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{
"abstract": "Pseudoaneurysms are vessel wall ruptures, that are often mistaken for deep vein thrombosis (DVT). A middle-aged man presented with right leg pain, swelling and erythema. His history was significant for persistent Staphylococcus aureus bacteraemia. Ultrasound revealed subacute DVT and laboratory parameters were suggestive of sepsis. He was started on intravenous heparin and antimicrobials. Owing to persistent anaemia despite blood transfusion, MRI of the right thigh was obtained. It revealed a 13×17 cm superficial femoral artery infected mycotic pseudoaneurysm (MPA) with a fresh haematoma. The patient underwent arterial ligation and extensive debridement. Intraoperative cultures revealed daptomycin-resistant vancomycin-intermediate S. aureus (VISA) and he was managed with 6 weeks of intravenous ceftaroline. MPAs are most common in the femoral artery and form <1% of aneurysms. Therapy involves surgical debridement and prolonged antimicrobials. VISA causing MPA is associated with worse outcomes. We report the first time use of ceftaroline in the management of a VISA MPA.",
"affiliations": "Department of Internal Medicine, Creighton University School of Medicine, Omaha, Nebraska, USA.;Department of Internal Medicine, Creighton University School of Medicine, Omaha, Nebraska, USA.;Department of Internal Medicine, Creighton University School of Medicine, Omaha, Nebraska, USA.;Division of Infectious Diseases, Department of Internal Medicine, Creighton University School of Medicine, Omaha, Nebraska, USA.",
"authors": "Mahfood Haddad|Toufik|T|;Vallabhajosyula|Saraschandra|S|;Sundaragiri|Pranathi Rao|PR|;Vivekanandan|Renuga|R|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C490727:T 91825; D014640:Vancomycin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D017541:Aneurysm, False; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D002511:Cephalosporins; D003646:Debridement; D003937:Diagnosis, Differential; D004352:Drug Resistance, Microbial; D005263:Femoral Artery; D006801:Humans; D008026:Ligation; D008297:Male; D008875:Middle Aged; D009181:Mycoses; D013211:Staphylococcus aureus; D013848:Thigh; D014640:Vancomycin; D020246:Venous Thrombosis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25833910",
"pubdate": "2015-04-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19199552;21115457;16933824;3395753;6436514;23756501;3335648;24947530;21208910;14506006;19476750;25321910;23037485;12203000;6687676;17961761;18325320;18713038",
"title": "Mycotic pseudoaneurysm by vancomycin-intermediate Staphylococcus aureus: a rare cause of persistent bacteraemia.",
"title_normalized": "mycotic pseudoaneurysm by vancomycin intermediate staphylococcus aureus a rare cause of persistent bacteraemia"
} | [
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},
{
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{
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}
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] |
{
"abstract": "To analyze the interaction between acenocoumarol and levofloxacin in the elderly. We also assessed how hypoalbuminemia affects international normalized ratio variation.\n\n\n\nRetrospective study carried on elderly institutionalized patients who were prescribed levofloxacin concomitantly with acenocoumarol. International normalized ratio variation during levofloxacin treatment was analyzed with the t-Student test. Correlation between albuminemia and international normalized ratio variation was calculated using Pearson´s correlation coefficient.\n\n\n\nThe mean international normalized ratio previous to treatment with levofloxacin was 2.5 (standard deviation: 0.6) and during treatment it was 4.7 (standard deviation: 1.9) (p < 0.05). In 54.3% of the cases, the international normalized ratio value was equal to or greater than 4.5. Not linear association between albuminemia and international normalized ratio increase was found using Pearson´s test (R = -0.16).\n\n\n\nIn more than half of the occasions international normalized ratio raised to clinically rellevant values (≥ 4.5). No influence of hypoalbuminemia in the increase in international normalized ratio was shown.",
"affiliations": "Servicio de Farmacia Hospitalaria, Hospital Universitario Santa María, Lleida. pitabo@hotmail.com.;Servicio de Farmacia Hospitalaria, Residencia para Personas Mayores Dependientes La Cañada, Paterna, Valencia. moreno_ana@gva.es.;Servicio de Farmacia Hospitalaria, Residencia para Personas Mayores Dependientes La Cañada, Paterna, Valencia. quintana_isa@gva.es.;Servicio de Farmacia Hospitalaria, Residencia para Personas Mayores Dependientes La Cañada, Paterna, Valencia. peris_jua@gva.es.",
"authors": "Taberner-Bonastre|Pilar|P|;Moreno-Miralles|Ana|A|;Quintana-Vargas|Isabel|I|;Peris-Martí|Juan Francisco|JF|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000925:Anticoagulants; D012709:Serum Albumin; D064704:Levofloxacin; D000074:Acenocoumarol",
"country": "Spain",
"delete": false,
"doi": "10.7399/fh.11111",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1130-6343",
"issue": "43(2)",
"journal": "Farmacia hospitalaria : organo oficial de expresion cientifica de la Sociedad Espanola de Farmacia Hospitalaria",
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"abstract": "We report a case of acute interstitial nephritis with associated nephrogenic diabetes insipidus in a patient treated with temozolomide and sulfamethoxazole-trimethoprim for glioblastoma multiforme. Kidney biopsy demonstrated focal tubulointerstitial change with tubular dilatation, epithelial change and interstitial inflammation. The patient's kidney function improved with cessation of sulfamethoxazole-trimethoprim and treatment with hydrochlorothiazide for nephrogenic diabetes insipidus. Recommencement of temozolomide did not result in further deterioration in kidney function. In this case report, we discuss the novel association between sulfamethoxazole-trimethoprim-induced acute interstitial nephritis and nephrogenic diabetes insipidus, and suggest possible mechanisms involved.",
"affiliations": "Department of Renal Medicine, Concord Repatriation General Hospital, Concord, New South Wales, Australia.;Department of Endocrinology and Metabolism, Concord Repatriation General Hospital, Concord, New South Wales, Australia.;Department of Renal Medicine, Concord Repatriation General Hospital, Concord, New South Wales, Australia.;Department of Renal Medicine, Concord Repatriation General Hospital, Concord, New South Wales, Australia.;Department of Renal Medicine, Concord Repatriation General Hospital, Concord, New South Wales, Australia.;Department of Renal Medicine, Concord Repatriation General Hospital, Concord, New South Wales, Australia.;Department of Renal Medicine, Concord Repatriation General Hospital, Concord, New South Wales, Australia.",
"authors": "Athavale|Akshay|A|https://orcid.org/0000-0002-1649-8101;Morris|Jack|J|;Jardine|Meg|M|;Gallagher|Martin|M|;Sen|Shaundeep|S|;Ritchie|Angus|A|https://orcid.org/0000-0002-8164-8786;Wang|Amanda Y|AY|https://orcid.org/0000-0002-0367-6677",
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"issue": "26(1)",
"journal": "Nephrology (Carlton, Vic.)",
"keywords": "acute interstitial nephritis; acute kidney injury; diabetes insipidus; drug induced; sulfamethoxazole; trimethoprim",
"medline_ta": "Nephrology (Carlton)",
"mesh_terms": "D058186:Acute Kidney Injury; D000900:Anti-Bacterial Agents; D018906:Antineoplastic Agents, Alkylating; D001932:Brain Neoplasms; D018500:Diabetes Insipidus, Nephrogenic; D005909:Glioblastoma; D006801:Humans; D006852:Hydrochlorothiazide; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial; D049993:Sodium Chloride Symporter Inhibitors; D000077204:Temozolomide; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Acute interstitial nephritis and nephrogenic diabetes insipidus following treatment with sulfamethoxazole-trimethoprim and temozolomide.",
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{
"abstract": "Idiopathic hypereosinophilic syndrome (IHES) is characterised by persistent eosinophilia and organ damage after ruling out other causes. IHES is clinically and pathologically heterogeneous, and several disease mechanisms have been described. Although neurological involvement with IHES is extremely rare, we report the first cases of acute myelitis with IHES, which are confirmed using MRI, fulfil the diagnostic criteria of IHES and pathologically reveal eosinophilic tissue infiltration in the liver and skin. Patient 1 had longitudinally extensive transverse myelitis, which developed in the absence of steroid therapy. Patient 2 developed acute myelitis with two short lesions during a 3 mg/day corticosteroid treatment. Both cases had eosinophilia (>1500/mm(3)) at the onset of myelitis. These findings suggest that earlier treatment and a sufficient dose of corticosteroids may prevent the lesional expansion in acute myelitis. Steroid therapy should be initiated early before organ involvement, because permanent neuronal damage with a larger lesion becomes more critical.",
"affiliations": "Department of Neurology, Tokyo Metropolitan, Neurological Hospital, Fuchu, Tokyo, Japan Department of Neurology, Osaka Red Cross Hospital, Osaka, Japan.;Department of Neurology, Tokyo Metropolitan, Neurological Hospital, Fuchu, Tokyo, Japan.;Department of Neurology, Osaka Red Cross Hospital, Osaka, Japan.;Department of Neurology, Tokyo Metropolitan, Neurological Hospital, Fuchu, Tokyo, Japan.",
"authors": "Tohge|Rie|R|;Warabi|Yoko|Y|;Takahashi|Makio|M|;Nagao|Masahiro|M|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": null,
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"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents; D006801:Humans; D017681:Hypereosinophilic Syndrome; D008279:Magnetic Resonance Imaging; D008297:Male; D008775:Methylprednisolone; D009188:Myelitis, Transverse",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24849647",
"pubdate": "2014-05-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1991924;22975856;19243381;11129275;7116688;3336446;20619905;19910029;16951266;483259;22151137;8180373;12793714;8380900;5653621",
"title": "Two cases of acute myelitis with idiopathic hypereosinophilic syndrome.",
"title_normalized": "two cases of acute myelitis with idiopathic hypereosinophilic syndrome"
} | [
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{
"abstract": "Cutaneous adnexal adenocarcinoma is a rare cancer that is occasionally human epidermal growth factor receptor-2 (HER-2)-positive, and demonstrates variable response to HER-2 inhibitors.\n\n\n\nWe report a case of adnexal adenocarcinoma of the scalp in a 56-year-old man. He underwent wide local excision with cervical node dissection followed by radiation, but had extensive local recurrence.\n\n\n\nPathology demonstrated a poorly differentiated adnexal adenocarcinoma with HER-2 overexpression by immunohistochemistry (IHC) and high HER-2 gene amplification by fluorescence in situ hybridization. The patient was treated with trastuzumab-based therapy with dramatic response and clinical resolution of the tumor. Upon pausing trastuzumab, he developed local relapse, but had an excellent response to restarting trastuzumab monotherapy. He lacks visible disease 43 months after the initial diagnosis.\n\n\n\nWe believe the exquisite sensitivity of the primary carcinoma and subsequent recurrence to trastuzumab therapy was due to strong HER-2 expression both at the protein and gene level. © 2017 Wiley Periodicals, Inc. Head Neck 39: E69-E71, 2017.",
"affiliations": "Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.;Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.;Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.;Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.;Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.;Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.;Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.;Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.",
"authors": "Brown|Timothy J|TJ|;Sher|David J|DJ|;Nedzi|Lucien A|LA|;Hughes|Randall S|RS|;Beg|Muhammad S|MS|;Mull|Jason|J|;Sarode|Venetia R|VR|;Khan|Saad A|SA|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000068878:Trastuzumab",
"country": "United States",
"delete": false,
"doi": "10.1002/hed.24682",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1043-3074",
"issue": "39(5)",
"journal": "Head & neck",
"keywords": "adnexal adenocarcinoma; human epidermal growth factor receptor-2; trastuzumab",
"medline_ta": "Head Neck",
"mesh_terms": "D000230:Adenocarcinoma; D000074322:Antineoplastic Agents, Immunological; D006258:Head and Neck Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D012878:Skin Neoplasms; D000068878:Trastuzumab",
"nlm_unique_id": "8902541",
"other_id": null,
"pages": "E69-E71",
"pmc": null,
"pmid": "28225558",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Cutaneous adnexal adenocarcinoma with exquisite sensitivity to trastuzumab.",
"title_normalized": "cutaneous adnexal adenocarcinoma with exquisite sensitivity to trastuzumab"
} | [
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"reaction": [
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"reactionmeddrapt": "No adverse event",
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},
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"reactionmeddrapt": "Off label use",
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"literaturereference": "BROWN T, SHER D, NEDZI L, HUGHES R, BEG M, MULL J, SARODE V AND KHAN S. CUTANEOUS ADNEXAL ADENOCARCINOMA WITH EXQUISITE SENSITIVITY TO TRASTUZUMAB. HEAD AND NECK 2017 FEB 22?:1-3.",
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}
] |
{
"abstract": "Traditional scalp closure technique following elective craniotomy involves placement of staples or a continuous running suture. Despite low complication rates, these techniques are often considered to be disfiguring by patients, contribute to the psychosocial trauma of brain surgery, and are associated with discomfort during postoperative staple or suture removal. Some authors have described scalp closure using intradermal absorbable suture, but this technique likely does not reach the tensile strength of closure using traditional methods, and requires knots at the apices of the incision, which can act as a nidus for infection.\n\n\n\nWe employed a barbed intradermal closure method in supratentorial elective craniotomies for tumor resection. Complication rates were recorded, and cosmetic outcomes were informally assessed. Intradermal closure with barbed sutures was utilized in 76 patients. At the 2-wk postoperative clinic visit, cosmetic outcomes were excellent in all cases. There was 1 superficial wound infection that presented 6 wk after a pterional craniotomy for low-grade glioma. This resolved with superficial wound revision and oral antibiotic therapy.\n\n\n\nWe present a novel scalp closure technique for craniotomies using intradermal barbed Monocryl suture. We have had excellent cosmetic outcomes, and the infection rate of 1.3% compares favorably to published rates. Further studies are required to quantify the improvement in patient satisfaction compared to conventional closure methods.",
"affiliations": "Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida.;Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida.;College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, Florida.;Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida.",
"authors": "Buttrick|Simon S|SS|;Eichberg|Daniel|D|;Ali|Sheikh C|SC|;Komotar|Ricardo J|RJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ons/opx195",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2332-4252",
"issue": "15(1)",
"journal": "Operative neurosurgery (Hagerstown, Md.)",
"keywords": null,
"medline_ta": "Oper Neurosurg (Hagerstown)",
"mesh_terms": "D001932:Brain Neoplasms; D003399:Craniotomy; D005260:Female; D005910:Glioma; D006801:Humans; D008297:Male; D008579:Meningioma; D008875:Middle Aged; D012535:Scalp; D013536:Suture Techniques; D013537:Sutures; D016896:Treatment Outcome; D058106:Wound Closure Techniques",
"nlm_unique_id": "101635417",
"other_id": null,
"pages": "E5-E8",
"pmc": null,
"pmid": "28962024",
"pubdate": "2018-07-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intradermal Scalp Closure Using Barbed Suture in Cranial Tumor Surgeries: A Technical Note.",
"title_normalized": "intradermal scalp closure using barbed suture in cranial tumor surgeries a technical note"
} | [
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"literaturereference": "BUTTRICK SS, ELCHBERG D, ALI SC, KOMOTAR RJ. INTRADERMAL SCALP CLOSURE USING BARBED SUTURE IN CRANIAL TUMOR SURGERIES: A TECHNICAL NOTE. OPERATIVE NEUROSURGERY (DOI:10.1093/ONS/OPX195). 2018?15:E5?E8",
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{
"abstract": "We report a case of acute oesophageal necrosis (AEN) and non-occlusive mesenteric ischaemia in an otherwise healthy 30-year-old man with cocaine and alcohol abuse. Although cocaine might be expected more frequently to cause oesophageal necrosis through sympathomimetic vasoconstriction, this is only the second known case report of AEN in a patient with cocaine abuse. His symptoms at presentation included epigastric abdominal pain, haematemesis and generalised weakness. He developed moderate neutropenia and severe lactic acidosis. Treatment consisted of intravenous proton-pump inhibitors, granulocyte colony stimulating factor, broad-spectrum antibiotics and ultimately exploratory laparotomy after his condition worsened. He died within 24 hours of presentation from a combination of systemic inflammatory response syndrome, acute respiratory distress syndrome and disseminated intravascular coagulation. AEN was discovered postmortem. We conclude that AEN should be suspected in any patient with haematemesis and substance abuse, and discovery of AEN should prompt a thorough evaluation for potentially lethal comorbid conditions.",
"affiliations": "Department of Community and Family Medicine, Duke University, Durham, North Carolina, USA.;University of Pittsburgh Medical Center Health System, Greenville, Pennsylvania, USA.",
"authors": "Pineo|Caleb Evans|CE|http://orcid.org/0000-0002-0400-2340;Pineo|Thomas Zeitler|TZ|http://orcid.org/0000-0001-5227-9486",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-216138",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000437:Alcoholism; D019970:Cocaine-Related Disorders; D004211:Disseminated Intravascular Coagulation; D004935:Esophageal Diseases; D004947:Esophagus; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D065666:Mesenteric Ischemia; D009336:Necrosis; D012128:Respiratory Distress Syndrome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27881583",
"pubdate": "2016-11-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19800431;21631276;5602573;25876741;25170416;15583247;25874134;15290579;25297468;15028327;24996722;2295407;17322991;22998988;16222758;15772787;9177533;17667501;21335118",
"title": "Acute oesophageal necrosis in a young man with cocaine and alcohol abuse.",
"title_normalized": "acute oesophageal necrosis in a young man with cocaine and alcohol abuse"
} | [
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"reaction": [
{
"reactionmeddrapt": "Intestinal ischaemia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Hepatic steatosis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Gastrointestinal haemorrhage",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Gastrointestinal necrosis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Disseminated intravascular coagulation",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Multiple organ dysfunction syndrome",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Lactic acidosis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug abuse",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20170224"
}
},
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"abstract": "The brachial artery is the commonest artery injured in the extremities. Although the patients present late, nevertheless reconstructions is advocated in other to salvage the limb and maintain function of the hand. We retrospectively examined 25 consecutive patients with vascular injuries treated at The Cardiovascular and Thoracic Surgery Unit of a tertiary health centre over a period of 4 years. We assessed the pre-tertiary methods of stopping of bleeding injured brachial arteries, mechanisms of injury, associated injuries, treatment and the outcome following vascular repair in terms of functionality of the forearm and the volume of the radial pulsation. A total of 12 patients (48.0%) had brachial artery injuries out of the 25 patients with different forms of vascular injuries during the period. There were 10 males and 2 females, aged 7.5-65 years. The aetiology of the brachial artery injuries were: Glass cut in 5 patients, knife cut in 3 patients, surgical complication of tendon release (iatrogenic) in 1 patient, injury from self injection of pentazocine in 1 patient, machete cut in 1 patient and blunt vascular injury from fan belt injury in 1 patient. Except for the young girl whose brachial artery was injured at surgery, and had lateral repair done within 3hours, the timing between injury and repair in the remaining 11 patients ranged between 6-288 hours. This was beyond the golden time in trauma cases. Two patients had the brachial artery revascularised using the Reversed Saphenous Vein Graft (RSVG). The wrist pulsation was small volume in one patient as felt by palpation before discharge though the forearm was viable. Otherwise the remaining patients' outcome was good. Most of the patients with brachial artery injury present late following injury. Revascularisation beyond the golden hour is still desirable as it will help to prevent limb loss. Plans should be put in place to train vascular surgeon to encourage prompt and expertise care.",
"affiliations": "Department of Surgery, University of Port Harcourt Teaching Hospital, Rivers State, Nigeria.;Department of Surgery, University of Port Harcourt Teaching Hospital, Rivers State, Nigeria.;Department of Surgery, University of Port Harcourt Teaching Hospital, Rivers State, Nigeria.",
"authors": "Okonta|Kelechi Emmanuel|KE|;Ocheli|Emmanuel Ossai|EO|;Gbeneol|Tombari Joseph|TJ|",
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"fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-27-23210.11604/pamj.2017.27.232.7291Case SeriesDelayed brachial artery reconstruction after traumatic injury: a case for sustainment of surgical intervention Okonta Kelechi Emmanuel 12&Ocheli Emmanuel Ossai 1Gbeneol Tombari Joseph 1\n1 Department of Surgery, University of Port Harcourt Teaching Hospital, Rivers State, Nigeria\n2 Federal Medical Centre Owerri, Nigeria& Corresponding author: Kelechi Emmanuel Okonta, Department of Surgery, University of Port Harcourt Teaching Hospital, Rivers State, Nigeria31 7 2017 2017 27 23217 6 2015 06 7 2017 © Kelechi Emmanuel Okonta et al.2017The Pan African Medical Journal - ISSN 1937-8688. This is an Open Access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The brachial artery is the commonest artery injured in the extremities. Although the patients present late, nevertheless reconstructions is advocated in other to salvage the limb and maintain function of the hand. We retrospectively examined 25 consecutive patients with vascular injuries treated at The Cardiovascular and Thoracic Surgery Unit of a tertiary health centre over a period of 4 years. We assessed the pre-tertiary methods of stopping of bleeding injured brachial arteries, mechanisms of injury, associated injuries, treatment and the outcome following vascular repair in terms of functionality of the forearm and the volume of the radial pulsation. A total of 12 patients (48.0%) had brachial artery injuries out of the 25 patients with different forms of vascular injuries during the period. There were 10 males and 2 females, aged 7.5-65 years. The aetiology of the brachial artery injuries were: Glass cut in 5 patients, knife cut in 3 patients, surgical complication of tendon release (iatrogenic) in 1 patient, injury from self injection of pentazocine in 1 patient, machete cut in 1 patient and blunt vascular injury from fan belt injury in 1 patient. Except for the young girl whose brachial artery was injured at surgery, and had lateral repair done within 3hours, the timing between injury and repair in the remaining 11 patients ranged between 6-288 hours. This was beyond the golden time in trauma cases. Two patients had the brachial artery revascularised using the Reversed Saphenous Vein Graft (RSVG). The wrist pulsation was small volume in one patient as felt by palpation before discharge though the forearm was viable. Otherwise the remaining patients’ outcome was good. Most of the patients with brachial artery injury present late following injury. Revascularisation beyond the golden hour is still desirable as it will help to prevent limb loss. Plans should be put in place to train vascular surgeon to encourage prompt and expertise care.\n\nBrachial arterydelayedinjuriesreconstruction\n==== Body\nIntroduction\nVascular injuries in the country pose a great deal of distress to patients as a result of dearth of vascular surgeons to deal with the challenge [1]. This is more often than not, leads to delayed presentations for specialist care [2, 3] with a poor outcome. It has been observed that patients with trauma have better outcomes if they are given definitive care within 1 hour of the occurrence of their injuries generally [4]. For vessels, there is the need to revascularised the injured vessel to improve outcome in terms of function and salvaging of the limb. The brachial artery is the most frequently injured artery in the upper limb [5, 6]. Yet most of the patients present late [2, 3, 6] when surgical intervention would have been thought not to be necessary. The repair of traumatic brachial artery injury beyond the ‘golden hour’ is still recommended [7]. It is advocated that prompt repair be effected as this is necessary for the survival of the patient and salvage of the limb [5]. Patients with traumatic brachial artery injury have delayed referral to the tertiary centres for arterial reconstruction in our practice. We review the early outcome of delayed surgical reconstruction of brachial artery injuries in these patients. The essence of vascular surgery is to save limb and preserve function.\n\nMethods\nWe retrospectively examined 25 consecutive patients with vascular injuries of the extremities treated at the Cardiovascular and Thoracic Surgery Unit of two tertiary health centres where the consultants worked over a period of 4 years. We assessed the mechanisms of injury, associated injuries, treatment and the outcome following vascular repair in terms of functionality of the forearm and the volume of the radial pulsation.\n\nPre-tertiary hospital center methods of stopping bleeding\nThe options used in stopping bleeding at peripheral hospitals or referral health centers prior to presentation at the tertiary hospital were the application of tourniquet, use of firm dressing over the lacerated area, use of forceps to hold the bleeding vessels and ligation of the bleeding vessel.\n\nSurgical technique\nThe diagnoses were made by mainly clinical evaluations while in some cases Doppler ultrasonography was used especially for the blunt vascular injuries and during post operative periods. The operations were done under general anaesthesia and the mercury sphygmomanometer was employed in place of Esmarch’s tourniquet to control active bleeding and provide intermittent, regularised limb tourniquet. Distal embolectomy was done with either fogarty catheter or improvised small – sized (size 6Fr) Foley urethral catheter followed by intravascular irrigation using heparinised solution (5,000in in 50mls) [8] through a canula of fair size. For patient requiring vein graft the leg was prepared and the great saphenous vein harvested and put in gallipot containing heparinised solution and papaveratum or lidocaine. Prolene 6/0 was used for the repairs (Figure 1, Figure 2, Figure 3, Figure 4). The success of revascularization was immediately assessed by feel for the return of the radial pulsation. Therapeutic antibiotics, analgesic, aspirin tablets and subcutaneous heparin were continued post - operatively in the patients.\n\nFigure 1 Injured forearm\n\nFigure 2 Greater saphaneous vein harvest\n\nFigure 3 Proximal anastomosis\n\nFigure 4 Distal anastomosis\n\nResults\nA total of 12 patients (48.0%) had brachial artery injuries out of the 25 patients with different forms of vascular injuries during the period (Table 1). There were 10 males and 2 females, aged 7.5-65 years. The aetiology of the brachial artery injuries were: Glass cut in 5 patients, knife cut in 3 patients, as a surgical complication during tendon release (iatrogenic) in 1 patient, injury from self injection of pentazocine in one patient, machete cut in 1 patient and blunt vascular injury from fan belt injury in 1 patient. (Diagram 1-4). It was only the young girl whom the brachial artery was injured at surgery who had lateral repair done within 3 hours while the time interval between brachial artery injury and repair in the remaining 11 patients ranged between 6-288 hours. Six patients had end to end anastomosis,3 patients had lateral repairs and 2 patients had the brachial artery revascularised using the RSVG. The use of forceps or ligature to stop bleeding before patients reported to the hospital did not affect the modality of repair in terms of the use of RSVG or end-to-end anastomisis. The wrist pulsation was small volume in one patient as felt by palpation before discharge though the forearm was viable. Otherwise the remaining patients’ outcome was good.\n\nTable 1 Patients with brachial artery injuries out with different forms of vascular injuries during the period\n\nS. No\tInitial\tAge\tSex\tAetiology\tArtery\tTiming\tTreatment\tOutcome\t\n1\tPO\t33\tF\tSelfinjection\tRBA\t240hrs\tLat Repair\tGood\t\n2\tEJ\t27\tM\tGlass cut\tLBA\t6 hrs\tRSVG\tGood\t\n3\tFJ\t7.5\tF\tIatrogenic\tLBA\t3hrs\tLat Repair\tGood\t\n4\tUG\t25\tM\tKnife Cut\tLBA\t288hrs\tRSVG\tGood\t\n5\tUM\t65\tM\tKnife Cut\tLBA\t21hrs\tE-n-E\tGood\t\n6\tEO\t47\tM\tBlunttrauma\tRBA\t11hrs\tE-n-E\tGood\t\n7\tAJ\t25\tM\tKnife Cut\tRBA\t11hrs\tLat Repair\tRP-not\t\n8\tGJ\t60\tM\tGlass Cut\tRBA\t8hrs\tE-n-E\tGood\t\n9\tND\t35\tM\tGlass Cut\tRBA\t7hrs\tE-n-E\tGood\t\n10\tOL\t8\tM\tGlass cut (Beer bottle)\tLBA\t7 hrs\tE-n-E\tGood\t\n11\tI P\t35\tM\tGlass Cut (Beer bottle)\tLBA\t20hrs\tE-n-E\tGood\t\n12\tUK\t29\tM\tMachete\tRBA\t48\tE-n-E\tGood\t\nDiscussion\nMost of the vascular injuries were caused by penetrating injuries from glass and knife cuts. One patient had blunt trauma when a fan belt from a grinding machine from a grinding machine hit his forearm. He sustained endothelial injury with associated intra-luminal thrombose formation in the brachial artery for which arteriotomy, embolectomy and lateral repair were done. Stab wounds and blunt trauma were the commonest modes of injury as observed in a study in our country about 3 decades ago [2]. In another country outside, stab injuries were the commonest while other causes included glass cut injuries, industrial accidents, road traffic crash, gunshots [9, 10]. One of the patients with penetrating vascular injury was from self injection of pentazocine which led to vascular laceration. The consequences of recreational drug use resulting in vascular injury and posing unique and challenging problems has been previously reported [11]. When vein graft was required, we preferred the saphenous graft as against the cephalic graft suggested by some authors [12] which in our view will affect the drainage of the upper limb especially the affected limb and technically more difficult than the greater saphenous vein to harvest.\n\nIn our study, most of the patients with traumatic brachial artery injuries had delayed presentation in our setting, thus making delayed arterial revascularization the treatment norm. This was the finding in other centers [2, 5]. So, it stands to reason that repair can be effected even beyond the golden hour [1]. This is unarguably so because no critical limb ischaemia occurred in any of the patients even after delayed revascularisations. This was the submission of Zellweger et al on the analysis of 124 patients with brachial artery injury whereby they stated that critical limb ischaemia rarely occurred [9]. The data available recommend brachial arterial repair in patients with traumatic artery injury even after golden time of arterial repair [7]. Upper limbs were saved in the remaining 26 cases (96%) [7]. Critical limb ischemia rarely occurred [9]. Equally Simmon et al specifically stated that delayed presentation greater than 6 hours amongst other things were not predictive of amputation for patients with brachial artery injuries [13]. Though prompt repair of traumatic brachial artery injuries is important to prevent compartment syndrome , which can lead to functional deficits [5]. However, when there is need, prophylactic fasciotomy should be considered [6]. The implication of this is that there is no need to waste time when the patients present for brachial artery revascularisation\n\nOne of the surgical options is reverse autogenous interpositions grafts using the saphenous or cephalic vein [12] when the defect is wide and requires bridging it up. Synthetic graft can also be used but the added cost in procuring the material in out setting is a discouraging factor. The other option is end to end anastomosis in a defect that is not wide, in which the anastomosis must not be under tension after repair. There is the lateral repair when there is lateral laceration or following arteriotomy to evacuate intraluminal clot as we did in one of the patients with blunt vascular injury in which intraluminal thrombose was formed.\n\nThe use of forceps or ligature to stop bleeding before patients reported to the hospital did not affect the modality of vascular repair in terms of the use of RSVG or end-to-end anastomisis. That manoeuvre actually prevented the exsanguinations of the patient. However, in other to achieve tension free anastomosis after cutting off the ligature or re-freshened ends of the vessel, both distal and proximal anastomosis were done and back slab put in some cases with the forearm slightly flexed.\n\nConclusion\nMost of the patients with brachial artery injury present late following injury. Revascularization beyond the golden hour is still desirable to prevent limb loss and restore function. Plans should be put in place to train vascular surgeons to encourage prompt and expertise care.\n\nWhat is known about this topic\nBrachial artery injury is the commonest artery affected in the limbs;\n\nBrachial artery injuries lead to upper limb loss;\n\nPatients with brachial artery injuries present late.\n\nWhat this study adds\nBrachial artery injury can be repair beyond the golden rule time;\n\nBrachial artery injury repair has good outcome;\n\nDelayed brachial artery repair prevents limb amputations.\n\nCompeting interests\nThe authors declare no competing interest.\n\nAuthors’ contributions\nDr Kelechi E. Okonta conceived; designed, analysed, interpreted, collected data, wrote the article, critically revised the article and undertaken by self funding. Drs Emmanuel O Ocheli & Tombari J Gbeneol collected data, wrote the article, critically revised the article. All authors have read and agreed to the final manuscript.\n==== Refs\nReferences\n1 Edaigbini SA Delia IZ Aminu MB Bosan IB Ibrahim A Anumenechi N Vascular surgeries in West Africa: challenges and prospects Asian Cardiovasc Thorac Ann. 2015 23 5 552 557 25429087 \n2 Adebo OA Osinowo OO Management of Peripheral Arterial Injuries at Ibadan: Case Report Vasc Endovascular Surg. 1986 20 1 55 60 \n3 Aduful H Hodasi W Peripheral vascular injuries and their management in accra Ghana Med J. 2007 41 4 186 9 18464905 \n4 Lerner BE Moscati RM The Golden Hour: Scientific Fact or Medical “Urban Legend”? Academic Emergency Medicine. 2001 7 8 7 758 60 11435197 \n5 Ekim H Tuncer M Management of traumatic brachial artery injuries: a report on 49 patients Ann Saudi Med. 2009 Mar-Apr 29 2 105 9 19318753 \n6 Kim JY Buck DW Forte AJ Subramanian VS Birman MV Schierle CF Risk factors for compartment syndrome in traumatic brachial artery injuries: an institutional experience in 139 patients J Trauma. 2009 67 6 1339 44 20009687 \n7 Moini M Hamedani K Rasouli MR Nouri M Outcome of delayed brachial artery repair in patients with traumatic brachial artery injury: prospective study Int J Surg. 2008 6 1 20 2 18178140 \n8 Adeoye PO Adebola SO Adesiyun OAM Brainoh Peripheral vascular surgical procedures in Ilorin, Nigeria: indications and outcome Afri Health Sc. 2011 11 3 433 7 \n9 Zellweger R Hess F Nicol A Omoshoro-Jones J Kahn D Navasaria P An analysis of 124 surgically managed brachial artery injuries Am J Surg. 2004 188 3 240 5 15450827 \n10 Ergunes K Yilik L Ozsoyler I Kestelli M Ozbek C Gurbuz A Traumatic brachial artery injuries Tex Heart Inst J. 2006 33 1 31 4 16572866 \n11 Coughlin PA Mavor AID Arterial Consequences of Recreational Drug Use Eur J Vasc Endovasc Surg. 2006 32 389 396 16682239 \n12 LoCicero J Talucci R Kertein MD Brachial artery reconstruction after traumatic disruption South Med J. 1982 75 9 1099 100 7123332 \n13 Simmons JD Schmieg RE Porter JM D’Souza SE Duchesne JC Mitchell ME Brachial artery injuries in a rural catchment trauma center: are the upper and lower extremity the same? J Trauma. 2008 65 2 327 30 18695466\n\n",
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"abstract": "An autoimmune response causing inflammation in the brain tissue is called autoimmune encephalitis. Autoantibodies directed against N-methyl-D-aspartate (NMDA) receptors cause a type of autoimmune encephalitis resulting in memory loss, confusion, and psychosis. A 28-year-old male with a history of schizophrenia, seizure disorder, and stroke presented with a 2-day history of bizarre behavior, restlessness, insomnia, agitation, and hallucinations. He was initially managed for acute psychosis without any improvement. Further workup for organic causes revealed positive NMDAR antibodies in both the cerebrospinal fluid and serum, confirming a diagnosis of autoimmune encephalitis. His condition later improved with steroids and intravenous immunoglobulins. This case signifies the importance of ruling out organic causes in patients with unexplained neuropsychiatric symptoms. NMDA encephalitis is more common in young females with underlying malignancies, especially ovarian teratomas. This case is unique, given the extremely rare occurrence of NMDA encephalitis in male patients without any malignancies.",
"affiliations": "Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA.;Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA.;Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA.;Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA.;Division of Infectious Disease, Nassau University Medical Center, East Meadow, NY, USA.",
"authors": "Sabbula|Bhanu R|BR|https://orcid.org/0000-0001-9096-7714;Yemmanur|Shravya|S|;Sanivarapu|Raghavendra|R|;Kagolanu|Deepthi|D|;Shadab|Ahmed|A|",
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"fulltext": "\n==== Front\nCase Rep Med\nCase Rep Med\nCRIM\nCase Reports in Medicine\n1687-9627 1687-9635 Hindawi \n\n10.1155/2020/2074704\nCase Report\nFinding the Cause of Psychosis: A Challenging Case of Anti-NMDAR Encephalitis\nhttps://orcid.org/0000-0001-9096-7714Sabbula Bhanu R. bsabbula@numc.edu\n1\n Yemmanur Shravya \n1\n Sanivarapu Raghavendra \n1\n Kagolanu Deepthi \n1\n Shadab Ahmed \n2\n \n1Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA\n\n2Division of Infectious Disease, Nassau University Medical Center, East Meadow, NY, USA\nAcademic Editor: Bernardo Carpiniello\n\n\n2020 \n13 10 2020 \n2020 20747048 10 2019 24 9 2020 4 10 2020 Copyright © 2020 Bhanu R. Sabbula et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.An autoimmune response causing inflammation in the brain tissue is called autoimmune encephalitis. Autoantibodies directed against N-methyl-D-aspartate (NMDA) receptors cause a type of autoimmune encephalitis resulting in memory loss, confusion, and psychosis. A 28-year-old male with a history of schizophrenia, seizure disorder, and stroke presented with a 2-day history of bizarre behavior, restlessness, insomnia, agitation, and hallucinations. He was initially managed for acute psychosis without any improvement. Further workup for organic causes revealed positive NMDAR antibodies in both the cerebrospinal fluid and serum, confirming a diagnosis of autoimmune encephalitis. His condition later improved with steroids and intravenous immunoglobulins. This case signifies the importance of ruling out organic causes in patients with unexplained neuropsychiatric symptoms. NMDA encephalitis is more common in young females with underlying malignancies, especially ovarian teratomas. This case is unique, given the extremely rare occurrence of NMDA encephalitis in male patients without any malignancies.\n==== Body\n1. Introduction\nAutoimmune encephalitis is caused by autoantibodies against neuronal cell surface/synaptic proteins called N-methyl-D-aspartate receptors (NMDARs) [1]. NMDARs play a significant role in maintaining synaptic plasticity and memory. Anti-NMDAR encephalitis has been associated with multiple infectious agents, including Mycoplasma pneumoniae, herpes simplex virus, measles virus, mumps, and group-A hemolytic Streptococcus [2]. Here, we describe the case of a young male with a known diagnosis of schizophrenia, presenting with confusion and hallucinations warranting psychiatric management and subsequently found to have anti-NMDAR encephalitis.\n\n2. Case Presentation\nA 28-year-old male presented with a 2-day history of restlessness, bizarre behavior, confusion, and hallucinations. His past medical history was significant for schizophrenia, seizure disorder, and stroke with residual left-sided facial droop. There was no family history of psychiatric disorders. His family reported that he had no recent fever, chills, nausea, vomiting, runny nose, sore throat, cough, headaches, urinary symptoms, loss of appetite, or loss of weight. On physical examination, he was afebrile and hemodynamically stable. He was alert, oriented to person and place, but not to time. His fiancé reported that he had been pacing around his room, not sleeping, acting paranoid, and hearing voices. He was admitted to the psychiatry department for acute psychosis, where he was unsuccessfully managed with valproic acid, risperidone, and benztropine, with haloperidol and diphenhydramine as needed. A review of his chart revealed two past admissions for a similar presentation of acute psychosis, and he was discharged with outpatient psychiatry follow-up recommendation. The patient failed to follow-up as an outpatient, and no further workup was done at that time. His hospital course was complicated by worsening mental status, and he continued to be unresponsive to the abovementioned medications.\n\nA thorough evaluation for organic causes was performed, including magnetic resonance imaging (MRI) of the brain with contrast, lumbar puncture (LP), and an autoimmune workup. The brain MRI with contrast showed multiple areas of bright signal intensity throughout the brain parenchyma, most notably in the medial temporal lobes and bilateral insular cortices, compatible with encephalitis (Figure 1). LP was performed, and cerebrospinal fluid (CSF) showed white blood cell count, 8 mm3; neutrophils, 1 mm3; lymphocytes, 95%; protein, 35 mg/dl; and glucose, 56 mg/dl. CSF testing for herpes simplex virus 1 and 2 DNA, varicella zoster PCR, VDRL, FTA ABS, enterovirus, and viral cultures were negative. A mild elevation of antinuclear antibody (1 : 40 titer) was noted. Blood and CSF were positive for oligoclonal bands.\n\nInitially, the patient was started on empirical treatment with vancomycin, ceftriaxone, and acyclovir for possible infectious causes of encephalitis. The diagnosis of anti-NMDAR encephalitis was confirmed when the CSF was found positive for NMDAR antibodies. Empiric antibiotics and acyclovir were discontinued, and the patient was treated with intravenous immunoglobulin (IVIG) 400 mg/kg/day for 5 days and methylprednisolone 1 g/day for 5 days.\n\nThe patient's condition improved significantly. He was observed to have more meaningful conversations and an improvement in his pressured speech. Repeat MRI after two weeks showed decreased bright signal intensity, although swelling remained the same (Figure 2). The patient was discharged and was followed up as an outpatient with complete resolution of his symptoms.\n\n3. Discussion\nAlthough this patient presented with features typical of anti-NMDAR encephalitis, his history of schizophrenia, seizures, and acute psychotic episodes contributed to delayed diagnosis. The classic presentation of this syndrome involves the development of psychiatric symptoms, memory loss, sleep disturbances, and seizures [3]. Malignancy is a known risk factor, and teratomas, germ cell tumors of the testes, and small cell lung cancer are specifically hypothesized to be associated with the disease [4, 5]. The presence of anti-NMDAR antibodies is specific for diagnosis. Although it has been associated with pathogens including Mycoplasma pneumoniae, herpes simplex virus, measles virus, mumps, and group-A hemolytic Streptococcus, these were all negative in our patient. The improvement of symptoms in our patient after treatment with IVIG and methylprednisolone further strengthens the diagnosis. The pathophysiology behind psychiatric manifestations of this disease is anti-NMDAR antibody inhibition of gamma-aminobutyric acid at the presynaptic junction in the thalamus and frontal cortex. Subsequently, postsynaptic glutaminergic neurons are uninhibited, resulting in dysregulation of the dopaminergic pathway [6].\n\nDiagnosis of probable anti-NMDAR encephalitis requires the onset of at least four of the following symptoms within 3 months: abnormal behavior or cognitive dysfunction, speech dysfunction, movement disorder, dyskinesia, rigidity/abnormal posture, decreased level of consciousness, autonomic dysfunction, or central hypoventilation. Patients must also have either an abnormal electroencephalogram or CSF with pleocytosis or oligoclonal bands and reasonable exclusion of other disorders [7].\n\nFor a definitive diagnosis of anti-NMDAR encephalitis, IgG anti-GluN1 antibodies (NMDA receptor antibodies) should be positive in the presence of one or more of the six major groups of symptoms, after exclusion of other disorders [8]. Our patient met the diagnostic criteria for definitive anti-NMDAR encephalitis. The treatment approach to anti-NMDAR encephalitis includes removal of the etiological agents such as a tumor or treatment of the underlying infectious source and immunotherapy. The immunotherapies commonly used are corticosteroids, intravenous immunoglobulins, and plasma exchange with plasmapheresis in severe cases [8]. In resistant cases, immunosuppression is induced using rituximab, cyclophosphamide, mycophenolate mofetil, azathioprine, and methotrexate. Our patient responded well to immunotherapy with methylprednisolone and IVIG. Although symptoms are usually severe, studies suggest that patients are usually highly responsive to therapy [9]. As per a reported case series of 99 patients with all-cause encephalitis, 9.1% were found to have anti-NMDAR encephalitis. The mean age of these patients was 28 years, and 5 of 9 were females. Follow-up of these patients showed zero mortality and complete symptomatic recovery after treatment with high-dose corticosteroids and intravenous immunoglobulin [9]. Prompt diagnosis and early treatment will reduce mortality and ensure complete recovery.\n\nIn conclusion, anti-NMDAR encephalitis is a very rare entity in male patients, especially in those without any underlying malignancies. However, physicians should consider this diagnosis as a differential in any young patient presenting with unexplained neuropsychiatric symptoms. Younger patients who present with an initial episode of bizarre behavior should be assessed to rule out major organic causes, as delay in diagnosis leads to poor patient outcomes. Although literature suggests a predominance of anti-NMDAR encephalitis occurs in women with ovarian teratomas, this case demonstrates that the diagnosis should also be considered in men without any signs and symptoms of a neoplastic process, and a thorough workup for the infectious source should be conducted [2].\n\nData Availability\nThe data used to support this study are restricted to protect patient privacy concern.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this article.\n\nFigure 1 Axial magnetic resonance images (MRIs) demonstrating bright signal intensity and gyriform swelling in the region of the uncus (a) and thalami and insular cortex (b). This is best appreciated on flair images (c) and is harder to detect on T2-weighted images. The contrast study (d) does not show enhancement.\n\nFigure 2 Axial magnetic resonance images (MRIs) one and a half weeks after treatment with immunoglobulin and methylprednisolone demonstrating gyriform swelling of the temporal lobes (a), especially medially, best seen on flair sequences (a, c, d). There is a faint bright signal intensity observed in the bilateral thalami and basal ganglia (c). Vague cortical brightness is also seen. There is no evidence of abnormal contrast enhancement (b). Compared to the earlier study, the degree of bright signal intensity is decreased, though swelling remains. These findings, with cortical, thalamic, and basal ganglia involvement, are typically seen in encephalitis.\n==== Refs\n1 Cai X. Zhou H. Xie Y. Yu D. Wang Z. Ren H. Anti-N-methyl-D-aspartate receptor encephalitis associated with acute Toxoplasma gondii infection: a case report Medicine (Baltimore) 2018 97 7 e9924 10.1097/md.0000000000009924 2-s2.0-85042191336 \n2 Dalmau J. Graus F. Antibody-mediated encephalitis New England Journal of Medicine 2018 378 9 840 851 10.1056/nejmra1708712 2-s2.0-85042849187 29490181 \n3 Kayser M. S. Titulaer M. J. Gresa-Arribas N. Dalmau J. Frequency and characteristics of isolated psychiatric episodes in anti-N-Methyl-D-Aspartate receptor encephalitis JAMA Neurology 2013 70 9 1133 1139 10.1001/jamaneurol.2013.3216 2-s2.0-84883787497 23877059 \n4 Lancaster E. Martinez-Hernandez E. Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins Neurology 2011 77 2 179 189 10.1212/wnl.0b013e318224afde 2-s2.0-80051504636 21747075 \n5 Dalmau J. Gleichman A. J. Hughes E. G. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies The Lancet Neurology 2008 7 12 1091 1098 10.1016/s1474-4422(08)70224-2 2-s2.0-55549135314 18851928 \n6 Baldridge E. B. Bessen H. A. Phencyclidine Emergency Medicine Clinics of North America 1990 8 3 541 550 2201519 \n7 Graus F. Titulaer M. J. Balu R. A clinical approach to diagnosis of autoimmune encephalitis The Lancet Neurology 2016 15 4 391 404 10.1016/s1474-4422(15)00401-9 2-s2.0-84960486545 26906964 \n8 Zhang L. Wu M.-Q. Hao Z.-L. Clinical characteristics, treatments, and outcomes of patients with anti-N-methyl-D-aspartate receptor encephalitis: a systematic review of reported cases Epilepsy & Behavior 2017 68 57 65 10.1016/j.yebeh.2016.12.019 2-s2.0-85009725261 28109991 \n9 Hoang M. N. T. Nguyen Hoan P. Le Van T. First reported cases of anti-NMDA receptor encephalitis in Vietnamese adolescents and adults Journal of the Neurological Sciences 2017 373 250 253 10.1016/j.jns.2017.01.004 2-s2.0-85008698651 28131199\n\n",
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"reaction": [
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SABBULA B, SANIVARAPU R, KAGOLANU D, SHADAB A, YEMMANUR S. FINDING THE CAUSE OF PSYCHOSIS: A CHALLENGING CASE OF ANTI-NMDAR ENCEPHALITIS. CASE REP MED. 2020?.",
"literaturereference_normalized": "finding the cause of psychosis a challenging case of anti nmdar encephalitis",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20201230",
"receivedate": "20201230",
"receiver": {
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},
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
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},
"serious": 2,
"seriousnesscongenitalanomali": null,
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"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210114"
}
] |
{
"abstract": "Some periprosthetic femoral fractures (PFFs) present history and radiographic aspect consistent with an atypical femoral fracture (AFF), fulfilling the criteria for AFF except that PFFs by themselves are excluded from the diagnosis of AFFs. The aim of this study is to evaluate in a single institution series of PFFs if any of them could be considered a periprosthetic atypical femoral fracture (PAFF), and their prevalence.\n\n\n\nSurgical records were searched for PFFs around a primary hip stem from January 2013 to December 2019. Cases were classified according to Vancouver classification. Demographic and medical history was extracted. Fisher's exact test was used for statistical analysis.\n\n\n\nOne hundred fifteen PFFs were identified, 59 of them were type B1 and 16 were type C. Radiographs and medical records were available for all patients. Twenty-four patients (32%) have been treated with bisphosphonates (BPs) for longer than 4 years. Four patients presented a fracture with characteristics of PAFF. When enlarged to all PFFs of the series, no other PAFF was found: prevalence of PAFFs was 5.3% for type B1 and C cases and 3.5% for all surgically treated PFFs. Statistical significative difference between PAFFs and PFFs was found for prolonged BP assumption and for the level of fracture clear of the stem.\n\n\n\nFracture with characteristics of AFFs can also happen over a prosthetic stem, configuring themselves as PAFFs, and they are related to prolonged BP use. As a correct diagnosis is mandatory for proper treatment, a revision of criteria for AFFs should be considered, accepting that PAFFs exist.",
"affiliations": "Department of Medicine Surgery and Neurosciences, The Section of Orthopedics, University of Siena, Azienda Ospedaliero-Universitaria Senese, Siena, Italy.;Department of Medicine Surgery and Neurosciences, The Section of Orthopedics, University of Siena, Azienda Ospedaliero-Universitaria Senese, Siena, Italy.;Department of Medicine Surgery and Neurosciences, The Section of Orthopedics, University of Siena, Azienda Ospedaliero-Universitaria Senese, Siena, Italy.;Department of Oncology, The Section of Orthopedic Oncology and Reconstructive Surgery, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy.;Department of Orthopedic and Trauma Surgery, Othopedic and Traumatology II, University of Pisa, Pisa, Italy.;Department of Medicine Surgery and Neurosciences, The Section of Orthopedics, University of Siena, Azienda Ospedaliero-Universitaria Senese, Siena, Italy.",
"authors": "Mondanelli|Nicola|N|;Facchini|Andrea|A|;Troiano|Elisa|E|;Muratori|Francesco|F|;Bottai|Vanna|V|;Giannotti|Stefano|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.arth.2021.01.066",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-5403",
"issue": "36(6)",
"journal": "The Journal of arthroplasty",
"keywords": "atypical femoral fracture; bisphosphonates; periprosthetic atypical femoral fracture; periprosthetic femoral fracture; vancouver B1; vancouver C",
"medline_ta": "J Arthroplasty",
"mesh_terms": "D019644:Arthroplasty, Replacement, Hip; D005264:Femoral Fractures; D006801:Humans; D057068:Periprosthetic Fractures; D015995:Prevalence; D012086:Reoperation; D012189:Retrospective Studies",
"nlm_unique_id": "8703515",
"other_id": null,
"pages": "2189-2196",
"pmc": null,
"pmid": "33610412",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Periprosthetic Atypical Femoral Fractures Exist: A Retrospective Study at a Single Institution. Prevalence on 115 Periprosthetic Femoral Fractures Around a Primary Hip Stem.",
"title_normalized": "periprosthetic atypical femoral fractures exist a retrospective study at a single institution prevalence on 115 periprosthetic femoral fractures around a primary hip stem"
} | [
{
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{
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"literaturereference": "Mondanelli N, Facchini A, Troiano E, Muratori F, Bottai V, Giannotti S.. Periprosthetic Atypical Femoral Fractures Exist: A Retrospective Study at a Single Institution Prevalence on 115 Periprosthetic Femoral Fractures Around a Primary Hip Stem.. Journal of Arthroplasty. 2021;36(6):2189-2196",
"literaturereference_normalized": "periprosthetic atypical femoral fractures exist a retrospective study at a single institution prevalence on 115 periprosthetic femoral fractures around a primary hip stem",
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},
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{
"abstract": "Schizophrenia is a chronic psychotic disorder in which patients experience positive and negative symptoms for over six months. Schizophrenia is associated with early mortality, with 40% of this excess mortality due to suicide. This is a case of patient with schizophrenia who was treated with quetiapine after suffering a traumatic brain injury and recovered enough to be discharged to a rehabilitation unit. This case illustrates the neuroprotective effects of quetiapine in treating neurologic deficits in a patient who recently suffered a traumatic brain injury.\n\n\n\nThis is a case report of a patient with schizophrenia treated in the hospital setting. He was placed on quetiapine after suffering a traumatic brain injury due to a suicide attempt in which he shot himself with a nail gun.\n\n\n\nThe patient initially presented with neurologic deficits suggestive of traumatic brain injury (inattention, memory loss, muscle weakness) and psychosis from schizophrenia. He was treated with quetiapine and recovered enough to be discharged to a rehabilitation unit.\n\n\n\nQuetiapine, a second-generation antipsychotic, has been shown to significantly decrease blood–brain barrier hyperpermeability by preserving tight junction integrity in small animal models. This anti-inflammatory effect may also help to preserve neurogenesis in patients with traumatic brain injury, as shown in this case. This case may help elucidate the nature of quetiapine’s neuroprotective effects in patients who have suffered traumatic brain injury and also highlights the need to further investigate other atypical antipsychotics and their potential neuroprotective role in treating traumatic brain injury.",
"affiliations": "Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA.;Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA.",
"authors": "Morra|Joseph A|JA|;Alao|Adekola O|AO|",
"chemical_list": "D014150:Antipsychotic Agents; D018696:Neuroprotective Agents; D000069348:Quetiapine Fumarate",
"country": "United States",
"delete": false,
"doi": "10.1177/0091217419838105",
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"issn_linking": "0091-2174",
"issue": "55(2)",
"journal": "International journal of psychiatry in medicine",
"keywords": "TBI; neurogenesis; neuroprotective; quetiapine; schizophrenia",
"medline_ta": "Int J Psychiatry Med",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D000070642:Brain Injuries, Traumatic; D006801:Humans; D008297:Male; D018696:Neuroprotective Agents; D000069348:Quetiapine Fumarate; D012559:Schizophrenia; D013406:Suicide, Attempted",
"nlm_unique_id": "0365646",
"other_id": null,
"pages": "67-73",
"pmc": null,
"pmid": "30913942",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Role of quetiapine in protection of neurodegeneration after traumatic brain injury.",
"title_normalized": "role of quetiapine in protection of neurodegeneration after traumatic brain injury"
} | [
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{
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},
{
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"reactionoutcome": "6"
},
{
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"reactionoutcome": "6"
}
],
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"literaturereference": "MORRA JA, ALAO AO. ROLE OF QUETIAPINE IN PROTECTION OF NEURODEGENERATION AFTER TRAUMATIC BRAIN INJURY. INTERNATIONAL JOURNAL OF PSYCHIATRY IN MEDICINE. 2020?55(2):67?73. DOI: 10.1177/0091217419838105.",
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{
"abstract": "We present the case of an immunocompetent 55-year-old woman, treated with corticosteroids, developing a cerebral fungal infection with autoptic ascertainment of aspergillosis and mucormycosis. This is the first report of cerebral co-infection by mucorales and aspergillus in an immunocompetent host. A possible explanation is that corticosteroids, even if taken for a short time, led to a transient lowering of immune function and contributed to negative outcome.",
"affiliations": "Neurology Unit, \"A. Manzoni\" Hospital - ASST Lecco, Via dell'Eremo 9/11, 23900, Lecco, Italy. vittorio.mantero@hotmail.com.;Neurology Unit, \"A. Manzoni\" Hospital - ASST Lecco, Via dell'Eremo 9/11, 23900, Lecco, Italy.;Department of Internal Medicine, \"A. Manzoni\" Hospital - ASST Lecco, Lecco, Italy.;Pathological Anatomy Unit, \"A. Manzoni\" Hospital - ASST Lecco, Lecco, Italy.;Laboratory Unit, \"A. Manzoni\" Hospital - ASST Lecco, Lecco, Italy.;Neurosurgery Unit, \"A. Manzoni\" Hospital - ASST Lecco, Lecco, Italy.;Neurology Unit, \"A. Manzoni\" Hospital - ASST Lecco, Via dell'Eremo 9/11, 23900, Lecco, Italy.;Neurology Unit, \"A. Manzoni\" Hospital - ASST Lecco, Via dell'Eremo 9/11, 23900, Lecco, Italy.",
"authors": "Mantero|Vittorio|V|0000-0002-1216-9853;Basilico|Paola|P|;Pozzetti|Ugo|U|;Tonolo|Silvia|S|;Rossi|Giorgio|G|;Spena|Giannantonio|G|;Rigamonti|Andrea|A|;Salmaggi|Andrea|A|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1007/s13365-019-00804-4",
"fulltext": null,
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"issn_linking": "1355-0284",
"issue": "26(2)",
"journal": "Journal of neurovirology",
"keywords": "Aspergillosis; Cerebral infection; Fungal infection; Mucormycosis",
"medline_ta": "J Neurovirol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D001927:Brain Diseases; D060085:Coinfection; D003882:Dermatomyositis; D005260:Female; D006801:Humans; D008875:Middle Aged; D009091:Mucormycosis; D020953:Neuroaspergillosis; D011241:Prednisone",
"nlm_unique_id": "9508123",
"other_id": null,
"pages": "277-280",
"pmc": null,
"pmid": "31713052",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Concomitant cerebral aspergillosis and mucormycosis in an immunocompetent woman treated with corticosteroids.",
"title_normalized": "concomitant cerebral aspergillosis and mucormycosis in an immunocompetent woman treated with corticosteroids"
} | [
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"abstract": "Localized malignant mesothelioma is rare. It has a histological pattern identical to diffuse malignant mesothelioma but without diffuse serosal spread. Localized malignant mesothelioma typically originates from the pleura, peritoneum or pericardium, but can occasionally develop from organs. Our cases represent what might be the largest mediastinal localized malignant mesothelioma described and the first presentation of the epithelioid type in the stomach of an adult.",
"affiliations": "Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark.;Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark.;Department of Surgery, Aarhus University Hospital, Aarhus, Denmark.;Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark.",
"authors": "Jeppesen|Tanita Drejer|TD|0000-0003-4185-139X;Højsgaard|Anette|A|0000-0003-4114-6201;Kjær|Daniel|D|0000-0003-0330-3624;Christensen|Thomas Decker|TD|0000-0001-6509-8510",
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"fulltext": "\n==== Front\nInteract Cardiovasc Thorac Surg\nInteract Cardiovasc Thorac Surg\nicvts\nInteractive Cardiovascular and Thoracic Surgery\n1569-9293\n1569-9285\nOxford University Press\n\n34586396\n10.1093/icvts/ivab276\nivab276\nThoracic\nBrief Communications\nAcademicSubjects/MED00920\nAcademicSubjects/MED00920\nLocalized malignant mesothelioma in the stomach and mediastinum\nhttps://orcid.org/0000-0003-4185-139X\nJeppesen Tanita Drejer 1\nhttps://orcid.org/0000-0003-4114-6201\nHøjsgaard Anette 1\nhttps://orcid.org/0000-0003-0330-3624\nKjær Daniel 23\nhttps://orcid.org/0000-0001-6509-8510\nChristensen Thomas Decker 13\n1 Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark\n2 Department of Surgery, Aarhus University Hospital, Aarhus, Denmark\n3 Department of Clinical Medicine, Aarhus University, Aarhus, Denmark\nCorresponding author. Department of Cardiothoracic and Vascular Surgery & Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, DK - Denmark. Tel: +45 2477 8857; e-mail: tdc@clin.au.dk (T.D. Christensen).\n3 2022\n29 9 2021\n29 9 2021\n34 3 485487\n15 4 2021\n20 8 2021\n27 8 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nLocalized malignant mesothelioma is rare. It has a histological pattern identical to diffuse malignant mesothelioma but without diffuse serosal spread. Localized malignant mesothelioma typically originates from the pleura, peritoneum or pericardium, but can occasionally develop from organs. Our cases represent what might be the largest mediastinal localized malignant mesothelioma described and the first presentation of the epithelioid type in the stomach of an adult.\n\nLocalized malignant mesothelioma (LMM) is a rare neoplasm [1].\n\nLocalized malignant mesothelioma\nMediastinum\nStomach\n==== Body\npmcINTRODUCTION\n\nLocalized malignant mesothelioma (LMM) is a rare neoplasm [1]. The histological pattern is identical to diffuse malignant mesothelioma (DMM) but without diffuse serosal spread [1]. LMM typically originates from the pleura, peritoneum, pericardium or tunica vaginalis [1, 2], but can occasionally develop in organs, such as lungs, gonads, liver, spleen, pancreas and the ventricle [1]. We present 2 cases with very uncommon presentations of LMM. To our knowledge, our cases represent the largest mediastinal LMM described and the first presentation of epithelioid LMM in the stomach of an adult.\n\nCASE DESCRIPTION\n\nCase 1\n\nA 66-year-old male, previously asbestos-exposed, non-smoker, presented with 3 months of intermittent fever, fatigue, mild cough, right-sided chest pain and a weight loss of 7 kg.\n\nA positron emission tomography-computed tomography (CT) showed an 8 × 6 × 9 cm tumour along the right side of the heart (Fig. 1). A biopsy revealed adenocarcinoma.\n\nFigure 1: Computed tomography scan showed an 8 × 6 × 9 cm tumorous process along the right side of the heart.\n\nThe tumour was considered a primary lung cancer, adjacent to the mediastinum and diaphragm and thought to be primary resectable. A right-sided anterior muscle-sparing thoracotomy was performed with the intention of resecting the tumour.\n\nDuring exploration, the tumour was found to extend more widely than expected. The thoracic part of the tumour was located on the right side of the mediastinum, measured 10 × 6 × 6 cm and continued in a large intraabdominal component, with no involvement of the right lung. The tumour was adjacent to the pericardium and right diaphragm. Re-evaluation of the preoperative CT and positron emission tomography-CT by liver surgeon and radiologist also suggested invasion to the left liver lobe, resembling an upper gastrointestinal tumour, which perioperative biopsy could not rule out. A perioperative gastroscopy showed no involvement of the oesophagus.\n\nThe procedure was terminated in order to re-evaluate and plan. The scans were consulted with a liver surgeon, and the surgical access was planned differently.\n\nThree weeks later, definitive surgery was performed: In toto resection of the tumour through a laparoscopic and midline trans-sternal approach. By laparoscopy, the tumour was dissected from the liver. There were no signs of invasion into the liver nor diaphragm from the abdomen. From the sternotomy, the mediastinal tumour including the affected pericardium and diaphragm was resected. For reconstruction of pericardium and diaphragm, 2 Goretex patches were used.\n\nHistological analysis revealed malignant epithelioid mesothelioma assumed to derive from the mediastinum.\n\nThe diaphragmatic resection margins contained tumour cells and the patient underwent adjuvant chemotherapy. A regime of 6 cycles of Cisplatin/Pemetrexed was planned, but only 3 cycles were given due to neutropenia.\n\nA CT scan 6 months after surgery detected recurrent disease with an 8-mm pleuritic thickening resulting in additional chemotherapy and subsequent palliative radiotherapy due to tumour progression and symptoms of dyspnoea and thoracic pain. After the conclusion of palliative radiotherapy, 22 months after surgery, the symptoms improved. The patient has resumed his usual daily activities, e.g. able to take a bicycle ride of 30 km. CT scans show stable cancer disease over a month. The patient is now part of a project of experimental oncological treatment.\n\nCase 2\n\nA 74-year-old female, former smoker, presented with long-lasting abdominal pain, and a weight loss of 5–7 kg. CT scan (Fig. 2A) and positron emission tomography-CT (Fig. 2B) showed a 5-cm tumour located in close relation to the fundus of the stomach and left adrenal gland.\n\nFigure 2: Computed tomography scan (A) and positron emission tomography-computed tomography scan (B) showed a 5-cm tumour located in close relation to the fundus of the stomach. (C) Photo of the resected material in Case 2.\n\nGastroscopy and endoscopic ultrasound revealed an indentation in the gastric wall of the fundic area and a tumour with a diameter of 5 cm. Endoscopic ultrasound biopsy showed malignant mesothelioma, epithelioid type.\n\nSystemic neoadjuvant chemotherapy was initiated. The patient received 6 cycles of Carboplatin/Pemetrexed resulting in a 1-cm tumour regression. Adjuvant radiotherapy was not included in the treatment strategy, partially because of problematic field delimitation.\n\nA tumour adherent to the greater curvature of the stomach, diaphragm, aorta, spleen and pancreas was removed.\n\nA laparoscopic approach was used. The tumour was dissected and freed from the close adherence to the aorta and the spleen, the relation to the pancreas warranted a tangential superficial wedge resection of the body and tail of the pancreas and then closure of the pancreatic defect with absorbable self-locking thread. In order to free the tumour, a wedge resection of the involved part of the diaphragm was performed. Finally, a proximal gastrectomy dividing the oesophagus just above the cardia and the stomach on the proximal part of the corpus was performed. Reconstructing continuity of the gastrointestinal tract was done with an oesophagogastric anastomosis using a circular OrVil 25-mm stapler device. The diaphragm was closed with several single stitches and covered with a BioMesh.\n\nPostoperative histological results confirmed malignant mesothelioma of epithelioid type with clear resection margins.\n\nThe patient remains recurrence-free 22 months after surgery.\n\nDISCUSSION\n\nLMM is rare with merely 101 cases described [1].\n\nLMM is a serosal or subserosal, non-organ-specific tumour with a histological and immunohistochemically pattern identical to DMM, but without diffuse serosal spread [1, 3]. Approximately 90% of LMM originates from the pleura, but it can also derive from the peritoneum, pericardium and tunica vaginalis [1, 2]. Primary LMM can occasionally develop from organs, such as lungs, spleen, pancreas and the stomach [1].\n\nWhen occurring in mediastinum, the mesothelial lining cells of the pericardium are considered as the most probable cells of origin [4].\n\nLMM is often unexpected due to its rarity and clinical presentation, but it can occur in all ages, with males representing 70–75% of cases [1]. Asbestosis is a known risk factor of DMM [1, 4], but it is undetermined whether exposure to asbestos increases the risk of developing LMM [1].\n\nDistinguishing mesothelioma from lung adenocarcinoma is histologically challenging when using only limited tissue from core biopsies [3]. The biopsies in our first case were mistaken for adenocarcinoma, and the diagnosis was unclear until the final histological analysis.\n\nEarly and correct diagnosis between LMM and DMM is important [1, 4], since DMM is a very aggressive neoplasm with a median survival of 6–18 months [1]. Distinguishing between LMM and DMM is also important, as the prognosis and the treatment options are different [1]. An estimated median survival for LMM is 29 months and for the epithelioid subtype 134 months [1, 5]. The difference in survival rates for DMM and LMM may be due to the fact that LMM often can be completely resected [5]. However, as seen in our first case, localized recurrence and even progression to DMM has been described after complete resection of LMM [5].\n\nWe have presented 2 unique cases: what might be the largest LMM tumour of mediastinal origin, with a rare tumour extension and disease recurrence, and the first epithelioid LMM with origin in the stomach in an adult.\n\nThese cases highlight the importance of considering mesothelioma in the differential diagnosis of a solid tumour, regardless of gender, asbestos exposure and especially organ of origin.\n\n \n\nConflict of interest: Thomas Decker Christensen has been on the speaker bureaus for AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche Diagnostics, Takeda, Merck Sharp & Dohme (MSD) and Bristol-Myers Squibb and has been in an Advisory Board for Bayer and MSD. O ther authors declared no conflict of interest.\n\nReviewer information\n\nInteractive CardioVascular and Thoracic Surgery thanks Rüdige r Autschbach, Matthieu Thumerel and the other anonymous reviewers for their contribution to the peer review process of this article.\n==== Refs\nREFERENCES\n\n1 Marchevsky AM , KhoorA, WaltsAE, NicholsonAG, ZhangYZ, RoggliV et al Localized malignant mesothelioma, an unusual and poorly characterized neoplasm of serosal origin: best current evidence from the literature and the International Mesothelioma Panel. Mod Pathol 2020;33 :281–96.31485011\n2 Hino T , KamitaniT, SagiyamaK, YamasakiY, OkamotoI, TagawaT et al Localized malignant pleural mesothelioma mimicking an anterior mediastinal tumor. Eur J Radiol Open 2019;6 :72–7.30740474\n3 Andrews W , PaulS, NarulaN, AltorkiNK. Localized mesothelioma tumour arising synchronously with a primary contralateral lung cancer. Interact CardioVasc Thorac Surg 2013;17 :1061–2.23956266\n4 Akamoto S , OnoY, OtaK, SuzakiN, SasakiA, MatsuoY et al Localized malignant mesothelioma in the middle mediastinum: report of a case. Surg Today 2008;38 :635–8.18612789\n5 Gelvez-Zapata SM , GaffneyD, ScarciM, CoonarAS. What is the survival after surgery for localized malignant pleural mesothelioma? Interact CardioVasc Thorac Surg 2013;16 :533–7.23328002\n\n",
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},
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},
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"drugdosagetext": "UNK, CYCLE",
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"drugindication": "Epithelioid mesothelioma",
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},
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"drugindication": "Mesothelioma malignant",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "CISPLATIN"
}
],
"patientagegroup": null,
"patientonsetage": "66",
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"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Malignant neoplasm progression",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Christensen TD, Jeppesen TD, Hojsgaard A, Kjaer D.. Localized malignant mesothelioma in the stomach and mediastinum. Interact CardioVasc Thorac Surg.. 2022;34:485-487",
"literaturereference_normalized": "localized malignant mesothelioma in the stomach and mediastinum",
"qualification": "3",
"reportercountry": "DK"
},
"primarysourcecountry": "DK",
"receiptdate": "20220610",
"receivedate": "20220606",
"receiver": {
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},
"reporttype": "1",
"safetyreportid": 20919805,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220721"
},
{
"companynumb": "DK-NOVARTISPH-NVSC2022DK095302",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
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"drugdosagetext": "3 CYCLIC",
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"drugindication": "Epithelioid mesothelioma",
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},
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"drugindication": "Mediastinum neoplasm",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "CISPLATIN"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMETREXED"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "214657",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "3 CYCLIC",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Epithelioid mesothelioma",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"medicinalproduct": "PEMETREXED"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMETREXED"
},
"drugadditional": null,
"drugadministrationroute": null,
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"drugcharacterization": "1",
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"drugcumulativedosageunit": null,
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"drugindication": "Mediastinum neoplasm",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "PEMETREXED"
}
],
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"patientonsetage": "66",
"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Jeppesen TD, Hojsgaard A, Kjaer D, Christense TD. Localized malignant mesothelioma in the stomach and mediastinum. INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY. 2022;34(3):485-7",
"literaturereference_normalized": "localized malignant mesothelioma in the stomach and mediastinum",
"qualification": "3",
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},
"primarysourcecountry": "DK",
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"receivedate": "20220607",
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},
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"safetyreportversion": 2,
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},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
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"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220720"
}
] |
{
"abstract": "We describe a 42-year-old professional driver with hypertension, obesity and recurrent episodes of highly symptomatic typical atrial flutter. Despite chronic sotalol treatment, 1:1 AV conduction with RBBB-morphology was observed. After excluding of thrombus in the heart chambers, the 'urgent' and successful RF ablation was performed.",
"affiliations": "Instytut Kardiologii, 04-628 Warszawa.",
"authors": "Zakrzewska-Koperska|Joanna|J|;Urbanek|Piotr|P|;Szufladowicz|Ewa|E|;Bodalski|Robert|R|;Szumowski|Łukasz|Ł|;Maryniak|Agnieszka|A|;Walczak|Franciszek|F|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D013015:Sotalol",
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-9032",
"issue": "67(3)",
"journal": "Kardiologia polska",
"keywords": null,
"medline_ta": "Kardiol Pol",
"mesh_terms": "D000328:Adult; D000889:Anti-Arrhythmia Agents; D001282:Atrial Flutter; D001334:Automobile Driving; D017115:Catheter Ablation; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D006329:Heart Conduction System; D006801:Humans; D006973:Hypertension; D008297:Male; D009765:Obesity; D012008:Recurrence; D013015:Sotalol; D016896:Treatment Outcome",
"nlm_unique_id": "0376352",
"other_id": null,
"pages": "331-6",
"pmc": null,
"pmid": "19378244",
"pubdate": "2009-03",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Next cardioversion or RF ablation in professional driver with recurrent typical atrial flutter and MAS syndromes.",
"title_normalized": "next cardioversion or rf ablation in professional driver with recurrent typical atrial flutter and mas syndromes"
} | [
{
"companynumb": "PL-MYLANLABS-2019M1062067",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SOTALOL"
},
"drugadditional": "1",
"drugadministrationroute": "065",
"drugauthorizationnumb": "077616",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ARRHYTHMIA",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "240",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "SOTALOL."
}
],
"patientagegroup": null,
"patientonsetage": "42",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Atrial flutter",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Adams-Stokes syndrome",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ZAKRZEWSKA-KOPERSKA J, URBANEK P, SZUFLADOWICZ E, BODALSKI R, SZUMOWSKI L, MARYNIAK A, ET AL. NEXT CARDIOVERSION OR RF ABLATION IN PROFESSIONAL DRIVER WITH RECURRENT TYPICAL ATRIAL FLUTTER AND MAS SYNDROMES. [POLISH]. KARDIOL-POL 2009?67(3):331-336.",
"literaturereference_normalized": "next cardioversion or rf ablation in professional driver with recurrent typical atrial flutter and mas syndromes",
"qualification": "3",
"reportercountry": "PL"
},
"primarysourcecountry": "PL",
"receiptdate": "20190703",
"receivedate": "20190703",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16526611,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20191004"
}
] |
{
"abstract": "BACKGROUND\nDirect amyloid invasion of prostate tissue resulting in massive bleeding may be fatal, and rapid diagnosis is difficult.\n\n\nMETHODS\nA 71-y-old male undergoing regular hemodialysis with primary light-chain (AL) amyloidosis was admitted due to gross hematuria for 2 days. Cystoscopy revealed oozing from the prostatic urethra. Therefore, electrocauterization was performed, and his symptoms resolved. Unfortunately, he experienced recurrent massive hematuria 3 months later. Tests for serum D-dimer and fibrin degradation products were both positive. Followed serum factor X level was low at 5.4%. Gross hematuria persisted despite of blood transfusions, desmopressin, and vitamin K therapy. Emergent cystoscopy revealed oozing from the prostatic urethra, as was found previously. Therefore, electrocauterization and transurethral resection of the prostate were performed. Analysis of a biopsy specimen of prostate demonstrated strong amyloid deposition in the vascular and perivascular regions. Electron microscopy showed relatively straight fibrils with diameters of 7-10nm in the perivascular region. Gross hematuria subsided then, and no recurrence was noted at a 6-month follow-up.\n\n\nCONCLUSIONS\nSystemic AL amyloidosis can cause potentially life-threatening hemorrhage. Hemostatic defects and direct invasion with amyloid angiopathy are main pathogenic factors. Timely surgical intervention may be imperative.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taiwan.;Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taiwan.;Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.;Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. Electronic address: l521116@ndmctsgh.edu.tw.",
"authors": "Hsiao|Po-Jen|PJ|;Chiang|Wen-Fang|WF|;Chao|Tai-Kuang|TK|;Lin|Shih-Hua|SH|",
"chemical_list": "D007147:Immunoglobulin Light Chains",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-8981",
"issue": "451(Pt B)",
"journal": "Clinica chimica acta; international journal of clinical chemistry",
"keywords": "Amyloid; Hematuria; Light-chain amyloidosis; Prostate bleeding",
"medline_ta": "Clin Chim Acta",
"mesh_terms": "D000368:Aged; D000686:Amyloidosis; D006417:Hematuria; D006470:Hemorrhage; D006801:Humans; D007147:Immunoglobulin Light Chains; D008297:Male; D008854:Microscopy, Electron; D006435:Renal Dialysis",
"nlm_unique_id": "1302422",
"other_id": null,
"pages": "180-2",
"pmc": null,
"pmid": "26434538",
"pubdate": "2015-12-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Life-threatening hematuria in a hemodialysis patient with systemic light-chain amyloidosis.",
"title_normalized": "life threatening hematuria in a hemodialysis patient with systemic light chain amyloidosis"
} | [
{
"companynumb": "TW-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-104443",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DESMOPRESSIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "078271",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HAEMATURIA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DESMOPRESSIN"
}
],
"patientagegroup": null,
"patientonsetage": "71",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HSIAO PJ, CHIANG WF, CHAO TK, LIN SH. LIFE-THREATENING HEMATURIA IN A HEMODIALYSIS PATIENT WITH SYSTEMIC LIGHT-CHAIN AMYLOIDOSIS. CLIN CHIM ACTA. 2015?OCT 1",
"literaturereference_normalized": "life threatening hematuria in a hemodialysis patient with systemic light chain amyloidosis",
"qualification": "3",
"reportercountry": "TW"
},
"primarysourcecountry": "TW",
"receiptdate": "20151021",
"receivedate": "20151021",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11647838,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160304"
}
] |
{
"abstract": "Dopamine dysregulation syndrome is a rare complication of Parkinson's disease (PD) treatment. We present a 70-year-old woman with a long-standing PD and a clinical picture compatible with dopaminergic dysregulation, which was ultimately revealed to be induced by her companion. Patient's exuberant choreiform dyskinesia led to a potential financial advantage when performed outside the hospital but excessive dopamine intake also occurred during hospital admission, without any obvious reward for the abuser. Even in cases where there is no place for a definitive diagnosis, deceptive behaviours must be identified as their management is based on psychological and social support in parallel to the adjustment of PD therapy.",
"affiliations": "Neurology Department, Centro Hospitalar e Universitário de Coimbra, Portugal.;Neurology Department, Centro Hospitalar e Universitário de Coimbra, Portugal.;Neurology Department, Centro Hospitalar e Universitário de Coimbra, Portugal.;Neurology Department, Centro Hospitalar e Universitário de Coimbra, Portugal.",
"authors": "Reis Carneiro|Diogo|D|http://orcid.org/0000-0001-8912-4736;Sousa|Mário|M|;Morgadinho|Ana|A|;Januário|Cristina|C|",
"chemical_list": "D004338:Drug Combinations; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D002230:Carbidopa",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-228495",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(5)",
"journal": "BMJ case reports",
"keywords": "Parkinson’s disease; impulse control disorders",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D002230:Carbidopa; D007174:Disruptive, Impulse Control, and Conduct Disorders; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007980:Levodopa; D010300:Parkinson Disease; D019966:Substance-Related Disorders; D013577:Syndrome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31101748",
"pubdate": "2019-05-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16100983;20686151;25274180;29018160",
"title": "Dopamine dysregulation syndrome induced by proxy.",
"title_normalized": "dopamine dysregulation syndrome induced by proxy"
} | [
{
"companynumb": "PT-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-210827",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MIANSERIN HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": null,
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"drugenddateformat": null,
"drugindication": "ANXIETY",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "MIANSERINE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"medicinalproduct": "SERTRALINE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadditional": "3",
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"drugauthorizationnumb": null,
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "FOR MANY YEARS",
"drugenddate": null,
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"drugindication": "MAJOR DEPRESSION",
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"abstract": "The authors present a case of a fatal intentional acetaminophen (APAP) overdose and remind the physician how ubiquitous the drug is. This case presentation highlights the clinical presentation and treatment options for APAP overdose in unresponsive patients. In cases of massive APAP overdose (> 300 µg/ml plasma at four hours post-ingestion), prompt administration of N-acetylcysteine (NAC) and early hemodialysis are indicated.",
"affiliations": "Emergency Medicine, Alpert Medical School of Brown University, Providence, USA.;Biochemistry & Molecular Biology, Brown University, Providence, USA.;Emergency Medicine, Envision Physician Services, Nashville, USA.;Emergency Medicine, University of Central Florida College of Medicine, Orlando, USA.",
"authors": "Stead|Thor S|TS|;Jeong|Jae Yun|JY|;Ganti|Latha|L|;Rubero|Jose|J|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.9262\nEmergency Medicine\nMassive Acetaminophen Overdose\nMuacevic Alexander Adler John R Stead Thor S 1 Jeong Jae Yun 2 Ganti Latha 345 Rubero Jose 6 \n1 \nEmergency Medicine, Alpert Medical School of Brown University, Providence, USA \n\n2 \nBiochemistry & Molecular Biology, Brown University, Providence, USA \n\n3 \nEmergency Medicine, Envision Physician Services, Nashville, USA \n\n4 \nEmergency Medicine, University of Central Florida College of Medicine/Hospital Corporation of America Graduate Medical Education Consortium of Greater Orlando, Orlando, USA \n\n5 \nEmergency Medical Services, Polk County Fire Rescue, Bartow, USA \n\n6 \nEmergency Medicine, University of Central Florida College of Medicine, Orlando, USA \n\nLatha Ganti latha.ganti@ucf.edu\n18 7 2020 \n7 2020 \n12 7 e92622 7 2020 18 7 2020 Copyright © 2020, Stead et al.2020Stead et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/36700-massive-acetaminophen-overdoseThe authors present a case of a fatal intentional acetaminophen (APAP) overdose and remind the physician how ubiquitous the drug is. This case presentation highlights the clinical presentation and treatment options for APAP overdose in unresponsive patients. In cases of massive APAP overdose (> 300 µg/ml plasma at four hours post-ingestion), prompt administration of N-acetylcysteine (NAC) and early hemodialysis are indicated.\n\nacetaminophentoxicologypoisoningThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nAcetaminophen (APAP) is the most widely used over-the-counter pain reliever and antipyretic medication around the world [1,2]. However, high doses of APAP are hepatotoxic and are the most common cause of drug-induced liver failure in the United States (US) [3-5]. APAP overdoses in the United States account for 50,000 ED visits per year, over 10,000 hospitalizations, and approximately 100 deaths [2]. The majority of APAP overdose cases are a result of intentional self-harm; however, overdose can also be due to a lack of consumer knowledge. Unintentional overdoses often occur because the victim was unaware that APAP was an ingredient in a combination drug they were taking or because of the belief that over-the-counter drugs are universally benign [5]. If APAP overdose is caught early (< eight hours after ingestion), it is usually reversible via gastric decontamination and administration of the antidote N-acetylcysteine (NAC) [6,7].\n\nCase presentation\nA 53-year-old male with unknown past medical history was brought in via ambulance after his neighbor called due to the patient being unresponsive. The patient was found by emergency medical services (EMS) with multiple bottles of empty acetaminophen around him on the bathroom floor and self-inflicted wounds on his wrist suggestive of a possible suicide attempt. He was in cardiac arrest with pulseless electrical activity (PEA). He received naloxone en route by the paramedics. Return of spontaneous circulation (ROSC) was achieved within 10 minutes of cardiopulmonary resuscitation. He had agonal breathing and pupils that were 3 mm, round, and sluggish bilaterally.\n\nUpon arrival at the ED, the patient was started on vasopressors and intubated. In the ED, the temperature was 89.90F, with a mean arterial pressure of 50 mmHg on norepinephrine infusion, a pulse between 90 and 100 beats per minute, a respiratory rate of 20 (ventilator rate), and oxygen saturation of 94% on 100% FiO2. Laboratory analysis was remarkable for a white blood cell count of 33 x 103/mm3 with neutrophilic predominance. Hepatic panel showed transaminitis with aspartate aminotransferase 1256 units/L (normal range 10-37) and alanine aminotransferase 232 units/L (normal range 12-78). Lactic acid level was 12 mg/dL. The patient had an anion gap metabolic acidosis with bicarbonate of 11 mmol/L, and evidence of acute kidney injury (AKI), with serum creatinine 7 mg/dL and creatine protein kinase >1000 units/L. Arterial blood gas revealed a pH of 6.88, CO2 of 51 mmHg, pO2 of 259 mmHg. The patient had an elevated troponin of 35 ng/mL, but cardiac echocardiogram revealed a normal left ventricular ejection fraction of 55% (Tables 1-4).\n\nTable 1 Complete blood count profile\nWBC, white blood cell count; RBC, red blood cell count; Hgb, hemoglobin; Hct, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; RDW, red cell distribution width; MPV, mean platelet volume\n\nWBC (4.0 - 12.0 K/mm3)\t32.82 *H\t\nRBC (4.6 - 6.0 M/mm3)\t4.66\t\nHgb (14.0 - 18.0 gm/dL)\t14.3\t\nHct (42.0 - 52.0 %)\t43.4\t\nMCV (80.0 - 100.0 fL)\t93.1\t\nMCH (27.0 - 31.0 pg) \t30.7\t\nMCHC (32 - 37.5 g/dL) \t32.9\t\nRDW (12.0 - 14.0 %) \t14.1 H\t\nPlt Count (130 - 400 K/mm3)\t282\t\nMPV (7.0 - 10.0 fL) \t10.3\t\nSegmented Neutrophils (38.0 - 74.0 %)\t69\t\nBand Neutrophils (5.0 - 11.0 %)\t14 H\t\nLymphocytes (20 - 45 %) \t6L\t\nMonocytes (3 - 10 %) \t10\t\nAtypical Lymphocytes (0 - 1 %)\t1\t\nTable 2 Chemistry profile\nBUN, blood urea nitrogen; GFR, glomerular filtration rate; AST, aspartate aminotransferase; ALT, alanine aminotransferase\n\nSodium (136 - 145 mmol/L)\t148 H\t\nPotassium (3.7 - 5.1 mmol/L)\t3.5 L\t\nChloride (98 - 107 mmol/L)\t102\t\nCarbon Dioxide (21 - 32 mmol/L)\t11 L\t\nAnion Gap\t38.5\t\nBUN (7 - 18 mg/dL)\t30 H\t\nCreatinine (0.55 - 1.3 mg/dL)\t4.30 H\t\nEstimated GFR mL/min \t15\t\nBUN/Creatinine Ratio\t7\t\nGlucose (74 - 106 mg/dL)\t176 H\t\nCalcium (8.4 - 10.1 mg/dL)\t7.2 L\t\nMagnesium (1.8 - 2.5 mg/dL)\t7.2 H\t\nTotal Bilirubin (0.2 - 1.5 mg/dL)\t2.7 H\t\nAST (10 - 37 unit/L)\t1256 H\t\nALT (12 - 78 unit/L)\t232 H\t\nTotal Alk Phosphatase (45 - 117 unit/L)\t89\t\nTotal Protein (6.4 - 8.2 g/dL)\t6.2 L\t\nAlbumin (3.4 - 5.0 g/dL)\t3.6\t\nTable 3 Arterial blood gas\nPOC ABG, point-of-care arterial blood gas test\n\nPuncture site\tR Radial\t\nPOC ABG pH (7.35 - 7.45)\t6.88L\t\nPOC ABG pCO2 (35 - 45 mmHg)\t51.8 H\t\nPOC ABG pO2 (80 - 105 mmHg)\t259 H\t\nABG PO2/FiO2 Ratio\t259\t\nPOC ABG HCO3 (22 - 26 mmol/L)\t9.7 L\t\nABG Total CO2 (23 - 27 mmol/L)\t11 L\t\nABG O2 Saturation (95 - 98 %)\t99 H\t\nPOC ABG Base Excess (-2 - 3 mmol/L)\t-23 L\t\nAllen Test\tPass\t\nSet Respiration Rate (/min)\t20\t\nO2 Delivery Device\tVent\t\nVent Mode\tCMV\t\nPOC FiO2 (%)\t100\t\nTidal Volume (mL)\t500\t\nPOC PEEP (cmH2O)\t5\t\nTable 4 Toxicology screen\nOpiates\tNegative\t\nMethadone\tNegative\t\nBarbituates\tNegative\t\nPhencyclidine\tNegative\t\nAmphetamines\tNegative\t\nBenzodazepines\tNegative\t\nCocaine\tNegative\t\nCannabinoids\tNegative\t\nAcetaminophen (10 - 30 mcg/ml)\t > 300 *H\t\nAlcohol, Quantitative (<5.0 mg/dl)\t< 3 L\t\nSalicylates (4 - 20 mg/dL)\t4.8\t\nThe acetaminophen level was >300 mcg/mL (normal range 10-30). Toxicology screen was negative for cocaine, barbiturates, methadone, phenylcyclidine, amphetamines benzodiazepines, or cannabinoids. Foley insertion revealed anuria since admission. Chest radiograph revealed mild bilateral perihilar airspace opacities (Figure 1).\n\nFigure 1 Chest radiograph demonstrating mild bilateral perihilar airspace opacities (arrows)\nA central line was placed in the right internal jugular vein, a trialysis catheter placed in the left internal jugular vein, and a right femoral arterial line was placed. The poison control center was called and NAC was initiated. Four ampules of bicarbonate were given and a bicarbonate infusion was started. Additional pressors including vasopressin, epinephrine, and neosynephrine were required. Active body warming was initiated and nephrology was consulted for continuous renal replacement therapy (CRRT). Aggressive intravenous fluids were initiated (>4L) without significant improvement. Approximately 12 hours later, the patient went into cardiopulmonary arrest and expired.\n\nDiscussion\nAPAP is primarily metabolized by adding a glucuronide or sulfate to the hydroxyl group, forming nontoxic mercaptate conjugates that are excreted. Above the toxic threshold, APAP administration produces NAPQI (N-acetyl-p-benzoquinoneimine), a toxic compound which binds proteins, resulting in hepatocyte necrosis. This occurs when glutathione concentration within the liver decreases to <30% of normal levels [5].\n\nThe range of symptoms in APPA overdose can be grouped into four stages (Figure 2). \n\nFigure 2 Stages of acetaminophen toxicity\nInterventions for APAP overdose include gastrointestinal decontamination through oral activated charcoal, NAC administration, and dialysis (Figure 3).\n\nFigure 3 Acetaminophen poisoning treatment options\nActivated charcoal should only be given if the ingestion occurred within the last two hours. It is administered as 1 g/kg of active charcoal in 200 mL water. NAC is available in both oral and intravenous formulations. In the ED, the IV formulations are most commonly used. IV NAC is given as 150 mg/kg infused in 200 mL of 5% dextrose over 30 min, followed by a four‐hour infusion of 50 mg/kg of acetylcysteine in 500 mL of 5% dextrose and a 16-hour of 100 mg/kg in 1 L of 5% dextrose. If serum APAP concentration is <10 micrograms/mL and transaminase concentrations are normal, then acetylcysteine therapy can be discontinued and discharge can be considered [5].\n\nTreatment threshold for NAC antidote treatment is based on the Rumack-Matthew nomogram which plots APAP levels against time (Figure 4).\n\nFigure 4 Acetaminophen nomogram adapted from Rumack BH, Matthew H: Pediatrics 55:871, 1975\nRecent studies show that IV NAC treatment administered at lower doses reduces potential side effects such as nausea and allergy [8]. Hemodialysis is recommended for patients with extreme plasma acetaminophen concentrations (> 200 µg/mL plasma at four hours post-ingestion) or displaying symptoms of mitochondrial dysfunction such as elevated lactate levels and acidosis [9,10]. CRRT is also suggested in severe cases in which patients display neurological, respiratory, or circulatory malfunctioning (encephalopathy or coma) as our patient did [11].\n\nPatients lacking glutathione reserves such as those with chronic alcohol use are especially at risk, but prompt acetylcysteine administration can effectively prevent acute liver failure. Our patient had likely overdosed the night prior given he arrived in multiorgan failure with irreversible damage to the liver. The patient had an acetaminophen level more than 10x normal. Other complications such as cardiac arrest, respiratory failure, rhabdomyolysis, and septic shock developed, rendering interventions ineffective. \n\nGrowth factors such as hepatocyte growth factor (HGF) are known to be crucial in liver regeneration, a continuous interest amongst researchers in their therapeutic application. However, higher concentrations of HGF in plasma were found in nonsurvivors as opposed to survivors, suggesting that interventions via other factors such as c-Met or TGF-β may be more effective for treatment [12]. In survivors, liver function is normally regained within three months.\n\nConclusions\nThis case demonstrates the evaluation and management of late-stage APAP overdose in an unresponsive patient. Key takeaways include the rapid administration of CRRT in the presence of renal failure, administration of pressors for hypotension, IV NAC dosed according to the APAP nomogram, and intubation if unresponsive.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study. HCA Centralized Algorithms for Research Rules on IRB Exemptions (CARRIE)/ IRB manager issued approval 2020-479. Based on the information provided and attested as true, the research plan described does not require IRB oversight. This is because you are either a) not engaging in research with human subjects as defined by federal regulations; b) engaging in research with human subjects deemed excluded from IRB oversight per 45CFR46.102(l) OR c) engaging in research with sufficient human subject protections in the design to meet one or more IRB exemption criteria set forth in 45CFR46.104.\n\nThis research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.\n==== Refs\nReferences\n1 Estimates of acetaminophen (paracetomal)-associated overdoses in the United States Pharmacoepidemiol Drug Saf Nourjah P Ahmad SR Karwoski C Willy M 398 405 15 2006 16294364 \n2 Acetaminophen (APAP) hepatotoxicity—isn’t it time for APAP to go away? J Hepatol Lee Lee WM WM 1324 1331 67 2017 28734939 \n3 Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study Hepatology Larson AM Polson J Fontana RJ 1364 1372 42 2005 16317692 \n4 Acetaminophen-induced hepatotoxicity: a comprehensive update J Clin Transl Hepatol Yoon E Babar A Choudhary M Kutner M Pyrsopoulos P 131 142 4 2016 27350943 \n5 Acetaminophen Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 9e 6 2020 Wightman RS Nelson LS New York, NY McGraw-Hill 1 2020 https://accessmedicine.mhmedical.com/content.aspx \n6 PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses Pharmacogenet Genomics Mazaleuskaya LL Sangkuhl K Thorn CF FitzGerald GA Altman RB Klein TE 416 426 25 2015 26049587 \n7 A review of acetaminophen poisoning Crit Care Clin Hodgman MJ Garrard AR 499 516 28 2012 22998987 \n8 Interventions for paracetamol (acetaminophen) overdose Cochrane Database Syst Rev Chiew AL Gluud C Brok J Buckley NA 0 2 2018 \n9 Paracetamol (acetaminophen) poisoning BMJ Clin Evid Park BK Dear JW Antoine DJ 2101 2015 2015 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610347/ \n10 Haemodialysis in acute paracetamol poisoning BMJ Case Rep Serjeant L Evans J Sampaziotis F Petchey WG 0 2017 2017 \n11 Renal replacement therapy in the management of intoxications in children: recommendations from the Pediatric Continuous Renal Replacement Therapy (PCRRT) workgroup Pediatr Nephrol Raina R Grewal MK Blackford M 2427 2448 34 2019 31446483 \n12 Liver regeneration after acetaminophen hepatotoxicity: mechanisms and therapeutic opportunities Am J Pathol Bhushan B Apte U 719 729 184 2019\n\n",
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"abstract": "A striking failure of modern medicine is the debilitating and lethal consequences of adverse drug reactions (ADRs), which rank as one of the top 10 leading causes of death and illness in the developed world with direct medical costs of 137-177 billion annually US dollars in the USA. Although many factors influence the effect of medications (e.g., age, organ function, drug interactions), genetic factors account for 20% to 95% of drug response variability and play a significant role in the incidence and severity of ADRs. The field of pharmacogenomics seeks to identify genetic factors responsible for individual differences in drug efficacy and ADRs. Pharmacogenomics has led to several genetic tests that provide clinical dosing recommendations. The Genetic Approaches to Therapy in Children (GATC) project is a national project established in Canada to identify novel predictive genomic markers for severe ADRs in children. An ADR surveillance network has been established in eight of Canada's major children's hospitals, serving up to 75% of all Canadian children. The goal of the project is to identify patients experiencing specific ADRs and matched controls, collect DNA samples, and apply genomics-based technologies to identify ADR-associated genetic markers with the goal of preventing serious ADRs in susceptible children.",
"affiliations": "Department of Medical Genetics, University of British Columbia, Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada.",
"authors": "Ross|Colin J D|CJ|;Carleton|Bruce|B|;Warn|Dana G|DG|;Stenton|Sunita B|SB|;Rassekh|Shahrad Rod|SR|;Hayden|Michael R|MR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1196/annals.1423.020",
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"issn_linking": "0077-8923",
"issue": "1110()",
"journal": "Annals of the New York Academy of Sciences",
"keywords": null,
"medline_ta": "Ann N Y Acad Sci",
"mesh_terms": "D002170:Canada; D002648:Child; D004194:Disease; D064420:Drug-Related Side Effects and Adverse Reactions; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D010597:Pharmacogenetics",
"nlm_unique_id": "7506858",
"other_id": null,
"pages": "177-92",
"pmc": null,
"pmid": "17911433",
"pubdate": "2007-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Genotypic approaches to therapy in children: a national active surveillance network (GATC) to study the pharmacogenomics of severe adverse drug reactions in children.",
"title_normalized": "genotypic approaches to therapy in children a national active surveillance network gatc to study the pharmacogenomics of severe adverse drug reactions in children"
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{
"abstract": "Immunocompromised patients are at high risk of invasive fungal infections (IFI), in particular those with haematological malignancies undergoing remission-induction chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) and recipients of allogeneic haematopoietic stem cell transplants (HSCT). Despite the development of new treatment options in the past decades, IFI remains a concern due to substantial morbidity and mortality in these patient populations. In addition, the increasing use of new immune modulating drugs in cancer therapy has opened an entirely new spectrum of at risk periods. Since the last edition of antifungal prophylaxis recommendations of the German Society for Haematology and Medical Oncology in 2014, seven clinical trials regarding antifungal prophylaxis in patients with haematological malignancies have been published, comprising 1227 patients. This update assesses the impact of this additional evidence and effective revisions. Our key recommendations are the following: prophylaxis should be performed with posaconazole delayed release tablets during remission induction chemotherapy for AML and MDS (AI). Posaconazole iv can be used when the oral route is contraindicated or not feasible. Intravenous liposomal amphotericin B did not significantly decrease IFI rates in acute lymphoblastic leukaemia (ALL) patients during induction chemotherapy, and there is poor evidence to recommend it for prophylaxis in these patients (CI). Despite substantial risk of IFI, we cannot provide a stronger recommendation for these patients. There is poor evidence regarding voriconazole prophylaxis in patients with neutropenia (CII). Therapeutic drug monitoring TDM should be performed within 2 to 5 days of initiating voriconazole prophylaxis and should be repeated in case of suspicious adverse events or of dose changes of interacting drugs (BIItu). General TDM during posaconazole prophylaxis is not recommended (CIItu), but may be helpful in cases of clinical failure such as breakthrough IFI for verification of compliance or absorption.",
"affiliations": "Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. sibylle.mellinghoff@uk-koeln.de.;Department of Oncology, Haematology, Haemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen, Aachen, Germany.;Department I of Internal Medicine, Haematology and Oncology, University Hospital Dresden, Dresden, Germany.;Division of Haematology and Oncology, Leipzig University Hospital, Leipzig, Germany.;Department of Internal Medicine-Haematology and Oncology, Mannheim University Hospital, Heidelberg University, Mannheim, Germany.;Department of Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;Clinic for Haematology and Medical Oncology with Department for Stem Cell Transplantation, University Medicine Göttingen, Göttingen, Germany.;Department I for Internal Medicine, Klinikum Frankfurt (Oder), Frankfurt (Oder), Germany.;Department of Bone Marrow Transplantation, West German Cancer Centre, University Hospital of Essen, University of Duisburg-Essen, Duisburg, Germany.;Department V for Internal Medicine, University Hospital Erlangen, Erlangen, Germany.;Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.;Department of Haematology and Oncology, University Hospital of Jena, Jena, Germany.;Department I of Internal Medicine, German Centre for Infection Research (DZIF), University Hospital of Cologne, University of Cologne, Cologne, Germany.;Department of Haematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Potsdam, Germany.;Department of Haematology, Medical Oncology, and Pneumology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.;Department II of Internal Medicine, University Hospital Wuerzburg, Wuerzburg, Germany.;Department for Haematology, Oncology and Tumour immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.;Department of Haematology and Oncology, Paracelsus-Kliniken Osnabrück, Osnabrück, Germany.;Department III of Internal Medicine, University Hospital Bonn, Bonn, Germany.;Department of Haematology and Oncology, University of Munich, Munich, Germany.;Department IV of Internal Medicine, University Hospital Halle, Halle, Germany.;Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.",
"authors": "Mellinghoff|Sibylle C|SC|http://orcid.org/0000-0003-3928-2503;Panse|Jens|J|;Alakel|Nael|N|;Behre|Gerhard|G|;Buchheidt|Dieter|D|;Christopeit|Maximilian|M|;Hasenkamp|Justin|J|;Kiehl|Michael|M|;Koldehoff|Michael|M|;Krause|Stefan W|SW|;Lehners|Nicola|N|;von Lilienfeld-Toal|Marie|M|;Löhnert|Annika Y|AY|;Maschmeyer|Georg|G|;Teschner|Daniel|D|;Ullmann|Andrew J|AJ|;Penack|Olaf|O|;Ruhnke|Markus|M|;Mayer|Karin|K|;Ostermann|Helmut|H|;Wolf|Hans-H|HH|;Cornely|Oliver A|OA|",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole; D065819:Voriconazole",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-017-3196-2",
