Psychiatry, Base Hospital Delhi Cantt , New Delhi, India .;Classified Specialist, Department of Psychiatry, Base Hospital Delhi Cantt , New Delhi, India .;Resident, Department of Psychiatry, Base Hospital Delhi Cantt , New Delhi, India .",
"authors": "Dixit|Siddharth|S|;Khan|Shahbaj A|SA|;Azad|Sudip|S|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2015/11394.5583",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "9(2)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Drug induced parkinsonism; Epidemiology; Fluoxetine; Sertraline",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "VD01-VD02",
"pmc": null,
"pmid": "25859504",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports",
"references": "11479393;8909330;18808960;26265886;20680187;21407001;18173026;11350533;16250023;24176515;21494451;10401924;9660102;21674626",
"title": "A Case of SSRI Induced Irreversible Parkinsonism.",
"title_normalized": "a case of ssri induced irreversible parkinsonism"
} | [
{
"companynumb": "PHHY2015IN020610",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nUstekinumab is a monoclonal antibody that targets interleukin-12/23. In Scotland, it was approved for the treatment of moderate to severe Crohn's disease in 2017. The objective of this study was to establish the real-world effectiveness and safety of ustekinumab in the treatment of Crohn's disease.\n\n\nMETHODS\nWe conducted a retrospective study of patients receiving ustekinumab across eight Scottish National Health Service health boards between 2017 and 2019. Inclusion criteria included a diagnosis of Crohn's disease with symptoms attributed to active disease plus objective signs of inflammation at baseline (C-reactive protein ≥ 5 mg/L or fecal calprotectin ≥ 250 μg/g or inflammation on endoscopy/magnetic resonance imaging) and completion of induction plus at least one clinical follow-up at 8 weeks. Kaplan-Meier survival analysis was used to establish 12-month cumulative rates of clinical remission, mucosal healing, deep remission, and perianal fistula response. Rates of serious adverse events were described quantitatively.\n\n\nRESULTS\nOur cohort consisted of 216 patients (female sex, 37.9%; median age, 39.0 years, interquartile range [IQR] 28.8-51.8 years; disease duration, 9.9 years, IQR 6.0-16.5 years; prior biologic, 98.6%) with a median follow-up of 35.0 weeks (IQR 17.4-52.0 weeks). Twelve-month cumulative rates of clinical remission, mucosal healing, and deep remission (clinical remission plus mucosal healing) were 32.0%, 32.7%, and 19.3%, respectively. In patients with active perianal disease (n = 37), the 12-month cumulative perianal response rate was 53.1%. The serious adverse event rate was 13.6 per 100 patient-years of follow-up.\n\n\nCONCLUSIONS\nUstekinumab is a safe and effective treatment for the treatment of complex Crohn's disease.",
"affiliations": "The Edinburgh IBD Unit, Western General Hospital, Edinburgh, UK.;The Edinburgh IBD Unit, Western General Hospital, Edinburgh, UK.;The Edinburgh IBD Unit, Western General Hospital, Edinburgh, UK.;Department of Gastroenterology, University Hospital Hairmyres, East Kilbride, UK.;Department of Gastroenterology, Ninewells Hospital, Dundee, UK.;Department of Gastroenterology, Raigmore Hospital, Inverness, UK.;Department of Gastroenterology, Raigmore Hospital, Inverness, UK.;Department of Gastroenterology, Royal Alexandra Hospital, Paisley, UK.;The Edinburgh IBD Unit, Western General Hospital, Edinburgh, UK.;Department of Gastroenterology, Aberdeen Royal Infirmary, Aberdeen, UK.;Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK.;Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK.;Department of Gastroenterology, University Hospital Hairmyres, East Kilbride, UK.;Department of Gastroenterology, Forth Valley Royal Hospital, Larbert, UK.;Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK.;Department of Gastroenterology, Victoria Hospital, Kirkcaldy, UK.;Department of Gastroenterology, Queen Elizabeth University Hospital, Glasgow, UK.;Department of Gastroenterology, Queen Elizabeth University Hospital, Glasgow, UK.;Department of Gastroenterology, Ninewells Hospital, Dundee, UK.;Department of Gastroenterology, Royal Alexandra Hospital, Paisley, UK.;Department of Gastroenterology, Raigmore Hospital, Inverness, UK.;Department of Gastroenterology, University Hospital Hairmyres, East Kilbride, UK.;Department of Gastroenterology, Forth Valley Royal Hospital, Larbert, UK.;The Edinburgh IBD Unit, Western General Hospital, Edinburgh, UK.;Department of Gastroenterology, Aberdeen Royal Infirmary, Aberdeen, UK.;The Edinburgh IBD Unit, Western General Hospital, Edinburgh, UK.;The Edinburgh IBD Unit, Western General Hospital, Edinburgh, UK.",
"authors": "Plevris|Nikolas|N|https://orcid.org/0000-0002-3229-8759;Fulforth|James|J|;Siakavellas|Spyros|S|;Robertson|Andrew|A|;Hall|Rebecca|R|;Tyler|Amy|A|;Jenkinson|Philip W|PW|;Campbell|Iona|I|;Chuah|Cher Shiong|CS|;Kane|Claire|C|;Veryan|Jennifer|J|;Lam|Wai Liam|WL|;Saunders|Jayne|J|;Kelly|Christopher|C|;Gaya|Daniel|D|;Jafferbhoy|Hasnain|H|;Macdonald|Jonathan C|JC|;Seenan|John Paul|JP|;Mowat|Craig|C|;Naismith|Graham|G|;Potts|Lindsay F|LF|;Sutherland|Diarmid Ian|DI|;Watts|David|D|;Arnott|Ian|I|;Bain|Gillian|G|;Jones|Gareth|G|;Lees|Charlie W|CW|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/jgh.15390",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0815-9319",
"issue": "36(8)",
"journal": "Journal of gastroenterology and hepatology",
"keywords": "Crohn's disease; mucosal healing; real world; ustekinumab",
"medline_ta": "J Gastroenterol Hepatol",
"mesh_terms": null,
"nlm_unique_id": "8607909",
"other_id": null,
"pages": "2067-2075",
"pmc": null,
"pmid": "33381875",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Real-world effectiveness and safety of ustekinumab for the treatment of Crohn's disease: the Scottish ustekinumab cohort.",
"title_normalized": "real world effectiveness and safety of ustekinumab for the treatment of crohn s disease the scottish ustekinumab cohort"
} | [
{
"companynumb": "GB-JNJFOC-20210108583",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "USTEKINUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe aim of our study was to assess the impact of psychiatric medications and concomitant risk factors on the prevalence of QTc prolongation and torsades de pointes (TdP) in hospitalized subjects. We examined the association between individual risk scores and QTc prolongation and proposed an evidence-based protocol for electrocardiogram monitoring on psychotropic medications.\n\n\nMETHODS\nElectrocardiograms (ECGs) of subjects hospitalized over a 1-year period were analyzed for QTc prolongation, associated risk factors, and use of medications. Analysis was performed using logistic regression to identify independent predictors of QTc prolongation, and the Pearson χ test was used for risk score assessment.\n\n\nRESULTS\nA total of 1249 ECGs of 517 subjects were included in this study. Eighty-seven subjects had QTcB intervals greater than 470 milliseconds for females and greater than 450 milliseconds for males. Twelve (2.3%) subjects had QTcB of 500 milliseconds or greater, or greater than 60 milliseconds of change from baseline. Of these subjects, only 1 case of QTc interval change was related to routine use of psychiatric medications. There were no incidents of TdP. Age, diabetes, hypokalemia, overdose, diphenhydramine, and haloperidol were significant independent predictors of QTc prolongation. Risk scores were significantly correlated with QTc prolongation (P = 0.001).\n\n\nCONCLUSIONS\nOur retrospective review study found that the occurrence of TdP and QTc prolongation was low in this subject population. QT abnormalities were associated with known risk factors, and risk scores correlated well with QTc prolongation. Providers can use the protocol proposed in this study, which incorporates risk scores and the CredibleMeds classification system to determine the need for ECG monitoring and to guide treatment.",
"affiliations": "Department of Psychiatry.;Department of Internal Medicine.;Center for Toxicology and Pharmacology Education and Research, and.;Office of Graduate Medical Education Research, University of Arizona College of Medicine, Phoenix Campus Banner-University Medical Center Phoenix, Phoenix, AZ.",
"authors": "Shao|Wanda|W|;Ayub|Shehzad|S|;Drutel|Robert|R|;Heise|William C|WC|;Gerkin|Richard|R|",
"chemical_list": "D011619:Psychotropic Drugs",
"country": "United States",
"delete": false,
"doi": "10.1097/JCP.0000000000000992",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-0749",
"issue": "39(1)",
"journal": "Journal of clinical psychopharmacology",
"keywords": null,
"medline_ta": "J Clin Psychopharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D003430:Cross-Sectional Studies; D004562:Electrocardiography; D005260:Female; D005845:Georgia; D006801:Humans; D007297:Inpatients; D008133:Long QT Syndrome; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011619:Psychotropic Drugs; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D016171:Torsades de Pointes; D055815:Young Adult",
"nlm_unique_id": "8109496",
"other_id": null,
"pages": "72-77",
"pmc": null,
"pmid": "30531476",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "QTc Prolongation Associated With Psychiatric Medications: A Retrospective Cross-Sectional Study of Adult Inpatients.",
"title_normalized": "qtc prolongation associated with psychiatric medications a retrospective cross sectional study of adult inpatients"
} | [
{
"companynumb": "PHHY2019US037333",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "The aim of this study was to evaluate the efficacy and tolerability of open-label lacosamide in patients with refractory sleep-related hypermotor epilepsy. The study was a case review of eight patients with refractory sleep-related hypermotor epilepsy treated with lacosamide. Seizure diaries compared the mean baseline seizure frequency with the most recent 3 months of follow-up. Five (62.5%) patients were responders, defined as ≥50% reduction in seizure frequency, over a mean duration of exposure of 21.5 months. The mean maintenance dose of lacosamide was 400 mg/day. No-one reported worsening of seizures. Lacosamide was well tolerated with initial fatigue being the main side-effect. Lacosamide is a potentially efficacious adjunctive therapy in patients with refractory sleep-related hypermotor epilepsy. A double-blind placebo-controlled study would determine its efficacy.",
"affiliations": "Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Vic., Australia.;Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Vic., Australia.;Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Vic., Australia.",
"authors": "Samarasekera|Shanika R|SR|0000-0002-4362-1208;Berkovic|Samuel F|SF|;Scheffer|Ingrid E|IE|",
"chemical_list": "D000927:Anticonvulsants; D000078334:Lacosamide",
"country": "England",
"delete": false,
"doi": "10.1111/jsr.12669",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0962-1105",
"issue": "27(5)",
"journal": "Journal of sleep research",
"keywords": "antiepileptic drugs; frontal lobe epilepsy",
"medline_ta": "J Sleep Res",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D004828:Epilepsies, Partial; D005260:Female; D006801:Humans; D000078334:Lacosamide; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9214441",
"other_id": null,
"pages": "e12669",
"pmc": null,
"pmid": "29479765",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case series of lacosamide as adjunctive therapy in refractory sleep-related hypermotor epilepsy (previously nocturnal frontal lobe epilepsy).",
"title_normalized": "a case series of lacosamide as adjunctive therapy in refractory sleep related hypermotor epilepsy previously nocturnal frontal lobe epilepsy"
} | [
{
"companynumb": "AU-JNJFOC-20200432584",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXCARBAZEPINE"
},
"drugadditional": "3",
... |
{
"abstract": "A 19-year-old Japanese male recipient, who received a living related kidney transplantation from his father at 5 years old, was hospitalized for second renal transplantation from a cadaveric donor. The recipient had had an antibody-mediated rejection (AMR) to the first transplanted kidney. HLA typing of A, B, and DRB showed 2 of 6 mismatches. Lymphocyte cytotoxicity test (LCT) and flow cytometry crossmatches (FCXM) were negative on T cells. Tacrolimus, mycophenolate mofetil, methylprednisolone, and basiliximab induction were used as the standard immunosuppressive therapy. After second renal transplantation, his serum creatinine level favorably decreased until postoperative day (POD) 7, but his serum creatinine level raised from POD 8. We performed steroid pulse and intravenous immunoglobulin (IVIG). The episode biopsy showed AMR although FCXM and LCT were still negative on T cell. To determine the cause of AMR, we examined LABScreen single antigen test (One Lambda, Canoga Park, Calif., United States), and there was a donor-specific antibody (DSA) that is DQB8 in pre- and post-second renal transplantation. The DSA was suspected de novo DSA for the first transplanted kidney. AMR was successfully treated with plasma exchange, IVIG, and rituximab.",
"affiliations": "Department of Urology, Osaka Medical College, Osaka, Japan, Takatsuki City, Osaka, Japan. Electronic address: uro065@osaka-med.ac.jp.;Department of Urology, Osaka Medical College, Osaka, Japan, Takatsuki City, Osaka, Japan.;Department of Urology, Osaka Medical College, Osaka, Japan, Takatsuki City, Osaka, Japan.;Department of Urology, Osaka Medical College, Osaka, Japan, Takatsuki City, Osaka, Japan.;Department of Urology, Osaka Medical College, Osaka, Japan, Takatsuki City, Osaka, Japan.;Department of Urology, Osaka Medical College, Osaka, Japan, Takatsuki City, Osaka, Japan.;Department of Urology, Osaka Medical College, Osaka, Japan, Takatsuki City, Osaka, Japan.;Department of Urology, Osaka Medical College, Osaka, Japan, Takatsuki City, Osaka, Japan.;Department of Urology, Osaka Medical College, Osaka, Japan, Takatsuki City, Osaka, Japan.;Department of Urology, Osaka Medical College, Osaka, Japan, Takatsuki City, Osaka, Japan.;Department of Urology, Osaka Medical College, Osaka, Japan, Takatsuki City, Osaka, Japan.;Department of Urology, Osaka Medical College, Osaka, Japan, Takatsuki City, Osaka, Japan.;Department of Urology, Osaka Medical College, Osaka, Japan, Takatsuki City, Osaka, Japan.;Department of Urology, Osaka Medical College, Osaka, Japan, Takatsuki City, Osaka, Japan.",
"authors": "Matsunaga|Tomohisa|T|;Hirano|Hajime|H|;Maenosono|Ryoichi|R|;Tsutsumi|Takeshi|T|;Tsujino|Takuya|T|;Yoshikawa|Yuki|Y|;Takai|Tomoaki|T|;Minami|Koichiro|K|;Uehara|Hirofumi|H|;Komura|Kazumasa|K|;Nomi|Hayahito|H|;Ibuki|Naokazu|N|;Inamoto|Teruo|T|;Azuma|Haruhito|H|",
"chemical_list": "D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D016756:Immunoglobulins, Intravenous; D007518:Isoantibodies",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.01.150",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "52(6)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D002102:Cadaver; D006084:Graft Rejection; D059866:HLA-DQ beta-Chains; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007518:Isoantibodies; D016030:Kidney Transplantation; D008297:Male; D012086:Reoperation; D014019:Tissue Donors; D055815:Young Adult",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1928-1930",
"pmc": null,
"pmid": "32444119",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment of Antibody-Mediated Rejection by De Novo Donor Specific Antibody After Primary Renal Transplantation in a Recipient From a Cadaveric Donor: A Case Report.",
"title_normalized": "successful treatment of antibody mediated rejection by de novo donor specific antibody after primary renal transplantation in a recipient from a cadaveric donor a case report"
} | [
{
"companynumb": "JP-SGP-000014",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
},
"drugadditional": "3",
"drugadm... |
{
"abstract": "Mesenteric panniculitis is a chronic inflammatory disease characterized by non-specific inflammation of the adipose tissue in the mesentery. Hemophagocytic lymphohistiocytosis is a life-threating disease associated with aberrant macrophage overactivation, in which infections can be a leading cause in immunocompromised hosts. Here, we report a rare case of mesenteric panniculitis and hemophagocytic lymphohistiocytosis complicated by disseminated Mycobacterium intracellulare. A 71-year-old male with mesenteric panniculitis was admitted to our hospital for fever and pancytopenia. He was treated with oral prednisolone (15 mg/day) and cyclosporin A (150 mg/day) at presentation. Physical and laboratory examinations revealed disseminated infection with nontuberculous mycobacteria; Mycobacterium intracellulare was detected in cultures of cerebrospinal fluid, blood, sputum, and gastric fluid. Patient signs and symptoms fulfilled the five criteria for a diagnosis of hemophagocytic lymphohistiocytosis, including fever, cytopenia, hemophagocytosis, hyperferritinemia, and high soluble interleukin-2 receptor levels. Therefore, the diagnosis of nontuberculous mycobacteria-associated hemophagocytic lymphohistiocytosis was established. An anti-mycobacterial chemotherapy including chloramphenicol (800 mg/day), rifampin (450 mg/day) and ethambutol (750 mg/day) together with streptomycin (750 mg twice per week) was initiated at 30 days after admission; maintenance doses of prednisolone were increased to 60 mg/day. Fever and pancytopenia improved in response to anti-mycobacterial chemotherapy. The present case suggests that mesenteric panniculitis could be complicated with hemophagocytic lymphohistiocytosis caused by immunosuppressive therapy-associated infections as well as underlying disease activity. In conclusion, the possibility of disseminated nontuberculous mycobacteria infection with hemophagocytic lymphohistiocytosis should be considered if unexplained fever or hematological dyscrasia were presented in patients of mesenteric panniculitis.",
"affiliations": "Department of Rheumatology, Fukushima Medical University School of Medicine.;Department of Rheumatology, Fukushima Medical University School of Medicine.;Department of Rheumatology, Fukushima Medical University School of Medicine.;Department of Rheumatology, Fukushima Medical University School of Medicine.;Department of Rheumatology, Fukushima Medical University School of Medicine.;Department of Rheumatology, Fukushima Medical University School of Medicine.;Department of Rheumatology, Fukushima Medical University School of Medicine.;Department of Neurology, Fukushima Medical University School of Medicine.;Department of Hematology, Fukushima Medical University School of Medicine.;Department of Internal Medicine, Takeda General Hospital.;Department of Pulmonary Medicine, Fukushima Medical University Aizu Medical Center.;Department of Rheumatology, Fukushima Medical University School of Medicine.;Department of Rheumatology, Fukushima Medical University School of Medicine.",
"authors": "Fujita|Yuya|Y|;Matsumoto|Haruki|H|;Asano|Tomoyuki|T|;Sato|Shuzo|S|;Yashiro-Furuya|Makiko|M|;Matsuoka|Naoki|N|;Temmoku|Jumpei|J|;Nakatani-Enomoto|Setsu|S|;Kimura|Satoshi|S|;Hoshi|Kenta|K|;Uematsu|Manabu|M|;Watanabe|Hiroshi|H|;Migita|Kiyoshi|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1620/tjem.253.151",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-8727",
"issue": "253(2)",
"journal": "The Tohoku journal of experimental medicine",
"keywords": "disseminated NTM infection; fever of unknown origin; hemophagocytic lymphohistiocytosis; immunocompromised host; mesenteric panniculitis ",
"medline_ta": "Tohoku J Exp Med",
"mesh_terms": "D000273:Adipose Tissue; D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow; D006801:Humans; D008198:Lymph Nodes; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D009165:Mycobacterium Infections, Nontuberculous; D015436:Panniculitis, Peritoneal; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0417355",
"other_id": null,
"pages": "151-157",
"pmc": null,
"pmid": "33658450",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hemophagocytic Lymphohistiocytosis Associated with Disseminated Nontuberculous Mycobacterial Infection in a Patient with Mesenteric Panniculitis.",
"title_normalized": "hemophagocytic lymphohistiocytosis associated with disseminated nontuberculous mycobacterial infection in a patient with mesenteric panniculitis"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1902277",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nDrug allergies (DA) are immunologically mediated adverse drug reactions and their manifestations depend on a variety of drug- and patient-specific factors. The dysregulated immune system underpinning rheumatological diseases may also lead to an increase in hypersensitivity reactions, including DA. The higher prevalence of reported DA, especially anti-microbials, also restricts the medication repertoire for these already immunocompromised patients. However, few studies have examined the prevalence and impact of reported DA in this group of patients.\n\n\nMETHODS\nPatients with a diagnosis of rheumatoid arthritis (RA), spondyloarthritis (SpA), or systemic lupus erythematosus (SLE) were recruited from the rheumatology clinics in a tertiary referral hospital between 2018 and 2019. Prevalence and clinical outcomes of reported DA among different rheumatological diseases were calculated and compared to a cohort of hospitalized non-rheumatology patients within the same period.\n\n\nRESULTS\nA total of 6081 patients (2541 rheumatology patients: 1286 RA, 759 SpA, and 496 SLE; and 3540 controls) were included. DA was more frequently reported among rheumatology patients compared to controls (23.8% vs. 13.8%, p < 0.01). Antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) were the two most commonly reported categories of DA with a prevalence of 12.0% and 5.1%, respectively. Reported antibiotics allergies were more frequent in patients with RA (OR = 1.20, 95% CI = 1.02-1.62, p = 0.03) and SLE (OR = 4.69, 95% CI = 3.69-5.95, p < 0.01); and associated with increased infection-related admissions among rheumatology patients (OR = 1.79, 95% CI = 1.09-2.95, p = 0.02). Among the subgroup of patients referred for allergy testing, 85.7% of beta-lactam antibiotic allergy labels were found to be inaccurate and de-labelled after negative drug provocation testing.\n\n\nCONCLUSIONS\nThe prevalence of reported DA was significantly higher in rheumatology patients. Reported antibiotic allergy was associated with increased rate of infection-related admissions. However, the rate of genuine antibiotic allergy was low. Further studies are needed to guide proper assessment of reported DA and impact of comprehensive allergy testing in this group of patients.",
"affiliations": "Division of Rheumatology and Clinical Immunology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.;Division of Rheumatology and Clinical Immunology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.;Division of Rheumatology and Clinical Immunology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.;Division of Rheumatology and Clinical Immunology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.;Division of Rheumatology and Clinical Immunology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.;Division of Rheumatology and Clinical Immunology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.;Division of Rheumatology and Clinical Immunology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.;Division of Rheumatology and Clinical Immunology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.;Division of Rheumatology and Clinical Immunology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.",
"authors": "Chan|Shirley Chiu Wai|SCW|0000-0002-0640-0676;Yeung|Winnie Wan Yin|WWY|;Wong|Jane Chi Yan|JCY|;Chui|Ernest Sing Hong|ESH|;Lee|Matthew Shing Him|MSH|;Chung|Ho Yin|HY|;Cheung|Tommy Tsang|TT|;Lau|Chak Sing|CS|0000-0001-6698-8355;Li|Philip Hei|PH|0000-0002-9155-9162",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/diagnostics10110918",
"fulltext": "\n==== Front\nDiagnostics (Basel)\nDiagnostics (Basel)\ndiagnostics\nDiagnostics\n2075-4418 MDPI \n\n33182278\n10.3390/diagnostics10110918\ndiagnostics-10-00918\nArticle\nPrevalence and Impact of Reported Drug Allergies among Rheumatology Patients\nhttps://orcid.org/0000-0002-0640-0676Chan Shirley Chiu Wai Yeung Winnie Wan Yin Wong Jane Chi Yan Chui Ernest Sing Hong Lee Matthew Shing Him Chung Ho Yin Cheung Tommy Tsang https://orcid.org/0000-0001-6698-8355Lau Chak Sing https://orcid.org/0000-0002-9155-9162Li Philip Hei * Division of Rheumatology and Clinical Immunology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong; shirleychan.ms09@gmail.com (S.C.W.C.); win_as@hotmail.com (W.W.Y.Y.); janewongcy@gmail.com (J.C.Y.W.); ernesto@connect.hku.hk (E.S.H.C.); mattlee233@gmail.com (M.S.H.L.); jameschunghoyin@gmail.com (H.Y.C.); tommyct@gmail.com (T.T.C.); cslau@hku.hk (C.S.L.)\n* Correspondence: liphilip@hku.hk; Tel.: +852-2255-3348\n09 11 2020 \n11 2020 \n10 11 91828 10 2020 07 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/).Background: Drug allergies (DA) are immunologically mediated adverse drug reactions and their manifestations depend on a variety of drug- and patient-specific factors. The dysregulated immune system underpinning rheumatological diseases may also lead to an increase in hypersensitivity reactions, including DA. The higher prevalence of reported DA, especially anti-microbials, also restricts the medication repertoire for these already immunocompromised patients. However, few studies have examined the prevalence and impact of reported DA in this group of patients. Methods: Patients with a diagnosis of rheumatoid arthritis (RA), spondyloarthritis (SpA), or systemic lupus erythematosus (SLE) were recruited from the rheumatology clinics in a tertiary referral hospital between 2018 and 2019. Prevalence and clinical outcomes of reported DA among different rheumatological diseases were calculated and compared to a cohort of hospitalized non-rheumatology patients within the same period. Results: A total of 6081 patients (2541 rheumatology patients: 1286 RA, 759 SpA, and 496 SLE; and 3540 controls) were included. DA was more frequently reported among rheumatology patients compared to controls (23.8% vs. 13.8%, p < 0.01). Antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) were the two most commonly reported categories of DA with a prevalence of 12.0% and 5.1%, respectively. Reported antibiotics allergies were more frequent in patients with RA (OR = 1.20, 95% CI = 1.02–1.62, p = 0.03) and SLE (OR = 4.69, 95% CI = 3.69–5.95, p < 0.01); and associated with increased infection-related admissions among rheumatology patients (OR = 1.79, 95% CI = 1.09–2.95, p = 0.02). Among the subgroup of patients referred for allergy testing, 85.7% of beta-lactam antibiotic allergy labels were found to be inaccurate and de-labelled after negative drug provocation testing. Conclusion: The prevalence of reported DA was significantly higher in rheumatology patients. Reported antibiotic allergy was associated with increased rate of infection-related admissions. However, the rate of genuine antibiotic allergy was low. Further studies are needed to guide proper assessment of reported DA and impact of comprehensive allergy testing in this group of patients.\n\nallergydrughypersensitivityprevalencerheumatology\n==== Body\n1. Introduction\nThe prevalence of reported drug allergy (DA) is common, affecting around 7% and 14% among the general population and hospitalized patients, respectively [1,2]. Correct diagnosis of genuine DA is important. For example, it is well reported that beta-lactam (BL) antibiotic allergies are common among the general population and come with a myriad of detrimental consequences [2,3,4,5,6,7,8]. However, inaccurate beta-lactam (BL) allergy labels lead to obligatory use of alternative antibiotics which are associated with a multitude of adverse clinical consequences including increased healthcare costs, intensive care admissions, longer hospital stays, and death; as well as increased risks of multi-drug resistant organisms [9,10,11,12,13]. Unfortunately, the majority of self- or physician-reported DA (especially with BL), are likely inaccurate. In both Western and Asian studies, we previously found that only around 10% of patients with reported BL allergies were found to be truly allergic after testing [1,2,14].\n\nThe pathophysiology and manifestations of genuine DA depends on a variety of drug and patient factors, including concomitant disease states such as rheumatological diseases [15,16]. Higher rates of DA have previously been reported among rheumatology patients, especially in patients with systemic lupus erythematosus (SLE) [17,18,19,20]. However, literature is scarce and very little is known about the prevalence or impact of DA, especially among other rheumatological diseases.\n\nPatients with rheumatological diseases are often immunosuppressed and are more susceptible to infectious complications. We postulate that having inaccurate DA labels in this population will lead to even greater consequences. The dysregulated immune system underpinning rheumatological diseases may also lead to an increase in hypersensitivity reactions. Rheumatology patients are predisposed to be exposed and sensitized to various immunosuppressants and immunomodulatory medications. However, the burden and adverse consequences of reported DA among rheumatology patients remains to be investigated. To elucidate these areas of uncertainty, this study aims to assess the prevalence and impact of reported DA among rheumatology patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and SLE.\n\n2. Methods\nAll patients with a diagnosis of RA, SpA, or SLE were recruited from the rheumatology clinics of Queen Mary Hospital (QMH) between 2018 and 2019. Baseline demographics, clinical parameters, and details of physician-reported DA were obtained by medical record review. Prevalence and categories of reported DA among patients with rheumatological diseases (“rheumatology patients”) were calculated and compared to a cohort of hospitalized patients admitted to the acute general medical wards of QMH without a diagnosis of RA, SpA, SLE, or other connective tissue diseases within the same period (“controls”). Number of hospital admissions and principal diagnoses of admissions (categorized into infection-related or not) were recorded. Hospital admissions with incomplete records or deemed not related to infections (after medical record review by 2 independent reviewers) were excluded. Frequency of infection-related admissions in rheumatology patients with or without DA were compared.\n\nAll rheumatology patients with infection-related admissions and reported DA to BL underwent formal BL allergy testing, including skin testing (ST) with or without drug provocation testing (DPT). All patients had ST performed with benzylpenicilloyl polylysine (0.04 mg/mL), sodium benzylpenilloate (0.5 mg/mL), benzylpenicillin (10,000 UI/mL), amoxicillin (25 mg/mL), and/or index BL as per European Network and European Academy of Allergy and Clinical Immunology recommendations [21]. Patients with positive ST were deemed genuinely allergic and did not proceed with subsequent DPT. Patients with negative ST proceeded with DPT with the same BL as per their index reaction (and if the index BL was unknown, DPT was performed with the BL most clinically relevant for the patient—in most cases, amoxicillin).\n\nQMH is the only public hospital in the Hong Kong West Cluster providing acute medical admissions via its Accident and Emergency Department. Patients therefore likely represent the general population of Hong Kong requiring acute medical care during the study period. Informed consent was waived, and data extraction was approved by the Institutional Review Board of the University of Hong Kong/ Hospital Authority Hong Kong West Cluster (Reference number: UW 18–669, approved 19 December 2018).\n\n3. Statistical Analysis\nBaseline characteristics of patients were compared using Student’s t-test for continuous variables and the χ2 test for categorical variables between patients with and without reported drug allergy (univariate analysis). The prevalence of DA between rheumatology patients and controls were compared with adjustment for age and sex. Logistic regression analysis (multivariate analysis) was performed to evaluate predictors of infection-related admissions using demographics and DA information. All statistics were performed using the International Business Machines Corporation Statistical Package for the Social Sciences (IBM SPSS) package 26.0.\n\n4. Results\nA total of 2541 unique rheumatology patients (1286 RA, 759 SpA, and 496 SLE) and 3540 controls were recruited during the study period. The baseline characteristics and demographics of all recruited patients are shown in Table 1.\n\n4.1. Prevalence of Reported DA Was Significantly Higher among Rheumatology Patients, Affecting 40.1% of SLE Patients and 22.3% of RA Patients\nOverall, reported DA was significantly more frequent among rheumatology patients compared with controls (OR = 1.96, 95% CI = 1.72–2.24, p < 0.01). When analysing individual rheumatological diseases, this difference was most significant among patients with SLE (OR = 4.20, 95% CI = 3.43–5.15, p < 0.01), followed by RA (OR = 1.81, 95% CI = 1.30–2.12, p < 0.01) patients. However, there was no significant difference between patients with SpA and controls (Figure 1).\n\n4.2. Antibiotics (Especially Beta-Lactams) and NSAID Were the Most Frequently Reported DA among Rheumatology Patients, and Significantly More Than Controls\nAmong rheumatology patients, the most commonly reported DA were to antibiotics (12.0%), especially BL antibiotics (7.6%), followed by non-steroidal anti-inflammatory drugs (NSAIDs; 5.1%), disease-modifying antirheumatic drugs/immunosuppressants (4.4%), cardiovascular medications (2.6%), and intravenous radiocontrast (1.3%; Table 2 and Supplementary Figure S1). Using multivariate analysis to adjust for age and sex, reported antibiotic DA was more frequent among rheumatology patients compared with controls, especially among patients with RA (OR = 1.20, 95% CI 1.02–1.62, p = 0.03) and SLE (OR = 4.29, 95% CI = 3.23–5.69, p < 0.01). Reported DA to NSAIDs was more frequent across all rheumatology patients compared with general patients. Age and sex-adjusted odds ratios of DA by disease and drug classes are shown in Figure 2.\n\n4.3. Reported Antibiotic DA Was Independently Associated with Increased Rate of Infection-Related Admissions\nWithin the study period, 4.1% of all rheumatology patients were hospitalized due to infections. Univariate analysis revealed that age (62.0 ± 14.5 vs. 54.9 ± 13.7 years, p < 0.01) and reported antibiotic allergy (20.4% vs. 11.7%, p = 0.01) were significantly associated with infection-related admissions (Table 3). The association between reported antibiotic allergy and infection-related admissions remained significant in multivariate analysis (OR = 1.79; 95% CI = 1.09–2.95, p = 0.02).\n\n4.4. Drug Allergy Testing Was Useful, and Genuine BL Allergy Was Infrequent among Rheumatology Patients\nThere were 13 rheumatology patients with infection-related admissions and reported DA to BL. Two patients succumbed during their infection-related admission before evaluation of their reported DA. The remaining 11 patients were referred to undergo formal BL allergy testing. Five patients with seven reported BL allergies (with two patients having multiple reported BL allergies) agreed and were able to complete BL allergy evaluation. Clinical histories and results of their BL allergy workup are shown in Supplementary Table S1. The majority (85.7%, 6/7) of reported BL allergy labels were proven to be inaccurate and removed after confirmation with DPT.\n\n5. Discussion\nAdverse drug reactions (ADR) are defined as a “response to a drug which is noxious and unintended, which occurs at doses normally used in man” which can occur via a variety of different immunological or non-immunological mechanisms [22]. DA is defined as an ADR which is immunological mediated, and can be classified according to the immunologic mechanism described in Gell and Coombs classification of hypersensitivity reactions, with the vast majority presumed to be either IgE- (type I) or T cell-mediated (type IV) hypersensitivity reactions (HSR) [23]. Rheumatological diseases and allergic conditions are both characterized by immune dysregulation, which might be one of the factors contributing to the prevalence of DA in this group of patients.\n\nThe dysregulated immune system is responsible for the inappropriate response towards autoantigens in rheumatological diseases, and to exogenous factors in allergic disorders including DA. It has been reported that allergic conditions are more common in patients with rheumatological diseases, such as RA, SpA, and SLE [24,25,26]. Studies examining the links between allergic airway disease and rheumatological diseases are more prominent, with multiple mechanisms proposed to account for the link, including genetic predisposition, environmental factors, and immune regulations involving the interplay between Th1 and Th2 immunity, mast cell responses, and role of regulatory B cells [27,28]. Even though it has been observed that DA is more common among patients with rheumatological diseases, little is known so far regarding the potential immunopathogenic pathways involved.\n\nOur study showed that the prevalence of reported DA was significantly higher among SLE and RA patients in comparison to hospitalized non-rheumatology, but not SpA. Susceptibility to more DA (both genuine DA and inaccurate DA labelling) in rheumatology patients could be due to various factors. Previous studies suggested other susceptible factors among rheumatology patients, such as gender, genetic polymorphism, and viral infections [29]. DA is more frequently reported in females, and genetic and hormonal factors have been proposed to play a role in this phenomenon [30]. Similarly, rheumatological diseases also have a predilection to affect female patients, especially SLE and RA. Although the proportion of female patients were much high than in the control group (70.1 vs. 53.4%), the risk of DA was still higher among patients with rheumatological diseases, adjusted by age and sex, implying that other factors are also involved.\n\nWe postulate additional mechanisms, such as with the example of immediate-type DA. Immediate type (type I) HSR are classically thought to be IgE-mediated. Another predominantly IgE-autoantibody (or IgG-autoantibody to IgE and FcεRI) mediated immunological condition which manifests very similarly is chronic spontaneous urticaria (CSU), with an autoimmune subset being increasingly recognized [31,32]. It is known that various autoimmune diseases, such as SLE and RA, are also prone to development of CSU [33]. One postulation is the development of autoantibodies to FcεRI or IgE on both mast cells and basophils. Furthermore, the role of IgE is likely shared amongst various autoimmune diseases. In fact, a study demonstrated the increased pathogenic role of IgE autoantibodies in SLE patients, in particular, increased IgE to anti-dsDNA, anti-Sm, anti-Ro/SSA, and anti-La/SSB, which had a positive correlation with active disease [34]. The propensity for production of IgE autoantibodies may have a role in production of drug specific IgE. On the contrary, the pathogenesis of SpA leans less towards B cell dysregulation, and we found SpA patients had similar reported DA compared to controls.\n\nFurthermore, rheumatology patients are more likely to have concomitant CSU, and urticaria flares are known to occur more frequently during infective episodes when new medications (especially antimicrobials) are prescribed. Similarly, NSAIDs use is frequent among rheumatology patients and may exacerbate urticaria in those with concomitant CSU (NSAIDs-exacerbated cutaneous disease). During episodes of acute urticarial flares, physicians may often wrongly label DA as a culprit of urticaria or angioedema, leading to an overall increased frequency of reported DA among rheumatology patients. Differentiating between a genuine allergy and an ADR is a diagnostic challenge [35], especially in rheumatology patients who may exhibit symptoms that mimic allergic reactions such as skin rash. Education and awareness of the complexity of diagnosing DA in rheumatology patients are important, and interdisciplinary collaboration between rheumatologist and allergist are imperative.\n\nOwing to the lack of allergists and DA testing services in Hong Kong, the waiting time for proper drug allergy workup can take months or years [36]. In our study, more than 85% of reported BL allergy in rheumatology patients previously admitted for infections were confirmed to be inaccurate by DPT. Only one patient, labelled with both an ampicillin and cloxacillin allergy after an index reaction of angioedema, was found to be genuinely allergic. Subsequent ST confirmed an IgE-mediated selective hypersensitivity to cloxacillin, and tolerance to amoxicillin was demonstrated by a negative DPT. Given this very low rate of genuine DA and our novel finding that reported antibiotic DA labels are associated with increased hospitalization rates among rheumatology patients, many infection-related hospital admissions may be avoided if adequate allergy testing services were readily available.\n\nThere are several limitations to our study. First, because of its observational nature, there were several factors that we were not able to be obtained from the computer records alone. For example, whether the DA was suspected to be immediate or delayed-type was often unclear or missing. Risk factors for DA labels, such as timing of the index reaction, are also missing but important independent variables. Additionally, other comorbidities, such as cardiovascular diseases, non-rheumatological pain syndromes, atopic diseases, and non-rheumatological immunosuppressive factors, were not included. This highlights the importance of dedicated and prospective studies in the future. Second, our control group consisted of hospitalized patients, and comparison between general rheumatology patients can be difficult. However, we know that the prevalence of reported DA is higher among hospitalized patients compared with the general population [1,2]. We would therefore expect a bias (if any) toward DA among the control cohort when compared to rheumatology patients. Despite this potential bias, rheumatology patients still had a significantly higher prevalence of DA labels, which further demonstrates the overwhelming higher prevalence of reported DA in this susceptible cohort. Third, our study mainly focused on antibiotic allergies. In particular, we focused on BL as it was the most common DA label reported. Additionally, skin tests for penicillin are well validated unlike other medications such as non-BL antibiotics and NSAIDs. Future studies looking at other allergies will be useful to get a broader sense of the burden DA have in this cohort. For example, workup for genuine NSAID allergy could be useful, especially in SpA patients where other non-biologic disease modifying agents remain limited. Similarly, proper evaluation of biologics allergy in the literature is also scarce and warrant studies to guide diagnostic algorithms in this special population [37,38].\n\nIn conclusion, our study sheds light on the burden and impact of DA in rheumatological diseases. The prevalence of reported DA was significantly higher in rheumatology patients, highlighting the importance for further research to understand the underlying mechanisms involved. Reported antibiotic allergy was also associated with increased rate of infection-related admissions among rheumatology patients, although the rate of genuine BL antibiotic allergy was low. Further studies are needed to guide proper assessment of reported DA and impact of comprehensive allergy testing in this group of patients.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary Materials\nThe following are available online at https://www.mdpi.com/2075-4418/10/11/918/s1, Figure S1: Frequency of reported DA in 2541 rheumatology patients; Table S1: Allergy histories and investigation results of patients who completed beta-lactam allergy testing.\n\nClick here for additional data file.\n\n Author Contributions\nConceptualization, J.C.Y.W., C.S.L., and P.H.L.; Data curation, S.C.W.C., J.C.Y.W., E.S.H.C., M.S.H.L., H.Y.C., T.T.C., and P.H.L.; Formal analysis, S.C.W.C., E.S.H.C., M.S.H.L., and P.H.L.; Investigation, S.C.W.C., W.W.Y.Y., and P.H.L.; Methodology, J.C.Y.W., C.S.L., and P.H.L.; Project administration, W.W.Y.Y., H.Y.C., T.T.C., C.S.L., and P.H.L.; Resources, C.S.L. and P.H.L.; Supervision, C.S.L. and P.H.L.; Validation, S.C.W.C., E.S.H.C., and M.S.H.L.; Writing—original draft, S.C.W.C. and P.H.L.; Writing—review & editing, W.W.Y.Y., J.C.Y.W., and P.H.L. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Prevalence of reported drug allergy among different rheumatological diseases.\n\nFigure 2 Age- and sex- adjusted odds ratios of DA (by disease and drug categories) compared to controls.\n\ndiagnostics-10-00918-t001_Table 1Table 1 Baseline characteristics and demographics of rheumatology patients (N = 2541) and controls (N = 3540).\n\nAll Patients (N = 6081)\t\n\n\tTotal\tNo drug allergy\tDrug allergy\tp value\t\nNumber\t6081\t4988 (82.0%)\t1093 (18.0%)\t\n\t\nAge (years)\t64.6 ± 18.0\t64.7 ± 18.3\t63.7 ± 16.0\t0.06\t\nMale\t2393 (39.4%)\t2089 (41.9%)\t304 (27.8%)\t<0.01\t\nControls (N = 3540)\t\n\n\tTotal\tNo drug allergy\tDrug allergy\tp value\t\nNumber\t3540\t3053 (86.2%)\t487 (13.8%)\t\n\t\nAge (years)\t71.3 ± 17.6\t71.4 ± 17.7\t71.0 ± 17.0\t0.65\t\nMale\t1649 (46.6%)\t1458 (47.8%)\t191 (39.2%)\t<0.01\t\nRheumatology patients (N = 2541)\t\n\n\tTotal\tNo drug allergy\tDrug allergy\tp value\t\nNumber\t2541\t1935 (76.2%)\t606 (23.8%)\t\n\t\nAge (years)\t55.2 ± 13.8\t54.3 ± 14.1\t57.9 ± 12.5\t<0.01\t\nMale\t744 (29.3%)\t631 (32.6%)\t113 (18.6%)\t<0.01\t\nRheumatoid arthritis (N = 1286)\t\n\n\tTotal\tNo drug allergy\tDrug allergy\tp value\t\nNumber \t1286\t999 (77.7%)\t287 (22.3%)\t\n\t\nAge (years)\t58.9 ± 12.1\t58.2 ± 12.2\t61.3 ± 11.8\t<0.01\t\nMale\t228 (17.7%)\t189 (18.9%)\t39 (13.6%)\t0.04\t\nSpondyloarthritis (N = 759)\t\n\n\tTotal\tNo drug allergy\tDrug allergy\tp value\t\nNumber\t759\t639 (84.2%)\t120 (15.8%)\t\n\t\nAge (years)\t49.5 ± 15.0\t48.8 ± 15.0\t53.3 ± 14.2\t<0.01\t\nMale\t473 (62.3%)\t416 (65.1%)\t57 (47.5%)\t<0.01\t\nSystemic lupus erythematosus (N = 496)\t\n\n\tTotal\tNo drug allergy\tDrug allergy\tp value\t\nNumber\t496\t297 (59.9%)\t199 (40.1%)\t\n\t\nAge (years)\t54.1 ± 12.7\t53.0 ± 13.6\t55.7 ± 11.1\t0.01\t\nMale\t43 (8.7%)\t17 (8.5%)\t26 (8.8%)\t0.94\t\ndiagnostics-10-00918-t002_Table 2Table 2 Frequency of different classes of reported drug allergies (DA).\n\n\n\t\nRheumatology Patients (N = 2541)\n\t\nControls (N = 3540)\n\t\n\n\t\nRA\n\t\nSLE\n\t\nSpA\n\t\nTotal\n\t\n%\n\t\nTotal\n\t\n%\n\t\nAny antibiotics\t113\t129\t64\t306\t12\t247\t7\t\nBeta-lactam antibiotics\t69\t82\t43\t194\t7.6\t170\t4.8\t\nNon-steroidal anti-inflammatory drugs\t73\t30\t27\t130\t5.1\t78\t2.2\t\nDisease-modifying antirheumatic drugs/immunosuppressants\t79\t19\t15\t113\t4.4\t0\t0\t\nCardiovascular drugs\t42\t19\t4\t65\t2.6\t59\t1.7\t\nIntravenous contrast\t14\t11\t8\t33\t1.3\t41\t1.2\t\nOther analgesics\t16\t6\t8\t30\t1.2\t12\t0.3\t\nAllopurinol\t3\t4\t1\t8\t0.3\t17\t0.5\t\nAnti-fungal\t4\t2\t2\t8\t0.3\t4\t0.1\t\nAnti-virals\t3\t4\t0\t7\t0.3\t3\t0.1\t\ndiagnostics-10-00918-t003_Table 3Table 3 Association analysis between clinical features and infection-related hospitalization.\n\nRheumatology Patients (N = 2541)\t\n\n\t\n\t\n\tUnivariate\tMultivariate\t\n\n\tAdmission\tNo Admission\tOR (95%CI)\tp Value\tOR (95%CI)\tp Value\t\nNumber of patients\t103 (4.1%)\t2438 (95.9%)\t------\t------\t------\t------\t\nAge\t62.0 ± 14.5\t54.9 ± 13.7\t------\t<0.01\t1.04 (1.03–1.06)\t<0.01\t\nMale\t33 (32.0%)\t711 (29.2%)\t1.15 (0.75–1.75)\t0.53\t------\t------\t\nRA\t52 (50.5%)\t1234 (50.6%)\t1.00 (0.67–1.48)\t0.98\t------\t------\t\nSpA\t26 (25.2%)\t733 (30.1%)\t0.79 (0.50–1.24)\t0.30\t------\t------\t\nSLE\t25 (24.3%)\t471 (19.3%)\t1.34 (0.84–2.12)\t0.21\t------\t------\t\nReported DA\t\n\t\n\t\n\t\n\t\n\t\n\t\nAntibiotics\t21 (20.4%)\t285 (11.7%)\t1.94 (1.18–3.17)\t0.01\t1.79 (1.09–2.95)\t0.02\t\nNSAIDs\t9 (8.7%)\t121 (5.0%)\t1.83 (0.90–3.72)\t0.09\t------\t------\t\nRA = rheumatoid arthritis, SpA = spondyloarthritis; SLE = systemic lupus erythematosus; NSAIDs = non-steroidal anti-inflammatory drugs.\n==== Refs\nReferences\n1. 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Pract. 2018 6 1649 1654.e4 10.1016/j.jaip.2017.12.033 29355644 \n10. MacFadden D.R. LaDelfa A. Leen J. Gold W.L. Daneman N. Weber E. Al-Busaidi I. Petrescu D. Saltzman I. Devlin M. Impact of Reported Beta-Lactam Allergy on Inpatient Outcomes: A Multicenter Prospective Cohort Study Clin. Infect. Dis. 2016 63 904 910 10.1093/cid/ciw462 27402820 \n11. Macy E. Contreras R. Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: A cohort study J. Allergy Clin. Immunol. 2014 133 790 796 10.1016/j.jaci.2013.09.021 24188976 \n12. Macy E. Addressing the epidemic of antibiotic “allergy” over-diagnosis Ann. Allergy Asthma Immunol. 2020 124 550 557 10.1016/j.anai.2019.12.016 31881269 \n13. Charneski L. Deshpande G. Smith S.W. Impact of an antimicrobial allergy label in the medical record on clinical outcomes in hospitalized patients Pharmacotherapy 2011 31 742 747 10.1592/phco.31.8.742 21923600 \n14. Siew L.Q.C. Li P.H. Watts T.J. Thomas I. Ue K.L. Caballero M.R. Rutkowski K. Till S.J. Pillai P. Haque R. Identifying Low-Risk Beta-Lactam Allergy Patients in a UK Tertiary Centre J. Allergy Clin. Immunol. Pract. 2019 7 2173 2181.e1 10.1016/j.jaip.2019.03.015 30922992 \n15. Thong B.Y. Tan T.C. Epidemiology and risk factors for drug allergy Br. J. Clin Pharmacol. 2011 71 684 700 10.1111/j.1365-2125.2010.03774.x 21480948 \n16. Dona I. Barrionuevo E. Blanca-Lopez N. Torres M.J. Fernandez T.D. Mayorga C. Canto G. Blanca M. Trends in hypersensitivity drug reactions: More drugs, more response patterns, more heterogeneity J. Investig. Allergol. Clin. Immunol. 2014 24 143 153 quiz 141 p following 153 \n17. Williams B.O. St Onge R.A. Young A. Nuki G. Dick W.C. Whaley K. Penicillin allergy in rheumatoid arthritis. With special reference to Sjogren’s syndrome Ann. Rheum Dis. 1969 28 607 611 10.1136/ard.28.6.607 5308134 \n18. Littlejohns D.W. Drug allergy in rheumatology Rheumatol. Phys. Med. 1972 11 435 436 10.1093/rheumatology/11.8.435 4266229 \n19. Pope J. Jerome D. Fenlon D. Krizova A. Ouimet J. Frequency of adverse drug reactions in patients with systemic lupus erythematosus J. Rheumatol. 2003 30 480 484 12610805 \n20. Aceves-Avila F.J. Benites-Godinez V. Drug allergies may be more frequent in systemic lupus erythematosus than in rheumatoid arthritis J. Clin. Rheumatol. 2008 14 261 263 10.1097/RHU.0b013e31817a241a 18679134 \n21. Brockow K. Garvey L.H. Aberer W. Atanaskovic-Markovic M. Barbaud A. Bilo M.B. Bircher A. Blanca M. Bonadonna B. Campi P. Skin test concentrations for systemically administered drugs—An ENDA/EAACI Drug Allergy Interest Group position paper Allergy 2013 68 702 712 10.1111/all.12142 23617635 \n22. World Health Organization Safety of Medicines: A Guide to Detecting and Reporting Adverse Drug Reactions World Health Organization Geneva, Switzerland 2002 \n23. Johansson S.G. Bieber T. Dahl R. Friedmann P.S. Lanier B.Q. Lockey R.F. Motala C. Ortega Martell J.A. Platts-Mills T.A. Ring J. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003 J. Allergy Clin. Immunol. 2004 113 832 836 10.1016/j.jaci.2003.12.591 15131563 \n24. Lai N.S. Tsai T.Y. Koo M. Lu M.C. Association of rheumatoid arthritis with allergic diseases: A nationwide population-based cohort study Allergy Asthma Proc. 2015 36 99 103 10.2500/aap.2015.36.3871 26314811 \n25. Chang W.P. Kuo C.N. Kuo L.N. Wang Y.T. Perng W.T. Kuo H.C. Wei J.C. Increase risk of allergic diseases in patients with ankylosing spondylitis: A 10-year follow-up population-based study in Taiwan Medicine (Baltimore) 2016 95 e5172 10.1097/MD.0000000000005172 27828843 \n26. Sequeira J.F. Cesic D. Keser G. Bukelica M. Karanagnostis S. Khamashta M.A. Hughes G.R. Allergic disorders in systemic lupus erythematosus Lupus 1993 2 187 191 10.1177/096120339300200311 8369810 \n27. Jeong H.E. Jung S.M. Cho S.I. Association between Rheumatoid Arthritis and Respiratory Allergic Diseases in Korean Adults: A Propensity Score Matched Case-Control Study Int. J. Rheumatol. 2018 2018 3798124 10.1155/2018/3798124 29849649 \n28. Sin E. Anand P. Frieri M. A link: Allergic rhinitis, Asthma & Systemic Lupus Erythematosus Autoimmun. Rev. 2016 15 487 491 10.1016/j.autrev.2016.02.003 26851551 \n29. Khan D.A. Solensky R. Drug allergy J. Allergy Clin. Immunol. 2010 125 S126 S137 10.1016/j.jaci.2009.10.028 20176256 \n30. Eaddy Norton A. Broyles A.D. Drug allergy in children and adults: Is it the double X chromosome? Ann. Allergy Asthma Immunol. 2019 122 148 155 10.1016/j.anai.2018.11.014 30465863 \n31. Konstantinou G.N. Asero R. Ferrer M. Knol E.F. Maurer M. Raap U. Schmid-Grendelmeier P. Skov P.S. Grattan C.E. EAACI taskforce position paper: Evidence for autoimmune urticaria and proposal for defining diagnostic criteria Allergy 2013 68 27 36 10.1111/all.12056 23157716 \n32. Kolkhir P. Church M.K. Weller K. Metz M. Schmetzer O. Maurer M. Autoimmune chronic spontaneous urticaria: What we know and what we do not know J Allergy Clin Immunol 2017 139 1772 1781.e1 10.1016/j.jaci.2016.08.050 27777182 \n33. Bracken S.J. Abraham S. MacLeod A.S. Autoimmune Theories of Chronic Spontaneous Urticaria Front. Immunol. 2019 10 627 10.3389/fimmu.2019.00627 30984191 \n34. Dema B. Pellefigues C. Hasni S. Gault N. Jiang C. Ricks T.K. Bonelli M.M. Scheffel J. Sacre K. Jablonski M. Autoreactive IgE is prevalent in systemic lupus erythematosus and is associated with increased disease activity and nephritis PLoS ONE 2014 9 e90424 10.1371/journal.pone.0090424 24587356 \n35. Leru P.M. Deleanu D.M. Romanian Allergology in the actual European context Rom. J. Intern. Med. 2015 53 111 117 10.1515/rjim-2015-0015 26402979 \n36. Lee T.H. Leung T.F. Wong G. Ho M. Duque J.R. Li P.H. Lau C.S. Lam W.F. Wu A. Chan E. The unmet provision of allergy services in Hong Kong impairs capability for allergy prevention-implications for the Asia Pacific region Asian Pac. J. Allergy Immunol. 2019 37 1 8 10.12932/AP-250817-0150 29223147 \n37. Li P.H. Watts T.J. Lui M.S. Lau C.S. Chung H.Y. Recall Urticaria in Adalimumab Hypersensitivity J Allergy Clin. Immunol. Pract. 2018 6 1032 1033 10.1016/j.jaip.2017.10.031 29175008 \n38. Li P.H. Watts T.J. Chung H.Y. Lau C.S. Fixed Drug Eruption to Biologics and Role of Lesional Patch Testing J. Allergy Clin. Immunol. Pract. 2019 7 2398 2399 10.1016/j.jaip.2019.06.028 31326380\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2075-4418",
"issue": "10(11)",
"journal": "Diagnostics (Basel, Switzerland)",
"keywords": "allergy; drug; hypersensitivity; prevalence; rheumatology",
"medline_ta": "Diagnostics (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101658402",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33182278",
"pubdate": "2020-11-09",
"publication_types": "D016428:Journal Article",
"references": "31881269;15479276;21480948;22289726;15131563;18679134;26402979;29849649;26851551;31551666;30984191;4266229;12610805;27828843;23157716;26314811;25011351;30465863;20176256;27402820;27777182;23617635;26970431;24188976;30922992;26662186;31326380;8369810;21923600;29175008;29223147;5308134;30558872;24587356;32374398;29355644",
"title": "Prevalence and Impact of Reported Drug Allergies among Rheumatology Patients.",
"title_normalized": "prevalence and impact of reported drug allergies among rheumatology patients"
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"companynumb": "HK-LUPIN PHARMACEUTICALS INC.-2022-08041",
"fulfillexpeditecriteria": "2",
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"abstract": "BACKGROUND Empagliflozin selectively reduces apical sodium-glucose co-transporter 2 function in the proximal convoluted tubules, increasing sodium and glucose excretion in the urine, ultimately reducing glucose reabsorption in the kidneys for diabetic management. Lithium, the gold-standard treatment for bipolar disorder, also utilizes sodium transporters in the proximal convoluted tubules. CASE REPORT Presenting with a manic relapse of refractory schizoaffective disorder, our patient was found to have subtherapeutic levels of lithium on admission due to poor outpatient medication compliance. Restoration to therapeutic lithium levels allowed inpatient blood glucose measurements, which led to a new diagnosis of type 2 diabetes mellitus. Given his comorbid severe hepatic impairment, obesity, and prior pancreatitis, the patient was started on empagliflozin to safely manage this new diagnosis without collateral organ injury. Routine monitoring found reproducible and clinically significant decreases in serum lithium levels in the presence of empagliflozin therapy, without obvious confounding factors. Subsequent discussion with specialist teams resulted in trialling metformin, which adequately controlled the new diabetic diagnosis without inpatient complications. CONCLUSIONS We suspect that empagliflozin reduced sodium-glucose and lithium-glucose reabsorption in the proximal connecting tubules, thereby increasing the renal excretion of sodium, glucose, and lithium. Applications include awareness of the interaction between these medications, support for the role of physiological SGLT-2-mediated lithium transport, and the possibility of using empagliflozin and other SGLT-2 inhibitors to treat life-threatening lithium toxicity.",
"affiliations": "Mental Health Services, Joondalup Health Campus, Joondalup, Perth, Australia.",
"authors": "Armstrong|Guy Philip|GP|",
"chemical_list": "D018692:Antimanic Agents; D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; D018020:Lithium Compounds; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D008687:Metformin; C570240:empagliflozin",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.923311",
"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\n32518219\n10.12659/AJCR.923311\n923311\nArticles\nEmpagliflozin-Mediated Lithium Excretion: A Case Study and Clinical Applications\nArmstrong Guy Philip ABCDEFG Mental Health Services, Joondalup Health Campus, Joondalup, Perth, Australia\nCorresponding Author: Guy Philip Armstrong, e-mail: ArmstrongG@ramsayhealth.com.auAuthors’ 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\n2020 \n10 6 2020 \n21 e923311-1 e923311-4\n06 2 2020 14 4 2020 13 5 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 30-year-old\n\nFinal Diagnosis: Schizoaffective disorder\n\nSymptoms: Renal excretion of lithium\n\nMedication: Empagliflozin\n\nClinical Procedure: —\n\nSpecialty: Nephrology • Psychiatry\n\nObjective:\nUnusual or unexpected effect of treatment\n\nBackground:\nEmpagliflozin selectively reduces apical sodium-glucose co-transporter 2 function in the proximal convoluted tubules, increasing sodium and glucose excretion in the urine, ultimately reducing glucose reabsorption in the kidneys for diabetic management. Lithium, the gold-standard treatment for bipolar disorder, also utilizes sodium transporters in the proximal convoluted tubules.\n\nCase Report:\nPresenting with a manic relapse of refractory schizoaffective disorder, our patient was found to have subtherapeutic levels of lithium on admission due to poor outpatient medication compliance. Restoration to therapeutic lithium levels allowed inpatient blood glucose measurements, which led to a new diagnosis of type 2 diabetes mellitus. Given his comorbid severe hepatic impairment, obesity, and prior pancreatitis, the patient was started on empagliflozin to safely manage this new diagnosis without collateral organ injury. Routine monitoring found reproducible and clinically significant decreases in serum lithium levels in the presence of empagliflozin therapy, without obvious confounding factors. Subsequent discussion with specialist teams resulted in trialling metformin, which adequately controlled the new diabetic diagnosis without inpatient complications.\n\nConclusions:\nWe suspect that empagliflozin reduced sodium-glucose and lithium-glucose reabsorption in the proximal connecting tubules, thereby increasing the renal excretion of sodium, glucose, and lithium. Applications include awareness of the interaction between these medications, support for the role of physiological SGLT-2-mediated lithium transport, and the possibility of using empagliflozin and other SGLT-2 inhibitors to treat life-threatening lithium toxicity.\n\nMeSH Keywords:\nDrug InteractionsLithiumRenal ExcretionSodium-Glucose Transporter 2\n==== Body\nBackground\nApproved by both the US Federal Drugs Administration and the Australian Therapeutic Goods Administration in 2014 for the control of type 2 diabetes mellitus (T2DM), empagliflozin and other sodium-glucose co-transporter 2 (SGLT2) inhibitors are now frequently used in the evidence-based treatment of T2DM [1]. This clinical success stems from satisfactory diabetic control, marked cardiovascular and renal benefits, and manageable adverse effects, including increased predisposition to urinary tract infections (a consequence of glycosuria) and euglycemic ketosis [1–3]. Pharmacologically, empagliflozin is a reversible, highly potent, and highly selective competitive inhibitor of SGLT2, a co-transporter found predominantly in the S1 segment of the proximal convoluted tubule (PCT) and responsible for approximately 90% of renal glucose reabsorption in healthy individuals [1–4]. However, evidence suggests that 25 mg empagliflozin daily linearly reduces excess glucose reabsorption by less than 40%, perhaps due to the capacity of the normally redundant spared SGLT1 (found more distally in the PCT) [2,4].\n\nEven more clinically successful is lithium; by virtue of its history, efficacy, availability, reduction in suicide rate, and purported role in neuroprotection, it remains the gold-standard mood stabilizer in those able to tolerate it [5]. However, the utility of lithium is limited by a narrow therapeutic index, highly variable clearance rates between individuals, and lethal toxicity, teratogenicity, and nephrotoxicity [5]. Since initial human trials in 1949, and FDA approval in 1970 for the treatment of mania, the renal clearance lithium has been extensively studied [5,6]. Like sodium and glucose, the majority (>60%) of filtered lithium is reabsorbed in the PCT, with distal epithelial sodium channels also contributing [7,8]. Established apical lithium transporters in proximal epithelial cells include the amiloride-sensitive sodium channel, the amiloride-sensitive sodium-proton exchanger, and, to a seemingly far lesser extent, the sodium-glucose and sodium-phosphate co-transporters (in typical human physiological conditions) [7–9]. Such utilization of sodium transporters by lithium is presumed to stem from their atomic similarities.\n\nThe following case report identifies a novel drug–drug interaction between empagliflozin and lithium.\n\nCase Report\nPresenting with a recurrence of insightless disinhibition, disorganization, uncontrollable drive, pressured speech, and exacerbated grandiose and religious delusions, an obese, 29-year-old man of Central American descent was admitted with a manic relapse of schizoaffective disorder. Since diagnosis in his late teens, various mood stabilizers and antipsychotics had been administered in the context of intellectual impairment and poor outpatient oral medication compliance; a severe, treatment-refractory schizoaffective illness; the gradual development of obesity and non-alcoholic fatty liver disease; and various adverse drug reactions, including valproate-induced pancreatitis, olanzapine-induced acute liver injury, and dose-related haloperidol-induced acute liver injury. The patient had been frequently treated by inpatient services, historically re-presenting following a reduction in the level of supervision by his supportive family and/or community outpatient supports, with subsequent non-compliance to oral lithium. The patient and family denied any smoking, alcohol, or illicit substances, yet poor appetite control had led to a body mass index (BMI) approaching 42 kg/m2. In addition to 1350 mg modified-release oral lithium daily, the patient’s regular medications on admission were 300 mg (long-acting injectable) aripiprazole monthly, 50 mg pregabalin at night, 5 mg haloperidol at night, 3 mg clonazepam daily, vitamin D supplementation, and melatonin.\n\nInitial difficulty in managing his drive, delusions, disinhibition, and disorganization led to administration of an intramuscular zuclopenthixol acetate course (125 mg, 150 mg, 150 mg every second day) and intramuscular benzodiazepines on a secure ward, with some settling effect. However, as in previous admissions, the restoration of therapeutic lithium levels (<0.2 mM to 1.1 mM by Day 4) with his regular dose of modified-release lithium (1350 mg daily) was found to markedly improve his manic and psychotic features.\n\nThis settling allowed the collection of routine nursing observations on Day 9, including blood sugar levels (BSLs), which were found to be 26.2 mM (without ketosis). Subsequent investigation found an HbA1c of 7.3%, leading to a new diagnosis of T2DM. Further exploration of the patient’s medical history found the previous use of metformin for pre-diabetes 1 year ago, which was ceased in the context of acute-on-chronic hepatic injury during trials of oral olanzapine and high-dose oral haloperidol. Consultation with medical staff, diabetic educator staff, and diabetic guidelines led to a mutual decision to trial empagliflozin over acarbose due to the relative safety profile, as all other oral diabetic medications were considered contra-indicated in the context of previous pancreatitis and severe liver impairment. Empagliflozin was commenced on Day 10 and uptitrated to 25 mg every morning over the following days, with excellent diabetic control (BSLs 6–11 mM throughout the day) and without physiological adverse effects. However, on Day 13, routine blood tests identified a subtherapeutic lithium level (0.4 mM). Repeat testing (Day 14) confirmed the subtherapeutic levels. Following a suspicion of empagliflozin-mediated lithium excretion, empagliflozin was withheld, and 10 units of covering Lantus at night ensured euglycemia. By Day 20 of admission, lithium levels had returned to therapeutic range (1.3 mM). A willingness of our patient and his family to re-trial empagliflozin at 25 mg every morning led to another subtherapeutic lithium level (0.5 mM) by Day 22 (confirmed on Day 23). No ketosis was detected on routine nursing bedside testing, the patient remained well hydrated, plasma sodium and potassium were preserved within the normal range, and an eGFR >90 ml/min/1.73 m2 was maintained throughout the admission.\n\nFollowing endocrinology consultation and recommendation, empagliflozin was ceased and instant-release metformin 500 mg was first re-trialled on Day 24 of admission. Euglycemia was then maintained without adverse effects such as LFT derangement, precipitation of lactic acidosis, or pancreatitis. With progressive stabilization and concurrent re-implementation of outpatient community supports, the patient was discharged home at baseline function and therapeutic lithium level (0.9 mM) a few days later. The sole change to regular medication throughout the admission was the re-introduction of metformin.\n\nDiscussion\nDespite the unexpected and previously undocumented strong negative correlation between a SGLT-2 inhibitor and serum lithium levels in this case, the connection between lithium (mostly absorbed by sodium transporters in the PCT) and empagliflozin (which impairs an apical sodium-glucose co-transporter in the PCT) is theoretically unsurprising. This parallels the discovery of how amiloride, through inhibition of the amiloride-sensitive sodium channel, reduces lithium reabsorption and subsequently manages nephrogenic diabetes insipidus (alongside a complex reversal of aquaporin downregulation) [9]. With a Naranjo Adverse Drug Reaction Probability Scale score of +8, further cases and/or prospective scientific enquiry are necessary to validate this case’s probable drug–drug interaction.\n\nThe reproducibility in this case also questions the consensus, founded on a heavily-referenced paper by Holstein-Rathlou in 1990 [10], about the theoretically-limited role of the sodium-glucose co-transporter in lithium reabsorption [7]. We suggest that a large amount of lithium must be transported by SGLT-2 for empagliflozin to have so markedly impaired our patient’s serum lithium levels, given the reported maximal 40% reduction of empagliflozin in clinical SGLT-2 function. Similarly, Uwai et al. [11] found (in rat studies) that two-thirds of lithium reabsorption occurred through the sodium-phosphate co-transporter, opposing the consensus that these transporters negligibly contribute. Given new empirical and recent investigative evidence opposing the existing theoretical model, further research should identify and/or confirm the relative efficacy of different apical PCT transporters and channels on lithium reabsorption.\n\nFinally, if lithium is substantially reabsorbed by SGLT-2 as empirically observed, and empagliflozin markedly reduces SGLT-2 function with a tolerable adverse effect profile, empagliflozin could improve the management of lithium toxicity. Lithium toxicity is life-threatening and can cause cardiac arrest, hyper-thermia, seizures, and potentially-irreversible tremor, ataxia, and nystagmus [12]. Due to a lengthy physiological half-life of 24 hours, lithium toxicity is currently managed through non-specific measures such gastric lavage, intravenous dilution, and/or haemodialysis to expedite clearance [12]. As oral empagliflozin reaches peak plasma concentrations within 1.5 hours, empagliflozin (and other SGLT-2 inhibitors) could improve best practice management of lithium toxicity by expediting renal excretion of lithium in a more cost-effective, convenient, and safe manner. Further research should seek to validate this hypothesis.\n\nConclusions\nOur unique case report of trialling empagliflozin in an inpatient with frequent lithium-monitoring empirically identified a reproducible effect of empagliflozin use on lithium levels. This Naranjo-probable suspected association is only partially supported by the current understanding of lithium and SGLT-2 inhibitor pharmacology; therefore, our experience in treating this patient raises questions about the previously proposed theoretical models, which possibly minimize the role of the SGLT in lithium reabsorption. With further research to validate the findings of this case study, subsequent research could assess the relative cost-efficacy, convenience, and safety of using SGLT-2 inhibitors to manage lithium toxicity over existing best practice.\n\nDr Amatul Uzma, Supervising Consultant Psychiatrist (Joondalup Health Campus Mental Health Services) and the Joondalup Health Campus Human Resource Ethics Committee, for their general supervision and permission to publish this case report.\n\nOur patient and his family, for their willingness to share this previously undocumented outcome with the world.\n\nConflicts of interest\n\nNone.\n==== Refs\nReferences:\n1. Therapeutic Goods Administration (AUS) Australian Register of Therapeutic Goods – Empagliflozin [Internet] Australia 2013 https://www.ebs.tga.gov.au/ \n2. Ferrannini E Sodium-glucose co-transporters and their inhibition: Clinical physiology Cell Metab 2017 26 1 27 38 28506519 \n3. Thomson SC Vallon V Renal effects of sodium-glucose co-transporter inhibitors Am J Cardiol 2019 124 1 S28 35 31741437 \n4. Al-Jobori H Daniele G Cersosimo E Empagliflozin and kinetics of renal glucose transport in healthy individuals and individuals with type 2 diabetes Diabetes 2017 66 7 1999 2006 28428225 \n5. Malhi GS Outhred T Morris G Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders: Bipolar disorder summary Med J Aust 2018 208 5 219 25 29540132 \n6. Oliveira JL Silva Júnior GB Abreu KL Lithium nephrotoxicity Rev Assoc Med Bras 2010 56 5 600 6 21152836 \n7. Timmer RT Sands JM Lithium intoxication J Am Soc Nephrol 1999 10 666 74 10073618 \n8. Schnaider A Azab AN Lithium-induced nephrogenic diabetes insipidus – a case report and discussion on the pathophysiological mechanism Int J Nephrol Kidney Failure 2015 1 3 1 4 \n9. Kortenoeven ML Li Y Shaw S Amiloride blocks lithium entry through the sodium channel thereby attenuating the resultant nephrogenic diabetes insipidus Kidney Int 2009 76 1 44 53 19367330 \n10. Holstein-Rathlou NH Lithium transport across biological membranes Kidney Int Supp 1990 28 4 9 \n11. Uwai Y Arima R Takatsu C Sodium-phosphate cotransporter mediates reabsorption of lithium in rat kidney Pharmacol Res 2014 87 94 98 24997387 \n12. Grandjean EM Aubry JM Lithium: Updated human knowledge using an evidence-based approach. Part II: Clinical pharmacology and therapeutic monitoring CNS Drugs 2009 23 4 331 49 19374461\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D018692:Antimanic Agents; D001559:Benzhydryl Compounds; D003924:Diabetes Mellitus, Type 2; D004347:Drug Interactions; D005960:Glucosides; D006801:Humans; D007004:Hypoglycemic Agents; D018020:Lithium Compounds; D008297:Male; D055118:Medication Adherence; D008687:Metformin; D011618:Psychotic Disorders; D000077203:Sodium-Glucose Transporter 2 Inhibitors",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e923311",
"pmc": null,
"pmid": "32518219",
"pubdate": "2020-06-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28428225;2182930;24997387;19374461;28506519;31741437;21152836;19367330;29540132;10073618",
"title": "Empagliflozin-Mediated Lithium Excretion: A Case Study and Clinical Applications.",
"title_normalized": "empagliflozin mediated lithium excretion a case study and clinical applications"
} | [
{
"companynumb": "AU-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-030004",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
... |
{
"abstract": "Purple glove syndrome is an uncommon but dreaded complication of intravenous phenytoin administration characterised by pain, oedema and purple-blue discolouration of the limb distal to the site of injection. We describe a 37-year-old gentleman having the characteristic purple glove appearance after phenytoin loading, and discuss the salient features of this syndrome highlighting the pathophysiological and preventive aspects.",
"affiliations": "Department of Neurology, Chhatrapati Shahuji Maharaj Medical University, Lucknow, Uttar Pradesh, India.",
"authors": "Lalla|Rakesh|R|;Malhotra|Hardeep Singh|HS|;Garg|Ravindra Kumar|RK|;Sahu|Ritesh|R|",
"chemical_list": "D000927:Anticonvulsants; D010672:Phenytoin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2012()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D000927:Anticonvulsants; D003875:Drug Eruptions; D004487:Edema; D004660:Encephalitis; D017809:Fatal Outcome; D006225:Hand; D006801:Humans; D008297:Male; D010146:Pain; D010672:Phenytoin; D010859:Pigmentation Disorders; D012640:Seizures; D013577:Syndrome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "22922927",
"pubdate": "2012-08-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1289432;9781525;6482941;17451091;15239684",
"title": "Purple glove syndrome: a dreadful complication of intravenous phenytoin administration.",
"title_normalized": "purple glove syndrome a dreadful complication of intravenous phenytoin administration"
} | [
{
"companynumb": "IN-VISTAPHARM, INC.-VER201801-000132",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LORAZEPAM"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND\nSingle-dose nevirapine is the cornerstone of the regimen for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings, but nevirapine frequently selects for resistant virus in mothers and children who become infected despite prophylaxis. The optimal antiretroviral treatment strategy for children who have had prior exposure to single-dose nevirapine is unknown.\n\n\nMETHODS\nWe conducted a randomized trial of initial therapy with zidovudine and lamivudine plus either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 6 to 36 months of age, in six African countries, who qualified for treatment according to World Health Organization (WHO) criteria. Results are reported for the cohort that included children exposed to single-dose nevirapine prophylaxis. The primary end point was virologic failure or discontinuation of treatment by study week 24. Enrollment in this cohort was terminated early on the recommendation of the data and safety monitoring board.\n\n\nRESULTS\nA total of 164 children were enrolled. The median percentage of CD4+ lymphocytes was 19%; a total of 56% of the children had WHO stage 3 or 4 disease. More children in the nevirapine group than in the ritonavir-boosted lopinavir group reached a primary end point (39.6% vs. 21.7%; weighted difference, 18.6 percentage-points; 95% confidence interval, 3.7 to 33.6; nominal P=0.02). Baseline resistance to nevirapine was detected in 18 of 148 children (12%) and was predictive of treatment failure. No significant between-group differences were seen in the rate of adverse events.\n\n\nCONCLUSIONS\nAmong children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission, antiretroviral treatment consisting of zidovudine and lamivudine plus ritonavir-boosted lopinavir resulted in better outcomes than did treatment with zidovudine and lamivudine plus nevirapine. Since nevirapine is used for both treatment and perinatal prevention of HIV infection in resource-limited settings, alternative strategies for the prevention of HIV transmission from mother to child, as well as for the treatment of HIV infection, are urgently required. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00307151.).",
"affiliations": "Department of Medicine, Dartmouth Medical School, Lebanon, NH 03765, USA. paul.e.palumbo@dartmouth.edu",
"authors": "Palumbo|Paul|P|;Lindsey|Jane C|JC|;Hughes|Michael D|MD|;Cotton|Mark F|MF|;Bobat|Raziya|R|;Meyers|Tammy|T|;Bwakura-Dangarembizi|Mutsawashe|M|;Chi|Benjamin H|BH|;Musoke|Philippa|P|;Kamthunzi|Portia|P|;Schimana|Werner|W|;Purdue|Lynette|L|;Eshleman|Susan H|SH|;Abrams|Elaine J|EJ|;Millar|Linda|L|;Petzold|Elizabeth|E|;Mofenson|Lynne M|LM|;Jean-Philippe|Patrick|P|;Violari|Avy|A|",
"chemical_list": "D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D011744:Pyrimidinones; D012367:RNA, Viral; D061466:Lopinavir; D019829:Nevirapine; D019438:Ritonavir",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa1000931",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "363(16)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D053208:Kaplan-Meier Estimate; D061466:Lopinavir; D008297:Male; D019829:Nevirapine; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011744:Pyrimidinones; D012367:RNA, Viral; D019438:Ritonavir; D017211:Treatment Failure",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "1510-20",
"pmc": null,
"pmid": "20942667",
"pubdate": "2010-10-14",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "15718842;11303838;11018164;16773030;16425126;15942889;17457089;11600822;19859531;10197376;11734746;17215531;11980557;15735445;19279441;15247339;20942666;17997151;10983633;11581480",
"title": "Antiretroviral treatment for children with peripartum nevirapine exposure.",
"title_normalized": "antiretroviral treatment for children with peripartum nevirapine exposure"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP010485",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
"drugadditional... |
{
"abstract": "To investigate the effect of ticagrelor combined with tirofiban versus clopidogrel combined with tirofiban on inflammation response and prognosis of patients with unstable angina pectoris (UA). The present prospective study included a total of 291 patients who were diagnosed as unstable UA from January 2018 to December 2019. All UA patients were divided into two groups: ticagrelor combined with tirofiban group (n = 159) and clopidogrel combined with tirofiban group (n = 132). Serum levels of C-reactive protein (CRP), interleukin-1β, interleukin-6, tumor necrosis factor-α, and matrix metalloproteinase-9 were measured using commercially available enzyme-linked immunosorbent assay kits. Kaplan-Meier (K-M) curve was performed for analysis of cumulative incidences of major adverse cardiovascular events (MACEs). Both ticagrelor combined with tirofiban and clopidogrel combined with tirofiban significantly decreased the serum levels of inflammatory factors in UA patients. Compared to clopidogrel combined with the tirofiban group, ticagrelor combined with the tirofiban group had a lower platelet aggregation rate and improved cardiac function of UA patients. Besides, ticagrelor combined with tirofiban group had a better prognosis and the K-M curve showed that UA patients treated by ticagrelor and tirofiban had lower incidences of MACEs in one-year follow-up. The treatment of ticagrelor combined with tirofiban significantly attenuated inflammation response and improved the prognosis of UA patients.",
"affiliations": "Department of Pharmacy, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China.;Department of Cardiovascular Medicine, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China.;Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, Wuhan, China.;Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, Wuhan, China.",
"authors": "Deng|Li|L|;Jia|Hai-Zhen|HZ|;Li|Mao-Chun|MC|;Zhu|Wei|W|https://orcid.org/0000-0002-1801-7367",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": "10.1002/kjm2.12421",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1607-551X",
"issue": "37(11)",
"journal": "The Kaohsiung journal of medical sciences",
"keywords": "clopidogrel; ticagrelor; tirofiban; unstable angina pectoris",
"medline_ta": "Kaohsiung J Med Sci",
"mesh_terms": null,
"nlm_unique_id": "100960562",
"other_id": null,
"pages": "1010-1015",
"pmc": null,
"pmid": "34338425",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Comparison of the effect of ticagrelor combined with tirofiban versus clopidogrel combined with tirofiban on inflammation response and prognosis of patients with unstable angina pectoris in long term follow-up.",
"title_normalized": "comparison of the effect of ticagrelor combined with tirofiban versus clopidogrel combined with tirofiban on inflammation response and prognosis of patients with unstable angina pectoris in long term follow up"
} | [
{
"companynumb": "CN-MEDICURE INC.-2115110",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThis study was designed to determine the incidence of venous and arterial thromboembolic events (TEEs) in patients treated with cisplatin-based chemotherapy and to analyze the prognostic value of patients' baseline and treatment characteristics in predicting TEE occurrence.\n\n\nMETHODS\nWe performed a large retrospective analysis of all patients treated with cisplatin-based chemotherapy for any type of malignancy at Memorial Sloan-Kettering Cancer Center in 2008. A TEE was cisplatin-associated if it occurred between the time of the first dose of cisplatin and 4 weeks after the last dose.\n\n\nRESULTS\nAmong 932 patients, 169 (18.1%) experienced a TEE during treatment or within 4 weeks of the last dose. TEEs included deep vein thrombosis (DVT) alone in 49.7%, pulmonary embolus (PE) alone in 25.4%, DVT plus PE in 13.6%, arterial TEE alone in 8.3%, or DVT plus arterial TEE in 3.0%. TEEs occurred within 100 days of initiation of treatment in 88% of patients. By univariate analysis, sex, age, race, Karnofsky performance status (KPS), exposure to erythropoiesis-stimulating agents, presence of central venous catheter (CVC), site of cancer, stage of cancer, leukocyte and hemoglobin levels, and Khorana score were all identified as risk factors. However, by multivariate analysis, only age, KPS, presence of CVC, and Khorana score retained significance.\n\n\nCONCLUSIONS\nThis large retrospective analysis confirms the unacceptable incidence of TEEs in patients receiving cisplatin-based chemotherapy. In view of the controversy associated with prophylactic anticoagulation in patients with cancer treated with chemotherapy, randomized studies are urgently needed in this specific cancer population treated with cisplatin-based regimens.",
"affiliations": "Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Room H709, New York, NY 10065, USA.",
"authors": "Moore|Russell A|RA|;Adel|Nelly|N|;Riedel|Elyn|E|;Bhutani|Manisha|M|;Feldman|Darren R|DR|;Tabbara|Nour Elise|NE|;Soff|Gerald|G|;Parameswaran|Rekha|R|;Hassoun|Hani|H|",
"chemical_list": "D000970:Antineoplastic Agents; D006397:Hematinics; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2011.35.5669",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "29(25)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D002945:Cisplatin; D005260:Female; D005500:Follow-Up Studies; D006397:Hematinics; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate; D013923:Thromboembolism; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "3466-73",
"pmc": null,
"pmid": "21810688",
"pubdate": "2011-09-01",
"publication_types": "D016428:Journal Article",
"references": "18043135;12814981;17008944;11117976;9521222;2189950;18824357;19398575;7534146;7931477;17922809;1679510;19217991;9390536;19752337;17968019;19726226;10811682;18216292;18509180;1988575;15666321;7908358;17319909;18766008;8874334;9817314;10737280;16505267;16722547;8201388;17179715;8319192;14515196;2644532;18349393;3528405;3340118;15767639;19055847",
"title": "High incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: a large retrospective analysis.",
"title_normalized": "high incidence of thromboembolic events in patients treated with cisplatin based chemotherapy a large retrospective analysis"
} | [
{