"fulltext": "\n==== Front\nAnn HematolAnn. HematolAnnals of Hematology0939-55551432-0584Springer Berlin Heidelberg Berlin/Heidelberg 319610.1007/s00277-017-3196-2Review ArticlePrimary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO) http://orcid.org/0000-0003-3928-2503Mellinghoff Sibylle C. sibylle.mellinghoff@uk-koeln.de 12Panse Jens 3Alakel Nael 4Behre Gerhard 5Buchheidt Dieter 6Christopeit Maximilian 7Hasenkamp Justin 8Kiehl Michael 9Koldehoff Michael 10Krause Stefan W. 11Lehners Nicola 12von Lilienfeld-Toal Marie 13Löhnert Annika Y. 2Maschmeyer Georg 14Teschner Daniel 15Ullmann Andrew J. 16Penack Olaf 17Ruhnke Markus 18Mayer Karin 19Ostermann Helmut 20Wolf Hans-H. 21Cornely Oliver A. 12221 0000 0000 8580 3777grid.6190.eCologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany 2 0000 0000 8580 3777grid.6190.eDepartment I of Internal Medicine, German Centre for Infection Research (DZIF), University Hospital of Cologne, University of Cologne, Cologne, Germany 3 0000 0000 8653 1507grid.412301.5Department of Oncology, Haematology, Haemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen, Aachen, Germany 4 0000 0001 1091 2917grid.412282.fDepartment I of Internal Medicine, Haematology and Oncology, University Hospital Dresden, Dresden, Germany 5 0000 0000 8517 9062grid.411339.dDivision of Haematology and Oncology, Leipzig University Hospital, Leipzig, Germany 6 0000 0001 2190 4373grid.7700.0Department of Internal Medicine–Haematology and Oncology, Mannheim University Hospital, Heidelberg University, Mannheim, Germany 7 0000 0001 2180 3484grid.13648.38Department of Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany 8 0000 0001 0482 5331grid.411984.1Clinic for Haematology and Medical Oncology with Department for Stem Cell Transplantation, University Medicine Göttingen, Göttingen, Germany 9 Department I for Internal Medicine, Klinikum Frankfurt (Oder), Frankfurt (Oder), Germany 10 0000 0001 2187 5445grid.5718.bDepartment of Bone Marrow Transplantation, West German Cancer Centre, University Hospital of Essen, University of Duisburg-Essen, Duisburg, Germany 11 0000 0000 9935 6525grid.411668.cDepartment V for Internal Medicine, University Hospital Erlangen, Erlangen, Germany 12 0000 0001 0328 4908grid.5253.1Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany 13 0000 0000 8517 6224grid.275559.9Department of Haematology and Oncology, University Hospital of Jena, Jena, Germany 14 0000 0004 0390 3563grid.419816.3Department of Haematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Potsdam, Germany 15 grid.410607.4Department of Haematology, Medical Oncology, and Pneumology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany 16 0000 0001 1378 7891grid.411760.5Department II of Internal Medicine, University Hospital Wuerzburg, Wuerzburg, Germany 17 0000 0001 2218 4662grid.6363.0Department for Haematology, Oncology and Tumour immunology, Charité Universitätsmedizin Berlin, Berlin, Germany 18 Department of Haematology and Oncology, Paracelsus-Kliniken Osnabrück, Osnabrück, Germany 19 0000 0000 8786 803Xgrid.15090.3dDepartment III of Internal Medicine, University Hospital Bonn, Bonn, Germany 20 0000 0004 1936 973Xgrid.5252.0Department of Haematology and Oncology, University of Munich, Munich, Germany 21 0000 0004 0390 1701grid.461820.9Department IV of Internal Medicine, University Hospital Halle, Halle, Germany 22 0000 0000 8580 3777grid.6190.eClinical Trials Centre Cologne (ZKS Köln), University of Cologne, Cologne, Germany 7 12 2017 7 12 2017 2018 97 2 197 207 7 10 2017 22 11 2017 © The Author(s) 2017\nOpen Access This 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.Immunocompromised patients are at high risk of invasive fungal infections (IFI), in particular those with haematological malignancies undergoing remission-induction chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) and recipients of allogeneic haematopoietic stem cell transplants (HSCT). Despite the development of new treatment options in the past decades, IFI remains a concern due to substantial morbidity and mortality in these patient populations. In addition, the increasing use of new immune modulating drugs in cancer therapy has opened an entirely new spectrum of at risk periods. Since the last edition of antifungal prophylaxis recommendations of the German Society for Haematology and Medical Oncology in 2014, seven clinical trials regarding antifungal prophylaxis in patients with haematological malignancies have been published, comprising 1227 patients. This update assesses the impact of this additional evidence and effective revisions. Our key recommendations are the following: prophylaxis should be performed with posaconazole delayed release tablets during remission induction chemotherapy for AML and MDS (AI). Posaconazole iv can be used when the oral route is contraindicated or not feasible. Intravenous liposomal amphotericin B did not significantly decrease IFI rates in acute lymphoblastic leukaemia (ALL) patients during induction chemotherapy, and there is poor evidence to recommend it for prophylaxis in these patients (CI). Despite substantial risk of IFI, we cannot provide a stronger recommendation for these patients. There is poor evidence regarding voriconazole prophylaxis in patients with neutropenia (CII). Therapeutic drug monitoring TDM should be performed within 2 to 5 days of initiating voriconazole prophylaxis and should be repeated in case of suspicious adverse events or of dose changes of interacting drugs (BIItu). General TDM during posaconazole prophylaxis is not recommended (CIItu), but may be helpful in cases of clinical failure such as breakthrough IFI for verification of compliance or absorption.\n\nElectronic supplementary material\nThe online version of this article (10.1007/s00277-017-3196-2) contains supplementary material, which is available to authorized users.\n\nKeywords\nInvasive fungal infectionAntifungal prophylaxisItraconazoleFluconazolePosaconazoleAmphotericin BLiposomalIsavuconazoleGerman Society for Haematology and Medical Oncologyissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2018\n==== Body\nIntroduction\nInvasive fungal infections (IFIs) cause substantial morbidity and mortality in patients with haematological malignancies, especially in those receiving remission-induction therapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) and allogeneic haematopoietic stem cell transplantation (HSCT) [53, 97]. In addition, the increasing use of new immune modulating drugs in cancer therapy has opened up an entirely new spectrum of patients at risk [57, 84]. Patients with haematological or oncological diseases without risk for prolonged neutropenia (< 500 cells/μL > 7 days) are not at increased risk for IFI and should therefore not receive routine prophylaxis (DI).\n\nEpidemiology of IFI varies upon host and environmental factors [63]. Aspergillus spp. and Candida spp. cause most cases of IFI in haematological patients [65, 81]. However, the introduction of routine prophylaxis for patients at high risk for IFI plus local environmental factors have caused a shift in epidemiology, in particular to non-albicans Candida spp. such as C. glabrata, C. krusei and C. Tropicalis [28, 78, 99, 112]. Despite improvements in diagnosis and treatment, IFI-associated mortality remains high [54, 78], and thus, antifungal prophylaxis represents an important strategy in patients at high risk for IFI.\n\nSince the 2014 edition of these recommendations [95], seven clinical trials regarding antifungal prophylaxis in patients with haematological malignancies have been published, comprising 1227 patients. This 2017 update intends to facilitate evidence-based decision making in daily clinical practice. Additional evidence from clinical trials and its impact on changes compared to our previous recommendations will be discussed.\n\nDesign and methods\nThe guideline was prepared by German clinical experts in haematology, oncology, stem cell transplantation and infectious diseases in a stepwise consensus process. Systematic literature search was conducted by OAC and SCM as previously described [15, 95]. Data were extracted and tabulated; preliminary recommendations for each patient group were proposed for discussion and sent to the committee, i.e. all authors. Tables were revised after email-based discussion and put up for final discussion at a telephone conference on June 20th, 2017. If no unanimous consensus was reached, majority vote of the conference was adopted. The final version of this guideline was approved by the AGIHO plenary session on September 30th, 2017.\n\nA major change to the 2014 edition of this guideline is the elimination of the recommendations for allogeneic HSCT recipients in order to avoid duplication. Instead, we refer to the guidelines for infectious complications after allogeneic HSCT provided by the Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology [104] and specifically developed for this patient group. For prophylaxis of Pneumocystis jirovecii pneumonia, please refer to the guidelines for primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumonia in patients with haematological malignancies and solid tumours provided by the AGIHO [75].\n\nIn contrast to the last edition, we used grading for strength of recommendation and quality of evidence (Table 1) established by the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and the European Confederation of Medical Mycology (ECMM) [17]. When propositions did not change since 2014, the reader may refer to that previous publication [95]. The synopsis of our recommendations is given in Tables 2, 3 and 4.Table 1 ESCMID-ECMM Grading 2017\n\nCategory, grade\tDefinition\t\nStrength of recommendation\tA\tStrongly supports a recommendation for use\t\nB\tModerate evidence to support a recommendation for use\t\nC\tPoor evidence to support a recommendation\t\nD\tSupports a recommendation against use\t\nQuality of evidence—level\tI\tEvidence from ≥ 1 properly randomised controlled trial\t\nII\tEvidence from ≥ 1 well-designed clinical trial, without randomisation; from cohort or case-controlled analytic studies (preferably from > 1 centre); from multiple time series; or from dramatic results from uncontrolled experiments\t\nIII\tEvidence from opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees\t\nQuality of evidence—index (for level II)\tr\tMeta-analysis or systematic review of randomised controlled trials\t\nt\tTransferred evidence, that is, results from different patients’ cohorts, or similar immune-status situation\t\nh\tComparator group is a historical control\t\nu\tUncontrolled trial\t\na\tPublished abstract (presented at an international symposium or meeting)\t\n\nTable 2 Recommended antifungal prophylaxis in patients with neutropenia (< 500 cells/μL > 7 days)\n\nIntention\tIntervention\tSoR\tQoE\t\nPrevent IFI in patients with neutropenia (< 500 cells/μL > 7 days), excluding alloSCTa\n\tPosaconazole\tA\tIb\n\t\nB\tIIIc\n\t\nAmphotericin B, liposomal, inhalation\tB\tIId\n\t\nAmphotericin B, liposomal, iv\tC\tI\t\nCaspofungin\tC\tI\t\nFluconazole\tC\tI\t\nItraconazole\tC\tI\t\nItraconazole, iv\tC\tI\t\nVoriconazole\tC\tII\t\nAmphotericin B deoxycholate\tD\tI\t\nMicafungin\tC\tIIh\t\nIsavuconazole\tC\tIIu\t\n\naCurrently, no recommendations for ALL patients applicable\n\n\nbStrong recommendation in AML/MDS remission induction chemotherapy only\n\n\ncOther settings, e.g. very severe aplastic anaemia and palliative treatment of MDS\n\n\ndAll patients received fluconazole—dose and route were not reported\n\n\nTable 3 Dosage of recommended drugs (please refer to Table 2)\n\nDrug\tDosage\t\nPosaconazole, oral suspension\t200 mg tid po\t\nPosaconazole, tablet\t300 mg qd po (bid on day 1)\t\nPosaconazole, iv\t300 mg/day iv (bid on day 1)\t\nAmphotericin B, liposomal, inhalation\t12.5 mg biw\t\nAmphotericin B, liposomal, iv\t50 mg q 48 h or 5 mg/kg biw (CI)\n15 mg/kg single infusion (CIII)\t\nCaspofungin\t50 mg qd iv\t\nFluconazole\t400 mg qd po\t\nItraconazole, capsules\tAny dose\t\nItraconazole, oral solution\t2.5–7.5 mg/kg/day or 200 mg\t\nItraconazole, iv\t200 mg qd iv\t\nVoriconazole\t200 mg bid iv\t\nAmphotericin B deoxycholate\tAny dose\t\nMicafungin\t50 mg iv\t\nIsavuconazole\t200 mg/d iv (tid on days 1–2)\t\n\nTable 4 Recommendations on therapeutic drug monitoring during antifungal prophylaxis\n\nIntention\tIntervention\tSoR\tQoE\t\nDrug\tTarget level\t\nAchieve exposure effective for antifungal prophylaxis and reduce toxicity\tVoriconazole\t1–2 mg/L\tB\tIItu\t\nPosaconazole\t> 500 ng/ml\tC\tIItu\t\n\n\n\nIn order to provide a complete overview, this paper includes tables of the trials on antifungal prophylaxis published to date by compound and comprising information about author, publishing year, trial design, medication/daily dose per treatment group, number of patients, risk factors, percentage of proven, probable and possible IFI and attributable and overall mortality (Supplementary Tables 5 to 11, updating previous information published here[15, 95]). Two authors (SCM and AYL) double-checked the detailed information provided.\n\nRecommendations apply for adult patients only, and clinical trials evaluating antifungal prophylaxis exclusively in paediatric patients are beyond the scope of our review. Status of approval of drugs in national health care systems was not taken into account.\n\nThese recommendations are evidence-based, but not necessarily follow approved indications or the respective labelling of antifungal compounds as they may differ substantially between countries and over time.\n\nResults\nTriazoles\nTriazoles represent an important class of antifungal drugs for both prevention and treatment of Aspergillus spp. and certain yeasts including many Candida spp. However, A. fumigatus being resistant to triazoles has emerged within the past decade [9, 45]. The SEPIA study assessed the epidemiology of invasive aspergillosis (IA) and azole resistant Aspergillus spp. in patients with acute leukaemia in 19 haematology centres in Germany. The authors found resistance in two in 179 (1.1%) cases [53]. A European expert group recently published a statement proposing that local resistance rates of < 5% should not trigger changes in national or international management recommendations [108]. Therefore, a modification of antifungal prophylaxis in Germany does not appear to be warranted. The 5% cut-off was not reached in any of the SEPIA study sites [53].\n\nFluconazole\nSince 2014, one prospective study on fluconazole prophylaxis was conducted. This small prospective study compared posaconazole with fluconazole for prophylaxis in 37 AML patients during induction and consolidation chemotherapy. IFI rates did not differ significantly (10 and 7 cases), but posaconazole direct costs exceeded fluconazole considerably (24€ and 2400€, respectively) [6]. However, posaconazole was demonstrated to have a survival benefit in prospective randomised controlled clinical trials (RCTs) when given for fungal prophylaxis treatment and decreased indirect and overall costs [22, 86]. Fluconazole is a weaker CYP3A4 inhibitor than other azoles and, specifically, fluconazole prophylaxis has been used in acute lymphoblastic leukaemia (ALL) induction chemotherapy, but there are no reliable data to support a recommendation for prophylaxis in this setting. Thus, our recommendation (CI) regarding fluconazole prophylaxis in patients with neutropenia remains unchanged.\n\nItraconazole\nA non-comparative prospective trial evaluated the administration of itraconazole prophylaxis in AML patients [52]. Eighty-four patients received 200-mg oral solution twice daily during induction, re-induction and consolidation chemotherapy. IFI occurred in 3.4%, adverse events occurred in 7%, none leading to discontinuation. The study added only little more information to the already vast body of evidence on the prophylactic use of the itraconazole oral solution; therefore, the recommendation with poor evidence to support the prophylactic use of itraconazole (CI) did not change.\n\nIsavuconazole\nIsavuconazole is a novel antifungal approved in 2015. An open-label dose escalation study in 23 patients with AML was conducted (ClinicalTrials.gov identifier NCT00413439): 11 patients received 200 mg and 12 received 400 mg isavuconazole intravenously as antifungal prophylaxis [16]. Two patients developed possible IFI; most adverse events were mild or moderate, leading to discontinuation in four cases. In this small, phase II study, isavuconazole appeared safe and tolerable as prophylaxis in immunosuppressed high-risk patients. Only a well-designed RCT could provide solid evidence of prophylactic efficacy of isavuconazole. Currently, there is poor evidence to recommend prophylactic isavuconazole (CIIu).\n\nPosaconazole\nWe strongly recommend antifungal prophylaxis with posaconazole (AI) in patients with neutropenia. Posaconazole is available in different formulations: oral suspension, tablet and iv formulation. Strong recommendation for posaconazole use bases on a large RCT with the oral suspension [22].\n\nPosaconazole oral suspension was used in a single-centre, retrospective cohort study since 2014. This study compared clinical effectiveness of posaconazole with fluconazole in 130 patients receiving prophylaxis during first induction or first re-induction chemotherapy for AML or MDS. The primary endpoint was possible, probable or definite breakthrough IFI. Efficacy of posaconazole was superior to fluconazole, probable/definite breakthrough IFI occurred in 9.2 and 27.0%, respectively. High differences of IFI in different studies can be explained by incomplete data sets due to retrospective acquisition and varying definitions of IFI despite wide spread use of EORCT criteria. Additionally, centre effects driven by differences in rigour of diagnostic strategies may contribute to discrepancy. These results support our previous strong recommendation for antifungal prophylaxis with posaconazole in patients at high risk for IFI (AI). In 2015, a retrospective analysis of 70 AML patients after induction chemotherapy found the frequent necessity of systemic antifungal treatment for probable or proven IFI despite prophylaxis with posaconazole oral suspension [92].\n\nNo data are available for populations with persisting neutropenia, e.g. very severe aplastic anaemia or MDS treated with hypomethylating agents. Thus, one must extrapolate from findings of other high-risk neutropenic patient studies [22]. The group recommends posaconazole prophylaxis in such clinical settings (BIIt), unless such prophylaxis is contraindicated because of drug-drug interactions, e.g. ALL patients [5, 20].\n\nNo evidence-based recommendations can be made on the duration of prophylaxis in patients with persisting neutropenia. There is poor evidence regarding posaconazole prophylaxis during AML consolidation therapy (CIIt). Further prospective trials on antifungal prophylaxis in patients with ALL, aplastic anaemia or MDS are required to give evidence-based recommendations in future.\n\nPosaconazole oral suspension has limited bioavailability underlining the need for better absorbable formulations [24, 92]. Since 2014, two studies have been published on prophylaxis with posaconazole delayed release (DR) tablets. One study compared 200 and 300 mg tablets in 54 patients to evaluate pharmacokinetics and safety profile (NCT01777763). The exposure target of a steady-state average concentration of > 500 ng/mL was reached in 15 of 19 patients receiving 200 mg once daily and in 31 of 32 on 300 mg once daily. Tablets were well tolerated [27]. The second study characterised posaconazole tablet pharmacokinetic and safety in 210 patients with neutropenia following chemotherapy for haematological malignancy or recipients of allogeneic HSCT. Patients took posaconazole 300 mg DR tablets once daily independent of food intake. Pre-specified exposure targets were achieved in almost all patients. The drug was well tolerated and safe, similar to posaconazole oral suspension [18]. The tablet formulation of posaconazole is safe, effective and provides predictable absorption. We thus recommend posaconazole tablets as drug of choice for IFI prevention in AML and MDS patients (AI).\n\nOne study evaluated pharmacokinetics and safety of intravenous posaconazole in antifungal prophylaxis of neutropenic patients with AML, MDS or in the context of allogeneic HSCT [20]. In total, 237 received 300 mg posaconazole iv twice daily on day 1 and thereafter 300 mg iv once daily for up to 28 days. Average concentrations were reached in 94% of patients between 500 and 2500 ng/mL. The most common treatment-related adverse events were diarrhoea, nausea and rash (8, 5 and 5%, respectively). We recommend posaconazole iv in patients when oral formulations are not appropriate, but emphasise the need for further randomised trials.\n\nVoriconazole\nVoriconazole has been shown to be efficacious in the treatment of IA [44], but—apart from haematopoietic stem cell recipients—data on prophylaxis in patients at risk for IFI is still scarce [62, 111]. One retrospective study compared safety and efficacy of voriconazole and oral suspension posaconazole prophylaxis in patients with haematological malignancies (n = 200) [39]. IFI occurred in 0 and 3%, respectively; symptomatic adverse events were more frequent in the voriconazole group (6 and 0%). Our CII recommendation for voriconazole remains therefore unchanged.\n\nClotrimazole, miconazole and ketoconazole\nNo additional literature has been published since 2014. There is poor evidence to support the prophylactic use of clotrimazole, miconazole or ketoconazole (DII).\n\nEchinocandins\nResistance to drugs of the echinocandin class remains low for most Candida spp., e.g. C. albicans at < 3% [10]. In contrast, C. glabrata shows increasing in vitro resistance to this drug class [1, 80]. Expanding use of echinocandins for prophylaxis in patients with high risk of invasive candidiasis has some potential to contribute to emergence of resistance. We hence recommend to consider antifungal prophylaxis with echinocandins on the basis of local epidemiology (BIII) [35].\n\nAnidulafungin and caspofungin\nNo additional relevant data have been published since 2014; our recommendation in patients with neutropenia remains unchanged (CI).\n\nMicafungin\nNo prospective clinical trial on micafungin prophylaxis in the non-transplant setting was published since 2014. Results from a retrospective single-centre observational study comparing micafungin 50 mg iv with posaconazole 200 mg orally (historical control) in the prevention of IFI in neutropenic patients with haematological malignancies (n = 302) showed that there was no statistically significant difference in IFI rates (6.0 versus 5.4%) [73]. The authors propose micafungin as a good alternative for antifungal prophylaxis in patients with neutropenia while posaconazole and liposomal amphotericin B should remain first-line therapy. Our recommendation in patients with neutropenia remains unchanged (CIIh).\n\nPolyenes\nLiposomal amphotericin B\nProphylactic aerosolized liposomal amphotericin B in severely neutropenic patients significantly reduced invasive pulmonary aspergillosis (IPA) rates, resulting in a BII recommendation in 2014 [87]. A recently published cohort study confirmed that prophylactic liposomal amphotericin B inhalation resulted in a substantial decrease in IPA incidence [12]; 235 AML patients inhaled 12.5 mg twice weekly from initiation of remission induction chemotherapy until recovery of their neutrophils. The primary endpoint was incidence of proven or probable IPA until 28 days after neutrophil recovery. IPA rates were 9.5% in the liposomal amphotericin B and 23.4% in the historical no-prophylaxis control group. Liposomal amphotericin B inhalation appeared cost saving. Considering increasing azole resistance, non-azoles may become an option for future strategies in antifungal prophylaxis. Our recommendation to BII recommendation remains unchanged.\n\nA prospective non-comparative trial has demonstrated feasibility and safety of prophylaxis with a single 15-mg/kg intravenous L-AmB dose in 48 AML patients undergoing induction chemotherapy [2]. Apart from six patients with hypokalaemia, no grade 3–4 adverse events were reported. This approach needs validation by further clinical trials and can only be recommended with poor evidence at this time (CIIu).\n\nLiposomal amphotericin B prophylaxis was also evaluated in adult patients with ALL receiving remission-induction chemotherapy (NCT01259713). Currently, there is no approved standard of care for this group of patients regarding antifungal prophylaxis. Azole antifungal drugs are problematic because of drug-drug interactions with vin-caalkaloids, an integral component of ALL induction chemotherapy regimens [5, 19]. The authors hypothesised that liposomal amphotericin B is an alternative due to its broad spectrum of activity [14, 21, 56]. Yet, IFI rates in the liposomal amphotericin B group (7.9%) did not significantly differ from the placebo group (11.7%). Given the high IFI rate in the placebo group, further clinical trials are needed to define an adequate antifungal prophylaxis strategy in ALL patients during remission-induction. Until then, there is poor evidence to recommend intravenous liposomal amphotericin B for prophylaxis in ALL (CI).\n\nAmphotericin B deoxycholate has been shown to be too toxic and therefore is not recommended for prophylactic use (DI).\n\nNystatin\nThe use of nystatin mouthwash was compared to placebo in patients with haematological malignancies (n = 158) and was—surprisingly—found effective for prophylaxis of pulmonary IFI (IFI rates 1.6 and 27.7%, respectively) [46]. Due to the missing mechanistic explanation of the result and the uncertain attribution of colonisation and IFI, the study did not impact our recommendations on antifungal prophylaxis in neutropenic patients (DII).\n\nRisk factors for IFI\nNovel targeted cancer therapy\nNew drug classes for haematological and oncologic diseases such as tyrosine kinase inhibitors (TKI) and other immunomodulatory drugs put a broader spectrum of patients at risk for IFI [84].\n\nAmong TKI, in particular inhibitors of bruton tyrosine kinase (BTK) [77, 84], mammalian target of rapamycin (mTOR) [31, 72, 88], janus kinase (JAK) [41, 70, 113] and phosphatidylinositol 3 kinase (PI3K) delta [58] showed attributable increase of risk of IFI. Targeting critical components of the immune system, they impair diverse features of immune cells (e.g. dendritic cells, T cells) [42, 91, 114]. However, underlying haematological disease, recent treatment, as well as neutropenia put these patients at an increased baseline risk for IFI. Currently, it remains unclear, if antifungal prophylaxis is indicated in these cases.\n\nInhibition of immune checkpoints, e.g. programmed cell death protein 1 (PD1) or cytotoxic T lymphocyte-associated protein 4 (CTLA4), shows wide-ranging, mostly immune-related adverse events [7, 59, 98]. Subsequent immunosuppression, primarily including corticosteroids, may result in opportunistic infections including fungi [32, 57, 110]. Prospective clinical trials may help optimizing management of immune-related adverse events.\n\nHypomethylating agents such as azacitidine put patients with AML or MDS at risk of IFI (probable/proven IFI 1.6%, n = 121, to 8.3%, n = 64) [30, 82]. Further, independent risk factors are low neutrophil and platelet counts [68], as well as prior intensive chemotherapy [30, 68]. Evaluation of risk factors should precede prescription of hypomethylating agents and antifungal prophylaxis could be considered accordingly.\n\nTargeting CD20 leads to prolonged B cell depletion and in rare cases to late-onset neutropenia [29, 106, 109]. One retrospective case-control study reported that a significantly higher IFI rate was reported in patients treated with rituximab regimens compared to chemotherapy alone (41.7 vs. 17.1% among all infections, n = 69) [61]. Large randomised trials evaluating efficacy and safety of adding rituximab to standard chemotherapy did not find increased IFI rates [13, 38]. Antifungal prophylaxis should only be considered in case of additional risk factors.\n\nFurther antibodies target CD19, CD33 or interleukin-2 (IL-2). Low evidence on risk of IFI makes it difficult to give specific recommendations and guidelines on empiric or pre-emptive therapy should be followed [43, 74]. In rare occasions where CD52 antibody is part of the antineoplastic strategy, mould directed prophylaxis should be considered [51, 71]. Bispecific antibodies frequently cause neutropenic fever and infections, but direct causal relationship with these drugs is difficult to attribute being used in patients with advanced lymphoma at high risk for infection anyhow [85]. An increased risk for IFI has not been reported to date.\n\nGiven the high attributable mortality of IFI, the individual risk of patients treated with the drug classes above should be evaluated, and antifungal prophylaxis prescribed on case by case basis. Guidance that is more precise needs prospective trials focussed on infections.\n\nInfection control for prevention of IFI\nInfection-control measures in the haematological and oncologic setting are heterogeneous and contentious, particularly about transmission of fungi. The Robert Koch-Institute in Germany published recommendations on hygiene requirements for the medical care of immunocompromised patients [3]. However, most recommendations are based on expert opinion rather than actual published evidence. We reviewed recent trials on infection-control measures intending to prevent or reduce the rate of IFI.\n\nMost studies focusing on the role of protective isolation are non-randomised and biased by renovation and reconstruction [67]. Available studies suggested clinical benefit of air filters and positive pressure environments, but mainly evaluated fungal conidia air concentration instead of patient outcome [55, 76]. None was randomised. One meta-analysis confirmed the low level of available evidence. No data showing a reduction of mould infections are available [90].\n\nSurgical masks are used for protection of immunocompromised high-risk patients, but a clinical benefit has not been demonstrated [64]. One RCT compared 80 adult patients treated for acute leukaemia or HSCT regarding standard hospital hygiene procedures with or without wearing masks. A reduction of IFI was not seen (proven/probable IFI in 19.5 and 20.5%) [66]. In contrast, one study compared neutropenic patients wearing surgical masks during hospital construction with a historical control and found a reduction in Aspergillus spp. infections [83]. Specific settings may justify the use of well-fitting face masks; routine use seems inappropriate.\n\nThe value of germ-reduced diet including so-called “neutropenic diet” is unproven. No RCT proved a benefit for prevention of infection and related outcomes. All studies had limitations regarding confounding interventions, outcome definitions, intervention and control diets [25, 33, 69, 105, 107].\n\nFurther clinical implications include appropriate hand hygiene. This aspect has recently been pointed out within the context of Candida auris transmission considering that hands can be key vectors in the transmission of yeasts [89]. Housing of patients as well as limitation of environmental exposure to air-borne conidia are matters of infection control and may outweigh impact of chemoprophylaxis. Because of difficulties in randomisation evidence remains low.\n\nDue to lack of evidence, we do not provide recommendations for clinical practice.\n\nRole of therapeutic drug monitoring\nTherapeutic drug monitoring (TDM) of serum samples may improve efficacy and safety of antifungal prophylaxis. Two variables influence the potential utility of TDM: variable pharmacokinetics and a clear correlation between plasma drug concentration and efficacy or toxicity [47, 94].\n\nVoriconazole meets both criteria: pharmacokinetics are variable while exhibiting difficulty to predict drug dose-exposure relationship [8, 50, 100, 101], and serum concentration was linked to efficacy [79, 102] and toxicity [26, 48, 79, 96, 100, 102, 115]. Voriconazole serum levels were often out of target range at the initiation of antifungal prophylaxis, 18% were sub-therapeutic (< 1 mg/L) and 11% too high (> 5.5 mg/L) (n = 107) [37]. Based on current literature, we recommend a concentration of 1–2 mg/L for prophylactic efficacy [79, 102]. In addition, concentrations > 5–6 mg/L should be avoided to prevent central nervous system and liver toxicity [26, 79, 102, 115]. TDM should be done within 2 to 5 days of treatment initiation, and repeatedly in case of suspicious adverse events, or initiation or termination of interacting drugs (BIItu).\n\nThere is no well-defined minimum serum concentration for posaconazole prophylaxis. Neither did serum concentrations of posaconazole correlate with efficacy nor with toxicity in the two large RCT [22, 103]. A level of 500 mg/L has been proposed, but was merely extrapolated from itraconazole data [34]. Despite lack of evidence [23, 49] to support a specific reference range, there is a general consensus of 500 to 700 mg/L being a desirable lower bound [4, 11, 40, 60, 93]. A retrospective study analysing posaconazole serum levels of 31 patients described lower serum levels in 43% of patients associated with advanced age and mucositis [36]. Routine TDM is not recommended (CIItu). Yet, in cases of clinical failure such as breakthrough IFI, it may be helpful for verification of compliance or absorption. An important parameter influencing usefulness of TDM is the turnaround time from sampling to result.\n\nConclusion\nThere is good evidence to recommend antifungal prophylaxis with posaconazole as oral suspension or—preferably—tablet in patients with remission induction chemotherapy for AML and MDS (AI). Posaconazole iv administration can be considered in those cases unable to take or absorb oral formulation. Liposomal amphotericin B did not significantly decrease IFI rates in ALL induction chemotherapy patients (CI). Since the IFI rate in ALL patients is considerable, further clinical trials are needed to find effective antifungal prophylaxis.\n\nTDM should be performed within 2 to 5 days of voriconazole prophylaxis initiation and should be repeated in case of suspicious adverse events or dose changes of interacting drugs (BIItu). TDM is not generally necessary during posaconazole prophylaxis (CIItu), although in individual cases, for example potential breakthrough infection, it may be helpful to evaluate compliance, absorption and likelihood of IF.\n\nCompared to the 2014 edition of this guideline, a further change is the elimination of the recommendations for allogeneic HSCT recipients regarding antifungal prophylaxis. We moved them to our guidelines specifically developed for this group of patients [104].\n\nElectronic supplementary material\n\nESM 1 (DOCX 232 kb)\n\n \n\n\nElectronic supplementary material\n\nThe online version of this article (10.1007/s00277-017-3196-2) contains supplementary material, which is available to authorized users.\n\nCompliance with ethical standards\nConflict of interest\nAuthor JP received honoraria, travel support by MSD Sharp & Dohme, Gilead Sciences, Pfizer, Astellas Pharma. Author DB has received honoraria and research grants by Astellas, Basilea, Gilead Sciences, Merck Sharp & Dohme/Merck (MSD), and Pfizer. Author MC has received fees by Basilea, Gilead, and MSD. Author MKi is a consultant and on the speakers’ bureaus of MSD, and he is a consultant for Gilead and on the speakers’ bureau of Astellas. Author MvLT is supported by the German Federal Ministry of Research and Education (BMBF grants 01EO1002 and 13GW0096D); has received research grants from Pfizer and MSD, is a consultant to Merck/MSD; and received honoraria or travel grants from Basilea, Gilead, Merck/MSD, and Astellas. Author GM has been a consultant to Gilead and F2G and received honoraria for lectures from Gilead, Pfizer, Basilea, and Astellas. Author DT received honoraria and travel grant from Gilead and MSD. Travel grant from Astellas and Jazz. Consultant of advisory board for MSD and Pfizer. Author AJU has received support for travel to meetings from Astellas and Basilea. He is a consultant and on the speakers’ bureaus of Astellas, Gilead, MSD, and Pfizer. He has also received support for travel and accommodation from Astellas, Boehringer Ingelheim, Gilead, MSD, and Pfizer for activities unrelated to the current study. His institution has received grants from Astellas, Gilead, MSD, and Pfizer. Author OP received research grants from Bio-Rad and Gilead; is consultant to Merck/MSD and Gilead; and received lecture honoraria and travel grants from Astellas, Gilead, Pfizer, and Merck/MSD. Author MR is commercially sponsored by Basilea. Author HO received research grants from Gilead and MSD; is consultant to Astellas and MSD; and received lecture honoraria and travel grants from Astellas, Basilea, Gilead, Pfizer, and Merck/MSD. Author OAC is supported by the German Federal Ministry of Research and Education and the European Commission and has received research grants from, is an advisor to, or received lecture honoraria from Achaogen, Actelion, Amplyx, Anacor, Arsanis, Astellas, AstraZeneca, Basilea, Bayer, Cidara, Da Volterra, F2G, Gilead, GSK, Janssen, Matinas, MedPace, Melinta, Menarini, Merck/MSD, Miltenyi, Paratek, Pfizer, Rempex, Roche, Sanofi Pasteur, Scynexis, Seres, Summit, Tetraphase, Medicines Company, and Vical. All remaining authors have declared no conflicts of interest.\n==== Refs\nReferences\n1. Alexander BD Johnson MD Pfeiffer CD Increasing echinocandin resistance in Candida Glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations Clin Infect Dis 2013 56 1724 1732 10.1093/cid/cit136 23487382 \n2. 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Herbrecht R Denning DW Patterson TF Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis N Engl J Med 2002 347 408 415 10.1056/NEJMoa020191 12167683 \n45. Howard SJ Cerar D Anderson MJ Frequency and evolution of azole resistance in aspergillus fumigatus associated with treatment failure Emerg Infect Dis 2009 15 1068 1076 10.3201/eid1507.090043 19624922 \n46. Hu R Jiang X Wu Y Prospective trial finds nystatin mouthwash effective prophylaxis for pulmonary invasive fungal infections that originate in the throat of patients with hematologic malignancies Neoplasma 2013 60 315 321 10.4149/neo_2013_042 23374002 \n47. Hussaini T Ruping MJ Farowski F Therapeutic drug monitoring of voriconazole and posaconazole Pharmacotherapy 2011 31 214 225 10.1592/phco.31.2.214 21275497 \n48. Imhof A Schaer DJ Schanz U Neurological adverse events to voriconazole: evidence for therapeutic drug monitoring Swiss Med Wkly 2006 136 739 742 17183438 \n49. 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Rieger CT Cornely OA Hoppe-Tichy T Treatment cost of invasive fungal disease (Ifd) in patients with acute myelogenous leukaemia (Aml) or myelodysplastic syndrome (Mds) in German hospitals Mycoses 2012 55 514 520 10.1111/j.1439-0507.2012.02193.x 22471310 \n87. Rijnders BJ Cornelissen JJ Slobbe L Aerosolized liposomal amphotericin B for the prevention of invasive pulmonary aspergillosis during prolonged neutropenia: arandomized, placebo-controlled trial Clin Infect Dis 2008 46 1401 1408 10.1086/586739 18419443 \n88. Sarkaria JN Galanis E Wu W Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks Clin Cancer Res 2010 16 5573 5580 10.1158/1078-0432.CCR-10-1453 20921209 \n89. Schelenz S Hagen F Rhodes JL First hospital outbreak of the globally emerging Candida Auris in a European hospital Antimicrob Resist Infect Control 2016 5 35 10.1186/s13756-016-0132-5 27777756 \n90. 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Stott KE Hope WW Therapeutic drug monitoring for invasive mould infections and disease: pharmacokinetic and pharmacodynamic considerations J Antimicrob Chemother 2017 72 i12 i18 10.1093/jac/dkx029 28355463 \n95. Tacke D Buchheidt D Karthaus M Primary prophylaxis of invasive fungal infections in patients with haematologic malignancies. 2014 update of the recommendations of the infectious diseases working Party of the German Society for Haematology and oncology Ann Hematol 2014 93 1449 1456 10.1007/s00277-014-2108-y 24951122 \n96. Tan K Brayshaw N Tomaszewski K Investigation of the potential relationships between plasma voriconazole concentrations and visual adverse events or liver function test abnormalities J Clin Pharmacol 2006 46 235 243 10.1177/0091270005283837 16432276 \n97. Teng JC Slavin MA Teh BW Epidemiology of invasive fungal disease in lymphoproliferative disorders Haematologica 2015 100 e462 e466 10.3324/haematol.2015.126698 26206797 \n98. Topalian SL Hodi FS Brahmer JR Safety, activity, and immune correlates of anti-PD-1 antibody in cancer N Engl J Med 2012 366 2443 2454 10.1056/NEJMoa1200690 22658127 \n99. Tortorano AM Peman J Bernhardt H Epidemiology of candidaemia in Europe: results of 28-month European Confederation of Medical Mycology (ECMM) hospital-based surveillance study Eur J Clin Microbiol Infect Dis 2004 23 317 322 10.1007/s10096-004-1103-y 15029512 \n100. Trifilio S Ortiz R Pennick G Voriconazole therapeutic drug monitoring in allogeneic hematopoietic stem cell transplant recipients Bone Marrow Transplant 2005 35 509 513 10.1038/sj.bmt.1704828 15654347 \n101. Trifilio S Pennick G Pi J Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients Cancer 2007 109 1532 1535 10.1002/cncr.22568 17351937 \n102. Ueda K Nannya Y Kumano K Monitoring trough concentration of voriconazole is important to ensure successful antifungal therapy and to avoid hepatic damage in patients with hematological disorders Int J Hematol 2009 89 592 599 10.1007/s12185-009-0296-3 19340528 \n103. Ullmann AJ Lipton JH Vesole DH Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease N Engl J Med 2007 356 335 347 10.1056/NEJMoa061098 17251530 \n104. Ullmann AJ Schmidt-Hieber M Bertz H Infectious diseases in allogeneic haematopoietic stem cell transplantation: prevention and prophylaxis strategy guidelines 2016 Ann Hematol 2016 95 1435 1455 10.1007/s00277-016-2711-1 27339055 \n105. Van Dalen EC Mank A Leclercq E Low bacterial diet versus control diet to prevent infection in cancer patients treated with chemotherapy causing episodes of neutropenia Cochrane Database Syst Rev 2016 4 Cd006247 27107610 \n106. 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"fulltext_license": "CC BY",
"issn_linking": "0939-5555",
"issue": "97(2)",
"journal": "Annals of hematology",
"keywords": "Amphotericin B; Antifungal prophylaxis; Fluconazole; Invasive fungal infection; Isavuconazole; Itraconazole; Liposomal; Posaconazole",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000935:Antifungal Agents; D002986:Clinical Trials as Topic; D016903:Drug Monitoring; D006405:Hematology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host; D060828:Induction Chemotherapy; D000072742:Invasive Fungal Infections; D015470:Leukemia, Myeloid, Acute; D008495:Medical Oncology; D009190:Myelodysplastic Syndromes; D011322:Primary Prevention; D012955:Societies, Medical; D014230:Triazoles; D065819:Voriconazole",
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"abstract": "BACKGROUND Pseudoaneurysms are a known pathology commonly recognized after disruption of the vascular wall leads to the development of a hematoma. Although pseudoaneurysms are common, occurrence in the location of the superior rectal artery is exceedingly rare, has been documented in the literature only 7 times, and can be extremely dangerous. Patients can present with vague abdominal complaints, pain, gastrointestinal bleeding, and development of hematomas, and can progress to hemodynamic instability related to hypovolemia. This phenomenon requires swift recognition and patient management, as well as stabilization, to achieve desired results and minimize morbidity and mortality. CASE REPORT We report the case of a 79-year-old man who presented after minor trauma with gastrointestinal bleeding and was diagnosed with a retroperitoneal hematoma. Although he was stabilized and discharged, conventional angiography diagnosing and treating his causative superior rectal artery pseudoaneurysm was not completed until a second traumatic event resulted in recurrent presentation with worsened symptoms and retroperitoneal hematoma enlargement. CONCLUSIONS Superior rectal artery pseudoaneurysm is a rarely-reported phenomenon, usually occurring after a traumatic event. It can lead to significant anemia, hypovolemic shock, blood transfusion, and other serious consequences. It can be difficult to diagnose given its location and obscurity. However, upon diagnosis, swift treatment is recommended, for which a variety of both surgical and endovascular approaches have been employed to prevent exsanguination.",
"affiliations": "Department of General Surgery, Duke LifePoint Conemaugh Memorial Medical Center, Johnstown, PA, USA.;Department of General Surgery, Duke LifePoint Conemaugh Memorial Medical Center, Johnstown, PA, USA.;Department of Trauma, Duke LifePoint Conemaugh Memorial Medical Center, Johnstown, PA, USA.;Department of Radiology, Duke LifePoint Conemaugh Memorial Medical Center, Johnstown, PA, USA.;Department of General Surgery, Duke LifePoint Conemaugh Memorial Medical Center, Johnstown, PA, USA.",
"authors": "Curfman|Karleigh R|KR|;Shuman|Mieka P|MP|;Gorman|Kimberly M|KM|;Schrock|Wesley B|WB|;Meade|Paul G|PG|",
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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\n32845874\n10.12659/AJCR.924529\n924529\nArticles\nPost-Traumatic Retroperitoneal Hematoma Caused by Superior Rectal Artery Pseudoaneurysm\nCurfman Karleigh R. ABEF1 Shuman Mieka P. ABEF1 Gorman Kimberly M. ABEF2 Schrock Wesley B. ABCD3 Meade Paul G. ABEF1 \n1 Department of General Surgery, Duke LifePoint Conemaugh Memorial Medical Center, Johnstown, PA, U.S.A.\n\n2 Department of Trauma, Duke LifePoint Conemaugh Memorial Medical Center, Johnstown, PA, U.S.A.\n\n3 Department of Radiology, Duke LifePoint Conemaugh Memorial Medical Center, Johnstown, PA, U.S.A.\nCorresponding Author: Karleigh R. Curfman, e-mail: kcurfman@conemaugh.orgAuthors’ 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 \n26 8 2020 \n21 e924529-1 e924529-6\n23 3 2020 18 6 2020 15 7 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, 79-year-old\n\nFinal Diagnosis: Superior rectal artery pseudoaneurysm\n\nSymptoms: Abdominal pain • gastrointestinal bleeding\n\nMedication:—\n\nClinical Procedure: Embolization\n\nSpecialty: Radiology • Surgery\n\nObjective:\nRare disease\n\nBackground:\nPseudoaneurysms are a known pathology commonly recognized after disruption of the vascular wall leads to the development of a hematoma. Although pseudoaneurysms are common, occurrence in the location of the superior rectal artery is exceedingly rare, has been documented in the literature only 7 times, and can be extremely dangerous. Patients can present with vague abdominal complaints, pain, gastrointestinal bleeding, and development of hematomas, and can progress to hemodynamic instability related to hypovolemia. This phenomenon requires swift recognition and patient management, as well as stabilization, to achieve desired results and minimize morbidity and mortality.\n\nCase Report:\nWe report the case of a 79-year-old man who presented after minor trauma with gastrointestinal bleeding and was diagnosed with a retroperitoneal hematoma. Although he was stabilized and discharged, conventional angiography diagnosing and treating his causative superior rectal artery pseudoaneurysm was not completed until a second traumatic event resulted in recurrent presentation with worsened symptoms and retroperito-neal hematoma enlargement.\n\nConclusions:\nSuperior rectal artery pseudoaneurysm is a rarely-reported phenomenon, usually occurring after a traumatic event. It can lead to significant anemia, hypovolemic shock, blood transfusion, and other serious consequences. It can be difficult to diagnose given its location and obscurity. However, upon diagnosis, swift treatment is recommended, for which a variety of both surgical and endovascular approaches have been employed to prevent exsanguination.\n\nMeSH Keywords:\nAneurysm, FalseAngiographyAnticoagulantsHematomaRetroperitoneal Space\n==== Body\nBackground\nPseudoaneurysm can be common within the human anatomy, in which a perivascular hematoma develops due to disruption of the vascular wall layers and results in a communicating hematoma [1]. This entity, although common in other vessels, is extremely rare in the superior rectal artery (SRA) and has been reported in only 7 published cases [2–8]. Although several of the prior reports were related to traumatic events and the others were caused by unique, varying factors, their presenting symptoms and treatment modalities were strikingly similar and successful. Here, we describe the presentation and hospital course of a 79-year-old man on therapeutic anticoagulation, who presented several days after a ground-level fall with complaints of abdominal pain, constipation requiring manual disimpaction, and subsequent gastrointestinal bleeding. At that time, he was diagnosed with a large retroperitoneal hematoma, stabilized, and discharged. It was not until after the patient’s second fall approximately 4 weeks later, for which he presented with worsened complaints and hematoma enlargement, that a bleeding SRA pseudoaneurysm was identified as the cause of his symptoms. Here, we discuss the hospital course and patient management and present a literature review of presentation, diagnosis, imaging, and recommended treatment options and strategies for management of SRA pseudoaneurysms.\n\nCase Report\nApproval to publish this case report was obtained from the facility’s Institutional Review Board prior to investigation and reporting. We describe a 79-year-old man who initially presented to the Emergency Department (ED) with acute onset of abdominal and rectal pain, as well as 1 episode of rectal bleeding. He reported that he had recently fallen 3–4 days prior to presentation and had been constipated, requiring manual disimpaction, which caused bleeding. Of note, he was on warfarin for a history of atrial fibrillation; thus, due to his symptoms and history, he underwent computed tomography angiography (CTA). His CTA was significant for a large, poorly-defined, retroperitoneal hematoma extending from the right abdomen into the pelvis, without obvious active bleeding (Figures 1, 2). Because a large hematoma was identified, his anticoagulation was held, serial abdominal examinations were performed, and his hemoglobin was serially trended. On presentation, his hemoglobin was 13.0 gm/dL; however, over the next 24 h it decreased to 8.5 gm/dL. The patient became tachycardic and thus was transfused with 2 units of packed red blood cells and 1 unit of fresh frozen plasma for an international normalized ratio of 1.7. His hemoglobin was then stable after transfusion for several days and remained stable after resumption of warfarin, and he was then discharged.\n\nThe patient was scheduled for repeat CTA imaging in 6 weeks, but 4 weeks after discharge he returned to the ED with similar complaints of abdominal pain, constipation, and urinary retention. His hemoglobin was stable upon his return, but he unfortunately signed out of the ED against medical advice prior to receiving any further interventions. Two days later, he returned after another fall, with complaints of worsening abdominal pain, distention, constipation, and urinary retention. His hemoglobin was relatively stable; however, his CTA was repeated, with new concerns for enlargement of the known retroperitoneal hematoma from the previous size of 9.0×4.5 cm to 9.9×7.4 cm, as well as signs of active bleeding and a questionable pseudoaneurysm (Figures 3, 4). He underwent pelvic and inferior mesenteric artery (IMA) angiograms with Interventional Radiology (IR), where a large blush off of the SRA was identified, suggestive of a pseudoaneurysm (Figure 5).\n\nSeveral attempts at embolization of the tiny feeding branch were unsuccessful; therefore, coil embolization of the SRA was performed (Figure 6). Following the procedure, the patient’s hemoglobin and vital signs were stable within baseline parameters. He was discharged home on post-procedure day 2 and continued on warfarin. He has yet to follow-up on an outpatient basis with either the Trauma or Interventional Radiology services. However, on evaluation in the ED for separate complaints, repeat imaging was performed, which demonstrated a slight decrease in his retroperitoneal hematoma to 9.0×7.0 cm and his hemoglobin level was stable at baseline.\n\nDiscussion\nPseudoaneurysm is a perivascular hematoma that develops as the result of a partial disruption of the vascular layers, which maintains communication with the vascular structure [1].\n\nThe significant difference distinguishing pseudoaneurysm from aneurysm is the involvement of wall layers – a true aneurysm involves all vessel wall layers, while a pseudoaneurysm is only associated with partial wall layer involvement [1]. There are various known causes of pseudoaneurysm, most importantly infection, inflammation, and trauma [2]. In addition, there can be significant complications associated with pseudoaneurysms, including rupture, massive hemorrhage, adjacent structure compression, and infection [2]. Thus, given the serious risk of complications, especially with an associated rupture mortality risk of nearly 50%, early diagnosis and immediate appropriate management are essential [2]. For diagnosis, imaging must be performed, for which the criterion standard is conventional angiography [1]. However, due to limitations in personnel and facility capabilities, pseudoaneurysms are often diagnosed via other imaging modalities such as ultrasound or contrast-enhanced computed tomography [1]. Another benefit of diagnosing pseudoaneurysm via conventional angiography is that conventional angiography can concomitantly be therapeutic [1]. Recommendations for management include angiographic embolization and/or stent placement, as well as the possible need for surgical intervention [2].\n\nInitially, there were concerns for colonic ischemia and infarction associated with angiographic embolization, which have since been resolved [9]. Prior angiographic interventions did not gain significant popularity due to the use of nonsteerable wires, and resulted in inadvertent dissections and embolization of marginal arteries, with subsequent ischemia [9]. With the development of steerable guidewires, the super-selective delivery of small embolization coils to vessels distal to the marginal arteries could be achieved, which significantly lowered the colonic ischemia and infarction risk [3,9]. Proceeding with surgical intervention is indicated when angiographic treatment modalities fail or if the patient is hemodynamically unstable [1]. There are several surgical options that can be used to achieve hemostasis, including pseudoaneurysm resection with bypass, ligation, or resection of the involved organ [1].\n\nThe occurrence of pseudoaneurysms throughout the body is often reported, especially after vascular or cardiac interventions; however, involvement of the SRA is rare. Our thorough literature search found only 7 other documented cases – 3 were related to trauma (2 were secondary to direct rectal injury, 1 occurred after colonoscopic polypectomy) [2–4], and the remaining 4 were atraumatic. One patient presented with bleeding, likely related to clopidogrel use, another was reported with a history of renovascular hypertension secondary to fibrodysplasia, 1 patient was recognized following malignant tumor erosion into the vessel, and 1 patient was identified after bevacizumab use for sigmoid adenocarcinoma [5–8]. Although the reported cases had various causes, their symptom complexes were similar. Six of the known cases presented with a chief complaint of lower-gastrointestinal bleeding [2–5,7,8], and the remaining patient presented with complaints of worsening abdominal pain [6]. In addition, although the causes varied, the management plans in each of these cases, as well as our own, followed the previously stated recommendations. In all of the reviewed cases, the patients were able to be safely treated via angio-graphic embolization, though 2 cases initially underwent open surgery [3–8]. In the published cases, the patients achieved hemodynamic stability and improvement in symptoms following intervention, without any reported pseudoaneurysm-related mortalities. As in the present case, the appropriate diagnosis could not be identified on initial presentation, and development of pseudoaneurysm may have been a delayed complication of the initial event. Regardless, delay in identification and management of a pseudoaneurysm can lead to worsening and possibly life-threatening bleeding. Table 1 summarizes the reported cases, their presenting symptoms, mechanism, treatment modality, and time to treatment, if available, for comparison and ease of review.\n\nFinally, in addition to the rarity of this phenomenon occurring in the SRA, there have been multiple other rare occur-rences seen in other sites throughout the body. Inadvertently-discovered occurrences have been reported in the peripheral arteries as a known complication of percutaneous interventions, but there are other unique locations and occurrences that have occurred without interventions, similar to our case. Some of these other rare cases included involvement of the middle meningeal artery, superior mesenteric artery, occipital artery, and palmar arch [10–14]. Such as the cases referenced in our SRA pseudoaneurysm review, these patients presented with varying symptoms, mechanisms, time to diagnosis, and treatment modalities. Their presenting symptoms were most commonly related to pseudoaneurysm location, and included drowsiness, headache, aphasia, pain, recurrent bleeding, and swelling [10–14]. The mechanisms also differed, with both traumatic and nontraumatic causes (acute head trauma, chronic development after head trauma, apixaban use, knife laceration) [10–14]. Similarly, treatment and time to treatment varied between endovascular and open approaches – immediate and months after initial injury, respectively. These treatments included cerebral angiogram with Histoacryl embolization of the middle meningeal artery, cerebral angiogram with glue embolization of middle meningeal artery, endovascular coiling, and open surgical ligation [10–14] (Table 1). Consistent with our SRA pseudoaneurysm review, the mechanism, presentation, timing, and management of these pseudoaneurysms varied, but all reported cases required appropriate identification and treatment to prevent further serious complications, bleeding, rupture, and death.\n\nConclusions\nSuperior rectal artery pseudoaneurysms are extremely rare but serious, with dire potential consequences. Due to the paucity of reported occurrences in the published literature, supporting evidence and recommendations are scarce, although existing recommendations appear to be effective. In the 7 previously published SRA pseudoaneurysm cases, and in our own, management techniques have yielded excellent results with minimal adverse effects and no mortalities. Given these findings, the success evidenced by angiographic management in our case and the significant adverse effects that are risked by delaying treatment, we are in agreement with the current recommendations and strongly support intervening and actively managing SRA pseudoaneurysms without delay.\n\nDisclosures\n\nThis report has been accepted for ePoster presentation at the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Virtual Annual Meeting on August 12–15, 2020 in Cleveland, Ohio, USA.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Initial presenting imaging of retroperitoneal hematoma. Coronal imaging of the patient’s presenting CTA scan demonstrating a poorly-defined hematoma beginning in the right hemi-abdomen near the duodenum and expanding inferiorly towards the pelvis, indicated by white arrows.\n\nFigure 2. Initial presenting imaging of retroperitoneal hematoma. Sagittal imaging of the patient’s presenting CTA scan demonstrating a poorly-defined hematoma beginning in the right hemi-abdomen near the duodenum and expanding inferiorly towards the pelvis, indicated by the white arrows with black outline.\n\nFigure 3. Increasing size of retroperitoneal hematoma with site of bleeding and pseudoaneurysm. After a second fall, the patient returned to the Emergency Department for further evaluation, where repeat computed tomography imaging was performed. The new imaging displayed a better-defined hematoma collection and an increase in size of the hematoma, indicated by the white arrows.\n\nFigure 4. Increasing size of retroperitoneal hematoma with site of bleeding and pseudoaneurysm. After a second fall, the patient returned to the Emergency Department for further evaluation, where repeat computed tomography imaging was performed. The new imaging displayed a better-defined hematoma collection and an increase in hematoma size, indicated in this image by the white arrows with black outline.\n\nFigure 5. Pelvic angiogram displaying a large superior rectal artery pseudoaneurysm. Demonstration of inferior mesenteric artery angiographic imaging in which a contrast blush suggestive of a superior rectal artery pseudoaneurysm was identified, indicated by black arrows.\n\nFigure 6. Control of superior rectal artery pseudoaneurysm after coil embolization. Inferior mesenteric artery angiographic imaging revealing the cessation of flow to the superior rectal artery pseudoaneurysm following successful coil embolization of the supplying vessel. This imaging shows no further active contrast blush, and the site of the coil embolization is indicated by black arrows.\n\nTable 1. Summary of reported cases of superior rectal artery pseudoaneurysm and summary of additional rare locations of pseudoaneurysms.\n\nPresenting symptoms\tMechanism of injury\tTreatment modality\tTime to treatment\t\nAbdominal pain, GI bleed\tFall while on anticoagulation\tAngiographic coil embolization of SRA\t4 weeks from initial presentation; 8 hours from re-presentation\t\nGI bleed\tPenetrating perineal wound\tHartmann’s procedure, emergent Hartmann’s revision, subsequent angiography\tPTD 0, PTD 3, PTD 19\t\n\t\tWith Gelfoam embolization of inferior mesenteric artery, anterior branch of\t\t\n\t\tBilateral internal iliac arteries\t\t\nGI bleed\tPenetrating perineal wound\tCeliotomy with sigmoid loop colostomy; angiography with\tPTD 11, PTD 17\t\n\t\tN-butyl cyanoacrylate (NBCA) embolization of SRA\t\t\nGI bleed\tEndoscopic polypectomy\tAngiographic glue embolization of SRA\t10 days after polypectomy\t\nGI bleed\tAntiplatelet use\tAngiographic coil embolization of SRA\t10 days after symptom onset\t\nAbdominal pain\tRenovascular hypertension, fibrodysplasia\tAngiographic coil embolization of SRA\t6 weeks after initial presentation\t\nGI bleed\tTumor induced SRA rupture\tAngiographic embolization\t1 day after symptom onset\t\nGI bleed\tHistory of bevacizumab therapy\tAngiographic coil embolization of SRA\tNot reported\t\nDrowsiness\tAcute head trauma\tCerebral angiogram with Histoacryl MMA embolization\tNot reported\t\nHeadache, aphasia\tHead trauma\tCerebral angiogram with glue MMA embolization\tPTD 5 months\t\nAbdominal pain\tApixaban use\tEndovascular coiling\tImmediate\t\nRecurrent bleeding\tHead trauma\tOpen surgical ligation\tPTD 4 weeks\t\nPain, swelling\tLaceration\tOpen surgical ligation\tPTD 3 weeks\t\nSummary of documented case details to aid in comparison of cases and results, including presenting symptom, mechanism, treatment modality, and time to treatment [2–8,10–14]. SRA – superior rectal artery; GI – gastrointestinal, PTD – post-trauma day; MMA – middle meningeal artery.\n==== Refs\nReferences:\n1. Choi PW Pseudoaneurysm rupture causing hemoperitoneum following rectal impalement injury: A case report Int J Surg Case Rep 2019 55 28 31 30684814 \n2. Kim KJ Seo JW Kim YS Traumatic pseudoaneurysm of the superior rectal artery with recurrent lower gastrointestinal and pelvic extraperitoneal bleeding: Importance of pretreatment recognition J Korean Soc Radiol, Jan 72 1 29 32 \n3. Iqbal J Kaman L Parkash M Traumatic pseudoaneurysm of superior rectal artery – an unusual cause of massive lower gastrointestinal bleed: A case report Gastroenterology Res 2011 4 1 36 38 27957012 \n4. Zakeri N Cheah SO A case of massive lower gastrointestinal bleeding: Superior rectal artery pseudoaneurysm Ann Acad Med Singapore 2012 41 11 529 31 23235730 \n5. Janmohamed A Noronha L Saini A Elton C An unusual cause of lower gastrointestinal haemorrhage BMJ Case Rep 2011 2011 bcr1120115102 \n6. Vieira M Sampaio S Lopes J [Endovascular management of a ruptured pseudoaneurysm of a rectal artery] Rev Port Cir Cardiotorac Vasc 2012 19 4 221 24 [in Portuguese] 24490200 \n7. Shirahata A Satou S Matsumoto T Superior rectal artery pseudoaneurysm caused by rectal cancer J Anus Rectum Colon 2014 67 6 408 12 \n8. Li CC Tsai HL Huang CW Iatrogenic pseudoaneurysm after bevacizumab therapy in patients with metastatic colorectal cancer: Two case reports Mol Clin Oncol 2018 9 5 499 503 30345042 \n9. Baig MK Lewis M Stebbing JF Marks CG Multiple microaneurysms of the superior hemorrhoidal artery: Unusual recurrent massive rectal bleeding: report of a case Dis Colon Rectum 2003 46 7 978 80 12847377 \n10. Paiva WS de Andrade AF Amorim RL Traumatic pseudoaneurysm of the middle meningeal artery causing an intracerebral hemorrhage Case Rep Med 2010 2010 219572 20589087 \n11. Umana GE Cristaudo C Scalia G Chronic epidural hematoma caused by traumatic intracranial pseudoaneurysm of the middle meningeal artery: Review of the literature with a focus on this unique entity World Neurosurg 2020 136 198 204 31927123 \n12. Guirgis M Xu JH Kaard A Mwipatayi BP Spontaneous superior mesenteric artery branch pseudoaneurysm: A rare case report EJVES Short Rep 2017 37 1 4 29234730 \n13. Woods M Moneley D Occipital artery pseudoaneurysm: A rare complication of head trauma EJVES 2014 27 4 34 35 \n14. Schoretsanitis N Moustafa E Beropoulis E Traumatic pseudoaneurysm of the superficial palmar arch: A case report and review of the literature J Hand Microsurg 2015 7 1 230 32 26078551\n\n",
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"title_normalized": "post traumatic retroperitoneal hematoma caused by superior rectal artery pseudoaneurysm"
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"abstract": "BACKGROUND\nRecurrent hepatitis C is very common leading to graft cirrhosis in a significant proportion of patients. Preliminary reports of combination therapy with interferon-ribavirin have been promising but generally applied to selected patients with chronic mild disease. Little is known, however, about the efficacy and risk of adverse effects when it is used in general clinical practice.\n\n\nOBJECTIVE\nTo analyse the efficacy (biochemical, virological and histological response) and tolerance of combination therapy in patients with recurrent hepatitis C genotype 1b.\n\n\nMETHODS\nTwenty-four patients (mean age 54 years; range 37-67 years; 75% male) with recurrent hepatitis C virus (histology at baseline: acute hepatitis (n = 3); chronic hepatitis (n = 21) with F3 or 4 in 77%) were treated with 12 months interferon (1.5-3 MU thrice weekly) + ribavirin (600-1200 mg daily) followed by 6 months ribavirin (58%), at a median of 427 days (56-2812) after transplantation.\n\n\nRESULTS\nSeven patients (29%) discontinued therapy due to side effects, mainly anaemia, at a median of 3 months since initiation. Dose modifications were required in 88% of those completing the whole course of therapy. Overall, the sustained virological and biochemical response was 12.5%. This rate was slightly higher (18%) if only the 17 patients who finished the whole course of therapy were analysed. Histological improvement was achieved in 31.5% of treated patients.\n\n\nCONCLUSIONS\nCombination therapy has a very limited efficacy in the liver transplant setting, although some benefit may be achieved, even in those with advanced graft fibrosis. Tolerance, however, remains a matter of concern.",
"affiliations": "Hepato-Gastroenterology Service, Pathology Service, Hospital Universitario La Fe, Avda Campanar 21, 46009 Valencia, Spain. mbhaym@teleline.es",
"authors": "Berenguer|Marina|M|;Prieto|Martín|M|;Palau|Antonio|A|;Carrasco|Domingo|D|;Rayón|José-Miguel|JM|;Calvo|Félix|F|;Berenguer|Joaquín|J|",
"chemical_list": "D000998:Antiviral Agents; D012254:Ribavirin; D007372:Interferons",
"country": "England",
"delete": false,
"doi": "10.1097/00042737-200411000-00020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-691X",
"issue": "16(11)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D006526:Hepatitis C; D019698:Hepatitis C, Chronic; D006801:Humans; D007372:Interferons; D008099:Liver; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D012008:Recurrence; D012254:Ribavirin; D016896:Treatment Outcome",
"nlm_unique_id": "9000874",
"other_id": null,
"pages": "1207-12",
"pmc": null,
"pmid": "15489583",
"pubdate": "2004-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Recurrent hepatitis C genotype 1b following liver transplantation: treatment with combination interferon-ribavirin therapy.",
"title_normalized": "recurrent hepatitis c genotype 1b following liver transplantation treatment with combination interferon ribavirin therapy"
} | [
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"companynumb": "ES-ROCHE-2412193",
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],
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{
"reactionmeddrapt": "Cardiac disorder",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Transplant rejection",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hepatitis C",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug intolerance",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hepatic failure",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Anaemia",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Leukopenia",
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}
],
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},
"primarysource": {
"literaturereference": "BERENGUER M, PRIETO M, PALAU A,CARRASCO D, RAYON J, CALVO F, BERENGUER J. RECURRENT HEPATITIS C GENOTYPE 1B FOLLOWING LIVER TRANSPLANTATION: TREATMENT WITH COMBINATION INTERFERON-RIBAVIRIN THERAPY. EUROPEAN JOURNAL OF GASTROENTEROLOGY + HEPATOLOGY 2004 NOV?16 (11):1207-12.",
"literaturereference_normalized": "recurrent hepatitis c genotype 1b following liver transplantation treatment with combination interferon ribavirin therapy",
"qualification": "1",
"reportercountry": "ES"
},
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"receiptdate": "20190923",
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},
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"transmissiondate": "20191005"
}
] |
{
"abstract": "Hematopoietic cell transplantation (HCT) offers long-term cure against early morbidity and mortality of hemoglobinopathies, such as sickle cell disease (SCD) and beta-thalassemia. Following HCT, sirolimus is an immunosuppressant used to prevent graft-versus-host disease (GVHD) while receiving trimethoprim-sulfamethoxazole (TMP-SMX) for Pneumocystis jirovecii prophylaxis and other antimicrobial agents (including acyclovir). One rare adverse event associated with both drugs is rhabdomyolysis, defined as creatine kinase (CK) elevation at least 5 to 10 times the upper limit of normal. This study was conducted to evaluate the rate of and risk factors for developing rhabdomyolysis in the post-HCT setting. Across 4 haploidentical and matched related donor (MRD) nonmyeloablative protocols, CK levels were prospectively monitored and patients were retrospectively identified for rhabdomyolysis. The rhabdomyolysis was graded based on the severity of CK elevation and other organ injury. At diagnosis, patients were queried for concurrent medication use (ie, sirolimus, TMP-SMX, acyclovir, or statins), sex, age, donor genotype, and time from transplantation. Among 127 patients with mostly SCD, rhabdomyolysis occurred in 22 (17%), including 2 recipients of haploidentical donor HCT and 20 recipients of MRD HCT. The time to the development of rhabdomyolysis was 61 and 73 days for the 2 recipients of haploidentical HCT and a median of 73 days for the MRD HCT recipients. Among the 22 patients who developed rhabdomyolysis, 20 (91%) were receiving sirolimus (2 haploidentical HCT recipients and 18 MRD HCT recipients), and 14 (64%) were also receiving TMP-SMX (all in the MRD HCT group). Seventy-five percent of the haploidentical donors and 69% of the MRDs had sickle cell trait. All but 2 patients with rhabdomyolysis were male. No patients who developed rhabdomyolysis were receiving statins at any point. Higher-than-expected rates of rhabdomyolysis were found post-transplantation for patients with SCD and beta-thalassemia. Contributing risk factors included immunosuppression with sirolimus, TMP-SMX, male sex, and sickle trait donor. These factors differ from the excessive muscle strain or injury, seizures, infections, or HMG-CoA inhibitors typically identified in non-HCT recipients.",
"affiliations": "National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.;National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.;National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.;National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland. Electronic address: matthewhs@mail.nih.gov.",
"authors": "Lew|Jeffrey|J|;Fitzhugh|Courtney D|CD|;Tisdale|John F|JF|;Hsieh|Matthew M|MM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jtct.2021.08.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2666-6367",
"issue": null,
"journal": "Transplantation and cellular therapy",
"keywords": "rhabdomyolysis; sickle celt trait; sirolimus; trimethoprim-sulfamethoxazole",
"medline_ta": "Transplant Cell Ther",
"mesh_terms": null,
"nlm_unique_id": "101774629",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34419651",
"pubdate": "2021-08-19",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Increased Rates of Rhabdomyolysis in Male Hematopoietic Cell Transplantation Recipients Taking Sirolimus and Trimethoprim/Sulfamethoxazole.",
"title_normalized": "increased rates of rhabdomyolysis in male hematopoietic cell transplantation recipients taking sirolimus and trimethoprim sulfamethoxazole"
} | [
{
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"reaction": [
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}
],
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},
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"literaturereference": "Lew J, Fitzhugh CD, Tisdale JF, Hsieh MM.. Increased Rates of Rhabdomyolysis in Male Hematopoietic Cell Transplantation Recipients Taking Sirolimus and Trimethoprim/Sulfamethoxazole.. The American Society for Transplantation and Cellular Therapy. 2021;27(12):1019.e1-1019.e4",
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{
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],
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},
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"literaturereference": "Lew J, Fitzhugh C, Tisdale J, Hsieh M. Increased Rates of Rhabdomyolysis in Male Hematopoietic Cell Transplantation Recipients Taking Sirolimus and Trimethoprim/Sulfamethoxazole. Transplant Cell Ther. 2021;27(12):1019.E1-4. doi:10.1016/j.jtct.2021.08.011",
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{
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},
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"reaction": [
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],
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},
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{
"abstract": "OBJECTIVE\nTo estimate the number of acetaminophen (APAP) toxicity-related emergency department (ED) visits, and to assess their associated clinical and economic burden in the USA from 2006 to 2010.\n\n\nMETHODS\nCross-sectional, retrospective, large-scale database study.\n\n\nMETHODS\nNon-federal, non-rehabilitation, community EDs in the USA.\n\n\nMETHODS\nInclusion criteria included any listed diagnosis identifying poisoning by aromatic analgesics paracetamol/APAP or associated supplementary code. Generalised linear models were used to investigate the association between outcomes of inpatient admission, mortality, requirement of invasive mechanical ventilation, charges and inpatient lengths of stay based on patient, hospital and clinical characteristics.\n\n\nRESULTS\nAcross the 625.2 million ED visits in the USA from 2006 to 2010, 411,811 APAP-related toxicity ED visits were observed, with 45.5% resulting in inpatient admission, 4.7% requiring invasive mechanical ventilation and 0.6% involving death. Overall, the incidence proportion was 27.10 per 100,000 US population, exceeding 70 per 100,000 at age 2 years and ages 16-18 years. The total national bill was $1.06 billion per year (US$ 2014), and predominantly involved females (65.5%) and intentional self-harm (58.4%), which were notably higher within the 12-20 years age category (female(12-20 years)=74.8%, intentional self-harm(12-20 years)=71.4%). Behavioural and mental health comorbidities were relatively common and associated with an increased relative risk of admission and likelihood of charges almost entirely across all age categories of ≥12 years within the multivariable analyses. The number of ED visits did not appreciably change over time, decreasing by <2% from 2006 to 2010 (n=1351). Multivariable results also suggested no consistent change in outcomes across the study's time horizon.\n\n\nCONCLUSIONS\nA substantial public health impact of APAP toxicity-related cases was observed in the US from 2006 to 2010, with incidence proportions peaking at age 2 years and ages 16-18 years. After controlling for numerous factors, no consistent change was observed over the 5-year time horizon concerning outcomes of admission, mortality, invasive mechanical ventilation, charges or length of stay.",
"affiliations": "The University of Arizona, Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, Tucson, Arizona, USA Currently at The Department of Clinical Pharmacy, King Abdulaziz University College of Pharmacy, Jeddah, Saudi Arabia.;The University of Arizona, Mel and Enid Zuckerman College of Public Health, Tucson, Arizona, USA.;The University of Arizona, Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, Tucson, Arizona, USA Currently at The University of Oklahoma Health Sciences Center, College of Pharmacy & Stephenson Cancer Center, Oklahoma City, Oklahoma, USA.",
"authors": "Altyar|Ahmed|A|;Kordi|Lama|L|;Skrepnek|Grant|G|",
"chemical_list": "D000082:Acetaminophen",
"country": "England",
"delete": false,
"doi": "10.1136/bmjopen-2014-007368",
"fulltext": "\n==== Front\nBMJ OpenBMJ OpenbmjopenbmjopenBMJ Open2044-6055BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bmjopen-2014-00736810.1136/bmjopen-2014-007368Health Services ResearchResearch15061704169117011723Clinical and economic characteristics of emergency department visits due to acetaminophen toxicity in the USA Altyar Ahmed 12Kordi Lama 3Skrepnek Grant 14\n1 The University of Arizona, Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, Tucson, Arizona, USA\n2 Currently at The Department of Clinical Pharmacy, King Abdulaziz University College of Pharmacy, Jeddah, Saudi Arabia\n3 The University of Arizona, Mel and Enid Zuckerman College of Public Health, Tucson, Arizona, USA\n4 Currently at The University of Oklahoma Health Sciences Center, College of Pharmacy & Stephenson Cancer Center, Oklahoma City, Oklahoma, USACorrespondence to Professor Grant Skrepnek; Grant-Skrepnek@ouhsc.edu and Ahmed Altyar; aealtyar@kau.edu.sa2015 9 9 2015 5 9 e0073683 12 2014 11 8 2015 14 8 2015 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions2015This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Objectives\nTo estimate the number of acetaminophen (APAP) toxicity-related emergency department (ED) visits, and to assess their associated clinical and economic burden in the USA from 2006 to 2010.\n\nDesign\nCross-sectional, retrospective, large-scale database study.\n\nSetting\nNon-federal, non-rehabilitation, community EDs in the USA.\n\nParticipants\nInclusion criteria included any listed diagnosis identifying poisoning by aromatic analgesics paracetamol/APAP or associated supplementary code. Generalised linear models were used to investigate the association between outcomes of inpatient admission, mortality, requirement of invasive mechanical ventilation, charges and inpatient lengths of stay based on patient, hospital and clinical characteristics.\n\nResults\nAcross the 625.2 million ED visits in the USA from 2006 to 2010, 411 811 APAP-related toxicity ED visits were observed, with 45.5% resulting in inpatient admission, 4.7% requiring invasive mechanical ventilation and 0.6% involving death. Overall, the incidence proportion was 27.10 per 100 000 US population, exceeding 70 per 100 000 at age 2 years and ages 16–18 years. The total national bill was $1.06 billion per year (US$ 2014), and predominantly involved females (65.5%) and intentional self-harm (58.4%), which were notably higher within the 12–20 years age category (female12–20 years=74.8%, intentional self-harm12–20 years=71.4%). Behavioural and mental health comorbidities were relatively common and associated with an increased relative risk of admission and likelihood of charges almost entirely across all age categories of ≥12 years within the multivariable analyses. The number of ED visits did not appreciably change over time, decreasing by <2% from 2006 to 2010 (n=1351). Multivariable results also suggested no consistent change in outcomes across the study's time horizon.\n\nConclusions\nA substantial public health impact of APAP toxicity-related cases was observed in the US from 2006 to 2010, with incidence proportions peaking at age 2 years and ages 16–18 years. After controlling for numerous factors, no consistent change was observed over the 5-year time horizon concerning outcomes of admission, mortality, invasive mechanical ventilation, charges or length of stay.\n\nEPIDEMIOLOGYHEALTH ECONOMICSPUBLIC HEALTH\n==== Body\nStrengths and limitations of this study\nThis study draws on an estimated 130 million emergency department visits per year within the USA to report national estimates of case incidence and to provide assessments of clinical and economic outcomes.\n\nNo specific categorisation existed to classify cases as being unsupervised ingestions or therapeutic misadventures (eg, overuse, medication errors); as per the type of acetaminophen (APAP) product consumed (eg, single-agent, combination products, tablets, liquid); and according to the amount ingested or serum levels observed.\n\nThe use of N-acetyl cysteine or gastric decontamination was also not consistently captured within the data set, nor was a designation of acute liver injury directly attributable to APAP toxicity.\n\nIntroduction\nAs one of the most frequently used analgesic and antipyretics worldwide, acetaminophen (APAP) is a common single or combination agent among the numerous over-the-counter and prescription products.1 Though considered generally safe at approved doses, APAP has a known and established toxicity pattern at higher doses.2 Of all pharmaceuticals involved in human overdoses, analgesics are considered the most frequently involved.2 US poison centre data indicate that APAP combinations were associated with the fourth highest number of fatalities compared with other medications in 2012, with APAP overdose being the principal cause of toxic drug ingestion that ultimately contributed to 39% of all acute liver failures.2\n3 Hepatotoxicity is a well-recognised adverse event associated with APAP overdose that may result in liver failure and death.4 The percentage of APAP-induced acute liver failure cases increased from 28% in 1998 to 51% in 2003, establishing this medication as the most common cause of acute liver failure in the USA.4 Overall, previous studies have suggested that APAP overdoses leads annually to 56 000–78 000 emergency department (ED) visits, 26 000–34 000 hospitalisations, and an estimated 500 deaths.5–8\n\nThe US Food and Drug Administration (FDA) has issued several updates in recent years involving APAP to increase the safety and limit the toxicity associated with the use of this medication, presented in figure 1.9–13\n\nFigure 1 US Food and Drug Administration sequence of updates concerning acetaminophen.\n\nGiven the aforementioned, the overall purpose of this investigation was to estimate the number of APAP toxicity-related ED visits, and to assess their associated clinical and economic burden in the USA from 2006 to 2010. More specifically, the objectives were to assess the relationships between outcomes of inpatient admission, mortality, requirement of invasive mechanical ventilation, charges and inpatient lengths of stay based on patient, hospital and clinical characteristics.\n\nMethods\nThis cross-sectional, retrospective investigation utilised 2006–2010 Nationwide Emergency Department Sample (NEDS) from the Agency for Healthcare Research and Quality (AHRQ).14 These data comprise nationally representative case presentations across hospital-based EDs within the non-federal, non-rehabilitation, community facilities and generalising, overall, to approximately 130 million ED visits that occur in the USA per year.14 Given the fully de-identified and anonymised data, this research is classified as exempt via human participants protection.14\n\nConsistent with previous research, ED visits involving APAP toxicity were identified based on the inclusion criteria of any listed diagnosis according to International Classification of Disease, Ninth edition, Clinical Manifestations (ICD-9-CM) codes identifying poisoning by aromatic analgesics paracetamol/APAP (ie, 965.4) or associated supplementary code (ie, E850.4: accidental poisoning by aromatic analgesics paracetamol/APAP).5–8\n15\n16 Previous research has addressed the challenges faced regarding the sensitivity and specificity of utilising diagnosis or supplementary codes to identify APAP toxicity-related cases, suggesting that the use of these aforementioned codes remains a valid approach.15 All ages were investigated and stratified according to the following age categories: (A) 0–11; (B) 12–20; (C) 21–64; and (D) ≥65 years.\n\nClinical outcomes assessed were admission to an inpatient setting from the ED, mortality and requirement of invasive mechanical ventilation (ie, as a proxy for acute respiratory distress syndrome and supportive care measures associated with APAP toxicity disease progression or acute liver failure).17\n18 Economic outcomes analysed involved inflation-adjusted charges (US$ 2014) and inpatient length of stay. Independent predictor variables analysed were patient demographics (ie, age category, sex, income quartile, age, primary payer, rural location defined by communities ≤50 000 residents), ED and hospital characteristics (geographic region, urban/rural location, teaching status), clinical case-mix disease severity measured via Elixhauser comorbidities (a validated case-mix risk severity measure comprising of 30 disease states), designation of intentional self-harm, and year (2006–2010).14\n19 Notably, if any given Elixhauser comorbidity was observed in <0. 1% of cases within any age category, it was omitted to allow for appropriate statistical inference; peptic ulcer disease with bleeding was consistently observed to be <0. 1% of cases and summarily removed from the study.6\n7\n\nMultivariable analyses for outcomes of admission to an inpatient setting from the ED and mortality were conducted using a multinomial logit regression, specifying treat-and-release ED cases as a baseline comparator.20\n21 The requirement of invasive mechanical ventilation was analysed via a logistic regression. Generalised linear models were used to analyse inflation-adjusted charges and inpatient length of stay, specified by a γ distribution with log link and negative binomial distribution with log link, respectively.21 Accordingly, results may be interpreted generally as relative risk measures, superficially as: a relative risk ratio (RRR) in a multinomial regression; an OR in a logistic regression; an exponentiated β value (exp(b)) in a γ regression; and an incidence ratio in a negative binomial regression.21 Therein, estimated coefficients may be interpreted as suggesting a reduced likelihood (<1.00) or no difference in likelihood (=1.00) or an increased likelihood (>1.00).\n\nThe Simes22 procedure to control for false-discovery rates was used to control for multiple comparisons across age categories within the analysis of invasive mechanical ventilation, charges and length of stay, yielding critical p values for significance of 0.028, 0.036 and 0.024, respectively. Inherently controlling for multiple comparisons by definition, the multinomial regression of disposition from the ED used an α level of 0.05 for significance and established treat-and-release cases as the baseline comparator. Owing to the complex nature of sampling employed by the NEDS, Taylor series weighting procedures were incorporated to yield national estimates.14 All analyses were conducted using SAS V.9.2 (Cary, North Carolina, USA) and STATA SE V.12.1 (College Station, Texas, USA).\n\nResults\nAcross the 625.2 million ED visits in the USA from 2006 to 2010, APAP-related toxicity was observed in 411 881 ED visits, with peaks occurring at approximately ages 0–5, 15–20 and 35–45 years (figure 2). Overall, the incidence proportion of APAP toxicity-related ED visits according to age per 100 000 per US population was 27.10, and by age category: 17.29 for ages 0–11 years; 63.17 for ages 12–20 years; 27.77 for ages 21–64 years; and 8.18 for ages 65 years and over. Reflected in figure 3, peak incidence proportions exceeding 70 per 100 000 US population were observed at age 2 years (78.39 per 100 000) and ages 16–18 years (76.16, 77.52 and 74.00 per 100 000, respectively). Inpatient admissions averaged 12.46 per 100 000 US population, being lowest for age group <12 years (0.50 per 100 000) and highest for cases from age group 12–20 years (23.34 per 100 000); peaks were noted at ages 18 (33.55 per 100 000) and 19 years (31.07 per 100 000).\n\nFigure 2 Overall number of acetaminophen (APAP) toxicity-related emergency department (ED) cases according to age, 2006–2010.\n\nFigure 3 Age-adjusted for acetaminophen (APAP) toxicity-related emergency department (ED) cases per 100 000 US population, 2006–2010. Base US populations for 2006–2010 obtained from the Centers for Disease Control and Prevention, National Vital Statistics System, Vintage 2012 bridged race postcensus US resident population estimates.\n\nIn general, cases involved females (65.5%) averaging 29.3 (±17.6) years of age with 3.1 (±4.4) days of inpatient lengths of stay, and these involved intentional self-harm (58.4%). Within the 12–20 years age category, cases were markedly female (74.8%) and involved intentional self-harm (71.4%). Among the APAP-related cases presenting to the ED, 45.4% resulted in direct inpatient admissions, highest in percentage terms among cases age ≥65 years (66.0%), even though this age category constituted an age-adjusted 5.68 admissions per 100 000 US population. Those treated-and-released directly in the ED involved 37.4% of cases, particularly characteristic among cases <12 years (92.7%). The most common Elixhauser comorbidities observed were depression (25.0%), drug abuse (15.6%), psychoses (15.3%), alcohol abuse (13.7%), and fluid and electrolyte disorders (13.6%); no Elixhauser comorbidities were noted among 38.0%. Inpatient mortality was low (0.6%), and the requirement of invasive mechanical ventilation was for 4.7%. The total national bill across the 5-year time horizon was $5.30 billion (US$ 2014), equating to $12 766 (±28 414) per case. The full descriptive statistics appear in table 1.\n\nTable 1 Descriptive statistics of ED cases associated with APAP toxicity according to age category in the USA, 2006–2010\n\n\tAge 11 years and below (N=42 623)\tAge 12–20 years (N=106 725)\tAge 21–64 years (N=246 640)\tAge 65 years and above (N=15 893)\tOverall (N=411 881)\t\nPatient characteristics\t\n Age (mean±SD)\t2.2±1.7\t16.9±2.1\t36.4±11.4\t75.2±7.9\t29.3±17.6\t\n Female sex\t48.3%\t74.8%\t64.4%\t68.0%\t65.5%\t\n Payer, commercial insurance\t38.1%\t26.4%\t20.4%\t1.6%\t23.1%\t\n Medicare\t≤0.1%\t0.2%\t10.0%\t88.3%\t9.5%\t\n Medicaid\t48.9%\t51.5%\t35.1%\t7.8%\t39.7%\t\n Other\t12.8%\t21.8%\t34.5%\t2.3%\t27.7%\t\n Income quartile, lowest\t24.3%\t23.2%\t28.1%\t24.4%\t26.3%\t\n 2nd quartile\t28.3%\t27.5%\t28.5%\t27.0%\t28.2%\t\n 3rd quartile\t25.5%\t25.6%\t24.5%\t25.4%\t24.9%\t\n 4th quartile\t21.9%\t23.8%\t18.9%\t23.3%\t20.6%\t\n Rural residence\t19.6%\t16.7%\t17.1%\t17.9%\t17.3%\t\nHospital characteristics\t\n Region, Northeast\t14.4%\t16.2%\t15.6%\t16.4%\t15.6%\t\n Midwest\t25.6%\t18.2%\t26.4%\t21.0%\t26.6%\t\n South\t32.1%\t30.0%\t34.7%\t34.5%\t33.2%\t\n West\t18.1%\t25.6%\t23.3%\t28.2%\t24.5%\t\n Rural facility\t18.5%\t15.3%\t15.3%\t16.2%\t15.6%\t\n Teaching facility\t38.9%\t39.9%\t39.5%\t35.7%\t39.4%\t\nClinical characteristics\t\n Congestive heart failure\t≤0.1%\t≤0.1%\t0.7%\t8.8%\t0.8%\t\n Valvular disease\t≤0.1%\t≤0.1%\t0.6%\t3.3%\t0.5%\t\n Pulmonary circulation disorders\t≤0.1%\t≤0.1%\t0.2%\t1.4%\t0.2%\t\n Peripheral vascular disorders\t≤0.1%\t≤0.1%\t0.3%\t3.8%\t0.3%\t\n Hypertension with complications\t≤0.1%\t≤0.1%\t0.7%\t7.6%\t0.7%\t\n Paralysis\t≤0.1%\t≤0.1%\t0.4%\t1.5%\t0.3%\t\n Other neurological disorders\t0.3%\t2.2%\t7.4%\t14.6%\t5.6%\t\n Chronic pulmonary disease\t2.0%\t4.9%\t7.8%\t19.2%\t6.9%\t\n Diabetes with complications\t≤0.1%\t≤0.1%\t0.5%\t2.0%\t0.4%\t\n Hypothyroidism\t≤0.1%\t0.5%\t2.9%\t11.9%\t2.3%\t\n Renal failure\t≤0.1%\t≤0.1%\t0.8%\t7.3%\t0.8%\t\n Liver disease\t≤0.1%\t0.2%\t2.2%\t1.7%\t1.4%\t\n HIV/AIDS\t≤0.1%\t≤0.1%\t0.2%\t≤0.1%\t≤0.1%\t\n PUD, excluding bleeding\t≤0.1%\t≤0.1%\t≤0.1%\t≤0.1%\t≤0.1%\t\n Lymphoma\t≤0.1%\t≤0.1%\t≤0.1%\t≤0.1%\t≤0.1%\t\n Metastatic cancer\t≤0.1%\t≤0.1%\t≤0.1%\t1.0%\t0.2%\t\n Solid tumour\t≤0.1%\t≤0.1%\t0.3%\t2.1%\t0.2%\t\n Rheumatoid arthritis/collagen vascular disease\t≤0.1%\t≤0.1%\t0.9%\t3.1%\t0.7%\t\n Coagulopathy\t≤0.1%\t0.5%\t2.3%\t4.2%\t1.7%\t\n Obesity\t≤0.1%\t1.2%\t3.3%\t2.4%\t2.4%\t\n Weight loss/cachexia\t≤0.1%\t≤0.1%\t0.8%\t3.2%\t0.6%\t\n Fluid and electrolyte disorders\t0.7%\t8.1%\t17.2%\t29.4%\t13.6%\t\n Blood loss or deficiency anaemia\t≤0.1%\t1.5%\t4.3%\t12.3%\t3.4%\t\n Alcohol abuse\t≤0.1%\t5.7%\t19.8%\t8.6%\t13.7%\t\n Drug abuse\t≤0.1%\t12.1%\t20.3%\t6.3%\t15.6%\t\n Psychoses\t≤0.1%\t11.2%\t19.8%\t13.3%\t15.3%\t\n Depression\t≤0.1%\t27.4%\t28.4%\t22.6%\t25.0%\t\n No Elixhauser comorbidities present\t96.4%\t47.0%\t25.7%\t12.6%\t38.0%\t\n Intentional self-harm\t≤0.1%\t71.4%\t64.2%\t34.9%\t58.4%\t\nCalendar year\t\n 2006\t18.1%\t21.1%\t19.5%\t17.5%\t19.7%\t\n 2007\t21.0%\t20.5%\t19.6%\t17.0%\t19.9%\t\n 2008\t21.8%\t21.1%\t20.6%\t20.1%\t20.8%\t\n 2009\t20.8%\t19.7%\t20.4%\t21.8%\t20.3%\t\n 2010\t18.3%\t17.6%\t20.0%\t23.6%\t19.3%\t\nOutcomes\t\n Disposition, treat-and-release\t92.7%\t38.4%\t28.1%\t23.8%\t37.4%\t\n Transfer\t2.5%\t22.4%\t14.0%\t6.3%\t14.7%\t\n Admission\t2.9%\t37.0%\t55.1%\t66.0%\t45.4%\t\n Death\t≤0.1%\t≤0.1%\t0.7%\t3.4%\t0.6%\t\n Other\t1.9%\t2.2%\t1.9%\t0.5%\t1.9%\t\nAverage ED and inpatient charge (US$ 2014) (mean±SD)\t$1343±3162\t$7884±13 034\t$15 824±31 404\t$28 631±50 515\t$12 766±28 414\t\nAnnual: total national bill (US$ 2014) (mean±SD)\t$11.45 million\t$168.28 million\t$789.11 million\t$91.00 million\t$1059.86 million\t\n2006–2010: total national bill (US$ 2014) (mean±SD)\t$0.06 billion\t$0.84 billion\t$3.95 billion\t$0.46 billion\t$5.30 billion\t\nInpatient length of stay (mean±SD)\t1.8±1.8\t2.3±2.2\t3.2±4.5\t4.9±6.9\t3.1±4.4\t\nInvasive mechanical ventilation\t≤0.1%\t1.2%\t6.8%\t8.6%\t4.7%\t\nED visits per 100 000 persons per year*\t17.29\t63.17\t27.77\t8.18\t27.10\t\nInpatient admissions per 100 000 persons per year*\t0.50\t23.34\t15.50\t5.68\t12.46\t\n*Base US populations for 2006–2010 obtained from the Centers for Disease Control and Prevention, National Vital Statistics System, Vintage 2012 bridged-race postcensus US resident population estimates.\n\nAPAP, acetaminpophen; ED, emergency department; PUD, peptic ulcer disease.\n\nMultivariable analysis: inpatient admission, mortality, invasive mechanical ventilation\nResults of the multinomial logit regression of patient disposition from the ED (table 2) indicated that numerous patient, hospital and clinical characteristics were associated with an increased likelihood of admission or death. After statistically controlling for numerous factors, rural patient residence suggested statistical significance (p<0.05), with increased relative risk of admission among the 0–11, 12–20, and 21–64-year-old categories (RRR0–11=2.26, RRR12–20=1.30, RRR21–64=1.24). Intentional self-harm was also associated with over a 3× increase odds of admission across all age categories ≥12 years (p<0.05); was almost perfectively predictive of mortality cases among those 12–20 years of age; and was associated with a 8.57× (p<0.001) for those aged ≥65 years.\n\nTable 2 Patient disposition of admission or mortality versus treat-and-release from APAP toxicity-related presentation to the ED, 2006–2010\n\n \tAge 11 years and below (N=42 623)\tAge 12–20 years (N=106 725)\tAge 21–64 years (N=246 640)\tAge 65 years and above (N=15 893)\t\n\tAdmission (RRR, 95th CI)\tMortality (RRR, 95th CI)\tAdmission (RRR, 95th CI)\tMortality (RRR, 95th CI)\tAdmission (RRR, 95th CI)\tMortality (RRR, 95th CI)\tAdmission (RRR, 95th CI)\tMortality (RRR, 95th CI)\t\nPatient characteristics\t\n Age\t1.11** (1.03 to 1.19)\t–\t1.09*** (1.06 to 1.11)\t1.49* (1.01 to 2.19)\t1.01*** (1.01 to 1.02)\t1.05*** (1.04 to 1.06)\t1.00 (0.99 to 1.01)\t1.09** (1.03 to 1.14)\t\n Female sex\t1.01 (0.77 to 1.33)\t–\t0.97 (0.89 to 1.06)\t1.94 (0.28 to 13.60)\t0.90*** (0.85 to 0.95)\t0.96 (0.76 to 1.22)\t1.24 (0.99 to 1.56)\t0.54 (0.25 to 1.15)\t\n Payer (vs commercial insurance)\t\n Medicare\t–\t–\t0.54* (0.30 to 0.97)\tOmittedA\t0.83** (0.75 to 0.92)\t0.87 (0.59 to 1.28)\t1.17 (0.49 to 2.78)\t0.12** (0.03 to 0.55)\t\n Medicaid\t0.62** (0.45 to 0.86)\t–\t0.97 (0.87 to 1.07)\t0.42 (0.09 to 1.85)\t1.02 (0.94 to 1.11)\t0.90 (0.64 to 1.27)\t0.64 (0.25 to 1.69)\t0.04** (0.01 to 0.28)\t\n Other\t0.58* (0.37 to 0.92)\t–\t0.86* (0.76 to 0.98)\t0.32 (0.07 to 1.46)\t0.90* (0.83 to 0.98)\t0.87 (0.62 to 1.22)\t0.31* (0.10 to 0.93)\tOmittedA\t\n Income quartile (vs lowest)\t\n 2nd quartile\t1.12 (0.79 to 1.59)\t–\t1.13* (1.00 to 1.27)\t2.50 (0.21 to 29.40)\t1.05 (0.97 to 1.14)\t0.93 (0.67 to 1.28)\t0.84 (0.61 to 1.14)\t0.23* (0.07 to 0.74)\t\n 3rd quartile\t0.75 (0.48 to 1.16)\t–\t1.15* (1.02 to 1.29)\t13.40* (1.59 to 113.21)\t1.08 (0.98 to 1.20)\t1.21 (0.86 to 1.69)\t1.08 (0.75 to 1.54)\t1.03 (0.32 to 3.24)\t\n 4th quartile\t0.90 (0.58 to 1.39)\t–\t1.24** (1.07 to 1.43)\tOmittedA\t1.26*** (1.13 to 1.41)\t1.20 (0.83 to 1.73)\t1.18 (0.83 to 1.69)\t1.76 (0.64 to 4.85)\t\n Rural residence\t2.26* (1.19 to 4.30)\t–\t1.30* (1.06 to 1.60)\t0.82 (0.18 to 3.78)\t1.24** (1.07 to 1.44)\t1.21 (0.72 to 2.03)\t1.36 (0.76 to 2.43)\t1.88 (0.44 to 7.97)\t\nHospital characteristics\t\n Rural location\t0.53 (0.26 to 1.12)\t–\t0.79* (0.62 to 0.99)\t1.48 (0.15 to 14.19)\t0.67*** (0.56 to 0.80)\t0.42** (0.21 to 0.81)\t0.63 (0.35 to 1.14)\t1.27 (0.34 to 4.68)\t\n Teaching facility\t3.13*** (2.17 to 4.50)\t–\t1.55*** (1.35 to 1.79)\t5.08 (0.82 to 31.72)\t0.98* (0.86 to 1.12)\t1.04 (0.79 to 1.37)\t1.31* (1.03 to 1.68)\t1.58 (0.68 to 3.66)\t\n Region (vs Northeast)\t\n Midwest\t0.72 (0.47 to 1.12)\t–\t0.96 (0.81 to 1.14)\t1.18 (0.11 to 13.16)\t0.87 (0.72 to 1.04)\t0.59* (0.40 to 0.90)\t0.63* (0.44 to 0.90)\t0.48 (0.16 to 1.45)\t\n South\t0.79 (0.51 to 1.22)\t–\t0.85 (0.72 to 1.02)\t1.92 (0.17 to 21.10)\t0.86 (0.72 to 0.99)\t0.79 (0.55 to 1.14)\t0.85 (0.61 to 1.18)\t0.36* (0.14 to 0.92)\t\n West\t0.65 (0.39 to 1.08)\t–\t0.62*** (0.52 to 0.74)\t0.39 (0.01 to 12.73)\t0.51*** (0.43 to 0.59)\t0.52** (0.35 to 0.77)\t0.54** (0.38 to 0.77)\t0.26* (0.08 to 0.82)\t\nClinical characteristics\t\n Congestive heart failure\t–\t–\t–\t–\t1.48 (0.95 to 2.31)\t1.67 (0.80 to 3.49)\t3.36*** (2.01 to 5.63)\t1.64 (0.55 to 4.87)\t\n Valvular disease\t–\t–\t3.94* (1.15 to 13.50)\tOmittedA\t4.47*** (2.70 to 7.40)\t2.06 (0.60 to 7.01)\t3.64** (1.67 to 7.92)\t3.55 (0.51 to 24.58)\t\n Pulmonary circulation disorders\t–\t–\t–\t–\t2.35* (1.03 to 5.40)\t8.50** (2.54 to 28.43)\t3.70 (0.39 to 35.40)\tOmittedA\t\n Peripheral vascular disorders\t–\t–\t–\t–\t3.15*** (1.55 to 6.37)\t2.64 (0.59 to 11.89)\t2.88** (1.32 to 6.28)\t5.77 (0.96 to 34.48)\t\n Hypertension with complications\t–\t–\t2.46*** (1.53 to 3.96)\tOmittedA\t2.27** (1.32 to 3.92)\t1.66 (0.59 to 4.68)\t5.74*** (2.32 to 14.21)\t0.66 (0.06 to 6.75)\t\n Paralysis\t–\t–\t1.54 (0.31 to 7.54)\tOmittedA\t3.28*** (1.90 to 5.65)\t11.47*** (4.84 to 27.23)\t1.75 (0.57 to 5.38)\t1.20 (0.14 to 10.13)\t\n Other neurological disorders\t24.83*** (10.48 to 58.83)\t–\t3.14*** (2.40 to 4.12)\t50.97***(10.75 to 241.71)\t2.19*** (1.95 to 2.47)\t2.21*** (1.55 to 3.15)\t1.97*** (1.40 to 2.78)\t1.48 (0.67 to 3.27)\t\n Chronic pulmonary disease\t1.94 (0.95 to 3.96)\t–\t2.35*** (1.93 to 2.86)\tOmittedA\t2.01*** (1.78 to 2.28)\t1.29 (0.83 to 2.00)\t3.21*** (2.27 to 4.54)\t5.16** (1.75 to 15.25)\t\n Diabetes with complications\t–\t–\t0.97 (0.58 to 1.64)\tOmittedA\t4.52*** (2.55 to 8.01)\t3.57* (1.01 to 12.64)\t2.34 (0.62 to 8.88)\t16.60 (0.12 to 225.36)\t\n Hypothyroidism\t–\t–\t1.04 (0.58 to 1.85)\tOmittedA\t2.67*** (2.16 to 3.31)\t1.52 (0.77 to 2.99)\t2.15*** (1.43 to 3.24)\t2.17 (0.75 to 6.33)\t\n Renal failure\t–\t–\t2.11 (0.24 to 18.52)\tOmittedA\t2.39*** (1.51 to 3.80)\t3.16** (1.38 to 7.25)\t0.50 (0.22 to 1.12)\t1.06 (0.13 to 8.44)\t\n Liver disease\t–\t–\t2.98* (1.03 to 8.64)\tOmittedB\t12.13*** (5.98 to 24.60)\t47.89*** (21.53 to 106.52)\tOmittedB\tOmittedB\t\n HIV/AIDS\t–\t–\t–\t–\t2.18 (0.82 to 5.83)\t6.86* (1.35 to 34.92)\t–\t–\t\n Lymphoma\t–\t–\t–\t–\t1.43 (0.60 to 3.43)\t4.24 (0.69 to 25.95)\t–\t–\t\n Metastatic cancer\t–\t–\t–\t–\t6.08*** (2.22 to 16.67)\t30.32*** (8.35 to 110.18)\t3.18 (0.78 to 13.04)\t1.76 (0.29 to 10.55)\t\n Solid tumour\t–\t–\t–\t–\t1.97* (1.09 to 3.55)\t5.77** (2.13 to 15.59)\t2.41 (0.98 to 5.91\t5.46 (0.94 to 31.63)\t\n Rheumatoid arthritis/collagen vascular disease\t–\t–\t0.80 (0.21 to 3.07)\tOmittedA\t2.66*** (1.89 to 3.76)\t2.28 (0.95 to 5.43)\t3.32* (1.24 to 8.90)\tOmittedA\t\n Coagulopathy\t–\t–\t21.75*** (7.70 to 61.42)\t178.62*** (10.96 to 291.11)\t16.06*** (9.70 to 26.57)\t72.42*** (39.91 to 131.40)\tOmittedB\tOmittedB\t\n Obesity\t–\t–\t6.29*** (3.95 to 10.01)\tOmittedA\t4.96*** (3.32 to 6.27)\t5.55*** (3.08 to 10.02)\t5.43** (1.68 to 17.54)\t0.10 (0.01 to 1.37)\t\n Weight loss\t–\t–\t–\t–\t20.51*** (7.35 to 57.18)\t25.74*** (7.64 to 86.71)\t19.01** (2.50 to 144.65)\t283.59*** (17.45 to 468.08)\t\n Fluid and electrolyte disorders\t20.75*** (9.22 to 46.70)\t–\t6.78*** (5.70 to 8.07)\t8.91** (2.48 to 31.96)\t7.97*** (7.09 to 8.96)\t28.45*** (21.84 to 37.07)\t9.77*** (6.85 to 13.92)\t56.28*** (22.19 to 142.71)\t\n Blood loss or deficiency anaemia\t13.27** (2.65 to 66.38)\t–\t4.17*** (2.83 to 6.15)\tOmittedA\t4.46*** (3.64 to 5.46)\t3.34*** (2.22 to 5.04)\t2.64*** (1.72 to 4.04)\t0.15 (0.01 to 4.35)\t\n Alcohol abuse\t–\t–\t2.32*** (1.94 to 2.77)\t1.16 (0.09 to 14.53)\t2.53*** (2.33 to 2.75)\t1.75*** (1.34 to 2.29)\t2.96*** (1.76 to 4.95)\t3.27 (0.71 to 15.09)\t\n Drug abuse\t–\t–\t2.02*** (1.77 to 2.30)\t3.02 (0.59 to 15.37)\t2.37*** (2.17 to 2.59)\t1.58** (1.17 to 2.13)\t1.71 (0.96 to 3.04)\t0.59 (0.06 to 5.44)\t\n Psychoses\t–\t–\t5.13*** (4.48 to 5.89)\t4.46 (0.91 to 21.85)\t4.44*** (4.00 to 4.93)\t1.42 (1.00 to 2.03)\t6.41*** (3.88 to 10.57)\t6.46 (0.84 to 49.84)\t\n Depression\t–\t–\t1.71*** (1.55 to 1.88)\t3.46 (0.94 to 12.70)\t1.75*** (1.62 to 1.89)\t1.10 (0.82 to 1.48)\t1.95*** (1.44 to 2.64)\t1.88 (0.79 to 4.49)\t\n Intentional self-harm\t–\t–\t3.40*** (3.07 to 3.77)\tOmittedB\t3.03*** (2.81 to 3.26)\t1.69*** (1.30 to 2.21)\t4.89*** (3.59 to 6.64)\t8.57*** (3.97 to 18.49)\t\nCalendar year\t\n 2007 (vs 2006)\t0.78 (0.48 to 1.28)\t–\t0.92 (0.80 to 1.06)\t0.95 (0.17 to 5.34)\t0.99 (0.88 to to 1.11)\t1.01 (0.69 to 1.49)\t1.29 (0.92 to 1.81)\t1.97 (0.39 to 9.87)\t\n 2008 (vs 2006)\t0.79 (0.49 to 1.26)\t–\t0.79** (0.68 to 0.92)\t0.65 (0.07 to 5.73)\t0.82** (0.72 to 0.94)\t0.82 (0.56 to 1.21)\t0.94 (0.67 to 1.32)\t3.13 (0.96 to 10.19)\t\n 2009 (vs 2006)\t0.67 (0.40 to 1.11)\t–\t0.84* (0.72 to 0.98)\t0.30 (0.03 to 3.17)\t0.87 (0.77 to 1.00)\t0.58* (0.38 to 0.88)\t0.79 (0.55 to 1.13)\t2.23 (0.65 to 7.64)\t\n 2010 (vs 2006)\t0.74 (0.45 to 1.22)\t–\t0.88 (0.74 to 1.03)\t0.56 (0.06 to 5.18)\t0.83** (0.73 to 0.95)\t0.78 (0.53 to 1.13)\t1.03 (0.74 to 1.45)\t2.57 (0.72 to 9.18)\t\nOmittedA, variable omitted due to near-perfect association with survival (ie, OR<0.01).\n\nOmittedB, variable omitted due to near-perfect association with mortality (ie, RRR>10 000).\n\n***Statistically significant at p<0.001.\n\n**Statistically significant at p<0.01.\n\n*Statistically significant at p<0.05.\n\n–, Variable omitted due to small sample size (n≤0.1%); APAP, acetaminophen; ED, emergency department; RRR, relative risk ratio.\n\nComorbidities of liver disease, coagulopathy, fluid and electrolyte disorders, and weight loss/cachexia were associated with statistical significance (p<0.05), and large relative risks for both admission and mortality across age groups (sample size permitting for analysis). Specifically among paediatric cases <12 years of age, other neurological disorders, fluid and electrolyte disorders, and blood or deficiency anaemia were significantly associated with increased admissions (p<0.05). Across other age categories while considering admissions alone, comorbid conditions of valvular disease, peripheral vascular disorders, hypertension with complications, other neurological disorders, obesity, deficiency or other anaemia, alcohol abuse, psychoses and depression were significantly associated with an increased relative risk across all age groups (p<0.05). Over time, no sustained decrease in admissions or mortality was observed consistently across the age categories.\n\nThe requirement of invasive mechanical ventilation (table 3) indicated that chronic pulmonary disease, coagulopathy, and fluid and electrolyte disorders were significant predictors among cases aged ≥12 years (p<0.028). Intentional self-harm was associated with a 1.49× higher odds among those aged 21–64 years, and a 2.42× higher odds among cases aged ≥65 years (p<0.028). Other neurological disorders, blood loss or deficiency anaemia, alcohol abuse, drug abuse and psychoses were associated with increased odds (p<0.028) among 12–20 and 21–64 years age groups. Several factors had near-perfect associations with invasive mechanical ventilation within the 12–20 years age group. Notably, over time, no consistent change in odds of requiring invasive mechanical ventilation across years was observed from 2006.\n\nTable 3 Invasive mechanical ventilation among APAP toxicity-related cases presenting to the ED according to age category, 2006–2010\n\n \tAge 11 years and below (N=42 623)\tAge 12–20 years (N=106 725)\tAge 21–64 years (N=246 640)\tAge 65 years and above (N=15 893)\t\nInvasive mechanical ventilation (OR, 95th CI)\tInvasive mechanical ventilation (OR, 95th CI)\tInvasive mechanical ventilation (OR, 95th CI)\tInvasive mechanical ventilation (OR, 95th CI)\t\nPatient characteristics\t\n Age\t–\t1.26* (1.16 to 1.36)\t1.03* (1.02 to 1.03)\t0.96* (0.95 to 0.98)\t\n Female sex\t–\t0.46* (0.35 to 0.60)\t0.85* (0.78 to 0.92)\t1.12 (0.84 to 1.50)\t\n Payer (vs commercial insurance)\t\n Medicare\t–\t0.62 (0.15 to 2.58)\t0.82* (0.72 to 0.95)\t1.03 (0.37 to 2.84)\t\n Medicaid\t–\t0.92 (0.67 to 1.28)\t1.05 (0.94 to 1.17)\t1.52 (0.52 to 4.45)\t\n Other\t–\t1.01 (0.71 to 1.43)\t0.78* (0.70 to 0.87)\t0.46 (0.12 to 1.79)\t\n Income quartile (vs lowest)\t\n 2nd quartile\t–\t0.92 (0.63 to 1.35)\t1.10 (0.99 to 1.23)\t1.12 (0.76 to 1.65)\t\n 3rd quartile\t–\t0.92 (0.62 to 1.37)\t1.23* (1.08 to 1.39)\t1.01 (0.69 to 1.48)\t\n 4th quartile\t–\t0.92 (0.61 to 1.40)\t1.08 (0.95 to 1.24)\t0.91 (0.58 to 1.41)\t\n Rural residence\t–\t1.96 (0.97 to 3.99)\t1.25 (1.01 to 1.55)\t1.07 (0.55 to 2.10)\t\nHospital characteristics\t\n Rural location\t–\t0.38* (0.16 to 0.91)\t0.61* (0.47 to 0.77)\t0.57 (0.26 to 1.26)\t\n Teaching facility\t–\t1.51* (1.12 to 2.03)\t1.10 (0.98 to 1.22)\t1.27 (0.95 to 1.71)\t\n Region (vs Northeast)\t\n Midwest\t–\t0.79 (0.53 to 1.18)\t0.87 (0.75 to 1.01)\t0.88 (0.56 to 1.36)\t\n South\t–\t0.77 (0.51 to 1.17)\t0.99 (0.86 to 1.15)\t0.90 (0.59 to 1.36)\t\n West\t–\t0.72 (0.45 to 1.13)\t0.94 (0.81 to 1.08)\t0.90 (0.57 to 1.42)\t\nClinical characteristics\t\n Congestive heart failure\t–\t–\t1.61* (1.17 to 2.21)\t1.39 (0.86 to 2.25)\t\n Valvular disease\t–\t8.31* (1.91 to 36.10)\t1.12 (0.78 to 1.62)\t0.77 (0.35 to 1.73)\t\n Pulmonary circulation disorders\t–\t–\t2.66* (1.46 to 4.86)\t0.83 (0.27 to 2.53)\t\n Peripheral vascular disorders\t–\t–\t1.25 (0.70 to 2.21)\t1.06 (0.56 to 2.02)\t\n Hypertension with complications\t–\t2.48* (1.11 to 5.56)\t0.86 (0.54 to 1.36)\t2.01 (0.91 to 4.45)\t\n Paralysis\t–\tOmittedA\t1.95* (1.29 to 2.94)\t0.26 (0.03 to 2.25)\t\n Other neurological disorders\t–\t7.11* (5.00 to 10.11)\t1.88* (1.66 to 2.13)\t1.10 (0.76 to 1.60)\t\n Chronic pulmonary disease\t–\t1.79* (1.09 to 2.92)\t1.34* (1.18 to 1.51)\t1.75* (1.26 to 2.44)\t\n Diabetes with complications\t–\t0.79 (0.13 to 4.81)\t0.91 (0.56 to 1.46)\t0.62 (0.21 to 1.79)\t\n Hypothyroidism\t–\t0.87 (0.25 to 3.09)\t0.91 (0.75 to 1.11)\t0.56* (0.35 to 0.89)\t\n Renal failure\t–\t1.78 (0.18 to 17.95)\t1.25 (0.82 to 1.92)\t0.42 (0.19 to 0.94)\t\n Liver disease\t–\t2.49 (0.44 to 14.03)\t2.23* (1.77 to 2.81)\t2.47* (1.17 to 5.21)\t\n AIDS\t–\t–\t2.11* (1.23 to 3.60)\t–\t\n Lymphoma\t–\t–\t1.93 (0.84 to 4.40)\t–\t\n Metastatic cancer\t–\t–\t1.68 (0.79 to 3.59)\t0.47 (0.09 to 2.47)\t\n Solid tumour\t–\t–\t0.68 (0.32 to 1.44)\t0.27 (0.06 to 1.22)\t\n Rheumatoid arthritis/collagen vascular disease\t–\tOmittedA\t1.59* (1.18 to 2.14)\t0.48 (0.18 to 1.25)\t\n Coagulopathy\t–\t2.58* (1.13 to 5.89)\t2.48* (2.10 to 2.94)\t2.17* (1.27 to 3.70)\t\n Obesity\t–\t0.98 (0.29 to 3.29)\t1.11 (0.91 to 1.36)\t0.49 (0.17 to 1.35)\t\n Weight loss/cachexia\t–\t–\t1.90* (1.43 to 2.53)\t1.92* (1.13 to 3.28)\t\n Fluid and electrolyte disorders\t–\t5.84* (4.26 to 8.00)\t4.08* (3.75 to 4.43)\t2.26* (1.71 to 3.00)\t\n Blood loss or deficiency anaemia\t–\t2.07* (1.33 to 3.97)\t1.36* (1.17 to 1.58)\t1.15 (0.79 to 1.67)\t\n Alcohol abuse\t–\t1.90* (1.34 to 2.71)\t1.26* (1.16 to 1.37)\t0.78 (0.47 to 1.29)\t\n Drug abuse\t–\t1.50* (1.10 to 2.04)\t1.16* (1.06 to 1.27)\t0.62 (0.32 to 1.18)\t\n Psychoses\t–\t1.62* (1.12 to 2.35)\t1.51* (1.37 to 1.67)\t1.28 (0.91 to 1.80)\t\n Depression\t–\t1.10 (0.81 to 1.49)\t1.04 (0.95 to 1.14)\t0.87 (0.61 to 1.23)\t\n Intentional self-harm\t–\t1.34 (0.96 to 1.87)\t1.49* (1.35 to 1.63)\t2.42* (1.80 to 3.25)\t\nCalendar year\t\n 2007 (vs 2006)\t–\t0.99 (0.64 to 1.55)\t0.99 (0.86 to 1.14)\t1.02 (0.63 to 1.67)\t\n 2008 (vs 2006)\t–\t0.98 (0.64 to 1.51)\t1.05 (0.92 to 1.20)\t0.81 (0.53 to 1.25)\t\n 2009 (vs 2006)\t–\t0.94 (0.60 to 1.48)\t0.92 (0.81 to 1.05)\t1.07 (0.69 to 1.65)\t\n 2010 (vs 2006)\t–\t0.96 (0.63 to 1.46)\t0.95 (0.83 to 1.10)\t1.12 (0.73 to 1.71)\t\nOmitted A, variable omitted due to near-perfect association with no requirement of intubation (ie, OR<0.01).\n\n*Statistically significant below the computed Simes (1986) false-discovery rate p value (p<0.036).\n\n‘–’, Variable omitted due to small sample size (n≤0.1%); APAP, acetaminophen; ED, emergency department.\n\nMultivariable analysis: charges, length of stay\nThe multivariable analysis of charges and length of stay (table 4) indicated varying associations with these economic outcomes. Suggestive of greater intensities of care required across all age categories, consistently significant increased charges and lengths of stay were associated with liver disease (p<0.036 for charges, p<0.024 for length of stay), while weight loss/cachexia and coagulopathy were significant across age groups 21–64 and ≥65 years; HIV/AIDS was significant in the 21–64 years age category. Increased charges alone were associated with intentional self-harm and most Elixhauser comorbidities: heart failure; hypertension with complications; other neurological disorders; coagulopathy; fluid and electrolyte disorders; blood loss or deficiency anaemia; alcohol abuse; psychoses; and depression (p<0.036). No consistent change across age categories was noted over time for either charges or length of stay.\n\nTable 4 Total charges and inpatient length of stay among APAP toxicity-related cases presenting to the ED according to age category, 2006–2010\n\n \tAge 11 years and below (N=42 623)\tAge 12–20 years (N=106 725)\tAge 21–64 years (N=246 640)\tAge 65 years and above (N=15 893)\t\n\tCharges (exp(b), 95th CI)\tLoS (IR, 95th CI)\tCharges (exp(b), 95th CI)\tLoS (IR, 95th CI)\tCharges (exp(b), 95th CI)\tLoS (IR, 95th CI)\tCharges (exp(b), 95th CI)\tLoS (IR, 95th CI)\t\nPatient characteristics\t\n Age\t1.04* (1.01 to 1.07)\t1.03 (0.99 to 1.07)\t1.05* (1.04 to 1.06)\t0.99 (0.98 to 1.01)\t1.01* (1.01 to 1.01)\t1.01* (1.01 to 1.01)\t1.00 (1.00 to 1.01)\t1.01 (1.00 to 1.01)\t\n Female sex\t0.94 (0.86 to 1.02)\t1.07 (0.88 to 1.31)\t0.97 (0.93 to 1.01)\t1.00 (0.95 to 1.05)\t0.96* (0.93 to 0.98)\t0.97* (0.94 to 0.99)\t0.91 (0.83 to 1.01)\t0.94 (0.85 to 1.03)\t\n Payer (vs commercial)\t\n Medicare\t–\t–\t0.93 (0.65 to 1.33)\t1.55 (0.90 to 2.65)\t0.98 (0.94 to 1.03)\t1.01 (0.96 to 1.06)\t1.14 (0.83 to 1.56)\t1.18 (0.81 to 1.72)\t\n Medicaid\t0.81* (0.71 to 0.92)\t0.96 (0.79 to 1.16)\t0.92* (0.87 to 0.96)\t0.94* (0.89 to 0.98)\t0.96* (0.93 to 0.98)\t0.86* (0.83 to 0.91)\t0.92 (0.65 to 1.31)\t1.12 (0.74 to 1.69)\t\n Other\t0.89 (0.71 to 1.05)\t1.08 (0.75 to 1.55)\t0.87* (0.82 to 0.92)\t0.92* (0.87 to 0.98)\t0.97 (0.94 to 1.01)\t0.94* (0.90 to 0.98)\t0.56* (0.36 to 0.86)\t0.93 (0.58 to 1.49)\t\n Income quartile (vs lowest)\t\n 2nd quartile\t1.06 (0.95 to 1.18)\t1.27 (0.97 to 1.66)\t1.04 (0.98 to 1.10)\t1.05 (0.99 to 1.11)\t1.01 (0.97 to 1.04)\t0.99 (0.95 to 1.02)\t0.98 (0.86 to 1.11)\t0.99 (0.88 to 1.12)\t\n 3rd quartile\t1.06 (0.88 to 1.28)\t1.33 (0.95 to 1.88)\t1.03 (0.97 to 1.10)\t1.05 (0.98 to 1.12)\t1.01 (0.96 to 1.06)\t1.00 (0.95 to 1.05)\t0.99 (0.87 to 1.14)\t0.92 (0.81 to 1.04)\t\n 4th quartile\t0.95 (0.79 to 1.14)\t1.28 (0.97 to 1.68)\t1.03 (0.95 to 1.12)\t1.00 (0.93 to 1.07)\t1.09* (1.02 to 1.17)\t0.99 (0.94 to 1.04)\t1.13 (0.96 to 1.33)\t0.95 (0.85 to 1.09)\t\n Rural residence\t1.19 (0.97 to 1.45)\t1.12 (0.71 to 1.75)\t1.00 (0.92 to 1.08)\t0.96 (0.86 to 1.07)\t1.03 (0.96 to 1.10)\t1.01 (0.94 to 1.09)\t0.93 (0.75 to 1.14)\t1.06 (0.88 to 1.27)\t\nHospital characteristics\t\n Rural location\t0.68* (0.55 to 0.87)\t0.86 (0.52 to 1.43)\t0.73* (0.66 to 0.81)\t0.80* (0.71 to 0.91)\t0.66* (0.60 to 0.72)\t0.76* (0.69 to 0.83)\t0.52* (0.42 to 0.66)\t0.67* (0.54 to 0.82)\t\n Teaching facility\t1.28* (1.10 to 1.49)\t1.23 (0.98 to 1.54)\t1.14* (1.06 to 1.24)\t1.03 (0.96 to 1.10)\t1.06 (0.99 to 1.13)\t1.09* (1.05 to 1.15)\t0.95 (0.84 to 1.07)\t1.02 (0.93 to 1.13)\t\n Region (vs Northeast)\t\n Midwest\t0.74* (0.64 to 0.87)\t0.72* (0.55 to 0.95)\t0.78* (0.71 to 0.86)\t0.83* (0.76 to 0.90)\t0.71* (0.65 to 0.78)\t0.79* (0.73 to 0.85)\t0.72* (0.61 to 0.85)\t0.74* (0.66 to 0.83)\t\n South\t0.89 (0.76 to 1.05)\t0.91 (0.68 to 1.23)\t0.88* (0.79 to 0.98)\t0.91* (0.85 to 0.97)\t0.87* (0.79 to 0.97)\t0.90* (0.85 to 0.96)\t0.88 (0.75 to 1.04)\t0.85* (0.75 to 0.96)\t\n West\t0.35* (0.27 to 0.45)\t0.71* (0.54 to 0.95)\t0.64* (0.57 to 0.73)\t0.76* (0.71 to 0.82)\t0.78* (0.70 to 0.86)\t0.82* (0.77 to 0.87)\t0.85 (0.71 to 1.02)\t0.74* (0.65 to 0.83)\t\nClinical characteristics\t\n Congestive heart failure\t–\t–\t–\t–\t1.52* (1.30 to 1.78)\t1.31* (1.14 to 1.50)\t1.39* (1.23 to 1.59)\t1.25* (1.12 to 1.40)\t\n Valvular disease\t–\t–\t1.36 (0.94 to 1.96)\t0.99 (0.68 to 1.44)\t1.42* (1.23 to 1.63)\t1.06 (0.95 to 1.18)\t1.56* (1.26 to 1.94)\t1.08 (0.91 to 1.29)\t\n Pulmonary circulation disorders\t–\t–\t–\t–\t1.90* (1.45 to 2.47)\t1.45* (1.19 to 1.77)\t1.27 (0.89 to 1.81)\t1.10 (0.79 to 1.54)\t\n Peripheral vascular disorders\t–\t–\t–\t–\t1.81* (1.47 to 2.23)\t1.40* (1.12 to 1.74)\t1.18 (0.98 to 1.42)\t1.01 (0.85 to 1.19)\t\n Hypertension with complications\t–\t–\t1.51* (1.28 to 1.79)\t1.35* (1.17 to 1.56)\t1.43* (1.19 to 1.71)\t1.23* (1.05 to 1.45)\t1.50* (1.23 to 1.84)\t1.17 (0.99 to 1.37)\t\n Paralysis\t–\t–\t1.79 (1.03 to 3.09)\t1.02 (0.70 to 1.48)\t1.60* (1.32 to 1.94)\t1.39* (1.19 to 1.63)\t1.94* (1.12 to 3.36)\t2.24 (1.08 to 4.62)\t\n Other neurological disorders\t7.00* (2.80 to 17.49)\t1.41 (1.02 to 1.96)\t1.61* (1.45 to 1.78)\t1.05 (0.94 to 1.17)\t1.29* (1.24 to 1.34)\t1.00 (0.97 to 1.04)\t1.15* (1.03 to 1.29)\t1.01 (0.90 to 1.13)\t\n Chronic pulmonary disease\t0.98 (0.80 to 1.20)\t0.81 (0.61 to 1.08)\t1.18* (1.11 to 1.26)\t0.97 (0.91 to 1.04)\t1.20* (1.15 to 1.26)\t1.02 (0.98 to 1.07)\t1.37* (1.23 to 1.52)\t1.03 (0.94 to 1.12)\t\n Diabetes with complications\t–\t–\t1.02 (0.86 to 1.20)\t0.90 (0.74 to 1.11)\t1.27* (1.11 to 1.45)\t1.07 (0.95 to 1.22)\t1.60 (0.97 to 2.66)\t1.07 (0.79 to 1.46)\t\n Hypothyroidism\t–\t–\t1.31 (1.00 to 1.72)\t1.39* (1.08 to 1.79)\t1.23* (1.15 to 1.31)\t1.01 (0.94 to 1.08)\t1.12 (1.00 to 1.25)\t0.89 (0.81 to 0.99)\t\n Renal failure\t–\t–\t1.41 (0.84 to 2.37)\t0.88 (0.51 to 1.51)\t1.43* (1.23 to 1.67)\t1.16 (1.00 to 1.33)\t1.03 (0.82 to 1.29)\t0.99 (0.80 to 1.22)\t\n Liver disease\t–\t–\t1.76* (1.30 to 2.39)\t1.53* (1.15 to 2.03)\t2.00* (1.80 to 2.23)\t1.52* (1.39 to 1.67)\t2.34* (1.66 to 3.31)\t1.52* (1.19 to 1.95)\t\n HIV/AIDS\t–\t–\t–\t–\t1.56* (1.18 to 2.06)\t1.30* (1.12 to 1.52)\t–\t–\t\n Lymphoma\t–\t–\t–\t–\t1.16 (0.86 to 1.57)\t1.02 (0.78 to 1.34)\t–\t–\t\n Metastatic cancer\t–\t–\t–\t–\t1.64* (1.16 to 2.31)\t1.48* (1.07 to 2.03)\t1.38 (0.89 to 2.15)\t1.06 (0.64 to 1.76)\t\n Solid tumour\t–\t–\t–\t–\t1.23 (0.97 to 1.56)\t1.12 (0.92 to 1.36)\t1.02 (0.84 to 1.24)\t0.88 (0.72 to 1.08)\t\n Rheumatoid arthritis/collagen vascular disease\t–\t–\t0.71 (0.38 to 1.32)\t0.84 (0.41 to 1.72)\t1.34* (1.21 to 1.49)\t1.12 (1.00 to 1.25)\t1.33* (1.07 to 1.64)\t1.02 (0.83 to 1.25)\t\n Coagulopathy\t–\t–\t3.04* (2.46 to 3.78)\t1.98* (1.63 to 2.41)\t2.08* (1.91 to 2.26)\t1.48* (1.39 to 1.59)\t1.54* (1.26 to 1.89)\t1.12 (0.92 to 1.36)\t\n Obesity\t–\t–\t1.58* (1.40 to 1.79)\t1.14 (1.01 to 1.28)\t1.39* (1.31 to 1.48)\t1.11 (1.01 to 1.22)\t1.18 (0.96 to 1.44)\t0.95 (0.76 to 1.20)\t\n Weight loss/cachexia\t–\t–\t–\t–\t1.99* (1.63 to 2.42)\t1.83* (1.58 to 2.13)\t1.68* (1.32 to 2.16)\t1.58* (1.31 to 1.89)\t\n Fluid and electrolyte disorders\t6.46* (3.26 to 12.81)\t1.93* (1.34 to 2.80)\t1.95* (1.84 to 2.08)\t1.04 (0.99 to 1.09)\t1.82* (1.76 to 1.88)\t1.16* (1.13 to 1.20)\t1.81* (1.62 to 2.02)\t1.18* (1.08 to 1.28)\t\n Blood loss or deficiency anaemia\t3.02* (1.67 to 5.47)\t1.28 (0.74 to 2.19)\t1.67* (1.43 to 1.94)\t1.20* (1.07 to 1.36)\t1.64* (1.55 to 1.74)\t1.27* (1.17 to 1.37)\t1.40* (1.23 to 1.59)\t1.11 (1.00 to 1.23)\t\n Alcohol abuse\t–\t–\t1.23* (1.14 to 1.31)\t1.01 (0.95 to 1.08)\t1.24* (1.21 to 1.27)\t0.98 (0.95 to 1.01)\t1.19* (1.06 to 1.34)\t1.01 (0.88 to 1.15)\t\n Drug abuse\t–\t–\t1.19* (1.13 to 1.20)\t1.11* (1.05 to 1.19)\t1.30* (1.26 to 1.34)\t1.11* (1.08 to 1.15)\t1.16 (0.99 to 1.36)\t1.09 (0.95 to 1.24)\t\n Psychoses\t–\t–\t1.65* (1.57 to 1.74)\t1.01 (0.95 to 1.08)\t1.50* (1.46 to 1.55)\t1.02 (0.98 to 1.07)\t1.50* (1.33 to 1.70)\t1.27* (1.13 to 1.43)\t\n Depression\t–\t–\t1.27* (1.22 to 1.33)\t0.87* (0.83 to 0.92)\t1.19* (1.16 to 1.23)\t0.84* (0.82 to 0.87)\t1.22* (1.10 to 1.35)\t0.90* (0.83 to 0.98)\t\n Intentional self-harm\t–\t–\t1.40* (1.33 to 1.49)\t1.16* (1.09 to 1.23)\t1.17* (1.13 to 1.21)\t1.09* (1.05 to 1.13)\t1.16* (1.06 to 1.28)\t1.02 (0.94 to 1.11)\t\n Invasive mechanical ventilation\t–\t–\t3.21* (2.84 to 3.63)\t1.60* (1.41 to 1.82)\t3.37* (3.20 to 3.55)\t1.57* (1.50 to 1.64)\t1.39* (1.23 to 1.59)\t1.57* (1.39 to 1.78)\t\nCalendar year\t\n 2007 (vs 2006)\t0.95 (0.80 to 1.13)\t1.12 (0.85 to 1.47)\t0.99 (0.91 to 1.08)\t1.02 (0.95 to 1.09)\t1.04 (0.98 to 1.10)\t1.03 (0.98 to 1.08)\t1.06 (0.90 to 1.24)\t1.01 (0.87 to 1.17)\t\n 2008 (vs 2006)\t1.04 (0.84 to 1.28)\t0.91 (0.68 to 1.23)\t0.99 (0.91 to 1.08)\t0.99 (0.92 to 1.07)\t1.03 (0.97 to 1.09)\t1.03 (0.98 to 1.07)\t1.02 (0.87 to 1.20)\t0.97 (0.85 to 1.10)\t\n 2009 (vs 2006)\t1.01 (0.84 to 1.22)\t0.91 (0.69 to 1.22)\t1.04 (0.96 to 1.13)\t1.01 (0.94 to 1.09)\t1.06 (1.00 to 1.12)\t0.98 (0.93 to 1.03)\t0.97 (0.83 to 1.12)\t0.90 (0.79 to 1.02)\t\n 2010 (vs 2006)\t1.16 (0.97 to 1.39)\t0.89 (0.69 to 1.15)\t1.08 (1.00 to 1.18)\t0.96 (0.90 to 1.03)\t1.07* (1.01 to 1.14)\t0.97 (0.93 to 1.02)\t1.09 (0.93 to 1.27)\t0.94 (0.83 to 1.07)\t\n*Statistically significant below the computed Simes (1986) false-discovery rate p value for charges (p<0.036) and LoS (p<0.024).\n\n–, Variable omitted due to small sample size (n≤0.1%); exp(b), exponentiated β coefficient; IR, incidence ratio; LoS, length of stay.\n\nDiscussion\nThis investigation examined nationally representative cases of APAP toxicity-associated ED visits in the USA from 2006 to 2010, assessing the independent associations between outcomes of inpatient admission, mortality, required use of invasive mechanical ventilation, charges and lengths of stay based on several patient, clinical and hospital characteristics. Overall, 411 881 ED visits were observed (82 376 per year), equating to 27.10 ED visits per 100 000 US population annually, and the summing up to a national bill of $1.06 billion per year (US$ 2014). Some 37.2% cases were treated-and-released directly from the ED (30 783 per year), 45.5% were admitted to the inpatient setting (37 877 per year) and 0.6% involved death (484 per year). The number of ED presentations did not appreciably change over time, decreasing by <2% from 2006 to 2010 (n=1351), though representing an overall change from 27.15 to 25.78 visits per 100 000 US population annually.\n\nComparatively, Nourjah et al5 estimated that attributable APAP overdoses from 1993 to 1999 were lower than aforementioned findings, with approximately 56 000 ED visits, 26 000 hospitalisations and 458 deaths per year; Li and Martin8 also reported a decrease in rates from 2001 to 2007 to slightly less than 45 000 ED visits per year. From 1993 to 1999, Li and Martin8 found a lower number of ED visits, at 21.03 visits per 100 000 persons per year and decreasing to 15.21 from 2000 to 2007. It is critical to note that Nourjah et al,5 and Li and Martin8 utilised different national data than the present study, data that have explicitly been identified with a discrepancy in the number of cases associated with intentional APAP overdose-related visits; however, unintentional poisonings appeared to be similar across various data sources.6\n7 Manthripragada et al6 presented results illustrating differences present within nationally representative studies, in which the number of APAP toxicity-associated ED visits may be potentially underestimated by perhaps one-third to one-half. More closely parallel to the present study, Budnitz et al7 reported 78 414 annual ED visits associated with APAP overdoses from 2005 to 2006 using data from the National Electronic Injury Surveillance System (NEISS), while Manthripragada et al6 found an age-adjusted rate of 13.9 hospitalisations per 100 000 US population from 2000 to 2006. Also consistent with the current work, a decrease in the number of ED visits or hospitalisations over time relating to APAP overdose was not observed.6\n\nThe average age in the present study was 29.3 years, with 60.0% of ED visits occurring across the 21–64-year age group. Though constituting 16.2% and 11.1% of the US population, some 10.3% and 25.9% of cases, respectively, involved persons 0–11 and 12–20 years of age. Furthermore, ED presentations exceeding 50 visits per 100 000 persons per year were noted from ages 1 to 2 and 15–22 years, peaking at over 70 per 100 000 specifically at age 2 years and ages 16–18 years. Broader surveillance figures suggest that age-adjusted overall non-fatal injuries relating to poisoning of any type was 36.14 per 100 000 in 2013, though the crude rate for ages 1–2 years is 12.27 per 100 000 and is 35.79 per 100 000 for ages 15–22 years.23 Prior investigations suggest a substantially large number of APAP toxicity-related ED visits occur among young children, adolescents and young adults; Li and Martin8 reported 72.42 visits per 100 000 for cases under 5 years of age, 61.91 per 100 000 for ages 15–17 years and 40.92 per 100 000 for ages 18–24 years.7\n24\n25 Budnitz et al7 found that 13.4% of APAP overdose ED visits were attributed to unsupervised ingestions by children aged 5 years and under, a finding which has been observed across other work.26–28 Others have found higher risks for APAP toxicity-related ED visits due, in part, to single ingredient unintentional overdose or high use of APAP products.24\n25\n28\n\nA majority of cases in the current work involved the female sex (65.5%) and intentional self-harm (58.4%): these were highest in the 12–20 years age category: 74.8% female and 71.4% intentional self-harm. Similar to Li and Bradly (2011), behavioural and mental health comorbidities were common and represented the largest proportions of Elixhauser comorbidities, including depression (25.0%), psychoses (15.3%), drug abuse (15.6%) and alcohol abuse (13.7%). Notably, these comorbid conditions were also associated with increased relative risk of admission and likelihood of charges almost entirely across all age categories ≥12 years within the multivariable analyses.8 Over most age categories ≥12 years, intentional self-harm was generally associated with increased odds of admission, mortality, requirement of invasive mechanical ventilation, charges and length of stay. Budnitz et al7 reported that 69.8% of ED visits involving APAP overdoses from 2006 to 2007 were associated with self-directed violence, peaking among those between 15 and 24 years of age, with 75% ultimately resulting in either psychiatric or inpatient hospitalisations. Surveillance data also suggest that one-quarter of all ED cases for intentional poisoning involve APAP.23 Budnitz et al7 also noted that females had the highest rates of intentional self-harm, especially as adolescents or young adults. It has been noted in prior work that suicide attempts via toxic medication ingestion is more frequently observed among adolescents and often associated with impulsivity, of which toxic APAP ingestion has been classified.7\n29–31 Importantly, Manthripragada et al6 emphasised that discerning whether self-harm was intentional versus accidental remains challenging to ascertain via secondary data, potentially resulting in the misclassification of cases involving non-accidental poisoning via supplementary ICD-9 codes (ie, E-codes) or differences in hospital reporting requirements.32\n33\n\nResults of the multivariable analysis indicated that rural patient residence (municipalities ≤50 000 persons) was associated with a higher odds of admission across age categories <65 years. Among age categories ≥12 years, an increased relative risk of admission and mortality was associated with liver disease, coagulopathy, fluid and electrolyte disorders, and weight loss/cachexia. With some exceptions, increased odds of invasive mechanical ventilation, charges and lengths of stay were also observed with these comorbidities as well. Li and Martin (2011) reported a 8.62× higher odds of ED visits attributed to APAP toxicity with alcohol abuse or dependence (p<0.001); findings from the current work also suggest over a 2× higher relative risk of admission (age categories ≥12 years), a 1.75× higher relative risk of mortality (ages 21–64 years), over 1.19× higher charges (age categories ≥12 years), and 1.26× or greater odds of invasive mechanical ventilation (ages 12–20 and 21–64 years). Paediatric admission cases of age <12 years were associated with other neurological disorders, fluid and electrolyte disorders, and blood loss or deficiency anaemia; Budnitz et al7 reported that most of the unsupervised ingestions of APAP were observed among children aged <6 years, typically treated-and-released from the ED setting via gastric decontamination or N-acetyl cysteine (NAS) treatment.\n\nAlthough findings from this study provide updated information concerning the burden of APAP-related ED visits in the USA, some important study limitations exist. While similar coding algorithms were used, as in other retrospective studies, to identify APAP-toxicity cases, no specific categorisation was present that may have classified cases as being unsupervised ingestions or therapeutic misadventures (eg, overuse, medication errors); as per the type of APAP product consumed (eg, single-agent, combination products, tablets, liquid), and according to the estimated amount ingested or serum levels observed.5–8\n15\n16 In this context, Budnitz et al7 reported that 13.4% of APAP toxicity-related ED visits were attributed to unsupervised ingestions and 16.7% involved therapeutic misadventures, with slightly over half involving overuse of agents versus dosage confusion or APAP overingestion from multiple source products. The use of NAS or gastric decontamination was also not consistently captured within the data set, nor was a designation of acute liver injury directly attributable to APAP toxicity.6\n7 Generalisations of findings beyond acute care settings are not appropriate to estimate the prevalence of APAP poisoning in the USA, as cases presenting to poison centres or within ambulatory practices are not captured. At the time of this study’s initiation, the 2006–2010 time frame reflected the entirety of HCUP NEDS data; the complex process of collecting, integrating, validating and distributing data of this nature typically takes 2 years.14 As such, given the time horizon of this study and available data, continued work is warranted to study the impact of more recent APAP dose limitations established by the FDA in addition to studies focusing directly on consumer perceptions, attitudes, beliefs, knowledge and health literacy.9–13\n34–45\n\nConclusion\nThis nationally representative study of ED visits in the USA highlights a substantial public health impact of APAP toxicity-related cases from 2006 to 2010. Overall, 82 376 cases per year were observed, summing up to a national bill of $1.06 billion. The ED visit average rate across all ages was 27.10 ED visits per 100 000 US population, exceeding 70 per 100 000 for age 2 years and ages 16–18 years. After controlling for numerous factors, no consistent temporal change was observed during the 5-year time horizon concerning outcomes of admission, mortality, invasive mechanical ventilation, charges or length of stay.\n\nTwitter: Follow Ahmed Altyar at @aealtyar\n\nPreliminary findings of this study were presented as a plenary presentation at the Western States Conference for Pharmacy Residents, Fellows, Preceptors and Sponsors, 21–24 May 2012, Pacific Grove, California, USA, and as a poster at the American Society of Health-System Pharmacists ASHP Summer Meeting and Exhibition, 31 May–4 June 2014, Las Vegas, Nevada, USA.\n\nContributors: AA and GS conducted the initial planning of this investigation. AA, LK and GS were involved in formalising and executing the study methodology, analysis, interpretation of results, and drafting and revisions of the manuscript. GS was involved in the acquisition of data and overall study supervision.\n\nFunding: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData sharing statement: No additional data are available.\n==== Refs\nReferences\n1 Governale L \nDrug utilization data analysis. Joint Meeting of the Drug Safety and Risk Management Advisory Committee with the Anesthetic and Life Support Drugs Advisory Committee and the Nonprescription Drugs Advisory Committee . Briefing Information. 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CDC's WISQARS™ (Web-based Injury Statistics Query and Reporting System) \nNational Center for Injury Prevention and Control, CDC \nhttp://www.cdc.gov/injury/wisqars/index.html (accessed 06 May 2014 ).\n24 Willy M , Kelly JP , Nourjah P \nEmergency department visits attributed to selected analgesics, United States, 2004–2005 . Pharmacoepidemiol Drug Saf \n2009 ;18 :188 –95 . 10.1002/pds.1691 19116955 \n25 McCaig LF , McCaig L , Burt CW \nPoisoning-related visits to emergency departments in the United States, 1993–1996 . Clin Toxicol \n1999 ;37 :817 –26 .\n26 Chien C , Marriott JL , Ashby K \nUnintentional ingestion of over the counter medications in children less than 5 years old . J Paediatr Child Health \n2003 ;39 :264 –9 . 10.1046/j.1440-1754.2003.00148.x 12755931 \n27 Schillie SF , Shehab N , Thomas KE \nMedication overdoses leading to emergency department visits among children . Am J Prev Med \n2009 ;37 :181 –7 . 10.1016/j.amepre.2009.05.018 19666156 \n28 Vernacchio L , Kelly JP , Kaufman DW \nCough and cold medication use by US children, 1999–2006: results from the Slone Survey . Pediatrics \n2008 ;122 :e323 –9 . 10.1542/peds.2008-0498 18676518 \n29 Centers for Disease Control, CDC . Fatal and nonfatal suicide attempts among adolescents—Oregon, 1988–1993 . MMWR Morb Mortal Wkly Rep \n1995 ;44 :312 –15 , 321–323 .7715589 \n30 Kingsbury S , Hawton K , Steinhardt K \nDo adolescents who take overdoses have specifıc psychological characteristics? A comparative study with Psychiatric and community controls . J Am Acad Child Adolesc Psychiatry \n1999 ;38 :1125 –31 . 10.1097/00004583-199909000-00016 10504811 \n31 Hawton K , Ware C , Mistry H \nParacetamol self-poisoning. Characteristics, prevention and harm reduction . Br J Psychiatry \n1996 ;168 :43 –8 . 10.1192/bjp.168.1.43 8770427 \n32 Centers for Disease Control, CDC . Strategies to improve external cause-of-injury coding in state-based hospital discharge and emergency department data systems: recommendations of the CDC Workgroup for Improvement of External Cause-of-Injury Coding . MMWR Recomm Rep \n2008 ;57: 1 –15 .\n33 Centers for Disease Control, CDC . National Center for Injury Prevention and Control recommended actions to improve external-cause-of-injury coding in state-based hospital discharge and emergency department data systems. Atlanta (GA): US Department of Health and Human Services . Centers for Disease Control and Prevention , 2009 .\n34 Alexander GC , Mohajir N , Meltzer DO \nConsumers’ perceptions about risk and access to nonprescription medications . J Am Pharm Assoc \n2005 ;45 :363 –70 . 10.1331/1544345054003868 \n35 Osborne ZP , Bryant SM \nPatients discharged with a prescription for acetaminophen-containing narcotic analgesics do not receive appropriate written instructions . Am J Emerg Med \n2003 ;21 :48 –50 . 10.1053/ajem.2003.50038 12563581 \n36 National Council on Patient Information and Education, NCPIE . Attitudes and beliefs about the use of over-the-counter medicines; a dose of reality . National Survey of Consumer Health Professionals , 2002 .\n37 Stumpf JL , Skyles AJ , Alaniz C \nKnowledge of appropriate acetaminophen doses and potential toxicities in an adult clinic population . J Am Pharm Assoc \n2007 ;47 :35 –41 . 10.1331/1544-3191.47.1.35.Stumpf \n38 Chen L , Schneider S , Wax P \nKnowledge about acetaminophen toxicity among emergency department visitors . Vet Hum Toxicol \n2002 ;44 :370 –3 .12458645 \n39 Litovitz T \nImplication of dispensing cups in dosing errors and pediatric poisonings: a report from the American Association of Poison Control Centers . Ann Pharmacother \n1992 ;26 :917 –18 .1504399 \n40 Barrett TW , Norton VC \nParental knowledge of different acetaminophen concentrations for infants and children . Acad Emerg Med \n2000 ;7 :718 –21 . 10.1111/j.1553-2712.2000.tb02054.x 10905654 \n41 Eiland LS , Salazar ML , English TM \nCaregivers’ perspectives when evaluating nonprescription medication utilization in children . Clin Pediatr \n2008 ;47 :578 –87 . 10.1177/0009922807310244 \n42 Simon HK , Weinkle DA \nOver-the-counter medications. Do parents give what they intend to give? \nArch Pediatr Adolesc Med \n1997 ;151 :654 –6 . 10.1001/archpedi.1997.02170440016003 9232037 \n43 Lokker N , Sanders L , Perrin EM \nParental misinterpretations of over-the-counter pediatric cough and cold medication labels . Pediatrics \n2009 ;123 :1464 –71 . 10.1542/peds.2008-0854 19482755 \n44 Sobhani P , Christopherson J , Ambrose PJ \nAccuracy of oral liquid measuring devices: comparison of dosing cup and oral dosing syringe . Ann Pharmacother \n2008 ;42 :46 –52 . 10.1345/aph.1K420 18056832 \n45 Cham E , Hall L , Ernst AA \nAwareness and use of over-the-counter pain medications: a survey of emergency department patients . South Med J \n2002 ;95 :529 –35 . 10.1097/00007611-200295050-00014 12005011\n\n",
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"keywords": "EPIDEMIOLOGY; HEALTH ECONOMICS; PUBLIC HEALTH",
"medline_ta": "BMJ Open",
"mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D004636:Emergency Service, Hospital; D005260:Female; D019538:Health Care Surveys; D017722:Hospital Charges; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D007902:Length of Stay; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011041:Poisoning; D012189:Retrospective Studies; D014481:United States; D055815:Young Adult",
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{
"abstract": "OBJECTIVE\nA case of apparent overdose of angiotensin-converting-enzyme inhibitors requiring hemodialysis is reported.\n\n\nCONCLUSIONS\nA 51-year-old white man (weight, 85 kg; height, 178 cm; body mass index, 28) with a history of hypertension, low back pain, and anxiety apparently took 27 lisinopril 10-mg tablets (3.18 mg/kg body weight) over a period of 3 or fewer days. The friend who brought him to the emergency department reported that the patient was hard to rouse and was speaking incoherently on the day of admission. Over the previous few days, the patient reportedly had visual hallucinations, incoherence, and inarticulate speech. Laboratory tests, electrocardiography, and computed tomography were performed. The patient was judged to have high-anion-gap metabolic acidosis, acute kidney injury, severe hyperkalemia, and rhabdomyolysis. He was given three doses of albuterol via a nebulizer, three doses of calcium gluconate 1 g i.v., two doses of sodium bicarbonate 100 meq i.v., two doses of sodium polystyrene sulfonate 30 g orally, three doses of insulin 10 units i.v., and three doses of dextrose 25 g (as 50% dextrose injection) i.v. He then underwent emergent hemodialysis and was admitted to the intensive care unit. The patient's confusion abated, kidney function improved, and acid-base and electrolyte imbalances resolved. The patient was discharged after 15 days.\n\n\nCONCLUSIONS\nA man who had evidently taken an overdose of lisinopril had multiorgan dysfunction in the absence of hypotension. The abnormalities resolved after he was treated for acidosis and hyperkalemia and received hemodialysis to remove the lisinopril.",
"affiliations": "Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA. belayti@marshall.edu",
"authors": "Belay|Tilahun W|TW|;Nusair|Ahmad R|AR|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D017706:Lisinopril",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp120734",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "70(14)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D058186:Acute Kidney Injury; D000806:Angiotensin-Converting Enzyme Inhibitors; D062787:Drug Overdose; D006801:Humans; D017706:Lisinopril; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "1226-9",
"pmc": null,
"pmid": "23820459",
"pubdate": "2013-07-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Apparent lisinopril overdose requiring hemodialysis.",
"title_normalized": "apparent lisinopril overdose requiring hemodialysis"
} | [
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{
"abstract": "Lipid-emulsion therapy (Intralipid®) has been advocated as a potential treatment for the management of cardio-toxicity arising from lipid-soluble drugs, particularly those acting upon sodium channels. This, on the basis of a number of ex vivo studies and animal models, suggests that partitioning a drug into lipid could alter its pharmacokinetics and result in significant clinical improvements. Its subsequent use in clinical case series has been seen as confirmation of this mechanism of action. While there are undoubtedly instances where lipid emulsion therapy has been associated with a desirable outcome in humans, as described in this case report, clinicians are reminded that they should not attribute causality, on this basis alone.",
"affiliations": "King's Health Partner, King's College Hospital, London, UK o.mukhtar@nhs.net.;Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK.;Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK, and King's College London, London, UK.;Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK, and King's College London, London, UK.",
"authors": "Mukhtar|Omar|O|;Archer|John Rh|JR|;Dargan|Paul I|PI|;Wood|David M|DM|",
"chemical_list": "D004655:Emulsions; D010743:Phospholipids; C545823:soybean oil, phospholipid emulsion; D013024:Soybean Oil; D005424:Flecainide",
"country": "England",
"delete": false,
"doi": "10.7861/clinmedicine.15-3-301",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2118",
"issue": "15(3)",
"journal": "Clinical medicine (London, England)",
"keywords": "Flecainide; Intralipid; lipid emulsion therapy; overdose; toxicity",
"medline_ta": "Clin Med (Lond)",
"mesh_terms": "D000293:Adolescent; D062787:Drug Overdose; D004655:Emulsions; D005260:Female; D005424:Flecainide; D006801:Humans; D010743:Phospholipids; D013024:Soybean Oil",
"nlm_unique_id": "101092853",
"other_id": null,
"pages": "301-3",
"pmc": null,
"pmid": "26031986",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20095812;20923546;21327839;2176700;21824065;22882363;23700986;3520324",
"title": "Lesson of the month 1: Acute flecainide overdose and the potential utility of lipid emulsion therapy.",
"title_normalized": "lesson of the month 1 acute flecainide overdose and the potential utility of lipid emulsion therapy"
} | [
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],
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"medicinalproduct": "ASPIRIN."
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},
{
"reactionmeddrapt": "Cardiac arrest",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Liver injury",
"reactionmeddraversionpt": "18.1",
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},
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "18.1",
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"literaturereference": "MUKHTAR O,ARCHER J,DARGAN P,WOOD D. LESSON OF THE MONTH 1: ACUTE FLECAINIDE OVERDOSE AND THE POTENTIAL UTILITY OF LIPID EMULSION THERAPY. CLINICAL MEDICINE (LONDON, ENGLAND) 2015 JUN;15:3:301-303.",
"literaturereference_normalized": "lesson of the month 1 acute flecainide overdose and the potential utility of lipid emulsion therapy",
"qualification": "3",
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "GB",
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}
] |
{
"abstract": "A 64-year-old man was diagnosed with limited cutaneous systemic sclerosis 5 years prior to this report. His sclerotic skin symptoms did not respond to oral low-dose prednisone (5-10 mg/day). Five years after the diagnosis, the patient presented with leukocytosis 3.8 × 109/L in a routine blood test, and was finally diagnosed with chronic-phase chronic myelogenous leukemia (CML). The leukemia responded optimally to initial dasatinib, and a complete cytogenetic response was achieved after 6 months of therapy. His skin symptoms dramatically improved in parallel with dasatinib therapy, as indicated by a decrease in the modified Rodnan skin score, from 12 points at diagnosis to 2 after 9 months. It has been reported that imatinib, a first-generation tyrosine kinase inhibitor, improves skin sclerosis in some patients with systemic sclerosis. To the best of our knowledge, this is the first report of simultaneous improvement of CML and limited cutaneous systemic sclerosis in response to dasatinib. Further study of the mechanism of action of dasatinib is crucial.",
"affiliations": "Department of Hematology, Ome Municipal General Hospital, 4-16-5, Higashiome, Ome, Tokyo, Japan. blue.blue.blue.212@gmail.com.;Department of Hematology, Ome Municipal General Hospital, 4-16-5, Higashiome, Ome, Tokyo, Japan.;Department of Hematology, Ome Municipal General Hospital, 4-16-5, Higashiome, Ome, Tokyo, Japan.;Department of Hematology, Ome Municipal General Hospital, 4-16-5, Higashiome, Ome, Tokyo, Japan.;Department of Hematology, Ome Municipal General Hospital, 4-16-5, Higashiome, Ome, Tokyo, Japan.;Department of Hematology, Ome Municipal General Hospital, 4-16-5, Higashiome, Ome, Tokyo, Japan.",
"authors": "Arai|Kosuke|K|http://orcid.org/0000-0003-1106-8329;Yoshifuji|Kota|K|;Motomura|Yotaro|Y|;Sonokawa|Saeko|S|;Suzuki|Sayaka|S|;Kumagai|Takashi|T|",
"chemical_list": "D000970:Antineoplastic Agents; D000069439:Dasatinib",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-019-02618-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "109(6)",
"journal": "International journal of hematology",
"keywords": "Chronic myelogenous leukemia; Dasatinib; Skin symptoms; Systemic sclerosis",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000970:Antineoplastic Agents; D000069439:Dasatinib; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D012595:Scleroderma, Systemic; D012867:Skin; D016896:Treatment Outcome",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "718-722",
"pmc": null,
"pmid": "30788724",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10403855;15930265;16790699;16987838;17151364;17332883;17640308;17761974;18326784;18648520;20525993;20525995;21398330;21769849;2408149;24122180;29027146;29121645;29138221;30151740;8308774",
"title": "Dasatinib for chronic myelogenous leukemia improves skin symptoms of systemic sclerosis.",
"title_normalized": "dasatinib for chronic myelogenous leukemia improves skin symptoms of systemic sclerosis"
} | [
{
"companynumb": "PHHY2019JP131985",
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"occurcountry": "JP",
"patient": {
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{
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"activesubstancename": "DASATINIB"
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{
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],
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{
"reactionmeddrapt": "Skin lesion",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Drug resistance",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ARAI K, YOSHIFUJI K, MOTOMURA Y, SONOKAWA S, SUZUKI S, KUMAGAI T. DASATINIB FOR CHRONIC MYELOGENOUS LEUKEMIA IMPROVES SKIN SYMPTOMS OF SYSTEMIC SCLEROSIS. INTERNATIONAL JOURNAL OF HEMATOLOGY. 2019?109:718-22",
"literaturereference_normalized": "dasatinib for chronic myelogenous leukemia improves skin symptoms of systemic sclerosis",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20190612",
"receivedate": "20190612",
"receiver": {
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"receivertype": "6"
},
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"safetyreportid": 16420177,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190711"
}
] |
{
"abstract": "BACKGROUND\nWe conducted this trial to determine the maximum tolerated dose (MTD) of temsirolimus added to an established regimen comprised of rituximab and cladribine for the initial treatment of mantle cell lymphoma.\n\n\nMETHODS\nA standard phase I cohort of three study design was utilized. The fixed doses of rituximab and cladribine were 375 mg/m(2) i.v. day 1 and 5 mg/m(2)/day i.v. days 1-5 of a 28-day cycle, respectively. There were five planned temsirolimus i.v. dose levels: 15 mg day 1; 25 mg day 1; 25 mg days 1 and 15; 25 mg days 1, 8 and 15; and 25 mg days 1, 8, 15, and 22.\n\n\nRESULTS\nSeventeen patients were treated: three each at levels 1-4 and five at dose level 5. The median age was 75 years (52-86 years). Mantle Cell International Prognostic Index (MIPI) scores were low in 6% (1), intermediate in 59% (10), and high in 35% (6) of patients. Five patients were treated at level 5 without dose limiting toxicity. Hematologic toxicity was frequent: grade 3 anemia in 12%, grade 3 thrombocytopenia in 41%, grade 4 thrombocytopenia in 24%, grade 3 neutropenia in 6%, and grade 4 neutropenia in 18% of patients. The overall response rate (ORR) was 94% with 53% complete response and 41% partial response. The median progression-free survival was 18.7 months.\n\n\nCONCLUSIONS\nTemsirolimus 25 mg i.v. weekly may be safely added to rituximab and cladribine at 375 mg/m(2) i.v. day 1 and 5 mg/m(2)/day i.v. days 1-5 of a 28-day cycle, respectively. This regimen had promising preliminary activity in an elderly cohort of patients with mantle cell lymphoma.\nNCT00787969.",
"affiliations": "Division of Hematology, Mayo Clinic, Rochester. Electronic address: inwards.david@mayo.edu.;Illinois Oncology Research Association, Peoria.;Division of Endocrinology, Mayo Clinic, Rochester.;Division of Endocrinology, Mayo Clinic, Rochester.;Division of Hematopathology, Mayo Clinic, Rochester.;Department of Medical Oncology, Essentia Duluth Clinic, Duluth.;Department of Oncology, Siouxland Hematology-Oncology Associates, Sioux City.;Department of Oncology, Iowa Oncology Research Association, Des Moines, USA.;Division of Hematology, Mayo Clinic, Rochester.",
"authors": "Inwards|D J|DJ|;Fishkin|P A|PA|;LaPlant|B R|BR|;Drake|M T|MT|;Kurtin|P J|PJ|;Nikcevich|D A|DA|;Wender|D B|DB|;Lair|B S|BS|;Witzig|T E|TE|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D017338:Cladribine; D000069283:Rituximab; C401859:temsirolimus; D020123:Sirolimus",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdu273",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "25(10)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "cladribine; mantle cell lymphoma; temsirolimus",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D017338:Cladribine; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012074:Remission Induction; D000069283:Rituximab; D020123:Sirolimus",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "2020-2024",
"pmc": null,
"pmid": "25057177",
"pubdate": "2014-10",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "16145068;23782157;15983389;22718839;18470909;18543327;16971665;17908623;19245430;21228334;23401442;18452065;19917845;11870171;17001068;18625886;21623691;16766582;18622414;23433739;15591112;20528872;21440503;15668467",
"title": "Phase I trial of rituximab, cladribine, and temsirolimus (RCT) for initial therapy of mantle cell lymphoma.",
"title_normalized": "phase i trial of rituximab cladribine and temsirolimus rct for initial therapy of mantle cell lymphoma"
} | [
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},
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},
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},
{
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{
"abstract": "Isolated intracranial fungal infection is infrequent and mostly seen in high-risk, immunocompromised patients. Fusarium, a primary plant fungus, rarely contributes to such disease. Amongst the very few cases of Fusarium brain abscess that have been reported, the infection has occurred mostly in adults. We present a case of a 6-year-old boy with tuberculous meningitis diagnosed with multiple Fusarium brain abscess caused by Fusarium falciforme during his clinical course. An immunocompromised state secondary to tuberculous meningitis presumably led to this infection. After tapping the abscesses, the child was treated with a combination of amphotericin B, voriconazole and terbinafine. Despite an aggressive therapy, he remained in poor neurological state. This is the second report of an isolated Fusarium abscess in pediatric age and the first one in a young child and provides pertinent review of this unusual central nervous system fungal infection. Such unusual infectious spectrum should be borne in mind in patients with co-existent immunosuppression.",
"affiliations": "Department of Neurosurgery, Postgraduate Institute of Medical Education & Research (PGIMER), Madhya Marg, Sector 12, Chandigarh, 160012, India. karthigeyanm82@gmail.com.;Department of Neurosurgery, Postgraduate Institute of Medical Education & Research (PGIMER), Madhya Marg, Sector 12, Chandigarh, 160012, India.;Department of Medical Microbiology, Mycology Division, Center of Advanced Research in Medical Mycology & WHO Collaborating Center, PGIMER, Madhya Marg, Sector 12, Chandigarh, 160012, India.;Department of Neurosurgery, Postgraduate Institute of Medical Education & Research (PGIMER), Madhya Marg, Sector 12, Chandigarh, 160012, India.;Department of Pediatrics, Division of Pediatric Critical Care, Advanced Pediatrics Centre, PGIMER, Madhya Marg, Sector 12, Chandigarh, 160012, India.;Department of Pediatrics, Division of Pediatric Critical Care, Advanced Pediatrics Centre, PGIMER, Madhya Marg, Sector 12, Chandigarh, 160012, India.",
"authors": "Karthigeyan|Madhivanan|M|http://orcid.org/0000-0001-7085-7251;Singh|Kavindra|K|;Kaur|Harsimran|H|;Salunke|Pravin|P|;Pandey|Jaya|J|;Nallasamy|Karthi|K|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00381-021-05320-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0256-7040",
"issue": null,
"journal": "Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery",
"keywords": "Central nervous system; Children; Fungus; Intracranial; Mycoses; Pediatric",
"medline_ta": "Childs Nerv Syst",
"mesh_terms": null,
"nlm_unique_id": "8503227",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34378119",
"pubdate": "2021-08-10",
"publication_types": "D016428:Journal Article",
"references": "6827355",
"title": "Multiple Fusarium brain abscesses in a young child.",
"title_normalized": "multiple fusarium brain abscesses in a young child"
} | [
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"abstract": "Thrombocytopenia is a frequent complication of cancer may be due to a variety of causes including malignancy itself, acute disease processes, or cancer therapy. Systemic cancer therapy is the most common cause of thrombocytopenia in cancer patients observed nearly two-thirds of patients with solid tumors. Thrombocytopenia with traditional chemotherapy agents is most frequently the result of megakaryocyte cytotoxicity. Oxaliplatin is a platinum derivative commonly used in gastrointestinal malignancies and is associated with drug-induced immune thrombocytopenia.",
"affiliations": "Department of Medicine, Keck School of Medicine of USC, Los Angeles, California, USA.;Department of Medicine, Keck School of Medicine of USC, Los Angeles, California, USA.;Division of Hematology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, California, USA.",
"authors": "Pan|Elizabeth|E|;Hsieh|Eric|E|;Piatek|Caroline|C|",
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"country": "Switzerland",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. 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 3068706510.1159/000495032cro-0011-0880Case ReportCase Report: Oxaliplatin-Induced Immune-Mediated Thrombocytopenia Pan Elizabeth aHsieh Eric a*Piatek Caroline baDepartment of Medicine, Keck School of Medicine of USC, Los Angeles, California, USAbDivision of Hematology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, California, USA*Eric Hsieh, MD, Department of Medicine, Keck School of Medicine of USC, 1450 San Pablo Street Suite 3000, Los Angeles, CA 90033 (USA), E-Mail ephsieh@usc.eduSep-Dec 2018 20 12 2018 20 12 2018 11 3 880 882 30 10 2018 30 10 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Thrombocytopenia is a frequent complication of cancer may be due to a variety of causes including malignancy itself, acute disease processes, or cancer therapy. Systemic cancer therapy is the most common cause of thrombocytopenia in cancer patients observed nearly two-thirds of patients with solid tumors. Thrombocytopenia with traditional chemotherapy agents is most frequently the result of megakaryocyte cytotoxicity. Oxaliplatin is a platinum derivative commonly used in gastrointestinal malignancies and is associated with drug-induced immune thrombocytopenia.\n\nKeywords\nAdenocarcinomaOxaliplatinThrombocytopenia\n==== Body\nCase Presentation\nA 36 year-old woman with Her-2 negative metastatic gastric adenocarcinoma currently on capecitabine and oxaliplatin presented for oxaliplatin infusion. Laboratory testing one day prior showed a platelet count of 237 × 109 and ahemoglobin of 10.9 g/dL with an MCV of 81.9 attributed to iron deficiency anemia, She had previously received 5-fluorouracil/leucovorin/oxaliplatin for 14 months and then was switched to single agent capecitabine for 2 months in the setting of stable disease. At progression of disease, oxaliplatin was added to capecitabine, which the patient had been on for the past 9 months.\n\nThirty minutes after the oxaliplatin infusion was started, the patient developed significant bleeding from her gums, epistaxis, and had 150 to 200 mL of bloody oral secretions. Laboratory testing showed a platelet count of < 5 × 109, white blood cell count of 2.6 × 109, hemoglobin 6.2 g/dL, PT 16.4, INR 1.4, total bilirubin 0.5 mg/dL, LDH 211 U/L. Peripheral smear showed few platelets and no schistocytes. The patient was admitted and received intravenous immunoglobulin 1 g/kg, dexamethasone 40 mg IV for 4 days, and oral aminocaproic acid, with resolution of bleeding after one day. No platelet transfusions were given. She received 1 unit of packed red blood cells. The platelet count improved to 77 × 109 after 4 days and normalized to 341 × 109 one month later. Oxaliplatin was definitively discontinued.\n\nDiscussion\nAlthough myelosuppression is the most common cause of thrombocytopenia in cancer patients receiving oxaliplatin, there are several other recognized mechanisms of oxaliplatin-induced thrombocytopenia [1, 2, 3, 4, 5]. With myelosuppression, thrombocytopenia is usually asymptomatic and is accompanied by anemia and neutropenia [6]. Management includes observation and the occasional need for dose reductions or delays [7]. Oxaliplatin-induced ITP is a well-recognized but uncommon etiology of thrombocytopenia. The mechanism is platelet destruction mediated by oxaliplatin-dependent antibodies to platelet antigens, leading to a sudden drop in platelet count to < 10 × 109 and bleeding manifestations within several hours of oxaliplatin infusion. This typically occurs after > 12 cycles of oxaliplatin and may be preceded by hypersensitivity reaction [7, 8]. Management includes platelet transfusion, corticosteroid therapy, and IV immunoglobulin therapy with resolution of thrombocytopenia within approximately 2 weeks. Definitive discontinuation of oxaliplatin is recommended [1, 9, 10].\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n==== Refs\nReferences\n1 Jardim DL Rodrigues CA Novis YA Rocha VG Hoff PM Oxaliplatin-related thrombocytopenia Ann Oncol 2012 8 23 (8) 1937 42 22534771 \n2 Bautista MA Stevens WT Chen CS Curtis BR Aster RH Hsueh CT Hypersensitivity reaction and acute immune-mediated thrombocytopenia from oxaliplatin: two case reports and a review of the literature J Hematol Oncol 2010 3 3 (1) 12 20346128 \n3 Taleghani BM Meyer O Fontana S Ahrens N Novak U Borner MM Oxaliplatin-induced immune pancytopenia Transfusion 2005 5 45 (5) 704 8 15847658 \n4 Curtis BR Kaliszewski J Marques MB Saif MW Nabelle L Blank J Immune-mediated thrombocytopenia resulting from sensitivity to oxaliplatin Am J Hematol 2006 3 81 (3) 193 8 16493620 \n5 Ohta S Cho Y Oshima S Hosoya O Juni K Kojima H Oxaliplatin-induced acute-onset thrombocytopenia and hemorrhage: case report and review of the literature Oncol Lett 2012 6 3 (6) 1297 300 22783437 \n6 Suh SE Jang MJ Chong SY Aster RH Curtis BR Oh D A case of oxaliplatin-induced immune-mediated thrombocytopenia Blood Res 2014 3 49 (1) 61 4 24724069 \n7 Wu Y Aravind S Ranganathan G Martin A Nalysnyk L Anemia and thrombocytopenia in patients undergoing chemotherapy for solid tumors: a descriptive study of a large outpatient oncology practice database, 2000–2007 Clin Ther 2009 31 (Pt 2) 2416 32 20110050 \n8 Dold FG Mitchell EP Sudden-onset thrombocytopenia with oxaliplatin Ann Intern Med 2003 7 139 (2) E156 \n9 Piatek CI Liebman HA Thrombocytopenia in patients with solid tumors or hematologic malignancies Platelets in Thrombotic and Non-Thrombotic Disorders DOI: 10.1007/978-3-319-47462-5_56 \n10 Liebman HA Thrombocytopenia in cancer patients Thromb Res 2014 5 133 Suppl 2 S63 9 24862148\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "11(3)",
"journal": "Case reports in oncology",
"keywords": "Adenocarcinoma; Oxaliplatin; Thrombocytopenia",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "880-882",
"pmc": null,
"pmid": "30687065",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "12859182;15847658;16493620;20110050;20346128;22534771;22783437;24724069;24862148",
"title": "Case Report: Oxaliplatin-Induced Immune-Mediated Thrombocytopenia.",
"title_normalized": "case report oxaliplatin induced immune mediated thrombocytopenia"
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"reactionmeddrapt": "Gingival bleeding",
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},
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"literaturereference": "PAN E, HSIEH E. CASE REPORT: OXALIPLATIN-INDUCED IMMUNE-MEDIATED THROMBOCYTOPENIA. CASE REPORTS IN ONCOLOGY. 2018?11(3):880-882.",
"literaturereference_normalized": "case report oxaliplatin induced immune mediated thrombocytopenia",
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},
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] |
{
"abstract": "OBJECTIVE\nTo discuss the manifestation of pseudotumor cerebri during the course of correcting the hypercortisolism of Cushing's disease.\n\n\nMETHODS\nWe describe the clinical, biochemical, and neuro-ophthalmologic findings in a patient in whom pseudotumor cerebri developed during correction of the hypercortisolism of Cushing's disease. In addition, we review the relationship between pseudotumor cerebri and Cushing's disease in the literature.\n\n\nRESULTS\nA 44-year-old woman with Cushing's disease underwent total adrenalectomy after two unsuccessful transsphenoidal operations. She developed daily headaches 2 weeks postoperatively while taking 60 mg of hydrocortisone daily. She noticed a visual floater 8 weeks postoperatively, and a prompt ophthalmologic evaluation revealed papilledema. We diagnosed pseudotumor cerebri on the basis of symptoms and signs of intracranial hypertension, unremarkable findings on neuroimaging and cerebrospinal fluid analysis, and a substantially increased cerebrospinal fluid pressure. After 8 weeks of treatment with furosemide, the headaches and papilledema resolved, and the patient was able to reduce her dose of hydrocortisone to 30 mg daily. Pseudotumor cerebri has been associated with adrenocortical insufficiency and gluco- corticoid withdrawal and can lead to loss of vision. A literature review revealed 6 previous patients in whom pseudotumor cerebri developed in association with Cushing's disease. In all but one case, the pseudotumor cerebri manifested 2 to 4 weeks after treatment of hypercortisolism or cessation of hydrocortisone replacement.\n\n\nCONCLUSIONS\nSymptoms of intracranial hypertension such as headache occurring in a patient recently withdrawn from exogenous or endogenous corticosteroids should prompt consideration of the presence of pseudotumor cerebri.",
"affiliations": "Department of Medicine, Division of Endocrinology, Diabetes &, Metabolism, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA.",
"authors": "Rickels|Michael R|MR|;Nichols|Charles W|CW|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4158/EP.10.6.492",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-891X",
"issue": "10(6)",
"journal": "Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists",
"keywords": null,
"medline_ta": "Endocr Pract",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D019721:Ophthalmoscopes; D047748:Pituitary ACTH Hypersecretion; D011559:Pseudotumor Cerebri; D014794:Visual Fields",
"nlm_unique_id": "9607439",
"other_id": null,
"pages": "492-6",
"pmc": null,
"pmid": "16033722",
"pubdate": "2004",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.; D016454:Review",
"references": null,
"title": "Pseudotumor cerebri in patients with Cushing's disease.",
"title_normalized": "pseudotumor cerebri in patients with cushing s disease"
} | [
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},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Idiopathic intracranial hypertension",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "RICKELS, M.. PSEUDOTUMOR CEREBRI IN PATIENTS WITH CUSHING^S DISEASE. ENDOCRINE PRACTICE. 2004;10 (6):492-496",
"literaturereference_normalized": "pseudotumor cerebri in patients with cushing s disease",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170419",
"receivedate": "20170419",
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},
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},
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"seriousnessdeath": null,
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"transmissiondate": "20170830"
}
] |
{
"abstract": "BACKGROUND\nSerotonin is a neurotransmitter synthesized from tryptophan. It is implied in the regulation of mood, cognition, sleep cycle, synthesis of cerebrospinal fluid, and other processes. Generally, it is implied in human pathology by hypofunction. However, there is a complication of unknown incidence related to treatment with drugs that increase the stimulation of 5-HT1A serotonin receptors, called serotonin syndrome (SS). Clinically, it is characterised by the presence of a triad of mental and autonomic disorders, and motor hyperactivity. This entity has not biological markers and its diagnosis could be done verifying the proposed criteria.\n\n\nMETHODS\nTwo cases of SS are presented, one of them related to the combination of risperidone and sertraline, as first report in the literature. Both cases had a favourable outcome employing support measures.\n\n\nCONCLUSIONS\nThe physiopathology, the diagnosis, the differential diagnosis, and the treatment are reviewed. We emphasize the potentially high frequency of this disorder, given the growing use of serotonin activity modifying drugs, and the typically benign course of the SS once the support measures are started.",
"affiliations": "Unidad de Neurología, Hospital Son Llàtzer, Palma de Mallorca. franciscoplus@hotmail.com",
"authors": "Alvarez-Pérez|F J|FJ|;Roca|M|M|;Martorell|E|E|;Espino|A M|AM|;Usón|M M|MM|;Figuerola|A|A|;Ballabriga|J|J|",
"chemical_list": "D012702:Serotonin Antagonists; D017367:Serotonin Uptake Inhibitors; D012701:Serotonin; D018967:Risperidone; D020280:Sertraline",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0210-0010",
"issue": "40(3)",
"journal": "Revista de neurologia",
"keywords": null,
"medline_ta": "Rev Neurol",
"mesh_terms": "D000368:Aged; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D008875:Middle Aged; D009474:Neurons; D018967:Risperidone; D012701:Serotonin; D012702:Serotonin Antagonists; D020230:Serotonin Syndrome; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline; D016896:Treatment Outcome",
"nlm_unique_id": "7706841",
"other_id": null,
"pages": "159-62",
"pmc": null,
"pmid": "15750901",
"pubdate": "2005",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Serotonin syndrome: report of two cases and review of the literature.",
"title_normalized": "serotonin syndrome report of two cases and review of the literature"
} | [
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"abstract": "Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and leads to deadly metastases for which there is no approved treatment. Genetic events driving early tumor development are well-described, but those occurring later during metastatic progression remain poorly understood. We performed multiregional genomic sequencing on 22 tumors collected from two patients with widely metastatic UM who underwent rapid autopsy. We observed multiple seeding events from the primary tumors, metastasis-to-metastasis seeding, polyclonal seeding, and late driver variants in ATM, KRAS, and other genes previously unreported in UM. These findings reveal previously unrecognized temporal and anatomic complexity in the genetic evolution of metastatic uveal melanoma, and they highlight the distinction between early and late phases of UM genetic evolution with implications for novel therapeutic approaches.",
"affiliations": "Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Lindeberger Comprehensive Cancer Center, UNC School of Medicine, Chapel Hill, NC, USA.;New York Genome Center, New York, NY, USA.;Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA. harbour@miami.edu.;Columbia University Irving Medical Center, Herbert Irving Comprehensive Cancer Center, New York, NY, USA.",
"authors": "Rodriguez|Daniel A|DA|http://orcid.org/0000-0001-7682-6106;Yang|Jessica|J|;Durante|Michael A|MA|http://orcid.org/0000-0003-3137-6847;Shoushtari|Alexander N|AN|;Moschos|Stergios J|SJ|;Wrzeszczynski|Kazimierz O|KO|http://orcid.org/0000-0001-6743-6149;Harbour|J William|JW|http://orcid.org/0000-0002-1104-9809;Carvajal|Richard D|RD|",
"chemical_list": null,
"country": "England",
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"doi": "10.1038/s41525-021-00233-5",
"fulltext": "\n==== Front\nNPJ Genom Med\nNPJ Genom Med\nNPJ Genomic Medicine\n2056-7944\nNature Publishing Group UK London\n\n233\n10.1038/s41525-021-00233-5\nCase Report\nMultiregional genetic evolution of metastatic uveal melanoma\nhttp://orcid.org/0000-0001-7682-6106\nRodriguez Daniel A. 123\nYang Jessica 4\nhttp://orcid.org/0000-0003-3137-6847\nDurante Michael A. 123\nShoushtari Alexander N. 4\nMoschos Stergios J. 5\nhttp://orcid.org/0000-0001-6743-6149\nWrzeszczynski Kazimierz O. 6\nhttp://orcid.org/0000-0002-1104-9809\nHarbour J. William harbour@miami.edu\n\n123\nCarvajal Richard D. 7\n1 grid.26790.3a 0000 0004 1936 8606 Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL USA\n2 grid.26790.3a 0000 0004 1936 8606 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL USA\n3 grid.26790.3a 0000 0004 1936 8606 Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL USA\n4 grid.51462.34 0000 0001 2171 9952 Memorial Sloan Kettering Cancer Center, New York, NY USA\n5 grid.10698.36 0000000122483208 Lindeberger Comprehensive Cancer Center, UNC School of Medicine, Chapel Hill, NC USA\n6 grid.429884.b 0000 0004 1791 0895 New York Genome Center, New York, NY USA\n7 grid.21729.3f 0000000419368729 Columbia University Irving Medical Center, Herbert Irving Comprehensive Cancer Center, New York, NY USA\n16 8 2021\n16 8 2021\n2021\n6 7028 3 2021\n26 7 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.\nUveal melanoma (UM) is the most common primary intraocular malignancy in adults and leads to deadly metastases for which there is no approved treatment. Genetic events driving early tumor development are well-described, but those occurring later during metastatic progression remain poorly understood. We performed multiregional genomic sequencing on 22 tumors collected from two patients with widely metastatic UM who underwent rapid autopsy. We observed multiple seeding events from the primary tumors, metastasis-to-metastasis seeding, polyclonal seeding, and late driver variants in ATM, KRAS, and other genes previously unreported in UM. These findings reveal previously unrecognized temporal and anatomic complexity in the genetic evolution of metastatic uveal melanoma, and they highlight the distinction between early and late phases of UM genetic evolution with implications for novel therapeutic approaches.\n\nSubject terms\n\nCancer genomics\nEye cancer\nUveal diseases\nhttps://doi.org/10.13039/100000002 U.S. Department of Health & Human Services | National Institutes of Health (NIH) P30CA240139 P30EY014801 Harbour J. William U.S. Department of Health & Human Services | National Institutes of Health (NIH)https://doi.org/10.13039/100001818 Research to Prevent Blindness (RPB) issue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\n\nUM is the most common primary cancer of the eye and leads to metastatic death in up to 50% of patients. The primary tumor arises through an initiating mutation in one of several genes in the Gaq/11 signaling pathway (GNAQ, GNA11, PLCB4, or CYSLTR2), followed by a “BSE” progression mutation in BAP1, SF3B1 (and rarely other splicing factors), or EIF1AX, associated with high, intermediate, and low metastatic risk, respectively1–7. These canonical mutations arise early in a punctuated burst or selective sweep within the primary tumor and are often accompanied or followed by copy number variations (CNVs) involving chromosomes 1, 3, 6, and 84,7. In contrast to primary UM, little is known about the genetic evolution of metastatic UM. Published studies to date evaluating metastatic UM either lack matching primary tumors, include only a small number of liver metastases or use targeted sequencing panels8–11, limiting the ability to assess tumor evolution over time and across anatomic locations. Here, we performed multiregional genomic sequencing of 22 tumors from two patients with widely metastatic UM involving 10 different organs and tissues using whole-exome sequencing (WES) or whole-genome sequencing (WGS).\n\nResults\n\nPatient 1\n\nA 51-year-old Caucasian man was diagnosed with UM involving the choroid of the left eye and underwent plaque brachytherapy. Three years later, he developed biopsy-proven liver metastasis (Supplementary Table 1 and Fig. 1). He was initially treated with ipilimumab and cyclophosphamide. Four months later, treatment was switched to vorinostat on clinical trial (NCT01587352) for disease progression. After new lesions were detected in the liver, lung, and around the spleen, his therapy was changed to pembrolizumab. Six months later, further disease progression was noted, and he was treated with everolimus and pasireotide on a clinical trial14. Several months later, further disease progression was detected in the liver, with new lesions in the peritoneum and the left 12th rib, and his treatment was changed to binimetinib and sotrastaurin on a clinical trial (NCT01801358). He was subsequently treated with sunitinib and sirolimus. He ultimately received temozolomide but experienced continued disease progression with the development of numerous subcutaneous metastases. He died 21 months after the initial detection of metastatic disease. The radiographic chronology of his disease course is summarized in Supplementary Table 2.Fig. 1 Molecular landscape of 22 tumors collected after rapid autopsy of two patients with metastatic uveal melanoma.\n\na Schematic of multiple metastasis and molecular studies. b, c Co-variant plot of deleterious variants found in Patients 1 and 2, respectively. The height of each colored bar represents the cancer cell fraction of that variant in the indicated sample. For Patient 1, letters correspond to tumors harvested from anatomic sites including: periocular tumor (A), liver segment 4/5 (B), liver segment 4B (C), periportal lymph node (D), 12th rib (E), perisplenic nodule (F), liver segment 2 (G), lung (H), supraclavicular lymph node (I), subcutaneous left abdomen (J), and subcutaneous right cheek (K). For Patient 2, letters correspond to tumor harvested from the indicated anatomic sites including: primary tumor (A), left upper lung (B), right upper lung (C), subcutaneous right chest (D), liver lesion 1 (E), liver lesion 2 (F), right caval lymph node (G), subcutaneous left chest (H), adrenal (I), omentum (J), and retroperitoneum (K). d, e Copy number variation (CNV) plot of all chromosomes for Patients 1 and 2, respectively. Blue indicates a loss and red indicated a gain. Chromosome numbers are labeled on the horizontal axis. Letters represent the same sample names in panels (b) and (c) for each respective patient.\n\nPatient 2\n\nA 69-year old woman was diagnosed with a stage T3b uveal melanoma involving the ciliary body and choroid of the right eye, treated by enucleation (Supplementary Tables 1 and 3 and Supplementary Fig. 2). Twenty-one months later, small pulmonary nodules were identified and were initially managed by expectant observation. One year later, two biopsy confirmed liver metastases were identified, and treatment with ipilimumab was initiated. Following further disease progression in the liver, she was treated with temozolomide and Yttrium-90 hepatic radioembolization. She then experienced rapid extrahepatic tumor progression and died one year after initial metastatic dissemination. The radiographic chronology of her disease course is summarized in Supplementary Table 3.\n\nVariant and copy number analysis\n\nAmong the two patients, 22 tumor samples were collected via rapid autopsy and processed for genomic analysis (Fig. 1a). In-Patient 1, a periocular tumor was obtained that most likely arose by direct extension from the primary tumor through the sclera, which occurs in about 8% of cases12, thereby representing the closest available surrogate for the primary tumor. WGS was performed on tumor samples from Patient 1 and WES was performed on tumor samples from Patient 2. Somatic variants across all 22 samples were tabulated (Supplementary Tables 4–9). The number of exonic variants per tumor ranged from 21 to 47 (median, 27 variants) in Patient 1, and from 13 to 49 (median, 27 variants) in Patient 2. In both patients, canonical mutations in GNA11 and BAP1 were present in all tumor samples (Fig. 1b, c and Supplementary Fig. 3). Primary and metastatic tumors also harbored non-canonical variants, some of which were present at or near 100% of tumor cells, while others were present in smaller clones or in a subset of tumors (Fig. 1b, c). CNVs and their cancer cell fractions (CCF) were assessed for all tumor samples (Fig. 1d, e, Supplementary Figs. 4–7, and Supplementary Table 10). CCFs for PPP1R15A or ATM are the same or higher for all metastatic tumors compared to the periocular tumor, further suggesting that this lesion is a direct extension of the primary lesion (Supplementary Table 6). Loss of heterozygosity (LOH) for chromosome 3, which unmasks BAP1 mutations in metastasizing Class 2 UM3, was detected in all tumor samples for both patients, consistent with a canonical aberration that arises early in tumor evolution4. There were several additional examples of LOH unmasking variants on the other chromosomal homolog in Patient 1: loss of 1p (including the RUNX3 locus) in 7 tumors, loss of 5q (FNIP1) in 5 tumors, loss of 11q (ATM) in 5 tumors, and loss of 19q (PPP1R15A) in 7 tumors. Interestingly, 5 tumors from Patient 1 and 4 tumors from Patient 2 exhibited isodisomy 3 in which the retained uniparental, BAP1-mutant copy of chromosome 3 underwent duplication. Similar uniparental isodisomy was observed for 1p, 6q, and 8p in some late metastases, suggesting that restoration of heterozygosity may provide a selective advantage during tumor evolution13,14. In addition, 10 and 13 nonsynonymous exonic variants were found exclusively in the periocular tumor in Patient 1 (Supplementary Tables 5 and 11) and in the primary tumor in Patient 2 (Supplementary Tables 8 and 11), respectively. These include variants in BAIAP3, TAT, THOP1, and ZBTB42 in Patient 1 and ACVR1B, ANKRD11, CHD4, HNRNPM, NCK2, PAK1IP1, and RPS6KA2 in Patient 2.\n\nMultiregional analysis\n\nMultiregional analysis of all 22 tumors was performed using variants and CNVs to reconstruct metastatic evolution over time and anatomic location (Fig. 2a–d and Supplementary Tables 4–10). In both patients, canonical aberrations (GNA11 and BAP1 variants, and LOH3) were present in most or all cancer cells from early and late tumors, consistent with punctuated evolution prior to the most recent common tumor ancestor4. In-Patient 1, variants in FNIP1, PPP1R15A, WDR19, and RUNX3 were present in ~100% of cancer cells across all samples. An ATMG2020C variant was present at ~2% of cancer cell fraction (CCF) in the periocular tumor and expanded to ~100% CCF in one metastatic branch (Branch 1) compared to only 0–44% CCF in the other branch (Branch 2). In Branch 1, expansion of the ATM variant during subsequent metastasis-to-metastasis seeding was accompanied by LOH for the other ATM allele (Fig. 2a, b and Supplementary Table 6). In Branch 2, by contrast, the ATM variant did not expand substantially and was not accompanied by LOH for the other allele, suggesting that it did not drive this metastatic branch. In addition to the ATM variant, the two metastatic branches can be distinguished by other variants that are present at ~100% CCF in Branch 1 and mostly absent in Branch 2 (e.g., WWOX, CTB-178M22.1, CDH26), and other variants that are present at ~100% CCF in Branch 2 but mostly absent in Branch 1 (e.g., DBH, CD6, PGAP2). Interestingly, one lung metastasis (UM-23) harbored the first set of variants at 23–41% and the second set of variants at 76–97%, consistent with polyclonal seeding from two liver metastases (UM-21 and UM-16), with UM-21 from Branch 1 contributing ~25% and UM-16 from Branch 2 contributing ~75% to UM-23 (Supplementary Table 6).Fig. 2 Multiregional tumor seeding analysis.\n\na Treeomic heatmap of Patient 1, showing the posterior probability of the presence of variants, with a color legend indicating probability of variant in each tumor sample. b Clonality tree and body map in Patient 1, indicating the inferred pattern of metastatic spread. Letters correspond to tumors harvested from indicated anatomic sites including: periocular tumor (A), liver segment 4/5 (B), liver segment 4B (C), periportal lymph node (D), rib (E), spleen (F), liver segment 2 (G), lung (H), supraclavicular lymph node (I), subcutaneous left abdomen (J), and subcutaneous right cheek (K). The dotted line represents a possible polyclonal seeding event. c Treeomic heatmap snapshots of Patient 2, showing the posterior probability of the presence of variants, with a color legend indicating probability of variant in each tumor sample. d Clonality tree and body map in Patient 2, indicating the inferred pattern of metastatic spread. Letters correspond to tumors harvested from indicated anatomic sites including: primary tumor (A), left lung (B), right lung (C), subcutaneous right chest (D), liver lesion 1 (E), liver lesion 2 (F), right caval lymph node (G), subcutaneous left chest (H), adrenal (I), omentum (J), and retroperitoneum (K).\n\nIn-Patient 2, non-canonical deleterious variants in FOXJ1, PRKDC, and TTN were detected in ~100% CCF across all tumor samples (Fig. 2c and Supplementary Table 9). There were also two independent seeding events from the primary tumor, one giving rise to a lung metastasis with variants in KAT2B, CAMK1D, and SLC16A, and the other giving rise to a liver metastasis with a subclonal KRASG12V variant which expanded to ~100% CCF in 6 downstream metastases that arose shortly before the patient’s death (Fig. 2d).\n\nDiscussion\n\nHere we present a genome-wide sequencing analysis of multi-organ metastatic disease in UM, revealing complex evolutionary events such as recurrent seeding from the eye, metastasis-to-metastasis seeding, and polyclonal seeding. The asymmetric clonal expansion was also observed, with an ATM variant in Patient 1 seemingly functioning as a driver in one branch and as a passenger in another. Such evolutionary events are potential mechanisms of heterogeneous treatment response and resistance15, and they would likely have been missed using small sequencing panels and small numbers of metastatic samples.\n\nThe periocular tumor in Patient 1 and the primary tumor in Patient 2 contained several genetic alterations that were not present in any of their associated metastases (Supplementary Tables 5, 8, and 11). As a possible explanation, the clone that disseminated from the primary tumor may not have contained all of the genomic aberrations found elsewhere in the primary tumor. Alternatively, the primary tumor may have acquired these alterations after the metastatic dissemination had occurred.\n\nIn a recent study using a targeted gene panel to analyze metastatic liver tumors and matched primary tumors10, it was suggested that LOH for GNAQ (but not GNA11) is a “tertiary driver” that is required to fully activate mutant GNAQ because it is less potent than mutant GNA1110. However, our findings do not support this claim. LOH for GNAQ was present in tumors from both patients despite neither having a GNAQ mutation. On the other hand, LOH for mutant GNA11 on chromosome 19p was observed in 7 tumors from Patient 1. In light of these findings, along with recent studies failing to show a worse prognosis associated with GNA11 mutations7,16, it seems more likely that LOH involving GNAQ and GNA11 is not targeting these genes but rather, one or more tumor suppressor genes on chromosomes 9q and 19p, respectively.\n\nThe prior study also suggested that 8q gain is an early aberration that drives metastasis through a progressive increase in copy number. We observed this pattern In Patient 1, where early metastatic tumors contained up to 4 copies of 8q and later tumors up to 12 copies (Supplementary Table 10). However, this pattern was not observed in Patient 2, where only 2 late metastases contained small subclones with one extra copy of 8q. Previous studies have shown that 8q gain occurs frequently, not only in metastasizing class 2 UM, but also in class 1 UM that do not metastasize (albeit usually at a lower dosage), and that 8q gain does not always occur early but can also arise later in tumor evolution4,17. As such, while 8q gain can evidently provide a selective advantage during tumor evolution in some cases, it is not a required early event and is not necessary for UM metastasis. Of note, 8q gain is most strongly associated with poor prognosis when it is accompanied by 8p loss, which may occur through the formation of an isochromosome 8q, unmasking a metastasis modifier locus on 8p18. Metastatic tumors from both patients in this study demonstrated loss of 8p, including an interstitial deletion spanning this metastasis modifier locus in 7 metastatic tumors from Patient 2 (Fig. 1e and Supplementary Table 10). Further work is needed to clarify the mechanistic role of 8p loss versus 8q gain in UM progression.\n\nFinally, this analysis underscores a key distinction in UM between early recurrent drivers (e.g., primary Gαq/11 and secondary BSE mutations) versus late variable “tertiary” variants10, which are rare or even one-off events that may provide a selective advantage in specific cases but are not generally necessary for UM development or progression. The KRASG12V variant, for example, arose in Patient 2 as a late driver concurrent with her rapid disease progression, yet this variant has never before been reported in UM. Given the genetic heterogeneity in these metastatic tumors and the frequent emergence of resistance to empiric monotherapy, our findings suggest that combination therapies may be necessary and that serial biopsies of metastatic lesions and/or serial sampling of circulating cell-free DNA (cfDNA) will be important to identify new potentially druggable driver mutations that emerge over time. Our study was limited by small sample size, primarily due to technical challenges associated with rapid autopsy tissue procurement, and inadequate information to correlate specific treatments with specific genetic aberrations. Future studies with more patients, serial biopsies in relation to disease progression and therapies administered, and newer technologies such as single-cell sequencing19 will continue to shed light on tumor evolution and uncover mechanisms of treatment resistance and opportunities for novel treatment approaches in UM.\n\nMethods\n\nOversight\n\nThe rapid autopsy for Patient 1 was performed at Memorial Sloan Kettering Cancer Center Department of Pathology. Patient 2 was performed at the University of North Carolina School of Medicine Department of Pathology and Laboratory Medicine. Both patients provided written informed consent. Both autopsies were conducted understudy protocols approved by the respective institutional review board. Genomic sequencing of the samples was performed understudy protocols approved by the institutional review boards of Memorial Sloan Kettering Cancer Center and Columbia University.\n\nPatient and specimen collection and processing\n\nAll tumor specimens were freshly frozen, with the exception of the primary tumor (specimen A; Supplementary Table 1) from Patient 2, which was formalin-fixed paraffin-embedded (FFPE). FFPE-derived DNA was repaired prior to library preparation using the PreCR repair mix (NEB, M0309L). The process also removes moieties from the 3′ end of DNA leaving a 3′ hydroxyl group compatible with the formation of phosphodiester bonds with 5′ phosphate groups. DNA integrity was subsequently assessed using the Fragment Analyzer (Advanced Analytical, Agilent).\n\nRadiographic imaging\n\nImaging studies performed on Patient 1 and Patient 2 throughout the disease course were available for central radiographic review and documentation of the time course for the development of the harvested lesions (Supplementary Tables 2 and 3).\n\nFor Patient 1, tumor specimen B (liver segment 4/5) was the first lesion to be radiographically observed. Specimen C (liver segment 4B) was the second observed 3 months later. Three lesions, including specimen E (bone, 12th rib), specimen G (liver segment 2), and specimen F (peritoneal perisplenic nodule) were the third group of lesions to be identified based upon imaging performed 5 months after tumor specimen B was first identified. Specimen H (lung nodule) was identified 2 months later. Four of the lesions, including specimen J (soft tissue subcutaneous nodule, left abdomen), the specimen I (left supraclavicular lymph node), specimen A (periocular tumor), and specimen K (soft tissue subcutaneous nodule, right cheek), were not identified on any of the imaging studies performed. As specimen J (soft tissue subcutaneous nodule, left abdomen), the specimen I (left supraclavicular lymph node), and specimen D (periportal lymph node) were harvested from locations covered by all scans, these three lesions likely represent developmentally late lesions. Specimen A (periocular tumor) and specimen K (soft tissue subcutaneous nodule, right cheek) were harvested from the head and neck region and would have only been potentially visible on the PET/CT images; thus, these lesions would have developed into clinically evident tumors after the last PET/CT scan performed 11 months after tumor specimen B was first identified.\n\nFor Patient 2, tumor specimens B (left upper lobe lung mass) and C (right upper lobe lung mass) were the first lesions to be radiographically observed; however, imaging was limited to the chest at this initial timepoint. Specimens E (liver mass) and F (liver mass) were first observed during chest, abdominal and pelvic imaging 11 months later. Six of the lesions, including specimen I (adrenal mass), G (right caval lymph node), H (subcutaneous nodule, left chest), D (subcutaneous nodule, right chest), J (omental mass), and K (retroperitoneal mass) were not identified on any of the imaging studies available for review and likely represent developmentally late lesions.\n\nDNA library preparation\n\nGenomic sequencing was performed using WES in Patient 1 and WGS in Patient 2. WGS libraries were prepared using the KAPA Hyper Library Preparation Kit in accordance with the manufacturer’s instructions. Briefly, 100–200 ηg of DNA was sheared using a Covaris LE220 sonicator (adaptive focused acoustics). DNA fragments were end-repaired, adenylated, and ligated to Illumina sequencing adapters. Ligated DNA libraries underwent bead-based size selection and were enriched with PCR amplification using 7 cycles. Final libraries were evaluated using fluorescent-based assays including PicoGreen (Life Technologies) or Qubit Fluorometer (Invitrogen) and Fragment Analyzer (Advanced Analytics) or BioAnalyzer (Agilent 2100). Libraries with adapter dimer evident in the final library QC underwent an additional bead-based size selection. All were subsequently sequenced on an Illumina HiSeq X sequencer (v2.5 chemistry) using 2 × 150 bp cycles. WES libraries were prepared using the Agilent SureSelect XT library preparation kit in accordance with the manufacturer’s instructions. Briefly, 1500 ng of DNA was sheared using a Covaris LE220 sonicator (adaptive focused acoustics). DNA fragments were end-repaired, adenylated, ligated to Illumina sequencing adapters. Ligated DNA libraries were enriched with PCR amplification using 6 cycles. Exome capture was performed on the SciClone with 750 ng of the pre-capture library using the SureSelect XT V4 Human All Exon probe set (Agilent) following the manufacturer’s recommendations. Enriched fragments are uniquely indexed during the final amplification process. Final libraries were quantified using fluorescent-based assays including PicoGreen (Life Technologies) or Qubit Fluorometer (invitrogen) and Fragment Analyzer (Advanced Analytics) or BioAnalyzer (Agilent 2100). All libraries were sequenced on an Illumina HiSeq2500 sequencer (v4 chemistry) using 2 × 125 bp cycles.\n\nSequence alignment\n\nFASTQ files containing WGS or WES data were processed by checking for quality using FASTQC and paired-end 2 × 150 bp reads were aligned to the human genome (hg19/GRCH37) using the Burrows–Wheeler Aligner (BWA v.0.7.8). Aligned reads were marked for duplicates using Picard and realigned using ABRA20. Alignments then underwent read mate fixing and reordering. Unknown or unplaced contigs and mitochondrial genes were excluded from further analysis.\n\nVariant calling\n\nPost processed alignments underwent variant calling for SNPs and Indels using MuTect221. Mutect2 was used in order to detect low coverage SNPs and to leverage its capability of handling tumors with purity less than 100%, presence of subclonal variants, and/or copy number variations. Variants for each tumor specimen were called against a matched blood specimen for each patient. Variants that were called and marked as passed were aggregated. These calls were further filtered by keeping variants that had an alternate tumor read count of ≥3 or variants that had an alternate tumor read count that was >20% of the total read count. For all sequencing specimens, the BAM files and raw MuTect2 calls were investigated manually for canonical UM variants (GNA11, GNAQ, BAP1, SF3B1, EIF1AX, CYSLTR2, and PLCB4), if present these variants were added to our final list. For all called variants Annovar was used for annotation22. Following annotation, variants were further filtered out if the minor allele frequency (MAF) was 1% greater in the 1000 Genomes Project population (2015 August), Exome Sequencing Project, or listed in dbSNP (v138). Functional consequences of variants were assessed by four predictor tools: SIFT23, Polyphen2 HDIV24, FATHMM25, and MetaLR26. Single nucleotide variants were considered deleterious if at least two out of the four tools predicted it as deleterious or possibly deleterious. Deletions and insertions were assessed using SIFTindel27 and were considered deleterious if predicted to be deleterious to the protein product or to result in nonsense-mediated decay (NMD).\n\nCopy number variations\n\nCopy number gains and losses were determined using CNVKit28. Copy number subclones, monosomy, and other duplication events were assessed using cgpBattenberg29. This was also used to assess the normal contamination and cellularity of each specimen.\n\nMetastatic seeding reconstruction\n\nWe utilized Treeomics (v1.7.13)30 in order to leverage both driver and passenger variants identified in the WGS and WES of each specimen to infer evolutionary phylogeny. Due to the large amounts of variants captured for the primary tumor in Patient 2, only variants shared in at least one other sample were used. This approach estimated the posterior probabilities for the presence or absence of a variant in a specimen based on a Bayesian binomial likelihood model. We calculated the Jaccard similarity coefficients for the various specimens present in each individual patient in order to assess the similarity of specimens and length of evolution after seeding. Variant clusters at phylogenic branching events were assessed in order to infer metastatic spread. CCF was determined for sets of variants in order to infer possible polyclonal seeding events.\n\nReporting summary\n\nFurther information on research design is available in the Nature Research Reporting Summary linked to this article.\n\nSupplementary information\n\nSupplementary Information\n\nReporting Summary\n\nSupplementary information\n\nThe online version contains supplementary material available at 10.1038/s41525-021-00233-5.\n\nAcknowledgements\n\nSupported by grants from the National Institutes of Health (F31CA243426, to D.A.R.; R01CA125970, to J.W.H.; P30CA240139, to Sylvester Comprehensive Cancer Center; and P30EY014801, to Bascom Palmer Eye Institute), Research to Prevent Blindness Unrestricted Grant (to Bascom Palmer Eye Institute), and a generous gift from Dr. Mark J. Daily (to J.W.H.). We thank Dr. Christine Iacobuzio-Donahue, Armida Fabius, and Taha Merghoub from Memorial Sloan Kettering Cancer Center (MSKCC) for their help in procuring samples, and Dr. Marc Z. Simmons for assistance in reviewing radiology scans. We acknowledge the support of the University of Miami Center for Computational Science (CCS) and the Institute of Data Science and Computing (IDSC).\n\nAuthor contributions\n\nJ.W.H. and R.D.C. conceived and supervised the study. J.Y. and A.N.S. oversaw sample collection and maintenance. S.J.M. provided study samples. K.O.W. processed and sequenced the samples. D.A.R. and M.A.D. analyzed and interpreted the data. J.Y., D.A.R., J.W.H., and R.D.C. wrote the manuscript. All authors read, edited, and approved the final manuscript. D.A.R. and J.Y. contributed equally to this article. J.W.H. and R.D.C. contributed equally to this article.\n\nData availability\n\nAll sequencing data generated in this study have been deposited in and are available from the dbGaP database under dbGaP accession phs002491.v1.p1.\n\nCode availability\n\nAll software used is publicly available including FastQC v0.11.3, BWA v.0.7.8, Picard v1.128, ABRA v0.94c, MuTect2, CNVKit, Annovar, cgpBattenberg, Treeomics v1.7.13. dbSNP v138 and Human genome hg19/GRCH37 were used throughout the analysis.\n\nCompeting interests\n\nJ.W.H. is the inventor of intellectual property related to prognostic testing for uveal melanoma. He is a paid consultant for Castle Biosciences, licensee of this intellectual property, and he receives royalties from its commercialization. The other authors declare no competing interests.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThese authors contributed equally: Daniel A. Rodriguez, Jessica Yang.\n\nThese authors jointly supervised this work: J. William Harbour, Richard D. Carvajal.\n==== Refs\nReferences\n\n1. Van Raamsdonk CD Mutations in GNA11 in uveal melanoma N. Engl. J. Med. 2010 363 2191 2199 10.1056/NEJMoa1000584 21083380\n2. Van Raamsdonk CD Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi Nature 2009 457 599 602 10.1038/nature07586 19078957\n3. Harbour JW Frequent mutation of BAP1 in metastasizing uveal melanomas Science 2010 330 1410 1413 10.1126/science.1194472 21051595\n4. Field MG Punctuated evolution of canonical genomic aberrations in uveal melanoma Nat. Commun. 2018 9 116 10.1038/s41467-017-02428-w 29317634\n5. Harbour JW Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma Nat. Genet. 2013 45 133 135 10.1038/ng.2523 23313955\n6. Martin M Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3 Nat. Genet. 2013 45 933 936 10.1038/ng.2674 23793026\n7. Robertson AG Integrative analysis identifies four molecular and clinical subsets in uveal melanoma Cancer Cell 2017 32 204 220 e15 10.1016/j.ccell.2017.07.003 28810145\n8. Rodrigues, M. et al. Evolutionary routes in metastatic uveal melanomas depend on MBD4 alterations. Clin. Cancer Res. 25, 5513–5524 (2019).\n9. Karlsson J Molecular profiling of driver events in metastatic uveal melanoma Nat. Commun. 2020 11 1894 10.1038/s41467-020-15606-0 32313009\n10. Shain AH The genetic evolution of metastatic uveal melanoma Nat. Genet. 2019 51 1123 1130 10.1038/s41588-019-0440-9 31253977\n11. Johansson PA Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours Nat. Commun. 2020 11 2408 10.1038/s41467-020-16276-8 32415113\n12. COMS. Histopathologic characteristics of uveal melanomas in eyes enucleated from the Collaborative Ocular Melanoma Study. COMS report no. 6 Am. J. Ophthalmol. 1998 125 745 766 10.1016/S0002-9394(98)00040-3 9645714\n13. Onken MD Loss of heterozygosity of chromosome 3 detected with single nucleotide polymorphisms is superior to monosomy 3 for predicting metastasis in uveal melanoma Clin. Cancer Res. 2007 13 2923 2927 10.1158/1078-0432.CCR-06-2383 17504992\n14. White VA McNeil BK Horsman DE Acquired homozygosity (isodisomy) of chromosome 3 in uveal melanoma Cancer Genet. Cytogenet. 1998 102 40 45 10.1016/S0165-4608(97)00290-2 9530338\n15. Gundem G The evolutionary history of lethal metastatic prostate cancer Nature 2015 520 353 357 10.1038/nature14347 25830880\n16. van Weeghel, C. et al. Do GNAQ and GNA11 Differentially Affect Inflammation and HLA Expression in Uveal Melanoma? Cancers 11, 1127 (2019).\n17. Durante, M. A. et al. Genomic evolution of uveal melanoma arising in ocular melanocytosis. Cold Spring Harb. Mol. Case Stud. 5, 4 (2019).\n18. Onken MD Worley L Harbour JW A metastasis modifier locus on human chromosome 8p in uveal melanoma identified by integrative genomic analysis Clin. Cancer Res. 2008 14 3737 3745 10.1158/1078-0432.CCR-07-5144 18559591\n19. Durante MA Single-cell analysis reveals new evolutionary complexity in uveal melanoma Nat. Commun. 2020 11 496 10.1038/s41467-019-14256-1 31980621\n20. Mose LE Wilkerson MD Hayes DN Perou CM Parker JS ABRA: improved coding indel detection via assembly-based realignment Bioinformatics 2014 30 2813 2815 10.1093/bioinformatics/btu376 24907369\n21. Cibulskis K Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples Nat. Biotechnol. 2013 31 213 219 10.1038/nbt.2514 23396013\n22. Wang K Li M Hakonarson H ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data Nucleic Acids Res. 2010 38 e164 10.1093/nar/gkq603 20601685\n23. Ng PC Henikoff S SIFT: Predicting amino acid changes that affect protein function Nucleic Acids Res. 2003 31 3812 3814 10.1093/nar/gkg509 12824425\n24. Adzhubei IA A method and server for predicting damaging missense mutations Nat. Methods 2010 7 248 249 10.1038/nmeth0410-248 20354512\n25. Shihab HA Gough J Cooper DN Day IN Gaunt TR Predicting the functional consequences of cancer-associated amino acid substitutions Bioinformatics 2013 29 1504 1510 10.1093/bioinformatics/btt182 23620363\n26. Dong C Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies Hum. Mol. Genet. 2015 24 2125 2137 10.1093/hmg/ddu733 25552646\n27. Hu J Ng PC SIFT Indel: predictions for the functional effects of amino acid insertions/deletions in proteins PLoS ONE 2013 8 e77940 10.1371/journal.pone.0077940 24194902\n28. Talevich E Shain AH Botton T Bastian BC CNVkit: genome-wide copy number detection and visualization from targeted DNA sequencing PLoS Comput. Biol. 2016 12 e1004873 10.1371/journal.pcbi.1004873 27100738\n29. Nik-Zainal S The life history of 21 breast cancers Cell 2012 149 994 1007 10.1016/j.cell.2012.04.023 22608083\n30. Reiter JG Reconstructing metastatic seeding patterns of human cancers Nat. Commun. 2017 8 14114 10.1038/ncomms14114 28139641\n\n",
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"abstract": "Thrombotic microangiopathy (TMA) is a rare complication associated with the use of calcineurin inhibitors in lung transplantation, irrespective of the underlying disease of the graft recipient. It usually occurs in incomplete forms, complicating and delaying diagnosis until damage is already irreversible. It is unrelated to time from transplantation and often presents with concomitant infection, which tends to confound diagnosis. The cases discussed here have a common causative agent and all present with concomitant infection. Treatment recommendations have changed in recent years with the introduction of plasmapheresis or, more recently, the availability of the antibody eculizumab. Notwithstanding, the most cost-effective measure is withdrawal or switching of the calcineurin inhibitor. TMA is an underdiagnosed clinical entity that should be considered in the management of transplantation patients.",
"affiliations": "Servicio de Neumología, Hospital Universitari i Politècnic la Fe, Valencia, España. Electronic address: jpreig@comv.es.;Unidad de Trasplante Pulmonar, Hospital Universitari i Politècnic la Fe, Valencia, España.;Unidad de Trasplante Pulmonar, Hospital Universitari i Politècnic la Fe, Valencia, España.;Unidad de Trasplante Pulmonar, Hospital Universitari i Politècnic la Fe, Valencia, España.;Unidad de Trasplante Pulmonar, Hospital Universitari i Politècnic la Fe, Valencia, España.;Servicio de Cirugía Torácica, Hospital Universitari i Politècnic la Fe, Valencia, España.",
"authors": "Reig Mezquida|Juan Pablo|JP|;Jover|Amparo Solé|AS|;Ansótegui Barrera|Emilio|E|;Escrivá Peiró|Juan|J|;Pastor Colom|Maria Desamparados|MD|;Pastor Guillem|Juan|J|",
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"keywords": "Hemolytic uremic syndrome; Lung transplantation; Microangiopatía trombótica; Síndrome hemolítico urémico; Tacrolimus; Thrombotic microangiopathy; Trasplante pulmonar",
"medline_ta": "Arch Bronconeumol",
"mesh_terms": "D000038:Abscess; D041221:Candida glabrata; D002177:Candidiasis; D003404:Creatinine; D004198:Disease Susceptibility; D057915:Drug Substitution; D004913:Erythrocytes, Abnormal; D000068338:Everolimus; D005260:Female; D006454:Hemoglobins; D006801:Humans; D007166:Immunosuppressive Agents; D007770:L-Lactate Dehydrogenase; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D009220:Myositis; D009617:Nocardia Infections; D017713:Platelet Transfusion; D011014:Pneumonia; D011183:Postoperative Complications; D016559:Tacrolimus; D057049:Thrombotic Microangiopathies; D055815:Young Adult",
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{
"abstract": "Pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) is technically demanding. We tried to identify the predictors for short- and long-term outcomes after PEA for CTEPH with aggressive use of pulmonary vasodilators, including epoprostenol sodium.\n\n\n\nFrom 2005 to 2013, 122 CTEPH patients, whose preoperative mean pulmonary artery pressure (mPAP) was 47 ± 10 mm Hg and pulmonary vascular resistance was 847 ± 373 dynes/s/cm5, underwent PEA with hypothermic circulatory arrest. Before PEA, all patients underwent pulmonary vasodilator therapy, including epoprostenol sodium of 2 to 6 ng/kg/min. We collected the perioperative and follow-up data retrospectively to identify the predictors for early and late outcomes after PEA.\n\n\n\nIn-hospital mortality was 7.4% (n = 9). Predictors for in-hospital death were age older than 65 years and New York Heart Association Functional Classification IV. Among the 113 PEA survivors, the mPAP and pulmonary vascular resistance significantly decreased. After the median follow-up of 6.8 years, the overall survival rates were 91.8%, 89.2%, 89.2%, 89.2%, and 86.1%, and the cardiac events-free rates were 100%, 98.1%, 95.8%, 85.5%, and 49.0%, at 1, 3, 5, 7, and 10 years, respectively, in the Kaplan-Meier model. A multivariate Cox proportional hazard model identified postoperative mPAP exceeding 30 mm Hg as the only predictor for late cardiac events.\n\n\n\nEarly and late outcomes of PEA for CTEPH with perioperative aggressive pulmonary vasodilator treatment seem satisfactory. However, residual pulmonary hypertension remains challenging to achieve further improvement of late outcomes.",
"affiliations": "Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Aichi, Japan. Electronic address: mytakami@fujita-hu.ac.jp.;Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Cardiovascular Surgery, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.",
"authors": "Sakurai|Yusuke|Y|;Takami|Yoshiyuki|Y|;Amano|Kentaro|K|;Higuchi|Yoshiro|Y|;Akita|Kiyotoshi|K|;Noda|Mika|M|;Tochii|Masato|M|;Ishida|Michiko|M|;Ishikawa|Hiroshi|H|;Ando|Motomi|M|;Ozaki|Yukio|Y|;Takagi|Yasushi|Y|",
"chemical_list": "D000959:Antihypertensive Agents; D014665:Vasodilator Agents; D011464:Epoprostenol",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.athoracsur.2019.03.100",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "108(4)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents; D002908:Chronic Disease; D004691:Endarterectomy; D011464:Epoprostenol; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D008875:Middle Aged; D011655:Pulmonary Embolism; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D014655:Vascular Resistance; D014665:Vasodilator Agents; D055815:Young Adult",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "1154-1161",
"pmc": null,
"pmid": "31075248",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Predictors of Outcomes After Surgery for Chronic Thromboembolic Pulmonary Hypertension.",
"title_normalized": "predictors of outcomes after surgery for chronic thromboembolic pulmonary hypertension"
} | [
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{
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{
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},
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},
{
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},
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"abstract": "Phenytoin is one of the most commonly used anticonvulsants in the developing world, but lack of monitoring and concurrent medications can easily lead to toxicity. We report the case of a 35-year-old female on phenytoin for symptomatic epilepsy due to previously treated glioblastoma multiforme, who presented with status epilepticus 1 week after being treated for a urinary tract infection. She was loaded with phenytoin and levetiracetam as per emergency protocol but had a persistently low level of consciousness, and her preloading phenytoin level result came back in the toxic range. She was managed conservatively, but after 4 days with no change she was dialyzed and her level of consciousness improved within 24 h, allowing for safe discharge home shortly after. Our case illustrates the option of haemodialysis in phenytoin-toxic patients who do not improve with conservative measures or who may need urgent reduction due to potentially fatal complications of phenytoin toxicity.",
"affiliations": "Department of Medicine, Faculty of Health Sciences, Aga Khan University (East Africa) Medical College, Nairobi, Kenya.;School of Medicine, University of Nairobi, Nairobi, Kenya.;Department of Medicine, Faculty of Health Sciences, Aga Khan University (East Africa) Medical College, Nairobi, Kenya.;Department of Medicine, Faculty of Health Sciences, Aga Khan University (East Africa) Medical College, Nairobi, Kenya.",
"authors": "Sharma|Karishma|K|;Vakil|Aditi|A|;Sokwala|Ahmed|A|;Sokhi|Dilraj|D|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000504470",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1662-680X",
"issue": "11(3)",
"journal": "Case reports in neurology",
"keywords": "Drug interactions; Haemodialysis; Phenytoin toxicity",
"medline_ta": "Case Rep Neurol",
"mesh_terms": null,
"nlm_unique_id": "101517693",
"other_id": null,
"pages": "344-350",
"pmc": null,
"pmid": "31911779",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "24259740;17975388;15340668;81279;20557868;20672505;23536644;27896804;18394052;12558586;16984852;27596563;26578149",
"title": "Phenytoin Toxicity Treatment with Haemodialysis in Epilepsy due to Glioblastoma Multiforme: Case Report and Review of the Literature.",
"title_normalized": "phenytoin toxicity treatment with haemodialysis in epilepsy due to glioblastoma multiforme case report and review of the literature"
} | [
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"literaturereference": "SHARMA, KARISHMA? ET AL. PHENYTOIN TOXICITY TREATMENT WITH HAEMODIALYSIS IN EPILEPSY DUE TO GLIOBLASTOMA MULTIFORME: CASE REPORT AND REVIEW OF THE LITERATURE. CASE REPORTS IN NEUROLOGY 11 (3) P.344-350, 9/2019",
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"abstract": "BACKGROUND\nStudies have shown that administration of anthelmintic drugs in pregnancy can reduce the incidence of maternal anaemia; however, data on other maternal and perinatal outcomes are limited.\n\n\nOBJECTIVE\nThis study was therefore conducted to evaluate the direct impact of mass deworming on delivery and perinatal outcome.\n\n\nMETHODS\nA total of 560 healthy pregnant women in their second trimester were randomised to receive a single dose of oral mebendazole (500 mg) and placebo. Each participant received the standard dose of iron supplement and malaria prophylaxis. They were followed up to delivery and immediate postpartum period to document the possible impact on maternal and perinatal outcomes.\n\n\nRESULTS\nThe prevalence of anaemia at term, 37 weeks gestation and above, among the treatment arm was 12.6% compared with 29.9% in the placebo arm (p < 0.001). Caesarean section rates was higher in the treated group and the placebo (p = 0.047). There were no statistically significant differences in incidences of postpartum haemorrhage (p = 0.119), Puerperal, pyrexia (p = 0.943), low birth weight (p = 0.556) asphyxia (p = 0.706) and perinatal death (p = 0.621).\n\n\nCONCLUSIONS\nPresumptive deworming during the antenatal period can significantly reduce the incidence of peripartum anaemia. However, more studies may be needed to prove any positive perinatal outcome.",
"affiliations": "Department of Obstetrics and Gynaecology, University of Calabar Teaching Hospital, Calabar, Cross River State, Nigeria.;Department of Family Medicine, University of Calabar Teaching Hospital, Calabar, Cross River State, Nigeria.;Department of Chemical Pathology, University of Calabar Teaching Hospital, Calabar, Cross River State, Nigeria.;Department of Community Medicine, University of Calabar Teaching Hospital, Calabar, Cross River State, Nigeria.;Department of Obstetrics and Gynaecology, University of Calabar Teaching Hospital, Calabar, Cross River State, Nigeria.",
"authors": "Akpan|Ubong Bassey|UB|;Asibong|Udeme|U|;Okpara|Henry Chima|HC|;Monjok|Emmanuel|E|;Etuk|Saturday|S|",
"chemical_list": null,
"country": "North Macedonia",
"delete": false,
"doi": "10.3889/oamjms.2018.143",
"fulltext": null,
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"issn_linking": "1857-9655",
"issue": "6(5)",
"journal": "Open access Macedonian journal of medical sciences",
"keywords": "Birth asphyxia; Childbirth; Low birth weight; Mebendazole; Postpartum haemorrhage; Puerperal pyrexia",
"medline_ta": "Open Access Maced J Med Sci",
"mesh_terms": null,
"nlm_unique_id": "101662294",
"other_id": null,
"pages": "901-907",
"pmc": null,
"pmid": "29875869",
"pubdate": "2018-05-20",
"publication_types": "D016428:Journal Article",
"references": "1512451;11386690;7658318;10755998;17002722;20090119;16940835;9922706;17327245;18092018;16131365;22811774;19323004;17299553;11355560;12548230;10209979;15364190;21969128;21251269;11009150;18240499;12592987;20067426",
"title": "Antenatal Deworming and Materno-Perinatal Outcomes in Calabar, Nigeria.",
"title_normalized": "antenatal deworming and materno perinatal outcomes in calabar nigeria"
} | [
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"activesubstancename": "FOLIC ACID"
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"reaction": [
{
"reactionmeddrapt": "Neonatal asphyxia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Congenital anomaly",
"reactionmeddraversionpt": "21.1",
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{
"reactionmeddrapt": "Death neonatal",
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"literaturereference": "AKPAN UB, ASIBONG U, OKPARA HC, MONJOK E, ETUK S. ANTENATAL DEWORMING AND MATERNO-PERINATAL OUTCOMES IN CALABAR, NIGERIA. OPEN ACCESS MACEDONIAN JOURNAL OF MEDICAL SCIENCES MAY-2018?6 (5):901-907.",
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{
"abstract": "To analyze the effect of adjuvant oral application of honey for treating postoperative pain after tonsillectomy.\n\n\n\nSingle centre prospective cohort study.\n\n\n\nTwo cohorts of patients after tonsillectomy.\n\n\n\n56 patients treated with honey 8 times per day (honey group), 18 patients treated without honey (control group); baseline analgesia were non-steroidal anti-inflammatory drugs (NSAID) or coxibs; opioids were used as pro re nata (PRN) medication; mean age 34.4 ± 13.4 years; 36% women.\n\n\n\nOn first to fifth postoperative day, patients rated their pain using the validated questionnaire of the German-wide project Quality Improvement in Postoperative Pain Treatment (QUIPS) including a numeric rating scale (NRS, 0-10) for determination of patient's pain. QUIPS allows standardized assessment of patients' characteristics andpain-associated patient-reported outcomes (PROs). The influence of preoperative and postoperative parameters on patients' postoperative pain were estimated by univariate and multivariate statistical analysis.\n\n\n\nAverage pain in activity in the control group was greater than 4 (NRS 4.4 ± 2.4) during the first five postoperative days, with a renewed increase in pain intensity on the fifth day (4.3 ± 2.5). In the honey group, the pain in activity decreased without any further pain increase and was only higher than 4 on the first three postoperative days (4.3 ± 2.1, all p>0.05). However; neither minimal nor maximal pain were significantly different between both groups on the first postoperative day (p = 0.217, p = 0.980). Over the five postoperative days, the minimal and maximal pain in the honey group decreased continuously and faster than in the control group. With regard to pain-related impairments on the first day, the honey group reported less pain-related sleep disturbance (p = 0.026), as well as significantly fewer episodes of postoperative oral bleeding (p = 0.028) than the control group. Patients without honey consumption had on the first and fifth postoperative day a higher risk of increased minimal pain (OR = -2.424, CI = -4.075 --0.385). Gender was an independent factor for compliance of honey consumption on the second postoperative day (p = 0.037). Men had a lower probability for compliance of honey consumption (OR = -0.288, CI = -2.863 --0.090).\n\n\n\nThere was a trend of reduced postoperative pain after oral honey application. Honey also seems to reduce pain-related impairments. The need for additional opioids on the first day could be reduced. A larger controlled trial is now needed to varify the effect of honey on pain after tonsillectomy.\n\n\n\nGerman Clinical Trials Register DRKS00006153. The authors confirm that all ongoing and related trials for this drug/intervention are registered.",
"affiliations": "Department of Otorhinolaryngology, Jena University Hospital, Jena, Germany.;Department of Otorhinolaryngology, Jena University Hospital, Jena, Germany.;Department of Otorhinolaryngology, Jena University Hospital, Jena, Germany.;Department of Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.;Department of Otorhinolaryngology, Jena University Hospital, Jena, Germany.",
"authors": "Geißler|Katharina|K|0000-0002-4271-5878;Schulze|Margaretha|M|;Inhestern|Johanna|J|;Meißner|Winfried|W|;Guntinas-Lichius|Orlando|O|",
"chemical_list": "D000277:Adjuvants, Pharmaceutic; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0228481",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0228481PONE-D-19-22078Research ArticleBiology and Life SciencesAgricultureAnimal ProductsHoneyBiology and Life SciencesNutritionDietFoodHoneyMedicine and Health SciencesNutritionDietFoodHoneyMedicine and Health SciencesPharmacologyDrugsAnalgesicsOpioidsMedicine and Health SciencesPain ManagementAnalgesicsOpioidsMedicine and Health SciencesPharmacologyDrugsOpioidsMedicine and Health SciencesSurgical and Invasive Medical ProceduresOtolaryngological ProceduresTonsillectomyBiology and Life SciencesPhysiologySensory PhysiologySomatosensory SystemPain SensationMedicine and Health SciencesPhysiologySensory PhysiologySomatosensory SystemPain SensationBiology and Life SciencesNeuroscienceSensory SystemsSomatosensory SystemPain SensationMedicine and Health SciencesInfectious DiseasesBacterial DiseasesPeritonsillar AbscessesMedicine and Health SciencesSurgical and Invasive Medical ProceduresMedicine and Health SciencesPain ManagementBiology and Life SciencesPhysiologyPhysiological ProcessesRespirationBreathingMedicine and Health SciencesPhysiologyPhysiological ProcessesRespirationBreathingThe effect of adjuvant oral application of honey in the management of postoperative pain after tonsillectomy in adults: A pilot study Postoperative pain after tonsillectomy: Effect of oral application of honeyhttp://orcid.org/0000-0002-4271-5878Geißler Katharina ConceptualizationData curationFormal analysisSupervisionWriting – original draft1*Schulze Margaretha Data curationFormal analysis1Inhestern Johanna Data curationWriting – review & editing1¤Meißner Winfried ConceptualizationInvestigation2Guntinas-Lichius Orlando ConceptualizationFormal analysisInvestigationMethodologySupervisionWriting – original draft11 \nDepartment of Otorhinolaryngology, Jena University Hospital, Jena, Germany2 \nDepartment of Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, GermanyFleckenstein Johannes EditorUniversity of Bern, SWITZERLANDCompeting Interests: The authors have declared that no competing interests exist.\n\n¤ Current address: Department of Otorhinolaryngology, Oberhavel Kliniken, Hennigsdorf, Germany\n\n* E-mail: katharina.geissler@med.uni-jena.de10 2 2020 2020 15 2 e022848114 8 2019 15 1 2020 © 2020 Geißler et al2020Geißler et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Objective\nTo analyze the effect of adjuvant oral application of honey for treating postoperative pain after tonsillectomy.\n\nDesign\nSingle centre prospective cohort study.\n\nSetting\nTwo cohorts of patients after tonsillectomy.\n\nParticipants\n56 patients treated with honey 8 times per day (honey group), 18 patients treated without honey (control group); baseline analgesia were non-steroidal anti-inflammatory drugs (NSAID) or coxibs; opioids were used as pro re nata (PRN) medication; mean age 34.4 ± 13.4 years; 36% women.\n\nMain outcome measures\nOn first to fifth postoperative day, patients rated their pain using the validated questionnaire of the German-wide project Quality Improvement in Postoperative Pain Treatment (QUIPS) including a numeric rating scale (NRS, 0–10) for determination of patient's pain. QUIPS allows standardized assessment of patients' characteristics andpain-associated patient-reported outcomes (PROs). The influence of preoperative and postoperative parameters on patients' postoperative pain were estimated by univariate and multivariate statistical analysis.\n\nResults\nAverage pain in activity in the control group was greater than 4 (NRS 4.4 ± 2.4) during the first five postoperative days, with a renewed increase in pain intensity on the fifth day (4.3 ± 2.5). In the honey group, the pain in activity decreased without any further pain increase and was only higher than 4 on the first three postoperative days (4.3 ± 2.1, all p>0.05). However; neither minimal nor maximal pain were significantly different between both groups on the first postoperative day (p = 0.217, p = 0.980). Over the five postoperative days, the minimal and maximal pain in the honey group decreased continuously and faster than in the control group. With regard to pain-related impairments on the first day, the honey group reported less pain-related sleep disturbance (p = 0.026), as well as significantly fewer episodes of postoperative oral bleeding (p = 0.028) than the control group. Patients without honey consumption had on the first and fifth postoperative day a higher risk of increased minimal pain (OR = -2.424, CI = -4.075 –-0.385). Gender was an independent factor for compliance of honey consumption on the second postoperative day (p = 0.037). Men had a lower probability for compliance of honey consumption (OR = -0.288, CI = -2.863 –-0.090).\n\nConclusion\nThere was a trend of reduced postoperative pain after oral honey application. Honey also seems to reduce pain-related impairments. The need for additional opioids on the first day could be reduced. A larger controlled trial is now needed to varify the effect of honey on pain after tonsillectomy.\n\nClinical trial registration number\nGerman Clinical Trials Register DRKS00006153. The authors confirm that all ongoing and related trials for this drug/intervention are registered.\n\nThe authors received no specific funding for this work. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nTonsillectomy, the surgical removal of the palatine tonsils, is still one of the most common surgical procedures in adults in Germany and around the world [1]. Tonsillectomy causes severe postoperative pain lasting for many days [2]. A prospective cohort study taking part in the Quality Improvement in Postoperative Pain Treatment (QUIPS) registry has shown that tonsillectomy was one of the most painful surgical procedures even compared to major surgery procedures [3]. For pain therapy in adults after tonsillectomy typically non-opioid analgesics are used, often combined with an opioid on demand [4, 5, 6, 7].\n\nEven though patients receive such a combination therapy postoperative pain after tonsillectomy remains at a high level and an improved therapy plan is needed [8, 9, 10].\n\nDifferent factors contribute to postoperative pain after tonsillectomy: the dense innervation with pain fibers in the area of tonsils [11], mediators of inflammation like bradykinin or prostaglandins, which irritate sensitive nerve endings and induce strong pain [12, 13], local infiltration of neutrophile granulocytes and cytokines [14]. Local application of honey reduces redness and swelling of infected wounds and reduces healing time. Honey seems to have a comparable effect to topic antibiotics on pathogenic bacterial infections of surgical wounds and conjunctiva [15]. Honey might affect the local inflammation and thereby reduce und diminish duration of wound pain. The studies performed so far studying the effect of honey on postoperative pain after tonsillectomy revealed inconsistent results or did not used standard pain outcome measures [16, 17, 18, 19, 20, 21, 22, 23, 24, 25].\n\nThe above mentioned project QUIPS was developed in 2005, consisting of standardized data acquisition and an analysis of quality and process indicators [26]. QUIPS and the international counterpart PAIN OUT are open for every hospital worldwide and are web-based [9, 27, 28]. The present prospective clinical study used QUIPS data to analyze if the additional oral application of honey several times a day reduces postoperative pain better than traditional pain therapy with a non-opioid (metamizole or etoricoxib), in combination with an opioid as PRN medication.\n\nMethods\nThe present prospective cohort study was part of the German-wide Quality Improvement in Postoperative Pain Treatment (QUIPS) registry (German Clinical Trials Register DRKS00006153, registration in May 2014). Institutional review board approval was obtained prior to study initiation in November 2012 by the Ethics Committee of the Jena University Hospital, Thuringia, Germany. For enrollment of participants in 2012 a positive approval by Ethics Committee was sufficient. Therefore there was a delay in registration the study. The authors confirm that all ongoing and related trials for this drug/intervention are registered.\n\nSubjects\nThe patients in the ENT department of Jena University Hospital had to fulfill the following inclusion criteria: age of 18 years and older, oriented and awake, linguistic and intellectual understanding, written consent, bilateral tonsillectomy, diagnosis of acute recurrent tonsillitis or chronic tonsillitis, peritonsillar abscess, obstructive sleep apnea or tumor of tonsil.\n\nExclusion criteria were age younger than 18 years, cognitive deficits, limited communication skills, diabetes mellitus, no written consent, tonsillectomy one side, postoperative admission on intensive care and previous allergic reaction to honey.\n\nPatients treated in the hospital as in-patients between December 2015 and March 2017 (honey group) and February 2013 and November 2013 (control group) were included by self-selection. The time for patient recruitment and follow-up was between February 2013 and April 2017. There were no changes in pain protocol between 2013 and 2017. 141 tonsillectomies were performed in patients with 18 years and older. 74 patients participated, 67 patients rejected or could not participate (Fig 1).\n\n10.1371/journal.pone.0228481.g001Fig 1 Enrolled patients.\nThe addition of honey to patients`food was introduced as part of the clinical routine. Patients received eight pots of honey of nectar of different blossoms (Blütenhonig, Transgourmet Deutschland, Riedstadt, Germany) with a content of 20g per day (maximum 160g per day). The honey was delivered in sterile packages. The dose of honey was chosen empirically. There is no reported dose related toxicity to honey for adults. An illustrated information brochure was handed to the patient. The honey should be applied into the mouth with a spoon and then distributed in the oral cavity for about five minutes. If the honey's sweetness made it impossible for the patient to apply honey this way, it was allowed to dissolve the honey in a half-filled cup with lukewarm water. The honey solution was then also applied over five minutes in the oral cavity. The empty honey pots were counted. The compliance of daily honey consumption was measured for all patients as the days on which all 8 honey pots were used.\n\nPain and pain management measures\nThe QUIPS questionnaires are presented in detail elsewhere [10]. Briefly, the QUIPS questionnaires consisted of two parts for each patient: This first part was covering the patient-reported outcome (PRO) parameters of the questionnaire, whereas the second part was filled by the investigator. After a standardized instruction, the patient itself completed the part one of the form. The patients received a validated 15-item QUIPS questionnaire from first till fifth postoperative day. QUIPS used 11-point numeric rating scales (NRS) to estimate the patient’s pain during activities, maximal pain and pain at rest. Generally, higher numbers are indicating more pain (0 = no pain; 10 = most imaginable pain). Furthermore, the patient was asked by dichotomized (yes/no) questions about pain-related impairments (mobility, breathing, sleep, mood), side effects of pain treatment (drowsiness, nausea, vomiting), and satisfaction with the pain management. The patients were also asked about the preoperative pain counselling in three categories (yes, in general; yes, specific; no). General pain counselling meant that education about postoperative pain and its management in general was part of the pre-surgical interview with the patients. Specific pain counselling assumed that it was talked about specific pain related to the surgical procedure the patient underwent. Furthermore, the interview had to include education on specific measures to prevent and manage postoperative pain before, during and after tonsillectomy exactly for the interviewed patient. The second part, which is filled by the investigator, was covering the relevant demographic and clinical parameters like age, gender, type of surgery, anaesthesia, and pain management.\n\nStatistical analysis\nIBM SPSS statistics software (Version 23.0.0.0) was used. Data is presented as mean ± standard deviation (SD) if not otherwise indicated. Clinical and outcome parameters of all patients were summarized descriptively. To study the metric data of two independent groups the nonparametric Mann-Whitney-U-test was used. If there were variables with more than 2 possible answers, they were analyzed by the nonparametric Kruskal-Wallis-ANOVA-test. To check for significance in nominal variables Pearson`s chi-square test was applied. For the comparison of dependent data, the nonparametric Wilcoxon-test was used. The significance level was set at p<0.05. Multivariate ordinal regression was used to analyze predictors for more postoperative pain for all significant parameters from the univariate analysis. Multivariable binary logistic regression models with stepwise entry were used for the dichotomized categorized outcome parameters to analyze the association to pain-related interferes and pain therapy side effects. In general, nominal p values of two-tailed tests are reported. Pain in activity was analysed with a repeated measures ANOVA with the within factor SESSION (five levels: first to fifth postoperative day) and the between factor GROUP.\n\nResults\nDemographic parameters\nAn overview on the comparison of the demographic and baseline parameters is given in Table 1. The mean age of the patients was 34.4 ± 13.4 years. In both patient groups, the proportion of male patients was about two-thirds. Patients’ characteristics were not different between both groups (all p>0.05). Postoperative bleeding, with or without need of surgery, on the first five days after surgery was more frequent in the control group (p = 0.028).\n\n10.1371/journal.pone.0228481.t001Table 1 Demographic parameters.\nParameter\thoney group n = 56\tcontrol group n = 18\tp-value\t\nGender\t\t\t0.416\t\n female\t22\t5\t\t\n Male\t34\t13\t\t\nage, years\t35.8 ± 13.9\t30.1 ± 11.2\t0.172\t\nDiagnosis\t\t\t0.383\t\n chronic tonsillitis\t24\t10\t\t\n peritonsillar abscess\t24\t8\t\t\n obstructive sleep\t6\t0\t\t\n apnoe\t\t\t\t\n tumor of tonsil\t2\t0\t\t\npostoperative complications\t\t\t0.028\t\n No\t54\t14\t\t\n Bleeding\t2\t4\t\t\nASA-classification\t\t\t0.283\t\n I\t32\t13\t\t\n II and III\t24\t5\t\t\nASA = American Society of Anesthesiologists\n\nThe highest compliance of honey consumption (% of patients applying all 8 honey pots) was measured on the first and second postoperative day. More than 90% of the patients in the honey group used all 8 honey pots (first day 94.6%, second day 91.1%, third day 87.5%, fourth day 80.4% and fifth day 76.8%).\n\nPostoperative results of QUIPS\nThe postoperative pain in activity was recorded in honey and control group for five days. Maximum and minimum pain was asked on the first postoperative day. The pain in activity decreased in both groups on the fourth postoperative day. On the fifth postoperative day pain in activity increased in the control group (4.3 ± 2.5), but not in the honey group (3.3 ± 2.2, p = 0.128, Table 2).\n\n10.1371/journal.pone.0228481.t002Table 2 Pain in activity in both groups on the first to fifth postoperative day.\npostoperative day\thoney group\tcontrol group\tp-value\t\n1\t4.6 ± 2.3\t5.0 ± 2.3\t0.529\t\n2\t4.6 ± 2.3\t4.4 ± 2.3\t0.854\t\n3\t4.1 ± 2.1\t4.2 ± 2.4\t0.806\t\n4\t3.6 ± 2.1\t4.0 ± 2.5\t0.536\t\n5\t3.3 ± 2.2\t4.3 ± 2.5\t0.128\t\n5–1\t-1.3 ± 0.1\t-0.7 ± 0.2\t0.458\t\nThe maximum and minimum pain on the first postoperative day was not significant different in both groups (p = 0.980, p = 0.217). In the honey group pain in activity, maximal and minimal pain continuously decreased over first to fifth postoperative day (Fig 2). In both groups over 90% of patients received a general or special medical education about pain therapy (p = 0.887).\n\n10.1371/journal.pone.0228481.g002Fig 2 Pain in activity, maximal and minimal pain in honey group.\nRegarding the repeated measures ANOVA there was a main effect for SESSION (F(4.272) = 7.85; p<0.001; partial Eta Squared = 0.103). There is a constant decrease of pain in activity across postoperative days. There was no interaction between GROUP and SESSION (F(4.272) = 1.69; no signifance) and no effect for GROUP (F(1.68) = 0.27; no significance).\n\nPostoperative pain and treatment-associated impairments\n52% of patients in honey group woke up during the night due to pain, compared to 83% in the control group (p = 0.026, Table 3). The satisfaction with pain therapy on the first postoperative day was indifferent between both groups (p = 0.453).\n\n10.1371/journal.pone.0228481.t003Table 3 Results of QUIPS questionnaire on the first postoperative day.\nParameter\thoney group n = 56\tcontrol group n = 18\tp-value\t\nmedical education\t\t\t0.887\t\n yes, general\t41\t14\t\t\n yes, special\t10\t3\t\t\n no\t5\t1\t\t\npreoperative chronic pain\t11\t6\t\t\n\tMean ± SD 0.7 ± 0.5\tMean ± SD 6.8 ± 1.7\t<0.001\t\npain on first postoperative day\t\t\t\t\n pain in activity\t4.6 ± 2.3\t5.0 ± 2.3\t0.529\t\n maximal pain\t5.8 ± 2.3\t5.9 ± 1.9\t0.980\t\n minimal pain\t2.3 ± 1.7\t1.8 ± 1.8\t0.217\t\npain-associated and pain therapy-associated impairments on first postoperative day\t\t\t\t\npain while breathing\t\t\t1.000\t\n yes\t38\t13\t\t\n no\t18\t5\t\t\nwaking up because of pain\t\t\t0.026\t\n yes\t29\t15\t\t\n no\t27\t3\t\t\nFatigue\t\t\t1.000\t\n yes\t26\t9\t\t\n no\t30\t9\t\t\nfeeling uncomfortable because of pain\t\t\t0.785\t\n yes\t22\t8\t\t\n no\t34\t10\t\t\ncomplaining by mobility restricts\t\t\t0.372\t\n yes\t16\t3\t\t\n no\t40\t15\t\t\nNausea\t\t\t0.102\t\n yes\t9\t0\t\t\n no\t47\t18\t\t\nVomitus\t\t\t-\t\n yes\t0\t0\t\t\n no\t56\t18\t\t\ndesire for pain killers\t\t\t1.000\t\n yes\t10\t3\t\t\n no\t46\t15\t\t\nsatisfaction with pain therapy\tMean ± SD 11.6 ± 2.5\tMean ± SD 11.2 ± 2.5\t0.453\t\nSD = standard deviation\n\nThe postoperative impairments in the honey group decreased throughout the first till the fifth postoperative day with the strongest decrease concerning the complaints of pain whilst breathing and waking up in the night due to pain (Fig 3).