"companynumb": "US-HQ SPECIALTY-US-2015INT000625",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Taxanes, including paclitaxel and docetaxel, are one of the most active cytotoxic agents in breast cancer treatment including Her-2 positive subtype characterized by aggressive clinical and pathological features since the early stage. However, their use is sometimes limited by the occurrence of hypersensivity reactions (HSRs) characterized by erythematous rashes, bronchospasm, respiratory distress, hypotension, and pulmonary edema. Cross-reactions between paclitaxel and docetaxel are described in literature with a rate ranging from 49% to 90%. Abraxane (nab-paclitaxel), an albumin-bound form of paclitaxel, has a different toxicity profile from solvent-based paclitaxel and a lower rate of HSRs. Interestingly, several authors have recently reported cases of patients who developed HSRs to taxanes, principally paclitaxel, and were then safety treated with Abraxane, suggesting the absence of cross-reactivity between these drugs. Based on these considerations, we report our clinical experience and perform a literature review on this topic with the aim to investigate the cross-reactivity between nab-paclitaxel and other taxanes, in particular with docetaxel.",
"affiliations": "University Hospital of Parma. benedetta.pellegrino@studenti.unipr.it.",
"authors": "Pellegrino|Benedetta|B|;Boggiani|Daniela|D|;Tommasi|Chiara|C|;Palli|Dante|D|;Musolino|Antonino|A|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel",
"country": "Italy",
"delete": false,
"doi": "10.23750/abm.v88i3.6138",
"fulltext": "\n==== Front\nActa BiomedActa BiomedActa Bio Medica : Atenei Parmensis0392-42032531-6745Mattioli 1885 Italy 29083340ACTA-88-32910.23750/abm.v%vi%i.6138Case ReportNab-paclitaxel after docetaxel hypersensitivity reaction: case report and literature review Pellegrino Benedetta 1Boggiani Daniela 12Tommasi Chiara 1Palli Dante 2Musolino Antonino 121 Medical Oncology Unit, University Hospital of Parma, Italy2 Breast Unit, University Hospital of Parma, ItalyCorrespondence: Benedetta Pellegrino MD Medical Oncology Unit, University Hospital of Parma, Via Gramsci, 14 - 43100 Parma, Italy Tel. +39 0521 702753 Fax +39 0521 703858 E-mail: benedettapellegrino@hotmail.it2017 88 3 329 333 23 1 2017 07 2 2017 Copyright: © 2017 ACTA BIO MEDICA SOCIETY OF MEDICINE AND NATURAL SCIENCES OF PARMA2017This work is licensed under a Creative Commons Attribution 4.0 International LicenseTaxanes, including paclitaxel and docetaxel, are one of the most active cytotoxic agents in breast cancer treatment including Her-2 positive subtype characterized by aggressive clinical and pathological features since the early stage. However, their use is sometimes limited by the occurrence of hypersensivity reactions (HSRs) characterized by erythematous rashes, bronchospasm, respiratory distress, hypotension, and pulmonary edema. Cross-reactions between paclitaxel and docetaxel are described in literature with a rate ranging from 49% to 90%. Abraxane (nab-paclitaxel), an albumin-bound form of paclitaxel, has a different toxicity profile from solvent-based paclitaxel and a lower rate of HSRs. Interestingly, several authors have recently reported cases of patients who developed HSRs to taxanes, principally paclitaxel, and were then safety treated with Abraxane, suggesting the absence of cross-reactivity between these drugs. Based on these considerations, we report our clinical experience and perform a literature review on this topic with the aim to investigate the cross-reactivity between nab-paclitaxel and other taxanes, in particular with docetaxel. (www.actabiomedica.it)\n\nhypersensivity reactionbreast cancernab-paclitaxelneoadjuvant chemotherapy\n==== Body\nIntroduction\nTaxanes, including paclitaxel and docetaxel, are one of the most active cytotoxic agents in breast cancer treatment (1-3). However their use is sometimes limited by the occurrence of hypersensivity reactions (HSRs) characterized by erythematous rashes, bronchospasm, respiratory distress, hypotension and pulmonary edema (4). The aetiology of HSRs to paclitaxel (P) and docetaxel (DOC) is poorly understood; some authors suggested it could be due to their solvents, Cremophor EL and polysorbate80, combined with paclitaxel and docetaxel, respectively (5). Hypersensitivity reactions occur in 10% of the patients receiving paclitaxel treatment with an incidence of severe events ranging from 2 to 5%, despite the use of premedication with dexamethasone and histamine receptor antagonists (6). According to Vasey et al (7), in a Taxane-naïive population, the incidence of allergic reactions to docetaxel is lower than 2%. Other authors suggested that HSR might be due to the direct effect of the taxane itself (8), not to its diluents, partially explaining the cross-reactivity between paclitaxel and docetaxel described in literature. Dizon et al. (9) performed a retrospective analysis of 10 patients who developed HSRs to paclitaxel; then they were treated with docetaxel and a cross-reactivity rate of 90% was registered. In a retrospective study conducted by Sánchez-Muñoz et al (10), 41% of patients had severe cross-HSRs (grade 3-4) between the two taxanes that led to a permanently discontinuation of the treatment, despite an adequate premedication and a prolonged infusion time. Abraxane, an albumin-bound form of paclitaxel, has a different toxicity profile from solvent-based paclitaxel and a lower rate of HSRs (11). This formulation delivers paclitaxel as a suspension of albumin nanoparticles in saline, avoiding the use of Cremophor EL, premedication and special infusion sets. Interestingly, several authors have recently reported cases of patients who had HSRs to taxanes, principally paclitaxel, and then were safety treated with Abraxane (1, 4, 5), suggesting the absence of cross-reactivity between these drugs. Based on these considerations, we report our clinical experience and perform a literature review on this topic with the aim to investigate the cross-reactivity between nab-paclitaxel and other taxanes, in particular with docetaxel.\n\nCase Report\nIn March 2016, a 65-years-old woman was diagnosed with a left breast ductal carcinoma. On the 6th April 2016, she underwent left para-central quadrantectomy; the sentinel node biopsy was negative. The histological exam confirmed infiltrating ductal carcinoma G3, 1,8 cm of diameter, estrogen receptor (ER) negative, progesterone receptor (PgR) negative, Her-2 positive, ki67=35% without lymphvascular infiltration. The staging CT-scan showed multiple axillar lymphadenopathies; a fine needle biopsy confirmed they were Her-2 positive breast cancer metastases. On the 6th of May 2016, she started a neoadjuvant chemo-immunotherapic treatment with Herceptin 560 mg, cyclophosphamide 1000 mg and threeweekly docetaxel 130 mg; she further developed afebrile grade 4 prolonged neutropenia so prophylactic G-CSF and antibiotic prophylaxis were administered. On the 27th of May 2016, during her second infusion of docetaxel, she started to complain itchy hands and feet, generalized weakness and thoracic oppression; the infusion was suddenly discontinued with symptoms regression. Docetaxel was replaced by weekly nab-paclitaxel and the patient was planned to receive two cycles of Abraxane 100 mg/m2 IV on days 1, 8, and 15, Herceptin 6mg/kg every 21 days and cyclophosphamide 600 mg/m2 IV on day 1 every 21 days. After 3 cycles of treatment, she achieved a complete metabolic response and not allergic reaction nor neutropenia have been registered. At the end of the chemo-immunotherapic treatment, she underwent axillary dissection and a pathological complete response was recorded.\n\nDiscussion and literature review\nTaxanes, including paclitaxel and docetaxel, are one of the most active drugs in breast cancer including Her-2 positive subtype (2), characterized by aggressive clinical and pathological features since the early stage (12). Unfortunately, their use is sometimes limited by the onset of HSR but Abraxane, an albumin-bound form of paclitaxel, seems to induce a lower rate of HRSs (11). Several studies explored the role of nab-paclitaxel in the neo-adjuvant setting for HER2-overexpressing breast cancer (13). A recent phase II study of preoperative nab-paclitaxel (260 mg/m2 q2w) followed by vinorelbine plus trastuzumab in HER2 positive breast cancer (N=27) reported a pathological Complete Response (pCR) of 48 % (14). Sub-analysis by Hormone Receptor (HR) status showed a pCR of 18% in patients with ER+/PgR+ disease and of 69 % in patients with ER-/PgR-disease. Six patients had grade 2/3 neuropathy, with no grade 4 neuropathy reported; no severe hypersensitivity reactions were recorded. Similarly, another phase II trial of neoadjuvant anthracycline followed by nabpaclitaxel (260 mg/m2 q3w) plus trastuzumab reported 49 % pCR in the group of operable HER2+ breast cancer (N=46) (15). A pCR of 71 % was achieved in cases with ER-disease compared with 36 % in ER + disease; no severe hypersensitivity reactions were recorded. The efficacy and safety of nab-paclitaxel in combination with HER2-targeted therapy were also evaluated in the adjuvant setting (16). In a pilot single-arm trial, Yardley et al. (17) evaluated the feasibility and toxicity of a nab-paclitaxel-containing adjuvant regimen in patients with early breast cancer. Sixty-three patients received nab-paclitaxel 100 mg/ m2 IV on days 1, 8, and 15 and cyclophosphamide 600 mg/m2 IV on day 1 every 21 days for 4 cycles. Trastuzumab was administered to patients with HER2+ tumors: 8 mg/kg on day 1, cycle 1, followed by 6 mg/ kg every 21 days for a total of 52 weeks. The regimen was well tolerated and full doses of all agents were administered in >90% of cycles. Thirty-three patients had grade 3/4 neutropenia; however only one patient developed febrile neutropenia. No severe hypersensitivity reactions were observed. With a median follow-up of 17.8 months, all 63 patients remained alive and no evidence of disease recurrence was observed. Standing the efficacy of Abraxane in this subset of patients, we performed a literature review, according to PRISMA guidelines (18), to explore the crossreactivity rate between nab-paclitaxel and docetaxel. The database searched was MEDLINE (2006 to 19th June 2016) and the research was complemented by additional sources, including Google Scholar and the original website of the journals where the papers were published. The search items were “nabpaclitaxel after taxane allergic reaction”; “nabpaclitaxel taxane allergic reaction”; “nab paclitaxel allergic reaction”; “nab paclitaxel allergy”; “abraxane after taxane allergic reaction”. Exclusion criteria were: articles not written in English, abstract only, not pertinent, review. The study population was limited to patients with previous hypersensivity reaction to docetaxel and HRSs to paclitaxel were excluded. Our search identified 32 abstracts and titles; 14 articles were excluded because not pertinent, 4 because not written in English and 11 because review articles. 4 articles with 9 patients’ reports were analysed: 7 patients were excluded because treated with paclitaxel and 1 because developed skin toxicity after docetaxel infusion and not HSR. Finally, only one patient met our inclusion criteria (Fig. 1). She was a 36-year-old female affected by locally advanced breast cancer (stage IIIC; T3N3bM0; ER-positive, PR-positive and HER2-negative) who underwent a pre-operative systemic therapy with 4 cycles of 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2) and cyclophosphamide (500 mg/m2) every 3 weeks, followed by 4 cycles of docetaxel (75 mg/ m2) every 3 weeks. Although dexamethasone (20 mg/ body) was used as premedication for docetaxel, she developed dyspnea and nausea 5 mins after the second administration. The infusion was suddenly stopped and, after 1 hour, the symptoms improved; subsequently, the regimen was adjusted to treatment with nab-paclitaxel. The patient was administered nab-paclitaxel (260 mg/m2) for 30 mins every 3 weeks for 3 cycles: she was premedicated with dexamethasone (8 mg) and she did not exhibit any HSRs. After this preoperative treatment, she experienced a clinically complete response and underwent a partial resection of the breast with axillary lymph node dissection. The case presented by Kimura et al (1) is similar to ours: both women were affected by locally advanced breast cancer and achieved a complete clinical response after the pre-operatory treatment. Conversely, our patient was affected by Her-2 positive breast cancer while Kimura’s one was affected by hormone-receptor positive, Her-2 negative breast cancer; the last was pretreated with anthracyclines and she did not receive Herceptin combined with docetaxel nor abraxane. Nab-paclitaxel was also administered with a different schedule: weekly and every three weeks, respectively. Both patients were pre-medicated with dexamethasone before the infusion of docetaxel and, interestingly, even if no symptoms were referred during and after their first administration, they developed a HRS during the second infusion of the taxane. Thus, these toxicities seemed to be correlated to an IgE-immune response against the specific drug (19), docetaxel, or one of its excipients or solvents, not to the mechanism of action of the taxane itself, partially explaining why patients did not react to abraxane.\n\nFigure 1 PRISMA flow diagram\n\nTable 1 Patients’ features\n\nAuthor\tKimura\tPellegrino\t\nAge\t36\t65\t\nSex\tFemale\tFemale\t\nType of cancer\tBreast\tBreast\t\nStage of disease\tIII\tIII\t\nSetting\tNeoadjuvant\tNeoadjuvant\t\nDose of docetaxel\t75 mg/m2 every 3 weeks\t75 mg/m2 every 3 weeks\t\nPremedication\tDexamethasone 20 mg\tDexamethasone and antihistamines\t\nConcomitant administration\tNone\tCyclophosphamide IV 1000 mg and Herceptin IV 560 mg\t\nNumber of previous cycles of docetaxel\t1\t1\t\nSymptoms associated with HSR\tDyspnea and nausea\tItchy hands and feet, generalized weakness and thoracic oppression\t\nTime from the allergic reaction to nab-paclitaxel infusion\t3 weeks\t3 weeks\t\nDose and schedule of nab-paclitaxel\t260 mg/m2 IV every 3 weeks\t100 mg/m2 IV on days 1, 8. and 15\t\nPremedication with nab-paclitaxel\tDexamethasone 8 mg\tDexamethasone 8 mg\t\nConcomitant administration\tNone\tHerceptin 6mg/kg IV every 21 days and cyclophosphamide 600 mg/m2 IV on day 1 every 21 days\t\nNumber of cycles of nab-paclitaxel administrated\t3\t3\t\nResponse to treatment\tComplete clinical response\tComplete clinical response\t\nConclusion\nOur clinical case suggests nab-paclitaxel can be a safe and efficient option in patients affected by Her-2 positive locally advanced breast cancer who developed a HRS to docetaxel; only one similar case is reported in literature and, for these reasons, further clinical trial should be encouraged to better investigate this topic.\n\n\nEthical approval: This article does not contain any studies with human participants or animals performed by any of the authors.\n==== Refs\nReferences\n1 Kimura K Satoru T Mitsuhiko I Safety of Nab-Ptx in breast cancer patients Oncology Letters 2013 6 881 4 24137430 \n2 De Laurentiis M Cancello G D’Agostino D Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials J Clin Oncol 2008 26 44 53 18165639 \n3 Piccart-Gebhart MJ Burzykowski T Buyse M Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer J Clin Oncol 2008 26 1980 6 18421049 \n4 Fader A Rose P Abraxane for the Treatment of Gynecologic Cancer Patients With Severe Hypersensitivity Reactions to Paclitaxel Int J Gynecol Cancer 2009 19 1281 3 19820391 \n5 De Leon M Bolla S Greene B Successful treatment with nab-paclitaxel after hypersensitivity reaction to paclitaxel and docetaxel Gynecologic Oncology Reports 2013 5 70 1 24371703 \n6 Moon C Verschraegen CF Bevers M Use of docetaxel (Taxotere) in patients with paclitaxel (Taxol) hypersensitivity Anticancer Drugs 2000 11 565 8 11036959 \n7 Vasey PA Atkinson R Coleman R Docetaxel-carboplatin as first line chemotherapy for epithelial ovarian cancer Br J Cancer 2001 84 170 8 11161372 \n8 Essayan DM Kagey-Sobatka A Colarusso PJ Successful parenteral desensitization to paclitaxel J Allergy Clin Immunol 1996 97 42 46 8568136 \n9 Dizon DS Schwartz J Rojan A Cross-sensitivity between paclitaxel and docetaxel in a women’s cancers program Gynecol Oncol 2006 100 149 51 16197986 \n10 Sánchez-Muñoz A Jiménez B García-Tapiador A Cross-sensitivity between taxanes in patients with breast cancer Clin Transl Oncol 2011 13 904 6 DOI 10.1007/ s12094-011-0753-3 22126735 \n11 Gradishar WJ Albumin-bound paclitaxel: a next-generation taxane Expert Opin Pharmacother 2006 7 1041 53 16722814 \n12 Musolino A Michiara M Conti GM Human Epidermal Growth Factor Receptor 2 Status and Interval Breast Cancer in a Population-Based Cancer Registry Study JCO 2012 30 no. 192362-2368 \n13 Ueno N Mamounas E Neoadjuvant nab-paclitaxel in the treatment of breast cancer Breast Cancer Res Treat 2016 156 427 40 DOI 10.1007/s10549-016-3778- 27072366 \n14 Zelnak AB Leyland-Jones B Gabram SG High pathologic complete response (pCR) in HER2-positive breast cancer to novel non-anthracycline neoadjuvant chemotherapy Presented at American Association for Cancer Research [abstract 2703] 2012 \n15 Tanaka S Iwamoto M Kimura K Phase II study of neoadjuvant anthracycline-based regimens combined with nanoparticle albumin-bound paclitaxel and trastuzumab for human epidermal growth factor receptor 2-positive operable breast cancer Clin Breast Cancer 2015 15 191 6 25579459 \n16 Megerdichian C Olimpiadi Y Hurvitz S Nab-Paclitaxel in combination with biologically targeted agents for early and metastatic breast cancer Cancer Treatment Reviews 2014 40 614 25 24560997 \n17 Yardley D Burris 3rd H Peacock N A pilot study of adjuvant nanoparticle albumin-bound (nab) paclitaxel and cyclophosphamide, with trastuzumab in HER2-positive patients, in the treatment of early-stage breast cancer Breast Cancer Res Treat 2010 123 2 471 5 20658263 \n18 Moher D Liberati A Tetzlaff J Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement Ann Intern Med 2009 151 264 9 W64 19622511 \n19 Joerger M Prevention and handling of acute allergic and infusion reactions in oncology Ann Oncol 2012 23 suppl 10 313-9.doi: 10.1093/annonc/mds314\n\n",
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"journal": "Acta bio-medica : Atenei Parmensis",
"keywords": "hypersensivity reaction, breast cancer, nab-paclitaxel, neoadjuvant chemotherapy",
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"mesh_terms": "D000368:Aged; D000418:Albumins; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D003429:Cross Reactions; D000077143:Docetaxel; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D017239:Paclitaxel; D043823:Taxoids",
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"title": "Nab-paclitaxel after docetaxel hypersensitivity reaction: case report and literature review.",
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"abstract": "OBJECTIVE\nTo explore the clinical and pathological features of microscopic polyangiitis (MPA) in children.\n\n\nMETHODS\nA retrospective analysis was performed of patients with pediatric MPA in our hospital over 10 years.\n\n\nRESULTS\nData for 20 patients were collected; 16 patients had primary MPA (4 boys, 12 girls), with a median age of 8.9 years at the time of disease onset; 4 patients, all female, had antithyroid drug (ATD)-associated MPA, with an age range of 12.5 to 16.2 years at the time of disease onset. All patients exhibited renal involvement. Renal biopsies were performed in 14 patients. Fibrinoid exudation and necrosis of the glomerular capillaries were observed in all biopsy specimens. Crescents and scleroses were noted in 92.9% and 85.7% of these cases, respectively. The most frequent extrarenal organs involved were lungs, followed by the central nervous system (CNS), skin, and digestive system. Ninety percent of patients were positive for perinuclear antineutrophil cytoplasmic antibody, 94.1% were positive for myeloperoxidase, and 88.2% were positive for both. Forty-five percent of the patients had received steroid plus cyclophosphamide (CTX) pulse therapy for more than 3 months, and varying degrees of remission had been achieved in 88.9% of the patients.\n\n\nCONCLUSIONS\nBoth primary and ATD-associated MPA showed a female predisposition. Renal involvement was the most frequently observed condition, followed by involvement of lungs. CNS involvement was not rare in these pediatric patients. The efficacy of steroid plus CTX as induction therapy was evident in these patients.",
"affiliations": "From the Children's Kidney Disease Center, Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.L. Sun, MD, PhD, Associate Chief Physician; H. Wang, MD, Resident; X. Jiang, MD, PhD, Chief Physician; Y. Mo, MD, Associate Chief Physician; Z. Yue, MD, Associate Chief Physician; L. Huang, MD, Associate Chief Physician; T. Liu, Graduate Student. Drs. Sun and Wang contributed equally to this study. xyjiang-3208@163.com sunlzh@mail.sysu.edu.cn.;From the Children's Kidney Disease Center, Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.L. Sun, MD, PhD, Associate Chief Physician; H. Wang, MD, Resident; X. Jiang, MD, PhD, Chief Physician; Y. Mo, MD, Associate Chief Physician; Z. Yue, MD, Associate Chief Physician; L. Huang, MD, Associate Chief Physician; T. Liu, Graduate Student. Drs. Sun and Wang contributed equally to this study.;From the Children's Kidney Disease Center, Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.L. Sun, MD, PhD, Associate Chief Physician; H. Wang, MD, Resident; X. Jiang, MD, PhD, Chief Physician; Y. Mo, MD, Associate Chief Physician; Z. Yue, MD, Associate Chief Physician; L. Huang, MD, Associate Chief Physician; T. Liu, Graduate Student. Drs. Sun and Wang contributed equally to this study. xyjiang-3208@163.com sunlzh@mail.sysu.edu.cn.;From the Children's Kidney Disease Center, Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.L. Sun, MD, PhD, Associate Chief Physician; H. Wang, MD, Resident; X. Jiang, MD, PhD, Chief Physician; Y. Mo, MD, Associate Chief Physician; Z. Yue, MD, Associate Chief Physician; L. Huang, MD, Associate Chief Physician; T. Liu, Graduate Student. Drs. Sun and Wang contributed equally to this study.;From the Children's Kidney Disease Center, Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.L. Sun, MD, PhD, Associate Chief Physician; H. Wang, MD, Resident; X. Jiang, MD, PhD, Chief Physician; Y. Mo, MD, Associate Chief Physician; Z. Yue, MD, Associate Chief Physician; L. Huang, MD, Associate Chief Physician; T. Liu, Graduate Student. Drs. Sun and Wang contributed equally to this study.;From the Children's Kidney Disease Center, Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.L. Sun, MD, PhD, Associate Chief Physician; H. Wang, MD, Resident; X. Jiang, MD, PhD, Chief Physician; Y. Mo, MD, Associate Chief Physician; Z. Yue, MD, Associate Chief Physician; L. Huang, MD, Associate Chief Physician; T. Liu, Graduate Student. Drs. Sun and Wang contributed equally to this study.;From the Children's Kidney Disease Center, Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.L. Sun, MD, PhD, Associate Chief Physician; H. Wang, MD, Resident; X. Jiang, MD, PhD, Chief Physician; Y. Mo, MD, Associate Chief Physician; Z. Yue, MD, Associate Chief Physician; L. Huang, MD, Associate Chief Physician; T. Liu, Graduate Student. Drs. Sun and Wang contributed equally to this study.",
"authors": "Sun|Liangzhong|L|;Wang|Haiyan|H|;Jiang|Xiaoyun|X|;Mo|Ying|Y|;Yue|Zhihui|Z|;Huang|Liuyi|L|;Liu|Ting|T|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D013956:Antithyroid Agents; D015415:Biomarkers; D013256:Steroids; D003520:Cyclophosphamide; D009195:Peroxidase",
"country": "Canada",
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"issn_linking": "0315-162X",
"issue": "41(8)",
"journal": "The Journal of rheumatology",
"keywords": "ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES; GLOMERULONEPHRITIS; MICROSCOPIC POLYANGIITIS; SYSTEMIC VASCULITIS",
"medline_ta": "J Rheumatol",
"mesh_terms": "D000293:Adolescent; D019268:Antibodies, Antineutrophil Cytoplasmic; D013956:Antithyroid Agents; D015415:Biomarkers; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007678:Kidney Glomerulus; D008297:Male; D055953:Microscopic Polyangiitis; D009195:Peroxidase; D020551:Pulse Therapy, Drug; D012189:Retrospective Studies; D013256:Steroids; D016896:Treatment Outcome",
"nlm_unique_id": "7501984",
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"pages": "1712-9",
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"pubdate": "2014-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Clinical and pathological features of microscopic polyangiitis in 20 children.",
"title_normalized": "clinical and pathological features of microscopic polyangiitis in 20 children"
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"abstract": "The aim of this open-label, multicenter, randomized phase II trial was to evaluate the efficacy and safety of zoledronic acid in combination with docetaxel in previously treated patients with non-small-cell lung cancer (NSCLC) and bone metastases. In this study, patients randomly received docetaxel (60 mg/m(2) ) with (group DZ) or without (group D) zoledronic acid every 21 days. There were 50 patients in each group, and the primary endpoint was progression-free survival. In an efficacy analysis of 94 patients (DZ, 48; D, 46), the median progression-free survival was 2.7 months (95% confidence interval [CI], 1.5-3.5 months) for the DZ group and 2.6 months (95% CI, 1.5-3.4 months) for the D group (stratified log-rank test, P = 0.89). The median overall survival was 10.4 months (95% CI, 7.0-15.8 months) for the DZ group and 9.7 months (95% CI, 6.1-12.5 months) for the D group (stratified log-rank test, P = 0.62). There were no clinically relevant differences in the frequencies of grade 3 or 4 adverse events between the two groups. No treatment-related deaths occurred in the DZ group. Zoledronic acid combined with docetaxel was well tolerated but did not meet the primary endpoint of demonstrating a longer progression-free survival in advanced NSCLC patients with bone metastases compared with docetaxel alone. This trial was registered with the University Hospital Medical Information Network (UMIN000001098).",
"affiliations": "Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.",
"authors": "Murakami|Haruyasu|H|;Yamanaka|Takeharu|T|;Seto|Takashi|T|;Sugio|Kenji|K|;Okamoto|Isamu|I|;Sawa|Toshiyuki|T|;Hirashima|Tomonori|T|;Takeda|Koji|K|;Atagi|Shinji|S|;Fukuoka|Masahiro|M|;Nakanishi|Yoichi|Y|;Nakagawa|Kazuhiko|K|;Yamamoto|Nobuyuki|N|",
"chemical_list": "D004164:Diphosphonates; D007093:Imidazoles; D043823:Taxoids; D000077143:Docetaxel; D000077211:Zoledronic Acid",
"country": "England",
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"fulltext": "\n==== Front\nCancer SciCancer ScicasCancer Science1347-90321349-7006Blackwell Publishing Ltd Oxford, UK 2483713710.1111/cas.12448Original ArticlesPhase II study of zoledronic acid combined with docetaxel for non-small-cell lung cancer: West Japan Oncology Group Murakami Haruyasu 1Yamanaka Takeharu 2Seto Takashi 3Sugio Kenji 34Okamoto Isamu 56Sawa Toshiyuki 7Hirashima Tomonori 8Takeda Koji 9Atagi Shinji 10Fukuoka Masahiro 11Nakanishi Yoichi 612Nakagawa Kazuhiko 5Yamamoto Nobuyuki 1131 Division of Thoracic Oncology, Shizuoka Cancer CenterShizuoka, Japan2 Department of Biostatistics, National Cancer CenterTokyo, Japan3 Department of Thoracic Oncology, National Kyushu Cancer CenterFukuoka, Japan4 Department of Thoracic and Breast Surgery, Faculty of Medicine, Oita UniversityOita, Japan5 Department of Medical Oncology, Kinki University Faculty of MedicineOsaka, Japan6 Center for Clinical and Translational Research, Kyusyu University HospitalFukuoka, Japan7 Division of Respiratory Medicine and Medical Oncology, Gifu Municipal HospitalGifu, Japan8 Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic DiseasesOsaka, Japan9 Department of Clinical Oncology, Osaka City General HospitalOsaka, Japan10 Department of Thoracic Oncology, Kinki-Chuo Chest Medical CenterOsaka, Japan11 Department of Medical Oncology, Izumi City HospitalOsaka, Japan12 Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu UniversityFukuoka, Japan13 Third Department of Internal Medicine, Wakayama Medical UniversityWakayama, JapanHaruyasu Murakami, Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho Sunto-gun, Shizuoka 411-8777, Japan. Tel: +81-55-989-5222; Fax: +81-55-989-5783; E-mail: ha.murakami@scchr.jpFunding information Haruyasu Murakami received research funding from Sanofi K.K. and Novartis Pharma K.K. Takashi Seto received research funding from Novartis Pharma K.K. Yoichi Nakanishi received research funding from Novartis Pharma K.K. and others from Novartis Pharma K.K.\n\n8 2014 12 7 2014 105 8 989 995 02 1 2014 12 5 2014 14 5 2014 © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.2014This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.The aim of this open-label, multicenter, randomized phase II trial was to evaluate the efficacy and safety of zoledronic acid in combination with docetaxel in previously treated patients with non-small-cell lung cancer (NSCLC) and bone metastases. In this study, patients randomly received docetaxel (60 mg/m2) with (group DZ) or without (group D) zoledronic acid every 21 days. There were 50 patients in each group, and the primary endpoint was progression-free survival. In an efficacy analysis of 94 patients (DZ, 48; D, 46), the median progression-free survival was 2.7 months (95% confidence interval [CI], 1.5–3.5 months) for the DZ group and 2.6 months (95% CI, 1.5–3.4 months) for the D group (stratified log-rank test, P = 0.89). The median overall survival was 10.4 months (95% CI, 7.0–15.8 months) for the DZ group and 9.7 months (95% CI, 6.1–12.5 months) for the D group (stratified log-rank test, P = 0.62). There were no clinically relevant differences in the frequencies of grade 3 or 4 adverse events between the two groups. No treatment-related deaths occurred in the DZ group. Zoledronic acid combined with docetaxel was well tolerated but did not meet the primary endpoint of demonstrating a longer progression-free survival in advanced NSCLC patients with bone metastases compared with docetaxel alone. This trial was registered with the University Hospital Medical Information Network (UMIN000001098).\n\nChemotherapydocetaxelnon–small-cell lung cancerphase IIzoledronic acid\n==== Body\nLung cancer is the leading cause of cancer death worldwide and non–small-cell lung cancer (NSCLC) accounts for more than 80% of all cases of lung cancer.(1) For individuals with advanced NSCLC, first-line treatment with platinum-based chemotherapy offers only a moderate improvement in survival and quality of life over best supportive care (BSC) alone.(2,3) Second-line treatment with docetaxel, despite a low tumor response rate, is a standard treatment option on the basis of phase III studies comparing docetaxel with ifosfamide, vinorelbine or BSC alone.(4,5) Thus, there is a need for new treatment options to prolong the survival of patients with advanced NSCLC. Approximately 30–40% of patients with NSCLC develop bone metastases, which often cause skeletal-related events (SRE) such as pathologic fracture, spinal cord compression, or the need for palliative radiation or surgery to the bone.(6) SRE are associated with decreased quality of life, increased health-care costs and poor survival; therefore, it is clinically imperative to prevent SRE during the treatment of advanced NSCLC.(7)– (10)\n\nZoledronic acid, a nitrogen-containing bisphosphonate, significantly delays the appearance of SRE and reduces the incidence of SRE compared with a placebo in patients with cancer and bone metastases, including those with NSCLC.(11,12) Furthermore, several preclinical and clinical studies provide evidence supporting the use of zoledronic acid for the treatment of patients with advanced NSCLC.(13)– (16) The inclusion of zoledronic acid in chemotherapy regimens has an additive and/or synergistic antitumor effect on NSCLC cell lines and may prolong survival and delay disease progression in patients with advanced NSCLC.(17)– (19) However, whether the inclusion of zoledronic acid in such regimens has clinically meaningful survival benefits in patients with NSCLC and bone metastases is uncertain. Therefore, we conducted this study to evaluate the efficacy and safety of zoledronic acid in combination with docetaxel in previously treated patients with NSCLC and bone metastases.\n\nPatients and Methods\nStudy design\nWe conducted an open-label, multicenter, randomized phase II study in Japan. The study protocol was approved by the West Japan Oncology Group (WJOG) Protocol Review Committee and the institutional review board of each participating institution. This trial was registered with the University Hospital Medical Information Network (UMIN000001098).\n\nEligibility criteria\nPatients were required to be histologically or cytologically diagnosed with NSCLC and bone metastases (at least one bone metastasis that had not been treated with radiation therapy) and to have had previous treatment with one or two chemotherapy regimens. Other inclusion criteria included an age of ≥20 years, Eastern Cooperative Oncology Group performance status of 0–2, measurable disease, no history of chemotherapy with docetaxel, no history of prior treatment with zoledronic acid, adequate baseline organ function (leukocyte count ≥3500/mm3; absolute neutrophil count ≥2000/mm3; hemoglobin ≥9.0 g/dL; platelet count ≥100 000/mm3; total bilirubin ≤2.0 mg/dL; aspartate aminotransferase and alanine aminotransferase [ALT] levels ≤100 IU/L; creatinine clearance, ≥30 mL/min; and SpO2 under room air, ≥90%). Written informed consent was obtained from all patients. Patients were ineligible if they had active concomitant malignancy, third-space fluid collection requiring drainage, radiographic signs of interstitial pneumonia or pulmonary fibrosis, active SRE at the time of registration, hypercalcemia requiring prompt treatment, active periodontal disease or severe comorbidities (active infectious disease, severe heart disease, uncontrolled diabetes mellitus, gastrointestinal bleeding, intestinal paralysis, bowel obstruction or psychiatric disease), or a history of drug allergy. Patients receiving systemic steroid medication and pregnant or breast-feeding women were also excluded.\n\nTreatment\nEqual numbers of patients randomly received 60 mg/m2 docetaxel intravenously for 1 h with (DZ group) or without (D group) intravenous zoledronic acid for 15 min. Random assignment was stratified by institution, gender and performance status (0–1 or 2). The dose of zoledronic acid for each patient was based on his or her creatinine clearance (>60 mL/min, 4 mg; 50–60 mL/min, 3.5 mg; 40–49 mL/min, 3.3 mg; 30–39 mL/min, 3.0 mg). Zoledronic acid was administered to patients in the DZ group immediately after docetaxel administration. Patients were treated every 3 weeks until their disease progressed, toxicity became intolerable or they refused additional treatment. The dose of docetaxel was decreased to 50 mg/m2 if any of the following was observed: leukocyte count <1000/mm3, platelet count <25 000/mm3, grade 3 febrile neutropenia or grade 3 nonhematological toxicity (with the exception of hyponatremia, hypocalcaemia and alopecia). In cases of grade 4 nonhematological toxicity or continued toxicity requiring a second dose reduction, the protocol treatment was terminated. Other criteria for protocol treatment termination included use of excluded concomitant therapy and physician recommendation.\n\nPatients received full supportive care as required, including transfusion of blood products. Granulocyte colony-stimulating factor was administered as needed. There was no restriction on subsequent chemotherapy after disease progression in this study.\n\nEvaluation\nPatient assessment, including physical examination, complete blood count and biochemistry, was performed every 1–2 weeks. Bone markers and levels of urinary N-terminal telopeptide of type I collagen (NTX) and serum C-terminal telopeptide of type I collagen (I-CTP) were evaluated every 4 weeks. SRE included pathologic fracture, spinal cord compression and need for palliative radiation or surgery to the bone, and were assessed every 6 weeks.\n\nPatients who received one or more protocol treatment were evaluated for safety during treatment. Adverse events were recorded and graded using the Common Terminology Criteria for Adverse Events, Version 3.0. The Response Evaluation Criteria in Solid Tumors guideline version 1.0 was used to evaluate tumor response.(20) Computed tomography was performed at baseline and every 6 weeks. A complete response (CR) or a partial response (PR) was confirmed at least 4 weeks after the first documentation of the response. Stable disease (SD) was defined as either sufficient tumor shrinkage to qualify as a CR or a PR or sufficient increase in tumor mass to qualify as progressive disease (PD) after at least 6 weeks. Progression-free survival (PFS) was defined as the time from patient registration to objective tumor progression or patient death. Patients whose disease had not progressed at the time of termination of protocol treatment were assessed until progression or death was documented. SRE-free survival was defined as the time from patient registration to the appearance of SRE or the death of the patient. Patients who had not experienced SRE at the time of termination of protocol treatment were assessed until SRE or death was documented. Overall survival (OS) was defined as the time from patient registration to death from any cause. All patients were followed up for 1 year after the last patient had enrolled.\n\nStudy endpoints and statistical analyses\nThe primary endpoint in this study was PFS. The secondary endpoints included OS, overall response rate (ORR), SRE rate, SRE-free survival and safety. This randomized phase II study was designed to detect a 1-month improvement in PFS, with an assumed PFS of 2 months in the D group and 3 months in the DZ group, with a two-sided alpha error of 20% and a power of approximately 80%. A total of 100 patients were registered over 2 years with a 1-year follow-up period after the last enrollment. Survival curves were estimated using the Kaplan–Meier method and compared by log-rank test. Fisher's exact test was used for categorical data. All analyses were performed using SAS version 9.1.3 (SAS Institute, Cary, NC, USA).\n\nResults\nPatient characteristics\nFrom May 2007 to March 2010, 100 patients from 15 Japanese institutions were enrolled in this study: 50 patients were randomly assigned to the DZ group and 50 to the D group (Fig. 1). Patient demographics and baseline disease characteristics were well-balanced between the two treatment groups (Table 1). While one patient in the DZ group did not receive any protocol treatment, 99 patients (49 for DZ and 50 for D) were assessable for safety. In the DZ group 1 patient and in the D group 4 patients were ineligible, and 94 patients (48 for DZ and 46 for D) were included in the efficacy analysis (Fig. 1). The median number of treatment cycles was three for the DZ group (range, 1–19 cycles) and three for the D group (range, 1–17 cycles). The median number of administered doses of zoledronic acid was 3 (range, 1–19), with a median drug exposure of 12.0 mg (range, 3.5–76.0 mg). Reasons for going off protocol included disease progression (37 for DZ and 33 for D), patient refusal (eight for DZ and eight for D), unacceptable toxicity (two for DZ and five for D) and others (two for DZ and four for D).\n\nTable 1 Patient demographics and baseline disease characteristics\n\nCharacteristic\tDZ group (N = 50)\tD group (N = 50)\t\nNumber\t%\tNumber\t%\t\nAge, years\t\n Median\t62\t\t63\t\t\n Range\t34–77\t\t45–79\t\t\nSex\t\n Female\t19\t38\t18\t36\t\n Male\t31\t62\t32\t64\t\nECOG performance status\t\n 0–1\t47\t94\t47\t94\t\n 2\t3\t6\t3\t6\t\nSmoking status\t\n Smoker\t19\t38\t15\t30\t\n Never smoked\t31\t62\t35\t70\t\nHistological subtype\t\n Adenocarcinoma\t39\t78\t38\t76\t\n Squamous cell carcinoma\t5\t10\t7\t14\t\n Others\t6\t12\t5\t10\t\nNumber of prior chemotherapies\t\n 1\t34\t68\t39\t78\t\n 2\t15\t30\t11\t22\t\n No data\t1\t2\t0\t0\t\nNumber of bone metastases\t\n Single\t11\t22\t12\t24\t\n Multiple\t39\t78\t38\t76\t\nPrior SRE\t\n No\t41\t82\t42\t84\t\n Yes\t8\t16\t8\t16\t\n No data\t1\t2\t0\t0\t\nUrinary NTX\t\n High level (≥64 nmol/mmol creatinine)\t20\t40\t22\t44\t\n Normal level (<64 nmol/mmol creatinine)\t23\t46\t22\t44\t\n No data\t7\t14\t6\t12\t\nSerum I-CTP\t\n High level (≥4.5 ng/mL)\t35\t70\t35\t70\t\n Normal level (<4.5 ng/mL)\t8\t16\t9\t18\t\n No data\t7\t14\t6\t12\t\nD, docetaxel alone; DZ, docetaxel with zoledronic acid; ECOG, Eastern Cooperative Oncology Group; I-CTP, C-terminal telopeptide of type I collagen; NTX, N-terminal telopeptide of type I collagen; SRE, skeletal-related event.\n\nFig. 1 Patient disposition. D, docetaxel alone; DZ, docetaxel with zoledronic acid.\n\nSafety\nAdverse events for the 99 patients included in the safety analysis are summarized in Table 2. The occurrence of adverse events was similar in the two groups, with the exception of any grade of hypocalcemia (76% vs 30%) and pyrexia (39% vs 10%), which were more frequent in the DZ group compared with the D group. One patient in the DZ group experienced periodontal disease, but no cases of osteonecrosis of the jaw (ONJ) were observed in either group. The most common adverse events worse than grade 3 were leukopenia (63% and 56% for DZ and D, respectively), neutropenia (78% and 80% for DZ and D, respectively), febrile neutropenia (4% and 12% for DZ and D, respectively) and elevated ALT level (27% and 30% for DZ and D, respectively). There were no clinically relevant differences in the frequencies of adverse events of grade 3 or higher between the two groups. The protocol treatment was terminated in seven patients because of unacceptable toxicity levels, including grade 3 nail change (N = 1) and grade 2 periodontal disease (N = 1) in the DZ group, and required a second dose reduction because of grade 4 leukopenia (N = 1) or grade 3 febrile neutropenia (N = 1), grade 4 infection (N = 1), grade 3 allergic reaction (N = 1) and grade 1 pneumonitis (N = 1) in the D group. No treatment-related deaths were observed in the DZ group, while two treatment-related deaths were observed in the D group (infection, N = 1; gastrointestinal perforation, N = 1).\n\nTable 2 Summary of adverse events (CTCAE)\n\nAdverse event\tDZ group (N = 49)\tD group (N = 50)\t\nAll\t≥Grade 3\tAll\t≥Grade 3\t\nNumber\t%\tNumber\t%\tNumber\t%\tNumber\t%\t\nLeukopenia\t45\t92\t31\t63\t47\t94\t28\t56\t\nNeutropenia\t45\t92\t38\t78\t46\t92\t40\t80\t\nAnemia\t33\t67\t3\t6\t31\t62\t3\t6\t\nThrombocytopenia\t2\t4\t0\t0\t5\t10\t0\t0\t\nElevated ALT level\t24\t49\t13\t27\t21\t42\t15\t30\t\nElevated AST level\t19\t39\t4\t8\t16\t32\t3\t6\t\nElevated creatinine level\t7\t14\t1\t2\t13\t26\t2\t4\t\nHypercalcemia\t2\t4\t0\t0\t8\t16\t1\t2\t\nHypocalcemia\t37\t76\t3\t6\t15\t30\t0\t0\t\nFebrile neutropenia\t2\t4\t2\t4\t6\t12\t6\t12\t\nInfection\t13\t27\t5\t10\t5\t10\t3\t6\t\nSensory neuropathy\t12\t24\t2\t4\t11\t22\t1\t2\t\nFatigue\t33\t67\t2\t4\t33\t66\t2\t4\t\nAnorexia\t30\t61\t2\t4\t30\t60\t1\t2\t\nNausea\t20\t41\t1\t2\t23\t46\t0\t0\t\nVomiting\t8\t16\t1\t2\t8\t16\t0\t0\t\nAllergic reaction\t3\t6\t0\t0\t2\t4\t1\t2\t\nGastrointestinal perforation\t0\t0\t0\t0\t1\t2\t1\t2\t\nPyrexia\t19\t39\t0\t0\t5\t10\t0\t0\t\nPeriodontal disease\t1\t2\t0\t0\t0\t0\t0\t0\t\nALT, alanine transaminase; AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events, version 3.0; D, docetaxel alone; DZ, docetaxel with zoledronic acid.\n\nEfficacy\nFor the 94 patients included in the efficacy analysis, the ORR was 8% for the DZ group (CR, N = 0; PR, N = 4; SD, N = 18; PD, N = 25; not evaluable, N = 1) and 4% for the D group (CR, N = 0; PR, N = 2; SD, N = 20; PD, N = 23; not evaluable, N = 1). The difference in ORR between the two groups was not statistically significant (P = 0.88). Median PFS was 2.7 (95% CI, 1.5–3.5) months for the DZ group and 2.6 (95% CI, 1.5–3.4) months for the D group (stratified log-rank test, P = 0.89; Fig. 2a). Median OS was 10.4 (95% CI, 7.0–15.8) months for the DZ group and 9.7 (95% CI, 6.1–12.5) months for the D group (stratified log-rank test, P = 0.62; Fig. 2b). No remarkable difference in PFS (Fig. 3a) or OS (Fig. 3b) was observed according to demographic characteristics (number of bone metastases, prior SRE, baseline urinary NTX and baseline serum I-CTP).\n\nFig. 2 (a) Progression-free survival and (b) overall survival in the DZ and D groups. D, docetaxel alone; DZ, docetaxel with zoledronic acid.\n\nFig. 3 (a) Subgroup analyses of hazard ratio for progression-free survival and (b) overall survival in the DZ and D groups. D, docetaxel alone; DZ, docetaxel with zoledronic acid; I-CTP, C-terminal telopeptide of type I collagen; NTX, N-terminal telopeptide of type I collagen; SRE, skeletal-related event.\n\nFor the 94 patients included in the efficacy analysis, the cumulative incidence rates of an SRE at 3, 6, 9 and 12 months were 17%, 20%, 27% and 30%, respectively, for the DZ group, and 16%, 27%, 39% and 39%, respectively, for the D group (Fig. 4a). Median SRE-free survival was 7.2 (95% CI, 4.9–10.7) months for the DZ group and 6.0 (95% CI, 4.4–8.5) months for the D group (stratified log-rank test, P = 0.84). In subset analyses of the SRE rate according to baseline bone marker levels (Fig. 4b), the cumulative incidence rates of SRE at 12 months were 44% for the DZ group (N = 19) and 48% for the D group (N = 19) in patients with high baseline urinary NTX levels, 24% for the DZ group (N = 29) and 30% for the D group (N = 27) in patients with normal or unknown baseline urinary NTX levels, 43% for the DZ group (N = 34) and 38% for the D group (N = 32) in patients with high baseline serum I-CTP levels, and 7% for the DZ group (N = 14) and 37% for the D group (N = 14) in patients with normal or unknown baseline serum I-CTP levels.\n\nFig. 4 (a) Cumulative incidence rate of SRE in the DZ and D groups. (b) Subgroup analyses of SRE rate according to baseline bone marker levels in the DZ and D groups. D, docetaxel alone; DZ, docetaxel with zoledronic acid; I-CTP, C-terminal telopeptide of type I collagen; NTX, N-terminal telopeptide of type I collagen; SRE, skeletal-related event.\n\nDiscussion\nThis is the first prospective, randomized, phase II study to evaluate the efficacy and safety of zoledronic acid in combination with docetaxel in previously treated advanced NSCLC patients with bone metastases. The similarity in the median PFS and OS of patients in the DZ and D groups suggests that the combination of zoledronic acid and docetaxel might not provide survival benefits to patients with NSCLC and bone metastases compared with docetaxel alone. In a previous randomized phase III study, a subgroup analysis of patients with NSCLC (N = 382) revealed that zoledronic acid significantly reduced the risk of a first on-study SRE compared with a placebo. However, there was no significant difference in OS between the two groups (median 187 days for zoledronic acid vs 157 days for placebo; P = 0.539).(11,12,14) Two randomized studies in which zoledronic acid was combined with standard treatment also showed no survival benefits for patients with NSCLC who had no bone involvement.(21,22) These results are consistent with our observation that zoledronic acid failed to prolong the survival of NSCLC patients with bone metastases. In a recent subgroup analysis of a randomized phase III study, denosumab significantly improved OS, whereas zoledronic acid did not. This analysis was conducted on a group of 811 patients with lung cancer and bone metastases (median 8.9 vs 7.7 months for denosumab and zoledronic acid, respectively; hazard ratio for death, 0.80; 95% CI, 0.67–0.95; P = 0.01) and 702 patients with NSCLC and bone metastases (median 9.5 vs 8.0 months for denosumab and zoledronic acid, respectively; hazard ratio for death, 0.78; 95% CI, 0.65–0.94; P = 0.01).(23,24) Denosumab, a human anti-RANKL monoclonal antibody, is a potential anticancer therapy for patients with NSCLC and bone metastases and should be evaluated further in future studies.\n\nFor patients with NSCLC and bone metastases, increased SRE risk correlated with a history of SREs, multiple bone metastases, and bone turnover markers.(25)– (27) Significantly high levels of urinary NTX, a sensitive bone resorption marker, were also associated with increased SRE risk and poor survival prognosis.(27) In agreement, the cumulative incidence rates of SRE were high in patients with high baseline urinary NTX levels in our study. A retrospective analysis of a phase III study revealed that zoledronic acid significantly reduces the risk of death compared with a placebo in 144 patients with NSCLC and high baseline NTX levels (hazard ratio for death, 0.65; 95% CI, 0.45–0.95; P = 0.025).(15) In our study, for 38 patients (19 for DZ and 19 for D) with NSCLC and high baseline NTX levels, the median OS was 8.6 months for the DZ group and 11.2 months for the D group (hazard ratio for death, 1.60; 95% CI, 0.75–3.44). Therefore, combination treatment with zoledronic acid and docetaxel did not improve OS in previously treated patients with NSCLC and bone metastases in addition to high baseline NTX levels. However, the number of patients in our study was small; as such, this study was not powered to detect differences in secondary variables, and statistical testing was performed for exploratory purposes.\n\nThe most common severe toxicities in the present study were leukopenia, neutropenia, febrile neutropenia and elevated ALT levels, which were similar in the two groups. No treatment-related deaths were observed in the DZ group. Although hypocalcemia and pyrexia were more frequent in the DZ group than in the D group, they were mild and manageable in most cases. A possible reason for the high incidence of hypocalcemia in this study was underuse of calcium supplements and vitamin D. Prophylactic oral administration of daily calcium supplements and vitamin D should be considered during treatment with zoledronic acid. No patient experienced ONJ in this study, although it may be argued that the duration of zoledronic acid treatment was too short for this to occur. No additional adverse events were observed in the present study compared with previous studies.(11,12,23,24)\n\nThe present study demonstrated the safety and tolerability of the combination of zoledronic acid and docetaxel but did not meet the primary endpoint of PFS in advanced NSCLC patients with bone metastasis. Based on these results, we abandoned assessment of the survival benefits of adding zoledronic acid to docetaxel treatment in a larger phase III study. There are potential limitations to our study. First, we used an open-label study design despite the use of PFS as the primary endpoint. Second, the sample size of the present study was relatively small. Third, we did not collect data regarding post-study treatment with zoledronic acid. New treatment options are still needed to prolong the survival of advanced NSCLC patients with bone metastasis.\n\nThe authors would like to thank Ms Kaori Mori and Mr Koichi Hosoda for data management and Dr Shinichiro Nakamura (WJOG Data Center) for oversight and management of the present study. The authors are also grateful to Dr Keisuke Tomii (Kobe City Medical Center General Hospital, Hyogo), Dr Hideo Saka (National Hospital Organization Nagoya Medical Center, Aichi), Dr Yasuo Iwamoto (Hiroshima City Hospital, Hiroshima), Dr Norihiko Ikeda (Tokyo Medical University Hospital, Tokyo), Dr Sunao Ushijima (Kumamoto Chuo Hospital, Kumamoto), Dr Masaaki Kawahara (Otemae Hospital, Osaka), Dr Takashi Kijima (Osaka University Hospital, Osaka) and Dr Shigeki Sato (Nagoya City University Hospital, Aichi) for their contributions to this study.\n\nDisclosure Statement\nHaruyasu Murakami received research funding from Sanofi K.K. and Novartis Pharma K.K. Takashi Seto received research funding from Novartis Pharma K.K. Yoichi Nakanishi received research funding from Novartis Pharma K.K. and others from Novartis Pharma K.K.\n==== Refs\nReferences\n1 Siegel R Naishadham D Jemal A Cancer statistics, 2013 CA Cancer J Clin 2013 63 11 30 23335087 \n2 Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group BMJ 1995 311 899 909 7580546 \n3 Azzoli CG Baker S Jr Temin S American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer J Clin Oncol 2009 27 6251 66 19917871 \n4 Shepherd FA Dancey J Ramlau R Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy J Clin Oncol 2000 18 2095 103 10811675 \n5 Fossella FV DeVore R Kerr RN Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group J Clin Oncol 2000 18 2354 62 10856094 \n6 Coleman RE Metastatic bone disease: clinical features, pathophysiology and treatment strategies Cancer Treat Rev 2001 27 165 76 11417967 \n7 Weinfurt KP Li Y Castel LD The significance of skeletal-related events for the health-related quality of life of patients with metastatic prostate cancer Ann Oncol 2005 16 579 84 15734776 \n8 Delea T Langer C McKiernan J The cost of treatment of skeletal-related events in patients with bone metastases from lung cancer Oncology 2004 67 390 6 15713995 \n9 Tsuya A Kurata T Tamura K Fukuoka M Skeletal metastases in non-small cell lung cancer: a retrospective study Lung Cancer 2007 57 229 32 17451841 \n10 Brodowicz T O'Byrne K Manegold C Bone matters in lung cancer Ann Oncol 2012 23 2215 22 22357445 \n11 Rosen LS Gordon D Tchekmedyian S Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial–The Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group J Clin Oncol 2003 21 3150 7 12915606 \n12 Rosen LS Gordon D Tchekmedyian NS Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial Cancer 2004 100 2613 21 15197804 \n13 Mahtani R Khan R Jahanzeb M The potential application of zoledronic acid as anticancer therapy in patients with non-small-cell lung cancer Clin Lung Cancer 2011 12 26 32 21273176 \n14 Lipton A Cook R Saad F Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid Cancer 2008 113 193 201 18459173 \n15 Hirsh V Major PP Lipton A Zoledronic acid and survival in patients with metastatic bone disease from lung cancer and elevated markers of osteoclast activity J Thorac Oncol 2008 3 228 36 18317064 \n16 Zarogoulidis K Boutsikou E Zarogoulidis P The impact of zoledronic acid therapy in survival of lung cancer patients with bone metastasis Int J Cancer 2009 125 1705 9 19521984 \n17 Ozturk OH Bozcuk H Burgucu D Cisplatin cytotoxicity is enhanced with zoledronic acid in A549 lung cancer cell line: preliminary results of an in vitro study Cell Biol Int 2007 31 1069 71 17418595 \n18 Lu S Zhang J Zhou Z Synergistic inhibitory activity of zoledronate and paclitaxel on bone metastasis in nude mice Oncol Rep 2008 20 581 7 18695909 \n19 Chang JW Hsieh JJ Shen YC Bisphosphonate zoledronic acid enhances the inhibitory effects of gefitinib on EGFR-mutated non-small cell lung carcinoma cells Cancer Lett 2009 278 17 26 19233551 \n20 Therasse P Arbuck SG Eisenhauer EA New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada J Natl Cancer Inst 2000 92 205 16 10655437 \n21 Pandya KJ Gajra A Warsi GM Multicenter, randomized, phase 2 study of zoledronic acid in combination with docetaxel and carboplatin in patients with unresectable stage IIIB or stage IV non-small cell lung cancer Lung Cancer 2010 67 330 8 19493585 \n22 Scagliotti GV Kosmidis P de Marinis F Zoledronic acid in patients with stage IIIA/B NSCLC: results of a randomized, phase III study Ann Oncol 2012 23 2082 7 22730101 \n23 Henry DH Costa L Goldwasser F Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma J Clin Oncol 2011 29 1125 32 21343556 \n24 Scagliotti GV Hirsh V Siena S Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study J Thorac Oncol 2012 7 1823 9 23154554 \n25 Hirsh V Tchekmedyian NS Rosen LS Clinical benefit of zoledronic acid in patients with lung cancer and other solid tumors: analysis based on history of skeletal complications Clin Lung Cancer 2004 6 170 4 15555218 \n26 Sekine I Nokihara H Yamamoto N Risk factors for skeletal-related events in patients with non-small cell lung cancer treated by chemotherapy Lung Cancer 2009 65 219 22 19081161 \n27 Brown JE Cook RJ Major P Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors J Natl Cancer Inst 2005 97 59 69 15632381\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1347-9032",
"issue": "105(8)",
"journal": "Cancer science",
"keywords": "Chemotherapy; docetaxel; non-small-cell lung cancer; phase II; zoledronic acid",
"medline_ta": "Cancer Sci",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D002289:Carcinoma, Non-Small-Cell Lung; D004164:Diphosphonates; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D006801:Humans; D007093:Imidazoles; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D043823:Taxoids; D000077211:Zoledronic Acid",
"nlm_unique_id": "101168776",
"other_id": null,
"pages": "989-95",
"pmc": null,
"pmid": "24837137",
"pubdate": "2014-08",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "19917871;22730101;15632381;18695909;21343556;18459173;22357445;18317064;17418595;15555218;21273176;23154554;10856094;10811675;11417967;19521984;19081161;10655437;17451841;15197804;15734776;12915606;7580546;19233551;19493585;23335087;15713995",
"title": "Phase II study of zoledronic acid combined with docetaxel for non-small-cell lung cancer: West Japan Oncology Group.",
"title_normalized": "phase ii study of zoledronic acid combined with docetaxel for non small cell lung cancer west japan oncology group"
} | [
{
"companynumb": "JP-SA-2014SA098677",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
"dru... |
{
"abstract": "Thiamine-responsive megaloblastic anemia (TRMA) syndrome is an autosomal recessive inherited disorder characterised by a triad of megaloblastic anemia, diabetes mellitus, and sensorineural deafness. We report a case of 2-year-old girl whose anemia improved following administration of thiamine. She came with the history of persistent anaemia for the last one year. Anaemia was not responding to iron, vitamin B12, and folate replacement therapy. The bone marrow aspiration revealed hypercellular marrow with megaloblastic changes and more than 15% ring sideroblasts. The hearing assessment revealed sensorineural hearing loss. Blood sugar random and HBA1c was raised. Final diagnosis of TRMA was made. She was started on thiamine 100 mg OD, with normal routine balanced diet. She responded very well to thiamine. Her haemoglobin improved and blood sugar fasting came down in normal range. This case report sensitises the early diagnosis, and treatment with thiamine in children presenting with anemia, diabetes and deafness.",
"affiliations": "Department of Haematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi.;Department of Haematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi.;Department of Haematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi.;Department of Haematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi.;Department of Haematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi.;Department of Histopathology, Armed Forces Institute of Pathology (AFIP), Rawalpindi.",
"authors": "Khurshid|Ayesha|A|;Fatima|Sarah|S|;Altaf|Chaudhry|C|;Malik|Hamid Saeed|HS|;Sajjad|Zunera|Z|;Khadim|Muhammad Tahir|MT|",
"chemical_list": "D001786:Blood Glucose; D006442:Glycated Hemoglobin A; D026901:Membrane Transport Proteins; C120043:SLC19A2 protein, human; C517652:hemoglobin A1c protein, human; D014803:Vitamin B Complex; D013831:Thiamine",
"country": "Pakistan",
"delete": false,
"doi": "10.29271/jcpsp.2018.09.S169",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1022-386X",
"issue": "28(9)",
"journal": "Journal of the College of Physicians and Surgeons--Pakistan : JCPSP",
"keywords": null,
"medline_ta": "J Coll Physicians Surg Pak",
"mesh_terms": "D000749:Anemia, Megaloblastic; D001786:Blood Glucose; D002675:Child, Preschool; D003920:Diabetes Mellitus; D005260:Female; D006442:Glycated Hemoglobin A; D006319:Hearing Loss, Sensorineural; D006801:Humans; D026901:Membrane Transport Proteins; D013831:Thiamine; D013832:Thiamine Deficiency; D014803:Vitamin B Complex",
"nlm_unique_id": "9606447",
"other_id": null,
"pages": "S169-S171",
"pmc": null,
"pmid": "30173687",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Thiamine Responsive Megaloblastic Anaemia, Diabetes Mellitus and Sensorineural Hearing Loss in a Child.",
"title_normalized": "thiamine responsive megaloblastic anaemia diabetes mellitus and sensorineural hearing loss in a child"
} | [
{
"companynumb": "PK-ACCORD-071668",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FOLIC ACID"
},
"drugadditional": "3",
"druga... |
{
"abstract": "BACKGROUND\nThe optimal weekly oral dose of sirolimus and intravenous nanoparticle albumin-bound paclitaxel (nab-paclitaxel) were evaluated.\n\n\nMETHODS\nA phase 1b study was performed to evaluate escalating doses of oral sirolimus (5-60 mg) on days 2, 9, and 16 with intravenous nab-paclitaxel (100 mg/m(2) ) on days 1, 8, and 15 in a 28-day cycle. A run-in treatment of nab-paclitaxel (day -14) and sirolimus (day -7) was administered for pharmacokinetic and pharmacodynamic assessments. Clinical trial endpoints included dose-limiting toxicities (DLTs), maximum tolerated doses, and response rates. Pharmacodynamics included immunohistochemistry for phosphatase and tensin homolog, mammalian target of rapamycin (mTOR), AKT, phosphorylated AKT, S6K1, and phosphorylated S6K1; exploratory gene expression analysis; and [(18) F]fludeoxyglucose (FDG) positron emission tomography.\n\n\nRESULTS\nTwenty-three patients with advanced solid tumors were treated. Fifteen patients had prior taxane therapy. Twenty-two patients were evaluable for responses. One patient had a complete response, and 5 patients had a partial response (3 confirmed). DLTs were seen in 1 patient each at 10 (grade 3 dyspnea/hypoxia) and 40 mg (grade 4 leukopenia/neutropenia) and in 2 patients at 60 mg (grade 3 fatigue and grade 4 pericardial effusion). Patients with higher expression of posttreatment AKT and a greater decline in FDG activity were more likely to have a treatment response or stable disease.\n\n\nCONCLUSIONS\nSirolimus showed an acceptable safety profile at a weekly dose of 40 mg with weekly intravenous nab-paclitaxel at 100 mg/m(2) on days 1, 8, and 15 every 28 days. The posttreatment AKT score and changes in FDG activity may have roles as early predictors of responses to mTOR inhibitors.",
"affiliations": "Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.;Department of Medical Oncology, University of Rochester, Rochester, New York.;Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.;Department of Diagnostic Imaging, Yale University School of Medicine, New Haven, Connecticut.;EMD Serono, Billerica, Massachusetts.;Celgene Corporation, Berkeley Heights, New Jersey.;Celgene Corporation, Berkeley Heights, New Jersey.;Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.;Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.;Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut.;Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.;Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.;Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.;Department of Gynecologic Oncology, Yale University School of Medicine, New Haven, Connecticut.;Department of Gynecologic Oncology, Yale University School of Medicine, New Haven, Connecticut.;Department of Medical Oncology, Case Western University, Cleveland, Ohio.",
"authors": "Abu-Khalaf|Maysa M|MM|;Baumgart|Megan A|MA|;Gettinger|Scott N|SN|;Doddamane|Indukala|I|;Tuck|David P|DP|;Hou|Shihe|S|;Chen|Nianhang|N|;Sullivan|Catherine|C|;Lezon-Geyda|Kimberly|K|;Zelterman|Daniel|D|;Hatzis|Christos|C|;Deshpande|Hari|H|;Digiovanna|Michael P|MP|;Azodi|Masoud|M|;Schwartz|Peter E|PE|;Harris|Lyndsay N|LN|",
"chemical_list": "D000068196:Albumin-Bound Paclitaxel; D000418:Albumins; D019788:Fluorodeoxyglucose F18; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D017239:Paclitaxel; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.29254",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "121(11)",
"journal": "Cancer",
"keywords": "[18F]fludeoxyglucose positron emission tomography (FDG-PET); mammalian target of rapamycin (mTOR); nanoparticle albumin-bound paclitaxel (nab-paclitaxel); sirolimus; solid tumors",
"medline_ta": "Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000068196:Albumin-Bound Paclitaxel; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D015331:Cohort Studies; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008297:Male; D008875:Middle Aged; D053758:Nanoparticles; D009369:Neoplasms; D017239:Paclitaxel; D049268:Positron-Emission Tomography; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "1817-26",
"pmc": null,
"pmid": "25649370",
"pubdate": "2015-06-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase 1b study of the mammalian target of rapamycin inhibitor sirolimus in combination with nanoparticle albumin-bound paclitaxel in patients with advanced solid tumors.",
"title_normalized": "phase 1b study of the mammalian target of rapamycin inhibitor sirolimus in combination with nanoparticle albumin bound paclitaxel in patients with advanced solid tumors"
} | [
{
"companynumb": "US-CELGENEUS-USA-2016112268",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Chylothorax after coronary artery bypass grafting is a rare complication. The treatment protocol is not well described because of its rarity. The current treatment options for chylothorax include conservative medical treatment or an interventional approach (ie, thoracic duct embolization or surgical ligation of the thoracic duct). With high chest tube output, medical treatment has a high failure rate, and early embolization or surgical ligation of the thoracic duct should be considered to reduce hospital stay cost and morbidity. This report presents 2 cases of chylothorax after coronary artery bypass grafting with different treatment approaches.",
"affiliations": "Department of General Surgery, University of California Riverside School of Medicine, Riverside, California. Electronic address: melf002@medsch.ucr.edu.;Department of Cardiothoracic Surgery, St Bernardine Medical Center, San Bernardino, California.;Department of Radiology, Loma Linda University Medical Center, Loma Linda, California.;Department of Cardiothoracic Surgery, St Bernardine Medical Center, San Bernardino, California.;Department of General Surgery, University of California Riverside School of Medicine, Riverside, California; Department of Cardiothoracic Surgery, St Bernardine Medical Center, San Bernardino, California.",
"authors": "El-Farra|Mohamed H|MH|;Pham|Nguyen|N|;Smith|Jason|J|;Kajitani|Michio|M|;Hasaniya|Nahidh|N|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.athoracsur.2021.02.057",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "112(5)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D002916:Chylothorax; D001026:Coronary Artery Bypass; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "e349-e352",
"pmc": null,
"pmid": "33689740",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment of Chylothorax After Coronary Artery Bypass Grafting.",
"title_normalized": "treatment of chylothorax after coronary artery bypass grafting"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-323894",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OCTREOTIDE"
},
"drug... |
{
"abstract": "We present a case that involves anesthetic resistance during anesthesia for electroconvulsive therapy. Despite adequate dosing of both intravenous and inhalation anesthetics, our patient was resistant to induction of the state of general anesthesia. Subsequently, we noticed extreme hyperlipidemia. We hypothesized that the patient's extreme hyperlipidemia served as an anesthetic \"sink\" and prevented the full dose of intravenous agents from quickly reaching their intended site of action.",
"affiliations": "Department of Anesthesiology, University of Buffalo, Buffalo, New York, NY.;Department of Anesthesiology, University of Buffalo, Buffalo, New York, NY. Electronic address: jay12p@yahoo.com.;Department of Anesthesiology, University of Buffalo, Buffalo, New York, NY.;Department of Anesthesiology, University of Buffalo, Buffalo, New York, NY.;Department of Pharmacy, University of Buffalo, Buffalo, New York, NY.;Department of Anesthesiology, University of Buffalo, Buffalo, New York, NY.",
"authors": "Johnson|Thomas J|TJ|;Porhomayon|Jahan|J|;Nader|Nader D|ND|;Eldesouki|Enas|E|;Smith|Kelly|K|;Hobika|Geoffrey G|GG|",
"chemical_list": "D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D008074:Lipoproteins; D008723:Methohexital; D015742:Propofol",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0952-8180",
"issue": "34()",
"journal": "Journal of clinical anesthesia",
"keywords": "Anesthesia; Delay; Hyperlipidemia; Induction; Propofol; Sink",
"medline_ta": "J Clin Anesth",
"mesh_terms": "D000328:Adult; D000769:Anesthesia, Inhalation; D000771:Anesthesia, Intravenous; D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D061218:Depressive Disorder, Treatment-Resistant; D004565:Electroconvulsive Therapy; D006801:Humans; D006949:Hyperlipidemias; D008074:Lipoproteins; D008297:Male; D008723:Methohexital; D015742:Propofol",
"nlm_unique_id": "8812166",
"other_id": null,
"pages": "436-8",
"pmc": null,
"pmid": "27687429",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hyperlipidemia sink for anesthetic agents.",
"title_normalized": "hyperlipidemia sink for anesthetic agents"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-48714YA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LOSARTAN"
},
"... |
{
"abstract": "Oncologists worldwide are often dealing with hepatitis C virus positive breast cancer patients, questioning adequate chemotherapy protocol, reduction of doses, delays, or even interruptions of treatment. We present a case of a woman in stage IIIB breast cancer, who after the completion of neoadjuvant treatment developed significant increase in liver enzymes and was diagnosed positive for HCV. She was treated with interferon and after the resolving of acute liver disease continued concomitant treatment with interferon, ribavirin, docetaxel, and trastuzumab. Grade 4 neutropenia and grade 3 hepatotoxicity occurred after the third cycle of chemo and 5 months of antiviral therapy. Interferon and chemotherapy were postponed for 1 week. There are no sufficient data in order to recommend the concomitant antiviral and antineoplastic therapy. Hepatitis C virus and antiviral therapy may increase the toxicities of antineoplastic treatment. However, when lifesaving oncologic treatment is necessary, concomitant antiviral therapy can be administered with more intensive follow up.",
"affiliations": null,
"authors": "Matovina-Brko|Gorana|G|;Ruzic|Maja|M|;Fabri|Milotka|M|;Popovic|Lazar|L|;Kolarov-Bjelobrk|Ivana|I|;Trifunovic|Jasna|J|;Petkovic|Danijela|D|",
"chemical_list": "D000998:Antiviral Agents; D007372:Interferons",
"country": "England",
"delete": false,
"doi": "10.1179/1973947813Y.0000000129",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-009X",
"issue": "26(3)",
"journal": "Journal of chemotherapy (Florence, Italy)",
"keywords": "Breast cancer,; Docetaxel,; Hepatitis C virus,; Interferon,; Trastuzumab",
"medline_ta": "J Chemother",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000998:Antiviral Agents; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D005260:Female; D006526:Hepatitis C; D006801:Humans; D007372:Interferons; D008875:Middle Aged",
"nlm_unique_id": "8907348",
"other_id": null,
"pages": "180-3",
"pmc": null,
"pmid": "24621156",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment of acute hepatitis C in breast cancer patient: a case report.",
"title_normalized": "treatment of acute hepatitis c in breast cancer patient a case report"
} | [
{
"companynumb": "PHHY2014RS129933",
"fulfillexpeditecriteria": "1",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Outcomes of patients with Shwachman-Diamond syndrome (SDS) who developed myeloid malignancies are poor because of refractory disease and high hematopoietic stem cell transplantation-related mortality. We herein report a case of a 7-year-old girl with SDS who developed acute myeloid leukemia with monosomy 7. She was successfully treated with chemotherapy followed by unrelated cord blood transplantation with reduced-intensity conditioning consisting of fludarabine, melphalan, and high-dose cytarabine without significant toxicity. Reduced-intensity conditioning presented in this report might be a preferable option for SDS patients with acute myeloid leukemia, although further evaluation in a larger number of similar cases is necessary.",
"affiliations": "Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.",
"authors": "Yoshimura|Satoshi|S|;Mizuno|Takanori|T|;Osumi|Tomoo|T|;Shioda|Yoko|Y|;Kiyotani|Chikako|C|;Terashima|Keita|K|;Deguchi|Takao|T|;Nakadate|Hisaya|H|;Kato|Motohiro|M|;Matsumoto|Kimikazu|K|;Tomizawa|Daisuke|D|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D007166:Immunosuppressive Agents; D019653:Myeloablative Agonists; D003561:Cytarabine; D014740:Vidarabine; C024352:fludarabine; D008558:Melphalan",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001773",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "43(3)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D002648:Child; D003561:Cytarabine; D005260:Female; D005312:Fetal Blood; D006801:Humans; D007166:Immunosuppressive Agents; D015470:Leukemia, Myeloid, Acute; D008558:Melphalan; D019653:Myeloablative Agonists; D000081003:Shwachman-Diamond Syndrome; D019172:Transplantation Conditioning; D014740:Vidarabine",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e414-e418",
"pmc": null,
"pmid": "32134838",
"pubdate": "2021-04-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Umbilical Cord Blood Transplantation With Reduced-intensity Conditioning for Acute Myeloid Leukemia in a Child With Shwachman-Diamond Syndrome.",
"title_normalized": "successful umbilical cord blood transplantation with reduced intensity conditioning for acute myeloid leukemia in a child with shwachman diamond syndrome"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1931241",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
... |
{
"abstract": "Chronic esophageal candidiasis is an infection that is mostly seen in immunocompromised conditions, among which is chronic mucocutaneous candidiasis (CMC). Recently an association between CMC and esophageal carcinoma has been reported. Here we present two patients with chronic esophageal candidiasis who developed esophageal squamous cell carcinoma and we discuss the etiologic role of Candida-induced nitrosamine production, the loss of STAT1 function and impaired tumor surveillance and T-lymphocyte function in the development of esophageal carcinoma.",
"affiliations": "Department of Medicine and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.;Department of Medicine and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.;Department of Medicine and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.;Department of medical oncology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.;Department of Medicine and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.;Department of Medicine and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.;Department of Medicine and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.",
"authors": "Delsing|C E|CE|;Bleeker-Rovers|C P|CP|;van de Veerdonk|F L|FL|;Tol|J|J|;van der Meer|J W M|JW|;Kullberg|B J|BJ|;Netea|M G|MG|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.mmcr.2012.02.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-7539",
"issue": "1(1)",
"journal": "Medical mycology case reports",
"keywords": "Chronic mucocutaneous candidiasis; Esophageal cancer; Esophageal candidiasis",
"medline_ta": "Med Mycol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101598259",
"other_id": null,
"pages": "5-8",
"pmc": null,
"pmid": "24371724",
"pubdate": "2012",
"publication_types": "D016428:Journal Article",
"references": "12162406;7405156;17852718;18949340;18798115;11324766;4358541;1586990;16997613;20304522;16582591;3411226;9636188;7015348;7068036;2181815;19863559;13130116;9081252;17195908;14189682;12823200;19778308;16684821;21714643",
"title": "Association of esophageal candidiasis and squamous cell carcinoma.",
"title_normalized": "association of esophageal candidiasis and squamous cell carcinoma"
} | [
{
"companynumb": "NL-MYLANLABS-2018M1070270",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "The optimal duration of androgen suppression for men with locally advanced prostate cancer receiving radiotherapy with curative intent is yet to be defined. Zoledronic acid is effective in preventing androgen suppression-induced bone loss, but its role in preventing castration-sensitive bone metastases in locally advanced prostate cancer is unclear. The RADAR trial assessed whether the addition of 12 months of adjuvant androgen suppression, 18 months of zoledronic acid, or both, can improve outcomes in men with locally advanced prostate cancer who receive 6 months of androgen suppression and prostatic radiotherapy. This report presents 10-year outcomes from this trial.\n\n\n\nFor this randomised, phase 3, 2 × 2 factorial trial, eligible men were 18 years or older with locally advanced prostate cancer (either T2b-4, N0 M0 tumours or T2a, N0 M0 tumours provided Gleason score was ≥7 and baseline prostate-specific antigen [PSA] concentration was ≥10 μg/L). We randomly allocated participants in a 2 × 2 factorial design by computer-generated randomisation (using the minimisation technique, and stratified by centre, baseline PSA concentration, clinical tumour stage, Gleason score, and use of a brachytherapy boost) in a 1:1:1:1 ratio to four treatment groups. Patients in the control group received 6 months of neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) and radiotherapy alone (short-term androgen suppression [STAS]); this treatment was either followed by another 12 months of adjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly; intermediate-term androgen suppression [ITAS]), or accompanied by 18 months of zoledronic acid (4 mg every 3 months, intravenously) starting at randomisation (STAS plus zoledronic acid), or both (ITAS plus zoledronic acid). All patients received radiotherapy to the prostate and seminal vesicles, starting from the end of the fifth month of androgen suppression; dosing options were 66, 70, and 74 Gy in 2-Gy fractions per day, or 46 Gy in 2-Gy fractions followed by a high-dose-rate brachytherapy boost dose of 19·5 Gy in 6·5-Gy fractions. Treatment allocation was open label. The primary endpoint was prostate cancer-specific mortality and was analysed according to intention-to-treat using competing-risks methods. The trial is closed to follow-up and this is the final report of the main endpoints. This trial is registered with ClinicalTrials.gov, number NCT00193856.\n\n\n\nBetween Oct 20, 2003, and Aug 15, 2007, 1071 men were enrolled and randomly assigned to STAS (n=268), ITAS (n=268), STAS plus zoledronic acid (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 10·4 years (IQR 7·9-11·7). At this 10-year follow-up, no interactions were observed between androgen suppression and zoledronic acid so the treatment groups were collapsed to compare treatments according to duration of androgen suppression: 6 months of androgen suppression plus radiotherapy (6AS+RT) versus 18 months of androgen suppression plus radiotherapy (18AS+RT) and to compare treatments according to whether or not patients received zoledronic acid. The total number of deaths was 375 (200 men receiving 6AS+RT and 175 men receiving 18AS+RT), of which 143 (38%) were attributable to prostate cancer (81 men receiving 6AS+RT and 62 men receiving 18AS+RT). When analysed by duration of androgen suppression, the adjusted cumulative incidence of prostate cancer-specific mortality was 13·3% (95% CI 10·3-16·0) for 6AS+RT versus 9·7% (7·3-12·0) for 18AS+RT, representing an absolute difference of 3·7% (95% CI 0·3-7·1; sub-hazard ratio [sHR] 0·70 [95% CI 0·50-0·98], adjusted p=0·035). The addition of zoledronic acid did not affect prostate cancer-specific mortality; the adjusted cumulative incidence of prostate cancer-specific mortality was 11·2% (95% CI 8·7-13·7) with zoledronic acid vs 11·7% (9·2-14·1) without, representing an absolute difference of -0·5% (95% CI -3·8 to 2·9; sHR 0·95 [95% CI 0·69-1·32], adjusted p=0·78). Although safety analysis was not prespecified for this 10-year analysis, one new serious adverse event (osteonecrosis of the mandible, in a patient who received 18 months of androgen suppression plus zoledronic acid) occurred since our previous report, bringing the total number of cases of this serious adverse event to three (<1% out of 530 patients who received zoledronic acid evaluated for safety) and the total number of drug-related serious adverse events to 12 (1% out of all 1065 patients evaluable for safety). No treatment-related deaths occurred during the study.\n\n\n\n18 months of androgen suppression plus radiotherapy is a more effective treatment option for locally advanced prostate cancer than 6 months of androgen suppression plus radiotherapy, but the addition of zoledronic acid to this treatment regimen is not beneficial. Evidence from the RADAR and French Canadian Prostate Cancer Study IV trials suggests that 18 months of androgen suppression with moderate radiation dose escalation is an effective but more tolerable option than longer durations of androgen suppression for men with locally advanced prostate cancer including intermediate and high risk elements.\n\n\n\nNational Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, AbbVie Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, Cancer Standards Institute New Zealand, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Newcastle Radiation Oncology Fund, and Maitland Cancer Appeal.",
"affiliations": "School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia. Electronic address: jim.denham@newcastle.edu.au.;Sir Charles Gairdner Hospital, Perth, WA, Australia; Department of Medicine and Surgery, University of Western Australia, Perth, WA, Australia.;Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand.;Sir Charles Gairdner Hospital, Perth, WA, Australia.;Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC, Australia.;Auckland City Hospital, Auckland, New Zealand.;St Georges Cancer Care Centre, Christchurch, New Zealand.;Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC, Australia.;Genesiscare, Tugun, QLD, Australia.;Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; School of Medicine, University of Queensland, QLD, Australia.;Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, NSW, Australia.;Mater Radiation Oncology Centre, Princess Alexandra Hospital, Brisbane, QLD, Australia.;St George Hospital, Department of Endocrinology, Kogarah, NSW, Australia.;Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand.;School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia.;School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia.;School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia.",
"authors": "Denham|James W|JW|;Joseph|David|D|;Lamb|David S|DS|;Spry|Nigel A|NA|;Duchesne|Gillian|G|;Matthews|John|J|;Atkinson|Chris|C|;Tai|Keen-Hun|KH|;Christie|David|D|;Kenny|Lizbeth|L|;Turner|Sandra|S|;Gogna|Nirdosh Kumar|NK|;Diamond|Terry|T|;Delahunt|Brett|B|;Oldmeadow|Chris|C|;Attia|John|J|;Steigler|Allison|A|",
"chemical_list": "D000726:Androgen Antagonists; D000077211:Zoledronic Acid; D017430:Prostate-Specific Antigen",
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(18)30757-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "20(2)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000368:Aged; D000726:Androgen Antagonists; D001315:Australia; D001918:Brachytherapy; D002423:Cause of Death; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009520:New Zealand; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms; D018570:Risk Assessment; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D000077211:Zoledronic Acid",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "267-281",
"pmc": null,
"pmid": "30579763",
"pubdate": "2019-02",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomised, phase 3, factorial trial.",
"title_normalized": "short term androgen suppression and radiotherapy versus intermediate term androgen suppression and radiotherapy with or without zoledronic acid in men with locally advanced prostate cancer trog 03 04 radar 10 year results from a randomised phase 3 factorial trial"
} | [
{
"companynumb": "AU-PFIZER INC-2018533311",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUPROLIDE ACETATE"
},
"drugadditional": "3",
... |
{
"abstract": "Although predominant negative symptoms of schizophrenia can be severe enough to cause persistent impairment, effective treatment options are lacking. We aimed to assess the new generation antipsychotic cariprazine in adult patients with predominant negative symptoms.\n\n\n\nIn this randomised, double-blind, phase 3b trial, we enrolled adults aged 18-65 years with long-term (>2 year), stable schizophrenia and predominant negative symptoms (>6 months) at 66 study centres (mainly hospitals and university clinics, with a small number of private practices) in 11 European countries. Patients were randomly assigned (1:1) by an interactive web response system to 26 weeks of monotherapy with fixed-dose oral cariprazine (3 mg, 4·5 mg [target dose], or 6 mg per day) or risperidone (3 mg, 4 mg [target dose], or 6 mg per day); previous medication was discontinued over 2 weeks. The primary outcome was change from baseline to week 26 or end of treatment on the Positive and Negative Syndrome Scale factor score for negative symptoms (PANSS-FSNS) analysed in a modified intention-to-treat population of patients who had follow-up assessments within 5 days after last receipt of study drugs with a mixed-effects model for repeated measures. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, number 2012-005485-36.\n\n\n\nBetween May 27, 2013, and Nov 17, 2014, 533 patients were screened and 461 (86%) patients were randomised to treatment (230 for cariprazine and 231 for risperidone); 460 were included in the safety population (one patient discontinued before study drug intake). 227 (99%) of 230 patients in the cariprazine group and 229 (99%) of 230 patients in the risperidone group were included in the modified intention-to-treat population (178 [77%] in each group completed 26 weeks of treatment). Mean daily doses were 4·2 mg (SD 0·6) for cariprazine and 3·8 mg (0·4) for risperidone. Treatment-emergent adverse events (eg, insomnia, akathisia, worsening of schizophrenia, headache, anxiety) were reported in 123 (54%) patients treated with cariprazine and 131 (57%) patients treated with risperidone. Use of cariprazine led to a greater least squares mean change in PANSS-FSNS from baseline to week 26 than did risperidone (-8·90 points for cariprazine vs -7·44 points for risperidone; least squares mean difference -1·46, 95% CI -2·39 to -0·53; p=0·0022; effect size 0·31). One patient in the risperidone group died of a cause regarded as unrelated to treatment.\n\n\n\nOur results support the efficacy of cariprazine in the treatment of predominant negative symptoms of schizophrenia.\n\n\n\nGedeon Richter Plc.",