\n\n10.1371/journal.pone.0228481.g003Fig 3 A–impairment whilst breathing (%), B–impairment in mobility (%), C–waking up due to pain (%), D–feeling uncomfortable because of pain (%), E–desire for more painkiller (%), F–fatigue (%), G–nausea (%), y-axis–postoperative impairments (%), x-axis–postoperative day, results of honey group.\n\nProcess parameter\nAll interventions were performed in general anesthesia, without local anesthesia. Intraoperatively two third of the honey group and one third of the control group received the highly potent and short acting opioid remifentanil (p = 0.058, Table 4). Half of the patients received an intravenous application of piritramid in the recovery room (p = 1.000, Table 4). On ward, a majority of the honey group received metamizole as basic analgesia on the first postoperative day, in the control group only one third. The other patients took etoricoxib (p<0.001). In the honey group 96% of patients received no additional non-opioid, in the control group nearly the half of patients additional metamizole (p<0.001). On the first postoperative day more than twice as much patients in the control compared to the honey group requested opioids (p = 0.004). In the honey group mostly tramadol, in the control group mostly piritramid were applied (p<0.001).\n\n10.1371/journal.pone.0228481.t004Table 4 Process parameter on the first postoperative day.\nparameter\thoney group n = 56\tcontrol group n = 18\tp-value\t\npreoperative\t\t\t\t\n regular intake of pain killers\t\t\t0.434\t\n yes\t9 (16.1%)\t1 (5.6%)\t\t\n no\t47 (83.9%)\t17 (94.4%)\t\t\n pain therapy\t\t\t1.000\t\n yes\t3 (5.4%)\t0\t\t\n no\t53 (94.6%)\t18 (100%)\t\t\n most used sedativum\t\t\t0.115\t\n no\t4 (7.1%)\t0\t\t\n midazolam\t43 (76.8%)\t17 (94.4%)\t\t\n clorazepat\t1 (1.8%)\t0\t\t\nIntraoperative\t\t\t\t\n remifentanil\t\t\t0.058\t\n yes\t34 (60.7%)\t6 (33.3%)\t\t\n no\t22 (39.3%)\t12 (66.7%)\t\t\nfirst postoperative day\t\t\t\t\n opioid in recovery room\t\t\t1.000\t\n yes (piritramid)\t29 (51.8%)\t9 (50%)\t\t\n no\t27 (48.2%)\t9 (50%)\t\t\n opioid on ward\t\t\t0.004\t\n yes\t16 (28.6%)\t13 (72.2%)\t\t\n no\t39 (69.6%)\t5 (27.8%)\t\t\n most used opioid on ward\t\t\t<0.001\t\n no\t39 (69.6%)\t5 (27.8%)\t\t\n tramadol\t10 (17.9%)\t1 (5.6%)\t\t\n piritramid\t4 (7.1%)\t12 (66.7%)\t\t\n tapentadol\t2 (3.6%)\t0\t\t\n additional opioid on ward\t\t\t0.046\t\n yes\t1 (1.8%)\t3 (16.7%)\t\t\n no\t54 (96.4%)\t15 (83.3%)\t\t\n most used non-opioid on ward\t\t\t<0.001\t\n No\t2 (3.6%)\t0\t\t\n metamizole\t53 (94.6%)\t6 (33.3%)\t\t\n acetaminophen\t1 (1.8%)\t0\t\t\n etoricoxib\t0\t12 (66.7%)\t\t\n additional non-opioid on ward\t\t\t<0.001\t\n no\t54 (96.4%)\t8 (44.4%)\t\t\n metamizole\t1 (1.8%)\t1 (5.6%)\t\t\n acetaminophen\t1 (1.8%)\t8 (44.4%)\t\t\n etoricoxib\t0\t1 (5.6%)\t\t\nThe changes of process parameters are described in detail for the honey group (Table 5). The highest demand after opioids on ward was on the second postoperative day.\n\n10.1371/journal.pone.0228481.t005Table 5 Process parameter on the first to fifth postoperative day in honey group.\nParameter\tpostoperative day\t\n\t1\t2\t3\t4\t5\t\npostoperative\t\t\t\t\t\t\n opioid on ward\t\t\t\t\t\t\n yes\t16\t22\t15\t10\t7\t\n no\t39\t33\t40\t45\t48\t\n most used opioid on ward\t\t\t\t\t\t\n no\t39\t33\t40\t45\t48\t\n tramadol\t10\t18\t13\t7\t7\t\n piritramid\t4\t3\t0\t1\t0\t\n tapentadol\t2\t1\t1\t2\t0\t\n codeine\t0\t0\t1\t0\t0\t\n additional opioid on ward\t\t\t\t\t\t\n yes\t1\t2\t0\t3\t0\t\n no\t54\t53\t55\t52\t55\t\n most used non-opioid on ward\t\t\t\t\t\t\n no\t2\t0\t1\t6\t6\t\n metamizole\t53\t54\t53\t48\t48\t\n acetaminophen\t1\t1\t1\t1\t1\t\n etoricoxib\t0\t1\t1\t1\t1\t\n additional non-opioid on ward\t\t\t\t\t\t\n no\t54\t53\t55\t55\t54\t\n ibuprofen\t1\t2\t1\t1\t1\t\n metamizole\t1\t1\t0\t0\t0\t\n indomethacin\t0\t0\t0\t0\t1\t\nDemographic parameters associated with PROs\nWith univariate analysis the influence of demographic parameters on QUIPS results were analyzed. On the second and fifth postoperative days women had more pain as men (p = 0.024, p = 0.025). On the second postoperative day patients with tumor of tonsil or acute recurrent tonsillitis had more pain than patients with obstructive sleep apnea or peritonsillar abscess (p = 0.018, S1 Table). On the first and second postoperative day patients with obstructive sleep apnea had the strongest and patients with peritonsillar abscess the weakest maximal pain (p = 0.004, p = 0.039, S2 Table). Women had on the first to fifth postoperative day significant higher minimal pain in comparison to men (p = 0.002 to p = 0.021). On the first postoperative day patients without honey consumption had twice as high minimal pain (p = 0.023), on the fifth postoperative day still significant higher minimal pain (p = 0.049, S3 Table).\n\nInfluence of process parameter on QUIPS results\nIn general, application of intraoperative remifentanil and/or postoperative opioids on demand was associated with higher pain scores on some postoperative days (see S4 to\nS6 Tables).\n\nMultivariate analysis of factors influencing postoperative pain in honey group\nThe diagnosis was an independent factor on pain in activity on the second postoperative day (p = 0.004): Patients with peritonsillar abscess had less pain in activity. Gender and honey consumption were independent factors on minimal pain on the first and fifth postoperative day (p = 0.016, p = 0.019, p = 0,023). On the first postoperative day women had a more two times higher risk of pain (OR = 2.491, CI = 0.206–1.907). Patients without honey application had a higher risk of pain on the first and fifth postoperative day (OR = -2.424, CI = -4.075 –-0.385, Table 6).\n\n10.1371/journal.pone.0228481.t006Table 6 Independent factors with influence on postoperative pain.\npain in activity on second postoperative day R2 = 0.241, p = 0.002\tOR\t95% CI lower limit\t95% CI upper limit\tp-value\t\ngender (male = 0, female = 1)\t0.214\t-0.233\t2.096\t0.114\t\ndiagnosis (acute recurrent tonsillitis = 0, peritonsillar abscess = 1)\t-0.399\t-2.878\t-0.567\t0.004\t\nminimal pain on first postoperative day R2 = 0.181, p = 0.005\t\t\t\t\t\ngender (male = 0, female = 1)\t2.491\t0.206\t1.907\t0.016\t\nhoney consumption (no = 0, yes = 1)\t-2.424\t-4.075\t-0.385\t0.019\t\nminimal pain on fifth postoperative day R2 = 0.286, p<0.001\t\t\t\t\t\ngender (male = 0, female = 1)\t0.331\t0.176\t1.656\t0.016\t\nhoney consumption (no = 0,yes = 1)\t-0.313\t-2.267\t-0.178\t0.023\t\nsatisfaction on first postoperative day R2 = 0.155, p = 0.096\t\t\t\t\t\nage in years (<33.5 = 0, >33.5 = 1)\t-0.015\t-1.500\t1.352\t0.917\t\ndiagnosis (acute recurrent tonsillitis = 0, peritonsillar abscess = 1)\t0.250\t-0.100\t2.621\t0.069\t\nR2 = coefficient of determination, CI = confidence interval, OR (Odds-Ratio) = standardized coefficient\n\nDiagnosis was an independent factor for satisfaction with pain therapy on second to fifth postoperative day (p = 0.009 to p = 0.044). Patients with acute recurrent tonsillitis had a higher risk of less satisfaction on second to fifth postoperative day (Table 7).\n\n10.1371/journal.pone.0228481.t007Table 7 Independent factors with influence on satisfaction with pain therapy.\nsatisfaction on second postoperative day R2 = 0.403, p = 0.002\tOR\t95% CI lower limit\t95% CI upper limit\tp-value\t\nage in years (<33.5 = 0, >33.5 = 1)\t-0.094\t-2.217\t1.239\t0.569\t\ndiagnosis (acute recurrent tonsillitis = 0, peritonsillar abscess = 1)\t0.434\t0.589\t3.917\t0.009\t\nsatisfaction on third postoperative day R2 = 0.314, p = 0.007\t\t\t\t\t\nage in years (<33.5 = 0, >33.5 = 1)\t0.048\t-1.449\t1.945\t0.769\t\ndiagnosis (acute recurrent tonsillitis = 0, peritonsillar abscess = 1)\t0.353\t0.052\t3.574\t0.044\t\nsatisfaction on fourth postoperative day R2 = 0.329, p = 0.002\t\t\t\t\t\ndiagnosis (acute recurrent tonsillitis = 0, peritonsillar abscess = 1)\t0.402\t0.529\t3.490\t0.009\t\nsatisfaction on fifth postoperative day R2 = 0.277, p = 0.011\t\t\t\t\t\ndiagnosis (acute recurrent tonsillitis = 0, peritonsillar abscess = 1)\t0.414\t0.492\t4.023\t0.014\t\nR2 = coefficient of determination, CI = confidence interval, OR (Odds-Ratio) = standardized coefficient\n\nGender was an independent factor for compliance of honey consumption on the second postoperative day (p = 0.037). Men had a lower probability for compliance of honey consumption (OR = -0.288, CI = -2.863 –-0.090), Table 8).\n\n10.1371/journal.pone.0228481.t008Table 8 Independent factors with influence on complicance of honey consumption.\nhoney consumption on second postoperative day R2 = 0.160, p = 0.017\tOR\t95% CI lower limit\t95% CI upper limit\tp-value\t\ngender (male = 0, female = 1)\t-0.288\t-2.863\t-0.090\t0.037\t\nR2 = coefficient of determination, CI = confidence interval, OR (Odds-Ratio) = standardized coefficient\n\nDiagnosis was an independent factor on impairment of breathing on the second and fifth postoperative day (p = 0.006, p = 0.031) and on night pain on the fourth postoperative day (p = 0.022). On the second postoperative day patients with acute recurrent tonsillitis had an eightfold higher risk of impairment of breathing (OR = 8.575, CI = 1.839–39.994), on the fifth postoperative day a fourfold higher risk (OR = 4.222, CI = 1.139–15.644). On the fourth postoperative day patients with acute recurrent tonsillitis had a fourfold higher risk of night pain (OR = 4.581, CI = 1.248–16.816, Table 9).\n\n10.1371/journal.pone.0228481.t009Table 9 Independent factors with influence on pain or pain-therapy related impairments.\nimpairment of breathing on the second postoperative day R2 = 0.373, p<0.001\tOR\t95% CI lower limit\t95% CI upper limit\tp-value\t\nage in years (<33.5 = 0, >33.5 = 1)\t2.428\t0.582\t10.127\t0.223\t\ndiagnosis (acute recurrent tonsillitis = 0, peritonsillar abscess = 1)\t8.575\t1.839\t39.994\t0.006\t\nimpairment of breathing on the fifth postoperative day R2 = 0.225, p = 0.017\t\t\t\t\t\ngender (male = 0, female = 1)\t2.609\t0.700\t9.719\t0.153\t\ndiagnosis (acute recurrent tonsillitis = 0, peritonsillar abscess = 1)\t4.222\t1.139\t15.644\t0.031\t\nnight pain on fourth postoperative day R2 = 0.210, p = 0.019\t\t\t\t\t\ngender (male = 0, female = 1)\t2.034\t0.567\t7.291\t0.276\t\ndiagnosis (acute recurrent tonsillitis = 0, peritonsillar abscess = 1)\t4.581\t1.248\t16.816\t0.022\t\nR2 = coefficient of determination, CI = confidence interval, OR (Odds-Ratio) = standardized coefficient\n\nApplication of opioids on ward was an independent factor on impairments of mobility on the third postoperative day (p = 0.046) and night pain on the first and fifth postoperative day (p = 0.022, p = 0.036). The application of opioids correlated with higher risk of impairments of mobility and night pain (p = 0.046, p = 0.022, p = 0.036, Table 10).\n\n10.1371/journal.pone.0228481.t010Table 10 Influence of opioid use on ward on pain or pain-therapy related impairments.\nimpairment of mobility on third postoperative day R2 = 0.265, p = 0.005\tOR\t95% CI lower limit\t95% CI upper limit\tp-value\t\nregular pain medication (no = 0, yes = 1)\t0.227\t0.044\t1.166\t0.076\t\nopioids on ward (no = 0, yes = 1)\t0.172\t0.043\t0,692\t0.046\t\nnight pain on first postoperative day R2 = 0.336, p = 0.001\t\t\t\t\t\nopioids on ward (no = 0, yes = 1)\t0.144\t0.027\t0.753\t0.022\t\nnight pain on the fourth pain R2 = 0.257, p = 0.004\t\t\t\t\t\nopioids on ward (no = 0, yes = 1)\t0.150\t0.026\t0.880\t0.036\t\nR2 = coefficient of determination, CI = confidence interval, OR (Odds-Ratio) = standardized coefficient\n\nDiscussion\nThe present pilot study evaluated whether oral application of honey as adjuvant therapy after tonsillectomy in adult patients can reduce postoperative pain as well as postoperative pain- or treatment-related impairments. There was a trend of reduced pain after honey application as well as diminished pain-related impairments.\n\nThe strengths of this pilot study are the standardized assessment of process and outcome parameters with the QUIPS instrument [8] and repeated measurements from the first to the fifth postoperative day. The weaknesses are the lack of randomization and a low number of patients in the control group. This was a pilot study with exploratory character. Current data were not sufficient to define a hypothesis on the effect of honey on postoperative pain. Furthermore, the correct oral application of honey with regard to a 2-hour intake interval and a 5-minute residence time in the mouth in all cases cannot be guaranteed. It was only feasible to count the empty honey pots after application.\n\nStudies investigating the effects of honey on tonsillectomy included Tualang honey from Southeast Asia [20, 18], unprocessed, pure honey from Malaysia [21], flower honey of thyme and tragacanth plants [16] and commercially available more or less undefined honey [17, 29]. Several studies described, that honey application, even on inflamed oral mucosa, is a painless procedure [30, 31]. The type of honey does not seem to have a significant impact on the results. The present study uses a standard honey (a blend of floral honey from EU and non-EU countries) provided by the University Hospital's kitchen for patient breakfast. The recommended frequency of oral honey application ranged from once [19] or three-times daily [20] to four-hourly [29] or even hourly intake during the waking phase [16]. Nevertheless, a clear recommendation for the application intervals cannot be deduced from these studies. Dosage and frequency of honey intake still has to be specifically investigated.\n\nThe multivariate analysis yielded an interesting result: Patients of the control group were about six times more likely to receive an opioid compared to patients in the honey group. Ingestion of another non-opioid on ward was more likely in patients of the control group. The lower demand for analgesics within the honey group may be related to lower postoperative pain. It is also possible that the patients on the first day waived additional analgesics, as they hoped for the pain-relieving effect of honey. However, based upon the available data this proposition cannot be verified.\n\nIn contrast to the honey group, other studies in children, adolescents and adults showed an increase in postoperative pain after tonsillectomy due to acute recurrent tonsillitis from the third postoperative day [32, 33]. Pain within the honey group decreased continuously without any further pain peaks, this could be a hint for accelerated wound healing by the applied honey.\n\nIn the pediatric study by Mohebbi et al., patients took much less painkillers when they took honey as the first on-demand medication [17]. The direct comparison with the pain values of other honey studies was not always possible because in the present study a more specific differentiation was made between maximal, minimal and pain in activity. In addition, the comparative studies had pediatric or mixed patient groups. Pain in the other studies in children was already below the intervention limit of NRS 4 [17] or even below 3.5 [16] on the first postoperative day, in contrast to the present study of more than 4 (pain in activity) and over 5 (maximal pain). The satisfaction with pain therapy was more than 11 out of 15 possible points on the first day after surgery in both groups. Despite some high pain values, the patients were satisfied with the pain therapy. This paradox appearing phenomenon has already been observed in several other studies [34, 35]. Even when pain relief was below preoperative expectations, patients are often satisfied with the pain therapy [36]. Not pain intensity or actual pain relief alone seem to be the key to patient satisfaction. Schwenkglenks et al. assumed a positive effect on satisfaction by including the patient in therapy planning and by their general well-being in the clinic [35].\n\nA larger controlled trial is now needed to confirm the effect of honey on pain after tonsillectomy. In order to make a more precise assessment of the effectiveness of the honey, a better defined honey with standard composition might be helpful. The impact of the mode of administration as well as the amount and frequency of oral honey application on postoperative pain should also be analyzed in further studies.\n\nConclusion\nBased on the survey of postoperative minimal, maximal and pain in activity over five days, the present study showed that the pain therapy after tonsillectomy needs further improvement. Even with additional two-hourly intake of honey (eight times daily, 20 g each time), maximal pain with values above the intervention limit of NRS 4 on all five days as well as the pain in activity on the first three days were clearly too high. This pilot study suggests that oral application of honey might prevent a postoperative pain increase on postoperative day 4 and 5, have an opioid-sparing effect.\n\nOverall, honey seems to have a healing and pain-relieving effect. The extent to which honey can be implemented in pain therapy regimes after tonsillectomy must be determined in further studies.\n\nSupporting information\nS1 Checklist TREND statement checklist.\n(PDF)\n\nClick here for additional data file.\n\n S1 Table Influence of demographic parameters on pain in activity.\n(DOCX)\n\nClick here for additional data file.\n\n S2 Table Influence of demographic parameters on maximal pain.\n(DOCX)\n\nClick here for additional data file.\n\n S3 Table Influence of demographic parameters on minimal pain.\n(DOCX)\n\nClick here for additional data file.\n\n S4 Table Influence of process parameter on pain in activity.\n(DOCX)\n\nClick here for additional data file.\n\n S5 Table Influence of process parameter on maximal pain.\n(DOCX)\n\nClick here for additional data file.\n\n S6 Table Influence of process parameter on minimal pain.\n(DOCX)\n\nClick here for additional data file.\n\n S1 Fig (JPG)\n\nClick here for additional data file.\n\n S1 File (PDF)\n\nClick here for additional data file.\n\n S2 File (PDF)\n\nClick here for additional data file.\n\n S3 File (DOCX)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Statistisches Bundesamt. Gesundheit. Fallpauschalenbezogene Krankenhausstatistik (DRG-Statistik) 2014. Statistisches Bundesamt. Gesundheit. Fallpauschalenbezogene Krankenhausstatistik (DRG-Statistik) 2014. (article in German) https://www.destatis.de/DE/Publikationen/Thematisch/Gesundheit/Krankenhaeuser/FallpauschalenKrankenhaus2120640147004.pdf?__blob=publicationFile.\n2 Ericsson E , Brattwall M , Lundeberg S . Swedish guidelines for the treatment of pain in tonsil surgery in pediatric patients up to 18 years . Int J Pediatr Otorhinolaryngol \n2015 ;79 (4 ):443 –450 . 10.1016/j.ijporl.2015.01.016 \n25677565 \n3 Gerbershagen HJ , Aduckathil S , van Wijck AJ , et al\nPain Intensity on the First Day after Surgery: A Prospective Cohort Study Comparing 179 Surgical Procedures . Anesthesiology \n2013 ;18 : 934 –944 .\n4 Picard P , Bazin JE , Conio N \net al\nKetorolac potentiates morphine in postoperative patient-controlled analgesia . 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Turkish Journal of Medical Sciences \n2013 ;43 (5 ):851 –857 .\n22 Hwang SH , Song JN , Jeong YM \net al\nThe efficacy of honey for ameliorating pain after tonsillectomy: a meta-analysis . European Archives of Oto-Rhino-Laryngology \n2016 ;273 (4 ):811 –818 . 10.1007/s00405-014-3433-4 \n25524642 \n23 Hatami M , Mirjalili M , Ayatollahi V \net al\nComparing the Efficacy of Peritonsillar Injection of Tramadol With Honey in Controlling Post-Tonsillectomy Pain in Adults . Journal of Craniofacial Surgery \n2018 ;29 (4 ):e384 –e387 . 10.1097/SCS.0000000000004393 \n29498972 \n24 Ochi JW . Acupuncture instead of codeine for tonsillectomy pain in children . International Journal of Pediatric Otorhinolaryngology \n2013 ;77 (12 ):2058 –2062 . 10.1016/j.ijporl.2013.10.008 \n24210291 \n25 Gilbey P , Bretler S , Avraham Y \net al\nAcupuncture for posttonsillectomy pain in children: a randomized, controlled study . Paediatric Anaesthesia \n2015 ;25 (6 ):603 –609 . 10.1111/pan.12621 \n25661270 \n26 Meissner W , Mescha S , Rothaug J , et al\nQuality improvement in postoperative pain management: results from the QUIPS project . Dtsch Arztebl Int \n2008 ;105 (50 ):865 –870 . 10.3238/arztebl.2008.0865 \n19561807 \n27 Rothaug J , Zaslansky R , Schwenkglenks M , et al\nPatients' perception of postoperative pain management: validation of the International Pain Outcomes (IPO) questionnaire . J Pain \n2013 ;14 (11 ):1361 –1370 . 10.1016/j.jpain.2013.05.016 \n24021577 \n28 Zaslansky R , Rothaug J , Chapman RC , et al\nPAIN OUT: an international acute pain registry supporting clinicians in decision making and in quality improvement activities . J Eval Clin Pract \n2014 ;20 (6 ):1090 –1098 . 10.1111/jep.12205 \n24986116 \n29 Prasad AS , Ahmed MN , Ahmed SM \net al\nPost-operative pain management of tonsillectomy patients; clinical evaluation of using oral honey in 78 patients . Journal of Evolution of Medical and Dental Sciences \n2015 ;4 (05 ):799 –807 .\n30 Liu TM , Luo YM , Tam KW \net al\nProphylactic and therapeutic effects of honey on radiochemotherapy-induced mucositis: a meta-analysis of randomized controlled trials . Support Care Cancer \n2019 , 27 (7 ): 2361 –2370 . 10.1007/s00520-019-04722-3 \n30919153 \n31 Motallebnejad M , Akram S , Moghadamnia A \net al\nThe effect of topical application of pure honey on radiation-induced mucositis: a randomized clinical trial . The Journal of Contemporary Dental Practice \n2008 ;9 (3 ): 40 –47 . 18335118 \n32 Purser S , Royse CF , Velkov HA \net al\n2000. Topical application of ethanol to the tonsillar bed immediately following tonsillectomy does not improve post-operative analgesia . The Journal of Laryngology and Otolaryngology \n2000 ;114 (9 ):671 –674 .\n33 Baumann I . [Outcome after tonsillectomy for chronic tonsillitis ]. HNO—Die Zeitschrift für Hals-, Nasen-, Ohrenheilkunde \n2005 ;53 (5 ):405 –407 .\n34 Ward SE , Gordon D . Application of the American Pain Society quality assurance standards . Pain \n1994 ;56 (3 ):299 –306 . 10.1016/0304-3959(94)90168-6 \n8022623 \n35 Schwenkglenks M , Gerbershagen HJ , Taylor RS \net al\nCorrelates of satisfaction with pain treatment in the acute postoperative period: Results from the international PAIN OUT registry . Pain \n2014 ;155 (7 ):1401 –1411 . 10.1016/j.pain.2014.04.021 \n24785269 \n36 Ward SE , Gordon DB . Patient satisfaction and pain severity as outcomes in pain management: a longitudinal view of one setting's experience . The Journal of Pain and Symptom Management \n1996 ;11 (4 ):242 –251 . 10.1016/0885-3924(95)00190-5 \n8869459\n\n",
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"abstract": "Supraventricular tachycardia is a common arrhythmia in pregnancy. During labor and delivery, neuraxial analgesia is important to prevent arrhythmia recurrence. We present the case of a 27-year-old gravida 2 para 1 woman at 35 weeks' gestation presenting with supraventricular tachycardia that converted to normal sinus rhythm with adenosine. To prevent recurrence of the arrhythmia, an early epidural was provided during labor to minimize catecholamine release.",
"affiliations": "Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.",
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{
"abstract": "Olanzapine is a second-generation antipsychotic (SGA) that has been shown to promote disease remission in persons with treatment-resistant depression when used in combination with fluoxetine. However, tolerability of treatment augmentation with SGAs may be limited because of common adverse effects, such as weight gain, hypertriglyceridemia, and elevated glucose. Data exist pertaining to rare localized edematous reactions or angioedema with use of SGAs, but diffuse whole-body edema has yet to be documented. A 47-year-old white female with treatment-resistant depression presented with a 5-day history of weight gain and swelling of her torso and extremities. Five days prior, she had initiated olanzapine/fluoxetine 6/50 mg daily following failure of fluoxetine 40 mg daily monotherapy. The patient was noted to have gained 3.6 kg since her last appointment and exhibited profuse pitting edema on her forearms, lower limbs, hands, and chest. Olanzapine/fluoxetine was discontinued and the patient was prescribed a 3-day course of a loop diuretic for symptomatic management. A follow-up visit 5 days later noted complete resolution of symptoms. Because of the temporal relationship of symptoms with initiation of olanzapine, we recommend monitoring for edema with initiation and/or titration of therapy.",
"affiliations": "Clinical Pharmacist Specialist, The Robert J. Dole Veteran Affairs Medical Center, Wichita, Kansas; previously: The University of Texas at Tyler, Ben and Maytee Fisch College of Pharmacy, Tyler, Texas, elizabeth.cook1@va.gov.;Clinical Pharmacist Specialist, The Robert J. Dole Veteran Affairs Medical Center, Wichita, Kansas; previously: The University of Texas at Tyler, Ben and Maytee Fisch College of Pharmacy, Tyler, Texas.;PGY-1 Pharmacy Resident, Christus Trinity Mother Frances Hospital, Tyler, Texas; previously: The University of Texas at Tyler, Ben and Maytee Fisch College of Pharmacy, Tyler, Texas.",
"authors": "Cook|Elizabeth A|EA|https://orcid.org/0000-0002-3496-9587;Shipman|Denver|D|https://orcid.org/0000-0002-6899-7084;Fowler|Tyler Gipson|TG|https://orcid.org/0000-0002-1229-251X",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.9740/mhc.2020.09.291",
"fulltext": "\n==== Front\nMent Health Clin\nMent Health Clin\nmhcl\nThe Mental Health Clinician\n2168-9709 College of Psychiatric & Neurologic Pharmacists \n\n10.9740/mhc.2020.09.291\nMHC-D-20-00024\nCase Report\nWhole-body edema with olanzapine: A case report and literature review\nhttps://orcid.org/0000-0002-3496-9587Cook Elizabeth A. PharmD, AE-C, BCACP, CDE1 https://orcid.org/0000-0002-6899-7084Shipman Denver PharmD, BCPP2 https://orcid.org/0000-0002-1229-251XFowler Tyler Gipson PharmD3 \n1 Clinical Pharmacist Specialist, The Robert J. Dole Veteran Affairs Medical Center, Wichita, Kansas; previously: The University of Texas at Tyler, Ben and Maytee Fisch College of Pharmacy, Tyler, Texas, elizabeth.cook1@va.gov\n\n\n2 Clinical Pharmacist Specialist, The Robert J. Dole Veteran Affairs Medical Center, Wichita, Kansas; previously: The University of Texas at Tyler, Ben and Maytee Fisch College of Pharmacy, Tyler, Texas\n\n\n3 PGY-1 Pharmacy Resident, Christus Trinity Mother Frances Hospital, Tyler, Texas; previously: The University of Texas at Tyler, Ben and Maytee Fisch College of Pharmacy, Tyler, Texas\n\nDisclosures: The authors have no actual or potential conflicts of interest to disclose.\n\n\n30 9 2020 \n9 2020 \n10 5 291 295\n© 2020 CPNP. The Mental Health Clinician is a publication of the College of Psychiatric and Neurologic Pharmacists.2020This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Olanzapine is a second-generation antipsychotic (SGA) that has been shown to promote disease remission in persons with treatment-resistant depression when used in combination with fluoxetine. However, tolerability of treatment augmentation with SGAs may be limited because of common adverse effects, such as weight gain, hypertriglyceridemia, and elevated glucose. Data exist pertaining to rare localized edematous reactions or angioedema with use of SGAs, but diffuse whole-body edema has yet to be documented. A 47-year-old white female with treatment-resistant depression presented with a 5-day history of weight gain and swelling of her torso and extremities. Five days prior, she had initiated olanzapine/fluoxetine 6/50 mg daily following failure of fluoxetine 40 mg daily monotherapy. The patient was noted to have gained 3.6 kg since her last appointment and exhibited profuse pitting edema on her forearms, lower limbs, hands, and chest. Olanzapine/fluoxetine was discontinued and the patient was prescribed a 3-day course of a loop diuretic for symptomatic management. A follow-up visit 5 days later noted complete resolution of symptoms. Because of the temporal relationship of symptoms with initiation of olanzapine, we recommend monitoring for edema with initiation and/or titration of therapy.\n\nolanzapinesecond-generation antipsychoticatypical antipsychoticedema\n==== Body\nBackground\nAntidepressants, such as selective serotonin reuptake inhibitors (SSRIs), are first-line agents for the treatment of major depressive disorder, as substantiated by robust efficacy and safety data from clinical trials.1,2 However, it is estimated that 25% to 65% of individuals who fail to respond to initial therapy with an SSRI will respond to a second, different course of treatment.3 The commonly accepted definition of treatment-resistant depression (TRD) is the failure to achieve a clinically meaningful response after a trial of 2 or more antidepressant agents, prescribed in adequate doses, for an adequate treatment duration and affirmation of treatment adherence.1,4 In persons with TRD who exhibit an insufficient response to monotherapy with an antidepressant, a variety of augmentation strategies are available, including the adjunctive use of second-generation antipsychotics (SGAs).1-3\n\nThe SGA and SSRI combination product, olanzapine/fluoxetine, was approved by the US Food and Drug Administration in 2003 for the management of TRD, as well as acute depressive episodes associated with bipolar 1 disorder.5 A Cochrane systematic review and meta-analysis6 analyzed the efficacy and safety of augmentation therapy with the SGAs aripiprazole, olanzapine, quetiapine, or risperidone, compared to placebo in individuals with major depressive disorder or dysthymia. Augmentation of antidepressant therapy with olanzapine compared with placebo resulted in a reduction in depressive symptoms and improvement in disease remission, but a large number of individuals discontinued therapy because of unacceptable side effects, such as weight gain, sedation, and prolactin elevation.6\n\nSedation, metabolic, and anticholinergic side effects are common with use of olanzapine. Although far less common, edema with olanzapine was noted to have occurred at a rate of approximately 15% in clinical trials.5,7 However, no reports exist to date that detail whole-body edema with the use of olanzapine. This case report describes a patient who exhibited diffuse edema and rapid weight gain, attributed to fluid retention, following initiation of olanzapine for the management of treatment-resistant depression.\n\nCase Report\nA 47-year-old white female presented to a primary care clinic with the chief complaints of weight gain and edema, which had progressed in severity during a 5-day period. The patient's past medical history was significant for generalized anxiety disorder, attention deficit hyperactivity disorder, insomnia, major depressive disorder, and nicotine dependence. She had no previous diagnoses affiliated with cardiac, hepatic, or renal dysfunction. Documented medication allergies included pruritus with exposure to penicillin and meloxicam. Her home medication regimen was composed of clonazepam, lisdexamfetamine, olanzapine/fluoxetine, and zolpidem, and she appeared to be adherent to all medication based on refill data. Medications that had previously failed to result in remission of her depressive symptoms included amitriptyline, bupropion extended release, citalopram, fluoxetine, and venlafaxine extended release, all of which were titrated to adequate doses, trialed for adequate durations, and appeared to have been taken in an adherent manner by the patient. Her only recent medication change was discontinuation of fluoxetine 40 mg by mouth daily and the initiation of the combination product, olanzapine/fluoxetine 6 mg/50 mg by mouth once daily, for TRD. Olanzapine/fluoxetine had been dispensed to the patient by the clinic pharmacy the same day of her appointment but was self-initiated by the patient 2 days after she had discontinued her fluoxetine monotherapy.\n\nThe patient presented to clinic for evaluation a total of 5 days after initiating olanzapine/fluoxetine. The patient stated that in the 3 days following initiation of olanzapine/fluoxetine, and 2 days prior to her presenting to clinic, she began to experience paresthesias in her oral cavity and lips. She denied symptoms indicative of angioedema, such as swelling of the tongue, throat, and other mucosal membranes. Additionally, she noticed that the sleeves of her shirts and jackets, as well as the legs of her pants, had become tight and uncomfortable due to swelling. These symptoms progressed in severity during the next 2 days, with the patient becoming unable to dress herself in long-sleeved shirts or pants without extreme discomfort, resulting in her scheduling an urgent appointment in clinic.\n\nVital signs were within normal limits, with the exception of the patient's weight, which increased by 3.6 kg (85.45-89.05 kg), and systolic blood pressure, which increased from 122/102 mm Hg to 140/80 mm Hg, from her last clinic appointment 1 week prior. A comprehensive physical exam noted no evidence of erythema, rash, or scaling on the patient's skin. However, the patient exhibited bilateral grade 3 pitting edema (noticeably swollen extremities, skin indentation of 13 mm with digital pressure, and indentation returning to normal in approximately 1 minute) on her forearms, lower limbs, feet, hands, and feet, as well as grade 2 pitting edema (no marked visual changes to skin, indentation of 6 mm with digital pressure, and indentation returning to normal within 15 seconds) on her chest.8 The patient's fingers and toes were visibly swollen, with blanching on the distal, middle, and proximal interphalangeal joints of the hands and feet. Dorsalis pedis, posterior tibial, and radial pulses were evident bilaterally, and there were no apparent changes in skin temperature.\n\nBased on physical findings and onset of symptoms, in conjunction with initiation of olanzapine, the provider deemed this to be a drug-induced reaction until further laboratory evidence was obtained. Olanzapine/fluoxetine was discontinued in clinic, and a 3-day course of furosemide 20 mg by mouth daily was initiated for symptomatic relief. A hepatic function panel, complete metabolic panel, thyroid panel, and complete blood count were obtained prior to the patient leaving the clinic. All laboratory values returned within normal limits, with the exception of her white blood cells, which were marginally elevated at 12.2 U/L (institutional reference range, 4.0-11.0 U/L). On subsequent follow-up, 5 days after the urgent encounter, assessment of edema using the digital pressure method on arms, legs, and chest was unremarkable, and the patient reported complete resolution of oral paresthesias. Additionally, the patient's weight was reduced to 85.6 kg at this follow-up visit. Therapy with furosemide was discontinued, and olanzapine was noted as a medication intolerance on the patient's electronic medical record.\n\nLiterature Search\nA literature search was conducted on PubMed through March 2020 using the following key words: antipsychotic edema, olanzapine edema, and olanzapine/fluoxetine edema. Results published in English were included. The initial search of antipsychotic edema yielded 458 articles. Of the initial 458 articles, a subsequent search of olanzapine edema yielded 33 articles, of which 14 detailed edema induced by olanzapine. Zero case reports concerning edema related to the search terms olanzapine/fluoxetine edema were found.\n\nDiscussion\nOlanzapine is an SGA that antagonizes serotonin 5HT2A/2C, 5HT6, dopamine D1-4, histamine H1, and adrenergic α1 receptors. The addition of olanzapine to fluoxetine is hypothesized to enhance antidepressant effects by interacting with serotonergic, dopaminergic, and noradrenergic monoamine pathways.9 The multiple receptor subtypes targeted by olanzapine offer a variety of hypotheses as to why whole-body edema may have developed in our patient when it was added to fluoxetine. One prominent mechanism speculated to induce olanzapine-related edema pertains to α1 adrenergic receptor blockade. Antagonism of these adrenergic-receptor subtypes may result in vasodilation, decreased vascular resistance, and subsequent movement of fluid into the intravascular space.10-12 Furthermore, blockade of H1 and 5HT-2 receptors has been shown to downregulate inositol triphosphate-sensitive calcium channels to promote smooth muscle relaxation in the vasculature, resulting in subsequent edema. Such effects may also be triggered through an alternative pathway mediated by 5-HT2 receptor blockade, which can potentially increase cyclic adenosine monophosphate, inhibiting phosphorylation of myosin light chain kinase, resulting in vascular relaxation.13 It may also be postulated that dopaminergic antagonism played a role in this adverse event, because hypodopaminergic states may disrupt fluid and electrolyte balance, resulting in idiopathic edema.14,15\n\nThis case described a patient who exhibited diffuse edema following initiation of olanzapine to augment existing fluoxetine therapy. The Naranjo Adverse Drug Reaction Probability Score for this case was 7, deeming it probable that the event was attributed to the addition of olanzapine.16 The acuity of symptom onset following the initiation of olanzapine, the patient's previous tolerance of fluoxetine monotherapy, and resolution of symptoms after stopping olanzapine are strong indicators that this reaction is affiliated with olanzapine. It is unlikely that metabolic side effects, such as accumulation of adipose tissue, could have resulted in the rapid weight gain exhibited by the patient during the course of 5 days.7 Additionally, the likelihood of the patient's medications, used prior to the introduction of olanzapine, inciting edema was determined to be negligible, because she had been stabilized on them for quite some time. Furthermore, clinical trial data for clonazapam, lisdexamfetamine, and zolpidem cite that edematous reactions are only noted to occur at a less than 1% rate, reducing the likelihood of these being confounding variables.17-19 Detailed clinical and laboratory assessments failed to detect any other causal condition for the whole-body edema pertaining to allergic, dermatologic, cardiac, renal, hepatic, or thyroid disorders. Additionally, significant pharmacodynamic and/or pharmacokinetic drug interactions that may have incited fluid retention were not evident between olanzapine and the patient's other home medications. Peripheral or localized edematous reactions have been reported more frequently in olanzapine and olanzapine/fluoxetine groups, compared with placebo (15% vs 2%), in clinical trials.5\n\nThe available literature11,12,14,20-25 suggests this reaction may occur at any dose of olanzapine, and it may not necessarily be dose dependent in nature, as noted by the cases describing persons who experienced edema with initiation of the drug (Table). Furthermore, timing of edema onset and resolution appears to be variable, ranging from 2 days to 2 months.11,12,14,20-30 In most cases, symptom resolution occurred after withdrawal, or dose reduction, of olanzapine.11,12,14,20-30 Based on these findings, it may be reasonable to rechallenge patients with a lower dose of olanzapine that was previously tolerated. It may also be reasonable to trial augmentation of antidepressants with an alternate SGA if olanzapine at any dose was not tolerated.\n\nTABLE Case reports of olanzapine-induced edema11,12,14,20-30\n\nSourcea\tStarting Dose, mg/d\tDose Inciting Symptoms, mg/d\tCharacteristics/ Location\tOnset\tDuration\tTreatment\t\nWilliams20 (2019)\t10\t10\tAngioedema\t2 d\t7 d\tOW, antihistamine, H2 antagonist, systemic corticosteroids\t\nArslan et al26 (2019)\t10\t15\tPericardium, hands, legs, ankles\t2 d\t14 d\tOW\t\nKuppili et al27 (2018)\t5\t12.5\tLower eyelids\t2 mo\tNR\tDose reduction of olanzapine to 5 mg\t\nUmar and Abdullahai11 (2016)\t10\t20\tHands, lower limbs\t1 mo\t3 wk\tOW, loop diuretic\t\n20\t20\tLower limbs\t2 wk\t1 wk\tDose reduction of olanzapine to 10 mg\t\nMenon et al28 (2015)\t10\t12.5\tLower limbs\t7 d\tNR\tOW\t\nMalhotra and Shrivastava21 (2013)\tNR\t20\tPeriorbital region\t7 mo\t3 d\tOW\t\n15\t15\tFace, periorbital region\t1 mo\t7 d\tOW\t\nAkın et al14 (2013)\t5\t5\tFace, hands, feet\t20 d\tNR\tOW\t\nHonma et al22 (2012)\t10\t10\tAngioedema, lower limbs\t2 wk\t1 mo\tOW, antihistamine, Th2 cytokine inhibitor, glycyrrhizic acid\t\nNayak et al23 (2009)\t7.5\t7.5\tFeet\t45 d\t20 d\tOW\t\nYaluğ et al12 (2007)\t10\t10\tNR\t1 mo\t1 mo\tOW\t\n10\t10\tNR\t1 mo\t1 wk\tDose reduction of olanzapine to 5 mg\t\nZink et al24 (2007)\t5\t5\tEyelids\t1 d\t1 wk\tOW\t\nDeshauer et al25 (2006)\t2.5\t2.5\tHands, ankles\t2 d\tNR\tLoop diuretic\t\nChristensen and Honsig29 (2003)\t10\t20\tAnkles, feet\t10 d\t7 d\tOW\t\nYovtcheva et al30 (2000)\t2.5\t10\tFeet\t2 mo\t2 wk\tOW\t\nNR = not reported; OW = olanzapine withdrawal.\n\na Studies organized in reverse chronological order, with reports listed most recently at the top.\n\nSeveral case reports detailed the use of loop diuretics to facilitate more rapid relief of edematous reactions.11,25 Most cases of olanzapine-induced edema did not have evidence of an immune-mediated reaction, but in the 2 cases20,22 presenting with olanzapine-induced angioedema, immune modulation medications, such as systemic corticosteroids or antihistamines, appeared helpful in resolving symptoms. There does not appear to be a set of patient-specific characteristics, or risk factors, among these cases that would compound the likelihood of experiencing olanzapine-associated edema. The degree of variability among case presentation and symptomatic management suggests that additional research on olanzapine-associated edema is warranted to determine when intervention beyond discontinuation of the drug alone is warranted.11,12,14,20-30\n\nConclusion\nThis case describes a patient who exhibited whole-body edema and rapid weight gain following the addition of olanzapine to fluoxetine. At present, limited data exist regarding the mechanism behind such reactions to SGAs. Because of the temporal relationship of symptoms with initiation of olanzapine, we recommend monitoring for edema with initiation and/or titration of therapy.\n==== Refs\nReferences\n1 Bauer M Pfennig A Severus E Whybrow PC Angst J Möller HJ World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders World J Biol Psychiatry 2013 14 5 334 85 DOI: 10.3109/15622975.2013.804195 PubMed PMID: 23879318 23879318 \n2 Gelenberg AJ Freeman MP Markowitz JC Rosenbaum JF Thase ME Trivedi MH Practice guideline for the treatment of patients with major depressive disorder, third edition Am J Psychiatry [Internet] 2010 [cited 2020 Jul 23]; 167 10 1 152 Available from: https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf 20068118 \n3 The Management of Major Depressive Disorder Working Group VA/DoD clinical practice guideline for the management of major depressive disorder 2016 [cited 2020 Jul 23] https://www.healthquality.va.gov/guidelines/MH/mdd/VADoDMDDCPGFINAL82916.pdf \n4 Rush AJ Trivedi MH Wisniewski SR Stewart JW Nierenberg AA Thase ME Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression N Engl J Med 2006 354 12 1231 42 DOI: 10.1056/NEJMoa052963 PubMed PMID: 16554525 16554525 \n5 Symbyax® (olanzapine and fluoxetine) [package insert] Indianapolis Eli Lilly and Co 2003 2017 \n6 Komossa K Depping AM Gaudchau A Kissling W Leucht S Second-generation antipsychotics for major depressive disorder and dysthymia Cochrane Database Syst Rev 2010 12 CD008121 DOI: 10.1002/14651858.CD008121.pub2 PubMed PMID: 21154393 \n7 Zyprexa® (olanzapine) [package insert] Indianapolis Lilly USA LLC 1997 \n8 Desseilles M Witte J Chang TE Iovieno N Dording CM Ashih H Assessing the adequacy of past antidepressant trials: a clinician's guide to the antidepressant treatment response questionnaire J Clin Psychiatry 2011 72 8 1152 4 DOI: 10.4088/JCP.11ac07225 PubMed PMID: 21899818 21899818 \n9 Brodovicz KG McNaughton K Uemura N Meininger G Girman CJ Yale SH Reliability and feasibility of methods to quantitatively assess peripheral edema Clin Med Res 2009 7 1-2 21 31 DOI: 10.3121/cmr.2009.819 PubMed PMID: 19251582 PubMed Central PMCID: PMC2705274 19251582 \n10 Zyprexa® (olanzapine) [package insert] Indianapolis Eli Lilly and Co 1997 2009 \n11 Umar MU Abdullahai AT Self-limiting atypical antipsychotics-induced edema: clinical cases and systematic review Indian J Psychol Med 2016 38 3 182 8 DOI: 10.4103/0253-7176.183089 PubMed PMID: 27335511 27335511 \n12 Yaluğ İ Evren Tufan A Özten E Alemdar M Cerit C Bilateral pedal edema associated with olanzapine use in manic episode of bipolar disorder: report of two cases Prog Neuropsychopharmacol Biol Psychiatry 2007 31 7 1541 2 DOI: 10.1016/j.pnpbp.2007.06.022 PubMed PMID: 17669575 17669575 \n13 Ng B Postlethwaite A Rollnik J Peripheral oedema in patients taking olanzapine Int Clin Psychopharmacol 2003 18 1 57 9 DOI: 10.1097/00004850-200301000-00010 PubMed PMID: 12490777 12490777 \n14 Akın S Bahat G Tufan F Saka B Öztop N Erten N Olanzapine as a cause of peripheric edema in an elderly man Aging Clin Exp Res 2013 25 1 115 7 DOI: 10.1007/s40520-013-0002-4 PubMed PMID: 23740642 23740642 \n15 Kuchel O Cuche JL Buu NT Guthrie GP Jr Unger T Nowaczynski W Catecholamine excretion in “idiopathic” edema: decreased dopamine excretion, a pathogenic factor? J Clin Endocrinol Metab 1977 44 4 639 46 DOI: 10.1210/jcem-44-4-639 PubMed PMID: 849977 849977 \n16 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 45 DOI: 10.1038/clpt.1981.154 PubMed PMID: 7249508 7249508 \n17 Klonopin® (clonazepam) [package insert] San Francisco Genentech 2013 \n18 Vyvanse® (lisdexamfetamine) [package insert] Lexington (MA) Shire US Inc 2007 2017 \n19 Ambien® (zolpidem) [package insert] Bridgewater (NJ) Sanofi-Aventis US LLC 1992 2008 \n20 Williams GD Cross-reaction of angioedema with clozapine, olanzapine, and quetiapine: a case report Ment Health Clin [Internet] 2019 9 5 315 7 DOI: 10.9740/mhc.2019.09.315 PubMed PMID: 31534873 PubMed Central PMCID: PMC6728117 \n21 Malhotra M Shrivastava MK Facial edema with olanzapine Gen Hosp Psychiatry 2013 35 6 682.e7 682.e8 DOI: 10.1016/j.genhosppsych.2013.06.012 PubMed PMID: 23993413 \n22 Honma M Minami-Hori M Tsuji H Komatsu S Iizuka H Olanzapine-induced limb edema simulating episodic angioedema with eosinophilia J Dermatol 2012 39 12 1105 6 DOI: 10.1111/j.1346-8138.2012.01545.x PubMed PMID: 22452653 22452653 \n23 Nayak V Chogtu B Devaramane V Bhandary PV Pedal edema with olanzepine Indian J Pharmacol 2009 41 1 49 50 DOI: 10.4103/0253-7613.48883 PubMed PMID: 20177583 PubMed Central PMCID: PMC2825016 20177583 \n24 Zink M Kuwilsky A Knopf U Olanzapine-associated bilateral eyelid edema J Clin Psychopharmacol 2007 27 2 214 5 DOI: 10.1097/01.jcp.0000264968.69958.28 PubMed PMID: 17414232 17414232 \n25 Deshauer D Erwin L Karagianis J Case report: edema related to olanzapine therapy Can Fam Physician 2006 52 5 620 1 PubMed PMID: 16739836 16739836 \n26 Arslan M Bulut U Naki DD Olanzapine associated acute peripheral edema and pericardial effusion: a case report Noro Psikiyatr Ars 2019 56 1 79 81 DOI: 10.29399/npa.22860 PubMed PMID: 30911243 PubMed Central PMCID: PMC6427082 30911243 \n27 Kuppili PP Nebhinani N Jain S Singhai K Olanzapine associated palpebral edema: an uncommon adverse effect of a commonly prescribed drug Asian J Psychiatr 2018 36 60 1 DOI: 10.1016/j.ajp.2018.06.010 PubMed PMID: 29966888 29966888 \n28 Menon V Muthukrishnan V Mathan K Olanzapine-induced tender pitting pre-tibial edema J Pharmacol Pharmacother 2015 6 2 114 5 DOI: 10.4103/0976-500X.155494 PubMed PMID: 25969664 PubMed Central PMCID: PMC4419245 25969664 \n29 Christensen RC Honsig T Olanzapine-associated bilateral pedal edema J Clin Psychiatry 2003 64 8 972 DOI: 10.4088/jcp.v64n0819d PubMed PMID: 12927019 12927019 \n30 Yovtcheva SP Yazel JJ Olanzapine-induced bilateral pedal edema: a case report Gen Hosp Psychiatry 2000 22 4 290 1 DOI: 10.1016/s0163-8343(00)00084-0 PubMed PMID: 11023366 11023366\n\n",
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] |
{
"abstract": "BACKGROUND\nMultidrug regimens are active against advanced colorectal cancer (ACRC). However, the increased toxicity requires the use of biomarkers to select the patients who will derive the most benefit. We assessed circulating tumor cells (CTCs) as a prognostic biomarker in patients treated with a 4-drug regimen.\n\n\nMETHODS\nA single-arm phase II trial (Erbitux Study of CPT11, Oxaliplatin, UFToral Targeted-therapy [eSCOUT]) was undertaken in patients with previously untreated KRAS wild-type ACRC using a regimen of irinotecan, oxaliplatin, and tegafur-uracil with leucovorin and cetuximab. Baseline CTCs were enumerated using CellSearch. The endpoints were an objective response rate (ORR) and overall survival (OS). We modeled our results and compared them with those modeled for the capecitabine, oxaliplatin, bevacizumab +/- cetuximab (CAIRO2) trial, stratifying patients a priori into low (< 3) and high (≥ 3) CTC groups.\n\n\nRESULTS\nFor 48 eligible patients, the best ORR from the 4-drug regimen was 71%, with a disease control rate of 98%. The median OS for patients with a high and low CTC count was 18.7 and 22.3 months (log-rank test, P = .038), respectively. In our modeled data, for patients with a low CTC count, no differences were found between the median OS in the eSCOUT trial and that in the CAIRO2 trial (22.2 vs. 22.0 months). However, for the high CTC group, a clinically relevant improvement was seen in median OS (eSCOUT vs. CAIRO2, 18.7 vs. 13.7 months; P = .001).\n\n\nCONCLUSIONS\nThese data are hypothesis generating-for patients with ACRC, stratification by CTC count can identify those who might benefit the most from an intensive 4-drug regimen, avoiding high-toxicity regimens in low CTC groups. This hypothesis warrants validation in a phase III biomarker-driven trial.",
"affiliations": "Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK; Institute of Cancer Sciences, University of Manchester, Manchester, UK.;Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK; Institute of Cancer Sciences, University of Manchester, Manchester, UK.;Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK.;North Wales Cancer Treatment Centre, Wales, UK.;The Royal Marsden Hospital, London, UK.;The Christie NHS Foundation Trust, Manchester, UK.;The Christie NHS Foundation Trust, Manchester, UK; Institute of Cancer Sciences, University of Manchester, Manchester, UK.;Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK.;The Christie NHS Foundation Trust, Manchester, UK.;The Christie NHS Foundation Trust, Manchester, UK.;The Christie NHS Foundation Trust, Manchester, UK. Electronic address: mark.saunders@christie.nhs.uk.;Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK.",
"authors": "Krebs|Matthew G|MG|;Renehan|Andrew G|AG|;Backen|Alison|A|;Gollins|Simon|S|;Chau|Ian|I|;Hasan|Jurjees|J|;Valle|Juan W|JW|;Morris|Karen|K|;Beech|Janette|J|;Ashcroft|Linda|L|;Saunders|Mark P|MP|;Dive|Caroline|C|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000068258:Bevacizumab; D000069287:Capecitabine; D000077146:Irinotecan; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1533-0028",
"issue": "14(2)",
"journal": "Clinical colorectal cancer",
"keywords": "Biomarker; CellSearch; Cetuximab; Circulating tumor cells; Colorectal cancer",
"medline_ta": "Clin Colorectal Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002166:Camptothecin; D000069287:Capecitabine; D000068818:Cetuximab; D015179:Colorectal Neoplasms; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate",
"nlm_unique_id": "101120693",
"other_id": null,
"pages": "115-22.e1-2",
"pmc": null,
"pmid": "25680623",
"pubdate": "2015-06",
"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": null,
"title": "Circulating Tumor Cell Enumeration in a Phase II Trial of a Four-Drug Regimen in Advanced Colorectal Cancer.",
"title_normalized": "circulating tumor cell enumeration in a phase ii trial of a four drug regimen in advanced colorectal cancer"
} | [
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{
"abstract": "Dermatopathic lymphadenopathy (DL) is well-known in inflammatory skin disease; however, it has not been reported in graft-versus-host disease (GvHD) after allogeneic stem cell transplantation. Here, we report 2 cases of DL in patients with acute GvHD of the skin and demonstrate complete donor chimerism of Langerhans cells within the lymph nodes.",
"affiliations": "Institute of Pathology, University Medical Centre Mainz, Mainz, Germany.;Institute of Pathology, University Medical Centre Mainz, Mainz, Germany.;Institute of Pathology, University of Würzburg and Comprehensive Cancer Centre, Würzburg, Germany.;Institute of Pathology, University Medical Centre Regensburg, Regensburg, Germany.;Department of Internal Medicine III, University Cancer Center, University Medical Centre Mainz, Mainz, Germany.",
"authors": "Kreft|Andreas|A|http://orcid.org/0000-0002-8644-6390;Krümpelmann|Kristina|K|;Rosenwald|Andreas|A|;Hollemann|David|D|;Wagner-Drouet|Eva Maria|EM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/ejh.12968",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "99(6)",
"journal": "European journal of haematology",
"keywords": "Langerhans cell; dermatopathic lymphadenopathy; graft-versus-host disease",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007801:Langerhans Cells; D000072281:Lymphadenopathy; D016399:Lymphoma, T-Cell; D008297:Male; D012871:Skin Diseases; D018183:Transplantation Chimera",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "582-585",
"pmc": null,
"pmid": "28888027",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Dermatopathic lymphadenopathy with Langerhans cell chimerism in graft-versus-host disease of the skin.",
"title_normalized": "dermatopathic lymphadenopathy with langerhans cell chimerism in graft versus host disease of the skin"
} | [
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{
"abstract": "Multivisceral transplantation (transplantation of the stomach, intestine, liver, and pancreas) is usually undertaken as a semi-elective procedure after thorough assessment in patients who have intestinal failure with cirrhosis, cirrhosis with portomesenteric venous thrombosis, or tumors such as desmoids involving the liver and mesentery.\n\n\n\nData were collected prospectively from the time of referral and held in a central database. We used it to report the first cases of urgent multivisceral transplantation (MVT) in patients with widespread splanchnic ischemia (occlusion of the celiac axis and superior mesenteric artery) resulting in small bowel infarction and hepatic failure.\n\n\n\nThree women (ages 33, 48, and 50 years) were referred to our center with superior mesenteric artery and celiac axis occlusion. All other modes of treatment had been considered and/or attempted. After transfer to our institution, all patients were assessed, urgently listed, and underwent transplantation in 10, 7, and 5 days. Two patients are still alive after 2 years and 1 died at 8 months from multiorgan failure due to infections and graft vs host disease.\n\n\n\nTreatment options for patients presenting with widespread splanchnic ischemia with hepatic and intestinal failure/infarction were previously limited to salvage surgery and attempted revascularization. In situations in which these failed, the only previous option would have been palliation. In selected cases, we propose that urgent multivisceral transplantation should be considered as a life-saving treatment. This represents a previously unreported indication for MVT.",
"affiliations": "Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom. Electronic address: Lisa.sharkey@addenbrookes.nhs.uk.;Department of Transplant Surgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.;Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.;Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.;Department of Surgery, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.;Department of Transplant Surgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.;Department of Surgery, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.",
"authors": "Sharkey|Lisa M|LM|;Russell|Neil K|NK|;Rutter|Charlotte S|CS|;Middleton|Stephen J|SJ|;Bradley|J Andrew|JA|;Jamieson|Neville V|NV|;Butler|Andrew J|AJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1072-7515",
"issue": "222(5)",
"journal": "Journal of the American College of Surgeons",
"keywords": null,
"medline_ta": "J Am Coll Surg",
"mesh_terms": "D000328:Adult; D001157:Arterial Occlusive Diseases; D002445:Celiac Artery; D005260:Female; D006801:Humans; D007421:Intestine, Small; D007511:Ischemia; D017093:Liver Failure; D016031:Liver Transplantation; D017538:Mesenteric Artery, Superior; D008875:Middle Aged; D016377:Organ Transplantation; D016035:Pancreas Transplantation; D013152:Splanchnic Circulation; D013270:Stomach; D013997:Time Factors; D014781:Viscera",
"nlm_unique_id": "9431305",
"other_id": null,
"pages": "760-5",
"pmc": null,
"pmid": "27113513",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Urgent Multivisceral Transplantation for Widespread Splanchnic Ischemia.",
"title_normalized": "urgent multivisceral transplantation for widespread splanchnic ischemia"
} | [
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{
"abstract": "Objective: To explore the efficacies of regimens of three-drug induction therapy (ATRA+ATO+anthracyclines) versus two-drug induction therapy (ATRA+ATO) in patients with acute promyelocytic leukemia (APL). Methods: Of 184 patients diagnosed with APL from January 2009 to March 2016, 58 patients underwent three-drug induction therapy, while the rest were treated with two-drug induction therapy. Three-drug induction therapy was of ATRA (20 mg·m(-2)·d(-1), d(1-28)) + ATO (0.16 mg·kg(-1)·d(-1), d(1-28)) + Idarubicin (8 mg·m(-2)·d(-1), d(3-5)) /daunorubicin (40 mg·m(-2)·d(-1), d(3-5)) , while two-drug induction therapy ATRA+ATO with the same doses and methods as above. Of 184 cases, 69 cases accompanied with WBC counts>10×10(9)/L, 115 cases with WBC counts≤10×10(9)/L at onset. Results: ①Short-term efficacy: After one cycle induction therapy, the rates of hematologic remission, genetic remission, molecular remission and induced differentiation syndrome (DS) in three-drug regimen group were 98.3%, 87.9%, 72.4% and 0 respectively, while those in two-drug regimen group were 87.3%, 65.9%, 51.6% and 12.7% respectively. In patients with WBC >10×10(9)/L, DS rate and early mortality in three-drug regimen group were lower than in two-drug regimen group (0 vs 15.6%, 4.2% vs 15.6%, respectively). In patients with WBC≤10×10(9)/L, DS rate in three-drug regimen group was also lower than in two-drug regimen group (0 vs 12.3%) , but there were no statistical differences in terms of relapse and early mortality. ② Long-term efficacy: The relapse rate, overall survival (OS) and disease free survival (DFS) in three-drug regimen group were 0, 98.5%, 96.6% respectively, while those in two-drug regimen group were 8.6%, 86.5% and 84.1% respectively; the advantages of three-drug over two-drug regimen, especially in cases of WBC >10×10(9)/L were observed. ③ Side effects: the incidences of gastrointestinal reaction, liver dysfunction, myocardial damage and headache in three-drug regimen group hardly increased. Conclusion: The efficacies of three-drug induction therapy were superior to two-drug one.",
"affiliations": "Department of Hematology, Henan Provincial People's Hospital, Zhengzhou 450003, China.",
"authors": "Ma|R J|RJ|;Zhu|Z M|ZM|;Yuan|X L|XL|;Jiang|L|L|;Yang|S W|SW|;Yang|J|J|;Guo|J M|JM|;Zhang|L|L|;Lei|P C|PC|;Wang|Z|Z|;Zang|Y Z|YZ|;Chen|Y Q|YQ|;Wang|T B|TB|;Kong|D|D|;Sun|K|K|;Zhang|Y|Y|",
"chemical_list": "D018943:Anthracyclines; D014212:Tretinoin; D015255:Idarubicin; D003630:Daunorubicin",
"country": "China",
"delete": false,
"doi": "10.3760/cma.j.issn.0253-2727.2017.06.011",
"fulltext": "\n==== Front\nZhonghua Xue Ye Xue Za Zhi\nZhonghua Xue Ye Xue Za Zhi\nCJH\nChinese Journal of Hematology\n0253-2727 2707-9740 Editorial office of Chinese Journal of Hematology No. 288, Nanjing road, Heping district, Tianjin \n\n28655097\ncjh-38-06-523\n10.3760/cma.j.issn.0253-2727.2017.06.011\n论著\n全反式维甲酸、砷剂联合蒽环类药物诱导方案治疗急性早幼粒细胞白血病的疗效分析\nEfficacy of combination of ATRA, ATO and anthracyclines induction therapy in patients with acute promyelocytic leukemia 马 荣军 Ma Rongjun 朱 尊民 Zhu Zunmin 袁 晓莉 Yuan Xiaoli 姜 丽 Jiang Li 杨 世伟 Yang Shiwei 杨 靖 Yang Jing 郭 建民 Guo Jianmin 张 琳 Zhang Lin 雷 平冲 Lei Pingchong 王 臻 Wang Zhen 臧 玉柱 Zang Yuzhu 陈 玉清 Chen Yuqing 王 同保 Wang Tongbao 孔 黛 Kong Dai 孙 恺 Sun Kai 张 茵 Zhang Yin 450003 郑州，河南省人民医院血液科Department of Hematology, Henan Provincial People's Hospital, Zhengzhou 450003, China\n王 叶青 通信作者：朱尊民(Zhu Zunmin)，Email：zhuzm1964@163.com\n6 2017 \n38 6 523 527\n25 10 2016 2017年版权归中华医学会所有Copyright © 2017 by Chinese Medical Association2017This work is licensed under a Creative Commons Attribution 3.0 License (CC-BY-NC). The Copyright own by Publisher. Without authorization, shall not reprint, except this publication article, shall not use this publication format design. Unless otherwise stated, all articles published in this journal do not represent the views of the Chinese Medical Association or the editorial board of this journal.目的\n比较全反式维甲酸（ATRA）、三氧化二砷（ATO）联合蒽环类药物三药诱导方案与ATRA联合ATO双药诱导方案治疗急性早幼粒细胞白血病（APL）的疗效。\n\n方法\n2009年1月至2016年3月确诊并治疗的APL患者184例，随机分为三药诱导组（58例）和双药诱导组（126例）。三药诱导方案为ATRA 20 mg·m−2·d−1，第1~28天；ATO 0.16 mg·kg−1·d−1，第1~28天；蒽环类药物去甲氧柔红霉素8 mg·m−2·d−1或柔红霉素40 mg·m−2·d−1，第3~5天。双药诱导方案为ATRA联合ATO，剂量用法同上。184例患者中WBC>10×109/L者69例，WBC≤10×109/L者115例。\n\n结果\n①近期疗效：三药诱导组1个疗程的血液学缓解率、遗传学缓解率、分子学缓解率及诱导分化综合征发生率分别为98.3%、87.9%、72.4%和0，双药诱导组分别为87.3%、65.9%、51.6%和12.7%，差异均有统计学意义（P值分别为0.017、0.002、0.008、0.005）；在WBC>10×109/L的患者中，三药诱导组诱导分化综合征的发生率及早期病死率低于双药诱导组（0对15.6%，P=0.042；4.2%对15.6%，P=0.246）；在WBC≤10×109/L的患者中，三药诱导组诱导分化综合征的发生率也低于双药诱导组（0对12.3%，P=0.032），但缓解率及早期病死率两组差异无统计学意义（P值均>0.05）。②远期疗效：三药诱导组的复发率、总生存率及无病生存率分别为0、98.5%、96.6%，双药诱导组分别为8.6%、86.5%、84.1%，差异均有统计学意义（P值分别为0.013、0.018、0.019）；尤其是WBC>10×109/L的患者，三药诱导组优势更加明显。③不良反应：三药诱导组的胃肠道反应、肝功能损害、心肌损伤及头痛的发生率未见明显增加。\n\n结论\n在APL的诱导治疗中，三药诱导方案的疗效优于双药诱导方案。\n\nObjective\nTo explore the efficacies of regimens of three-drug induction therapy (ATRA+ATO+anthracyclines) versus two-drug induction therapy (ATRA+ATO) in patients with acute promyelocytic leukemia (APL).\n\nMethods\nOf 184 patients diagnosed with APL from January 2009 to March 2016, 58 patients underwent three-drug induction therapy, while the rest were treated with two-drug induction therapy. Three-drug induction therapy was of ATRA (20 mg·m−2·d−1, d1–28) + ATO (0.16 mg·kg−1·d−1, d1–28) + Idarubicin (8 mg·m−2·d−1, d3–5) /daunorubicin (40 mg·m−2·d−1, d3–5), while two-drug induction therapy ATRA+ATO with the same doses and methods as above. Of 184 cases, 69 cases accompanied with WBC counts>10×109/L, 115 cases with WBC counts≤10×109/L at onset.\n\nResults\n①Short-term efficacy: After one cycle induction therapy, the rates of hematologic remission, genetic remission, molecular remission and induced differentiation syndrome (DS) in three-drug regimen group were 98.3%, 87.9%, 72.4% and 0 respectively, while those in two-drug regimen group were 87.3%, 65.9%, 51.6% and 12.7% respectively. In patients with WBC >10×109/L, DS rate and early mortality in three-drug regimen group were lower than in two-drug regimen group (0 vs 15.6%, 4.2% vs 15.6%, respectively). In patients with WBC≤10×109/L, DS rate in three-drug regimen group was also lower than in two-drug regimen group (0 vs 12.3%), but there were no statistical differences in terms of relapse and early mortality. ②Long-term efficacy: The relapse rate, overall survival (OS) and disease free survival (DFS) in three-drug regimen group were 0, 98.5%, 96.6% respectively, while those in two-drug regimen group were 8.6%, 86.5% and 84.1% respectively; the advantages of three-drug over two-drug regimen, especially in cases of WBC >10×109/L were observed. ③Side effects: the incidences of gastrointestinal reaction, liver dysfunction, myocardial damage and headache in three-drug regimen group hardly increased.\n\nConclusion\nThe efficacies of three-drug induction therapy were superior to two-drug one.\n\n白血病，早幼粒细胞，急性诱导治疗抗肿瘤联合化疗方案Leukemia, promyelocyte, acuteInduction therapyAntineoplastic combined chemoerapy protocols\n==== Body\n随着全反式维甲酸（ATRA）及三氧化二砷（ATO）在急性早幼粒细胞白血病（APL）中的应用，APL已经成为预后最好的白血病亚型[1]。虽然其完全缓解（CR）率达90%~95%，5年无病生存（DFS）率达76%~88%[1]–[4]，但仍有5%~10%的患者早期死亡，13%~31%的患者复发[2],[4]–[6]。能否降低APL的早期病死率及复发率是目前探讨的热点。为此我们比较分析了ATRA、ATO联合蒽环类药物三药诱导方案与ATRA联合ATO双药诱导方案治疗初诊APL患者的疗效，现报告如下。\n\n病例与方法\n1. 病例：2009年1月至2016年3月在我院首次确诊并治疗的184例APL患者，男103例，女81例，中位年龄35（12~65）岁，初诊时WBC>10×109/L 69例，WBC≤10×109/L 115例。应用抽签法，按照1∶2的比例随机分为三药诱导组和双药诱导组。\n\n2. 入组及排除标准：入组标准为同时满足以下三个条件：①符合WHO（2008）MICM分型诊断标准；②首次确诊为APL；③年龄在12~65岁。\n\n排除标准为出现以下任意一种情况：①诱导治疗3 d内死亡或终止治疗者；②对ARTA、ATO或蒽环类药物不耐受者；③伴严重的心肺功能不全或Ⅳ级高血压病者；④伴有第二肿瘤的患者。\n\n3. 治疗方案：诱导治疗：三药诱导方案为ATRA 20 mg·m−2·d−1，第1~28天；ATO 0.16 mg·kg−1·d−1，第1~28天；蒽环类药物去甲氧柔红霉素（IDA）8 mg·m−2·d−1或柔红霉素（DNR）40 mg·m−2·d−1，第3~5天。双诱导方案为ATRA联合ATO，剂量方法同上。缓解后治疗：蒽环类药物（IDA 10 mg·m−2·d−1×3 d或DNR 40 mg·m−2·d−1×3 d）×4个疗程，期间交替ATRA（20 mg·m−2·d−1×20 d）或ATO（0.16 mg·kg−1·d−1×20 d），各疗程之间间歇20 d。常规药物预防中枢神经系统白血病（CNSL）。\n\n4. 疗效评价：参考文献[7]进行疗效评价，早期死亡定义为自诱导治疗3 d后至诱导治疗结束前任何原因引起的死亡事件。\n\n5. 随访：电话随访至2016年5月31日，中位随访时间39（2~80）个月。\n\n6. 统计学处理：应用SPSS17.0软件进行统计学分析，符合正态分布的计量资料数据以x±s表示，两组间均数比较采用t检验，非正态分布的计量资料数据以M（范围）表示，两组比较采用秩和检验，两组间率的比较采用卡方检验或Fisher确切概率检验，总生存（OS）、DFS采用Kaplan-Meier法分析并进行Breslow（B）检验。全部统计方法均采用双侧检验，P<0.05为差异有统计学意义。\n\n结果\n1. 患者基本情况：三药诱导组58例，双药诱导组126例，两组患者的主要临床和实验室特征见表1，差异均无统计学意义（P值均>0.05）。\n\n表1 三药诱导组与双药诱导组基线指标的比较\n基线指标\t例数\t性别（例，男/女）\t年龄［岁，M（范围）］\tWBC分层（例，高危/中低危）\tFig<2.0 g/L［例(%)］\t\n三药诱导组\t58\t33/25\t37(12～63)\t24/34\t38(65.5)\t\n双药诱导组\t126\t70/56\t35(12～65)\t45/81\t87(69.0)\t\n\t\n统计量\t\t0.029\t−0.121a\t0.544\t0.227\t\nP值\t\t0.865\t0.904\t0.461\t0.634\t\n注：高危患者为WBC>10×109/L者，中低危患者为WBC≤10×109/L者；Fig：纤维蛋白原。统计量中a为u值，余均为χ2值\n\n2. 近期疗效：184例患者1个疗程的血液学缓解率为90.8%，遗传学缓解率为72.8%，分子学缓解率为58.2%，诱导分化综合征的发生率为8.7%，早期病死率为6.0%。\n\n两组患者的近期疗效详见表2。三药诱导组的血液学缓解率、遗传学缓解率、分子学缓解率均高于双药诱导组，诱导分化综合征发生率低于双药诱导组，差异均有统计学意义（P值分别为0.017、0.002、0.008、0.005）；但早期病死率两组差异无统计学意义（P=0.099）。\n\n表2 三诱导组与双诱导组的疗效比较\n组别\t例数\t血液学缓解［例(%)］\t遗传学缓解［例(%)］\t分子学缓解［例(%)］\tWBC峰值(×109/L)\t诱导分化综合征［例(%)］\t早期死亡［例(%)］\t\n三药诱导组\t58\t57(98.3)\t51(87.9)\t42(72.4)\t39.2±35.3\t0\t1(1.7)\t\n双药诱导组\t126\t110(87.3)\t83(65.9)\t65(51.6)\t53.6±44.6\t16(12.7)\t10(7.9)\t\n\t\n统计量\t\t5.704\t9.765\t7.079\t6.230a\t8.067\t2.727\t\nP值\t\t0.017\t0.002\t0.008\t0.014\t0.005\t0.099\t\n注：统计量中a为F值，余均为χ2值\n\nWBC>10×109/L患者69例，三药诱导治疗24例，双药诱导治疗45例。三药诱导组的遗传学缓解率、分子学缓解率及诱导分化综合征发生率均优于双药诱导组（83.3%对53.3%，χ2=6.097，P=0.014；70.8%对40.0%，χ2=5.953，P=0.015；0对15.6%，χ2=4.155，P=0.042）；三药诱导组的早期病死率也低于双药诱导组（4.2%对15.6%），但差异无统计学意义（P=0.246）。\n\nWBC≤10×109/L患者115例，三药诱导治疗34例，双药诱导治疗81例。三药诱导组诱导分化综合征的发生率为0，低于双药诱导组的12.3%（χ2=4.597，P=0.032）。但1个疗程的血液学缓解率、分子学缓解率及早期病死率两组之间差异无统计学意义（100.0%对92.6%，P=0.177；73.5%对58.0%，χ2=2.459，P=0.117；0对3.7%，χ2=1.293，P=0.258）。\n\n3. 远期疗效：184例患者总的复发率为5.8%、总生存（OS）率为90.2%，无病生存（DFS）率为88.0%。三药诱导组的复发率为0，OS率为98.5%，DFS率为96.6%；双药诱导组分别为8.6%、86.5%、84.1%，差异具有统计学意义（χ2值分别为6.110、5.639、5.504，P值分别为0.013、0.018、0.019）（图1A、B）。\n\n图1 三药诱导组与双药诱导组患者的总生存（A）和无病生存（B）比较\n在WBC>10×109/L患者中，三药诱导组的复发率明显低于双药诱导组（0对15.8%，χ2=4.028，P=0.045），OS及DFS率均高于双药诱导组（95.5%对75.6%，χ2=3.968，P=0.046；91.7%对71.1%，χ2=4.059，P=0.044）（图2A、B）。\n\n图2 WBC>10×109/L的患者中接受三药诱导与双药诱导者的总生存（A）和无病生存（B）比较\n在WBC≤10×109/L患者中，三药诱导与双药诱导组的复发率分别为0和5.2%，OS率分别为100%和91.4%，DFS率分别为100%和91.4%，两组之间差异无统计学意义（P值均>0.05）。\n\n4. 不良反应：主要包括口腔干燥、胃肠道反应、肝功能损害（ALT>80 U/L）、心肌损伤（CK-MB>25 U/L）、头痛等，两组的发生率见表3，多为Ⅰ~Ⅱ级，给予对症治疗后均好转。\n\n表3 接受三药诱导与双药诱导患者的不良反应发生率比较[例（%）]\n组别\t例数\t口腔干燥\t胃肠道反应\t肝功能损伤\t心肌损伤\t头痛\t\n三药诱导组\t58\t41(70.7)\t23(39.7)\t17(29.3)\t8(13.8)\t13(22.4)\t\n双药诱导组\t126\t88(69.5)\t41(32.5)\t31(24.6)\t15(11.9)\t36(28.6)\t\n\t\nχ2值\t\t0.014\t0.886\t0.456\t0.129\t0.771\t\nP值\t\t0.907\t0.346\t0.499\t0.719\t0.380\t\n讨论\nAPL是急性髓系白血病（AML）的一种特殊亚型，占AML的5%~10%[8]–[9]，其特点是染色体存在t（15;17）（q22;q21），形成PML-RARα融合基因并编码融合蛋白。PML-RARα融合蛋白与野生型RARα蛋白竞争结合RARE，抑制其下游靶基因活性，使粒细胞分化阻滞在早幼粒细胞阶段，从而导致APL的发生。在维甲酸前时代，APL被认为是最恶性的急性白血病，大多数患者在确诊几周内死亡，只有35%~45%的患者可以长生存[1]。\n\n1988年，ATRA被报道可以诱导早幼粒细胞分化成熟，对APL治疗具有里程碑意义。ATRA诱导治疗的CR率达75%~85%，5年OS率接近70%，但仍有较高早期病死率及复发率[1],[10]。1990年以后，国内外学者普遍采用ATRA联合化疗作为APL诱导的一线方案，ATRA联合蒽环类药物可以使APL的缓解率达到90%，5年OS率达到76%~84%[4],[11]。\n\n20世纪90年代后期，研究发现ATO可以通过降解PML而降解PML-RARα融合蛋白，具有促进APL细胞分化及凋亡的双重作用,可用于复发难治的APL，单药ATO的CR率达80%~90%，2年的DFS率为60%~70%[1],[12]–[13]。自2004年，国内陆续出现使用ATRA联合ATO作为APL一线诱导方案的报道，ATRA联合ATO方案的CR率为90%~95%，5年OS率达90%[3],[9],[14]–[16]。\n\n尽管ATRA联合ATO使APL成为目前治愈率最高的白血病类型，但仍有5%~10%的早期病死率及13%~31%的复发率[2],[4]–[6]，较高的早期病死率及复发率依然是影响APL疗效的主要原因。我们的研究结果显示，由ATRA、ATO联合蒽环类药物组成的三药诱导方案，缓解率接近100%，OS率为98.5%，DFS率达96.6%，早期病死率及复发率分别为1.7%和0，与澳大利亚Iland等[17]的报道一致。\n\nATRA、ATO可促进APL细胞向下游分化成熟，但也促进白细胞增殖，过高的白细胞容易导致出血及诱导分化综合征。而在高白细胞时加入细胞毒药物，可引起大量肿瘤细胞裂解，诱发DIC，导致患者死亡。三药诱导方案在治疗早期加用蒽环药物，可有效控制白细胞增殖、预防诱导分化综合征、降低早期病死率[17]。\n\n缓解后复发是影响APL预后的另一重要因素，以中枢神经系统复发最为常见[6],[18]。有学者认为，较高的中枢神经系统复发率可能与使用ATRA有关，ATRA可使黏附分子CD13、CD56表达增高，有利于白血病细胞渗透入中枢神经系统，而ARTA及ATO很难在脑脊液中达到杀灭APL细胞的有效浓度[19]–[20]。三药诱导方案含有蒽环类药物，特别是IDA，可以透过血脑屏障预防中枢神经系统复发[18]。本研究中，三药诱导组无一例患者复发，而双药诱导组有10例复发，其中7例为中枢神经系统复发。\n\n三药诱导组与双药诱导组相比，患者的胃肠道反应、肝功能损害、心肌损伤、头痛及感染的发生率未见明显增加。甚至有学者认为三药诱导方案可以适当减少ATO的剂量，减轻肝脏损伤[17]。\n\n综上所述，三药诱导方案提高了APL患者的细胞遗传学及分子遗传学缓解率，降低了早期病死率及复发率，改善了长期生存，且未明显增加不良反应的发生率，故三药诱导方案的疗效优于双药诱导方案。\n==== Refs\nReferences\n1 Wang ZY Chen Z Acute promyelocytic leukemia: from highly fatal to highly curable[J] Blood 2008 111 5 2505 2515 10.1182/blood-2007-07-102798 18299451 \n2 裴 仁治 斯 婷 陆 滢 高危急性早幼粒细胞白血病临床特征及预后分析[J] 中华血液学杂志 2016 37 5 360 365 10.3760/cma.j.issn.0253-2727.2016.05.002 \n3 袁 晓莉 朱 尊民 张 茵 不同方案诱导治疗急性早幼粒细胞白血病的疗效分析[J] 中华血液学杂志 2010 31 7 478 480 10.3760/cma.j.issn.0253-2727.2010.07.012 \n4 Adès L Guerci A Raffoux E Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience[J] Blood 2010 115 9 1690 1696 10.1182/blood-2009-07-233387 20018913 \n5 Park JH Qiao B Panageas KS Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid[J] Blood 2011 118 5 1248 1254 10.1182/blood-2011-04-346437 21653939 \n6 孙 艳花 陈 子兴 吴 伟林 110例成人中枢神经系统白血病患者临床分析[J] 中华血液学杂志 2009 30 7 480 482 10.3760/cma.j.issn.0253-2727.2009.07.015 \n7 张 之南 沈 悌 血液病诊断及疗效标准[M] 3版 北京 科学出版社 2007 131 134 \n8 Shigeto S Matsuda K Yamaguchi A Rapid diagnosis of acute promyelocytic leukemia with the PML-RARA fusion gene using a combination of droplet-reverse transcription-polymerase chain reaction and instant-quality fluorescence in situ hybridization[J] Clin Chim Acta 2016 453 38 41 10.1016/j.cca.2015.12.001 26656442 \n9 Cicconi L Lo-Coco F Current management of newly diagnosed acute promyelocytic leukemia[J] Ann Oncol 2016 27 8 1474 1481 10.1093/annonc/mdw171 27084953 \n10 Huang ME Ye YC Chen SR Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia[J] Blood 1998 72 2 567 572 \n11 Iland H Bradstock K Seymour J Results of the APML3 trial incorporating all-trans-retinoic acid and idarubicin in both induction and consolidation as initial therapy for patients with acute promyelocytic leukemia[J] Haematologica 2012 97 2 227 234 10.3324/haematol.2011.047506 21993673 \n12 Ghavamzadeh A Alimoghaddam K Ghaffari SH Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy[J] Ann Oncol 2006 17 1 131 134 10.1093/annonc/mdj019 16227315 \n13 Powell BL Moser B Stock W Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710[J] Blood 2010 116 19 3751 3757 10.1182/blood-2010-02-269621 20705755 \n14 陆 滢 李 枫林 牧 启田 全反式维甲酸联合三氧化二砷治疗177例急性早幼粒细胞白血病患者的临床观察[J] 中华血液学杂志 2015 36 5 372 377 10.3760/cma.j.issn.0253-2727.2015.05.004 \n15 de Thé H Chen Z Acute promyelocytic leukaemia: novel insights into the mechanisms of cure[J] Nat Rev Cancer 2010 10 11 775 783 10.1038/nrc2943 20966922 \n16 Ma Y Liu L Jin J All-Trans Retinoic Acid plus Arsenic Trioxide versus All-Trans Retinoic Acid plus Chemotherapy for Newly Diagnosed Acute Promyelocytic Leukemia: A Meta-Analysis[J] PLoS One 2016 11 7 e0158760 10.1371/journal.pone.0158760 27391027 \n17 Iland HJ Bradstock K Supple SG All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4)[J] Blood 2012 120 8 1570 1580; quiz 1752 10.1182/blood-2012-02-410746 22715121 \n18 杨 力 胡 彩华 董 剑明 24例急性早幼粒细胞白血病合并中枢神经系统浸润临床分析[J] 中华血液学杂志 2013 34 3 261 263 10.3760/cma.j.issn.0253-2727.2013.03.019 \n19 Sanz MA Tallman MS Lo-Coco F Practice points, consensus, and controversial issues in the management of patients with newly diagnosed acute promyelocytic leukemia[J] Oncologist 2005 10 10 806 814 10.1634/theoncologist.10-10-806 16314291 \n20 Raanani P Shpilberg O Ben-Bassat I Extramedullary disease and targeted therapies for hematological malignancies—is the association real?[J] Ann Oncol 2007 18 1 7 12 10.1093/annonc/mdl129 16790518\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-2727",
"issue": "38(6)",
"journal": "Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi",
"keywords": "Antineoplastic combined chemoerapy protocols; Induction therapy; Leukemia, promyelocyte, acute",
"medline_ta": "Zhonghua Xue Ye Xue Za Zhi",
"mesh_terms": "D018943:Anthracyclines; D000971:Antineoplastic Combined Chemotherapy Protocols; D003630:Daunorubicin; D018572:Disease-Free Survival; D006801:Humans; D015255:Idarubicin; D015473:Leukemia, Promyelocytic, Acute; D020360:Neoadjuvant Therapy; D012008:Recurrence; D012074:Remission Induction; D014212:Tretinoin",
"nlm_unique_id": "8212398",
"other_id": null,
"pages": "523-527",
"pmc": null,
"pmid": "28655097",
"pubdate": "2017-06-14",
"publication_types": "D016428:Journal Article",
"references": "23683430;26656442;27210868;27084953;16790518;22715121;20966922;16227315;21653939;27391027;20705755;21993673;16314291;3165295;20018913;26031521;18299451",
"title": "Efficacy of combination of ATRA, ATO and anthracyclines induction therapy in patients with acute promyelocytic leukemia.",
"title_normalized": "efficacy of combination of atra ato and anthracyclines induction therapy in patients with acute promyelocytic leukemia"
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"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cardiomyopathy",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Headache",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MA RJ, ZHU ZM, YUAN XL, JIANG L, YANG SW, YANG J, ET AL. [EFFICACY OF COMBINATION OF ATRA, ATO AND ANTHRACYCLINES INDUCTION THERAPY IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI. 2017?38(6):523-7.",
"literaturereference_normalized": "efficacy of combination of atra ato and anthracyclines induction therapy in patients with acute promyelocytic leukemia",
"qualification": "3",
"reportercountry": "CN"
},
"primarysourcecountry": "CN",
"receiptdate": "20180604",
"receivedate": "20180604",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 14967144,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20180711"
}
] |
{
"abstract": "The present study aimed to demonstrate the potential advantage of oral uracil-tegafur (UFUR)/leucovorin (LV) as the subsequent therapy in patients with stage III colon cancer following adjuvant LV, 5-fluorouracil and oxaliplatin (FOLFOX4) chemotherapy. Of a total 143 patients, 62 patients received only FOLFOX adjuvant chemotherapy (FOLFOX4 biweekly × 12 cycles for 6 months), and 81 patients received FOLFOXU adjuvant treatment (which consisted of FOLFOX4 biweekly × 12 cycles for 6 months followed by oral UFUR/LV for an additional 6 months). The 3-year disease-free survival (DFS) rate of the FOLFOXU group was 74.3%; which was superior to that of the FOLFOX4 group (59.9%). The average DFS time of the FOLFOXU group was superior to that of the FOLFOX4 group (P=0.003). The 5-year overall survival (OS) rate of the FOLFOXU group was 76.9%, which was also superior to that of the FOLFOX4 group (63.8%). The average OS time of patients in the FOLFOXU group was longer than that of the patients in the FOLFOX4 group (hazard ratio, 0.155; 95% confidence interval, 0.054-0.450; P=0.001). In comparison to the FOLFOX regimen, the FOLFOXU regimen achieved a more favorable response and survival time without a significant increase of toxicities in patients with stage III colon cancer as the adjuvant chemotherapy.",
"affiliations": "Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.;Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.;Division of General Surgery Medicine, Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.;Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.;Department of Public Health, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.;Division of Colorectal Surgery, Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.;Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.;Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.;Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.",
"authors": "Huang|Ming-Yii|MY|;Huang|Chun-Ming|CM|;Tsai|Hsiang-Lin|HL|;Huang|Ching-Wen|CW|;Hsieh|Hui-Min|HM|;Yeh|Yung-Sung|YS|;Wu|Jeng-Yih|JY|;Wang|Wen-Ming|WM|;Wang|Jaw-Yuan|JY|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2017.7073",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-1074",
"issue": "14(6)",
"journal": "Oncology letters",
"keywords": "FOLFOX4; FOLFOXU; disease-free survival; overall survival; stage III colon cancer",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "6754-6762",
"pmc": null,
"pmid": "29163699",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": "3286830;8831547;7931471;8831543;7388740;7964943;14233766;7847642;19451431;16314627;9716766;28179352;15987918;2300087;7922973;26360411;11098486;2202842;8831545;7715291;7828128;11496320;9216691;9440756;4850862;15175436;8410113;26335750;8612313",
"title": "Comparison of adjuvant FOLFOX4 chemotherapy and oral UFUR/LV following adjuvant FOLFOX4 chemotherapy in patients with stage III colon cancer subsequent to radical resection.",
"title_normalized": "comparison of adjuvant folfox4 chemotherapy and oral ufur lv following adjuvant folfox4 chemotherapy in patients with stage iii colon cancer subsequent to radical resection"
} | [
{
"companynumb": "TW-FRESENIUS KABI-FK201710351",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "COLON CANCER STAGE III",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LEUCOVORIN."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "078811",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "COLON CANCER STAGE III",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "85",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "OXALIPLATIN (MANUFACTURER UNKNOWN)"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "040278",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "600",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FLUOROURACIL (MANUFACTURER UNKNOWN)"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"drugadministrationroute": "040",
"drugauthorizationnumb": "040278",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "COLON CANCER STAGE III",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "400",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FLUOROURACIL (MANUFACTURER UNKNOWN)"
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Peripheral sensory neuropathy",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HUANG M,HUANG C,TSAI H,HUANG C,HSIEH H,YEH Y. COMPARISON OF ADJUVANT FOLFOX4 CHEMOTHERAPY AND ORAL UFUR/LV FOLLOWING ADJUVANT FOLFOX4 CHEMOTHERAPY IN PATIENTS WITH STAGE III COLON CANCER SUBSEQUENT TO RADICAL RESECTION. ONCOLOGY LETTERS 2017;14:6754-6762.",
"literaturereference_normalized": "comparison of adjuvant folfox4 chemotherapy and oral ufur lv following adjuvant folfox4 chemotherapy in patients with stage iii colon cancer subsequent to radical resection",
"qualification": "3",
"reportercountry": "TW"
},
"primarysourcecountry": "TW",
"receiptdate": "20171201",
"receivedate": "20171201",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14244764,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180321"
}
] |
{
"abstract": "OBJECTIVE\nWe retrospectively investigated the significance of pre-treatment interferon-gamma release (IGR) as a biomarker for predicting the efficacy of immune checkpoint inhibitor treatment (ICI-tx).\n\n\nMETHODS\nThis study included non-small-cell lung cancer patients who received ICI-tx between January 1, 2016 and April 30, 2019. IGR was measured using the positive control of an enzyme-linked immunosorbent assay. We defined the pre-treatment cut-off level of IGR as 10 IU/ml.\n\n\nRESULTS\nFifty-four patients were divided into two groups; those with an IGR ≤10 IU/ml (lower group: LG) (n=15) and those with >10 IU/ml (higher group: HG) (n=39). The time to treatment failure (TTF) in the HG was significantly longer than that in the LG. In multivariate analyses, C-reactive protein and IGR levels were significant risk factors for TTF.\n\n\nCONCLUSIONS\nPre-treatment IGR level of >10 IU/ml is recommended to identify those patients who will respond favourably to ICI-tx.",
"affiliations": "Department of Thoracic Oncology, Osaka Habikino Medical Center, Osaka, Japan hirashimat@ra.opho.jp.;Department of Thoracic Oncology, Osaka Habikino Medical Center, Osaka, Japan.;Department of Thoracic Oncology, Osaka Habikino Medical Center, Osaka, Japan.;Department of Clinical Laboratory, Osaka Habikino Medical Center, Osaka, Japan.;Department of Clinical Laboratory, Osaka Habikino Medical Center, Osaka, Japan.;Department of Clinical Laboratory, Osaka Habikino Medical Center, Osaka, Japan.;Department of Thoracic Oncology, Osaka Habikino Medical Center, Osaka, Japan.;Department of Thoracic Oncology, Osaka Habikino Medical Center, Osaka, Japan.;Department of Thoracic Oncology, Osaka Habikino Medical Center, Osaka, Japan.;Department of Clinical Pathology, Osaka Habikino Medical Center, Osaka, Japan.;Department of Clinical Laboratory, Osaka Habikino Medical Center, Osaka, Japan.;Department of Thoracic Oncology, Osaka Habikino Medical Center, Osaka, Japan.",
"authors": "Hirashima|Tomonori|T|;Kanai|Tomohiro|T|;Suzuki|Hidekazu|H|;Yoshida|Hiroko|H|;Matsusita|Akane|A|;Kawasumi|Hiromi|H|;Nasu|Shingo|S|;Tanaka|Ayako|A|;Morishita|Naoko|N|;Kawahara|Kunimitsu|K|;Tamura|Yoshitaka|Y|;Okamoto|Norio|N|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D014408:Biomarkers, Tumor; D000082082:Immune Checkpoint Inhibitors; D007371:Interferon-gamma",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.14721",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "40(12)",
"journal": "Anticancer research",
"keywords": "Interferon-gamma release; biomarker; immune checkpoint inhibitor; non-small-cell lung cancer; time to treatment failure",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007371:Interferon-gamma; D059425:Interferon-gamma Release Tests; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D017211:Treatment Failure; D016896:Treatment Outcome",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "6971-6978",
"pmc": null,
"pmid": "33288591",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Significance of Pre-treatment Interferon-gamma Release in Patients With Non-small-cell Lung Cancer Receiving Immune Checkpoint Inhibitors.",
"title_normalized": "significance of pre treatment interferon gamma release in patients with non small cell lung cancer receiving immune checkpoint inhibitors"
} | [
{
"companynumb": "JP-ROCHE-2748276",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ATEZOLIZUMAB"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "761034",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-SMALL CELL LUNG CANCER",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": null,
"drugrecurrence": null,
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"medicinalproduct": "ATEZOLIZUMAB."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
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"drugcumulativedosageunit": null,
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"drugindication": "NON-SMALL CELL LUNG CANCER",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "PEMBROLIZUMAB."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-SMALL CELL LUNG CANCER",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "NIVOLUMAB"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Renal impairment",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Interstitial lung disease",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rash",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hepatic function abnormal",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Thyroid disorder",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Colitis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Myositis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HIRASHIMA T, KANAI T, SUZUKI H, YOSHIDA H, MATSUSITA A, KAWASUMI H, NASU S, TANAKA A, MORISHITA N, KAWAHARA K, TAMURA Y AND OKAMOTO N. SIGNIFICANCE OF PRE?TREATMENT INTERFERON?GAMMA RELEASE IN PATIENTS WITH NON?SMALL?CELL LUNG CANCER RECEIVING IMMUNE CHECKPOINT INHIBITORS. ANTICANCER RESEARCH 2020 DEC?40 (12):6971?8.",
"literaturereference_normalized": "significance of pre treatment interferon gamma release in patients with non small cell lung cancer receiving immune checkpoint inhibitors",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20210120",
"receivedate": "20210120",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "3",
"safetyreportid": 18763070,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210419"
}
] |
{
"abstract": "The authors present a case-report of a 73 years old woman treated for arterial hypertension within past 15 years with diuretics (thiazides, amiloride and indapamide) and concomitantly with antidepressive trazodone. The patient developed severe osteoporosis after 6 years of such a treatment with multiple fractures even after minor trauma; during whole this period severe hyponatremia without adequate supplementation was documented. Most probably, there exists tight relationship of osteoporosis and hyponatremia in this patient - the authors discuss possible pathophysiological mechanisms at the level of renal tubules, osteoblasts and osteoclasts, hypopituitary-skeletal axis, syndrome of inadequate adiuretin secretion (SIADH) and possible influence of acid-base balance disturbances.",
"affiliations": null,
"authors": "Polák|Pavel|P|;Husa|Petr|P|;Kubešová|Hana Matějovská|HM|",
"chemical_list": "D000928:Antidepressive Agents; D004232:Diuretics",
"country": "Czech Republic",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0042-773X",
"issue": "62(2)",
"journal": "Vnitrni lekarstvi",
"keywords": null,
"medline_ta": "Vnitr Lek",
"mesh_terms": "D000368:Aged; D000928:Antidepressive Agents; D004232:Diuretics; D005260:Female; D006801:Humans; D006973:Hypertension; D007010:Hyponatremia; D010024:Osteoporosis",
"nlm_unique_id": "0413602",
"other_id": null,
"pages": "152-6",
"pmc": null,
"pmid": "27172443",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe osteoporosis - the story of chronic medication-related hyponatremia.",
"title_normalized": "severe osteoporosis the story of chronic medication related hyponatremia"
} | [
{
"companynumb": "CZ-PAR PHARMACEUTICAL COMPANIES-2016SCPR015611",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMILORIDE HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "070346",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK UNK, UNKNOWN",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HYPERTENSION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
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"medicinalproduct": "AMILORIDE HCL"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "UNSPECIFIED INGREDIENT"
},
"drugadditional": "3",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK UNK, UNKNOWN",
"drugenddate": null,
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"drugindication": "HYPERTENSION",
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"medicinalproduct": "THIAZIDES"
},
{
"actiondrug": "5",
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"activesubstancename": "TRAZODONE HYDROCHLORIDE"
},
"drugadditional": "3",
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"drugcumulativedosagenumb": null,
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"drugdosagetext": "UNK, UNKNOWN",
"drugenddate": null,
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"drugindication": "ANTIDEPRESSANT THERAPY",
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{
"abstract": "Standard-of-care for newly-diagnosed, autologous hematopoietic stem cell transplantation (auto-HCT)-eligible, multiple myeloma (MM) patients includes bortezomib, lenalidomide, and dexamethasone (VRD) induction followed by melphalan 200 mg/m2 (Mel200)-conditioned auto-HCT and lenalidomide maintenance. We completed a retrospective case series assessing outcomes of 187 MM patients who received this regimen at our institution. The 100-day non-relapse mortality incidence was zero. Before auto-HCT, 9.6 and 52.9% of patients achieved a complete response (CR) or ≥ very good partial response (VGPR), respectively. At day-100 post-transplant, 29.4 and 74.9% had achieved a CR/stringent-CR (sCR) or ≥ VGPR, respectively. At the last evaluation, 57.2% of patients had CR/sCR and 87.1% had ≥ VGPR. Median follow-up, progression-free survival (PFS), and overall survival (OS) were 63.2, 50, and 101.7 months, respectively. The 5-year PFS and OS were 43.1 and 79%. High-risk cytogenetics was associated with worse outcomes. This study illustrates that VRD induction, Mel200-conditioned auto-HCT, and lenalidomide maintenance are associated with good outcomes in MM.",
"affiliations": "Department of Stem Cell Transplantation & Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Biostatistics, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Stem Cell Transplantation & Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Stem Cell Transplantation & Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Stem Cell Transplantation & Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Stem Cell Transplantation & Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Stem Cell Transplantation & Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Stem Cell Transplantation & Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Stem Cell Transplantation & Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Stem Cell Transplantation & Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Stem Cell Transplantation & Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Division of Pathology and Laboratory Medicine, Department of Hematopathology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Lymphoma/Myeloma, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Lymphoma/Myeloma, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Lymphoma/Myeloma, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Lymphoma/Myeloma, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Ameer-ud-Din Medical College, Lahore General Hospital, Lahore, Pakistan.;Department of Stem Cell Transplantation & Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Lymphoma/Myeloma, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Lymphoma/Myeloma, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Lymphoma/Myeloma, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Stem Cell Transplantation & Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Stem Cell Transplantation & Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.;Department of Stem Cell Transplantation & Cellular Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.",
"authors": "Gaballa|Mahmoud R|MR|;Ma|Junsheng|J|;Tanner|Mark R|MR|;Al-Juhaishi|Taha|T|;Bashir|Qaiser|Q|;Srour|Samer A|SA|;Saini|Neeraj Y|NY|;Ramdial|Jeremy L|JL|;Nieto|Yago|Y|;Murphy|Regan|R|;Rezvani|Katayoun|K|;Tang|Guilin|G|0000-0002-9482-4806;Lee|Hans C|HC|;Patel|Krina K|KK|;Kaufman|Gregory P|GP|;Manasanch|Elisabet E|EE|;Ullah|Muhammad R|MR|;Kebriaei|Partow|P|;Thomas|Sheeba K|SK|;Weber|Donna M|DM|;Orlowski|Robert Z|RZ|;Shpall|Elizabeth J|EJ|;Champlin|Richard E|RE|;Qazilbash|Muzaffar H|MH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2021.1992763",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": null,
"journal": "Leukemia & lymphoma",
"keywords": " outcomes; Mel200; Multiple myeloma; VRD; lenalidomide; transplantation",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": null,
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1-12",
"pmc": null,
"pmid": "34686083",
"pubdate": "2021-10-22",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Real-world long-term outcomes in multiple myeloma with VRD induction, Mel200-conditioned auto-HCT, and lenalidomide maintenance.",
"title_normalized": "real world long term outcomes in multiple myeloma with vrd induction mel200 conditioned auto hct and lenalidomide maintenance"
} | [
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"literaturereference": "Qazilbash; M, H. Real-world long-term outcomes in multiple myeloma with VRD induction, Mel200-conditioned auto-HCT, and lenalidomide maintenance. Leukemia + Lymphoma. 2022;63 (2):710-721",
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{
"abstract": "Direct antiviral agents (DAAs) have become the treatment of choice for patients with chronic hepatitis C virus (HCV) infection. As these drugs are new, it is important to learn the adverse events of these drugs in the short and long terms. We report on 7 patients who developed malignancies during treatment with DAAs or a short time after finishing treatment.\n\n\n\nWe treated 133 patients with DAAs in our unit between January 2015 and June 2016, 100 (75%) of whom were treated with the combination of paritaprevir/ritonavir/ombitasvir with/without dasabuvir (PrOD). The distribution of HCV genotypes was as follow: G1b 114 (85.7%), G1a 3 (2.2%), G2 3 (2.2%), G3 10 (7.5%), G4 2 (1.5%). One hundred ten (82.7%) patients finished treatment. Adverse events were recorded during treatment and after finishing treatment. Efficacy was determined by assessment of serum HCV RNA.\n\n\n\nWe observed malignancies in 7 patients: 1 developed laryngeal carcinoma, 1 developed pancreatic adenocarcinoma, 1 developed oropharyngeal lymphoma, 1 developed recurrent aggressive transitional cell carcinoma of the urinary bladder, 1 developed recurrent aggressive hepatocellular carcinoma, and 2 patients developed de novo hepatocellular carcinoma. All of these patients had advanced liver disease.\n\n\n\nThis report raises questions about DAAs and the possible development of malignancies. It will be important to look at large clinical trial data and real-world experience to determine if this relationship is real.",
"affiliations": "Liver Unit.;Liver Unit.",
"authors": "Saadi|Tarek|T|;Khoury|Johad|J|",
"chemical_list": "D000998:Antiviral Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/MCG.0000000000000853",
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"issn_linking": "0192-0790",
"issue": "52(4)",
"journal": "Journal of clinical gastroenterology",
"keywords": null,
"medline_ta": "J Clin Gastroenterol",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D006528:Carcinoma, Hepatocellular; D015331:Cohort Studies; D005260:Female; D006526:Hepatitis C; D006801:Humans; D007557:Israel; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "7910017",
"other_id": null,
"pages": "353-359",
"pmc": null,
"pmid": "28590324",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Is There a Relationship Between Treatment With Direct Antiviral Agents for HCV Infection and the Development of Malignancies?",
"title_normalized": "is there a relationship between treatment with direct antiviral agents for hcv infection and the development of malignancies"
} | [
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{
"abstract": "BACKGROUND\nOrthostatic tremor (OT) is a disabling movement disorder manifested by postural and gait disturbance. Primarily a condition of elderly people, it can be progressive in up to 15% of patients. The primary treatments are medications that are often ineffective.\n\n\nMETHODS\nA 75-year-old male presented with a 10-year history of progressive and disabling OT. He had tried various medications without significant benefits. He underwent bilateral thalamic Vim deep brain stimulation (DBS). At 30-month follow-up, he has had continued significant improvement of his OT.\n\n\nCONCLUSIONS\nBilateral thalamic DBS may be a viable option for medically refractory OT.",
"affiliations": "Department of Neurological Surgery, Mayo Clinic, Phoenix, Arizona, Unites States of America.",
"authors": "Lyons|Mark K|MK|;Behbahani|Mandana|M|;Boucher|Orland K|OK|;Caviness|John N|JN|;Evidente|Virgilio Gerald H|VG|",
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"fulltext": "\n==== Front\nTremor Other Hyperkinet Mov (N Y)Tremor Other Hyperkinet Mov (N Y)TOHMTremor and Other Hyperkinetic Movements2160-8288Columbia University Libraries/Information Services tre-30-85-9Case ReportOrthostatic Tremor Responds to Bilateral Thalamic Deep Brain Stimulation DBS for Orthostatic TremorLyons Mark K. 1*Behbahani Mandana 2Boucher Orland K. 1Caviness John N. 3Evidente Virgilio Gerald H. 31 Department of Neurological Surgery, Mayo Clinic, Phoenix, Arizona, Unites States of America2 University of Arizona College of Medicine, Phoenix, Arizona, Unites States of America3 Department of Neurology, Mayo Clinic, Phoenix, Arizona, Unites States of AmericaLouis Elan D. Columbia University, United States of America*To whom correspondence should be addressed. E-mail: lyons.mark2@mayo.edu2012 20 2 2012 2 tre-02-30-85-928 4 2011 27 5 2011 2012Lyons et alThis is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommerical–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original author and source are credited; that no commercial use is made of the work; and that the work is not altered or transformed.Background\nOrthostatic tremor (OT) is a disabling movement disorder manifested by postural and gait disturbance. Primarily a condition of elderly people, it can be progressive in up to 15% of patients. The primary treatments are medications that are often ineffective.\n\nCase Report\nA 75-year-old male presented with a 10-year history of progressive and disabling OT. He had tried various medications without significant benefits. He underwent bilateral thalamic Vim deep brain stimulation (DBS). At 30-month follow-up, he has had continued significant improvement of his OT.\n\nDiscussion\nBilateral thalamic DBS may be a viable option for medically refractory OT.\n\nOrthostatic tremordeep brain stimulationthalamus\n==== Body\nIntroduction\nOrthostatic tremor (OT) was first described in 1984 by Heilman.1 He reported three patients who presented with leg and trunk tremor upon standing that was relieved by walking, sitting, lying down, or leaning against a wall or object.1 OT most commonly affects middle-aged and elderly people. They most commonly describe unsteadiness in the legs and a fear of falling upon standing. However, in certain cases the symptoms can involve the trunk and upper extremities. There is a latency of several seconds or, rarely, a few minutes.2,3 Since the tremor can also be evoked by strong tonic contraction of the leg muscles and is, hence, not exclusively orthostatic, the term “shaky-legs syndrome” has been suggested.4 The latter term though does not take into account the involvement of the trunk and upper extremity muscles in some patients with OT. Psychological stress, slow walking, or standing on a narrow base may increase OT.5 Electromyography (EMG) shows high frequency 13–18 Hz tremor discharges in weight-bearing muscles, most prominently in the legs.\n\nThe most commonly used medication for OT is clonazepam,1,3 but many patients are unresponsive to it or are unable to tolerate the side effects. We previously reported the beneficial effects of gabapentin in patients with OT, including those who were unresponsive to clonazepam.6 Other medications used in patients with OT include primidone, clonazepam, phenobarbital, valproic acid, propranolol, phenytoin, and carbamazepine.7–9 OT can profoundly impact the quality of life in those patients suffering from this condition and more effective treatments need to be developed.7 Pharmacological treatment of OT is the primary therapeutic option, but often with limited success.10 Deep brain stimulation of the ventralis intermedius nucleus of the thalamus may offer a treatment option for those patients with medically refractory and severely disabling OT.\n\nDeep brain stimulation (DBS) has been reported as a treatment option in three cases of OT in the literature. Espay and colleagues reported two patients who underwent thalamic DBS for refractory OT.11 However, only one of the two patients had sustained relief of symptoms. Guridi et al.12 described a single case of a patient with severe medically refractory OT successfully treated with thalamic Vim DBS.\n\nCase Report\nWe report a 75-year-old male with a 10-year history of progressive OT and unsuccessful medical treatment. He used a portable stool or cane when he had to stand in place. Upon standing, he would have the immediate onset of fine tremors in both legs. He could only stand in place for 20 seconds at most before needing to sit, lean, or hold on to something. The patient had been initially trialed on acetazolamide and primidone over the course of 5 years prior to his referral to our institution. He tolerated the medications, but they were discontinued because of ineffectiveness. He was then started on topiramate, up to 50 mg twice per day, but discontinued because of side effects of anorexia and significant weight loss. He was subsequently begun on clonazepam, up to 0.5 mg twice per day, but was discontinued because of sedation. Gabapentin and then valproic acid were trialed without any improvement in his symptoms. The severity of the side effects of the clonazepam and topiramate and the ineffectiveness of the other medications resulted in referral for consideration of DBS surgery.\n\nPre-operative surface EMG showed 13 Hz tremors of the lower extremities upon standing, which spread upwards to his paraspinal, truncal, and upper limb muscles. The patient underwent bilateral thalamic DBS. The target coordinates were based upon the midcomissural point and 11.5 mm lateral to the wall of the ipsilateral third ventricle. Intraoperative electrophysiology was performed to locate and confirm the leg portion of the Vim nucleus. Microelectrode recordings were followed by microstimulation looking for sensory side effects in the contralateral leg. In the right brain, leg side effects were noted at 13 mm lateral to the ipsilateral wall of the third ventricle, whereas in the left brain, final laterality was 11.5 mm. Macrostimulation was carried out to further refine final electrode placement based upon intraoperative improvement of contralateral leg tremor. This was assisted by surface EMG recordings of the legs, asking the patient to push down on each leg against resistance or on a footboard (Figure 1). Final electrode placement per side was determined based on stimulation side effects (sensory symptoms in the contralateral leg) and improvement of the contralateral leg tremor on surface EMG with macrostimulation (Figure 2).\n\nFigure 1. Pre-operative surface EMG of the right anterior tibialis in the movement neurophysiology laboratory shows well-formed, continuous, and rhythmic 13 Hz tremor bursts, which are noted immediately upon standing in place from a seated position. The tracing shows a 2-second epoch.\nFigure 2. 3-month postoperative surface EMG of the right anterior tibialis in the movement neurophysiology laboratory demonstrates less continuous, less rhythmic, and slower frequency (5–10 Hz) tremor bursts. The tracing shows a 2-second epoch.\nOne month following surgery, initial programming was done. The left Implantable Programmable Generator (IPG) settings were: contacts 0 and 1(−); contact 2(+); amplitude 4 volts; pulse width 60 milliseconds; and frequency 185 Hz. The right IPG settings were: contact 4(−); contact 5(+); amplitude 2.5 volts; pulse width 90 milliseconds; and frequency 185 Hz.\n\nHe reported an 80% subjective improvement of his OT in the left leg and 50% improvement in the right leg. He was able to stand in place for 7 minutes before needing to sit. He no longer required his portable stool/cane. A repeat surface EMG study was performed 3 months post-DBS. On standing from a seated position, there was immediate onset of tremor in the lower extremities on surface EMG, although the tremor bursts were less continuous, less rhythmic, and often showing bursts of slower frequency than the previous 13 Hz tremor seen pre-operatively (Figures 3–4). At 11 months post-DBS, the patient developed an infection and skin erosion around the IPG, which required removal of the pulse generator. Interestingly, it took 1 month before he returned to baseline severity of his OT. A new pulse generator was placed 2 months later, resulting in prompt improvement of his OT. The patient has been followed at our institution by the treating movement disorders neurologist and implanting neurosurgeon. Since surgery, the patient has had 19 visits to the DBS clinic demonstrating continued improvement. At last follow-up 30 months following DBS, he continued to experience a good response to stimulation alone (with no anti-tremor medications). He was able to stand in place at least 7 minutes or more before needing to sit or lean on something. The left IPG settings on last follow-up were: contacts 4 and 5(−); contact 6(+); amplitude 2.2 volts; pulse width 90 milliseconds; and frequency 185 Hz. The right IPG settings were: contact 0(−); contact 1(+); amplitude 2.7 volts; pulse width 90 milliseconds; and frequency 185 Hz.\n\nFigure 3. Intraoperative surface EMG recordings of the right anterior tibialis prior to stimulation with the patient supine in the operating table shows irregular 12–15 Hz tremor bursts while having the patient push down on the leg against resistance. The tracing shows a 1-second epoch. RATIB, Right anterior tibialis (muscle).\nFigure 4. Intraoperative surface EMG recordings of the right anterior tibialis during macrostimulation with the patient supine in the operating table shows no definite tremor bursts while pushing down on the leg against resistance. The tracing shows a 1-second epoch. RATIB, Right anterior tibialis (muscle).\nDiscussion\nOur case further supports the efficacy of thalamic Vim DBS in treating medically refractory OT. Electrophysiological mapping intraoperatively helps localize the leg area in the Vim subnucleus. Although OT is a tremor disorder that appears on standing, we have demonstrated that the tremor can also be detected on surface EMG with the patient lying on the operating table by asking the patient to put pressure on the legs against resistance or by stepping down on a footboard. This technique allows monitoring of response of the leg tremor to microstimulation and macrostimulation. On surface EMG with the patient supine with macrostimulation, and post-operatively in our movement disorders laboratory while standing with the stimulators on, the leg tremor still persists though is less continuous, less rhythmic and of lower frequency. Thus, thalamic Vim DBS does not completely eradicate the tremor but rather modifies its consistency, rhythmicity and frequency characteristics.\n\nOT is considered to be a rare disorder and the incidence and prevalence are unknown.7 The pathophysiology is unclear. Gerschlager and colleagues7 studied 41 patients with OT, noting that, while in most cases the symptoms remained unchanged over years, approximately 15% of patients developed progressive symptoms. Medications have been generally ineffective. There have been three reported case of OT treated with DBS. Espay and co-workers11 reported two patients who underwent thalamic DBS for refractory OT. Both patients, as in our case, had progressive symptoms for nearly three decades. One patient underwent bilateral thalamic Vim DBS with sustained improvement at last follow-up 18 months after surgery. The second patient underwent unilateral thalamic Vim DBS, but relapsed 3 months after surgery.11 Although the patient undergoing bilateral DBS noted significant improvement in unsteadiness and quality of life, the 15 Hz oscillatory activity and posturographic measures were unchanged. They postulated that the absence of reduction in postural stability, in the absence of visual or proprioceptive inputs, argues against the attenuation of tremor disruption of the proprioceptive afferent pathways as the pathophysiologic mechanism underlying OT.11,13\n\nGuridi et al.12 described a case of a patient with severe medically refractory OT successfully treated with thalamic Vim DBS. They noted that the minimally effective current was 1.3 volts. Interestingly, during the 4-year follow-up period there were three occasions where the tremor worsened, which coincided with spontaneous disruption of unilateral stimulation. This finding is consistent with our case and the observation by Espay and colleagues11 that bilateral DBS may be necessary for efficacy of DBS in OT. Krauss et al.14 reported a single case of successful treatment of OT with spinal cord stimulation. The subjective improvement, however, was only noted with stimulation in the 50–150 Hz range and required stimulation induced paresthesias. Espay has postulated that since thalamic and spinal stimulation produce similar results in OT, perhaps a common modulatory role of the “cerebello-thalamo-cortico-spinal system” is being affected at different levels of the neural axis.11 Our case is consistent with the few reported cases in the literature. Sustained long-term improvement in OT, as noted in our case, suggests that thalamic Vim DBS may be an option for these patients. Although unilateral thalamic Vim DBS may benefit OT, bilateral stimulation appears to have more consistent and enduring effects.\n\nThe major limitation of this report is that it is a single case. The paucity of these cases makes any conclusions regarding the efficacy of DBS for medically refractory OT premature. However, this disease can be extremely disabling to those patients afflicted. Thalamic DBS is a safe procedure and the clinical application of DBS to OT is intriguing. Bilateral thalamic DBS may be a viable option for medically refractory OT. Monitoring of surface EMG intraoperatively may help locate the optimal lead position to achieve tremor control. Deep brain stimulation does not eradicate the tremor completely, but tends to modulate the tremor making it slower in frequency, consistency and rhythmicity. This can lead to functional improvement of the patient's ability to stand despite persistence of the tremor. Controlled clinical trials are needed and long term responses need to be monitored and observed.\n\nFunding: None.\n\nCompeting Interests: The authors report no conflict of interest.\n==== Refs\nReferences\n1 Heilman KM Orthostatic tremor Arch Neurol 1984 41 880 881 10.1001/archneur.1984.04050190086020 6466163 \n2 McManis PG Sharbrough FW Orthostatic tremor: clinical and electrophysiologic characteristics Muscle Nerve 1993 16 1254 1260 10.1002/mus.880161117 8413379 \n3 Walker FO McCormick GM Hunt VP Isometric features of orthostatic tremor: an electromyographic analysis Muscle Nerve 1990 13 918 922 10.1002/mus.880131006 2233849 \n4 Veilleux M Sharbrough FW Kelly JJ Westmoreland BF Daube JR Shaky-legs syndrome J Clin Neurophys 1987 4 304 305 \n5 Gabellini AS Martinelli P Gulli MR et al Orthostatic tremor: essential and symptomatic cases Acta Neurol Scand 1990 81 113 117 10.1111/j.1600-0404.1990.tb00944.x 2327230 \n6 Evidente VG Adler CH Caviness JN et al Effective treatment of orthostatic tremor with gabapentin Mov Disord 1998 13 829 831 10.1002/mds.870130513 9756154 \n7 Gerschlager W Munchau A Katzenschlager R et al Natural history and syndromic associations of orthostatic tremor: A review of 41 patients Mov Disord 2004 19 788 795 10.1002/mds.20132 15254936 \n8 Cabrera-Valdivia F Jimenez-Jimenez FJ Albea EG et al Orthostatic tremor: successful treatment with phenobarbital Clin Neuropharmacol 1991 14 438 441 10.1097/00002826-199110000-00008 1742753 \n9 McManis PG Sharbrough FW Orthostatic tremor: clinical and electrophysiologic characteristics Muscle Nerve 1993 16 1254 1260 10.1002/mus.880161117 8413379 \n10 Gerschlager W Katzenschlager R Schrag A et al Quality of life in patients with orthostatic tremor J Neurol 2003 250 212 215 10.1007/s00415-003-0980-9 12574953 \n11 Espay AJ Duker AP Chen R et al Deep brain stimulation of the ventral intermediate nucleus of the thalamus in medically refractory orthostatic tremor: preliminary observations Mov Disord 2008 23 2357 2362 10.1002/mds.22271 18759339 \n12 Guridi J Rodriguez-Oroz MC Arbizu J et al Successful thalamic deep brain stimulation for orthostatic tremor Mov Disord 2008 23 1808 1811 10.1002/mds.22001 18671286 \n13 Fung VS Sanuner D Day BL A dissociation between subjective and objective unsteadiness in primary orthostatic tremor Brain 2001 124 322 330 10.1093/brain/124.2.322 11157559 \n14 Krauss JK Weigel R Blahak C et al Chronic spinal cord stimulation in medically intractable orthostatic tremor J Neurol Neurosurg Psychiatry 2006 77 1013 1016 10.1136/jnnp.2005.086132 16735398\n\n",
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"abstract": "BACKGROUND\nBilateral femoral neck fractures without major trauma are rare and related to several conditions. Insufficiency fractures due to the use of anti-epileptic drug are one of the rare causes. This case study is about bilateral femoral neck insufficiency fractures resulting from chronic use of anti-epileptic drug.\n\n\nMETHODS\nA 26-year-old woman was referred to our emergency department with a complaint of bilateral groin pain and a 12-year history of irregular carbamazepine use. The diagnosis was bilateral femoral neck insufficiency fractures due to irregular long-term carbamazepine use. One-stage bilateral dynamic hip screw osteosynthesis was performed. After 2 years of follow up, good result was obtained.\n\n\nCONCLUSIONS\nThere are several risk factors for insufficiency fracture, and antiepileptic drug related osteoporosis is one of the reason. These drugs have negative effect on bone methabolism and bone mineral density.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first case in the literature of bilateral femoral neck insufficiency fracture due to chronic carbamazepine use. Joint and bone pain with a history of long-term use of anti-epileptic drug should be investigated carefully, and insufficiency fractures should be kept in mind.",
"affiliations": "Department of Orthopedics and Traumatology, Acibadem Atakent Hospital, Istanbul, Turkey. Electronic address: ksariyilmaz@gmail.com.;Department of Orthopedics and Traumatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. Electronic address: barisgulenc@yahoo.com.;Department of Orthopedics and Traumatology, Acibadem Atakent Hospital, Istanbul, Turkey. Electronic address: drdeto@gmail.com.;Department of Orthopedics and Traumatology, Acibadem Atakent Hospital, Istanbul, Turkey. Electronic address: fatihdikici71@hotmail.com.;Department of Orthopedics and Traumatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.",
"authors": "Sariyilmaz|Kerim|K|;Gulenc|Baris|B|;Ozkunt|Okan|O|;Dikici|Fatih|F|;Yazicioglu|Onder|O|",
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"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(14)00454-410.1016/j.ijscr.2014.12.019Case ReportBilateral femoral neck fractures secondary to chronic carbamazepine use treated by bilateral dynamic hip screw: A case report Sariyilmaz Kerim ksariyilmaz@gmail.comkerim.sariyilmaz@acibadem.com.tra⁎Gulenc Baris barisgulenc@yahoo.combOzkunt Okan drdeto@gmail.comaDikici Fatih fatihdikici71@hotmail.comaYazicioglu Onder ba Department of Orthopedics and Traumatology, Acibadem Atakent Hospital, Istanbul, Turkeyb Department of Orthopedics and Traumatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey⁎ Corresponding author at: Halkali Merkez Mahallesi, Turgut Ozal Bulvari, No: 16, Department of Orthopedics and Traumatology, Acibadem Atakent Hospital, Halkali, Istanbul 34303, Turkey. Tel.: +90 212 404 44 44; fax: +90 212 404 44 45. ksariyilmaz@gmail.comkerim.sariyilmaz@acibadem.com.tr15 12 2014 15 12 2014 2015 6 111 113 26 5 2014 11 12 2014 11 12 2014 © 2014 The Authors2014This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).Highlights\n• Insufficiency fractures due to antiepileptic drug use is one of the rare cause.\n\n• Insufficiency fractures should be kept in mind for joint and bone pain with a history of long term anti-epileptic drug use.\n\n• Carbamazepine could be a result of insufficiency fracture.\n\n\n\nIntroduction\nBilateral femoral neck fractures without major trauma are rare and related to several conditions. Insufficiency fractures due to the use of anti-epileptic drug are one of the rare causes. This case study is about bilateral femoral neck insufficiency fractures resulting from chronic use of anti-epileptic drug.\n\nPresentation of case\nA 26-year-old woman was referred to our emergency department with a complaint of bilateral groin pain and a 12-year history of irregular carbamazepine use. The diagnosis was bilateral femoral neck insufficiency fractures due to irregular long-term carbamazepine use. One-stage bilateral dynamic hip screw osteosynthesis was performed. After 2 years of follow up, good result was obtained.\n\nDiscussion\nThere are several risk factors for insufficiency fracture, and antiepileptic drug related osteoporosis is one of the reason. These drugs have negative effect on bone methabolism and bone mineral density.\n\nConclusion\nTo our knowledge, this is the first case in the literature of bilateral femoral neck insufficiency fracture due to chronic carbamazepine use. Joint and bone pain with a history of long-term use of anti-epileptic drug should be investigated carefully, and insufficiency fractures should be kept in mind.\n\nKeywords\nBilateral femoral neck fractureInsufficiency fracturesCarbamazepineAntiepileptic drugDynamic hip screw\n==== Body\n1 Introduction\nSeveral adverse effects of long-term use of anti-epileptic drug (AED) on bone metabolism have been reported [1–3]. The most common bone metabolism disorders due to AED use are osteoporosis and rickets.\n\nThe exact mechanism of the effect of AEDs on bone metabolism is unclear. Vitamin D deficiency may occur with enzyme-inducing AEDs. It has been suggested that inducing the cytochrome p450 enzyme system is associated with vitamin D deficiency because enzyme induction may lead to increased catabolism of vitamin D [4]. Non-enzyme-inducing AEDs have no effect on vitamin D metabolism [5]. It is also reported that direct inhibitor effect on osteoblast proliferation, decreased calcium absorption, and endocrinopathy are the other suggested mechanisms [6].\n\nThere are studies about increased fracture risk with AED use. Although these fractures mostly occur during seizures, nontraumatic fractures can be seen [7,8].\n\nIn this paper, we present a case of nontraumatic bilateral collum femoris fracture due to chronic carbamazepine use, treated by bilateral dynamic hip screw. To our knowledge, there is no report yet of bilateral femoral neck insufficiency fracture due to carbamazepine use, until now.\n\n2 Presentation of case\nA 26-year-old woman was referred to our emergency department with a complaint of ongoing bilateral groin pain for 3 months and with difficulty in walking. Her pain was aggravated by weight bearing and so she was unable to walk.\n\nOn examination, both active and passive motions were painful but she had normal range of motion in both hips. Her pain was increased with axial loading to her lower extremities.\n\nIn her personal history, it was learned that she was using carbamazepine irregularly for 12 years due to epilepsy, and she did not attempt her neurological controls for a long time. She had her last seizure 6 months ago, and she did not have any complaint just after the seizure; she also had no recent trauma history. Moreover, she does not have smoking history, and she did not use a medication except carbamazepine as well.\n\nAnteroposterior view of both hips was taken and a fracture line on the left femoral neck and an uncertain fracture on right femoral neck was seen (Fig. 1).\n\nWhereon, computerized tomography (CT) and magnetic resonance imaging (MRI) of both hips were taken. In coronal CT images, fracture lines were seen in the inferomedial border of both femoral necks (Fig. 2). In T2 weighted images, edema and fracture line were seen in the left femoral neck, and a fracture line was seen in the inferomedial border of the right femoral neck (Fig. 3).\n\nBone mineral density of the femoral neck was measured by dual-energy X-ray absorptiometry (DEXA) using a densitometer, and the T score of both hips was −3.\n\nSurgery was done using regional anesthesia with the patient on supine position, and one-stage bilateral dynamic hip screw osteosynthesis was performed.\n\nOsteoporosis therapy was started immediately after surgery. Weight bearing was restricted for 3 months, and after 3 months, she was able to walk without crutches and she had normal range of motions in both hips. After 2 years of follow up, she had no complaint; osteosynthesis was good, and the Harris Hip Score was 96 (Fig. 4).\n\n3 Discussion\nFractures resulting from cyclic mechanical stresses can be classified as either fatigue or insufficiency fractures. If the fracture occurs in normal bone of a healthy individual, it is defined as a fatigue fracture. These fractures are common in athletes, dancers, and military personnel [9].\n\nInsufficiency fractures are another type of stress fracture, which is the result of normal stresses on a bone with reduced strength. There are several risk factors for insufficiency fracture and osteoporosis is the most common cause. The other causes for insufficiency fractures are long-term corticosteroid treatment, renal osteodystrophy, amenorrhea, osteomalacia, rheumatoid arthritis, scurvy, fluoride treatment, and pelvic irradiation [10].\n\nSeveral reports mention unusual causes of insufficiency fractures of femoral neck. Kim et al. reported a patient with a femoral neck insufficiency fracture, who had taken long-time bisphosphonate treatment for osteoporosis [11]. Carpintero et al. reported bilateral insufficiency femoral neck fracture in a male patient with anorexia nervosa [12]. In a pregnant woman, Baki et al. reported a bilateral femoral neck insufficiency fractures due to osteomalacia [13].\n\nIt is known that long-term AED usage has several adverse affects on calcium metabolism and bone mineral density. Osteopenia/osteoporosis, osteomalacia, and bone fractures are disorders attributed to the use of these drugs [4,5]. Although hypocalcemia and decreased vitamin D levels are related particularly to children and institutionalized patients with AED usage [14], in mobile and non-institutionalized patients, there is no relation between calcium and vitamin D levels [15]. It was also cited that in young male patients who are taking AEDs, decreased bone density was found without any differences on vitamin D levels [1]. In our case, the patient was active and mobile, and upon analysis of her laboratory tests, calcium and vitamin D levels were normal; however, bone mineral density was decreased.\n\nSimultaneous femoral neck fractures are mostly seen after high-energy trauma; however, they may be associated with repetitive minor trauma, seizure, bone metabolism disorders, and endocrinopathies [16–20], but bilateral collum femoris insufficiency fracture due to AED use is not reported.\n\nThe distinctive features of this case include bilateral insufficiency fractures with a strong relation to chronic carbamazepine use and simultaneous surgery of both hips.\n\n4 Conclusion\nJoint and bone pain with a history of long-term AED use should be investigated carefully, and insufficiency fractures should be kept in mind. In these conditions, the accurate history of the patient, sufficient imaging, laboratory tests for bone metabolism, and bone mineral density studies must be considered, and adequate treatment should be performed according to the results.\n\nConflicts of interest\nNone.\n\nFunding\nNone.\n\nEthical approval\nNone.\n\nAuthor contribution\nKS, corresponding author of the case, did the literature search, manuscript writing, worked in data collection(follow-up data). BG had attended the surgery and also worked in data collecting (follow-up data). OO did the literature search and helped the manuscript writing. FD performed the surgery, made study design and helped in manuscript editing. OY made the initial study design, joined the surgery and made the general supervision of the case report. All authors read and approved the final manuscript.\n\nConsent\nThis is a statement that the patient had her given informed consent for the case report to be published.\n\nGuarantor\nKerim Sariyilmaz.\n\nFig. 1 Anteroposterior view of both hips.\n\nFig. 2 Coronal CT view of both hips.\n\nFig. 3 T2 weighted coronal images of both hips.\n\nFig. 4 AP view of both hips after 2 years follow-up.\n==== Refs\nReferences\n1 Andress D.L. Antiepileptic drug-induced bone loss in young male patients who have seizures Arch. Neurol. 59 5 2002 781 786 12020260 \n2 Farhat G. Effect of antiepileptic drugs on bone density in ambulatory patients Neurology 58 9 2002 1348 1353 12011279 \n3 Stephen L.J. Bone density and antiepileptic drugs: a case-controlled study Seizure 8 6 1999 339 342 10512774 \n4 Pack A.M. Bone mineral density in an outpatient population receiving enzyme-inducing antiepileptic drugs Epilepsy Behav. 4 2 2003 169 174 12697142 \n5 Kulak C.A. Bone mineral density and serum levels of 25 OH vitamin D in chronic users of antiepileptic drugs Arq. Neuropsiquiatr 62 4 2004 940 948 15608949 \n6 Petty S.J. O'Brien T.J. Wark J.D. Anti-epileptic medication and bone health Osteoporosis Int. 18 2 2007 129 142 \n7 Shiek Ahmad B. Falls and fractures in patients chronically treated with antiepileptic drugs Neurology 79 2 2012 145 151 22700806 \n8 Jette N. Association of antiepileptic drugs with nontraumatic fractures: a population-based analysis Arch. Neurol. 68 1 2011 107 112 21220681 \n9 Rome K. Handoll H.H. Ashford R. Interventions for preventing and treating stress fractures and stress reactions of bone of the lower limbs in young adults Cochrane Database Syst. Rev. 2 2005 CD000450 15846606 \n10 Egol K.A. Stress fractures of the femoral neck Clin. Orthop. Relat. Res. 348 1998 72 78 9553536 \n11 Kim D.H. Lee E.C. Kang S.K. Insufficiency fracture of ipsilateral femur neck in patient treated with long term bisphosphonate treatment – a case report J. Bone Metab. 19 2 2012 159 162 24524048 \n12 Carpintero P. Bilateral insufficiency fracture of the femoral neck in a male patient with anorexia nervosa Acta Orthop. Belg. 79 1 2013 111 113 23547526 \n13 Baki M.E. Bilateral femoral neck insufficiency fractures in pregnancy Eklem Hastalik Cerrahisi 25 1 2014 60 62 24650388 \n14 Fischer M.H. Bone status in nonambulant: epileptic, institutionalized youth: improvement with vitamin D therapy Clin. Pediatr. (Phila.) 27 10 1988 499 505 2844466 \n15 Weinstein R.S. Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment J. Clin. Endocrinol. Metab. 58 6 1984 1003 1009 6725504 \n16 Schroder J. Marti R.K. Simultaneous bilateral femoral neck fractures: case report Swiss Surg. 7 5 2001 222 224 11678022 \n17 Hootkani A. Moradi A. Vahedi E. Neglected simultaneous bilateral femoral neck fractures secondary to narcotic drug abuse treated by bilateral one-staged hemiarthroplasty: a case report J. Orthop. Surg. Res. 5 2010 41 20579374 \n18 Rahman M.M. Awada A. Bilateral simultaneous hip fractures secondary to an epileptic seizure Saudi Med. J 24 11 2003 1261 1263 14647567 \n19 Chadha M. Spontaneous bilateral displaced femoral neck fractures in nutritional osteomalacia – a case report Acta Orthop. Scand. 72 1 2001 94 96 11327423 \n20 Chen C.E. Kao C.L. Wang C.J. Bilateral pathological femoral neck fractures secondary to ectopic parathyroid adenoma Arch. Orthop. Trauma Surg. 118 3 1998 164 166 9932193\n\n",
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"journal": "International journal of surgery case reports",
"keywords": "Antiepileptic drug; Bilateral femoral neck fracture; Carbamazepine; Dynamic hip screw; Insufficiency fractures",
"medline_ta": "Int J Surg Case Rep",
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"title": "Bilateral femoral neck fractures secondary to chronic carbamazepine use treated by bilateral dynamic hip screw: A case report.",
"title_normalized": "bilateral femoral neck fractures secondary to chronic carbamazepine use treated by bilateral dynamic hip screw a case report"
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"literaturereference": "SARIYILMAZ K, GULENC B, OZKUNT O, DIKICI F, YAZICIOGLU O. BILATERAL FEMORAL NECK FRACTURES SECONDARY TO CHRONIC CARBAMAZEPINE USE TREATED BY BILATERAL DYNAMIC HIP SCREW: A CASE REPORT.. INTERNATIONAL JOURNAL OF SURGERY CASE REPORTS. 2015;6:111-113",
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"abstract": "Uterine contractions are recognized as a potential manifestation of anaphylaxis, but literature on their proper management is limited. It is widely recognized that anaphylactic reactions can cause uterine contractions, but little is known about their optimal management.\n\n\n\nReview potential treatments for painful uterine contractions associated with anaphylaxis or mast cell activation.\n\n\n\nThis systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. PubMed, Embase, and Cochrane were searched in English, French, and Spanish for reports of uterine anaphylaxis published up until July 2020. The search strategy used a combination of Boolean operators and included the following Medical Subject Heading terms and keywords: hypersensitivity; anaphylaxis; mastocytosis; uterus; uterine contraction; pelvic pain; labor, obstetric; labor, premature; and endometriosis.\n\n\n\nThis systematic review identified 19 studies reporting on 31 cases of painful uterine contractions occurring during anaphylaxis or other events associated with mast cell activation. Nine patients were pregnant. We present 2 additional cases in nonpregnant women, one associated with an oral food challenge and the other associated with oral food desensitization. The most frequent triggers were subcutaneous immunotherapy (14 cases), food (6 cases), and drugs (4 cases). Uterine cramps were associated with systemic symptoms in 24 cases and lasted on average for 2.4 hours. Pretreatment with antihistamines and montelukast generally failed to prevent recurrence, but nonsteroidal anti-inflammatory drugs were used successfully in some reports. Response to intramuscular epinephrine was inconsistent. Data from ex vivo models indicate that epinephrine may paradoxically contribute to uterine contractions through alpha-receptor activity. A small number of cases showed good response to beta-2 agonists.\n\n\n\nThere is a lack of quality data on painful uterine contractions occurring in the context of anaphylactic reactions and on their optimal management. In the absence of counterindication, use of a beta-2 agonist and premedication with nonsteroidal anti-inflammatory drugs could be the preferred options.",
"affiliations": "Division of Allergy, Department of Medicine, Centre Hospitalier de l'Université de Montreal, Montreal, QC, Canada.;Division of Allergy, Department of Medicine, Centre Hospitalier de l'Université de Montreal, Montreal, QC, Canada; Division of Allergy, Department of Pediatrics, Centre Hospitalier Universitaire Ste-Justine, Montreal, QC, Canada.;Division of Allergy, Department of Medicine, Centre Hospitalier de l'Université de Montreal, Montreal, QC, Canada; Division of Allergy, Department of Pediatrics, Centre Hospitalier Universitaire Ste-Justine, Montreal, QC, Canada.;Division of Allergy, Department of Pediatrics, Centre Hospitalier Universitaire Ste-Justine, Montreal, QC, Canada.;Division of Allergy, Department of Medicine, Centre Hospitalier de l'Université de Montreal, Montreal, QC, Canada; Division of Allergy, Department of Pediatrics, Centre Hospitalier Universitaire Ste-Justine, Montreal, QC, Canada. Electronic address: philippe.begin@umontreal.ca.",
"authors": "D'Astous-Gauthier|Katherine|K|;Graham|Francois|F|;Paradis|Louis|L|;Des Roches|Anne|A|;Bégin|Philippe|P|",
"chemical_list": "D000485:Allergens; D004837:Epinephrine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaip.2020.10.047",
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"issue": "9(3)",
"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "Allergy; Anaphylaxis; Endometriosis; Mast cell activation; Pelvic pain; Preterm labor; Uterine contractions; Uterus",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D000485:Allergens; D000707:Anaphylaxis; D003888:Desensitization, Immunologic; D004837:Epinephrine; D005260:Female; D006801:Humans; D011247:Pregnancy; D014590:Uterine Contraction",
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"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D000078182:Systematic Review",
"references": null,
"title": "Beta-2 Agonists May be Superior to Epinephrine to Relieve Severe Anaphylactic Uterine Contractions.",
"title_normalized": "beta 2 agonists may be superior to epinephrine to relieve severe anaphylactic uterine contractions"
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"abstract": "BACKGROUND\nThe combination of boceprevir or telaprevir with peginterferon-alfa and ribavirin for the treatment of patients infected with HCV genotype 1 has led to significantly increased rates of sustained virological response (SVR) in phase III trials. There is only limited data regarding the safety and efficacy in a \"real-life\" cohort.\n\n\nMETHODS\nWe analyzed a cohort of 110 unselected HCV patients who started triple therapy from September 2011 to February 2013 by chart review with focus on the individual course of treatment, complications and outcome. We excluded 8 patients from analysis because of HIV-coinfection (N = 6) or status post liver transplant (N = 2). Importantly, 41 patients displayed F3 or F4 fibrosis, 10 patients had a history of treatment with protease/polymerase inhibitors and 15 patients were prior partial- or null-responder.\n\n\nRESULTS\nSVR12 was achieved in 62 of the 102 patients (60.8%). A high rate of serious adverse events (N = 30) was observed in 22 patients including 2 fatalities in cirrhotic diabetes patients. Age >50 years, liver cirrhosis, bilirubin >1.1 mg/dl (P < 0.01, each), platelets <100,000/μl (P = 0.01), ASAT >100 U/l (P = 0.03) and albumin ≤35 g/l (P = 0.04) at baseline were associated with occurence of a SAE.\n\n\nCONCLUSIONS\nThe frequency of SVR in a \"real-life\" treatment setting is slightly lower as compared to the results of the phase III trials for telaprevir or boceprevir. Importantly, we observed a high frequency of SAE in triple therapy, especially in patients with liver cirrhosis.",
"affiliations": "I, Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Martinistr, 52, Hamburg 20246, Germany. j.schulze-zur-wiesch@uke.de.",
"authors": "Wehmeyer|Malte H|MH|;Eißing|Friederike|F|;Jordan|Sabine|S|;Röder|Claudia|C|;Hennigs|Annette|A|;Degen|Olaf|O|;Hüfner|Anja|A|;Hertling|Sandra|S|;Schmiedel|Stefan|S|;Sterneck|Martina|M|;van Lunzen|Jan|J|;Lohse|Ansgar W|AW|;Schulze zur Wiesch|Julian|J|;Lüth|Stefan|S|",
"chemical_list": "D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D011480:Protease Inhibitors; D011092:Polyethylene Glycols; D012254:Ribavirin; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline",
"country": "England",
"delete": false,
"doi": "10.1186/1471-230X-14-87",
"fulltext": "\n==== Front\nBMC GastroenterolBMC GastroenterolBMC Gastroenterology1471-230XBioMed Central 1471-230X-14-872488440010.1186/1471-230X-14-87Research ArticleSafety and efficacy of protease inhibitor based combination therapy in a single-center “real-life” cohort of 110 patients with chronic hepatitis C genotype 1 infection Wehmeyer Malte H 1m.wehmeyer@uke.deEißing Friederike 1friederikeeissing@googlemail.comJordan Sabine 1s.jordan@uke.deRöder Claudia 1c.roeder@uke.deHennigs Annette 1a.hennigs@uke.deDegen Olaf 2degen@uke.deHüfner Anja 2a.huefner@uke.deHertling Sandra 2s.hertling@uke.deSchmiedel Stefan 1s.schmiedel@uke.deSterneck Martina 1sterneck@uke.devan Lunzen Jan 2v.lunzen@uke.deLohse Ansgar W 1sekretariatlohse@uke.dezur Wiesch Julian Schulze 1j.schulze-zur-wiesch@uke.deLüth Stefan 1s.lueth@uke.de1 I. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, Hamburg 20246, Germany2 Ambulanzzentrum des UKE, Fachbereich Infektiologie, Hamburg Germany2014 5 5 2014 14 87 87 13 12 2013 28 4 2014 Copyright © 2014 Wehmeyer et al.; licensee BioMed Central Ltd.2014Wehmeyer et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe combination of boceprevir or telaprevir with peginterferon-alfa and ribavirin for the treatment of patients infected with HCV genotype 1 has led to significantly increased rates of sustained virological response (SVR) in phase III trials. There is only limited data regarding the safety and efficacy in a “real-life” cohort.\n\nMethods\nWe analyzed a cohort of 110 unselected HCV patients who started triple therapy from September 2011 to February 2013 by chart review with focus on the individual course of treatment, complications and outcome. We excluded 8 patients from analysis because of HIV-coinfection (N = 6) or status post liver transplant (N = 2). Importantly, 41 patients displayed F3 or F4 fibrosis, 10 patients had a history of treatment with protease/polymerase inhibitors and 15 patients were prior partial- or null-responder.\n\nResults\nSVR12 was achieved in 62 of the 102 patients (60.8%). A high rate of serious adverse events (N = 30) was observed in 22 patients including 2 fatalities in cirrhotic diabetes patients. Age >50 years, liver cirrhosis, bilirubin >1.1 mg/dl (P < 0.01, each), platelets <100,000/μl (P = 0.01), ASAT >100 U/l (P = 0.03) and albumin ≤35 g/l (P = 0.04) at baseline were associated with occurence of a SAE.\n\nConclusions\nThe frequency of SVR in a “real-life” treatment setting is slightly lower as compared to the results of the phase III trials for telaprevir or boceprevir. Importantly, we observed a high frequency of SAE in triple therapy, especially in patients with liver cirrhosis.\n\nBoceprevirSerious adverse eventsSAESide effectsSustained virological responseSVRTelaprevir\n==== Body\nBackground\nAn estimated 170 million people are chronically infected with the hepatitis C virus (HCV) [1] and have an elevated risk for liver-related mortality [2]. Recently, introduction of the serine protease inhibitors (PI) boceprevir (BOC) and telaprevir (TPR) which are used in combination with peginterferon-alfa 2a or 2b (pegIFN) and ribavirin (RBV) has increased cure rates of patients with chronic HCV genotype 1 infection in the US, Canada and many European countries in phase III trials with sustained virological response (SVR) rates of 67 to 75% in treatment naive patients [3-5]. Even higher SVR rates have been achieved in patients with history of relapse following a previous therapy [6,7]. Interestingly, first “real-life” efficacy data revealed a significantly lower frequency of SVR [8]. On the other hand, treatment with a PI is associated with high rates of side-effects, such as fatigue, anemia and high-grade neutropenia [3-7]. Skin reactions and gastrointestinal disorders were frequently observed side-effects of TPR in the phase II and III trials [4,5,7].\n\nHowever, the overall safety-profile of the PIs was acceptable in phase III trials [3-7], which included highly selected patients. Most recently, preliminary “real-life” data covering the first 12 to 16 weeks of therapy revealed considerably increased risk for severe and in some instances even lethal complications of PI-based treatment in cirrhotic patients [9,10]. The most common cause of death was sepsis, with staphylococcus being the most frequent causative organism [10].\n\nDespite the approval of alternative direct acting antivirals (DAA) in Northern America and Europe, TPR and BOC have just arrived in many parts of the world. Given the increased likelihood of serious adverse events (SAE) provided by the preliminary reports on “real-life” data [9,10], we examined the outcomes and complications of triple therapy throughout the treatment course within our local “real-life”, difficult-to-treat cohort, which includes a number of patients with comorbidities, cirrhosis or previous DAA experience.\n\nMethods\nStudy population and chart review\nWe analyzed clinical and laboratory data of 110 unselected patients who were chronically infected with HCV genotype 1 and in whom treatment with pegIFN, RBV and TPR or BOC was initiated from September 2011 to February 2013 at the viral hepatitis clinics of the University Medical Center Hamburg-Eppendorf, which is representative of a tertiary care referral center for antiviral HCV therapy in Germany. Liver transplant recipients (N = 2) and patients coinfected with human immunodeficiency virus were excluded (N = 6).\n\nAll patients received an abdominal ultrasound prior to the start of therapy. The grade of liver fibrosis was measured in the majority of patients by transient elastography (Fibroscan, Echosens, France) [11] or liver biopsy before the initiation of treatment (Table 1).\n\nTable 1 Baseline characteristics\n\n \tAll patients\tTelaprevir\tBoceprevir\t\n(N = 102)\t(N = 65)\t(N = 37)\t\n \tN (%); median (range)\tN (%); median (range)\tN (%); median (range)\t\nMale sex\t63 (62%)\t43 (66%)\t20 (54%)\t\nExclusion criteria for appropriate phase III trials\t65 (64%)\t42 (65%)\t23 (62%)\t\nTreatment naïve\t47 (46%)\t23 (35%)\t24 (65%)\t\nTreatment experienced\t55 (54%)\t42 (65%)\t13 (35%)\t\nRelapse\t25 (25%)\t18 (28%)\t7 (19%)\t\nNull/partial response\t15 (15%)\t13 (20%)\t2 (5%)\t\nBreakthrough\t6 (6%)\t5 (8%)\t1 (3%)\t\nDiscontinuation\n§\n\t5 (5%)\t3 (5%)\t2 (5%)\t\nUnknown outcome\t4 (4%)\t3 (5%)\t1 (3%)\t\nDAA experienced\t10 (10%)\t9 (14%)\t1 (3%)\t\nRVR\t38 (37%)\t21 (32%)\t17 (46%)\t\nGenotype\t \t \t \t\nGenotype 1a\t39 (38%)\t20 (31%)\t19 (51%)\t\nGenotype 1b\t53 (52%)\t37 (57%)\t16 (43%)\t\nNo subtype provided\t9 (9%)\t7 (11%)\t2 (5%)\t\nUnknown\t1 (1%)\t1 (2%)\t0\t\nIL28B (N = 70)\t \t \t \t\nC/C\t16 (24%)\t10 (20%)\t6 (29%)\t\nC/T\t42 (60%)\t32 (65%)\t10 (48%)\t\nT/T\t12 (17%)\t7 (14%)\t5 (24%)\t\nStage of fibrosis (N = 92)\t \t \t \t\nNo or mild fibrosis (F0-F2)\t51 (55%)\t32 (49%)\t19 (59%)\t\nBridging fibrosis (F3)\t12 (13%)\t6 (10%)\t6 (19%)\t\nLiver cirrhosis\t29 (32%)\t22 (37%)\t7 (22%)\t\nHemoglobin [g/dl]\t14.7 (10.3-18.8)\t14.7 (11.1-18.8)\t14.6 (10.3-17.6)\t\nLeukocytes [x10^9/l]\t6.1 (2.7-13.1)\t5.9 (2.7-13.1)\t6.3 (3.9-12.4)\t\nPlatelets [x10^9/l]\t188 (48–377)\t180 (48–377)\t203 (67–338)\t\nASAT [U/l]\t50.5 (16–328)\t52 (16–328)\t44 (19–156)\t\nALAT [U/l]\t75.5 (16–271)\t87 (16–271)\t72 (19–227)\t\nγGT [U/l]\t66.5 (25–1274)\t67 (25–1274)\t62 (25–217)\t\nBilirubin [mg/dl]\t0.5 (0.2-2.2)\t0.6 (0.3-2.2)\t0.5 (0.2-1.4)\t\nAlbumin [g/l]\t40 (25–50)\t40 (25–47)\t39 (30–50)\t\nProthrombin time [INR]\t1.00 (0.90-3.29)\t1.02 (0.90-3.29)\t1.00 (0.92-2.33)\t\nCreatinine [mg/dl]\t0.8 (0.5-5.8)\t0.8 (0.5-1.1)\t0.8 (0.5-5.8)\t\nViral load undetectable at\t \t \t \t\nEOT\t82 (80%)\t51 (78%)\t31 (84%)\t\nSVR12\t62 (61%)\t40 (62%)\t22 (59%)\t\n[N = number; DAA = direct acting antivirals; RVR = rapid virological response; IL28B = interleukin-28B polymorphism; EOT = end of treatment; SVR12 = sustained virological response 12 weeks after last ribavirin dose; § = cessation of prior therapy due to side-effects].\n\nPatient charts were analyzed regarding demographics, clinical data, HCV genotype, interleukin 28B (IL28B) rs12979860 polymorphism, as well as laboratory values and HCV viral load at different time points. The lower detection limit of the HCV PCR was 15 IU/ml (COBAS TaqMan HCV Qualitative, v2.0, Roche). The Child-Pugh score and the MELD score were assessed in all cirrhotic patients at baseline using the established formula [12,13].\n\nStatistical analysis\nVariables of patients with SVR12 were compared with those of patients experiencing a treatment failure by univariate analysis using Fisher’s exact text, t-test (for variables with assumed Gaussian’ distribution, e.g. age) and Mann–Whitney-U-Test (for variables without assumed Gaussian’ distribution, e.g. laboratory values), respectively. The same analysis was conducted for patients suffering from predefined SAEs. Thresholds for continuous variables were defined according to the results from the CUPIC cohort [10] or by clinical judgement. Variables which reached P < 0.1 in univariate analysis were entered in a backward step logistic regression model.\n\nThe respective grading of laboratory events, adverse event definitions and virological definitions are described in the supplementary materials (text document, Additional file 1). All analyses were performed using SPSS Version 20. The figures were created using GraphPad Prism 4. The study was approved at the local ethics board (Ethik-Kommission der Ärztekammer Hamburg).\n\nResults\nCharacterization of the study population\nWe describe here the detailed clinical course and treatment outcome of 102 patients who started triple therapy from September 2011 to February 2013 at our university viral hepatitis clinics. Baseline characteristics of all patients are summarized in Table 1. Fibroscan or liver biopsy was performed in 92 patients (90.2%) and diagnosis of bridging fibrosis (F3) or cirrhosis (F4) was established in 41 patients (40.2%). The 10 remaining patients, who did not receive a transient elastography or a liver biopsy prior to the HCV therapy, did not have any laboratory or sonographical evidence for high grade fibrosis or cirrhosis, respectively. IL28B polymorphism was assessed in 70 patients (68.6%), of whom 16 individuals displayed the favorable C/C IL28 haplotype (22.9%). Fifty five patients (53.9%) were HCV treatment experienced (25 patients with a prior relapse, 15 patients with prior partial- or null-response), including 10 patients who previously received a DAA based therapy in clinical trials. The exclusion criteria for registration trials for TPR or BOC [3-7] were met by 65 patients (64%, e.g. history of hepatocellular carcinoma, history of stem cell transplantation, renal dialysis, Crohn’s disease, thalassaemia major, autoimmune hepatitis and primary biliary cirrhosis). Twenty patients (19.6%) suffered from concomittant psychiatric disorders such as major depression (N = 18), anxiety disorder (N = 2), borderline psychosis (N = 1), post traumatic stress disorder (N = 1) and anorexia (N = 1) and were treated with psychotropics. Additionally, 10 patients were DAA experienced as participants of several phase II and III trials performed at our center.\n\nIn 15 patients virologic failure occured during PI treatment (Figure 1). The PI was discontinued early in 25 of the remaining 87 patients (28.7%) for various reasons (e.g. patient’s wish, side-effects, provider’s individual decision; Figure 2). After PI withdrawal, 5 additional patients experienced a viral breakthrough on dual therapy (Figure 1) and 24 of the remaining 82 patients (29.3%) discontinued pegIFN and RBV prematurely as compared to the guidelines for PI based therapy [14,15] (Figure 2). Seventeen patients treated with TPR (26.2%) and all patients treated with BOC received a lead-in phase with pegIFN and RBV prior to triple therapy (mean duration 4.7 weeks (TPR, standard deviation (SD) = 1.2) and 5.3 weeks (BOC, SD = 5.2), Figure 2). The rationale for starting therapy with a lead-in phase in TPR patients was to avoid the administration of a PI after a possible RVR under pegIFN/RBV [14].\n\nFigure 1 Efficacy of triple therapy. SVR rates for different subgroups are displayed in A and B, a characterization of treatment failures for the total study population [C] and for BOC versus TPR [D] are given, too. Patients who died after discontinuation of therapy (N = 3) and patients who were lost to follow up (N = 8) were not regarded as being at risk for relapse in C and D. [SVR = sustained virological response; BOC = boceprevir; TPR = telaprevir; IL28B = interleukin 28B polymorphism; BT = breakthrough; PI = protease inhibitor].\n\nFigure 2 Individualized courses of treatment in our “real-life” cohort. Patients are grouped according to the respective guidelines [14,15]. Each symbol represents one patient. Patients with partial response or breakthrough under BOC/TPR are not depicted in A and B, patients with partial response or breakthrough at any time are not depicted in C and D. All BOC patients and TPR patients who received a dual lead-in phase prior to BOC/TPR are included in E. [BOC = boceprevir; TPR = telaprevir; PR = pegylated interferon and ribavirin; SVR = sustained virological response; EOT = patient concluded therapy, but is short of 12 weeks after last ribavirin dose].\n\nAs of now (April 2014), 7 patients (6.9%) are lost to follow-up and are therefore regarded as treatment failures in this analysis.\n\nEfficacy of triple therapy\nOverall, 62 patients (60.8%) were successfully treated and achieved a SVR12. As expected, prior relapsers displayed the highest SVR rate of 72% and prior partial- or null-responders were less likely to achieve SVR12 (46.7%). SVR12 was achieved by 57.4% of treatment naive patients (including cirrhotics) and by 51.2% of patients with bridging fibrosis or liver cirrhosis (Figure 1). Finally, SVR 12 was achieved by 5/10 DAA experienced patients (see figure in Additional file 2, which includes an overview of the treatment regimen and clinical or virological outcome of the trial and the course of therapy with TPR or BOC for each DAA experienced patient, as well as the course of therapy of patients with special comorbidities. Further information on the clinical history of the DAA experienced patients are shown in the Additional file 1).\n\nThe HCV subtype was not significantly associated with SVR12 in our study. However, patients infected with HCV genotype 1a displayed an odds ratio (OR) of 0.4 to achieve SVR12 (95% confidence interval (95%CI) 0.2-1.0, P = 0.06), while patients with HCV genotype 1b displayed an OR of 2.2 to achieve SVR12 (95% CI 1.0-5.0; P = 0.07; see table in Additional file 3). Further analysis of our small cohort revealed that neither the grade of fibrosis, nor the IL28B haplotype, treatment experience, diabetes mellitus type 2, psychiatric disorders, the occurence of a RVR or a reduction of the pegIFN or RBV dose were associated with SVR12 in the univariate analysis (see table in Additional file 3). No independent predictors for SVR12 were identified in the multivariate analysis.\n\nWe also examined the frequency and possible consequences of a shortening of the duration of PI medication from the recommended length [15,16]. This analysis revealed that a higher number of patients on BOC treatment (17/37, 45.9%, mean duration of shortening 3.8 weeks, SD = 8.1) compared to patients on TPR treatment (9/65, 13.8%, mean duration of shortening 0.7 weeks, SD = 2.0, P < 0.01) reduced the time of protease therapy. The mean shortening of TPR duration was 0.8 weeks (SD = 2.2) in patients with later SVR12 and 0.9 weeks (SD = 2.1) in patients who later experienced a viral breakthrough or relapse (P = 0.78, Figure 2B). Patients who experienced virological failure after BOC discontinuation, displayed a mean reduction of BOC medication time of 5.4 weeks (SD = 10.0), compared to 4.0 weeks (SD = 8.1) in BOC patients who achieved SVR12 (P = 0.68, Figure 2A). Patients who experienced a relapse discontinued pegIFN and RBV 6.5 weeks prematurely (SD = 13.4) compared to patients who achieved SVR12 (0.4 weeks (SD = 10.7), P = 0.03, Figure 2C and D). An early termination of pegIFN/RBV frequently led to treatment failures in patients who qualified for shorter treatment duration (24 weeks for TPR or 28 weeks for BOC, respectively), as well as in patients who were at need for 48 weeks of therapy (Figure 2C and D). Due to the small number of patients in each group, we did not perform a subgroup analysis. The duration of the lead-in phase had no statistically significant impact on the treatment outcome, neither in patients treated with TPR (P = 0.30), nor in patients receiving BOC (P = 0.68, Figure 2E).\n\nSide-effects and complications of triple therapy\nDetailed information about all side-effects are shown in Table 2. Severe flu-like symptoms were reported by 44 patients (43.1%) and 43 patients (42.2%) showed gastrointestinal symptoms. Patients receiving BOC suffered more often from dysgeusia (24.3%) and fatigue (40.5%) than patients receiving TPR (1.5% and 18.5%, P < 0.01 and P = 0.02), while TPR based treatment was associated with a high risk for anorectal dyscomfort (36.9% (TPR) versus 2.7% (BOC), P < 0.01).\n\nTable 2 Side effects and serious adverse events in patients receiving triple therapy\n\n \tNumber\tBOC\tTPR\t\nP-V\nalue\t\n \t(N = 102)\t(N = 37)\t(N = 65)\t \t\nGrade 3/4 anemia\t13 (12.7%)§\t4 (10.8%)\t9 (13.8%)\t0.77\t\nGrade 3/4 neutropenia\t25 (24.5%)\t12 (32.4%)\t13 (20%)\t0.23\t\nGrade 3/4 thrombopenia\t14 (13.7%)\t3 (8.1%)\t11 (16.9%)\t0.25\t\nFlu-like symptoms\t44 (43.1%)\t20 (54.1%)\t24 (36.9%)\t0.10\t\nGI disorders\t43 (42.2%)\t16 (43.2%)\t27 (41.5%)\t1\t\nGrade 1/2 rash\t35 (34.3%)\t11 (29.7%)\t24 (36.9%)\t0.52\t\nPsychiatric disorder\t29 (28.4%)§§\t11 (29.7%)\t18 (27.7%)\t1\t\nFatigue\t27 (26.5%)\t15 (40.5%)\t12 (18.5%)\t0.02\t\nAnorectal dyscomfort\t25 (24.5%)\t1 (2.7%)\t24 (36.9%)§§§\t<0.01\t\nInsomnia\t23 (22.5%)\t7 (18.9%)\t16 (24.6%)\t0.63\t\nBronchopulmonal symptoms\t20 (19.6%)\t9 (24.3%)\t11 (16.9%)\t0.44\t\nDysgeusia\t10 (9.8%)\t9 (24.3%)\t1 (1.5%)\t<0.01\t\nImmunothyreoiditis\t4 (3.9%)\t0\t4 (6.2%)\t0.29\t\nSerious adverse event\tNumber\tComments/Outcome\t\nGrade 4 anemia\t2\tBoth patients received blood transfusions\t\nGrade 4 neutropenia\t3\t1 patient with neutropenic sepsis; all 3 recovered after dose reduction of peginterferon\t\nGrade 4 thrombopenia\t6\t1 patient received a platelet concentrate\t\nGrade 3 rash\t4\tTPR was discontinued early in 1 patient\t\nDRESS/SJS\tNone\t-\t\nNeurological symptoms\t2\tRadial nerve paresis (recovery after physiotherapy) and urine incontinency (ongoing)\t\nLocalized infections\t3\tAll fully recovered (balanitis, epididymitis, perspiratory gland abscess)\t\nSepsis\t4\t2 patients recovered; 2 patients died\t\nHepatic decompensation\t2\tBoth recovered, but 1 patient died 6 weeks after discontinuation of treatment\t\nDecompensation of autoimmune disorder\t1\tFirst manifestation of autoimmune diabetes mellitus.\t\nIleus\t2\tFully recovered after surgical intervention (1x) or conservative treatment (1x)\t\nCardiac complications\t1\tUnstable angina pectoris, full recovery after PTCA with stent implantation\t\n30 SAE occured in 22 individuals. [BOC = boceprevir; TPR = telaprevir; N = number; GI = gastrointestinal; DRESS = drug induced rash and eosinophilia with systemic symptoms; SJS = Stevens Johnson syndrome; PTCA = percutaneous coronary angiography; § = 5 patients received transfusion; §§ = 9 patients with history of psychiatric illness; §§§ = hemorrhagic proctitis in 5 patients].\n\nThirty serious adverse events (SAE) occured in 22/102 patients (21.6%). Details on the nature and outcome of the SAE are shown in Table 2.\n\nTragically, two patients died directly following therapy (mortality 1.9%). Both suffered from cirrhosis (baseline Child-Pugh score: 5 and 7; baseline MELD score: 7 and 12) and the patients received TPR after a four week lead-in phase with pegIFN and RBV. More notable, both patients had known diabetes mellitus type 2 with a baseline HbA1c of 7.1 and 7.8%. The patient with the Child-Pugh score of 7 had also a serum albumin < 35 g/l and a thrombocytopenia < 100,000/µl.\n\nIn the univariate analysis advanced age (P = 0.02) and existence of liver cirrhosis (P < 0.01) were both associated with incidence of a predefined SAE. Furthermore, low platelet count and high INR (P < 0.01, each), as well as high ASAT and bilirubin (P = 0.04 and 0.01, respectively) were associated with risk for an episode of a SAE.\n\nAge above 50 years (P < 0.01), thrombocytes < 100,000/μl (P = 0.01), serum albumin < 35 g/l (P = 0.04), ASAT > 100 U/l (P = 0.03) and bilirubin ≥ 1.2 mg/dl (P < 0.01) were significantly associated with the occurence of a SAE (Table 3). Bilirubin ≥ 1.2 mg/dl (OR 13.1; 95%CI 2.1-81.4; P < 0.01) and ASAT > 100 U/l (OR 4.6; 95%CI 1.4-15.1; P = 0.01) were independent predictors for a SAE in the multivariate analysis.\n\nTable 3 Risk factors for occurence of serious adverse events in patients receiving triple therapy\n\n \tNo SAE (N = 80)\tSAE (N = 22)\t\nP\n-Value\t\n \tNumber (%)\tNumber (%)\t \t\n \tMean (±SD)\tMean (±SD)\t \t\n \tMedian (range)\tMedian (range)\t \t\nMale sex\t50 (62.5%)\t13 (59.1%)\t0.81\t\nAge [years]\t46.7 (±12.4)\t53.5 (±7.3)\t0.02\t\nAge > 50 years\t32 (40%)\t16 (72.7%)\t<0.01\t\nLiver cirrhosis\t17 (23.9%)\t12 (57.1%)\t<0.01\t\nDiabetes mellitus type 2\t8 (10%)\t5 (22.7%)\t0.15\t\nPsychiatric disorders\t16 (20%)\t4 (18.2%)\t1\t\nExclusion criteria for registration trials\t48 (60%)\t17 (77.3%)\t0.210\t\nDrug\t \t \t0.45\t\nTelaprevir\t49 (61.3%)\t16 (72.7%)\t \t\nBoceprevir\t31 (38.8%)\t6 (27.3%)\t \t\nBaseline laboratory\t \t \t \t\nHemoglobin [g/dl]\t14.7 (10.3-18.8)\t14.6 (12.3-18.0)\t0.69\t\nLeukocytes [x10^9/l]\t6.2 (3.1-13.1)\t5.9 (2.7-9.5)\t0.79\t\nPlatelets [x10^9/l]\t199.5 (85–377)\t127 (48–329)\t<0.01\t\nASAT [U/l]\t49.5 (16–156)\t67.5 (26–328)\t0.04\t\nALAT [U/l]\t70 (16–255)\t91 (22–271)\t0.28\t\nγGT [U/l]\t62.5 (57–1274)\t72 (25–459)\t0.18\t\nBilirubin [mg/dl]\t0.5 (0.2-1.5)\t0.75 (0.2-2.2)\t0.01\t\nAlbumin [g/l]\t40 (29–50)\t39 (25–44)\t0.11\t\nProthrombin time [INR]\t1.00 (0.9-3.3)\t1.13 (1.0-2.3)\t<0.01\t\nCreatinine [mg/dl]\t0.8 (0.5-5.8)\t0.8 (0.5-1.1)\t0.97\t\nPlatelets < 100,000/μl\t5 (6.3%)\t6 (27.3%)\t0.01\t\nASAT > 100 U/l\t11 (13.8%)\t8 (36.4%)\t0.03\t\nBilirubin ≥ 1.2 mg/dl\t2 (2.5%)\t6 (27.3%)\t<0.01\t\nAlbumin ≤ 35 g/l\t3 (3.8%)\t4 (18.2%)\t0.04\t\nProthrombin time [INR] > 1.2\t4 (5.3%)\t3 (13.6%)\t0.17\t\n[SAE = serious adverse event; N = number; SD = standard deviation; ASAT = aspartate aminotransferase; ALAT = alanine aminotransferase; γGT = gamma-glutamyltransferase; INR = international normalized ratio].\n\nThe frequency of SAE in patients with liver cirrhosis was 41.4% (12/29). In the subgroup analysis of patients with liver cirrhosis, median MELD score of patients with a SAE was higher as compared to patients without complications (9 versus 7; P < 0.01). Low thrombocytes and elevated INR (P < 0.01 and 0.01, respectively) were associated with a SAE, too (see Table in Additional file 4, which displays risk factors for a SAE in cirrhotic patients). The multivariate analysis did not identify any independent predictors for a SAE in the subgroup of cirrhotic patients.\n\nDiscussion\nOur study aimed to extend the data obtained by the registration trials of TPR and BOC and to describe our “real-life” experiences of triple therapy in a large cohort of more than 100 patients including “difficult-to-treat” patients (including patients suffering from autoimmune disorders, as well as patients with a major depression) as well as a great number of patients with advanced liver disease. The frequency of F3 or F4 fibrosis (40.2%) was substantially higher as compared to the frequency of bridging fibrosis or cirrhosis in the participants of the registration trials (F3/F4 in 10 to 28% of patients) [3-7]. Of note, almost two-thirds of our patients would have been ineligible for the various registration trials of TPR or BOC [3-7], 15 patients (14.7%) had a history of partial- or null-response in previous treatment and 10 patients were DAA experienced. Astonishingly, these patients displayed a reasonable chance for SVR and the frequency of SVR12 (60.8%) in our “real-life” cohort was only slightly lower as compared to the results from the registration trials [3-7], but still higher than previous “real-life” data on dual treatment with pegIFN/RBV by us and others [17].\n\nAt the same time – and in concordance with previous reports [9,10] – we saw a high incidence of SAEs especially in patients with liver cirrhosis and even two fatal outcomes in our cohort. Counterintuitively, patients with psychiatric disorders displayed neither a higher rate of treatment failures, nor a higher risk for the incidence of SAE.\n\nThe frequency of treatment failure at week 12 of PI administration was reported to be as high as 29% in previous “real-life” reports [9]. Interestingly, in our cohort only 14.7% of patients experienced a treatment failure until week 12 of PI (13 patients with partial response and 2 patients stopping therapy due to moderate side-effects, Figures 1 and 2). Furthermore, the frequency of SVR was higher as compared to the SVR rate in a most recently published “real-life” cohort [8]. However, our observations might (at least partly) be explained by a higher rate of patients with bridging fibrosis or cirrhosis in these studies, as compared to our cohort [8,9]. On the one hand, the reduction of the pegIFN or RBV dose due to side-effects, as well as an early PI withdrawal (when appropriate) were not associated with lower chances for SVR in our small cohort. On the other hand, an early termination of pegIFN and RBV was determined by us as a risk factor for later relapse. Future prospective studies have to determine whether treatment individualization and de-escalation are indeed a valid option in difficult-to-treat patients to manage side-effects and to achieve a reasonable chance for SVR as seen in this retrospective study.\n\nOur data also indicate, that triple therapy may be a reasonable option for certain DAA-experienced patients, too (Additional file 2). This is an important finding, since the number of DAA-experienced patients will rapidly increase in the future. However, in the future testing of protease inhibitor escape mutations before initiation of re-treatment might be useful in these cases.\n\nWhilst IL28B polymorphism is the strongest pretreatment predictor for SVR in pegIFN/RBV based treatment [18], our results confirm previous reports of limited practical value of IL28B polymorphism for prediction of SVR in patients treated with BOC or TPR [19,20].\n\nElevated ASAT and bilirubin at baseline were the only independent predictors of SAE in our cohort. However, thrombocytopenia and low serum albumin, which have been identified as the key risk factors for hepatic decompensation and death under triple therapy before [10], were also associated with occurence of a SAE in the univariate analysis in our cohort. Since all deceased patients had cirrhosis and diabetes mellitus type 2, cirrhotic patients with diabetes should be treated with special care since they are most likely to experience severe complications. Furthermore, we recommend that patients who display risk factors for complications, should be referred to an experienced viral hepatitis center.\n\nAs a consequence of the treatment complexity of triple therapy with an increased risk for relevant and potentially lethal side-effects, we significantly remodelled procedures at our clinics. Every patient is discussed in a multidisciplinary hepatitis board before HCV triple therapy is initiated. Additionally, every cirrhotic patient is seen by the transplant team before treatment initiation and listed for liver transplantation if deemed necessary.\n\nOur retrospective study has certain limitations. First, in a minority of less than 10% of patients liver cirrhosis was not formally excluded, although none of the patients had any clinical or laboratory signs of liver cirrhosis. Second, we only recorded the fact of RBV dose reduction rather than the individual RBV dose. Since we are associated with a viral hepatitis study center, 81 additional patients (many of them treatment naive) recruited to clinical phase II or III trials during the study period. Finally, our cohort included patients who were previously treated with DAA. Although 50% of the DAA experienced patients achieved SVR12, our study was too small to identify patients who should receive TPR or BOC-based treatment after a virological failure in a DAA based therapy and no assessment of protease excape mutations was performed. However, we believe that this study reflects the “real-life” situation in many large tertiary referral centers and our study provides important learning points in these “challenging-to-treat” patients for other HCV therapy providers worldwide.\n\nConclusions\nIn conclusion, triple therapy with first generation PI provides a reasonable chance for SVR even in “difficult-to-treat” patients, as presented here. However, considering high rates of complications as reported from us and others [9,10], careful patient selection, extensive patient education and precise monitoring are essential, especially in patients with liver cirrhosis.\n\nCompeting interests\nMalte H. Wehmeyer has served as a speaker for BMS. Sabine Jordan, Olaf Degen, Martina Sterneck, Jan van Lunzen, Ansgar W. Lohse, Julian Schulze zur Wiesch and Stefan Lüth have served as speakers for Roche, Janssen-Cilag and MSD. Annette Hennigs has served as a speaker for Janssen-Cilag. Friederike Eißing, Claudia Röder, Anja Hüfner, Sandra Hertling and Stefan Schmiedel declare no conflict of interest.\n\nAuthors’ contributions\nMHW drafted the originial manuscript, contributed to study design, performed the statistical analysis, interpreted the results and collected the data; FE performed additional statistical analysis and collected the data. SJ, AHe, OD, AHü, SH, SS and MS collected the data; CR contributed to the study design; JvL contributed to study design and data collection; AWL critically revised the manuscript; JSzW and SL contributed to study design, collected data and critically revised the manuscript. All authors read and approved the final manuscript.\n\nPre-publication history\nThe pre-publication history for this paper can be accessed here:\n\nhttp://www.biomedcentral.com/1471-230X/14/87/prepub\n\nSupplementary Material\nAdditional file 1\nVirological and adverse events definitions, grading of laboratory events and further information on the DAA experienced patients.\n\nClick here for file\n\n Additional file 2\nCourse of therapy in DAA-experienced patients, as well as in patients with special comorbidities.\n\nClick here for file\n\n Additional file 3\nEvaluation of predictors for SVR12.\n\nClick here for file\n\n Additional file 4\nEvaluation of risk factors for SAE in cirrhotic patients.\n\nClick here for file\n\n Acknowledgements\nBesides the named authors of this manuscript, no further persons contributed to the conception, design, acquisition of data, data analysis, interpretation of data, or was involved in drafting of the manuscript or revising it, respectively.\n\nWe declare no sources of funding regarding this study.\n==== Refs\nGlobal surveillance and control of hepatitis C: report of a WHO consultation organized in collaboration with the viral hepatitis prevention board, Antwerp, Belgium J Viral Hepat 1999 6 35 47 10847128 \nAmin J Law MG Bartlett M Kaldor JM Dore GJ Causes of death after diagnosis of hepatitis B or hepatitis C infection: a large community-based linkage study Lancet 2006 368 938 945 10.1016/S0140-6736(06)69374-4 16962883 \nPoordad F McCone J Bacon BR Bruno S Manns MP Sulkowski MS Jacobson IM Reddy KR Goodman ZD Boparai N DuNubile MJ Sniukiene V Brass CA Albrecht JK Bronowicki JP Boceprevir for untreated chronic HCV genotype 1-infection N Engl J Med 2011 364 1195 206 10.1056/NEJMoa1010494 21449783 \nJacobson IM McHutchison JG Dusheiko G Di Bisceglie AM Reddy KR Bzowej NH Marcellin P Muir AJ Ferenci P Flisiak R George J Rizzetto M Shouval D Sola R Terg RA Yoshida EM Adda N Bengtsson L Sankoh AJ Kieffer TL George S Kauffman RS Zeuzem S Telaprevir for previously untreated chronic hepatitis C virus infection N Engl J Med 2011 364 2405 16 10.1056/NEJMoa1012912 21696307 \nSherman KE Flamm SL Afdhal NH Nelson DR Sulkowski MS Everson GT Fried MW Adler M Reesink HW Martin M Sankoh AJ Adda N Kauffman RS George S Wright CI Poordad F Response-guided telaprevir combination treatment for hepatitis C virus infection N Engl J Med 2011 365 1014 24 10.1056/NEJMoa1014463 21916639 \nBacon BR Gordon SC Lawitz E Marcellin P Vierling JM Zeuzem S Poordad F Goodman ZD Sings HL Boparai N Burroughs M Brass CA Albrecht JK Esteban R Boceprevir for previously treated chronic HCV genotype 1 infection N Engl J Med 2011 364 1207 17 10.1056/NEJMoa1009482 21449784 \nZeuzem S Andreone P Pol S Lawitz E Diago M Roberts S Focaccia R Younossi Z Foster GR Horban A Ferenci P Nevens F Müllhaupt B Pockros P Terg R Shouval D van Hoek B Weiland O Van Heeswijk R De Meyer S Luo D Boogaerts G Polo R Picchio G Beumont M Telaprevir for retreatment of HCV infection N Engl J Med 2011 364 2417 28 10.1056/NEJMoa1013086 21696308 \nBackus LI Belperio PS Shahoumian TA Cheung R Mole LA Comparative effectiveness of the hepatitis C virus protease inhibitors boceprevir and telaprevir in a large U.S. cohort Aliment Pharmacol Ther 2014 39 93 103 10.1111/apt.12546 24206566 \nMaasoumy B Port K Markova AA Serrano BC Rogalska-Taranta M Sollik L Mix C Kirschner J Manns MP Wedemeyer H Cornberg M Eligibility and safety of triple therapy for hepatitis C: lessons learned from the first experience in a real world setting PLoS ONE 8 2 e55285 doi:10.1371/journal.pone.0055285 23383319 \nHézode C Fontaine H Dorival C Larrey D Zoulim F Canva V de Ledinghen V Poynard T Samuel D Bourlière M Zarski JP Raabe JJ Alric L Marcellin P Riachi G Bernard PH Loustaud-Ratti V Métivier S Tran A Serfaty L Abergel A Causse X Di Martino V Guyader D Lucidarme D Grando-Lemaire V Hillon P Feray C Dao T Cacoub P Triple therapy in treatment-experienced patients with hcv-cirrhosis in a multicentre cohort from the french early access programme (anrs co20-CUPIC) – NCT01514890 J Hepatol 2013 59 434 441 10.1016/j.jhep.2013.04.035 23669289 \nCastera L Forns X Alberti A Non-invasive evaluation of liver fibrosis using transient elastography J Hepatol 2008 48 835 47 10.1016/j.jhep.2008.02.008 18334275 \nPugh RNH Murray-Lyon IM Dawson JL Pietroni MC Williams R Transection of the oesophagus for bleeding oesophageal varices Br J Surg 1973 60 646 9 10.1002/bjs.1800600817 4541913 \nKamath PS Wiesner RH Malinchoc M Kremers W Therneau TM Kosberg CL D’Amico G Dickson ER Kim WR A model to predict survival in patients with end-stage liver disease Hepatology 2001 33 464 70 10.1053/jhep.2001.22172 11172350 \nFried MW Hadziyannis SJ Shiffman ML Messinger D Zeuzem S Rapid virological response is the most important predictor of sustained virological response across genotypes in patients with chronic hepatitis C virus infection J Hepatol 2011 55 69 75 10.1016/j.jhep.2010.10.032 21145856 \nGhany MG Nelson DR Strader DB Thomas DL Seeff LB An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American association for the study of liver diseases Hepatology 2011 54 1433 44 10.1002/hep.24641 21898493 \nSarrazin C Berg T Cornberg M Dollinger M Ferenci P Hinrichsen H Klinker H Kraus M Manns M Mauss S Peck-Radosavljevic M Schmidt H Spengler U Wedemeyer H Wirth S Zeuzem S Expert opinion on boceprevir- and telaprevir-based triple therapies of chronic hepatitis C Z Gastroenterol 2012 50 57 72 22222799 \nSchulze zur Wiesch J Pudelski N Hoepner L Supplieth M Buggisch P Lohse AW Lüth S “Real-life” comparison of pegylated-interferon 2a versus 2b combination therapy of chronic hepatitis c virus Hepatology 2011 53 1405 1406 10.1002/hep.24233 21480360 \nThompson AJ Muir AJ Sulkowski MS Ge D Fellay J Shianna KV Urban T Afdhal NH Jacobson IM Esteban R Poordad F Lawitz EJ McCone J Shiffman ML Galler GW Lee WM Reindollar R King JW Kwo PY Ghalib RH Freilich B Nyberg LM Zeuzem S Poynard T Vock DM Pieper KS Patel K Tillmann HL Noviello S Koury K Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virological response in genotype 1 hepatitis C virus Gastroenterology 2010 139 120 129 10.1053/j.gastro.2010.04.013 20399780 \nPol S Aerssens J Zeuzem F Andreone P Lawitz EJ Roberts S Younossi Z Foster GR Focaccia R Horban A Pockros PJ Van Heeswijk RP De Meyer S Luo D Botfield M Beumont M Picchio G Limited impact of IL28B genotype on response rates in telaprevir-treated patients with prior treatment failure J Hepatol 2013 58 883 889 10.1016/j.jhep.2012.12.023 23321318 \nPoordad F Bronowicki JP Gordon SC Zeuzem S Jacobson IM Sulkowski MS Poynard T Morgan TR Molony C Pedicone LD Sings HL Burroughs MH Sniukiene V Boparai N Goteti VS Brass CA Albrecht JK Bacon BR Factors that predict response of patients with hepatitis C virus infection to boceprevir Gastroenterology 2012 143 608 618 10.1053/j.gastro.2012.05.011 22626609\n\n",
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"issn_linking": "1471-230X",
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"mesh_terms": "D000998:Antiviral Agents; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D016898:Interferon-alpha; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides; D011092:Polyethylene Glycols; D011392:Proline; D011480:Protease Inhibitors; D012254:Ribavirin; D016896:Treatment Outcome; D019562:Viral Load",
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"title": "Safety and efficacy of protease inhibitor based combination therapy in a single-center \"real-life\" cohort of 110 patients with chronic hepatitis C genotype 1 infection.",
"title_normalized": "safety and efficacy of protease inhibitor based combination therapy in a single center real life cohort of 110 patients with chronic hepatitis c genotype 1 infection"
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"literaturereference": "WEHMEYER MH, EIBING F, JORDAN S, RODER C, HENNINGS A, DEGEN O, ET AL.. SAFETY AND EFFICACY OF PROTEASE INHIBITOR BASED COMBINATION THERAPY IN A SINGLE CENTER REAL-LIFE COHORT OF 110 PATIENTS WITH CHRONIC HEPATITIS C GENOTYPE 1 INFECTION.. MBC GASTROENTEROLOGY. 2014;14:10",
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{
"abstract": "It is unclear whether immunosuppression is a risk factor for herpes encephalitis. Herein, we describe a rare case of herpes simplex virus type 2 encephalitis in a patient treated with low-dose methotrexate for HLA-B27-associated spondyloarthritis. The patient was successfully treated with acyclovir but presented sequelae of encephalitis. Here we discuss the possible role of low-dose methotrexate therapy as a risk factor of neurological herpes reactivation and severe disease. The host-related and viral risk factors are also addressed.",
"affiliations": "Laboratory of Virology, University Hospital of Grenoble, Grenoble, France.;Infectious Diseases Department, University Hospital of Grenoble, Grenoble, France.;Laboratory of Virology, University Hospital of Grenoble, Grenoble, France.;Laboratory of Virology, University Hospital of Grenoble, Grenoble, France.;Infectious Diseases Department, University Hospital of Grenoble, Grenoble, France.;Infectious Diseases Department, University Hospital of Grenoble, Grenoble, France.;Laboratory of Virology, University Hospital of Grenoble, Grenoble, France.",
"authors": "Lupo|Julien|J|;Dos Santos|Ophélie|O|;Germi|Raphaele|R|;Baccard-Longère|Monique|M|;Stahl|Jean-Paul|JP|;Epaulard|Olivier|O|;Morand|Patrice|P|",
"chemical_list": "D000998:Antiviral Agents; D015796:HLA-B27 Antigen; D007166:Immunosuppressive Agents; D000212:Acyclovir; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.3851/IMP3110",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1359-6535",
"issue": "22(4)",
"journal": "Antiviral therapy",
"keywords": null,
"medline_ta": "Antivir Ther",
"mesh_terms": "D000212:Acyclovir; D000368:Aged; D000998:Antiviral Agents; D000075203:Contraindications, Drug; D020803:Encephalitis, Herpes Simplex; D015870:Gene Expression; D015796:HLA-B27 Antigen; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008727:Methotrexate; D012307:Risk Factors; D013167:Spondylitis, Ankylosing",
"nlm_unique_id": "9815705",
"other_id": null,
"pages": "357-359",
"pmc": null,
"pmid": "27879484",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Herpes simplex type 2 encephalitis and methotrexate medication: a fortuitous or causative association in a patient with spondyloarthritis?",
"title_normalized": "herpes simplex type 2 encephalitis and methotrexate medication a fortuitous or causative association in a patient with spondyloarthritis"
} | [
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{
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},
{
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},
{
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},
{
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},
{
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},
{
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},
{
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{
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{
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},
{
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},
{
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{
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{
"reactionmeddrapt": "Electroencephalogram abnormal",
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}
],
"summary": null
},
"primarysource": {
"literaturereference": "LUPO, J.. HERPES SIMPLEX TYPE 2 ENCEPHALITIS AND METHOTREXATE MEDICATION: A FORTUITOUS OR CAUSATIVE ASSOCIATION IN A PATIENT WITH SPONDYLOARTHRITIS?. ANTIVIRAL THERAPY. 2016?22 (4):357-359",
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},
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}
] |
{
"abstract": "Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is a granulomatous, non-IgE-mediated hypersensitivity reaction of the alveoli and distal bronchioles presenting as an acute, subacute or chronic condition. It is most commonly associated with exposure to extrinsic allergens (eg, avian dust, mould and tobacco) and medications including antiarrhythmics (eg, amiodarone), cytotoxics (eg, methotrexate) and antiepileptics (eg, carbamazepine). Individuals diagnosed with this condition can present with severe hypoxia and respiratory failure. The fundamental principle of management is to remove the causative allergen. Evidence implicating selective serotonin reuptake inhibitors as a causative agent is limited, and this case report describes a rare clinical presentation of HP associated with sertraline, how it was diagnosed and subsequently treated. It is anticipated that raising awareness of this interaction will assist multidisciplinary teams, managing patients diagnosed with HP, to be more cognisant of sertraline as being an aetiological factor for this condition.",
"affiliations": "Pharmacy Department, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK gursharan.vryaparj@nhs.net.;Critical Care Services, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.;Mental Health, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.;Critical Care Services, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.",
"authors": "Virdee|Gursharan|G|;Bleasdale|John|J|;Ikramullah|Mohammed|M|;Graham-Clarke|Emma|E|http://orcid.org/0000-0001-5657-778X",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D020280:Sertraline",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-230724",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(12)",
"journal": "BMJ case reports",
"keywords": "Unwanted effects / adverse reactions; adult intensive care; interstitial lung disease; psychiatry (drugs and medicines); respiratory medicine",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000542:Alveolitis, Extrinsic Allergic; D002637:Chest Pain; D003371:Cough; D003937:Diagnosis, Differential; D004417:Dyspnea; D005260:Female; D006801:Humans; D008875:Middle Aged; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31862812",
"pubdate": "2019-12-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sertraline-induced hypersensitivity pneumonitis.",
"title_normalized": "sertraline induced hypersensitivity pneumonitis"
} | [
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}
},
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}
},
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{
"abstract": "A 55-year-old Filipina with Grave's disease, diabetes, hypertension, bronchial asthma, Parkinson's disease and a history of adverse drug reaction to penicillin consulted due to high-grade fever and sore throat. Patient was diagnosed with aplastic anaemia secondary to methimazole and was treated with high-dose granulocyte colony stimulating factor, thrombopoietin and mesterolone. Antibiotics used included levofloxacin, clindamycin, amikacin and fluconazole. Due to bleeding and slow recovery of blood parameters, 30 units of platelets and 7 units of packed red blood cells were transfused during her 22-day admission. This case presents a life-threatening adverse drug reaction in a patient with co-morbid conditions that complicate recovery and limit one's therapeutic options.",
"affiliations": "Medicine Department, University of the Philippines Philippine General Hospital, Manila, Philippines. josolcindy@yahoo.co006D",
"authors": "Josol|Cindy V|CV|;Buenaluz-Sedurante|Myrna|M|;Sandoval|Mark Anthony|MA|;Castillo|Gerry|G|",
"chemical_list": "D013956:Antithyroid Agents; D008713:Methimazole",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2010()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000741:Anemia, Aplastic; D013956:Antithyroid Agents; D048909:Diabetes Complications; D005260:Female; D006111:Graves Disease; D006801:Humans; D008713:Methimazole; D008875:Middle Aged; D012074:Remission Induction; D012720:Severity of Illness Index",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "22802368",
"pubdate": "2010-12-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18549331;15242574;9462542;18816182;171299;16553037;9777751;11443640;6188311;15072706;10544668;2000892;10627862;15745981",
"title": "Successful treatment of methimazole-induced severe aplastic anaemia in a diabetic patient with other co-morbidities.",
"title_normalized": "successful treatment of methimazole induced severe aplastic anaemia in a diabetic patient with other co morbidities"
} | [
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},
{
"reactionmeddrapt": "Aplastic anaemia",
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},
{
"reactionmeddrapt": "Rhonchi",
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},
{
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},
{
"reactionmeddrapt": "Oropharyngeal pain",
"reactionmeddraversionpt": "18.0",
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},
{
"reactionmeddrapt": "Micrococcus infection",
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},
{
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},
{
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},
{
"reactionmeddrapt": "Pneumonia klebsiella",
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},
{
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{
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{
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{
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}
] |
{
"abstract": "This report describes a single institution's recent experience with six patients fulfilling the diagnostic criteria of chronic neutrophilic leukemia. No patient had the Philadelphia chromosome or the BCR/ABL fusion gene. None of the common cytogenetic abnormalities characteristic of myeloid disorders were detected. Two patients demonstrated clonal evolution during the course of the disease. All responded initially to therapy with hydroxyurea with control of leukocytosis and reduction in splenomegaly. Three patients eventually became refractory to hydroxyurea, manifesting progressive neutrophilia without blastic transformation. Aggressive chemotherapy to control progressive leukocytosis resulted in death due to cytopenias in two of these patients. The third patient received less intensive chemotherapy and died of progressive disease. One patient died after transformation of the disease into undifferentiated acute myeloid leukemia. Two patients remain alive with stable disease on hydroxyurea therapy, 12 and 54 months after initial diagnosis. Chronic neutrophilic leukemia is a rare clinicopathologic entity that can be distinguished from chronic myelogenous leukemia, the recently described neutrophilic-chronic myelogenous leukemia, and myelodysplastic syndrome. The clinical course is heterogeneous, with a definite risk of death from either blastic transformation or progressive neutrophilic leukocytosis. Continued study and reporting of these cases must be encouraged.",
"affiliations": "Division of Hematology and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.",
"authors": "Elliott|M A|MA|;Dewald|G W|GW|;Tefferi|A|A|;Hanson|C A|CA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/sj.leu.2401993",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "15(1)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D006801:Humans; D015467:Leukemia, Neutrophilic, Chronic",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "35-40",
"pmc": null,
"pmid": "11243396",
"pubdate": "2001-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Chronic neutrophilic leukemia (CNL): a clinical, pathologic and cytogenetic study.",
"title_normalized": "chronic neutrophilic leukemia cnl a clinical pathologic and cytogenetic study"
} | [
{
"companynumb": "US-PFIZER INC-2018151803",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
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"medicinalproduct": "CYTARABINE."
}
],
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"reaction": [
{
"reactionmeddrapt": "Cytopenia",
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"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ELLIOTT, M.. CHRONIC NEUTROPHILIC LEUKEMIA (CNL): A CLINICAL, PATHOLOGIC AND CYTOGENETIC STUDY. LEUKEMIA. 2001?15 (1):35-40",
"literaturereference_normalized": "chronic neutrophilic leukemia cnl a clinical pathologic and cytogenetic study",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180413",
"receivedate": "20180413",
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},
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"safetyreportversion": 1,
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
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"seriousnessdeath": 1,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20180711"
},
{
"companynumb": "US-PFIZER INC-2018151395",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
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"medicinalproduct": "CYTARABINE."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IDARUBICIN HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": null,
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"medicinalproduct": "IDARUBICIN HCL"
}
],
"patientagegroup": null,
"patientonsetage": "66",
"patientonsetageunit": "801",
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cytopenia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ELLIOTT, M.. CHRONIC NEUTROPHILIC LEUKEMIA (CNL): A CLINICAL, PATHOLOGIC AND CYTOGENETIC STUDY. LEUKEMIA. 2001?15 (1):35-40",
"literaturereference_normalized": "chronic neutrophilic leukemia cnl a clinical pathologic and cytogenetic study",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180413",
"receivedate": "20180413",
"receiver": {
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},
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20180711"
}
] |
{
"abstract": "Enteric-coated mycophenolate sodium (EC-MPS) has a mean half-life of 11.7 hours, which encouraged hope of using this drug once daily in a nonadherent adolescent SLE patient. This is a case report on a 17-year-old adolescent with a history of noncompliance who was switched from twice-daily mycophenolate mofetil (MMF) to once-daily EC-MPS. The EC-MPS dose was equimolar to the daily MMF dose (1 g MMF BID and 1.44 g of EC-MPS OD). The active compound of both drugs, mycophenolic acid, was measured using a commercially available EMIT assay. Both drugs were well-tolerated and maintained remission of the SLE. The average of three 12-hour areas under the time-concentration curves (AUC) on 1 g of MMF BID was 59.0 mgxh/L. In contrast, the 24-hour AUC after 1.44 g EC-MPS OD was 283.2 mgxh/L, more than double the expected 118.0 mgxh/L of two MMF dosing intervals. A repeat 24-hour AUC after 1.08 g of EC-MPS was 218.2 mgxh/L. EC-MPS once daily may be a well-tolerated therapeutic option for nonadherent adolescent lupus patients, but may be associated with a significantly higher exposure than the equivalent MMF BID dose.",
"affiliations": "Division of Nephrology, Children's Hospital of Eastern Ontario, University of Ottawa, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada. filler@cheo.on.ca",
"authors": "Filler|Guido|G|;Lathia|Anita|A|;LeBlanc|Claire|C|;Christians|Uwe|U|",
"chemical_list": "D013608:Tablets, Enteric-Coated; D009173:Mycophenolic Acid",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-006-0139-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-041X",
"issue": "21(8)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": null,
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D000293:Adolescent; D004334:Drug Administration Schedule; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D009173:Mycophenolic Acid; D013608:Tablets, Enteric-Coated",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "1206-8",
"pmc": null,
"pmid": "16721583",
"pubdate": "2006-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14565799;12687454;16269051;16418692;12189120;15569333;9636479;15907141;8699340;15816878;11750390;14974944;15163278;15803925",
"title": "Unexpectedly high exposure to enteric-coated mycophenolate sodium upon once-daily dosing.",
"title_normalized": "unexpectedly high exposure to enteric coated mycophenolate sodium upon once daily dosing"
} | [
{
"companynumb": "NVSC2019CA048269",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
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"drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS",
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"medicinalproduct": "AZATHIOPRINE."
},
{
"actiondrug": "1",
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"activesubstancename": "PREDNISONE"
},
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"drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS",
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"medicinalproduct": "PREDNISONE."
},
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
"drugadministrationroute": "048",
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"drugdosagetext": "900 MG/M2, QD",
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"drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS",
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"medicinalproduct": "MYCOPHENOLATE MOFETIL."
},
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
"drugadministrationroute": "048",
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"drugcumulativedosagenumb": null,
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"drugdosagetext": "1322 MG/M2, QD",
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"drugintervaldosagedefinition": "804",
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"medicinalproduct": "MYCOPHENOLATE MOFETIL."