"affiliations": "Medical Division, Gedeon Richter Plc, Budapest, Hungary. Electronic address: gy.nemeth@richter.hu.;Medical Division, Gedeon Richter Plc, Budapest, Hungary.;Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary.;Medical Division, Gedeon Richter Plc, Budapest, Hungary.;Medical Division, Gedeon Richter Plc, Budapest, Hungary.;Medical Division, Gedeon Richter Plc, Budapest, Hungary.;Medical Division, Gedeon Richter Plc, Budapest, Hungary.;Medical Division, Gedeon Richter Plc, Budapest, Hungary.;Clinical Development, Forest Research Institute, an Allergan affiliate, Jersey City, NJ, USA.;Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary.;Section on Psychosis, Semel Institute for Neuroscience at University of California Los Angeles, Los Angeles, CA, USA.;Department of Psychiatry, Psychotherapy and Psychosomatics, Medical University Innsbruck, Innsbruck, Austria.",
"authors": "Németh|György|G|;Laszlovszky|István|I|;Czobor|Pál|P|;Szalai|Erzsébet|E|;Szatmári|Balázs|B|;Harsányi|Judit|J|;Barabássy|Ágota|Á|;Debelle|Marc|M|;Durgam|Suresh|S|;Bitter|István|I|;Marder|Stephen|S|;Fleischhacker|W Wolfgang|WW|",
"chemical_list": "D014150:Antipsychotic Agents; D010879:Piperazines; C533287:cariprazine; D018967:Risperidone",
"country": "England",
"delete": false,
"doi": "10.1016/S0140-6736(17)30060-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "389(10074)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001526:Behavioral Symptoms; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D018967:Risperidone; D012559:Schizophrenia; D012565:Schizophrenic Psychology; D016896:Treatment Outcome",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "1103-1113",
"pmc": null,
"pmid": "28185672",
"pubdate": "2017-03-18",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial.",
"title_normalized": "cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia a randomised double blind controlled trial"
} | [
{
"companynumb": "HU-JNJFOC-20160116914",
"fulfillexpeditecriteria": "1",
"occurcountry": "HU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "Acute generalized exanthematous pustulosis (AGEP) is a rare, severe cutaneous reaction that usually occurs following medication exposure. Clindamycin has rarely been linked to dermatologic side effects, including AGEP.\n\n\nMETHODS\nThis report details the case of a patient who developed AGEP with vancomycin and clindamycin use. After discontinuing clindamycin, the rash improved significantly.\n\n\nCONCLUSIONS\nTimely management of adverse skin reactions to antibiotics is paramount, and early identification of the culprit agent can allow for an alternative agent to be utilized. Clindamycin should be considered a potential causative agent for patients with skin reactions.",
"affiliations": "Department of Pharmacy, Medical University of South Carolina Medical Center, Charleston, SC, USA.;Department of Pharmacy, Franciscan St. Francis Health Indianapolis, Indianapolis, IN, USA.;Department of Pharmacy, University of Chicago Medicine, Chicago, IL, USA.",
"authors": "Croy|C|C|;Buehrle|K|K|;Austin Szwak|J|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002981:Clindamycin; D014640:Vancomycin",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12528",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "42(4)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "adverse event; drug-related",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000900:Anti-Bacterial Agents; D002981:Clindamycin; D006801:Humans; D008297:Male; D014640:Vancomycin; D055815:Young Adult",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "499-501",
"pmc": null,
"pmid": "28417476",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Clindamycin-associated acute generalized exanthematous pustulosis.",
"title_normalized": "clindamycin associated acute generalized exanthematous pustulosis"
} | [
{
"companynumb": "US-BAUSCH-BL-2017-013610",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "The presentation of a cardiac hamartoma, an exceedingly rare and histologically benign cardiac tumor, can be variable. We describe a case of refractory ventricular tachycardia in a patient with a cardiac mass failing multiple pharmacologic and procedural interventions, ultimately treated by cardiac transplantation and diagnosed with a mesenchymal cardiac hamartoma. (Level of Difficulty: Intermediate.).",
"affiliations": "Division of Cardiology, Department of Medicine, UCLA Medical Center, Los Angeles, California.;Division of Cardiology, Department of Medicine, UCLA Medical Center, Los Angeles, California.;UCLA Department of Pathology and Laboratory Medicine, UCLA Health, Los Angeles, California.;Division of Cardiology, Department of Medicine, UCLA Medical Center, Los Angeles, California.;Division of Cardiology, Department of Medicine, UCLA Medical Center, Los Angeles, California.;Division of Cardiology, Department of Medicine, UCLA Medical Center, Los Angeles, California.;UCLA Department of Pathology and Laboratory Medicine, UCLA Health, Los Angeles, California.;UCLA Department of Pathology and Laboratory Medicine, UCLA Health, Los Angeles, California.;Division of Cardiology, Department of Medicine, UCLA Medical Center, Los Angeles, California.;Division of Cardiology, Department of Medicine, UCLA Medical Center, Los Angeles, California.",
"authors": "Feng|Zekun|Z|;Philipson|Daniel|D|;Uzzell|Jamar P|JP|;Stein-Merlob|Ashley|A|;Yang|Eric H|EH|;Middlekauff|Holly R|HR|;Lau|Ryan P|RP|;Fishbein|Gregory A|GA|;Bradfield|Jason S|JS|;Ajijola|Olujimi A|OA|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jaccas.2020.04.038",
"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(20)30446-0\n10.1016/j.jaccas.2020.04.038\nCase Report\nClinical Case\nA Case of Ventricular Tachycardia Caused by a Rare Cardiac Mesenchymal Hamartoma\nFeng Zekun MD, PharmD a\nPhilipson Daniel MD a\nUzzell Jamar P. MD b\nStein-Merlob Ashley MD a\nYang Eric H. MD ac\nMiddlekauff Holly R. MD a\nLau Ryan P. MD b\nFishbein Gregory A. MD b\nBradfield Jason S. MD ac\nAjijola Olujimi A. MD, PhD oajijola@mednet.ucla.edu\n@zekunfengmd\nacd∗\na Division of Cardiology, Department of Medicine, UCLA Medical Center, Los Angeles, California\nb UCLA Department of Pathology and Laboratory Medicine, UCLA Health, Los Angeles, California\nc Cardio-Oncology Program, Division of Cardiology, Department of Medicine, University of California-Los Angeles, Los Angeles, California\nd UCLA Cardiac Arrhythmia Center, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California\n∗ Address for correspondence: Dr. Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Los Angeles, California 90095. oajijola@mednet.ucla.edu@zekunfengmd\n17 6 2020\n17 6 2020\n17 6 2020\n2 7 10491055\n18 2 2020\n19 4 2020\n28 4 2020\n© 2020 The Authors\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nThe presentation of a cardiac hamartoma, an exceedingly rare and histologically benign cardiac tumor, can be variable. We describe a case of refractory ventricular tachycardia in a patient with a cardiac mass failing multiple pharmacologic and procedural interventions, ultimately treated by cardiac transplantation and diagnosed with a mesenchymal cardiac hamartoma. (Level of Difficulty: Intermediate.)\n\nGraphical abstract\n\nThe presentation of a cardiac hamartoma, an exceedingly rare and histologically benign cardiac tumor, can be variable. We describe a case of…\n\nKey Words\n\ncardiac hamartoma\nelectrophysiology\nrefractory ventricular tachycardia\nAbbreviations and Acronyms\n\nAAD, antiarrhythmic drug\nCMR, cardiac magnetic resonance\nHCM, hypertrophic cardiomyopathy\nICD, implantable cardioverter-defibrillator\nLV, left ventricular\nVT, ventricular tachycardia\n==== Body\nHistory of Presentation\n\nA 33-year-old woman with 3-year history of asymmetric cardiac hypertrophy and sustained ventricular tachycardia (VT) was treated with antiarrhythmic drug (AAD) therapy and placement of an implantable cardioverter-defibrillator (ICD). Prior to the current admission, she had recurrent VT despite multiple AADs (metoprolol, amiodarone, sotalol, and dofetilide), requiring several ICD shocks, prompting an unsuccessful endocardial radiofrequency catheter ablation and subcutaneous ICD array placement for elevated defibrillation thresholds. Six months prior to her current presentation, she underwent cardiac sympathetic denervation followed by renal artery denervation, given that her VT was precipitated by stress. The current admission was precipitated by symptomatic recurrent VT and a total of 22 ineffective ICD shocks. A single external 200 J shock successfully converted her to sinus rhythm, and she was transferred to our center. On arrival, her heart rate and blood pressure were within normal limits. Her physical examination was unremarkable, and labs showed troponin of 11.1 ng/ml with normal electrolyte levels. A 12-lead electrocardiogram showed normal sinus rhythm with T-wave inversions in the inferior and septal leads, extreme left axis deviation, left ventricular (LV) hypertrophy, and incomplete right bundle branch block (Figure 1A). Prior transthoracic echocardiography revealed asymmetric inferolateral LV wall hypertrophy with myocardial enhancement measuring 19 × 45 mm and an ejection fraction of 55% to 60% (Figures 2A and 2B).Learning Objectives\n\n• To recognize the challenges in diagnosing cardiac hamartoma.\n\n• To recognize the difficulties in controlling ventricular tachycardia associated with cardiac hamartoma.\n\n• To review the treatment options reported in the literature for ventricular tachyarrhythmias associated with cardiac hamartoma.\n\n• To review the histopathology of the rare mesenchymal cardiac hamartoma.\n\nFigure 1 Electrocardiogram\n\n(A) Electrocardiogram at baseline showing normal sinus rhythm with extreme left axis deviation, left ventricular hypertrophy, and incomplete right bundle branch block. (B) Electrocardiogram during VT episode showing monomorphic wide complex tachycardia at a rate of 150 beats/min.\n\nFigure 2 Transthoracic Echocardiogram\n\n(A) Parasternal long-axis and (B) short-axis views of transthoracic echocardiogram demonstrating an asymmetrical and enlarged thickened inferolateral left ventricular wall (red arrow).\n\nDifferential Diagnosis\n\nAtypical hypertrophic cardiomyopathy (HCM) was considered, given the atypical isolated segment involvement of inferolateral LV wall seen on transthoracic echocardiography. Benign primary cardiac tumors were considered more likely than primary malignant cardiac tumors or metastatic cardiac tumors, given the patient’s age and her otherwise unremarkable medical history. Although many benign tumors present themselves early on in infancy or childhood, benign tumors including fibroma, hemangioma, lipoma, and hamartoma may also present in adulthood (1). Cardiac sarcoidosis was also considered. Diagnoses including channelopathies such as congenital long QT syndrome and catecholaminergic polymorphic VT were excluded based on electrocardiogram findings and lack of response to denervation procedures, respectively.\n\nInvestigations\n\nThe UCLA Institutional Review Board approved this study. The patient underwent extensive diagnostic work-up in the 3 years prior to presentation. Cardiac magnetic resonance (CMR) showed similar findings with delayed hyperenhancement and a hypokinetic center suggesting asymmetric HCM versus infiltrative process (Figures 3A and 3B). Coronary angiography revealed normal coronary arteries. A fluorodeoxyglucose positron emission tomography scan did not demonstrate evidence of active sarcoidosis and high-grade neoplasm. An incisional myocardial biopsy was performed, with pathology showing fibrosis and nonspecific myocardial hypertrophy. At electrophysiology study, multiple VT morphologies were induced, and ablation was unsuccessful (Figures 4A and 4B).Figure 3 Cardiac Magnetic Resonance\n\nCardiac magnetic resonance in (A) short-axis view and (B) 3-chamber view showing asymmetric inferolateral wall with late gadolinium enhancement (red arrows).\n\nFigure 4 Electrophysiology Study and VT Ablation\n\n(A) Multiple ventricular tachycardia (VT) morphologies observed during electrophysiology study and programmed stimulation; VT ablation was unsuccessful due to the thickened extensive transmural scar without good endocardial targets and ineffective ablation lesions. (B) Activation map for VT 1 (the predominant VT morphology) showing the earliest activation (exit) site on the basal anterolateral LV (red arrows point to exit site). Right anterior oblique view on the left panel, left anterior oblique view on center panel, and posteroanterior view on the right panel.\n\nManagement\n\nUpon arrival, oral metoprolol and intravenous lidocaine suppressed her VT, but neurotoxicity necessitated lidocaine discontinuation. Mexiletine (150 mg 3 times a day), metoprolol tartrate (200 mg twice a day), and dofetilide (250 μg twice a day) were then started. Given the difficulty in controlling her VT despite multiple antiarrhythmic therapies, failure of tachyarrhythmia suppression despite sympathetic and renal artery denervation, and multiple VT morphologies with poor ablation targets on electrophysiology study, the team felt that the myocardial enhancement seen on imaging studies was most consistent with a cardiac tumor, rather than with asymmetric HCM. Cardiothoracic surgery was consulted for debulking of the mass but was deemed not a candidate because of its large size. Stereotactic body radiation therapy to the LV was considered for drug-refractory VT but was declined by the patient. With limited noninvasive options remaining but persistent VT, she underwent orthotopic heart transplantation. The final histopathology revealed mature cardiac myocytes with fibrosis, adipose tissue, nerves, and smooth muscle, consistent with a cardiac mesenchymal hamartoma (Figure 5D).Figure 5 Gross and Histopathology\n\n(A, B) Gross specimen images showing thickened left ventricular wall and mass (black arrow). (C) Histopathology slide showing the ill-defined tumor (right side) with an infiltrative border, along with the normal myocardium (left side) (hematoxylin and eosin, 40× magnification). (D) Tumor contains cardiac myocytes (yellow arrow), fibrosis (black arrow), adipose tissue (blue arrow), blood vessels (red arrow), and nerve tissue (green arrow) (trichrome a elastin stain, 100× magnification), consistent with the mesenchymal subtype of cardiac hamartoma. The inset shows nerve tissue (hematoxylin and eosin, 100x magnification).\n\nDiscussion\n\nCardiac hamartomas, including rhabdomyomas and fibromas (2), are rare and typically present in the pediatric population. A mesenchymal subtype of cardiac hamartoma, as seen in our patient, is exceedingly rare, with only 1 previously reported case in the literature (2). Cardiac hamartomas present variably, ranging from asymptomatic to sudden cardiac death (2). The cardiac hamartoma literature consists of case reports, with limited treatment options for VT. Our case demonstrates the challenge in diagnosing cardiac hamartomas and the difficulty in managing associated life-threatening refractory VT.\n\nOwing to rarity and nonspecific presentation, cardiac hamartomas are difficult to diagnose noninvasively. Differentiating cardiac hamartomas from other masses such as HCM, thrombus, or malignant cardiac tumors can be challenging, as imaging findings are often nonspecific. On echocardiography, hamartomas are reported as hyperechoic intracavitary masses with predilection for the LV (3,4). On CMR, the appearance of a hamartoma ranges from mildly hypointense to hyperintense signal on T2-weighted images, and enhancement on early and delayed phase post-contrast images (4). CMR may exclude thrombus or malignant lesions by first pass and delayed contrast enhancement, and regional variation in vascularity (3). Fluorodeoxyglucose positron emission tomography may also help differentiate benign from malignant lesions (4). Incisional biopsy may be inconclusive (as in this case), as the hamartoma tissue can be nonspecific and similar to the surrounding myocardium.\n\nGiven its rarity, current guidelines do not address VT management related to cardiac hamartoma. Existing published case reports of VT associated with hamartoma are mostly in the pediatric population. In a case series of 21 infants (mean 14.9 months of age) with incessant VT owing to cardiac hamartoma, AADs (lidocaine, procainamide, amiodarone, propranolol, digoxin, verapamil, mexiletine, phenytoin, and propafenone) failed in all patients (5). Surgical intervention with epicardial mapping–guided resection and cryoablation resulted in complete cure of VT in all 21 pediatric patients (5). Case reports of adults with VT owing to hamartoma are limited, but all cases required surgery. For example, a 33-year-old patient underwent successful surgical resection with resolution of VT (6). A 19-year-old patient whose large hamartoma was a contraindication to surgical resection underwent successful cardiac transplantation (7). A 55-year-old patient with partial resection of cardiac hamartoma presented with a late recurrence of VT, which was successfully treated with radiofrequency catheter ablation (8). In our case, surgical debulking may have eliminated VT; however, this was contraindicated because of the size of the mass.\n\nICDs remain a cornerstone of VT therapy to reduce sudden cardiac death but do not address the underlying cause. In this case, the asymmetric hypertrophy relative to the ICD shock vector may have caused ineffective shocks, as more than 20 ICD shocks failed to cardiovert her VT, whereas 1 external shock was successful. Novel interventions such as stellate ganglion block and renal artery denervation have shown promise as adjunctive therapy for recurrent VT, especially those thought to be triggered by sympathetic activation accompanying physical or emotional stress, as in our patient (9,10). Stereotactic body radiotherapy is a noninvasive and reportedly effective strategy to reduce VT burden for patients with structural heart disease failing catheter ablation (11). Definitive therapy with cardiac transplantation in cases not amenable for resection is considered a therapy of last resort.\n\nCardiac hamartomas include hamartomas of mature cardiac myocytes, vascular hamartomas, and least commonly, cardiac mesenchymal hamartomas. Hamartomas of mature cardiac myocytes are composed of a well-circumscribed proliferation of cardiac myocytes with myofiber disarray. In contrast, HCM is characterized by a poorly demarcated area of cardiac hypertrophy most frequently located in the anterior ventricular septum, with microscopic findings of diffuse myocyte hypertrophy, focal myofiber disarray, and intramural coronary thickening (12). Vascular hamartomas are characterized by markedly abnormal vascular proliferation, whereas cardiac mesenchymal hamartomas are composed of a well-circumscribed but disorganized proliferation of cardiac myocytes, smooth muscle, blood vessels, fibroblasts, mature fat, and nerves (2). The presence of all 6 components distinguishes mesenchymal hamartoma from other benign cardiac tumors (Figure 5D).\n\nFollow-Up\n\nThe patient underwent uncomplicated orthotopic heart transplant and later removal of her ICD generator and leads. She continues close follow-up with her care team.\n\nConclusions\n\nBenign cardiac tumors are rare, and cardiac hamartomas are among the rarest. This case report highlights the diagnostic challenge posed by the rare subtype of mesenchymal cardiac hamartoma and the therapeutic dilemma in managing associated tachyarrhythmias. Given the similarities to HCM on clinical presentation and diagnostic imaging, it is prudent to maintain an appropriate index of suspicion and to seek for an alternative diagnosis in future cases of young patients with treatment refractory VT in the setting of an atypical cardiac mass. Cardiac transplantation should remain in the diagnostic and therapeutic armamentarium—but should be used as a last resort.\n\nDr. Bradfield has received speaker honoraria from Biosense Webster. Dr. Ajijola has received research grant support from Biosense Webster; and owns equity in NeuCures. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Case Reportsauthor instructions page.\n==== Refs\nReferences\n\n1 Jayaprakash S. Clinical presentations, diagnosis, and management of arrhythmias associated with cardiac tumors J Arrhythm 34 2018 384 393 30167009\n2 Bradshaw S.H. Hendry P. Boodhwani M. Dennie C. Veinot J.P. Left ventricular mesenchymal hamartoma, a new hamartoma of the heart Cardiovasc Pathol 20 2011 307 314 20850353\n3 Hoey E.T. Mankad K. Puppala S. Gopalan D. Sivananthan M.U. MRI and CT appearances of cardiac tumours in adults Clin Radiol 64 2009 1214 1230 19913133\n4 Abuzaid A.S. Gakhal M. Montgomery E. LaPoint R. Horn R. Banbury M.K. Cardiac hamartoma: a diagnostic challenge CASE (Phila) 1 2017 59 61 30062244\n5 Garson A. Jr. Smith R.T. Jr. Moak J.P. Incessant ventricular tachycardia in infants: myocardial hamartomas and surgical cure J Am Coll Cardiol 10 1987 619 626 3624668\n6 Dinh M.H. Galvin J.M. Aretz T.H. Torchiana D.F. Left ventricular hamartoma associated with ventricular tachycardia Ann Thorac Surg 71 2001 1673 1675 11383821\n7 Hsu P.S. Chen J.L. Hong G.J. Tsai Y.T. Tsai C.S. Heart transplantation for ventricular arrhythmia caused by a rare hamartoma J Heart Lung Transplant 28 2009 1114 1115 19782298\n8 Xu J. Chen Y. Ying X. He B. Radiofrequency ablation of ventricular tachycardia originating from a lipomatous hamartoma localized in the right ventricle cavity HeartRhythm Case Rep 3 2017 369 372 28840101\n9 Meng L. Tseng C.H. Shivkumar K. Ajijola O. Efficacy of stellate ganglion blockade in managing electrical storm: a systematic review J Am Coll Cardiol EP 3 2017 942 949\n10 Remo B.F. Preminger M. Bradfield J. Safety and efficacy of renal denervation as a novel treatment of ventricular tachycardia storm in patients with cardiomyopathy Heart Rhythm 11 2014 541 546 24389229\n11 Cuculich P.S. Schill M.R. Kashani R. Noninvasive cardiac radiation for ablation of ventricular tachycardia N Engl J Med 377 2017 2325 2336 29236642\n12 Burke A.P. Ribe J.K. Bajaj A.K. Edwards W.D. Farb A. Virmani R. Hamartoma of mature cardiac myocytes Hum Pathol 29 1998 904 909 9744305\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2666-0849",
"issue": "2(7)",
"journal": "JACC. Case reports",
"keywords": "AAD, antiarrhythmic drug; CMR, cardiac magnetic resonance; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter-defibrillator; LV, left ventricular; VT, ventricular tachycardia; cardiac hamartoma; electrophysiology; refractory ventricular tachycardia",
"medline_ta": "JACC Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101757292",
"other_id": null,
"pages": "1049-1055",
"pmc": null,
"pmid": "34317413",
"pubdate": "2020-06-17",
"publication_types": "D002363:Case Reports",
"references": "28840101;9744305;11383821;19913133;3624668;29236642;30062244;30167009;29270467;24389229;20850353;19782298",
"title": "A Case of Ventricular Tachycardia Caused by a Rare Cardiac Mesenchymal Hamartoma.",
"title_normalized": "a case of ventricular tachycardia caused by a rare cardiac mesenchymal hamartoma"
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"abstract": "Dexamethasone intravitreal implant and intravitreal ranibizumab are indicated for the treatment of macular edema secondary to retinal vein occlusion. This non-inferiority study compared dexamethasone with ranibizumab in patients with branch retinal vein occlusion.\nIn this randomized, 12-month head-to-head comparison, subjects with branch retinal vein occlusion were assigned to dexamethasone 0.7 mg at day 1 and month 5 with the option of retreatment at month 10 or 11, or ranibizumab 0.5 mg at day 1 and monthly through month 5 with subsequent as-needed injections at month 6-month 11. The primary efficacy outcome was the mean change from baseline in best-corrected visual acuity at month 12; secondary outcomes included average change in best-corrected visual acuity, proportion of eyes with ≥10- and ≥15-letter gain/loss, change in central retinal thickness, and change in Vision Functioning Questionnaire-25 score.\nIn all, 307 of a planned 400 patients were enrolled in the study and received (mean) 2.5 dexamethasone injections (n = 154) and 8.0 ranibizumab injections (n = 153) over 12 months. The mean change from baseline in best-corrected visual acuity at month 12 was 7.4 letters for dexamethasone versus 17.4 letters for ranibizumab (least-squares mean difference (dexamethasone minus ranibizumab), -10.1 letters; 95% confidence interval, -12.9, -7.2; p = 0.0006).\nDexamethasone and ranibizumab improved best-corrected visual acuity and anatomical outcomes; however, dexamethasone did not show non-inferiority to ranibizumab in this under-powered study. Dexamethasone was associated with an increased risk of intraocular pressure elevation and cataract progression, but a lower injection burden, compared to ranibizumab.",
"affiliations": "1 Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy.;2 Department of Ophthalmology, Staedtisches Klinikum Karlsruhe, Karlsruhe, Germany.;3 Moorfields Eye Hospital, London, UK.;4 Allergan Limited, Marlow, UK.",
"authors": "Bandello|Francesco|F|;Augustin|Albert|A|;Tufail|Adnan|A|;Leaback|Richard|R|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D004343:Drug Implants; D005938:Glucocorticoids; D003907:Dexamethasone; D000069579:Ranibizumab",
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"doi": "10.1177/1120672117750058",
"fulltext": "\n==== Front\nEur J OphthalmolEur J OphthalmolEJOspejoEuropean Journal of Ophthalmology1120-67211724-6016SAGE Publications Sage UK: London, England 10.1177/112067211775005810.1177_1120672117750058Original Research ArticlesA 12-month, multicenter, parallel group comparison of dexamethasone intravitreal implant versus ranibizumab in branch retinal vein occlusion Bandello Francesco 1Augustin Albert 2Tufail Adnan 3Leaback Richard 41 Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy2 Department of Ophthalmology, Staedtisches Klinikum Karlsruhe, Karlsruhe, Germany3 Moorfields Eye Hospital, London, UK4 Allergan Limited, Marlow, UKFrancesco Bandello, Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, via Olgettina 60, 20132 Milan, Italy. Email: bandello.francesco@hsr.it09 4 2018 11 2018 28 6 697 705 4 10 2017 4 12 2017 © The Author(s) 20182018SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Purpose:\nDexamethasone intravitreal implant and intravitreal ranibizumab are indicated for the treatment of macular edema secondary to retinal vein occlusion. This non-inferiority study compared dexamethasone with ranibizumab in patients with branch retinal vein occlusion.\n\nMethods:\nIn this randomized, 12-month head-to-head comparison, subjects with branch retinal vein occlusion were assigned to dexamethasone 0.7 mg at day 1 and month 5 with the option of retreatment at month 10 or 11, or ranibizumab 0.5 mg at day 1 and monthly through month 5 with subsequent as-needed injections at month 6–month 11. The primary efficacy outcome was the mean change from baseline in best-corrected visual acuity at month 12; secondary outcomes included average change in best-corrected visual acuity, proportion of eyes with ≥10- and ≥15-letter gain/loss, change in central retinal thickness, and change in Vision Functioning Questionnaire-25 score.\n\nResults:\nIn all, 307 of a planned 400 patients were enrolled in the study and received (mean) 2.5 dexamethasone injections (n = 154) and 8.0 ranibizumab injections (n = 153) over 12 months. The mean change from baseline in best-corrected visual acuity at month 12 was 7.4 letters for dexamethasone versus 17.4 letters for ranibizumab (least-squares mean difference (dexamethasone minus ranibizumab), −10.1 letters; 95% confidence interval, −12.9, −7.2; p = 0.0006).\n\nConclusion:\nDexamethasone and ranibizumab improved best-corrected visual acuity and anatomical outcomes; however, dexamethasone did not show non-inferiority to ranibizumab in this under-powered study. Dexamethasone was associated with an increased risk of intraocular pressure elevation and cataract progression, but a lower injection burden, compared to ranibizumab.\n\nBranch retinal vein occlusiondexamethasone intravitreal implantnon-inferiority studyranibizumab\n==== Body\nIntroduction\nThrombotic occlusion of the retinal vein is the second most common retinal vascular disorder after diabetic retinopathy.1 With consequences that include increased intracapillary pressure, capillary leakage, retinal hemorrhage and edema, and accompanying capillary closure and retinal ischemia, retinal vein occlusion (RVO) is an important cause of vision loss.2–4 Macular edema secondary to branch RVO (BRVO) is typically associated with reduced visual acuity.5 Current treatment options include laser photocoagulation, intravitreal corticosteroids, and anti-vascular endothelial growth factor (VEGF) agents.6\n\nDexamethasone (DEX) intravitreal implant (Ozurdex®; Allergan plc, Dublin, Ireland) is a sustained delivery, biodegradable implant that releases drug for up to 6 months post-injection.7 In two identical registration studies (the GENEVA studies), the efficacy and safety of DEX implant were compared with sham injection in patients with macular edema secondary to branch or central RVO (CRVO).8,9 In the randomized, 6-month, double-masked, sham-controlled phase, a single injection of DEX implant 0.7 or 0.35 mg reduced the risk of vision loss and improved the speed of visual improvement.8 A 6-month open-label extension phase allowed the option of repeat DEX implant injection in eyes meeting prespecified retreatment criteria. Overall, single and repeat DEX implant had a favorable safety profile over the 12-month study period, and the efficacy of the second implant was similar to that of the initial implant.9 Another registration study (the BRAVO study) compared the efficacy and safety of intravitreal ranibizumab with sham injection in BRVO.10,11 During the randomized, 6-month, double-masked, sham-controlled phase, monthly injections of ranibizumab 0.5 or 0.3 mg provided rapid improvements in best-corrected visual acuity (BCVA), with low rates of ocular events;10 these benefits were maintained during a subsequent 6-month phase of as-needed ranibizumab treatment.11\n\nDifferences in patient populations and study methodologies preclude direct comparison of the GENEVA and BRAVO findings. In addition to enrolling patients with BRVO, the GENEVA studies included patients with CRVO.8 Enrollees in GENEVA were required to have a central retinal thickness (CRT) ≥300 µm compared with ≥250 µm in BRAVO.8,10 In addition, the duration of macular edema was longer in GENEVA than in BRAVO (mean ~5 vs 3.5 months). This study was designed as a head-to-head comparison to evaluate the efficacy and safety of DEX implant versus ranibizumab in patients with BRVO.\n\nMethods\nStudy design and participants\nThe COMO (COmparison of intravitreal dexamethasone implant and ranibizumab for Macular Oedema in BRVO) study was a 12-month, multicenter, randomized, open-label study conducted in France, Germany, Israel, Italy, Spain, and the United Kingdom. The study complied with the tenets of the Declaration of Helsinki and the International Conference on Harmonisation guidelines for Good Clinical Practice and was approved by independent ethics committees at each study center. The study is registered with the identifier NCT01427751 at clinicaltrials.gov.\n\nSubjects were randomized 1:1 to treatment with DEX implant or intravitreal ranibizumab and stratified based on the pre-enrollment BCVA (≤55 vs >55 letters) of their study eye. DEX implant 0.7 mg was administered at day 1 and month 5, with the option of a single retreatment at month 10 or 11. Intravitreal ranibizumab 0.5 mg was administered at day 1 and monthly through month 5, with subsequent as-needed injections at months 6–11. Retreatment criteria included BCVA <70 Early Treatment Diabetic Retinopathy Study (ETDRS) letters; CRT >300 µm, as assessed by optical coherence tomography (OCT); more than five letters loss of BCVA from any previous visit; >40 µm increase in CRT from the previous visit; or likely benefit, in the investigator’s opinion, from retreatment. If no improvement in visual acuity was evident by month 3, continued treatment was discouraged.\n\nMale or female subjects ≥18 years of age, with macular edema secondary to BRVO, CRT ≥300 µm, recent-onset (<3 months) visual symptoms, and BCVA ≥20 to ≤70 ETDRS letters (20/40 to 20/400 Snellen equivalent) in the study eye, in the absence of severe macular ischemia, were eligible for study inclusion. Exclusion criteria included ocular hypertension, defined as an intraocular pressure (IOP) >22 mm Hg, and recent (<3 months) laser photocoagulation, intravitreal anti-VEGF, or intravitreal corticosteroid therapy. All subjects provided written informed consent prior to study entry.\n\nEfficacy endpoints\nThe primary efficacy endpoint was the mean change from baseline in BCVA at month 12. Secondary endpoints comprised the average change from baseline in BCVA to month 12; the proportion of study eyes with ≥10- and ≥15-letter gain or loss at month 12; time to ≥15-letter gain or loss; change from baseline in CRT at month 12; change from baseline in composite (near-vision, far-vision, and vision-related dependency) score of the Vision Functioning Questionnaire-25 (VFQ-25)12 at months 3, 6, and 12; and treatment failure (study discontinuation before month 12 due to lack of efficacy). Safety endpoints included assessment for adverse events and IOP changes.\n\nStatistical analyses\nThis was designed as a non-inferiority study using a non-inferiority margin of five ETDRS letters, with an intergroup difference in BCVA score within +5 and −5 ETDRS letters representing equivalent efficacy, consistent with the non-inferiority margin used in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) study.13 The null hypothesis was that the mean improvement from baseline in BCVA at month 12 was more than five letters less with DEX implant than with ranibizumab. Applying a non-inferiority margin of five ETDRS letters and assuming a common standard deviation (SD) of 10 ETDRS letters for a study with 80% power, the number of subjects required for each treatment arm was 176. Based on an anticipated dropout rate of 10%, the planned study enrollment was 400 patients. The primary endpoint of mean change in BCVA at month 12 was evaluated by analysis of covariance (ANCOVA). Because of large numbers of mis-stratifications of baseline BCVA and treatment imbalance in the actual strata, baseline BCVA was used as a covariate instead of baseline BCVA category (≤55 vs >55 letters). A two-sided 95% confidence interval (CI) for the least-squares (LS) mean difference in BCVA response between the two treatment groups (DEX implant minus ranibizumab) was calculated from the ANCOVA model. If the lower bound of the 95% CI was greater (i.e. less negative) than −5 ETDRS letters, the null hypothesis was rejected and DEX implant declared non-inferior to ranibizumab. A supportive analysis was based on the average change from baseline in BCVA over time using an area-under-the-curve (AUC) approach. Analysis of CRT and VFQ-25 outcomes was based on ANCOVA, using terms for treatment, baseline VFQ-25 composite score, lens status (pseudophakic/phakic), machine type (Spectralis OCT/Cirrus OCT), and baseline CRT. For all efficacy analyses, missing data were imputed using the last-observation-carried-forward approach.\n\nResults\nPatient disposition and baseline characteristics\nRecruitment difficulties restricted study enrollment to 307 of the planned 400 patients. Consequently, the statistical power of the primary analysis to detect non-inferiority was reduced from 80% to 73%, thereby increasing the possibility of non-rejection of the null hypothesis. All 307 patients were randomized to treatment (154 to DEX implant and 153 to ranibizumab; intent-to-treat (ITT) population), of whom 303 patients received more than one dose of study drug (safety population). The ITT population was of mean age 67.0 years and predominantly presented with unilateral BRVO (95.7%) and a phakic study eye (82.1%). The study arms were generally well-balanced for demographic and baseline clinical characteristics, apart from baseline BCVA (mean 56.6 and 59.2 ETDRS letters in DEX implant- and ranibizumab-treated eyes, respectively; Table 1). Patients assigned to DEX implant received a mean of 2.5 (median 3; range, 0–3) injections, with 19 (12.3%), 41 (26.6%), and 93 (60.4%) eyes receiving 1, 2, and 3 injections, respectively, over the 12-month study period. Patients assigned to ranibizumab received a mean of 8.0 (median 8; range, 0–12) injections, with 64% of eyes receiving ≥8 injections. The distribution of intravitreal treatment administration over the study period is depicted in Figure 1. In total, 42 patients in the DEX implant arm and 14 patients in the ranibizumab arm failed to complete the study; reasons included adverse events (DEX, n = 18; ranibizumab, n = 2), protocol violation (DEX, n = 6; ranibizumab, n = 4), no expectation of further treatment benefit (DEX, n = 5; ranibizumab, n = 1), loss to follow-up (DEX, n = 3; ranibizumab, n = 1), withdrawal of consent (DEX, n = 2; ranibizumab, n = 2), or other (DEX, n = 8; ranibizumab, n = 1).\n\nTable 1. Patient demographics and baseline clinical characteristics (ITT population).\n\n\tDEX implant (N = 154)\tRanibizumab (N = 153)\tTotal (N = 307)\t\nAge, years\t\n Mean (±SD)\t68.4 (10.6)\t65.5 (12.0)\t67.0 (11.4)\t\nGender, n (%)\t\n Male\t92 (59.7)\t87 (56.9)\t179 (58.3)\t\nRace, n (%)\t\n Caucasian\t147 (95.5)\t148 (96.7)\t295 (96.1)\t\n Black\t2 (1.3)\t3 (2.0)\t5 (1.6)\t\n Asian\t4 (2.6)\t1 (0.7)\t5 (1.6)\t\n Other\t1 (0.6)\t1 (0.7)\t2 (0.6)\t\nBRVO, n (%)\t\n Unilateral\t147 (95.5)\t147 (96.0)\t294 (95.7)\t\n Bilateral\t6 (3.9)\t5 (3.3)\t11 (3.6)\t\n Unknown\t1 (0.6)\t1 (0.7)\t2 (0.7)\t\nStudy eye lens status, n (%)\t\n Phakic\t127 (82.5)\t125 (81.7)\t252 (82.1)\t\n Pseudophakic\t26 (16.9)\t27 (17.6)\t53 (17.3)\t\n Unknown\t1 (0.6)\t1 (0.7)\t2 (0.7)\t\nBaseline BCVA, ETDRS lettersa\t\n Mean (±SD)\t56.6 (10.9)\t59.2 (10.9)\t\t\nBaseline BCVA, n (%)b\t\n ≤55 ETDRS letters\t61 (39.6)\t47 (30.7)\t108 (35.2)\t\n >55 ETDRS letters\t93 (60.4)\t106 (69.3)\t199 (64.8)\t\nBaseline CRT, µma\t\n Mean (±SD)\t547 (163)\t544 (168)\t\t\nTime from onset of symptoms to first treatment, daysc\t\n Mean (±SD)\t49.4 (28.7)\t46.1 (25.9)\t47.8 (27.3)\t\nDEX: dexamethasone; SD: standard deviation; BRVO: branch retinal vein occlusion; BCVA: best-corrected visual acuity; ETDRS: Early Treatment Diabetic Retinopathy Study; CRT: central retinal thickness; ITT: intent-to-treat.\n\na Baseline BCVA and CRT data were available for 306 study eyes (DEX implant, n = 153; ranibizumab, n = 153).\n\nb After correction for mis-stratifications.\n\nc Time to treatment data were available for 290 study eyes (DEX implant, n = 146; ranibizumab, n = 144).\n\nFigure 1. Number and distribution of study treatments administered over the study period.\n\nChange from baseline in BCVA\nFor the ITT population, the LS mean improvement from baseline in BCVA at month 12 was 7.4 ETDRS letters for DEX implant compared with 17.4 ETDRS letters for ranibizumab (LS mean difference (DEX implant minus ranibizumab), −10.1 ETDRS letters; 95% CI, −12.9, −7.2; p = 0.0006); accordingly, the lower bound of the 95% CI for the treatment difference was less (i.e. more negative) than −5 letters (Supplementary Table). Post hoc analysis of those DEX implant-treated patients who received treatment beyond month 5 (n = 94) likewise indicated that the lower bound of the 95% CI for the treatment difference extended below −5 letters (LS mean improvement in BCVA at month 12 of 6.1 vs 17.3 ETDRS letters for DEX implant and ranibizumab, respectively; LS mean difference, −11.2 ETDRS letters; 95% CI, −14.2, −8.1; p < 0.0001). In the supportive AUC analysis of average change in BCVA from baseline, the LS mean difference for the ITT population was −2.8 ETDRS letters (95% CI, −4.5, −1.1; p = 0.0096) at month 3 (AUC0–3) and −6.3 ETDRS letters (95% CI, −8.3, −4.2; p = 0.2190) at month 12 (AUC0–12) (Supplementary Table). Accordingly, the lower bound of the 95% CI for the treatment difference was greater than −5 letters over the first 3 months, but less than −5 letters over 12 months. Among pseudophakic study eyes (n = 53), the LS mean improvement from baseline in BCVA at month 12 was 4.4 ETDRS letters in the DEX implant group compared with 11.7 ETDRS letters in the ranibizumab group (LS mean difference, −7.4 ETDRS letters; 95% CI, −16.0, +1.3; p = 0.5829), mirroring the findings of the overall ITT population (Supplementary Table). The mean changes from baseline in BCVA over time for the overall study population and for the subset of pseudophakic eyes are shown in Figure 2(a) and (b), respectively.\n\nFigure 2. Mean change from baseline in BCVA (ETDRS letters) over 12 months: (a) overall ITT population (DEX implant, n = 153; ranibizumab, n = 153) and (b) pseudophakic eyes, ITT population (DEX implant, n = 26; ranibizumab, n = 27).\n\nPercentage of eyes with ≥10-letter and ≥15-letter gain and loss from baseline\nAt any time during the study, BCVA gains of ≥10 and ≥15 letters were achieved in 86.4% and 67.5% of DEX implant-treated eyes and 87.6% and 76.5% of ranibizumab-treated eyes, respectively. BCVA losses of ≥10 and ≥15 letters were seen in 19.5% and 14.9% of DEX implant-treated eyes and 5.2% and 4.6% of ranibizumab-treated eyes, respectively. The percentage of study eyes with ≥10-letter and ≥15-letter gains over time is shown in Figure 3. At month 12, the proportion of study eyes with ≥10-letter gain was 51.3% in the DEX implant arm versus 73.2% in the ranibizumab arm (odds ratio (OR), 0.30; 95% CI, 0.20, 0.55; p < 0.0001), while the proportion with ≥15-letter gain was 33.8% in the DEX implant arm versus 59.5% in the ranibizumab arm (OR, 0.30; 95% CI, 0.18, 0.48; p < 0.0001). The proportion of study eyes with ≥10-letter loss was 11.7% in the DEX implant versus 2.0% in the ranibizumab arm (OR, 6.2; 95% CI, 1.8, 21.4; p = 0.0043), while the proportion with ≥15-letter loss was 9.1% in the DEX implant versus 0.7% in the ranibizumab arm (OR, 14.4; 95% CI, 1.9, 111.6; p = 0.0104).\n\nFigure 3. Proportion of study eyes with ≥10-letter and ≥15-letter gain from baseline in BCVA over 12 months, ITT population (DEX implant, n = 153; ranibizumab, n = 153).\n\nChange from baseline in CRT\nFor the ITT population, the mean (±SD) baseline CRT was 547 (±163) µm in the DEX implant arm and 544 (±168) µm in the ranibizumab arm. The mean change from baseline in CRT versus time profile over 12 months is shown in Figure 4. The LS mean change from baseline in CRT at month 12 was −227 µm for DEX implant versus −252 µm for ranibizumab (LS mean difference, 24.7 µm; 95% CI, −3.3, +52.8; p = 0.0839).\n\nFigure 4. Mean change from baseline in central retinal thickness over 12 months, ITT population (DEX implant: n = 153; ranibizumab, n = 153).\n\nChange from baseline in VFQ-25 composite score at month 12 and treatment failure\nFor the ITT population, the mean (±SD) baseline VFQ-25 composite score was 78.1 (±16.6) in the DEX implant arm and 80.7 (±14.3) in the ranibizumab arm. The LS mean change from baseline in VFQ-25 composite score at month 12 was 2.9 for DEX implant versus 7.2 for ranibizumab (LS mean difference, 4.3; 95% CI, −6.9, −1.8; p = 0.0011). Treatment failure rate was 4.5% in the DEX implant arm compared with 0.7% in the ranibizumab arm (p = 0.0668).\n\nOcular and systemic safety\nThe most common treatment-emergent ocular adverse events with either DEX implant or ranibizumab were increased IOP, conjunctival hemorrhage, macular edema, reduced visual acuity, cataract, lenticular opacities, ocular hypertension, and blepharitis; all occurred more frequently with DEX implant than with ranibizumab (Table 2). Dry eye, vitreous floaters, and nasopharyngitis occurred at similar frequency (≥5%) in the two treatment groups, whereas eye pain, conjunctivitis, hypertension, and headache occurred more frequently with ranibizumab. Contrasting IOP profiles were noted, with DEX implant-treated eyes showing a saw-tooth pattern and ranibizumab-treated eyes exhibiting a linear change over time (Supplementary Figure). IOP elevations ≥10 mm Hg from baseline were more common with DEX implant than with ranibizumab (38.6% vs 5.3%), as were cataract progression, defined as an increase in lens opacity (59.8% vs 30.9%), and cataract surgery (3.1% vs 0%).\n\nTable 2. Summary of most frequent (≥5% incidence) treatment-emergent ocular adverse events, safety population.\n\nTreatment-emergent adverse event, n (%)\tDEX implant (N = 153)\tRanibizumab (N = 150)\t\nIncreased IOP\t50 (32.7)\t16 (10.7)\t\nConjunctival hemorrhage\t28 (18.3)\t17 (11.3)\t\nMacular edema\t20 (13.1)\t4 (2.7)\t\nReduced visual acuity\t18 (11.8)\t3 (2.0)\t\nCataract\t13 (8.5)\t2 (1.3)\t\nLenticular opacities\t10 (6.5)\t0\t\nOcular hypertension\t9 (5.9)\t1 (0.7)\t\nBlepharitis\t9 (5.9)\t3 (2.0)\t\nDry eye\t9 (5.9)\t7 (4.7)\t\nVitreous floaters\t9 (5.9)\t9 (6.0)\t\nNasopharyngitis\t8 (5.2)\t5 (3.3)\t\nEye pain\t6 (3.9)\t9 (6.0)\t\nConjunctivitis\t6 (3.9)\t9 (6.0)\t\nHypertension\t5 (3.3)\t10 (6.7)\t\nHeadache\t4 (2.6)\t9 (6.0)\t\nDEX: dexamethasone; IOP: intraocular pressure.\n\nDiscussion\nBased on the primary outcome of change from baseline in BCVA at month 12, the null hypothesis of a more than five-letter difference in BCVA gain between DEX implant and ranibizumab at month 12 was not rejected, indicating that DEX implant did not demonstrate non-inferiority vis-à-vis ranibizumab in the treatment of macular edema secondary to BRVO. The difference in average change in BCVA from baseline to month 3 (AUC0–3) was within the five-letter non-inferiority margin for the supportive analysis, although AUC0–3 was significantly greater with ranibizumab than with DEX implant. At 12 months, the proportions of eyes with ≥10- and ≥15-letter gains were significantly greater, and the proportions with ≥10- and ≥15-letter losses significantly lower, for ranibizumab compared with DEX implant. Furthermore, the improvement in VFQ-25 composite score was significantly greater with ranibizumab than with DEX implant. Despite the overall superior improvement in visual acuity achieved with ranibizumab, DEX implant showed comparable efficacy with respect to time to ≥10- and ≥15-letter gain, CRT reduction, and treatment failure rate. Unlike ranibizumab, which was associated with consistent changes from baseline in CRT, DEX implant resulted in a fluctuating pattern of CRT, which may have contributed to the more modest improvement in visual acuity. To place this finding in context, the present results were achieved with a median of eight ranibizumab injections and three DEX implant injections over 12 months. As a reflection of the low rate of retreatment with DEX implant, 12% of study eyes did not receive a second implant and 40% did not receive a third implant; in contrast, almost two-thirds (64%) of ranibizumab-treated eyes received eight or moreinjections. The saw-tooth pattern of CRT response seen with DEX implant suggests that some patients may benefit from more frequent DEX implant injections.\n\nConsistent with a postulated cataract-associated attenuation of BCVA response to DEX implant in phakic eyes,9 narrowing of the differential in treatment efficacy was noted in pseudophakic eyes. No conclusion can be drawn, however, as to whether DEX implant is non-inferior to ranibizumab in pseudophakic eyes, since the study was under-powered for this particular analysis. Restoration of BCVA gains would be expected after cataract surgery in eyes with lens opacities. However, in this study cataract surgery was uncommon in both DEX implant- and ranibizumab-treated eyes (3% vs 0%, respectively), despite the high incidence of increased lens opacity (59.8% vs 30.9% of phakic DEX implant- and ranibizumab-treated eyes).\n\nThe ocular safety profile of DEX implant was consistent with previously published reports of its use in RVO.8,9,14 Treatment with DEX implant was associated with a higher risk of IOP elevation/ocular hypertension, lenticular opacities, and cataract progression or surgery than treatment with ranibizumab. The IOP elevation observed with DEX implant was transient but recurrent.\n\nRecent short-term (6-month), head-to-head controlled comparisons in BRVO (COMRADE B) and CRVO (COMRADE C) have demonstrated superior BCVA outcomes with monthly ranibizumab compared with single-dose DEX implant.15,16 Whereas ranibizumab maintained its efficacy over 6 months, the efficacy of single-dose DEX implant declined over this period. In clinical practice, DEX implant is often re-administered at approximately 4- or 5-month intervals, and the observed BCVA improvements in RVO are greater with multiple-dose than with single-dose DEX implant.17 In RVO, the visual acuity response to DEX implant is influenced by the duration of macular edema,18 with the greatest BCVA gain being achieved in recent-onset BRVO.19 This study extends these findings by demonstrating, in a controlled clinical trial, a visual acuity advantage with ranibizumab compared with multiple-dose DEX implant over a 12-month treatment period in BRVO. However, since anti-VEGF dosing intensity and treatment efficacy are greater in controlled trials than in clinical practice,20 a real-world comparison of DEX implant and ranibizumab would be instructive.\n\nA strength of this study is its head-to-head treatment comparison. However, the study also has several limitations. Compared with real-world scenarios, the frequency of ranibizumab retreatment was high. For those DEX implant-treated eyes that did not receive a third implant, the interval from treatment administration to 12-month efficacy assessment was excessive. Patients and investigators were not masked to treatment assignment, which introduces potential bias. Patient recruitment was lower than planned, reducing the statistical power to detect non-inferiority. Furthermore, despite randomization to treatment, intergroup imbalances occurred through mis-stratification of baseline BCVA. Collectively, these limitations prevent generalization of the study findings.\n\nIn conclusion, the primary analysis findings fail to demonstrate that DEX implant is non-inferior to intravitreal ranibizumab in improving visual acuity in BRVO. This suggested efficacy disadvantage, together with the added risk of IOP elevation and cataract progression, is partly mitigated by the lower treatment burden associated with DEX implant.\n\nSupplemental Material\nCOMO_Supplementary_Fig – Supplemental material for A 12-month, multicenter, parallel group comparison of dexamethasone intravitreal implant versus ranibizumab in branch retinal vein occlusion\nClick here for additional data file.\n\nSupplemental material, COMO_Supplementary_Fig for A 12-month, multicenter, parallel group comparison of dexamethasone intravitreal implant versus ranibizumab in branch retinal vein occlusion by Francesco Bandello, Albert Augustin, Adnan Tufail and Richard Leaback in European Journal of Ophthalmology\n\n Supplemental Material\nCOMO_Supplementary_Table – Supplemental material for A 12-month, multicenter, parallel group comparison of dexamethasone intravitreal implant versus ranibizumab in branch retinal vein occlusion\nClick here for additional data file.\n\nSupplemental material, COMO_Supplementary_Table for A 12-month, multicenter, parallel group comparison of dexamethasone intravitreal implant versus ranibizumab in branch retinal vein occlusion by Francesco Bandello, Albert Augustin, Adnan Tufail and Richard Leaback in European Journal of Ophthalmology\n\n The authors thank the study site personnel who participated in this study (see Appendix 1). Medical writing and editorial assistance was provided to the authors by Andrew Fitton, PhD, of Evidence Scientific Solutions (Horsham, UK) and funded by Allergan plc, Dublin, Ireland.\n\nDeclaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: F.B. reports financial support from Alcon, Allergan, Alimera Sciences, Bayer, Bausch & Lomb, Boehringer-Ingelheim, Farmila Thea, Roche/Genentech, Novartis, Sanofi, Santen, SIFI SpA, SOOFT Italia, Thrombogenics, and Zeiss; A.A. reports financial support from Allergan; A.T. reports consultancy fees from Allergan, Bayer, Novartis, and Roche/Genentech. R.L. is an employee of Allergan Limited.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by Allergan plc, Dublin, Ireland. All authors met the ICMJE authorship criteria. No honoraria or payments were made for authorship.\n\nSupplementary Material: Supplementary Material for this article is available online.\n\nAppendix 1\nNames and affiliations of the principal investigators who participated in the COMO study: Luis Arias, Hospital Universitari de Bellvitge, Barcelona, Spain; Félix Armadá-Maresca, Hospital La Paz, Madrid, Spain; Albert Augustin, Augenklinik Stadtisches Klinikum Karlsruhe, Karlsruhe, Germany; Clare Bailey, Bristol Eye Hospital, Bristol, United Kingdom; Francesco Bandello, University Vita-Salute Scientific Institute San Raffaele, Milan, Italy; Adiel Barak, Tel Aviv Medical Center, Tel Aviv, Israel; Christopher Brand, Royal Hallamshire Hospital, Sheffield, United Kingdom; Michael Briggs, Royal Liverpool University Hospital, Liverpool, United Kingdom; Victor Chong, Oxford Eye Hospital, Oxford, United Kingdom; Salomon Yves Cohen, Centre d’imagerie Laser, Paris, France; Catherine Creuzot-Garcher, Centre Hospitalier Universitaire, Dijon, France; Manuel Diaz-Llopis, Hospital Universitario y Politécnico La Fe, Valencia, Spain; Narendra Dhingra, Pinderfields General Hospital, Wakefield, United Kingdom; José Juan Escobar Barranco, Hospital Dos de Maig, Barcelona, Spain; Eduardo Esteban-González, Hospital Universitario Virgen Macarena, Seville, Spain; Nicolas Feltgen, University Eye Hospital, Goettingen, Germany; Joseph R. Ferencz, Meir Medical Center, Kfar Saba, Israel; Álvaro Fernández-Vega Sanz, Instituto Oftalmológico Fernández-Vega, Oviedo, Spain; Marta S. Figueroa, Vissum Madrid, Madrid, Spain; Roberto Gallego-Pinazo, Hospital Universitario y Politécnico La Fe, Valencia, Spain; Lars-Olof Hattenbach, Klinikum Ludwigshafen Augenklinik, Ludwigshafen, Germany; Frank Holz, University of Bonn, Bonn, Germany; Antonia Joussen, Charité CVK Augenklinik, Berlin, Germany; Anselm Kampik, Ludwig Maximilian University, Munich, Germany; Javeed Khan, St Mary’s Hospital, Newport, Isle of Wight, United Kingdom; Itamar Klemperer, Soroka University Medical Center, Beer-Sheva, Israel; Jean-François Korobelnik, Groupe Hospitalier Pellegrin—CHU de Bordeaux, Bordeaux, France; Paolo Lanzetta, University of Udine, Udine, Italy; Maddalena Quaranta-El Maftouhi, Centre Ophtalmologique Rabelais, Lyon, France; Laura Sararols Ramsay, Vallès Oftalmologia Recerca, Hospital Universitari General de Catalunya, Barcelona, Spain; Maria Socorro Alforja, Instituto Clinico de Oftalmologia—Hospital Clinic de Barcelona, Barcelona, Spain; Eric Souied, Centre Hospitalier Intercommunal de Créteil, Créteil, France; David Steel, Sunderland Eye Infirmary, Sunderland, United Kingdom; Simon Taylor, Royal Surrey County Hospital, Guildford, United Kingdom; Monica Varano, IRCCS Fondazione G. B. Bietti, Rome, Italy; Francesco Viola, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Yit Yang, Wolverhampton Eye Infirmary, Wolverhampton, United Kingdom; Saad Younis, Western Eye Hospital, London, United Kingdom.\n==== Refs\nReferences\n1 \nRogers S McIntosh RL Cheung N et al \nThe prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia . Ophthalmology \n2010 ; 117 (2 ): 313 –319.e1 .20022117 \n2 \nJaulim A Ahmed B Khanam T et al \nBranch retinal vein occlusion: epidemiology, pathogenesis, risk factors, clinical features, diagnosis, and complications. An update of the literature . Retina \n2013 ; 33 (5 ): 901 –910 .23609064 \n3 \nOta T Tsujikawa A Murakami T et al \nSubfoveal serous retinal detachment associated with extramacular branch retinal vein occlusion . Clin Ophthalmol \n2013 ; 7 : 237 –241 .23390359 \n4 \nFlammer J Konieczka K. \nRetinal venous pressure: the role of endothelin . EPMA J \n2015 ; 6 : 21 .26504500 \n5 \nRogers SL McIntosh RL Lim L et al \nNatural history of branch retinal vein occlusion: an evidence-based systematic review . Ophthalmology \n2010 ; 117 (6 ): 1094 –1101.e5 .20430447 \n6 \nRegnier SA Larsen M Bezlyak V et al \nComparative efficacy and safety of approved treatments for macular oedema secondary to branch retinal vein occlusion: a network meta-analysis . BMJ Open \n2015 ; 5 (6 ): e007527 .\n7 \nChang-Lin JE Attar M Acheampong AA et al \nPharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant . Invest Ophthalmol Vis Sci \n2011 ; 52 (1 ): 80 –86 .20702826 \n8 \nHaller JA Bandello F Belfort R et al \nOZURDEX GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion . Ophthalmology \n2010 ; 117 (6 ): 1134 –1146.e3 .20417567 \n9 \nHaller JA Bandello F Belfort R et al \nOzurdex GENEVA Study Group. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion: twelve-month study results . Ophthalmology \n2011 ; 118 (12 ): 2453 –2460 .21764136 \n10 \nCampochiaro PA Heier JS Feiner L et al \nRanibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study . Ophthalmology \n2010 ; 117 (6 ): 1102 –1112e1 .20398941 \n11 \nBrown DM Campochiaro PA Bhisitkul RB et al \nSustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study . Ophthalmology \n2011 ; 118 (8 ): 1594 –1602 .21684606 \n12 \nMarella M Pesudovs K Keeffe JE et al \nThe psychometric validity of the NEI VFQ-25 for use in a low-vision population . Invest Ophthalmol Vis Sci \n2010 ; 51 (6 ): 2878 –2884 .20089878 \n13 \nMartin DF Maguire MG Ying GS et al \nRanibizumab and bevacizumab for neovascular age-related macular degeneration . N Engl J Med \n2011 ; 364 (20 ): 1897 –1908 .21526923 \n14 \nMayer WJ Wolf A Kernt M et al \nTwelve-month experience with Ozurdex for the treatment of macular edema associated with retinal vein occlusion . Eye \n2013 ; 27 (7 ): 816 –822 .23598674 \n15 \nHattenbach LO Feltgen N Bertelmann T et al \nHead-to-head comparison of ranibizumab PRN versus single-dose dexamethasone for branch retinal vein occlusion (COMRADE-B) . Acta Ophthalmol \n2018 ; 96 (1 ): e10 –e18 .28251811 \n16 \nHoerauf H Feltgen N Weiss C et al \nClinical efficacy and safety of ranibizumab versus dexamethasone for central retinal vein occlusion (COMRADE C): a European label study . Am J Ophthalmol \n2016 ; 169 : 258 –267 .27163237 \n17 \nSallam AAI Stratton I \nUK Dexamethasone Implant for Retinal Vein Occlusion Study Group. UK Dexamethasone Implant for Retinal Vein Occlusion Study Group .\nUnited Kingdom national database study of intravitreal dexamethasone implant (Ozurdex) for retinal vein occlusion-related macular edema: visual outcome and safety of treatment . Invest Ophthalmol Vis Sci \n2015 ; 56 (7 ): 5805 \n18 \nYeh WS Haller JA Lanzetta P et al \nEffect of the duration of macular edema on clinical outcomes in retinal vein occlusion treated with dexamethasone intravitreal implant . Ophthalmology \n2012 ; 119 (6 ): 1190 –1198 .22361318 \n19 \nYoon YH Kim JW Chang DJ et al \nA 12 month, open-label, multicenter study to assess the safety and efficacy of Ozurdex 0.7 mg for the treatment of macula edema related to branch retinal vein occlusion in Korea: the COBALT study . Poster presented at the annual meeting of the Association for Research in Vision and Ophthalmology , Seattle, WA, USA , 1–5 May 2016 Available at: http://www.docplayer.net/39897605-Arvo-2016-annual-meeting-abstracts.html (accessed 28 February 2018 ).\n20 \nKiss S Liu Y Brown J et al \nClinical utilization of anti-vascular endothelial growth-factor agents and patient monitoring in retinal vein occlusion and diabetic macular edema . Clin Ophthalmol \n2014 ; 8 : 1611 –1621 .25210429\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1120-6721",
"issue": "28(6)",
"journal": "European journal of ophthalmology",
"keywords": "Branch retinal vein occlusion; dexamethasone intravitreal implant; non-inferiority study; ranibizumab",
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D003907:Dexamethasone; D004343:Drug Implants; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D058449:Intravitreal Injections; D008269:Macular Edema; D008297:Male; D008875:Middle Aged; D000069579:Ranibizumab; D012170:Retinal Vein Occlusion; D014792:Visual Acuity",
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "697-705",
"pmc": null,
"pmid": "29631435",
"pubdate": "2018-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "21684606;20417567;27163237;21764136;20089878;26048209;23390359;23609064;25210429;21526923;23598674;28251811;20702826;20430447;20022117;22361318;20398941;26504500",
"title": "A 12-month, multicenter, parallel group comparison of dexamethasone intravitreal implant versus ranibizumab in branch retinal vein occlusion.",
"title_normalized": "a 12 month multicenter parallel group comparison of dexamethasone intravitreal implant versus ranibizumab in branch retinal vein occlusion"
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"abstract": "Coronavirus disease 2019 (CoVID-19) is a viral disease. Although the predominant presentation is respiratory disease, other manifestations such as gastrointestinal manifestations are commonly reported. Nevertheless, it has not been associated with chronic cholangitis or hepatic injury. In this study, we report three cases of severe CoVID-19 infection that required ICU admission, intubation, and sedation with ketamine. All three patients had abnormal liver function despite recovery and were diagnosed with cholangitis in the context of CoVID-19.",
"affiliations": "Service de Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, AP-HP, 75018 Paris, France.;Service de Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, AP-HP, 75018 Paris, France.;Service de Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, AP-HP, 75018 Paris, France.;Service de Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, AP-HP, 75018 Paris, France.;Service de Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, AP-HP, 75018 Paris, France.;Service de Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, AP-HP, 75018 Paris, France.;Service de maladies infectieuses et tropicale, Hôpital René Dubos, Pontoise, France.;Service de Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, AP-HP, 75018 Paris, France.;Groupe hospitalier intercommunal Montfermeil, France.;Centre National de la Recherche Scientifique, Formation de Recherche en Evolution, 2443 Paris, France.;Service de Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, AP-HP, 75018 Paris, France.;Service de Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, AP-HP, 75018 Paris, France.;Service de Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, AP-HP, 75018 Paris, France.;Service de Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, AP-HP, 75018 Paris, France.",
"authors": "Gourjault|Cyrille|C|;Tarhini|Hassan|H|;Rahi|Mayda|M|;Thy|Michael|M|;Le Pluart|Diane|D|;Rioux|Christophe|C|;Parisey|Marion|M|;Ismael|Sophie|S|;Aidibi|Ali Al Rida|AAR|;Paradis|Valerie|V|;Ghosn|Jade|J|;Yazdanpanah|Yazdan|Y|;Lescure|François-Xavier|FX|;Gervais|Anne|A|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2021.e01267",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00223-7\n10.1016/j.idcr.2021.e01267\ne01267\nArticle\nCholangitis in three critically ill patients after a severe CoVID-19 infection\nGourjault Cyrille gourcy@hotmail.com\na⁎1\nTarhini Hassan hassan.tarhini@aphp.fr\nhassantarhini01@gmail.com\na⁎1\nRahi Mayda a\nThy Michael a\nLe Pluart Diane a\nRioux Christophe a\nParisey Marion c\nIsmael Sophie a\nAidibi Ali al rida d\nParadis Valerie ef\nGhosn Jade ab\nYazdanpanah Yazdan ab\nLescure François-Xavier ab\nGervais Anne a\na Service de Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, AP-HP, 75018 Paris, France\nb Université de Paris, Infection Modelisation Antimicrobial Evolution (IAME), Inserm UMR1137, 75006 Paris, France\nc Service de maladies infectieuses et tropicale, Hôpital René Dubos, Pontoise, France\nd Groupe hospitalier intercommunal Montfermeil, France\ne Centre National de la Recherche Scientifique, Formation de Recherche en Evolution, 2443 Paris, France\nf Service d′Anatomie Pathologique, Hôpital Beaujon, Clichy, France\n⁎ Corresponding authors. gourcy@hotmail.comhassan.tarhini@aphp.frhassantarhini01@gmail.com\n1 Cyrille Gourjault and Hassan Tarhini contributed equally to this work as First authors.\n\n31 8 2021\n2021\n31 8 2021\n26 e0126723 7 2021\n12 8 2021\n30 8 2021\n© 2021 Published by Elsevier Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nCoronavirus disease 2019 (CoVID-19) is a viral disease. Although the predominant presentation is respiratory disease, other manifestations such as gastrointestinal manifestations are commonly reported. Nevertheless, it has not been associated with chronic cholangitis or hepatic injury. In this study, we report three cases of severe CoVID-19 infection that required ICU admission, intubation, and sedation with ketamine. All three patients had abnormal liver function despite recovery and were diagnosed with cholangitis in the context of CoVID-19.\n\nKeywords\n\nSARS-CoV-2\nCoVID-19\nCholangitis\nICU\nLiver transplantation\nHepatobiliary diseases\n==== Body\npmcIntroduction\n\nThe CoVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). It was first identified in Wuhan China, in December 2019, then spread throughout other continents since January 2020 [1], [2]. The main presentation of CoVID-19 is respiratory symptoms such as cough, fever, and dyspnea. Many studies show an impact of Sars-CoV-2 on other organs. Gastrointestinal manifestations such as diarrhea, vomiting, and hepatobiliary abnormalities are recently noted in CoVID-19 patients [3].\n\nDuring the first epidemic wave in France, from the late of February to mid-June 2020, 1271 patients with CoVID-19 infection were admitted to Bichat University Hospital in Paris. Four hundred and seventy-five patients developed severe respiratory manifestations, and 96 of them had critical manifestations with acute respiratory distress syndrome (ARDS) requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO). We noted that 3 male patients without medical history of liver injury developed chronic cholangitis. Here we report these 3 cases and discuss the hypotheses for the underlying etiology.\n\nCase reports\n\nThe demographics and clinical characteristics of patients were collected from the electronic medical record of our hospital (Table 1). All three patients were followed up as a part of their routine clinical care.Table 1 Main characteristics of patients presenting with cholangitis post Covid-19 infection.\n\nTable 1\tPatient 1\tPatient 2\tPatient 3\t\nPatient demographics\t\nSex\tMale\tMale\tMale\t\nAge (years)\t55\t45\t30\t\nBody Mass Index (Kg/m2)\t33\t32\t23\t\nComorbidities\tNone\tNone\tNone\t\nCharacteristics at initial admission\t\nSymptoms at admission\tFever, dyspnea, cough\tFever, dyspnea, cough\tFever, dyspnea\t\nWhite-blood cells (/mm3)\t15 000\t7 200\t10 680\t\nNeutrophils (/mm3)\t13 000\t5 440\t9 010\t\nLymphocytes (/mm3)\t1 400\t1 500\t1 470\t\nEosinophils (/mm3)\t0\t0\t0\t\nCRP (mg/L)\t251\t65\t141\t\nCreatinine (µmol/L)\t81\t87\t125\t\nASAT (UI/L)\t55\t58\t118\t\nALAT (UI/L)\t23\t44\t39\t\nGGT (UI/L)\t48\t62\t25\t\nALP (UI/L)\t80\t41\t31\t\nBilirubin (µmol/L)\t18\t10\t21\t\nLDH (UI/L)\t630\t695\t5 260\t\nICU stay\t\nPeriod (days)\t23\t52\t74\t\nInfectious complications\tProteus vulgaris pneumonia.\tStaphylococcus aureus pulmonary infection.\tStaphylococcus aureus and Klebsiella aerogenes pneumonia, Neisseria subflava pneumonia\t\nMedications received\tDexamethasone, lopinavir /ritonavir, Anakinra\tDexamethasone, lopinavir /ritonavir, Tocilizumab\tDexamethasone, lopinavir /ritonavir, Anakinra, Tocilizumab\t\nAntibiotics\tCefotaxime, amoxicillin\tCefazoline\tCefotaxime Spiramycin, Piperacillin /Tazobactam, Meropenem, Amikacin\t\nIntubation (days)\t20\t26\t12\t\nVasopressor support\tYes (4 days)\tYes (2 days)\tYes (9 days)\t\nKetamine (grams)\t25\t27\t6\t\nECMO\tNo\t18 days\t29 days\t\nProne positioning\t4\t2\t6\t\nCurative anticoagulation\tYes\tYes\tYes\t\nHaemodialysis\tNo\t15 sessions\t30 sessions\t\nComplications on follow up\t\nSecondary infections\tCholangitis and Enterococcus faecalis bacteremia\tEBV reactivation\tCMV viremia\nEBV reactivation\t\nAnti-microbial medications\tPiperacillin /tazobactam, Amoxicillin\tNone\tGanciclovir\t\nOther complications\tPeripheral neuropathy\tPersistent chronic kidney disease (Stage 3)\tAcute hepatic injury,\nNeuropathy\t\nCRP: C reactive protein; ASAT: Aspartate aminotransferase; ALAT: Alanine aminotransferase; GGT: Gamma glutamyl transferase; ALP: Alkaline phosphatase; ICU: Intensive care unit; ECMO: Extracorporeal membrane oxygenation\n\nPatient 1\n\nA previously healthy 55-year-old obese patient presented with dyspnea, fever, and cough for four days. He was diagnosed with SARS-CoV-2 infection on nasopharyngeal swab test. His initial assessment showed high inflammatory markers (CRP 251 mg/L) with normal renal and hepatic function tests. On day two, he had sudden ARDS with pulmonary embolism. He was transferred to the intensive care unit (ICU), intubated for 20 days, and sedated with ketamine (total 25 g). Four sessions of prone positioning were done. He was treated with dexamethasone, lopinavir /ritonavir, anakinra, and therapeutic anticoagulation.\n\nDuring his stay, the patient had disturbed liver function tests that worsened gradually (Fig. 1). On day 25, he was diagnosed with cholangitis and Enterococcus faecalis bacteremia treated with a course of piperacillin /tazobactam. A liver ultrasound showed no biliary dilatation. He had neither active HIV, viral hepatitis (A, B, C, and E), EBV, nor CMV infection. Also, the autoimmune workup was negative. Hepatic MRI on day 66 showed a periportal hypersignal without hepatic biliary dilatation. A liver biopsy performed on day 74 showed interlobular biliary lesions with cholestasis, without evidence for infection. He was discharged home the day after.Fig. 1 Trends of liver function test of patients with cholangitis since their Day one of admission to one year of follow up. ALT: alanine transaminase (normal 16–63 U/L), ALP: alkalin phosphatase (normal 50–136 U/L), Bilirubin (normal<17 µmol/L). Line in panel C indicate the date of transplantation.\n\nFig. 1\n\nOn day 84, he was readmitted with recurrent cholangitis and Enterococcus faecalis bacteremia treated with amoxicillin for seven days. On day 88, endoscopic retrograde cholangiopancreatography showed irregular intrahepatic bile ducts suggesting ischemic cholangitis. He had sphincterotomy and removal of an uncalcified semi-solid stone. On 10 months follow-up, he still had persistent obstructive jaundice with prolonged prothrombin time. Follow up liver MRI after ten months of his illness showed findings suggestive of portal hypertension. He is currently in the pre-liver transplant evaluation process.\n\nPatient 2\n\nA previously healthy 45-year-old obese patient presented with 4-day history of fever, cough and dyspnea. SARS-CoV-2 infection was diagnosed on nasopharyngeal swab. Admission laboratory profile showed significant inflammatory state (CRP 65 mg/L) with normal renal and liver function tests. Due to severe hypoxia on day 4, he was transferred to the ICU, intubated for 26 days, and sedated with ketamine (total 27 g) for 24 days. Two sessions of prone positioning were performed. Also, he was placed on ECMO for 18 days. He was treated with dexamethasone, lopinavir /ritonavir, and tocilizumab. His ICU stay was complicated by diffuse venous thrombosis post ECMO treated with therapeutic anticoagulation. Besides, he had acute kidney injury that required 15 sessions of haemodialysis.\n\nThroughout his stay, he had gradual worsening of his liver function tests (Fig. 1). Workup showed neither active HIV nor viral hepatitis (A, B, and C) infections, but previous EBV and CMV immunity with reactivation of EBV that resolved spontaneously. No autoimmune antibodies were detectable. Abdominal ultrasound on day 96 showed hepatic steatosis without hepatomegaly or biliary dilatation. Hepatic MRI on day 130 showed diffuse intra-hepatic dilatation and liver steatosis without any focal obstructing lesion. Transaminases resumed to normal values, but cholestasis persisted. Repeat liver MRI on day 200 showed unchanged aspect of intrahepatic bile duct wall irregularities in keeping with cholangitis along with partial resolution of bile ducts wall enhancement and hepatic perfusion disorders. On 1-year follow up after his illness, the patient had significant clinical and biochemical improvement.\n\nPatient 3\n\nA previously healthy 30-year-old patient presented with 2 days history of fever and dyspnea. His initial assessment showed high inflammatory markers (CRP 141 mg/L) accompanied with mild disturbance in his hepatic profile. He was diagnosed with SARS-CoV-2 infection on nasopharyngeal swab. On day two, he was admitted to the ICU for severe hypoxia and acute hepatic cytolysis. In the setting of severe ARDS, he was intubated for 12 days, placed on ECMO for 29 days, and sedated with ketamine (total 6 g) for 8 days. Six sessions of prone positioning were performed. His hospitalization was complicated by venous thrombosis and acute kidney injury that required 30 sessions of haemodialysis. He was treated with dexamethasone, lopinavir /ritonavir, tocilizumab, anakinra, and therapeutic anticoagulation.\n\nDuring his stay, the patient had abnormal liver function tests (Fig. 1). He had neither active HIV nor viral hepatitis (A, B, C, and E) infections. He had EBV reactivation with spontaneous resolution and CMV reactivation with viremia (3.3Log) treated with ganciclovir for 14 days. Plasma CMV viral load was undetectable on day 60. No autoimmune antibodies were detectable.\n\nHepatic ultrasound was normal. Histology of liver biopsy done on day 62 showed cholestatic hepatitis lesions and bile ducts dystrophy suggesting a viral cytopathic effect. Viral panel performed on liver biopsy was negative (SARS-CoV-2, CMV, EBV, HSV-1, HSV-2, VZV, adenovirus and enterovirus). Throughout his hospital stay, his hepatic profile showed only persistent cholestatic disturbance. After nine months from his CoVID-19 illness, he developed liver failure with ascites and prolonged prothrombin time (54 s). On a follow up hepatic MRI, findings of progressive irregular intrahepatic ductal dilatation with narrowing were highly suggestive of diffuse cholangitis. He ended up having a liver transplant 11 months after his admission for CoVID-19. Histology report of hepatic explant showed extensive portal fibrosis, biliary infarction, and cholangitic lesions. Also, there was atrophy of central areas suggesting an ischemic etiology.\n\nDiscussion\n\nMildly elevated liver function tests are frequently observed in CoVID-19 patients. In general, this usually spontaneously resolved, and does not lead to liver failure nor specific treatment [4]. Remdesivir can aggravate the perturbation in liver tests [5]. This was not the case the reported patients, none of them had received remdesivir and all of them developed a chronic liver failure and did not have spontaneous resolution of abnormal liver tests.\n\nChronic cholangitis is an infrequent entity in critically ill patients and occurs in 1 per 2000 ICU patients [6]. Recently, it has been reported in CoVID-19 patients after ICU stay [7], [8]. In our study, 3 out of 475 ICU patients had cholangitis which is around 10 times more frequent than what has been previously reported in the literature. In addition, post-CoVID-19 cholangitis may lead to severe hepatic injury and consequently liver transplantation as reported in the third patient of our study.\n\nARDS occurs in 15–31% of CoVID-19 patients [2], particularly obese patients. Obesity is thought to promote ischemia-hypoxemia through the use of small volumes during protective ventilation, high PEEP and multiple prone sessions [9]. In our study, all three patients shared these conditions. Obesity might have been, through hypoxemia, a contributing factor to ischemic cholangitis.\n\nA second contributing factor could be direct viral injury on cholangiocytes. ACE2, which facilitates SARS-CoV-2 infection, is expressed by cholangiocytes as by lung alveolar cells [10]. However, detection of SARS-CoV-2 in cholangiocytes on liver biopsy has not been reported before. In our third case report (patient 3), dystrophic intrahepatic bile ducts in liver biopsy could suggest a viral cytopathic effect on cholangiocytes. In fact, CMV hepatitis in this patient was ruled out by the absence of hepatocellular abnormalities (viral inclusion) and negative CMV PCR on biopsy.\n\nThirdly, cholangiocytes play an important role in liver regeneration and immune regulation [11]. The release of pro-inflammatory cytokines TNF-alfa, IL-1, or IL-6, which is common in patients with SARS-CoV-2 infection, especially ICU patients, induce hyperviscosity, hyper-coagulopathy, thromboembolic event which may worsen the hypoxic phenomenon [12]. Pro-inflammatory cytokines alter the hepato-biliary transporters function, pAE2 anion exchangers which allow protective micelles in bile ducts. The defect of protective micelles leads to bile toxicity [13] and may be a risk factor of chronic cholangitis.\n\nThe fourth and crucial cause might be the use of ketamine in these three patients, known to induce sclerosing cholangitis associated with high doses or prolonged use [14]. We cannot exclude that our patients had genetic predisposition such as MDR3 polymorphism promoting drug-induced cholangitis [15]. Getting the result of this genetic testing needs around one-year duration which was not feasible to perform in our institution. These three patients received two to three grams of ketamine per day during the first week of management (between 0.6 and 1.2 mg/kg/h) with cumulative doses ranging from 10 to 25 g, which is consistent with Leonhart's study, reporting cholangitis [16].\n\nIn conclusion, Patients with severe SARS-CoV-2 infection are prone to develop chronic cholangitis, which may result from cumulative events: thrombotic events, hypoxemia, direct viral injury, and use of ketamine in patients with genetic promoting factors. However, none of the three patients reported here underwent MDR3 genetic analysis. Further studies are in progress to address this question.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthics approval\n\nOur three patients were a part of a research study entitled \"Sociodemographic characteristics and transmission risk factors in patients hospitalized for CoVID-19 before and during the lockdown in France\". This study was approved by the local ethics committee, IRB number 00006477.\n\nConsent\n\nAll patients involved in this research study have declared voluntary participation without any opposition.\n\nCRediT authorship contribution statement\n\nAll authors attest that they meet the current ICMJE criteria for Authorship. All authors treated and followed patients. CG, HT, AA, DLP and AG collected the data and performed the literature search. CG, HT, MR, CR and MP drafted the initial manuscript. MT prepared the figure. SI prepare the table. VP, JG, YY, FXL and AG edited and supervised the manuscript. All authors had access to the underlying data, which they verified. All authors revised the manuscript before approving its final version.\n\nDeclaration of Competing Interest\n\nNone of the authors has any financial/competing interests to disclose.\n==== Refs\nReferences\n\n1 Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 395 2020 497 506 31986264\n2 Wiersinga W.J. Rhodes A. Cheng A.C. Peacock S.J. Prescott H.C. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review JAMA 324 2020 782 793 32648899\n3 Parasa S. Desai M. Thoguluva Chandrasekar V. Patel H.K. Kennedy K.F. Roesch T. Prevalence of gastrointestinal symptoms and fecal viral shedding in patients with coronavirus disease 2019 JAMA Netw Open 3 2020 2011335\n4 Bertolini A. van de Peppel I.P. Bodewes F.A.J.A. Moshage H. Fantin A. Farinati F. Abnormal liver function tests in patients with COVID‐19: relevance and potential pathogenesis Hepatology 72 2020 1864 1872 32702162\n5 Aleem A. Mahadevaiah G. Shariff N. Kothadia J.P. Hepatic manifestations of COVID-19 and effect of remdesivir on liver function in patients with COVID-19 illness Proc (Bayl Univ Med Cent) 34 2021 473 477 34219928\n6 Martins P. Verdelho Machado M. Secondary sclerosing cholangitis in critically Ill patients: an underdiagnosed entity GE Port J Gastroenterol 27 2020 103 114 32266307\n7 Roth N.C. Kim A. Vitkovski T. Xia J. Ramirez G. Bernstein D. Post–COVID-19 cholangiopathy: a novel entity Am J Gastroenterol 116 2021 1077 1082 33464757\n8 Edwards K. Allison M. Ghuman S. Secondary sclerosing cholangitis in critically ill patients: a rare disease precipitated by severe SARS-CoV-2 infection BMJ Case Rep 13 2020 11\n9 Gelbmann C.M. Rümmele P. Wimmer M. Hofstädter F. Göhlmann B. Endlicher E. Ischemic-like cholangiopathy with secondary sclerosing cholangitis in critically Ill patients Am J Gastroenterol 102 2007 1221 1229 17531010\n10 X. Chai, L. Hu, Y. Zhang, et al., Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-ncov infection, bioRxiv, (2020).\n11 Banales J.M. Huebert R.C. Karlsen T. Strazzabosco M. LaRusso N.F. Gores G.J. Cholangiocyte pathobiology Nat Rev Gastroenterol Hepatol 16 2019 269 281 30850822\n12 Panigada M. Bottino N. Tagliabue P. Grasselli G. Novembrino C. Chantarangkul V. Hypercoagulability of COVID‐19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis J Thromb Haemost JTH 18 2020 1738 1742 32302438\n13 Fouassier L. Beaussier M. Schiffer E. Rey C. Barbu V. Mergey M. Hypoxia-induced changes in the expression of rat hepatobiliary transporter genes Am J Physiol Gastrointest Liver Physiol 293 2007 25 35\n14 Gudnason H.O. Björnsson H.K. Gardarsdottir M. Thorisson H.M. Olafsson S. Bergmann O.M. Secondary sclerosing cholangitis in patients with drug-induced liver injury Dig Liver Dis J Ital Soc Gastroenterol Ital Assoc Study Liver 47 2015 502 507\n15 Trauner M. Fickert P. Wagner M. MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes Semin Liver Dis 27 2007 77 98 17295178\n16 Leonhardt S. Veltzke-Schlieker W. Adler A. Schott E. Hetzer R. Schaffartzik W. Trigger mechanisms of secondary sclerosing cholangitis in critically ill patients Crit Care 19 2015 131 25886728\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "26()",
"journal": "IDCases",
"keywords": "Cholangitis; CoVID-19; Hepatobiliary diseases; ICU; Liver transplantation; SARS-CoV-2",
"medline_ta": "IDCases",
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"pubdate": "2021",
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"title": "Cholangitis in three critically ill patients after a severe CoVID-19 infection.",
"title_normalized": "cholangitis in three critically ill patients after a severe covid 19 infection"
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"abstract": "Next-generation sequencing was performed for 2 families with an undiagnosed neurologic disease. Analysis revealed X-linked mutations in the proteolipid protein 1 (PLP1) gene, which is associated with X-linked Pelizaeus-Merzbacher disease and Spastic Paraplegia type 2. In family A, the novel PLP1 missense mutation c.617T>A (p.M206K) was hemizygous in the 2 affected male children and heterozygous in the mother. In family B, the novel de novoPLP1 frameshift mutation c.359_369del (p.G120fs) was hemizygous in the affected male child. Although PLP1 mutations have been reported to cause an increasingly wide range of phenotypes inclusive of the dystonia, spastic paraparesis, motor neuronopathy, and leukodystrophy observed in our patients, atypical features included the cerebrospinal fluid deficiency of neurotransmitter and pterin metabolites and the delayed appearance of myelin abnormalities on neuroimaging studies. Next-generation sequencing studies provided a diagnosis for these families with complex leukodystrophy disease phenotypes, which expanded the spectrum of PLP1-associated leukodystrophy clinical phenotypes.",
"affiliations": "ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT, USA.;ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT, USA.;ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT, USA.;Pediatric Motor Disorders Research Program, Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA.;Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.;ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT, USA.;ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT, USA.;Department of Endocrinology, University of Nebraska Medical Center, Omaha, NE, USA.;Pediatric Motor Disorders Research Program, Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA.",
"authors": "Margraf|Rebecca L|RL|;Durtschi|Jacob|J|;Krock|Bryan|B|;Newcomb|Tara M|TM|;Bonkowsky|Joshua L|JL|;Voelkerding|Karl V|KV|;Bayrak-Toydemir|Pinar|P|;Lutz|Richard E|RE|;Swoboda|Kathryn J|KJ|",
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"doi": "10.1177/2329048X18789282",