}
],
"patientagegroup": null,
"patientonsetage": "17",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Glomerulonephritis rapidly progressive",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Systemic lupus erythematosus",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Haematuria",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FILLER G, LATHIA A, LEBLANC C, CHRISTIANS U. UNEXPECTEDLY HIGH EXPOSURE TO ENTERIC-COATED MYCOPHENOLATE SODIUM UPON ONCE-DAILY DOSING. PEDIATRIC NEPHROLOGY. 2006?2006(21):1206-8",
"literaturereference_normalized": "unexpectedly high exposure to enteric coated mycophenolate sodium upon once daily dosing",
"qualification": "3",
"reportercountry": "CA"
},
"primarysourcecountry": "CA",
"receiptdate": "20191129",
"receivedate": "20191129",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17094148,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200122"
}
] |
{
"abstract": "OBJECTIVE\nOptimal function of both the olfactory sensory neurons and the olfactory mucosa is a prerequisite for normal olfactory perception. Both the olfactory neurons and mucosa might be subjects to the neurotoxic and mucotoxic effects of chemotherapy. Despite the recognized importance of olfaction in nutrition and quality of life, the potential olfactory toxicity of chemotherapy regimens has not been adequately assessed. The aim of this study is to investigate whether mucotoxic and/or neurotoxic drugs compromise olfactory performance.\n\n\nMETHODS\nForty-four consecutive patients completed the \"Sniffin' Sticks\" test, an objective quantitative/qualitative method to assess olfactory function, at diagnosis and immediately before the infusion of the last session of three to four chemotherapy cycles, according to the therapeutic protocol. The patients underwent therapy containing oxaliplatin and antimetabolites (5-FU or capecitabine; O+A group), taxanes and platinum analogues (cisplatin and carboplatin; T+P group), or taxanes and anthracyclines (doxorubicin or liposomal doxorubicin; T+A group).\n\n\nRESULTS\nA significant decrease was noted for olfactory threshold (OT), olfactory discrimination (OD), olfactory identification (OI), and the composite threshold-discrimination-identification (TDI) score. A significant deterioration of all olfactory indices was found for each chemotherapy group. Pairwise comparisons revealed significant differences between the O+A and the T+P group regarding OT and TDI. TDI scores were significantly lower after chemotherapy in all age groups. Patients older than 50 years were found to be more susceptible to olfactory toxicity than younger patients.\n\n\nCONCLUSIONS\nPatients who undergo chemotherapy experience significant compromise in their olfactory function. A grading system for olfactory toxicity is proposed.",
"affiliations": "University Clinic of Otorhinolaryngology, Democritus University of Thrace, Alexandroupolis, Greece, mariariga@hotmail.com.",
"authors": "Riga|Maria|M|;Chelis|Leonidas|L|;Papazi|Theano|T|;Danielides|Vasilios|V|;Katotomichelakis|Michael|M|;Kakolyris|Stylianos|S|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-015-2675-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "23(10)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": null,
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000857:Olfaction Disorders; D011788:Quality of Life; D012684:Sensory Thresholds; D012903:Smell",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "3053-8",
"pmc": null,
"pmid": "25739754",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article",
"references": "11377146;23604521;20084814;17265664;20603708;19289621;8866108;24830939;14627537;15827551;11545724;17202939;17280921;18948833;11603794;18677278;22481492;24272785;22682776;9056084",
"title": "Hyposmia: an underestimated and frequent adverse effect of chemotherapy.",
"title_normalized": "hyposmia an underestimated and frequent adverse effect of chemotherapy"
} | [
{
"companynumb": "GR-ROCHE-1631182",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "OXALIPLATIN."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "020896",
"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugcumulativedosageunit": null,
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CAPECITABINE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Anosmia",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "RIGA M, CHELIS L, PAPAZI T, DANIELIDES V, KATOTOMICHELAKIS M AND KAKOLYRIS S. HYPOSMIA: AN UNDERESTIMATED AND FREQUENT ADVERSE EFFECT OF CHEMOTHERAPY. SUPPORTIVE CARE IN CANCER 2015;23 (10):3053-3058.",
"literaturereference_normalized": "hyposmia an underestimated and frequent adverse effect of chemotherapy",
"qualification": "3",
"reportercountry": "GR"
},
"primarysourcecountry": "GR",
"receiptdate": "20150909",
"receivedate": "20150909",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 11475295,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20151125"
}
] |
{
"abstract": "Tuberculosis (TB) of thyroid gland is rare entity even in solid organ transplant recipients who have a high risk of TB. Thyroid TB is easily diagnosed by fine needle aspiration cytology. The majority of cases require only antitubercular drugs for treatment, and surgical intervention is required only in few patients. We here describe a case of thyroid TB presenting as an acute abscess in postrenal transplant recipient with a background of acute rejection treated with steroid and antithymocyte globulin.",
"affiliations": "Department of Nephrology and Renal Transplantation, BLK Super Speciality Hospital, New Delhi, India.;Department of Nephrology and Renal Transplantation, BLK Super Speciality Hospital, New Delhi, India.;Department of Nephrology and Renal Transplantation, BLK Super Speciality Hospital, New Delhi, India.;Department of Nephrology and Renal Transplantation, BLK Super Speciality Hospital, New Delhi, India.;Department of Nephrology and Renal Transplantation, BLK Super Speciality Hospital, New Delhi, India.;Department of Nephrology and Renal Transplantation, BLK Super Speciality Hospital, New Delhi, India.;Department of Nephrology and Renal Transplantation, BLK Super Speciality Hospital, New Delhi, India.",
"authors": "Engineer|D P|DP|;Prakash|S|S|;Yadav|A|A|;Kumhar|J|J|;Biswas|A|A|;Kunal|G|G|;Goel|A|A|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijn.IJN_335_16",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-27-46210.4103/ijn.IJN_335_16Case ReportAcute Thyroid Swelling in Renal Transplant Recipient Engineer D. P. Prakash S. Yadav A. Kumhar J. Biswas A. Kunal G. Goel A. Department of Nephrology and Renal Transplantation, BLK Super Speciality Hospital, New Delhi, IndiaAddress for correspondence: Dr. D. P. Engineer, Department of Nephrology and Renal Transplantation, BLK Super Speciality Hospital, New Delhi - 110 005, India. E-mail: engineerdivyeshp@gmail.comNov-Dec 2017 27 6 462 464 Copyright: © 2017 Indian Journal of Nephrology2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Tuberculosis (TB) of thyroid gland is rare entity even in solid organ transplant recipients who have a high risk of TB. Thyroid TB is easily diagnosed by fine needle aspiration cytology. The majority of cases require only antitubercular drugs for treatment, and surgical intervention is required only in few patients. We here describe a case of thyroid TB presenting as an acute abscess in postrenal transplant recipient with a background of acute rejection treated with steroid and antithymocyte globulin.\n\nRenal transplantthyroid glandtuberculosis\n==== Body\nIntroduction\nTuberculosis (TB) of the thyroid gland is rare even in areas where the prevalence of TB is very high.[1] There is no case report or case series of thyroid TB among solid organ transplant (SOT) recipients who otherwise have a very high risk of acquiring TB. The condition usually mimics more common thyroid conditions such as adenoma, carcinoma, lymphoma, or multinodular goiter. This leads to a delay in diagnosis and unnecessary surgical intervention. We describe a case of a renal transplant recipient who had TB of the thyroid gland that presented as acute thyroid abscess.\n\nCase Report\nA 51-year-old male patient underwent spousal renal transplantation in February 2014 for chronic kidney disease of undetermined etiology. He was on maintenance hemodialysis through arteriovenous fistula for 10 months before transplant. Pretransplant complement-dependent cytotoxicity crossmatch was negative with six human leukocyte antigen (HLA) mismatch. HLA panel reactive antibody screen by Luminex was negative. Induction was done with rabbit antithymocyte globulin (rATG) 1 mg/kg/day for 3 days (total dose of 3 mg/kg). Maintenance immunosuppression consisted of prednisolone, tacrolimus, and mycophenolate mofetil. Mycophenolate sodium dose was 720 mg twice a day for first 6 months and subsequently reduced to 360 mg thrice a day. Cytomegalovirus (CMV) status was D+/R+ and patient received valganciclovir prophylaxis for 3 months. The immediate posttransplant course was uneventful, and he was discharged on posttransplant day 7 with serum creatinine of 1.03 mg/dl.\n\nHe presented to the hospital with a fever and productive cough 2 years after transplant in January 2016. On evaluation, he was found to have acute graft dysfunction with rise of serum creatinine from baseline of 1.1 mg/dl to 3.08 mg/dl. The patient was drug compliant and his trough tacrolimus level was 6.5 ng/ml. Sputum for Gram-stain and for acid-fast bacilli (AFB) was negative. Sputum culture was sterile. High-resolution computed tomography (CT) thorax was normal. Allograft biopsy was done which was suggestive of acute cellular rejection (ACR, Banff Ib) with plasma cell infiltration and negative C4d. He was given pulse methylprednisolone (500 mg intravenous daily for 3 days). There was no response to pulse steroid with serum creatinine hovering around 3.5 mg/dl for the next 7 days. In view of steroid resistant ACR, rATG was administered at dose of 1 mg/kg/day for 3 days. There was no response to rATG, and serum creatinine remained between 3.5 and 3.8 mg/dl on follow-up. Unfortunately, he developed herpes zoster of thoracic dermatome in March 2016. He was treated with acyclovir with temporary cessation of mycophenolate mofetil.\n\nHe was again admitted to the hospital in April 2016 with a rapidly increasing painful swelling in anterior part of neck with low-grade fever for 5 days. On examination, there was a 4 cm × 4 cm size, rounded, fluctuant, tender midline swelling in anterior neck [Figure 1]. There was no palpable cervical or axillary lymphadenopathy and rest of the clinical examination was unremarkable. There were no signs or symptoms suggestive of hypothyroidism or hyperthyroidism.\n\nFigure 1 Rounded midline swelling in anterior neck\n\nInvestigations\nHematological investigations revealed hemoglobin of 10 g% and total leukocyte count 12,500/mm3 with 72% neutrophils. Thyroid function test was normal. Serum creatinine was 4.56 mg/dl. Chest X-ray was unremarkable. CT neck was suggestive of thyroid abscess [Figure 2].\n\nFigure 2 Sagittal section of computed tomography scan of neck showing thyroid abscess\n\nTreatment and follow-up\nIncision and drainage was done and around 20 ml pus was drained. Pus was positive for AFB. Culture of pus was positive for Mycobacterium tuberculosis and was sensitive to all first-line antitubercular drugs. He was started on the intensive phase of antitubercular therapy consisting of isoniazid, pyrazinamide, ethambutol with moxifloxacin for first 2 months. Mycophenolate was stopped. Tubercular abscess responded to treatment with complete disappearance of fever and neck swelling in 2 weeks. Subsequently, the patient was started on maintenance phase of antitubercular therapy consisting of isoniazid, ethambutol, and moxifloxacin for the next 10 months. During subsequent follow-up, there was gradual rise of serum creatinine, and he was started on maintenance hemodialysis in July 2016. Until the last follow-up, the patient was afebrile and doing well on regular maintenance hemodialysis.\n\nDiscussion\nIndia is a country with the highest burden of TB. The World Health Organisation statistics for 2015 gives an estimated incidence of 2.2 million cases of TB in India; the global incidence is 9.6 million. In 2015, the estimated prevalence of TB in India was 2.5 million.[2]\n\nThe incidence of TB among recipients of SOT is estimated to be 20–74 times more than the general population.[3] The incidence among renal transplant recipients was 0.35%–1.2% in the United States, 0.7%–5% in Europe, 3.1%–5% in Southeast Asia, and 5%–15% in India and Pakistan.[3] The incidence of TB in south India in pretransplant patients is 8.7%, and that in renal allograft recipients is 12.3%.[4] The reported incidence from North Indian centre is similar.[5] In the study by Das et al., the incidence of tuberculous thyroiditis was 0.6%.[6]\n\nSeveral studies have described risk factors for the development of TB in transplant recipients. Among the risk factors are immunosuppressive treatment with OKT3 or anti-T cell antibodies, diabetes mellitus, chronic liver disease (in kidney transplant recipients), coexisting infections (e.g., Cytomegalovirus infection, deep mycosis, Pneumocystis jirovecii pneumonia, and nocardia infection), and lesions on a chest radiograph suggestive of previous TB infection.[7] Our patient received rATG both for induction and as part of anti-rejection therapy which might have predisposed him to TB. There was no family history or history of TB or history of any contact.\n\nAbout one-third to one-half of all cases of active TB after transplantation are disseminated or occur at extrapulmonary sites, compared to only about 15% of cases in the general population.[8] Although extrapulmonary TB is common in transplant recipients, the involvement of thyroid is very rare. Reasons for the uncommon involvement of thyroid by infections is unknown, but possible explanations are its encapsulation, high iodide content, rich blood supply, and extensive lymphatic drainage. Suppurative thyroiditis is usually caused by bacterial infection, but fungal, mycobacterial, or parasitic infections can also occur.[9]\n\nThyroid TB is usually seen secondary to tubercular infection of other organ or tissue due to hematogenous spread. Clinical presentation of thyroid TB varies widely. More common is miliary spread to thyroid gland as part of the generalized dissemination or, less commonly, focal caseous TB presenting as a thyroid nodule mimicking carcinoma or in late stages forming a cold abscess.[10] Five patterns have been described: multiple lesions associated with miliary TB, goiter with caseation, cold abscess formation, chronic fibrosing TB, and acute abscess.[11] Our patient presented with an acute abscess.\n\nThyroid function usually remains normal, but cases of hypothyroidism due to extensive glandular destruction by caseous necrosis have been described.[12] A case of hyperthyroidism preceding hypothyroidism has also been described signifying tubercular thyroiditis.[13]\n\nThe diagnosis is usually made by fine needle aspiration cytology (FNAC) or after histopathological examination of the resected surgical specimen when FNAC is negative. Characteristic finding of central caseous necrosis with peripheral lymphocytic infiltration and Langhans giant cells is typical of TB. In addition, the presence of AFB confirms the diagnosis. On histopathology many conditions affecting thyroid cause granulomatous inflammation such as granulomatous thyroiditis, TB, fungal infection, sarcoidosis, granulomatous vasculitis, and foreign body reaction. However, caseous necrosis is seen only in tuberculous inflammation.[14]\n\nTreatment with antitubercular therapy has been shown to result in complete resolution of thyroid TB in the majority of cases, although adjunctive drainage of abscess can be useful in case of the large abscess.[14]\n\nAntitubercular therapy in transplant recipients differs from that in the general population due to potential interactions between rifampicin and immunosuppressive medications. Potential drug interactions of rifampicin with calcineurin inhibitors, mycophenolate, mammalian target of rapamycin (mTOR) inhibitor and corticosteroid increase risk of allograft rejection. Rifabutin is a good option as it has similar efficacy and less risk of drug interaction but experience in transplant recipients is limited.[15] When rifampicin is used, the dose of calcineurin inhibitor and mTOR is increased 3–5-fold because of induction of cytochrome P450 3A4 by rifampicin. Close monitoring of drug levels and close follow-up of patients is also required. In developing country like India, this increases cost of posttransplant care. In patients with severe or disseminated forms of TB or with suspicion of resistance to isoniazid, rifampicin should be used. In localized, nonsevere form of TB, rifampicin sparing regimen can be used. Duration of treatment is controversial in view of lack of studies in SOT recipients. In rifampicin-based regimen total duration of therapy is 9 months. In rifampicin sparing regimen, treatment should continue for 12–18 months with use of isoniazid and ethambutol. The addition of third drug such as levofloxacin or pyrazinamide may be considered which may help to reduce the duration of maintenance phase.[15]\n\nConclusion\nTB of the thyroid is rare and may mimic more common thyroid conditions such as adenoma, carcinoma, lymphoma, or multinodular goiter. This diagnosis should always be considered in a patient with neck swelling especially among residents of endemic countries and in SOT recipients.[1]\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Raman L Murray J Banka R Primary tuberculosis of the thyroid gland: An unexpected cause of thyrotoxicosis BMJ Case Rep 2014 2014 pii: Bcr2013202792 \n2 TB Statistics for India | National and State Statistics 2016 Last cited on 2016 Sep 09 Available from: http://www.tbfacts.org/tb-statistics-india/ \n3 Muñoz P Rodríguez C Bouza E Mycobacterium tuberculosis infection in recipients of solid organ transplants Clin Infect Dis 2005 40 581 7 15712081 \n4 John G Infections after renal transplantation in India Transplant Rev 1999 13 183 91 \n5 Sakhuja V Jha V Varma PP Joshi K Chugh KS The high incidence of tuberculosis among renal transplant recipients in India Transplantation 1996 61 211 5 8600625 \n6 Das DK Pant CS Chachra KL Gupta AK Fine needle aspiration cytology diagnosis of tuberculous thyroiditis. A report of eight cases Acta Cytol 1992 36 517 22 1636345 \n7 Aguado JM Torre-Cisneros J Fortún J Benito N Meije Y Doblas A Tuberculosis in solid-organ transplant recipients: Consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish society of infectious diseases and clinical microbiology Clin Infect Dis 2009 48 1276 84 19320593 \n8 Singh N Paterson DL Mycobacterium tuberculosis infection in solid-organ transplant recipients: Impact and implications for management Clin Infect Dis 1998 27 1266 77 9827281 \n9 Pearce EN Farwell AP Braverman LE Thyroiditis N Engl J Med 2003 348 2646 55 12826640 \n10 Soni RK Sinha A Tuberculosis of the thyroid-a diagnostic enigma Indian J Surg 2015 77 Suppl 1 179 81 25972689 \n11 Kataria SP Tanwar P Singh S Kumar S Primary tuberculosis of the thyroid gland: A case report Asian Pac J Trop Biomed 2012 2 839 40 23569858 \n12 Chaudhary A Nayak B Guleria S Arora R Gupta R Sharma MC Tuberculosis of the thyroid presenting as multinodular goiter with hypothyroidism: A rare presentation Indian J Pathol Microbiol 2010 53 579 81 20699540 \n13 Luiz HV Pereira BD Silva TN Veloza A Matos C Manita I Thyroid tuberculosis with abnormal thyroid function – Case report and review of the literature Endocr Pract 2013 19 e44 9 23337150 \n14 Majid U Islam N Thyroid tuberculosis: A case series and a review of the literature J Thyroid Res 2011 2011 359864 21603164 \n15 Meije Y Piersimoni C Torre-Cisneros J Dilektasli AG Aguado JM ESCMID Study Group of Infection in Compromised Hosts Mycobacterial infections in solid organ transplant recipients Clin Microbiol Infect 2014 20 Suppl 7 89 101 24707957\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "27(6)",
"journal": "Indian journal of nephrology",
"keywords": "Renal transplant; thyroid gland; tuberculosis",
"medline_ta": "Indian J Nephrol",
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"title": "Acute Thyroid Swelling in Renal Transplant Recipient.",
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}
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] |
{
"abstract": "Examine the presentation and management characteristics of seven patients with melanoma of the external auditory canal (EAC).\n\n\n\nRetrospective case series and review of the relevant literature.\n\n\n\nRecords of seven patients from 2003 to 2017 with melanoma of the EAC were reviewed for characteristics of presentation, subsequent management, and outcomes. A thorough review of relevant literature is presented.\n\n\n\nThe median age is 52 years, with four females. The average Breslow depth was 3.6 mm, with five patients having a Clark level IV or greater on presentation. Six patients underwent lateral temporal bone resection, and one patient underwent wide local excision of the cartilaginous canal. Sentinel lymph node biopsy (SLNB) was performed in three patients. Three patients experienced distant recurrence an average of 20 months following primary therapy. Median follow-up was 21 months. At last follow-up, four were free of disease, one had active disease, and two were deceased from melanoma.\n\n\n\nThis is the largest series and the first to report the use of SLNB for patients with EAC melanoma in the peer-reviewed literature. Patients with external auditory canal melanoma present with higher Breslow thickness and stage relative to all external ear melanomas. Management should include wide local excision, which entails lateral temporal bone resection when the bony ear canal is involved. SLNB has a critical role in identifying patients with early metastatic disease. Postoperative radiation therapy should be considered for patients with high-risk features to reduce the risk of locoregional relapse. Chemotherapy, and especially immunotherapy, has an emerging role for this disease.\n\n\n\n4 Laryngoscope, 131:165-172, 2021.",
"affiliations": "Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, U.S.A.;Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas.",
"authors": "Appelbaum|Eric N|EN|0000-0003-2501-8242;Gross|Neil D|ND|;Diab|Adi|A|;Bishop|Andrew J|AJ|;Nader|Marc-Elie|ME|0000-0001-9295-0174;Gidley|Paul W|PW|0000-0003-3706-8781",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/lary.28548",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0023-852X",
"issue": "131(1)",
"journal": "The Laryngoscope",
"keywords": "Melanoma; auricular melanoma; external auditory canal; otologic malignancies; sentinel lymph node biopsy.",
"medline_ta": "Laryngoscope",
"mesh_terms": "D004424:Ear Canal; D004428:Ear Neoplasms; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma; D012189:Retrospective Studies; D021701:Sentinel Lymph Node Biopsy; D062606:Tertiary Care Centers",
"nlm_unique_id": "8607378",
"other_id": null,
"pages": "165-172",
"pmc": null,
"pmid": "32065414",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Melanoma of the External Auditory Canal: A Review of Seven Cases at a Tertiary Care Referral Center.",
"title_normalized": "melanoma of the external auditory canal a review of seven cases at a tertiary care referral center"
} | [
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"companynumb": "US-009507513-2105USA004938",
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"drugdosagetext": "UNK",
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"seriousnessother": null,
"transmissiondate": "20210717"
}
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"abstract": "Afatinib is an oral tyrosine kinase inhibitor (TKI) that inhibit Endothelial Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4. The common side effects of EGFR TKI are rash, acne, diarrhea, stomatitis, pruritus, nausea, and loss of appetite. Drug induced pneumonitis is the less common adverse effects of EGFR TKI. Afatinib, 2nd generation EGFR TKI is anticipated to overcome drug resistance from 1st generation EGFR TKI according to preclinical study, and several studies are being conducted to compare clinical efficacy between 1st and 2nd EGFR TKI. Several cases of rug induced acute fatal pneumonitis were reported after use of erlotinib or gefitinib. However, a case of acute fatal pneumonitis associated with afatinib was note reported except drug induced pneumonitis in other clinical study. Here, we present a cases of acute severe pneumonitis related with afatinib in metastatic lung adenocarcinoma with literature review.",
"affiliations": "Department of Internal Medicine, Daejeon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Daejeon, Korea.;Department of Internal Medicine, Daejeon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Daejeon, Korea.;Department of Internal Medicine, Daejeon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Daejeon, Korea.;Department of Internal Medicine, Daejeon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Daejeon, Korea.;Department of Internal Medicine, Daejeon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Daejeon, Korea.;Department of Internal Medicine, Daejeon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Daejeon, Korea.;Department of Internal Medicine, Daejeon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Daejeon, Korea.;Department of Internal Medicine, Daejeon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Daejeon, Korea.;Department of Internal Medicine, Daejeon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Daejeon, Korea.;Department of Internal Medicine, Daejeon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Daejeon, Korea.",
"authors": "Yoo|Sang Hoon|SH|;Ryu|Jin Ah|JA|;Kim|Seo Ree|SR|;Oh|Su Yun|SY|;Jung|Gu Sung|GS|;Lee|Dong Jae|DJ|;Kwak|Bong Gyu|BG|;Nam|Yu Hyun|YH|;Kim|Kyung Hyun|KH|;Yang|Young Jun|YJ|",
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"country": "Korea (South)",
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"doi": "10.4082/kjfm.2016.37.6.351",
"fulltext": "\n==== Front\nKorean J Fam MedKorean J Fam MedKJFMKorean Journal of Family Medicine2005-64432092-6715The Korean Academy of Family Medicine 10.4082/kjfm.2016.37.6.351Case ReportAfatinib-Induced Acute Fatal Pneumonitis in Metastatic Lung Adenocarcinoma Yoo Sang Hoon †Ryu Jin Ah †Kim Seo Ree Oh Su Yun Jung Gu Sung Lee Dong Jae Kwak Bong Gyu Nam Yu Hyun Kim Kyung Hyun Yang Young Jun Department of Internal Medicine, Daejeon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Daejeon, Korea.Corresponding Author: Young Jun Yang. Tel: +82-42-220-9100, Fax: +82-42-220-9037, yyj7009@daum.net†These authors contributed equally to this work.\n\n11 2016 18 11 2016 37 6 351 355 19 1 2016 22 2 2016 03 3 2016 Copyright © 2016 The Korean Academy of Family Medicine2016This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Afatinib is an oral tyrosine kinase inhibitor (TKI) that inhibit Endothelial Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4. The common side effects of EGFR TKI are rash, acne, diarrhea, stomatitis, pruritus, nausea, and loss of appetite. Drug induced pneumonitis is the less common adverse effects of EGFR TKI. Afatinib, 2nd generation EGFR TKI is anticipated to overcome drug resistance from 1st generation EGFR TKI according to preclinical study, and several studies are being conducted to compare clinical efficacy between 1st and 2nd EGFR TKI. Several cases of rug induced acute fatal pneumonitis were reported after use of erlotinib or gefitinib. However, a case of acute fatal pneumonitis associated with afatinib was note reported except drug induced pneumonitis in other clinical study. Here, we present a cases of acute severe pneumonitis related with afatinib in metastatic lung adenocarcinoma with literature review.\n\nAfatinibAcute Fatal PneumonitisMetastatic Lung Adenocarcinoma\n==== Body\nINTRODUCTION\nLung cancer is the leading cause of death due to malignancy. It has a poor prognosis and the 5-year survival rate is only 15%. Most lung cancers are asymptomatic; therefore, the majority of patients are diagnosed with late-stage disease, which restricts treatment options, with the exception of chemotherapy.\n\nHowever, the identification of EGFR mutations and the introduction of epithelial growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) have expanded treatment options and improved results. On average, acquired drug resistance to erlotinib and gefitinib, 1st-generation EGFR-TKIs, has been observed between 8 and 16 months of use.1) Afatinib, a 2nd-generation EGFR-TKI, is expected to overcome the acquired resistance that develops with 1st-generation EGFR-TKIs by irreversibly blocking not only EGFR but also human epidermal growth factor receptor 2 (HER2) dimer formation. Currently, there is an ongoing comparative study investigating the efficacy of 1st- and 2nd-generation EGFR-TKIs in lung cancer. In addition to erlotinib and gefitinib, afatinib has been reported to be responsible for drug-induced pneumonitis as a common adverse effect in clinical trials.23) Several preclinical studies have reported acute drug-induced pneumonitis after erlotinib and gefitinib use, whereas there have been no reports of the same fatal adverse effects with afatinib. In the present case, we emphasize the need for caution with afatinib use as it may result in fatal pulmonary complications.\n\nCASE REPORT\nA 78-year-old woman was admitted for dry cough and weight loss via our outpatient clinic on 8 August 2015. She had been undergoing medical treatment for diabetes, dyslipidemia, and osteoporosis since 20 years. The patient was a social drinker and a nonsmoker. She was diagnosed with metastatic lung adenocarcinoma (T1b N0 M1a, stage IV) with EGFR mutations on the basis of the findings obtained with chest computed tomography (CT), positive emission tomography-CT, percutaneous transthoracic needle aspiration (PCNA) of the left superior lobe, and wedge resection of the right superior lobe (Figures 1, 2). The biopsy results from the PCNA results were obtained on August 22nd and the wedge resection results were obtained on August 28th. Afatinib treatment (40 mg/d) was initiated on 2 September 2015; no specific complications were observed during afatinib use and the patient was discharged. She was re-admitted for acute dyspnea on 7 September 2015 via the outpatient clinic; she had been consuming afatinib daily for 6 days.\n\nThe patient's initial vital signs were as follows: blood pressure, 110/70 mm Hg; heart rate, 100 beats/min; respiratory rate, 20 breaths/min; body temperature, 37.7℃; and oxygen saturation, 63% as room air. On auscultation, coarse breathing sounds and crackles were heard over both the lungs fields. Initial laboratory test results were as follows: total leukocyte count, 10,300/mm3; hemoglobin, 9.6 g/dL; platelet count, 217,000/mm3; C-reactive protein, 18.66 mg/dL; and D-dimer, 1.78 mg fibrinogen equivalent units/mL. All other parameters were within their respective normal limits.\n\nA chest CT was conducted on the suspicion of pulmonary thromboembolism and drug-induced pneumonitis. It showed that there were new consolidations and ground glass opacity shadows, whereas the size of lung cancer itself had decreased. A pulmonary thromboembolism was not observed (Figure 3). The patient was diagnosed with acute severe drug-induced pneumonitis after afatinib use. This diagnosis was based on the following: the onset of symptoms after drug application, the absence of another explanatory cause for the hypoxia, the results of the chest CT, and the negative results of the nasal swab and sputum study tests for pneumocystis pneumonia and viral pneumonia, which are frequently found in immune-depressed patients. Moreover, pathogens such as bacteria or fungus were not detected. We planned to perform bronchoalveolar lavage, a transbronchial lung biopsy, and PCNA to exclude other infectious causes and confirm the diagnosis of acute drug-induced pneumonitis. However, the patient refused to undergo the invasive procedures. Despite the intensive care provided, which included oxygen therapy via a high-flow nasal cannula, steroid pulse therapy (methylprednisolone, 500 mg daily for 3 days), and broad spectrum antibiotics, the patients died of hypoxia aggravation on 27 September 2015.\n\nDISCUSSION\nLung cancer is a major cause of malignancy-associated mortality worldwide, and the 5-year survival rate is as low as 15%. Widely recognized risk factors of lung cancer include direct or indirect smoking, radon gas, and asbestos.\n\nThere is no specific treatment because most lung cancer patients are diagnosed with late stage disease. Until EGFR-TKIs were introduced, intravenous chemotherapy was the only treatment option and the average survival time was less than 12 months. The discovery of EGFR mutations and the introduction of oral EGFR-TKI agents expanded the treatment options.\n\nEGFR is a receptor tyrosine kinase located on the cell surface. It mediates intracellular signaling and promotes cell growth, division, and migration. Activated EGFR mutations in lung adenocarcinoma have been confirmed. This mutation is more prevalent in young women, Asian people, and non-smokers. Lung adenocarcinomas with EGFR mutations are dependent on EGFR to activate intracellular signaling. When this system is blocked by EGFR-TKIs, the lung cancer cells cannot proliferate and they undergo apoptosis.\n\nErlotinib and gefitinib, 1st-generation EGFR-TKIs, reversibly bind to EGFR, preventing its dimerization. Most lung cancers with EGFR mutations develop resistance to the 1st-generation EGFR-TKIs within, on average, 8 to 16 months of use. The most common acquired resistance is a T790M missense mutation in exon 20, which is reported in 50% to 60% of advanced stage patients after 1st-generation EGFR-TKI use. Afatinib, a 2nd-generation EGFR-TKI, is expected to overcome the acquired resistance that develops after 1st-generation EGFR-TKI use, by irreversibly blocking, not only EGFR, but also HER2 dimerization. Currently, there is an ongoing comparative study of 1st- and 2nd-generation EGFR-TKIs with regard to treatment efficacy in lung cancer.23)\n\nCommon complications associated with afatinib use include gastrointestinal and dermatologic complications such as diarrhea, vomiting, fatigue, loss of appetite, and skin rash. In addition, drug-induced pneumonitis has been reported, albeit not as frequently as with 1st-generation EGFR-TKI use.23) Acute fatal drug-induced pneumonitis was reported in several preclinical studies after treatment with erlotinib and gefitinib, and a number of meta-analyses and literature studies of drug-induced pneumonitis, including acute fatal drug-induced pneumonitis, have been conducted.45678) Contrary to the erlotinib and gefitinib results, drug-induced pneumonitis, a common complication of EGFR-TKI use, had been rarely reported with afatinib use. Acute fatal pneumonitis after afatinib use, as in the current study, has been reported in only 1 previous study.9)\n\nIt is yet unknown how drug-induced pneumonitis occurs after 1st-generation EGFR-TKI use. On the basis of the results of previous studies, we have identified a possible mechanistic link between the 1st-generation EGFR-TKI gefitinib use and drug-induced pneumonitis.910) As we mentioned above, EGFR-TKIs block EGFR phosphorylation, thus preventing injured epithelium from regenerating and proliferating.9) In addition, when an acute lung injury occurs, expression is upregulated in order to promote regeneration of the damaged epithelium. In other words, EGFR-TKIs interrupt this damage-repair mechanism of EGFR, and if these interruptions accumulate, fatal drug-induced pneumonitis may result.10) This mechanism was identified based on gefitinib, not afatinib, use. However, afatinib and gefitinib share common characteristics, such as EGFR-blocking functions, so we assume that this potential mechanism could also apply to afatinib. We could not identify a specific and effective treatment for EGFR-TKI-induced pneumonitis. We found only 2 cases of gefitinib-induced pneumonitis that were cured by drug cessation, high dose steroids, and mechanical ventilation.45) These treatments were identical to those administered for general drug-induced pneumonitis. Further studies should be performed to identify the exact mechanism of, and treatment for, afatinib-induced pneumonitis.\n\nIn summary, in the treatment of metastatic lung adenocarcinoma, 2nd-generation EGFR-TKIs are expected to overcome the acquired resistance which occurs after 1st-generation EGFR-TKI use. An ongoing comparative study is evaluating the treatment efficacy of 1st- and 2nd-generation EGFR-TKIs in lung cancer. Various target treatment agents, including EGFR-TKIs such as afatinib, have been developed and are now widely used; consequently, treatment efficacy has improved and chemotherapy is no longer the only treatment option. However, the incidence of various complications, including pulmonary toxicity, which are not widely researched, will inevitably increase. Therefore, based on the results in this case report, clinicians should be aware of the potential for afatinib treatment-associated complications.\n\nCONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.\n\nFigure 1 (A) A chest CT scan showing a solid nodule, approximately 2.7 cm in size, with peripheral GGO, spiculated margins in the left upper lobe, and lobular GGO with some consolidation and mild interlobular septal thickening in the right upper lobe. (B) A positron emission tomography-CT scan showing irregular consolidation with increased uptake in the left upper lobe and active inflammation in the right upper lobe. CT, computed tomography; GGO, ground glass opacity.\nFigure 2 Tissue from the PCNA showing acinar adenocarcinoma, papillary adenocarcinoma, and lymphovascular tumor emboli. (A) H&E, ×100. (B) H&E, ×200. The morphology of the tissue from wedge resection is similar to that of the PCNA biopsy. (C) H&E, ×100. (D) H&E, ×200. PCNA, percutaneous needle aspiration.\nFigure 3 (A) A chest computed tomography scan showing the slight decrease of the lung cancer in the left upper lobe. (B) A chest computed tomography scan showing newly developed diffuse ground glass opacity and multifocal patchy consolidation with interstitial thickening in both the lungs.\n==== Refs\n1 Pao W Miller VA Politi KA Riely GJ Somwar R Zakowski MF Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain PLoS Med 2005 2 e73 15737014 \n2 Soria JC Felip E Cobo M Lu S Syrigos K Lee KH Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial Lancet Oncol 2015 16 897 907 26156651 \n3 Yang JC Shih JY Su WC Hsia TC Tsai CM Ou SH Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial Lancet Oncol 2012 13 539 548 22452895 \n4 Zhang Y Yang H Zhao M He J Successful treatment of gefitinib-induced acute interstitial pneumonitis with corticosteroid and non-invasive BIPAP-ventilation J Thorac Dis 2012 4 316 319 22754672 \n5 Lai YC Lin PC Lai JI Hsu SY Kuo LC Chang SC Successful treatment of erlotinib-induced acute hepatitis and acute interstitial pneumonitis with high-dose corticosteroid: a case report and literature review Int J Clin Pharmacol Ther 2011 49 461 466 21726497 \n6 Chang SC Chang CY Chen CY Yu CJ Successful erlotinib rechallenge after gefitinib-induced acute interstitial pneumonia J Thorac Oncol 2010 5 1105 1106 20581580 \n7 Qi WX Sun YJ Shen Z Yao Y Risk of interstitial lung disease associated with EGFR-TKIs in advanced non-small-cell lung cancer: a meta-analysis of 24 phase III clinical trials J Chemother 2015 27 40 51 24724908 \n8 Shi L Tang J Tong L Liu Z Risk of interstitial lung disease with gefitinib and erlotinib in advanced non-small cell lung cancer: a systematic review and meta-analysis of clinical trials Lung Cancer 2014 83 231 239 24332320 \n9 Suzuki H Aoshiba K Yokohori N Nagai A Epidermal growth factor receptor tyrosine kinase inhibition augments a murine model of pulmonary fibrosis Cancer Res 2003 63 5054 5059 12941834 \n10 Ando M Okamoto I Yamamoto N Takeda K Tamura K Seto T Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib J Clin Oncol 2006 24 2549 2556 16735708\n\n",
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"abstract": "Idiopathic hypereosinophilic syndrome (HES) is a condition of unknown origin characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. Cardiac involvement is rare and threatening accounting for 33% to 43% of death in HES. Management of pregnant patients with HES is challenging and have rarely been reported, particularly in the setting of heart failure.We here report on the case of a 29-year-old woman with HES who developed severe endomyocardial fibrosis with heart failure during pregnancy. Outcome was favorable under treatment with prednisone and azathioprine.This case illustrates a favorable outcome of endomyocardial fibrosis during pregnancy.",
"affiliations": "From the Service de Médecine Interne 2 (MPdC, JH, ZA, FCA), Institut E3M, Centre National de Référence Lupus Systémique, Syndrome des Anticorps Anti-Phospholipides et Maladies Auto-Immunes Systémiques Rares, Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, France; Université Pierre et Marie Curie (MPdC, DV-B, PCluzel, JH, ZA, FCA), Sorbonnes Universités, Paris, France; Centre de Référence Maladies Cardiaques Héréditaires (PCharron), ICAN, Inserm UMR_1166, Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France; Université de Versailles-Saint Quentin (PCharron), Hôpital Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt, France; Service de Gynécologie Obstétrique (DV-B), Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France; Département d'Imagerie Cardiovasculaire et de Radiologie Interventionnelle (PCluzel), Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France; Institut National de la Santé et de la Recherche Médicale (PCluzel), INSERM-CNRS-LIB, Paris, France; Service de Médecine Interne (JEK), Hôpital Foch, Suresnes, France; and French Eosinophil Network (JEK), Institut d'Immunologie, Université de Lille, Lille, France.",
"authors": "Pineton de Chambrun|Marc|M|;Charron|Philippe|P|;Vauthier-Brouzes|Danièle|D|;Cluzel|Philippe|P|;Haroche|Julien|J|;Kahn|Jean-Emmanuel|JE|;Amoura|Zahir|Z|;Aubart|Fleur Cohen|FC|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2626637210.1097/MD.0000000000001307013073600Research ArticleClinical Case ReportReversible Severe Eosinophilic Endomyocardial Fibrosis During Pregnancy A Case ReportPineton de Chambrun Marc MDCharron Philippe MD, PhDVauthier-Brouzes Danièle MDCluzel Philippe MD, PhDHaroche Julien MD, PhDKahn Jean-Emmanuel MD, PhDAmoura Zahir MD, MScAubart Fleur Cohen MD, PhDAnastasios Lymperopoulos. From the Service de Médecine Interne 2 (MPdC, JH, ZA, FCA), Institut E3M, Centre National de Référence Lupus Systémique, Syndrome des Anticorps Anti-Phospholipides et Maladies Auto-Immunes Systémiques Rares, Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, France; Université Pierre et Marie Curie (MPdC, DV-B, PCluzel, JH, ZA, FCA), Sorbonnes Universités, Paris, France; Centre de Référence Maladies Cardiaques Héréditaires (PCharron), ICAN, Inserm UMR_1166, Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France; Université de Versailles-Saint Quentin (PCharron), Hôpital Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt, France; Service de Gynécologie Obstétrique (DV-B), Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France; Département d’Imagerie Cardiovasculaire et de Radiologie Interventionnelle (PCluzel), Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France; Institut National de la Santé et de la Recherche Médicale (PCluzel), INSERM-CNRS-LIB, Paris, France; Service de Médecine Interne (JEK), Hôpital Foch, Suresnes, France; and French Eosinophil Network (JEK), Institut d’Immunologie, Université de Lille, Lille, France.Correspondence: Fleur Cohen Aubart, Service de Médecine Interne 2, Institut E3M, Hôpital de la Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75651-Paris Cedex 13, France (e-mail: fleur.cohen@psl.aphp.fr).8 2015 14 8 2015 94 32 e130728 5 2015 22 6 2015 22 6 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nIdiopathic hypereosinophilic syndrome (HES) is a condition of unknown origin characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. Cardiac involvement is rare and threatening accounting for 33% to 43% of death in HES. Management of pregnant patients with HES is challenging and have rarely been reported, particularly in the setting of heart failure.\n\nWe here report on the case of a 29-year-old woman with HES who developed severe endomyocardial fibrosis with heart failure during pregnancy. Outcome was favorable under treatment with prednisone and azathioprine.\n\nThis case illustrates a favorable outcome of endomyocardial fibrosis during pregnancy.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nIdiopathic hypereosinophilic syndrome (HES) is a condition of unknown origin characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. Cardiac involvement is rare and threatening accounting for 33% to 43% of death in HES. Management of pregnant patients with HES is challenging and rarely been reported, particularly in the setting of heart failure.\n\nCASE REPORT\nA 29-year-old woman returning from Saint Martin Island presented in April 2013 with dyspnea and chest pain, which were then diagnosed as clinically suspected eosinophils-associated myocarditis because of pulmonary edema, elevated troponin, and high eosinophils blood count. She received 3 pulses of steroids and was also treated with 2 doses of ivermectine as Strongyloides serology was positive. In July 2013, troponin dosage, eosinophils blood count, echocardiography, and cardiac magnetic resonance imaging (MRI) were normal.\n\nIn December 2013, when she was pregnant with 18 weeks of amenorrhea (WA), she was admitted to the intensive cardiology unit department for respiratory distress. Electrocardiogram was normal but chest x-ray was consistent with pulmonary edema. Blood tests showed elevated ultrasensitive troponin: 139 ng/mL (N < 0.14), NT-proBNP: 3350 ng/L, and markedly increased circulating eosinophils at 4.75 ×109/L. Renal and liver tests were normal. A transthoracic echocardiogram revealed hyperkinetic left ventricular with subtotal thrombotic occlusion of left ventricle (LV) (Figure 1C and E). Systolic pulmonary artery pressure was elevated at 75 mm Hg. Cardiac MRI revealed diffuse LV endomyocardial fibrosis with circumferential intraventricular adherent LV thrombus (Figure 1A). No extra-cardiac involvement (i.e., neurological, pulmonary, cutaneous, or gastrointestinal) was detected. Screening for all etiology of secondary or clonal eosinophilia was negative including extended lymphoid phenotyping, janus kinase 2 mutation (JAK2), and factor interacting with PAPOLA and CPSF1 (FIP1L1)–α-type platelet-derived growth factor receptor (PDGFRA) transcript fusion testing. Bone marrow biopsy was also normal despite marked eosinophil infiltration. The diagnosis of idiopathic hypereosinophilic syndrome (HES)-associated severe endomyocardial fibrosis was suspected.\n\nFIGURE 1 (A) Four-chamber view during cine acquisition after gadolinium injection shows subendocardial enhancement of the left ventricle (LV) with a large adherent thrombus inside the ventricular cavity. (B) Remission after treatment. (C and E) Echocardiogram findings during heart failure. Apical and parasternal short-axis view reveal subtotal occlusion of LV with thrombus. Dynamic studies revealed hyperkinetic LV with high ejection fraction. (D and F) Echocardiogram findings 6 month after delivery showing complete disappearance of LV thrombus and normal LV ejection fraction.\n\nSymptomatic treatment included diuretics, low-dose β-blockers, and curative anticoagulation with enoxaparin. Three intravenous pulses of 1 g methylprednisolone were administrated followed by 1 mg/kg/d of oral prednisone. She quickly improved, keeping a class III New York Heart Association (NYHA) dyspnea. Despite persistent severe postcapillary pulmonary hypertension, pregnancy was continued. One month later, echocardiography was stable and eosinophils were still at 1.0 g/L (Figure 2). Azathioprine was introduced (2 mg/kg/d) and steroids were progressively tapered down.\n\nFIGURE 2 Eosinophils blood count evolution during pregnancy.\n\nAt 35 WA, she underwent a C-section because of fetal heart rate abnormalities. The newborn's weight was 1900 g (between 10th and 25th percentile), and birth blood pH and lactate were 7.26 and 3 mmol/L, respectively. Early outcome was favorable for the mother and the baby. Under azathioprine, 6 months after delivery, she was asymptomatic, and eosinophils blood count as well as echocardiography and cardiac MRI had normalized (Figure 1).\n\nDISCUSSION\nHere we described a case of severe eosinophilic endomyocardial fibrosis occurring during pregnancy. Under treatment with steroids and azathioprine, despite severe pulmonary hypertension, pregnancy had a favorable outcome. Six months after delivery, the patient had fully recovered from endomyocardial fibrosis.\n\nAcquired eosinophilia is classified as secondary (parasitic, drug-induced, vasculitis, …), clonal (myeloid or lymphoid malignancies, …), or idiopathic. After exclusion of secondary causes of eosinophilia, a stepwise diagnostic algorithm should include peripheral blood screening for FIP1L1–PDGFRA transcript fusion, bone marrow biopsy, JAK2 mutation testing, peripheral blood lymphocytes phenotyping, and T-cell receptor gene rearrangement studies in order to discard clonal causes of eosinophilia. The diagnostic of HES can be advocated in case of negativity of all the test cited above.1 Cardiac involvement of HES is rare and life-threatening, accounting for 33% to 43% of deaths, with a frequency reported from 5% to 72%.2–4\n\nTreatment of chronic acquired eosinophilia strongly depends on whatever the cause of eosinophilia. In clonal eosinophilia, treatment mainly consists of kinase inhibitor. In HES, corticosteroids remain the first-line treatment and corticosteroid-sparing agents nowadays mainly rely on hydroxyurea, interferon-α, or cyclosporine. Despite a promising preliminary study, mepolizumab and other anti-interleukin-5 antibodies have not been approved in this setting. No specific drugs have been advocated in cardiac involvement of HES except for heart failure treatment and anticoagulation therapy because of the high frequency of intracardiac thrombus. The use of azathioprine as a corticosteroid-sparing agent for HES has been only anecdotally reported without clear information about its efficacy.4\n\nOnly 3 cases of pregnancy during HES have been reported, all with favorable outcomes.5–7 Two patients were treated with steroids (maintenance doses between 20 and 25 mg/d) and the last one was left untreated. One of those patients had a cardiac involvement consisting in right and LV thrombus but without cardiac failure. Cardiac MRI was not performed because of pregnancy.\n\nOur patient suffered from a particularly severe cardiac manifestation of HES during pregnancy. Steroids allowed quick improvement but the patient still complained of NYHA III dyspnea. The persistence of pulmonary hypertension and elevated circulating eosinophils counts led us to introduce a corticosteroid-sparing agent, namely, azathioprine, because of the safety profile during pregnancy. Outcome was good for the mother and baby. Six months after delivery, echocardiography and cardiac MRI confirmed full resolution of interventricular thrombus with regression of endomyocardial fibrosis.\n\nIn conclusion, even in a severe cardiac involvement of HES, pregnancy can successfully be conducted using steroids and azathioprine. This study has been approved by the ethics committee: Comité de Protection des Personnes (CPP) “Ile-de-France VI,” Hôpital Pitié-Salpêtrière, Paris, France.\n\nACKNOWLEDGMENTS\nThe authors would like to thank Professor David Grant for his help in editing the manuscript.\n\nAbbreviations: FIP1L1 = factor interacting with PAPOLA and CPSF1, HES = hypereosinophilic syndrome, JAK2 = janus kinase 2, LV = left ventricle, MRI = magnetic resonance imaging, NYHA = New York Heart Association, PDGFRA = α-type platelet-derived growth factor receptor, WA = week of amenorrhea.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1. Tefferi A Gotlib J Pardanani A \nHypereosinophilic syndrome and clonal eosinophilia: point-of-care diagnostic algorithm and treatment update . Mayo Clin Proc \n2010 ; 85 :158 –164 .20053713 \n2. Podjasek JC Butterfield JH \nMortality in hypereosinophilic syndrome: 19 years of experience at Mayo Clinic with a review of the literature . Leuk Res \n2013 ; 37 :392 –395 .23332454 \n3. Rothenberg ME Klion AD Roufosse FE \nTreatment of patients with the hypereosinophilic syndrome with mepolizumab . N Engl J Med \n2008 ; 358 :1215 –1228 .18344568 \n4. Ogbogu PU Bochner BS Butterfield JH \nHypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy . J Allergy Clin Immunol \n2009 ; 124 :1319 –1325 .19910029 \n5. Ault P Cortes J Lynn A \nPregnancy in a patient with hypereosinophilic syndrome . Leuk Res \n2009 ; 33 :186 –187 .18597844 \n6. Darki A Kodali PP McPheters JP \nHypereosinophilic syndrome with cardiac involvement in a pregnant patient with multiple sclerosis . Tex Heart Inst J \n2011 ; 38 :163 –165 .21494528 \n7. Albrecht AE Hartmann BW Kurz C \nIdiopathic hypereosinophilic syndrome and pregnancy . Acta Obstet Gynecol Scand \n1997 ; 76 :485 –486 .9197455\n\n",
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"mesh_terms": "D000328:Adult; D001379:Azathioprine; D004719:Endomyocardial Fibrosis; D005260:Female; D006333:Heart Failure; D006801:Humans; D017681:Hypereosinophilic Syndrome; D007166:Immunosuppressive Agents; D011241:Prednisone; D011247:Pregnancy",
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"title": "Reversible Severe Eosinophilic Endomyocardial Fibrosis During Pregnancy: A Case Report.",
"title_normalized": "reversible severe eosinophilic endomyocardial fibrosis during pregnancy a case report"
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{
"abstract": "Phospholipase A2 receptor (PLA2R) is the most common primary target antigen of idiopathic membranous nephropathy (MN) although PLA2R antibodies are also reported to be present in malignancy-associated MN. However, a case of PLA2R-positive MN secondary to PLA2R-positive carcinoma has not been reported. A 26-year-old Japanese woman presented with general fatigue, fever, and nonproductive cough. Computed tomography demonstrated a left kidney mass with pathologic diagnosis of Xp11.2 translocation renal cell carcinoma (RCC). After the second time of administration with Sunitinib, the patients exhibited significant proteinuria and hypoalbuminemia. Renal biopsy revealed a diagnosis of diffuse MN secondary to RCC. Immunofluorescence staining showed granular patterns positive for immunoglobulin (Ig) G, IgA, and C3c. PLA2R and IgG1-3 were positive, while IgG4 was negative. For the treatment of severe nephrotic syndrome, we attempted steroid therapy without any clinical improvement. Open nephrectomy was performed and surprisingly, RCC was stained for PLA2R with polarity for the basal side. At outpatient follow-up, 4 months after the operation, urinary protein had still persisted, although serum albumin was slightly increased. We report a case of PLA2R-positive MN secondary to PLA2R-positive RCC.",
"affiliations": "Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Department of Pathology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Department of Urology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Division of Urology, Sendai City Hospital, Sendai, Japan.;Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. swakino@z8.keio.jp.;Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.",
"authors": "Yasuda|Itaru|I|;Tokuyama|Hirobumi|H|;Hashiguchi|Akinori|A|;Hasegawa|Kazuhiro|K|;Uchiyama|Kiyotaka|K|;Ryuzaki|Masaki|M|;Yasuda|Marie|M|;Mizuno|Ryuichi|R|;Ishidoya|Shigeto|S|;Wakino|Shu|S|;Itoh|Hiroshi|H|",
"chemical_list": "D054507:Receptors, Phospholipase A2",
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-020-00556-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "10(2)",
"journal": "CEN case reports",
"keywords": "Immunoglobulin G subclass; Membranous nephropathy; Phospholipase A2 receptor; Xp 11.2 translocation renal carcinoma",
"medline_ta": "CEN Case Rep",
"mesh_terms": "D000328:Adult; D002277:Carcinoma; D005260:Female; D015433:Glomerulonephritis, Membranous; D006801:Humans; D007678:Kidney Glomerulus; D054507:Receptors, Phospholipase A2",
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "281-286",
"pmc": null,
"pmid": "33393071",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports",
"references": "28674044;21566055;21976738;21271860;23196797;30454884;23328976;24667060;22956816;27192690;23364522;28947992;18790651;28035718;30727973;30665573;26251712;29104026;16919315;24993974;22194972;23364518;31243053;10200982;10411717;24657971;26672991;13645677;14767011",
"title": "Malignancy-associated membranous nephropathy with PLA2R double-positive for glomeruli and carcinoma.",
"title_normalized": "malignancy associated membranous nephropathy with pla2r double positive for glomeruli and carcinoma"
} | [
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"literaturereference": "YASUDA I, TOKUYAMA H, HASHIGUCHI A, HASEGAWA K, UCHIYAMA K, RYUZAKI M, ET AL. MALIGNANCY?ASSOCIATED MEMBRANOUS NEPHROPATHY WITH PLA2R DOUBLE?POSITIVE FOR GLOMERULI AND CARCINOMA. CEN?CASE?REP 2021?10(2):281?286.",
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"abstract": "Primary pulmonary diffuse large B-cell lymphoma (PPDLBCL) is extremely rare. Its clinical symptoms and signs are nonspe cific, and imaging features also have not yet been well-defined. Further description is important for the diagnosis and treatment of PPDLBCL. Herein, we reported a case of a patient who suffered from bilateral chest pain and dyspnea. Computed tomography (CT) of chest demonstrated bilateral lung mass, consolidations and reverse halo sign, while consolidations and reverse halo sign are uncommon according to previous reports. Tissue samples were taken by CT guided needle biopsy. The histological samples showed PPDLBCL. This case was special in view of positive expression of CD5. After the case was treated by cyclophosphamide pirarubicin vindesine dexamethasone (CHOP) chemotherapy for six courses, her clinical symptoms were partially alleviated, while CT showed progression disease. This case report highlights different imaging features and characteristics of molecular biology, and reviews study progress of PPDLBCL.",
"affiliations": "Department of Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China; Department of Critical Care Medicine, the Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong, China.;Department of Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China; Department of Critical Care Medicine, the Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong, China.;Department of Hematology, the Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong, China.;Department of Critical Care Medicine, the Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong, China.;Emergency Department, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.;Department of Critical Care Medicine, the Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong, China.;Department of Pathology, the Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong, China.;Department of Critical Care Medicine, the Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong, China.;Department of Critical Care Medicine, the Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong, 256603, China . Tel: 13561578530.;Department of Critical Care Medicine, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, China . Tel: 18560081001.",
"authors": "Wang|Tao|T|;Zhang|Mingming|M|;Sun|Jianrong|J|;Hao|Dong|D|;Qi|Zhijiang|Z|;Lu|Feng|F|;Ji|Hong|H|;Liu|Weili|W|;Wang|Xiaozhi|X|;Wu|Dawei|D|",
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"fulltext": "\n==== Front\nOpen Med (Wars)Open Med (Wars)medmedOpen Medicine2391-5463De Gruyter Open med-2016-001010.1515/med-2016-0010Case ReportA rare case of primary pulmonary diffuse large B cell lymphoma with CD5 positive expression Wang Tao hxicuwxz@163.com34Zhang Mingming hxicuwxz@163.com34Sun Jianrong 5Hao Dong 4Qi Zhijiang 6Lu Feng 4Ji Hong 7Liu Weili 4Wang Xiaozhi 2Wu Dawei wdw.55@163.com11Department of Critical Care Medicine, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, China. Tel: 18560081001, Fax: 0531-869275442Department of Critical Care Medicine, the Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong, 256603, China. Tel: 13561578530, Fax: 0543-32585953Department of Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China4Department of Critical Care Medicine, the Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong, China5Department of Hematology, the Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong, China6Emergency Department, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China7Department of Pathology, the Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong, China#Tao Wang and Mingming Zhang are first co-authors to this article.\n\n2016 29 2 2016 11 1 49 51 17 1 2016 27 1 2016 © 2016 Tao Wang et al.2016This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.Abstract\nPrimary pulmonary diffuse large B-cell lymphoma (PPDLBCL) is extremely rare. Its clinical symptoms and signs are nonspe cific, and imaging features also have not yet been well-defined. Further description is important for the diagnosis and treatment of PPDLBCL. Herein, we reported a case of a patient who suffered from bilateral chest pain and dyspnea. Computed tomography (CT) of chest demonstrated bilateral lung mass, consolidations and reverse halo sign, while consolidations and reverse halo sign are uncommon according to previous reports. Tissue samples were taken by CT guided needle biopsy. The histological samples showed PPDLBCL. This case was special in view of positive expression of CD5. After the case was treated by cyclophosphamide pirarubicin vindesine dexamethasone (CHOP) chemotherapy for six courses, her clinical symptoms were partially alleviated, while CT showed progression disease. This case report highlights different imaging features and characteristics of molecular biology, and reviews study progress of PPDLBCL.\n\nKey words\nPrimary pulmonary diffuse large B cell lymphomaCD5Multidetector Computed Tomography\n==== Body\n1. Introduction\nPrimary pulmonary lymphoma (PPL) is rare. The majority of PPLs are mucosa-associated lymphoid tissue lymphoma. Primary pulmonary diffuse large B-cell lymphoma (PPDLBCL) is particularly rare and occurs only in 10% cases of primary pulmonary NHL [1]. To our knowledge, PPDLBCL has been reported only in case reports or small sample studies [2-4]. Thus, its clinical characteristics, treatment and prognosis have not been clearly delineated. We present a case of PPDLBCL which had multiple imaging manifestations, and this case was special because of its positive expression of CD5. In addition, we briefly review the literature related to PPDLBCL.\n\n2. Case report\nA 71-year-old female was taken to our hospital after experiencing bilateral chest pain and dyspnea for 20 days. She had no other complaints, such as fever, cough and bloody sputum. The patient had a history of arthritis pauperum for 20 years, and denied traditional Chinese medicines for treatment. She had no personal history of smoking and family history of cancer. On clinical examination, no palpable lymph nodes and hepatosplenomegaly were found. There was no obvious rale in bilateral lungs. Computed tomography (CT) of the chest demonstrated a high density shadow in the right middle lower lobe and left lower lobe, and air bronchogram was obvious (Figure 1 C). Bilateral hilar masses exits (Figure 1 E) and low density area was visible (green arrow). Mediastinal lymph nodes enlarged. The crescent shaped liquid density was in right pleura (Figure 1 D). CT of abdomen showed no abnormalities. Bone marrow biopsy showed no infiltration. CT-guided transthoracic core needle biopsy was performed (Figure 2). Pathological section demonstrated diffuse large B cell infiltration in small fibrous tissue. Immunohistochemical staining showed Mum-1(-), Ki-67 index 70%, Cyclin D1(-), CD43(+), CD5(+), Bcl-2(-), CD3(-), CD79a(+), CD23(-), CD10(-), Bcl-6(-), Syn(-), CD20(++), CD56(-) (Figure 3). Based on these findings, PPDLBCL was diagnosed. Due to personal reasons, the patient underwent cyclophosphamide pirarubicin vindesine dexamethasone (CHOP) chemotherapy without rituximab, which was planned to be repeated every 21 days for 6 cycles. Following the administration of 6 cycles of CHOP chemotherapy, chest pain and dyspnea were alleviated. Nevertheless, CT demonstrated bilateral masses and consolidation partially diminished (Figure 4 E F), while a new mass emerged in the right upper lobe (Figure 4 A D blue arrow). Unfortunately, at 9 months of follow-up, the patient died.\n\nFigure 1 Initial chest computed tomography. Lung window: A B C; mediastinal window: D E F. Red arrow indicates reversed halo sign, and green arrow indicates low density area in left hilar mass.\n\nFigure 2 Computed tomography guided transthoracic core needle. Puncture needle is in the consolidation area of right lower lobe.\n\nFigure 3 Hematoxylin and eosin (H&E) staining and immunohisto-chemical staining. A: Alveolar septal broadens, and tumor cells infiltrate (HEx100); B: The tumor cells are large and rich in cytoplasm, the karyotype is slightly irregular, and nucleolus is visible (HEx400); C: immunohistochemical staining for cytokeratin (CK) (x400); D: immunohistochemical staining for CD-5 (x400); immunohistochemical staining for CD20 (x400); immunohistochemical staining for Ki-67 (x400).\n\nFigure 4 Chest computed tomography after 6 cycles of chemotherapy. A B C; mediastinal window: D E F. Blue arrow indicates newly emerging mass.\n\n3. Disscussion\nPPDLBCL is extremely rare in primary lung malignant lymphomas. Some case reports and small sample studies delineate the clinical characteristics. Its respiratory symptoms are nonspecific [5]. The key features of CT are single or multiple solid pulmonary nodules or masses, cavitation and mediastinal lymph node enlargement (3, 6 and 7). Consolidation is seldom [5]. In addition to enlarged mediastinal lymph nodes, necrosis in right hilar mass is also visible in this case (Figure 1 F green arrow). Consolidation was obvious. Pathological specimen was from consolidation area (Figure 2), so it indicated that PPDLBCL could cause consolidation. Notably, Marchiori et al reported the reversed halo sign (RHS) can be useful for differentiating invasive pulmonary aspergillosis from pulmonary lymphoma [8]. Nevertheless, we also found RHS in this case (Figure 1 F red arrow). In a word, imaging of PPDLBCL is complex and diverse.\n\nNow that the imaging of this case was different from common cases’ imaging, we further observed its biological characteristics. Immunohistochemical staining demonstrated positive expression of CD5. CD5+ DLBCL represents 5% to 10% of DLBCLs [9], and has some differences from other typical DLBCLs. CD5 molecule can promote B-cell survival. The precise mechanisms with which expression of CD5 alters the behavior of B cells in DLBCL are unclear [10]. In general, these patients have more aggressive clinical courses and poor diagnosis. At present, we have not found the report of imaging characteristics of CD5+ PPDLBCL.\n\nThe CHOP chemotherapy regimen has been the mainstay of therapy [11]. The addition of the anti-CD20 monoclonal antibody rituximab to this chemotherapy dramatically improved the outcomes, resulting in a 16% absolute improvement in 10-year overall survival in elderly patients ≥60 years of age [12]. Additional trials further demonstrate the benefit of rituximab and establishment of R-CHOP as the standard of care [13]. Rituximab based regimens can improve the outcomes of patients with CD5+ DLBCL, but this improvement in outcome is inferior to that seen in patients with CD5-DLBCL. Due to personal reasons, CHOP chemotherapy was performed without rituximab in this case. The result showed that simple CHOP chemotherapy is not ideal. Further studies are warranted to investigate a more effective therapy.\n\nConflict of interests: No authors report any conflict of interest.\n==== Refs\nReferences\n[1] Zinzani PL Martelli M Poletti V Italian Society of Hematology; Italian Society of Experimental Hematology; Italian Group for Bone Marrow Transplantation: Practice guidelines for the management of extranodal non-Hodgkin’s lymphomas of adult non-immunodeficient patients. Part I: primary lung and mediastinal lymphomas. A project of the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation Haematologica 2008 93 1364 1371 18603558 \n[2] Neri N Jesús Nambo M Avilés A Diffuse large B-cell lymphoma primary of lung Hematology 2011 16 110 112 21418743 \n[3] Yoshino N Hirata T Takeuchi C Usuda J Hosone M A case of primary pulmonary diffuse large B-cell lymphoma diagnosed by transbronchial biopsy Ann Thorac Cardiovasc Surg 2015 21 396 398 25912218 \n[4] Jiang AG Gao XY Lu HY Diagnosis and management of a patient with primary pulmonary diffuse large B-cell lymphoma: A case report and review of the literature Exp Ther Med 2014 8 797 800 25120602 \n[5] Kim JH Lee SH Park J Kim HY Lee SI Park JO Primary pulmonary non-Hodgkin’s lymphoma Jpn J Clin Oncol 2004 34 510 514 15466823 \n[6] Hare SS Souza CA Bain G Seely JM Frcpc, Gomes MM The radiological spectrum of pulmonary lymphoproliferative disease Br J Radiol 2012 85 848 864 22745203 \n[7] Piña-Oviedo S Weissferdt A Kalhor N Moran CA Primary Pulmonary Lymphomas Adv Anat Pathol 2015 22 355 375 26452211 \n[8] Marchiori E Godoy MC Zanetti G Hochhegger B Rodrigues RS The reversed halo sign.Another CT finding useful for distinguish invasive pulmonary aspergillosis andpulmonary lymphoma Eur J Radiol 2011 79 e96 97 21546185 \n[9] Harada S Suzuki R Uehira K Yatabe Y Kagami Y Ogura M Molecular and immunological dissection of diffuse large B cell lymphoma: CD5+, and CD5- with CD10+ groups may constitute clinically relevant subtypes Leukemia 1999 13 1441 1447 10482997 \n[10] Jain P Fayad LE Rosenwald A Young KH O’Brien S Recent advances in de novo CD5+ diffuse large B cell lymphoma. Am J Hematol 2013 88 798 802 23695956 \n[11] Fisher RI Gaynor ER Dahlberg S Oken MM Grogan TM Mize EM Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma N Engl J Med 1993 328 1002 1006 7680764 \n[12] Coiffier B Thieblemont C Van Den Neste E Lepeu G Plantier I Castaigne S Long-term outcome of pat ients in the LNH-98.5 trial, the first randomized study com paring rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte Blood 2010 116 2040 2045 20548096 \n[13] Pfreundschuh M Schubert J Ziepert M Schmits R Mohren M Lengfelder E Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60) Lancet Oncol 2008 9 105 116 18226581\n\n",
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"abstract": "BACKGROUND\nThis study was conducted at Hamad General Hospital to determine the incidence of fungal peritonitis and to describe its clinical and microbiological findings in patients undergoing continuous ambulatory peritoneal dialysis in Qatar.\n\n\nMETHODS\nThe medical records of these patients between 1 January 2005 and 31 December 2008 were retrospectively reviewed and the collected data were analysed.\n\n\nRESULTS\nDuring the study period, 141 episodes of peritonitis were observed among 294 patients. In 14 of these episodes (9.9%), fungal peritonitis was reported in 14 patients with a rate of 0.05 episodes per patient year, while the bacterial peritonitis rate was 0.63 per patient year. Thirteen (93%) patients had one or more previous episodes of bacterial peritonitis that was treated with multiple broad-spectrum antibiotics, 11 (85%) had received broad-spectrum antibiotics within the preceding month, 12 (92%) within three months, and 8 (62%) within six months. Candida species were the only fungal species isolated from the dialysate with predominance of non-albicans Candida species (especially Candida parapsilosis). Therapeutic approach was immediate catheter removal, followed by systemic antifungal therapy and temporary haemodialysis. Nine patients (64.3%) were continued on haemodialysis, whereas five patients (35.7%) died.\n\n\nCONCLUSIONS\nPrior antibiotic use was an important risk factor predisposing patients to the development of fungal peritonitis. Early detection of fungal peritonitis would lead to early institution of appropriate therapy and prevention of complications.",
"affiliations": "Department of Medicine, General Medicine, Hamad General Hospital, Doha, Qatar. fakhanqal@yahoo.co.uk",
"authors": "Khan|Fahmi Yousef|FY|;Elsayed|Mohammed|M|;Anand|Deshmukh|D|;Abu Khattab|Mohammed|M|;Sanjay|Doiphode|D|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D015314:Dialysis Solutions; D015725:Fluconazole",
"country": "Italy",
"delete": false,
"doi": "10.3855/jidc.1519",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1972-2680",
"issue": "5(9)",
"journal": "Journal of infection in developing countries",
"keywords": null,
"medline_ta": "J Infect Dev Ctries",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D001424:Bacterial Infections; D002175:Candida; D020878:Device Removal; D015314:Dialysis Solutions; D005260:Female; D015725:Fluconazole; D017408:Guidelines as Topic; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009181:Mycoses; D010531:Peritoneal Dialysis, Continuous Ambulatory; D010538:Peritonitis; D011780:Qatar; D012189:Retrospective Studies; D012307:Risk Factors; D018461:Soft Tissue Infections; D016896:Treatment Outcome",
"nlm_unique_id": "101305410",
"other_id": null,
"pages": "646-51",
"pmc": null,
"pmid": "21918305",
"pubdate": "2011-09-14",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Fungal peritonitis in patients undergoing continuous ambulatory peritoneal dialysis in Qatar.",
"title_normalized": "fungal peritonitis in patients undergoing continuous ambulatory peritoneal dialysis in qatar"
} | [
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{
"abstract": "The anticonvulsant topiramate not only decreases ethanol consumption in alcohol dependence (AD) but also may produce several adverse events including cognitive impairment. Zonisamide is a structurally related anticonvulsant that is a promising agent for the treatment of AD and may have greater tolerability than topiramate. This study evaluated the effects of zonisamide (400 mg/d) on alcohol consumption and its neurotoxic effects in subjects with AD. A double-blind placebo-controlled clinical trial was conducted using 2 comparator anticonvulsant drugs, topiramate (300 mg/d) and levetiracetam (2000 mg/d), which does not impair cognition. Study medications were administered for 14 weeks, including a 2-week taper period. Medication adherence was facilitated using Brief Behavioral Compliance Enhancement Treatment. The neurotoxicity of the study drugs was assessed using neuropsychological tests and the AB-Neurotoxicity Scale. Compared with placebo, both zonisamide and topiramate produced significant reductions in the drinks consumed per day, percent days drinking, and percent days heavy drinking. Only the percent days heavy drinking was significantly decreased in the levetiracetam group. The topiramate cell was the only group that had a significant increase on the mental slowing subscale of the Neurotoxicity Scale compared with placebo at study weeks 11 and 12. Topiramate and zonisamide both produced modest reductions in verbal fluency and working memory. These findings indicate that zonisamide may have efficacy in the treatment of AD, with effect sizes similar to topiramate. Both of these drugs produced similar patterns of cognitive impairment, although only the topiramate group reported significant increases in mental slowing.",
"affiliations": "From the Departments of *Psychiatry, †Psychology and Brain Sciences, and ‡Neurology, Boston University School of Medicine; §Department of Psychiatry, Harvard Medical School; and ∥Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA.",
"authors": "Knapp|Clifford M|CM|;Ciraulo|Domenic A|DA|;Sarid-Segal|Ofra|O|;Richardson|Mark A|MA|;Devine|Eric|E|;Streeter|Chris C|CC|;Oscar-Berman|Marlene|M|;Surprise|Caitlin|C|;Colaneri|Laurie|L|;Putnam|Meghan|M|;Waters|Megan|M|;Richambault|Courtney|C|",
"chemical_list": "D000927:Anticonvulsants; D007555:Isoxazoles; D000077236:Topiramate; D005632:Fructose; D000077287:Levetiracetam; D000078305:Zonisamide; D010889:Piracetam",
"country": "United States",
"delete": false,
"doi": "10.1097/JCP.0000000000000246",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-0749",
"issue": "35(1)",
"journal": "Journal of clinical psychopharmacology",
"keywords": null,
"medline_ta": "J Clin Psychopharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000428:Alcohol Drinking; D019973:Alcohol-Related Disorders; D000927:Anticonvulsants; D003072:Cognition Disorders; D004311:Double-Blind Method; D005260:Female; D005632:Fructose; D006801:Humans; D007555:Isoxazoles; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010889:Piracetam; D000077236:Topiramate; D016896:Treatment Outcome; D055815:Young Adult; D000078305:Zonisamide",
"nlm_unique_id": "8109496",
"other_id": null,
"pages": "34-42",
"pmc": null,
"pmid": "25427171",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "115675;7796795;22722516;17409025;8749824;21653714;2597811;22000706;23858325;17482246;10923061;24525690;20811276;3098556;12904467;18691980;22324516;16188429;24523671;12767733;20633037;13638508;18584574;22827489;20473070;18687081;21401921;8611059;444788;21421049;19331489;18855810;19417176;24119876;17925516;19388676;18541827;15511695;18215213;19637104;14078168;18482157;12743236;9720801;12941455;17194267;23106522;24205976;21278619;16961786;19643672;20337506;15210974;19513128;9548821",
"title": "Zonisamide, topiramate, and levetiracetam: efficacy and neuropsychological effects in alcohol use disorders.",
"title_normalized": "zonisamide topiramate and levetiracetam efficacy and neuropsychological effects in alcohol use disorders"
} | [
{
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{
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],
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},
{
"reactionmeddrapt": "Product use issue",
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}
],
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},
"primarysource": {
"literaturereference": "KNAPP CM, CIRAULO DA, SEGAL OS, RICHARDSON MA, DEVINE E, PUTNAM M, ET AL. ZONISAMIDE, TOPIRAMATE, AND LEVETIRACETAM: EFFICACY AND NEUROPSYCHOLOGICAL EFFECTS IN ALCOHOL USE DISORDERS.. JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY FEB-2015;35 (1):34-42.",
"literaturereference_normalized": "zonisamide topiramate and levetiracetam efficacy and neuropsychological effects in alcohol use disorders",
"qualification": "3",
"reportercountry": "US"
},
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},
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"sendertype": "2"
},
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
},
{
"companynumb": "US-JNJFOC-20150103654",
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"occurcountry": "US",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
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"medicinalproduct": "TOPIRAMATE."
}
],
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{
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"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Speech disorder",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Erectile dysfunction",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Memory impairment",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Irritability",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use issue",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Paraesthesia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KNAPP CM, CIRAULO DA, SEGAL OS, RICHARDSON MA, DEVINE E, PUTNAM M, ET AL. ZONISAMIDE, TOPIRAMATE, AND LEVETIRACETAM: EFFICACY AND NEUROPSYCHOLOGICAL EFFECTS IN ALCOHOL USE DISORDERS.. JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY FEB-2015;35 (1):34-42.",
"literaturereference_normalized": "zonisamide topiramate and levetiracetam efficacy and neuropsychological effects in alcohol use disorders",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150114",
"receivedate": "20150114",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
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"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150721"
}
] |
{
"abstract": "The goal of this study is to report on the treatment of obsessive-compulsive disorder (OCD), a chronic disabling condition that often presents during childhood and adolescence. Reports on adults using clonazepam for the treatment of OCD are more numerous than on children. Clonazepam as an augmentative treatment in OCD is still controversial. Our aim is to illustrate in a case report the efficacy of clonazepam as an augmentative treatment for severe childhood onset OCD. We report on the case of a young teenage girl with an extremely severe form of obsessive-compulsive disorder (score of 32 on the Children's Yale-Brown Obsessive Compulsive Scale), who, after a mild improvement with a combination of serotonin recapture inhibitors and second generation antipsychotics at high doses, has responded to clonazepam (3mg/day) augmentation of sertraline (200mg/day) and olanzapine (15mg/day). Clonazepam was effective not only in reducing anxiety symptoms, but also in lowering compulsions and obsessions frequency within 6 weeks with a drop in the Children's Yale-Brown Obsessive Compulsive Scale of 16 points. It may be asserted that clonazepam could be useful in the initial stage for severe OCD in young patients.",
"affiliations": null,
"authors": "Halayem|Soumeyya|S|;Othman|Sami|S|;Ben Youssef|Hajer|H|;Belhaj|Ahlem|A|;Bouasker|Anissa|A|;Ghachem|Rym|R|;Tabbane|Karim|K|;Bouden|Asma|A|",
"chemical_list": "D018757:GABA Modulators; D001569:Benzodiazepines; D002998:Clonazepam; D000077152:Olanzapine; D020280:Sertraline",
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1300-2163",
"issue": "26(4)",
"journal": "Turk psikiyatri dergisi = Turkish journal of psychiatry",
"keywords": null,
"medline_ta": "Turk Psikiyatri Derg",
"mesh_terms": "D000293:Adolescent; D001569:Benzodiazepines; D002998:Clonazepam; D004359:Drug Therapy, Combination; D005260:Female; D018757:GABA Modulators; D006801:Humans; D009771:Obsessive-Compulsive Disorder; D000077152:Olanzapine; D020280:Sertraline; D012720:Severity of Illness Index; D014421:Turkey",
"nlm_unique_id": "9425936",
"other_id": null,
"pages": "291-4",
"pmc": null,
"pmid": "26731026",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The Usefulness of Clonazepam as an Augmentative Treatment in a Case of Severe Childhood Onset Obsessive-Compulsive Disorder.",
"title_normalized": "the usefulness of clonazepam as an augmentative treatment in a case of severe childhood onset obsessive compulsive disorder"
} | [
{
"companynumb": "TR-ACCORD-037197",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
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"drugdosagetext": "RAISED TO 15 MG/DAY IN TWO WEEKS",
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"drugindication": "OBSESSIVE-COMPULSIVE DISORDER",
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"medicinalproduct": "OLANZAPINE."
},
{
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"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadditional": null,
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"drugauthorizationnumb": "202825",
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"drugdosagetext": "SIX WEEKS IN 150 MG/DAY INCREASING DOSE",
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"drugindication": "OBSESSIVE-COMPULSIVE DISORDER",
"drugintervaldosagedefinition": "804",
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"medicinalproduct": "SERTRALINE"
},
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": null,
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"drugauthorizationnumb": "077147",
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"drugindication": "OBSESSIVE-COMPULSIVE DISORDER",
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"medicinalproduct": "CLONAZEPAM."
}
],
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"patientonsetage": "13",
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"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Extrapyramidal disorder",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
}
],
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},
"primarysource": {
"literaturereference": "HALAYEM S, OTHMAN S, YOUSSEF HB, BELHAJ A, BOUASKER A, GHACHEM R ET AL.[THE USEFULNESS OF CLONAZEPAM AS AN AUGMENTATIVE TREATMENT IN A CASE OF SEVERE CHILDHOOD ONSET OBSESSIVE-COMPULSIVE DISORDER]. TURK PSIKIYATRI DERG. 2016 WINTER?26(4):291-4.",
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"qualification": "1",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20160125",
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},
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"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160526"
}
] |
{
"abstract": "In recent years, cases involving terbinafine-resistant Trichophyton isolates have been reported increasingly, particularly in India. We present 14 cases of terbinafine treatment failure in Trichophyton-infected Danish patients due to acquired resistance. Patients infected with Trichophyton rubrum (n = 12) or Trichophyton interdigitale (n = 2) with elevated terbinafine MICs during 2013-2018 were included. Antifungal susceptibility testing (AFST) was performed following a modified EUCAST E.Def 9.3.1 method (5 days of incubation) with or without cycloheximide and chloramphenicol (CC) supplementation of the growth medium. The squalene epoxidase (SE) target gene was sequenced, and 3-dimensional enzyme homology modeling was performed. Most patients (12/14 [86%]) were male. The mean age was 53.5 years (range, 11 to 77 years). The mean duration of infections was 4.8 years at the time of resistance detection. Prior systemic terbinafine treatment was documented for all patients, and topical therapy for 62% (information was missing in one case). Overall, nine isolates (64%) displayed high terbinafine resistance (MICs, 4 to >8 mg/liter), while two (14%) displayed moderate (MICs, 1 to 2 mg/liter) and three (21%) displayed low (MICs, 0.125 to 0.25 mg/liter) terbinafine resistance compared with control isolates. MICs generated with or without CC supplementation were similar, but CC prevented contamination. Known and novel SE amino acid substitutions (F397L, L393F, L393S, F415S, H440Y F484Y, and I121M V237I) were detected in resistant but not control isolates. Three-dimensional homology modeling suggested a role of the novel I121M and V237I alterations. Terbinafine resistance has been detected in Denmark using a modified EUCAST method, which facilitated susceptibility testing of dermatophytes. Action is needed for this emerging public health problem.",
"affiliations": "Department of Dermatology, Zealand University Hospital, Roskilde, Denmark disa@regionsjaelland.dk maca@ssi.dk.;Unit of Mycology, Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark.;Unit of Mycology, Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark.;Unit of Mycology, Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark.;Department of Dermatology and Venereology, Aarhus University Hospital, Aarhus, Denmark.;Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.;Department of Dermato-Venereology and Wound Healing Centre, Bispebjerg Hospital, Copenhagen, Denmark.;Dermatologic Clinic, Horsens, Denmark.;Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.;Unit of Mycology, Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark disa@regionsjaelland.dk maca@ssi.dk.",
"authors": "Saunte|Ditte M L|DML|0000-0001-7953-1047;Hare|Rasmus K|RK|0000-0002-9796-023X;Jørgensen|Karin M|KM|;Jørgensen|René|R|0000-0003-0672-466X;Deleuran|Mette|M|;Zachariae|Claus O|CO|;Thomsen|Simon F|SF|;Bjørnskov-Halkier|Lars|L|;Kofoed|Kristian|K|;Arendrup|Maiken C|MC|0000-0002-4747-0144",
"chemical_list": "D000935:Antifungal Agents; D005656:Fungal Proteins; D050603:Squalene Monooxygenase; D000077291:Terbinafine",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.01126-19",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0066-4804",
"issue": "63(10)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": "Trichophyton\n; antifungal resistance; dermatophytes; squalene epoxidase mutations; terbinafine",
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D002648:Child; D025141:Drug Resistance, Fungal; D005656:Fungal Proteins; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009154:Mutation; D050603:Squalene Monooxygenase; D000077291:Terbinafine; D014249:Trichophyton; D055815:Young Adult",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31383665",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": "9536247;27171353;27502503;18215316;30210155;21229992;30768808;29341312;12499173;25757042;29577447;22098752;30275090;29980898;28416557;24134487;29530857;21411586;30058568;29916221;15682641;19499576;16723593;28582544;15980358;17043127",
"title": "Emerging Terbinafine Resistance in Trichophyton: Clinical Characteristics, Squalene Epoxidase Gene Mutations, and a Reliable EUCAST Method for Detection.",
"title_normalized": "emerging terbinafine resistance in trichophyton clinical characteristics squalene epoxidase gene mutations and a reliable eucast method for detection"
} | [
{
"companynumb": "DK-MYLANLABS-2019M1108604",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TERBINAFINE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "077195",
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"drugcharacterization": "1",
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"drugdosageform": null,
"drugdosagetext": "1 COURSE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "TRICHOPHYTOSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": "2014",
"drugstartdateformat": "602",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "TERBINAFINE."
}
],
"patientagegroup": null,
"patientonsetage": "65",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Pathogen resistance",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SAUNTE DML, HARE RK, JORGENSEN KM, JORGENSEN R, DELEURAN M, ZACHARIAE CO, ET AL. EMERGING TERBINAFINE RESISTANCE IN TRICHOPHYTON: CLINICAL CHARACTERISTICS, SQUALENE EPOXIDASE GENE MUTATIONS, AND A RELIABLE EUCAST METHOD FOR DETECTION. ANTIMICROB-AGENTS-CHEMOTHER 2019?63(10):1-24.",
"literaturereference_normalized": "emerging terbinafine resistance in trichophyton clinical characteristics squalene epoxidase gene mutations and a reliable eucast method for detection",
"qualification": "3",
"reportercountry": "DK"
},
"primarysourcecountry": "DK",
"receiptdate": "20191112",
"receivedate": "20191112",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 17021364,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200122"
},
{
"companynumb": "DK-MYLANLABS-2020M1002444",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TERBINAFINE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "077195",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "TABLET",
"drugdosagetext": "UNK (1 COURSE OF TREATMENT (2 WEEKS))",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "TRICHOPHYTOSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": "2014",
"drugstartdateformat": "602",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "TERBINAFINE."
}
],
"patientagegroup": null,
"patientonsetage": "65",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pathogen resistance",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SAUNTE DML, HARE RK, JORGENSEN KM, JORGENSEN R, DELEURAN M, ZACHARIAE CO, ET.AL. EMERGING TERBINAFINE RESISTANCE IN TRICHOPHYTON: CLINICAL CHARACTERISTICS, SQUALENE EPOXIDASE GENE MUTATIONS, AND A RELIABLE EUCAST METHOD FOR DETECTION.. ANTIMICROB. AGENTS CHEMOTHER.. 2019?63:10",
"literaturereference_normalized": "emerging terbinafine resistance in trichophyton clinical characteristics squalene epoxidase gene mutations and a reliable eucast method for detection",
"qualification": "3",
"reportercountry": "DK"
},
"primarysourcecountry": "DK",
"receiptdate": "20200110",
"receivedate": "20200110",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17257947,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
},
{
"companynumb": "DK-MYLANLABS-2019M1108666",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "TRICHOPHYTOSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ITRACONAZOLE."
},
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"abstract": "Immune checkpoint inhibition is part of standard systemic management for many advanced malignancies. Toxicities from this treatment approach are unpredictable, though usually reversible with management per established guidelines. Some patients suffer major morbidity and treatment-related mortality from these agents in an unpredictable manner. Cardiac and neurologic complications are rare, but can result in serious clinical consequences.\nWe describe the presentation, management, and outcomes of eight sequential cases of combined cardiac and neurologic toxicities resulting in severe illness and demonstrating lack of rapid response to immunosuppression.\nOur cohort consisted of six males and two females with an average age of 73.5 years (61-89 years). There were four patients with melanoma, and one patient each with urothelial carcinoma, renal cell carcinoma, breast cancer, and non-small cell lung cancer. Four patients received combination immunotherapy and four patients received monotherapy. The median time to presentation from treatment initiation was 27 days (11-132 days). All patients had a cardiovascular and neurologic toxicity, and most had hepatitis and myositis. The cardiac signs and symptoms were the prominent initial features of the clinical presentation. Each patient was managed by a multidisciplinary team and received a range of immunosuppressive agents. All patients died as a consequence of the immune related adverse events.\nThe evaluation of patients with cardiac adverse events from immunotherapy, should include assessment of overlapping toxicities such as myasthenia gravis and myositis. Providers should be aware of the potential for an extended duration of disability and slow improvement for certain toxicities as these expectations may factor prominently in goals of care decisions.",
"affiliations": "University Hospitals Siedman Cancer Center, Westlake, OH USA.;Department of Medicine, Division of Hematology, Duke University, Durham, NC USA.;Department of Medicine, Division of Hematology and Medical Oncology, University of Virginia, PO Box 800716, Charlottesville, VA 22908 USA.;Department of Medicine, Division of Hematology and Medical Oncology, University of Virginia, PO Box 800716, Charlottesville, VA 22908 USA.;Department of Medicine, Division of Hematology and Medical Oncology, University of Virginia, PO Box 800716, Charlottesville, VA 22908 USA.;Department of Medicine, Division of Cardiovascular Medicine, Noninvasive Cardiovascular Imaging, Nuclear Medicine, University of Virginia, Charlottesville, VA USA.;Department of Surgery, Division of Surgical Oncology, University of Virginia, Charlottesville, VA USA.;Department of Medicine, Division of Hematology and Medical Oncology, University of Virginia, PO Box 800716, Charlottesville, VA 22908 USA.",
"authors": "Arora|Puja|P|;Talamo|Laura|L|;Dillon|Patrick|P|;Gentzler|Ryan D|RD|;Millard|Trish|T|;Salerno|Michael|M|;Slingluff|Craig L|CL|;Gaughan|Elizabeth M|EM|0000-0003-3841-8915",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40959-020-00076-6",
"fulltext": "\n==== Front\nCardiooncology\nCardiooncology\nCardio-oncology\n2057-3804 BioMed Central London \n\n76\n10.1186/s40959-020-00076-6\nResearch\nSevere combined cardiac and neuromuscular toxicity from immune checkpoint blockade: an institutional case series\nArora Puja 1 Talamo Laura 2 Dillon Patrick 3 Gentzler Ryan D. 3 Millard Trish 3 Salerno Michael 4 Slingluff Craig L. Jr5 http://orcid.org/0000-0003-3841-8915Gaughan Elizabeth M. egaughan@virginia.edu 3 1 grid.241104.20000 0004 0452 4020University Hospitals Siedman Cancer Center, Westlake, OH USA \n2 grid.26009.3d0000 0004 1936 7961Department of Medicine, Division of Hematology, Duke University, Durham, NC USA \n3 grid.27755.320000 0000 9136 933XDepartment of Medicine, Division of Hematology and Medical Oncology, University of Virginia, PO Box 800716, Charlottesville, VA 22908 USA \n4 grid.27755.320000 0000 9136 933XDepartment of Medicine, Division of Cardiovascular Medicine, Noninvasive Cardiovascular Imaging, Nuclear Medicine, University of Virginia, Charlottesville, VA USA \n5 grid.27755.320000 0000 9136 933XDepartment of Surgery, Division of Surgical Oncology, University of Virginia, Charlottesville, VA USA \n23 9 2020 \n23 9 2020 \n2020 \n6 211 7 2020 11 9 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nImmune checkpoint inhibition is part of standard systemic management for many advanced malignancies. Toxicities from this treatment approach are unpredictable, though usually reversible with management per established guidelines. Some patients suffer major morbidity and treatment-related mortality from these agents in an unpredictable manner. Cardiac and neurologic complications are rare, but can result in serious clinical consequences.\n\nMethods\nWe describe the presentation, management, and outcomes of eight sequential cases of combined cardiac and neurologic toxicities resulting in severe illness and demonstrating lack of rapid response to immunosuppression.\n\nResults\nOur cohort consisted of six males and two females with an average age of 73.5 years (61–89 years). There were four patients with melanoma, and one patient each with urothelial carcinoma, renal cell carcinoma, breast cancer, and non-small cell lung cancer. Four patients received combination immunotherapy and four patients received monotherapy. The median time to presentation from treatment initiation was 27 days (11–132 days). All patients had a cardiovascular and neurologic toxicity, and most had hepatitis and myositis. The cardiac signs and symptoms were the prominent initial features of the clinical presentation. Each patient was managed by a multidisciplinary team and received a range of immunosuppressive agents. All patients died as a consequence of the immune related adverse events.\n\nConclusions\nThe evaluation of patients with cardiac adverse events from immunotherapy, should include assessment of overlapping toxicities such as myasthenia gravis and myositis. Providers should be aware of the potential for an extended duration of disability and slow improvement for certain toxicities as these expectations may factor prominently in goals of care decisions.\n\nKeywords\nCombination immunotherapyImmune related adverse eventsMyocarditisMyasthenia gravisMyositisissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nImmune checkpoint inhibitors (ICI), including antibodies against cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), programmed cell death-1 (PD-1), and programmed-death-ligand-1 (PD-L1), function to help the body overcome potential barriers to the recognition and elimination of cancer by the host immune system. There are numerous monotherapy and combination indications for these drugs in the management of advanced cancer. Approvals in the adjuvant setting have further expanded the population of patients with both potential benefit and toxicity from treatment [1, 2]. Patient exposure to ICI will continue to increase, as there are several new agents in development.\n\nToxicities from ICI therapy, termed immune related adverse events (irAEs), can occur with any ICI agent, and can manifest any time during or after therapy. Constitutional symptoms, dermatologic, gastrointestinal, hepatic, and endocrine toxicities are the most common irAEs and management strategies are outlined in published guidelines and expert reviews [3–6]. Less common irAEs, such as cardiac and neurologic toxicities, have emerged with increasing utilization. Despite the low frequency, these complications are often serious, with a variety of clinical profiles described [6]. There are reports of fulminant fatal cardiac toxicity, electrical dysfunction, acute coronary syndrome, pericarditis, and acute systolic heart failure occurring after ICI therapy [7–13]. Defining the frequency and patterns of cardiac toxicity from ICI therapy is an area of active investigation [14]. The spectrum of neurologic toxicity can range from non-specific symptoms, such as headache and weakness, to classic findings of well-defined neurologic disorders. A 2019 pharmacovigilance study reported an increased incidence of myasthenia gravis (MG), encephalitis, peripheral neuropathy and meningitis with use of ICI therapy [15].\n\nDespite the low frequency of these toxicities, our single academic institution managed eight patient cases since April 2016 of severe clinical illness resulting from concurrent cardiac and neurologic irAEs, all resulting in fatal outcomes.\n\nMethods\nPatients were identified through clinical care at admission to the University of Virginia (UVA) Health System. After Institutional Review Board review, we collected clinical and pathologic data related to malignancy diagnosis and treatment and past medical history. We evaluated the presentation of each subject, including clinical descriptions in progress notes, results from laboratory testing, cardiovascular analysis, and cross-sectional imaging. We outlined the immunosuppressive regimens used in each case and the recorded outcomes. Descriptive statistics were reported.\n\nCase 1\nThe patient was a 70-year-old male with metastatic melanoma treated with combination ipilimumab and nivolumab. He presented on cycle 1, day 12, with palpitations, double vision, right ptosis and pre-syncope. Initial troponin was 3.65 ng/mL and creatinine kinase (CK) was 3549 U/L. Transthoracic echocardiogram (TTE) showed normal left and right ventricular (LV/RV) function and electrocardiogram (ECG) revealed sinus tachycardia, right bundle branch block, and premature atrial contractions. The patient was started on IV steroids at 1 mg/kg for presumed checkpoint inhibitor induced myocarditis. Cardiac magnetic resonance imaging (CMR) revealed evidence of myocardial edema and late gadolinium enhancement in the subepicardial mid-inferior wall consistent with acute myocarditis (Fig. 1). The patient developed progressive cardiac electrical abnormalities and the troponin continued to rise to 29.69 ng/mL. Anti-thymocyte globulin (ATG) was started and the steroid dose was increased to one-gram methylprednisolone with his declining clinical status. The patient had cardiac arrest and responded to CPR. Telemetry demonstrated bradycardia with complete heart block and pacing was initiated. Patient had short periods of clinical stabilization but no sustained improvement from a cardiac or neurologic standpoint with aggressive supportive care and immunosuppression. On hospital day 5, mycophenolate mofetil (MMF) and cyclophosphamide were added to the regimen but by the next day, the patient had significant global weakness with progressive bilateral ptosis and dyspnea. Plasmapheresis was started for the clinically diagnosis of Myasthenia gravis (MG) and anti-acetylcholine-receptor (AChR) antibody was positive. Repeat TTE demonstrated worsening LV and RV function with LVEF of 40–45% and troponin rose to 90.58 ng/mL. He required intubation for respiratory failure, developed progressive and refractory electrical abnormalities and ultimately died after unsuccessful resuscitation efforts (Fig. 2).\nFig. 1 Cardiac MRI from Case 1: T2 maps (top row) demonstrate patchy focal areas of myocardial edema in the anterior wall and inferior wall (black arrows). Late gadolinium enhancement (LGE) images (bottom row) demonstrate patchy focal areas of scar (yellow arrows). These findings are consistent with myocarditis\n\nFig. 2 Electrocardiogram for Case 1. Taken on the final hospital day in the setting of clinical decline and three hours prior to final cardiac arrest. Junctional tachycardia, abnormal R-wave progression, prolonged QTc (532 msec)\n\n\n\nCase 2\nhe patient was a 79-year-old male with metastatic melanoma treated with pembrolizumab. He presented with blurred vision, diplopia, fatigue, lower extremity weakness and diffuse pain. The patient was found to be in complete heart block with an initial troponin of 16.45 ng/mL and CK of 11,953 U/L, as well as hepatitis (ALT 395 U/L, AST 710 U/L) (Fig. 3). Bedside TTE showed a LVEF of 60–65%. His exam was notable for ophthalmoplegia, bilateral fatigable ptosis, and diffuse weakness with muscle pain during strength testing. The patient was started on IV steroids at 1 mg/kg initially, but the dose was increased to 1 g daily on hospital day (HD) 1 along with initiation of ATG and MMF with rising biomarkers. Intravenous cyclophosphamide was started on hospital day 3. Cardiac biomarkers ultimately decreased with this therapy, to a nadir of troponin 0.34 ng/mL and CK 247 U/L. He completed the planned courses of intravenous steroid and ATG and was transitioned to oral prednisone. A permanent pacemaker was placed, and he had no further cardiac events during his illness. Intravenous Immunoglobulin (IVIg) was initiated for the clinical diagnosis of MG, but there was no improvement in generalized weakness or ophthalmoplegia. His anti-AChR antibody testing was negative. His course was further complicated by an upper gastrointestinal bleed due to erosive duodenopathy and a pulmonary embolism. Patient opted to transition to hospice care due to lack of significant clinical improvement.\nFig. 3 Presenting Electrocardiogram for Case 2. Complete atrioventricular block with wide QRS complex\n\n\n\nCase 3\nThe patient was a 61-year-old female with metastatic breast cancer treated with combination durvalumab and tremelimumab on trial. The patient presented for dose two of therapy with several days of right ptosis and was found to have hepatitis (AST 720 U/L, ALT 327 U/L), myositis (CK 8082 U/L) and elevated troponin (1.03 ng/mL). She was started on IV steroids at 2 mg/kg and was admitted to the hospital. TTE was performed and demonstrated LVEF of 60–65% and CMR did not show evidence of myocarditis. Urgent brain MRI was negative for brain metastases or leptomeningeal disease. For a clinical diagnosis of MG, she received pyridostigmine with symptomatic improvement. Her anti-AChR antibody testing was negative. The IV steroids induced steady improvement in transaminases, and CK. She experienced episodes of chest pain, dizziness, dyspnea, and developed premature atrial contractions and QTc prolongation on ECG (Fig. 4). Her troponin initially improved to 0.86 ng/mL with therapy, but on it rose again to a maximum of 1.24 ng/mL. MMF was added and the troponin steadily improved to 0.65 ng/mL at discharge. She returned to the hospital within 2 days of discharge with chest pressure and dizziness. Her troponin was 0.39 ng/dL and her transaminases were also trending downward. Her sodium, normal at discharge, was 119 mmol/L and the patient was transitioned back to IV steroids. For a diagnosis of syndrome of inappropriate antidiuretic hormone (SIADH), she required hypertonic saline. She declined quickly with the development of hypercapnic respiratory failure and was transitioned to comfort measures.\nFig. 4 Electrocardiogram from Patient 3. Taken in the setting of chest pain, dizziness and dyspnea. Prolonged QTc 519 msec (baseline 437 msec)\n\n\n\nCase 4\nThe patient was a 69-year-old male with metastatic urothelial carcinoma treated with pembrolizumab. The patient presented with diffuse body pain and weakness on cycle 5, day 2, of pembrolizumab. His troponin was elevated at 1.42 ng/mL, and he was managed for non-ST-elevation myocardial infarction (NSTEMI). His troponin continued to climb to a peak of 23 ng/mL over the first 24 h. CK peak was 372 U/L at arrival but then normalized with supportive care. TTE demonstrated mild concentric hypertrophy with EF of 40–45% and CMR was not pursued due to chronic kidney disease. IV steroids were initiated at 1 mg/kg initially along with MMF given concern for ICI-induced myocarditis. Cardiac catheterization did not show evidence of acute coronary artery obstruction. A course of ATG was initiated and the steroids were increased to one gram of methylprednisolone daily for rising cardiac biomarkers. The patient clinically improved and troponin levels peaked at 58.99 ng/mL on HD 6 and then decreased to 20.21 ng/mL by the end of the clinical course. CK remained low and no clinically significant cardiac electrical abnormalities were identified. The presenting global weakness, disconjugate gaze and diffuse body pain did not improve. On HD 4, the patient developed altered mental status due to multiple cerebrovascular accidents resulting in left hemiparesis. Further workup for the etiology of the strokes was unrevealing, with vasculitis or cholesterol-emboli from the catheterization as the leading considerations. The patient opted to transition to comfort measures.\n\nCase 5\nThe patient was a 67-year-old female with metastatic melanoma treated with combination ipilimumab and nivolumab. She presented on cycle 1 day 5 with diffuse body weakness, dyspnea, and dysphagia and was found to have hepatitis (ALT 563 U/L, AST 353 /L) and a troponin of 1.8 ng/mL. Once hospitalized, she soon developed hypercapnic respiratory failure and was intubated. TTE demonstrated preserved EF, pro-B-type NP was 1370 pg/mL, and CK was 7244 IU/L. She was considered unstable for cardiac catheterization. Patient was started on IV steroids at 2 mg/kg and MMF. The troponin rose to 12.02 ng/mL, while CK and transaminases trended down. With failure to clinically improve, she was transferred to our institution and the steroids were increased to methylprednisolone 1 g per day and ATG was added. Repeat TTE demonstrated an EF of 60–65%. Her troponin peaked at 18.42 ng/dL and then declined. CMR was performed 8 days after starting immunosuppression with improving cardiac biomarkers (CK 231, Troponin 1.86) and did not demonstrate imaging evidence of myocarditis. Immunosuppression was tapered and cardiac and hepatic biomarkers showed steady improvement. The patient remained ventilator-dependent due to respiratory muscle weakness from a clinical diagnosis of MG. Her anti-AChR antibody testing was positive. Plasmapheresis was initiated but failed to impact her clinical status and she was transitioned to comfort measures.\n\nCase 6\nThe patient was an 83-year-old male with melanoma treated with nivolumab in the adjuvant setting. One month after his first dose, he developed marked fatigue, weakness, chest pain and orthopnea. His troponin was 0.78 ng/mL and he was diagnosed with pericarditis and medically managed with colchicine and naproxen. The next day, he presented again with chest tightness, dysphagia, and progressive left eye ptosis. TTE showed LVEF of 55% and treatment for pericarditis was continued. On examination, he had proximal muscle weakness, areflexia and ocular muscle abnormalities. He had both hepatitis (ALT 166 U/L, AST 510 U/L) and an elevated CK (2886 U/L). MRI of the brain was unremarkable. The patient was started on IV methylprednisolone at 1 mg/kg and plasmapheresis was started for a clinical diagnosis of MG. His anti-AChR antibody testing was negative. He required intubation for hypercapnic respiratory failure. Over the course of the next several days his troponin, CK and liver function tests all improved, but he had persistent respiratory compromise with inability to reduce ventilatory support. The patient was transitioned to comfort measures.\n\nCase 7\nThe patient was a 70-year-old male with metastatic kidney cancer treated with ipilimumab and nivolumab in combination. He presented on cycle 1 day 21 with generalized weakness and fatigue. He was identified to have a CK of 11,000 U/L and troponin of 36 ng/mL. The patient was treated with IV steroids and supportive care with stabilization of clinical status and biochemical improvement. He was discharged to a rehabilitation facility and transitioned to oral prednisone for a taper. The patient clinically deteriorated with progressive dysphagia, globus sensation, dyspnea and weakness on prednisone at 60 mg (approximately 0.5 mg/kg). He was admitted with a clinical diagnosis of ICI-induced MG and plasmapheresis was started. His anti-AChR antibody testing was negative. The patient required intubation for respiratory failure and then the steroids were increased to methylprednisolone 1 g per day. His troponin level peak value was 0.28 ng/mL on this hospitalization. His echocardiogram demonstrated a preserved LVEF of 60–65% and no major rhythm abnormalities were identified. He developed upper gastrointestinal bleeding from immune-related gastritis and Infliximab was given. The patient had persistent respiratory failure and was transitioned to comfort measures.\n\nCase 8\nThe patient is an 89-year-old male with non-small cell lung cancer treated with pembrolizumab. The patient presented 10 days after dose 2 with disconjugate gaze, dysphagia, blurred vision and imbalance and was found to have hepatitis (ALT 243 U/L, AST 416 U/L). For a clinical diagnosis of MG, he was started on IV steroids at 1 mg/kg. The anti-AChR testing was negative. He had an elevated troponin to 1.66 ng/mL at presentation that peaked at 2.34 ng/mL, favored clinically to be checkpoint-inhibitor-induced myocarditis. TTE was technically limited and cardiac MRI had evidence of a prior infarct with no clear evidence of myocarditis and an ejection fraction of 47%. He showed multiple episodes of non-sustained ventricular tachycardia and developed high-degree atrioventricular block. For elevated CK to 3843 U/L, he underwent EMG showing myopathic changes expected with myositis. Liver function tests and CK improved with steroids but patient had persistent weakness, dysphagia and blurred vision. The patient and family opted to pursue comfort measures.\n\nResults\nClinical and oncologic data\nEight successive cases of combined neurologic and cardiac toxicities presented to the UVA Health System, including four patients who received oncologic care outside of our institution and were transferred for toxicity management (Table 1). This group included six males and two females, all Caucasian, with an average age of 73.5 years (range, 61–89 years). There were five diseases represented, including four patients with melanoma, and one patient each with urothelial carcinoma, breast carcinoma, renal cell carcinoma, and non-small cell lung cancer.\nTable 1 Demographics and Patient Information\n\nCase\tAge\tSex\tDisease\tICI Therapy\tTime to Presentation from ICI Initiation\tBaseline Medical History\t\n1\t70\tMale\tMelanoma\tIpilimumab/Nivolumab\t11 Days\tHypertension Colon Cancer\t\n2\t79\tMale\tMelanoma\tPembrolizumab\t26 Days\tCLL\t\n3\t61\tFemale\tBreast Cancer\tDurvalumab/Tremelimumab\t28 Days\tNone\t\n4\t69\tMale\tUrothelial Carcinoma\tPembrolizumab\t132 Days\tCKD, Hypertension, Hyperlipidemia\t\nType 2 DM\t\nCAD\t\n5\t67\tFemale\tMelanoma\tIpilimumab/Nivolumab\t14 Days\tNone\t\n6\t83\tMale\tMelanoma\tNivolumab, Adjuvant\t31 Days\tHypertension,\t\nHyperlipidemia\t\nAtrial fibrillation\t\n7\t70\tMale\tRenal Cell Carcinoma\tIpilimumab/Nivolumab\t21 Days\tHypertension, CKD, Atrial Fibrillation\t\n8\t89\tMale\tNon-Small Cell Lung Carcinoma\tPembrolizumab\t32 Days\tHypertension, Hyperlipidemia, CAD, CKD, Type 2 DM\t\nBaseline data, disease and treatment information for each patient. CLL chronic lymphocytic leukemia, CAD coronary artery disease, Type 2 DM type 2 diabetes mellitus, CKD chronic kidney disease\n\n\n\nFour patients received combination anti-CTLA4 and anti-PD1, including two patients with melanoma, one with breast cancer and one patient with renal cell carcinoma (Table 1). Four patients received anti-PD-1 monotherapy, including one patient being treated in the adjuvant setting for melanoma. Five patients had baseline cardiovascular comorbidities, including coronary artery disease, hypertension, type 2 diabetes mellitus, and atrial fibrillation (Table 1). One patient had a concurrent diagnosis of chronic lymphocytic leukemia requiring chemotherapy and one patient had a remote history of resected colon cancer. None had prior autoimmune disease.\n\nToxicity presentation\nThe patients presented at a median of 27 days (range, 11–132 days) from the initiation of ICI therapy. All cases had a cardiovascular toxicity recognized early in the acute presentation (Table 2). Seven cases had a clinical syndrome consistent with myocarditis, including three with high-degree atrioventricular conduction block. The eighth patient was diagnosed with pericarditis. All patients were diagnosed with presumed checkpoint-inhibitor myocarditis based on clinical features (history, examination, biomarkers, electrocardiogram and cardiac imaging) and each patient was assessed by a Cardiology specialist. There were no cardiac biopsies or autopsies performed for histologic assessment.\nTable 2 Range of toxicities for each case\n\nCase\tCardiovascular Toxicity\tNeurologic/Ocular Toxicity\tMyositis\tHepatitis\tRespiratory Failure\tOther\t\n1\tMyocarditis Complete Heart Block\tMyasthenia Gravis\t+\t+\t+\t–\t\n2\tMyocarditis, Complete Heart Block, Pulmonary Embolism\tMyasthenia Gravis\t+\t+\t–\tGastritis\t\n3\tMyocarditis\tMyasthenia Gravis\t+\t+\t–\tSIADH\t\n4\tMyocarditis\tStroke\t–\t–\t–\t–\t\n5\tMyocarditis\tMyasthenia Gravis\t+\t+\t+\t–\t\n6\tPericarditis\tMyasthenia Gravis\t+\t+\t+\t–\t\n7\tMyocarditis\tMyasthenia Gravis\t+\t+\t+\tGastritis\t\n8\tMyocarditis, Complete Heart Block\tMyasthenia Gravis\t+\t+\t–\t–\t\nEach case had multiple overlapping toxicities after presenting with primarily a cardiac symptom. SIADH syndrome of inappropriate anti-diuretic hormone\n\n\n\nAll cases had a neurologic toxicity, primarily MG (Table 2). The eighth patient had multiple strokes. Of the cases of MG, five had ophthalmoplegia and four developed respiratory failure requiring intubation. Most patients had concurrent myositis, diagnosed by elevated creatine kinase (CK) and clinical symptoms. There were no muscle biopsies performed but one patient had characteristic myositis findings on EMG. All patients were evaluated by Neurology specialists.\n\nTwo patients developed severe gastritis/duodenitis with upper gastrointestinal bleeding, favored immune in origin. Gastric biopsy from case seven showed findings consistent with checkpoint inhibitor gastritis. One patient ultimately died of hypercapnic respiratory failure in the setting of complications from the syndrome of inappropriate anti-diuretic hormone (SIADH) and the relationship with the checkpoint inhibitor therapy is not known.\n\nToxicity treatment\nMultiple immunosuppressive agents were used in each case. All patients were treated with steroids with starting doses between 1 and 2 mg/kg and additional agents were added in a stepwise approach determined by the patient’s clinical status and response. Steroids were continued for the duration of the clinical course. Guidelines from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN®) were followed and expert opinion was sought within and outside of our academic medical center. Four patients ultimately received five-day courses of one-gram intravenous methylprednisolone. Several of these patients presented within months of each other, which impacted the immunosuppression dosing and agent timing and selection. Four patients (50%) received anti-thymocyte globulin, four (50%) received mycophenolate mofetil, and two patients (25%) had cyclophosphamide added to the regimen for lymphodepletion in the setting of persistent clinical illness. For the MG, all patients were treated symptomatically with pyridostigmine. Four patients (50%) underwent plasmapheresis and one received intravenous immunoglobulin. One patient received infliximab for irAE management. The early immunosuppressant choices were targeted at the cardiac abnormalities and the antibody depleting therapies for MG tended to start in the first several days of admission.\n\nOutcomes\nAll patients died as a result of the immunotherapy toxicity (Table 3). The average time between the last treatment and death was 32.5 days (range, 17–67 days). One patient died rapidly in the hospital despite maximal interventions. The other seven opted for withdrawal of aggressive care with transition to comfort measures. In six cases (75%), the cardiac components improved with down-trending biomarkers, maintenance of stable ejection fraction, and lack of significant electrical instability apart from the pacemaker required for cases with complete heart block. One patient died of progressive cardiac failure on a fulminant course. One patient was showing developing cardiac electrical changes including high-degree atrioventricular block at the time that care was transitioned to comfort measures.\nTable 3 Patient Outcome\n\nCase\tCardiac Improvement\tNeurologic Improvement\tMyositis Improvement\tHepatitis Improvement\tRespiratory Improvement\tCancer Response\tWithdrawal of Care/Hospice Decision\tTime from last treatment to Death\t\n1\t–\t–\t+\t+\t–\tSD\t–\t17 Days\t\n2\t+\t–\t+\t+\tNA\tPR\t+\t21 Days\t\n3\t+\t+\t+\t+\tNA\tNR\t+\t41 Days\t\n4\t+\t–\tNA\tNA\tNA\tSD\t+\t17 Days\t\n5\t+\t–\t+\t+\t–\tSD\t+\t34 Days\t\n6\t+\t–\t+\t+\t–\tNA\t+\t42 Days\t\n7\t+\t–\t+\t+\t–\tNR\t+\t67 Days\t\n8\t–\t–\t–\t–\tNA\tNR\t+\t21 Days\t\nOutcome of immunosuppression on toxicity course by organ system and overall course. For organ toxicities “+” = improved, “- “= did not improve. NA Not applicable, SD stable disease, PR Partial response, NR Not reported\n\n\n\nOnly one case had notable improvement from the neurologic toxicity and the generalized weakness was a prominent aspect of the toxicity course for each patient. None of the patients with respiratory failure requiring mechanical ventilation recovered sufficiently to be removed from the ventilator. As each of these patients and/or families made the decision to withdraw care, the trajectory and potential neurologic and respiratory recovery with prolonged support is not known.\n\nSix of the seven (86%) cases with myositis showed significant improvement in CK levels with immunosuppression. Six of the seven (86%) of the cases with hepatitis showed significant improvement in transaminase levels with immunosuppression. The seventh patient in both of these groups discontinued interventions prior to evidence of improvement.\n\nFour of the eight (50%) cases had cross-sectional imaging done during the disease course that allowed assessment of cancer response to therapy. Of these four, one patient showed a partial response to therapy and three had stable disease.\n\nDiscussion\nToxicities from ICI are variable in onset, presentation, and severity. In current experience, there are no patient or tumor characteristics that reliably predict irAEs. Our cases included men and women, ages from 61 to 83 years, with varied cancers and ICI-treatments represented (Table 1). All patients had metastatic disease, including one patient that had undergone melanoma resection to no evidence of disease and was receiving therapy in the adjuvant setting. Three patients had minimal comorbid conditions. Each patient had evidence of a cardiovascular insult and a neurologic insult, and most had concurrent hepatitis and myositis. Toxicities tended to onset early following initiation of ICI therapy, often after the first dose. In this cohort, the cardiovascular signs and symptoms were visible early in the presentation and were the focus of initial diagnostics and immunosuppressive interventions. The neurologic insults, however, proved to be the most symptomatic and the primary determinants of the clinical course.\n\nCardiac toxicity from ICI therapy was a rare immune-related adverse event in the early ICI trials, but this complication is becoming increasingly recognized and reported [16, 17]. In one series of over 20,000 patients treated with nivolumab, ipilimumab or combined ipilimumab and nivolumab, cardiovascular irAEs were rare (0.09%) [7]. In addition, Mahmood identified an overall incidence of myocarditis of 1.14% from a multicenter registry [18]. With increasing use of ICI agents, the spectrum of associated cardiovascular toxicity is expanding. In this cohort, clinical profiles included fulminant myocarditis, complete heart block, QTc prolongation, pulmonary embolism, and pericarditis. Each patient also had several concurrent irAEs, many with overlapping myocarditis, myositis, and Myasthenia gravis. In 2018, Moslehi et al. reported on 101 cases of severe myocarditis from ICI therapy and noted that in 42% of cases, there was a concurrent severe irAE, most commonly myositis and Myasthenia [19]. Mortality reported from these cases of myocarditis ranged from 36% for patients treated with anti-PD-1 or anti-PD-L1 antibodies to 67% for patients treated with combination anti-CTLA-4 and anti-PD1/PD-L1 therapy.\n\nIn 2016, Johnson reported two cases of fulminant myocarditis in patients receiving combination ipilimumab and nivolumab for advanced melanoma [8]. Both patients received aggressive immunosuppression and supportive care but quickly died from the irAE. The clinical course for two of our cases followed a similar fulminant pattern with early onset symptoms after ICI initiation, electrical instability, and rapid clinical deterioration. One patient died and one patient survived the initial cardiac instability. For most of our patients, the cardiac insults proved manageable in the short term with aggressive supportive care, including device placement and immunosuppression, evidenced by preserved ejection fraction, lack of major electrical dysfunction, and improving cardiac biomarkers. As each patient died, we can make no comments regarding the long-term cardiac outcomes.\n\nSeven of our cases had a clinical syndrome consistent with Myasthenia gravis. MG occurs in approximately 0.15% of patients treated with anti-PD1 therapy [20]. This is an antibody-mediated disorder of the post-synaptic membrane at the neuromuscular junction, and, in its severe form, can impact respiratory muscle function [21, 22]. The diagnosis of MG is usually clinical but can be supported by the presence of autoantibodies, typically against the acetylcholine receptor [21]. In each of our cases, the MG diagnosis was made on clinical grounds by a Neurologist. Antibody testing was done on each patient, but results took several days to return, and treatment decisions were required without the results. There are several other autoantibodies less commonly implicated in the development of MG, including antibodies against the voltage-gated potassium channel Kv1.4, which are associated with cardiac involvement of the Myasthenia [23, 24]. Treatment for MG often includes immunosuppression and antibody-depleting therapy, such as plasmapheresis and/or intravenous immunoglobulin. While corticosteroids are the mainstay of management for irAEs, there is a concern about worsening of weakness early in the course of MG with initiation of steroids. Early multidisciplinary input is invaluable to management of these complex toxicities.\n\nAs with all irAEs, ICI-induced MG presents with a spectrum of severity with some patients only developing limited symptoms that respond to immunosuppression and pyridostigmine [25, 26]. Overall, ICI-induced MG tends to have a more aggressive clinical course than non-ICI-related disease and patients often show signs of myositis and myocarditis [20, 27]. The triad of MG, myositis and myocarditis has been reported in case reports of ICI-treated patients with a variety of cancers [20, 28–34]. Suzuki et al. reported the results of a safety database in Japan including outcomes of 10,277 patients treated with either single-agent nivolumab or ipilimumab [27]. Twelve patients developed MG, with early onset of symptoms with rapid clinical deterioration. Ten of these 12 patients had elevated CK levels, four with confirmed concurrent myositis, and three with concurrent myocarditis. Six of these patients developed a myasthenic crisis including five patients that required respiratory support for a median duration of 54 days (range 10–128 days). The authors report that the patients with severe myasthenia had a slow recovery with improvement in muscle strength occurring over 4–8 weeks. In a review by Kao et al., the rates of respiratory failure with ICI-induced MG were as high as 50% of reported cases, and most patients presented with elevated levels of CK [20]. In our cohort, four patients out of seven with a clinical syndrome of MG required intubation for respiratory failure and each had an elevated CK.\n\nClinically significant objective and subjective weakness was a prominent issue throughout the clinical course for most of our cases. In the setting of advanced cancer, the marked clinical deterioration and prolonged duration of symptoms were central components of the care decisions. Seven of the patients opted to transition to best supportive care due to ongoing setbacks and/or severe weakness after 2–4 weeks of aggressive care. Despite objective improvements in measurable laboratory and clinical parameters, and supportive interventions for mobility and strength, the patient-reported weakness failed to meaningfully improve. In contrast to the expected rapid improvement with immunosuppression often seen in management of most irAEs, the clinical course for our cases was strikingly different with improvement in objective measures, but minimal overall clinical change for these patients. Providers should be aware of the potential long duration of illness and debility from some severe irAEs in order to counsel patients and family members, as these expectations will likely factor into care decisions.\n\nWe remain without clinical, pathologic, or pharmacologic predictive features for the development of the combination of cardiac and neurologic irAEs and therefore, oncologists and patients balance the risk of rare serious toxicity with the substantial potential benefit of the treatments. The heterogeneity of our cases reflects the general experience that these toxicities can impact any patient on any checkpoint inhibitor and providers need to be aware of the potential for rapid onset of toxicity and clinical deterioration. The potential for long and slow recovery is an important expectation to set with patients experiencing certain combined irAEs. Providers are encouraged to evaluate for overlapping irAEs particularly in the setting of severe presentations and a multidisciplinary management approach should be strongly considered. The morbidity and mortality from these rare irAEs will take on additional significance as the ICI agents move further into the adjuvant setting.\n\nConclusions\nIn the evaluation of patients with cardiac adverse events from immunotherapy, providers should evaluate for overlapping toxicities such as myasthenia gravis and myositis. Providers should be aware of the potential for an extended duration of disability and slow improvement for certain toxicities as these expectations may factor prominently in goals of care decisions.\n\nAbbreviations\nICIImmune checkpoint inhibition\n\nCTLA-4Cytotoxic T-lymphocyte associated protein-4\n\nPD-1Programmed cell death protein 1\n\nPD-L1Programmed death-ligand 1\n\nirAEsImmune-related adverse events\n\nMGMyasthenia gravis\n\nUVAUniversity of Virginia\n\nCKCreatine Kinase\n\nSIADHSyndrome of inappropriate anti-diuretic hormone\n\nCLLChronic lymphocytic leukemia\n\nCADCoronary artery disease\n\nCKDChronic kidney disease\n\nType 2 DMType 2 diabetes mellitus\n\nATGAnti-thymocyte globulin\n\nMMFMycophenolate mofetil\n\nCyclophosCyclophosphamide\n\nIVIgIntravenous immunoglobulin\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nPuja Arora and Laura Talamo contributed equally to this work.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nPA contributed to the design of the study, obtained patient data and wrote and edited the manuscript. LT contributed to the design of the study, obtained patient data and wrote and edited the manuscript. PD provided patient care to one of the cases, contributed to the concept and design of the study and edited the manuscript. RG provided patient care to two of the cases, contributed to the concept and design of the study and edited the manuscript. TM provided patient care to one of the cases and edited the manuscript. MS provided cardiology imaging and patient care to several of the cases and edited the manuscript. CLS contributed to the design of the study and edited the manuscript. EG contributed to the design of the study, obtained patient data, edited the manuscript and submitted for publication. All authors read and approved the final manuscript.\n\nFunding\nThere was no funding source for this manuscript.\n\nSources of support that require acknowledgement: This work was supported by the UVA Cancer Center Support Grant P30CA044579.\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nEthics approval and consent to participate\nRequest to review and report on deceased patient records was reviewed by the University of Virginia Institutional Review Board and did not require approval.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Weber J Mandala M Del Vecchio M Gogas HJ Arance AM Cowey CL Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma N Engl J Med 2017 377 19 1824 1835 10.1056/NEJMoa1709030 28891423 \n2. 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Bonaca MP Olenchock BA Salem J Wiviott SD Ederhy S Cohen A Myocarditis in the setting of cancer therapeutics. Proposed case definitions for emerging clinical syndromes in cardio-oncology Circulation. 2019 140 2 80 91 10.1161/CIRCULATIONAHA.118.034497 31390169 \n15. Johnson DB Manouchehri A Haugh AM Quach HT Balko JM Lebrun-Vignes B Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study J Immunother Cancer. 2019 7 1 134 10.1186/s40425-019-0617-x 31118078 \n16. Postow MA Chesney J Pavlick AC Robert C Grossmann K McDermott D Nivolumab and ipilimumab versus ipilimumab in untreated melanoma N Engl J Med 2015 372 21 2006 2017 10.1056/NEJMoa1414428 25891304 \n17. Voskens CJ Goldinger SM Loquai C Robert C Kaehler KC Berking C The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network PLoS One 2013 8 1 e53745 10.1371/journal.pone.0053745 23341990 \n18. Mahmood SS Fradley MG Cohen JV Nohria A Reynolds KL Heinzerling LM Myocarditis in patients treated with immune checkpoint inhibitors J Am Coll Cardiol 2018 71 16 1755 1764 10.1016/j.jacc.2018.02.037 29567210 \n19. Moslehi JJ Salem JE Sosman JA Lebrun-Vignes B Johnson DB Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis Lancet. 2018 391 10124 933 10.1016/S0140-6736(18)30533-6 29536852 \n20. Kao JC Brickshawana A Liewluck T Neuromuscular complications of programmed cell death-1 (PD-1) inhibitors Curr Neurol Neurosci Rep 2018 18 10 63 10.1007/s11910-018-0878-7 30078154 \n21. Gilhus NE Skeie GO Romi F Lazaridis K Zisimopoulou P Tzartos S Myasthenia gravis - autoantibody characteristics and their implications for therapy Nat Rev Neurol 2016 12 5 259 268 10.1038/nrneurol.2016.44 27103470 \n22. Gilhus NE Myasthenia gravis N Engl J Med 2016 375 26 2570 2581 10.1056/NEJMra1602678 28029925 \n23. Romi F Suzuki S Suzuki N Petzold A Plant GT Gilhus NE Anti-voltage-gated potassium channel Kv1.4 antibodies in myasthenia gravis J Neurol 2012 259 7 1312 1316 10.1007/s00415-011-6344-y 22167224 \n24. Suzuki S, Baba A, Kaida K, Utsugisawa K, Kita Y, Tsugawa J, et al. Cardiac involvements in myasthenia gravis associated with anti-Kv1.4 antibodies. Eur J Neurol. 2014;21(2):223–230. doioi: 10.1111/ene.12234.\n25. Becquart O, Lacotte J, Malissart, P, Nadal J, Lesage C, Guillot B, et al. Myasthenia gravis induced by immune checkpoint inhibitors. J Immunother. 2019;42(8):309–312. Doi:CJI0000000000000278.\n26. Werner JM Schweinsberg V Schroeter M von Reutern B Malter MP Schlaak M Successful treatment of myasthenia gravis following PD-1/CTLA-4 combination checkpoint blockade in a patient with metastatic melanoma Front Oncol 2019 9 84 10.3389/fonc.2019.00084 30828569 \n27. Suzuki S Ishikawa N Konoeda F Seki N Fukushima S Takahaski K Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan Neurology. 2017 89 11 1127 1134 10.1212/WNL.0000000000004359 28821685 \n28. Suzuki S Utsugisawa K Yoshikawa H Motomura M Matsubara S Yokoyama K Autoimmune targets of heart and skeletal muscles in myasthenia gravis Arch Neurol 2009 66 11 1334 1338 10.1001/archneurol.2009.229 19752287 \n29. Möhn N Suhs KW Gingele S Angela Y Stangel M Gutzmer R Acute progressive neuropathy-myositis-myasthenia-like syndrome associated with immune-checkpoint inhibitor therapy in patients with metastatic melanoma Melanoma Res 2019 29 4 435 440 10.1097/0000000000000598 30855529 \n30. Kimura T Fukushima S Miyashita A Aoi J Jinnin M Kosaka T Myasthenic crisis and polymyositis induced by one dose of nivolumab Cancer Sci 2016 107 7 1055 1058 10.1111/cas.12961 27420474 \n31. Kon T Mori F Tanji K Miki Y Kimura T Wakabayashi K Giant cell polymyositis and myocarditis associated with myasthenia gravis and thymoma Neuropathology. 2013 33 3 281 287 10.1111/j.1440-1789.2012.01345.x 22989101 \n32. Chen Q Huang DS Zhang LW Li YQ Wang HW Liu HB Fatal myocarditis and rhabdomyolysis induced by nivolumab during the treatment of type B3 thymoma Clin Toxicol (Phila) 2018 56 7 667 671 10.1080/15563650.2017.1401079 29126352 \n33. Fukasawa Y Sasaki K Natsume M Nakashima M Ota S Watanabe K Nivolumab-induced myocarditis concomitant with myasthenia gravis Case Rep Oncol 2017 10 3 809 812 10.1159/000479958 29070994 \n34. Mahmood SS Chen CL Shapnik N Krishnan U Singh H Makker V Myocarditis with tremelimumab plus durvalumab combination therapy for endometrial cancer: a case report Gynecol Oncol Rep 2018 25 74 77 10.1016/j.gore.2018.05.014 29922709\n\n",
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},
{
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"literaturereference": "Arora P, Talamo L, Dillon P, Gentzler R, Millard T, Salerno M, Slingluff Jr C, Gaughan E. Severe combined cardiac and neuromuscular toxicity from immune checkpoint blockade: an institutional case series. Cardio-oncology. 2020 SEP 23;6:21:1-11. doi:10.1186/s40959-020-00076-6",
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},
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] |
{
"abstract": "Pneumocystis jirovecii pneumonia (PCP) is a relatively rare complication in non-HIV patients receiving immunosuppressive treatment. Since the introduction of tumour necrosis factor-α inhibitors cases of this complication have increased. We report the case of a 54-year-old, HIV-negative patient, who presented to our department with a long history of pustular psoriasis with poor response to traditional treatments. During the last admission he developed a severe flare that was unresponsive to cyclosporine, therefore infliximab was initiated. After the third dose he developed PCP that required admission to the intensive care unit, with a positive response to i.v. administration of trimethoprim/sulfamethoxazole. During follow up a mutation in the IL36RN gene compatible with an IL-36RN deficiency was found and anakinra was started, with rapid improvement of his psoriasis. PCP is a severe complication in patients receiving immunosuppressive therapy and is probably underreported by dermatologists. There are no clinical guidelines for PCP prophylaxis in dermatological patients who will receive immunosuppressive or biological treatments. We believe that it is necessary to report the cases of PCP to assess the real impact of this complication and develop appropriate prophylaxis guidelines.",
"affiliations": "Department of Dermatology, Hospital Clinic, University of Barcelona, Barcelona, Spain.;Department of Internal Medicine, Hospital Clinic, University of Barcelona, Barcelona, Spain.;Department of Dermatology, Hospital Clinic, University of Barcelona, Barcelona, Spain.;Department of Dermatology, Hospital Clinic, University of Barcelona, Barcelona, Spain.",
"authors": "Podlipnik|Sebastian|S|;de la Mora|Lorena|L|;Alsina|Mercè|M|;Mascaró|José M|JM|",
"chemical_list": "C122187:IL36RN protein, human; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D007378:Interleukins; D000069285:Infliximab",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajd.12489",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-8380",
"issue": "58(2)",
"journal": "The Australasian journal of dermatology",
"keywords": "IL-36RN deficiency; Pneumocystis jiroveci pneumonia; anti-TNFα; infliximab; pustular psoriasis",
"medline_ta": "Australas J Dermatol",
"mesh_terms": "D006801:Humans; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D000069285:Infliximab; D053590:Interleukin 1 Receptor Antagonist Protein; D007378:Interleukins; D008297:Male; D008875:Middle Aged; D011020:Pneumonia, Pneumocystis; D011565:Psoriasis",
"nlm_unique_id": "0135232",
"other_id": null,
"pages": "e44-e47",
"pmc": null,
"pmid": "27170513",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pneumocystis jirovecii pneumonia in a patient with pustular psoriasis with an IL-36RN deficiency treated with infliximab: Case report and review of the literature.",
"title_normalized": "pneumocystis jirovecii pneumonia in a patient with pustular psoriasis with an il 36rn deficiency treated with infliximab case report and review of the literature"
} | [
{
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],
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"reaction": [
{
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"reactionmeddraversionpt": "19.0",
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}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20140830"
}
},
"primarysource": {
"literaturereference": "SEBASTIAN P, MORA L , ALSINA M, MASCARO JM. PNEUMOCYSTIS JIROVECII PNEUMONIA IN A PATIENT WITH PUSTULAR PSORIASIS WITH AN IL-36RN DEFICIENCY TREATED WITH INFLIXIMAB: CASE REPORT AND REVIEW OF THE LITERATURE. AUSTRALASIAN J DERMATOL 2016.",
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},
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}
] |
{
"abstract": "The shift to injection therapy, after failure of oral antidiabetic agents, is often considered as a difficult step by both the patient with type 2 diabetes and the physician, a situation that may lead to clinical inertia. Schematically, two options may be considered, either starting insulin therapy with a preference for basal insulin analogues, or adding a glucagon-like peptide-1 receptor agonist (GLP-1 RA). Each option has its advantages and disadvantages, which opens the road to personalized medicine. Nevertheless, the preference is increasingly given to GLP-1 AR, yet this solution is more limited by reimbursement conditions. A combination of the two approaches is also possible, with the recent commercialisation of fixed-ratio specialities combining a basal insulin analogue and a GLP-1 RA. This clinical case offers the opportunity to discuss all these different therapeutic options in a patient with poorly controlled type 2 diabetes despite a combination of oral antidiabetic agents, taking also into account the current conditions for reimbursement in Belgium.",
"affiliations": "Service de Diabétologie, Nutrition et Maladies métaboliques, CHU Liège, Belgique.;Service de Diabétologie, Nutrition et Maladies métaboliques, CHU Liège, Belgique.",
"authors": "Scheen|A J|AJ|;Paquot|N|N|",
"chemical_list": "D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D052216:Glucagon-Like Peptide 1",
"country": "Belgium",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0370-629X",
"issue": "75(1)",
"journal": "Revue medicale de Liege",
"keywords": " Combined therapy ; GLP; Injectable therapy ; Oral antidiabetic agents ; Type 2 diabetes; 1 receptor agonist ; Basal insulin ",
"medline_ta": "Rev Med Liege",
"mesh_terms": "D000284:Administration, Oral; D003924:Diabetes Mellitus, Type 2; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin",
"nlm_unique_id": "0404317",
"other_id": null,
"pages": "60-66",
"pmc": null,
"pmid": "31920046",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Which injectable therapy after failure of oral antidiabetic agents in type 2 diabetes ?",
"title_normalized": "which injectable therapy after failure of oral antidiabetic agents in type 2 diabetes"
} | [
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{
"abstract": "Context: Few cases of neuromyelitis optica spectrum disorder (NMOSD) with an onset older than 75 years old have been reported.Finding: Herein, we report an 81-year-old Chinese male initially suspected of acute stroke but was ultimately diagnosed with NMOSD.Conclusion: Even in the elderly, a diagnosis of NMOSD should be considered for patients with myelitis, especially those with longitudinally extensive spinal cord involvement. Testing for aquaporin 4 antibody in this scenario is recommended for further confirmation. Once diagnosed, careful consideration of treatment options and close monitoring of side effects are important to improve prognosis in elderly patients.",
"affiliations": "Department of Neurology, Zhejiang Chinese Medicine and Western Medicine Integrated Hospital, Hangzhou, People's Republic of China.;Department of Neurology, Zhejiang Chinese Medicine and Western Medicine Integrated Hospital, Hangzhou, People's Republic of China.;Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.;Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.",
"authors": "Li|Lei|L|;Fang|Gao-Li|GL|;Zheng|Yang|Y|;Zhang|Yin-Xi|YX|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/10790268.2020.1749475",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-0268",
"issue": null,
"journal": "The journal of spinal cord medicine",
"keywords": "Immunosuppressive therapy; Myelitis; Neuromyelitis optica spectrum disorder; Stroke; Very late-onset",
"medline_ta": "J Spinal Cord Med",
"mesh_terms": null,
"nlm_unique_id": "9504452",
"other_id": null,
"pages": "1-3",
"pmc": null,
"pmid": "32298226",
"pubdate": "2020-04-16",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Late-onset neuromyelitis optica spectrum disorder mimicking stroke in an elderly Chinese man: Case report.",
"title_normalized": "late onset neuromyelitis optica spectrum disorder mimicking stroke in an elderly chinese man case report"
} | [
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"literaturereference_normalized": "late onset neuromyelitis optica spectrum disorder mimicking stroke in an elderly chinese man case report",
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{
"abstract": "Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been reported as possibly associated with Fournier's gangrene (FG). This case report describes a 34-year-old Japanese man who was diagnosed with FG after the administration of empagliflozin for type 2 diabetes mellitus (T2DM). He presented with pain and swelling in the perineum and groin 142 days after initiating empagliflozin. The clinical features, laboratory data, and computed tomographic findings were consistent with FG. Surgical drainage and debridement of necrotic tissues were performed immediately after admission to our hospital. The patient had no complications of diabetes before the onset of FG. Glycemic management was good at the time of FG onset. This case suggests a possible association between empagliflozin and FG. We report a case of FG in a patient during a period of good glycemic management following treatment with empagliflozin. We recommend further awareness of this relationship and suggest the need for additional research.",
"affiliations": "Department of Pharmacy, Sanraku Hospital, 2-5 Kandasurugadai, Chiyoda-ku, Tokyo, 1018326, Japan. nagano8931@sanraku.or.jp.;Department of Pharmacy, Sanraku Hospital, 2-5 Kandasurugadai, Chiyoda-ku, Tokyo, 1018326, Japan.;Department of Surgery, Sanraku Hospital, 2-5 Kandasurugadai, Chiyoda-ku, Tokyo, 1018326, Japan.;Department of Endocrinology and Metabolism, Sanraku Hospital, 2-5 Kandasurugadai, Chiyoda-ku, Tokyo, 1018326, Japan.;Department of Surgery, Sanraku Hospital, 2-5 Kandasurugadai, Chiyoda-ku, Tokyo, 1018326, Japan.",
"authors": "Nagano|Yasunori|Y|http://orcid.org/0000-0002-5746-8937;Yakame|Naomi Kashiwagi|NK|;Aoki|Hisae|H|;Yamakawa|Tamaki|T|;Kondo|Naoko Iwahashi|NI|http://orcid.org/0000-0001-6881-3807",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40800-019-0105-8",
"fulltext": "\n==== Front\nDrug Saf Case RepDrug Saf Case RepDrug Safety - Case Reports2199-11622198-977XSpringer International Publishing Cham 3162855210510.1007/s40800-019-0105-8Case ReportFournier’s Gangrene in a Patient with Type 2 Diabetes Mellitus Treated with Empagliflozin: A Case Report http://orcid.org/0000-0002-5746-8937Nagano Yasunori +81-3-3292-3981nagano8931@sanraku.or.jp 1Yakame Naomi Kashiwagi 1Aoki Hisae 2Yamakawa Tamaki 3http://orcid.org/0000-0001-6881-3807Kondo Naoko Iwahashi 21 0000 0004 1795 090Xgrid.415142.7Department of Pharmacy, Sanraku Hospital, 2-5 Kandasurugadai, Chiyoda-ku, Tokyo, 1018326 Japan 2 0000 0004 1795 090Xgrid.415142.7Department of Surgery, Sanraku Hospital, 2-5 Kandasurugadai, Chiyoda-ku, Tokyo, 1018326 Japan 3 0000 0004 1795 090Xgrid.415142.7Department of Endocrinology and Metabolism, Sanraku Hospital, 2-5 Kandasurugadai, Chiyoda-ku, Tokyo, 1018326 Japan 18 10 2019 18 10 2019 12 2019 6 1 11© The Author(s) 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial 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.Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been reported as possibly associated with Fournier’s gangrene (FG). This case report describes a 34-year-old Japanese man who was diagnosed with FG after the administration of empagliflozin for type 2 diabetes mellitus (T2DM). He presented with pain and swelling in the perineum and groin 142 days after initiating empagliflozin. The clinical features, laboratory data, and computed tomographic findings were consistent with FG. Surgical drainage and debridement of necrotic tissues were performed immediately after admission to our hospital. The patient had no complications of diabetes before the onset of FG. Glycemic management was good at the time of FG onset. This case suggests a possible association between empagliflozin and FG. We report a case of FG in a patient during a period of good glycemic management following treatment with empagliflozin. We recommend further awareness of this relationship and suggest the need for additional research.\n\nissue-copyright-statement© The Author(s) 2019\n==== Body\nKey Points\n\nFournier’s gangrene (FG) is a severe polymicrobial infection that results in necrosis of the perineal and genital fasciae, with rapid progression and a high mortality rate.\t\nIt is important to know that sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, may potentially cause FG even when a patient has good glycemic management.\t\n\n\n\nIntroduction\nFournier’s gangrene (FG), named by Jean Alfred Fournier in 1883 [1], is a severe polymicrobial infection that results in necrosis of the perineal and genital fasciae. The common symptoms of FG are perianal or genital pain, redness, swelling, and skin necrosis, followed by gangrenous changes. Reports of case series have indicated rapid progression and 20% mortality rates for patients with FG [2]. Alcoholism, liver or kidney failure, cancer, obesity, and smoking are known risk factors [3]. Diabetes mellitus is a comorbid condition in approximately 50% of cases. Early diagnosis is important, and standard management consists of broad-spectrum antibiotics, resuscitation, and aggressive debridement [4].\n\nThe mechanism of action of sodium glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes mellitus (T2DM) involves the inhibition of SGLT2 in the proximal convoluted tubule to prevent the reabsorption of glucose and facilitate its excretion in urine. As glucose is excreted, its plasma levels fall, leading to improvements in all glycemic parameters [5].\n\nSeveral SGLT2 inhibitors, including dapagliflozin, canagliflozin, and empagliflozin, are already available in many countries. Empagliflozin is one of the SGLT2 inhibitors currently approved for use in adult patients with T2DM as an adjunct to diet and exercise to improve glycemic control [6]. Similar to other SGLT2 inhibitors, empagliflozin is associated with a higher rate of genital infections and urinary tract infections [7].\n\nSeveral case reports have suggested that SGLT2 inhibitors may be implicated as a possible cause of FG [8–13]. Here, we describe a Japanese male who developed FG during empagliflozin treatment.\n\nCase Presentation\nA 34-year-old Japanese man was referred to our hospital with a 3-day history of pain and swelling in the perineum and the groin. His T2DM had been moderately well managed for 2 years.\n\nA general physician prescribed sitagliptin 50 mg/day, glibenclamide 2.5 mg/day, and empagliflozin 10 mg/day to this patient as first-line antidiabetic therapy. At 19 days after initiating these medications, the glibenclamide was increased to 5 mg/day. He had no complications of diabetes. His body mass index was 28 kg/m2 and he was otherwise in good general health and had no history of genital or urinary infections. He had no significant past medical history and received no concomitant medications. He had a history of smoking but not of alcohol intake.\n\nThe first episode of pain in the perineal region occurred 142 days after medication initiation. On admission to our hospital, his body temperature was 38.0 °C. He was not in a state of shock and vital signs were stable: blood pressure 137/76 mmHg, heart rate 120 beats per min, and respiratory rate 13 breaths per min. Skin redness, induration, swelling, and tenderness were observed in the perineum, the scrotum, and the left inguinal region. There was no urinary tract infection or trauma.\n\nRoutine laboratory data revealed a white blood cell count 21.7 × 109/L, C-reactive protein 41 mg/L, and glycated hemoglobin 6.5% (per the National Glycohemoglobin Standardization Program). Table 1 summarizes the patient’s baseline clinical data. Computed tomography scan of the lower abdomen and pelvis revealed findings consistent with FG (Fig. 1).Table 1 Laboratory data at baseline\n\nClinical parameter (units)\tValue\t\nWBC (count/L)\t21.7 × 109\t\nRBC (count/L)\t544 × 1010\t\nHb (g/L)\t165\t\nHct (/L)\t0.48\t\nPlt (count/L)\t282 × 109\t\nNa (mEq/L)\t136\t\nCl (mEq/L)\t100\t\nK (mEq/L)\t4.0\t\nCRP (mg/L)\t41\t\nAlb (g/L)\t45\t\nAST (U/L)\t12\t\nALT(U/L)\t18\t\nT-Bil (μmol/L)\t15.4\t\nCK (U/L)\t97\t\nAmy (U/L)\t73\t\nBUN (mg/dL)\t5.7\t\nCr (mg/dL)\t69\t\nGlu (mg/dL)\t6.1\t\nHbA1c, per NGSP (%)\t6.5\t\nAlb albumin, ALT alanine transaminase, Amy amylase, AST aspartate transaminase, BUN blood urea nitrogen, CK creatinine phosphokinase, Cl chloride, Cr creatinine, CRP C-reactive protein, Glu glucose, Hb hemoglobin, HbA1c glycated hemoglobin, Hct hematocrit, K potassium, Na sodium, NGSP National Glycohemoglobin Standardization Program, Plt platelets, RBC red blood cell, T-Bil total bilirubin, WBC white blood cell\n\n\nFig. 1 A computed tomography scan of the lower abdomen and pelvis showing pathologic Fournier’s gangrene. Evidence of fat stranding and gas (arrow) in the perineum, the scrotum, and the left inguinal region\n\n\n\n\nThe patient underwent emergency surgery under general anesthesia, consisting of incision, debridement, and drainage. Intravenous administration of meropenem 3 g/day and clindamycin 1800 mg/day was initiated. The patient’s antibiotic was changed from a combination of meropenem and clindamycin to intravenous vancomycin 2 g/day because methicillin-resistant Staphylococcus aureus (MRSA) was cultured from the resected tissue on the second postoperative day (Fig. 2).Fig. 2 Clinical course and laboratory data. CRP C-reactive protein, Glu glucose, HbA1c glycated hemoglobin, NGSP National Glycohemoglobin Standardization Program, RBC red blood cell, WBC white blood cell\n\n\n\n\nWe suspected empagliflozin as a possible cause of FG because the pharmacist in our hospital knew about the warning regarding the association of SGLT2 inhibitors with an increased risk of FG issued by the US FDA [13], although FG is not cited in the prescribing information for empagliflozin in Japan. In addition, assessment using the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 5) between FG and empagliflozin therapy in the patient [14]. However, “improvement after drug withdrawal”, as an axis of the Naranjo scale, cannot be considered truly informative, as factors other than the suspected drug, such as surgery and antibiotic treatment, may have caused resolution of the adverse event in this case. Furthermore, alternative causes could have contributed to the onset of FG, including diabetes, smoking habits, and obesity. Given this information, we downgraded the Naranjo scale score from “probable” to “possible”.\n\nPostoperatively, the medications for T2DM were discontinued, and insulin injections were started according to a sliding scale. Sitagliptin 50 mg/day was restarted 9 days after surgery, and metformin 500 mg/day was started 21 days after surgery. The patient’s wounds healed gradually. He was discharged from the hospital 41 days after surgery and continued his treatment for T2DM.\n\nDiscussion\nEmpagliflozin was approved by the FDA in 2014 [6]. Similar to other SGLT2 inhibitors, empagliflozin is associated with high rates of genital infections, urinary tract infections, and lower limb amputations [7, 15]. In this case, we propose that empagliflozin facilitated the occurrence and/or progression of FG. Our rationale is outlined as follows.\n\nFirst, 12 case reports (seven men and five women) of FG after treatment with SGLT2 inhibitors have been documented from May 2013 to May 2018, although FG is a rare disease [13]. SGLT2 inhibitors are associated with an increased risk for FG, according to an analysis performed by the FDA and an initial warning they issued in 2018 about the potential association [13]. A search of the FDA Adverse Event Reporting System (FAERS) database until January 2019 as per Bersoff-Matcha et al. [16], identified 55 cases of FG in patients receiving SGLT2 inhibitors between March 2013 and January 2019. In comparison, 19 cases of FG associated with other antihyperglycemic agents were identified between 1984 and 2019 [16]. There have been many previous reports of FG associated with SGLT2 inhibitors, compared with few reports of associations with other hypoglycemic drugs. However, there have been too few cases to be sure that FG is related to the use of SGLT2 inhibitors.\n\nWe searched the medical literature in PubMed and Google Scholar between May 2013 and July 2019 with the keywords SGLT2 inhibitors and Fournier’s gangrene and retrieved five reports that were described in detail. Each report described a patient who developed FG after commencing treatment with dapagliflozin and empagliflozin (Table 2) [8–12]. Most of those cases involved patients who had T2DM that was reasonably or poorly managed [glycated hemoglobin (HbAlc) > 7.0%], unlike our patient, who had good glycemic management (HbAlc < 7.0%) at the time of FG onset. Thus, the risk for development of FG remains despite good glycemic management with SGLT2 inhibitors.Table 2 Summary of 6 case reports of Fournier’s gangrene associated with SGLT2 inhibitor treatment\n\nReference\tAge, sex\tSGLT2 inhibitor\tTime to onset (weeks)\tHbA1c (%)\tRenal and hepatic function\tComorbidities\tConcurrent drug therapy\t\nCecilia-Chi et al. [8]\t67, male\tDapagliflozin\t3\t10.8\tUnknown\tObesity\tUnknown\t\nKumar et al. [9]\t41, male\tEmpagliflozin\t49\t11.2\tUnknown\tObesity, thrush\tMetformin\t\nOmer et al. [10]\t60, male\tDapagliflozin\t28\tUnknown\tUnknown\tUnknown\tUnknown\t\nOnder et al. [11]\t64, male\tDapagliflozin\t42\t7.4\tBUN: 17 mmol/L; Cr: 162 μmol/L; ALT: 21 U/L\tObesity\tPremixed insulin, vildagliptin, metformin\t\nGhada et al. [12]\t57, male\tEmpagliflozin\t2\tUnknown\tUnknown\tObesity, peripheral neuropathy, Hashimoto’s hypothyroidism\tGlipizide, metformin, linagliptin\t\nOur patient\t34, male\tEmpagliflozin\t20\t6.5\tBUN: 5.7 mmol/L; Cr: 69 μmol/L; ALT: 18 U/L\tObesity\tSitagliptin, glibenclamide\t\nSGLT2 sodium-glucose cotransporter-2, HbA1c glycated hemoglobin, BUN blood urea nitrogen, Cr creatinine, ALT alanine transaminase\n\n\n\nSecond, the pharmacologically induced increased urinary glucose concentration associated with SGLT2 inhibitors might provide a favorable growth environment for otherwise commensal genital microorganisms and could potentially increase the risk for FG, although the mechanism through which SGLT2 inhibitors causes FG is unclear. It cannot be ruled out that the pharmacological effects of SGLT2 inhibitors, such as the stimulation of urinary glucose excretion, play a role in the onset of FG.\n\nThe patient in our case had T2DM, was obese, and had a smoking habit, all of which are factors that elevate the risk for FG [3]. These risk factors may have contributed to the development of FG during empagliflozin treatment, although there was no predisposing genital infection or urinary intervention.\n\nConcomitant medications, such as sitagliptin and glibenclamide, may not have been related to the development and/or progression of FG in this case. The inflammatory reactions did not increase in severity when sitagliptin was discontinued and subsequently reintroduced. To the best of our knowledge, a relationship between glibenclamide and FG has not been reported. The mechanism of action of glibenclamide consists of inhibition of the ATP-sensitive K+ channels, which leads to depolarization of the cells, insulin secretion, and a subsequent decrease in plasma glucose levels [17]. Although the mechanism by which FG occurs is unknown, given the pharmacological mechanism of glibenclamide, it may be less likely to be associated with FG. It can be conjectured that the FG likely developed in response to empagliflozin and not glibenclamide.\n\nWe report a case of FG in a patient whose glycemic management was good as a result of empagliflozin treatment. In addition, this is the first confirmed case report in Japan of FG that may have been related to treatment with SGLT2 inhibitors.\n\nConclusion\nIf FG is suspected in a patient receiving SGLT2 inhibitors, we recommend ceasing that medication and immediately starting combination treatment with broad-spectrum antibiotics and surgical debridement.\n\nAuthor Contributions\nYN designed the study and wrote the manuscript. NIK contributed to the analysis and interpretation of the data and assisted in the preparation of the manuscript. NKY, HA, and TY contributed to data collection and interpretation and critically reviewed the manuscript. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work and to ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nCompliance with Ethical Standards\nFunding\nNo sources of funding were used to assist in the preparation of this case report.\n\nConflict of Interest\nYasunori Nagano, Naomi Kashiwagi Yakame, Hisae Aoki, Tamaki Yamakawa, and Naoko Iwahashi Kondo have no conflicts of interest that are directly relevant to the content of this case report.\n\nPatient Consent\nWritten informed consent was obtained from the patient for the publication of this case report and any accompanying images. A copy of the written consent may be requested for review from the corresponding author.\n\nEthics Approval\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee Ministry of Health, Labor and Welfare and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\n==== Refs\nReferences\n1. Fournier JA Gangrène foudroyante de la verge (overwhelming gangrene). Sem Med. 1883 Dis Colon Rectum. 1988 31 984 988 10.1007/BF02554904 3063473 \n2. McCormack M Valiquette AS Ismail S Fournier’s gangrene: a retrospective analysis of 26 cases in a Canadian hospital and literature review Can Urol Assoc J. 2015 9 E407 E410 10.5489/cuaj.2445 26225189 \n3. Sorensen MD Krieger JN Fournier’s gangrene: epidemiology and outcomes in the general US population Urol Int 2016 97 249 259 10.1159/000445695 27172977 \n4. Yanar H Taviloglu K Ertekin C Guloglu R Zorba U Cabioglu N Baspinar I Fournier’s gangrene: risk factors and strategies for management World J Surg 2006 30 1750 1754 10.1007/s00268-005-0777-3 16927060 \n5. Riser Taylor S Harris KB The clinical efficacy and safety of sodium glucose cotransporter-2 inhibitors in adults with Type 2 diabetes mellitus Pharmacotherapy. 2013 33 984 999 10.1002/phar.1303 23744749 \n6. U.S. Food and Drug Administration. JARDIANCE 10 mg (Labeling-Medication Guide). In: Drugs@FDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204629s008lbl.pdf. Accessed 22 July 2019.\n7. Zinman B Wanner C Lachin JM Fitchett D Bluhmki E Hantel S Mattheus M Devins T Johansen OE Woerle HJ Broedl UC Inzucchi SE EMPA-REG OUTCOME Investigators Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes N Engl J Med. 2015 373 2117 2128 10.1056/NEJMoa1504720 26378978 \n8. Cecilia-Chi WC, Lim-Tio S. Fournier’s syndrome: a life threatening complication of SGLT2 inhibition in poorly controlled diabetes mellitus. In: Presented at: ADS ADEA Annual Scientific Meeting; August 24–26, 2016. Abstract no. 265.\n9. Kumar S Costello AJ Colman PG Fournier’s gangrene in a man on empagliflozin for treatment of type 2 diabetes Diabet Med 2017 34 1646 1648 10.1111/dme.13508 28887847 \n10. Omer T Dharan SS Adler A Sodium-glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin and Fournier’s gangrene: a life threatening severe adverse outcome: case report Diabet Med 2018 35 100 \n11. Onder CE Gursoy K Kuskonmaz SM Kocer U Culha C Fournier’s gangrene in a patient on dapagliflozin treatment for type 2 diabetes J Diabetes. 2019 11 348 350 10.1111/1753-0407.12896 30604507 \n12. Elshimy G Correa R Alsayed M Jyothinagaram S Early presentation of a rare complication of sodium-glucose cotransporter-2 inhibitors 10 days after initiation: case report and literature review Cureus. 2019 11 7 e5173 10.7759/cureus.5173 31423402 \n13. U.S. Food and Drug Administration. FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. In: Drug safety and Availability. 2019. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrences-serious-infection-genital-area-sglt2-inhibitors-diabetes. Accessed 22 July 2019.\n14. Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA Janecek E Domecq C Greenblatt DJ A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 10.1038/clpt.1981.154 7249508 \n15. Khouri C Cracowski JL Roustit M SGLT-2 inhibitors and the risk of lower-limb amputation: is this a class effect? Diabetes Obes Metab 2018 20 1531 1534 10.1111/dom.13255 29430814 \n16. Bersoff-Matcha SJ Chamberlain C Cao C Kortepeter C Chong WH Fournier gangrene associated with sodium-glucose cotransporter-2 inhibitors Ann Intern Med 2019 170 764 769 10.7326/M19-0085 31060053 \n17. Luzi L Pozza G Glibenclamide: an old drug with a novel mechanism of action? Acta Diabetol 1997 34 239 244 10.1007/s005920050081 9451465\n\n",
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{
"abstract": "Aims: To determine real-life biologic/targeted synthetic disease-modifying anti-rheumatic drug (b/tsDMARD) retention rates in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS), explore reasons for switching and to compare results to previously published data. Methods: Time-to-event analysis for mean treatment duration (estimated as the Restricted Mean Survival Time), b/tsDMARD failure, and b/tsDMARDs switching was performed for 230 patients (n = 147 RA, 46 PsA, 37 AS) who commenced their first b/tsDMARD between 2008 and 2018. Patients were managed in a dedicated \"biologics\" clinic in a tertiary hospital; the choice of b/tsDMARD was clinician driven based on medical factors and patient preferences. The effect of covariates on switching risk was analysed by a conditional risk-set Cox proportional-hazards model. Treatment retention data was compared to a historical analysis (2002-2008). Results: The proportions remaining on treatment (retention) were similar, throughout follow-up, for the first, second and third b/tsDMARDs across all patients (p = 0.46). When compared to RA patients, the risk of b/tsDMARD failure was halved in PsA patients [Hazard Ratio (HR) = 0.50], but no different in AS patients (HR = 1.0). The respective restricted mean (95%CI) treatment durations, estimated at 5 years of follow-up, were 3.1 (2.9, 3.4), 4.1 (3.7, 4.6), and 3.3 (2.8, 3.9) years, for RA, PsA, and AS, respectively. Age, gender, disease duration, smoking status and the use of concomitant csDMARDS were not associated with the risk of bDMARD failure. The most common reasons for switching in the first and subsequent years were secondary (n = 62) and primary (n = 35) failure. Comparison with historical data indicated no substantive differences in switching of the first biologic for RA and PsA. Conclusion: Similar retention rates of the second and third compared to the first b/tsDMARD in RA, PsA, and AS support a strategy of differential b/tsDMARDs use informed by patient presentation. Despite greater availability of b/tsDMARDs with differing mechanisms of action, retention rates of the first b/tsDMARD remain similar to previous years.",
"affiliations": "Rheumatology Unit, Flinders Medical Centre, Adelaide, SA, Australia.;Rheumatology Unit, Queen Elizabeth Hospital, Adelaide, SA, Australia.;Rheumatology Unit, Flinders Medical Centre, Adelaide, SA, Australia.;Division of Medicine, Flinders Medical Centre, Adelaide, SA, Australia.;Rheumatology Unit, Flinders Medical Centre, Adelaide, SA, Australia.;Rheumatology Unit, Flinders Medical Centre, Adelaide, SA, Australia.;Rheumatology Unit, Queen Elizabeth Hospital, Adelaide, SA, Australia.;Rheumatology Unit, Queen Elizabeth Hospital, Adelaide, SA, Australia.;Rheumatology Unit, Flinders Medical Centre, Adelaide, SA, Australia.;Rheumatology Unit, Flinders Medical Centre, Adelaide, SA, Australia.;Rheumatology Unit, Flinders Medical Centre, Adelaide, SA, Australia.;Rheumatology Unit, Flinders Medical Centre, Adelaide, SA, Australia.",
"authors": "Bhushan|Vandana|V|;Lester|Susan|S|;Briggs|Liz|L|;Hijjawi|Raif|R|;Shanahan|E Michael|EM|;Pontifex|Eliza|E|;Ninan|Jem|J|;Hill|Catherine|C|;Cai|Fin|F|;Walker|Jennifer|J|;Goldblatt|Fiona|F|;Wechalekar|Mihir D|MD|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fmed.2021.708168",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.708168\nMedicine\nOriginal Research\nReal-Life Retention Rates and Reasons for Switching of Biological DMARDs in Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis\nBhushan Vandana 1 2\n\nLester Susan 3 4\n\nBriggs Liz 1\nHijjawi Raif 2\nShanahan E. Michael 1 5\nPontifex Eliza 1 5\nNinan Jem 3\nHill Catherine 3 4\nCai Fin 1 5\nWalker Jennifer 1 5\n\nGoldblatt Fiona 1 5\nWechalekar Mihir D. 1 5 *\n\n1Rheumatology Unit, Flinders Medical Centre, Adelaide, SA, Australia\n2Division of Medicine, Flinders Medical Centre, Adelaide, SA, Australia\n3Rheumatology Unit, Queen Elizabeth Hospital, Adelaide, SA, Australia\n4Discipline of Medicine, The University of Adelaide, Adelaide, SA, Australia\n5College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia\nEdited by: Enrique Roberto Soriano, Italian Hospital of Buenos Aires, Argentina\n\nReviewed by: Victoria Navarro Compán, University Hospital La Paz, Spain; Fernando Sommerfleck, Sanatorio Julio Mendez, Argentina\n\n*Correspondence: Mihir D. Wechalekar mihir.wechalekar@sa.gov.au\nThis article was submitted to Rheumatology, a section of the journal Frontiers in Medicine\n\n27 9 2021\n2021\n8 70816811 5 2021\n29 7 2021\nCopyright © 2021 Bhushan, Lester, Briggs, Hijjawi, Shanahan, Pontifex, Ninan, Hill, Cai, Walker, Goldblatt and Wechalekar.\n2021\nBhushan, Lester, Briggs, Hijjawi, Shanahan, Pontifex, Ninan, Hill, Cai, Walker, Goldblatt and Wechalekar\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nAims: To determine real-life biologic/targeted synthetic disease-modifying anti-rheumatic drug (b/tsDMARD) retention rates in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS), explore reasons for switching and to compare results to previously published data.\n\nMethods: Time-to-event analysis for mean treatment duration (estimated as the Restricted Mean Survival Time), b/tsDMARD failure, and b/tsDMARDs switching was performed for 230 patients (n = 147 RA, 46 PsA, 37 AS) who commenced their first b/tsDMARD between 2008 and 2018. Patients were managed in a dedicated “biologics” clinic in a tertiary hospital; the choice of b/tsDMARD was clinician driven based on medical factors and patient preferences. The effect of covariates on switching risk was analysed by a conditional risk-set Cox proportional-hazards model. Treatment retention data was compared to a historical analysis (2002–2008).\n\nResults: The proportions remaining on treatment (retention) were similar, throughout follow-up, for the first, second and third b/tsDMARDs across all patients (p = 0.46). When compared to RA patients, the risk of b/tsDMARD failure was halved in PsA patients [Hazard Ratio (HR) = 0.50], but no different in AS patients (HR = 1.0). The respective restricted mean (95%CI) treatment durations, estimated at 5 years of follow-up, were 3.1 (2.9, 3.4), 4.1 (3.7, 4.6), and 3.3 (2.8, 3.9) years, for RA, PsA, and AS, respectively. Age, gender, disease duration, smoking status and the use of concomitant csDMARDS were not associated with the risk of bDMARD failure. The most common reasons for switching in the first and subsequent years were secondary (n = 62) and primary (n = 35) failure. Comparison with historical data indicated no substantive differences in switching of the first biologic for RA and PsA.\n\nConclusion: Similar retention rates of the second and third compared to the first b/tsDMARD in RA, PsA, and AS support a strategy of differential b/tsDMARDs use informed by patient presentation. Despite greater availability of b/tsDMARDs with differing mechanisms of action, retention rates of the first b/tsDMARD remain similar to previous years.\n\nbiologic DMARDs\nretention\nswitching\nrheumatoid arthritis\npsoriatic arthritis\nankylosing spondylitis\n==== Body\npmcIntroduction\n\nBiologic (b-) and targeted synthetic (ts-) disease-modifying anti-rheumatic drugs (DMARDs) represent a major therapeutic advance in rheumatology. However, response rates to b/tsDMARDs are variable (1); the evidence-base for directing switching from one agent to another is limited with most switches being empirical (2, 3); and, responses to b/tsDMARDs regardless of the mechanism of action are generally similar (4). Furthermore, the overall rates of sustained remission and improvement in function are relatively modest (5), owing to several potential factors including lack of established criteria to direct initial or subsequent choice of one b/tsDMARD over another with a different MoA, following failure or inadequate response.\n\nThe efficacy of a drug can be reliably determined by its retention rate or persistence (6, 7). Data from randomised control trials (RCTs) involving b/tsDMARDs is beset by limited trial duration, and switching, if allowed, is limited at the most to one another agent (8, 9). In addition, trials often have rigid entry criteria and relatively uniform patient populations with less co-morbidities, that cannot easily be generalised to real-life routine medical care (10, 11). In contrast, in the clinic, rather than “entry criteria” the b/tsDMARD choice is directed with due consideration of the diversity of patient presentation and patient-related contextual factors. Thus, although clinic data yield outcomes less impressive than those from RCTs (12), studies with real-life data are invaluable in providing significant insights in order to guide treatment individualisations and improve outcomes (13, 14).\n\nAlthough international guidelines are available on the prescription of biologics in rheumatic disease, these do not generally recommend any single agent or class (15). The initial and subsequent choice of b/tsDMARD can be influenced by several variables which include route and frequency of administration, potential side-effects, co-morbidities and mandatory regulation requirements for concomitant conventional synthetic disease-modifying antirheumatic drug(s) (csDMARD).\n\nMultiple studies, including real-life studies, have analysed cycling to another agent with the same MoA and also looked at switching to an alternative agent, in patients who have failed or have been intolerant to their current biologic agent (8, 16). The decades-long availability of TNFi with 5 agents in this class have led TNFi usually being the first biologic prescribed and to several studies assessing “cycling” within the same MoA. These studies revealed that using a second TNFi following the failure of the first TNFi can be an effective treatment approach (9, 17–19). However, larger and more studies appear to suggest that switching to an agent with a different MoA is more effective than cycling agents within the same class (6, 20–24). There is evidence to suggest greater retention of treatment (20, 22, 24, 25), lower chance of treatment failure (26) and a greater reduction in the disease activity (8, 24). Studies have also found that a change in MoA led to an improvement in physical function (27–29). Although these studies included real-life data, data on long-term retention rates and switching between the various b/tsDMARDs is limited. Furthermore, although there are some data suggesting greater retention of b/tsDMARDs in PsA vs. RA (30), few studies have assessed retention rates between RA, PsA, and AS; such data are expected to provide insights into comparative retention rates, effects of concomitant csDMARDs on retention rates, and in doing so, inform clinical practise and regulatory prescribing policy.\n\nThis study was conducted to assess retention rates of the first-, second-, and third-b/tsDMARDs in RA, PsA and AS in a tertiary hospital clinic setting. We also sought to compare b/tsDMARD retention rates between these diseases, assess the effect of concomitant DMARDs, explore trends of and reasons for switching, and compare with the historical data from this clinic.\n\nMethods\n\nThe Australian Medicare/PBS System\n\nThe current prescription of b/tsDMARDs in Australia is mandated by the Australian Medicare system, which provides subsidised treatment at a uniform cost, regardless of the type of b/tsDMARD. A patient becomes “eligible” for a b/tsDMARD following failure of csDMARDs for RA and PsA, or for AS, failure of a trial of non-steroidal anti-inflammatory drugs. The choice of b/tsDMARD (apart from Rituximab, that mandates failure of a TNF inhibitor) is physician-driven and directed by patient demographics, comorbidities, and patient preferences. Specifically, to qualify for PBS subsidised b/tsDMARDs for RA and PsA, patient must have at least 20 active (both swollen and tender) or 4 active large joints. Patients who present with axial disease in the context of PsA are classified as AS. Patients with AS require to have radiographic sacroiliitis (grade 2 bilaterally or grade 3 unilaterally), and failure of at least 2 NSAIDs, to qualify for access to a b/tsDMARD. In Australia, bDMARDs were introduced for the treatment of rheumatic conditions around 2003, with Infliximab and Etanercept as the initial agents, followed by Adalimumab (2004), Abatacept and Rituximab (2007), Tocilizumab (2009), Golimumab and Certolizumab (2010), Ustekinumab and Secukinumab (2016). Tofacitinib, a synthetic small molecule Janus kinase (JAK) inhibitor, is a tsDMARD and was available in 2015.\n\nThe “Biologics” Clinic\n\nThe Southern Adelaide Local Health Network (SALHN) in Adelaide, South Australia, comprises of three teaching hospitals offering rheumatological services, which include a dedicated, weekly, registrar-run and consultant-supervised, biologics clinic, established in 2002. Approximately 500 patients are enrolled in this clinic with the patient database being maintained by a dedicated “biologics” nurse. The majority of patients on b/tsDMARDs for RA, PsA, and AS, diagnosed within SALHN are referred to and managed in this clinic.\n\nStudy Design\n\nIn this retrospective, longitudinal, observational study, we included all adult (>18 years) patients with RA, PsA, and AS, commencing first and subsequent b/tsDMARDs between July 1, 2008 and June 30, 2018. The diagnoses of RA, PsA and AS were made by their treating rheumatologist and at the time of enrolment, all patients were biologic naïve. We excluded patients if they did not receive or take b/tsDMARD treatment (despite enrolment), those with incomplete data or those who were subsequently lost to follow-up. Biologics for non-radiographic axial spondyloarthritis (nr-AxSpA) were not available on the PBS for most of the period covered by this study, and this group of patients were also excluded. This study was submitted to and approved by the Southern Adelaide Clinical Human Research Ethics Committee to proceed and to be published. However, because this study was designed for and intended to lead to iterative refinement in service provision, the Southern Adelaide Clinical Human Research Ethics Committee determined that it did not require a full formal ethical review.\n\nData Capture\n\nData was collected retrospectively from the patient medical records. Data collected included demographics, duration of disease prior to commencing their first b/tsDMARD, csDMARD and prednisolone use, reasons for and dates of commencement and switching of b/tsDMARDs. Reasons for switching were classified as primary or secondary failure, adverse events, extra-musculoskeletal manifestations, comorbid conditions, infection or other.\n\nSince there is no universally accepted consensus definition of primary and secondary failure, for the purposes of this study, primary failure was defined as not demonstrating efficacy with treatment within 3–6 months of treatment initiation and secondary failure as an initial response, subsequently lost on continued treatment. Persistence was defined as the time from initiation to discontinuation of biologic therapy.\n\nData was also compared to previous similar analysis undertaken in this centre prior to 2008 (31).\n\nStatistical Analysis\n\nAll statistical analysis was performed in Stata v16.1 (StataCorp LLC, TX, USA). The proportion of patients remaining on their prescribed b/tsDMARD therapy (retention) was analysed using time-to-event analysis methods for censored data to account for incomplete follow-up in patients without b/tsDMARD failure. Results were initially explored by Kaplan-Meier curves, but as patients experienced up to three b/tsDMARD failure events, further analysis was performed using conditional risk set time-to-event regression models for multiple failures (32).\n\nSummary measures of the b/tsDMARD treatment retention curves over time included the %bDMARD retention and the mean treatment duration, both estimated at 5 years of follow-up. The mean treatment duration was estimated as the Restricted Mean Survival Time (RMST) (33), defined as the area under the treatment retention curve up to a fixed time t*, which estimated the failure-free treatment duration expectancy in the restricted follow-up period. The 25 and 50% centiles of the failure-time distribution were also determined. These estimated the treatment time by which 25 and 50% of patients had experienced b/tsDMARD failure, with the 50% centile being the overall median treatment duration. All summary measures were estimated from a spline-smoothed time-to-event regression model, which included covariates for both diagnosis and b/tsDMARD treatment episode, using the Stata user-defined (ado) programs “stpm2” (34) and “standsurv” (35). Overall summary estimates (for example, for each diagnosis) were obtained from the mean treatment retention curve derived from the three treatment episodes.\n\nPoint estimates of the mean treatment duration at 60 months (5 years) from previously published (31) historical data (for the first b/tsDMARD treatment only) were obtained by digitising the image of the Kaplan-Meier curves, using Digitizelt (v2.3.3 https://www.digitizeit.xyz/) software, and integration of the area under the curve using the trapezoidal rule.\n\nPatient-level predictors for b/tsDMARD treatment failure were evaluated by a Cox regression model, with results reported as Hazard Ratios (HR). Reasons for b/tsDMARD treatment failure were compared using a competing risks analysis of the individual cause-specific cumulative incidence functions over time, estimated using the Stata ado program “stcompet” (36).\n\nResults\n\nParticipants\n\nThe study included 230 patients: 147 RA (81% seropositivity), 46 PsA and 37 with AS (Table 1). The median age at diagnosis across all groups was 44 years, with a median disease duration of 6.4 years prior to commencement of their first biologic. As expected, there was a female predominance in RA patients (69%), and under-representation in AS (24%). The majority of the cohort (123, 53%) patients were either current or reformed smokers.\n\nTable 1 Baseline demographics (at the time of the first b/tsDMARD) for rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients.\n\nDescriptor\tRA\tPsA\tAS\tAll\t\nN\t147\t46\t37\t230\t\nFemale (%)\t102 (69%)\t26 (57%)\t9 (24%)\t137 (60%)\t\nDiagnosis age (yrs): median (IQR)\t48 (35, 60)\t40 (31, 49)\t37 (27, 45)\t44 (29, 53)\t\nDisease duration (yrs): median (IQR)\t5.8 (3.6, 6.5)\t5.2 (2.6, 7.6)\t5.3 (1.9, 10.9)\t6.4 (1.9, 10.9)\t\nSmoking\t\nNever\t59 (40%)\t30 (65%)\t18 (49%)\t107 (47%)\t\nReformed\t64 (44%)\t13 (28%)\t9 (24%)\t86 (37%)\t\nCurrent\t24 (16%)\t3 (7%)\t10 (27%)\t37 (16%)\t\nSeropositive\t119 (81%)\t\t\t\t\n\nb/tsDMARD Treatment\n\nThe most common initial b/tsDMARD was a TNFi, prescribed in 109 (74%), 44 (96%), and 37 (100%) of RA, PSA, and AS patients, respectively. However, there was diversification in the class of newly prescribed b/tsDMARD over the second and third treatment episodes, with the proportion of patients prescribed another TNFi declining in all three diagnosis groups (Table 2). The most frequently prescribed TNFi were Etanercept (44%), Adalimumab (33%), and Golimumab (14%).\n\nTable 2 Treatments, failures, retention rates and duration for each episode of b/tsDMARD use by diagnosis groups.\n\n\tb/tsDMARD 1\tb/tsDMARD 2\tb/tsDMARD 3\t\nRheumatoid Arthritis\t\nN\t147\t70\t25\t\nb/tsDMARD:\t\nTNFi\t109 (74%)\t33 (47%)\t7 (28%)\t\nTocilizumab\t22 (15%)\t24 (34%)\t6 (24%)\t\nAbatacept\t14 (10%)\t7 (10%)\t5 (20%)\t\nTofacitinib\t1 (1%)\t5 (7%)\t3 (12%)\t\nRituximab\t1 (1%)\t1 (1%)\t4 (16%)\t\nConcomitant csDMARD (%)\t95 (65%)\t31 (44%)\t11 (44%)\t\nb/tsDMARD failures\t72\t28\t7\t\nMaximum follow-up (years)\t9.9\t7.7\t7.4\t\nTime at risk (person-years)\t407.2\t127.6\t66.3\t\n% Retention at 5 years (95% CI)\t45 (37, 53)\t47 (33, 59)\t63 (39, 79)\t\nMean treatment duration at 5 years (95% CI)\t3.1 (2.8, 3.4)\t3.1 (2.6, 3.6)\t3.7 (2.9, 4.4)\t\nPsoriatic arthritis\t\nN\t46\t13\t3\t\nb/tsDMARD:\t\nTNFi\t44 (96%)\t10 (77%)\t1 (33%)\t\nSecukinumab\t1 (2%)\t1 (7%)\t2 (67%)\t\nUstekinumab\t1 (2%)\t2 (1%)\t0 (0%)\t\nConcomitant csDMARD (%)\t29 (50%)\t7 (54%)\t2 (100%)\t\nMaximum follow-up (years)\t10.0\t9.2\t6.0\t\nb/tsDMARD failures\t13\t3\t1\t\nTime at risk (person-years)\t175.7\t33.0\t6.2\t\n% Retention at 5 years (95% CI)\t69 (53, 80)\t70 (50, 83)\t80 (56, 92)\t\nMean treatment duration at 5 years (95% CI)\t4.1 (3.6, 4.6)\t4.1 (3.5, 4.7)\t4.4 (3.9, 4.9)\t\nAnkylosing spondylitis\t\nN\t37\t16\t5\t\nb/tsDMARD:\t\nTNFi\t37 (100%)\t15\t3\t\nSecukinumab\t0\t1\t2\t\nConcomitant csDMARD (%)\t5 (14%)\t1 (6%)\t0 (0%)\t\nb/tsDMARD failures\t18\t6\t1\t\nMaximum follow-up (years)\t9.9\t8.8\t4.0\t\nTime at risk (person-years)\t124.9\t45.3\t5.6\t\n% Retention at 5 years (95% CI)\t52 (38, 64)\t53 (36, 68)\t68 (42, 84)\t\nMean treatment duration at 5 years (95% CI)\t3.3 (2.7, 3.9)\t3.3 (2.6, 3.9)\t3.8 (2.8, 3.9)\t\n\nTabulation of all b/tsDMARD switching events in RA (Figure 1) demonstrated that 41/71 (64%) of patients who failed a TNFi were switched to a non-TNFi b/tsDMARD predominantly tocilizumab. Conversely, 14/23 (61%) of RA patients who failed a non-TNFi b/tsDMARD were switched to a TNFi.\n\nFigure 1 Types of b/tsDMARD switching in Rheumatoid Arthritis patients.\n\nAs expected, the majority of b/tsDMARD switching in both PsA and AS patients was within TNFi. In PsA, 3/16 patients who switched treatment switched from TNFi to secukinumab, and a further two switched to ustekinumab. In AS, 3/21 patients who switched treatment switched from TNFi to secukinumab.\n\nb/tsDMARD Retention/Failure\n\nb/tsDMARD retention was estimated as the proportion remaining on treatment from Kaplan-Meier curves. Treatment retention and the restricted mean treatment duration at 5 years of follow-up for each treatment and each diagnosis are reported in Table 2. Examination of the Kaplan-Meier curves indicated that there was no difference in treatment retention between different treatment episodes (plogrank test = 0.46, Figure 2A), indicating that initial treatment failure did not select for individuals who were subsequently inherently more likely to fail treatment. However, there was a difference in treatment retention by diagnosis (plogrank test = 0.016, Figure 2B), with the best b/tsDMARD treatment retention observed in PsA patients.\n\nFigure 2 Kaplan-Meier curves for b/tsDMARD treatment retention. (A) b/tsDMARD treatment episodes (adjusted for diagnosis group). (B) Diagnosis group (adjusted for treatment episodes).\n\nA summary of b/tsDMARD retention for each diagnosis is reported in Table 3. At 5 years of follow-up, the overall treatment retention was 47% for RA, 70% for PsA and 53% for AS, and the overall median treatment duration before failure was 4.0, 8.2, and 6.2 years, respectively. Notably, 25% of b/tsDMARD failures in both RA and PsA patients occurred within the first year of follow-up.\n\nTable 3 Summary measures from mean b/tsDMARD retention curves for rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients.\n\nSummary measure\tRA\tPsA\tAS\tALL\t\nAt 5 years follow-up:\t\nMean b/tsDMARD duration (yrs)\t3.1 (2.9, 3.4)\t4.1 (3.7, 4.6)\t3.3 (2.8, 3.9)\t3.3 (3.1, 3.6)\t\n% Retention\t47 (41, 55)\t70 (58, 85)\t53 (42, 67)\t52 (47, 58)\t\nFailure-time centiles (years):\t\n25% Failures\t0.8 (0.6, 1.2)\t4.0 (1.9, 8.6)\t0.9 (0.1, 6.5)\t1.0 (0.6, 1.6)\t\n50% Failures (median duration)\t4.0 (2.6, 6.2)\t8.2 (5.4, 12.4)\t6.2 (3.7, 10.5)\t5.5 (4.1, 7.5)\t\nFailure-time centiles define the treatment duration time by which the specified % of failures have occurred. Numbers in brackets represent 95% confidence intervals.\n\nPatient-level determinants of b/tsDMARD failure were explored by multivariable cox regression with results reported as hazard ratios (HR), (Table 4). When compared to RA patients, the risk of b/tsDMARD failure was halved in PsA patients (HR = 0.50), but no different in AS patients (HR = 1.0). Contrary to expectations, none of the additional covariates (age, gender, disease duration, smoking status and the use of concomitant csDMARDS) were associated with the risk of b/tsDMARD failure. Further, in an analysis restricted to RA patients, there was no relationship between seropositivity and b/tsDMARD failure (HR 0.89, 95% CI 0.53, 1.50, p = 0.66).\n\nTable 4 Multivariable conditional risk set cox regression model (for multiple events) for predictors of b/tsDMARD failure.\n\nCovariate\tHR (95% CI)\tp-value\t\nDiagnosis group (base = rheumatoid arthritis)\t\nPsoriatic arthritis\t0.50 (0.27, 0.90)\t0.022\t\nAnkylosing spondylitis\t1.00 (0.61, 1.64)\t0.99\t\nGender (base = male)\t\nFemale\t1.14 (0.76, 1.69)\t0.53\t\nConcomitant csDMARD (base = no)\t\nYes\t1.19 (0.82, 1.71)\t0.36\t\nCurrent smoker (base = no)\t\nYes\t1.10 (0.70, 1.72)\t0.69\t\nAge (years)\t1.00 (0.99, 1.01)\t0.71\t\nDisease duration (years)\t1.01 (0.99, 1.02)\t0.56\t\nResults are expressed as hazard ratios (HR) with 95% confidence intervals.\n\nb/tsDMARD retention rates were also compared to historical, non-overlapping data from the same clinic (31), for which appropriate comparison data was only available for the first b/tsDMARD treatment. To enable comparison, the digitised data from the Kaplan-Meier curves reported in Figure 1 (31) for the first b/tsDMARD were overlaid against the Kaplan-Meier curves for the first b/tsDMARD in the current study (Figure 3). b/tsDMARD retention was comparable between the current and earlier study for both RA (Figure 3A) and PsA (Figure 3B). For RA, the point estimate of the restricted mean treatment duration at 60 months (5 years) in the historical study was 34.6 months (or 2.9 years), very similar to the current estimate of 3.1 at 5 years of follow-up reported in Table 2. Similarly, for PsA, the point estimate of the mean treatment duration at 60 months for the historical data was 48.0 months (4.0 years), again comparable to the current estimate of 4.1 years reported in Table 2. However, treatment retention for AS appeared somewhat worse in the current study, with the retention curve for the historical data, which had only one b/tsDMARD failure, clearly outside the confidence intervals for the current data (Figure 3C).\n\nFigure 3 Comparison of the first b/tsDMARD treatment retention rates in the current study (post-July 2008) with earlier (pre-July 2008) data from Ninan et al. (31) for: (A) Rheumatoid Arthritis (RA), (B) Psoriatic Arthritis (PsA), (C) Ankylosing Spondylitis (AS). The digitised data from the Kaplan-Meier curves in Ninan et al. (31). Figure 1 was overlaid against the Kaplan-Meier treatment retention curves for the first b/tsDMARD in the current study, with shaded areas representing 95% confidence intervals.\n\nReasons for b/tsDMARD Failure/Switching\n\nThe most frequent reasons for b/tsDMARD failure/switching were secondary failure (n = 62), primary failure (n = 35) and side effects (n = 24), Figure 4A. “Other” reasons for switching (n = 12) included pregnancy, malignancy and non-compliance.\n\nFigure 4 Reasons for b/tsDMARD failure over all patients and all treatment failures. (A) Frequency of specific failure types. EA, extra-articular/extra-musculoskeletal. (B) Cumulative Incidence of b/tsDMARD failure types over time (competing risks analysis).\n\nThe time-course for each type of treatment failure was examined by the cumulative incidence curve for each reason, estimated by a competing risks analysis (Figure 4B). Primary failure was the most likely reason for switching b/tsDMARDs during the first 12 months, with other reasons for b/tsDMARD failure/switching accruing over the longer term, with secondary failure accruing at the fastest rate.\n\nDiscussion\n\nIn the absence of strict evidence-based established guidelines, biologic prescribing patterns vary across the world, directed by physician and patient preferences, and by b/tsDMARD availability and regulatory policy given the significant cost of b/tsDMARDs to funding bodies. Previous studies have analysed physician biologic prescribing patterns to better understand contemporaneous clinical practise (37–39). Erkan et al. (37) found that doctor preference and experience, and medication costs were important factors that influence treatment decisions. Other studies (40, 41) reflect the importance of patient preferences in b/tsDMARD choice, with regard to route of administration, frequency of dosing, tablet or injection formulation and previous experiences and drug-related adverse events. This was also taken in account in this study but medication costs however were not a factor given that these medications are not funded by the patient, but subsidised by the federal government PBS. Comparison between previous studies and ours is made difficult because of heterogeneity in b/tsDMARD availability, patient populations and contextual factors and regulatory policy; in addition, definitions of discontinuation and duration of follow-up are variable, with most studies limiting b/tsDMARD retention data to 1 year.\n\nOur reported mean retention rates over 5 years of 47% for RA, 70% for PsA and 53% for AS and percentage retention for the first biologic (RA 45%, PsA 69%, and AS 52%) appear to be generally similar to those reported previously, with 12-month retention rates reported as 62.2–68.9% (42), 42–56% (43, 44), and 48–51% (45), and 5-year retention rate of 31–49% in a single study (46).\n\nData on the long-term retention of b/tsDMARDs in PsA and AS, in comparison to those in RA, are limited. In a study by Lyu et al. (47), bDMARD persistence ≥ 12 months was 57.9% for PsA, and 51.9 and 48.1% for RA and AS, respectively, generally reflecting our data, in contrast to a much lower proportion (36.1%) at 48 months, reported from the Corrona registry, of patients with PsA (48).\n\nIn a recent study by Murray et al. (30), b/tsDMARD retention rates for PsA were 58.9% at 1 year, and 52.3% at 12 years, with better retention rates with PsA compared to RA (49.6% at 1 year, 38.2% at 12 years). A significantly better retention rate was seen with PsA vs. RA in our current study also. Explanations for the higher retention rates in PsA vs. RA may be the earlier achievement of remission and possibly milder disease in PsA, as found in a study by Saber et al. (49) which showed that 58% of patients with PsA achieved remission with a TNFi compared to 44% of RA patients.\n\nRetention rates of second and third b/tsDMARDs are more difficult to compare with our current study, as there are few studies that have analysed similar data. Two available studies on RA have reported results similar to ours with second b/tsDMARD (TNFi) retention rates of 46–56% (50) and 56.8% (51). In the latter study, the TNFi (vs. non-TNFi) group had a lower rate (53.5 vs. 66.7%) and retention was similar for different episodes of use. Previous studies have reported an inversely proportional relationship between drug survival and b/tsDMARD failure (6, 52–55) and we thus expected lower retention rates with subsequent episodes of b/tsDMARD use. This is also because tighter disease control is now the target of treatment, with earlier switching, especially in the setting of a greater number of agents now available (56).\n\nOne reason for the better than expected retention rates in our study with subsequent b/tsDMARDs may be our practise of switching to a b/tsDMARD with a different MoA, rather than to an alternative agent in the same class; this strategy is supported by previous studies (6, 20–25). With regard to TNFis specifically, several previous studies have found non-responders to TNFi therapy respond better to a b/tsDMARD with a differing mechanism of action as their next choice biologic (8, 23, 26).\n\nPrevious studies reflect our results of TNFi being the most commonly prescribed first line bDMARD (57). This is not surprising, as TNFi were the first class of b/tsDMARDs to be licenced for clinical practise, with much greater physician familiarity with efficacy, safety and short- and long-term potential adverse events. In our study, appropriately, in those that required to be switched to their second and third b/tsDMARDs for RA, there was an increase in switching to a different class of agents—usually tocilizumab and abatacept.\n\nUnexpectedly, we did not find an association between b/tsDMARD failure and concomitant csDMARD use in RA, in contrast to previous studies that have demonstrated superior b/tsDMARD retention rates in RA, in particular with TNFis, with concomitant csDMARDs (58–60). In contrast to the aforementioned studies, Bechman et al. (61) found that TNFi monotherapy had equivalent retention to TNFi-csDMARD combination therapy in patients >75 years, perhaps as a result of immunosenescence. In our study however, only 17.7% were over 75 years.\n\nAn increased use of tocilizumab, often as monotherapy without csDMARDs, especially during class switching, may also have contributed to the lack of an association between b/tsDMARD failure and concomitant csDMARD use in our study. Previous studies have demonstrated the equivalent efficacy (62) and retention rates (63, 64) of Tocilizumab monotherapy as the first-line or subsequent bDMARD. We do acknowledge however that had there been increased use of Tofacitinib, there may have been a change in the results given that Tofacitinib has a synergistic effect when combined with methotrexate (65, 66). We aim to assess this in the next iteration of this study by which time we expect to have higher number of patients on JAK inhibitors.\n\nWe also did not find any significant association with b/tsDMARD failure with female gender, smoking, age, and disease duration, or seropositivity. Courvoisier et al. (67) recently published a pooled analysis of observational data, of those on treatment with Rituximab, Abatacept, Tocilizumab or TNFi, and demonstrated greater effectiveness of non-TNFi bDMARDs, especially Rituximab and Abatacept (vs. TNF) in seropositive patients with RA. This association with Abatacept response and seropositive RA has been reported in other studies (68, 69). Smoking is associated with a higher disease activity and lower retention of bDMARD, which is in line with previous studies (55, 70). Our study did not show any association between bDMARD retention and smoking and this could be attributed to a significant proportion of patients in this study having never smoked (47%) and only a small percentage (16%) as current smokers.\n\nExisting literature confirms our findings of inefficacy (primary or secondary) as the most common reason for discontinuing or switching bDMARD therapy, followed by adverse events to the agent (7, 29, 71–73).\n\nWe did not find significant differences in the first bDMARD retention over time, as compared to previously published data from our clinic (31). This was contrary to our expectation of earlier and more frequent switching in recent years in order to achieve tighter disease control and with the availability of multiple new b/tsDMARDs with differing MoA. Our results contrast to those reported by Du Pan et al. (52), who found an inversely proportional relationship with initiating biologic treatment in a later year and drug survival, which they attributed to greater availability of the number of b/tsDMARDs. Our results are probably explained by the ongoing practise of TNFi being the most common initial bDMARD, similar to the previous study from this clinic, although at that time, few other classes of b/tsDMARDs existed.\n\nThe strengths of this study lies in it being a real-world study representing contemporaneous clinical practise, rather than a RCT. Additionally, it is one of very few studies comparing data from three inflammatory arthritides, over a 10-year period, with a follow-up period of minimum 5 years, and with an added advantage of comparison with previous data from the same centre, enabling observations of changes in trends over time.\n\nThe limitations of this study are its observational nature with relatively limited patient numbers and use of retrospectively collected data from patient medical records, that relied upon accurate documentation, which was not always present and led to those patients being excluded from the analysis. Although AS and PsA have a similar prevalence in Australia as compared to the rest of the world, the specialised clinic that this data is drawn from receives patient referrals from the Southern region of Adelaide, which may be a reason as to why sample size was limited; in addition, the Australian subsidised PBS criteria for access to biologics are relatively strict and inflexible. The latter reason means that some patient who would clinically benefit from addition of a b/tsDMARD are unable to access these drugs.\n\nIn the absence of randomisation, patients may have been guided to a specific drug, producing selection bias. Additionally, in this long-term drug survival analyses, the number of patients at risk progressively decreased by time, being lower at the end of the evaluated follow-up period and this trend may partially influence the results. Some b/tsDMARDs were not available until later in the period and therefore their penetration in this study may have been limited.\n\nConclusion\n\nSimilar retention rates of the second and third compared to the first b/tsDMARD support a strategy of differential b/tsDMARD use informed by patient presentation. Despite greater availability of b/tsDMARDs with differing mechanisms of action, retention rates of the first b/tsDMARD remain similar to previous years.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Southern Adelaide Clinical Human Research Ethics Committee. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.\n\nAuthor Contributions\n\nMW contributed to conception and design of the study. LB organised and maintained the database. VB and RH collected and entered patient data. SL performed the statistical analysis and wrote the results section. VB wrote the first draught of the manuscript. MW, SL, and VB wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nThe authors acknowledge the contribution, over the years, of the several Rheumatology Advanced Trainees who worked in the biologic clinic at the Flinders Medical Centre.\n==== Refs\nReferences\n\n1. Courvoisier DS Alpizar-Rodriguez D Gottenberg JE Hernandez MV Iannone F Lie E . 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The effectiveness of leflunomide as a co-therapy of tumour necrosis factor inhibitors in rheumatoid arthritis: a population-based study. Ann Rheum Dis. (2009) 68 :33–9. 10.1136/ard.2007.085696 18230627\n69. Gottenberg JE Courvoisier DS Hernandez MV Iannone F Lie E Canhao H . Brief report: association of rheumatoid factor and anti-citrullinated protein antibody positivity with better effectiveness of abatacept: results from the Pan-European registry analysis. Arthritis Rheumatol. (2016) 68 :1346–52. 10.1002/art.39595 26815727\n70. Soderlin MK Petersson IF Geborek P . The effect of smoking on response and drug survival in rheumatoid arthritis patients treated with their first anti-TNF drug. Scand J Rheumatol. (2012) 41 :1–9. 10.3109/03009742.2011.599073 22118371\n71. Oei HB Hooker RS Cipher DJ Reimold A . High rates of stopping or switching biological medications in veterans with rheumatoid arthritis. Clin Exp Rheumatol. (2009) 27 :926–34. 20149307\n72. Remy A Avouac J Gossec L Combe B . Clinical relevance of switching to a second tumour necrosis factor-alpha inhibitor after discontinuation of a first tumour necrosis factor-alpha inhibitor in rheumatoid arthritis: a systematic literature review and meta-analysis. Clin Exp Rheumatol. (2011) 29 :96–103. 21269578\n73. Zhang J Shan Y Reed G Kremer J Greenberg JD Baumgartner S. . Thresholds in disease activity for switching biologics in rheumatoid arthritis patients: experience from a large US cohort. Arthritis Care Res (Hoboken). (2011) 63 :1672–9. 10.1002/acr.20643 21954144\n\n",
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"literaturereference": "Bhushan V, Lester S, Briggs L, Hijjawi R, Shanahan EM, Pontifex E, et al Real-Life Retention Rates and Reasons for Switching of Biological DMARDs in Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis. FrontiersinMedicine 2021 Sep 27;8:295-303.",
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{
"abstract": "Concern has arisen about the development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection treated with direct-acting antivirals (DAAs). To identify patients at risk for HCC, we evaluated serum levels of immune mediators before, during, and after DAA treatment of HCV infection. Our study included 13 patients who developed HCC within 18 months after treatment (3 with HCC recurrence and 10 with new HCC) and 10 patients who did not develop HCC (controls), within at least 24 months of treatment (median, 26 months). We identified a set of 12 immune mediators (cytokines, growth factors, and apoptosis markers) whose levels were significantly higher in serum before DAA treatment of patients who eventually developed de novo HCC compared with controls. A panel of 9 cytokines, measured in serum before treatment (MIG, IL22, TRAIL, APRIL, VEGF, IL3, TWEAK, SCF, IL21), identified patients who developed de novo HCC with an area under the receiver operating characteristic curve value higher than 0.8. Further analyses of changes in levels of inflammatory cytokines during DAA treatment also provides important information about HCV-induced carcinogenesis and the effects of DAAs.",
"affiliations": "Department of Medicine, University of Minnesota, Minneapolis, Minnesota; Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.;Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.;Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.;Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands; Institute of Health Policy, Management and Evaluation (IHPME), University of Toronto, Toronto, Canada; Toronto Center for Liver Disease, University Health Network, Toronto, Canada.;Department of Internal Medicine, University Medical Center, Hamburg-Eppendorf, Germany.;Department of Internal Medicine, University Medical Center, Hamburg-Eppendorf, Germany.;Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.;Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands. Electronic address: p.a.boonstra@erasmusmc.nl.",
"authors": "Debes|Jose D|JD|;van Tilborg|Marjolein|M|;Groothuismink|Zwier M A|ZMA|;Hansen|Bettina E|BE|;Schulze Zur Wiesch|Julian|J|;von Felden|Johann|J|;de Knegt|Robert J|RJ|;Boonstra|Andre|A|",
"chemical_list": "D000998:Antiviral Agents; D016207:Cytokines; D018836:Inflammation Mediators",
"country": "United States",
"delete": false,
"doi": "10.1053/j.gastro.2017.10.035",
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"issn_linking": "0016-5085",
"issue": "154(3)",
"journal": "Gastroenterology",
"keywords": "AUROC; Biomarker; Interleukin; Liver Cancer; Prognostic Factor",
"medline_ta": "Gastroenterology",
"mesh_terms": "D000998:Antiviral Agents; D019540:Area Under Curve; D006528:Carcinoma, Hepatocellular; D016022:Case-Control Studies; D016207:Cytokines; D016174:Hepacivirus; D006526:Hepatitis C; D054884:Host-Pathogen Interactions; D006801:Humans; D018836:Inflammation Mediators; D008113:Liver Neoplasms; D008875:Middle Aged; D011237:Predictive Value of Tests; D012372:ROC Curve; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0374630",
"other_id": null,
"pages": "515-517.e3",
"pmc": null,
"pmid": "29102620",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Levels of Cytokines in Serum Associate With Development of Hepatocellular Carcinoma in Patients With HCV Infection Treated With Direct-Acting Antivirals.",
"title_normalized": "levels of cytokines in serum associate with development of hepatocellular carcinoma in patients with hcv infection treated with direct acting antivirals"
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}
],
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"reaction": [
{
"reactionmeddrapt": "Hepatocellular carcinoma",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hepatitis C",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hepatic mass",
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}
],
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},
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"literaturereference": "DEBES JD, TILBORG MV, GROOTHUISMINK ZMA, HANSEN BE, WIESCH JSZ, FELDEN JV ET AL.. LEVELS OF CYTOKINES IN SERUM ASSOCIATE WITH DEVELOPMENT OF HEPATOCELLULAR CARCINOMA IN PATIENTS WITH HCV INFECTION TREATED WITH DIRECT-ACTING ANTIVIRALS. GASTROENTEROLOGY. 2018?154(3):515-7",
"literaturereference_normalized": "levels of cytokines in serum associate with development of hepatocellular carcinoma in patients with hcv infection treated with direct acting antivirals",
"qualification": "3",
"reportercountry": "US"
},
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},
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},
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}
] |
{
"abstract": "Eruptive melanocytic nevi (EMN) are rare multiple benign melanocytic nevi that develop within a few months. The phenomenon has been associated with a variety of dermatologic and systemic conditions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, epidermolysis bullosa, Addison disease, human immunodeficiency virus infection, and internal malignancy, among others. It also is commonly attributed to medications, particularly immunosuppressive and chemotherapeutic agents. We report a case of EMN in a 50-year-old man undergoing azathioprine therapy for antisynthetase syndrome.",
"affiliations": "Department of Dermatology, University of Maryland Medical Center, Baltimore, USA.;Department of Dermatology, University of Maryland Medical Center, Baltimore, USA.;Department of Dermatology, University of Maryland Medical Center, Baltimore, USA.;Department of Dermatology, University of Maryland Medical Center, Baltimore, USA.",
"authors": "Steinweg|Stephanie A|SA|;Halvorson|Christian R|CR|;Kao|Grace F|GF|;Dronavalli|Sridhar|S|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D001379:Azathioprine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-4162",
"issue": "99(4)",
"journal": "Cutis",
"keywords": null,
"medline_ta": "Cutis",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D001379:Azathioprine; D003937:Diagnosis, Differential; D005260:Female; D005528:Foot; D006225:Hand; D006801:Humans; D008875:Middle Aged; D009220:Myositis; D009508:Nevus, Pigmented; D012878:Skin Neoplasms",
"nlm_unique_id": "0006440",
"other_id": null,
"pages": "268-270",
"pmc": null,
"pmid": "28492593",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Eruptive melanocytic nevi during azathioprine therapy for antisynthetase syndrome.",
"title_normalized": "eruptive melanocytic nevi during azathioprine therapy for antisynthetase syndrome"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-18-02019",
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"actiondrug": "4",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
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"drugindication": "ANTISYNTHETASE SYNDROME",
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"medicinalproduct": "AZATHIOPRINE."
}
],
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"patientonsetage": "50",
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"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Melanocytic naevus",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rash",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "STEINWEG S,HALVORSON C,KAO G,DRONAVALLI S. ERUPTIVE MELANOCYTIC NEVI DURING AZATHIOPRINE THERAPY FOR ANTISYNTHETASE SYNDROME. CUTIS 2017?99(4):268-270.",
"literaturereference_normalized": "eruptive melanocytic nevi during azathioprine therapy for antisynthetase syndrome",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180316",
"receivedate": "20180316",
"receiver": {
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"receivertype": "6"
},
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},
"serious": 1,
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] |
{
"abstract": "BACKGROUND\nNeuroleptic malignant syndrome (NMS) and serotonin syndrome (SS) are serious medical conditions associated with commonly prescribed psychiatric medications. Although the mechanisms differ, they can be clinically difficult to distinguish. We report a case of a pediatric patient with complicated psychiatric history that developed features of both syndromes in the setting of polypharmacy.\n\n\nMETHODS\nA 12-year-old boy with a history of developmental delay, attention-deficit hyperactivity disorder, and posttraumatic stress disorder presented to the emergency department with behavior changes consisting of delayed reactions, gait instability, drooling, and slowed movements. Ten days before presentation, his outpatient psychiatrist had made multiple medication changes including discontinuation of cyproheptadine (an appetite stimulant) and initiation of aripiprazole. On arrival, the patient was noted to be tachycardia and hypertensive for age. He was disoriented, intermittently agitated, and tremulous with increased tonicity, clonus in the lower extremities, and mydriasis. He was supportively treated with lorazepam and intravenous fluids while discontinuing potential offending agents. His course was complicated by hypertension and agitation managed with dexmedetomidine infusion and benzodiazepines. His mental status, tremors, and laboratory values began to improve over the next 2 days, and eventually transitioned to the inpatient psychiatric unit on hospital day 7.\n\n\nCONCLUSIONS\nDiagnosis of NMS or SS can be difficult when there is overlap between syndromes, particularly in the setting of multiple potential offending agents or underlying developmental delay. In addition, pediatric patients may present atypically as compared with adult patients with the same condition.\n\n\nCONCLUSIONS\nThe use of antipsychotic medications for young children with behavioral problems has risen dramatically in the last decade, increasing their risk for developing SS or NMS.",
"affiliations": "From the Division of Medical Toxicology.;Department of Child and Adolescent Psychiatry, University of California San Diego, San Diego, CA.;From the Division of Medical Toxicology.;Department of Child and Adolescent Psychiatry, University of California San Diego, San Diego, CA.;Department of Child and Adolescent Psychiatry, University of California San Diego, San Diego, CA.",
"authors": "Sun|Christie|C|;Sweet|Hannah|H|;Minns|Alicia B|AB|;Shapiro|Desiree|D|;Jenkins|Willough|W|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000001477",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "36(10)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D014150:Antipsychotic Agents; D002648:Child; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D009459:Neuroleptic Malignant Syndrome; D019338:Polypharmacy; D020230:Serotonin Syndrome",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "e589-e591",
"pmc": null,
"pmid": "29698346",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Mixed Presentation of Serotonin Syndrome vs Neuroleptic Malignant Syndrome in a 12-Year-Old Boy.",
"title_normalized": "a mixed presentation of serotonin syndrome vs neuroleptic malignant syndrome in a 12 year old boy"
} | [
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"medicinalproduct": "CLONIDINE."
},
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},
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{
"abstract": "A Han Chinese patient failed CYP2D6 genotype analysis with the AmpliChip CYP450 Test™. The CYP2D6 gene locus of the patient and her son were extensively genotyped including copy number variation and gene resequencing. Two SNPs were discovered on the patient's CYP2D6*1 allele, -498C>A and 1661G>C, while the son's CYP2D6*1 allele had -498C>A only. AmpliChip failure was attributed to the presence of a CYP2D6*1 allele carrying the 1661G>C SNP. Functional analyses of -498C>A did not reveal altered activity in vitro or in vivo suggesting that both novel CYP2D6*1 subvariants are functional. The implementation of pharmacogenetics-guided drug therapy relies on accurate clinical-grade genotype analysis. Although the AmpliChip is a reliable platform, numerous allelic (sub)variants and gene arrangements are not detected or may trigger no calls. While such cases may be rare, the clinical/genetic testing community must be aware of the challenges of CYP2D6 testing on the AmpliChip platform and implications regarding accuracy of test results.",
"affiliations": "Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Hospital, 2401 Gilham Road, Kansas City, MO 64108, USA.",
"authors": "Gaedigk|Andrea|A|;Garcia-Ribera|Carles|C|;Jeong|Hye-Eun|HE|;Shin|Jae-Gook|JG|;Hernandez-Sanchez|Juanjo|J|;Hernandez-Sanchez|Juanjo T|JT|",
"chemical_list": "D019389:Cytochrome P-450 CYP2D6",
"country": "England",
"delete": false,
"doi": "10.2217/pgs.14.94",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-2416",
"issue": "15(9)",
"journal": "Pharmacogenomics",
"keywords": "AmpliChip CYP450 Test™; CYP2D6; CYP2D6*10; cytochrome CYP450; genotyping; pharmacogenetics",
"medline_ta": "Pharmacogenomics",
"mesh_terms": "D000369:Aged, 80 and over; D000483:Alleles; D044466:Asians; D019389:Cytochrome P-450 CYP2D6; D056915:DNA Copy Number Variations; D005260:Female; D006239:Haplotypes; D006801:Humans; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide",
"nlm_unique_id": "100897350",
"other_id": null,
"pages": "1175-84",
"pmc": null,
"pmid": "25141893",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Resolution of a clinical AmpliChip CYP450 Test™ no call: discovery and characterization of novel CYP2D6*1 haplotypes.",
"title_normalized": "resolution of a clinical amplichip cyp450 test no call discovery and characterization of novel cyp2d6 1 haplotypes"
} | [
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"abstract": "Data suggest selective internal radiotherapy (SIRT) in third-line or subsequent therapy for metastatic colorectal cancer has clinical benefit in patients with colorectal liver metastases with liver-dominant disease after chemotherapy. The FOXFIRE, SIRFLOX, and FOXFIRE-Global randomised studies evaluated the efficacy of combining first-line chemotherapy with SIRT using yttrium-90 resin microspheres in patients with metastatic colorectal cancer with liver metastases. The studies were designed for combined analysis of overall survival.\n\n\n\nFOXFIRE, SIRFLOX, and FOXFIRE-Global were randomised, phase 3 trials done in hospitals and specialist liver centres in 14 countries worldwide (Australia, Belgium, France, Germany, Israel, Italy, New Zealand, Portugal, South Korea, Singapore, Spain, Taiwan, the UK, and the USA). Chemotherapy-naive patients with metastatic colorectal cancer (WHO performance status 0 or 1) with liver metastases not suitable for curative resection or ablation were randomly assigned (1:1) to either oxaliplatin-based chemotherapy (FOLFOX: leucovorin, fluorouracil, and oxaliplatin) or FOLFOX plus single treatment SIRT concurrent with cycle 1 or 2 of chemotherapy. In FOXFIRE, FOLFOX chemotherapy was OxMdG (oxaliplatin modified de Gramont chemotherapy; 85 mg/m2 oxaliplatin infusion over 2 h, L-leucovorin 175 mg or D,L-leucovorin 350 mg infusion over 2 h, and 400 mg/m2 bolus fluorouracil followed by a 2400 mg/m2 continuous fluorouracil infusion over 46 h). In SIRFLOX and FOXFIRE-Global, FOLFOX chemotherapy was modified FOLFOX6 (85 mg/m2 oxaliplatin infusion over 2 h, 200 mg leucovorin, and 400 mg/m2 bolus fluorouracil followed by a 2400 mg/m2 continuous fluorouracil infusion over 46 h). Randomisation was done by central minimisation with four factors: presence of extrahepatic metastases, tumour involvement of the liver, planned use of a biological agent, and investigational centre. Participants and investigators were not masked to treatment. The primary endpoint was overall survival, analysed in the intention-to-treat population, using a two-stage meta-analysis of pooled individual patient data. All three trials have completed 2 years of follow-up. FOXFIRE is registered with the ISRCTN registry, number ISRCTN83867919. SIRFLOX and FOXFIRE-Global are registered with ClinicalTrials.gov, numbers NCT00724503 (SIRFLOX) and NCT01721954 (FOXFIRE-Global).\n\n\n\nBetween Oct 11, 2006, and Dec 23, 2014, 549 patients were randomly assigned to FOLFOX alone and 554 patients were assigned FOLFOX plus SIRT. Median follow-up was 43·3 months (IQR 31·6-58·4). There were 411 (75%) deaths in 549 patients in the FOLFOX alone group and 433 (78%) deaths in 554 patients in the FOLFOX plus SIRT group. There was no difference in overall survival (hazard ratio [HR] 1·04, 95% CI 0·90-1·19; p=0·61). The median survival time in the FOLFOX plus SIRT group was 22·6 months (95% CI 21·0-24·5) compared with 23·3 months (21·8-24·7) in the FOLFOX alone group. In the safety population containing patients who received at least one dose of study treatment, as treated, the most common grade 3-4 adverse event was neutropenia (137 [24%] of 571 patients receiving FOLFOX alone vs 186 (37%) of 507 patients receiving FOLFOX plus SIRT). Serious adverse events of any grade occurred in 244 (43%) of 571 patients receiving FOLFOX alone and 274 (54%) of 507 patients receiving FOLFOX plus SIRT. 10 patients in the FOLFOX plus SIRT group and 11 patients in the FOLFOX alone group died due to an adverse event; eight treatment-related deaths occurred in the FOLFOX plus SIRT group and three treatment-related deaths occurred in the FOLFOX alone group.\n\n\n\nAddition of SIRT to first-line FOLFOX chemotherapy for patients with liver-only and liver-dominant metastatic colorectal cancer did not improve overall survival compared with that for FOLFOX alone. Therefore, early use of SIRT in combination with chemotherapy in unselected patients with metastatic colorectal cancer cannot be recommended. To further define the role of SIRT in metastatic colorectal cancer, careful patient selection and studies investigating the role of SIRT as consolidation therapy after chemotherapy are needed.\n\n\n\nBobby Moore Fund of Cancer Research UK, Sirtex Medical.",
"affiliations": "Imperial College Healthcare NHS Trust and Imperial College, Hammersmith Hospital, London, UK.;Western Hospital, Footscray, VIC, Australia.;Division of Radiation Oncology, Penn State Hershey Cancer Centre, School of Medicine, Hershey, PA, USA.;Sorbonne Paris Cité, Université Paris Descartes, Georges Pompidou European Hospital, Department of Hepatogastroenterology and GI Oncology, Paris, France.;Department of Medical Oncology and Comprehensive Cancer Centre, Klinikum Grosshadern, Ludwig-Maximilian, University of Munich, Munich, Germany.;Department of Radiology and Nuclear Medicine, University of Magdeburg, Magdeburg, Germany.;Antwerp University Hospital, Antwerp, Belgium.;Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.;Oxford University NHS Foundation Trust, Churchill Hospital, Oxford, UK.;Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.;Cambridge University Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge, UK.;School of Medicine, Cardiff University, Cardiff, UK.;Oncology Clinical Trials Office, Department of Oncology, University of Oxford, Oxford, UK.;Centre for Statistics in Medicine, University of Oxford, Oxford, UK.;Centre for Statistics in Medicine, University of Oxford, Oxford, UK.;Centre for Statistics in Medicine, University of Oxford, Oxford, UK.;Centre for Statistics in Medicine, University of Oxford, Oxford, UK.;National Health and Medical Research Council (NHMRC) Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.;Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK.;School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.;Cancer Research UK Medical Research Council (CRUK-MRC) Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK; National Institute for Health Research University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, London, UK. Electronic address: ricky.sharma@oncology.ox.ac.uk.",
"authors": "Wasan|Harpreet S|HS|;Gibbs|Peter|P|;Sharma|Navesh K|NK|;Taieb|Julien|J|;Heinemann|Volker|V|;Ricke|Jens|J|;Peeters|Marc|M|;Findlay|Michael|M|;Weaver|Andrew|A|;Mills|Jamie|J|;Wilson|Charles|C|;Adams|Richard|R|;Francis|Anne|A|;Moschandreas|Joanna|J|;Virdee|Pradeep S|PS|;Dutton|Peter|P|;Love|Sharon|S|;Gebski|Val|V|;Gray|Alastair|A|;|||;|||;|||;van Hazel|Guy|G|;Sharma|Ricky A|RA|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "England",
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"doi": "10.1016/S1470-2045(17)30457-6",
"fulltext": "\n==== Front\nLancet OncolLancet OncolThe Lancet. Oncology1470-20451474-5488Lancet Pub. Group S1470-2045(17)30457-610.1016/S1470-2045(17)30457-6ArticlesFirst-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials Wasan Harpreet S MRCPa*Gibbs Peter MDb*Sharma Navesh K FACROcTaieb Julien ProfMDdHeinemann Volker ProfMDeRicke Jens ProfMDfPeeters Marc ProfMDgFindlay Michael ProfMDhWeaver Andrew MDiMills Jamie FRCRjWilson Charles FRCRkAdams Richard ProfMDlFrancis Anne DPhilmMoschandreas Joanna PhDnVirdee Pradeep S MScnDutton Peter MScnLove Sharon BScnGebski Val ProfMStatqGray Alastair ProfPhDoFOXFIRE trial investigatorsAdams Richard Bateman Andrew Blesing Claire Brown Ewan Chau Ian Cummins Sebastian Cunningham David Falk Stephen Hadaki Maher Hall Marcia Hickish Tamas Hornbuckle Joanne Lofts Fiona Lowndes Sarah Mayer Astrid Metcalfe Matthew Middleton Gary Mills Jamie Montazeri Amir Muirhead Rebecca Polychronis Andreas Purcell Colin Ross Paul Sharma Ricky A Sherwin Liz Smith David Soomal Rubin Swinson Daniel Walther Axel Wasan Harpreet Weaver Andrew Wilson Charles Wilson Greg †SIRFLOX trial investigatorsAmin Pradip Angelelli Bruna Balosso Jacques Beny Alex Bloomgarden Daniel Boucher Evelyn Brown Michael Bruch Harald-Robert Bui James Burge Matthew Cardaci Giuseppe Carlisle James Chai Seungjean Chen Yi-Jen Chevallier Patrick Chuong Michael Clarke Stephen Coveler Andrew Craninx Michael Delanoit Thierry Deleporte Amélie Eliadis Paul Facchini Francis Ferguson Thomas Ferrante Michel Findlay Michael Frenette Gary Frick Jacob Ganju Vinod Garofalo Michael Geboes Karen Gehbauer Gerald George Benjamin Geva Ravit Gibbs Peter Gordon Michael Gregory Kate Gulec Seza Hannigan James van Hazel Guy Heching Norman Heinemann Volker Helmberger Thomas Hendlisz Alain Hendrickx Koen Holtzman Matthew Isaacs Richard Jackson Christopher James Philip Kaiser Adeel Karapetis Chris Kaubisch Andreas Ko Yon-Dschun Kröning Hendrik Lammert Frank Liauw Winston Limentani Steven Louafi Samy de Man Marc Margolis Jeffrey Martin Robert Martoni Andrea Marx Gavin Matos Marco Monsaert Els Moons Veerle Nott Louise Nusch Arnd O'Donnell Anne Ozer Howard Padia Siddarth Pavlakis Nick Peeters Marc Perez David Pluntke Stefan Polus Marc Powell Alex Pracht Marc Price Timothy Ransom David Rebischung Christine Ricke Jens Ridwelski Karsten Riera-Knorrenschild Jorge Riess Hanno Rilling William Robinson Bridget Rodríguez Javier Sanchez Federico Sauerbruch Tilmann Savin Michael Scheidhauer Klemens Schneiderman Elyse Seeger Grant Segelov Eva Schmueli Einat Shaham Shani Adi Shannon Jenny Sharma Navesh Shibata Stephen Singhal Nimit Smith Denis Smith Randall Stemmer Salomon Stötzer Oliver Strickland Andrew Taieb Julien Tatsch Klaus Terrebonne Eric Tichler Thomas Vehling-Kaiser Ursula Vera-Garcia Ruth Vogl Thomas Walpole Euan Wang Eric Whiting Samuel Wolf Ido †FOXFIRE-Global trial investigatorsAdes Steven Aghmesheh Morteza Angelelli Bruna Auber Miklos Ayala Hubert Beny Alex Bloomgarden Daniel Boland Patrick Bouche Eveline Bowers Charles Bremer Christoph Bui James Burge Mathew Carlisle James Casado Ana Ruiz Chai Seungjean Chuong Michael Cooray Prasad Crain Martin De Wit Maike Deleporte Amelie Dowling Kyran Durand Aurelie Facchini Francis Faivre Sandrine Feeney Kynan Ferguson Tom Ferru Aurelie Findlay Michael Fragoso Maria Frenette Gary Frick Jacob Ganju Vinod Geva Ravit Gibbs Peter Granetto Cristina Hammel Pascal van Hazel Guy Heching Norman Hendlisz Alain Hendrickx Koen Holtzman Matthew Issacs Richard Iyer Renuka Jackson Christopher Kaiser Adeel Kaubisch Andreas Kim Yeul Hong Kröning Hendrik Liang Jin Tung Lim Lionel Limentani Steven Liu Jin Hwang Louafi Samy de Man Marc Masi Gianluca Matos Marco Monsaert Els Mosconi Stefania Nott Louise Numico Gianmauro O'Donnell Anne Peeters Marc Polus Marc Pracht Marc Ratner Lynn Rebischung Christine Sae-Won Han Sanchez Federico Shani Adi Sharma Navesh Singh Madhu Singhal Nimit Smith Denis Stoltzfus Patricia Strickland Andrew Taieb Julien Tan Iain Terrebonne Eric Tichler Thomas Trogu Antonio Underhill Craig Vera-Garcia Ruth Walpole Euan Wang Eric Westcott Mark †van Hazel Guy ProfMBBSr*Sharma Ricky A ProfPhDricky.sharma@oncology.ox.ac.ukps**a Imperial College Healthcare NHS Trust and Imperial College, Hammersmith Hospital, London, UKb Western Hospital, Footscray, VIC, Australiac Division of Radiation Oncology, Penn State Hershey Cancer Centre, School of Medicine, Hershey, PA, USAd Sorbonne Paris Cité, Université Paris Descartes, Georges Pompidou European Hospital, Department of Hepatogastroenterology and GI Oncology, Paris, Francee Department of Medical Oncology and Comprehensive Cancer Centre, Klinikum Grosshadern, Ludwig-Maximilian, University of Munich, Munich, Germanyf Department of Radiology and Nuclear Medicine, University of Magdeburg, Magdeburg, Germanyg Antwerp University Hospital, Antwerp, Belgiumh Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealandi Oxford University NHS Foundation Trust, Churchill Hospital, Oxford, UKj Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UKk Cambridge University Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge, UKl School of Medicine, Cardiff University, Cardiff, UKm Oncology Clinical Trials Office, Department of Oncology, University of Oxford, Oxford, UKn Centre for Statistics in Medicine, University of Oxford, Oxford, UKo Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UKp Cancer Research UK Medical Research Council (CRUK-MRC) Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UKq National Health and Medical Research Council (NHMRC) Clinical Trials Centre, University of Sydney, Sydney, NSW, Australiar School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australias National Institute for Health Research University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, London, UK* Correspondence to: Prof Ricky Sharma, NIHR University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, London WC1E 6DD, UKCorrespondence to: Prof Ricky SharmaNIHR University College London Hospitals Biomedical Research CentreUCL Cancer InstituteLondonWC1E 6DDUK ricky.sharma@oncology.ox.ac.uk* These authors contributed equally\n\n† Full list of members in the appendix\n\n1 9 2017 9 2017 18 9 1159 1171 © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Summary\nBackground\nData suggest selective internal radiotherapy (SIRT) in third-line or subsequent therapy for metastatic colorectal cancer has clinical benefit in patients with colorectal liver metastases with liver-dominant disease after chemotherapy. The FOXFIRE, SIRFLOX, and FOXFIRE-Global randomised studies evaluated the efficacy of combining first-line chemotherapy with SIRT using yttrium-90 resin microspheres in patients with metastatic colorectal cancer with liver metastases. The studies were designed for combined analysis of overall survival.\n\nMethods\nFOXFIRE, SIRFLOX, and FOXFIRE-Global were randomised, phase 3 trials done in hospitals and specialist liver centres in 14 countries worldwide (Australia, Belgium, France, Germany, Israel, Italy, New Zealand, Portugal, South Korea, Singapore, Spain, Taiwan, the UK, and the USA). Chemotherapy-naive patients with metastatic colorectal cancer (WHO performance status 0 or 1) with liver metastases not suitable for curative resection or ablation were randomly assigned (1:1) to either oxaliplatin-based chemotherapy (FOLFOX: leucovorin, fluorouracil, and oxaliplatin) or FOLFOX plus single treatment SIRT concurrent with cycle 1 or 2 of chemotherapy. In FOXFIRE, FOLFOX chemotherapy was OxMdG (oxaliplatin modified de Gramont chemotherapy; 85 mg/m2 oxaliplatin infusion over 2 h, L-leucovorin 175 mg or D,L-leucovorin 350 mg infusion over 2 h, and 400 mg/m2 bolus fluorouracil followed by a 2400 mg/m2 continuous fluorouracil infusion over 46 h). In SIRFLOX and FOXFIRE-Global, FOLFOX chemotherapy was modified FOLFOX6 (85 mg/m2 oxaliplatin infusion over 2 h, 200 mg leucovorin, and 400 mg/m2 bolus fluorouracil followed by a 2400 mg/m2 continuous fluorouracil infusion over 46 h). Randomisation was done by central minimisation with four factors: presence of extrahepatic metastases, tumour involvement of the liver, planned use of a biological agent, and investigational centre. Participants and investigators were not masked to treatment. The primary endpoint was overall survival, analysed in the intention-to-treat population, using a two-stage meta-analysis of pooled individual patient data. All three trials have completed 2 years of follow-up. FOXFIRE is registered with the ISRCTN registry, number ISRCTN83867919. SIRFLOX and FOXFIRE-Global are registered with ClinicalTrials.gov, numbers NCT00724503 (SIRFLOX) and NCT01721954 (FOXFIRE-Global).\n\nFindings\nBetween Oct 11, 2006, and Dec 23, 2014, 549 patients were randomly assigned to FOLFOX alone and 554 patients were assigned FOLFOX plus SIRT. Median follow-up was 43·3 months (IQR 31·6–58·4). There were 411 (75%) deaths in 549 patients in the FOLFOX alone group and 433 (78%) deaths in 554 patients in the FOLFOX plus SIRT group. There was no difference in overall survival (hazard ratio [HR] 1·04, 95% CI 0·90–1·19; p=0·61). The median survival time in the FOLFOX plus SIRT group was 22·6 months (95% CI 21·0–24·5) compared with 23·3 months (21·8–24·7) in the FOLFOX alone group. In the safety population containing patients who received at least one dose of study treatment, as treated, the most common grade 3–4 adverse event was neutropenia (137 [24%] of 571 patients receiving FOLFOX alone vs 186 (37%) of 507 patients receiving FOLFOX plus SIRT). Serious adverse events of any grade occurred in 244 (43%) of 571 patients receiving FOLFOX alone and 274 (54%) of 507 patients receiving FOLFOX plus SIRT. 10 patients in the FOLFOX plus SIRT group and 11 patients in the FOLFOX alone group died due to an adverse event; eight treatment-related deaths occurred in the FOLFOX plus SIRT group and three treatment-related deaths occurred in the FOLFOX alone group.\n\nInterpretation\nAddition of SIRT to first-line FOLFOX chemotherapy for patients with liver-only and liver-dominant metastatic colorectal cancer did not improve overall survival compared with that for FOLFOX alone. Therefore, early use of SIRT in combination with chemotherapy in unselected patients with metastatic colorectal cancer cannot be recommended. To further define the role of SIRT in metastatic colorectal cancer, careful patient selection and studies investigating the role of SIRT as consolidation therapy after chemotherapy are needed.\n\nFunding\nBobby Moore Fund of Cancer Research UK, Sirtex Medical.\n==== Body\nIntroduction\nMetastatic disease affects approximately 40–50% of the more than one million patients diagnosed with colorectal cancer worldwide each year.1, 2 5-year overall survival for patients with metastatic colorectal cancer is approximately 13%.1 The liver is the dominant site of metastases in colorectal cancer and liver metastases are the commonest cause of death for patients with colorectal cancer.3\n\nModest, but steady, advances in systemic therapy have improved the outlook for patients with metastatic colorectal cancer over the past two decades.4 Nevertheless, surgery remains the only curative treatment. In this disease, compelling evidence suggests that improved local control of colorectal liver metastases could translate into prolonged overall survival. After complete resection of liver metastases from metastatic colorectal cancer, approximately 35–40% of patients survive for 5 years.5 In the European Organisation for Research and Treatment of Cancer (EORTC) intergroup CLOCC 400046 randomised study of the addition of radiofrequency ablation with or without surgery to chemotherapy in 119 patients with up to nine colorectal liver metastases, a significant effect on progression-free survival did translate into a significant overall survival benefit.\n\nResearch in context\nEvidence before this study\n\nMetastatic disease affects up to 50% of the more than one million patients diagnosed with colorectal cancer worldwide every year. The liver is the dominant site of metastases in colorectal cancer; liver metastases are the commonest cause of death for patients with colorectal cancer. Amongst the liver-directed therapies that might improve local control and increase downsizing of tumours to operability, selective internal radiotherapy (SIRT) is a new technology. The efficacy of SIRT in third-line or subsequent therapy for metastatic colorectal cancer has been evaluated and there are data to suggest that SIRT has clinical benefit in patients with colorectal liver metastases with liver-dominant disease after chemotherapy. We previously published a phase 1/2 trial that established the maximum tolerated dose of oxaliplatin-fluorouracil (FOLFOX) chemotherapy to combine as concomitant radiosensitising chemotherapy with SIRT. At the time of planning our studies in 2006, we searched PubMed and Web of Science for articles published between Jan 1, 1980, and May 31, 2006, with the search terms: “colorectal cancer”, “colon cancer”, “rectal cancer”, “oxaliplatin chemotherapy”, “5-fluourouracil chemotherapy”, “fluoropyrimidine”, “selective internal radiotherapy”, “yttrium-90 microsphere”, “radio-embolization”, “radio-embolisation”, “trans-arterial radio-embolization”, “liver metastasis”, and “hepatic metastasis” Original articles and review articles, published in English, were reviewed. No meta-analyses of SIRT treatment of liver metastasis were identified at the time of protocol writing in 2006.\n\nAdded value of this study\n\nThe FOXFIRE, SIRFLOX, and FOXFIRE-Global, randomised clinical trials were designed to study whether SIRT in combination with FOLFOX chemotherapy as first-line therapy for metastatic colorectal cancer can improve overall survival compared with FOLFOX alone. To our knowledge, the combined study represents the largest, randomised analysis performed in the field of interventional oncology to address the question of whether improved local control of colorectal liver metastases impacts on overall survival. Despite higher proportions of patients achieving a response and improved liver-specific progression-free survival, the addition of SIRT to first-line oxaliplatin-fluorouracil chemotherapy for patients with liver-only and liver-dominant metastatic colorectal cancer did not improve overall survival or progression-free survival. Additionally, to our knowledge, this study provides the most comprehensive account of the risk of adverse events which can occur secondary to SIRT when it is used in combination with FOLFOX chemotherapy.\n\nImplications of all the available evidence\n\nBecause of the absence of overall survival benefit, early use of SIRT in combination with first-line, oxaliplatin-fluorouracil-based chemotherapy in unselected patients with metastatic colorectal cancer cannot be recommended. Careful patient selection and studies investigating the role of SIRT as a post-chemotherapy consolidation therapy are required to define the role of SIRT in treating metastatic colorectal cancer.\n\n\n\nAt present, the proportion of patients eligible for surgical resection is only 20%.7 Among the liver-directed therapies that might improve local control and increase downsizing of tumours to operability, selective internal radiation therapy (SIRT) is a leading technology.8 SIR-Spheres Y-90 resin microspheres (Sirtex Medical Limited; Sydney, NSW, Australia) containing the β-emitter yttrium-90 (Y-90) are delivered into the arterial supply of the liver under fluoroscopic guidance. The delivery of the resin microspheres into branches of the hepatic artery, which supplies the majority of blood to liver tumours, results in selective targeting by high-dose radiotherapy because the healthy liver is supplied predominantly by the portal venous system and therefore relatively spared from radiation exposure.9\n\nBuilding on our phase 1/2 trial, in which we established the maximum tolerated dose of oxaliplatin-fluorouracil (FOLFOX) chemotherapy to combine as concomitant radiosensitising chemotherapy with SIRT,10 the FOXFIRE, SIRFLOX, and FOXFIRE-Global clinical trials were designed to study SIRT in combination with FOLFOX chemotherapy compared with FOLFOX alone as first-line therapy for metastatic colorectal cancer.11, 12 Eligibility criteria and trial designs were pre-planned to be similar so that the three trials could be prospectively combined for analysis of overall survival and secondary endpoints. We previously reported that the combination of SIRT with FOLFOX in SIRFLOX13 increased liver-specific progression-free survival compared with FOLFOX chemotherapy alone, but there was no effect on overall progression-free survival. In this combined study, we sought to address the question of whether improved local control of colorectal liver metastases impacts on overall survival.\n\nMethods\nStudy design and participants\nThe FOXFIRE, SIRFLOX, and FOXFIRE-Global randomised, phase 3 trials were done in 14 countries (Australia, Belgium, France, Germany, Israel, Italy, New Zealand, Portugal, South Korea, Singapore, Spain, Taiwan, the UK, and the USA): in 28 hospitals and specialist liver centres for FOXFIRE, 87 hospitals or centres for SIRFLOX, and 69 hospitals or centres for FOXFIRE-Global (appendix pp 28–34). Two complementary trials were originally planned (FOXFIRE and SIRFLOX), but the FOXFIRE study took longer than anticipated to set up and recruit, so a third study (FOXFIRE-Global) was added as an independent trial.\n\nPatients had to be eligible for systemic chemotherapy as first-line treatment for metastatic colorectal cancer.11, 12, 13, 14 Eligibility criteria were similar between the three trials, but not identical. Similarities and differences are highlighted in the combined study protocol paper.14 Inclusion criteria included histologically confirmed colorectal cancer with liver-only or liver-dominant metastases with or without the primary tumour in situ, WHO performance status of 0 or 1, limited extrahepatic disease, age of 18 years or older, and life expectancy 3 months or longer. The full list of inclusion criteria have previously been published.11, 12, 13, 14 Eligibility was confirmed by haematological, renal, and hepatic function tests. Exclusion criteria included ascites, cirrhosis, or portal hypertension (all established by clinical or radiological assessment); thrombosis of the main portal vein; and peripheral neuropathy grade 1 or worse. Full lists of exclusion criteria have previously been published.11, 12, 13, 14\n\nThe trials were done according to the principles of ISO14155 Good Clinical Practice and the Declaration of Helsinki. All participants provided written, informed consent. The protocols for FOXFIRE and SIRLOX trials and for this combined study have previously been published.11, 12, 14\n\nRandomisation and masking\nIn all three trials, patients were randomly assigned (1:1) to either FOLFOX chemotherapy alone or FOLFOX plus SIRT with minimisation, based on the strata metastasis site (liver-only vs liver plus extrahepatic metastases), extent of tumour involvement of the liver (≤25% vs >25% measured objectively on baseline CT scan), planned use of a biological agent, and investigational centre.\n\nIn FOXFIRE, patients were allocated using minimisation with a probability of 0·8 to the treatment that most reduced the imbalance of the above factors. If there were equal numbers of patients in each treatment group, then patients were allocated to each treatment with a probability of 0·5. The first 30 treatments were allocated using (simple) block randomisation (using variable block sizes of 2, 4, and 6 in a ratio of 1:2:1). In SIRFLOX and FOXFIRE-Global, an imbalance window of 5 was used; if the treatment imbalance between the two groups was less than 5, the treatment was randomly allocated. If the treatment imbalance reached 5, the next treatment allocation was forced to reduce the imbalance. In FOXFIRE, computer-based randomisation was done centrally at the Oncology Clinical Trials Office (OCTO; Oxford, UK). While the trial was in progress, access to the full randomisation lists was restricted to the Database Development Manager at OCTO and the trial statistician at the Centre for Statistics in Medicine (CSM; Oxford, UK). In SIRFLOX and FOXFIRE-Global, randomisation was done centrally at the National Health and Medical Research Council Clinical Trials Centre (Camperdown, NSW, Australia) via an interactive voice response system. Participants were enrolled by the investigators in all three trials. As none of the trials were masked, once patients were allocated to treatment, participants, all members of the trial team, and treating medical staff knew the treatment allocation.\n\nProcedures\nIn FOXFIRE, systemic FOLFOX chemotherapy consisted of OxMdG (oxaliplatin modified de Gramont chemotherapy; 85 mg/m2 oxaliplatin infusion over 2 h, L-leucovorin 175 mg or D,L-leucovorin 350 mg infusion over 2 h, and 400 mg/m2 bolus fluorouracil followed by a 2400 mg/m2 continuous fluorouracil infusion over 46 h). Systemic FOLFOX chemotherapy in SIRFLOX and FOXFIRE-Global consisted of modified FOLFOX6 (85 mg/m2 oxaliplatin infusion over 2 h, 200 mg leucovorin, and 400 mg/m2 bolus fluorouracil followed by a 2400 mg/m2 continuous fluorouracil infusion over 46 h). Oxaliplatin and fluorouracil were from hospital stock; D,L-leucovorin referred to the racemic mixture. In FOXFIRE, protocol chemotherapy was 12 cycles; in SIRFLOX and FOXFIRE-Global, protocol chemotherapy continued until disease progression or dose-limiting toxicity. The oxaliplatin dose was reduced from 85 mg/m2 to 60 mg/m2 for three cycles from the cycle coinciding with SIRT administration and for two cycles thereafter, based on phase 1/2 data.10 Dose modifications were permitted in line with standard care (appendix pp 3–8). Each chemotherapy cycle lasted 14 days. We used a hepatic arteriogram and a liver-to-lung breakthrough nuclear medicine scan to assess patient suitability to receive SIRT. We used the patient's body surface area, percentage of tumour involvement, and magnitude of liver-to-lung shunting to establish the activity (GBq) per dosing chart.12 Planned SIRT was done on cycle 1 day 3 or 4 or cycle 2 day 3 or 4.10 In FOXFIRE, patients could receive anti-VEGF (eg, bevacizumab) or anti-EGFR (eg, cetuximab) from cycle 1 in the FOLFOX alone group and from cycle 7 onwards in the FOLFOX plus SIRT group. In SIRFLOX and FOXFIRE-Global, patients could receive bevacizumab from cycle 1 in the FOLFOX alone group and from cycle 4 onwards in the FOLFOX plus SIRT group. The addition of anti-VEGF or anti-EGFR treatments to protocol therapy was at the discretion of the treating physician and doses prescribed were according to local policy at the treating centre.\n\nWe assessed patients by CT scan every 8–12 weeks until hepatic progression. Follow-up assessments included clinical assessment; CT of chest, abdomen, and pelvis; and health related quality-of-life (HRQoL) assessment.11, 12, 14 Scans were independently reviewed by Pharmtrace (Berlin, Germany) for overall and hepatic progression in FOXFIRE using Response Evaluation Criteria in Solid Tumors (RECIST; version 1.0) and in SIRFLOX with RECIST (version 1.0) with minor modifications.13 Independent reviews were not done in FOXFIRE-Global. We assessed all patients for suitability for liver resection at 6 months. After protocol therapy, patients could receive any subsequent treatment as best available care determined by the treating physician. All patients were followed up until death or for a minimum of 2 years.\n\nHealth-related quality of life was assessed with the EuroQol-5D three-level questionnaire (EQ-5D-3L), a generic HRQoL instrument15 measuring health in five dimensions (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression), which is summarised as a utility score.16 The EQ-5D-3L was administered during clinic visits at baseline, between the second and the third months after randomisation, at 6 months, at 12 months, and once per year until 60 months from the start of protocol treatment. Grading of adverse events used the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3).