"fulltext": "\n==== Front\nChild Neurol OpenChild Neurol OpenCNOspcnoChild Neurology Open2329-048XSAGE Publications Sage CA: Los Angeles, CA 10.1177/2329048X1878928210.1177_2329048X18789282Case ReportNovel PLP1 Mutations Identified With Next-Generation\nSequencing Expand the Spectrum of PLP1-Associated Leukodystrophy Clinical\nPhenotypes Margraf Rebecca L. PhD1Durtschi Jacob BS1Krock Bryan PhD12Newcomb Tara M. MS3Bonkowsky Joshua L. MD, PhD4Voelkerding Karl V. MD12Bayrak-Toydemir Pinar MD, PhD12Lutz Richard E. MD56Swoboda Kathryn J. MD347\n1 ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories,\nSalt Lake City, UT, USA\n2 Department of Pathology, University of Utah School of Medicine, Salt Lake\nCity, UT, USA\n3 Pediatric Motor Disorders Research Program, Department of Neurology,\nUniversity of Utah School of Medicine, Salt Lake City, UT, USA\n4 Division of Pediatric Neurology, Department of Pediatrics, University of\nUtah School of Medicine, Salt Lake City, UT, USA\n5 Department of Endocrinology, University of Nebraska Medical Center, Omaha,\nNE, USA\n6 Department of Genetics, University of Nebraska Medical Center, Omaha, NE,\nUSA\n7 Department of Neurology, Center for Genomic Medicine, Massachusetts General\nHospital, Boston, MA, USARebecca L. Margraf, PhD, ARUP Institute for Clinical\nand Experimental Pathology, ARUP Laboratories, 500 Chipeta Way, Salt Lake City, UT 84108,\nUSA. Email: rebecca.margraf@aruplab.com23 7 2018 2018 5 2329048X1878928225 4 2018 12 6 2018 © The Author(s) 20182018SAGE PublicationsThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits\nnon-commercial use, reproduction and distribution of the work without further permission\nprovided the original work is attributed as specified on the SAGE and Open Access pages\n(https://us.sagepub.com/en-us/nam/open-access-at-sage).Next-generation sequencing was performed for 2 families with an undiagnosed neurologic\ndisease. Analysis revealed X-linked mutations in the proteolipid protein\n1 (PLP1) gene, which is associated with X-linked\nPelizaeus-Merzbacher disease and Spastic Paraplegia type 2. In family A, the novel\nPLP1 missense mutation c.617T>A (p.M206K) was hemizygous in the 2\naffected male children and heterozygous in the mother. In family B, the novel de\nnovo\nPLP1 frameshift mutation c.359_369del (p.G120fs) was hemizygous in the\naffected male child. Although PLP1 mutations have been reported to cause\nan increasingly wide range of phenotypes inclusive of the dystonia, spastic paraparesis,\nmotor neuronopathy, and leukodystrophy observed in our patients, atypical features\nincluded the cerebrospinal fluid deficiency of neurotransmitter and pterin metabolites and\nthe delayed appearance of myelin abnormalities on neuroimaging studies. Next-generation\nsequencing studies provided a diagnosis for these families with complex leukodystrophy\ndisease phenotypes, which expanded the spectrum of PLP1-associated leukodystrophy clinical\nphenotypes.\n\nPelizaeus-Merzbacher diseaseproteolipid protein 1spastic paraplegia type 2PLP1leukodystrophyPMDSPG2dystoniabraindevelopmental delaygeneticsmutationnext-generation sequencingspasticityNIH grantDP2 MH100008edited-statecorrected-proof\n==== Body\nNext-generation sequencing has identified causal mutations in families with inherited disease\nof unknown etiology and, in some cases, has facilitated intervention with disease-modifying therapies.1–4 Genome and exome sequencing is especially helpful when the phenotype is genetically\nheterogeneous and complex, as in the hereditary spastic paraparesis and spinocerebellar ataxia syndromes.5–7 Next-generation sequencing has also proved instrumental in associating novel phenotypes\nwith known genes. For instance, we used exome sequencing to identify de novo\npathogenic mutations in ATP1A3 in alternating hemiplegia of childhood;\ndominantly inherited mutations in this gene had been previously associated with rapid-onset\ndystonia parkinsonism.4\n\n\nPLP1 is a transmembrane myelin proteolipid protein and is the predominant protein in central\nnervous system myelin. Pathogenic proteolipid protein 1\n(PLP1) mutations, including missense mutations, duplications, and\ndeletions, are known to cause X-linked Pelizaeus-Merzbacher disease and Spastic Paraplegia\ntype 2.8\nPLP1 mutations are increasingly associated with a broad spectrum of disease\nseverity and age of onset.9–11 The connatal and classic forms of Pelizaeus-Merzbacher disease are associated with\ncongenital or early-onset nystagmus and progressive spasticity in association with a\nleukodystrophy consisting of a severe hypomyelination. Spastic Paraplegia type 2 falls at the\nmilder end of this spectrum, in which central nervous system myelin abnormalities are more\nsubtle or absent, becoming evident only later in the clinical course. In the severe connatal\nform of Pelizaeus-Merzbacher disease, eye movement abnormalities are present from birth,\nbulbar and respiratory insufficiency present early, and progressive spasticity and cognitive\nimpairment are universal. Death can occur from infancy to the third decade, and these children\ntypically do not achieve independent sitting or verbal communication. Seizures may or may not\nbe present. In a pediatric population cohort of leukodystrophies, 7.4% had\nPelizaeus-Merzbacher disease, the second most frequently observed cause of leukodystrophy.12 In Spastic Paraplegia type 2 phenotypes associated with PLP1\nmutations, progressive spastic paraparesis is the predominant phenotype, and affected males\nare reported to have normal or near-normal cognition. A null phenotype related to missense\nmutations has also been described; patients reported tend to have a milder\nPelizaeus-Merzbacher disease–like phenotype or pure or complicated spastic paraparesis\nphenotype and may manifest an associated demyelinating peripheral neuropathy. In\nPLP1-associated syndromes, approximately 60% to 70% are associated with\ngene duplication events of variable size and 10% to 20% with intragenic mutations or smaller deletions/duplications.9\n\n\nThe phenotypes in the affected children in the 2 families described in this report were\ncomplex, with unique phenotypic features in each case. To discover the genetic cause for these\nfamilies which could lead to diagnosis, genomic analyses were performed via genome sequencing\non a research basis in family A, and in family B, clinical exome sequencing was performed. By\nthis approach, novel PLP1 mutations were identified in both families. The clinical phenotypes\ndetailed in this report highlight the unique phenotypic features in these patients (eg,\ndelayed appearance and recognition of central nervous system myelin abnormalities) that led to\nthe diagnostic odyssey these families experienced that spanned more than a decade.\n\nMaterials and Methods\nSamples\nPatients and their family members were consented under the University of Utah\ninstitutional review board protocol #25651. For family A, DNA extraction from peripheral\nblood samples was performed by the genomic core facility at the University of Utah\nClinical Center for Translational Science and submitted to ARUP Laboratories for genomic\nanalysis. Family A analysis included the 2 affected male children (II-2 and II-3), an\nunaffected female half-sibling (II-1), and the unaffected parents (I-2 and I-3; pedigree\nin Figure 1A). For family B,\nperipheral blood samples were submitted to the ARUP Laboratories Genomics Section for\nclinical exome sequencing. Family B consists of 1 affected male child (II-1) and the\nunaffected parents (I-1 and I-2; pedigree in Figure 1B).\n\nFigure 1. A-B, Family pedigrees. The circles represent female and the squares represent male.\nThe affected male family members are represented by filled squares. A, Family A\npedigree. B, Family B pedigree. C-D, Family A mutation data. C, Sanger sequencing\ntraces for the PLP1 c.617T>A mutation (location boxed in red) are\nshown for five family A members. D, Multiple sequence alignment. PLP1 protein\nsequences for several species shown. Amino acid differences from the human PLP1\nsequence are in bold blue text. Amino acid 206, where the family A mutation “K”\n(p.M206K) is located, is boxed in red. The other locations of nearby known\nPelizaeus-Merzbacher disease (PMD) causative mutations are starred. E, Sanger\nsequencing traces are shown for the family B proband II-1 and mother I-1 at the\nPLP1 mutation position (11 base pair de novo\nmutation in bracket).\n\nNext-Generation Sequencing\nFive members of family A (I-2, I-3, II-1, II-2, and II-3; Figure 1A) underwent genome sequencing on the HiSeq\n2000 instrument (Illumina Inc, San Diego, California) with 100 base length pair end reads.\nDNA from the parents and affected child in family B (Figure 1B) were exome sequenced using methods\npresented by Wooderchak-Donahue et al13 with the following exceptions: the Agilent SureSelectXT Human All Exon V4 kit\n(Agilent Technologies, Inc, Santa Clara, California) was used on the automated library\ngeneration Bravo instrument option A (Agilent), and the sequencing was done on the HiSeq\n2500 instrument (Illumina).\n\nData Analysis\nIllumina Fastq files were aligned to the human reference genome (GRCh37) and variants\nfrom the reference were called using BWA, Samtools, and GATK software. After the first\nalignment, a second refined alignment was done, which removed polymerase chain reaction\nduplicate reads, identified read bias, and realigned around deletions and insertions.\n\nFor family A, analyzed via genome sequencing, the candidate gene identification for the\nexpected X-linked or recessive disease inheritance was approached using 2 methods. Golden\nHelix software (SNP and Variation Suite; Golden Helix Inc, Bozeman, Montana) used\nheuristic filtering (such as requiring >3× read depth) and family intersects or\nsubtractions to identify suspect genes. VAAST is a probabilistic algorithm14,15 that performs family inheritance analysis and comparison of variants to a\nbackground variant file of 250 Caucasian data sets. After applying VarBin16 to identify false-positive variants, requiring Mendelian segregation with disease,\nlimiting to exons ±10 bases, and eliminating genes with functions that are unlikely to be\nphenotypically relevant, these methods yielded 16 candidate genes. These 16 genes were\nfurther analyzed with respect to minor allele population frequency, predicted\npathogenicity using SIFT17 scores, variant’s potential to affect gene function, literature searches, disease\ndatabase information, gene function, and potential phenotype relevance.\n\nAnalyses of exome data for family B excluded variants with a variant quality score <10\nand with >1% population frequency from further analysis. Family members’ variants were\nintersected or subtracted for analysis of different inheritances patterns possible for\nfamily B. Then high-priority variants were identified based on predicted variant\npathogenicity and phenotypic correlation with the proband. Variants were further analyzed\nfor those that were predicted to be pathogenically most relevant using SIFT scores and\nvariant’s potential to affect gene function, as well as the gene function being\nphenotypically relevant to symptoms of the proband.\n\nClinical Report\nFamily A\nThe proband, II-2, was born at 37 weeks’ gestation to unrelated parents of European\nCaucasian ancestry. He was delivered via vacuum-assisted vaginal birth following a\nprolonged labor lasting 3 days, with Apgar scores of 5 and 6, and a birth weight of 7 lbs\n10 oz. He had hypotonia and a weak suck from birth and had failed to achieve head control\nby 3 months of age. Shortly thereafter, he began manifesting dystonic posturing of limbs,\ninvoluntary head turning, and eye movement abnormalities. High-resolution karyotype and\nFluorescence In Situ Hybridization analysis for Prader-Willi syndrome were negative. Brain\nmagnetic resonance imaging (MRI) at 4 months of age was reported as normal. He received a\ntentative diagnosis of cerebral palsy but had additional diagnostic testing including\nnormal plasma very long chain fatty acids, lysosomal enzymes, cerebrospinal fluid and\nblood lactate, carnitine and acylcarnitine studies, and urine organic acids. By 12 months,\nhe was noted to track poorly and was thought to have optic nerve pallor; electroretinogram\ntesting was normal but visual-evoked responses were impaired. By 18 months of age, he was\nseverely developmentally delayed from a gross motor standpoint and was unable to sit or\nroll. By that point, his younger brother had been born and appeared similarly affected,\nand further diagnostic workup included muscle and skin biopsies to exclude defects in\nenergy metabolism proved unrevealing. A follow-up brain MRI at 23 months demonstrated an\ninterval increase in the size of the lateral and third ventricles and diffuse reversal of\nthe normal gray and white matter signal intensity. Over the ensuing years, he made little\ndevelopmental progress with regard to gross or fine motor skills but could spell his name\nand knew his colors. At that time, the parents saw a television program featuring a child\nwith an inherited defect in neurotransmitter biosynthesis who responded dramatically to\ntreatment with l-dopa/carbidopa therapy. Thus, the family pursued further\ndiagnostic workup including cerebrospinal fluid neurotransmitter metabolite, pterin, and\nfolate studies. Levels of homovanillic acid (a dopamine metabolite), 5-hydroxyindoleacetic\nacid (a serotonin metabolite), and tetrahydrobiopterin levels in the cerebrospinal fluid\nwere low. He was begun on treatment with l-dopa/carbidopa, and parents reported\nincreased alertness, a reduction in abnormal limb and trunk posturing, improved use of his\nhands, reduced arching, and improved visual tracking. He was referred to our institution\nfor further evaluation at 5 years of age. Although he appeared bright and attentive, he\nwas unable to speak due to bulbar involvement; he had severe axial hypotonia, fluctuating\nlimb hypertonia, and dystonic posturing and brisk deep tendon reflexes. However, he had no\nnystagmus. A cytokine-stimulated fibroblast assay demonstrated impaired\ntetrahydrobiopterin biosynthesis thought to be consistent with GTP cyclohydrolase 1\ndeficiency. However, Sanger sequencing and Multiplex Ligation-dependent Probe\nAmplification analysis of the GTP cyclohydrolase 1 gene did not reveal\nmutations. Despite an initial response to l-dopa/carbidopa therapy, over the\nensuing years, his symptoms progressed. By age 9, he began manifesting painful\nopisthotonic crises (Figure 2A).\nHe also developed a persistent postural deformity associated with progressive\nkyphoscoliosis and lumbar lordosis (Figure 2B). At 11 years of age, he died in his sleep following an episode of\npneumonia and was found with his neck hyperextended.\n\nFigure 2. A, Family A proband II-2 in opisthotonic crisis. B, Family A proband II-2 showing\npersistent postural deformity associated with progressive kyphoscoliosis and lumbar\nlordosis. C, Family A affected brother II-3 showing axial hypotonia, significant\ndystonia, and lower limb spasticity.\n\nHis brother, II-3, was born at 39 weeks following an unremarkable pregnancy and vaginal\ndelivery, with a birth weight of 8 lbs 1 oz and Apgar scores of 71 and 10.5 He first manifested abnormal eye movements at 2 weeks of age and had poor suck,\nhead control, and gross motor delays comparable to his brother. Brain MRI at 7 months of\nage noted possible hypoplasia of the anterior lobe of the pituitary and optic chiasm, but\nwas otherwise deemed unremarkable. At almost 4 years of age, he had severe motor\ndevelopmental delay, axial hypotonia, poor head control, significant dystonia, and lower\nlimb spasticity (Figure 2C). A\nlumbar puncture revealed low cerebrospinal fluid homovanillic acid, 5-hydroxyindoleacetic\nacid, and pterin abnormalities. He demonstrated a modest improvement in generalized\ndystonia with treatment with l-dopa/carbidopa. At the age of 10 years, we pursued\nfurther diagnostic evaluation, as the clinical features and evident progression of\nsymptoms were not consistent with GTP cyclohydrolase 1 deficiency. Cytokine-stimulated\nfibroblast culture failed to confirm a defect in tetrahydrobiopterin biosynthesis, in\ncontrast to his brother’s result. A brain MRI revealed diffuse signal intensity throughout\nthe central nervous system myelin and generalized cortical atrophy consistent with a\nleukodystrophy. He remains unable to speak, sit unsupported, or roll and has developed\nprogressive spasticity over time.\n\nFamily history was notable for a maternal aunt with intellectual disability and a\npossible mild gait disorder; she had been born a twin, and the maternal grandmother\nreported that she had been told her daughter had “arrested hydrocephalus.” No records or\nneuroimaging studies dating back to infancy or childhood were available for review.\nHowever, the family arranged for her to undergo a lumbar puncture for cerebrospinal fluid\nanalysis. Her studies, in contrast to her nephews, did not reveal evident abnormalities in\ncerebrospinal fluid dopamine, serotonin, or pterin metabolites. The boy’s mother denied\nany symptoms, was of normal intelligence, and her neurologic examination was\nunremarkable.\n\nTo further elucidate the genetic basis of these neurological symptoms in the 2 affected\nmale siblings, whole-genome sequencing was performed for 5 family members (Figure 1A). Based on the family A\npedigree, X-linked and autosomal recessive inheritance patterns were considered most\nlikely, and data were analyzed as described in Materials and Methods. Based on this\nanalysis, a missense mutation in the PLP1 gene appeared to be the best\ncandidate for the causal gene within the family, particularly since mutations, gene\nduplications, and deletions in PLP1 are associated with several of the\nfeatures noted in our patients, including dystonia, spasticity, abnormal eye movements,\nand leukodystrophy.\n\nThe identified PLP1 missense mutation c.617T>A (NM_000533, p.M206K)\nis found at genomic position chrX:103,042,890 (NC_000023.10, human reference genome\nGRCh37). This PLP1 mutation is found within exon 4; hence, the mutation\nis present in both PLP1 and the alternatively spliced PLP1 isoform, DM20. The presence and\nthe segregation of this mutation with disease in the family were confirmed by Sanger\nsequencing (Figure 1C). This\nmutation was not found in several human mutation databases: NCBI dbSNP database (build 151),18 1000 Genomes,19 Exome Sequencing Project,20 gnomAD,21 ClinVar,22 or Human Gene Mutation Database Professional 2018.123; so it appears to be novel. Of note, an adjacent, extremely rare variant\nc.618G>A (chrX:103,042,891, NM_000533, p.M206I) was present in the gnomAD database at 1\nallele in 178,486 alleles tested. This c.618G>A variant was found in a hemizygous\nsample, but associated clinical information was not available. Several mutations of known\npathogenicity for Pelizaeus-Merzbacher disease have been reported in the literature and in\nHuman Gene Mutation Database flanking either side of the novel p.M206K mutation (Figure 1D).10,11,24–26 Although the PLP1 protein is 100% conserved between mice and humans,27 for some more divergent species, the amino acid at position 206 is glutamine (eg, Q\nin zebrafish PLP1a; Figure 1D).\nEven so, lysine (K) was not seen in these multiple sequence alignments at amino acid\nresidue 206.\n\nFamily B\nThe proband, II-1, was born at term to unrelated parents of European Caucasian heritage\nfollowing an unremarkable gestation and vaginal delivery. Parents became concerned when he\nfailed to achieve independent sitting by 8 months of age. When first examined at 11 ½\nmonths of age, he was diffusely hypotonic, unwilling to bear weight on his lower\nextremities, unable to sit independently, or crawl. He had preserved deep tendon reflexes\nbut hypotonic lower extremities. An electromyogram and nerve conduction study revealed\nevidence of chronic and ongoing denervation in the lower extremities, suggesting a\npossible motor neuron disorder. A muscle biopsy showed “subtle myopathic features”. By 2 ½\nyears of age, he had speech delay and had developed significant lower extremity\nspasticity. A brain MRI at 24 months of age was reported as normal. Additional metabolic\nscreening was performed including cerebrospinal fluid quantitative amino acids and\nneurotransmitter and pterin metabolites; methyltetrahydrofolate, glucose, protein, and\ncell count; serum creatinine kinase, leukocyte lysosomal enzymes, thin layer\nchromatography for mucopolysaccharides, and urine organic acids; all of which were\nunremarkable. A tentative diagnosis of hereditary spastic paraparesis was made, but no\nfurther genetic testing pursued at that time. Subsequently, spasticity and weakness\ncontinued to progress and he developed ataxia and was manifesting more obvious significant\ncognitive impairment and slow speech. He had undergone more than 16 tendon releases and/or\ntransfers. At age 5 years, he could speak in sentences but was dysarthric. He could\nscribble and knew a few letters of the alphabet; he could eat with a fork or spoon. His\nleg weakness and spasticity had progressed, and he had axial hypotonia, oculomotor\napraxia, increased deep tendon reflexes, but no frank ataxia. He was able to walk on his\ntoes very slowly and with much effort using a walker. Additional workup included a normal\nspine MRI. Brain MRI revealed diffuse signal abnormalities of myelin throughout the\ncentral nervous system, especially the parieto-occipital areas. An inpatient trial of\nintrathecal baclofen resulted in a loss of his ability to ambulate. An electromyography\nrevealed a progressive distally predominant motor axonal neuropathy. He received a\nclinical diagnosis of hereditary spastic paraparesis with motor neuronopathy, but genetic\ntesting was deferred due to the lack of insurance coverage. Follow-up at age 7 years\nindicated some gains in understandable speech, but he was having increasing difficulties\nusing his walker. His trunk was weaker and he had developed an upper extremity tremor. At\n10 years of age, sequencing of SPG11 was negative for mutations. At that\npoint, exome sequencing was recommended.\n\nClinical exome sequencing was performed for all 3 family B members (Figure 1B). Based on the absence of family history of\na similar condition, X-linked and autosomal recessive inheritance as well as de\nnovo mutation were considered for family B. Two blinded, independent analyses\nboth identified an 11 base pair deletion in the PLP1 gene as the top\ncandidate. This conclusion was primarily based on the clear pathogenicity of this variant\n(expected to cause a frameshift in the resulting messenger RNA [mRNA]), the apparent\nde novo nature of the variant in the proband, and phenotypic match to\nthe proband’s symptoms.\n\nThe PLP1 frameshift variant c.359_369delGCCAGAAGGGG (NM_000533,\np.G120fs) is caused by an 11 base pair deletion from chrX:103,041,561 to chrX:103,041,571\n(NC_000023.10). This PLP1 variant is found within exon 3B, which is\nretained in the full length PLP1 transcript, but is spliced out of the shorter DM20\nisoform. Next-generation sequencing analyses demonstrated this variant arose de\nnovo in the proband, as it was not observed in either parent. Sanger sequencing\nof this locus confirmed the next-generation sequencing data (Figure 1E). As this variant was not found in NCBI\ndbSNP database, 1000 Genomes, Exome Sequencing Project, gnomAD, ClinVar, or Human Gene\nMutation Database, it appears to be novel as well as de novo. This\nframeshift deletion is near the location of a previously published pathogenic frameshift\ndeletion c.354_355delAG (presented by Osaka et al. as c.352_353delAG).28 Both frameshift deletions resulted in the same alternate reading frame after amino\nacid residue 124 until a stop codon is reached.\n\nDiscussion\nThe unique clinical features in each of the families reported here contributed to the\ndiagnostic odyssey they experienced, and interestingly, both families were found to have\nmutations in the well-described PLP1 gene. The diagnostic odyssey was\ncompounded by features in each proband that delayed the proper diagnosis by several years,\nbecause the phenotypes have not been reported previously in patients with\nPLP1 mutations. In family A, the normal brain myelination led clinicians\nto discount Pelizaeus-Merzbacher disease and subsequently the abnormal cerebrospinal fluid\nneurotransmitter and biopterin studies supporting a putatively reasonable alternative\ndiagnosis of GTP cyclohydrolase 1 deficiency. In family B, the diagnosis of motor\nneuronopathy in infancy, which manifested well prior to the spastic paraparesis, was the\nprimary factor delaying diagnosis. This was confounded further by the lack of insurance\ncoverage early on for diagnostic confirmation of the suspected clinical diagnosis of a\nvariant of hereditary spastic paraparesis with motor neuronopathy. These cases markedly\nillustrate how increased access to exome and genome sequencing continues to transform\nclinical diagnosis and care for children with complex neurologic phenotypes.\n\nThe PLP1 protein is the predominant myelin protein present in the central nervous system\nand it plays a role in the stabilization and maintenance of myelin sheaths, as well as in\noligodendrocyte development and axonal survival. Mutations in PLP1 cause\nthe X-linked disorders: Spastic Paraplegia type 2, PLP1 null syndrome, and\nPelizaeus-Merzbacher disease.8–11,26 These disorders present with varying severity but include symptoms of spasticity,\nhypotonia, and motor delay. Other symptoms may include nystagmus, dystonic posturing,\nataxia, intellectual disability, absent or dysarthric speech, and impaired ambulation.\nPeripheral nervous system myelin may be affected, causing symptoms suggestive of spinal\nmuscular atrophy.\n\nThe PLP1 locus also encodes a splice isoform called DM20, which lacks exon\n3B in the mature transcript.29 Both PLP1 and DM20 proteins are major components of myelin. PLP1 is the predominant\npostnatal expressed isoform, but DM20 isoform plays a key role in the formation of myelin in\nthe prenatal period. PLP1 is 276 amino acids long, and the DM20 isoform lacks 35 amino acids\nencoded by PLP1 exon 3B. Nonsense mutations within exon 3B affect only the\nfull length PLP1 isoform and have been reported in milder forms of Pelizaeus-Merzbacher disease.10,28 However, missense mutations that affect both isoforms of the protein (PLP1 and DM20)\ntend to result in more severe phenotypes. In either case, the course of the disease can be\nheterogeneous.\n\nThe family A missense mutation, p.M206K, is found in both protein isoforms (DM20 and PLP1).\nPLP1 is highly conserved among mammalian species, with 100% identity at the amino acid level\nbetween humans, rats, and mice.27 Changes in the more conserved amino acids across species lead to more severe disease.10 The PLP1 amino acid 206 is conserved across many species including the zebra-fish PLP\n1b protein, which has only 51% overall identity to the human PLP1 protein. The family A\nmutation is found in the C-D extracellular loop of the protein, where many\nPelizaeus-Merzbacher disease-causative mutations are located.10 Also many known Pelizaeus-Merzbacher disease mutations are adjacent to PLP1 amino\nacid 206, at amino acids 203, 205, and 207.10,11,24–26\n\n\nFamily B has a de novo frameshift mutation (c.359_369del; p. Gly120fs).\nThis mutation deletes 11 nucleotides from the coding region of the PLP1\ngene, resulting in a shift in the reading frame of the mRNA starting at codon 120. The\nc.359_369del mutation is located in exon 3B and is therefore present only in the PLP1\nisoform and not in the DM20 isoform, which lacks exon 3B. Considering the available clinical\nevidence and a pathogenic deletion causing a PLP1 frameshift at a similar location,28 this identified mutation in the PLP1 gene is predicted to be\ncausative for the patient’s clinical findings.\n\nIn the 2 cases presented in this report, genome or exome sequencing enabled a specific\nclinical diagnosis where traditional diagnostic and clinical practices had not. Although\nphenotypic heterogeneity is a well-known entity for certain genetic diseases, the\napplication of exome and genome sequencing is expanding our understanding of phenotypic\nheterogeneity in a broader spectrum of disorders. The lack of obvious abnormalities in\ncentral nervous system myelin on the initial neuroimaging studies contributed to the delay\nin diagnosis; in the affected child in family B, the brain MRI was reported as normal, but\nthe digital images were not reviewed. Family A had 2 affected male siblings who presented\nwith infantile onset dystonia in association with abnormalities in cerebrospinal fluid\nneurotransmitter and biopterin metabolites, with delayed onset of progressive central\nnervous system demyelination, spasticity, and premature death in 1 of the 2 boys. Family B\nhad an affected boy who presented in infancy with hypotonia and delayed motor development in\nassociation with a motor neuronopathy, only later to manifest progressive spastic\nparaparesis, ataxia, cognitive impairment, and leukodystrophy. Although all 3 boys\nultimately manifested abnormalities of central nervous system myelin on neuroimaging\nstudies, the delayed appearance of abnormalities until after 2 years of age contributed to\ndiagnostic confusion. Both families in this report had endured more than a decade without\nanswers prior to the identification of the novel PLP1 mutations discovered by\nnext-generation sequencing technologies. Thus, genomic studies proved extremely useful in\nproviding a diagnosis for these families.\n\nAcknowledgments\nThe authors thank the families for participating in this study. The authors thank K.\nMallempati for Sanger sequencing the family members.\n\nAuthor Contributions: RM contributed to design, contributed to acquisition, analysis, and interpretation,\ndrafted the manuscript, and gave final approval; JD contributed to analysis, critically\nrevised the manuscript, and gave final approval; BK contributed to conception, contributed\nto analysis, critically revised the manuscript, and gave final approval; TN contributed to\nacquisition, critically revised the manuscript, and gave final approval; JB contributed to\nacquisition and interpretation, critically revised the manuscript, and gave final\napproval; KV contributed to conception, contributed to interpretation, critically revised\nthe manuscript, and gave final approval; P B-T contributed to conception, contributed to\ninterpretation, critically revised the manuscript, and gave final approval; RL contributed\nto acquisition and interpretation, critically revised the manuscript, and gave final\napproval; KJS contributed to conception and design, contributed to acquisition, analysis,\nand interpretation, drafted the manuscript, critically revised the manuscript, and gave\nfinal approval. All authors agree to be accountable for all aspects of work ensuring\nintegrity and accuracy.\n\nDeclaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research,\nauthorship, and/or publication of this article.\n\nFunding: The authors disclosed receipt of the following financial support for the research,\nauthorship, and/or publication of this article: This work was supported by the European\nLeukodystrophy Association and NIH grant DP2 MH100008. Additional funding was generously\ndonated to KJS to the Pediatric Motor Disorders Research Fund, University of Utah\nDepartment of Neurology.\n\nEthical Approval: Patients and their family members were consented under the University of Utah\ninstitutional review board protocol #25651.\n==== Refs\nReferences\n1 \nBainbridge MN Wiszniewski W Murdock DR \nWhole-genome sequencing for optimized patient\nmanagement . 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"fulltext_license": "CC BY-NC",
"issn_linking": "2329-048X",
"issue": "5()",
"journal": "Child neurology open",
"keywords": "PLP1; PMD; Pelizaeus-Merzbacher disease; SPG2; brain; developmental delay; dystonia; genetics; leukodystrophy; mutation; next-generation sequencing; proteolipid protein 1; spastic paraplegia type 2; spasticity",
"medline_ta": "Child Neurol Open",
"mesh_terms": null,
"nlm_unique_id": "101691975",
"other_id": null,
"pages": "2329048X18789282",
"pmc": null,
"pmid": "30046645",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
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"title": "Novel PLP1 Mutations Identified With Next-Generation Sequencing Expand the Spectrum of PLP1-Associated Leukodystrophy Clinical Phenotypes.",
"title_normalized": "novel plp1 mutations identified with next generation sequencing expand the spectrum of plp1 associated leukodystrophy clinical phenotypes"
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"abstract": "Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor indicated for treatment of patients with chronic hepatitis B virus (CHB) and human immunodeficiency virus (HIV) infections. Despite the good safety profile of the drug, Fanconi syndrome is a possible adverse reaction of TDF treatment, especially in HIV-infected patients. Only a few cases have been reported in patients with CHB-monoinfections. This report presents a case of a 58-year-old man with mild HBeAg-negative CHB who was exposed to TDF and developed drug-induced Fanconi syndrome. Renal dysfunction reverted after TDF discontinuation and a switch to entecavir, and viral replication remained suppressed. A literature review yielded six additional cases of TDF-induced Fanconi syndrome, all with risk factors for renal dysfunction despite the patients having normal glomerular filtration rates. We discuss the overall risk for Fanconi syndrome in CHB-monoinfected patients exposed to TDF and the importance of careful monitoring of glomerular and tubular functions even when pre-existing kidney disease is not present.",
"affiliations": "Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy.;Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy.;Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy.;Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy.;Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy.",
"authors": "Conti|Fabio|F|;Vitale|Giovanni|G|;Cursaro|Carmela|C|;Bernardi|Mauro|M|;Andreone|Pietro|P|",
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"abstract": "The incidence of Dressler's syndrome after myocardial infarction (MI) has decreased in the reperfusion therapy era. Although guidelines recommend high-dose aspirin for treatment based on evidence from the pre-percutaneous coronary intervention (pre-PCI) era, bleeding and thrombotic concerns occurred upon aspirin administration after coronary stenting. A 69-year-old man with recent MI was admitted to our hospital. The patient presented with chest pain 1 week before admission. Electrocardiography revealed newly detected atrial fibrillation with no ST segment change. Urgent coronary angiography demonstrated a left circumflex artery occlusion. He underwent PCI, and a sirolimus-eluting stent was deployed. Aspirin, prasugrel, and apixaban were administered. However, hospital discharge was delayed because he developed heart failure during hospitalization. Twenty-three days after admission, he developed a fever of >39 °C. Electrocardiography showed anterior ST segment elevation, and echocardiography revealed a 6-mm pericardial effusion. We diagnosed the patient with Dressler's syndrome, and colchicine 0.5 mg/day + acetaminophen 2000 mg/day were administered. His condition clinically improved after treatment and he was discharged 32 days after admission. There was hesitation about administration of high-dose aspirin in a patient who has undergone recent coronary stenting. Combination therapy of colchicine and acetaminophen could be a treatment option for Dressler's syndrome. <Learning objective: Guidelines recommend high-dose aspirin for the treatment of Dressler's syndrome based on evidence from the pre-percutaneous coronary intervention (pre-PCI) era. However, bleeding and thrombotic concerns are present upon high-dose aspirin administration in patients who have undergone PCI. Therefore, a combination therapy of low-dose colchicine and acetaminophen could be a treatment option for patients with Dressler's syndrome who have undergone recent coronary stenting.>.",
"affiliations": "Department of Cardiovascular Medicine, Minaminagano Medical Center, Shinonoi General Hospital, Nagano, Japan.;Department of Cardiovascular Medicine, Minaminagano Medical Center, Shinonoi General Hospital, Nagano, Japan.;Department of Cardiovascular Medicine, Minaminagano Medical Center, Shinonoi General Hospital, Nagano, Japan.;Department of Cardiovascular Medicine, Minaminagano Medical Center, Shinonoi General Hospital, Nagano, Japan.;Department of Cardiovascular Medicine, Minaminagano Medical Center, Shinonoi General Hospital, Nagano, Japan.;Department of Cardiovascular Medicine, Minaminagano Medical Center, Shinonoi General Hospital, Nagano, Japan.;Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Cardiovascular Medicine, Minaminagano Medical Center, Shinonoi General Hospital, Nagano, Japan.;Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan.",
"authors": "Nomoto|Fumika|F|;Suzuki|Sho|S|;Hashizume|Naoto|N|;Kanzaki|Yusuke|Y|;Maruyama|Takuya|T|;Kozuka|Ayako|A|;Saigusa|Tatsuya|T|;Ebisawa|Soichiro|S|;Okada|Ayako|A|;Motoki|Hirohiko|H|;Yahikozawa|Kumiko|K|;Kuwahara|Koichiro|K|",
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"fulltext": "\n==== Front\nJ Cardiol Cases\nJ Cardiol Cases\nJournal of Cardiology Cases\n1878-5409\nJapanese College of Cardiology\n\nS1878-5409(20)30146-8\n10.1016/j.jccase.2020.10.019\nCase Report\nA case of Dressler’s syndrome successfully treated with colchicine and acetaminophen\nNomoto Fumika MD a\nSuzuki Sho MD jersey0042@gmail.com\na⁎\nHashizume Naoto MD a\nKanzaki Yusuke MD a\nMaruyama Takuya MD a\nKozuka Ayako MD a\nSaigusa Tatsuya MD b\nEbisawa Soichiro MD b\nOkada Ayako MD b\nMotoki Hirohiko MD b\nYahikozawa Kumiko MD a\nKuwahara Koichiro MD, FJCC b\na Department of Cardiovascular Medicine, Minaminagano Medical Center, Shinonoi General Hospital, Nagano, Japan\nb Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan\n⁎ Corresponding author at: Department of Cardiovascular Medicine, Minaminagano Medical Center, Shinonoi General Hospital, Ai 666-1, Shinonoi, Nagano 388-8004, Japan. jersey0042@gmail.com\n21 11 2020\n3 2021\n21 11 2020\n23 3 131135\n10 4 2020\n18 9 2020\n3 10 2020\n© 2020 Japanese College of Cardiology. Published by Elsevier Ltd.\n2020\nJapanese College of Cardiology\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nThe incidence of Dressler’s syndrome after myocardial infarction (MI) has decreased in the reperfusion therapy era. Although guidelines recommend high-dose aspirin for treatment based on evidence from the pre-percutaneous coronary intervention (pre-PCI) era, bleeding and thrombotic concerns occurred upon aspirin administration after coronary stenting. A 69-year-old man with recent MI was admitted to our hospital. The patient presented with chest pain 1 week before admission. Electrocardiography revealed newly detected atrial fibrillation with no ST segment change. Urgent coronary angiography demonstrated a left circumflex artery occlusion. He underwent PCI, and a sirolimus-eluting stent was deployed. Aspirin, prasugrel, and apixaban were administered. However, hospital discharge was delayed because he developed heart failure during hospitalization. Twenty-three days after admission, he developed a fever of >39 °C. Electrocardiography showed anterior ST segment elevation, and echocardiography revealed a 6-mm pericardial effusion. We diagnosed the patient with Dressler’s syndrome, and colchicine 0.5 mg/day + acetaminophen 2000 mg/day were administered. His condition clinically improved after treatment and he was discharged 32 days after admission. There was hesitation about administration of high-dose aspirin in a patient who has undergone recent coronary stenting. Combination therapy of colchicine and acetaminophen could be a treatment option for Dressler’s syndrome.\n\n<Learning objective: Guidelines recommend high-dose aspirin for the treatment of Dressler’s syndrome based on evidence from the pre-percutaneous coronary intervention (pre-PCI) era. However, bleeding and thrombotic concerns are present upon high-dose aspirin administration in patients who have undergone PCI. Therefore, a combination therapy of low-dose colchicine and acetaminophen could be a treatment option for patients with Dressler’s syndrome who have undergone recent coronary stenting.>\n\nKeywords\n\nDressler’s syndrome\nAcute pericarditis\nColchicine\nRecent myocardial infarction\n==== Body\nIntroduction\n\nThe incidence of Dressler’s syndrome has decreased owing to reperfusion therapy. It can now be experienced only in patients with recent myocardial infarction (MI) who have not undergone primary percutaneous coronary intervention (PCI). Although guidelines recommend high-dose aspirin administration for the treatment of Dressler’s syndrome [1], [2], [3], the background evidence for these recommendations was amassed in the pre-PCI era. Although coronary stenting has become a standard therapy against MI, bleeding and thrombotic concerns on high-dose aspirin administration have occurred in the modern era. Herein, we present a case of Dressler’s syndrome successfully treated with colchicine and acetaminophen.\n\nCase report\n\nA 69-year-old man with no prior medical history visited a clinic for persistent chest discomfort. He presented with severe chest pain 1 week before admission; he was subsequently referred to our hospital for suspected acute coronary syndrome. On physical examination, the patient was afebrile with an irregular pulse of 108 beats/min and a blood pressure of 98/69 mmHg. The oxygen saturation was 98% on room air. No heart murmurs or edema were noted. Electrocardiography revealed newly detected atrial fibrillation with no ST segment change (Fig. 1A). Moreover, echocardiography showed inferior-lateral wall asynergy, with mild mitral valve regurgitation and no pericardial effusion (Fig. 2A). Left ventricular contraction was preserved, with an ejection fraction of 50%. Laboratory tests showed an elevation of myocardial and liver enzymes and signs of heart failure as follows: white blood cell count, 11,000 cells/μL (neutrophils, 69%; eosinophils, 0.5%); C-reactive protein, 14.3 mg/dL; creatinine kinase (CK), 197 U/L; CK-muscle/brain, 7 U/L; troponin I, 4.4 ng/mL; B-type natriuretic peptide, 357 pg/mL; aspartate transaminase, 81 U/L; alanine aminotransferase, 77 U/L; and total bilirubin level, 2.1 mg/dL. Chest radiography revealed mild left pleural effusion with no congestion. Urgent coronary angiography demonstrated a middle left circumflex artery occlusion (Online Fig. S1). The patient underwent PCI, and a sirolimus-eluting stent was successfully deployed. The levels of myocardial enzymes were monitored by laboratory tests every 4 h after admission, although no CK elevation was noted. Considering the clinical course and results from the examinations, we diagnosed the patient with recent MI, which developed 1 week before admission. We administered aspirin 100 mg/day, prasugrel 3.75 mg/day, and apixaban 10 mg/day as antithrombotic therapy. Hospital discharge was delayed because of worsening heart failure. Considering the high bleeding risk, we reduced antiplatelet drugs to clopidogrel 75 mg/day (single antiplatelet therapy) on post-admission day 14. On post-admission day 23, the patient developed a fever of 39.6 °C and experienced a left lateral chest pain. Pericardial friction rub was audible on auscultation with the forward leaning position. Widespread ST segment elevation and PR segment depression were demonstrated in the electrocardiogram (Fig. 1B). No signs of infection or acute coronary syndrome were detected after performing laboratory tests, urinary test, computed tomography, echocardiography, and coronary angiography. The eosinophil count increased to 5.1% (291 cells/μL) in the laboratory test, and echocardiography revealed a newly detected pericardial effusion of 6 mm (Fig. 2B). We diagnosed the patient as having Dressler’s syndrome and administered colchicine and acetaminophen at 0.5 and 2000 mg/day, respectively. His physical signs and laboratory data improved within several days, and he was discharged on post-admission day 32 (Online Fig. S2).Fig. 1 Electrocardiography on admission (A), day 23 (B), and 3 (C) and 6 (D) months after discharge.\n\nFig. 1\n\nFig. 2 Echocardiography on admission (A), day 23 (B), and 3 (C) and 6 (D) months after discharge. The yellow arrowhead indicates the pericardial effusion.\n\nFig. 2\n\nThree months later, his widespread ST segment elevation had returned to normal (Fig. 1C), and his pericardial effusion had improved (Fig. 2C). Colchicine 0.5 mg/day was continued without any side effects for 6 months, with no recurrence in symptoms noted or examinations repeated (Figs. 1D, 2D).\n\nDiscussion\n\nWe report a patient with Dressler’s syndrome successfully treated with colchicine and acetaminophen. Dressler’s syndrome, which is a secondary form of pericarditis that is typically demonstrated weeks to months after MI, is presumed to be mediated by an autoimmune mechanism [2]. The incidence of this syndrome has remarkably decreased in the reperfusion therapy era and is reported as only 0.1% in patients with acute MI [4].\n\nHigh-dose aspirin administration (2000–4000 mg/day) is recommended as class I therapy in guidelines [1], [2], [3], and administration of other non-steroidal anti-inflammatory drugs should be avoided because they may impair scar formation [5] or diminish coronary blood flow [6]. Corticosteroids are suggested as a second option because of the risk of favoring the chronic evolution of the disease and promoting drug dependence [1]. However, the background evidence for these recommendations was amassed in the pre-PCI era, and there is no established treatment after primary PCI has become a standard therapy. Fig. 3 shows the history of PCI and the evidence of high-dose aspirin administration against Dressler’s syndrome over time. Dressler’s syndrome was first reported in 1956. The beneficial effects of aspirin were reported around the 1970s, which was before coronary stenting became a standard therapy in the 1990s. Evidence is lacking after primary PCI has become a standard therapy in MI patients due to the decreased morbidity.Fig. 3 The history of percutaneous coronary intervention and the evidence of high-dose aspirin administration against Dressler’s syndrome over time.\n\nFig. 3\n\nThere are thrombotic and bleeding concerns in the administration of high-dose aspirin in patients who underwent recent coronary stenting or those who take other antithrombotic drugs. High-dose aspirin may have a different antithrombotic effect compared with the low dose, a complex mechanism known as the aspirin dilemma. Aspirin inhibits two major mechanisms to obtain antithrombotic effects: platelet thromboxane-A2 production and cyclooxygenase enzyme in the vascular endothelium [7]. The antithrombotic effect differs according to the aspirin dose. While lower doses inhibit the endothelial cyclooxygenase activity mildly, higher doses can achieve the inhibition more completely and rapidly, which may weaken the antithrombotic effect [7]. Aspirin dilemma is a mechanism that occurs with high-dose aspirin and might have thrombotic concerns compared with the low dose. Therefore, we decided to continue clopidogrel and apixaban as antithrombotic therapy instead of prescribing high-dose aspirin. As atrial fibrillation was not observed after successful reperfusion therapy, there was an option to stop anticoagulants (i.e. apixaban). However, since the patient had developed heart failure during hospitalization, his CHA2DS2-VASc score was 3 points (age ≥65 years, heart failure, and vascular disease). Considering the result from the Canadian Registry of Atrial Fibrillation study that approximately half of all newly detected atrial fibrillations would recur [8], we chose to continue anticoagulants in this patient.\n\nColchicine is an anti-inflammatory medication that targets the white blood cells and causes microtubule depolymerization, which in turn causes motility, phagocytosis, and degranulation. It also inhibits interleukin-1 beta and interleukin-18 by interfering with the NLRP3 inflammasome protein complex, which is increasingly recognized to have a role in acute coronary syndrome. In addition to the fact that colchicine is an inexpensive drug with only a few reports of serious side effects, it may reduce adverse cardiovascular events [9] or recurrent pericarditis [1]. Under these circumstances, we suggest that colchicine administration could be a treatment option for Dressler’s syndrome.\n\nAlthough the pathogenesis of early post-infarction pericarditis (typically a few days after acute MI) is believed to be different from that of Dressler’s syndrome, combination therapy of high-dose aspirin and colchicine is recommended for treatment. Colchicine is already reported as a useful agent for acute pericarditis to improve remission rates in the acute phase and reduce recurrence rates in the chronic phase [10]. From these reports, combination therapy of colchicine and acetaminophen can be one of the treatment options for acute pericarditis in patients with an indeterminate response to high-dose aspirin administration.\n\nIn the present case, there was hesitation about high-dose aspirin administration because the patient had undergone recent coronary stenting, and clopidogrel + apixaban were already prescribed. We successfully treated the patient with low-dose colchicine and acetaminophen without any side effects. Considering the risk of aspirin dilemma and the reported beneficial effect against recent MI, combination therapy of colchicine and acetaminophen could be a treatment option for patients with Dressler’s syndrome who underwent recent coronary stenting. The pharmacological mechanism of aspirin dilemma remains unclear and further research is necessary. As a limitation of this case report, the use of colchicine for Dressler’s syndrome is not covered by insurance in Japan, and careful informed consent is necessary upon prescription. Furthermore, although guidelines recommend continuing colchicine for 3–6 months [3], it remains unclear when to stop the therapy. In our case, we stopped prescribing colchicine after 6 months from discharge.\n\nIn conclusion, we experienced a case of Dressler’s syndrome that developed during hospitalization. There was hesitation about the administration of high-dose aspirin in a patient who has undergone recent coronary stenting due to thrombotic and bleeding concerns. Combination therapy of colchicine and acetaminophen could be a treatment option for patients with Dressler’s syndrome who underwent recent coronary stenting.\n\nConflict of interest\n\nThe authors declare that there is no conflict of interest.\n\nAppendix A Supplementary data\n\nThe following are Supplementary data to this article:Fig. S1\n\nCoronary angiography. (A) The right coronary artery is normal (left anterior oblique 45° view). (B) A middle left circumflex artery occlusion is revealed (right anterior oblique caudal view, yellow arrowhead). (C) The patient underwent urgent percutaneous coronary intervention, and reperfusion was achieved.\n\nFig. S2\n\nA chart showing the serial change of body temperature, white blood cell count (WBC), and C-reactive protein (CRP) after developing Dressler’s syndrome.\n\nAcknowledgment\n\nNone.\n\nAppendix A Supplementary material related to this article can be found, in the online version, at https://doi.org/10.1016/j.jccase.2020.10.019.\n==== Refs\nReferences\n\n1 Adler Y. Charron P. Imazio M. Badano L. Barón-Esquivias G. Bogaert J. ESC guidelines for the diagnosis and management of pericardial diseases: the Task Force for the diagnosis and management of pericardial diseases of the European Society of Cardiology (ESC) endorsed by: the European Association for Cardio-Thoracic Surgery (EACTS) Eur Heart J 36 2015 2921 2964 26320112\n2 Little W.C. Freeman G.L. Pericardial disease Circulation 113 2006 1622 1632 16567581\n3 Ibanez B. James S. Agewall S. Antunes M.J. Bucciarelli-Ducci C. Bueno H. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC) Eur Heart J 39 2018 119 177 28886621\n4 Imazio M. Negro A. Belli R. Beqaraj F. Forno D. Giammaria M. Frequency and prognostic significance of pericarditis following acute myocardial infarction treated by primary percutaneous coronary intervention Am J Cardiol 103 2009 1525 1529 19463510\n5 Jugdutt B.I. Basualdo C.A. Myocardial infarct expansion during indomethacin or ibuprofen therapy for symptomatic post infarction pericarditis. Influence of other pharmacologic agents during early remodelling Can J Cardiol 5 1989 211 221 2567203\n6 Schifferdecker B. Spodick D.H. Nonsteroidal anti-inflammatory drugs in the treatment of pericarditis Cardiol Rev 11 2003 211 217 12852799\n7 Ozturk O. Greaves M. Templeton A. Aspirin dilemma. Remodeling the hypothesis from a fertility perspective Hum Reprod 17 2002 1146 1148 11980730\n8 Humphries K.H. Kerr C.R. Connolly S.J. Klein G. Boone J.A. Green M. New-onset atrial fibrillation: sex differences in presentation, treatment, and outcome Circulation 103 2001 2365 2370 11352885\n9 Tardif J.C. Kouz S. Waters D.D. Bertrand O.F. Diaz R. Maggioni A.P. Efficacy and safety of low-dose colchicine after myocardial infarction N Engl J Med 381 2019 2497 2505 31733140\n10 Massimo I. Fiorenzo G. Martin L. Evaluation and treatment of pericarditis: a systematic review JAMA 314 2015 1498 1506 26461998\n\n",
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"abstract": "The incidence of pancreatic cancer is increasing. Most patients have advanced disease at diagnosis, and therapeutics is limited in this setting. Gemcitabine and nab-paclitaxel combination is indicated as first-line treatment in patients with metastatic cancer of pancreas. The most common adverse events of Grade 3 or higher gemcitabine and nab-paclitaxel combination are neutropenia, fatigue and neuropathy. In this report, we describe a rare case of organizing pneumonia associated with the use of nab-paclitaxel and gemcitabine in metastatic pancreatic cancer. A 68-year-old female underwent total splenopancreatectomy for ductal adenocarcinoma of the neck of the pancreas, followed by adjuvant chemoradiation therapy. Afterwards she relapsed and received first-line chemotherapy with gemcitabine plus nab-paclitaxel combination for 12 cycles. Following the administration of the 12th cycle of gemcitabine plus nab-paclitaxel, the patient experienced low-grade pyrexia, effort dyspnoea, persistent non-productive cough and malaise. High-resolution CT scan of chest revealed new-onset bilateral peripheral ground-glass opacities, smooth interlobular septal thickening and patchy subpleural consolidation areas, findings consistent with organizing pneumonia. A thorough microbiological workup was negative. Treatment with steroids resulted in prompt clinical and radiological improvement. Organizing pneumonia closely mimics infection or progressive disease and can be difficult to diagnose in the setting of malignancy. Correct diagnosis is of primary importance since delay in treatment can result in significantly adverse patient outcomes.",
"affiliations": "Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy.;Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy.;Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy.;Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy.;Department of Radiology, Sant'Orsola-Malpighi Hospital, Bologna, Italy.;Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy.;Department of Medical and Surgical Sciences, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy.;Department of Medical and Surgical Sciences, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy.;Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy.",
"authors": "Comito|Francesca|F|;Grassi|Elisa|E|;Poerio|Antonio|A|;Freier|Eva|E|;Calculli|Lucia|L|;Zompatori|Maurizio|M|;Ricci|Claudio|C|;Casadei|Riccardo|R|;Di Marco|Mariacristina|M|",
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"fulltext": "\n==== Front\nBJR Case RepBJR Case RepbjrcrBJR Case Reports2055-7159The British Institute of Radiology. bjrcr.20170008610.1259/bjrcr.20170086Case ReportOrganizing pneumonia after pancreatic cancer treatment with nab-paclitaxel and gemcitabine: a case report Organizing pneumonia after nab-paclitaxel and gemcitanine treatmentComito et alComito Francesca MD1comito.francesca@gmail.comGrassi Elisa MD1elisa.grax@gmail.comPoerio Antonio MD1a.poerio@alice.itFreier Eva MD1eva.freier@gmail.comCalculli Lucia MD2lucia.calculli@aosp.bo.itZompatori Maurizio MD1maurizio.zompatori@unibo.itRicci Claudio MD3claudio.ricci@aosp.bo.itCasadei Riccardo MD, PhD3riccardo.casadei@unibo.itDi Marco Mariacristina MD, PhD1mariacristina.dimarco@unibo.it1 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Sant’Orsola-Malpighi Hospital, Bologna, Italy2 Department of Radiology, Sant’Orsola-Malpighi Hospital, Bologna, Italy3 Department of Medical and Surgical Sciences, University of Bologna, Sant’Orsola-Malpighi Hospital, Bologna, ItalyAddress correspondence to: Dr Francesca Comito. E-mail: comito.francesca@gmail.com2018 05 2 2018 4 2 2017008610 8 2017 27 12 2017 29 11 2017 04 1 2018 © 2018 The Authors. Published by the British Institute of Radiology.2018The Authors.This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 Unported License, which permits unrestricted non-commercial reuse, provided the original author and source are credited.The incidence of pancreatic cancer is increasing. Most patients have advanced disease at diagnosis, and therapeutics is limited in this setting. Gemcitabine and nab-paclitaxel combination is indicated as first-line treatment in patients with metastatic cancer of pancreas. The most common adverse events of Grade 3 or higher gemcitabine and nab-paclitaxel combination are neutropenia, fatigue and neuropathy. In this report, we describe a rare case of organizing pneumonia associated with the use of nab-paclitaxel and gemcitabine in metastatic pancreatic cancer. A 68-year-old female underwent total splenopancreatectomy for ductal adenocarcinoma of the neck of the pancreas, followed by adjuvant chemoradiation therapy. Afterwards she relapsed and received first-line chemotherapy with gemcitabine plus nab-paclitaxel combination for 12 cycles. Following the administration of the 12th cycle of gemcitabine plus nab-paclitaxel, the patient experienced low-grade pyrexia, effort dyspnoea, persistent non-productive cough and malaise. High-resolution CT scan of chest revealed new-onset bilateral peripheral ground-glass opacities, smooth interlobular septal thickening and patchy subpleural consolidation areas, findings consistent with organizing pneumonia. A thorough microbiological workup was negative. Treatment with steroids resulted in prompt clinical and radiological improvement. Organizing pneumonia closely mimics infection or progressive disease and can be difficult to diagnose in the setting of malignancy. Correct diagnosis is of primary importance since delay in treatment can result in significantly adverse patient outcomes.\n==== Body\nBackground\nPancreatic cancer is one of the most challenging human malignancies and ranks as the fourth leading cause of cancer-related mortality in the United States and Europe,1 with a 5-year survival rate of 7 to 8% among all disease stages.2–4 Surgery offers the only curative treatment for pancreatic cancer; however, in the large majority of cases, diagnosis is made at an advanced stage, when patients already have metastases or locoregional extension precluding curative surgical resection.5 Therapeutic options in this setting remain limited. During the past 5 years, two Phase III studies demonstrated that the FOLFIRINOX regimen (oxaliplatin, irinotecan, fluorouracil and leucovorin) and then the gemcitabine plus nab-paclitaxel regimen significantly improve survival in patients with metastatic adenocarcinoma of the pancreas.6, 7 Both regimens are currently considered standards of care for first-line treatment in patients with advanced pancreatic cancer and good general condition [performance status (PS) Eastern Cooperative Oncology Group (ECOG) 0–1 for FOLFIRINOX and PS ECOG 0–2 for gemcitabine plus nab-paclitaxel].\n\nNab-paclitaxel (nanoparticle albumin-bound paclitaxel) is a solvent-free, albumin-coupled formulation of paclitaxel, indicated for the treatment of breast cancer, non-small cell lung cancer (NSCLC) and pancreatic cancer.\n\nGemcitabine is a pyramidine antimetabolite and incorporates its active metabolite into the DNA, resulting in inhibition of DNA synthesis. It is used for the adjuvant and metastatic treatment of a wide variety of malignancies including breast, ovary, pancreas, bladder and NSCLC.\n\nThe most common adverse events of Grade 3 or higher, according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0, gemcitabine and nab-paclitaxel combination are neutropenia, fatigue and neuropathy. The Phase 3 study MPACT reported significantly increased pneumonitis rates with the combination of gemcitabine and nab-paclitaxel compared to gemcitabine alone (4 vs 1%, respectively).7\n\nHere, we present a rare case of organizing pneumonia (OP) following long-term treatment with nab-paclitaxel and gemcitabine for metastatic pancreatic cancer.\n\nCase presentation\nA Caucasian 68-year-old non-smoker female, without a significant medical history except for hypertension and family history of pancreatic cancer, underwent total splenopancreatectomy for ductal adenocarcinoma associated with branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) of the neck of the pancreas. Since May to September 2014 she received adjuvant treatment in another hospital: 3 cycles of weekly gemcitabine (1000 mg m–2) followed by chemoradiation with gemcitabine (50.4 Gy in 28 fr). A thoracoabdominopelvic computer-assisted tomography (TAP-CT) performed in March 2015 showed the presence of cancer recurrence locally, in retroperitoneal lymph nodes and in lungs. A positron emission tomography with 18-fluoro-deoxyglucose was also performed in order to confirm the diagnosis of relapse. Since April 2015 the patient received first-line chemotherapy at our oncology department. We administered gemcitabine plus nab-paclitaxel combination (gemcitabine 1000 mg m–2 and nab-paclitaxel 125 mg m–2 on days 1, 8 and 15 every 4 weeks) for 12 cycles. The CT scans performed every two cycles showed stable disease, while a metabolic response was seen on positron emission tomography with 18-fluoro-deoxyglucose.\n\nFollowing the administration of cycle 12, day 15 of gemcitabine plus nab-paclitaxel, the patient experienced low-grade pyrexia, effort dyspnoea, persistent non-productive cough and malaise. She was empirically treated with a 5-day course of levofloxacin as outpatient, without any beneficial effects, and for the worsening of the symptoms she was eventually hospitalized. On admission, blood examination revealed moderate anaemia (haemoglobin 9.3 g dl−1) and an increased level of C-reactive protein (8.2 mg dl−1), whereas white cell differential count, electrolytes and glucose levels and renal and liver function were within normal limits. A chest X-ray showed diffuse reduction of normal lung lucency, both perihilar and peripherical. High-resolution computed tomography (HRCT) scan showed new-onset bilateral peripheral ground-glass opacities, smooth interlobular septal thickening and patchy subpleural consolidation areas. These findings were consistent with OP (Figure 1).\n\nFigure 1. (a) Coronal and (b) axial images from thorax CT at diagnosis. Bilateral peripheral ground-glass opacities, smooth interlobular septal thickening and patchy subpleural consolidation areas in upper lobes interspersed between known pulmonary metastasis.\n\nBlood cultures were negative, as well as urine was negative for Legionella and Pneumococcal antigens. Serology tests for Mycoplasma, Legionella, cytomegalovirus, Epstein–Barr virus, adenovirus, influenza, parainfluenza and respiratory syncitial virus were negative, as was the Quantiferon-TB gold In-tube. The patient underwent bronchoscopy for bronchoalveolar lavage, and cytopathological and microbiological analyses were negative for infectious causes; the cell findings in bronchoalveolar lavage fluid were total cell count 271,000 ml–1; macrophages 60%; lymphocytes 30%; neutrophils 10%; eosinophils 0%; no neoplastic cells. Chronic medications at diagnosis consisted in pancreatic enzyme supplements, insulin, amlodipine, pantoprazole and furosemide.\n\nSuspecting chemotherapy-induced pneumonitis, nab-paclitaxel and gemcitabine were discontinued; the patient was started on treatment with prednisone 1 mg kg–1 day–1, which led to rapid clinical improvement. HRCT scan performed after 2 months showed disappearance of alveolar infiltrates and complete resolution of consolidation (Figure 2).\n\nFigure 2. (a) Coronal and (b) axial images from thorax CT performed after 2 months of steroid treatment. Complete resolution of the diffuse and bilateral ground-glass opacities and of the consolidation areas, with an increase in the size of the nodules, known as lung metastases.\n\nDiscussion\nOP or bronchiolitis obliterans OP is a known manifestation of drug-induced lung injury. It is a histopathological reaction to a nonspecific inflammatory insult and can occur after exposure to a number of drugs including many antineoplastic agents.8\n\nPatients with OP typically present with a subacute illness of relatively short duration (median, less than 3 months) with low-grade fever and variable degrees of dyspnoea and non-productive cough. HRCT characteristically shows patchy and often migratory consolidation in a subpleural, peribronchial or band-like pattern, commonly associated with ground-glass opacities. Perilobular opacities and reversed halo sign may be helpful in suggesting the diagnosis. In 10–30% of patients, small unilateral or bilateral pleural effusion may occur.9 The radiographic differential diagnosis of OP includes alveolar cell carcinoma, lymphoma, vasculitis, sarcoidosis and infection (particularly tuberculosis or atypical mycobacterial infection). When the consolidation is subpleural, the diagnosis of chronic eosinophilic pneumonia should also be considered.10\n\nThe pathology of OP is inflammatory fibrin filling the alveoli and spreading to the alveolar ducts and terminal bronchioles, with peculiar endoluminal buds of granulation tissue; an interstitial inflammatory infiltrate can be associated with these abnormalities. However, histological diagnosis, in the same way as in other interstitial lung disease, is no longer deemed to be the gold standard. Analysis of all available data in a multidisciplinary meeting should be performed in order to define the settings where biopsy is more informative than HRCT and those where biopsy is not needed.\n\nThe majority of patients recover completely with oral corticosteroids, with the symptoms resolving within days or weeks. However, sporadic reports have identified a subgroup of patients with OP that does not completely resolve in spite of prolonged treatment. Some of these cases show residual or progressive interstitial fibrosis, often with recurrent episodes of OP.9, 10\n\nSome cases of gemcitabine-induced OP have been reported to date (Table 1). Among those, two patients received single-agent gemcitabine treatment for pancreatic cancer, while the other three cases describe OP occurring in patients affected by lung cancer receiving a gemcitabine-containing doublet chemotherapy.11–15 A case of OP has also been described in a patient on treatment with trastuzumab and nab-paclitaxel for metastatic breast cancer, as well as fatal interstitial pneumonitis in a patient with refractory small cell lung cancer after two cycles of single-agent nab-paclitaxel.16, 17\n\nTable 1. Reports of gemcitabine organizing pneumonia\n\nReferences\tPrimary diagnosis\tChemotherapeutic agents\tTreatment(type and dosage)\tOutcomes\t\n Shaib et al11\n\tPancreatic cancer\tGemcitabine alone\tSteroids(not reported)\tClinical and CT improvement\t\n Kawsar et al12\tNon-small cell lung cancer\tCarboplatin, gemcitabine\tSteroids(not reported)\tClinical and CT improvement\t\n Cobo Dols et al13\n\tNon-small cell lung cancer\tDocetaxel, gemcitabine\tSteroids(methylprednisone, 160 mg day−1)\tClinical and CT improvement\t\n Aguiar Bujanda D et al14\tNon-small cell lung cancer\tPaclitaxel, carboplatin, gemcitabine\tSteroids (not reported)\tRapid clinical improvement within 24 h and chest X-ray improvement after 3 weeks\t\n Hiraya et al15\n\tPancreatic cancer\tGemcitabine alone\tSteroids(methylprednisone 500 mg day−1 for 3 days and afterwards tapered off)\tRapid clinical improvement and CT improvement after 3 weeks\t\nGemcitabine is generally a well-tolerated chemotherapeutic agent; however, a wide spectrum of lung toxicities have been reported with its use. Gemcitabine-related pneumonitis has been documented in patients with varied cancers in sites such as lung, ovary, breast, gallbladder and pancreas and is a potentially fatal complication that may cause significant morbidity and, rarely, mortality.18–22 The incidence of gemcitabine-induced pneumonitis has been reported in different studies at rates ranging from 0.06 to 2.15%,23, 24 and several clinical trials report a higher rate of pneumonitis in treatment that combines gemcitabine with other agents such as nab-paclitaxel and erlotinib.7, 25\n\nPaclitaxel is also known to cause pneumonitis with an incidence ranging from 1 to 4%, increasing when paclitaxel is combined with other cytotoxic drugs or radiation therapy.26\n\nWhen considering risk factors of pulmonary toxicity one might hypothesize that combination chemotherapy, pre-existing pulmonary disease such as pulmonary metastatic disease and prior or concurrent radiation therapy play a role.27\n\nRegarding our patient’s risk factors, she did have pulmonary metastases and received combination chemotherapy.\n\nPatients receiving antineoplastic treatment who develop new respiratory symptoms or have abnormal chest radiographs are frequently encountered. Typically, the first concern is either progressive disease or an infectious process. These conditions are not easily differentiated on the basis of clinical presentation and radiographic findings. Moreover, as patients usually receive multiple antineoplastic agents, it is usually problematic to identify the culprit agent. Regardless of these difficulties, clinicians should consider this diagnosis when evaluating a patient receiving chemotherapeutic agents with a new pulmonary process. Discontinuation of the implicated causative agent and treatment with systemic corticosteroids may result in an excellent outcome.\n\nTo our knowledge, this is a rare case report of OP in a patient treated with gemcitabine and nab-paclitaxel for pancreatic cancer. This case report highlights the necessity of a high level of alertness for emerging respiratory symptoms for early intervention and management of a potential diagnosis of pneumonitis during gemcitabine and nab-paclitaxel therapy, which is now a commonly used first-line standard therapy for patients with metastatic pancreatic adenocarcinoma.\n\nLearning points\nOP is a distinct disorder of lungs that can clinically present with subacute illness with low-grade fever and variable degrees of non-productive cough and dyspnoea.\n\nOP diagnosis is mainly radiological. HRCT shows patchy and often migratory consolidation in a subpleural, peribronchial, or band-like pattern, commonly associated with ground-glass opacity.\n\nOP is a rare, but possible consequence of treatment with nab-paclitaxel and gemcitabine. To confirm an association between a drug and OP, other causes, especially infectious, must be ruled out.\n\nOnce the diagnosis of OP is confirmed, early intervention including withdrawal of the chemotherapeutic agent and prompt use of corticosteroids is recommended.\n\nACKNOWLEDGMENTS\nWritten informed consent for the case to be published (including images, case history and data) was obtained from the patient(s) for publication of this case report, including accompanying images.\n==== Refs\nREFERENCES\n1. Siegel R , Naishadham D , Jemal A \nCancer statistics, 2013 . CA Cancer J Clin \n2013 ; 63 : 11 –30 . doi: 10.3322/caac.21166 23335087 \n2. Ferlay J , Steliarova-Foucher E , Lortet-Tieulent J , Rosso S , Coebergh JW , Comber H , et al \nCancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012 . Eur J Cancer \n2013 ; 49 : 1374 –403 . doi: 10.1016/j.ejca.2012.12.027 23485231 \n3. American Cancer Society . Cancer facts & figures 2016 . 2016 Available from: http://www.cancer. org/acs/groups/content/@research/documents/document/acspc-047079.pdf [Accessed 1 May 2017 ]\n4. National Cancer Institute . SEER Stat Fact Sheets: pancreatic cancer \nAvailable from: \nhttp://seer.cancer.gov/statfacts/ html/pancreas.html [Accessed 1 May 2017 ]\n5. Ryan DP , Hong TS , Bardeesy N \nPancreatic adenocarcinoma . N Engl J Med \n2014 ; 371 : 1039 –49 . doi: 10.1056/NEJMra1404198 25207767 \n6. Conroy T , Desseigne F , Ychou M , Bouché O , Guimbaud R , Bécouarn Y , et al \nFOLFIRINOX versus gemcitabine for metastatic pancreatic cancer . N Engl J Med \n2011 ; 364 : 1817 –25 . doi: 10.1056/NEJMoa1011923 21561347 \n7. Von Hoff DD , Ervin T , Arena FP , Chiorean EG , Infante J , Moore M , et al \nIncreased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine . N Engl J Med \n2013 ; 369 : 1691 –703 . doi: 10.1056/NEJMoa1304369 24131140 \n8. Epler GR \nBronchiolitis obliterans organizing pneumonia, 25 years: a variety of causes, but what are the treatment options? \nExpert Rev Respir Med \n2011 ; 5 : 353 –61 . doi: 10.1586/ers.11.19 21702658 \n9. Travis WD , Costabel U , Hansell DM , King TE , Lynch DA , Nicholson AG , et al \nAn official American thoracic society/European respiratory society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias . Am J Respir Crit Care Med \n2013 ; 188 : 733 –48 . doi: 10.1164/rccm.201308-1483ST 24032382 \n10. Travis WD , King TE , Bateman ED , Lynch DA , Capron F , Center D , et al \nAmerican thoracic society/European respiratory society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias . Am J Respir Crit Care Med \n2002 ; 165 : 277 –304 .11790668 \n11. Shaib W , Lansigan F , Cornfeld D , Syrigos K , Saif MW \nGemcitabine-induced pulmonary toxicity during adjuvant therapy in a patient with pancreatic cancer . JOP \n2008 ; 9 : 708 –14 .18981552 \n12. Kawsar HI , Spiro TP , Cocco A , Daw HA \nBOOP as a rare complication of gemcitabine therapy . BMJ Case Rep \n2011 ; 2011 : bcr0420114055. doi: 10.1136/bcr.04.2011.4055 \n13. Cobo Dols M , Gil Calle S , Alés Díaz I , Villar Chamorro E , Alcaide García J , Gutiérrez Calderón V , et al \nBronchiolitis obliterans organizing pneumonia simulating progression in bronchioloalveolar carcinoma . Clin Transl Oncol \n2006 ; 8 : 133 –5 . doi: 10.1007/s12094-006-0171-0 16632429 \n14. Aguiar Bujanda D , Aguiar Morales J , Bohn Sarmiento U \nBronchiolitis obliterans organizing pneumonia induced by chemotherapy . Arch Bronconeumol \n2004 ; 40 : 290.\n15. Hiraya D , Kagohashi K , Sakamoto N , Kondo T , Satoh H \nGemcitabine-induced pulmonary toxicity in a patient with pancreatic cancer . JOP \n2010 ; 11 : 186 –8 .20208333 \n16. Gupta A , Teo L , Masel P , Godbolt D , Beadle G \nTranstuzumab induced organizing pneumonia: a case report . Springerplus \n2016 ; 5 : 1964. doi: 10.1186/s40064-016-3647-6 27933242 \n17. Wang B , Yang J , Luo D , Qiao H , Xie Z , Zhang X , et al \nComplete remission and fatal interstitial pneumonitis related to nab-paclitaxel in refractory small cell lung cancer: a case report and review of the literature . Thorac Cancer \n2012 ; 3 : 84 –7 . doi: 10.1111/j.1759-7714.2011.00086.x 28920260 \n18. Chi DC , Brogan F , Turenne I , Zelonis S , Schwartz L , Saif MW \nGemcitabine-induced pulmonary toxicity . Anticancer Res \n2012 ; 32 : 4147 –9 .22993376 \n19. Gupta N , Ahmed I , Steinberg H , Patel D , Nissel-Horowitz S , Mehrotra B \nGemcitabine-induced pulmonary toxicity: case report and review of the literature . Am J Clin Oncol \n2002 ; 25 : 96 –100 .11823707 \n20. Galvão FH , Pestana JO , Capelozzi VL \nFatal gemcitabine-induced pulmonary toxicity in metastatic gallbladder adenocarcinoma . Cancer Chemother Pharmacol \n2010 ; 65 : 607 –10 . doi: 10.1007/s00280-009-1167-6 19904536 \n21. Rosado MF , Kett DH , Schein RM , Baraona FJ , Sridhar KS \nSevere pulmonary toxicity in a patient treated with gemcitabine . Am J Clin Oncol \n2002 ; 25 : 31 –3 . doi: 10.1097/00000421-200202000-00005 11823691 \n22. Dunsford ML , Mead GM , Bateman AC , Cook T , Tung K \nSevere pulmonary toxicity in patients treated with a combination of docetaxel and gemcitabine for metastatic transitional cell carcinoma . Ann Oncol \n1999 ; 10 : 943 –7 . doi: 10.1023/A:1008377819875 10509156 \n23. Roychowdhury DF , Cassidy CA , Peterson P , Arning M \nA report on serious pulmonary toxicity associated with gemcitabine-based therapy . Invest New Drugs \n2002 ; 20 : 311 –5 . doi: 10.1023/A:1016214032272 12201493 \n24. Hamada T , Yasunaga H , Nakai Y , Isayama H , Matsui H , Fushimi K , et al \nInterstitial lung disease associated with gemcitabine: a Japanese retrospective cohort study . Respirology \n2016 ; 21 : 338 –43 . doi: 10.1111/resp.12665 26775618 \n25. Moore MJ , Goldstein D , Hamm J , Figer A , Hecht JR , Gallinger S , et al National Cancer Institute of Canada Clinical Trials Group \nErlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the national cancer institute of Canada clinical trials group . J Clin Oncol \n2007 ; 25 : 1960 –6 . doi: 10.1200/JCO.2006.07.9525 17452677 \n26. Goldberg HL , Vannice SB \nPneumonitis related to treatment with paclitaxel . J Clin Oncol \n1995 ; 13 : 534 –5 . doi: 10.1200/JCO.1995.13.2.534 7844618 \n27. Vahid B , Marik PE \nPulmonary complications of novel antineoplastic agents for solid tumors . Chest \n2008 ; 133 : 528 –38 . doi: 10.1378/chest.07-0851 18252919\n\n",
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"pubdate": "2018",
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"title": "Organizing pneumonia after pancreatic cancer treatment with nab-paclitaxel and gemcitabine: a case report.",
"title_normalized": "organizing pneumonia after pancreatic cancer treatment with nab paclitaxel and gemcitabine a case report"
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"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
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"abstract": "A 77-year-old patient treated with ipilimumab (anti-CTLA-4 antibody) for metastatic melanoma developed autoimmune pancytopenia (anemia, thrombocytopenia, and neutropenia) 8 days after the fourth infusion. This pancytopenia was resistant to high-dose oral corticosteroids (1 mg/kg) and to hematopoietic growth factors. It resolved after intravenous immunoglobulins injection. To date, only 1 case of autoimmune pancytopenia has been reported after this treatment. According to the case that we report, it seems essential to control the leukocyte count before any injection of ipilimumab.",
"affiliations": "Departments of *Dermato-Oncology †CIC Biotherapy INSERM U892, Hôtel-Dieu University Hospital, Nantes, France.",
"authors": "du Rusquec|Pauline|P|;Saint-Jean|Melanie|M|;Brocard|Anabelle|A|;Peuvrel|Lucie|L|;Khammari|Amir|A|;Quéreux|Gaelle|G|;Dréno|Brigitte|B|",
"chemical_list": "D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D016756:Immunoglobulins, Intravenous; D000074324:Ipilimumab",
"country": "United States",
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"issue": "37(6)",
"journal": "Journal of immunotherapy (Hagerstown, Md. : 1997)",
"keywords": null,
"medline_ta": "J Immunother",
"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D001327:Autoimmune Diseases; D060908:CTLA-4 Antigen; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007167:Immunotherapy; D000074324:Ipilimumab; D007958:Leukocyte Count; D008545:Melanoma; D008991:Monitoring, Physiologic; D009362:Neoplasm Metastasis; D010198:Pancytopenia; D020127:Recovery of Function; D012878:Skin Neoplasms",
"nlm_unique_id": "9706083",
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"pages": "348-50",
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"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ipilimumab-induced autoimmune pancytopenia in a case of metastatic melanoma.",
"title_normalized": "ipilimumab induced autoimmune pancytopenia in a case of metastatic melanoma"
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"companynumb": "FR-MYLANLABS-2014S1015980",
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"abstract": "OBJECTIVE\nThis phase III study compared docetaxel and doxorubicin in patients with metastatic breast cancer who had received previous alkylating agent-containing chemotherapy.\n\n\nMETHODS\nPatients were randomized to receive an intravenous infusion of docetaxel 100 mg/m(2) or doxorubicin 75 mg/m(2) every 3 weeks for a maximum of seven treatment cycles.\n\n\nRESULTS\nA total of 326 patients were randomized, 165 to receive doxorubicin and 161 to receive docetaxel. Overall, docetaxel produced a significantly higher rate of objective response than did doxorubicin (47.8% v 33.3%; P =.008). Docetaxel was also significantly more active than doxorubicin in patients with negative prognostic factors, such as visceral metastases (objective response, 46% v 29%) and resistance to prior chemotherapy (47% v 25%). Median time to progression was longer in the docetaxel group (26 weeks v 21 weeks; difference not significant). Median overall survival was similar in the two groups (docetaxel, 15 months; doxorubicin, 14 months). There was one death due to infection in each group, and an additional four deaths due to cardiotoxicity in the doxorubicin group. Although neutropenia was similar in both groups, febrile neutropenia and severe infection occurred more frequently in the doxorubicin group. For severe nonhematologic toxicity, the incidences of cardiac toxicity, nausea, vomiting, and stomatitis were higher among patients receiving doxorubicin, whereas diarrhea, neuropathy, fluid retention, and skin and nail changes were higher among patients receiving docetaxel.\n\n\nCONCLUSIONS\nThe observed differences in activity and toxicity profiles provide a basis for therapy choice and confirms the rationale for combination studies in early breast cancer.",
"affiliations": "Department of Clinical Oncology, City Hospital, Nottingham, and CRC Wessex Medical Oncology Unit, Royal South Hants Hospital, Southampton, United Kingdom.",
"authors": "Chan|S|S|;Friedrichs|K|K|;Noel|D|D|;Pintér|T|T|;Van Belle|S|S|;Vorobiof|D|D|;Duarte|R|R|;Gil Gil|M|M|;Bodrogi|I|I|;Murray|E|E|;Yelle|L|L|;von Minckwitz|G|G|;Korec|S|S|;Simmonds|P|P|;Buzzi|F|F|;González Mancha|R|R|;Richardson|G|G|;Walpole|E|E|;Ronzoni|M|M|;Murawsky|M|M|;Alakl|M|M|;Riva|A|A|;Crown|J|J|;|||",
"chemical_list": "D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin; D017239:Paclitaxel",
"country": "United States",
"delete": false,
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"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel; D043823:Taxoids",
"nlm_unique_id": "8309333",
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"pages": "2341-54",
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"pubdate": "1999-08",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer.",
"title_normalized": "prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer"
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"companynumb": "GB-PFIZER INC-2021209143",
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"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
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{
"abstract": "Ketamine associated urinary dysfunction has become increasingly more common worldwide. Point-of-care ultrasound (POCUS) is an established modality for diagnosing hydronephrosis in the emergency department. We describe a case of a young male ketamine abuser with severe urinary urgency and frequency in which POCUS performed by the emergency physician demonstrated bilateral hydronephrosis and a focally thickened irregular shaped bladder. Emergency physicians should consider using POCUS evaluate for hydronephrosis and bladder changes in ketamine abusers with lower urinary tract symptoms. The mainstay of treatment is discontinuing ketamine abuse.",
"affiliations": "Albert Einstein College of Medicine, Jack D. Weiler Hospital, Bronx, New York.;Hofstra North Shore-LIJ School of Medicine, Department of Emergency Medicine, Hempstead, New York.;Hofstra North Shore-LIJ School of Medicine, Department of Emergency Medicine, Hempstead, New York.;Hofstra North Shore-LIJ School of Medicine, Department of Emergency Medicine, Hempstead, New York.",
"authors": "Tran|Vu Huy|VH|;Nelson|Mathew|M|;Nogar|Joshua|J|;Bramante|Robert M|RM|",
"chemical_list": "D000700:Analgesics; D000900:Anti-Bacterial Agents; D007649:Ketamine",
"country": "United States",
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"doi": "10.5811/westjem.2014.4.20571",
"fulltext": "\n==== Front\nWest J Emerg MedWest J Emerg MedWestJEMWestern Journal of Emergency Medicine1936-900X1936-9018Department of Emergency Medicine, University of California, Irvine School of Medicine 2503573810.5811/westjem.2014.4.20571wjem-15-382Diagnostic AcumenCase ReportBilateral Hydronephrosis and Cystitis Resulting from Abuse Chronic Ketamine Tran Vu Huy MD*Nelson Mathew DO†Nogar Joshua MD†Bramante Robert M. MD†* Albert Einstein College of Medicine, Jack D. Weiler Hospital, Bronx, New York† Hofstra North Shore-LIJ School of Medicine, Department of Emergency Medicine, Hempstead, New YorkAddress for Correspondence: Robert M. Bramante, MD. Hofstra North Shore-LIJ Medical Center Department of Emergency Medicine, 300 Community Drive, Manhasset, NY 11030. Email: rbramante@nshs.edu.Supervising Section Editor: Rick A. McPheeters, DO\n\n7 2014 15 4 382 384 24 11 2013 10 3 2014 Copyright © 2014 the authors.2014This is an open access article distributed in accordance with the terms of the Creative Commons\nAttribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by-nc/4.0/.Ketamine associated urinary dysfunction has become increasingly more common worldwide. Point-of-care ultrasound (POCUS) is an established modality for diagnosing hydronephrosis in the emergency department. We describe a case of a young male ketamine abuser with severe urinary urgency and frequency in which POCUS performed by the emergency physician demonstrated bilateral hydronephrosis and a focally thickened irregular shaped bladder. Emergency physicians should consider using POCUS evaluate for hydronephrosis and bladder changes in ketamine abusers with lower urinary tract symptoms. The mainstay of treatment is discontinuing ketamine abuse.\n==== Body\nINTRODUCTION\nKetamine induced urinary dysfunction (KAUD) is a syndrome first described in the literature in 2007. Patients suffer from irritative lower urinary tract symptoms and can develop varying degrees of hydronephrosis and interstitial cystitis. We describe a case of a young man with a history of heavy ketamine abuse who presented to the emergency department (ED) with lower urinary tract irritation and flank pain.\n\nWhy should an emergency physician (EPs) be aware of this?\nAlthough previously unreported in United States ED literature, ketamine associated urinary dysfunction has become increasingly more common in EDs worldwide. Point-of-care ultrasound (POCUS) is an established modality for diagnosing hydronephrosis in the ED. EPs should consider using POCUS evaluate for hydronephrosis and bladder changes in ketamine abusers with lower urinary tract symptoms. The mainstay of treatment is discontinuing ketamine abuse.\n\nCASE REPORT\nTwenty four-year-old Chinese-American male with a history of ketamine abuse (3–5 times daily for 4 years), as well as cocaine and intravenous drug abuse, who presented to the ED with bilateral flank pain for 2 weeks. He noted 2 days of increasing pain, described as dull, waxing and waning. Associated symptoms included fever, chills, urinary frequency, dysuria, urgency, and more recently, urinary incontinence (requiring diapers). There was no history of weakness, bowel incontinence, or saddle anesthesia. On physical examination, the patient appeared uncomfortable and anxious. He complained of severe urgency, requiring frequent urination during the interaction. Mild bilateral costo-vertebral tenderness was noted, with an otherwise unremarkable abdominal and genitourinary examination. Neurologic examination was normal except for slight ataxia when performing tandem gait.\n\nThe treating ED physician performed POCUS that revealed bilateral moderate hydroureteronephrosis (Figure 1) and a contracted bladder with an irregular shape and areas of focal wall thickening (Figure 2). The patient complained of frequency and urgency throughout the study and requested multiple times to pause the exam to urinate. Pain was elicited on suprapubic transducer application.\n\nLaboratory studies revealed an elevated creatinine (1.32 mg/dL) and urinalysis was positive for red blood cells (5–10/high powered field), white blood cells (10–25/hpf), few bacteria, protein (75 md/dL) and trace leukocyte esteraste. The remainder of his lab work (CBC, chemistry, coagulation profile) was negative.\n\nA computed tomography was ordered to rule out obstructive pathology and ultimately confirmed our POCUS findings. The final reading was “moderate bilateral hydroureteronephrosis, and a small deformed urinary bladder.” A urology consult was obtained. An outpatient workup was recommended for ketamine induced urinary tract disease. The patient was sent home with antibiotics for a urinary tract infection and encouraged to discontinue ketamine abuse. Upon review, the urine culture was negative and the patient was lost to follow up.\n\nDISCUSSION\nKetamine is an N-methyl-D-aspartate receptor antagonist, used therapeutically as a dissociative anesthetic. Recreationally, it is frequently abused at raves, parties, and nightclubs. Patients with acute ketamine toxicity most often present to EDs with neurologic complaints such as confusion, loss of consciousness, agitation, and drowsiness. Recent literature suggests that many patients with chronic ketamine abuse also experience ketamine-associated urinary tract dysfunction (KAUD). To our knowledge, this is the first case of KAUD associated with bilateral hydronephrosis reported from a United States ED. This may be due to the fact that recreational ketamine occurs with much higher frequency outside the U.S., especially in East and South-East Asian countries.1–3\n\nKetamine associated urinary tract dysfunction (KAUD) is a syndrome first described by Shahani et al in 2007.4 Since then, there has been over 110 cases reported in the literature.5 About 20–30% of patients who abuse ketamine suffer from lower urinary tract symptoms (LUTS).6,7 Since most cases of KAUD have been reported in case reports, case series, and letters, the true prevalence of this disease is unknown. In a recent large community–based study, Pal et al1, report a prevalence of LUTS of 30% among recent users. Furthermore, they conclude that recent ketamine users had increased odds of LUTS compared with non-users.\n\nThe exact mechanism of ketamine associated urinary destruction is unknown. Some proposed mechanisms include: direct epithelial damage, microvascular injury, or immune-related damage to the urinary tract by ketamine or its metabolites.6,9 Damage to the lower urinary tract damage is more common than upper urinary tract, although the latter occurs relatively frequently. These symptoms can be attributed to chronic inflammation, low bladder capacities, decreased bladder compliance, and/or detrusor overactivity.9 Symptoms can become quite debilitating, causing frequent urination every 15–45 minutes, as described in our case.\n\nCurrently, this disease entity is a diagnosis of exclusion that typically occurs after ruling-out obstructive lesions. Patients with severe irritative lower urinary tract symptoms, a history of ketamine abuse, and no other cause for symptoms should be considered to have KAUD.5 We believe point-of-care ultrasound is a safe, rapid, first-line imaging modality to consider in patients with suspected KAUD. POCUS for the detection of hydronephrosis in the ED has a sensitivity and specificity of 80–87% and 82–83%, respectively.10,11 In addition, it is rapid, available, and free of ionizing radiation. One limitation of POCUS is the ability to rule out obstructing lesions and masses.\n\nAlthough the true incidence of positive findings of renal and bladder ultrasound in patients with KAUD is unknown, recent case series and reports suggest sonographic findings are frequent. Mason et al12 reported that 12 of 23 patients in their case series had positive finding on renal ultrasound that included bladder wall thickening and small bladder volumes. Thirteen percent of these patients were found to have upper urinary tract involvement. Four patients were unable to fill their bladder and had to stop in the middle of the exam to empty their bladders.12\n\nChu et al9 described 59 patients from two hospitals in Hong Kong with ketamine-associated cystitis. Fifty-one percent of these patients had unilateral hydronephrosis, while 44% had bilateral hydronephrosis. They report that most of these patients showed hydronephrosis and hydroureter that extended down to the vesiculo-uteric junction. It is postulated that upper tract involvement likely results from long-term decrease in bladder compliance.9,12 Tsai et al8, reported 5 of 11 patients in their case series had bilateral hydronephrosis. These patients exhibited detrusor overactivity with small bladder capacities on urodynamic studies.8\n\nCurrently, the mainstay of therapy has been the discontinuation of ketamine use. Most patients have sterile pyuria where antibiotics are ineffective.9 Other treatment modalities have included antimuscarinics and steroids, which have demonstrated limited efficacy for KAUD.8 Surgical interventions (augmentation enterocystoplasty, ureteroplasty, cystectomy9, and ileal neobladder12) have been performed for patients with continued use and refractory symptoms.\n\nKetamine associated urinary dysfunction is becoming an increasingly common and recognized syndrome associated with chronic ketamine abuse. Emergency physicians should consider the use of point-of-care ultrasound as a first-line imaging modality in patients with suspected KAUD. Patients should be advised to discontinue ketamine abuse and referred to a urologist to exclude alternative causes.\n\nFull text available through open access at http://escholarship.org/uc/uciem_westjem\n\nConflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.\n\nFigure 1 Longitudinal view of the right kidney showed moderate hydroureteronephrosis (arrow).\n\nFigure 2 Transverse view of the bladder shows a small, irregularly shaped bladder wall with areas of focal thickening (arrow).\n==== Refs\nREFERENCES\n1 Pal R Balt S Erowid E Ketamine is associated with lower urinary tract signs and symptoms Drug Alcohol Depend 2013 132 1–2 189 194 23474358 \n2 Morgan EJ Curan HV Ketamine use: a review Addiction 2012 107 27 38 21777321 \n3 Wood D Cottrell A Baker SC Recreational ketamine: from pleasure to pain BJU Int 2011 107 1881 1884 21314885 \n4 Shahani R Streutker C Dickson B Ketamine-associated ulcerative cystitis: a new clinical entity Urology 2007 69 5 810 812 17482909 \n5 Middela S Pearce I Ketamine-induced vesicopathy: a literature review Int J Clin Pract 2011 65 1 27 30 21155941 \n6 Chu PS Ma WK Wong SC The destruction of the lower urinary tract by ketamine abuse: a new syndrome? BJU Int 2008 102 11 1616 1622 18680495 \n7 Muetzelfeltdt L Kamboj SK Rees H Journey through the K-hole: phenomenological aspects of ketamine use Drug Alcohol Depend 2008 95 219 229 18355990 \n8 Tsai TH Cha L Lin CM Ketamine-associated bladder dysfunction Int J Urol 2009 16 826 829 19659678 \n9 Chu PS Kwok SC Lam KM Street ketamine – associated bladder dysfunction: a report of ten cases Hong Kong Med J 2007 13 4 311 313 17592176 \n10 Watkins S Bowra J Sharma P Validation of emergency physician ultrasound in diagnosing hydronephrosis in ureteric colic Emerg Med Australas 2007 19 3 188 195 17564683 \n11 Gaspari RJ Horst K Emergency Ultrasound and Urinalysis in the Evaluation of Flank Pain Acad Emerg Med 2005 12 1180 1184 16282510 \n12 Mason K Cottrell AM Corrigan AG Ketamine-associated lower urinary tract destruction: a new radiological challenge Clin Radiol 2010 65 10 795 800 20797465\n\n",
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"issue": "15(4)",
"journal": "The western journal of emergency medicine",
"keywords": null,
"medline_ta": "West J Emerg Med",
"mesh_terms": "D000700:Analgesics; D000900:Anti-Bacterial Agents; D003556:Cystitis; D003937:Diagnosis, Differential; D006801:Humans; D006869:Hydronephrosis; D007649:Ketamine; D008297:Male; D055815:Young Adult",
"nlm_unique_id": "101476450",
"other_id": null,
"pages": "382-4",
"pmc": null,
"pmid": "25035738",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19659678;21155941;20797465;16282510;17482909;17564683;23474358;18355990;18680495;21314885;17592176;21777321",
"title": "Bilateral hydronephrosis and cystitis resulting from chronic ketamine abuse.",
"title_normalized": "bilateral hydronephrosis and cystitis resulting from chronic ketamine abuse"
} | [
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"abstract": "OBJECTIVE\nTo present a new treatment modality for recurrent corneal melting in a patient with a Boston type I keratoprosthesis (B-KPro) including in situ corneal cross-linking (CXL) and lamellar keratoplasty (LKP) as combined treatment.\n\n\nMETHODS\nCase report.\n\n\nRESULTS\nOur report concerns a 27-year-old man whose case history involved a severe chemical burn of his left eye. After failed penetrating keratoplasty and limbal stem cell transplantation, the patient underwent B-KPro implantation. Starting 1 month after surgery, recurrent corneal melting around the B-KPro developed, which was eventually treated by combining LKP, amniotic membrane transplantation, and in situ CXL. Optical coherence tomography imaging and follow-up for 12 months showed stable corneal healing without new melting or erosion. The ultraviolet A treatment did not seem to damage the material of the B-KPro.\n\n\nCONCLUSIONS\nIn situ CXL using riboflavin and ultraviolet A light combined with LKP and amniotic membrane transplantation can be an effective management option to treat recurrent corneal melting after B-KPro implantation.",
"affiliations": "*Department of Ophthalmology, Semmelweis University, Budapest, Hungary; †Department of Ophthalmology, University of Cologne, Cologne, Germany; and ‡Department of Ophthalmology, Saarland University Medical Center, Homburg, Saar, Germany.",
"authors": "Tóth|Gábor|G|;Bucher|Franziska|F|;Siebelmann|Sebastian|S|;Bachmann|Björn|B|;Hermann|Manuel|M|;Szentmáry|Nóra|N|;Nagy|Zoltán Zsolt|ZZ|;Cursiefen|Claus|C|",
"chemical_list": "D003432:Cross-Linking Reagents; D017319:Photosensitizing Agents; D003094:Collagen; D012256:Riboflavin",
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000000830",
"fulltext": null,
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"issn_linking": "0277-3740",
"issue": "35(6)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000328:Adult; D000650:Amnion; D001705:Bioprosthesis; D002057:Burns, Chemical; D003094:Collagen; D003316:Corneal Diseases; D003319:Corneal Stroma; D016039:Corneal Transplantation; D003432:Cross-Linking Reagents; D005126:Eye Burns; D006801:Humans; D008297:Male; D017319:Photosensitizing Agents; D019736:Prostheses and Implants; D019919:Prosthesis Implantation; D012008:Recurrence; D012256:Riboflavin; D014466:Ultraviolet Rays",
"nlm_unique_id": "8216186",
"other_id": null,
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "In Situ Corneal Cross-Linking for Recurrent Corneal Melting After Boston Type 1 Keratoprosthesis.",
"title_normalized": "in situ corneal cross linking for recurrent corneal melting after boston type 1 keratoprosthesis"
} | [
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"abstract": "OBJECTIVE\nRituximab is a chimeric anti-CD20 IgG1 monoclonal antibody for the treatment of various forms of lymphoma and haematological autoimmune diseases. Interstitial lung disease is a rare but lethal pulmonary toxicity of rituximab. Nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a molecular platform activated upon signs of cellular 'danger' to trigger the maturation of pro-inflammatory cytokines. We report the first case of rituximab-induced interstitial lung disease (R-ILD) with NLRP3 inflammasome activation in the lung.\n\n\nMETHODS\nA 30-year-old male patient diagnosed with idiopathic thrombocytopenic purpura (ITP) was treated with four cycles of rituximab in one month. Three weeks after last rituximab administration, he developed progressive dyspnoea associated with respiratory failure, which was diagnosed as R-ILD. The patient showed a good response to steroid treatment, and lung biopsy was performed 5 days after the treatment. Immunohistopathological studies of lung specimens showed high expressions of inflammasome components NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1 in lung interstitium with a heavy infiltration of CD19-positive cells. The levels of inflammasome-related cytokines IL-1β and IL-18 in the serum were declined during the therapy.\n\n\nCONCLUSIONS\nThis is the first report confirmed the role of NLRP3 inflammasome in pulmonary toxicity of rituximab. Inhibited activation of NLRP3 inflammasome in lung by steroid treatment could reverse R-ILD and block subsequent lung fibrosis. This result could open a new sight into the pathogenesis and provide a new target for the treatment of R-ILD.",
"affiliations": "Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.",
"authors": "Kong|H|H|;Wang|Y|Y|;Zeng|X|X|;Zhu|Q|Q|;Xie|W|W|;Dai|S|S|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D002352:Carrier Proteins; D016207:Cytokines; D005938:Glucocorticoids; D007155:Immunologic Factors; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12198",
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"issue": "39(6)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "inflammasome; interstitial lung disease; rituximab",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived; D002352:Carrier Proteins; D016207:Cytokines; D004417:Dyspnea; D005938:Glucocorticoids; D006801:Humans; D007155:Immunologic Factors; D058847:Inflammasomes; D017563:Lung Diseases, Interstitial; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D016553:Purpura, Thrombocytopenic, Idiopathic; D000069283:Rituximab",
"nlm_unique_id": "8704308",
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"pages": "691-4",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Involvement of NLRP3 inflammasome in rituximab-induced interstitial lung disease: a case report.",
"title_normalized": "involvement of nlrp3 inflammasome in rituximab induced interstitial lung disease a case report"
} | [
{
"companynumb": "CN-ROCHE-1454119",
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"activesubstancename": "RITUXIMAB"
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"abstract": "Patients with 21-hydroxylase deficiency (21-OHD) are at risk of reduced bone mineral density (BMD) and fracture due to long-term glucocorticoid treatment. Trabecular bone score (TBS) is complementary to conventional BMD as a marker for bone quality in patients with glucocorticoid-induced osteoporosis. The purpose of this study is to evaluate the BMD and TBS in a cohort of patients with 21-OHD and analyse factors related to TBS.\n\n\n\nAn observational study.\n\n\n\nA total of 46 21-OHD adult patients treated with glucocorticoid for over 10 years who visited Peking Union Medical College Hospital between 2015 and 2019 were recruited. Eight male patients included in this study were all under 50 years old, and 38 female patients were all premenopausal.\n\n\n\nDiagnosis was confirmed by multiplex ligation-dependent probe amplification combined with sequencing. Data were collected on physical characteristics, serum hormones and glucocorticoid treatment. Skeletal quality was evaluated by BMD and TBS, and factors related to TBS were analysed.\n\n\n\nAmong the 46 patients, 2 (4.3%) had low BMD (Z-score ≤ -2), while 11 (23.9%) patients had low TBS (degraded or partially degraded microarchitecture). The proportion of bone abnormality evaluated by TBS was higher than that by BMD (p < .001). Patients with lower TBS had significantly higher daily hydrocortisone dosage (p = .009 for males; p = .019 for females). TBS value was negatively correlated with daily hydrocortisone dosage (r = -.317, p = .026), and positively correlated with BMI in female patients (r = .345, p = .034). And there was a negative correlation between TBS value and the current age in male patients (r = -.741, p = .036). The distribution of genotypes (p = 1.000 for male; p = .567 for female) or phenotypes (p = .486 for male; p = .075 for female) had no statistical difference in patients with normal or abnormal TBS.\n\n\n\nApproximately 24% of patients with 21-OHD had abnormal microarchitecture of their bone in our study, and TBS score was negatively correlated with daily glucocorticoid dosage in patients. TBS may be used alongside conventional BMD as a complementary marker for bone evaluation in 21-OHD patients.",
"affiliations": "NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.;NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.;Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.;NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.;NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.;NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.;Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.;NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.",
"authors": "Gao|Yinjie|Y|;Wang|Ou|O|0000-0002-0395-8789;Guan|Wenmin|W|;Wu|Xueyan|X|;Mao|Jiangfeng|J|0000-0003-0157-1545;Wang|Xi|X|;Yu|Wei|W|;Nie|Min|M|0000-0001-7179-0044",
"chemical_list": "D005938:Glucocorticoids",
"country": "England",
"delete": false,
"doi": "10.1111/cen.14391",
"fulltext": null,
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"issn_linking": "0300-0664",
"issue": "94(5)",
"journal": "Clinical endocrinology",
"keywords": "21-hydroxylase deficiency; bone mineral density; glucocorticoid treatment; trabecular bone score",
"medline_ta": "Clin Endocrinol (Oxf)",
"mesh_terms": "D015502:Absorptiometry, Photon; D000312:Adrenal Hyperplasia, Congenital; D015519:Bone Density; D000071556:Cancellous Bone; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008159:Lumbar Vertebrae; D008297:Male; D008875:Middle Aged; D058866:Osteoporotic Fractures",
"nlm_unique_id": "0346653",
"other_id": null,
"pages": "765-773",
"pmc": null,
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"pubdate": "2021-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Bone mineral density and trabecular bone score in patients with 21-hydroxylase deficiency after glucocorticoid treatment.",
"title_normalized": "bone mineral density and trabecular bone score in patients with 21 hydroxylase deficiency after glucocorticoid treatment"
} | [
{
"companynumb": "CN-LUPIN PHARMACEUTICALS INC.-2021-21406",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
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"abstract": "OBJECTIVE\nWhen metformin is insufficient for patients with type 2 diabetes mellitus (T2DM), the optimal adjunctive therapy is unclear. This meta-analysis was to compare the efficacy and safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors with sulfonylureas (SUs) as second-line therapy in patients with T2DM inadequately controlled on metformin.\n\n\nMETHODS\nWe systematically searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for randomized controlled trials comparing SGLT2 inhibitors with SUs as add-on to metformin. Our primary endpoints were glycemic control, hypoglycemia, and change in weight. We assessed pooled data using a random-effects model.\n\n\nRESULTS\nFive trials involving 4300 participants were included in our meta-analysis. Compared with SUs, SGLT2 inhibitors led to no significant reduction in changes in HbA1c (mean difference [MD] - 0.06; 95% confidence interval [CI] [- 0.12, 0.08]), but less hypoglycemia as add-on to metformin (odds ratio [OR] 0.12; 95% CI [0.07, 0.21]). SGLT2 inhibitors led to a reduction in weight by about 3.5 kg; however, SUs caused a gain in weight by about 1 kg (MD - 4.39; 95% CI [- 4.64, - 4.14]). SGLT2 inhibitors also showed a reduction in blood pressure, but increased the incidence of genital tract infections compared with SUs. Interestingly, subgroup analysis by duration of interventions showed that reduction of HbA1c from baseline was similar between the two groups at 12-52 weeks, but SGLT2 inhibitors led to a greater reduction in HbA1c at 104-208 weeks.\n\n\nCONCLUSIONS\nDespite similar glycemic efficacy in a relatively short term, SGLT2 inhibitors are more effective in the longer term than SUs as add-on to metformin. In addition, SGLT2 inhibitors produce less hypoglycemic events and lead to greater reductions in weight and blood pressure compared with SUs.",
"affiliations": "School of Medicine, Wuhan University, No. 115 Donghu Road, Wuhan, 430071, Hubei, China. chenze19@whu.edu.cn.;School of Medicine, Wuhan University, No. 115 Donghu Road, Wuhan, 430071, Hubei, China.",
"authors": "Chen|Ze|Z|http://orcid.org/0000-0002-1780-4764;Li|Gerui|G|",
"chemical_list": "D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013453:Sulfonylurea Compounds; D008687:Metformin",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40261-019-00781-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1173-2563",
"issue": "39(6)",
"journal": "Clinical drug investigation",
"keywords": null,
"medline_ta": "Clin Drug Investig",
"mesh_terms": "D001786:Blood Glucose; D001794:Blood Pressure; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2; D006801:Humans; D007003:Hypoglycemia; D007004:Hypoglycemic Agents; D008687:Metformin; D016032:Randomized Controlled Trials as Topic; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013453:Sulfonylurea Compounds",
"nlm_unique_id": "9504817",
"other_id": null,
"pages": "521-531",
"pmc": null,
"pmid": "31041606",
"pubdate": "2019-06",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D017418:Meta-Analysis; D000078182:Systematic Review",
"references": "12111919;12958120;17145742;18435668;18539916;18784090;19324482;19622511;19655124;20587587;21816980;21877761;22238392;22492586;22526604;22555472;23375850;23425655;23850055;24113667;24186878;24320621;24919526;24948511;25006351;25113816;25205142;25246775;25735400;26732230;26773934;26889911;27059700;27862830;27979895;28606343;29020355;29098566;29222379;29282633;29327406;30178023;30291106;30424892;30506378",
"title": "Sodium-Glucose Co-Transporter 2 Inhibitors Compared with Sulfonylureas in Patients with Type 2 Diabetes Inadequately Controlled on Metformin: A Meta-Analysis of Randomized Controlled Trials.",
"title_normalized": "sodium glucose co transporter 2 inhibitors compared with sulfonylureas in patients with type 2 diabetes inadequately controlled on metformin a meta analysis of randomized controlled trials"
} | [
{
"companynumb": "MY-ALKEM LABORATORIES LIMITED-MY-ALKEM-2019-04871",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT).\n\n\n\nWe performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics.\n\n\n\nWe retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure.\n\n\n\nOverall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%.\n\n\n\nHSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.",
"affiliations": "Department of Pediatric Immunology and HSCT, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address: ferrua.francesca@hsr.it.;Center of Biostatistics for Clinical Epidemiology, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.;Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France.;Department of Pediatric Immunology and HSCT, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom; Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.;Department of Pediatric Immunology, Great Ormond Street Hospital, London, United Kingdom.;Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France.;Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France.;Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France.;Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Biotherapy Department, Necker Children's Hospital, AP-HP, Paris, France; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, Paris, France; INSERM UMR 1163, Laboratory of Human Lymphohematopoiesis, Paris, France.;Dmitry Rogachev Federal Research Centre of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.;Dmitry Rogachev Federal Research Centre of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.;Dmitry Rogachev Federal Research Centre of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.;Pediatric Oncology-Hematology and BMT Unit, Spedali Civili di Brescia, Brescia, Italy.;Pediatric Oncology-Hematology and BMT Unit, Spedali Civili di Brescia, Brescia, Italy.;Department of Pediatrics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.;Department of Pediatrics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.;Department of Pediatrics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.;Department of Pediatrics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.;Department of Pediatric Hematology and Oncology, University Hospital Motol Prague, Prague, Czech Republic.;Institut d'Hematologie et d'Oncologie Pediatrique, Hospices Civils de Lyon, Lyon, France.;L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland; Lower Silesian Center for Cellular Transplantation & National Bone Marrow Donor Registry, Wrocław, Poland.;Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Australia.;Immunology Department, Children's Memorial Health Institute, Warsaw, Poland.;Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, Dallas, Tex.;Division of Pediatric Allergy, Immunology & Bone Marrow Transplantation, University of California, San Francisco, Calif.;Department of Pediatrics, Sahlgrenska Academy at University of Gothenburg and Queen Silvia Children's Hospital, Gothenburg, Sweden.;Pediatric Oncology and Hematology Unit, Children Hospital, University Hospital Nancy, Vandoeuvre-les-Nancy, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France.;Pediatric Clinic, Rigshospitalet, Copenhagen, Denmark.;Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.;Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.;Department of Pediatrics, Division of Allergology, Clinical Immunology, Respiratory Diseases and Rheumatology, University Hospital Center Zagreb, Zagreb, Croatia.;Department of Pediatrics/Willem-Alexander Children's hospital, Leiden University Medical Center, Leiden, The Netherlands.;Department of Pediatrics/Willem-Alexander Children's hospital, Leiden University Medical Center, Leiden, The Netherlands.;Department of Pediatrics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.;Hématologie Adulte, Hôpital Necker, AP-HP, Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France.;Division of Allergy Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pa.;Pediatric Hematology/Oncology, Dr. von Hauner University Children's Hospital, Munich, Germany.;Department of Pediatric Hematology and Oncology, Wroclaw Medical University, Wrocław, Poland.;Service d'hématologie pédiatrique, Hôpital de la Timone Enfants, Marseille, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France.;Pediatric Stem Cell Transplantation, Columbia University College of Physicians and Surgeons, New York, NY.;Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.;University Children's Hospital of Cracow, Cracow, Poland.;Pediatric Hematology and Oncology Department, Hospital Universitario MaternoInfantil Vall d'Hebron, Barcelona, Spain.;Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey.;Department of Clinical Immunology and Transplantology, Jagiellonian University, Medical Collage, Transplantation Center, University Children's Hospital, Cracow, Poland.;Department of Pediatric Immunology-Allergy and BMT Unit, Ankara University Medical School, Ankara, Turkey.;Department of Pediatric Hematology and Stem Cell Transplantation United St. István and St László Hospital, Budapest, Hungary.;Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.;Department of Pediatrics, University Hospitals Leuven, Division of Pediatric Immunology, Department of Immunology and Microbiology, Catholic University Leuven, Leuven, Belgium.;Nationwide Children's Hospital, Columbus, Ohio.;Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minn.;Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Division of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden; Pediatric Blood Disorders, Immunodeficiency and SCT, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.;Cancer Centre for Children, Children's Hospital at Westmead, Sydney, Australia.;Cancer Centre for Children, Children's Hospital at Westmead, Sydney, Australia; University of Sydney Medical Program, Sydney, Australia.;Department of Pediatrics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, BMT and Cell Therapies Program, New York, NY; Laboratory for Translational Immunology, Tumor-immunology, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.;Department of Pediatric Hematology and Oncology, University Hospital Motol Prague, Prague, Czech Republic.;Department of BMT, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.;Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France; INSERM UMR 1163, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris, France.;Center for Pediatrics and Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Freiburg, Germany.;Department of Pediatric Immunology, Great Ormond Street Hospital, London, United Kingdom.;Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France; College de France, Paris, France.;Division of Pediatric Allergy, Immunology & Bone Marrow Transplantation, University of California, San Francisco, Calif.;Department of Pediatric Immunology and HSCT, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom; Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.",
"authors": "Ferrua|Francesca|F|;Galimberti|Stefania|S|;Courteille|Virginie|V|;Slatter|Mary Anne|MA|;Booth|Claire|C|;Moshous|Despina|D|;Neven|Benedicte|B|;Blanche|Stephane|S|;Cavazzana|Marina|M|;Laberko|Alexandra|A|;Shcherbina|Anna|A|;Balashov|Dmitry|D|;Soncini|Elena|E|;Porta|Fulvio|F|;Al-Mousa|Hamoud|H|;Al-Saud|Bandar|B|;Al-Dhekri|Hasan|H|;Arnaout|Rand|R|;Formankova|Renata|R|;Bertrand|Yves|Y|;Lange|Andrzej|A|;Smart|Joanne|J|;Wolska-Kusnierz|Beata|B|;Aquino|Victor M|VM|;Dvorak|Christopher C|CC|;Fasth|Anders|A|;Fouyssac|Fanny|F|;Heilmann|Carsten|C|;Hoenig|Manfred|M|;Schuetz|Catharina|C|;Kelečić|Jadranka|J|;Bredius|Robbert G M|RGM|;Lankester|Arjan C|AC|;Lindemans|Caroline A|CA|;Suarez|Felipe|F|;Sullivan|Kathleen E|KE|;Albert|Michael H|MH|;Kałwak|Krzysztof|K|;Barlogis|Vincent|V|;Bhatia|Monica|M|;Bordon|Victoria|V|;Czogala|Wojciech|W|;Alonso|Laura|L|;Dogu|Figen|F|;Gozdzik|Jolanta|J|;Ikinciogullari|Aydan|A|;Kriván|Gergely|G|;Ljungman|Per|P|;Meyts|Isabelle|I|;Mustillo|Peter|P|;Smith|Angela R|AR|;Speckmann|Carsten|C|;Sundin|Mikael|M|;Keogh|Steven John|SJ|;Shaw|Peter John|PJ|;Boelens|Jaap Jan|JJ|;Schulz|Ansgar S|AS|;Sedlacek|Petr|P|;Veys|Paul|P|;Mahlaoui|Nizar|N|;Janda|Ales|A|;Davies|E Graham|EG|;Fischer|Alain|A|;Cowan|Morton J|MJ|;Gennery|Andrew Richard|AR|;|||",
"chemical_list": "D023201:CD40 Ligand",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaci.2018.12.1010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-6749",
"issue": "143(6)",
"journal": "The Journal of allergy and clinical immunology",
"keywords": "CD40 ligand; X-linked hyper-IgM syndrome; hematopoietic stem cell transplantation; primary immunodeficiency",
"medline_ta": "J Allergy Clin Immunol",
"mesh_terms": "D023201:CD40 Ligand; D002648:Child; D002675:Child, Preschool; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016896:Treatment Outcome; D053632:X-Linked Combined Immunodeficiency Diseases",
"nlm_unique_id": "1275002",
"other_id": null,
"pages": "2238-2253",
"pmc": null,
"pmid": "30660643",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study.",
"title_normalized": "hematopoietic stem cell transplantation for cd40 ligand deficiency results from an ebmt esid iewp scetide pidtc study"
} | [
{
"companynumb": "GB-OTSUKA-2019_023583",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": null,
"d... |
{
"abstract": "Introduction: This paper aims to evaluate the toxicity profile of additive gemcitabine to adjuvant taxane-based chemotherapy in breast cancer patients. Methods: Patients enrolled in this open-label randomized controlled Phase III study were treated with 3 cycles of epirubicin-fluorouracil-cyclophosphamide (FEC) chemotherapy followed by 3 cycles of docetaxel with those receiving 3 cycles of FEC followed by 3 cycles of gemcitabine-docetaxel (FEC-DG). 3690 patients were evaluated according to National Cancer Institute (NCI) toxicity criteria (CTCAE). The study medications were assessed by the occurrence of grade 3-4 adverse events, dose reductions, postponements of treatment cycles and granulocyte colony-stimulating factor (G-CSF) support. Results: No differences in neutropenia or febrile neutropenia were demonstrated. However, thrombocytopenia was significantly increased with FEC-DG treatment (2.0 vs. 0.5 %, p < 0.001), as was leukopenia (64.1 vs. 58.5 %, p < 0.001). With FEC-DG significantly more G-CSF support in cycles 4 to 6 (FEC-DG: 57.8 %, FEC-D: 36.3 %, p < 0.001) was provided. Transaminase elevation was significantly more common with FEC-DG (SGPT: 6.3 %, SGOT: 2 %), whereas neuropathy (1.2 %), arthralgia (1.6 %) and bone pain (2.6 %) were more common using FEC-D. Dose reductions > 20 % (4 vs. 2.4 %) and postponement of treatment cycles (0.9 vs. 0.4 %) were significantly more frequent in the FEC-DG arm. Eight deaths occurred during treatment in the FEC-DG arm and four in the FEC-D arm. Conclusion: The addition of gemcitabine increased hematological toxicity and was associated with more dose reductions and postponements of treatment cycles.",
"affiliations": "Department of Gynecology and Obstetrics, Ludwig-Maximilians-University, Munich.;Department of Gynecology and Obstetrics, Ludwig-Maximilians-University, Munich.;Department of Gynecology and Obstetrics, Ludwig-Maximilians-University, Munich.;Department of Gynecology and Obstetrics, Ludwig-Maximilians-University, Munich.;Department of Gynecology and Obstetrics, Ludwig-Maximilians-University, Munich.;Department of Gynecology and Obstetrics, University of Ulm, Ulm.;Head of Division Gynecologic Oncology National Center for Tumor Diseases, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg.;Luisenkrankenhaus Düsseldorf, Düsseldorf.;Gemeinschaftspraxis Dr. R. Lorenz/N. Hecker, Braunschweig.;Department of Gynecology and Obstetrics, Heinrich Heine University of Düsseldorf, Düsseldorf.;Department of Gynecology and Obstetrics, University of Ulm, Ulm.;Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen.;Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen.;Department of Gynecology and Obstetrics, University of Ulm, Ulm.;Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen.;Department of Gynecology and Obstetrics, University of Ulm, Ulm.",
"authors": "Schröder|L|L|;Rack|B|B|;Sommer|H|H|;Koch|J G|JG|;Weissenbacher|T|T|;Janni|W|W|;Schneeweiss|A|A|;Rezai|M|M|;Lorenz|R|R|;Jäger|B|B|;Schramm|A|A|;Häberle|L|L|;Fasching|P A|PA|;Friedl|T W P|TW|;Beckmann|M W|MW|;Scholz|C|C|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0042-106209",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-5751",
"issue": "76(5)",
"journal": "Geburtshilfe und Frauenheilkunde",
"keywords": "adjuvant chemotherapy; breast cancer; gemcitabine; hematological; toxicity",
"medline_ta": "Geburtshilfe Frauenheilkd",
"mesh_terms": null,
"nlm_unique_id": "0370732",
"other_id": null,
"pages": "542-550",
"pmc": null,
"pmid": "27239063",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": "23940225;24771909;17169763;7595731;12637460;9704715;16163537;10885899;21084429;18665163;17116941;25797960;22689092;24620009;24771886;15585753;19418823;15897552;12928125;16316459;24360787;8996158;18711184;22276821;24321851;18952557;15894097;11408796;12618923",
"title": "Toxicity Assessment of a Phase III Study Evaluating FEC-Doc and FEC-Doc Combined with Gemcitabine as an Adjuvant Treatment for High-Risk Early Breast Cancer: the SUCCESS-A Trial.",
"title_normalized": "toxicity assessment of a phase iii study evaluating fec doc and fec doc combined with gemcitabine as an adjuvant treatment for high risk early breast cancer the success a trial"
} | [
{
"companynumb": "DE-SA-2017SA126481",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "A case of spontaneous recurrent acute tumor lysis syndrome is presented in a woman with inflammatory breast cancer. The occurrence of tumor lysis syndrome in solid tumors is unusual, and spontaneous cases are rare. This and other unusual aspects of this case are discussed.",
"affiliations": "Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York.",
"authors": "Sklarin|N T|NT|;Markham|M|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/00000421-199502000-00015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3732",
"issue": "18(1)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000208:Acute Disease; D000230:Adenocarcinoma; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D008875:Middle Aged; D012008:Recurrence; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "71-3",
"pmc": null,
"pmid": "7847263",
"pubdate": "1995-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Spontaneous recurrent tumor lysis syndrome in breast cancer.",
"title_normalized": "spontaneous recurrent tumor lysis syndrome in breast cancer"
} | [
{
"companynumb": "US-PFIZER INC-2021486872",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TAMOXIFEN"
},
"drugadditional": "3",
... |
{
"abstract": "On average, two-thirds of individuals treated for alcohol use disorder (AUD) relapse within six months. There is a critical need to identify modifiable risk factors associated with relapse that can be addressed during AUD treatment. Candidate factors include mood disorders and cigarette smoking, which frequently co-occur with AUD. We predicted that co-occurrence of mood disorders, cigarette smoking, and other modifiable conditions will predict relapse within six months of AUD treatment. Ninety-five Veterans, 23-91 years old, completed assessments of multiple characteristics including demographic information, co-occurring psychiatric disorders, and medical conditions during residential treatment for AUD. Participants' alcohol consumption was monitored over six months after participation. Logistic regression was used to determine if, mood disorders, cigarette smoking status, alcohol consumption, educational level, and comorbid general medical conditions are associated with relapse after AUD treatment. Sixty-nine percent of Veterans (n = 66) relapsed within six months of study while 31% remained abstinent (n = 29). While education, comorbid general medical conditions, and mood disorder diagnoses were not predictors of relapse, Veterans with greater symptoms of anhedonia, active smokers, and fewer days of abstinence prior to treatment showed significantly greater odds for relapse within six months. Anhedonia and cigarette smoking are modifiable risk factors, and effective treatment of underlying anhedonic symptoms and implementation of smoking cessation concurrent with AUD-focused interventions may decrease risk of relapse.",
"affiliations": "Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.;Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.;Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.;Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.;Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.;Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.;Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. Electronic address: padula@stanford.edu.",
"authors": "Nguyen|Linh-Chi|LC|;Durazzo|Timothy C|TC|;Dwyer|Candice L|CL|;Rauch|Andrew A|AA|;Humphreys|Keith|K|;Williams|Leanne M|LM|;Padula|Claudia B|CB|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jpsychires.2020.04.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3956",
"issue": "126()",
"journal": "Journal of psychiatric research",
"keywords": "Alcohol use disorders; Anhedonia; Cigarette smoking; Relapse; Veterans",
"medline_ta": "J Psychiatr Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000437:Alcoholism; D059445:Anhedonia; D006801:Humans; D008875:Middle Aged; D012008:Recurrence; D012907:Smoking; D016540:Smoking Cessation; D055815:Young Adult",
"nlm_unique_id": "0376331",
"other_id": null,
"pages": "1-7",
"pmc": null,
"pmid": "32403028",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article",
"references": "25336410;27150382;19283568;25630963;15919159;24724879;18818189;15990430;8979210;31725426;17060998;17488322;20001818;8997790;21679263;9881538;20378281;10787393;26259094;22943795;28535406;17874878;18657940;26435383;27196143;30611836;25358471;17355897;16445550;27624615;15939839;27098451;18715746;30408209;11027896;27021146;7897050;21688208;18076750;28376287;16406196;19748166;21410483;23157448;25882685;24924665;26246792;24948080;22177980;20060237;29197929;25622198;17986708;20230726;22959116;27619009;20545871;17364419;18571890;17526627;28322982;26151807;17505465;21256179;21443289;19219669;20472297;21546204;29885861;12966322;7897037;27883214;7551619;2378290;21480681;1889923;26365044;26039070",
"title": "Predicting relapse after alcohol use disorder treatment in a high-risk cohort: The roles of anhedonia and smoking.",
"title_normalized": "predicting relapse after alcohol use disorder treatment in a high risk cohort the roles of anhedonia and smoking"
} | [
{
"companynumb": "US-OTSUKA-2020_021180",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Staphylococcus-associated glomerulonephritis (SAGN) is a rare immune complex-mediated glomerulonephritis associated with active Staphylococcus infection. We report a case illustrating the importance of clinical history and kidney biopsy findings in establishing the correct diagnosis.\nWe report the case of a 64-year-old man with alcohol-associated cirrhosis, type 2 diabetes mellitus, and hypertension who presented to hospital with lower back and abdominal pain, rectal bleeding, a purpuric lower extremity rash, and oliguric acute kidney injury with microscopic hematuria and nephrotic-range proteinuria.\nSkin biopsy revealed IgA leukocytoclastic vasculitis. Serum cryoglobulins were positive and there was hypocomplementemia with a low C3 level. Magnetic resonance imaging of the lumbar spine revealed septic discitis and epidural abscesses caused by a recent Staphylococcus aureus bacteremia. Kidney biopsy showed IgA-dominant and C3-dominant proliferative glomerulonephritis with subepithelial humps in keeping with SAGN.\nUrgent hemodialysis was initiated along with a prolonged course of intravenous cefazolin.\nRemarkably, the patient demonstrated a complete recovery of renal function after 2 months of dialysis dependence and successful treatment of the epidural abscesses.\nThis case shows that SAGN can closely mimic the clinical, laboratory, and histological presentation of Henoch-Schönlein Purpura or cryoglobulinemic vasculitis. Clinical history and kidney biopsy, particularly electron microscopic analysis, are essential to establishing the correct diagnosis to avoid the unnecessary and potentially harmful administration of immunosuppression. Despite the typically poor prognosis of SAGN, this case report illustrates that full renal recovery remains possible with supportive care and eradication of the underlying infection.",
"affiliations": "Department of Medicine, University of Toronto, Ontario, Canada.;Department of Medicine, University of Toronto, Ontario, Canada.;Department of Anatomic Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.;Division of Nephrology, Institute of Health Policy, Management and Evaluation, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.",
"authors": "Mahmood|Tahrin|T|;Puckrin|Robert|R|;Sugar|Linda|L|;Naimark|David|D|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2054358118776325",
"fulltext": "\n==== Front\nCan J Kidney Health DisCan J Kidney Health DisCJKspcjkCanadian Journal of Kidney Health and Disease2054-3581SAGE Publications Sage CA: Los Angeles, CA 10.1177/205435811877632510.1177_2054358118776325Educational Case ReportStaphylococcus-Associated Glomerulonephritis Mimicking Henoch-Schönlein Purpura and Cryoglobulinemic Vasculitis in a Patient With an Epidural Abscess: A Case Report and Brief Review of the Literature Mahmood Tahrin 1Puckrin Robert 1Sugar Linda 2Naimark David 31 Department of Medicine, University of Toronto, Ontario, Canada2 Department of Anatomic Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada3 Division of Nephrology, Institute of Health Policy, Management and Evaluation, Sunnybrook Health Sciences Centre, Toronto, Ontario, CanadaDavid Naimark, Division of Nephrology, Institute of Health Policy, Management and Evaluation, Sunnybrook Health Sciences Centre, Room 386, 1929 Bayview Avenue, Toronto, Ontario, Canada M4G 3E8. Email: david.naimark@sunnybrook.ca31 5 2018 2018 5 205435811877632514 9 2017 29 1 2018 © The Author(s) 20182018Canadian Society of Nephrology, unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Rationale:\nStaphylococcus-associated glomerulonephritis (SAGN) is a rare immune complex–mediated glomerulonephritis associated with active Staphylococcus infection. We report a case illustrating the importance of clinical history and kidney biopsy findings in establishing the correct diagnosis.\n\nPresenting concerns of the patient:\nWe report the case of a 64-year-old man with alcohol-associated cirrhosis, type 2 diabetes mellitus, and hypertension who presented to hospital with lower back and abdominal pain, rectal bleeding, a purpuric lower extremity rash, and oliguric acute kidney injury with microscopic hematuria and nephrotic-range proteinuria.\n\nDiagnoses:\nSkin biopsy revealed IgA leukocytoclastic vasculitis. Serum cryoglobulins were positive and there was hypocomplementemia with a low C3 level. Magnetic resonance imaging of the lumbar spine revealed septic discitis and epidural abscesses caused by a recent Staphylococcus aureus bacteremia. Kidney biopsy showed IgA-dominant and C3-dominant proliferative glomerulonephritis with subepithelial humps in keeping with SAGN.\n\nInterventions:\nUrgent hemodialysis was initiated along with a prolonged course of intravenous cefazolin.\n\nOutcomes:\nRemarkably, the patient demonstrated a complete recovery of renal function after 2 months of dialysis dependence and successful treatment of the epidural abscesses.\n\nLessons learned:\nThis case shows that SAGN can closely mimic the clinical, laboratory, and histological presentation of Henoch-Schönlein Purpura or cryoglobulinemic vasculitis. Clinical history and kidney biopsy, particularly electron microscopic analysis, are essential to establishing the correct diagnosis to avoid the unnecessary and potentially harmful administration of immunosuppression. Despite the typically poor prognosis of SAGN, this case report illustrates that full renal recovery remains possible with supportive care and eradication of the underlying infection.\n\nAbrégé\nExposition:\nLa glomérulonéphrite aigüe post-infection à Staphylococcus (GNAS) est une glomérulonéphrite rare, médiée par un complexe immunitaire et associée à une infection active à Staphylococcus aureus. Nous présentons un cas qui illustre l’importance des antécédents médicaux et des résultats de la biopsie rénale dans la pose d’un diagnostic.\n\nPrésentation du cas:\nNous rapportons le cas d’un homme de 64 ans atteint d’une cirrhose alcoolique, de diabète de type 2 et d’hypertension qui s’est présenté à l’hôpital avec des douleurs lombaires et abdominales, un saignement rectal, une éruption purpurique des extrémités inférieures et une insuffisance rénale aigüe oligurique avec hématurie microscopique et protéinurie néphrotique.\n\nDiagnostic:\nLa biopsie cutanée a révélé une vascularite leucocytoclastique à IgA. Les cryoglobulines sériques étaient positives et une hypocomplémentémie avec un faible taux de C3 a été constatée. L’imagerie par résonnance magnétique du rachis lombal a permis de détecter une discite septique et des abcès périduraux causés par une récente bactériémie à Staphylococcus aureus. La biopsie rénale a quant à elle montré la présence d’une glomérulonéphrite proliférative à IgA et à C3 dominants et de volumineux dépôts sous-épithéliaux en bosse (humps) conformes à une GNAS.\n\nTraitement:\nOn a amorcé une hémodialyse d’urgence et un traitement prolongé à la céfazoline par voie intraveineuse.\n\nRésultats:\nFait remarquable, après le traitement des abcès périduraux et deux mois de dépendance à l’hémodialyse, la fonction rénale du patient a été complètement rétablie.\n\nConclusion:\nCe cas démontre que la GNAS peut simuler la présentation clinique, biologique et histologique du purpura d’Henoch-Schönlein ou celle de la vascularite cryoglobulinémique. La revue des antécédents médicaux et l’analyse d’une biopsie rénale (particulièrement par microscopie électronique) sont essentielles pour établir un diagnostic juste et pour éviter l’administration superflue, voire néfaste, d’immunosuppresseurs. Malgré le pronostic sombre normalement associé à la GNAS, ce cas démontre que le rétablissement complet de la fonction rénale demeure possible, pour autant que l’on procède à un traitement symptomatique et que l’on éradique l’infection sous-jacente.\n\nstaphylococcus-associated glomerulonephritisHenoch-Schönlein Purpuracryoglobulinemic vasculitiskidney biopsycover-dateJanuary-December 2018\n==== Body\nWhat was known before\nStaphylococcus-associated glomerulonephritis (SAGN) is a rare immune complex–mediated glomerulonephritis that can present with oliguric acute kidney injury and nephrotic-range proteinuria.\n\nWhat this adds\nThe clinical and histological presentation of SAGN can closely mimic that of Henoch-Schönlein Purpura or cryoglobulinemic vasculitis with cutaneous leukocytoclastic vasculitis, positive serum cryoglobulins, hypocomplementemia, and IgA-dominant glomerulonephritis. Clinical history and kidney biopsy findings are essential to establishing the correct diagnosis. Recovery of renal function is possible with treatment of the underlying infection and avoidance of immunosuppression.\n\nIntroduction\nInfections caused by the virulent pathogen Staphylococcus aureus are increasing in incidence and often associated with antibiotic resistance and potentially life-threatening complications.1 A rare, but well-recognized, complication of S aureus is an immune complex–mediated glomerulonephritis triggered by a persistent active infection.2 We report the case of a patient with S aureus bacteremia who developed an epidural abscess and oliguric acute kidney injury (AKI) with nephrotic-range proteinuria secondary to staphylococcus-associated glomerulonephritis (SAGN). His clinical presentation was deceptively similar to that of Henoch-Schönlein Purpura (HSP) and cryoglobulinemic vasculitis. We review the epidemiology and clinical features of SAGN with discussion of the essential role for kidney biopsy in establishing the correct diagnosis to prevent the unnecessary and potentially harmful administration of immunosuppression in the setting of Staphylococcus infection.\n\nCase Presentation\nA 64-year-old man with no history of renal disease was referred to our Nephrology service due to oliguric AKI. The patient presented to hospital with a 2-day history of decreased urine output, new-onset rash over the lower extremities, intermittent bright red blood per rectum, and lower abdominal tenderness. He had been discharged from another hospital 3 days prior to presentation after an admission for community-acquired pneumonia complicated by methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia which had been treated with a 2-week course of intravenous vancomycin. He had also developed acute worsening of his chronic low back pain and received a lumbar epidural corticosteroid injection while in hospital.\n\nThe patient was of South Asian ancestry and previously worked in the manufacturing industry. His medical history also included compensated alcohol-associated cirrhosis Child-Pugh A, resistant hypertension, poorly controlled type 2 diabetes mellitus, obesity, asthma, gastroesophageal reflux disease (GERD), and lumbar spinal stenosis. His medications at the time of admission were acetylsalicylic acid (ASA), valsartan, diltiazem, amlodipine, furosemide, hydrochlorothiazide, metformin, canagliflozin, sitagliptin, insulin lispro, rosuvastatin, theophylline, tiotropium, fluticasone propionate/salmeterol, and salbutamol. He consumed 2 to 3 servings of alcohol per day and was a former smoker with a 25 pack-year smoking history. He denied intravenous or other recreational drug use.\n\nPhysical examination revealed an elevated blood pressure of 184/79 mm Hg with otherwise normal vital signs and mental status. Bilateral basilar crackles were detected upon pulmonary auscultation but he appeared otherwise euvolemic. The abdomen was soft and nontender and there was scant red blood on digital rectal examination. There was tenderness to palpation of the lumbar spine with normal tone, power, reflexes, and sensation in the lower extremities. Skin examination revealed multiple patches of nonpalpable purpura in the lower extremities. A Foley catheter was inserted which yielded less than 200 mL of urine over 12 hours.\n\nLaboratory investigations revealed an elevated creatinine of 493 µmol/L from a baseline of 91 µmol/L at the time of discharge 5 days previously from another hospital. There were significant biochemical abnormalities with hyperkalemia (potassium 6.0 mEq/L), hyponatremia (sodium 126 mEq/L), acidemia (bicarbonate 17 mmol/L), and hyperphosphatemia (phosphate 1.78 mmol/L). Urinalysis was remarkable for 1 g/L of albumin and 250 red blood cells (RBC)/µL although no casts were noted on microscopic examination of urine sediment. A urinalysis 6 months ago was negative for protein or microscopic hematuria, which suggests a diagnosis of preexisting diabetic nephropathy or IgA nephropathy. Serum albumin was 30 g/L and there was nephrotic-range proteinuria with a spot urine albumin-creatinine ratio (UACR) 317 mg/mmol and urine protein-creatinine ratio (UPCR) 359 mg/mmol. The most recent UACR done prior to this was more than 1 year ago, at which point it was mildly elevated at 2.6 mg/mmol and was normal 2 years ago. The remaining initial investigations were notable for mild normocytic anemia (hemoglobin 117 g/L), neutrophilia (neutrophil count 10.6 × 109/L), and elevated inflammatory markers with C-reactive protein 91 mg/L and erythrocyte sedimentation rate 60 mm/h. Ultrasound of the abdomen showed a cirrhotic liver with splenomegaly and mild ascites; the kidneys were normal in size and echogenicity with no evidence of hydronephrosis.\n\nA trial of intravenous furosemide failed to improve the oliguria and hyperkalemia so a temporary right femoral vein dialysis catheter was inserted under ultrasound guidance. The patient was urgently initiated on intermittent hemodialysis (IHD) while investigations for the cause of his renal dysfunction were undertaken. There was no clinical evidence of prerenal or postrenal AKI and the time course and systemic symptoms were not in keeping with vancomycin-induced nephrotoxicity. His presentation was therefore felt to be consistent with a rapidly progressive glomerulonephritis (RPGN), particularly given the purpuric rash, microscopic hematuria, and heavy proteinuria. Initial suspicion for endocarditis-associated glomerulonephritis secondary to the recent MSSA bacteremia was discounted by negative serial blood cultures and the absence of valvular vegetations on transthoracic and transesophageal echocardiograms. Consideration was given to other diagnoses including postinfectious glomerulonephritis or immune complex–mediated membranoproliferative glomerulonephritis, which were consistent with the recent infection and presence of hypocomplementemia with slightly low C3 at 0.64 g/L and normal C4. Interestingly, serum cryoglobulin testing was positive for 1 g/L of cryoprecipitate although several repeat samples taken in the following weeks were negative. A work-up for other causes of glomerulonephritis was negative for antinuclear antibody (ANA), anticytoplasmic antibody (ANCA), anti-glomerular basement membrane (GBM) antibody, and rheumatoid factor. Serologies were also negative for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). Serum and urine protein electrophoresis were unremarkable. Skin biopsy of the purpuric rash revealed a leukocytoclastic vasculitis with positive staining for IgA, IgM, and C3 on immunofluorescence. The presence of IgA raised concern for HSP (also known as IgA vasculitis), particularly with the suggestive history of a recent respiratory tract infection and purpuric rash, abdominal pain, and gastrointestinal bleeding.\n\nDespite the diagnostic uncertainty regarding the etiology of the RPGN, there was initial reluctance to pursue a kidney biopsy or empiric pulsed corticosteroids in light of the patient’s recent infection and medical comorbidities. Furthermore, magnetic resonance imaging (MRI) of the lumbar spine demonstrated septic discitis at the L4-L5 interspace along with epidural abscesses extending from L3 to L5 and S1 to S2 (see Figure 1). The likely etiology of these findings was the recent MSSA bacteremia. The patient was administered a prolonged course of intravenous cefazolin while continuing on thrice-weekly IHD. Following completion of 6 weeks of antibiotic therapy, the patient’s low back pain had significantly diminished, serum complement levels were normalized, and there was radiographic improvement of the epidural abscesses on follow-up MRI.\n\nFigure 1. Magnetic resonance imaging of the lumbar spine performed without the administration of intravenous contrast demonstrating septic discitis at the L4-L5 interspace along with epidural abscesses extending from L3 to L5 and S1 to S2.\n\nWith this controlled infection no longer posing a contraindication to immunosuppressive therapy, a renal biopsy was performed 7 weeks after presentation to identify treatable etiologies of RPGN, such as HSP or cryoglobulinemic vasculitis. Kidney biopsies are often done and are a recommended procedure to rule out other causes of glomerulonephritis, including C3 nephritis.3 Pathological examination of the biopsy specimen revealed 17 glomeruli of which 4 were globally sclerosed. No features of acute tubular necrosis were found. There was diffuse global hypercellularity with mesangial and endocapillary proliferation as well as infiltrating monocytes and occasional neutrophils, consistent with proliferative glomerulonephritis (see Figure 2). No crescents or necrotizing lesions were identified on light microscopy and there was minimal glomerular sclerosis, suggesting a potential for recovery of renal function. Immunofluorescence revealed diffuse staining with IgA (+2) and C3 (+3) throughout the mesangium and GBM. There was no evidence of interstitial eosinophils, which helped to exclude other diagnosis such as vancomycin-induced nephrotoxicity. There was trace staining for IgG, lambda, and kappa and negative staining for IgM and C1q (see Figure 3). The preliminary interpretation of the light microscopy findings and strong IgA staining on immunofluorescence was thought to be consistent with IgA nephropathy or HSP, prompting the initiation of prednisone at a dose of 1 mg/kg daily. However, electron microscopy performed the following day demonstrated large subepithelial deposits with a hump-like appearance (see Figure 4). The presence of these subepithelial humps and stronger staining for C3 over IgA was finally deemed to be more consistent with the diagnosis of SAGN, and the corticosteroids were immediately discontinued. The diagnosis of SAGN was further supported by the recent MSSA bacteremia, ongoing epidural abscess, and, ultimately, improvement of renal function with eradication of the underlying infection.\n\nFigure 2. Light microscopy of a renal biopsy demonstrating diffuse global hypercellularity with mesangial and endocapillary proliferation as well as infiltrating monocytes and occasional neutrophils.\n\nFigure 3. Immunofluorescence of a renal biopsy demonstrating diffuse granular staining for C3 (left) and IgA (right) in the glomerular basement membrane and mesangium.\n\nFigure 4. Electron microscopy of a renal biopsy demonstrating a large subepithelial deposit with a hump-like appearance as well as some mesangial and paramesangial electron dense deposits.\n\nThe patient showed promising signs of renal recovery with increasing urine output and stabilization of the interdialytic rise in creatinine. Remarkably, 9 weeks after initiation of IHD for RPGN with oliguric AKI, he was successfully transitioned off dialysis and demonstrated full recovery of renal function. Eight months after his initial presentation to hospital, the patient is clinically well and has resumed his usual activities of daily living. At this time, he has some evidence of residual renal injury with ongoing Grade A3 proteinuria (UACR 65 mg/mmol) which could represent irreversible glomerular injury from SAGN, but serum creatinine remains stable at 93 µmol/L.\n\nDiscussion\nStaphylococcus-associated glomerulonephritis is a rare, recently described immune complex–mediated glomerulonephritis associated with Staphylococcus infection. Unlike postinfectious glomerulonephritis (PIGN) which typically presents 1 to 3 weeks after resolution of a streptococcal skin or respiratory tract infection, SAGN usually arises concurrently with persistent active staphylococcal cellulitis, endocarditis, osteomyelitis, abscess, or infection of an indwelling shunt.4,5 Staphylococcus-associated glomerulonephritis commonly presents with AKI with hypertension, hypocomplementemia, elevated creatinine, microscopic hematuria, and variable proteinuria which reaches the nephrotic range in 21% to 48% of patients.6,7 The pathophysiology of SAGN is poorly understood but is postulated to involve massive T-cell activation by a staphylococcal superantigen that results in cytokine release; polyclonal B-cell overproduction of IgA, IgG, and IgM; and systemic vasculitis with IgA-staphylococcal antigen immune complex formation and deposition.2 This is a rare diagnosis with the largest published review of the literature to date identifying only 83 reported cases of biopsy-proven SAGN.7 Our patient is illustrative of the typical demographic affected by SAGN, with the most common risk factors being male sex (77%), age >65 years old (41%), diabetes mellitus (24%), and absence of previous renal disease (100%).7 Other risk factors include chronic HCV infection, malignancy, cardiac disease, hypertension, intravenous drug use, trauma, and the postoperative state.6,8 Clinicians should consider the diagnosis of SAGN in patients with new-onset renal dysfunction in the setting of an active staphylococcal infection and these underlying risk factors.\n\nA key learning point of this case report is that SAGN can closely mimic the clinical, laboratory, and pathological presentation of HSP and cryoglobulinemic vasculitis. Indeed, our patient presented with cardinal features of HSP including abdominal pain, gastrointestinal bleeding, IgA cutaneous leukocytoclastic vasculitis, and IgA-dominant glomerulonephritis. A purpuric rash and acute glomerulonephritis can also be seen in mixed cryoglobulinemic vasculitis, and positive cryoglobulin testing has been reported in at least one other patient with SAGN in addition to this case.9 Indeed, more than 20% of patients with SAGN present with a leukocytoclastic vasculitis and lower extremity purpuric rash.10 Clinical characteristics were present in our patient that favor the diagnosis of SAGN over HSP including older age, diabetes mellitus, active staphylococcal infection, and presentation with AKI and hypocomplementemia. As in the case of this patient, renal biopsy may ultimately be required to distinguish SAGN from other glomerular diseases, although the histopathological findings of SAGN and IgA vasculitis are often challenging to differentiate.4 Typical microscopic findings of SAGN include mesangioproliferative and/or endocapillary proliferative immune complex glomerulonephritis with crescent formation in 30% to 40% of patients.6,7 Immunofluorescence is similar to HSP and IgA nephropathy with granular IgA and/or C3 immune complex deposition. However, SAGN can be distinguished by stronger immunofluorescent staining for C3 than IgA.4 Subepithelial hump-like deposits can be found on electron microscopy in 31% to 45% of cases of SAGN which also supports this diagnosis over that of IgAN.6,7 The presence of an inflammatory infiltrate with neutrophils can support the diagnosis of SAGN over IgAN, but this is not a universal finding as the largest review of the literature to date showed neutrophilic infiltration in only 24/83 patients with SAGN.7 As in the case of this patient, a renal biopsy can be invaluable in establishing the correct diagnosis and guiding management, particularly when the presentation of SAGN mimics other steroid-responsive disease processes such as HSP or cryoglobulinemic vasculitis. Timely electron micrographic analysis is particularly important in SAGN because of the resemblance to other glomerulopathies on light and immunofluorescence microscopy. The rapid availability of electron micrographs in this case spared the patient from an unnecessary and potentially harmful prolonged course of corticosteroids.\n\nA remarkable feature of this patient’s clinical course was the complete recovery of renal function after a clinically aggressive presentation with oliguric AKI and more than 2 months of dialysis dependence. This is particularly noteworthy given the typically poor prognosis of SAGN which carries a 15% mortality rate, 18% rate of persistent renal dysfunction, and 23% rate of dialysis-dependent end-stage renal disease.7 Older age, elevated serum creatinine, tubulointerstitial scarring, and underlying diabetes mellitus are all predictive of adverse renal outcomes.6,7 As in the case of our patient, recovery from renal injury tends to occur with treatment and resolution of the underlying infection with antibiotics and, in some cases, surgical source control. This differs from other causes of RPGN, which are often empirically treated with pulse dose of steroids in clinical practice, even though there is sparse randomized control trial data supporting this practice.11 Treatment with immunosuppressive agents such as corticosteroids has been reported to be successful in a small number of case reports,10,12 but is generally not advised due to the lack of supportive data and significant risk of sepsis and uncontrolled staphylococcal infection.5,6 The unique clinical course of our patient demonstrates that despite adverse prognostic indicators and prolonged dialysis dependence, complete recovery of renal function remains possible in SAGN with supportive care and successful eradication of the underlying infection without the administration of prolonged immunosuppressive therapy.\n\nConclusion\nStaphylococcus-associated glomerulonephritis is a rare immune complex–mediated glomerulonephritis which can manifest with oliguric AKI and nephrotic-range proteinuria. With positive serum cryoglobulins, hypocomplementemia, abdominal pain, gastrointestinal bleeding, and cutaneous leukocytoclastic vasculitis, this patient’s clinical presentation was deceptively similar to that of HSP or cryoglobulinemic vasculitis. His epidemiological risk factors (eg, older age and diabetes mellitus), history of MSSA bacteremia and epidural abscess, and kidney biopsy findings were essential to establishing the correct diagnosis of SAGN. Although this patient had multiple negative prognostic indicators and more than 2 months of dialysis dependence, his remarkable clinical course demonstrates that full renal recovery is possible with supportive care and treatment of the underlying infection. Clinicians should consider this rare diagnosis in patients who develop RPGN in the setting of active Staphylococcus infection, perform a kidney biopsy if there is diagnostic uncertainty, and avoid immunosuppressive therapies due to the risk of uncontrolled Staphylococcus sepsis.\n\nEthics Approval and Consent to Participate: The patient provided informed written consent for publication of this case report and accompanying images. Institutional ethics board approval is not required for this type of study.\n\nConsent for Publication: The patient and all contributing authors consented to publication of this case report.\n\nAvailability of Data and Materials: Not applicable.\n\nAuthors’ Note: These authors contributed equally to this work. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nAuthor Contributions: TM and RP performed the literature review and wrote the manuscript. LS provided pathology images and edited the manuscript. DN supervised the case report and edited the manuscript.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n1. \nTong SY Davis JS Eichenberger E Holland TL Fowler VG Jr. \nStaphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management . Clin Microbiol Rev . 2015 ;28 (3 ):603 -661 .26016486 \n2. \nKoyama A Kobayashi M Yamaguchi N. \nGlomerulonephritis associated with MRSA infection: a possible role of bacterial superantigen . Kidney Int . 1995 ;47 (1 ):207 -216 .7731148 \n3. \nCattran DC Feehally J Cook HT et al \nKidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO clinical practice guideline for glomerulonephritis . Kidney Inter Suppl . 2012 ;2 :156 -162 .\n4. \nNadasdy T Hebert LA. \nInfection-related glomerulonephritis: understanding mechanisms . Semin Nephrol . 2011 ;31 (4 ):369 -375 .21839370 \n5. \nGlassock RJ Alvarado A Prosek J. \nStaphylococcus-related glomerulonephritis and poststreptococcal glomerulonephritis: why defining “post” is important in understanding and treating infection-related glomerulonephritis . Am J Kidney Dis . 2015 ;65 (6 ):826 -832 .25890425 \n6. \nHemminger J Satoskar A \nStaphylococcus infection-associated glomerulonephritis . In: Satoskar A Nadasdy T eds. Bacterial Infections and the Kidney . New York, NY : Springer ; 2017 :37 -61 .\n7. \nWang SY Bu R Zhang Q et al \nClinical, pathological, and prognostic characteristics of glomerulonephritis related to staphylococcal infection . Medicine (Baltimore) . 2016 ;95 (15 ):e3386 .27082609 \n8. \nWehbe E Salem C Simon JF Navaneethan SD Pohl M. \nIgA-dominant Staphylococcus infection-associated glomerulonephritis: case reports and review of the literature . NDT Plus . 2011 ;4 (3 ):181 -185 .25984152 \n9. \nSatoskar AA Nadasdy G Plaza JA et al \nStaphylococcus infection-associated glomerulonephritis mimicking IgA nephropathy . Clin J Am Soc Nephrol . 2006 ;1 (6 ):1179 -1186 .17699345 \n10. \nSatoskar AA Molenda M Scipio P et al \nHenoch-Schonlein purpura-like presentation in IgA-dominant Staphylococcus infection–associated glomerulonephritis—a diagnostic pitfall . Clin Nephrol . 2013 ;79 (4 ):302 -312 .23320971 \n11. \nGreenhall G Salama A. \nWhat is new in the management of glomerulonephritis? \nClin Kidney J . 2015 ;8 (2 ):143 -150 .25815169 \n12. \nOkuyama S Wakui H Maki N et al (2008 ). Successful treatment of post-MRSA infection glomerulonephritis with steroid therapy . Clin Nephrol . 2008 ;70 (4 ):344 -347 .18826861\n\n",
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"journal": "Canadian journal of kidney health and disease",
"keywords": "Henoch-Schönlein Purpura; cryoglobulinemic vasculitis; kidney biopsy; staphylococcus-associated glomerulonephritis",
"medline_ta": "Can J Kidney Health Dis",
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"pages": "2054358118776325",
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"pmid": "29900000",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "7731148;18826861;21839370;26016486;25815169;25890425;27082609;17699345;25984152;23320971",
"title": "Staphylococcus-Associated Glomerulonephritis Mimicking Henoch-Schönlein Purpura and Cryoglobulinemic Vasculitis in a Patient With an Epidural Abscess: A Case Report and Brief Review of the Literature.",
"title_normalized": "staphylococcus associated glomerulonephritis mimicking henoch sch nlein purpura and cryoglobulinemic vasculitis in a patient with an epidural abscess a case report and brief review of the literature"
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"abstract": "There is no standard of care in elderly classical Hodgkin lymphoma (cHL) patients. ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), the standard chemotherapy for younger patients, is also used in elderly patients but little is known about toxicity and efficacy. We retrospectively analysed 147 patients aged 60 years and over treated with ABVD in three French haematological centres. Treatment regimen modification was applied in 56 patients for toxicity or HL progression. Bleomycin was removed or reduced in 53 patients, mainly for pulmonary toxicity. Neither initial characteristics nor treatment characteristics were found to correlate with lung toxicity. One hundred and seventeen patients achieved a complete remission, 6 a partial remission, 16 had refractory disease and 8 were non-evaluable. Five-year overall survival was estimated at 67%. With a median follow-up of 58 months, 51 patients died and 14% of deaths were related to lung toxicity. Our study confirms the efficacy of ABVD in elderly patients even if results are inferior to those obtained in younger patients with the same regimen. ABVD can be proposed as front-line chemotherapy in selected elderly cHL patients. The frequency of pulmonary events leads us to propose to either reduce the dose of bleomycin or to remove it from the regimen.",
"affiliations": "Henri Becquerel Centre, Rouen University, Rouen, France.;Saint Louis Hospital, Paris, France.;Paoli Calmette Institute, Marseille, France.;Henri Becquerel Centre, INSERM U918, Rouen, France.;Henri Becquerel Centre, Rouen University, Rouen, France.;Paoli Calmette Institute, Marseille, France.;Saint Louis Hospital, Paris, France.;Henri Becquerel Centre, Rouen University, Rouen, France.;Henri Becquerel Centre, Rouen University, Rouen, France.",
"authors": "Stamatoullas|Aspasia|A|;Brice|Pauline|P|;Bouabdallah|Reda|R|;Mareschal|Sylvain|S|;Camus|Vincent|V|;Rahal|Ilhem|I|;Franchi|Patricia|P|;Lanic|Hélène|H|;Tilly|Hervé|H|",
"chemical_list": "D001761:Bleomycin; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.13419",
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"issn_linking": "0007-1048",
"issue": "170(2)",
"journal": "British journal of haematology",
"keywords": "Hodgkin lymphoma; doxorubicin, bleomycin, vinblastine and dacarbazine; elderly; pulmonary toxicity",
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"title": "Outcome of patients older than 60 years with classical Hodgkin lymphoma treated with front line ABVD chemotherapy: frequent pulmonary events suggest limiting the use of bleomycin in the elderly.",
"title_normalized": "outcome of patients older than 60 years with classical hodgkin lymphoma treated with front line abvd chemotherapy frequent pulmonary events suggest limiting the use of bleomycin in the elderly"
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"abstract": "BACKGROUND Despite advances in diagnosis and treatment, epithelial ovarian cancer (EOC) continues to be highly lethal. Undoubtedly, the introduction of poly(adenosine diphosphate-ribose) polymerase inhibitors such as olaparib will alter this clinical picture. Phase III studies have already documented clinically relevant outcomes, particularly among patients with BRCA mutations and homologous recombination deficiency. CASE REPORT Here we present a case report that documents the evolution of refractory multidrug-resistant, BRCA1-mutated EOC in a patient who had advanced clinical deterioration, carcinomatosis, and central nervous system (CNS) involvement that responded favorably to olaparib, resulting in a tripling of her progression-free survival. CONCLUSIONS Olaparib proved to be a safe and effective option for the treatment of a patient with multidrug-resistant, BRCA1-mutated EOC with CNS metastases. This suggests that early initiation of the drug in similar cases can be very useful.",
"affiliations": "Department of Medical Oncology, National Cancer Institute, Mexico City, Mexico.;Department of Oncologic Surgery, National Cancer Institute, Mexico City, Mexico.;Department of Embryology, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico.;Medical Intern in Social Service, National Cancer Institute, Mexico City, Mexico.",
"authors": "Morales Vázquez|Flavia|F|;López Basave|Horacio Noé|HN|;Méndez Herrera|María Del Carmen|MDC|;Peña González|Ricardo Raziel|RR|",
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"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\n33226974\n10.12659/AJCR.925990\n925990\nArticles\nClinically Relevant Response to Treatment with Olaparib in a Patient with Refractory Multidrug-Resistant Ovarian Cancer and Central Nervous System Involvement: A Case Report\nVásquez Flavia Morales ABCDEFG1 Basave Horacio Noé López BDEF2 Herrera María del Carmen Méndez BCDE3 González Ricardo Raziel Peña BCF4 \n1 Department of Medical Oncology, National Cancer Institute, Mexico City, Mexico\n\n2 Department of Oncologic Surgery, National Cancer Institute, Mexico City, Mexico\n\n3 Department of Embryology, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico\n\n4 Medical Intern in Social Service, National Cancer Institute, Mexico City, Mexico\nCorresponding Author: Flavia Morales Vásquez, e-mail: fmoralesv@incan.edu.mxAuthors’ 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: AztraZeneca México provided medical writing assistance with the manuscript but was not involved in the analysis of the data or the final content\n\n\n2020 \n23 11 2020 \n21 e925990-1 e925990-5\n14 5 2020 24 9 2020 09 10 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 52-year-old\n\nFinal Diagnosis: Epithelial ovarian cancer with central nervous system involvement\n\nSymptoms: Abdominal pain • convulsions • dyspnea • weigh loss\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Oncology\n\nObjective:\nUnusual or unexpected effect of treatment\n\nBackground:\nDespite advances in diagnosis and treatment, epithelial ovarian cancer (EOC) continues to be highly lethal. Undoubtedly, the introduction of poly(adenosine diphosphate-ribose) polymerase inhibitors such as olaparib will alter this clinical picture. Phase III studies have already documented clinically relevant outcomes, particularly among patients with BRCA mutations and homologous recombination deficiency.\n\nCase Report:\nHere we present a case report that documents the evolution of refractory multidrug-resistant, BRCA1-mutated EOC in a patient who had advanced clinical deterioration, carcinomatosis, and central nervous system (CNS) involvement that responded favorably to olaparib, resulting in a tripling of her progression-free survival.\n\nConclusions:\nOlaparib proved to be a safe and effective option for the treatment of a patient with multidrug-resistant, BRCA1-mutated EOC with CNS metastases. This suggests that early initiation of the drug in similar cases can be very useful.\n\nMeSH Keywords:\nGenes, BRCA1Neoplasm MetastasisOvarian NeoplasmsPoly(ADP-ribose) Polymerases\n==== Body\nBackground\nEpithelial ovarian cancer (EOC), which is characterized by persistent recurrences and lethality, is the third leading cause of death in women aged 40 to 59 years [1,2]. Poly(adenosine di-phosphate-ribose) polymerase (PARP) inhibitors are effective in controlling the disease and increasing progression-free survival (PFS) [3]. Olaparib, a PARP inhibitor that induces death in BRCA1/2-deficient cell lines, has significant activity in patients with BRCA-mutated, platinum-resistant ovarian cancer (31% response rate and 40% rate of disease stabilization for >8 weeks) [4]. It has been proposed as maintenance monotherapy in patients with platinum-sensitive recurrences [5]. We report the case of a 52-year-old woman with high-grade serous papillary EOC and central nervous system (CNS) metastases who received multiple treatments, including radiation therapy, and responded very favorably to olaparib, with a tripling of PFS (Figure 1).\n\nCase Report\nThe patient was a 52-year-old Mexican woman with a 6-month history of abdominal pain, increased abdominal circumference, dyspnea, pleuritic pain, and weight loss (6 kg in 2 months), with no relevant medical history. A computed tomography (CT) scan of her abdomen and thorax revealed a cystic tumor in the pelvic cavity that involved both ovaries, with peritoneal carcinomatosis (Figure 2A), as well as an accumulation of ascitic fluid and pleural effusion (Figure 2B).\n\nThe woman’s cancer antigen 125 (CA-125) level was 5923 UI/mL, a biopsy showed a high-grade serous papillary tumor, and cytologic testing of the pleural effusion confirmed a diagnosis of stage IVA EOC. After she received genetic counseling and provided informed consent for testing, a pathogenic mutation in exon 11 of BRCA1 was documented.\n\nThe patient was deemed not to be a candidate for surgical re-section because of the extent of the carcinomatosis and the presence of pleural effusion. Therefore, she was treated with 6 cycles of first-line chemotherapy with carboplatin plus paclitaxel, but her EOC responded poorly and she had persistent elevation of CA-125 (240 UI/mL at the lowest point). Lacking surgery to reduce tumor burden, second-line chemotherapy was started with tamoxifen plus thalidomide as palliation in the absence of bevacizumab. After 6 months of treatment, the patient’s CA-125 level was undetectable and no tumor activity was seen on CT scan.\n\nEleven months later, a CT scan showed new tumor activity and her CA-125 level had risen to 1097 UI/mL. She was then started on third-line chemotherapy with trabectedin plus liposomal doxorubicin. After 6 cycles, a positron emission tomography CT (PET-CT) scan showed a complete metabolic response.\n\nFive months later, the patient had a new recurrence and surgical tumor debulking was attempted but was unsuccessful. She then began experiencing episodes of convulsive crisis, whereupon fourth-line chemotherapy was started with gemcitabine plus carboplatin. After an 8-mm lesion in the right frontal lobe and a second lesion in the left cerebellar hemisphere were seen on CNS CT and the findings were corroborated with magnetic resonance imaging (Figure 3), the patient received whole-brain radiation therapy.\n\nFive months later, she received 4 cycles of liposomal adriamycin (5th-line treatment), and PET-CT showed an increase in tumor activity. Etoposide therapy was begun and after 2 cycles, the patient’s CA-125 level was 860 UI/mL, PET-CT showed stable disease, and her clinical condition deteriorated. Therefore, weekly paclitaxel was started, without good results, and compassionate use of letrozole was begun. After 3 months, the patient’s clinical condition continued to worsen, with increased dyspnea, neurological deterioration, and an elevated CA-125 level (2334 UI/mL). Ninth-line therapy then was started with gemcitabine, but her CA-125 level remained unchanged (2525 UI/mL) and she had continued neurological worsening, characterized by poor response to stimuli and inability to walk, and she was confined to bed most of the day.\n\nGiven that the patient’s tumor was BRCA1-mutated, olaparib was begun at 400 mg twice daily. Seven days after initiation of therapy, the patient had significant neurologic improvement (alert, oriented, and able to walk again), and her abdominal pain and dyspnea diminished considerably.\n\nAt the start of treatment with olaparib, the patient only had grade 1 nausea, fatigue, and dizziness. By Week 4, all her symptoms of toxicity had disappeared, except for vertigo, which was adequately controlled with diphenidol. After 8 weeks of treatment, the patient presented with anemia, neutropenia, and an increased CA-125 level (313 UI/mL), which prompted treatment interruption. One month later, when a PET-CT scan and CA-125 level (431 UI/mL) indicated activity in the remaining tumor, olaparib was restarted at a lower dose (300 mg twice daily).\n\nFor 8 more months, the patient continued to improve while she was being treated with olaparib and her disease was biochemically stable. She had only very low toxicity: Grade 1 anemia and no thrombocytopenia or changes on tests of renal or hepatic function.\n\nNine months after olaparib therapy was begun, disease progression was document again, with an increase in CA-125 level (1816 UI/mL), evidence on CT of peritoneal and lymph node progression, and peripheral edema in the left leg due to superficial and deep vein thrombosis. Those findings prompted the definitive suspension of olaparib. Disease progression continued and she died 2 months later.\n\nDiscussion\nThe most relevant characteristic of this case is the excellent clinical response to treatment with olaparib that was seen even after prior disease progression and multidrug resistance. The patient recovered from near total incapacity and deep neurological deterioration. Olaparib treatment kept her disease at bay for nearly a year with neurological recovery, something seldom seen after a lack of response to whole-brain radiation therapy.\n\nThe patient’s EOC failed to respond to any treatment in a sustained fashion, and olaparib was the tenth-line treatment. In 2016, the drug was not available in México and had to be imported specifically for this patient, and its use was not as widespread then as it is today.\n\nPrevious cases have been documented in the literature of successful olaparib monotherapy in patients with BRCA2-mutated EOC and leptomeningeal disease [6], and in patients with primary peritoneal BRCA1-mutated cancer with persistently elevated CA-125 levels [7].\n\nMutations in BRCA1 and BRCA2, which have been reported in 5.8% to 24.8% of all cases, are a major risk factor in EOC [8]. They are associated with earlier presentation, greater susceptibility to chemotherapy, and overall better prognosis. BRCA1 and BRCA2 are suppressor genes whose function is to maintain genomic stability and regulate cell growth. Mutations in the genes are seen in 90% of cases of hereditary breast-ovarian cancer syndrome. The average age of patients at presentation of EOC with BRCA1 mutation is 45 years vs. 57 years for BRCA2 mutation [9].\n\nIn general with EOC, recurrences happen locally; however, the literature suggests that BRCA mutation carriers may have an increased rate of distant metastases [10]. BRCA screening is recommended for patients recently diagnosed with EOC because a mutation has implications for prognosis, prevention, and treatment.\n\nPARP is crucial for DNA repair through base excision. Thus, inhibition of PARP leads to breaks in double-stranded DNA that cannot be adequately repaired in tumors with homologous recombination deficiency because of the aberrant activation of low-fidelity repair mechanisms mediated by non-homologous end unions, a process known as synthetic lethality [5,11].\n\nOlaparib is a PARP inhibitor that induces synthetic lethality in BRCA1/2-deficient cell lines [12]. Currently, olaparib is used as monotherapy in patients with platinum-sensitive disease (defined as an objective response to platinum-based therapy for >6 months) that has recurred. A dosage of 400 mg twice daily has been shown to significantly improve PFS compared with placebo [13]. Since 2014, the average PFS for the drug has increased (11.2 months with olaparib vs. 4.3 months with placebo, P=0.0001) [14]. Because olaparib has significant activity in BRCA-mutated, platinum-resistant ovarian cancer, it has been suggested as fourth-line treatment in that setting [4].\n\nOur patient had received multiple treatments and her disease had responded poorly to most of them, whereas monotherapy with olaparib resulted in very meaningful benefits. Her PFS was nearly triple that reported for best responses to treatment, and her evident and clear clinical improvement lends credence to earlier documentation in the literature. Nevertheless, caution is warranted regarding the outcomes described here because ours is only a case report, in which the patient’s response and PFS were evaluated clinically. More evidence must be gathered about olaparib monotherapy for EOC. Pharmacokinetic studies of the drug have demonstrated that it is able to penetrate the blood-brain barrier, and research in animal models has shown that it has intracerebral antitumor activity [15].\n\nClinical reports exist about the antimetastatic activity of olaparib within the CNS. Experimental models have shown that the drug increases the sensitivity of certain tumors to chemotherapy and radiation therapy [16]. Our case report is not useful in determining whether olaparib has an effect on overall survival in patients with EOC and clinical studies should be performed to investigate whether the drug is useful as a last-recourse rescue therapy.\n\nConclusions\nOur study underscores the usefulness of BRCA testing in all patients with EOC and suggests that olaparib has antitumor activity against BRCA-mutated EOC metastases within the CNS, even after the failure of 10 lines of treatment, radiation therapy, and advanced clinical deterioration in a patient. Starting olaparib early could be very beneficial in cases like ours.\n\nConflicts of interest\n\nAztraZeneca México provided medical writing assistance with the manuscript but was not involved in the analysis of the data or the final content.\n\nFigure 1. Timeline from first visit to death.\n\nFigure 2. Computed tomography (CT) scans at the start of treatment. (A) Abdominal CT scan showing carcinomatosis. (B) Thoracic CT scan showing pleural effusion.\n\nFigure 3. Magnetic resonance imaging of the head 23 months after the first visit (A: Midline plane; B: Coronal plane). The arrows point to metastatic lesions.\n==== Refs\nReferences:\n1. Siegel RL Miller KD Jemal A Cancer statistics, 2018 Cancer J Clin 2018 68 1 7 30 \n2. Jayson GC Kohn EC Kitchener HC Ledermann JA Ovarian cancer Lancet 2014 384 9951 1376 88 24767708 \n3. Patel AG Sarkaria JN Kaufmann SH Nonhomologous end joining drives poly (ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells Proc Natl Acad Sci USA 2011 108 8 3406 11 21300883 \n4. Kaufman B Shapira-Frommer R Schmutzler RK Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation J Clin Oncol 2015 33 3 244 50 25366685 \n5. Ledermann JA Pujade-Lauraine E Olaparib as maintenance treatment for patients with platinum-sensitive relapsed ovarian cancer Ther Adv Med Oncol 2019 11 1758835919849753 31205507 \n6. Bangham M Goldstein R Walton H Ledermann JA Olaparib treatment for BRCA-mutant ovarian cancer with leptomeningeal disease Gynecol Oncol Rep 2016 18 22 24 27819019 \n7. Sakamoto I Hirotsu Y Nakagomi H Durable response by olaparib for a Japanese patient with primary peritoneal cancer with multiple brain metastases: A case report J Obstet Gynaecol Res 2019 45 3 743 47 30565790 \n8. Kobel M Kalloger SE Boyd N Ovarian carcinoma subtypes are different diseases: implications for biomarker studies PLoS Med 2008 5 12 e232 19053170 \n9. Gershenson DM Sun CC Lu KH Clinical behavior of stage II–IV low-grade serous carcinoma of the ovary Obstet Gynecol 2006 108 2 361 68 16880307 \n10. Jernigan AM Mahdi H Rose PG Epithelial ovarian cancer metastatic to the central nervous system and a family history concerning for hereditary breast and ovarian cancer – a potential relationship Int J Gynecol Cancer 2015 25 1232 38 26067864 \n11. Santillan A Kim YW Zahurak ML Differences of chemoresistance assay between invasive micropapillary/low-grade serous ovarian carcinoma and high-grade serous ovarian carcinoma Int J Gynecol Cancer 2007 17 3 601 6 17504374 \n12. Ozols RF Bundy BN Greer BE Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A Gynecologic Oncology Group study J Clin Oncol 2003 21 17 3194 200 12860964 \n13. Cancer Genome Atlas Research Network Integrated genomic analyses of ovarian carcinoma Nature 2011 474 7353 609 15 21720365 \n14. Ledermann J Harter P Gourley C Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: A preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial Lancet Oncol 2014 15 8 852 61 24882434 \n15. Sun K Mikule K Wang Z A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models Oncotarget 2018 9 98 37080 96 30647846 \n16. Senra JM Telfer BA Cherry KE Inhibition of PARP-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft Mol Cancer Ther 2011 10 10 1949 58 21825006\n\n",
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"mesh_terms": "D000970:Antineoplastic Agents; D000077216:Carcinoma, Ovarian Epithelial; D002490:Central Nervous System; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors",
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"title": "Clinically Relevant Response to Treatment with Olaparib in a Patient with Refractory Multidrug-Resistant Ovarian Cancer and Central Nervous System Involvement: A Case Report.",
"title_normalized": "clinically relevant response to treatment with olaparib in a patient with refractory multidrug resistant ovarian cancer and central nervous system involvement a case report"
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"abstract": "Giant cell tumor of bone (GCTB) is a rare, benign, but locally aggressive bone tumor. It has a high tendency for local recurrence, which may increase the incidence of lung metastasis. Currently, an optimal treatment strategy has not been established because of the rarity of pulmonary metastatic GCTB. Denosumab is the preferred regimen for unresectable metastatic lesions; however, there are no alternative treatment options when patients are resistant to denosumab. Apatinib is a small-molecule tyrosine kinase inhibitor that selectively competes for the vascular endothelial growth factor receptor 2 (VEGFR-2) ATP binding site, and several studies have analyzed the effectiveness of apatinib in advanced or metastatic tumors. However, there is no report of apatinib as an anti-angiogenesis therapy for pulmonary metastatic GCTB to date. Here, we present a case of a 26-year-old female who was diagnosed with recurrent and pulmonary metastatic GCTB. Immunohistochemical (IHC) staining indicated that the tumor cells were positive for VEGFR-2. Denosumab was administered to control the metastases; nevertheless, disease progression was confirmed after four months of treatment. Given the IHC results and rapid disease progression, apatinib was added to the treatment strategy. After 42 months of treatment, the patient showed noticeable symptomatic improvement and considerable tumor shrinkage.",
"affiliations": "Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.;Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.;Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.;Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.;Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.;Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.;Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.;Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.",
"authors": "Gong|Taojun|T|;Luo|Yi|Y|;Wang|Yitian|Y|;Zheng|Chuanxi|C|;Fang|Jianguo|J|;Min|Li|L|0000-0002-5035-1672;Zhou|Yong|Y|;Tu|Chongqi|C|0000-0001-9546-7428",
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"fulltext": "\n==== Front\nCancer Manag Res\nCancer Manag Res\ncmar\ncancmanres\nCancer Management and Research\n1179-1322\nDove\n\n312846\n10.2147/CMAR.S312846\nCase Report\nMultiple Pulmonary Metastases of Recurrent Giant Cell Tumor of Bone with Expression of VEGFR-2 Successfully Controlled by Denosumab and Apatinib: A Case Report and Literature Review\nGong et al\nGong et al\nGong Taojun 1*\nLuo Yi 1*\nWang Yitian 1\nZheng Chuanxi 1\nFang Jianguo 1\nhttp://orcid.org/0000-0002-5035-1672\nMin Li 1\nZhou Yong 1\nhttp://orcid.org/0000-0001-9546-7428\nTu Chongqi 1\n1 Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China\nCorrespondence: Chongqi Tu Department of Orthopedics, West China Hospital, Sichuan University, Guoxue Xiang No. 37, Chengdu, Sichuan, 610041, People’s Republic of China Email tuchongqibone@hotmail.com\n* These authors contributed equally to this work\n\n03 6 2021\n2021\n13 44474454\n26 3 2021\n15 5 2021\n© 2021 Gong et al.\n2021\nGong et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ 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).\nAbstract\n\nGiant cell tumor of bone (GCTB) is a rare, benign, but locally aggressive bone tumor. It has a high tendency for local recurrence, which may increase the incidence of lung metastasis. Currently, an optimal treatment strategy has not been established because of the rarity of pulmonary metastatic GCTB. Denosumab is the preferred regimen for unresectable metastatic lesions; however, there are no alternative treatment options when patients are resistant to denosumab. Apatinib is a small-molecule tyrosine kinase inhibitor that selectively competes for the vascular endothelial growth factor receptor 2 (VEGFR-2) ATP binding site, and several studies have analyzed the effectiveness of apatinib in advanced or metastatic tumors. However, there is no report of apatinib as an anti-angiogenesis therapy for pulmonary metastatic GCTB to date. Here, we present a case of a 26-year-old female who was diagnosed with recurrent and pulmonary metastatic GCTB. Immunohistochemical (IHC) staining indicated that the tumor cells were positive for VEGFR-2. Denosumab was administered to control the metastases; nevertheless, disease progression was confirmed after four months of treatment. Given the IHC results and rapid disease progression, apatinib was added to the treatment strategy. After 42 months of treatment, the patient showed noticeable symptomatic improvement and considerable tumor shrinkage.\n\nKeywords\n\ngiant cell tumor of bone\npulmonary metastasis\nVEGFR-2\ndenosumab\napatinib\nChengdu Science and Technology Program Projects National Natural Science Foundation of China 10.13039/501100001809 National Key Research and Development Program of China This work was supported, in part, by the Chengdu Science and Technology Program Projects (No. 2017-CY02-00032-GX, Dr. Zhou), the National Natural Science Foundation of China (No. 81801852, Dr. Zhou), and the National Key Research and Development Program of China (No. 2017YFB0702604, Dr. Min).\n==== Body\nIntroduction\n\nGiant cell tumor of bone (GCTB) is a rare, benign, but locally aggressive bone tumor, accounting for 3%~5% of all primary bone tumors.1 It typically occurs between the ages of 20−40, is generally more common in females,2 and has a high tendency for local recurrence.1,3 Pulmonary metastasis rarely occurs, affecting only 1%−3.9% of patients without local recurrence and 6%−21.1% of patients with local recurrence. The overall mortality rate of these patients varies widely from 0 to 23%.4\n\nGCTB has been shown to overexpress receptor activator of nuclear factor κB ligand (RANKL), the action of which is specifically blocked by denosumab. Denosumab is a monoclonal antibody specifically targeting human RANKL that inhibits the formation of osteoclast-like giant cells and their precursors. This inhibition leads to a reduction or elimination of giant cells and impedes osteolysis, thereby allowing replacement of diseased bone with dense and new bone.5 Surgical removal of resectable metastases is the main treatment. For patients with unresectable metastases, denosumab is an option. However, effective systemic therapies for this rare disease are lacking for patients who are resistant to denosumab.\n\nPathological angiogenesis plays a key role in the invasion, progression, and metastasis of tumor cells. Apatinib is a small-molecule tyrosine kinase inhibitor (TKI) that selectively binds to and strongly inhibits vascular endothelial growth factor receptor 2 (VEGFR-2), which leads to a decrease in vascular endothelial growth factor (VEGF)-mediated endothelial cell migration, proliferation, and tumor microvascular density. Apatinib has been demonstrated to improve progression-free survival and overall survival in patients with advanced gastric cancer.6 Recent studies have analyzed the effectiveness of apatinib in advanced or metastatic bone tumors.7–10 However, treatment of pulmonary metastatic GCTB with apatinib has not been reported by far.\n\nCase Presentation\n\nA 26-year-old female was referred to our hospital in June 2014 with a complaint of dull pain in the right knee for six months. Physical examination showed tenderness in the proximal right tibia. Radiography and computed tomography (CT) revealed eccentric, well-defined osteolytic destruction in the proximal metaphysis of the right tibia, suggesting the imaging diagnosis of GCTB (Campanacci grade II) (Figure 1A–D). Chest CT scan (Figure 2A) and single-photon emission CT (Figure 1E) did not reveal any metastatic lesions.An open biopsy from a lateral incision was performed thereafter, and pathological results showed multinucleated osteoclast giant cells with a large number of nuclei scattered among mononuclear tumor cells, which confirmed the diagnosis of a benign GCTB (Figure 3A). Subsequently, the patient underwent intralesional curettage following the biopsy tract. Utilizing high-speed drilling and ethyl alcohol, 1 cm of spongy bone and 1 mm of cortical bone were removed. The remaining cavity was then packed with cement (Figure 4A and B). After the procedures, immobilization was recommended to prevent pathological fracture. However, nine months later, a palpable mass was detected in the right popliteal fossa. Radiography, CT, and magnetic resonance imaging revealed local cortical bone destruction with soft tissue extension (Figure 4C–F) which indicated Campanacci grade III. Chest CT showed no evidence of metastases. Because of the extensive recurrence and stage III rating, the patient underwent wide resection of the lesion with prosthetic reconstruction. Postoperative pathologic features and presence of multinucleated giant cells were detected by immunohistochemical (IHC) staining with a monoclonal antibody against CD68 (PG-M1) and were similar to that of the pre-surgical specimens, revealing the recurrence of GCTB without malignant transformation (Figure 3B and C). The IHC staining also identified tumor cells positive for VEGFR-2 (Figure 3D). The patient was regularly followed-up every three months in our orthopedic clinic.Figure 1 Radiological images of the proximal right tibia. Radiograph (A and B) and CT (C and D) showed osteolytic bony destruction. SPECT (E) images were negative for metastatic lesions.\n\nFigure 2 CT of the chest. (A) Local recurrence but without pulmonary metastasis. (B) Multiple pulmonary metastases were found and denosumab initiated. (C) 4 months after denosumab therapy. (D) 3 months after denosumab and apatinib therapy. (E) 15 months after denosumab and apatinib therapy. (F) 33 months after denosumab and apatinib therapy.\n\nFigure 3 Pathological features of the local lesions. (A) High-magnification observation of numerous multinucleated giant cells (Hematoxylin and eosin stain, 200x). (B) High-magnification observation of local recurrence but without sarcomatous change (Hematoxylin and eosin stain, 200x). (C) Presence of multinucleated giant cells indicates a recurrence of GCTB (Immunohistochemical staining, 100x). (D) Expression of VEGFR-2 as assessed by immunohistochemistry (Immunohistochemical staining, 100x).\n\nFigure 4 Radiological images of the proximal right tibia. Radiograph (A and B), postoperative films following the curettage and packing with cement; Radiograph (C and D), and CT (E, bone window) showed a circumferential lucency around the bone cement and local cortical bone destruction. MRI (F, T1-weight) showed a soft tissue mass.\n\nTwo years after the latest surgery, the patient presented to our clinic with a complaint of hemoptysis. The lung CT scans were evaluated by experienced musculoskeletal surgeons and radiologists who verified more than 100 pulmonary nodules in both lungs (Figure 2B). Although biopsy of the lung mass was not performed owing to the refusal of the patient, the imaging diagnosis of metastatic GCTB was considered based on the presence of multiple lesions. Meanwhile, lung cancer was excluded because the level of serum cytokeratin fragment antigen 21-1, a sensitive tumor marker of lung cancer, was negative.\n\nSince both biopsy and resection are traumatic operations with risks and complications, and the multiple metastases could not be completely removed by surgery or benefit from it. On the other hand, our patient could not tolerate chemotherapy because of an Eastern Cooperative Oncology Group performance status score of 3. Therefore, the patient chose subcutaneous denosumab administration, which was initiated at a dose of 120 mg every 28 days, with additional doses on days 8 and 15 of the first month. The patient was also supplemented with calcium and vitamin D. However, after four months of denosumab therapy, the symptoms of hemoptysis became more severe. The lung CT scan showed the metastatic nodules had increased in size and number, indicating progression of disease (Figure 2C). After multiple interdisciplinary team discussions, and in view of the high-level VEGFR-2 expression and rapidly progression, the patient was tentatively administered the TKI apatinib in combination with denosumab treatment. Denosumab was injected every month with a dose of 120 mg and apatinib was administered with an oral dosage of 500 mg daily. After three months of denosumab and apatinib treatment, the patient showed noticeable improvement of hemoptysis and visibly reduced tumor size (Figure 2D).\n\nAt a follow-up of 42 months, chest CT images showed a significant size reduction in the lung nodules. The largest one had greatly decreased in size from 12.2×8.5 cm to 3.5×1.5 cm (Figure 2E and F), and the tumor volume shrinkage rate was 95%. Moreover, the number of metastatic nodules decreased to less than 30. After initiation of apatinib therapy, a few drug-related toxicity reactions were noted, including hand-foot skin syndrome, gastrointestinal discomfort, and hypopigmentation of the hair. All adverse reactions were mild (grade 1 or 2) according to the Common Terminology Criteria for Adverse Events and were easily controlled by symptomatic treatments. The efficacy was evaluated as a significant partial response (PR) to denosumab and apatinib treatment by the Response Evaluation Criteria for Solid Tumors 1.1. The patient is under stable condition at the time of this writing.\n\nDiscussion\n\nAlthough GCTB is classified as a benign tumor, lung metastasis rates vary from 1%−21.1%.3,11 Since the incidence of pulmonary metastasis of GCTB is rather rare, there is no definite protocol for the treatment of metastatic GCTB. According to the National Comprehensive Cancer Network guidelines, surgical excision is the mainstay of the treatment for patients with resectable metastases. Denosumab is a recommended regimen for patients with unresectable metastatic lesions.1,5,12 Other alternatives include interferon alpha-2b, radiation therapy, or observation. However, interferon therapy has limited efficacy in treating metastases in most patients, and radiation therapy may increase the risk of malignant transformation. Therefore, we did not recommend those therapies to this patient.\n\nThe role of denosumab in controlling unresectable (local or metastatic) tumors has been well established.1,5 Luo et al reported seven patients with pulmonary metastatic GCTB who received denosumab treatment. None of these patients showed disease progression during an average of 28.6 months follow-up period. Three patients showed a PR and four patients were stabilized by denosumab treatment.13 An open-label, Phase II study incorporated 169 patients with unresectable GCTB treated with denosumab. After a median follow-up of 13 months, 96% (163 of 169) of evaluable patients had no disease progression.14 Nevertheless, for our patient, denosumab alone was invalid in managing pulmonary metastases, and the disease progressed after four months of denosumab therapy.\n\nAs specimens of the lung metastases were not available, we could not determine the pathological features of the metastatic lesions. We speculate whether sarcomatous changes had occurred in the metastatic nodules. Although extremely rare, progressive disease caused by malignant transformation in benign GCTB after denosumab therapy has been reported previously, and most patients treated with cytotoxic chemotherapy had an unfavorable prognosis (Table 1).1,16–19 The recurrent bone tumor was positive for VEGFR-2 in our patient, indicating antiangiogenic therapy might be a potential therapeutic target. Although denosumab seemed inadequate to control the pulmonary metastases in our patient, a cessation of denosumab therapy might lead to local recurrence and critical hypercalcemia.20,21 Therefore, the patient was administered apatinib but did not discontinue the denosumab treatment completely.Table 1 Literature Review of Therapy After Progression of GCTB\n\nReport\tPatient (NO.)\tAge\tSex\tPrimary Site\tPulmonary Metastases\tLocal Recurrence\tFollow-Up Time (Year)\tTherapy Before Progression\tTherapy After Progression\tTherapeutic Response\t\nWang et al19\t1\t16\tM\tSpine\tYes\tYes\t4\tWide resection +denosumab\tSunitinib\tSD\t\nTsukamoto et al17\t1\t29\tF\tLeft pelvis\tYes\tYes\t10\tCurettage+denosumab\tChemotherapy\tDied\t\nBroehm et al16\t2\t59\tM\tRight pelvis\tYes\tYes\t12\tWide resection+ denosumab\tChemotherapy\tNM\t\n56\tM\tLeft femur\tNo\tYes\t7\tCurettage+denosumab+ wide resection\tChemotherapy\tDied\t\nAponte-Tinao et al18\t1\t15\tF\tRight tibia\tNo\tYes\t5\tCurettage+denosumab+ wide resection\tAmputation\tDisease-free\t\nThomas et al1\t1\tNM\tF\tNM\tYes\tYes\tNM\tDenosumab+ resection\tNM\tDied\t\nCurrent study\t1\t26\tF\tRight tibia\tYes\tYes\t3\tWide resection+ denosumab\tApatinib\tPR\t\nAbbreviations: GCTB, giant cell tumor of bone; M, male; F, female; SD, stable disease; PR, partial response; NM, not mentioned.\n\nPathological angiogenesis is important in growth and differentiation processes of numerous tumors. VEGF, overexpressed in many solid tumors including GCTB, is one of the central triggers for angiogenesis.22,23 VEGFR-2, which presents a strong tyrosine kinase activity towards pro-angiogenic signals, is the key mediator underlying VEGF-induced phenotypes.24 Apatinib is a small-molecule TKI that selectively competes for the VEGFR-2 ATP binding site, blocking downstream signaling and inhibiting tumor angiogenesis.8 This therapy is effective for a wide range of primary malignancies and metastatic lesions, such as advanced gastric cancer, osteosarcoma, rhabdomyosarcoma, synovial sarcoma, and alveolar soft part sarcoma.6–10 Wang et al showed a satisfactory result of the application of apatinib in 6 cases of pulmonary metastatic alveolar soft part sarcoma, namely one complete response and five PRs.10 Zhu et al reported an objective response rate of 33.3% and a clinical benefit rate of 75.0% when apatinib was administered to 31 advanced sarcoma patients including 18 cases of pulmonary metastases.7 To our knowledge, only two case reports discussed the efficiency of tyrosine kinase inhibition in the treatment of GCTB. Wang et al presented a case of GCTB with pulmonary and bone metastases that were treated with denosumab and sunitinib, and their patient’s condition was stabilized after four years of treatment.19 Li et al reported a multicentric GCTB patient treated with apatinib, and CT in the fourth month identified a PR.25 However, both studies lacked pathological evidence supporting the use of TKIs.\n\nWe recognize that our report has some limitations. First, we did not obtain the pathologic evidence of pulmonary metastases. The patient did not undergo surgery based on risk considerations and personal preference. Second, it is unclear when denosumab and apatinib treatments should be discontinued, which should be the subject of ongoing research.\n\nConclusion\n\nWe present a case of multiple pulmonary metastases of recurrent GCTB successfully controlled by a novel combination of denosumab and apatinib, indicating that VEGFR-2 may provide an effective therapeutic target to control progressive pulmonary metastatic GCTB. This may provide a reference for the treatment of clinically-related cases.\n\nAcknowledgments\n\nWe thank for the support of Professor Xianliang Zhang, Dr. Yahan Zhang, Department of Pathology, West China Hospital.\n\nAbbreviations\n\nGCTB, giant cell tumor of bone; CT, computed tomography; IHC, immunohistochemical; PR, Partial response; VEGF, vascular endothelial growth factor; VEGFR-2, vascular endothelial growth factor receptor 2; TKI, tyrosine kinase inhibitor; SPECT, single-photon emission computed tomography; RANKL, nuclear factor κB ligand.\n\nData Sharing Statement\n\nAll data used or analyzed during this study are included in this published article.\n\nEthics Statement\n\nThis study was approved by the institutional Ethics Committee of West China Hospital, Sichuan University. Institutional approval was required for the publication of the case details. The patient provided written, informed consent for the publication of the case details.\n\nDisclosure\n\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n\n1. Thomas D, Henshaw R, Skubitz K, et al. Denosumab in patients with giant-cell tumour of bone: an open-label, Phase 2 study. Lancet Oncol. 2010;11 (3 ):275–280. doi:10.1016/S1470-2045(10)70010-3 20149736\n2. Mendenhall WM, Zlotecki RA, Scarborough MT, Gibbs CP, Mendenhall NP. Giant cell tumor of bone. Am J Clin Oncol. 2006;29 (1 ):96–99. doi:10.1097/01.coc.0000195089.11620.b7 16462511\n3. Wang J, Liu X, Yang Y, et al. Pulmonary metastasis of giant cell tumour: a retrospective study of three hundred and ten cases. Int Orthop. 2021;45 (3 ):769–778. doi:10.1007/s00264-020-04907-0 33427899\n4. Bertoni F, Present D, Sudanese A, Baldini N, Bacchini P, Campanacci M. Giant-cell tumor of bone with pulmonary metastases. Six case reports and a review of the literature. Clin Orthop Relat Res. 1988;237 :275–285.\n5. Chawla S, Blay JY, Rutkowski P, et al. Denosumab in patients with giant-cell tumour of bone: a multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20 (12 ):1719–1729. doi:10.1016/S1470-2045(19)30663-1 31704134\n6. Li J, Qin S, Xu J, et al. Randomized, double-blind, placebo-controlled Phase III Trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol. 2016;34 (13 ):1448–1454. doi:10.1200/JCO.2015.63.5995 26884585\n7. Zhu B, Li J, Xie Q, Diao L, Gai L, Yang W. Efficacy and safety of apatinib monotherapy in advanced bone and soft tissue sarcoma: an observational study. Cancer Biol Ther. 2018;19 (3 ):198–204. doi:10.1080/15384047.2017.1416275 29261005\n8. Li J, Zhao X, Chen L, et al. Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies. BMC Cancer. 2010;10 :529. doi:10.1186/1471-2407-10-529 20923544\n9. Xie L, Guo W, Wang Y, Yan T, Ji T, Xu J. Apatinib for advanced sarcoma: results from multiple institutions’ off-label use in China. BMC Cancer. 2018;18 (1 ):396. doi:10.1186/s12885-018-4303-z 29625604\n10. Wang Y, Min L, Zhou Y, et al. The efficacy and safety of apatinib in metastatic alveolar soft part sarcoma: a case series of six patients in one institution. Cancer Manag Res. 2019;11 :3583–3591. doi:10.2147/CMAR.S198429 31118781\n11. Yang Y, Huang Z, Niu X, Xu H, Li Y, Liu W. Clinical characteristics and risk factors analysis of lung metastasis of benign giant cell tumor of bone. J Bone Oncol. 2017;7 :23–28. doi:10.1016/j.jbo.2017.04.001 28443231\n12. Biermann JS, Chow W, Reed DR, et al. NCCN guidelines insights: bone cancer, version 2.2017. J Natl Compr Canc Netw. 2017;15 (2 ):155–167. doi:10.6004/jnccn.2017.0017 28188186\n13. Luo Y, Tang F, Wang Y, et al. Safety and efficacy of denosumab in the treatment of pulmonary metastatic giant cell tumor of bone. Cancer Manag Res. 2018;10 :1901–1906. doi:10.2147/CMAR.S161871 30013396\n14. Chawla S, Henshaw R, Seeger L, et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. 2013;14 (9 ):901–908. doi:10.1016/S1470-2045(13)70277-8 23867211\n15. López-Pousa A, Martín Broto J, Garrido T, Vázquez J. Giant cell tumour of bone: new treatments in development. Clin Transl Oncology. 2015;17 (6 ):419–430. doi:10.1007/s12094-014-1268-5\n16. Broehm CJ, Garbrecht EL, Wood J, Bocklage T. Two cases of sarcoma arising in giant cell tumor of bone treated with denosumab. Case Rep Med. 2015;2015 :767198. doi:10.1155/2015/767198 26798348\n17. Tsukamoto S, Righi A, Vanel D, Honoki K, Donati DM, Errani C. Development of high-grade osteosarcoma in a patient with recurrent giant cell tumor of the ischium while receiving treatment with denosumab. Jpn J Clin Oncol. 2017;47 (11 ):1090–1096. doi:10.1093/jjco/hyx112 29048579\n18. Aponte-Tinao LA, Piuzzi NS, Roitman P, Farfalli GL, High-grade Sarcoma A. Arising in a patient with recurrent benign giant cell tumor of the proximal tibia while receiving treatment with denosumab. Clin Orthop Relat Res. 2015;473 (9 ):3050–3055. doi:10.1007/s11999-015-4249-2 25758379\n19. Wang G, Jiang S, Li Z, Dong Y. Denosumab and Sunitinib in the treatment of giant-cell tumor of bone with pulmonary and bone metastases in an adolescent: a case report. Medicine (Baltimore). 2019;98 (46 ):e17778. doi:10.1097/MD.0000000000017778 31725619\n20. Gossai N, Hilgers MV, Polgreen LE, Greengard EG. Critical hypercalcemia following discontinuation of denosumab therapy for metastatic giant cell tumor of bone. Pediatr Blood Cancer. 2015;62 (6 ):1078–1080. doi:10.1002/pbc.25393 25556556\n21. Matcuk GR Jr, Patel DB, Schein AJ, White EA, Menendez LR. Giant cell tumor: rapid recurrence after cessation of long-term denosumab therapy. Skeletal Radiol. 2015;44 (7 ):1027–1031. doi:10.1007/s00256-015-2117-5 25712768\n22. English WR, Lunt SJ, Fisher M, et al. Differential expression of VEGFA isoforms regulates metastasis and response to anti-VEGFA therapy in sarcoma. Cancer Res. 2017;77 (10 ):2633–2646. doi:10.1158/0008-5472.CAN-16-0255 28377452\n23. Zhang J, Dong J, Yang Z, et al. Expression of ezrin, CD44, and VEGF in giant cell tumor of bone and its significance. World J Surg Oncol. 2015;13 :168. doi:10.1186/s12957-015-0579-5 25929323\n24. Shibuya M. Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J Biochem. 2013;153 (1 ):13–19. doi:10.1093/jb/mvs136 23172303\n25. Li J, Zhou J, Liu Y, Sun X, Song W. Comprehensive treatment for multicentric giant cell tumors of the pelvis and spine using apatinib: a case report and literature review. J Cancer Res Ther. 2020;16 (5 ):1020–1026. doi:10.4103/jcrt.JCRT_892_19 33004743\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-1322",
"issue": "13()",
"journal": "Cancer management and research",
"keywords": "VEGFR-2; apatinib; denosumab; giant cell tumor of bone; pulmonary metastasis",
"medline_ta": "Cancer Manag Res",
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"nlm_unique_id": "101512700",
"other_id": null,
"pages": "4447-4454",
"pmc": null,
"pmid": "34113170",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
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"title": "Multiple Pulmonary Metastases of Recurrent Giant Cell Tumor of Bone with Expression of VEGFR-2 Successfully Controlled by Denosumab and Apatinib: A Case Report and Literature Review.",
"title_normalized": "multiple pulmonary metastases of recurrent giant cell tumor of bone with expression of vegfr 2 successfully controlled by denosumab and apatinib a case report and literature review"
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"abstract": "Were to identify the advantages and disadvantages of different protocols of antihypertensive therapy in women with arterial hypertension during the process of labour and their effects on the labour progressing and perinatal complications.\n\n\n\n228 women who had childbirth in 2013-2018 in the Ternopil perinatal centre \"Mother and Child\" were surveyed. The study included full-term singleton pregnancies in cephalic presentation. According to the treatment program, women were divided into 4 groups: Group 1: 58 pregnant women who neglected treatment or had insufficient compliance; Group 2: 57 pregnant women who used methyldopa and classic beta-blockers during pregnancy and labor; Group 3: 57 pregnant women who received high selective beta-blocker with vasodilating properties nebivolol in addition to methyldopa; Group 4: 56 healthy pregnant women with normal blood pressure and without other somatic pathology.\n\n\n\nHypertension and inadequate hemodynamic control can become risk factors for higher incidence of low birth weight, prolonged or discoordinated labour, excessive blood loss during and after delivery. The program of treating hyper- tension in pregnant women with nebivolol hydrochloride provides sufficient control of blood pressure and helps to avoid blood pressure spikes or an excessive increase of systolic and diastolic blood pressure and heart rate during childbirth, which could endanger the mother's health.\n\n\n\nThe treatment with nebivolol hydrochloride for women with chronic arterial hypertension during pregnancy and delivery allows to normalize the progress and duration of labour, decrease the incidence of low birth weight and the percentage of excessive blood loss during labour.",
"affiliations": "Department of Obstetrics and Gynecology No 2 of the Ternopil State Medical University, Ternopil, Ukraine. 22_leonora@ukr.net.;Department of Obstetrics and Gynecology No 2 of the Ternopil State Medical University, Ternopil, Ukraine.;Department of Obstetrics and Gynecology No 2 of the Ternopil State Medical University, Ternopil, Ukraine.",
"authors": "Humenna|Iryna Yevhenivna|IY|;Heryak|Svitlana Nikolayivna|SN|;Dobryanska|Victoryya Yuriyivna|VY|",
"chemical_list": "D000959:Antihypertensive Agents; D000068577:Nebivolol",
"country": "Poland",
"delete": false,
"doi": "10.5603/GP.2019.0037",
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"issue": "90(4)",
"journal": "Ginekologia polska",
"keywords": "arterial hypertension; delivery; nebivolol hydrochloride; rational control",
"medline_ta": "Ginekol Pol",
"mesh_terms": "D000959:Antihypertensive Agents; D005260:Female; D006801:Humans; D006973:Hypertension; D007743:Labor, Obstetric; D000068577:Nebivolol; D007744:Obstetric Labor Complications; D011247:Pregnancy; D012307:Risk Factors",
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"publication_types": "D016428:Journal Article",
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"title": "Rational control of arterial pressure during labor in women with arterial hypertension.",
"title_normalized": "rational control of arterial pressure during labor in women with arterial hypertension"
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"abstract": "Haloperidol decanoate is a typical antipsychotic drug used as maintenance therapy for schizophrenia and mood disorders formulated as an ester for intramuscular injection. Cases of oral haloperidol decanoate intoxications have not been described in literature. In this report, we present for the first time a case of an oral ingestion of haloperidol decanoate of a young woman who presented to the emergency department following an intentional oral ingestion of 1 ampoule of haloperidol decanoate 100mg. At presentation, she had a bilateral rest tremor of both hands and mild hypothermia. No other obvious signs of an intoxication were observed. She was treated with a single dose of activated charcoal and laxative and was admitted to the intensive care for rhythm monitoring and observation. During the night the QTc interval increased to 453ms, but stayed within the normal range. Haloperidol plasma levels increased as well, but also stayed within therapeutic ranges. These findings indicate that treatment with oral activated charcoal was sufficient to prevent any serious events.",
"affiliations": "Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Electronic address: B.G.J.Dekkers@umcg.nl.;Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.;Department of Internal Medicine, Emergency Department, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.;Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.",
"authors": "Dekkers|Bart G J|BGJ|;Eck|Ruben J|RJ|;Ter Maaten|Jan C|JC|;Touw|Daniël J|DJ|",
"chemical_list": "D014150:Antipsychotic Agents; D054368:Laxatives; D002606:Charcoal; C033563:haloperidol decanoate; D006220:Haloperidol",
"country": "United States",
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"issue": "35(9)",
"journal": "The American journal of emergency medicine",
"keywords": "Antipsychotic; Blood plasma concentrations; ECG; Oral haloperidol decanoate intoxication; QTc",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000284:Administration, Oral; D014150:Antipsychotic Agents; D001145:Arrhythmias, Cardiac; D002606:Charcoal; D004562:Electrocardiography; D005260:Female; D006220:Haloperidol; D006801:Humans; D054368:Laxatives; D008297:Male; D012559:Schizophrenia; D055815:Young Adult",
"nlm_unique_id": "8309942",
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"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "An acute oral intoxication with haloperidol decanoate.",
"title_normalized": "an acute oral intoxication with haloperidol decanoate"
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"abstract": "Holt-Oram syndrome (HOS) (OMIM#142900) is a rare condition with upper extremity malformations as well as structural and conduction cardiac anomalies. There are sparse reports in the literature documenting malignancy in association with HOS. We report a pediatric patient clinically diagnosed with HOS (missing thumbs bilaterally, atrial septal defect, ventricular septal defect, and first-degree heart block), who also developed B precursor acute lymphoblastic leukemia. During induction of chemotherapy with steroids, she developed profound bradycardia without clinical symptoms. The bradycardia resolved without intervention, but this case highlights the challenges of managing chemotherapy side effects in a patient with congenital heart disease. A literature review pertinent to the associated findings in the case is also presented.",
"affiliations": "Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA.;Rush Medical College, Rush University, Chicago, IL, USA.;Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA.;Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA.;Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA.",
"authors": "Morales|Raymond|R|;Clayton|Bishir|B|;Nguyen|Hoang H|HH|;Giordano|Lisa|L|;Muller|Brieann A|BA|",
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"country": "India",
"delete": false,
"doi": "10.4103/apc.APC_87_19",
"fulltext": "\n==== Front\nAnn Pediatr Cardiol\nAnn Pediatr Cardiol\nAPC\nAnnals of Pediatric Cardiology\n0974-2069 0974-5149 Wolters Kluwer - Medknow India \n\nAPC-13-241\n10.4103/apc.APC_87_19\nCase Report\nSteroid-associated bradycardia in a newly diagnosed B precursor acute lymphoblastic leukemia patient with Holt–Oram syndrome\nMorales Raymond 1 Clayton Bishir 2 Nguyen Hoang H 1 Giordano Lisa 1 Muller Brieann A 1 1 Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA\n2 Rush Medical College, Rush University, Chicago, IL, USA\nAddress for correspondence: Dr. Raymond Morales, Department of Pediatrics, Rush University Medical Center, 1653 W Congress Parkway, Pavilion 654, Chicago 60612, IL, USA. E-mail: raymond_morales@rush.edu\nJul-Sep 2020 \n02 6 2020 \n13 3 241 243\n12 6 2019 26 10 2019 23 3 2020 Copyright: © 2020 Annals of Pediatric Cardiology2020This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Holt–Oram syndrome (HOS) (OMIM#142900) is a rare condition with upper extremity malformations as well as structural and conduction cardiac anomalies. There are sparse reports in the literature documenting malignancy in association with HOS. We report a pediatric patient clinically diagnosed with HOS (missing thumbs bilaterally, atrial septal defect, ventricular septal defect, and first-degree heart block), who also developed B precursor acute lymphoblastic leukemia. During induction of chemotherapy with steroids, she developed profound bradycardia without clinical symptoms. The bradycardia resolved without intervention, but this case highlights the challenges of managing chemotherapy side effects in a patient with congenital heart disease. A literature review pertinent to the associated findings in the case is also presented.\n\nAcute lymphoblastic leukemiabradycardiaHolt-Oramsteroid-associated bradycardia\n==== Body\nINTRODUCTION\nHolt–Oram syndrome (HOS) is a rare autosomal dominant condition that was first identified in a family with generational anomalies of the upper extremity, arrhythmias, and suspicion of atrial septum defects.[1] Few cases of malignancy have been documented previously in association with this syndrome, and to the best of our knowledge, we document the first case of B precursor acute lymphoblastic leukemia (B-ALL) in a patient with HOS. We further document the challenges faced addressing the side effects of the chemotherapeutic regimen for a patient with congenital conduction anomalies.\n\nCASE REPORT\nA 12-year-old female with clinically diagnosed HOS status postatrial septal defect and ventricular septal defect repair at 3 months of life and known first-degree heart block was admitted to Rush University Medical Center for newly diagnosed B-ALL. She presented to Pediatric Cardiology Clinic for transient, position-dependent presyncopal episodes over a 2-month period. A 30-day event monitor was placed and did not reveal any heart block during a syncopal episode. During this period, she also presented to her primary care provider for pallor. A complete blood count revealed thrombocytopenia and anemia. The patient was subsequently admitted due to concern for leukemia on further workup [Table 1]. Her physical examination was remarkable for bilateral submandibular and anterior cervical lymphadenopathy, a systolic murmur, hepatosplenomegaly, pallor, and absence of thumbs bilaterally.\n\nTable 1 Baseline characteristics and laboratories at the time of admission\n\nBaseline characteristics\tResult\t\nHeight\t154.7 cm\t\nWeight\t52.1 kg\t\nBSA\t1.5 m2\t\nWBC\t14.9 K/µL\t\nHemoglobin\t6.7 g/dL\t\nPlatelet\t68 K/µL\t\nNeutrophil\t940 K/µL\t\nLDH\t304 U/L\t\nUric acid\t6.7 mg/dL\t\nFolic acid\t5.2 ng/mL\t\nFerritin\t490 ng/mL\t\nChest X-ray\tnormal\t\nPR interval\t192 ms\t\nQT/QTc\t406 ms/477 ms\t\nBSA: Body surface area, WBC: White blood cell, K: 1000, U: Units, LDH: Lactate dehydrogenase\n\nOn the day of admission, hospital day 0 (HD0), a baseline echocardiogram revealed normal function and no residual septal defects. A baseline electrocardiogram (ECG) demonstrated a normal sinus rhythm with first-degree AV block and a QTc of 479 ms [Figure 1a]. On HD1, a bone marrow biopsy confirmed the diagnosis of B-ALL. On HD3, intrathecal cytarabine was administered for day of induction 1 (DOI#1). She was given a single dose of intravenous vincristine and daunorubicin followed by oral prednisone after recovery from anesthesia. During DOI#2, she was noted to have a heart rate (HR) between 40 and 50 bpm even while awake after the fourth dose of steroid. She was asymptomatic with normal orthostatic blood pressure measurements, normal electrolytes, and a 12-lead ECG with sinus bradycardia and first-degree AV block [Figure 1b]. A 24-h Holter monitor was placed on DOI#3 and revealed an average HR of 50 bpm (range: 36–81 bpm). The patient experienced significant nausea during induction that was only responsive to ondansetron. She underwent continuous monitoring with daily ECGs without issue. She was asymptomatic from the bradycardia throughout the hospitalization and was discharged on DOI#5 with a HR 56 bpm. At follow-up visits, her HR range was predominantly within normal limits. On subsequent admissions, the lowest HR documented was 42 bpm with HR predominantly above 50 bpm.\n\nFigure 1 (a) Baseline electrocardiogram on the day of admission demonstrating a prolonged PR interval and mild QTc prolongation. (b) Electrocardiogram obtained during bradycardic episodes demonstrating sinus bradycardia, prolonged PR interval, and no QTc prolongation\n\nDISCUSSION\nWhile leukemia is the most common form of cancer in pediatric patients, no cases have been documented in a patient with HOS.[2] To the best of our knowledge, HOS in association with malignancy is rare, with six cases documented in the literature [Table 2].[345678] From these documented cases, only Yoshihara et al. reported challenges and limitations before chemotherapy treatment due to concern for side effects in the context of acute heart failure.\n\nTable 2 The case reports previously published on patients with Holt-Oram syndrome and identified malignancy\n\nAge/sex\tMalignancy\tSkeletal anomalies\tHeart defect\tReferences\t\n16 years/female\tAdenocarcinoma\tShort upper appendages with small scapulae, humeri, radii, and phalanges\tAtrial septal defect*\tRabinowitz et al. 1971\t\n24 years/male\tLymphosarcoma\tLeft arm 10 cm shorter than the right. Deformity of the end of the humerus with the congenital subluxation of the elbow; fusion of metacarpal bones; absence of left thumb, fifth finger, first and fifth metacarpal bones\tAtrial septal defect\tNik-Akhtar et al. 1974\t\n23 years/female\tPheochromocytoma\tBilateral agenesis of radial bone and first finger\tDextrocardia, single ventricle, pulmonary atresia\tYoshihara et al. 2008\t\n41 years/male\tAdenocarcinoma\tBilateral radial foreshortening, triphalangeal thumbs, digit aplasia\tNot reported\tAherne et al. 2013\t\n7 months/female\tNephroblastoma\tBilateral absence of the radial bones; deformed, shortened ulna bones; and bony ankylosis of the elbows\tVentricular septal defect\tUsang et al. 2016\t\n31 years/male\tSquamous cell carcinoma\tBilateral thumb anomalies\tAtrial septal defect\tRana et al. 2017\t\nThe patient HOS and malignancy characteristics are provided when available. *Patient refused catheterization but had findings consistent with ASD. HOS: Holt-Oram syndrome, ASD: Atrial septal defect\n\nOur patient experienced bradycardia on DOI#2. We postulated that her bradycardia may have been due to three potential etiologies: first, this was a natural progression of her underlying conduction defect; second, this was an acute change secondary to the oncologic burden; and third, this was chemotherapy-related, specifically steroid-associated bradycardia. The first two theories were contradicted by the fact that the patient's resting HR during the portion of the admission before DOI#1 was within the normal limits (average HR 68 with range 61–97 bpm). This differed significantly from the 24-h Holter monitor completed on DOI#3 (average HR 50 with range 36–81 bpm). Moreover, the acute onset of the bradycardia without symptoms [Figure 2] and the lack of return at follow-up visitsfurther support the theory that this was a response to the initiation of potent steroids. Another potential cause of bradycardia could be attributed to the patient's hypervolemic state while undergoing hydration therapy. The patient received other medications during this time; however, the incidence of bradycardia occurred long after their administration.\n\nFigure 2 Box plot demonstrating heart rate trend during hospitalization. The y-axis is heart rate and x-axis is time based on the day of chemotherapy induction. Horizontal red line indicates steroid administration. Horizontal blue line encompasses the time period when Holter monitor was completed\n\nCorticosteroid-associated bradycardia is a physiologic response first noted in patients with rheumatoid arthritis receiving pulse intravenous methylprednisolone.[9] There are numerous reports of patients developing this response to receiving pulse steroids for rheumatologic as well as oncologic conditions with one report demonstrating a nadir after 5–10 doses of steroids.[101112] We speculate that the initiation of high-dose steroids may modulate a bradycardic response through androgen receptors that are not sustained during prolonged exposure. However, further research is needed to elucidate the mechanism. We further summarize that her presyncopal episodes before admission were vasovagal in nature confounded by anemia due to B-ALL.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Holt M Oram S Familial heart disease with skeletal malformations Br Heart J 1960 22 236 42 14402857 \n2 Siegel DA King J Tai E Buchanan N Ajani UA Li J Cancer incidence rates and trends among children and adolescents in the United States, 2001-2009 Pediatr 2014 134 e945 55 \n3 Rabinowitz JG Camera A Oran E Holt Oram syndrome associated with carcinoma Clin Radiol 1971 22 346 9 5559104 \n4 Akhtar NB Khakpour M Rashed AM Hakami F Association of Holt Oram syndrome and lymphosarcoma Chest 1974 66 729 31 4479617 \n5 Yoshihara A Tanabe A Saito H Hizuka N Ishizawa A Horikawa R A case of malignant pheochromocytoma with Holt-Oram syndrome Endocr J 2008 55 153 9 18250543 \n6 Aherne NJ Rangaswamy G Thirion P Prostate cancer in a male with Holt-Oram syndrome: First clinical association of the TBX5 mutation Case Rep Urol 2013 2013 405343 23984174 \n7 Usang UE Agan TU Inyang AW Emehute JD Itam IH Syndromic anorectal malformation associated with Holt-Oram syndrome, microcephaly, and bilateral corneal opacity: A case report J Med Case Rep 2016 10 216 27495810 \n8 Rana M Solanki SL Agarwal V Divatia JV Holt-Oram syndrome: Anesthetic challenges and safe outcome Ann Card Anaesth 2017 20 110 1 28074809 \n9 Tvede N Nielsen LP Andersen V Bradycardia after high-dose intravenous methylprednisolone therapy Scand J Rheumatol 1986 15 302 4 3798047 \n10 Akikusa JD Feldman BM Gross GJ Silverman ED Schneider R Sinus bradycardia after intravenous pulse methylprednisolone Pediatr 2007 119 e778 82 \n11 Der GA Bierings M Frenkel J Glucocorticoid-associated Bradycardia 2008 30 172 5 \n12 Duffy C Hall L Godown J Tatsuki K Borinstein SC Steroid induced bradycardia in acute lymphoblastic leukemia patients Blood 2017 130 5012\n\n",
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"issue": "13(3)",
"journal": "Annals of pediatric cardiology",
"keywords": "Acute lymphoblastic leukemia; Holt-Oram; bradycardia; steroid-associated bradycardia",
"medline_ta": "Ann Pediatr Cardiol",
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"pubdate": "2020",
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"title": "Steroid-associated bradycardia in a newly diagnosed B precursor acute lymphoblastic leukemia patient with Holt-Oram syndrome.",
"title_normalized": "steroid associated bradycardia in a newly diagnosed b precursor acute lymphoblastic leukemia patient with holt oram syndrome"
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"abstract": "BACKGROUND\nStudies show tranexamic acid can reduce the risk of death and early neurological deterioration after intracranial haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in intracerebral haemorrhage patients susceptible to haemorrhage expansion.\n\n\nMETHODS\nWe did a prospective, double-blind, randomised, placebo-controlled trial at 10 stroke centres in China. Acute supratentorial intracerebral haemorrhage patients were eligible if they had indication of haemorrhage expansion on admission imaging (eg, spot sign, black hole sign or blend sign), and were treatable within 8 hours of symptom onset. Patients were randomly assigned (1:1) to receive either tranexamic acid or a matching placebo. The primary outcome was intracerebral haematoma growth (>33% relative or >6 mL absolute) at 24 hours. Clinical outcomes were assessed at 90 days.\n\n\nRESULTS\nOf the 171 included patients, 124 (72.5%) were male, and the mean age was 55.9±11.6 years. 89 patients received tranexamic acid and 82 received placebo. The primary outcome did not differ significantly between the groups: 36 (40.4%) patients in the tranexamic acid group and 34 (41.5%) patients in the placebo group had intracranial haemorrhage growth (OR 0.96, 95% CI 0.52 to 1.77, p=0.89). The proportion of death was lower in the tranexamic acid treatment group than placebo group (8.1% vs 10.0%), but there were no significant differences in secondary outcomes including absolute intracranial haemorrhage growth, death and dependency.\n\n\nCONCLUSIONS\nAmong patients susceptible to haemorrhage expansion treated within 8 hours of stroke onset, tranexamic acid did not significantly prevent intracerebral haemorrhage growth. Larger studies are needed to assess safety and efficacy of tranexamic acid in intracerebral haemorrhage patients.",
"affiliations": "Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Beijing, China.;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Medicine and Therapeutics, Prince of Wales Hospital, Shatin, Hong Kong.;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Tangshan People's Hospital, Tangshan, China.;Department of Neurology, Tangshan Gongren Hospital, Tangshan, China.;Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Beijing Pinggu Hospital, Beijing, China.;Department of Neurology, Liangxiang Hospital of Beijing Fangshan District, Beijing, China.;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China yongjunwang@ncrcnd.org.cn.",
"authors": "Liu|Jingyi|J|http://orcid.org/0000-0001-7360-0267;Nie|Ximing|X|http://orcid.org/0000-0002-8380-4076;Gu|Hongqiu|H|http://orcid.org/0000-0003-1608-1856;Zhou|Qi|Q|;Sun|Haixin|H|;Tan|Ying|Y|;Liu|Dacheng|D|http://orcid.org/0000-0003-3786-9255;Zheng|Lina|L|;Zhao|Jiahui|J|;Wang|Yan|Y|;Cao|Yibin|Y|;Zhu|Haomeng|H|;Zhang|Yunpeng|Y|;Yi|Lijin|L|;Pu|Yuehua|Y|;Wen|Miao|M|;Yang|Zhonghua|Z|;Sun|Shengjun|S|;Wang|Wenzhi|W|;Zhao|Xingquan|X|;Liu|Liping|L|http://orcid.org/0000-0003-2943-055X;Wang|Yongjun|Y|http://orcid.org/0000-0002-9976-2341",
"chemical_list": null,
"country": "England",
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"doi": "10.1136/svn-2021-000942",
"fulltext": "\n==== Front\nStroke Vasc Neurol\nStroke Vasc Neurol\nsvnbmj\nsvn\nStroke and Vascular Neurology\n2059-8696\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n33795488\nsvn-2021-000942\n10.1136/svn-2021-000942\nOriginal Research\n1506\n1507\nTranexamic acid for acute intracerebral haemorrhage growth based on imaging assessment (TRAIGE): a multicentre, randomised, placebo-controlled trial\nhttp://orcid.org/0000-0001-7360-0267\nLiu Jingyi 12\nhttp://orcid.org/0000-0002-8380-4076\nNie Ximing 12\nhttp://orcid.org/0000-0003-1608-1856\nGu Hongqiu 12\nZhou Qi 12\nSun Haixin 3\nTan Ying 4\nhttp://orcid.org/0000-0003-3786-9255\nLiu Dacheng 12\nZheng Lina 5\nZhao Jiahui 12\nWang Yan 6\nCao Yibin 7\nZhu Haomeng 8\nZhang Yunpeng 9\nYi Lijin 10\nPu Yuehua 12\nWen Miao 12\nYang Zhonghua 12\nSun Shengjun 311\nWang Wenzhi 3\nZhao Xingquan 12\nhttp://orcid.org/0000-0003-2943-055X\nLiu Liping 12\nhttp://orcid.org/0000-0002-9976-2341\nWang Yongjun 12\n1 Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China\n2 China National Clinical Research Center for Neurological Diseases, Beijing, China\n3 Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China\n4 Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Beijing, China\n5 Department of Medicine and Therapeutics, Prince of Wales Hospital, Shatin, Hong Kong\n6 Department of Neurology, Tangshan People’s Hospital, Tangshan, China\n7 Department of Neurology, Tangshan Gongren Hospital, Tangshan, China\n8 Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China\n9 Department of Neurology, Beijing Pinggu Hospital, Beijing, China\n10 Department of Neurology, Liangxiang Hospital of Beijing Fangshan District, Beijing, China\n11 Department of Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China\nCorrespondence to Dr Yongjun Wang; yongjunwang@ncrcnd.org.cn\n6 2021\n1 4 2021\n6 2 160169\n15 2 2021\n23 3 2021\n26 3 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nBackground\n\nStudies show tranexamic acid can reduce the risk of death and early neurological deterioration after intracranial haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in intracerebral haemorrhage patients susceptible to haemorrhage expansion.\n\nMethods\n\nWe did a prospective, double-blind, randomised, placebo-controlled trial at 10 stroke centres in China. Acute supratentorial intracerebral haemorrhage patients were eligible if they had indication of haemorrhage expansion on admission imaging (eg, spot sign, black hole sign or blend sign), and were treatable within 8 hours of symptom onset. Patients were randomly assigned (1:1) to receive either tranexamic acid or a matching placebo. The primary outcome was intracerebral haematoma growth (>33% relative or >6 mL absolute) at 24 hours. Clinical outcomes were assessed at 90 days.\n\nResults\n\nOf the 171 included patients, 124 (72.5%) were male, and the mean age was 55.9±11.6 years. 89 patients received tranexamic acid and 82 received placebo. The primary outcome did not differ significantly between the groups: 36 (40.4%) patients in the tranexamic acid group and 34 (41.5%) patients in the placebo group had intracranial haemorrhage growth (OR 0.96, 95% CI 0.52 to 1.77, p=0.89). The proportion of death was lower in the tranexamic acid treatment group than placebo group (8.1% vs 10.0%), but there were no significant differences in secondary outcomes including absolute intracranial haemorrhage growth, death and dependency.\n\nConclusions\n\nAmong patients susceptible to haemorrhage expansion treated within 8 hours of stroke onset, tranexamic acid did not significantly prevent intracerebral haemorrhage growth. Larger studies are needed to assess safety and efficacy of tranexamic acid in intracerebral haemorrhage patients.\n\nhemorrhage\nstroke\nCT angiography\nCT\ndrug\nBeijing Science and Technology Commission D141100000114002 http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 81820108012 81870913 81971614 Key R&D program of China 2016YFC1307301 special-featureunlocked\nspecial-featureeditors-choice\n==== Body\nIntroduction\n\nSpontaneous intracerebral haemorrhage (ICH) is one of the most lethal and disabling form of strokes. Almost 40% of patients with ICH die within the first month and only about 12%–39% of survivors achieve long-term functional independence.1 2 In past decades, many strategies, including blood pressure control, iron supplements and haemostatic therapies have been investigated to treat acute ICH, but few have demonstrated any potential clinical benefit.3\n\nIntracerebral haematoma expansion is a modifiable independent predictor of poor clinical outcome.4 Antifibrinolytic agents such as tranexamic acid may have the potential in reducing intracranial haematoma formation.5 Previous trials investigating recombinant factor VIIa and tranexamic acid for ICH showed a reduction in haematoma expansion, but failed to show a clinical benefit.6 There was even a potential risk of developing ischaemic events.7 8 This lack of clinical effect might be from the unselective inclusion of ICH patients.\n\nICH patients at a higher risk of haematoma expansion may benefit more from therapies targeting active bleeding. In recent years, several non-contrast CT (NCCT) indicators emerged as promising markers for identification of patients at higher risk of haematoma expansion and unfavourable clinical outcome.9 10 Independent imaging predictors include the blend sign and the black hole sign.11 Furthermore, the spot sign on CT angiography (CTA) is a validated biomarker for active intracerebral bleeding and is associated with clinical deterioration and poor outcome.12–15\n\nWe, therefore, designed a randomised controlled trial to investigate whether tranexamic acid could reduce the risk of haematoma expansion in ICH patients with either the spot, black hole or blend sign.\n\nMethods\n\nThe protocol and statistical plan of TRAIGE trial has been published earlier.16 Written informed consent was obtained from all patients or their legal representatives before enrolment.\n\nThe inclusion process consisted of two periods. Between January 2015 and January 2017, eligible patients aged between 18 and 79 years old presenting to the emergency department at three hospitals in China with an acute primary spontaneous ICH within 6 hours of symptom onset (or time last seen well) and a spot sign were enrolled (online supplemental table 1). A spot sign was defined as a focus of contrast enhancement of a serpiginous or spot-like appearance within a parenchymal haematoma identified on CTA source images without connection to a vessel outside the haematoma margin and corresponding hyperdensity on the NCCT indicative of calcification.17 However, since 2015, two new heterogeneous density on NCCT have been identified as predictors of haematoma expansion in ICH with considerable sensitivity and specificity: the blend and black hole signs.18 19 To better include all ICH patients susceptible to haematoma expansion, broadening the inclusion criteria to include these two signs was proposed. Therefore, between January 2017 and March 2020, an additional seven hospitals recruited eligible primary spontaneous ICH patients with either a blend sign or a black hole sign on NCCT within 6 hours of symptom onset, while the original three hospitals continued to enrol patients with the spot sign throughout the trial. Protocol changes are described in the online supplemental file. Blend sign and black hole sign were of equivalent value in inclusion screening, enrolled patients could be positive of either sign, or both. The blend sign was defined as blending of relatively hypoattenuating area with the adjacent hyperattenuating region within a haematoma with a well-defined margin. The black hole sign was defined as a round, oval or rod-like hypoattenuating area adjacent to the hyperattenuating region within a haematoma with an identifiable border. The spot sign, blend sign and black hole sign were adjudicated in real time by radiologists at each corresponding site not involved in the study. ICH Patients without these signs or declined to participate in the tranexamic acid study were enrolled in an observational registry (online supplemental table 1). All randomised patients received therapy within 8 hours of onset.\n\n10.1136/svn-2021-000942.supp1 Supplementary data\n\nExclusion criteria included ICH secondary to tumour, trauma, aneurysm, vascular malformation, haemorrhagic conversion of ischaemic stroke, venous sinus thrombosis or central nervous system infection, use of oral anticoagulant therapy with abnormal laboratory values, infratentorial ICH, Glasgow Coma Scale (GCS) score <8, an ICH volume >70 mL, parenchymal haemorrhage expanding to fill one side of the lateral ventricle or more than half of both lateral ventricles, clinical history or current evidence suggestive of venous or arterial thrombotic events within the previous 6 months, pregnancy, within 30 days post partum or lactating, planned surgery for the ICH within 24 hours of onset, contraindication of tranexamic acid and prestroke dependency with a modified Rankin Scale (mRS) score >2. Full inclusion and exclusion criteria is described in the online supplemental file.\n\nRandomisation and masking\n\nPatients were randomly assigned to receive either placebo (0.9% NaCl) or tranexamic acid (1:1) using a computer-generated procedure with randomly permuted blocks of varying size. The treatment number was allocated using a centralised treatment allocation system at the baseline visit. The investigational product was distributed to the participating centres in externally indistinguishable sealed treatment kits containing either tranexamic acid or placebo contained in the identical standard off-the-shelf ampoules. Ampoules and the treatment pack were labelled with a unique pack number. After randomisation, the treatment pack corresponding to the treatment number was handed to a nurse or care provider not involved in patient management or evaluation to be prepared for administration. If there was no occurrence of a serious adverse event due to study medication, the investigators do not have access to the randomisation code throughout the trial. Treatment allocation was concealed from all patients and investigators involved in the trial.\n\nProcedures\n\nAll participants received either intravenous tranexamic acid 1 g in 100 mL 0·9% NaCl over 10 min followed by 1 g in 250 mL 0·9% NaCl infusion over 8 hours or placebo, with the same administration regimen. The study drug was to be administered as soon as possible after randomisation, within 8 hours from onset.\n\nBaseline head CT and CTA were assessed for eligibility in real time by enrolling investigators who determined if there was a spot sign, blend sign or black hole sign, and calculated the ICH volumes by using the ABC/2 method.20 Follow-up CT scan was performed at 24 hours (±2) after drug administration to assess for any haemorrhage growth.\n\nVital signs were closely monitored and recorded during and after the infusion. Investigators were advised to follow the China National Guidelines for the management of spontaneous ICH for blood pressure and general ICH management.21 ECGs were performed at baseline and 24 hours as per protocol. Serum troponin, cerebral imaging, vascular ultrasound, pulmonary arteries CT angiograms, and other auxiliary examinations were conducted as necessary. The published International Health Guidelines (Declaration of Helsinki, 2008) was followed for the handling of data for all ICH patients\n\nOutcomes\n\nThe primary outcome measure was the presence of expansion of intracerebral haematoma by 24 hours (±2) after start of drug administration, as defined by an absolute increase of more than 6 mL or a relative growth of more than 33% from the baseline.\n\nPrespecified secondary safety outcomes included major thromboembolic events (acute myocardial ischaemia, acute cerebral ischaemia and acute pulmonary embolism). Safety outcomes were collected through day 90. Secondary efficacy outcome measures included absolute ICH growth volume and absolute intraventricular haemorrhage (IVH) growth volume at 24 hours (±2), poor clinical outcome, defined as death or major disability (mRS 4–6), other thromboembolic events (venous thrombosis and other peripheral arterial embolisms), and death due to any cause, all by 90±7 days.\n\nStatistical analysis\n\nWe initially defined a sample size of 240 patients, providing an 80% power to detect a significant absolute difference of 30% in the proportion of patients with haemorrhage enlargement at 24 hours (42% in treatment vs 61% in control arm) at a two-sided statistical significance threshold of p=0·05, and a 10% drop-out rate. Justified by absence of previous efficacy data, we performed a sample size re-estimation with a renewed sample size of 188 participants. Because of the neutral results reported from the STOP-AUST trial, this study was terminated in March 2020, and the final number of patients enrolled was 171.22\n\nThe primary analysis was based on the intention-to-treat principle and was conducted according to a prespecified statistical analysis plan. Univariate analyses were performed for examining associations of demographic, clinical, laboratory and imaging variables with clinical outcome. Continuous endpoints were summarised by means or medians, with treatment effects tested by the Student’s t-test or Mann-Whitney U test. Differences between treatment groups are listed as OR and 95% CI. The presence of haematoma growth between the two groups was compared using binary logistic regression. Statistical analysis was done using SAS V.9.4 (SAS Institute).\n\nAn independent data and safety monitoring board assessed the safety of the trial participants, and efficacy and overall progress of the study was analysed after all the patients (n=171) were enrolled. The data analysis started after the last patient enrolled completed the 3-month follow-up. Missing outcome values were imputed assuming the worst possible primary outcome (haematoma growth). The primary analysis was unadjusted. The baseline volume was assessed on the most recent scan before randomisation, whether that was the NCCT or CT angiogram. Both baseline and 24 hours ICH volumes were obtained using the ABC/2 method by central independent assessors, who were masked to treatment assignment.\n\nThe trial is registered at ClinicalTrials.gov (NCT02625948) entitled ‘Tranexamic Acid for Acute ICH Growth prEdicted by Spot Sign (TRAIGE)’.\n\nResults\n\nBetween 16 January 2015 and 14 February 2020, 696 patients with supratentorial ICH shown on imaging within 6 hours of onset from 10 sites were screened. Among them, 171 (24.6%) were enrolled and underwent randomisation. Of these, 169 (98.9%) patients had 24 hours follow-up CT scans; 89 patients were assigned to the tranexamic acid group; 82 assigned to the placebo group. 2 patients assigned tranexamic acid had missing 24 hours data. All 171 patients received the allocated treatment and were included in the intention-to-treat analysis. By May 2020, a 90-day follow-up for all patients was requested. Day 90 mRS was available in 164 (95.9%) patients (figure 1). Study masking was not broken in any individual. All 171 patients met the inclusion and exclusion criteria.\n\nFigure 1 Trial profile. GCS, glasgow coma scale; ICH, intracerebral haemorrhage; TXA, tranexamic acid.\n\nTheir mean age was 55.9±11.6 years, and 124 (72.5%) were male. The median GCS score was 14 (11-15), and the median National Institutes of Health Stroke Scale score was 11 (7–15). The mean volume of ICH at baseline was 23.7±18.7 mL, and median haematoma volume was 19.8 mL (IQR 11.0–31.5). The lobar regions were involved in 44 (25.7%) patients, and the deep grey matter was involved in 127 (74.3%), of which 16 (12.6%) were located in the thalamus and 111 (87.4%) in the basal ganglia. IVH was present in 33 (19.3%) patients. The baseline characteristics of the two treatment groups were similar, except that the platelet count was less in the placebo group, although still within normal range. Furthermore, involvement of the thalamus occurred more frequently in the tranexamic acid group, whereas haemorrhage involving basal ganglia was more frequent in the placebo group (table 1).\n\nTable 1 Baseline characteristics of the participants\n\nCharacteristics\tTotal\n(n=171)\tTXA\n(n=89)\tPlacebo\n(n=82)\tP value\t\nAge, mean±SD, year\t55.9±11.6\t56.7±12.2\t55.0±10.8\t0.36\t\nMale, n (%)\t124 (72.5)\t63 (70.8)\t61 (74.4)\t0.60\t\nNIHSS, median (IQR)\t11.0 (7.0–15.0)\t11.0 (7.0–15.0)\t10.0 (6.0–15.0)\t0.54\t\nGCS, median (IQR)\t14.0 (11.0–15.0)\t14.0 (11.0–15.0)\t14.0 (11.0–15.0)\t0.64\t\nHistory, n (%)\t\t\t\t\t\nStroke/TIA\t8 (4.7)\t5 (5.6)\t3 (3.7)\t0.54\t\n CHD/MI\t3 (1.8)\t1 (1.1)\t2 (2.4)\t0.51\t\n Hypertension\t114 (66.7)\t64 (71.9)\t50 (61.0)\t0.13\t\n Diabetes\t18 (10.5)\t12 (13.5)\t6 (7.3)\t0.26\t\n Smoking\t45 (26.3)\t21 (23.6)\t24 (29.3)\t0.40\t\n Alcohol\t56 (32.7)\t30 (33.7)\t26 (31.7)\t0.78\t\nPrevious antiplatelet therapy, n (%)\t5 (2.9)\t4 (4.5)\t1 (1.2)\t0.39\t\nPrevious antihypertensive therapy, n (%)\t43 (25.1)\t24 (27.0)\t19 (23.2)\t0.19\t\nAdmission SBP, mean±SD, mm Hg\t173.7±27.7\t176.2±27.5\t171.1±27.9\t0.23\t\nAdmission DBP, mean±SD, mm Hg\t101.2±18.5\t99.7±16.5\t102.9±20.4\t0.27\t\nAdmission lab test, mean±SD\t\t\t\t\t\n Glucose, mmol/L\t7.8±2.8\t8.2±3.0\t7.4±2.6\t0.10\t\n WCC, 109/L\t9.7±4.9\t9.8±5.8\t9.6±3.9\t0.77\t\n PLT, 109/L\t226.8±106.6\t243.2±137.7\t209.2±52.4\t0.04\t\n INR\t1.0±0.1\t1.0±0.1\t1.0±0.1\t0.29\t\n Fbg, g/L\t2.7±1.4\t2.8±1.6\t2.7±1.0\t0.79\t\n APTT, s\t29.2±6.4\t28.7±5.9\t29.7±7.0\t0.35\t\n PT, s\t11.8±2.9\t11.7±2.7\t12.0±3.1\t0.42\t\nICH Volume, Mean±SD, mL\t23.7±18.7\t25.3±19.7\t22.0±17.5\t0.25\t\nMidline shift, Mean±SD, mm\t2.5±3.7\t2.6±4.0\t2.3±3.4\t0.60\t\nICH Location, n (%)\t\t\t\t\t\n Supratentorial lobar\t44 (25.7)\t22 (24.7)\t22 (26.8)\t0.75\t\n Supratentorial deep\t127 (74.3)\t67 (75.3)\t60 (73.2)\t0.75\t\n Thalamus\t16/127 (12.6)\t13/67 (19.4)\t3/60 (5.0)\t0.01\t\n Basal ganglia\t111/127 (87.4)\t54/67 (80.6)\t57/60 (95.0)\t0.01\t\nIntraventricular tricular haemorrhage, n (%)\t33 (19.3)\t18 (20.2)\t15 (18.3)\t0.75\t\nSpot sign*, n (%)\t94 (55.0)\t50 (56.2)\t44 (53.7)\t0.49\t\nBlack Hole sign†, n (%)\t47 (27.5)\t25 (28.1)\t22 (26.8)\t0.85\t\nBlend sign‡, n (%)\t107 (62.6)\t56 (62.9)\t51 (62.2)\t0.62\t\nICH aetiology, n (%)\t\t\t\t0.31\t\n Hypertension\t166 (97.1)\t88 (98.9)\t78 (95.1)\t\t\n CAA\t1 (0.6)\t\t1 (1.2)\t\t\n Others\t4 (2.3)\t1 (1.1)\t3 (3.7)\t\t\nP value for comparison between patients with TXA and placebo.\n\n*Ninety-four of 171 patients were enrolled in this trial via three subcentres using the spot sign on CTA as the entry criterion.\n\n†Seventy-seven of 171 patients were enrolled in this trial via seven subcentres using black hole sign and blend sign on NCCT as the entry criterion. Twenty-four of 77 patients in seven subcentres (NCCT screening) were positive for black hole sign (+), 23 of 94 patients in three subcentres (CTA screening) were positive for black hole sign (+).\n\n‡Fifty-six of 77 patients in seven subcentres (NCCT screening) were positive for blend sign (+), 51 of 94 patients in three subcentres (CTA screening) were positive for blend sign (+).\n\nAPTT, activated partial thromboplastin time; CAA, cerebral amyloid angiopathy; CHD, coronary heart disease; CTA, CT angiography; DBP, diabolic blood pressure; Fbg, fibrinogen; GCS, Glasgow Coma Scale; ICH, intracerebral haemorrhage; INR, international normalised ratio; MI, myocardial infarction; mRS, modified Rankin Scale; NCCT, non-contrast CT; NIHSS, National Institutes of Health Stroke Scale; PLT, platelet; PT, prothrombin time; SBP, systolic blood pressure; TIA, transient ischaemic attack; TXA, tranexamic acid; WCC, white cell count.\n\nAmong the 10 sites, 3 sites enrolled 94 patients used the spot sign on CT angiogram as inclusion criteria, and 7 sites enrolled 77 patients used the black hole sign and/or the blend sign on NCCT as inclusion criteria (online supplemental table 2). More than one sign could be positive in a given patient. Of the 77 patients, 24 (31.2%) had black hole sign and 56 (72.7%) had blend sign. Of 94 patients, 23 (24.5%) had black hole sign, and 51 (54.3%) had blend sign, although these two signs were not regarded sufficient or necessary for inclusion in these three sites (table 1). All 94 patients also had a spot sign.\n\nMedian time from onset to arrival at hospital was 120 (69–190) min, onset to treatment was 290 (185–370) min and imaging to treatment was 108 (73–161) min. Eighteen (10.5%) patients were treated within 2 hours after onset, 66 (37.4%) within 4 hours and 123 (70.8%) within 6 hours (table 2 and figure 2). All patients were treated within the 8-hour time window. As shown in table 2, there were no significant differences between the two groups with respect to the medical care provided during the hospitalisation. Pulmonary infection was the most common complication (20 (22.5%) in the tranexamic acid group vs 16 (19.5%) in the placebo group, p=0.64), followed by gastrointestinal bleeding and DVT (table 2).\n\nTable 2 Time metrics, treatment and complications of the participants\n\nCharacteristics\tTotal\n(n=171)\tTXA\n(n=89)\tPlacebo\n(n=82)\tP value\t\nTime intervals, median (IQR), min\t\t\t\t\t\n Onset to door\t120.0 (69.0–190.0)\t120.0 (77.0–184.0)\t120.0 (66.0–190.0)\t0.76\t\n Onset to treatment\t290.0 (185.0–370.0)\t290.0 (205.0–369.0)\t285.0 (180.0–378.0)\t0.87\t\n Imaging to treatment\t107.5 (73.0–161.0)\t128.0 (67.0–172.0)\t103.0 (74.0–160.0)\t0.40\t\nBP during TXA (Placebo) mean±SD, mm Hg\t\t\t\t\t\n SBPmax\t170.3±24.3\t170.1±24.8\t170.4±23.8\t0.95\t\n DBPmax\t100.5±16.0\t99.5±13.8\t101.5±18.0\t0.48\t\n MAPmax\t123.3±17.7\t122.8±16.4\t123.9±19.0\t0.70\t\nConcomitant therapy during hospitalisation, n (%)\t\t\t\t\t\n Antihypertensive therapy\t142 (83.0)\t77 (86.5)\t65 (79.3)\t0.21\t\n Osmotic therapy\t125 (73.1)\t67 (75.3)\t58 (70.7)\t0.50\t\n Statin therapy\t11 (6.4)\t7 (7.9)\t4 (4.9)\t0.43\t\nSurgical intervention during hospitalisation, n (%)\t\t\t\t\t\n Evacuation of intracranial haematoma\t29 (17.0)\t16 (18.0)\t13 (15.9)\t0.71\t\n Decompressive craniectomy\t2 (1.2)\t1 (1.1)\t1 (1.2)\t0.95\t\n EVD\t3 (1.8)\t2 (2.2)\t1 (1.2)\t0.61\t\nDVT prophylaxis, n (%)\t\t\t\t\t\n Anticoagulation\t16 (9.4)\t11 (12.4)\t5 (6.1)\t0.16\t\n Compression\t51 (29.8)\t31 (34.8)\t20 (24.4)\t0.14\t\nComplications, n(%)\t\t\t\t\t\n Epilepsy\t1 (0.6)\t\t1 (1.2)\t0.30\t\n Pulmonary infection\t36 (21.1)\t20 (22.5)\t16 (19.5)\t0.64\t\n Gastrointestinal bleeding\t17 (9.9)\t9 (10.1)\t8 (9.8)\t0.94\t\n DVT\t13 (7.6)\t8 (9.0)\t5 (6.1)\t0.48\t\nP value for comparison between patients with TXA and placebo.\n\nBP, blood pressure; DBP, diastolic blood pressure; DVT, deep venous thrombosis; EVD, external ventricular drain; MAP, mean arterial pressure; SBP, systolic blood pressure; TXA, tranexamic acid.\n\nFigure 2 Post hoc forest plot of primary outcome in subgroups stratified by demographic and clinical characteristics. OR less than 1 favours tranexamic acid over placebo. GCS, Glasgow Coma Scale; NIHSS, National Institutes of Health Stroke Scale; SBP: systolic blood pressure; TXA, tranexamic acid.\n\nHaematoma expansion was seen in 70 (40.9%) patients and 58 (34.9%) patients had poor clinical outcome. In the primary analysis evaluating the effect of tranexamic acid on the primary efficacy outcome of ICH expansion, there was no difference between the two groups: 36 (40.4%) of 89 patients in the tranexamic acid group and 34 (41.5%) of 82 patients in the placebo group had haematoma expansion at 24 hours (OR 0.96, 95% CI 0.52 to 1.77, p=0.89). The mean ICH volume change from baseline to 24 hours was 7.1±16.0 mL, being 6.6±16.5 mL in the tranexamic acid group and 7.6±15.6 mL in the placebo group (p=0.70) (table 3).\n\nTable 3 Primary and secondary outcomes\n\nOutcomes\tTotal (n=171)\tTXA (n=89)\tPlacebo (n=82)\tOR (95% CI)\tP value\t\nPrimary outcome\t\t\t\t\t\t\nHaematoma expansion at 24 hours*, n (%)\t70 (40.9)\t36 (40.4)\t34 (41.5)\t0.96 (0.52 to 1.77)\t0.89\t\nSecondary outcomes\t\t\t\t\t\t\nmRS at 90 days‡, n (%)\t\t\t\t\t0.78\t\n0\t7 (4.2)\t5 (5.8)\t2 (2.5)\t\t\t\n1\t47 (28.3)\t21 (24.4)\t26 (32.5)\t\t\t\n2\t27 (16.3)\t15 (17.4)\t12 (15.0)\t\t\t\n3\t27 (16.3)\t13 (15.1)\t14 (17.5)\t\t\t\n4\t35 (21.1)\t20 (23.3)\t15 (18.8)\t\t\t\n5\t8 (4.8)\t5 (5.8)\t3 (3.8)\t\t\t\n6\t15 (9.0)\t7 (8.1)\t8 (10.0)\t\t\t\nmRS 4–6 at 90 days‡, n (%)\t58 (34.9)\t32 (37.2)\t26 (32.5)\t1.23 (0.65 to 2.33)\t0.53\t\nDeath at 90 days‡, n (%)\t15 (9.0)\t7 (8.1)\t8 (10.0)\t0.82 (0.28 to 2.37)\t0.71\t\nImaging at 24 hours*\t\t\t\t\t\t\nICH growth volume, mean±SD, mL\t7.1±16.0\t6.6±16.5\t7.6±15.6\t\t0.70\t\nICH growth volume >6 mL, n (%)\t54 (31.6)\t26 (29.2)\t28 (34.1)\t0.80 (0.42 to 1.52)\t0.49\t\nICH growth rate >33%, n (%)\t48 (28.1)\t23 (25.8)\t25 (30.5)\t0.80 (0.41 to 1.55)\t0.50\t\nMidline shift, mean±SD, mm\t2.6±3.7\t2.8±4.0\t2.4±3.5\t\t0.50\t\nMedian NIHSS score*, Median (IQR)\t\t\t\t\t\t\nAt 24 hours\t10.5 (5.0–15.0)\t11.0 (6.0–14.0)\t10.0 (5.0–16.0)\t\t0.94\t\nAt discharge\t8.0 (3.0–11.0)\t8.0 (3.0–11.0)\t8.0 (3.0–11.0)\t\t0.40\t\nMajor thromboembolic events (ACI) at 90 days†, n (%)\t2 (1.2)\t1 (1.2)\t1 (1.3)\t\t0.96\t\n*modified intention-to-treat analysis for 171 patients at 24 hours. Haematoma expansion defined as an increase of >6 mL or a growth of >33%.\n\n†A total of 166 patients were analysed at 90 days (five lost to follow-up).\n\nACI, acute cerebral infarction; ICH, intracranial haemorrhage; mRS, modified Rankin Scale; TXA, tranexamic acid.\n\nThere was no significant difference in the distribution (shift) of the mRS scores at day 90 (GenOR 1.11, 95% CI 0.65 to 1.90, p=0.70) (table 3 and figure 3). The proportion of 90-day mortality from any cause was lower in the tranexamic group than the controlled group (8.1% vs 10.0%, p=0.71). In the prespecified subgroup analysis, there was no heterogeneity of treatment effect by time of administration, whether dichotomised as less than 3 hours vs 3 hours or longer (interaction p=0.85) or as less than 4.5 hours vs 4.5 hours or longer (interaction p=0.14) (figure 4). A trend of benefit of treatment was seen in patients with GCS score greater than 11 (interaction p=0.07) (figure 2). Two patients had major thromboembolic events (acute cerebral infarction), one in each group (p=0.96) (table 3).\n\nFigure 3 Modified Rankin Scale (mRS) distribution at 90 days. A score of 0 represents no symptoms, 1 represents no disability despite symptoms, 2 represents slight disability but able to look after own affairs, 3 represents moderate disability but able to walk without assistance, 4 represents moderately severe disability (unable to walk or attend to own bodily needs), 5 represents severely disabled (bedridden and requiring constant nursing care) and 6 represents death. GenOR=1.11 (0.65 to 1.90), p=0.70. TXA, tranexamic acid.\n\nFigure 4 Post hoc forest plot of primary outcome in subgroups stratified by imaging characteristics. OR less than 1 favours tranexamic acid over placebo. ICH, intracerebral haemorrhage; TXA, tranexamic acid.\n\nDiscussion\n\nOur trial was designed on the premise that image-guided patient selection could identify a subgroup of high risk ICH patients that could benefit from tranexamic acid in terms of haematoma expansion. We used three highly predictive imaging biomarkers of haematoma expansion, the spot, blend and black hole signs to select ICH patients for target haemostatic therapy. In patients who had imaging findings suggestive of haematoma expansion and were treated within 8 hours from the onset, tranexamic acid did not result in a significant reduction in haemorrhage growth at 24 hours. This result is consistent with several studies regarding haemostatic therapies in high risk ICH patients.22 23 However, in the secondary outcome analysis, the proportion of death at day 90 was lower among patients assigned to tranexamic acid group compared with the placebo group, although statistically insignificant.\n\nThere was a trend of effect of treatment in patients who were treated very early (within 4.5 hours) comparing to those treated later on, though statistically insignificant. The treatment windows used in the subgroup analysis is in accordance to those of (Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage) TICH-2 and (the Spot sign and Tranexamic acid On Preventing ICH growth—AUStralasia Trial) STOP-AUST, both of which also suggested that an earlier treatment window might have a clear effect on reducing haematoma growth.6 22 Despite the effort to do rapid screening, most of the patients in our trial were treated beyond 4.5 hours, which was the reason for the limited power of the subgroup analysis. Furthermore, although tranexamic acid did not reduce haematoma expansion, the proportion of mortality at 90 days was lower in the tranexamic acid group, suggesting potential other mechanisms involved in this positive trending of benefit. Further evaluation testing of tranexamic acid in a tighter treatment window may be warranted.\n\nBaseline haematoma volume is a known strong predictor of haematoma expansion and outcome, particularly in patients with haematoma volume greater than 30 mL.24 In a post-hoc analysis of the TICH-2 trial, participants with a baseline haematoma volume between 30 and 60 mL who received tranexamic acid seemed to have better outcomes.6 In the subgroup analysis, a trend of benefit of treatment was seen in patients with a baseline haematoma volume of greater than 45 mL. It is fair to postulate that patients with moderate size haematoma at baseline might benefit more from tranexamic acid, and could be the targeted population for future studies.\n\nOur study was designed at a time when there were no published results of tranexamic acid treatment on ICH patients; therefore, sample size was indirectly estimated. Based on our results, haematoma growth was observed in 40% of patients, distinctly lower than previously reported, therefore, a positive result could be seen with a substantially large sample size. Recruitment based on a positive spot sign was difficult, as many sites did not routinely perform CTA for ICH patients. Furthermore, to perform CTA probably would require longer time before treatment, as seen in this trial. This appeared as a universal limitation, as two large randomised studies using the spot sign to select patients for haemostatic treatment were terminated prematurely due to recruiting difficulties.23 To mitigate slow enrollment, we expanded our inclusion criteria to include those with newly discovered NCCT findings of blend sign and black hole sign in the second phase of our trial. This trial was the first to screen patients using all three imaging markers. Furthermore, this was the largest randomised controlled trial to test tranexamic acid among patients with acute ICH that were at high risk of haematoma expansion.\n\nThe strengths of this study included its double-blinding, allocation concealment, high adherence to treatment protocol and very few missing data on primary outcome. Treatment groups were well balanced at baseline. Some limitations should also be noted. First, it was prematurely stopped with 85% of the planned sample enrolled so the analysis was underpowered. However, as our results highly coincided with other similar trials, our estimates were likely to indicate a true effect. Second, patient outcome may have been confounded by concomitant use of additional agents (blood-lowering therapy, osmotic therapy, statin therapy, etc), which could influence the outcome through unexplained mechanisms. Third, the median delay from arrival at the hospital to treatment of 170 min may have extended the time to treatment, though still within the prespecified time window. As several studies suggested that treating early may be more applicable for haemostatic treatment, this may have limited our findings.\n\nIn summary, among patients susceptible to haematoma expansion treated within 8 hours of onset, tranexamic acid did not significantly prevent the growth of ICH. Larger studies with more specified population and very early treatment are needed to further assess safety and efficacy of tranexamic acid in patients with ICH.\n\nThanks to Fudong Shi, Yaozhi Chen, Xiaoyun Zhang, Xiaochen Wang, Yingying Li, Yanyan Ma and other study coordinators’ meticulous work for data quality control. Thanks to all the participants and investigators who took part in the TRAIGE trial.\n\nData availability statement\n\nData are available on reasonable request. All data are available to researchers on request for purposes of reproducing the results or replicating the procedure by directly contacting the corresponding author.\n\nEthics statements\n\nPatient consent for publication\n\nNot required.\n\nEthics approval\n\nEthics approval was reobtained from the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University in November 2016.\n\nLL and YW contributed equally.\n\nCollaborators: List of Study Sites and Investigators: Sites that recruited patients by CT angiography: Beijing Tiantan Hospital: Liping Liu (PI), Zhonghua Yang, Miao Wen, Ximing Nie, Ying Tan, Yaozhi Chen, Dacheng Liu, Lina Zheng, Jingyi Liu, Jiahui Zhao. Tangshan People’s Hospital: Yan Wang (PI), Mingyang Sun, Wenjian Shi. Tangshan Gongren Hospital: Yibin Cao (PI), Zilong Rao, Yakun Wu, Fengqun Mu, Fengjie Kan, Haiying Wang, Xin Li, Nan Shi, Min Yuan, Yuling Yang, Lingyun Wu, Jingjing Li, Peng Sun, Hong Zhang, Jing Liu, Yueming Tian, Sujie Wang, Qian Li, Lili Chen, Pei Li, Jinghua Liu, Lijuan Liu. Sites that recruited patients by noncontrast CT: Beijing Luhe Hospital: Haomeng Zhu (PI), Huishan Du, Yan’na Tong, Nan Zhang, Fengli Che. Beijing Pinggu Hospital: Yunpeng Zhang (PI), Changbao Li, Yan Wang, Yuming Li, Jincheng Zhang, Jinju Yang Liangxiang. Hospital of Beijing Fangshan District: Lijin Yi (PI), Qingwei Meng, Wenqin Han, Lan Ma, Xinzhang Mu, Jing Yin, Ningning Qin. Kailuan General Hospital: Hebei Ying Ma (PI), Nannan Zhang, Ya Ou, Lifu Zhou, Yujie Sun, Meng Zhao, Lili Zhang, Yesong Liu, Xiaodong Yuan. Beijing Huairou Hospital of University of Chinese Academy of Sciences: Fuying Yu (PI), Lijun Huang, Lixin Song, Jian Wang. Beijing Daxing District People’s Hospital: Fuming Shi (PI), Liping Dong. Beijing Haidian Hospital: Fengchun Yu (PI), Yongzhen Liu, Xiaomei Tang, Wei Liu, Ke Jia, Zhenghong Zhou, Qunyan Li, Hao Feng, Lei Liu, Fenghui Sun.\n\nContributors: JL, XN, HG, QZ, LL and YW had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. YT, DL, LZ, JZ, YW, YC, HZ, YZ, LY, MW, ZY, SS, WW and XZ contributed to the study concept and design. HG, QZ, HS and YP analysed the data. JL, XN, LL and YW drafted the manuscript. All authors have read and approved the final manuscript.\n\nFunding: This work was supported by the National Key R&D program of China (2016YFC1307301), National Natural Science Foundation of China (81820108012), National Natural Science Foundation of China (81870913), National Natural Science Foundation of China (81971614) and Beijing Science and Technology Commission (D141100000114002).\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 Liu L , Liu J , Wang Y , et al . Substantial improvement of stroke care in China. Stroke 2018;49 :3085–91. 10.1161/STROKEAHA.118.022618 30571434\n2 An SJ , Kim TJ , Yoon B-W . Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: an update. J Stroke 2017;19 :3–10. 10.5853/jos.2016.00864 28178408\n3 Dastur CK , Yu W . Current management of spontaneous intracerebral haemorrhage. 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Radiology 2017;285 :932–40. 10.1148/radiol.2017162839 28678670\n13 Koculym A , Huynh TJ , Jakubovic R , et al . CT perfusion spot sign improves sensitivity for prediction of outcome compared with CTA and postcontrast CT. AJNR Am J Neuroradiol 2013;34 :965–70. S961. 10.3174/ajnr.A3338 23124643\n14 Al-Shahi Salman R , Frantzias J , Lee RJ , et al . Absolute risk and predictors of the growth of acute spontaneous intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data. Lancet Neurol 2018;17 :885–94. 10.1016/S1474-4422(18)30253-9 30120039\n15 Phan TG , Krishnadas N , Lai VWY , et al . Meta-analysis of accuracy of the spot sign for predicting hematoma growth and clinical outcomes. Stroke 2019;50 :2030–6. 10.1161/STROKEAHA.118.024347 31272327\n16 Liu L , Wang Y , Meng X , et al . Tranexamic acid for acute intracerebral hemorrhage growth predicted by spot sign trial: rationale and design. Int J Stroke 2017;12 :326–31. 10.1177/1747493017694394 28381202\n17 Thompson AL , Kosior JC , Gladstone DJ , et al . Defining the CT angiography 'spot sign' in primary intracerebral hemorrhage. Can J Neurol Sci 2009;36 :456–61. 10.1017/S0317167100007782 19650356\n18 Li Q , Zhang G , Huang Y-J , et al . Blend sign on computed tomography: novel and reliable predictor for early hematoma growth in patients with intracerebral hemorrhage. Stroke 2015;46 :2119–23. 10.1161/STROKEAHA.115.009185 26089330\n19 Li Q , Zhang G , Xiong X , et al . Black hole sign: novel imaging marker that predicts hematoma growth in patients with intracerebral hemorrhage. Stroke 2016;47 :1777–81. 10.1161/STROKEAHA.116.013186 27174523\n20 Kothari RU , Brott T , Broderick JP , et al . The ABCs of measuring intracerebral hemorrhage volumes. Stroke 1996;27 :1304–5. 10.1161/01.STR.27.8.1304 8711791\n21 Cao Y , Yu S , Zhang Q , et al . Chinese stroke association guidelines for clinical management of cerebrovascular disorders: Executive summary and 2019 update of clinical management of intracerebral haemorrhage. Stroke Vasc Neurol 2020;5 :396–402. 10.1136/svn-2020-000433 33262243\n22 Meretoja A , Yassi N , Wu TY , et al . Tranexamic acid in patients with intracerebral haemorrhage (STOP-AUST): a multicentre, randomised, placebo-controlled, phase 2 trial. Lancet Neurol 2020;19 :980–7. 10.1016/S1474-4422(20)30369-0 33128912\n23 Gladstone DJ , Aviv RI , Demchuk AM , et al . Effect of recombinant activated coagulation factor VII on hemorrhage expansion among patients with spot sign-positive acute intracerebral hemorrhage: the spotlight and STOP-IT randomized clinical trials. JAMA Neurol 2019. 10.1001/jamaneurol.2019.2636. [Epub ahead of print: 19 Aug 2019].\n24 Law ZK , Ali A , Krishnan K , et al . Noncontrast computed tomography signs as predictors of hematoma expansion, clinical outcome, and response to tranexamic acid in acute intracerebral hemorrhage. Stroke 2020;51 :121–8. 10.1161/STROKEAHA.119.026128 31735141\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2059-8696",
"issue": "6(2)",
"journal": "Stroke and vascular neurology",
"keywords": "CT; CT angiography; drug; hemorrhage; stroke",
"medline_ta": "Stroke Vasc Neurol",
"mesh_terms": null,
"nlm_unique_id": "101689996",
"other_id": null,
"pages": "160-169",
"pmc": null,
"pmid": "33795488",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "30741383;32847959;18480205;23124643;28959487;31272327;28701501;33262243;28178408;8711791;30120039;29778325;16636233;28678670;15728810;33128912;26089330;27323314;27174523;31735141;28381202;31424491;30571434;19650356",
"title": "Tranexamic acid for acute intracerebral haemorrhage growth based on imaging assessment (TRAIGE): a multicentre, randomised, placebo-controlled trial.",
"title_normalized": "tranexamic acid for acute intracerebral haemorrhage growth based on imaging assessment traige a multicentre randomised placebo controlled trial"
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"abstract": "Excessive neutrophil migration has been correlated with influenza symptom severity. Danirixin (GSK1325756), a selective and reversible antagonist of C-X-C chemokine receptor 2, decreases neutrophil activation and transmigration to areas of inflammation. This study evaluated the efficacy and safety of intravenous (IV) danirixin co-administered with oseltamivir for the treatment of adults hospitalized with influenza.\nIn this phase 2b, double-blind, 3-arm study (NCT02927431), influenza-positive participants were randomized 2:2:1 to receive danirixin 15mg intravenously (IV) twice daily (bid) + oral oseltamivir 75mg bid (OSV), danirixin 50mg IV bid + OSV, or placebo IV bid + OSV, for up to 5 days. The primary endpoint was time to clinical response (TTCR).\nIn total, 10 participants received study treatment (danirixin 15mg + OSV, n = 4; danirixin 50mg + OSV, n = 4; placebo + OSV, n = 2) before the study was terminated early due to low enrollment. All participants achieved a clinical response. Median (95% confidence interval) TTCR was 4.53 days (2.95, 5.71) for danirixin 15mg + OSV, 4.76 days (2.71, 5.25) for danirixin 50mg + OSV, and 1.33 days (0.71, 1.95) for placebo + OSV. Adverse events (AEs) were generally of mild or moderate intensity; no serious AEs were considered treatment-related. Interleukin-8 levels increased in nasal samples (using synthetic absorptive matrix strips) and decreased serum neutrophil-elastase-mediated degradation of elastin decreased in danirixin-treated participants, suggesting effective target engagement.\nInterpretation of efficacy results is restricted by the low participant numbers. The safety and tolerability profile of danirixin was consistent with previous studies.\nThe registration data for the trial are in the ClinicalTrials.gov database, number NCT02927431, and in the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/) as GSK study 201023, EudraCT 2016-002512-40. Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.",
"affiliations": "GlaxoSmithKline, Upper Providence, Pennsylvania.;GlaxoSmithKline, Upper Providence, Pennsylvania.;GlaxoSmithKline, Stevenage, United Kingdom.;GlaxoSmithKline, Upper Providence, Pennsylvania.;GlaxoSmithKline, Research Triangle Park, North Carolina.;GlaxoSmithKline, Upper Providence, Pennsylvania.;GlaxoSmithKline, Upper Providence, Pennsylvania.;Stamford Hospital, Stamford, Connecticut.;Natchitoches Regional Medical Center, Natchitoches, Louisiana.;Duke University Center for Applied Genomics and Precision Medicine, Durham, North Carolina.;GlaxoSmithKline, Upper Providence, Pennsylvania.",
"authors": "Madan|Anuradha|A|;Chen|Shuguang|S|;Yates|Phillip|P|;Washburn|Michael L|ML|;Roberts|Grace|G|;Peat|Andrew J|AJ|;Tao|Yu|Y|;Parry|Michael F|MF|;Barnum|Otis|O|;McClain|Micah T|MT|;Roy-Ghanta|Sumita|S|",
"chemical_list": null,
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"doi": "10.1093/ofid/ofz163",
"fulltext": "\n==== Front\nOpen Forum Infect DisOpen Forum Infect DisofidOpen Forum Infectious Diseases2328-8957Oxford University Press US 10.1093/ofid/ofz163ofz163Major ArticlesEfficacy and Safety of Danirixin (GSK1325756) Co-administered With Standard-of-Care Antiviral (Oseltamivir): A Phase 2b, Global, Randomized Study of Adults Hospitalized With Influenza Madan Anuradha 1Chen Shuguang 1Yates Phillip 2Washburn Michael L 1Roberts Grace 3Peat Andrew J 1Tao Yu 1Parry Michael F 4Barnum Otis 5McClain Micah T 6Roy-Ghanta Sumita 11 GlaxoSmithKline, Upper Providence, Pennsylvania2 GlaxoSmithKline, Stevenage, United Kingdom3 GlaxoSmithKline, Research Triangle Park, North Carolina4 Stamford Hospital, Stamford, Connecticut5 Natchitoches Regional Medical Center, Natchitoches, Louisiana6 Duke University Center for Applied Genomics and Precision Medicine, Durham, North CarolinaCorrespondence: A. Madan, PhD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA (Anu.2.Madan@gsk.com).4 2019 03 4 2019 03 4 2019 6 4 ofz16319 11 2018 29 3 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract\nBackground\nExcessive neutrophil migration has been correlated with influenza symptom severity. Danirixin (GSK1325756), a selective and reversible antagonist of C-X-C chemokine receptor 2, decreases neutrophil activation and transmigration to areas of inflammation. This study evaluated the efficacy and safety of intravenous (IV) danirixin co-administered with oseltamivir for the treatment of adults hospitalized with influenza.\n\nMethods\nIn this phase 2b, double-blind, 3-arm study (NCT02927431), influenza-positive participants were randomized 2:2:1 to receive danirixin 15mg intravenously (IV) twice daily (bid) + oral oseltamivir 75mg bid (OSV), danirixin 50mg IV bid + OSV, or placebo IV bid + OSV, for up to 5 days. The primary endpoint was time to clinical response (TTCR).\n\nResults\nIn total, 10 participants received study treatment (danirixin 15mg + OSV, n = 4; danirixin 50mg + OSV, n = 4; placebo + OSV, n = 2) before the study was terminated early due to low enrollment. All participants achieved a clinical response. Median (95% confidence interval) TTCR was 4.53 days (2.95, 5.71) for danirixin 15mg + OSV, 4.76 days (2.71, 5.25) for danirixin 50mg + OSV, and 1.33 days (0.71, 1.95) for placebo + OSV. Adverse events (AEs) were generally of mild or moderate intensity; no serious AEs were considered treatment-related. Interleukin-8 levels increased in nasal samples (using synthetic absorptive matrix strips) and decreased serum neutrophil-elastase–mediated degradation of elastin decreased in danirixin-treated participants, suggesting effective target engagement.\n\nConclusions\nInterpretation of efficacy results is restricted by the low participant numbers. The safety and tolerability profile of danirixin was consistent with previous studies.\n\nClinical trial information\nThe registration data for the trial are in the ClinicalTrials.gov database, number NCT02927431, and in the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/) as GSK study 201023, EudraCT 2016-002512-40. Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.\n\nIn this phase 2b, randomized, placebo-controlled study of intravenous danirixin in hospitalized influenza patients, all participants achieved a clinical response; danirixin had an acceptable safety profile. Early termination due to low recruitment and small sample size limits interpretation.\n\nCXCR2 antagonistdanirixinhospitalizationinfluenzaneutrophilsGlaxoSmithKline10.13039/100004330GSK201023\n==== Body\nDuring the 2016–17 influenza season in the United States, a total of 18 184 laboratory-confirmed influenza-related hospitalizations were reported, with a cumulative incidence for all age groups of 65 per 100 000 population [1]. The investigation of novel treatments to reduce severity of disease and length of time spent in hospital, which in turn can reduce healthcare burden, is thus merited. One promising therapeutic approach is to target overactive and harmful aspects of the host response to influenza viruses. Neutrophils are the most abundant cells that migrate to the lungs following influenza virus infection, and excessive migration has been demonstrated to cause lung damage through the release of tissue-destructive enzymes and reactive oxygen species and the formation of neutrophil extracellular traps [2]. Levels of neutrophils or chemokines, or both, involved in neutrophil recruitment in the nasal or bronchoalveolar lavage fluid are correlated with clinical symptom severity of influenza infection in humans [3, 4].\n\nDanirixin (GSK1325756) is a selective and reversible antagonist of the C-X-C chemokine receptor 2 (CXCR2), which is expressed on the surface of neutrophils [5]. In preclinical studies, CXCR2 antagonism has been shown to decrease neutrophil activation and transmigration to areas of inflammation [6]. Phase 1 studies in healthy adults showed that danirixin generally was tolerated well at single doses up to 400 mg and with once-daily repeat dosing for 14 days at doses of 50 mg and 200 mg, all administered orally [7]. Oral danirixin also has been evaluated in a phase 2 outpatient study in adults with acute uncomplicated influenza, given either as monotherapy or in combination with the neuraminidase inhibitor, oseltamivir, a current standard-of-care antiviral therapy [8]. In addition to the phase 2 outpatient study, further phase 2 studies have been conducted (and are ongoing) in patients with chronic obstructive pulmonary disease (COPD), which have provided a sufficient body of evidence on the safety profile of danirixin, providing support for its evaluation in a critically ill population hospitalized with influenza [8, 9].\n\nThe objective of the current study was to investigate the efficacy and safety of intravenous (IV) danirixin when co-administered with oral oseltamivir for the treatment of adults hospitalized with influenza. This is the first study in which hospitalized influenza patients were treated with IV danirixin.\n\nMETHODS\nStudy Design\nThe Danirixin in Hospitalized Influenza (DAHLIA) study was a phase 2b, randomized, double-blind, placebo-controlled, 3-arm study of adult participants hospitalized with influenza (GlaxoSmithKline study 201023, EudraCT 2016-002512-40, and NCT02927431). Participants were randomized in a 2:2:1 ratio to receive danirixin 15 mg IV twice daily (bid) + oral oseltamivir 75 mg bid (hereafter referred to as the danirixin 15 mg + OSV group), danirixin 50 mg IV bid + oral oseltamivir 75 mg bid (the danirixin 50 mg + OSV group), or placebo IV bid + oral oseltamivir 75 mg bid (the placebo + OSV group). Treatment duration was up to 5 days, after which the investigator could elect to continue treatment with oral OSV. Follow-up continued until Day 45 for all participants (Figure 1A). Participants were enrolled in a stepwise manner, using 3 sentinel cohorts with increasing levels of renal impairment and disease severity, for enhanced safety monitoring (Figure 1B). The results from each cohort were to be reviewed by an independent data monitoring committee at regular intervals and before enrollment of subsequent sentinel cohorts. Participants were to be enrolled over 3 influenza seasons. However, the study was terminated after 1 season due to low enrollment.\n\nFigure 1. Study Design and Enrollment Cohorts. A, Study design. B, Participant enrollment and evaluation. Less severely ill hospitalized participants were defined as those with a hemodynamically stable status, requiring oxygenation with face mask, face tent, or nasal cannula, with or without radiological signs of lower respiratory tract disease or exacerbation of underlying chronic disease, including asthma, chronic obstructive pulmonary disease, or other cardiovascular conditions not leading to hemodynamic compromise. Critically ill hospitalized participants were defined as those requiring continuous positive airway pressure, bi-level positive airway pressure or mechanical ventilation, with hemodynamic instability (with or without pressor support) or illness with CNS involvement (eg, encephalopathy or encephalitis). CrCL indicates creatinine clearance; IDMC, Independent Data Monitoring Committee.\n\nWritten informed consent was obtained from each participant. The study was conducted in accordance with the International Conference on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline for Good Clinical Practice, applicable country-specific requirements, and the Declaration of Helsinki. The study was approved by the appropriate institutional review boards and independent ethics committees.\n\nRandomization and Blinding\nParticipants and site staff were blinded to danirixin and the placebo, but OSV was given open-label in all treatment arms. Participants were assigned to study treatment in accordance with the randomization schedule generated by GlaxoSmithKline (GSK) prior to the start of the study using validated internal software.\n\nParticipant Population\nEligible participants were required to have onset of influenza symptoms within 6 days prior to study enrollment, to have required hospitalization for treatment and supportive care for influenza, and to have tested positive for influenza by a next-generation rapid reverse transcriptase-polymerase chain reaction (RT-PCR) test or other molecular-based assay.\n\nAdditional eligibility criteria were as follows: age ≥18 years; presence of fever at baseline, indicated by ≥38.0°C/≥100.4°F, or history of fever during the prior 48 hours; oxygen saturation <95% on room air by transcutaneous method, or the need for supplemental oxygen or ventilator support, or increase in oxygen supplementation requirement of ≥2 liters for participants with chronic oxygen dependency, or an oxygen saturation of at least 3% below the participant’s historical baseline oxygen saturation for those with a history of chronic hypoxia (without supplemental oxygen). At least 2 of the following were also required: respiratory rate >24 breaths/min, heart rate >100 beats/min, or systolic blood pressure (BP) <90 mm Hg.\n\nBaseline renal criteria were as shown in Figure 1B. Baseline liver function test eligibility criteria were bilirubin ≤2× upper limit of normal (ULN) with alanine aminotransferase (ALT) ≤5× ULN or ALT >5–≤8× ULN if bilirubin <1.5× ULN.\n\nEndpoints and Outcome Measures\nThe primary endpoint was time to clinical response (TTCR), defined as hospital discharge due to clinical improvement or normalization of temperature and oxygen saturation (≥95%, without supplemental oxygen), with 2 out of 3 of the following parameters also normalized: respiratory status (return to pre-morbid oxygen requirement in participants with chronic oxygen use, reversal of need for supplemental oxygen, or respiratory rate ≤24 breaths/min without supplemental oxygen); heart rate ≤100 beats/min; or systolic BP ≥90 mmHg. Normalization of all these parameters had to be maintained for 24 hours or confirmed by hospital discharge.\n\nKey secondary endpoints included time to respiratory response (TTRR), defined as a return to pre-morbid oxygen requirement (in participants with chronic oxygen use), a return to no requirement of supplemental oxygen, or a respiratory rate ≤24 breaths/min (without supplemental oxygen); clinical measures of influenza illness, including antibiotic use; safety and tolerability, including frequency of adverse events (AEs), serious AEs (SAEs), and change from baseline in clinical laboratory and electrocardiogram parameters.\n\nKey exploratory endpoints included change in influenza viral load as determined by quantitative RT-PCR, assessment of co-infection as determined by multiplex RT-PCR (BioFire Diagnostics, Salt Lake City, UT), and evaluation of biomarkers of inflammation and immune response, including but not limited to interleukin (IL)-8, inducible protein (IP)-10, myeloperoxidase, neutrophil elastase and matrix metalloprotease (MMP) degraded type I collagen (C1M), MMP-degraded type III collagen (C3M), specific fragment human neutrophil-elastase–mediated degradation of elastin (EL-NE), surfactant protein D (SP-D), and soluble receptor for advanced glycoprotein end product (sRAGE) from nasal samples or fluid, whole blood, bronchoalveolar lavage, or serum, or some combination therein.\n\nThe following samples were collected throughout the study: nasal swab samples, nasopharyngeal swab samples, nasal swab samples using synthetic absorptive matrix (SAM) strips (Hunt Developments Ltd, West Sussex, UK), and optional nasal washes, whole blood samples, serum, and bronchoalveolar lavage (BAL) samples from participants where part of routine management. Nasopharyngeal samples were used for diagnosis, subtyping, and quantification. Nasal swab samples were used for diagnosis. BAL, nasal SAM strips, and nasal wash samples were used for biomarker analysis.\n\nStatistical Methods\nApproximately 300 participants were planned to be enrolled in the study over 3 influenza seasons, with approximately 100 participants per season. This sample size was selected to achieve ≥80% overall power to detect a difference, under an assumption of a hazard ratio of 1.2 for danirixin 15 mg and 1.5 for danirixin 50 mg, and to retain a type I error <10% under the no-effect assumption.\n\nAnalyses of participant disposition, baseline characteristics, and safety analyses used the intent-to-treat exposed (ITT-E) and safety populations, which consisted of all randomized participants who received ≥1 dose of investigational product. The influenza-positive (IP) population consisted of all participants in the ITT-E population with confirmed influenza infection and was used as the primary population for the primary endpoint and all other efficacy analyses.\n\nThis study was terminated early due to only a small number of participants having been treated; thus, no formal hypothesis testing was performed. All analyses are descriptive and are not intended for making definitive conclusions. Median TTCR in each treatment arm was determined from Kaplan–Meier (KM) analyses. Due to limited data, median TTRR could not be calculated for any of the treatment arms.\n\nInformation on GSK’s data sharing commitments and requesting access can be found at https://www.clinical studydatarequest.com/.\n\nRESULTS\nStudy Population and Participant Disposition\nAlthough the study was planned to take place across multiple sites in multiple countries (including France, the Netherlands, the Republic of Korea, Romania, the Russian Federation, Spain, Sweden, and the United States), participants were enrolled from 5 sites in the United States and 1 each in Romania and Sweden. Enrollment occurred between January 19 and May 24, 2017 (the date of the last participant visit). Eleven participants were randomized into the study, of whom 10 received ≥1 dose of study medication; 1 participant was randomized but did not receive treatment owing to testing negative for influenza. All 10 participants were included in the ITT-E, IP, and safety populations. Participant numbers for the 3 groups were as follows: danirixin 15 mg + OSV, n = 4; danirixin 50 mg + OSV, n = 4; and placebo + OSV, n = 2.\n\nSix participants completed the 5-day study treatment. Four participants received fewer than 5 days’ treatment because of clinical improvement, as determined by the investigator: 1 participant in the placebo + OSV arm was discharged from hospital on Day 2, and 3 participants in the danirixin + OSV arms were discharged from hospital on Day 4 or Day 5 (prior to the last danirixin bid dose). There was 1 withdrawal of the 10 ITT-E participants from the danirixin 50 mg + OSV treatment arm during follow-up, because the participant withdrew consent on Day 15. None of the placebo participants had received OSV or steroids prior to study entry for influenza symptoms. One participant in the 15 mg OSV group and 2 in the 50 mg + OSV group received OSV as prior anti-influenza therapy, and 1 participant each in the danirixin groups received steroids for their symptoms prior to study entry. Participants in the placebo group had fewer influenza symptoms at entry into the study whereas participant in the danirixin + OSV groups reported increased symptoms at study entry (Supplementary Table 1).\n\nBaseline demographic characteristics for the 10 participants were as follows: median (min, max) age was 68.5 (34, 90) years, 60% of participants were female, and the majority (70%) of participants were of white/Caucasian/European heritage.\n\nTime to Clinical Response\nAll 10 (100%) participants in the IP population achieved a protocol-defined clinical response, with clinical improvement leading to discharge from hospital or vital sign resolution that was maintained for 24 hours. Median (95% confidence interval) TTCR by KM estimation was 4.53 (2.95, 5.71) days for danirixin 15 mg + OSV, 4.76 (2.71, 5.25) days for danirixin 50 mg + OSV, and 1.33 (0.71, 1.95) days for placebo + OSV (Table 1). Results for individual participants showed that 7 participants in the danirixin + OSV groups achieved TTCR between >2 and <6 days, and 2 participants in the placebo + OSV group achieved TTCR in ≤2 days. One participant in the danirixin 15 mg + OSV group achieved TTCR (vital sign resolution) at baseline after determination of eligibility and receiving the first dose (counted as achieving clinical response but not included in the KM estimate for TTCR).\n\nTable 1. Clinical Response in the Influenza-Positive Population\n\n\tPlacebo + oseltamivir 75 mg (n = 2)\tDanirixin 15 mg + oseltamivir 75 mg (n = 4)a\tDanirixin 50 mg + oseltamivir 75 mg (n = 4)b\t\n\nClinical Response, n\n\t2\t4\t4\t\nYes, n (%)\t2 (100)\t4 (100)\t4 (100)\t\nHospital discharge due to clinical improvement, n (%)\t0\t1 (25)\t2 (50)\t\nHospital discharge as 24-hr confirmation,c n (%)\t1 (50)\t2 (50)\t1 (25)\t\nVital signs resolved, n (%)\t1 (50)\t1 (25)\t1 (25)\t\n\nClinical Outcome, n\n\t2\t4\t4\t\nClinical improvement, n (%)\t2 (100)\t4 (100)\t4 (100)\t\n\nKaplan–Meier Estimate, n\n\t2\t3\t4\t\nMedian, days\t1.33\t4.53\t4.76\t\n95% confidence interval \t0.71, 1.95\t2.95, 5.71\t2.71, 5.25\t\n25%–75%\t0.71–1.95\t2.95–5.71\t3.66–5.08\t\n\naOne participant in the danirixin 15 mg + oseltamivir 75 mg group had vital sign resolution at baseline and was counted as having a clinical response but was not included in the Kaplan–Meier estimates.\n\n\nbOne participant in the danirixin 50 mg + oseltamivir 75 mg group received oseltamivir 30 mg.\n\n\ncHospital discharge due to clinical improvement served as 24-hour confirmation for the clinical response.\n\nTime to Respiratory Response\nFive (50%) participants in the IP population achieved a protocol-defined respiratory response, with 50% of participants in all groups returning to no requirement for supplemental oxygen (Table 2).\n\nTable 2. Respiratory Response in the Influenza-Positive Population\n\n\tPlacebo + oseltamivir 75 mg (n = 2)\tDanirixin 15 mg + oseltamivir 75 mg (n = 4)\tDanirixin 50 mg + oseltamivir 75 mg (n = 4)a\t\n\nPositive Respiratory Response, n\n\t2\t4\t4\t\nYes, n (%)\t1 (50)\t2 (50)\t2 (50)\t\nRespiratory rate ≤24/min (without supplemental oxygen)\t0\t0\t0\t\nReturn to no requirement of supplemental oxygen, n (%)\t1 (50)\t2 (50)\t2 (50)\t\nReturn to pre-morbid oxygen (participants with chronic oxygen use)\t0\t0\t0\t\n\naOne participant in the danirixin 50 mg + oseltamivir 75 mg group received oseltamivir 30 mg.\n\nClinical Measures of Influenza-Related Complications\nOne participant from each treatment arm received concomitant antibiotics (benzylpenicillin sodium, ceftriaxone, or levofloxacin) for the treatment of influenza complications. Of these 3 participants, 1 received antibiotics starting 1 day before study Day 1, 1 participant starting on Day 1, and 1 participant starting on Day 2. One participant in the danirixin 50 mg + OSV group entered the study on mechanical ventilation due to a prior chronic condition and received bi-level positive airway pressure (BIPAP) on Day 20. A second participant, in the placebo + OSV group, received BIPAP on Day 2.\n\nSafety\nNo AEs were reported for the 2 participants in the placebo + OSV arm. All participants in the danirixin + OSV treatment arms experienced 1 or more AEs (Table 3), all of which were of mild/Grade 1 or moderate/Grade 2 intensity. Laboratory assessments considered clinically significant by investigators were to be reported as AEs. No AEs of neutropenia were reported. One participant in the 50 mg danirixin +OSV group experienced neutropenia based on central laboratory results 3 days after end of treatment. The same participant reported a fungal infection, starting 2 days after the last dose of treatment, resolving in 4 days. This participant, who had a history of asthma, also reported bronchitis, which started 41 days after the last dose of treatment, and from which they were recovering at the end of the study (Day 45). This participant had 1 on-therapy AE of sinusitis on the second day of treatment, which resolved by Day 7. One participant in the danirixin 50 mg + OSV group experienced an AE of monocytosis, which started 6 days after the start of study medication and was classed by the investigator to be related possibly to study medication. This participant, who entered the study with a history of tracheostomy for mechanical ventilation, Clostridium difficile infection, and oxygen supplementation also had recurrence of C. difficile infection post-treatment on Day 8 and Day 33. One participant receiving danirixin 15 mg + OSV reported an AE of bacterial pneumonia, 1 day after the last dose, which was considered neither serious nor related to treatment by study investigators.\n\nTable 3. Adverse Events Reported by Overall Frequency in the Safety Population\n\nPreferred Term\tPlacebo + oseltamivir 75 mg (n = 2)\tDanirixin 15 mg + oseltamivir 75 mg (n = 4)\tDanirixin 50 mg + oseltamivir 75 mga (n = 4)\tTotal (N = 10)\t\nAny event, n (%)\t0\t4 (100)\t4 (100)\t8 (80)\t\nAsthma\t0\t1 (25)\t0\t1 (10)\t\nAtelectasis\t0\t0\t1 (25)\t1 (10)\t\nBronchitis\t0\t0\t1 (25)\t1 (10)\t\nCardiac failure\t0\t0\t1 (25)\t1 (10)\t\nChills\t0\t0\t1 (25)\t1 (10)\t\nCOPD\t0\t0\t1 (25)\t1 (10)\t\n\nClostridium difficile infection\t0\t0\t1 (25)\t1 (10)\t\nContusion\t0\t1 (25)\t0\t1 (10)\t\nCough\t0\t1 (25)\t0\t1 (10)\t\nDyspnea\t0\t0\t1 (25)\t1 (10)\t\nFungal infection\t0\t0\t1 (25)\t1 (10)\t\nHemoglobin decreased\t0\t0\t1 (25)\t1 (10)\t\nHyperglycemia\t0\t1 (25)\t0\t1 (10)\t\nHypokalemia\t0\t0\t1 (25)\t1 (10)\t\nInfusion-site extravasation\t0\t0\t1 (25)\t1 (10)\t\nMonocytosis\t0\t0\t1 (25)\t1 (10)\t\nPneumonia bacterial\t0\t1 (25)\t0\t1 (10)\t\nSinusitis\t0\t0\t1 (25)\t1 (10)\t\nVertigo\t0\t1 (25)\t0\t1 (10)\t\nAbbreviation: COPD, chronic obstructive pulmonary disease.\n\n\naOne participant in the danirixin 50 mg + oseltamivir 75 mg group received oseltamivir 30 mg.\n\nTwo participants in the danirixin 50 mg + OSV treatment arm reported non-fatal SAEs considered by the investigators not to be related to study medication: aggravated heart failure in 1 participant with a history of heart failure and atrial fibrillation in 1 participant and COPD exacerbation in the other participant. Both participants required hospital readmission on Day 8 for these conditions; both recovered and were discharged on Days 13 and 11, respectively. There were no fatal AEs or any AEs that led to withdrawal from the study or discontinuation of treatment.\n\nExploratory Endpoints\nVirology\n Similar reductions in viral load occurred across all treatment arms (Supplementary Figure 1). All participants were infected with either influenza A or B virus, and no participants were found to be co-infected with other viruses. Two neuraminidase resistance-associated substitutions (S245N and V149A) were detected in 7 and 1 participants, respectively, at baseline (prior to receipt of study medication). No participants harbored the most common neuraminidase OSV resistance substitution, H275Y.\n\nBiomarkers\n IL-8 levels increased in nasal SAM samples during treatment through Day 5 in danirixin + OSV-treated participants and declined towards physiological baseline levels by Day 43–47. One placebo-treated participant also had an increase in IL-8 and the other placebo-treated participant had a high baseline level of IL-8 that was maintained over time (Figure 2A). No trends were observed in IL-8 nasal wash samples due to limited samples being collected.\n\nFigure 2. Individual Plots of Nasal SAM Strips Biomarkers by Visit and Participant: (A) IL-8, (B) EL-NE and (C) IP-10. A, IL-8; B, EL-NE; C, IP-10. EL-NE indicates specific fragment human neutrophil elastase mediated degradation of elastin; IL-8, interleukin (IL)-8; IP-10, inducible protein-10.\n\nLung-damage–associated biomarkers C1M, C3M, EL-NE, SP-D, and sRAGE were detectable in all matrixes analyzed. A trend of decreasing serum EL-NE in both danirixin + OSV-treated groups was observed (Figure 2B), indicating fewer neutrophil- elastase–driven lung elastin degradation events, but interpretation is limited due to the small participant population. No trends in the small set of biomarkers tested were observed between treatment arms for other lung damage associated biomarkers. High levels of IP-10 were observed at baseline, which declined over time (Figure 2C).\n\nDISCUSSION\nOf the 10 evaluable participants in this small phase 2b study, all 10 achieved a clinical response leading to hospital discharge or vital sign resolution that was maintained for 24 hours. Five of the 10 participants achieved a respiratory response with resolution of the need for supplemental oxygen. However, owing to the low number of participants enrolled, the conclusions that can be drawn from this participant population are limited. Recruitment challenges are common in studies of patients with influenza, primarily due to the short high-incidence periods and opportunistic enrollment [10]. Influenza activity during the 2016–2017 season was generally moderate in both the United States and Europe, where the study was conducted, suggesting that the mild nature of the influenza season may have contributed to the low participant numbers [1, 11]. Eligibility criteria were relatively stringent with regards to concurrent conditions and medical history as this was the first study in hospitalized patients receiving IV danirixin, but participants had to be severe enough to require hospitalization for their influenza. Following efforts to enroll participants for the entire season, only 10 participants met eligibility criteria and could be enrolled. Although reasons for not enrolling subjects were not formally captured prospectively, information received from some investigators indicated that a large majority of potential participants did not meet eligibility criteria based on existing hospital records; this led to the conclusion that the probability of enrolling 300 participants in 2 more seasons would be very low. As such, the decision was made to terminate the study.\n\nCurrent treatment guidelines for influenza requiring hospitalization recommend neuraminidase inhibitors as standard-of-care therapy, primarily oseltamivir and zanamivir [12]. However, the majority of clinical data for these antivirals come from outpatient studies of patients with mild, uncomplicated influenza [10]. Although observational studies have indicated that neuraminidase inhibitors may reduce severe clinical outcomes in patients hospitalized for influenza [13, 14], these findings have not been supported by clinical trials [15, 16]; and, as yet, no treatment has been approved based on controlled studies in this population. Treatment of hospitalized patients presents multiple challenges, given the severity of disease and potential for complications, secondary infections, and requirement for intensive care [17]. Thus, there is a clear need for efficacious therapies in this high-risk group. Data from the phase 2 trials of danirixin, although affected by low sample sizes, are therefore worthy of consideration, and further studies of this novel treatment are warranted.\n\nIn the current study, although the primary outcome of TTCR was observed to be longer in the majority (n = 7) of participants in the danirixin + OSV arms than in the 2 participants in the placebo + OSV arm, 10 participants form too small a group from which to draw conclusions. With such a small population, differences at baseline likely impacted study outcomes. A higher percentage in the danirixin arms had received prior oseltamivir or steroids, or both, as well as supplemental oxygen. Based on baseline characteristics, participants in the placebo group may have been less ill than in the danirixin groups at study entry. Although cross-trial comparisons should be interpreted with caution, a larger-scale phase 3 trial with over 600 participants hospitalized with influenza reported a median TTCR with placebo + OSV of 5.63 days; this is similar to that seen in the danirixin + OSV arms of this study [16].\n\nIL-8 levels increased in nasal SAM samples in danirixin + OSV-treated participants, which may be indicative of target engagement, although variability and limited placebo samples for comparison prevent clear conclusions of the data. Interpretation of nasal wash analysis was hampered by the limited sample number, as samples were obtained from only 3 participants. Serum samples were taken for follow-up evaluation, but the samples were not tested for cytokines or chemokines due to the early termination of the study. This is in line with other clinical and preclinical studies, suggesting IL-8 increase as an indicator of CXCR2 antagonism [18–20].\n\nThe trend of decreasing serum EL-NE in both danirixin + OSV-treated groups in the current study, indicating fewer neutrophil-elastase–driven lung elastin degradation events, but interpretation is again limited by the low participant numbers.\n\nThe safety and tolerability of IV danirixin in our inpatient study was in line with the profile presented in outpatient studies in which danirixin was administered orally [8, 21]. One participant developed neutropenia 3 days post-treatment, based on laboratory results, which was not reported as an AE by the investigator. The 2 SAEs in this inpatient study (aggravated cardiac failure and COPD exacerbation) were not considered by the investigators to be related to study treatment, and there were neither fatal AEs nor any AEs leading to study withdrawal or discontinuation.\n\nCONCLUSIONS\nAlthough the potential for interpretation leading to general conclusions in this study was clearly restricted by the low number of participants, this small phase 2 study evaluating the efficacy and safety of IV danirixin in combination with oral OSV showed that all 10 influenza-positive participants achieved the primary endpoint of TTCR that enabled hospital discharge or the resolution of vital signs that were maintained for 24 hours. The study also showed danirixin to have a safety and tolerability profile congruous with that observed in other studies of this selective and reversible antagonist of CXCR2.\n\nSupplementary Data\nSupplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.\n\nSupplementary_Figure_1 Click here for additional data file.\n\n Supplementary_Material Click here for additional data file.\n\n Acknowledgments\nThe authors would like to thank the participants, investigators, and study staff for their contributions to this study. Heather St Michael of Fishawack Indicia Ltd, UK, provided medical writing support, which was funded by GlaxoSmithKline.\n\n\nAuthor contributions.A.M., S.C., P.Y., M.L.W., G.R., A.J.P., and S.R.-G. were involved with the concept and design of the study as well as data analysis and interpretation. M.F.P., O.B. and M.T.M. were involved with the concept and design of the study, patient recruitment and enrollment, and data acquisition. Y.T. was involved in data analysis and interpretation. All authors were involved in the drafting, critical revision, and approval of the article.\n\n\nFinancial support. This work was supported by GlaxoSmithKline (GSK study number GSK201023).\n\n\nPotential conflicts of interest. A.M., S.C., P.Y., M.L.W., G.R., Y.T. and S.R.-G. are employees of GSK. A.J.P is an employee of GSK and has a patent WO2017093912 pending. M.F.P. received compensation as a trial investigator from GSK. M.T.M. received no other support from GSK outside the submitted work and has a patent pending on Biomarkers for the Molecular Classification of Viral and Bacterial Infection. O.B. report no conflicts of interest, aside from participation in this study. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1. \nBlanton L , Alabi N , Mustaquim D , et al \nUpdate: influenza activity in the United States during the 2016–17 season and composition of the 2017–18 influenza vaccine . MMWR Morb Mortal Wkly Rep 2017 ; 66 :668 –76 .28662019 \n2. \nNarasaraju T , Yang E , Samy RP , et al. \nExcessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis . Am J Pathol 2011 ; 179 :199 –210 .21703402 \n3. \nShort KR , Kroeze EJBV , Fouchier RAM , Kuiken T \nPathogenesis of influenza-induced acute respiratory distress syndrome . Lancet Infect Dis 2014 ; 14 :57 –69 .24239327 \n4. \nHayden FG , Fritz R , Lobo MC , et al. \nLocal and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense . J Clin Invest 1998 ; 101 :643 –9 .9449698 \n5. \nBusch-Petersen J , Carpenter DC , Burman M , et al. \nDanirixin: a reversible and selective antagonist of the CXC chemokine receptor 2 . J Pharmacol Exp Ther 2017 ; 362 :338 –46 .28611093 \n6. \nWashburn M , Crosby R , Remlinger K , et al \nTherapeutically attenuating neutrophil recruitment with a CXCR2 antagonist in combination with oseltamivir ameliorates influenza induced lung injury and disease [published online ahead of print March 7, 2019) . Open Forum Infect Dis . 2019 ; doi:10.1093/ofid/ofz106 .\n7. \nMiller BE , Mistry S , Smart K , et al. \nThe pharmacokinetics and pharmacodynamics of danirixin (GSK1325756)–a selective CXCR2 antagonist –in healthy adult subjects . BMC Pharmacol Toxicol 2015 ; 16 :18 .26092545 \n8. \nRoberts G , Chen S , Yates P , et al \nA randomized, double-blind, placebo-controlled study of the safety, tolerability and clinical effect of oral danirixin in the treatment of healthy adults with acute, uncomplicated influenza . Open Forum Infect Dis . (accepted for publication, OFID-D 18–0069)\n9. \nLazaar AL , Miller BE , Tabberer M , et al \nEffect of the CXCR2 antagonist danirixin on symptoms and health status in COPD . Eur Respir J 2018 ; 52 : 1801020. doi: 10.1183/13993003.01020-2018 .\n10. \nJefferson T , Jones M , Doshi P , et al. \nOseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments . BMJ 2014 ; 348 :g2545 .24811411 \n11. European Centre for Disease Prevention and Control. Summary of the influenza 2016–2017 season in Europe. Available at: https://ecdc.europa.eu/en/publications-data/summary-influenza-2016-2017-season-europe\n12. \nFiore AE , Fry A , Shay D , et al. ; Centers for Disease Control and Prevention (CDC) \nAntiviral agents for the treatment and chemoprophylaxis of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP) . MMWR Recomm Rep 2011 ; 60 :1 –24 .\n13. \nMcGeer A , Green KA , Plevneshi A , et al. ; Toronto Invasive Bacterial Diseases Network \nAntiviral therapy and outcomes of influenza requiring hospitalization in Ontario, Canada . Clin Infect Dis 2007 ; 45 :1568 –75 .18190317 \n14. \nLee N , Choi KW , Chan PK , et al. \nOutcomes of adults hospitalised with severe influenza . Thorax 2010 ; 65 :510 –5 .20522848 \n15. \nde Jong MD , Ison MG , Monto AS , et al. \nEvaluation of intravenous peramivir for treatment of influenza in hospitalized patients . Clin Infect Dis 2014 ; 59 :e172 –85 .25115871 \n16. \nMarty FM , Vidal-Puigserver J , Clark C , et al. \nIntravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial . Lancet Respir Med 2017 ; 5 :135 –46 .28094141 \n17. \nGarg S , Jain S , Dawood FS , et al \nPneumonia among adults hospitalized with laboratory-confirmed seasonal influenza virus infection-United States, 2005-2008 . BMC Infect Dis 2015 ; 15 :369 . 26307108 \n18. \nJurcevic S , Humfrey C , Uddin M , et al. \nThe effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions . Br J Clin Pharmacol 2015 ; 80 :1324 –36 .26182832 \n19. \nMoss RB , Mistry SJ , Konstan MW , et al. ; CF2110399 Investigators \nSafety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis . J Cyst Fibros 2013 ; 12 :241 –8 .22995323 \n20. \nThatcher TH , McHugh NA , Egan RW , et al. \nRole of CXCR2 in cigarette smoke-induced lung inflammation . Am J Physiol Lung Cell Mol Physiol 2005 ; 289 :L322 –8 .15833762 \n21. \nMiller BE , Smart K , Mistry S , et al. \nThe pharmacokinetics of conventional and bioenhanced tablet formulations of danirixin (GSK1325756) following oral administration in healthy, elderly, human volunteers . Eur J Drug Metab Pharmacokinet 2014 ; 39 :173 –81 .24504700\n\n",
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"keywords": "CXCR2 antagonist; danirixin; hospitalization; influenza; neutrophils",
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"title": "Efficacy and Safety of Danirixin (GSK1325756) Co-administered With Standard-of-Care Antiviral (Oseltamivir): A Phase 2b, Global, Randomized Study of Adults Hospitalized With Influenza.",
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"abstract": "Chemotherapy-related myelopathy mimicking subacute combined degeneration (SCD) has rarely been reported. We encountered a 35-year-old female with sensory ataxia after intrathecal chemotherapy. Spinal magnetic resonance imaging showed localized abnormal signal areas in the lateral and dorsal white matter, mimicking SCD. Diffusion imaging showed restricted water diffusion and increased microstructural complexity, and cerebrospinal fluid analysis showed increased levels of myelin basic proteins, indicating demyelinating myelopathy. Advanced diffusion imaging can provide more information on the microstructure of chemotherapy-related myelopathy.",
"affiliations": "Department of Neurology, Department of Internal Medicine, Tokyo, Japan ; Department of Radiology, Juntendo University School of Medicine, Tokyo, Japan.",
"authors": "Saito|Fumine|F|;Hatano|Taku|T|;Hori|Masaaki|M|;Kawamura|Miwako|M|;Sasaki|Makoto|M|;Aoki|Shigeki|S|;Hattori|Nobutaka|N|",
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"fulltext": "\n==== Front\nCase Rep NeurolCase Rep NeurolCRNCase Reports in Neurology1662-680XS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000351848crn-0005-0110Published online: June, 2013Lateral and Dorsal Column Hyperintensity on Magnetic Resonance Imaging in a Patient with Myelopathy Associated with Intrathecal Chemotherapy Saito Fumine acHatano Taku a*Hori Masaaki cKawamura Miwako aSasaki Makoto bAoki Shigeki cHattori Nobutaka aaDepartment of Neurology, Department of Internal Medicine, Tokyo, JapanbDivision of Hematology, Department of Internal Medicine, Tokyo, JapancDepartment of Radiology, Juntendo University School of Medicine, Tokyo, Japan*Taku Hatano, MD, PhD, Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan), E-Mail thatano@juntendo.ac.jpMay-Aug 2013 6 6 2013 6 6 2013 5 2 110 115 Copyright © 2013 by S. Karger AG, Basel2013This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Chemotherapy-related myelopathy mimicking subacute combined degeneration (SCD) has rarely been reported. We encountered a 35-year-old female with sensory ataxia after intrathecal chemotherapy. Spinal magnetic resonance imaging showed localized abnormal signal areas in the lateral and dorsal white matter, mimicking SCD. Diffusion imaging showed restricted water diffusion and increased microstructural complexity, and cerebrospinal fluid analysis showed increased levels of myelin basic proteins, indicating demyelinating myelopathy. Advanced diffusion imaging can provide more information on the microstructure of chemotherapy-related myelopathy.\n\nKey words\nMagnetic resonance imagingDiffusion imagingSpinal cordCytosine arabinosideMethotrexateSubacute combined degeneration\n==== Body\nIntroduction\nIntrathecal chemotherapy combined with systemic chemotherapy has been used for both the prophylactic and therapeutic treatment of hematologic malignancies in the central nervous system. However, intrathecal chemotherapy has been associated with neurotoxic adverse effects, including myelopathy, encephalopathy, seizure, and cauda equina syndrome [1]. Although myelopathy is the most common adverse effect associated with intrathecal chemotherapy, magnetic resonance imaging (MRI) has rarely been reported in the literature. Here, we report a case of a 35-year-old female presenting with paraparesis, sensory ataxia, and loss of position sense in her lower limbs after systemic high-dose methotrexate and cytosine arabinoside (HD-MTX/Ara-C) therapy and intrathecal Ara-C therapy. Spinal T2-weighted (T2-WI) MRI demonstrated abnormal intensity lesions in the dorsolateral column, mimicking subacute combined degeneration (SCD). In addition, we assessed diffusion tensor/kurtosis imaging (DTI/DKI) and q-space imaging (QSI) metrics in this myelopathy.\n\nCase Presentation\nA 35-year-old female underwent partial tumor resection and postoperative steroid therapy for a cerebellopontine angle tumor. Three years after treatment, she developed a headache along with vomiting. Cranial MRI revealed a lesion with abnormal intensity in the third ventricle, and transventricular endoscopic biopsy and ventriculostomy were performed. Histological examination revealed the characteristic findings of a diffuse, large B-cell lymphoma. A course of systemic HD-MTX/Ara-C treatment diminished the tumor on brain MRI and improved the clinical symptoms. The patient received an additional 3 courses of HD-MTX/Ara-C and repetitive lumbar intrathecal Ara-C (100 mg) and dexamethasone (4 mg). One month after the first round of intrathecal chemotherapy, the patient complained of bilateral numbness in her lower legs despite normal spinal MRI. She received a repetitive course of intrathecal Ara-C (40 mg) and prednisolone (4 mg) with or without intrathecal MTX (15 mg) for 6 months, along with whole-brain radiotherapy for 1 month. Nine months after the first round of intrathecal chemotherapy, the patient gradually developed an unstable gait. Neurological examination revealed a mild lower-limb weakness and a sensory ataxic gait with a positive Romberg's sign. Pinprick, light touch, vibration sensation, and proprioception were impaired below the level of the Th10 dermatome. Deep tendon reflexes were normal in all limbs, but diminished abdominal reflexes and bilateral extensor planter responses were noted. Macrocytic anemia was present: red blood cells 2.64 × 104 μl, hemoglobin 9.7 g/dl, mean corpuscular volume 112.5 fl, with a reduced thrombocyte count. The results of routine biochemistry, autoantibodies, and a thyroid function test were unremarkable. Her serum vitamin B12 level was in the lower limits of normal [286 pg/ml (normal range 180–914)], and her serum levels of folate and copper were slightly reduced [2.8 ng/ml (normal range >3.1) and 65 mg/dl (normal range 68–128), respectively]. Cerebrospinal fluid (CSF) studies revealed a white blood cell count of 1/μl, a protein level of 24 mg/dl, and increased levels of myelin basic protein (MBP; 502 pg/ml). Nerve conduction velocities and compound muscle action potentials were normal, while somatosensory evoked potentials demonstrated a normal N 20 latent time (19.50 ms) but prolonged P 40 responses (44.1 ms). The patient's spinal T2-WI MRI demonstrated abnormal signal intensity in the bilateral and dorsal columns in the thoracic cord, extending from Th3 to Th10 (fig. 1).\n\nWe performed DTI, DKI, and QSI and calculated each parameter (as described previously [2, 3, 4]), in the regions of interest on the dorsal column at Th7–9 and C3–5 of the patient, along with 4 control subjects. The results at Th7–9 of the patient and control subjects (mean ± standard deviation) were as follows: apparent diffusion coefficient (ADC) (10−3 mm2/s): 0.55 and 1.16 ± 0.10; fractional anisotropy (FA): 0.41 and 0.61 ± 0.14; lambda (λ1) (10−3 mm2/s): 0.78 and 2.11 ± 0.19; (λ2 + λ3)/2 (10−3 mm2/s): 0.45 and 0.69 ± 0.19; full width half maximum (μm): 17.45 and 20.32 ± 0.34; mean diffusional kurtosis (MDK): 1.65 and 0.85 ± 0.15. We also obtained MDK at C3–5:1.72, 1.21, 0.78 and 1.00 ± 0.11 (fig. 1, fig. 2).\n\nThe disease course, hematological findings, and MRI suggested a diagnosis of demyelinating myelopathy due to the combined effect of intrathecal chemotherapy and vitamin and mineral deficiencies. The patient's condition did not deteriorate, but also did not improve despite therapy with intravenous administration of vitamin B12 and folic acid. Seventeen months after the first round of chemotherapy, the patient died of recurrent brain lymphoma. Permission for an autopsy was not granted.\n\nDiscussion\nMyelopathy has been reported as a significant adverse effect of combination therapy with intrathecal Ara-C and systemic HD-MTX [5, 6]. Risk factors for the development of intrathecal chemotherapy-related myelopathy include a high-dose and/or frequent exposure to central nervous system-directed therapy. In most patients, paraplegia with bowel and urinary disability is commonly prominent, developing within a few days to several months after intrathecal chemotherapy. MBP levels are frequently increased in the CSF, as previously reported [7]. MRI findings of intrathecal chemotherapy-related myelopathy include high signal intensity in T2-WI within the central and posterior columns [8], cord swelling, gadolinium enhancement restricted to the lateral columns [9], and the features of arachnoiditis [10].\n\nOur patient presented with a slowly developing weakness and an impairment of position sense in the lower limbs during repetitive intrathecal Ara-C combined with HD-MTX therapy. Her CSF cell count was unremarkable with increased MBP levels, as previously seen in myelopathy due to intrathecal chemotherapy. Conventional MRI findings consisted of abnormal signal intensity in the bilateral and dorsal columns in the thoracic cord, extending from Th3 to Th10, mimicking SCD of the spinal cord. However, our patient did not present with any other clinical features of SCD, such as peripheral neuropathy and dementia. Lu et al. [11] reported 2 cases of intrathecal MTX-related myelopathy that mimicked the MRI findings of SCD, as seen in our patient. In both patients, vitamin B12 levels were within normal limits. In this context, myelopathy due to intrathecal chemotherapy can mimic SCD.\n\nBreuer et al. [5] described the pathological findings of intrathecal myelopathy as microvacuolization, axonal swelling, and the loss of myelin within the white matter of the spinal cord. The mechanisms underlying chemotherapy-related myelopathy mimicking SCD are still unknown. In a rabbit model, intrathecally injected Ara-C penetrated the peripheral white matter and geniculate body in the spinal cord [12], suggesting that Ara-C may have toxic demyelinating effects on the dorsolateral columns. Additionally, our patient showed slightly low vitamin and copper levels. It is well known that although vitamin B12 and folate acid levels are in the lower limits, measuring homocysteine and methylmalonic acid levels can be useful in diagnosing patients with SCD who have not received treatment [13,14]. We could not confirm homocysteine and methylmalonic acid levels in our patient without vitamin treatment; therefore, the possibility that a deficiency in several vitamins and minerals may have been associated with the development of SCD should be considered in our patient [13, 14, 15, 16]. Furthermore, MTX is a folic acid antagonist and causes chemotherapy-related myelopathy [1, 17]. Therefore, a deficiency in vitamins and minerals may have worsened the spinal toxicity of chemotherapy in our patient.\n\nDiffusional MRI analysis revealed microstructural information in addition to that provided by conventional MRI. Our patient showed a decreased ADC and FA at the Th7–9 levels due to markedly decreased λ1, which indicated the preferential restriction of water diffusion along the long tracts such as the corticospinal tract and dorsal column. Increased MDK indicated increased microstructural complexity. These results showed that normal and well-organized white matter structures were damaged predominantly in the long tracts. The patient also showed an increased or decreased MDK at levels C3–5, in spite of the absence of substantial intensity abnormalities on conventional and advanced diffusion MRI. MDK may be a more sensitive parameter of microstructural changes than other measurements. Taken together, conventional and advanced MRI findings in our patient suggested that cytotoxic demyelination had occurred along the lateral and posterior columns from the lower cervical down to the middle thoracic cord.\n\nIn conclusion, we reported a case of subacute dorsolateral column myelopathy associated with intrathecal chemotherapy. Vitamin and mineral deficiencies may have played a role, in part, in the pathomechanisms of myelopathy in this patient. Spinal diffusion MRI revealed cytotoxic demyelination along the posterior columns, which assisted in the diagnosis of demyelinated myelopathy. Our findings suggest that spinal DTI, QSI, and DKI are useful tools in the diagnosis of chemotherapy-related myelopathy.\n\nDisclosure Statement\nThe authors declare that they have no competing interests.\n\nAcknowledgment\nThis work was supported in part by grants for Young Scientists B (to T.H.) from the Japanese Ministry of Education, Culture, Sports, Science and Technology.\n\nFig. 1 Conventional and advanced diffusion MR images of the thoracic spine 9 months after the first round of intrathecal chemotherapy. a A T2-weighted sagittal image shows high signal intensity in the thoracic spine from Th3 to Th10. The arrow points to the Th8 level. b–e Axial spinal cord images at the level of Th8. b T2-weighted image showing high signal intensity in the bilateral and dorsal columns (arrows). c ADC map shows low signal intensity (decreased ADC value). d FA map shows low signal intensity (decreased FA value). e MDK map shows high signal intensity (increased MDK value) in the dorsal column (arrows in c–e).\n\nFig. 2 Advanced diffusion axial MR images of the C3 cervical spine 9 months after the first round of intrathecal chemotherapy. a ADC values are normal. b Increased MDK values in the dorsal column (arrow in b).\n==== Refs\nReferences\n1 Kwong YL Yeung DY Chan JC Intrathecal chemotherapy for hematologic malignancies: drugs and toxicities Ann Hematol 2009 88 193 201 19050889 \n2 Hori M Fukunaga I Masutani Y Nakanishi A Shimojo K Kamagata K Asahi K Hamasaki N Suzuki Y Aoki S New diffusion metrics for spondylotic myelopathy at an early clinical stage Eur Radiol 2012 22 1797 1802 22411307 \n3 Farrell JA Zhang J Jones MV Deboy CA Hoffman PN Landman BA Smith SA Reich DS Calabresi PA van Zijl PC q-space and conventional diffusion imaging of axon and myelin damage in the rat spinal cord after axotomy Magn Reson Med 2010 63 1323 1335 20432303 \n4 Jensen JH Helpern JA Ramani A Lu H Kaczynski K Diffusional kurtosis imaging: the quantification of non-Gaussian water diffusion by means of magnetic resonance imaging Magn Reson Med 2005 53 1432 1440 15906300 \n5 Breuer AC Pitman SW Dawson DM Schoene WC Paraparesis following intrathecal cytosine arabinoside: a case report with neuropathologic findings Cancer 1977 40 2817 2822 271037 \n6 Resar LM Phillips PC Kastan MB Leventhal BG Bowman PW Civin CI Acute neurotoxicity after intrathecal cytosine arabinoside in two adolescents with acute lymphoblastic leukemia of B-cell type Cancer 1993 71 117 123 8416707 \n7 Watterson J Toogood I Nieder M Morse M Frierdich S Lee Y Moertel CL Priest JR Excessive spinal cord toxicity from intensive central nervous system-directed therapies Cancer 1994 74 3034 3041 7954266 \n8 Counsel P Khangure M Myelopathy due to intrathecal chemotherapy: magnetic resonance imaging findings Clin Radiol 2007 62 172 176 17207701 \n9 McLean DR Clink HM Ernst P Coates R al Kawi MZ Bohlege S Omer S Myelopathy after intrathecal chemotherapy. A case report with unique magnetic resonance imaging changes Cancer 1994 73 3037 3040 8200001 \n10 Bay A Oner AF Etlik O Yilmaz C Caksen H Myelopathy due to intrathecal chemotherapy: report of six cases J Pediatr Hematol Oncol 2005 27 270 272 15891563 \n11 Lu CH Yao M Liu HM Chen YF MR findings of intrathecal chemotherapy-related myelopathy in two cases: mimicker of subacute combined degeneration J Neuroimaging 2007 17 184 187 17441843 \n12 Burch PA Grossman SA Reinhard CS Spinal cord penetration of intrathecally administered cytarabine and methotrexate: a quantitative autoradiographic study J Natl Cancer Inst 1988 80 1211 1216 3418727 \n13 Stabler SP Vitamin B12 deficiency N Engl J Med 2013 368 149 160 23301732 \n14 Reynolds E Vitamin B12, folic acid, and the nervous system Lancet Neurol 2006 5 949 960 17052662 \n15 Ravakhah K West BC Case report: subacute combined degeneration of the spinal cord from folate deficiency Am J Med Sci 1995 310 214 216 7485226 \n16 Jaiser SR Winston GP Copper deficiency myelopathy J Neurol 2010 257 869 881 20232210 \n17 Vezmal S Becker A Bode U Jaehde U Biochemical and clinical aspects of methotrexate neurotoxicity Chemotherapy 2003 49 92 104 12714818\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-680X",
"issue": "5(2)",
"journal": "Case reports in neurology",
"keywords": "Cytosine arabinoside; Diffusion imaging; Magnetic resonance imaging; Methotrexate; Spinal cord; Subacute combined degeneration",
"medline_ta": "Case Rep Neurol",
"mesh_terms": null,
"nlm_unique_id": "101517693",
"other_id": null,
"pages": "110-5",
"pmc": null,
"pmid": "23874296",
"pubdate": "2013-05",
"publication_types": "D002363:Case Reports",
"references": "19050889;7485226;20432303;17441843;8416707;15906300;23301732;17207701;15891563;7954266;17052662;12714818;8200001;22411307;271037;20232210;3418727",
"title": "Lateral and dorsal column hyperintensity on magnetic resonance imaging in a patient with myelopathy associated with intrathecal chemotherapy.",
"title_normalized": "lateral and dorsal column hyperintensity on magnetic resonance imaging in a patient with myelopathy associated with intrathecal chemotherapy"
} | [
{
"companynumb": "PHHY2013JP113755",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"d... |
{
"abstract": "The patient was a 42-year-old man who presented with dysphagia.Upper gastrointestinal endoscopy revealed a protruding lesion in the lower thoracic esophagus.Pathological analysis of the lesion showed squamous cell carcinoma.Laboratory data showed leukocytosis(21,200/mL)despite no evidence of infection, and the serum levels of granulocyte colony-stimu- lating factor(G-CSF)were elevated to 283 pg/mL.We diagnosed him with esophageal squamous cell carcinoma(Lt, type 1, cT4N4M0, cStage IV a).After administering 2 courses of docetaxel plus cisplatin plus S-1(DCS)as neoadjuvant chemotherapy, the patient underwent surgery.The pathological diagnosis was pType 2, T2, N4, M0, pStage IV a. G-CSF immunostaining was positive in tumor cells.After the surgery, the number of leukocytes and serum G-CSF levels decreased to within normal limits.Adjuvant chemotherapy was administered.",
"affiliations": "Dept. of Surgery, Yokohama Sakae Kyosai Hospital.",
"authors": "Tochimoto|Masataka|M|;Watanabe|Toru|T|;Koyama|Kazunori|K|;Sadamura|Karin|K|;Iwaki|Yoshitaka|Y|;Katoh|Hideaki|H|;Kawaguchi|Masahiko|M|;Tawaraya|Kanae|K|;Hosokawa|Osamu|O|;Yanagimoto|Kunio|K|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "45(9)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D003680:Deglutition Disorders; D004938:Esophageal Neoplasms; D000077277:Esophageal Squamous Cell Carcinoma; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008297:Male",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1353-1355",
"pmc": null,
"pmid": "30237380",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Granulocyte-Colony Stimulating Factor Producing Esophageal Carcinoma.",
"title_normalized": "a case of granulocyte colony stimulating factor producing esophageal carcinoma"
} | [
{
"companynumb": "JP-ACCORD-096324",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"dr... |
{
"abstract": "Skin localization occurs in about 25% of women with metastatic breast cancer and represents a major therapeutic challenge. Although clinical literature on response of cutaneous metastases to chemotherapy is scarce, good response to eribulin has been reported. Herein, the clinical courses of three women with skin lesions secondary to metastatic breast cancer are described. The first patient achieved a complete clinical response in skin metastases with good tolerability to fourth-line eribulin (progression-free survival [PFS]: 8.5 months). In the second case, eribulin administered as fifth-line chemotherapy produced an objective response and PFS of 6 months with good tolerability. The third patient also received eribulin in the fifth line and had a visible skin response from the first administration (PFS: 5 months).",
"affiliations": "Medical Oncology Department, Hospital Mancha Centro, Ciudad Real, Spain.;Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain.;Medical Oncology Department, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, La Coruña, Spain.;Medical Oncology Department, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, La Coruña, Spain.;Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain.;Medical Oncology Department, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, La Coruña, Spain.",
"authors": "Espinosa Aunión|Ruth|R|;Ramírez Ruda|Carmen Aida|CA|;Rodríguez López|Carmela|C|;Curiel García|Teresa|T|;García Saénz|José Ángel|JÁ|;López López|Rafael|R|",
"chemical_list": "D000970:Antineoplastic Agents; D005663:Furans; D007659:Ketones; C490954:eribulin",
"country": "England",
"delete": false,
"doi": "10.2217/fon-2017-0360",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1479-6694",
"issue": "14(7s)",
"journal": "Future oncology (London, England)",
"keywords": "breast cancer; cutaneous metastases; eribulin",
"medline_ta": "Future Oncol",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D005260:Female; D005663:Furans; D006801:Humans; D007659:Ketones; D008875:Middle Aged; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "101256629",
"other_id": null,
"pages": "37-44",
"pmc": null,
"pmid": "29611759",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Experience with eribulin in patients with breast cancer and cutaneous metastases: case studies.",
"title_normalized": "experience with eribulin in patients with breast cancer and cutaneous metastases case studies"
} | [
{
"companynumb": "PHHY2018ES076531",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALENDRONIC ACID"
},
"drugadditional": "3",
"... |
{
"abstract": "OBJECTIVE\nVoriconazole has significant drug interactions due to metabolism by CYP enzymes. Subtherapeutic voriconazole concentrations associated with concomitant dexamethasone are not well described.\n\n\nMETHODS\nAn 84-year-old male was started on voriconazole for a fungal brain abscess. He was readmitted due to clinical failure thought to be the result of subtherapeutic voriconazole concentrations. Dexamethasone was identified as a potential cause due to its induction of CYP enzymes. This interaction was substantiated by sequential troughs that demonstrated a rise in voriconazole concentrations as dexamethasone was tapered off.\n\n\nCONCLUSIONS\nTherapeutic drug monitoring for patients on voriconazole and dexamethasone is essential to prevent suboptimal clinical outcomes.",
"affiliations": "Pharmacy, University of Kentucky Healthcare, Lexington, KY, USA.;UMass Memorial Health Care, Worcester, MA, USA.;University of Texas Southwestern Medical Center, Dallas, TX, USA.;Pharmacy, Wake Forest Baptist Health, Winston-Salem, NC, USA.",
"authors": "Wallace|K L|KL|;Filipek|R L|RL|;La Hoz|R M|RM|;Williamson|J C|JC|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12401",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "41(4)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "dexamethasone; drug-drug interaction; fungal brain abscess; therapeutic drug monitoring; voriconazole",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": null,
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "441-443",
"pmc": null,
"pmid": "27207573",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Subtherapeutic voriconazole concentrations associated with concomitant dexamethasone: case report and review of the literature.",
"title_normalized": "subtherapeutic voriconazole concentrations associated with concomitant dexamethasone case report and review of the literature"
} | [
{
"companynumb": "US-APPCO PHARMA LLC-1063102",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Reactivation of the hepatitis B virus (HBV) has been reported in patients with occult infection (OBI), i.e. HBV surface antigen (HBsAg) negative, HBV core antibody (anti-HBc) positive ± antibodies against HBsAg (anti-HBs) and detectable HBV DNA in serum or liver, receiving immunosuppressive or cytotoxic therapies. Recently, concerns have been raised regarding the risk of HBV reactivation in OBI patients treated with direct acting antiviral agents (DAAs) for chronic hepatitis C (CHC). Here we describe a case of HBV reactivation in a 72-year-old woman with OBI as a possible consequence of effective treatment with sofosbuvir (SOF) and ribavirin (Rbv) for genotype 2a/2c CHC.",
"affiliations": "Clinic of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy.;Clinic of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy.;Clinic of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy.;Clinic of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy.;Clinic of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy.;Clinic of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy.;Clinic of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy.;Clinic of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy.;Laboratory of Microbiology, Brescia Spedali Civili General Hospital, Brescia, Italy.;Laboratory of Microbiology, Brescia Spedali Civili General Hospital, Brescia, Italy.;Laboratory of Microbiology, Brescia Spedali Civili General Hospital, Brescia, Italy.;Clinic of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy.;Laboratory of Microbiology, Brescia Spedali Civili General Hospital, Brescia, Italy.;Hepatology Unit, Ospedale San Giuseppe, University of Milan, Milan, Italy.",
"authors": "Odolini|Silvia|S|;Lanza|Paola|P|;Angiola|Angiola|A|;Zaltron|Serena|S|;Urbinati|Lucia|L|;Vavassori|Andrea|A|;Nasta|Paola|P|;Festa|Elena|E|;Gargiulo|Franco|F|;Rodella|Anna|A|;Caruso|Arnaldo|A|;Casari|Salvatore|S|;Castelli|Francesco|F|;Viganò|Mauro|M|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000998:Antiviral Agents; D004279:DNA, Viral; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D007155:Immunologic Factors; D012254:Ribavirin; D000069283:Rituximab; C413685:entecavir; D006147:Guanine; D011239:Prednisolone; D000069474:Sofosbuvir",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1121-7138",
"issue": "40(3)",
"journal": "The new microbiologica",
"keywords": "DAAs; HCV; Occult B hepatitis; Reactivation",
"medline_ta": "New Microbiol",
"mesh_terms": "D000368:Aged; D000893:Anti-Inflammatory Agents; D000998:Antiviral Agents; D003449:Cryoglobulinemia; D004279:DNA, Viral; D005260:Female; D006147:Guanine; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D006526:Hepatitis C; D006801:Humans; D007155:Immunologic Factors; D011239:Prednisolone; D012008:Recurrence; D012254:Ribavirin; D000069283:Rituximab; D000069474:Sofosbuvir; D019562:Viral Load",
"nlm_unique_id": "9516291",
"other_id": null,
"pages": "218-220",
"pmc": null,
"pmid": "28513813",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatitis B virus reactivation after effective sofosbuvir and ribavirin treatment in a patient with occult hepatitis B virus infection.",
"title_normalized": "hepatitis b virus reactivation after effective sofosbuvir and ribavirin treatment in a patient with occult hepatitis b virus infection"
} | [
{
"companynumb": "IT-ROCHE-1950162",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "A 47-year-old woman had a swelling in the floor of the mouth and in the submandibular area on the left side. About four hours earlier, a dentist had extracted the mandibular left second premolar and first molar. The rate and degree of the distension were alarming; the floor of the mouth was at a level with the incisal edges of the mandibular incisors. Five hours later, the floor of the mouth was elevated about 1 1/2 cm above the incisal edges of the teeth. Treatment of the patient and her unusual sensitivity to meperidine and promethazine that caused a depression into Cheyne-Stokes respiration and hypotension are described.",
"affiliations": null,
"authors": "Sakamoto|E|E|;Miller|R|R|;Stratigos|G T|GT|;Arthur|A|A|",
"chemical_list": "D010406:Penicillins; D009270:Naloxone; D008012:Lidocaine; D008614:Meperidine; D011398:Promethazine; D010100:Oxygen",
"country": "England",
"delete": false,
"doi": "10.14219/jada.archive.1975.0141",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-8177",
"issue": "90(3)",
"journal": "Journal of the American Dental Association (1939)",
"keywords": null,
"medline_ta": "J Am Dent Assoc",
"mesh_terms": "D001794:Blood Pressure; D002639:Cheyne-Stokes Respiration; D005260:Female; D006406:Hematoma; D006801:Humans; D007442:Intubation, Intratracheal; D008012:Lidocaine; D008614:Meperidine; D008875:Middle Aged; D009060:Mouth Floor; D009270:Naloxone; D006472:Oral Hemorrhage; D010100:Oxygen; D010406:Penicillins; D011398:Promethazine; D011674:Pulse; D012119:Respiration; D012131:Respiratory Insufficiency; D014081:Tooth Extraction",
"nlm_unique_id": "7503060",
"other_id": null,
"pages": "654-8",
"pmc": null,
"pmid": "1078674",
"pubdate": "1975-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Serious postextraction hemorrhage into the submandibular space: report of case.",
"title_normalized": "serious postextraction hemorrhage into the submandibular space report of case"
} | [
{
"companynumb": "US-PFIZER INC-2020510570",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": null,
"drugautho... |
{
"abstract": "We studied elderly Medicare enrollees newly diagnosed with early-stage breast cancer to examine the association between adjuvant chemotherapy and acute kidney injury (AKI).\n\n\n\nUsing the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we conducted a retrospective cohort study including women diagnosed with stages I-III breast cancer at ages 66-89 years between 1992 and 2007. We performed one-to-one matching on time-dependent propensity score on the day of adjuvant chemotherapy initiation within 6 months after the first cancer-directed surgery based on the estimated probability of chemotherapy initiation at each day for each patient, using a Cox proportional hazards model. We estimated the cumulative incidence of AKI using Kaplan-Meier methods. We used Cox proportional hazards models to evaluate the association between chemotherapy and the risk of AKI, and compared the risk among major chemotherapy types.\n\n\n\nThe study included 28,048 women. The 6-month cumulative incidence of AKI was 0.80% for chemotherapy-treated patients, compared with 0.30% for untreated patients (P < 0.001). Adjuvant chemotherapy was associated with a nearly threefold increased risk of AKI [hazard ratio (HR) 2.73; 95% CI 1.8-4.1]. Compared with anthracycline-based chemotherapy, the HRs (95% CIs) were 1.66 (0.94-2.91), 0.88 (0.53-1.47), and 1.15 (0.57-2.32) for taxane-based, CMF, and other chemotherapy, respectively.\n\n\n\nOur findings showed that adjuvant chemotherapy was associated with increased risk of AKI in elderly women diagnosed with early-stage breast cancer. The risk seemed to vary by regimen type, but the differences were not statistically significant.",
"affiliations": "Chronic Disease Research Group, Minneapolis Medical Research Foundation, 914 South 8th Street, Suite S2.100, Minneapolis, MN, 55404, USA. slli@cdrg.org.;Chronic Disease Research Group, Minneapolis Medical Research Foundation, 914 South 8th Street, Suite S2.100, Minneapolis, MN, 55404, USA.;Division of Health Services Research and Policy, School of Public Health, University of Minnesota, Minneapolis, MN, USA.;Chronic Disease Research Group, Minneapolis Medical Research Foundation, 914 South 8th Street, Suite S2.100, Minneapolis, MN, 55404, USA.",
"authors": "Li|Shuling|S|;Liu|Jiannong|J|;Virnig|Beth A|BA|;Collins|Allan J|AJ|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10549-016-4074-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6806",
"issue": "161(3)",
"journal": "Breast cancer research and treatment",
"keywords": "Acute kidney injury; Adjuvant chemotherapy; Breast cancer; Medicare",
"medline_ta": "Breast Cancer Res Treat",
"mesh_terms": "D058186:Acute Kidney Injury; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D015897:Comorbidity; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008207:Lymphatic Metastasis; D006278:Medicare; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D012306:Risk; D018426:SEER Program; D014481:United States",
"nlm_unique_id": "8111104",
"other_id": null,
"pages": "515-524",
"pmc": null,
"pmid": "27933451",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Association between adjuvant chemotherapy and risk of acute kidney injury in elderly women diagnosed with early-stage breast cancer.",
"title_normalized": "association between adjuvant chemotherapy and risk of acute kidney injury in elderly women diagnosed with early stage breast cancer"
} | [
{
"companynumb": "US-JNJFOC-20170217180",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "The potent opioid and veterinary drug, carfentanil has recently entered the illicit drug market, especially in relation to heroin and cocaine. Recent publications have reported carfentanil concentrations found in fatalities occurring in the USA. This article presents the toxicological findings in seven heroin/cocaine cases occurring in the UK within a short period of time where carfentanil was detected and measured. Carfentanil was detected along with other drugs in all cases with no alcohol detected in the post-mortem blood in any of the cases. Of the other drugs detected, of particular note, cannabinoids were detected in three, cocaine in four, other opioids (methadone, dihydrocodeine and tramadol) in four and benzodiazepines were detected in four of the seven fatalities. A high concentration of ketamine and norketamine was found in one case. Morphine and its glucuronide metabolites were also measured where detected in six of the seven cases. The carfentanil concentrations were found to be between 0.22 and 3.3 ng/mL (mean 0.93, median 0.66 ng/mL) in post-mortem femoral blood. In one case where aortic and ventricular post-mortem blood was submitted for analysis in addition to femoral blood, comparative concentrations of 1.05 (aortic), 0.57 (ventricular) and 0.50 (femoral) ng/mL were found. The concentrations support the necessity to ensure laboratory detection methods for carfentanil and subsequent measurement are appropriate as concentrations below 0.3 ng/mL may be present in post-mortem blood. The concentrations also support the notion that there is no particular \"toxic\" or \"fatal\" post-mortem blood carfentanil concentration associated with its use.",
"affiliations": "Alere Forensics, Malvern Hills Science Park, Geraldine Road, Malvern WR14 3SZ, UK.;Alere Forensics, Malvern Hills Science Park, Geraldine Road, Malvern WR14 3SZ, UK.",
"authors": "Elliott|Simon P|SP|;Hernandez Lopez|Elena|E|",
"chemical_list": "D000701:Analgesics, Opioid; C017114:carfentanil; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkx109",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "42(4)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D019970:Cocaine-Related Disorders; D005260:Female; D005283:Fentanyl; D053593:Forensic Toxicology; D006556:Heroin Dependence; D006801:Humans; D008297:Male",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "e41-e45",
"pmc": null,
"pmid": "29329388",
"pubdate": "2018-05-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Series of Deaths Involving Carfentanil in the UK and Associated Post-mortem Blood Concentrations.",
"title_normalized": "a series of deaths involving carfentanil in the uk and associated post mortem blood concentrations"
} | [
{
"companynumb": "GB-PFIZER INC-2018029717",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARFENTANIL"
},
"drugadditional": null,
... |
{
"abstract": "Although breast cancer is, unfortunately, not uncommon in women, a mere 0.04% of malignant breast tumours are primary angiosarcomas. Chemotherapy is advocated for treatment of breast angiosarcomas; however, no guidelines exist regarding optimal chemotherapeutics or protocols. Presently, the prognosis for breast angiosarcomas is poor. This case report describes a 24-year old woman diagnosed with primary breast angiosarcoma. She initially refused to receive treatment, but later returned to the hospital four years later with a haemopneumothorax. She was treated with rescue chemotherapy using a combination of high-dose tamoxifen plus ifosfamide and epirubicin (an anthracycline). She achieved a partial response, but died 16 months after therapy was initiated. More research is needed to devise novel chemotherapeutics and protocols to improve outcomes in women diagnosed with primary angiosarcomas of the breast.",
"affiliations": "Division of Hematology-Oncology, Department of Internal Medicine, Far-Eastern Memorial Hospital, Taiwan; and Cancer Research Center, National Taiwan University, Taiwan. ch_hsiao@icloud.com.;Cancer Research Center; and Department of Oncology, College of Medicine, National Taiwan University, Taiwan.;Department of Chest Surgery, Far-Eastern Memorial Hospital, Taiwan.;Department of Pathology, Far-Eastern Memorial Hospital, Taiwan.",
"authors": "Hsiao|C-H|CH|;Yeh|K-H|KH|;Chang|Y-C|YC|;Tsai|C-C|CC|",
"chemical_list": "D018943:Anthracyclines; D013629:Tamoxifen; D007069:Ifosfamide",
"country": "Jamaica",
"delete": false,
"doi": "10.7727/wimj.2012.317",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0043-3144",
"issue": "62(7)",
"journal": "The West Indian medical journal",
"keywords": null,
"medline_ta": "West Indian Med J",
"mesh_terms": "D018943:Anthracyclines; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017809:Fatal Outcome; D005260:Female; D006394:Hemangiosarcoma; D006801:Humans; D007069:Ifosfamide; D013629:Tamoxifen; D055815:Young Adult",
"nlm_unique_id": "0417410",
"other_id": null,
"pages": "651-3",
"pmc": null,
"pmid": "24831906",
"pubdate": "2013-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "High-dose tamoxifen plus ifosfamide and anthracycline in a patient with angiosarcoma of the breast.",
"title_normalized": "high dose tamoxifen plus ifosfamide and anthracycline in a patient with angiosarcoma of the breast"
} | [
{
"companynumb": "TW-CIPLA LTD.-2015TW03890",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TAMOXIFEN"
},
"drugadditional": null,
... |
{
"abstract": "Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a multisystem autoinflammatory disease due to an underlying plasma cell disorder that lacks a standard treatment strategy because of its rarity. We report a case of relapsed POEMS syndrome successfully treated with a second ambulatory autologous hematopoietic-cell transplantation (AHCT) after a daratumumab desensitization protocol performed during the coronavirus disease (COVID-19) pandemic in a patient with coexisting human immunodeficiency virus (HIV), hepatitis B virus (HBV) and syphilis infections. He is a 37-year old Latin-American male who had been treated with radiation, CyBorD regimen, AHCT and bortezomib therapy before being referred to our service. It was decided to administer daratumumab therapy and subsequently perform the transplant. Placement of central venous access, fluid infusion, conditioning regimen with melphalan and previously cryopreserved autograft infusion were carried out in an outpatient basis. Following second AHCT, the patient demonstrated clinical, VEGF, hematological response and remains SARS-CoV-2 infection-free and in POEMS remission with excellent quality-of-life at last follow up (6 months). We evidenced that thanks to an outpatient transplant program, the best therapeutic modalities can be offered to patients with hematologic malignancies in the context of present or future pandemics. Finally, high-complexity patients with HIV infection should have access to the same treatment strategies as non-infected patients. A second AHCT in the outpatient setting is feasible, safe and highly effective to treat patients with relapsed POEMS syndrome.",
"affiliations": "Department of Hematology, Dr. José Eleuterio González University Hospital, School of Medicine, Universidad Autónoma de Nuevo León, Monterrey, Mexico.;Department of Hematology, Dr. José Eleuterio González University Hospital, School of Medicine, Universidad Autónoma de Nuevo León, Monterrey, Mexico. Electronic address: carjaime@hotmail.com.;Department of Dermatology, Dr. José Eleuterio González University Hospital, School of Medicine, Universidad Autónoma de Nuevo León, Monterrey, Mexico.;Department of Dermatology, Dr. José Eleuterio González University Hospital, School of Medicine, Universidad Autónoma de Nuevo León, Monterrey, Mexico.;Department of Hematology, Dr. José Eleuterio González University Hospital, School of Medicine, Universidad Autónoma de Nuevo León, Monterrey, Mexico.",
"authors": "Hernández-Coronado|Marcela|M|;Jaime-Pérez|José Carlos|JC|;Villarreal-Martínez|Alejandra|A|;Ocampo-Candiani|Jorge|J|;Gómez-Almaguer|David|D|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C556306:daratumumab; D000069286:Bortezomib",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.trim.2021.101412",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0966-3274",
"issue": "67()",
"journal": "Transplant immunology",
"keywords": "Autologous transplant; Daratumumab; HIV; Hematopoietic cell transplantation; Outpatient HCT; POEMS syndrome",
"medline_ta": "Transpl Immunol",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000069286:Bortezomib; D000086382:COVID-19; D015658:HIV Infections; D018380:Hematopoietic Stem Cell Transplantation; D019694:Hepatitis B, Chronic; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D016878:POEMS Syndrome; D000086402:SARS-CoV-2; D013587:Syphilis; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "9309923",
"other_id": null,
"pages": "101412",
"pmc": null,
"pmid": "34020046",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful second outpatient autologous hematopoietic cell transplant for relapsed POEMS syndrome in a patient with coexisting HIV, HBV and syphilis infections during the COVID-19 pandemic.",
"title_normalized": "successful second outpatient autologous hematopoietic cell transplant for relapsed poems syndrome in a patient with coexisting hiv hbv and syphilis infections during the covid 19 pandemic"
} | [
{
"companynumb": "MX-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-312193",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drug... |
{
"abstract": "BACKGROUND\nVolatile anesthetics provide myocardial preconditioning in coronary surgery patients. We hypothesized that sevoflurane compared with propofol reduces the incidence of myocardial ischemia in patients undergoing major noncardiac surgery.\n\n\nRESULTS\nWe enrolled 385 patients at cardiovascular risk in 3 centers. Patients were randomized to maintenance of anesthesia with sevoflurane or propofol. We recorded continuous ECG for 48 hours perioperatively, measured troponin T and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) on postoperative days 1 and 2, and evaluated postoperative delirium by the Confusion Assessment Method. At 6 and 12 months, we contacted patients by telephone to assess major adverse cardiac events. The primary end point was a composite of myocardial ischemia detected by continuous ECG and/or troponin elevation. Additional end points were postoperative NT-proBNP concentrations, major adverse cardiac events, and delirium. Patients and outcome assessors were blinded. We tested dichotomous end points by χ(2) test and NT-proBNP by Mann-Whitney test on an intention-to-treat basis. Myocardial ischemia occurred in 75 patients (40.8%) in the sevoflurane and 81 (40.3%) in the propofol group (relative risk, 1.01; 95% confidence interval, 0.78-1.30). NT-proBNP release did not differ across allocation on postoperative day 1 or 2. Within 12 months, 14 patients (7.6%) suffered a major adverse cardiac event after sevoflurane and 17 (8.5%) after propofol (relative risk, 0.90; 95% confidence interval, 0.44-1.83). The incidence of delirium did not differ (11.4% versus 14.4%; P=0.379).\n\n\nCONCLUSIONS\nCompared with propofol, sevoflurane did not reduce the incidence of myocardial ischemia in high-risk patients undergoing major noncardiac surgery. The sevoflurane and propofol groups did not differ in postoperative NT-proBNP release, major adverse cardiac events at 1 year, or delirium.",
"affiliations": "Department of Anesthesia and Intensive Care Medicine, University Hospital Basel, Spitalstrasse 21, CH-4031 Basel, Switzerland. glurati@uhbs.ch",
"authors": "Lurati Buse|Giovanna A L|GA|;Schumacher|Philippe|P|;Seeberger|Esther|E|;Studer|Wolfgang|W|;Schuman|Regina M|RM|;Fassl|Jens|J|;Kasper|Jorge|J|;Filipovic|Miodrag|M|;Bolliger|Daniel|D|;Seeberger|Manfred D|MD|",
"chemical_list": "D000777:Anesthetics; D008738:Methyl Ethers; D000077149:Sevoflurane; D015742:Propofol",
"country": "United States",
"delete": false,
"doi": "10.1161/CIRCULATIONAHA.112.126144",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-7322",
"issue": "126(23)",
"journal": "Circulation",
"keywords": null,
"medline_ta": "Circulation",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000777:Anesthetics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007431:Intraoperative Complications; D008297:Male; D008738:Methyl Ethers; D008875:Middle Aged; D017202:Myocardial Ischemia; D019990:Perioperative Care; D015742:Propofol; D012307:Risk Factors; D000077149:Sevoflurane; D016037:Single-Blind Method",
"nlm_unique_id": "0147763",
"other_id": null,
"pages": "2696-704",
"pmc": null,
"pmid": "23136158",
"pubdate": "2012-12-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Randomized comparison of sevoflurane versus propofol to reduce perioperative myocardial ischemia in patients undergoing noncardiac surgery.",
"title_normalized": "randomized comparison of sevoflurane versus propofol to reduce perioperative myocardial ischemia in patients undergoing noncardiac surgery"
} | [
{
"companynumb": "CH-ABBVIE-12P-151-1025796-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ETOMIDATE"
},
"drugadditional": null,
... |
{
"abstract": "Glutamate is the major excitatory neurotransmitter in the central nervous system and, as such, many brain regions, including the basal ganglia, are rich in glutamatergic neurons. The importance of the basal ganglia in the control of voluntary movement has long been recognised, with the effect of dysfunction of the region exemplified by the motor symptoms seen in Parkinson's disease (PD). However, the basal ganglia and the associated glutamatergic system also play a role in the modulation of emotion, nociception and cognition, dysregulation of which result in some of the non-motor symptoms of PD (depression/anxiety, pain and cognitive deficits). Thus, while the treatment of PD has traditionally been approached from the perspective of dopaminergic replacement, using agents such as levodopa and dopamine receptor agonists, the glutamatergic system offers a novel treatment target for the disease. Safinamide has been approved in over 20 countries globally for fluctuating PD as add-on therapy to levodopa regimens for the management of 'off' episodes. The drug has both dopaminergic and non-dopaminergic pharmacological effects, the latter including inhibition of abnormal glutamate release. The effect of safinamide on the glutamatergic system might present some advantages over dopamine-based therapies for PD by providing efficacy for motor (levodopa-induced dyskinesia) as well as non-motor (anxiety, mood disorders, pain) symptoms. In this article, we discuss the potential role of glutamatergic inhibition on these symptoms, using illustrative real-world examples of patients we have treated with safinamide.",
"affiliations": "Movement Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Electronic address: JPagonabarraga@santpau.cat.;Neurology Unit, Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy. Electronic address: michele.tinazzi@univr.it.;CNS Preclinical Pharmacology, Independent Advisor, Milan, Italy. Electronic address: caccia.carla@gmail.com.;Parkinson-Klinik Ortenau, Wolfach, Germany. Electronic address: w.jost@parkinson-klinik.de.",
"authors": "Pagonabarraga|Javier|J|;Tinazzi|Michele|M|;Caccia|Carla|C|;Jost|Wolfgang H|WH|",
"chemical_list": "D000978:Antiparkinson Agents; D001596:Benzylamines; C092797:safinamide; D000409:Alanine",
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2021.05.056",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "90()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Case reports; Glutamic acid; Parkinson disease; Safinamide",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000368:Aged; D000409:Alanine; D000978:Antiparkinson Agents; D001596:Benzylamines; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009474:Neurons; D010300:Parkinson Disease; D009435:Synaptic Transmission",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "178-183",
"pmc": null,
"pmid": "34275546",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "The role of glutamatergic neurotransmission in the motor and non-motor symptoms in Parkinson's disease: Clinical cases and a review of the literature.",
"title_normalized": "the role of glutamatergic neurotransmission in the motor and non motor symptoms in parkinson s disease clinical cases and a review of the literature"
} | [
{
"companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-307138",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PRAMIPEXOLE"
},
"dru... |
{
"abstract": "After the approval of bevacizumab for the first-line treatment of metastatic colorectal cancer (mCRC) in China, published information was still limited. This observational cohort study enrolled 175 mCRC patients who initiated bevacizumab-containing first-line chemotherapies at Sun Yet-sen University Cancer Center. Backbone chemotherapies included FOLFIRI (45.6 %), FOLFOX (34.9 %), and XELOX (19.5 %). Effectiveness data, safety profiles, and treatment patterns were collected and compared between oxaliplatin- and irinotecan-based groups. The median treatment durations of bevacizumab in first-line and total were equivalent between oxaliplatin- and irinotecan-based group (5.0 vs. 4.8 and 6.0 vs. 5.9 months, respectively). Median progression-free survival (PFS) was 10.6 months, and median overall survival (OS) was 24.2 months in entire population. No significant difference was found between irinotecan- and oxaliplatin-based groups in PFS (10.8 vs. 10.1 months, p = 0.21) or in OS (27.5 vs. 23.7 months, p = 0.68). Overall response rate in entire population was 38.3 %, and the disease control rate was 86.3 %. Bevacizumab-associated serious adverse events included hypertension (4.2 %), bleeding (3.6 %), proteinuria (3.0 %), venous thromboembolism (0.6 %), and wound-healing complications (0.6 %). Curative-intent surgery after conversion chemotherapy was carried out in 23 patients (13.7 %). Multivariate analyses showed that maintenance therapy (p = 0.001), resection of metastatic sites (p = 0.002), and disease-free interval (p = 0.003) were independent prognostic factors for OS survival. In spite of small discrepancies in treatment patterns, irinotecan- and oxaliplatin-based chemotherapeutic regimens are equally compatible partners for bevacizumab in first-line Chinese mCRC treatment.",
"affiliations": "Department of Medical Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.",
"authors": "Bai|Long|L|;Zhang|Dong-Sheng|DS|;Wu|Wen-Jing|WJ|;Ren|Chao|C|;Wang|De-Shen|DS|;Wang|Feng|F|;Qiu|Miao-Zhen|MZ|;Xu|Rui-Hua|RH|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab",
"country": "United States",
"delete": false,
"doi": "10.1007/s12032-014-0469-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1357-0560",
"issue": "32(2)",
"journal": "Medical oncology (Northwood, London, England)",
"keywords": null,
"medline_ta": "Med Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D044466:Asians; D000068258:Bevacizumab; D015331:Cohort Studies; D015179:Colorectal Neoplasms; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9435512",
"other_id": null,
"pages": "469",
"pmc": null,
"pmid": "25582893",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "20647712;17103254;23881988;21673685;22240792;21959045;18421054;18467725;15175435;23168366;22477726;11896089;21047491;19726453;17548840;18854567;18358928;18596824;19942597;20587616;22943913;20504361;12637872;16356309;19406901;15319715;18854571;22414244;21358960;21285134;22969910;20008641;23015662;22171947;19273699;17947725;21386839;22658457",
"title": "Clinical outcomes of Chinese patients with metastatic colorectal cancer receiving first-line bevacizumab-containing treatment.",
"title_normalized": "clinical outcomes of chinese patients with metastatic colorectal cancer receiving first line bevacizumab containing treatment"
} | [
{
"companynumb": "CN-ROCHE-1439472",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "The patient was 32-year-old man, who received olanzapine for schizophrenia and developed polyuria and thirst without drinking soft-drinks after 4 months. Five months after the initiation of treatment, he developed diabetic ketoacidosis (blood glucose: 490 mg/dL, HbA1c: 15.5%). He was diagnosed with type 1 diabetes (glutamic acid decarboxylase (GAD)-Ab: 5.6 U/mL, IA-2 Ab: 5.9 U/mL, fasting C-peptide: 0.12 ng/mL) and was put on intensive insulin therapy. At four months after the onset of 1A diabetes, he experienced a honeymoon phase that was sustained until the 40th month of treatment. We hypothesize that the administration of olanzapine to a patient with pre-type 1A diabetes induced marked hyperglycemia and accelerated the onset of type 1A diabetes.",
"affiliations": "Department of Internal Medicine, Division of Endocrinology and Metabolism, Showa-University Fujigaoka Hospital, Japan.",
"authors": "Iwaku|Kenji|K|;Otuka|Fumiko|F|;Taniyama|Matsuo|M|",
"chemical_list": "D014150:Antipsychotic Agents; D001786:Blood Glucose; D007328:Insulin; D001569:Benzodiazepines; D000077152:Olanzapine",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.56.7010",
"fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.56.7010Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 28154279Case ReportAcute-Onset Type 1 Diabetes that Developed During the Administration of Olanzapine Iwaku Kenji 1Otuka Fumiko 1Taniyama Matsuo 11 Department of Internal Medicine, Division of Endocrinology and Metabolism, Showa-University Fujigaoka Hospital, JapanCorrespondence to Dr. Kenji Iwaku, k-iwaku@ito-hospital.jp\n\n1 2 2017 56 3 335 339 22 12 2015 20 6 2016 The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).The patient was 32-year-old man, who received olanzapine for schizophrenia and developed polyuria and thirst without drinking soft-drinks after 4 months. Five months after the initiation of treatment, he developed diabetic ketoacidosis (blood glucose: 490 mg/dL, HbA1c: 15.5%). He was diagnosed with type 1 diabetes (glutamic acid decarboxylase (GAD)-Ab: 5.6 U/mL, IA-2 Ab: 5.9 U/mL, fasting C-peptide: 0.12 ng/mL) and was put on intensive insulin therapy. At four months after the onset of 1A diabetes, he experienced a honeymoon phase that was sustained until the 40th month of treatment. We hypothesize that the administration of olanzapine to a patient with pre-type 1A diabetes induced marked hyperglycemia and accelerated the onset of type 1A diabetes. \n\nmulti-acting-receptor-targeted anti-psychoticstype 1 diabetes mellitushyperglycemiaschizophrenia\n==== Body\nIntroduction\nSerotonin-dopamine antagonists (SDAs) are effective for treating schizophrenia (1,2). These compounds are listed in the American Psychological Association (APA) guidelines as the first choice in acute phase treatment (3). However, one side effect of these SDAs is glucose intolerance (4-9), which occasionally causes a hyperglycemic crisis, and a few fatal cases have been reported (5,10-12). There are no reports of these drugs being associated with the onset of type 1A diabetes.\n\nMeanwhile, type 1A diabetes causes a decrease in endogenous insulin secretion due to pancreatic β-cell dysfunction via an immunological mechanism (13,14). As the damage to the pancreatic β-cells progresses, the activity of the remaining β-cells decreases by approximately 20-30%, causing hyperglycemia and the onset of type 1A diabetes (15-17). However, even before this stage, exposure to severe stress can cause hyperglycemia and accelerate the onset of type 1A diabetes (18,19). In the present report, we describe a case of type 1A diabetes that was triggered by the administration of SDAs during the treatment of schizophrenia.\n\nCase Report\nThe patient was a 32-year-old man with no history of obesity and no family history of diabetes. At 23 years of age, he had developed schizophrenia and underwent treatment. He did not suffer from eating disorders during the clinical course of schizophrenia, and blood tests revealed no glucose intolerance or gastrointestinal disorders. More recently, the patient received risperidone (3 mg/day) and fluvoxamine maleate (50 mg/day). Because of the varied improvement of the patient's symptoms, the treatment was changed to olanzapine (5 mg/day) when the patient was 31 years and 4 months of age. Quetiapine (25 mg/day) was added at 1 month after the start of olanzapine treatment. A marked improvement in the psychiatric symptoms was observed 4 months later, when olanzapine was withdrawn and the patient was switched to quetiapine (50 mg/day). However, approximately 3 months after the initiation of olanzapine, the subject developed polyuria, polydipsia, oral dryness (he drank approximately 4 L of water per day) despite abstaining from soft-drink consumption. Four months after the start of olanzapine treatment, he lost approximately 10 kg (52→42 kg, BMI:16.9→13.6 kg/m2). The symptoms associated with hyperglycemia, such as polyuria, oral dryness, and compensatory polydipsia, gradually worsened. However, the treatment was continued because of the substantial improvement in the patient's psychiatric symptoms. Five months after the start of olanzapine, the subject exhibited general fatigue and presented to a local physician complaining of a loss of appetite and nausea. Blood tests revealed high blood glucose levels (540 mg/dL), and he was referred to our hospital for examination. When he arrived at our hospital, his blood glucose was 490 mg/dL, with an HbA1c of 15.5% National Glycohemoglobin Standardization Program (NGSP), positive urinary ketones (3+), and acidosis (pH 7.250) (Table 1). He was diagnosed with diabetic ketoacidosis and admitted as an emergency case, and we performed an acute metabolic correction (Fig. 1). After admission, the patient was fasted and given a continuous intravenous insulin infusion. Oral intake was restarted on the 2nd day of hospitalization (hereafter, day 2), after we corrected the hyperglycemia and the associated acute metabolic disorder. He was then put on intensive insulin therapy with Lispro and Glargine. The blood tests performed after admission showed that the patient tested negative for islet-cell antibodies (indirect immunofluorescence) (20). The patient did, however, test positive for pancreatic islet autoantibodies (with a glutamic acid decarboxylase (GAD)-antibody titer of 5.6 U/mL and an IA-2-antibody titer of 5.9 U/mL), and we noted that endogenous insulin secretion was reduced (Table 2). He met the criteria stated in the Diagnostic Criteria for Acute Type 1 Diabetes Mellitus (2012) and was therefore diagnosed with diabetes mellitus (21). After the introduction of intensive insulin therapy, the patient's blood glucose levels improved, and on day 32, the patient was discharged from the hospital (Fig. 2). The subject passed into a “honeymoon phase,” where he required an insulin dose of <0.5 U/kg/day and his HbA1c values remained at <7% (22), from 4 months after discharge. This was maintained until the 40th month of treatment. The clinical course is shown in Fig. 3.\n\nTable 1. Laboratory Findings on Admission.\n\n<Blood gas analysis>\t\t<Biochemical>\t\t\t\t\npH\t7.25\t\tTp\t7.4g/dL\t\tAMY\t36U/L\t\npCO2\t21.0mmHg\t\tAlb\t4.9g/dL\t\tCK \t41U/L\t\npO2\t123.6mmHg\t\tBUN\t13.3mg/dL\t\tCRP\t0.2mg/dL\t\nHCO3-\t9.0mmol/L\t\tUA\t6.6mg/dL\t\tP-Glu\t490mg/dL\t\nBE\t-15.7mml/L\t\tCre\t0.4mg/dL\t\tHbA1c (NGSP)\t15.5%\t\n\t\t\tNa\t134mEq/L\t\tFasting C-peptide\t0.12ng/mL\t\n<Complete blood count>\t\tCl\t95mEq/L\t\t※P fasting-Glu 221mg/dL\t\t\nWBC\t10,500/μL\t\tK\t3.9mEq/L\t\t\t\t\nHb\t16.5g/dL\t\tCa\t9.4mg/dL\t\tFT3\t0.8pg/mL\t\nHct\t49.3%\t\ti-P\t3.9mg/dL\t\tFT4\t0.87ng/dL\t\nPLT\t21.1×104/μL\t\tT-Bil\t0.5mg/dL\t\tTSH\t0.32μIU/m L\t\n\t\t\tD-Bil\t0.1mg/dL\t\tTgAb\t<0.3U/mL\t\n<Urinalysis>\t\tAST\t13IU/L\t\tTPOAb\t<0.3U/mL\t\nPH\t5.0\t\tALT\t14IU/L\t\tTRAb\t6.2%\t\nprotein\t+\t\tLDH\t306IU/L\t\t\t\t\nglucose\t4+\t\tALP\t170IU/L\t\t\t\t\nketon body\t3+\t\tChE\t253IU/L\t\t\t\t\nFigure 1. Clinical course to be hospitalized from olanzapine start.\n\nTable 2. Diabetes-related Laboratory Findings.\n\nGAD antibody titer(RIA)\t5.6U/mL\t\n\treference range <1.5U/mL\t\nIA-2 antibody titer(RIA)\t5.9U/mL\t\n\treference range <0.4U/mL\t\nInsulin antibody binding rate(RIA)\t<1.0%\t\n\ttotal IRI 1.7μU/mL, Free IRI 1.6μU/mL\t\n\treference range <10%\t\n\t\t\nIslet-cell antibodies(IIF)\t(-)\t\n\treference range <1.25JDF units\t\nglucagon stimulation test\t\t\n(after hyperglycemia corrective)\t\t\n\tFasting C-peptide\t0.41ng/mL\t\n\t6-min C-peptide\t0.75ng/mL\t\n\t\t\t\nHLA allele\t\tDRB1*09(Homo)\t\n\t\t\t\n\t<urine analysis>\t\t\nU-CPR\t\t12.3μg/24h\t\nalbumin excretion rate\t\t 2.5μg/min\t\nCcr\t\t155mL/min\t\nFigure 2. Development after hospital admission.\n\nFigure 3. Insulin dose and HbA1c after the onset of type 1A diabetes.\n\nDiscussion\nSDAs are first-generation antipsychotics that are used to treat schizophrenia, and which block both dopamine D2 and serotonin 5-HT2 receptors. They also alleviate side effects such as extrapyramidal symptoms and hyperprolactinemia; they have also been observed to have effects on negative symptoms. SDAs demonstrate a similar affinity for several receptors, including the adrenergic (α1), histaminic (H1), and muscarinic receptors (1,2), and have been shown to be effective in the treatment of schizophrenia. The APA guidelines, list SDAs as the first choice for acute treatment (3); however, these drugs are associated with the side effect of glucose intolerance (4-9). This may occasionally trigger a hyperglycemic crisis, and some fatal cases have been reported (5,10-12). The mechanisms underlying the onset of glucose intolerance are reported to be as follows. 1) increased insulin resistance caused by weight gain as a result of overeating due to the principal activity of SDAs, which increase the ghrelin levels by blocking the 5-HT 2C (25), D2 (26), α1 (23), and H1 receptors (23). 2) Pancreatic β-cell dysfunction (27) 3) increases the insulin resistance caused by impaired glyconeogenesis and the insulin signal transduction in L6 skeletal muscle cells (28). However, these mechanisms are associated with the onset of type 2 diabetes, and there are no reports of the onset of type 1 diabetes in relation to immunological mechanisms.\n\nIt is possible that some environmental factors (in addition to hereditary factors) contribute to the destruction of pancreatic β-cells via an immunological mechanism in type 1 diabetes. When <20-30% of the pancreatic β-cells remain, the consequent hyperglycemia leads to the onset of type 1A diabetes (13-17). However, even if >30% of the pancreatic β-cells remain, stresses such as trauma or severe infection, steroid therapy, or polydipsia can trigger a hyperglycemic state, which might accelerate the onset of type 1 diabetes (18,19). In the present case, we found no clear causal relationship between SDA therapy and the onset of type 1A diabetes. Hypothetically, an immunological mechanism may speed up the progression of pancreatic β-cell dysfunction in pre-type 1 diabetic patients who may not necessarily present a hyperglycemic state. During this stage, the administration of SDAs and factors other than immunological mechanisms may cause marked hyperglycemia and accelerate the onset of type 1A diabetes. Thus, the administration of SDAs may be a factor that exacerbates hyperglycemia.\n\nIn the present case, the SDA-associated hyperglycemia was not caused by overeating after the start of olanzapine treatment. Thus, the possibility that the increase in the patient's insulin resistance was caused by weight gain, as a primary effect of the administration of SDAs, can be rejected. The honeymoon phase lasted for 32 months after the onset of type 1A diabetes. Although it is unlikely that olanzapine caused the destruction of the pancreatic β-cells, we cannot rule out the possibility that it caused reversible β-cell damage. Thus, a single, definitive cause of diabetes could not be established in the present case. Olanzapine therapy, in association with multiple factors, may have caused the patient's significant hyperglycemia, which may have precipitated or accelerated the onset of type 1A diabetes.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Leucht S , Corves C , Arbter D , Engel RR , Li C , Davis JM \nSecond-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis . Lancet \n373 : 31 -41 , 2009 .19058842 \n2. Lieberman JA , Stroup TS , McEvoy JP , et al \nClinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia . N Engl J Med \n353 : 1209 -1223 , 2005 .16172203 \n3. Lehman AF , Lieberman JA , Dixon LB , et al \nAmerican Psychiatric Association; Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition . Am J Psychiatry \n161 (Suppl ): 1 -56 , 2004 .\n4. Lipscombe LL , Austin PC , Alessi-Severini S , et al \nCanadian Network for Observational Drug Effect Studies (CNODES) Investigators. Atypical antipsychotics and hyperglycemic emergencies: Multicentre, retrospective cohort study of administrative data . Schizophr Res \n154 : 54 -60 , 2014 .24581419 \n5. Koller EA , Doraiswamy PM \nOlanzapine-associated diabetes mellitus . Pharmacotherapy \n22 : 841 -852 , 2002 .12126218 \n6. Sernyak MJ , Leslie DL , Alarcon RD , Losonczy MF , Rosenheck R \nAssociation of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia . Am J Psychiatry \n159 : 561 -566 , 2002 .11925293 \n7. Yasui-Furukori N , Sato Y , Furukori H , Saito M , Nakagami T , Kaneko S \nGlucose metabolism in Japanese schizophrenia patients treated with risperidone or olanzapine . J Clin Psychiatry \n70 : 95 -100 , 2009 .19026267 \n8. Henderson DC , Cagliero E , Copeland PM , et al \nElevated hemoglobin A1c as a possible indicator of diabetes mellitus and diabetic ketoacidosis in schizophrenia patients receiving atypical antipsychotics . J Clin Psychiatry \n68 : 533 -541 , 2007 .17474808 \n9. Lambert BL , Cunningham FE , Miller DR , Dalack GW , Hur K \nDiabetes risk associated with use of olanzapine, quetiapine, and risperidone in veterans health administration patients with schizophrenia . Am J Epidemiol \n164 : 672 -681 , 2006 .16943266 \n10. Ely SF , Neitzel AR , Gill JR \nFatal diabetic ketoacidosis and antipsychotic medication . J Forensic Sci \n58 : 398 -403 , 2013 .23278567 \n11. Ramaswamy K , Kozma CM , Nasrallah H \nRisk of diabetic ketoacidosis after exposure to risperidone or olanzapine . Drug Saf \n30 : 589 -599 , 2007 .17604410 \n12. Seaburg HL , McLendon BM , Doraiswamy PM \nOlanzapine-associated severe hyperglycemia, ketonuria, and acidosis: case report and review of literature . Pharmacotherapy \n21 : 1448 -1454 , 2001 .11714220 \n13. Eisenbarth GS \nType I diabetes mellitus. A chronic autoimmune disease . N Engl J Med \n314 : 1360 -1368 , 1986 .3517648 \n14. Atkinson MA , Maclaren NK \nThe pathogenesis of insulin-dependent diabetes mellitus . N Engl J Med \n331 : 1428 -1436 , 1994 .7969282 \n15. Atkinson MA , Eisenbarth GS \nType 1 diabetes: new perspectives on disease pathogenesis and treatment . Lancet \n358 : 221 -229 , 2001 .11476858 \n16. Daneman D \nType 1 diabetes . Lancet \n367 : 847 -858 , 2006 .16530579 \n17. Atkinson MA , Eisenbarth GS , Michels AW \nType 1 diabetes . Lancet \n383 : 69 -82 , 2014 .23890997 \n18. Abdul-Rasoul M , Habib H , Al-Khouly M \nThe honeymoon phase' in children with type 1 diabetes mellitus: frequency, duration, and influential factors . Pediatr Diabetes \n7 : 101 -107 , 2006 .16629716 \n19. Törn C , Landin-Olsson M , Lernmark A , et al \nPrognostic factors for the course of beta cell function in autoimmune diabetes . JCEM \n85 : 4619 -4623 , 2000 .11134117 \n20. Bonifacio E , Bingley PJ , Shattock M , et al \nQuantification of islet-cell antibodies and prediction of insulin-dependent diabetes . Lancet \n335 : 147 -149 , 1990 .1967440 \n21. Kawasaki E , Maruyama T , Imagawa A , et al \nDiagnostic criteria for acute-onset type 1 diabetes mellitus (2012): Report of the Committee of Japan Diabetes Society on the Research of Fulminant and Acute-onset Type 1 Diabetes Mellitus . J Diabetes Investig \n5 : 115 -118 , 2014 .\n22. Lombardo F , Valenzise M , Wasniewska M , et al \nTwo-year prospective evaluation of the factors affecting honeymoon frequency and duration in children with insulin dependent diabetes mellitus: the key-role of age at diagnosis . Diabetes Nutr Metab \n15 : 246 -251 , 2002 .12416662 \n23. Reynolds GP , Kirk SL \nMetabolic side effects of antipsychotic drug treatment--pharmacological mechanisms . Pharmacol Ther \n125 : 169 -179 , 2010 .19931306 \n24. Bonhaus DW , Weinhardt KK , Taylor M , et al \nRS-102221: a novelhighaffinity and selective, 5-HT2Creceptorantagonist . Neuropharmacology \n36 : 621 -629 , 1997 .9225287 \n25. Jin H , Meyer JM , Mudaliar S , Jeste DV \nImpact of atypical antipsychotic therapy on leptin, ghrelin, and adiponectin . Schizophr Res \n100 : 70 -85 , 2008 .18206351 \n26. Mizrahi R , Rusjan P , Agid O , et al \nAdversesubjectiveexperience with antipsychotics and its relationship to striatal and extrastriatalD2receptors: a PETstudy in schizophrenia . Am J Psychiatry \n164 : 630 -637 , 2007 .17403977 \n27. Ozasa R , Okada T , Nadanaka S , et al \nThe antipsychotic olanzapine induces apoptosis in insulin-secreting pancreatic β cells by blocking PERK-mediated translational attenuation . Cell Struct Funct \n38 : 183 -195 , 2013 .23812432 \n28. Engl J , Laimer M , Niederwanger A , et al \nOlanzapineimpairsglycogensynthesis and insulinsignaling in L6skeletalmusclecells . Mol Psychiatry \n10 : 1089 -1096 , 2005 .16130009\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "56(3)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D001786:Blood Glucose; D003922:Diabetes Mellitus, Type 1; D016883:Diabetic Ketoacidosis; D006801:Humans; D006943:Hyperglycemia; D007328:Insulin; D008297:Male; D000077152:Olanzapine; D011236:Prediabetic State; D012559:Schizophrenia",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "335-339",
"pmc": null,
"pmid": "28154279",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9225287;16629716;17403977;16130009;1967440;24581419;17604410;17474808;19931306;11476858;15000267;19026267;23278567;24843746;16172203;16943266;23812432;12126218;7969282;3517648;11134117;16530579;18206351;19058842;23890997;11714220;12416662;11925293",
"title": "Acute-Onset Type 1 Diabetes that Developed During the Administration of Olanzapine.",
"title_normalized": "acute onset type 1 diabetes that developed during the administration of olanzapine"
} | [
{
"companynumb": "JP-MACLEODS PHARMACEUTICALS US LTD-MAC2022034421",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugad... |
{
"abstract": "OBJECTIVE\nAdult-onset Still's disease (AOSD) is a systemic inflammatory disorder with clinical heterogeneity. Although tocilizumab (TCZ), an interleukin (IL)-6 receptor inhibitor, is an effective treatment for AOSD, the evidence regarding its efficacy on systemic or articular subtypes is conflicting. Furthermore, the predictors of therapeutic response are still elusive and worthy of exploration.\n\n\nMETHODS\nThis two-center retrospective study analyzed the effectiveness and safety profile of TCZ treatment in 28 patients with refractory AOSD. The 28-joint disease activity score (DAS28) and systemic activity score were assessed before and during TCZ treatment period at weeks 12, 24, 36, and 48. Plasma levels of proinflammatory cytokines at baseline were determined using ELISA method.\n\n\nRESULTS\nAmong the systemic subtype patients, 10 (58.8%), 13 (76.5%), 14 (82.4%), and 15 (88.2%) patients achieved complete remission at week 12, 24, 36, and 48, respectively, in comparison to 2 (22.2%), 5 (55.6%), 6 (66.7%), and 7 (77.8%) who achieved disease remission (DAS28 < 2.6) at weeks 12, 24, 36, and 48, respectively, among articular subtype patients. The systemic activity scores and inflammatory parameters were significantly decreased after 12-week TCZ therapy, and TCZ could significantly reduce corticosteroid dose in AOSD patients. Multivariate analysis reveals that baseline IL-18 level is a significant predictor of poor therapeutic response at week 24 (odds ratio 7.86, p < 0.05).\n\n\nCONCLUSIONS\nAOSD patients refractory to high-dose corticosteroids and methotrexate may respond well to TCZ treatment with a steroid-sparing effect and an acceptable safety. A high baseline IL-18 level may be a predictor of poor therapeutic response. Key Points • Tocilizumab may be effective and well-tolerated in refractory AOSD patients regardless of disease subtypes. • High plasma levels of IL-18 may predict poor response to tocilizumab in AOSD patients.",
"affiliations": "Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan.;Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan.;Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan.;Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan.;Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan.;Rheumatology and Immunology Center, China Medical University Hospital, No. 2, Yude Road, Taichung, 40447, Taiwan.;Rheumatology and Immunology Center, China Medical University Hospital, No. 2, Yude Road, Taichung, 40447, Taiwan.;Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan. dychen1957@gmail.com.",
"authors": "Tang|Kuo-Tung|KT|;Hsieh|Chia-Wei|CW|;Chen|Hsin-Hua|HH|;Chen|Yi-Ming|YM|;Chang|Shih-Hsin|SH|;Huang|Po-Hao|PH|;Lan|Joung-Liang|JL|;Chen|Der-Yuan|DY|http://orcid.org/0000-0003-1266-1423",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-021-05921-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": null,
"journal": "Clinical rheumatology",
"keywords": "Adult-onset Still’s disease; Effectiveness; Subtype; Therapy; Tocilizumab",
"medline_ta": "Clin Rheumatol",
"mesh_terms": null,
"nlm_unique_id": "8211469",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34535869",
"pubdate": "2021-09-17",
"publication_types": "D016428:Journal Article",
"references": "3325642;25613167;26672682;28540751;27886796;26970681;14677188;11465725;28507179;30218025;27263804;30069732;23108887;24515813;25401229;24697199;27462914;29044212;30827128;29251027;30279267;20506370;25183244;30755262;1578458;20810496;7818570;20215140;24005839;21841340;33332679;26666737;29416343;31379214;33652679;24134323;27778518;20737186;32130578;29657144",
"title": "The effectiveness of tocilizumab in treating refractory adult-onset Still's disease with dichotomous phenotypes: IL-18 is a potential predictor of therapeutic response.",
"title_normalized": "the effectiveness of tocilizumab in treating refractory adult onset still s disease with dichotomous phenotypes il 18 is a potential predictor of therapeutic response"
} | [
{
"companynumb": "TW-STRIDES ARCOLAB LIMITED-2022SP005793",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditiona... |
{
"abstract": "Nivolumab is a fully human immunoglobulin G4 immune checkpoint inhibitor antibody approved for use in the treatment of several malignancies. Severe side effects such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) have only extremely rarely been reported with this drug. We present herein a patient who developed SJS after 16 weeks of therapy with nivolumab. A week prior to this event, he developed a pruriginous papulo-erythematous rash. Prompt recognition of this phenomenon, immune checkpoint inhibitor discontinuation and steroid therapy are necessary steps in order to avoid dismal outcomes.",
"affiliations": "Lucy Curci Cancer Center, Eisenhower Medical Center, Rancho Mirage, CA, USA.",
"authors": "Dasanu|Constantin A|CA|https://orcid.org/0000-0003-0425-8394",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D007074:Immunoglobulin G; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.1177/1078155219830166",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(8)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": null,
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D006528:Carcinoma, Hepatocellular; D005076:Exanthema; D006801:Humans; D007074:Immunoglobulin G; D008113:Liver Neoplasms; D008297:Male; D000077594:Nivolumab; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "2052-2055",
"pmc": null,
"pmid": "30782092",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late-onset Stevens-Johnson syndrome due to nivolumab use for hepatocellular carcinoma.",
"title_normalized": "late onset stevens johnson syndrome due to nivolumab use for hepatocellular carcinoma"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-022521",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "The case of a 68 year old man in whom hydrochlorothiazide induced pulmonary oedema with hypovolaemic shock is presented. The condition was misdiagnosed as myocardial infarction until an early echocardiogram excluded a cardiac cause. The diagnosis was confirmed by an oral challenge.",
"affiliations": "Department of Internal medicine, County Central Hospital, Naestved, Denmark.",
"authors": "Høegholm|A|A|;Rasmussen|S W|SW|;Kristensen|K S|KS|",
"chemical_list": "D006852:Hydrochlorothiazide",
"country": "England",
"delete": false,
"doi": "10.1136/hrt.63.3.186",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0769",
"issue": "63(3)",
"journal": "British heart journal",
"keywords": null,
"medline_ta": "Br Heart J",
"mesh_terms": "D000368:Aged; D003937:Diagnosis, Differential; D004452:Echocardiography; D006801:Humans; D006852:Hydrochlorothiazide; D008297:Male; D009203:Myocardial Infarction; D011654:Pulmonary Edema; D012769:Shock",
"nlm_unique_id": "0370634",
"other_id": null,
"pages": "186",
"pmc": null,
"pmid": "2328172",
"pubdate": "1990-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "3786931;6937754;378156;3344418;20742268;4869646;6666261;525442;6837011;6617501;3789469",
"title": "Pulmonary oedema with shock induced by hydrochlorothiazide: a rare side effect mimicking myocardial infarction.",
"title_normalized": "pulmonary oedema with shock induced by hydrochlorothiazide a rare side effect mimicking myocardial infarction"
} | [
{
"companynumb": "DK-RANBAXY-2013R1-73632",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND\nLevetiracetam is increasingly used as antiepileptic drug (AED) of choice in children as well as in adults with complex diseases due to its lack of interactions and a large spectrum of action. Secondary graft failure, i.e. loss of donor cells after initial engraftment, is a relatively uncommon but serious and life-theatening complication after pediatric hematopoietic stem cell transplantation.\n\n\nRESULTS\nWe report a case of secondary graft failure after hematopoietic stem cell transplantation for treatment-related myelodysplastic syndrome during antiepileptic treatment with levetiracetam. Exclusion of all other possible etiologies left levetiracetam as the most likely cause of the imminent complete secondary graft failure after hematopoietic stem cell transplantation. Furthermore, the blood cell count improved just a few days after cessation of levetiracetam medication.\n\n\nCONCLUSIONS\nThus, we recommend that in case of secondary graft failure after hematopoietic stem cell transplantation, all possible causes should carefully be excluded, including adverse events through new generation AED agents. Switching to different AEDs with less harming effect on bone marrow function should strongly be considered.",
"affiliations": "Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany; Department of Pediatrics, Medical University of Vienna, Vienna, Austria. Electronic address: andreas.peyrl@meduniwien.ac.at.;Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany.;Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany.;Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany.;Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany.",
"authors": "Peyrl|Andreas|A|;Weichert|Nina|N|;Kühl|Jörn-Sven|JS|;Ebell|Wolfram|W|;Hernáiz Driever|Pablo|P|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010634:Phenobarbital; D010889:Piracetam",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1090-3798",
"issue": "19(1)",
"journal": "European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society",
"keywords": "Allogenic hematopoietic stem cell transplantation; Levetiracetam; Myelosuppression; Secondary graft failure",
"medline_ta": "Eur J Paediatr Neurol",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D001772:Blood Cell Count; D006084:Graft Rejection; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007958:Leukocyte Count; D000077287:Levetiracetam; D008297:Male; D009190:Myelodysplastic Syndromes; D010634:Phenobarbital; D010889:Piracetam; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; D012640:Seizures; D017211:Treatment Failure",
"nlm_unique_id": "9715169",
"other_id": null,
"pages": "75-7",
"pmc": null,
"pmid": "25468262",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Levetiracetam as a possible cause of secondary graft failure after allogenic hematopoietic stem cell transplantation.",
"title_normalized": "levetiracetam as a possible cause of secondary graft failure after allogenic hematopoietic stem cell transplantation"
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"abstract": "OBJECTIVE\nPneumatosis intestinalis (PI) is a condition in which multiple gas-filled mural cysts develop in the gastrointestinal tract. Although its exact etiology remains obscure, PI is rarely observed in liver transplant (LT) recipients.\n\n\nMETHODS\nIn 317 cases of adult living donor LT (LDLT) performed during 2011, PI developed in three patients during the 3 year follow-up.\n\n\nRESULTS\nOf these three patients, the two who demonstrated PI at 6 weeks and 2 months after LT, respectively, were asymptomatic and showed no signs of secondary complications. Diagnosis was made incidentally using abdominal radiographs and computed tomography (CT) scans. PI was identified in the right ascending colon with concomitant pneumoperitoneum. These two patients received supportive care and maintained a regular diet. Follow-up CT scans demonstrated spontaneous resolution of PI with no complications. The third patient was admitted to the emergency room 30 months after LDLT. His symptoms included poor oral intake and intermittent abdominal pain with no passage of gas. Abdominal radiography and CT scans demonstrated PI in the entire small bowel, with small bowel dilatation, pneumoperitoneum, and pneumoretroperitoneum, but no peritonitis. Physical examination revealed abdominal distension but no tenderness or rebound tenderness. After 1 week of conservative treatment, including bowel rest and antibiotics therapy, PI and pneumoperitoneum resolved spontaneously without complications.\n\n\nCONCLUSIONS\nWe suggest that adult LDLT recipients who develop asymptomatic or symptomatic PI with no signs of secondary complications can be successfully managed with conservative treatment.",
"affiliations": "Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea.;Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.",
"authors": "Park|Cheon-Soo|CS|;Hwang|Shin|S|;Jung|Dong-Hwan|DH|;Song|Gi-Won|GW|;Moon|Deok-Bog|DB|;Ahn|Chul-Soo|CS|;Park|Gil-Chun|GC|;Kim|Ki-Hun|KH|;Ha|Tae-Yong|TY|;Lee|Sung-Gyu|SG|",
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"doi": "10.14701/kjhbps.2015.19.1.25",
"fulltext": "\n==== Front\nKorean J Hepatobiliary Pancreat SurgKorean J Hepatobiliary Pancreat SurgKJHBPSKorean Journal of Hepato-Biliary-Pancreatic Surgery1738-63492288-9213Korean Association of Hepato-Biliary-Pancreatic Surgery 10.14701/kjhbps.2015.19.1.25Original ArticlePneumatosis intestinalis after adult living donor liver transplantation: report of three cases and collective literature review Park Cheon-Soo 1Hwang Shin 2Jung Dong-Hwan 2Song Gi-Won 2Moon Deok-Bog 2Ahn Chul-Soo 2Park Gil-Chun 2Kim Ki-Hun 2Ha Tae-Yong 2Lee Sung-Gyu 21 Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea.2 Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.\nCorresponding author: Shin Hwang. Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. Tel: +82-2-3010-3930, Fax: +82-2-3010-6701, shwang@amc.seoul.kr2 2015 28 2 2015 19 1 25 29 10 12 2014 22 1 2015 10 2 2015 Copyright © 2015 by The Korean Association of Hepato-Biliary-Pancreatic Surgery2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Backgrounds/Aims\nPneumatosis intestinalis (PI) is a condition in which multiple gas-filled mural cysts develop in the gastrointestinal tract. Although its exact etiology remains obscure, PI is rarely observed in liver transplant (LT) recipients.\n\nMethods\nIn 317 cases of adult living donor LT (LDLT) performed during 2011, PI developed in three patients during the 3 year follow-up.\n\nResults\nOf these three patients, the two who demonstrated PI at 6 weeks and 2 months after LT, respectively, were asymptomatic and showed no signs of secondary complications. Diagnosis was made incidentally using abdominal radiographs and computed tomography (CT) scans. PI was identified in the right ascending colon with concomitant pneumoperitoneum. These two patients received supportive care and maintained a regular diet. Follow-up CT scans demonstrated spontaneous resolution of PI with no complications. The third patient was admitted to the emergency room 30 months after LDLT. His symptoms included poor oral intake and intermittent abdominal pain with no passage of gas. Abdominal radiography and CT scans demonstrated PI in the entire small bowel, with small bowel dilatation, pneumoperitoneum, and pneumoretroperitoneum, but no peritonitis. Physical examination revealed abdominal distension but no tenderness or rebound tenderness. After 1 week of conservative treatment, including bowel rest and antibiotics therapy, PI and pneumoperitoneum resolved spontaneously without complications.\n\nConclusions\nWe suggest that adult LDLT recipients who develop asymptomatic or symptomatic PI with no signs of secondary complications can be successfully managed with conservative treatment.\n\nPneumatosis intestinalisLiving donor liver transplantationPneumoperitoneum\n==== Body\nINTRODUCTION\nPneumatosis intestinalis (PI) is a condition in which multiple gas-filled mural cysts develop in the gastrointestinal tract,1 and is characterized by accumulation of gas in the submucosa or subserosa of the colon or small bowel. In a retrospective review published by Koss in 1952,2 15% of cases were classified as primary or idiopathic PI, 75% were considered secondary PI, and 10% had an unknown underlying disease. The majority of secondary PI cases are related to gastrointestinal disorders.3 Although PI has been observed occasionally in recipients of liver transplantation (LT), the exact etiology remains obscure.456 PI is diagnosed via computed tomography (CT) scan and simple abdomen radiographs and is managed surgically in most cases, despite high rates of mortality associated with surgery (33-44%).7\n\nBecause the clinical presentation of PI after LT ranges widely from asymptomatic to fatal, we present our PI cases that occurred after LT with collective literature review.\n\nMATERIALS AND METHODS\nDuring one year of 2011, we performed 403 LT operations, of which 317 were adult living donor LT (LDLT). PI developed in three patients (0.94%) who underwent LDLT and was successfully treated with conservative treatment. The clinical courses of these PI patients were retrospectively analyzed through the review of medical records. This study was approved by the Institutional Review Board of Asan Medical Center.\n\nRESULT\nCase 1 presentation\nA 48-year-old woman with underlying diabetes mellitus and chronic renal failure had undergone dual-graft LDLT using two left lobes due to hepatitis B virus (HBV)- associated liver cirrhosis (LC). Biliary reconstruction was performed using duct-to-duct anastomosis in the right graft and hepaticojejunostomy in the left graft (Table 1). Six weeks after LDLT, PI was diagnosed incidentally on abdomen radiographs and CT scans, which demonstrated PI in the right ascending colon with small pneumoperitoneum (Fig. 1). The patient showed no symptoms associated with PI and no sign of secondary complications such as peritonitis, bowel ischemia, or perforation. She was maintained on a regular diet and was not administered antibiotics. Routine immunosuppressive agents, except for steroids, were continued. After 4 weeks, a follow-up CT scan demonstrated spontaneous resolution of PI with no complications.\n\nCase 2 presentation\nA 53-year-old man with no underlying diseases underwent LDLT using a modified right lobe due to HBV-associated LC and hepatocellular carcinoma (HCC). The biliary reconstruction method was duct-to-duct anastomosis (Table 1). After 2 months, diagnosis of PI was made incidentally on a routine CT scan, which demonstrated PI in the right ascending colon with small pneumoperitoneum (Fig. 2). The patient had no symptoms associated with PI and no sign of secondary complications, and was well maintained on a regular diet without specific antibiotic therapy. Routine immunosuppressive agents, except for steroids, were maintained. A follow-up CT scan after 3 weeks revealed spontaneous resolution of PI with no complications.\n\nCase 3 presentation\nA 66-year-old man with previous diagnosis of diabetes mellitus was admitted to the emergency room 30 months after LDLT due to HBV-associated LC and HCC. He had undergone a LDLT operation using a modified right lobe with a biliary reconstruction of Roux-en-Y hepaticojejunostomy (Table 1). The patient had undergone explorative abdominal surgery for small bowel internal herniation 6 months before LT. At admission, he complained of poor oral intake and intermittent abdominal pain with no passage of gas. Abdomen radiographs and a CT scan demonstrated PI in the entire small bowel and right ascending and transverse colon, along with small bowel dilation, pneumoperitoneum, and pneumoretroperitoneum. The patient's vital signs were stable, and laboratory findings indicated mild leukocytosis (10,200/mm3) and slightly elevated C-reactive protein (4.51 mg/dl), but no evidence of lactic acidosis or peritonitis. Physical examination revealed abdominal distension but no tenderness or rebound tenderness. After 1 week of conservative treatment that included bowel resting, antibiotics therapy, and withdrawal of immunosuppressive agents, PI and pneumoperitoneum spontaneously resolved without any complications. No other abnormalities occurred for 1 year following initial presentation.\n\nDISCUSSION\nPI has been reported rarely in patients who have undergone LT.4568 It is characterized by the following symptoms in decreasing order of frequency: diarrhea, abdominal pain, abdominal distension, bloody stool, constipation, weight loss, and tenesmus.9 Several investigators have suggested that PI after solid organ transplantation is likely benign and precipitated by pre-transplantation chemotherapy and radiotherapy, immunosuppressive therapy (most notably steroid-based treatments), opportunistic enteric infections (particularly cytomegalovirus), and sympathetic reaction to inflamed allograft.4689 Additionally, glucocorticoid therapy alone may significantly increase the risk of PI development because glucocorticoids may induce atrophy of gastrointestinal tract lymphoid aggregates,10 which results in mucosal defects that allow dissection of intraluminal air/gas into the submucosal or subserosal regions.11\n\nPI is diagnosed via CT scan and simple abdomen radiography and is typically managed surgically, despite a high mortality rate (33-44%) associated with PI-related surgery.7 CT scan is a more sensitive and specific test than simple abdomen radiography or ultrasonography.12 Spontaneous pneumoperitoneum, which is frequently observed in PI, is presumably due to the rupture of subserosal cysts and usually does not worsen or turn into peritonitis.4\n\nThe literature review regarding PI after LT is summarized in Table 2 and includes 31 PI cases.568131415 Most patients recovered with supportive care, although one study of 22 cases reported four mortalities. These mortality cases showed fever, hypotension, and CT scan findings of infarcts at the spleen and liver, small bowel ileus, and hemorrhagic ascites.8\n\nIn our study, the incidence of PI after adult LDLT was approximately 1%, and all three cases showed involvement of the right ascending colon. One patient had symptoms of abdominal pain and poor oral intake, whereas the other patients were asymptomatic. The former had received only low-dose cyclosporine as immunosuppressive therapy, while the others had received tacrolimus and steroids with or without mycophenolate mofetil.\n\nThe tendency of indolent PI to affect the right ascending colon has been demonstrated in previous studies of patients who received bone marrow transplantation.16 Preservation of structural integrity in the right ascending colon may depend on immunocompetent lymphoid tissue, which may be impaired by immunosuppression and steroid therapy. This impairment may be a precondition to the development of PI in LT patients and may explain why all of our patients experienced PI in the right ascending colon.817\n\nAlthough our study is limited by the small sample size, the findings suggest that if patients develop PI after LDLT but exhibit no secondary complications, they can be successfully managed with conservative treatment that includes bowel rest, antibiotic therapy, and withdrawal of immunosuppressive agents.\n\nFig. 1 Imaging of the case 1 and 2: Computed tomography (CT) scans of case 1 patient revealed pneumatosis intestinalis (PI) (white arrows) involving the right ascending colon on an axial image (A) and a coronal image (B). CT scans of case 2 patient revealed PI (white arrows) involving the right ascending colon (C), which was spontaneously resolved after 3 weeks (D).\nFig. 2 Imaging of the case 3: Computed tomography (CT) scan demonstrated pneumatosis intestinalis (white arrows) involving the entire bowel with pneumoperitoneum (white arrowheads) and pneumoretroperitoneum (white arrowheads) (A-C). After 1 week of treatment, gas was almost completely resolved (D).\nTable 1 Clinical features and treatment for liver transplant recipients showing pneumatosis intestinalis (PI)\nCT, computed tomography; D-D, duct-to-duct anastomosis; GRWR, graft-recipient weight ratio; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; H-J, hepaticojejunostomy; LC, liver cirrhosis; LL, left liver graft; LT, liver transplantation; MELD, model for end-stage liver disease; RL, right liver graft\n\nTable 2 Collective review of liver transplant recipients showing pneumatosis intestinalis\nCMV, cytomegalovirus\n==== Refs\n1 Ecker JA Williams RG Clay KL Pneumatosis cystoides intestinalis--bullous emphysema of the intestine. A review of the literature Am J Gastroenterol 1971 56 125 136 4938483 \n2 Koss LG Abdominal gas cysts (pneumatosis cystoides intestinorum hominis); an analysis with a report of a case and a critical review of the literature AMA Arch Pathol 1952 53 523 549 14923068 \n3 Galm O Fabry U Adam G Osieka R Pneumatosis intestinalis following cytotoxic or immunosuppressive treatment Digestion 2001 64 128 132 11684828 \n4 Andorsky RI Pneumatosis cystoides intestinalis after organ transplantation Am J Gastroenterol 1990 85 189 194 2405645 \n5 Sachse RE Burke GW 3rd Jonas M Milgrom M Miller J Benign pneumatosis intestinalis with subcutaneous emphysema in a liver transplant recipient Am J Gastroenterol 1990 85 876 879 2371990 \n6 Janssen DA Kalayoglu M Sollinger HW Pneumatosis cystoides intestinalis following lactulose and steroid treatment in a liver transplant patient with an intermittently enlarged scrotum Transplant Proc 1987 19 2949 2952 3551239 \n7 Wiesner W Mortelé KJ Glickman JN Ji H Ros PR Pneumatosis intestinalis and portomesenteric venous gas in intestinal ischemia: correlation of CT findings with severity of ischemia and clinical outcome AJR Am J Roentgenol 2001 177 1319 1323 11717075 \n8 Kwon HJ Kim KW Song GW Kim DY Chung SY Hwang S Pneumatosis intestinalis after liver transplantation Eur J Radiol 2011 80 629 636 20807675 \n9 Jamart J Pneumatosis cystoides intestinalis. A statistical study of 919 cases Acta Hepatogastroenterol (Stuttg) 1979 26 419 422 525221 \n10 Hepgur M Ahluwalia MS Anne N Thomas J Liu H Schiff MD Medical management of pneumatosis intestinalis in patients undergoing allogeneic blood and marrow transplantation Bone Marrow Transplant 2011 46 876 879 20871638 \n11 Jones B Fishman EK Kramer SS Siegelman SS Saral R Beschorner WE Computed tomography of gastrointestinal inflammation after bone marrow transplantation AJR Am J Roentgenol 1986 146 691 695 3513488 \n12 Knechtle SJ Davidoff AM Rice RP Pneumatosis intestinalis. Surgical management and clinical outcome Ann Surg 1990 212 160 165 2375647 \n13 Koep LJ Peters TG Starzl TE Major colonic complications of hepatic transplantation Dis Colon Rectum 1979 22 218 220 380946 \n14 King S Shuckett B Sonographic diagnosis of portal venous gas in two pediatric liver transplant patients with benign pneumatosis intestinalis. Case reports and literature review Pediatr Radiol 1992 22 577 578 1491932 \n15 Kim JM Park Y Joh JW Kwon CH Kim SJ Hong SH Pneumatosis intestinalis after adult liver transplantation J Korean Surg Soc 2011 80 Suppl 1 S47 S50 22066083 \n16 Day DL Ramsay NK Letourneau JG Pneumatosis intestinalis after bone marrow transplantation AJR Am J Roentgenol 1988 151 85 87 3287869 \n17 Wood BJ Kumar PN Cooper C Silverman PM Zeman RK Pneumatosis intestinalis in adults with AIDS: clinical significance and imaging findings AJR Am J Roentgenol 1995 165 1387 1390 7484571\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-6349",
"issue": "19(1)",
"journal": "Korean journal of hepato-biliary-pancreatic surgery",
"keywords": "Living donor liver transplantation; Pneumatosis intestinalis; Pneumoperitoneum",
"medline_ta": "Korean J Hepatobiliary Pancreat Surg",
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"other_id": null,
"pages": "25-9",
"pmc": null,
"pmid": "26155273",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article",
"references": "3513488;2405645;380946;20871638;3287869;3551239;20807675;4938483;2371990;1491932;525221;22066083;11684828;14923068;11717075;2375647;7484571",
"title": "Pneumatosis intestinalis after adult living donor liver transplantation: report of three cases and collective literature review.",
"title_normalized": "pneumatosis intestinalis after adult living donor liver transplantation report of three cases and collective literature review"
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"abstract": "Diabetes and cancer are both multifactorial diseases, and epidemiologic evidence indicates that diabetes may be associated with the incidence of certain types of cancer. In diabetes the risk of pancreatic cancer is increased significantly. However, whether certain diabetes treatment being related with the risk of pancreatic cancer remains unclear. In this report, we presented a case of pancreatic ductal adenocarcinoma in a diabetic patient in China after being treated with liraglutide, a novel glucagon-like peptide-1 (GLP-1) analog.\n\n\n\nA 71-year-old Han Chinese man who had had a type 2 diabetes for 25 years presented at the endocrinology department with discomfort in the left upper quadrant of abdomen for 10 days. The patient's vital signs and laboratory findings were unremarkable except for the elevated level of carbohydrate antigen (CA19-9). The upper abdomen routine enhanced computed tomography (CT) scan showed low density of the pancreatic body and tail, and the histopathological result of the pancreatic biopsy samples was pancreatic ductal adenocarcinoma with regional lymph node metastasis. We reviewed his former medical records and found that liraglutide was added to his hypoglycemic treatment regimen 20 months ago. At that time, the level of tumor biomarkers and upper abdomen routine CT were unremarkable. We estimated the causality between liraglutide and pancreatic cancer by the Naranjo Adverse Drug Reaction Probability scale and WHO-Uppsala Monitoring Centre (WHO-UMC) system, and the causality turned out to be possible.\n\n\n\nOur report suggests that liraglutide may be related with the genesis and development of pancreatic cancer and also highlights the importance of regular checkups in diabetic patients treated with liraglutide. However, our report has some notable limitations, and further longer-term follow-up trials with larger sample should be conducted in future to assess the causality between liraglutide and pancreatic cancer.",
"affiliations": "Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Department of Pharmacy, Taizhou Municipal Hospital, Taizhou, China.;Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.;Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.",
"authors": "Wu|Shengjie|S|;Wang|Jiabing|J|;Jing|Li|L|;Chen|Liping|L|",
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"doi": "10.3389/fendo.2020.608966",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)\nFront Endocrinol (Lausanne)\nFront. Endocrinol.\nFrontiers in Endocrinology\n1664-2392 Frontiers Media S.A. \n\n10.3389/fendo.2020.608966\nEndocrinology\nCase Report\nA Diabetic Patient Complicated With Pancreatic Cancer After Using Liraglutide: A Case Report\nWu Shengjie \n1\n\n†\n Wang Jiabing \n2\n\n†\n Jing Li \n3\n\n*\n Chen Liping \n1\n\n*\n \n1\nDepartment of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China\n\n\n2\nDepartment of Pharmacy, Taizhou Municipal Hospital, Taizhou, China\n\n\n3\nDepartment of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, China\n\nEdited by: Rosamaria Lappano, University of Calabria, Italy\n\nReviewed by: Constantin Tamvakopoulos, Biomedical Research Foundation of the Academy of Athens (BRFAA), Greece; Rosario Le Moli, University of Catania, Italy\n\n*Correspondence: Li Jing, lilyj1008@163.com; Liping Chen, chenliping1993@zju.edu.cn\nThis article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology\n\n†These authors have contributed equally to this work\n\n\n28 1 2021 \n2020 \n11 60896622 9 2020 11 12 2020 Copyright © 2021 Wu, Wang, Jing and Chen2021Wu, Wang, Jing and ChenThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background\nDiabetes and cancer are both multifactorial diseases, and epidemiologic evidence indicates that diabetes may be associated with the incidence of certain types of cancer. In diabetes the risk of pancreatic cancer is increased significantly. However, whether certain diabetes treatment being related with the risk of pancreatic cancer remains unclear. In this report, we presented a case of pancreatic ductal adenocarcinoma in a diabetic patient in China after being treated with liraglutide, a novel glucagon-like peptide-1 (GLP-1) analog.\n\nCase report\nA 71-year-old Han Chinese man who had had a type 2 diabetes for 25 years presented at the endocrinology department with discomfort in the left upper quadrant of abdomen for 10 days. The patient’s vital signs and laboratory findings were unremarkable except for the elevated level of carbohydrate antigen (CA19-9). The upper abdomen routine enhanced computed tomography (CT) scan showed low density of the pancreatic body and tail, and the histopathological result of the pancreatic biopsy samples was pancreatic ductal adenocarcinoma with regional lymph node metastasis. We reviewed his former medical records and found that liraglutide was added to his hypoglycemic treatment regimen 20 months ago. At that time, the level of tumor biomarkers and upper abdomen routine CT were unremarkable. We estimated the causality between liraglutide and pancreatic cancer by the Naranjo Adverse Drug Reaction Probability scale and WHO-Uppsala Monitoring Centre (WHO-UMC) system, and the causality turned out to be possible.\n\nConclusion\nOur report suggests that liraglutide may be related with the genesis and development of pancreatic cancer and also highlights the importance of regular checkups in diabetic patients treated with liraglutide. However, our report has some notable limitations, and further longer-term follow-up trials with larger sample should be conducted in future to assess the causality between liraglutide and pancreatic cancer.\n\nglucagon-like peptide-1 (GLP-1)glucose-dependent insulinotrophic polypeptide (GIP)liraglutidepancreatic cancerdiabetes mellitus\n==== Body\nIntroduction\nIn type 2 diabetes mellitus, the progressive β-cell failure is partly due to the abnormalities in the incretin axis. Deficiency of GLP-1 and resistance to the action of glucose-dependent insulinotrophic polypeptide (GIP) are the main characteristics of the abnormal incretin effect in type 2 diabetes mellitus (1), for GLP-1 and GIP accounting for ~90% of incretin effect (2, 3). GLP-1 deficiency occurs in the natural history of type 2 diabetes, it is rational to restore the falling insulin response with GLP-1 replacement therapy. Since liraglutide (Victoza), a novel GLP-1 analog approved by FDA in 2010, it has been vastly used in the treatment of type 2 diabetes due to its effective impact on glycemic control, weight loss, and fewer major adverse cardiovascular events (MACEs) occurrence (4). The most frequently reported adverse drug reactions of liraglutide are gastrointestinal ones, such as nausea, diarrhea, and vomiting. However, further studies triggered some concerns that long-term usage of GLP-1 analogs have been shown to result in a massive expansion of exocrine and endocrine pancreatic cells with a potential association with pancreatic cancers (5), and liraglutide is one of the widely used GLP-1 analogs. Clinical data and animal studies published so far remains controversial, and the correlation between liraglutide and pancreatic cancer is not clear yet (6).\n\nCase Presentation\nWe report on a case of pancreatic cancer in association with liraglutide in China. A 71-year-old Han Chinese man who had had a type 2 diabetes for 25 years presented at the endocrinology department with discomfort in the left upper quadrant of abdomen for 10 days. His medical history was significant as it indicated he suffered from coronary atherosclerotic heart disease (CHD), lacunar infarction (LI), and hypertension. His family history was not notable for the presence of diabetes mellitus or hypertension. His psychosocial history was unremarkable either. The patient was an ex-smoker of 10 years ago with a 10-pack year history but never a drinker. Medication included metformin, liraglutide, mixed protamine zinc recombinant human insulin lispro (50R), clopidogrel, and atorvastatin. At the time of admission, the patient’s body mass index (BMI) value was 24.9 kg/m2, and his vital signs were unremarkable. Physical examination revealed left upper quadrant tenderness. A blood routine test was within the normal limits. Other laboratory findings showed a blood glucose level of 17.27 mmol/L (3.90–6.10 mmol/L), and a hemoglobin A1c (HbA1C) level of 10.8% (4.0–6.0%). The patient’s CA19-9 was >1,000.00 U/ml (<27.00 U/ml), whereas amylase level in blood and urine were unremarkable (\nTable 1\n). Upper abdomen routine enhanced CT scan showed low density of the pancreatic body and tail and partly coarse wall of splenic artery (\nFigure 1\n). Regarding that GLP-1 analogs may be involved in the development and progression of pancreatitis or pancreatic cancer, the patient’s antidiabetic regimen was switched from liraglutide to dapagliflozin (10 mg qd po) for his poor glycemic control. After discussing treatment options with the general surgery team, the patient was recommended a CT-guided percutaneous needle biopsy or endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) of pancreas. On the fourth day of hospitalization, the histopathological result of the pancreatic biopsy samples was pancreatic ductal adenocarcinoma with regional lymph node metastasis (\nFigure 2\n). He asked for discharge on the fifth day, and unfortunately he has since been lost to follow-up.\n\nTable 1 Tumor biomarker values in the case.\n\nTumor biomarkers\tBefore using liraglutide\tAfter using liraglutide\tRange of normal values\t\nAFP (alpha fetoprotein)\t1.63 ng/ml\t1.8 ng/ml\t0.89–8.78 ng/ml\t\nCEA (carcinoembryonic antigen)\t3.95 ng/ml\t9.38 ng/ml\t<5.00 ng/ml\t\nCA19-9 (carbohydrate antigen)\t23 U/ml\t>1,000 U/ml\t<27.00 U/ml\t\nFigure 1 Upper abdomen routine enhanced CT scan of the diabetic patient.\n\nFigure 2 H-E staining of the pancreatic biopsy samples.\n\nTo investigate the relation between liraglutide and pancreatic cancer, we reviewed the patient’s former medical records in our hospital and found that after early treatment with metformin and mixed protamine zinc recombinant human insulin lispro for more than 5 years, liraglutide (1.2 mg ih qn) was also added to the regimen 20 months ago for his unsatisfactory blood glucose control. He complied with the regimen ever since. We also noticed that before adding liraglutide to antidiabetic regimen, pancreas-related screening was performed in this patient. The level of tumor biomarkers was within the normal limits and the upper abdomen routine CT scan was also unremarkable. We then used the Naranjo Adverse Drug Reaction Probability scale to assess the causality (7), and the score was added up to 3 (\nTable 2\n) indicating that causality between liraglutide and pancreatic cancer was possible. The causality was reassessed by the WHO-UMC system (8), and still categorized as possible. Therefore, the conclusion could be only drawn that the patient’s pancreatic cancer may be induced by liraglutide.\n\nTable 2 ADR probability scale of liraglutide in the case.\n\n\tYes\tNo\tDo not known\tScore\t\n1. Are there previous conclusive reports on this reaction?\t+1\t0\t0\t1\t\n2. Did the adverse event appear after the suspected drug was administered?\t+2\t−1\t0\t2\t\n3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?\t+1\t0\t0\t0\t\n4. Did the adverse reaction reappear when the drug was readministered?\t+2\t−1\t0\t0\t\n5. Are there alternative causes (other than the drug) that could on their own have caused the reaction?\t−1\t+2\t0\t−1\t\n6. Did the reaction reappear when a placebo was given?\t−1\t+1\t0\t0\t\n7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?\t+1\t0\t0\t0\t\n8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?\t+1\t0\t0\t0\t\n9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?\t+1\t0\t0\t0\t\n10. Was the adverse event confirmed by any objective evidence?\t+1\t0\t0\t1\t\n\t\t\tTotal Score\t3\t\nDiscussion and Conclusion\nDiabetes and cancer are both multifactorial diseases, and epidemiologic evidence suggests that diabetes is associated with the incidence of certain types of cancer (9). These types of cancer may be induced by the potential effects of hyperglycemia, hyperinsulinemia, and increases in the growth factors or just share certain identical risk factors with diabetes. Ning et al. investigated the risk of 23 common types of cancer among 410,191 patients with type 2 diabetes using the Shanghai Hospital Link database, and the risk of pancreatic cancer was increased significantly (10). Studies also found that certain antidiabetic drugs may be associated with pancreatic cancer. Nowadays, safety concerns of GLP-1 analog therapies being related with pancreatic cancer have been raised. However, evidence from LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) cohort indicated that liraglutide was not associated with malignant pancreatic neoplasms. It is worth noting that LEADER was not primarily designed to assess neoplasm risk and firm conclusions cannot be made regarding the numeric imbalances observed for the infrequently occurred pancreatic cancer in individuals (11). To date, evidence from fundamental researches, randomized controlled trials, and real-world studies do not support or refute the association of liraglutide and the increased risk of pancreatic cancer, which still needs to be further studied.\n\nEarly in 2017, Talmon et al. reported on a case of GLP-1 analogs induced pancreatic adenocarcinoma in a diabetic patient (12). Whereas in Talmon’s report, the patient was switched from liraglutide to exenatide, and then to glimepiride and insulin before the diagnosis of invasive pancreatic adenocarcinoma was confirmed, which makes the causality assessment complex. Although our case is not the first reported case of pancreatic cancer associated with GLP-1 analogs, it is still necessary to report on this case for not only narrowing down to the liraglutide to blame but highlighting the importance of regular checkups in type 2 diabetic patients treated with liraglutide. Owing to the increased risk of pancreatic cancer in type 2 diabetes mellitus, it will be necessary to fully evaluate the patient’s pancreas condition before started on liraglutide, and to those who have multiple risk factors treated with liraglutide, the regular screening for pancreatic cancer may be particularly important. In practice, asymptomatic, high-risk individuals may derive benefits from surveillance, for pancreatic cancer-specific symptoms occur only at an advanced stage (13). Two former studies used symptoms and CA 19-9 elevation to screen pancreatic cancer in diabetes. Although the prevalence of pancreatic cancer in the screened population was high, most cancers identified were unresectable (14, 15). In our case report, symptoms, tumor biomarkers CA19-9 detection, and upper abdomen routine CT scan provided some clues to the diagnosis of pancreatic cancer, and the EUS-FNA and histopathological testing ultimately confirmed the diagnosis. However, currently we still do not have an optimal screening approach, which may include a unique clinical phenotype, one or more reliable marker(s) of early pancreatic cancer in asymptomatic diabetes and non-invasive imaging with high sensitivity and specificity.\n\nHonestly, the limitations in our report are quite obvious. Smoking habit, alcohol consumption, unsatisfactory blood glucose control, obesity, and chronic pancreatitis are all well-known risk factors in pancreatic cancer (16). In our report, risk factors in the patient include smoking habit, high HbA1C level, overweight, and other medication usage (17). With all these risk factors, the causality between liraglutide and pancreatic cancer can only be categorized as possible. Meanwhile, the development of pancreatic cancer is a multistage process which takes 10 to 15 years (18), 20 months of liraglutide usage in our report seems to be a short time for tumorigenesis. However, Funch et al. found that median days from the initiation of liraglutide to the pancreatic cancer diagnosis were 369 (interquartile range, 226–1,099) (19), and Knapen et al. found that the risk of pancreatic cancer almost doubled in those who had recently initiated GLP-1 analogs therapy (20), which makes the time interval of 20 months plausible. Owing to the relatively low prevalence of pancreatic cancer, this is our first case of pancreatic cancer diagnosed in a diabetic patient treated with liraglutide since 2011 (liraglutide being approved by the National Medical Products Administration of China). This sole case may have some potential bias, and the question whether the liraglutide worked as an independent risk factor in the genesis and development of pancreatic cancer or worked as a triggering factor cannot be answered so far. Therefore, further researches with larger sample on a global scale using the optimal screening approach should be conducted in future to assess whether liraglutide or other GLP-1 analogs are associated with pancreatic cancer or just our “notoriety bias”.\n\nData Availability Statement\nThe original contributions presented in the study are included in the article/supplementary materials. Further inquiries can be directed to the corresponding authors.\n\nEthics Statement\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifying images or data included in this article.\n\nAuthor Contributions\nSW and JW participated in the acquisition and analysis of data, as well as writing the manuscript. LC participated in the conceptualization and editing of the manuscript. LJ reviewed the manuscript. All authors contributed to the article and approved the submitted version.\n\nFunding\nThis work was supported by the Zhejiang Province Youth Talent Project, part of the Medical and Health Department (2019RC190).\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1 \nDeFronzo RA \nFrom the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus\n. Diabetes (2009 ) 58 :773–95. 10.2337/db09-9028 \n\n2 \nDrucker DJ Nauck MA \nThe incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes\n. Lancet (2006 ) 368 :1696–705. 10.1016/S0140-6736(06)69705-5 \n\n3 \nMeier JJ Nauck MA \nIncretins and the development of type 2 diabetes\n. Curr Diab Rep (2006 ) 6 :194 –201\n. 10.1007/s11892-006-0034-7 \n16898571 \n4 \nMarso SP Daniels GH Brown-Frandsen K Kristensen P Mann JFE Nauck MA \nLiraglutide and cardiovascular outcomes in type 2 diabetes\n. N Engl J Med (2016 ) 375 :311–22. 10.1056/NEJMoa1603827 \n\n5 \nButler AE Campbell-Thompson M Gurlo T Dawson DW Atkinson M Butler PC \nMarked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors\n. Diabetes (2013 ) 62 :2595–604. 10.2337/db12-1686 \n\n6 \nZhao HJ Wei R Wang L Tian Q Tao M Ke J \nActivation of glucagon-like peptide-1 receptor inhibits growth and promotes apoptosis of human pancreatic cancer cells in a cAMP-dependent manner\n. Am J Physiol Endocrinol Metab (2014 ) 306 :E1431–41. 10.1152/ajpendo.00017.2014 \n\n7 \nNaranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA \nA method for estimating the probability of adverse drug reactions\n. Clin Pharmacol Ther (1981 ) 30 :239–45. 10.1038/clpt.1981.154 \n\n8 \nBehera SK Das S Xavier AS Velupula S Sandhiya S \nComparison of different methods for causality assessment of adverse drug reactions\n. Int J Clin Pharm (2018 ) 40 :903–10. 10.1007/s11096-018-0694-9 \n\n9 \nWang TG Ning G Bloomgarden Z \nDiabetes and cancer relationships\n. J Diabetes (2013 ) 5 :378–90. 10.1111/1753-0407.12057 \n\n10 \nQi JY He P Yao HY Song RG Ma CL Cao M \nCancer risk patients with type 2 diabetes: A real-world study in Shanghai, China\n. J Diabetes (2019 ) 11 :878–83. 10.1111/1753-0407.12926 \n\n11 \nNauck MA Jensen TJ Rosenkilde C Calanna S Buse JB \nNeoplasms reported with liraglutide or placebo in people with type 2 diabetes: results from the LEADER randomized trial\n. Diabetes Care (2018 ) 41 :1663–71. 10.2337/dc17-1825 \n\n12 \nTalmon GA Wren JD Nguyen CL Pour PM \nPancreatic polypeptide cell proliferation in the pancreas and duodenum coexisting in a patient with pancreatic adenocarcinoma treated with a GLP-1 analog\n. Pancreas (2017 ) 46 :820–1. 10.1097/MPA.0000000000000844 \n\n13 \nLucas AL Kastrinos F \nScreening for Pancreatic Cancer\n. JAMA (2019 ) 322 :407–8. 10.1001/jama.2019.9690 \n\n14 \nOgawa Y Tanaka M Inoue K Yamaguchi K Chijiiwa K Mizumoto K \nA prospective pancreatographic study of the prevalence of pancreatic carcinoma in patients with diabetes mellitus\n. Cancer (2002 ) 94 :2344–9. 10.1002/cncr.10493 \n\n15 \nDamiano J Bordier L Le Berre JP Margery J Dupuy O Mayaudon H \nShould pancreas imaging be recommanded in patients over 50 years when diabetes is discovered because of acute symptoms\n? Diabetes Metab (2004 ) 30 :203–7. 10.1016/S1262-3636(07)70111-8 \n\n16 \nKrzysztof L Michał K Dawid S Sikorska P Kozłowska M Okopień B \nIncretin-based therapies in the treatment of type 2 diabetes–more than meets the eye\n? Eur J Intern Med (2013 ) 24 :207–12. 10.1016/j.ejim.2013.01.009 \n\n17 \nLu YX Rodríguez L Malgerud L González-Pérez A Martín-Pérez M Lagergren J \nNew-onset type 2 diabetes, elevated HbA1c, anti-diabetic medications, and risk of pancreatic cancer\n. Br J Cancer (2015 ) 113 :1607–14. 10.1038/bjc.2015.353 \n\n18 \nYachida S Jones S Bozic I Antal-Pérez T Leary R Fu BJ \nDistant metastasis occurs late during the genetic evolution of pancreatic cancer\n. Nature (2010 ) 4677319 :1114–7. 10.1038/nature09515 \n\n19 \nFunch D Mortimer K Ziyadeh NJ Seeger JD Li L Norman H \nLiraglutide use and evaluation of pancreatic outcomes in a US commercially insured population\n. Diabetes Obes Metab (2019 ) 21 :1837–48. 10.1111/dom.13739 \n\n20 \nKnapen LM Dalem J Keulemans YC Erp NP Bazelier MT Bruin MLD \nUse of incretin agents and risk of pancreatic cancer: a population-based cohort study\n. Diabetes Obes Metab (2016 ) 18 :258–65. 10.1111/dom.12605\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2392",
"issue": "11()",
"journal": "Frontiers in endocrinology",
"keywords": "diabetes mellitus; glucagon-like peptide-1 (GLP-1); glucose-dependent insulinotrophic polypeptide (GIP); liraglutide; pancreatic cancer",
"medline_ta": "Front Endocrinol (Lausanne)",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D021441:Carcinoma, Pancreatic Ductal; D003924:Diabetes Mellitus, Type 2; D006801:Humans; D007004:Hypoglycemic Agents; D000069450:Liraglutide; D008207:Lymphatic Metastasis; D008297:Male; D010179:Pancreas; D010190:Pancreatic Neoplasms; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101555782",
"other_id": null,
"pages": "608966",
"pmc": null,
"pmid": "33584541",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": "23524641;15223996;23574745;24801389;31070008;17098089;19336687;27295427;31386115;20981102;7249508;26537555;30945402;26575601;23375875;12015758;29898902;28609372;30051231;16898571",
"title": "A Diabetic Patient Complicated With Pancreatic Cancer After Using Liraglutide: A Case Report.",
"title_normalized": "a diabetic patient complicated with pancreatic cancer after using liraglutide a case report"
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"companynumb": "CN-NOVOPROD-795767",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
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"activesubstance": {
"activesubstancename": "INSULIN LISPRO"
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