\n\nOutcomes\nThe primary outcome of this analysis was overall survival, defined as the time from randomisation to death from any cause, with patients who were still alive censored at their last known follow-up date. Secondary outcomes included progression-free survival, liver-specific progression-free survival, HRQoL, tumour response, liver resection rate, and adverse event profiles. The primary and secondary outcomes in each of the individual trials are in the appendix (p 13). We defined progression-free survival as the time from randomisation to radiological progression or death from any cause, whichever occurred first. Patients who did not progress or die during the trial were censored at their last known progression-free follow-up date. Liver-specific progression-free survival was defined as the time from randomisation to radiological hepatic progression. Progression not involving the liver and death before progression were regarded as competing events. We deemed hepatic progression to have occurred immediately before non-liver progression in patients who had identical hepatic and extrahepatic progression dates. Patients who withdrew from study treatment before documented progression were censored at commencement of non-study treatment for both the progression-free survival and liver-specific progression-free survival endpoints. Time of resection was not deemed a censoring point for progression-free survival or liver-specific progression-free survival. The proportion of patients achieving an objective response in each treatment group was defined as the number of patients achieving a complete or partial response at any point during the trial, up to their first occurrence of hepatic resection, over the number randomised in that group (early deaths by any cause and unknown responses were included in the demominator). The percentage resected in each group was defined as the number of patients who underwent a hepatic resection divided by the number randomly assigned to that group.\n\nStatistical analysis\nFor the primary combined overall survival analysis, a sample size of 810 was originally calculated, but subsequently updated to 1075 patients (710 deaths) using a protocol-specified hazard ratio (HR) of 0·8, with a control group median overall survival of 19·7 months and SIRT group median overall survival of 24·6 months, two-sided 5% significance, 80% power, and allowing for 5% non-compliance.14 The updated sample size allowed for a higher median overall survival, the addition of biological agents to protocol chemotherapy (planned use added as a stratification factor to the randomisation in May, 2011, for FOXFIRE and SIRFLOX, and incorporated in FOXFIRE-Global since set-up) and crossover in both directions. The study also had 80% power to detect a 6-month overall survival benefit in the subgroup of patients with metastatic disease restricted to the liver: 708 patients (463 deaths) were needed. The cutoff for analysis was chosen such that there was a minimum of 710 deaths overall and 463 deaths in the liver-only subgroup (assuming a 6-month increase in overall survival in the SIRT-treated, liver-metastasis-only patients) and a minimum follow-up of 2 years since the last patient was randomly assigned to treatment. We did two interim toxicity and safety analyses with the combined data from the FOXFIRE and SIRFLOX trials 8 months after at least 80 patients were randomly assigned (40 patients per trial) and 8 months after 300 were randomly assigned (minimum of 120 patients per trial); FOXFIRE-Global was not included in the interim analyses on the combined data.\n\nWe calculated median follow-up time using the reverse Kaplan-Meier method. We did all efficacy analyses on an intention-to-treat basis per the published statistical analysis plan.14 We estimated overall survival and progression-free survival for each trial using Kaplan-Meier survival curves, unadjusted log-rank tests, and Cox proportional hazards survival models. We checked the proportionality assumption using Schoenfeld residuals. HRs for overall survival and progression-free survival from the individual trials were combined using a two-stage, fixed-effect, inverse-variance weighted individual participant data meta-analysis approach.17 The I2 statistic indicates the proportion of variation in the treatment effect that is due to heterogeneity rather than chance. Sensitivity analyses included using only eligible patients, and using radiological scan data as reported by sites for all three trials. We assessed liver-specific progression-free survival using cumulative incidence curves, and Fine and Gray subdistribution hazard regression models18 stratified by trial. We checked model assumptions by including a time-varying coefficient for treatment. We also estimated cause-specific hazards.19 For overall survival, progression-free survival, and liver-specific progression-free survival, we investigated the potential treatment benefit in patients presenting with disease confined to the liver using survival models stratified by trial (prespecified subgroup analysis). The odds of patients having a resection or achieving a response (overall and liver-specific) were compared between treatment groups by pooling individual trial odds ratios (OR) using two-stage individual participant data meta-analysis. The EQ-5D-3L health states reported by patients were expressed as utility scores derived by weighting the responses using US EQ-5D valuations16 with a score of 1 corresponding to full health and 0 to death. A minimum clinically significant difference in EQ-5D scores of 0·08 has been suggested across all cancers.20 We used analysis of covariance to analyse differences in EQ-5D-3L utility scores between the two treatment groups, adjusted for EQ-5D-3L baseline values. We made post-hoc comparisons between treatment groups of treatment received after protocol therapy using the Mantel-Haenszel test, stratifying by trial.\n\nWe did safety analyses on patients who received at least one dose of chemotherapy in either group and on an as-treated basis. We included adverse events reported up to 28 days after the end of trial treatment or 7 months after randomisation, whichever was earlier (deemed the safety window). We combined individual trial ORs using two-stage individual participant data meta-analysis to assess the association of grade 3 or worse adverse events with treatment. An independent data and safety monitoring committee oversaw the study. Formal interim monitoring of the accumulating data was done at regular intervals (approximately every 6 months) by the independent data and safety monitoring committee for each trial separately.\n\nData were analysed with Stata (version 14.1) and R (version 3.3.2). All hypothesis tests were two-sided. We used a significance level of 5%. Partial dates were imputed, but no statistical imputation techniques were used.\n\nFOXFIRE is registered with the ISRCTN registry, number ISRCTN83867919. SIRFLOX and FOXFIRE-Global are registered with ClinicalTrials.gov, numbers NCT00724503 (SIRFLOX) and NCT01721954 (FOXFIRE-Global).\n\nRole of the funding source\nThe sponsor had no role in the FOXFIRE study design, data collection, or data analysis. Employees of Sirtex were involved in all stages of the SIRFLOX and FOXFIRE-Global studies, and in the process of combining the three trial datasets. The funders had no role in data analysis or interpretation for the combined study. The sponsor reviewed the manuscript and provided comments. JMo, PD, PSV, and SL had full access to all of the data in the study and the corresponding author had final responsibility for the decision to submit for publication.\n\nResults\nBetween Oct 11, 2006, and Dec 23, 2014, 1103 patients were enrolled and randomly assigned to either FOLFOX chemotherapy (n=549) or FOLFOX plus single treatment SIRT (n=554) (figure 1). Patients were recruited for the FOXFIRE study between Nov 13, 2009, and Oct 31, 2014. Patients in the SIRFLOX study were recruited between Oct 11, 2006, and April 25, 2013. Patients were recruited for the FOXFIRE-Global study between May 20, 2013, and Dec 23, 2014. End of follow-up was Oct 31, 2016, for FOXFIRE, June 1, 2016, for SIRFLOX, and Nov 30, 2016, for FOXFIRE-Global, ensuring 2 years of follow-up after the last patient was enrolled (appendix p 13). The data lock dates for analysis were Dec 23, 2016, for SIRFLOX and FOXFIRE-Global and Feb 6, 2017, for FOXFIRE. Minimisation factors and other baseline characteristics were evenly balanced between treatment groups and between trials (table 1, appendix pp 14–15). Median follow-up was 43·3 months (IQR 31·6–58·4).Figure 1 Trial profile\n\nOxMdG and mFOLFOX6 are equivalent oxaliplatin-fluorouracil-based FOLFOX chemotherapy regimens. FOLFOX=leucovorin, fluorouracil, and oxaliplatin. MDT=multidisciplinary team. mFOLFOX6=modified FOLFOX. OxMdG=oxaliplatin modified de Gramont chemotherapy. SIRT=selective internal radiotherapy. *Includes 122 ineligible patients; 49 protocol waivers and 73 retrospectively identified. †Discontinuation data were available for patients in FOXFIRE and for a subset of patients in SIRFLOX, but were not available for patients in FOXFIRE-Global.\n\nTable 1 Baseline characteristics of participants in the combined study\n\n\t\tFOLFOX alone (n=549)\tFOLFOX plus SIRT (n=554)\t\nAge at randomisation (years)\t62·7 (23·1–89·0)\t63·4 (28·4–89·6)\t\nTime since diagnosis of primary tumour to randomisation (months)\t1·4 (0·9–2·3)\t1·4 (0·9–2·3)\t\nTime since diagnosis of liver metastases to randomisation (months)\t1·2 (0·8–1·8)\t1·2 (0·7–1·8)\t\nSex\t\n\tMale\t361 (66%)\t363 (66%)\t\n\tFemale\t187 (34%)\t191 (34%)\t\n\tMissing\t1 (<1%)\t0\t\nWHO performance status\t\n\t0\t347 (63%)\t354 (64%)\t\n\t1\t200 (36%)\t198 (36%)\t\n\tMissing\t2 (<1%)\t2 (<1%)\t\nPrimary tumour site\t\n\tColon\t392 (71%)\t421 (76%)\t\n\tRectum\t137 (25%)\t116 (21%)\t\n\tNot categorisable*\t8 (1%)\t5 (1%)\t\n\tMissing\t12 (2%)\t12 (2%)\t\nPrimary tumour in situ\t\n\tYes\t302 (55%)\t278 (50%)\t\n\tNo\t246 (45%)\t275 (50%)\t\n\tMissing\t1 (<1%)\t1 (<1%)\t\nPrevious adjuvant chemotherapy\t\n\tYes\t28 (5%)\t31 (6%)\t\n\tNo\t520 (95%)\t523 (94%)\t\n\tMissing\t1 (<1%)\t0\t\nMetastases present at initial diagnosis\t\n\tYes (synchronous)\t475 (87%)\t483 (87%)\t\n\tNo (metachronous)\t71 (13%)\t68 (12%)\t\n\tMissing\t3 (1%)\t3 (1%)\t\nExtrahepatic metastases status†‡\t\n\tNo\t358 (65%)\t355 (64%)\t\n\tYes\t191 (35%)\t199 (36%)\t\nExtent of liver involvement†\t\n\t≤25%\t380 (69%)\t374 (68%)\t\n\t>25%\t168 (31%)\t179 (32%)\t\n\tMissing\t1 (<1%)\t1 (<1%)\t\nIntention to treat with biological agents†\t\n\tYes\t299 (54%)\t298 (54%)\t\n\tNo\t153 (28%)\t153 (28%)\t\n\tNot applicable§\t97 (18%)\t103 (19%)\t\nData are median (range) for age, median (IQR) for times since diagnosis, or n (%). SIRT=selective internal radiotherapy.\n\n* Site of primary tumour recorded as both colon and rectum; the only options in FOXFIRE were colon or rectum.\n\n† Minimisation factors; treating site was also a minimisation factor.\n\n‡ Extrahepatic disease permitted as per trial protocols were FOXFIRE: no more than five metastases in the lung and metastases should have been, in the opinion of either the local multidisciplinary team meeting or after central review of scans arranged via the trials office, amenable to future definitive local therapy, in addition to lung metastases, a single site of other extrahepatic disease was permitted (eg, multiple lymph nodes in one lymph node region) after approval by the trials office; for SIRFLOX and FOXFIRE-Global: limited extrahepatic metastases in the lung, lymph nodes, or both were permitted, no more than five nodules in the metastases in the lung were allowed, which were no more than 1 cm in diameter or up to 1·7 cm in diameter per single lesion; involvement of lymph nodes in one single anatomic area (pelvis, abdomen, or chest) was permitted provided their longest diameter measured less than 2 cm.\n\n§ Intention to treat with a biological agent was not a minimisation factor for these patients because it was introduced after these patients entered the study.\n\n\n\nIn the first 12 cycles of treatment, 3193 (59% of 5369) oxaliplatin cycles in the FOLFOX plus SIRT group and 3608 (68%) of 5344 cycles in the FOLFOX alone group were at full protocol dose. Dose reduction data were not readily available. The median number of cycles of FOLFOX treatment was 12 (IQR 7–13) in the FOLFOX plus SIRT group and 12 (7–15) in the FOLFOX alone group. Bevacizumab was given to 197 (36%) of 554 patients in the FOLFOX plus SIRT group and 256 (47%) of 549 patients in the FOLFOX alone group. In FOXFIRE, 13 (4%) of 364 patients received cetuximab (four in the FOLFOX plus SIRT group and nine in the FOLFOX group). After finishing protocol therapy, fewer patients in the FOLXFOX plus SIRT group were given irinotecan, fluoropyrimidine, anti-VEGF, or anti-EGFR systemic therapies upon progression than were patients in the FOLFOX alone group (appendix p 16). 66 (12%) of 549 patients randomly assigned to the FOLFOX alone group received SIRT in a later course of therapy, whereas 47 (8%) of 554 patients randomly assigned to SIRT did not receive SIRT.\n\nThere were 844 (77%) deaths in 1103 patients in the intention-to-treat population over the follow-up period: 296 (81%) deaths in 364 patients in FOXFIRE, 424 (80%) in 530 patients in SIRFLOX, and 124 (59%) in 209 patients in FOXFIRE-Global. There were 433 (78%) deaths in 554 patients in the FOLFOX plus SIRT group and 411 (75%) in 549 patients in the FOLFOX alone group. The median survival time in the FOLFOX plus SIRT group was 22·6 months (95% CI 21·0–24·5) compared with 23·3 months (21·8–24·7) in the FOLFOX alone group; the pooled HR was 1·04 (95% CI 0·90–1·19, p=0·61; figure 2A, C). Overall survival in each trial is shown in the appendix (p 9). No difference between treatment groups was found in the prespecified, liver-metastasis-only subgroup analysis of overall survival (261 [73%] of 358 patients in the FOLFOX group, median overall survival 24·6 months, 95% CI 22·1–26·4; 264 [74%] of 355 patients in the FOLFOX plus SIRT group, 24·5 months, 22·3–26·3; pooled HR 1·00, 95% CI 0·85–1·19, p=0·96). In a sensitivity analysis of overall survival excluding ineligible patients (62 [11%] of 549 patients in the FOLFOX group and 60 [11%] of 554 patients in the FOLFOX plus SIRT group were ineligible; reasons for ineligibility not reported), there were 360 deaths (74%) in 487 patients in the FOLFOX group and 382 deaths (77%) in 494 patients in the FOLFOX plus SIRT group. Median overall survival was 23·9 months (95% CI 21·8–25·0) in the FOLFOX group and 23·4 months (21·8–25·2) in the FOLFOX plus SIRT group; pooled HR was 1·01 (95% CI 0·88–1·17, p=0·86). Subgroup comparisons for overall survival of the prespecified subgroups metastatic site, liver involvement, age, sex, WHO performance status, and tumour in situ, and the post-hoc subgroups primary tumour site, bevacizumab administration, and timing of metastasis are shown in figure 3.Figure 2 Overall survival (A, C) and progression-free survival (B, D) in the intention-to-treat population\n\nHR=hazard ratio. SIRT=selective internal radiotherapy. Red line indicates the overall, pooled estimate. Size of shaded grey boxes indicates the relative weight of the study.\n\nFigure 3 Treatment effect on overall survival by subgroup\n\nHR=hazard ratio. SIRT=selective internal radiotherapy.\n\n\n\n941 (85%) of 1103 patients had an observed radiological progression or died before progression: 304 (84%) of 364 patients in FOXFIRE, 452 (85%) of 530 patients in SIRFLOX, and 185 (89%) of 209 patients in FOXFIRE-Global. 467 (85%) of 549 patients in the FOLFOX group and 474 (86%) of 554 patients in the FOLFOX plus SIRT had progression or died. Progression-free survival was not significantly different between treatment groups (pooled HR 0·90, 95% CI 0·79–1·02, p=0·11; figure 2B, D). The median progression-free survival in the FOLFOX plus SIRT group was 11·0 months (95% CI 10·2–11·8) compared with 10·3 months (9·7–10·9) in the FOLFOX alone group. Similar results were found in the prespecified subgroup analysis restricted to patients with liver-only metastatic colorectal cancer at baseline; 297 (83%) of 358 patients in the FOLFOX group had progressed or died in the liver-only subgroup analysis (median progression-free survival 11·1 months, 95% CI 10·0–12·1); 292 (82%) of 355 patients in the FOLFOX plus SIRT group had progressed or died (11·9 months, 11·0–13·8; HR 0·86, 95% CI 0·73–1·01, p=0·066). The results of a prespecified sensitivity analysis using radiological scan data as reported by sites from all three trials were consistent with the analysis of the centrally reviewed data (HR 0·91, 95% CI 0·80–1·03, p=0·15).\n\nIn 271 (49%) of 549 patients in the FOLFOX and 173 (31%) of 554 patients in the FOLFOX plus SIRT group, first progression events were radiologically observed in the liver (figure 4A). The cumulative incidence of first progression in the liver was lower in the FOLFOX plus SIRT group than the FOLFOX alone group (figure 4A; appendix p 17). The cumulative incidence of progression within the liver in the first 12 months of follow-up was 22% (95% CI 19–26) in the FOLFOX plus SIRT group and 39% (35–43) in the FOLFOX alone group. In 196 (36%) of 549 patients in the FOLFOX group and 301 (54%) of 554 patients in the FOLFOX plus SIRT group, first progression was extrahepatic or death occurred before recorded radiological progression (figure 4B, appendix p 17). The cumulative incidence of first progression occurring outside the liver or death before recorded radiological progression was higher in the FOLFOX plus SIRT group than in the FOLFOX alone group (figure 4B; appendix p 17). The cumulative incidence of progression outside the liver or death before recorded radiological progression in 12 months of follow-up was 33% (95% CI 29–37) in the FOLFOX plus SIRT group and 19% (16–23) in the FOLFOX alone group. Cause-specific HRs were in the same direction as, and of similar magnitudes to, the subdistribution HRs (appendix p 17).Figure 4 Cumulative incidence of radiological progression within the liver (A) and non-liver progression or death without radiological progression having been documented (B)\n\nHR=hazard ratio. SIRT=selective internal radiotherapy.\n\n\n\nAn objective (complete or partial) response over the study duration was achieved in 746 (68%) of 1103 patients; 400 (72%) of 554 in the FOLFOX plus SIRT group and 346 (63%) of 549 in the FOLFOX alone group (pooled OR 1·52, 95% CI 1·18–1·96, p=0·0012; appendix pp 10, 17). An objective response was observed in more patients in the FOLFOX plus SIRT group than in the FOLFOX alone group in each of the individual trials (appendix p 17). The odds of achieving an objective response in the liver were also higher in the FOLFOX plus SIRT group than in the FOLFOX alone group (pooled OR 1·78, 95% CI 1·37–2·31, p<0·0001; appendix p 18).\n\nOver the follow-up period, 182 (17%) of 1103 patients had at least one hepatic resection. Overall, 94 (17%) of 554 patients in the FOLFOX plus SIRT group and 88 (16%) of 549 patients in the FOLFOX alone group had a resection. The odds of undergoing a resection were not significantly different between treatment groups (pooled OR 1·07, 95% CI 0·78–1·48, p=0·67; appendix p 11).\n\nThe proportion of patients who had a grade 3 or worse adverse event at each treatment cycle by treatment group, overall and for haematological adverse events, non-haematological adverse events, and neutropenia are shown in the appendix (p 12). Of 1078 patients who received at least one dose of study treatment in the as-treated population, 755 (70%) had a grade 3 or worse adverse event (up to 28 days after the end of protocol chemotherapy or in the first 7 months after randomisation, whichever was earlier); 375 (74%) of 507 patients in the FOLFOX plus SIRT group and 380 (67%) of 571 patients in the FOLFOX alone group (table 2). The odds of a patient having a grade 3 or worse adverse event were higher in the FOLFOX plus SIRT group than in the FOLFOX alone group (pooled OR 1·42, 95% CI 1·09–1·85, p=0·0089, appendix p 13). Of 507 patients who received SIRT, 231 (46%) had a haematological grade 3 or worse adverse event, whereas 165 (29%) of the 571 patients who did not have SIRT had a haematological grade 3 or worse adverse event, the most frequent being neutropenia (186 [37%] in the FOLFOX plus SIRT group vs 138 [24%] in the FOLFOX alone group; table 2). Adverse events of grade 1 or 2 occurring in 10% of patients or more and all grade 3 or worse events are shown in the appendix (pp 18–26). In FOXFIRE, 15 (8%) of 182 patients in the FOLFOX group and 25 (14%) of 182 patients in the FOLFOX plus SIRT group discontinued treatment because of an adverse event or serious adverse event; data were not fully available for SIRFLOX and not available for FOXFIRE-Global. Serious adverse events of any grade occurred in 244 (43%) of 571 patients receiving FOLFOX alone and 274 (54%) of 507 patients receiving FOLFOX plus SIRT (appendix p 27). 10 patients in the FOLFOX plus SIRT group and 11 patients in the FOLFOX alone group died due to an adverse event during the main safety window (appendix p 26). 11 (1%) of 844 deaths were treatment-related (appendix p 27); eight in FOLFOX plus SIRT group and three in the FOLFOX alone group. Of the eight treatment-related deaths in the FOLFOX plus SIRT group, three deaths due to radiation-induced liver disease, two due to complications of surgery, one due to liver failure, one due to drug-induced pneumonitis, and one due to off-target delivery of microspheres. There were three treatment-related deaths in the FOLFOX alone group: one due to complications of surgery, one due to neutropenic sepsis, and one due to bowel perforation. With specific reference to risk of long-term toxicity to the liver from protocol treatment, during continued observation after the main safety window until the end of the follow-up period, there were two deaths due to hepatic events (hepatic failure or ascites) in the FOLFOX plus SIRT group.Table 2 Adverse events reported in each treatment group\n\n\t\tFOLFOX alone (n=571)\tFOLFOX plus SIRT (n=507)\t\n\t\tGrade 1–2\tGrade 3\tGrade 4\tGrade 5\tGrade 1–2\tGrade 3\tGrade 4\tGrade 5\t\nOverall\t189 (33%)\t266 (47%)\t103 (18%)\t11 (2%)\t131 (26%)\t239 (47%)\t126 (25%)\t10 (2%)\t\nHaematological\t102 (18%)\t108 (19%)\t56 (10%)\t1 (<1%)\t109 (21%)\t144 (28%)\t86 (17%)\t1 (<1%)\t\n\tNeutropenia\t50 (9%)\t89 (16%)\t48 (8%)\t1 (<1%)\t55 (11%)\t115 (23%)\t71 (14%)\t0\t\n\tFebrile neutropenia\t0\t11 (2%)\t5 (1%)\t0\t0\t25 (5%)\t7 (1%)\t1 (<1%)\t\n\tThrombocytopenia\t77 (13%)\t6 (1%)\t1 (<1%)\t0\t153 (30%)\t37 (7%)\t2 (<1%)\t0\t\n\tLeucopenia\t28 (5%)\t10 (2%)\t3 (1%)\t0\t41 (8%)\t20 (4%)\t10 (2%)\t0\t\nNon-haematological\t265 (46%)\t232 (41%)\t61 (11%)\t10 (2%)\t219 (43%)\t218 (43%)\t59 (12%)\t9 (2%)\t\n\tFatigue\t275 (48%)\t28 (5%)\t0\t0\t261 (51%)\t43 (8%)\t0\t0\t\n\tDiarrhoea\t256 (45%)\t35 (6%)\t2 (<1%)\t0\t189 (37%)\t33 (7%)\t1 (<1%)\t0\t\n\tPulmonary embolism\t1 (<1%)\t7 (1%)\t19 (3%)\t0\t2 (<1%)\t4 (1%)\t24 (5%)\t0\t\n\tNeuropathy peripheral\t307 (54%)\t32 (6%)\t1 (<1%)\t0\t273 (54%)\t18 (4%)\t0\t0\t\n\tAbdominal pain\t95 (17%)\t13 (2%)\t0\t0\t151 (30%)\t30 (6%)\t1 (<1%)\t0\t\nSIRT-associated\t13 (2%)\t9 (2%)\t1 (<1%)\t0\t52 (10%)\t24 (5%)\t3 (1%)\t3 (1%)\t\n\tAscites\t2 (<1%)\t4 (1%)\t0\t0\t23 (5%)\t6 (1%)\t0\t0\t\n\tBlood bilirubin increased\t3 (1%)\t2 (<1%)\t0\t0\t6 (1%)\t3 (1%)\t0\t0\t\n\tGastric ulcer\t0\t0\t0\t0\t8 (2%)\t3 (1%)\t1 (<1%)\t0\t\n\tHyperbilirubinaemia\t1 (<1%)\t1 (<1%)\t0\t0\t2 (<1%)\t3 (1%)\t0\t0\t\n\tGastrointestinal haemorrhage\t0\t0\t1 (<1%)\t0\t2 (<1%)\t1 (<1%)\t2 (<1%)\t0\t\n\tRadiation hepatitis\t0\t0\t0\t0\t2 (<1%)\t2 (<1%)\t0\t2 (<1%)\t\n\tDuodenal ulcer\t1 (<1%)\t0\t0\t0\t4 (1%)\t3 (1%)\t0\t0\t\n\tPancreatitis\t0\t0\t0\t0\t1 (<1%)\t2 (<1%)\t0\t0\t\n\tHepatic failure\t0\t0\t0\t0\t0\t1 (<1%)\t0\t1 (<1%)\t\n\tJaundice\t0\t2 (<1%)\t0\t0\t0\t0\t0\t0\t\n\tJaundice cholestatic\t0\t0\t0\t0\t0\t2 (<1%)\t0\t0\t\n\tHepatic encephalopathy\t0\t0\t0\t0\t0\t2 (<1%)\t0\t0\t\n\tDuodenitis\t0\t0\t0\t0\t4 (1%)\t1 (<1%)\t0\t0\t\n\tPortal hypertension\t1 (<1%)\t0\t0\t0\t0\t1 (<1%)\t0\t0\t\n\tDuodenal ulcer haemorrhage\t0\t0\t1 (<1%)\t0\t0\t0\t0\t0\t\n\tCholecystitis acute\t0\t0\t0\t0\t0\t1 (<1%)\t0\t0\t\n\tPerihepatic abscess\t0\t0\t0\t0\t0\t1 (<1%)\t0\t0\t\n\tGastritis\t4 (1%)\t0\t0\t0\t18 (4%)\t0\t0\t0\t\n\tOesophagitis\t3 (1%)\t0\t0\t0\t2 (<1%)\t0\t0\t0\t\n\tSplenomegaly\t1 (<1%)\t0\t0\t0\t2 (<1%)\t0\t0\t0\t\n\tOesophageal ulcer\t0\t0\t0\t0\t1 (<1%)\t0\t0\t0\t\nData are n (%). Table shows grade 3 or worse haematological events occurring in at least 5% of patients, grade 3 or worse non-haematological events occurring in at least 5% of patients, and all SIRT-associated adverse events. Worst grade reported per patient per category, sorted by prevalence of grade 3 or worse. SIRT=selective internal radiotherapy.\n\n\n\nEQ-5D-3L results were reported for the first 24 months of the trial using US EQ-5D valuations; questionnaire mean utility value at each timepoint is shown in the appendix (p 27). Average unadjusted EQ-5D-3L utility scores were not significantly different between treatment groups at any time point except at 2–3 months (appendix p 27); however, this difference would not be deemed clinically meaningful.\n\nDiscussion\nThe FOXFIRE, SIRFLOX, and FOXFIRE-Global randomised studies designed to definitively assess the combination of SIRT with FOLFOX versus FOLFOX alone for colorectal liver metastases in the first-line setting have not shown a benefit of adding SIRT on overall survival. The combined analysis of these three randomised clinical trials shows that a global, multidisciplinary trial involving a complex liver-directed therapy can be done with adequate power to answer an important clinical question.\n\nThe efficacy of SIRT in third-line or subsequent therapy for metastatic colorectal cancer (ie, salvage therapy of chemotherapy-refractory disease) has previously been evaluated.21 A randomised trial22 of salvage in patients with metastatic colorectal cancer with liver-confined disease showed a significant benefit of chemotherapy plus SIRT versus chemotherapy alone in time to progression. These data suggest that SIRT has clinical benefit in patients with colorectal liver metastases with liver-dominant disease after chemotherapy.\n\nMetastatic colorectal cancer in which the liver is the only site of disease occurs frequently in a subset of patients; some of these patients can be resected with long-term cures.23 In our study, the significant improvement in liver disease control assessed by competing risk analyses did not translate to a benefit in overall survival. This finding contrasts with that from the EORTC CLOCC study,6 which showed that a significant effect of radiofrequency ablation with or without surgery on progression-free survival translated into a highly significant overall survival benefit in patients who did not have primary tumour in situ or extrahepatic metastases at trial entry. The absence of benefit of the addition of SIRT to FOLFOX on progression-free survival and overall survival in our combined study could be partly explained by the high proportion of patients who developed first progression at an extrahepatic site, independently of whether the metastases were liver-only at baseline or whether there were extrahepatic metastases or primary tumour in situ at baseline. Despite the better liver control in the FOLFOX plus SIRT group compared with the FOLFOX alone group, this observation of extrahepatic progression might also explain the absence of a significant difference between the groups in the frequency of surgical resection of the liver metastases being done during or after protocol therapy. To avoid possible ascertainment bias in interpreting responses and difficulties differentiating disease progression from radiation reaction of the hepatic parenchyma in patients undergoing the interventional radiotherapy liver procedure, scans were centrally reviewed by independent readers. The absence of an overall survival benefit suggests that early use of SIRT in combination with first-line oxaliplatin-based chemotherapy cannot be recommended in unselected patients with metastatic colorectal cancer.\n\nIn our study, the SIRT-treated patients had a similar quality of life to the patients who had chemotherapy only. Toxicity was higher in the SIRT group, particularly neutropenia and SIRT-related expected toxicities. In the as-treated population in the FOLFOX plus SIRT group (n=507 patients), hepatic failure resulted in death of one patient during the main safety window and death of a further two patients during extended follow-up. The increased toxicity in the SIRT-treated patients did not translate into inferior overall survival. This study provides the most comprehensive account of the risk of adverse events that might occur secondary to SIRT when used in combination with FOLFOX chemotherapy.\n\nOne possible limitation of our study is that significant changes to the management of metastatic colorectal cancer occurred during the 8-year recruitment period with the introduction of bevacizumab and EGFR inhibitors as first-line standards of care, and increased use of liver interventions such as surgery and ablation. However, there is no reason to believe that treatment differences occurred between treatment groups. Another limitation is that some patients were found not to have met the entry criteria after randomisation. Sensitivity analyses excluding all ineligible patients indicated that the findings were robust. The non-identical design of the individual trials might also be considered a limitation, but is accounted for by the use of appropriate statistical methods.\n\nLittle progress has been reported in improving overall survival in molecularly unselected populations since the CRYSTAL, PRIME, and TRIBE studies.24, 25, 26, 27 In our study, crossover was anticipated and 12% of patients randomised to FOLFOX alone received SIRT with a later line of therapy. Furthermore, 8% of patients assigned to SIRT did not receive SIRT, a proportion consistent with our previously published data in patients with metastatic colorectal cancer.13 The difference in exposure to post-trial treatments between the two treatment groups might have affected the primary endpoint. It is possible that the improved liver disease control observed in the FOLFOX plus SIRT group might have influenced physicians to bias towards less intensive subsequent treatment, particularly as so-called treatment-holiday strategies were evolving during the recruitment and follow-up periods of these trials. Alternatively, it could be postulated that the reduced use of irinotecan after protocol therapy might have been related to increased or prolonged toxicities in the patients in the FOLFOX plus SIRT group, including the risk of myelosuppression. Our analysis of these toxicities for both groups over time showed an apparent increase of grade 3 or worse adverse events in the FOLFOX plus SIRT group, particularly haematological events, with the curves gradually converging after 6 months of protocol therapy.\n\nIn the past decade, the focus of clinical trials has been on improving outcomes for selected biological subtypes in metastatic colorectal cancer with predefined molecular criteria (eg, mutant RAS or BRAF). Several studies from the past 2 years have reported that patients with right-sided primary tumours have worse survival outcomes and it is possible that these patients benefit less from standard therapies.28, 29, 30 Molecular subtypes in our study are not currently available, but in the dataset available, 179 (25%) of 718 patients had right sided-tumours. Based on preliminary data currently available, patients with colorectal liver metastases from right-sided primary tumours could be a clinical subgroup that benefits from SIRT. Further analyses are underway to investigate this exploratory finding, with specific scrutiny of RAS mutation, BRAF mutation, and tumour location in study populations who have received SIRT in clinical trials. Further studies designed to define the potential benefit of SIRT to treat colorectal liver metastases from right-sided primaries are warranted.\n\nIn conclusion, despite better liver-specific disease control and improved radiological response, the FOXFIRE prospective trials did not show a benefit of the combination of SIRT with FOLFOX for progression-free survival or overall survival. The routine early integration of SIRT in combination with oxaliplatin-based, first-line chemotherapy cannot be recommended as therapy for metastatic colorectal cancer. Further studies are needed to study the role of SIRT in carefully selected patient populations and as a consolidation therapy after chemotherapy.\n\nSupplementary Material\nSupplementary appendix\n \n\nAcknowledgments\nThe FOXFIRE study design was reviewed and endorsed by the Clinical Trials Awards and Advisory Committee of Cancer Research UK, was approved by the National Research Ethics Service Committee South Central-Berkshire (research ethics committee reference 09/H0505/1), was developed by the National Cancer Research Institute Colorectal Clinical Study Group and the National Institute for Health Research Clinical Research Network and equivalents in devolved nations, and was sponsored by the University of Oxford. Sirtex provided an unrestricted educational grant for the FOXFIRE study. The SIRFLOX and FOXFIRE-Global studies were sponsored by Sirtex. We thank Georgie Perry for secretarial support.\n\nContributors\nHSW, PG, SL, VG, AG, GvH, and RAS designed the study and wrote the protocol. HSW, PG, NKS, JT, VH, JR, MP, MF, AW, JMi, CW, RA, AF, JMo, PSV, PD, SL, VG, AG, GVH, and RAS led the trial, recruited patients, and collected data. JMo, PSV, PD, SL, and VG analysed the data. HSW, PG, NKS, JT, VH, JR, MP, MF, AW, JMi, CW, RA, AF, JMo, PSV, PD, SL, VG, AG, GvH, and RAS interpreted the data, wrote the manuscript, and approved the paper.\n\nDeclaration of interests\nHSW reports grants, personal fees, non-financial support, and other uncompensated work from Sirtex Medical and Merck Serono; personal fees and non-financial support from Celgene; grants and non-financial support from Pfizer; personal fees and non-financial support from Roche and Lily outside the submitted work. PG reports personal fees from SIRTEX; grants and personal fees from Roche, Amgen, Pfizer, Merck, Bayer, and Servier, during the conduct of the study. NKS reports speakers' bureau and travel fees from Sirtex Medical, outside the submitted work. JT reports honoraria from Roche, Amgen, Merck, Lilly, Sanofi, Baxalta, Celgene, and Servier, outside the submitted work. VH reports grants, personal fees, and non-financial support from Sirtex Medical, Merck, and Roche, during the conduct of the study; involvement in a scientific project on radiological imaging from Sirtex Medical; grants, personal fees, and non-financial support from Merck and Roche; grants and non-financial support from Amgen; grants and personal fees from Sanofi; grants from Pfizer and Boehringer Ingelheim; and personal fees from Bristol-Myers Squibb, MSD, and Novartis, outside the submitted work. JR reports personal fees from Sirtex Medical, during the conduct of the study; and grants from Sirtex Medical, outside the submitted work. MP reports personal fees from Sirtex Medical, during the conduct of the study and outside the submitted work. MF reports grants from Sirtex Medical, during the conduct of the study. JMi reports personal fees from Sirtex Medical, during the conduct of the study; grants from Sirtex Medical; and personal fees from Sirtex Medical, Astellas, Jannessen, Lily, and Roche, outside the submitted work. CW reports receiving travel grants from Sirtext, outside the submitted work. RA reports personal fees and non-financial support from Merck Serono, Amgen, Bristol-Myers Squibb, and Sanofi, outside the submitted work. AF reports grants from Cancer Research UK; and grants and non-financial support from Sirtex Medical, during the conduct of the study. JMo reports grants from Cancer Research UK and Sirtex Medical, during the conduct of the study; and non-financial support from Sirtex Medical, outside the submitted work. PD reports grants from Cancer Research UK and Sirtex Medical, during the conduct of the study; and non-financial support from Sirtex Medical, outside the submitted work. PSV reports grants from Sirtex Medical and Cancer Research UK, during the conduct of the study. SL reports grants from Sirtex Medical and Cancer Research UK, during the conduct of the study. VG reports personal fees from Sirtex Medical, during the conduct of the study; and grants and personal fees from Sirtex Medical, outside the submitted work. AG reports grants from Cancer Research UK during the conduct of the study. GvH reports personal fees and non-financial support from Sirtex Medical, during the conduct of the study; and personal fees and non-financial support from Sirtex Medical, outside the submitted work. RAS is a consultant for and reports grants and personal fees from Sirtex Medical and BTG, during the conduct of the study; and reports personal fees from Affidea, AstraZeneca, Boston Scientific, Cancer Research Technology, Eisai, Terumo, and Varian, outside the submitted work. AW declares no competing interests.\n==== Refs\nReferences\n1 National Cancer Institute SEER cancer stat facts: colon and rectum cancer, 2003–2009 https://seer.cancer.gov/statfacts/html/colorect.html 2013 (accessed May 30, 2017). \n2 Cancer Research UK Bowel cancer incidence statistics http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer/incidence (accessed May 30, 2017). \n3 Helling TS Martin M Cause of death from liver metastases in colorectal cancer Ann Surg Oncol 21 2014 501 506 24081807 \n4 Strickler JH Hurwitz HI Palliative treatment of metastatic colorectal cancer: what is the optimal approach? Curr Oncol Rep 16 2014 363 24293074 \n5 Kanas GP Taylor A Primrose JN Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors Clin Epidemiol 4 2012 283 301 23152705 \n6 Ruers T Van Coevorden F Punt CJ Local treatment of unresectable colorectal liver metastases: results of a randomized phase II trial J Natl Cancer Inst 109 2017 djx015 \n7 Jones RP Poston GJ Resection of liver metastases in colorectal cancer in the era of expanding systemic therapy Annu Rev Med 68 2017 183 196 27686016 \n8 Nicolay NH Berry DP Sharma RA Liver metastases from colorectal cancer: radioembolization with systemic therapy Nat Rev Clin Oncol 6 2009 687 697 19884901 \n9 Wang LM Jani AR Hill EJ Sharma RA Anatomical basis and histopathological changes resulting from selective internal radiotherapy for liver metastases J Clin Pathol 66 2013 205 211 23162108 \n10 Sharma RA Van Hazel GA Morgan B Radioembolisation of liver metastases from colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil and leucovorin chemotherapy J Clin Oncol 25 2007 1099 1106 17369573 \n11 Dutton SJ Kenealy N Love SB FOXFIRE protocol: an open-label, randomised, phase III trial of 5-fluorouracil, oxaliplatin and folinic acid (OxMdG) with or without interventional Selective Internal Radiation Therapy (SIRT) as first-line treatment for patients with unresectable liver-only or liver-dominant metastatic colorectal cancer BMC Cancer 14 2014 497 25011439 \n12 Gibbs P Gebski V Van Buskirk M Selective Internal Radiation Therapy (SIRT) with yttrium-90 resin microspheres plus standard systemic chemotherapy regimen of FOLFOX versus FOLFOX alone as first-line treatment of non-resectable liver metastases from colorectal cancer: the SIRFLOX study BMC Cancer 14 2014 897 25487708 \n13 van Hazel GA Heinemann V Sharma NK SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer J Clin Oncol 34 2016 1723 1731 26903575 \n14 Virdee PS Moschandreas J Gebski V Protocol for combined analysis of FOXFIRE, SIRFLOX, and FOXFIRE-global randomized phase III trials of chemotherapy +/- selective internal radiation therapy as first-line treatment for patients with metastatic colorectal cancer JMIR Res Protoc 6 2017 e43 28351831 \n15 Rabin R de Charro F EQ-5D: a measure of health status from the EuroQol Group Ann Med 33 2001 337 343 11491192 \n16 Shaw JW Johnson JA Coons SJ US valuation of the EQ-5D health states: development and testing of the D1 valuation model Med Care 43 2005 203 220 15725977 \n17 Deeks JJ Altman DG Bradburn MJ Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis Egger M Davey-Smith G Altman DG Systematic reviews in health care: meta-analysis in context 2nd edn. 2001 BMJ Publication Group London \n18 Fine J Gray RJ A proportional hazards model for the subdistribution of a competing risk J Am Stat Assoc 94 1999 496 508 \n19 Prentice RL Kalbfleisch JD Peterson AV Jr Flournoy N Farewell VT Breslow NE The analysis of failure times in the presence of competing risks Biometrics 34 1978 541 554 373811 \n20 Pickard AS Neary MP Cella D Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer Health Qual Life Outcomes 5 2007 70 18154669 \n21 Seidensticker R Denecke T Kraus P Matched-pair comparison of radioembolization plus best supportive care versus best supportive care alone for chemotherapy refractory liver-dominant colorectal metastases Cardiovasc Intervent Radiol 35 2012 1066 1073 21800231 \n22 Hendlisz A Van den Eynde M Peeters M Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy J Clin Oncol 28 2010 3687 3694 20567019 \n23 Nordlinger B Sorbye H Glimelius B Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial Lancet 371 2008 1007 1016 18358928 \n24 Van Cutsem E Kohne CH Hitre E Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer N Engl J Med 360 2009 1408 1417 19339720 \n25 Loupakis F Cremolini C Masi G Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer N Engl J Med 371 2014 1609 1618 25337750 \n26 Douillard JY Siena S Cassidy J Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer Ann Oncol 25 2014 1346 1355 24718886 \n27 Van Cutsem E Lenz HJ Kohne CH Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer J Clin Oncol 33 2015 692 700 25605843 \n28 Petrelli F Tomasello G Borgonovo K Prognostic survival associated with left-sided vs right-sided colon cancer: a systematic review and meta-analysis JAMA Oncol 3 2017 211 219 \n29 Tejpar S Stintzing S Ciardiello F Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials JAMA Oncol 3 2017 194 201 \n30 Venook AP Niedzwiecki D Innocenti F Impact of primary (1°) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance) Proc Am Soc Clin Oncol 34 suppl 15 2016 3504 (abstr).\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1470-2045",
"issue": "18(9)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D015179:Colorectal Neoplasms; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D018714:Radiotherapy, Adjuvant; D016896:Treatment Outcome",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "1159-1171",
"pmc": null,
"pmid": "28781171",
"pubdate": "2017-09",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "20567019;24081807;18358928;23152705;21800231;11491192;17369573;15725977;26903575;19339720;27686016;28351831;373811;18154669;25011439;25605843;24293074;25487708;27722750;24718886;23162108;19884901;27787550;28376151;25337750",
"title": "First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials.",
"title_normalized": "first line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer foxfire sirflox and foxfire global a combined analysis of three multicentre randomised phase 3 trials"
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{
"abstract": "Men with metastatic prostate cancer who have a poor response to initial androgen-deprivation therapy (ADT), as reflected by a prostate-specific antigen (PSA) level higher than 4.0 ng/mL after 7 months of ADT, have a poor prognosis, based on historical controls.\nTo determine the efficacy of abiraterone acetate with prednisone in these high-risk patients with a suboptimal response to hormonal induction.\nA phase 2 single-arm study was conducted through the National Clinical Trials Network-Southwest Oncology Group. Eligible patients had metastatic prostate cancer and a PSA level higher than 4.0 ng/mL between 6 and 12 months after starting ADT. The PSA level could be rising or falling at the time of enrollment, but had to be higher than 4.0 ng/mL. No previous chemotherapy or secondary hormonal therapies were allowed, except in patients receiving a standard, first-generation antiandrogen agent with a falling PSA level at the time of enrollment; this therapy was continued in this cohort. Abiraterone acetate, 1000 mg, once daily with prednisone, 5 mg, twice daily was administered to all participants. A total of 41 men were enrolled between the trial's activation on August 9, 2011, and closure on August 1, 2013. Data analysis was conducted from March 21 to November 29, 2016.\nAbiraterone acetate, 1000 mg, once daily by mouth with prednisone, 5 mg, by mouth twice daily.\nThe primary end point was a PSA level of 0.2 ng/mL or lower within 12 months of starting abiraterone acetate plus prednisone. A partial response (PR) was a secondary end point, defined as a PSA level reduction to lower than 4.0 ng/mL but higher than 0.2 ng/mL.\nOf the 41 men enrolled, 1 did not receive any protocol treatment and was excluded from analysis. The median (range) age of the 40 participants was 66 (39-85) years. Five (13%) patients achieved a PSA level of 0.2 ng/mL or lower (95% CI, 4%-27%). Thirteen (33%) additional patients achieved a partial response, with a reduction in the PSA level to lower than 4.0 ng/mL but higher than 0.2 ng/mL. Sixteen (40%) patients had no PSA response and 6 (15%) were not assessable and assumed to be nonresponders. The median progression-free survival was 17.5 months (95% CI, 8.6-25.0 months) and the median overall survival was 25.8 months (95% CI, 15.7-25.8 months). There was 1 incident each of grade 4 adverse events of alanine aminotransferase level elevation and rectal hemorrhage. Eleven patients reported grade 3 adverse events.\nThis study did not reach its prescribed level of 6 PSA responses of 0.2 ng/mL or lower, although 5 responses were observed. The overall survival and progression-free survival rates observed in this trial are encouraging compared with historical controls. The therapy was generally well tolerated, without any clear signal of any unexpected adverse effects.",
"affiliations": "Division of Medical Oncology, University of Colorado, School of Medicine, University of Colorado Cancer Center, Aurora.;Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.;Departments of Medicine and Urology, University of Michigan Comprehensive Cancer Center, Ann Arbor.;Department of Medicine, Huntsman Cancer Institute at the University of Utah, Salt Lake City.;Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.;Department of Medicine, Yale Cancer Center, New Haven, Connecticut.;Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.;Department of Urology, The University of Texas Health Science Center at San Antonio.",
"authors": "Flaig|Thomas W|TW|;Plets|Melissa|M|;Hussain|Maha H A|MHA|;Agarwal|Neeraj|N|;Mitsiades|Nicholas|N|;Deshpande|Hari A|HA|;Vaishampayan|Ulka N|UN|;Thompson|Ian M|IM|",
"chemical_list": "D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; D000069501:Abiraterone Acetate; D011241:Prednisone",
"country": "United States",
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"doi": "10.1001/jamaoncol.2017.0231",
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"issn_linking": "2374-2437",
"issue": "3(11)",
"journal": "JAMA oncology",
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"medline_ta": "JAMA Oncol",
"mesh_terms": "D000069501:Abiraterone Acetate; D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D006801:Humans; D007610:Kallikreins; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "101652861",
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"pages": "e170231",
"pmc": null,
"pmid": "28358937",
"pubdate": "2017-11-09",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": "18309951;25311217;16096414;25184630;26719232;26244877;7165009;19097774;16921051;21612468;23228172",
"title": "Abiraterone Acetate for Metastatic Prostate Cancer in Patients With Suboptimal Biochemical Response to Hormone Induction.",
"title_normalized": "abiraterone acetate for metastatic prostate cancer in patients with suboptimal biochemical response to hormone induction"
} | [
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"literaturereference": "FLAIG TW, PLETS M, HUSSAIN MH, AGARWAL N, MITSIADES N, DESHPANDE HA, ET AL. ABIRATERONE ACETATE FOR METASTATIC PROSTATE CANCER IN PATIENTS WITH SUBOPTIMAL BIOCHEMICAL RESPONSE TO HORMONE INDUCTION. JAMA ONCOL 30-MAR-2017. FLAIG TW, PLETS M, HUSSAIN MH, AGARWAL N, MITSIADES N, DESHPANDE HA, ET AL. ABIRATERONE ACETATE FOR METASTATIC PROSTATE CANCER IN PATIENTS WITH SUBOPTIMAL BIOCHEMICAL RESPONSE TO HORMONE INDUCTION. JAMA ONCOLOGY 30-MAR-2017;3 (11) :E1-6.",
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{
"abstract": "BACKGROUND\nAlthough acute graft-vs-host disease (aGvHD) is a rare complication of liver transplantation, it is poorly understood and has an extremely high mortality rate. No standardized diagnostic criteria or treatment regimens currently exist.\n\n\nMETHODS\nThe present study investigated the etiology, diagnosis, and treatment of aGvHD following liver transplantation. Presentation, diagnosis, disease course, histology, and treatment of an aGvHD case are reported, and associated literature is reviewed. A 64-year-old female required LTx due to primary biliary cirrhosis. The donor was a 12-year-old male. Three weeks following liver transplantation, the recipient developed pyrexia, diarrhea, rashes, and antibiotic-unresponsive pancytopenia. Clinical symptoms together with laboratory investigations suggested a diagnosis of aGvHD, which was confirmed via peripheral blood fluorescent in situ hybridization. Donor XY chromosome fluorescent in situ hybridization indicating early chimerism achieved 93% sensitivity in the detection of GvHD. Existing immunosuppressants were discontinued, and high-dose intravenous methylprednisolone was initiated along with antibiotics. While diarrhea resolved, the patient's general condition continued to deteriorate until demise due to multi-system organ failure at 37 d post-liver transplantation. This case illustrates the life-threatening nature of aGvHD.\n\n\nCONCLUSIONS\nHerein, we have summarized a post-LTx aGvHD case and reviewed associated literature in order to increase awareness and provide potentially risk-mitigating recommendations.",
"affiliations": "School of Clinical Medicine, Guizhou Medical University, Guiyang 550004, Guizhou Province, China.;School of Clinical Medicine, Guizhou Medical University, Guiyang 550004, Guizhou Province, China.;School of Clinical Medicine, Guizhou Medical University, Guiyang 550004, Guizhou Province, China.;School of Clinical Medicine, Guizhou Medical University, Guiyang 550004, Guizhou Province, China.;School of Clinical Medicine, Guizhou Medical University, Guiyang 550004, Guizhou Province, China.;Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.;Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.;Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.;Department of Pediatric Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China. zhaoyaree@sina.com.",
"authors": "Xiao|Jing-Jing|JJ|;Ma|Jin-Yu|JY|;Liao|Jun|J|;Wu|Di|D|;Lv|Chao|C|;Li|Hai-Yang|HY|;Zuo|Shi|S|;Zhu|Hai-Tao|HT|;Gu|Hua-Jian|HJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4240/wjgs.v13.i9.1102",
"fulltext": "\n==== Front\nWorld J Gastrointest Surg\nWJGS\nWorld Journal of Gastrointestinal Surgery\n1948-9366\nBaishideng Publishing Group Inc\n\njWJGS.v13.i9.pg1102\n10.4240/wjgs.v13.i9.1102\nCase Report\nFluorescence in situ hybridization-based confirmation of acute graft-vs-host disease diagnosis following liver transplantation: A case report\nXiao JJ et al. FISH-based confirmation of aGvHD\nXiao Jing-Jing School of Clinical Medicine, Guizhou Medical University, Guiyang 550004, Guizhou Province, China\n\nMa Jin-Yu School of Clinical Medicine, Guizhou Medical University, Guiyang 550004, Guizhou Province, China\n\nLiao Jun School of Clinical Medicine, Guizhou Medical University, Guiyang 550004, Guizhou Province, China\n\nWu Di School of Clinical Medicine, Guizhou Medical University, Guiyang 550004, Guizhou Province, China\n\nLv Chao School of Clinical Medicine, Guizhou Medical University, Guiyang 550004, Guizhou Province, China\n\nLi Hai-Yang Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China\n\nZuo Shi Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China\n\nZhu Hai-Tao Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China\n\nGu Hua-Jian Department of Pediatric Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China. zhaoyaree@sina.com\n\nAuthor contributions: Xiao JJ and Ma JY were the patients’ surgeons and designed the research; Liao J, Wu D, and Lv C reviewed the literature and contributed to the drafting of the manuscript; Li HY and Zhu HT collected the surgical data and recordings; Zuo S processed the operation screenshots; Gu HJ was responsible for language editing and revision of the manuscript and supervised the revision of the manuscript; All authors took part in the final approval for the version to be submitted.\n\nCorresponding author: Hua-Jian Gu, MD, Chief Physician, Department of Pediatric Surgery, The Affiliated Hospital of Guizhou Medical University, No. 16 Beijing Road, Guiyang 550004, Guizhou Province, China. zhaoyaree@sina.com\n\n27 9 2021\n27 9 2021\n13 9 11021109\n20 3 2021\n5 6 2021\n20 7 2021\n©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/\nBACKGROUND\n\nAlthough acute graft-vs-host disease (aGvHD) is a rare complication of liver transplantation, it is poorly understood and has an extremely high mortality rate. No standardized diagnostic criteria or treatment regimens currently exist.\n\nCASE SUMMARY\n\nThe present study investigated the etiology, diagnosis, and treatment of aGvHD following liver transplantation. Presentation, diagnosis, disease course, histology, and treatment of an aGvHD case are reported, and associated literature is reviewed. A 64-year-old female required LTx due to primary biliary cirrhosis. The donor was a 12-year-old male. Three weeks following liver transplantation, the recipient developed pyrexia, diarrhea, rashes, and antibiotic-unresponsive pancytopenia. Clinical symptoms together with laboratory investigations suggested a diagnosis of aGvHD, which was confirmed via peripheral blood fluorescent in situ hybridization. Donor XY chromosome fluorescent in situ hybridization indicating early chimerism achieved 93% sensitivity in the detection of GvHD. Existing immunosuppressants were discontinued, and high-dose intravenous methylprednisolone was initiated along with antibiotics. While diarrhea resolved, the patient’s general condition continued to deteriorate until demise due to multi-system organ failure at 37 d post-liver transplantation. This case illustrates the life-threatening nature of aGvHD.\n\nCONCLUSION\n\nHerein, we have summarized a post-LTx aGvHD case and reviewed associated literature in order to increase awareness and provide potentially risk-mitigating recommendations.\n\nLiver transplantation\nGraft-vs-host disease\nFluorescence in situ hybridization cytogenetics\nChimerism\nDiagnosis\nCase report\n==== Body\npmcCore Tip: At present, the risk factors, pathogenesis, optimal treatment, and prognosis associated with acute graft-vs-host disease following liver transplantation are unclear. Currently, the most reliable diagnostic method is specific immunostaining for donor-specific antigens. If the donor is male and the recipient is female, fluorescent in situ hybridization-based detection of the Y chromosome is a diagnostic option. In the present case, acute graft-vs-host disease was confirmed via fluorescent in situ hybridization, demonstrating the presence of male donor DNA.\n\nINTRODUCTION\n\nAcute graft-vs-host disease (aGvHD) is one of the most dangerous complications following liver transplantation (LTx)[1]. It involves overactivation of donor helper T lymphocytes by recipient antigen-presenting cells, leading to a local inflammatory reaction against recipient tissue. Although the rate of aGvHD incidence after LTx is low (1%-2%), the mortality rate is extremely high (85%-90%)[2]. Skin rash and pyrexia are the most frequently noted early signs, followed by leukopenia. Although aGvHD was first proposed as a clinical entity in 1988, its mechanisms and optimal treatment strategies remain controversial[3]. Modification of the post-transplant treatment plan, including incorporation of more effective immunosuppressants, has a limited effect on the course of aGvHD[4,5]. In most cases, death results from overwhelming sepsis or gastrointestinal hemorrhage as a consequence of bone marrow involvement[6]. Due to the low incidence (but high mortality) of aGvHD following LTx, analysis of the present case with respect to existing literature is worthwhile in order to raise awareness regarding the condition, which may assist in the early diagnosis of suspected cases. It will also help improve diagnostic criteria and establish standardized evidence-based treatment regimens. Moreover, we wish to draw attention to the diagnostic utility of sex chromosome fluorescent in situ hybridization (FISH) when the donor and recipient are of different chromosomal sexes.\n\nCASE PRESENTATION\n\nChief complaints\n\nThe patient was a 64-year-old female with primary biliary cirrhosis, esophageal-fundal variceal hemorrhages, and decompensated hepatocirrhosis in September 2017.\n\nHistory of present illness\n\nA 64-year-old female received a liver from an ABO-matched (A-positive) 12-year-old male cadaveric donor. The donor and recipient details are shown in Table 1. The donor was a 12-year-old male. Three weeks following liver transplantation, the recipient developed pyrexia, diarrhea, rashes, and antibiotic-unresponsive pancytopenia.\n\nTable 1 Recipient and donor demographic, clinical, and typing data\n\nRecipient\tDonor\t\t\nAge\t64\t12\t\nSex\tFemale\tMale\t\nPrimary complaint\tPBC\tHypoxic-ischemic encephalopathy\t\nSpecial history\tLow-dose glucocorticoids\tNA\t\nBlood group\tA\tA\t\nHLA\tNA\tNA\t\nPBC: Primary biliary cirrhosis; HLA: Human leukocyte antigen; NA: Not applicable.\n\nHistory of past illness\n\nA 64-year-old female with primary biliary cirrhosis, esophageal-fundal variceal hemorrhages, and decompensated hepatocirrhosis.\n\nPersonal and family history\n\nThe patient grew up in her locality, denies any contact with contaminated water or radiation exposure, and denies smoking and alcohol consumption.\n\nPhysical examination\n\nOn physical examination, we found her poor nutritional status, the abdomen was moderately distended with mild tenderness, and there was moderately yellow staining of the skin and mucous membranes. The rest of the physical examination revealed no abnormal findings.\n\nLaboratory examinations\n\nThe following timeline of events refers to post-operative days. On day 22, the patient developed pyrexia of unknown origin, fluctuating between 38.2 °C and 39.3 °C. On day 26, sex chromosome FISH was performed on peripheral venous blood samples. No gastrointestinal tract lesions were apparent, and no evidence of aGvHD was noted on gastrointestinal endoscopic biopsy (histologically normal esophagus, stomach, and ileum). On day 31, the presumptive diagnosis of GvHD was made based on the following clinical ground observations: Generalized maculopapular eruption (largely involving the back, neck, and face), pyrexia, pancytopenia, low blood pressure, and watery diarrhea (Figure 1 and Table 2). FISH revealed chimerism (presence of the fluorescently stained donor XY chromosome) consistent with aGvHD (Figure 2).\n\nFigure 1 Clinical ground observations of graft-vs-host disease. A: Anterior cervical rash on post-operative day 24; B: Oral ulcers on post-operative day 25; C: Dorsal rash on post-operative day 25; D and E: Palmar rash on post-operative day 22; F: Scalp rash on post-operative day 27; G: Passage of three or more loose or liquid stools per day.\n\nFigure 2 Twelve erythrocytes analyzed, 11 showed an XY signal pattern, while one showed an XX signal pattern (91.7% showed one X and one Y signal, and 8.3% showed two X signals). Y is the red fluorescent signal; X is the green fluorescent signal.\n\nTable 2 Clinical manifestation and treatment timeline\n\n\tManifestations\tDrugs\t\nPO day\tTemperature (°C)\tSkin rash\tDiarrhea\tMyelosuppression\tTacrolimus (mg/d)\tMMF (g/d)\tMP\tIgG (g/d)\tAntibiotics\t\n22\t38.3\tPalm\t2\tNA\t3\t0.25\t500\t10\tYes\t\n24\t38.6\tNeck\t3\tNA\t2\t0\t500\t10\tYes\t\n26\t38.5\tFace\t6\tYes\t2\t0\t120\tNA\tYes\t\n28\t38.2\tTrunk\t7\tYes\t2\t0\t40\tNA\tYes\t\n30\t39\t> 35%\t6\tYes\t2\t0\t20\tNA\tYes\t\n32\t38.6\t> 50%\t5\tYes\t1.5\t0\t20\t10\tYes\t\n34\t38.7\t> 55%\t4\tYes\t1.5\t0\t20\t10\tNA\t\n36\tDemise\t\nPO: Post-operative; NA: Not applicable; MMF: Two oral formulations of mycophenolate mofetil; MP: Methylprednisolone; IgG: Immunoglobulin G. Antibiotics: Melophenan (1 g every 8 h) + carpophennet (50 mg per day) + vancomycin (0.5 g every 6 h).\n\nTwo days following the development of thrombocytopenia, a bone marrow biopsy revealed marked hypocellularity. No skin rash was yet apparent. The findings of detailed post-operative laboratory investigation are summarized in Table 3. Because no sample of indwelling peripheral blood from the donor prior to LTx was available, donor lymphocytes could not be identified in recipient peripheral blood using short tandem repeat sequencing or human leukocyte antigen (HLA) typing.\n\nTable 3 Post-operative laboratory investigation timeline\n\nPost-operative laboratory investigation timeline\t\nValue/PO day\t0\t4\t8\t12\t16\t20\t24\t26\t30\t34\t36\t\nAST (U/L)\t643\t47.6\t56\t48\t64\t75\t63\t56\t44\t52\t74\t\nALT (U/L)\t772\t88.1\t96\t86\t107.3\t62\t59\t64\t66\t71\t83\t\nTotal bilirubin (mg/dL)\t231.4\t123.5\t119.5\t76.9\t65.5\t23.7\t25.8\t24.2\t35.1\t45.6\t48.7\t\nDirect bilirubin (mg/dL)\t146.1\t63.2\t59.3\t43.2\t38.1\t13.3\t15.6\t16.5\t24.7\t28.5\t31.2\t\nLeukocyte count × 109/L\t17.5\t8.7\t12.4\t17.3\t7.2\t6.7\t1.3\t0.39\t0.24\t0.12\t0.08\t\nNeutrophil %\t93\t79\t86\t92\t81\t80\t63\t17.9\t0\t0\t0\t\nHemoglobin (g/L)\t89\t92\t176\t113\t92\t85\t75\t63\t58\t53\t47\t\nHematocrit %\t42\t46\t50\t32\t26.5\t23.3\t22\t17.6\t16.5\t15.6\t14.8\t\nPlatelets × 109/L\t21\t26\t44\t58\t77\t73\t71\t56\t47\t46\t41\t\nProthrombin time (s)\t17.9\t19.9\t16.5\t22.4\t13.5\t13.1\t12.7\t13.1\t12.8\t13.2\t13.6\t\nINR\t1.82\t1.7\t1.34\t1.98\t1.05\t1.01\t0.97\t0.99\t0.98\t1.02\t1.07\t\nSodium (mmol/L)\t147\t145\t142\t139\t136\t134\t143\t141\t138\t139\t143\t\nPotassium (mmol/L)\t3.8\t4.5\t3.1\t3.4\t3.6\t3.8\t3.9\t4.2\t4.1\t3.9\t3.7\t\nUrea (mmol/L)\t32.52\t29.8\t16.42\t4.55\t4.77\t4.46\t4.13\t3.8\t4.17\t3.74\t4.02\t\nCreatinine (μmol/L)\t89.73\t85.64\t64.59\t43.78\t58.44\t53.76\t49.19\t46.52\t27.26\t24.54\t30.45\t\nPCT (ng/mL)\t5.73\t3.86\t11.5\t5.1\t1.86\t2.65\t2.58\t2.45\t2.18\t3.65\t4.53\t\nPO: Post-operative; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; INR: International normalized ratio; PCT: Procalcitonin.\n\nImaging examinations\n\nAbdominal computed tomography and color ultrasound findings suggested laminar portal vein, inferior vena cava, hepatic artery, and hepatic venous flow (Figure 3).\n\nFigure 3 The portal vein, inferior vena cava, hepatic artery, and hepatic venous blood flow were smooth.\n\nFINAL DIAGNOSIS\n\naGvHD, primary biliary cirrhosis, esophageal-fundal variceal hemorrhages, and decompensated hepatocirrhosis.\n\nTREATMENT\n\nInitial treatment involved tapering the dosage of immunosuppressants to allow the recipient immune system to reject donor lymphocytes. Due to the inefficacy of this approach, the following treatment was administered subsequently: High-dose (500 mg/d) intravenous methylprednisolone, antibiotics, and immunoglobulin G (Table 2).\n\nOUTCOME AND FOLLOW-UP\n\nSevere inflammation induced multi-system organ failure, which led to the patient’s demise on post-operative day 37.\n\nDISCUSSION\n\nAt present, the risk factors, pathogenesis, optimal treatment, and prognosis associated with aGvHD following LTx are unclear. Current (incomplete) understanding of aGvHD pathogenesis may be summarized as follows. The conditioning regimen induces initial recipient tissue damage, followed by auto- and alloantigen denudation in the recipient concomitant with antigen-presenting cell activation and massive inflammatory cytokine release (a “cytokine storm”). If a sufficient number of donor lymphocytes, especially T lymphocytes, of the correct specificity are present, direct recognition of and activation by antigen-presenting cell (either locally or within secondary lymphoid tissues) results in T lymphocyte interleukin (IL)-2 and IL-2R expression. Activated T-cells then stimulate donor monocytes to produce significant levels of myeloid cytokines (e.g., IL-1 and tumor necrosis factor) and also trigger a cascade of cytotoxic signal transduction pathways, such as the perforin/granzyme B or Fas/FasL pathways (although direct cytokine-mediated injury is also possible). Finally, inflammatory infiltration in the digestive tract, skin, and bone marrow leads to severe clinical presentations[7]. In the present case, abnormally high numbers of CD8+ T lymphocytes were present during the acute phase of GvHD, while the CD4+ T lymphocyte:CD8+ T lymphocyte ratio was less than 0.1. This indicates that perhaps cytotoxic T lymphocytes (with a minor contribution by helper T lymphocytes) are the cells primarily involved in GvHD pathogenesis. In summary, the necessary conditions for the occurrence of aGvHD[8-10] include the presence of donor immunoreactive cells within graft tissue, presence of recipient tissue antigens not present in donor organ tissue, and inability of the recipient immune system to eliminate effectively donor leukocytes.\n\nTriulzi et al[9] have described the diagnostic criteria for aGvHD following LTx in the following three requirements: (1) Characteristic clinical symptoms affecting related organ systems (e.g., skin, gastrointestinal tract, and bone marrow), including rash, diarrhea, and pancytopenia, among others; (2) Abnormal skin or digestive tract histology; and (3) HLA or DNA evidence of donor immunoreactive lymphocytes in involved organs or peripheral blood of the recipient. In addition to the above criteria, T lymphocyte counts and cytokine quantitation provide clear diagnostic support. Currently, the most reliable diagnostic method is specific immunostaining for donor-specific antigens. If the donor is male and the recipient is female, FISH-based detection of the Y chromosome is a diagnostic option[9,11,12]. At present, no false negatives have been reported for this method. In the present case, aGvHD was confirmed via FISH, demonstrating the presence of male donor DNA.\n\nDue to inter-individual differences in post-operative GvHD pathogenesis and presentation, no unified treatment plan exists. Each hospital follows a unique treatment plan associated with unique advantages and disadvantages. A commonality across most centers is reduction of the tacrolimus dose, cessation of anti-metabolic immunosuppressants, decreasing the steroid dose, and administering antilymphocyte globulin[13-15]. Successful treatment via increasing immunosuppressant dosages has also been reported, with recommendations for cessation of all immunosuppressants in favor of isolated anti-human thymocyte globulin treatment[16]. Certain patients also exhibit drug resistance or even resistance to the effects of some hormones[17]. Treatment with anti-tumor necrosis factor-α or anti-IL-2 receptor monoclonal antibodies may prove beneficial[18,19]. Currently, corticosteroids are the best-recognized first-line treatment agents for GvHD. Glucocorticoids exert efficient anti-inflammatory effects and can induce donor lymphocyte apoptosis. High-dose corticosteroid pulse therapy is administered during the acute phase of GvHD. It can inhibit inflammatory cell activation, thereby blocking the inflammatory cytokine cascade to improve systemic signs and symptoms. In cases of observation of GvHD symptoms (gastrointestinal disturbance, immunodeficiency despite overzealous inflammation, and deficient coagulation), hydration, electrolyte and acid-base rebalancing, nutritional support, restoration of gastrointestinal mucosal integrity, correction of microfloral imbalance, and transfusion of plasma and platelets can help mitigate poor outcomes, including severe infection[13,20].\n\nIn order to lessen mortality resulting from aGvHD, early detection and optimal standardized treatment are paramount. Additionally, an improved understanding of pathogenesis may assist in the prevention and treatment of this disorder. Based on our experience and the literature review, we make the following recommendations: Baseline (presurgical) donor and recipient blood samples should be obtained and cryopreserved. High-risk patients should routinely undergo HLA typing as a preliminary risk evaluation step. Ideally, the age difference between matched donors and recipients should not exceed 20 years. Pre-existing use of oral immunosuppressants should be minimized or discontinued prior to transplantation wherever possible. During perfusion of the donor abdominal aorta and portal vein, the effluent should run clear and the liver texture should soften. Finally, minimizing blood product infusion may lessen the rate of complications[15].\n\nCONCLUSION\n\nIn the present case, aGvHD was confirmed via FISH, demonstrating the presence of male donor DNA. If the donor is male and the recipient is female, FISH-based detection of the Y chromosome is a diagnostic option.\n\nInformed consent statement: Informed written consent was obtained from the patients for publication of this report and any accompanying images.\n\nConflict-of-interest statement: The authors declare that they have no conflict of interest.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: March 20, 2021\n\nFirst decision: June 5, 2021\n\nArticle in press: July 20, 2021\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry/Territory of origin: China\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B\n\nGrade C (Good): 0\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Ferreira GSA S-Editor: Wu YXJ L-Editor: Filipodia P-Editor: Wu RR\n==== Refs\n1 Perri R Assi M Talwalkar J Heimbach J Hogan W Moore SB Rosen CB Graft vs. host disease after liver transplantation: a new approach is needed Liver Transpl 2007 13 1092 1099 17663410\n2 Taylor AL Gibbs P Bradley JA Acute graft vs host disease following liver transplantation: the enemy within Am J Transplant 2004 4 466 474 15023138\n3 Burdick JF Vogelsang GB Smith WJ Farmer ER Bias WB Kaufmann SH Horn J Colombani PM Pitt HA Perler BA Severe graft-versus-host disease in a liver-transplant recipient N Engl J Med 1988 318 689 691 3278235\n4 Lee SJ Onstad L Chow EJ Shaw BE Jim HSL Syrjala KL Baker KS Buckley S Flowers ME Patient-reported outcomes and health status associated with chronic graft-versus-host disease Haematologica 2018 103 1535 1541 29858386\n5 Qian L Dima D Berce C Liu Y Rus I Raduly LZ Petrushev B Berindan-Neagoe I Irimie A Tanase A Jurj A Shen J Tomuleasa C Protein dysregulation in graft vs host disease Oncotarget 2018 9 1483 1491 29416707\n6 Taylor AL Gibbs P Sudhindran S Key T Goodman RS Morgan CH Watson CJ Delriviere L Alexander GJ Jamieson NV Bradley JA Taylor CJ Monitoring systemic donor lymphocyte macrochimerism to aid the diagnosis of graft-versus-host disease after liver transplantation Transplantation 2004 77 441 446 14966423\n7 Schrager JJ Vnencak-Jones CL Graber SE Neff AT Chari RS Wright KJ Jr Pinson CW Stewart JH Gorden DL Use of short tandem repeats for DNA fingerprinting to rapidly diagnose graft-versus-host disease in solid organ transplant patients Transplantation 2006 81 21 25 16421472\n8 Jacobs MT Olson M Ferreira BP Jin R Hachem R Byers D Witt C Ghobadi A DiPersio JF Pusic I The use of ruxolitinib for acute graft-versus-host disease developing after solid organ transplantation Am J Transplant 2020 20 589 592 31446673\n9 Triulzi D Duquesnoy R Nichols L Clark K Jukic D Zeevi A Meisner D Fatal transfusion-associated graft-versus-host disease in an immunocompetent recipient of a volunteer unit of red cells Transfusion 2006 46 885 888 16734803\n10 Kanehira K Riegert-Johnson DL Chen D Gibson LE Grinnell SD Velgaleti GV FISH diagnosis of acute graft-versus-host disease following living-related liver transplant J Mol Diagn 2009 11 355 358 19460938\n11 Gonultas F Akbulut S Barut B Kutluturk K Yilmaz S Graft-versus-host disease after living donor liver transplantation: an unpredictable troublesome complication for liver transplant centers Eur J Gastroenterol Hepatol 2020 32 95 100 31524772\n12 Di Ianni M Del Papa B Baldoni S Di Tommaso A Fabi B Rosati E Natale A Santarone S Olioso P Papalinetti G Giancola R Accorsi P Di Bartolomeo P Sportoletti P Falzetti F NOTCH and Graft-Versus-Host Disease Front Immunol 2018 9 1825 30147692\n13 Triulzi DJ Nalesnik MA Microchimerism, GVHD, and tolerance in solid organ transplantation Transfusion 2001 41 419 426 11274601\n14 Perkins JL Neglia JP Ramsay NK Davies SM Successful bone marrow transplantation for severe aplastic anemia following orthotopic liver transplantation: long-term follow-up and outcome Bone Marrow Transplant 2001 28 523 526 11593328\n15 Ramachandran V Kolli SS Strowd LC Review of Graft-Versus-Host Disease Dermatol Clin 2019 37 569 582 31466596\n16 Hill L Alousi A Kebriaei P Mehta R Rezvani K Shpall E New and emerging therapies for acute and chronic graft versus host disease Ther Adv Hematol 2018 9 21 46 29317998\n17 Schroeder T Haas R Kobbe G Treatment of graft-versus-host disease with monoclonal antibodies and related fusion proteins Expert Rev Hematol 2010 3 633 651 21083479\n18 Aladağ E Kelkitli E Göker H Acute Graft-Versus-Host Disease: A Brief Review Turk J Haematol 2020; 37: 1-4\n19 Murray J Stringer J Hutt D Graft-Versus-Host Disease (GvHD). 2017 Nov 22. In: Kenyon M, Babic A, editors. The European Blood and Marrow Transplantation Textbook for Nurses: Under the Auspices of EBMT [Internet]. Cham (CH): Springer; 2018 Chapter 11\n20 Whalen JG Jukic DM English JC 3rd Rash and pancytopenia as initial manifestations of acute graft-versus-host disease after liver transplantation J Am Acad Dermatol 2005 52 908 912 15858489\n\n",
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"title": "Fluorescence in situ hybridization-based confirmation of acute graft-vs-host disease diagnosis following liver transplantation: A case report.",
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"abstract": "As soon as uveal melanoma has metastasized to the liver, response rates to systemic chemotherapy are low. It can be improved by development of special locoregional procedures. A 24-year-old woman suffered from inoperable hepatic metastases which grew to life-endangering size despite both systemic chemotherapy with gemcitabine/treosulfan and conventional intrahepatic chemoembolization with fotemustine and starch particles. We subsequently performed two angiographic C-arm CT-guided, superselective chemoembolizations of the hepatic arteries feeding the tumor, using cisplatin, starch microspheres and ethiodized oil. Following this treatment, no vital tumor tissue was detectable by MRI. This remission lasted for more than 6 months and the patient's quality of life was good. A subsequent local relapse could not be treated with chemoembolization because of thrombosis of the portal vein due to tumor compression. And the patient died 20 months after first detection of metastases. However, the selective angiographic C-arm CT-guided chemoembolization resulted in prolongation of life with good quality despite the advanced stage of the disease.",
"affiliations": "Clinic for Dermatology, University Hospital of Münster, Münster, Germany.",
"authors": "Sunderkötter|Cord|C|;Eickelmann|Mareike|M|;Köhler|Michael|M|;Schmittel|Alexander|A|;Wacker|Frank K|FK|",
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"mesh_terms": "D000328:Adult; D016461:Chemoembolization, Therapeutic; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008545:Melanoma; D015641:Radiography, Interventional; D012074:Remission Induction; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014604:Uveal Neoplasms",
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"title": "Remission of extensive intrahepatic metastasis by C-arm computed tomography guided chemoembolization in uveal melanoma.",
"title_normalized": "remission of extensive intrahepatic metastasis by c arm computed tomography guided chemoembolization in uveal melanoma"
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"literaturereference": "SUNDERKOTTER C, EICKELMANN M, KOHLER M, SCHMITTEL A, WACKER FK. REMISSION OF EXTENSIVE INTRAHEPATIC METASTASIS BY C-ARM COMPUTED TOMOGRAPHY GUIDED CHEMOEMBOLIZATION IN UVEAL MELANOMA. J-DTSCH-DERMATOL-GES 2010?8(7):525-527.",
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"abstract": "Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a subtype of T-acute lymphoblastic leukemia (T-ALL) arising from a primitive precursor. We present a unique case of an infant with ETP-ALL with a missense NRAS mutation in codon 61 (c.182A>G, p.Q61R). The patient also had a minor population of non-ETP T-ALL blasts and clinical features typically associated with juvenile myelomonocytic leukemia (JMML), namely, absolute monocytosis, splenomegaly, and elevated hemoglobin F. The treatment was initiated with chemotherapy, followed by cord blood transplantation. The patient achieved remission, but unfortunately died from transplant-related complications. This case highlights an NRAS mutation in ETP-ALL with JMML-like phenotype.",
"affiliations": "Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, Georgia.;Department of Laboratory Medicine, University of Washington, Seattle, Washington.;Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, Georgia.;Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, Georgia.;Department of Laboratory Medicine, University of Washington, Seattle, Washington.;Department of Pediatrics, Seattle Children's Hospital, Seattle, Washington.;Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, Georgia.;Department of Laboratory Medicine, University of Washington, Seattle, Washington.;Department of Pathology, Children's Healthcare of Atlanta and Emory University, Atlanta, Georgia.",
"authors": "Raikar|Sunil S|SS|;Scarborough|John D|JD|;Sabnis|Himalee|H|;Bergsagel|John|J|;Wu|David|D|;Cooper|Todd M|TM|;Keller|Frank G|FG|;Wood|Brent L|BL|;Bunting|Silvia T|ST|",
"chemical_list": "D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26050",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "63(9)",
"journal": "Pediatric blood & cancer",
"keywords": "ETP-ALL; JMML; NRAS",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D036101:Cord Blood Stem Cell Transplantation; D020558:GTP Phosphohydrolases; D006801:Humans; D007223:Infant; D054429:Leukemia, Myelomonocytic, Juvenile; D008297:Male; D008565:Membrane Proteins; D020125:Mutation, Missense; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "1667-70",
"pmc": null,
"pmid": "27145535",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Early T-Cell Precursor Acute Lymphoblastic Leukemia in an Infant With an NRAS Q61R Mutation and Clinical Features of Juvenile Myelomonocytic Leukemia.",
"title_normalized": "early t cell precursor acute lymphoblastic leukemia in an infant with an nras q61r mutation and clinical features of juvenile myelomonocytic leukemia"
} | [
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"medicinalproduct": "MYCOPHENOLATE MOFETIL."
}
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"reaction": [
{
"reactionmeddrapt": "Graft versus host disease in gastrointestinal tract",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Adenovirus infection",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Multiple organ dysfunction syndrome",
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"reactionoutcome": "5"
}
],
"summary": null
},
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"literaturereference": "BUNTING ST, RAIKAR SS, SCARBOROUGH JD, SABNIS H, BERGSAGEL J, WU D ET AL.. EARLY T-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA IN AN INFANT WITH AN NRAS Q61R MUTATION AND CLINICAL FEATURES OF JUVENILE MYELOMONOCYTIC LEUKEMIA. PEDIATRIC BLOOD AND CANCER. 2016;1-4",
"literaturereference_normalized": "early t cell precursor acute lymphoblastic leukemia in an infant with an nras q61r mutation and clinical features of juvenile myelomonocytic leukemia",
"qualification": "3",
"reportercountry": "US"
},
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},
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},
"serious": 1,
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"seriousnessother": 1,
"transmissiondate": "20160815"
}
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{
"abstract": "Every year, thousands of suspicious deaths are accounted for by an overdose of opioids. Occasionally all traditional matrices are unavailable due to decomposition. Skeletal tissue may pose a valid alternative. However, reference data on post-mortem concentrations in bone tissue and bone marrow is sparse. Therefore, a liquid chromatography tandem mass spectrometry method was developed and fully validated for the analysis of 4 opioids and 2 metabolites (tramadol, O-desmethyltramadol, morphine, fentanyl, norfentanyl, codeine) in bone tissue and bone marrow. Sample preparation was performed using solid phase extraction (bone marrow), methanolic extraction (bone) and a protein precipitation (whole blood). All validation parameters were successfully fulfilled. This method was applied to analyze 22 forensic cases involving opioids. All 6 opioids were proven to be detectable and quantifiable in all specimens sampled. When tramadol blood concentrations were correlated with bone concentrations, a linear trend could be detected. The same was seen between tramadol blood and bone marrow concentration. A similar linear trend was seen when correlating codeine blood concentration with bone and bone marrow concentration. Although some variability was detected, the same linear trend was seen for morphine. For fentanyl and norfentanyl, the sample size was too small to draw conclusions, regarding correlation. As far as the authors know this is the first-time fentanyl and norfentanyl are quantified in skeletal tissue. In conclusion, due to the absence of reference data for drugs in skeletal tissue, these findings are a step forward towards a more thorough understanding of drug concentration found in post-mortem skeletal tissue.",
"affiliations": "KU Leuven Toxicology and Pharmacology, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, PO box 922, 3000 Leuven, Belgium.;KU Leuven Toxicology and Pharmacology, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, PO box 922, 3000 Leuven, Belgium.;KU Leuven, Imaging and Pathology Department, Division Forensic Biomedical Sciences, Campus Sint-Rafaël, Kapucijnenvoer 33, 3000 Leuven, Belgium.;KU Leuven, Imaging and Pathology Department, Division Forensic Biomedical Sciences, Campus Sint-Rafaël, Kapucijnenvoer 33, 3000 Leuven, Belgium.;KU Leuven, Imaging and Pathology Department, Division Forensic Biomedical Sciences, Campus Sint-Rafaël, Kapucijnenvoer 33, 3000 Leuven, Belgium.;KU Leuven Toxicology and Pharmacology, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, PO box 922, 3000 Leuven, Belgium.",
"authors": "Vandenbosch|Michiel|M|0000-0002-0427-416X;Pajk|Stane|S|;Van Den Bogaert|Wouter|W|;Wuestenbergs|Joke|J|;Van de Voorde|Wim|W|;Cuypers|Eva|E|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkab095",
"fulltext": "\n==== Front\nJ Anal Toxicol\nJ Anal Toxicol\njat\nJournal of Analytical Toxicology\n0146-4760\n1945-2403\nOxford University Press US\n\n34480794\n10.1093/jat/bkab095\nbkab095\nArticle\nAcademicSubjects/MED00305\nAcademicSubjects/SCI01040\nAcademicSubjects/SCI00030\nPostmortem Analysis of Opioids and Metabolites in Skeletal Tissue\nhttps://orcid.org/0000-0002-0427-416X\nVandenbosch Michiel KU Leuven, Toxicology and Pharmacology, Department of pharmaceutical sciences, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, Leuven 3000, Belgium\nMaastricht University, M4I Institute, Division of Imaging Mass Spectrometry, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands\n\nPajk Stane KU Leuven, Toxicology and Pharmacology, Department of pharmaceutical sciences, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, Leuven 3000, Belgium\nUniversity of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia\n\nVan Den Bogaert Wouter KU Leuven, Imaging and Pathology Department, Division Forensic Biomedical Sciences, Campus Sint-Rafaël, Kapucijnenvoer 33, 3000 Leuven, Belgium\n\nWuestenbergs Joke KU Leuven, Imaging and Pathology Department, Division Forensic Biomedical Sciences, Campus Sint-Rafaël, Kapucijnenvoer 33, 3000 Leuven, Belgium\n\nVan de Voorde Wim KU Leuven, Imaging and Pathology Department, Division Forensic Biomedical Sciences, Campus Sint-Rafaël, Kapucijnenvoer 33, 3000 Leuven, Belgium\n\nCuypers Eva KU Leuven, Toxicology and Pharmacology, Department of pharmaceutical sciences, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, Leuven 3000, Belgium\nMaastricht University, M4I Institute, Division of Imaging Mass Spectrometry, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands\n\n*Author to whom correspondence should be addressed. Email: e.cuypers@maastrichtuniversity.nl\n9 2022\n05 9 2021\n05 9 2021\n46 7 783790\n18 2 2021\n20 8 2021\n09 9 2021\n02 9 2021\n15 9 2021\n© The Author(s) 2021. Published by Oxford University Press.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nEvery year, thousands of suspicious deaths are accounted for by an overdose of opioids. Occasionally all traditional matrices are unavailable due to decomposition. Skeletal tissue may pose a valid alternative. However, reference data on postmortem concentrations in bone tissue and bone marrow (BM) is sparse. Therefore, a liquid chromatography--tandem mass spectrometry method was developed and fully validated for the analysis of four opioids and two metabolites (tramadol, O-desmethyltramadol, morphine, fentanyl, norfentanyl, codeine) in bone tissue and BM. Sample preparation was performed using solid phase extraction (BM), methanolic extraction (bone) and a protein precipitation (whole blood). All validation parameters were successfully fulfilled. This method was applied to analyze 22 forensic cases involving opioids. All six opioids were proven to be detectable and quantifiable in all specimens sampled. When tramadol blood concentrations were correlated with bone concentrations, a linear trend could be detected. The same was seen between tramadol blood and BM concentration. A similar linear trend was seen when correlating codeine blood concentration with bone and BM concentration. Although some variability was detected, the same linear trend was seen for morphine. For fentanyl and norfentanyl, the sample size was too small to draw conclusions, regarding correlation. As far as the authors know this is the first-time fentanyl and norfentanyl are quantified in skeletal tissue. In conclusion, due to the absence of reference data for drugs in skeletal tissue, these findings are a step forward toward a more thorough understanding of drug concentration found in postmortem skeletal tissue.\n\nKU Leuven 10.13039/501100004040\n==== Body\npmcIntroduction\n\nOpioids are the most (ab)used drugs in the world today (1). They exhibit selective binding to receptors at several sites in the central nervous system. This makes them extremely useful in the medical world where they are used as anesthetics and painkillers (2). Sadly, most of the opioids are also widely abused. The analgesic effect can produce euphoria in some instances. This feeling of euphoria makes the opioid drugs attractive for recreational usage (1). Due to the inhibiting effects of these drugs on the central nervous system, risks are involved when using these drugs. These risks include a chance of hypotension, hypothermia, pulmonary effects, gastrointestinal effects, seizures and even eventually coma (2). As a result, in Europe 85% of the deaths due to a drug overdose can be accounted for by one or more opioids (3).\n\nIn forensic toxicology, usually body fluids are used for analysis (4). For blood as well as for urine, a lot of reference material is available to determine correlation between drug concentration and effect. However, in some cases when extended time has elapsed before a body is discovered, blood and urine are not available anymore (5). Since skeletal tissue withstands degradation, it may pose a valid alternative when other specimens are degraded. Starting from the seventies, multiple case reports can be found describing the detection of drugs in skeletal tissue (6, 7). Most of them use bone marrow (BM), since marrow is highly vascularized and well protected by bone. Many studies show BM to act as an excellent drugs depot (8, 9). A discrepancy exists between studies regarding correlation between drug blood concentration and BM concentration. Several studies using animal models show a good correlation between blood concentration and BM concentration (10, 11). Nevertheless, almost an equal amounts of studies show poor correlation (8, 12).\n\nWhen looking at publications regarding bone tissue, a similar trend is seen. Starting from the seventies, a paucity of studies has been published regarding detection of drugs in human bone tissue (13, 14). The last decade, several studies have been undertaken using animal models to study drug distribution in bone tissue (15–17). Multiple drugs have been detected in bone tissue. In addition, some parts of the bone prove to be more suitable for analysis than others. Parts containing more vascularization like trabecular bone tend to give higher concentrations (18). The same is true when comparing whole bones. Bones with a higher vascularization rate resulted in higher concentrations (19). No correlation could be found between blood concentration and bone tissue in animal studies but there are some indications for a correlation between administered dose and bone drug concentration (19).\n\nUsing animal models, it is possible to broadly study any correlation between drug concentrations in peri/postmortem skeletal tissue with considerably greater statistical power. Nevertheless, obtained data using animals cannot be extrapolated to casework involving humans (20). Different authors have used a variety of methodologies for drug extraction and detection but studies performed using human bones are still scarce. To-date there is no standardized protocol for sample preparation and analysis. Despite the considerable renewal of interest in the topic over the last 20 years, the drug concentration found in skeletal tissue of postmortem human samples remains poorly understood. One of the possible reasons for the lack of research on bone (marrow) is the difficulty in obtaining bones from cases. In a previous project, a linear trend could be found in human autopsy samples between blood and bone concentration for methadone (21). When methadone concentrations in blood and BM were compared, an exponential trend could be seen. This study aims to expand this study to other opioids in order to increase the understanding of drug concentration in skeletal tissue. In term, this will increase the utility of this matrix in toxicological examinations by collecting reference data.\n\nMaterials and Methods\n\nChemicals and reagent\n\nAnalytical reference standards of tramadol (1 mg/mL), cis-tramadol-13 C-d3 (100 µg/mL), O-desmethyltramadol (1 mg/mL), morphine-d3 (100 µg/mL), morphine (1 mg/mL), norfentanyl (1 mg/mL), norfentanyl-d5 (100 µg/mL), fentanyl (1 mg/mL) fentanyl-d5 (1 mg/mL), codeine (1 mg/mL) and codeine-d3 (100 µg/mL) were purchased from LGC standards (Teddington, UK). For making calibrators, reference standards were mixed to different concentrations in methanol. Separate methanolic standard stock solutions of deuterated analogues and the 13C-labeled analogue were prepared. All standard solutions were stored at −20°C.\n\nAll solvents, chemicals and reference standards were at least of analytical or HPLC grade. Acetonitrile and methanol were obtained from Biosolve (Valkenswaard, The Netherlands). Dichloromethane, acetic acid, 2-propanol, monopotassium phosphate and ammonium hydroxide that were used in the sample preparation were purchased from Merck (Darmstadt, Germany).\n\nFormic acid and ammonium formate were purchased from Sigma-Aldrich (Bornem, Belgium). Deionized water was prepared using a Milli-Q Water Purification System (Millipore, Brussels, Belgium). The aqueous buffer was prepared by adding 10 mM ammonium bicarbonate and setting the pH at 9.0 with ammonium hydroxide.\n\nBond Elut Plexa PCX cartridges (60 mg, 3 mL) were purchased from Varian (Sint-Katelijne-Waver, Belgium). All solid phase extractions (SPEs) were carried out on a Vac Elut SPS 24 (Varian, Sint-Katelijne-Waver, Belgium).\n\nSample collection\n\nDuring the period from April 2018 to March 2020, samples were obtained during autopsies of legal cases at UZ Leuven (Belgium). The clavicle bone was chosen as specimen of choice due to the high accessibility during autopsy. For each case, the case background and the medical history was reported as provided by the legal system. A brief summary including postmortem intervals can be found in Supplementary Table S1. Cases were selected after a positive screening result for tramadol, morphine, fentanyl, codeine, cocaine or any of their metabolites in blood using the method as described by Vandenbosch et al. (21). Twenty-two cases were selected. Six females and 16 males were analyzed. The age of the deceased ranged from 21 to 83 years old with a median of 40 years old. Samples were collected and treated as described in Vandenbosch et al. (21). Blood was sampled from the vena saphena magna. Approval for this study was received from the Medical Ethics Committee of the faculty of Medicine of the University Hospital of Leuven, Belgium.\n\nSpecimen preparation\n\nBlood samples were extracted using a simple protein precipitation procedure as reported by our group (19, 22). One-hundred microliters of this blood was spiked with 10 μL of codeine-d3 (1 μg/mL), 10 μL of morphine-d3 (1 μg/mL), 10 μL of cis-tramadol-C13-d3 (1 μg/mL), 10 μL of fentanyl-d5 (1 μg/mL) and 10 μL of norfentanyl-d5 (1 μg/mL) followed by a protein precipitation. A ring of 1 cm width was serrated 1 cm from the center of the proximal clavicle head. More information can be found in the supplementary SOP. The bone samples were extracted using a methanolic extraction as recently reported by our group (19, 22). At the start of the extraction, single full bones were spiked with internal standards (IS) by addition 50 ng of codeine-d3, 50 ng of morphine-d3, 50 ng of cis-tramadol-C13-d3, 50 ng of fentanyl-d5 and 50 ng of norfentanyl-d5 in the extraction solvent. BM was extracted using SPE as described by our group (21). The 100 mg of BM was mixed with 10 μL of codeine-d3 (10 μg/mL), 10 μL of morphine-d3 (10 μg/mL), 10 μL of cis-tramadol-C13-d3 (10 μg/mL), 10 μL of fentanyl-d5 (10 μg/mL) and 10 μL of norfentanyl-d5 (10 μg/mL).\n\nLC--MS-MS method\n\nSeparation of the compounds was performed on a Shimadzu Prominence Ultra-Fast Liquid Chromatograph XR System (Shimadzu Benelux, Jette, Belgium) in combination with an Acquity UPLC® BEH C18 LC Column (50 mm × 2.1 mm, 1.7 μm particle size) (Waters, Milford, Massachusetts, United States). The column oven and autosampler cooler were set at a temperature of respectively 45°C and 10°C.\n\nThe method uses a gradient elution with an aqueous buffer at pH 9 (solvent A) and methanol (solvent B): 0–10 min: 25–90%, 10–11 min: 90%, 11–11.5 min: 25%, 11.5–13 min: 25%. The system was kept at starting conditions for 5 min to re-equilibrate. The total analytical run time was 13 min. The flow rate was set at 0.5 mL/min with an injection volume of 10 µL.\n\nA triple quadrupole MS (3200 QTRAP, Sciex Halle) was operated in scheduled multiple reaction monitoring mode in combination with a Turbo V ion source with positive electrospray ionization (Sciex, Halle, Belgium). Following source parameters were set: curtain gas: nitrogen, 25 psi; nebulizing gas: nitrogen, 55 psi; heater gas: nitrogen, 55 psi; ion source temperature: 550°C; ion source voltage: + 5,500 V. MRM transitions, retention times and MS parameters are presented in Supplementary Table S2. These MS parameters were determined by direct infusion. The mass spectrometer was coupled to a Dell Precision™ 390 Workstation equipped with Analyst software version 1.5.1. (Sciex, Halle, Belgium) for data acquisition. The screening method is validated and commercially available as iMethod™ Test for Cliquid Software (Sciex, Halle, Belgium).\n\nMethod validation\n\nThe method is fully validated for bone tissue and BM as prescribed by international guidelines (23). The following parameters were assessed: selectivity, linearity, matrix effect, recovery, limit of quantification (LOQ), limit of detection (LOD), precision, accuracy and stability. For the validation, blank bone tissue and blank BM were used. The blank bone and BM were taken from forensic cases, which tested, negative for all 415 compounds using a screening method on blood that is described in Vandenbosch et al. (21). Selectivity was tested by analyzing five zero samples from five different donors. LOQs were set as the lowest points of the calibration curve, which fulfilled the criteria of sufficient precision and accuracy using spiked quality control samples. The LODs were estimated using a linear calibration curve containing negative controls n = 2, LOQ n = 5 and the second lowest calibrator n = 5 as described by Polettini et al. (24). Matrix effect was evaluated by testing a methanolic standard A and post-extraction spiked sample B at two concentrations low and high using samples from five different donors as described by Matuszewski et al (25). Recovery was evaluated by testing a methanolic standard (A) and pre-extraction spiked sample (C) at two concentrations (low and high) using samples from five different donors as described by Matuszewski et al. (25). Processed sample stability was tested by analyzing two samples at high and low concentration after 72 h of storage in the 10°C cooled autosampler.\n\nBone tissue and bone marrow\n\nMatrix-matched calibration curves were created using skeletal tissue from five different donors. For all analytes, calibration curves were created (1, 5, 50, 500, 1,000, 2,000, 3,000 and 4,000 ng/g) (n = 5 at all concentrations). Different regression models were evaluated: linear least squares un-weighted and weighted (1/x, 1/x2) regression models and quadratic least squares un-weighted and weighted (1/x, 1/x2) regression models. The best calibration models were selected based on the lowest back-calculated values. For all analytes, deuterated standards were available and used as IS with exception of O-desmethyltramadol. For these analytes, cis-tramadol-13C-d3 was used as an IS. These ISs were selected based on their similar properties during ionization. Precision and accuracy were evaluated in duplicate on seven different days using quality control samples at low (1 ng/g), medium (500 ng/g) and high concentration (4,000 ng/g). Calibrators were prepared by spiking 100 mg of tissue with different concentrations of methanolic standards. This was done for bone tissue as well as for BM.\n\nBlood\n\nSelectivity was tested by analyzing five zero samples from five different donors. For all analytes matrix-matched calibration curves were created (n = 5 at all concentration). Different regression models were evaluated: linear least squares un-weighted and weighted (1/x, 1/x2) regression models and quadratic least squares unweighted and weighted (1/x, 1/x2) regression models.\n\nResults\n\nMethod validation\n\nBone marrow\n\nBlank samples and zero samples showed no interfering peaks for our analytes. Matrix-matched calibration curves were constructed. LODs range from 0.1 to 0.75 ng/g. LOQ has been set as the lowest calibrator, which fulfilled the criteria of sufficient precision and accuracy using spiked quality control samples. Accuracy expressed as bias (%) was in the proposed acceptance limit for all analytes at all concentrations and ranged from −5.86 to 9.65% (23). Repeatability and intermediate precision expressed as relative standard deviations (RSDs) (%) ranged, respectively, from 1.07–8.87% and 0.45–14.93%. All were within the proposed acceptance criteria as prescribed by international guidelines (23). The matrix effects ranged from 66.7 to 105.0%. The recovery ranged from 80.3 to 92.1%. Processed samples were stable in the autosampler, with <10% deviation from starting concentration observed in calculated concentrations up to 72 h post-extraction. Results are summarized in Supplementary Tables S2 and S3.\n\nBone\n\nThe method showed no interfering peaks. Matrix-matched calibration curves were constructed. LODs range from 0.1 to 1 ng/g. LOQ has been set as the lowest calibrator, which fulfilled the criteria of sufficient precision and accuracy using spiked quality control samples. Bone concentrations below the LOQ are considered as semi-quantitative. Accuracy expressed as bias (%) was in the proposed acceptance limit for all analytes at all concentrations and ranged from −5.43 to 7.14% (23). Repeatability and intermediate precision expressed as RSD (%) ranged respectively from 0.6–14.4% and 0.5–14.6%. All were within the proposed acceptance criteria as prescribed by international guidelines (23). The matrix effects ranged from 66.5 to 113.0%. The recovery ranged from 76.3 to 96.1%. Processed samples were stable in the autosampler, with <10% deviation from starting concentration observed in calculated concentrations up to 72 h post-extraction. Results are summarized in Supplementary Tables S5 and S6.\n\nBlood\n\nNo interfering peaks were observed. The best fitted calibration curve showed to be linear for codeine, fentanyl and norfentanyl. For tramadol and O-desmethyltramadol the best fit was linear with weighing factor 1/x. The best fitted curve for morphine was with weighing factors of 1/x2. All curves showed good correlation factors (R > 0.99).\n\nCase studies\n\nRoutine toxicological screening\n\nUsing the iMethod™ Test for Cliquid Software screening method blood, bone and BM of all cases was screened for 415 compounds of forensic interest in positive ion mode. A total of 22 cases were identified with involvement of opioids. In 12 cases tramadol was detected. For codeine, 12 cases were screened positive. Morphine was also detected in 11 of these 12 cases. No heroin (diacetylmorphine) could be detected in these cases, but in five cases 6-acetylmorphine (6-AM) could be detected. In five cases (6, 10, 17, 21, 22), 6-AM was detected in blood. In two cases (10, 21), traces of 6-AM were detected in bone tissue. Only in case 10, 6-AM was detected in BM. All of these 22 cases were selected for further analysis using the quantitative methods.\n\nTramadol\n\nA total number of 12 tramadol positive cases (blood) were analyzed. All results are summarized in Table I. Blood tramadol concentrations ranged between 0.3 and 6,800 ng/mL. The blood concentration of case 15 and 18 was outside the linear range and was thus diluted 1/10 using blank donor blood and the dilution factor. Case 15 and 18 showed blood tramadol concentrations that well exceeded the level to cause coma or even death (26). For the other cases, blood tramadol concentrations can be considered as therapeutic and were well above the LOQ with exception of case 8, 11, 20 and 21. The blood concentration of these latter was below the therapeutic threshold. BM tramadol concentration ranged between 1.3 and 2,200 ng/g. The BM tramadol and O-desmethyltramadol concentration of case 15 were also out of our linear range. Therefore, the sample was diluted 1/10 using blank BM and the concentration was back calculated. Bone tramadol concentration ranged between 0.02 and 6,000 ng/g.\n\nTable I. Concentrations Found in Each Biological Matrix\n\nCase #\tDrugs detected\tBlood concentration\tBone concentration\tBone marrow (ng/g)\tRatio blood/bone\tRatio blood/bone marrow\t\n1\tTramadol\t81 ng/mL\t18 ng/g\t91 ng/g\t4.4\t0.9\t\n\tO-desmethyltramadol\t15 ng/mL\t1.8 ng/g\t31 ng/g\t8.4\t0.5\t\n2\tTramadol\t480 ng/mL\t69 ng/g\t500 ng/g\t7.0\t0.9\t\n\tO-desmethyltramadol\t140 ng/mL\t4.7 ng/g\t25 ng/g\t29.6\t5.5\t\n3\tCodeine\t11 ng/mL\t0.3 ng/g\t5.2 ng/g\t32.3\t2.0\t\n\tMorphine\t80 ng/mL\t0.8 ng/g\t31 ng/g\t96.3\t2.5\t\n4\tFentanyl\t9.2 ng/mL\t3.6 ng/g\t12 ng/g\t2.6\t0.8\t\n\tNorfentanyl\t6.5 ng/mL\t1.1 ng/g\t1.5 ng/g\t5.7\t4.3\t\n5\tFentanyl\t1.2 ng/mL\tn.d.\t1.1 ng/g\tn/a\t1.1\t\n\tNorfentanyl\t0.4 ng/mL\tn.d.\t0.2 ng/g\tn/a\t1.7\t\n6\tCodeine\t17 ng/mL\t1.3 ng/g\t12 ng/g\t12.9\t1.4\t\n\tMorphine\t180 ng/mL\t3.3 ng/g\t71 ng/g\t55.7\t2.6\t\n7\tCodeine\t33 ng/mL\t2.0 ng/g\t78 ng/g\t16.6\t0.4\t\n\tMorphine\t41 ng/mL\tn.d.\t99 ng/g\tn/a\t0.4\t\n8\tTramadol\t0.6 ng/mL\t0.0\t1.3 ng/g\t24.2\t0.4\t\n9\tTramadol\t2,100 ng/mL\t270 ng/g\t300 ng/g\t7.6\t0.7\t\n\tO-desmethyltramadol\t560 μg/mL\t98 ng/g\t840 ng/g\t5.7\t0.7\t\n\tFentanyl\t7.9 ng/mL\t1.4 ng/g\t25 ng/g\t5.7\t0.3\t\n\tCodeine\t160 ng/mL\t29 ng/g\t380 ng/g\t5.6\t0.4\t\n10\tTramadol\t130 ng/mL\t3.3 ng/g\t140 ng/g\t40.7\t0.9\t\n\tO-desmethyltramadol\t8.1 ng/mL\t0.2 ng/g\t33 ng/g\t35.1\t0.2\t\n\tCodeine\t120 μg/mL\t5.4 ng/g\t230 ng/g\t22.3\t0.5\t\n\tMorphine\t1,200 ng/mL\t20 ng/g\t1,800 ng/g\t60.5\t0.7\t\n11\tTramadol\t0.4 ng/mL\t0.2 ng/g\t4.9 ng/g\t1.9\t0.1\t\n\tO-desmethyltramadol\t0.3 ng/mL\t0.0 ng/g\t1.3 ng/g\t6.5\t0.2\t\n\tCodeine\t1,200 ng/mL\t140 ng/g\t3,600 ng/g\t7.9\t32.0\t\n\tMorphine\t26 ng/mL\t3.6 ng/g\t74 ng/g\t7.1\t0.3\t\n12\tTramadol\t1,700 ng/mL\t320 ng/g\t1,900 ng/g\t5.4\t0.9\t\n\tO-desmethyltramadol\t270 ng/mL\t51 ng/g\t28 ng/g\t5.3\t9.9\t\n13\tCodeine\t5.0 ng/mL\t1.0 ng/g\t9.4 ng/g\t4.8\t0.5\t\n\tMorphine\t52 ng/mL\t8.1 ng/g\t50 ng/g\t6.4\t1.0\t\n14\tNorfentanyl\t2.8 ng/mL\tn.d.\t2.1 ng/g\tn/a\t1.3\t\n15\tTramadol\t2,500 ng/mL\t6,100 ng/g\t22,000 ng/g\t4.2\t1.1\t\n\tO-desmethyltramadol\t8,900 ng/mL\t670 ng/g\t6,000 ng/g\t13.4\t1.5\t\n16\tMorphine\t1,800 ng/mL\t170 ng/g\t1,300 μg/g\t10.5\t1.4\t\n17\tCodeine\t31 ng/mL\t2.1 ng/g\t20 ng/g\t15.1\t1.5\t\n\tMorphine\t500 ng/mL\t38 ng/g\t190 ng/g\t13.1\t2.5\t\n18\tTramadol\t6,800 ng/mL\t61 ng/g\t19 ng/g\t1,133.1\t3,604.8\t\n\tO-desmethyltramadol\t2,600 ng/mL\t4.6 ng/g\t0.5 ng/g\t563.4\t4,775.5\t\n19\tCodeine\t25 ng/mL\t5.1 ng/g\t3.0 ng/g\t4.9\t8.5\t\n\tMorphine\t330 ng/mL\t21 ng/g\t0.0 ng/g\t16.0\tn/a\t\n20\tTramadol\t0.3 ng/mL\t1.7 ng/g\t4.1 ng/g\t0.2\t0.1\t\n\tO-desmethyltramadol\tn.d.\t0.2 ng/g\t0.3 ng/g\tn/a\tn/a\t\n21\tTramadol\t0.9 ng/mL\t2.6 ng/g\t1.3 ng/g\t0.3\t0.7\t\n\tCodeine\t33 ng/mL\t7.9 ng/g\t1,400 ng/g\t4.2\t0.02\t\n\tMorphine\t310 ng/mL\t22 ng/g\t12 ng/g\t13.9\t25.5\t\n22\tTramadol\t110 ng/mL\t72 ng/g\t4.9 ng/g\t1.5\t22.2\t\n\tO-desmethyltramadol\t0.2 ng/mL\t0.3 ng/g\tn.d.\t0.8\tn/a\t\n\tCodeine\t14 ng/mL\t4.6 ng/g\t14 ng/g\t1.5\t1.0\t\n\tMorphine\t150 ng/mL\t25 ng/g\t96 ng/g\t3.0\t1.6\t\nn.d. = Not detected.\n\nThe metabolite O-desmethyltramadol was present in all tramadol positive cases with exception of 8, 21 and 22. Blood O-desmethyltramadol concentration ranged from 0.24 to 8,900 ng/mL. Bone O-desmethyltramadol concentration ranged from 0.28 to 660 ng/g. BM O-desmethyltramadol concentration ranged from 0.34 to 6,000 ng/g.\n\nCodeine\n\nA total number of 11 codeine positive cases (blood) were identified. Results are shown in Table I. Blood concentrations ranged between 5.0 and 160 ng/mL. The blood concentration of cases 3, 7, 9, 17, 19 and 21 were within the therapeutic range (26). Case 11 was above the threshold to be comatose or even lethal. All other cases were considered to have toxic blood concentrations. Blood concentrations were higher than bone concentration in all cases sampled. Bone tissue concentrations ranged between 0.33 and 29 ng/g. Only the bone concentration of case 3 was below the LOQ and will be considered as semi-quantitative. BM concentrations ranged between 2.9 and 1,400 ng/g.\n\nMorphine\n\nA total number of 11 morphine positive cases (blood) were identified. Results are shown in Table I. Blood concentrations ranged between 9.2 and 1,700 ng/mL. Multiple cases (6, 10, 16, 19, 21) were above the therapeutic threshold. BM concentrations ranged between 12 and 1,800 ng/g. Bone tissue concentrations ranged between 0.8 and 170 ng/g. The bone concentration in case 3 was below our LOQ. This value will be interpreted semi-quantitative.\n\nFentanyl\n\nA total number of four cases were analyzed where fentanyl was involved. Results are shown in Table I. Blood fentanyl concentration ranged from 1.2 to 9.2 ng/mL. Bone fentanyl concentration ranged between 1.4 and 3.6 ng/mL. BM fentanyl concentration ranged between 1.1 and 25 ng/g.\n\nBlood norfentanyl concentration ranged between 0.4 and 6.9 ng/mL. Bone norfentanyl concentration was two times 1.1 ng/g. BM norfentanyl concentration ranged from 0.21 and 490 ng/g.\n\nDiscussion\n\nPrevious studies showed the sample collection procedures of skeletal tissue to be of the most utter importance since sampling location plays a major role in drug concentration (18). However, the sample collection has not been standardized between labs. In a previous study, it was shown that a possible correlation may exist between bone, BM and blood concentration for methadone (21). The current study aims to extend this knowledge to other opioids. Therefore, samples were taken in the same standardized method as described in Vandenbosch et al. (21). Postmortem intervals are reported in Supplementary Table S1. Since PMI are most of the time less than 48 h with a few exceptions and no clear signs of decomposition have been described by the forensic pathologist with exception of one case, the samples in this study can be considered as fresh. Therefore, caution is advised when interpreting skeletal tissue drug concentrations found in heavily decomposed remains. As decomposition proceeds, bones may be soaked in the decomposition fluids from tissues with a high drug concentration (e.g., liver and lung). Due to its more porous structure, spongy bone may be more susceptible to this type of contamination. Furthermore, very little information is known about acute or chronic drugs usage of the deceased. It is possible that uptake into bone is slower than into most tissues. As a result, the bone concentration may not reflect acute overdoses as distinct from long-term therapeutic use leading to a slow accumulation of drug in this tissue. When looking at the case reports, very often polypharmacy is detected. Since no information is available about co-ingestion of certain medication over a period of time or at the same time, caution is advised when interpreting the obtained results. The consequences on the obtained results should be further investigated. This applies to all obtained results in this project. Nevertheless, the findings presented here, pose a starting point toward a better understanding of drug concentration in skeletal tissue and give rise to a starting frame of reference data to conduct toxicological analysis on skeletal tissue when other matrices are unavailable. Some measurements were outside the dynamic range of the calibration curve. The results from these samples should be interpreted as semi-quantitative.\n\nTramadol\n\nApart from case 15 and 18, tramadol drug concentration was always the highest in BM. Blood concentrations exceeded bone concentration with the exception of case 20 and 21. For O-desmethyltramadol, it is more variable which specimen showed a higher concentration. When the drug-to-metabolite relationship is assessed, the ratios were highly variable. Drug-to-metabolite ratios are shown in Supplementary Table S7. But for all cases sampled, the concentration of the more polar metabolite is lower compared to its parent molecule. These ratios are also an indication that measured drug concentrations are not measured from residues of blood. If this was the case a higher concentration of metabolites would be expected similar to those seen in blood. As a result, drugs inside bone tissue may be a distinct compartment.\n\nThis explanation is supported when looking at the trend between blood tramadol concentration and bone concentration. A linear trend can be seen. This is shown in Figure 1A. When looking at the trend between blood and BM concentration, a similar linear trend can be seen. This is shown in Figure 1B. In this trend, case 8 and 18 fall slightly outside the linear trend. Case 18 had blood concentrations well above the toxic threshold. This may explain the outlier. Tramadol concentration in BM may be a delayed representation of blood concentration. A similar thing was described for diazepam in rat studies (27). These results give a good indication of the broad range in which skeletal tissue concentration can be found.\n\nFigure 1. Results based on different postmortem cases. (A) Relation between bone concentrations and blood concentration for each compound. (B) Relation between bone marrow concentrations and blood concentrations for each compound.\n\nCodeine\n\nWhen correlating blood with BM codeine concentration, a linear trend is seen. Results are shown in Figure 1B. Case 21 is identified as an outlier. A higher concentration of codeine was found in BM as expected.\n\nWhen looking at the trend between blood concentrations and bone concentrations, a linear trend can be seen. Results are shown in Figure 1A. Although a clear trend is visible, variance still exists. An explanation for the discrepancy and high variability could be found in the working mechanism of codeine (28). Codeine is a prodrug. It works on the opioid receptors throughout the body but should first be converted into morphine. Normally around 5–10% of the administered codeine is converted in this way. However, a high inter-individual variability exists.\n\nMorphine\n\nWhen the concentrations in this project are compared with a similar case report from Raikos et al (16)., similar BM concentrations are seen. Bone concentrations are lower than seen in the case report by Raikos et al. (16). This could be due to a different extraction solvent and the usage of powdered bone instead of rings. They also suggest a higher morphine concentration due the hydrolysis of 6-AM.\n\nWhen correlating blood concentration to bone concentration, a linear trend can be seen. This is shown in Figure 1A. When correlating blood concentration to BM concentration, a lot of variability is seen. This is shown in Figure 1B. Still a linear trend could be distinguished. The high variability that is seen, can be explained in a similar trend as for codeine. Since codeine is partly converted into the active morphine, it is not possible to determine which morphine comes from the codeine metabolism. When looking at the results in this project also morphine was detected in every case involving codeine with exception of case 9. The drug-to-metabolite ratio showed to be highly variable. Drug-to-metabolite ratios are shown in Supplementary Table S8. Another possibility is that the detected morphine and codeine are metabolites from heroin usage. This was checked using the screening protocol for heroin and its metabolite 6-AM (29). Case 10 was the only case were 6-AM was detected in BM. Studies have also shown that blood concentrations of codeine are several times higher than morphine after intake of codeine (30). According to forensic recommendations, a morphine-to-codeine value below 1 is considered to be indicative for sole codeine intake, whereas values above 1 are considered to indicate use of heroin (31). When looking at the blood results in our study, the ratios morphine over codeine appear to be high with exception of cases 9 and 11. The ratios are shown in Supplementary Table S8. Cases 9 and 11 show a morphine to codeine ratio that is below 1. Co-ingestion of morphine with heroin and codeine could not be ruled out as a contributing source to measured morphine. This can also account for the variability.\n\nWhen analyzing the ratios in bone tissue, similar results are obtained as in blood. The morphine-to-codeine ratio was above 1 in all cases with exception of case 9 and 11. So, the morphine-to-codeine ratio in bone tissue may also be valuable to determine heroin usage or codeine ingestion.\n\nWhen looking at the ratios in BM, the ratios were also above 1 except for cases 11 and 21. In case 21, the ratio is different than in blood or bone tissue. In the BM of this case, the ratio of morphine-to-codeine is well below 1. This may be due the advanced stage of decomposition of the body (32). Since the cases presented here show postmortem intervals ranging from 12 to 168 h, this factor should be considered and further investigated.\n\nFentanyl\n\nAs far as the author knows, this is the first-time fentanyl is detected and quantified in bone tissue. Fentanyl is a 100 time more potent opioid than morphine. As a result, therapeutic blood concentrations are rather low. Case 5 showed a fentanyl level below the therapeutic threshold. Fentanyl and norfentanyl were undetected in bone tissue of case five. BM fentanyl concentrations were higher than blood in 2 out of 3 cases. This may prove useful to detect fentanyl when blood is unavailable or concentrations are below the LOD. Blood fentanyl concentrations and BM fentanyl concentrations were higher than bone concentrations. The drug-to-metabolite relationship showed to be highly variable for all matrices analyzed. Fentanyl was always present in a higher concentration than norfentanyl with exception of the BM of case 9. In case 14 only norfentanyl could be detected and no fentanyl.\n\nConclusion\n\nAn LC--MS-MS method was successfully optimized and validated for the analysis of six opioids in skeletal tissue. As far as the author knows, for the first-time codeine, tramadol, O-desmethyltramadol, fentanyl and norfentanyl concentrations were determined in postmortem bone and BM of 22 forensic cases. Furthermore, the morphine concentrations were also determined in bone and BM. When plotting blood concentration of tramadol against bone and BM concentrations, a linear trend could be seen. The same trend was seen when codeine blood concentrations were plotted against their corresponding bone and BM concentrations. However, cases with excessive overdose blood concentrations were clear outliers from these trends. For fentanyl and its metabolite norfentanyl, no conclusions could be drawn because of the small sample size. The results presented here show what concentrations of tramadol, codeine and morphine might be found in the clavicle and its BM. All these findings pose a starting frame of reference to conduct toxicological analysis on skeletal tissue.\n\nSupplementary Material\n\nbkab095_Supp Click here for additional data file.\n\nAcknowledgments\n\nWe thank the staff of the morgue of UZ Leuven (Belgium) for their help in collecting the samples. We are also very grateful to the lab toxicology and pharmacology (KU Leuven) for the illuminating discussions and support.\n\nSupplementary Data\n\nSupplementary Data is available at Journal of Analytical Toxicology online.\n\nFunding\n\nThe funding for this research was provided by KU Leuven (FLOF). There was no funding from the private sector.\n\nAuthor contributions\n\nExperimental design: MV, EC\n\nSample collection: WVDB, JW, WVDV\n\nConduct experiments: MV, SP\n\nData analysis: MV, EC\n\nManuscript writing: MV, EC\n\nManuscript revision: MV, EC\n==== Refs\nReferences\n\n1. Manchikanti L. , HelmS., FellowsB., JanataJ.W., PampatiV., GriderJ.S., et al. (2012) Opioid epidemic in the United States. Pain Physician, 15 , ES9–38.\n2. Hemmings H.C.J. , LambertD.G. (2019) The good, the bad, and the ugly: the many faces of opioids. British Journal of Anaesthesia, 122 , 705–707.31005244\n3. EMCDA (2019) Drug-related Deaths and Mortality in Europe: Update from the EMCDDA Expert Network. Publications Office of the European Union, LISBON.\n4. Negrusz A. , CooperG. Clarke’s Analytical Forensic Toxicology , 2nd edition. Pharmaceutical Press: London, 2013\n5. Dent B.B. , ForbesS.L., StuartB.H. (2004) Review of human decomposition processes in soil. Environmental Geology, 45 , 576–585.\n6. 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(2001) Determination of opiates in postmortem bone and bone marrow. Forensic Science International, 123 , 140–141.11728739\n17. Orfanidis A. , GikaH., ZaggelidouE., MastrogianniO., RaikosN. (2018) Alprazolam and zolpidem in skeletal tissue of decomposed body confirms exposure. Journal of Forensic Sciences, 64 , 643–646. doi: 10.1111/1556-4029.13890.\n18. Watterson J.H. , DonohueJ.P. (2011) Relative distribution of ketamine and norketamine in skeletal tissues following various periods of decomposition. Journal of Analytical Toxicology, 35 , 452–458.21871154\n19. Vandenbosch M. , SomersT., CuypersE. (2018) Distribution of methadone and metabolites in skeletal tissue. Journal of Analytical Toxicology, 42 , 400–408.29490025\n20. Gasser J.A. , KneisselM. (2017) Bone toxicology. http://link.springer.com/10.1007/978-3-319-56192-9 (accessed May 2020).\n21. Vandenbosch M. , RooseleersL., Van Den BogaertW. Skeletal Tissue, A Viable Option in Forensic Toxicology? A View into Post Mortem Cases . Forensic Science International, 2020; Elsevier, Amsterdam, p. 309.\n22. Vandenbosch M. , SomersT., CuypersE. (2019) Distribution of clomipramine, citalopram, midazolam, and metabolites in skeletal tissue after chronic dosing in rats. Drug Testing and Analysis, 11 , 1083–1093.30817095\n23. Peters F.T. , DrummerO.H., MusshoffF. (2007) Validation of new methods. Forensic Science International, 165 , 216–224.16781833\n24. Polettini A. Applications of LC-MS in Toxicology , 1st edition. Pharmaceutical Press: London, 2006\n25. Matuszewski B.K. , ConstanzerM.L., Chavez-EngC.M. (2003) Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on HPLC-MS/MS. Analytical Chemistry, 75 , 3019–3030.12964746\n26. Regenthal R. , KruegerM., KoeppelC., PreissR. (1999) Drug levels: therapeutic and toxic serum/plasma concentrations of common drugs. Journal of Clinical Monitoring and Computing, 15 , 529–544.12578052\n27. Watterson J.H. , BotmanJ.E. (2009) Detection of acute diazepam exposure in Bone and Marrow: influence of tissue type and the dose-death interval on sensitivity of detection by ELISA with liquid chromatography tandem mass spectrometry confirmation. Journal of Forensic Sciences, 54 , 708–714.19432747\n28. Smith H.S. (2009) Opioid Metabolism. Mayo Clinic Proceedings, 84 , 613–624.19567715\n29. Dinis-Oliveira R.J. (2019) Metabolism and metabolomics of opiates: a long way of forensic implications to unravel. Journal of Forensic and Legal Medicine, 61 , 128–140.30621882\n30. Liao Q. , DengY., XieZ., PanB., ZhangL. (2009) Rapid simultaneous determination of codeine and morphine in plasma using LC-ESI-MS/MS: application to a clinical pharmacokinetic study. Journal of Separation Science, 32 , 202–211.19156643\n31. He Y.J. , BrockmöllerJ., SchmidtH., RootsI., KirchheinerJ. (2008) CYP2D6 ultrarapid metabolism and morphine/codeine ratios in blood: was it codeine or heroin? 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"drugindication": "Product used for unknown indication",
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"medicinalproduct": "TRAMADOL"
}
],
"patientagegroup": null,
"patientonsetage": "23",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Vandenbosch M, Pajk S, Bogaert W, Wuestenbergs J, Van de Voorde W, Cuypers E. Post Mortem Analysis of Opioids and Metabolites in Skeletal Tissue. J Anal Toxicol. 2021;00:1-8.",
"literaturereference_normalized": "post mortem analysis of opioids and metabolites in skeletal tissue",
"qualification": "3",
"reportercountry": "BE"
},
"primarysourcecountry": "BE",
"receiptdate": "20211129",
"receivedate": "20211129",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20127813,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 1,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220303"
},
{
"companynumb": "BE-GRUNENTHAL-2021-269943",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MORPHINE SULFATE"
},
"drugadditional": "4",
"drugadministrationroute": "065",
"drugauthorizationnumb": "019516",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Product used for unknown indication",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "MORPHINE SULFATE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
},
"drugadditional": "4",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Product used for unknown indication",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TRAMADOL HYDROCHLORIDE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CODEINE"
},
"drugadditional": "4",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Product used for unknown indication",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CODEINE"
}
],
"patientagegroup": null,
"patientonsetage": "25",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Death",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DOI:10.1093/jat/bkab095 Vandenbosch M, Pajk S, Van Den Bogaert W, Wuestenbergs J, Van de Voorde W, Cuypers E.. Post Mortem Analysis of Opioids and Metabolites in Skeletal Tissue. J Anal Toxicol. 2021;00:1-8",
"literaturereference_normalized": "post mortem analysis of opioids and metabolites in skeletal tissue",
"qualification": "3",
"reportercountry": "BE"
},
"primarysourcecountry": "BE",
"receiptdate": "20211004",
"receivedate": "20211004",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 19914123,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 1,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220303"
}
] |
{
"abstract": "Citalopram is a bicyclic phthalate compound approved in 1998 by the U.S. Food and Drug Administration for the treatment of depression. It is a highly selective serotonin reuptake inhibitor that appears to have little effect on noradrenaline or dopamine reuptake. Since this drug has only recently been released on the U.S. market, information regarding therapeutic, toxic, and lethal concentrations is sparse. This study reports the detection of citalopram in 22 postmortem cases. Citalopram was identified and quantitated by capillary column gas chromatography with nitrogen phosphorus detection after basic liquid-liquid extraction. Confirmation was achieved by full scan electron impact gas chromatography/mass spectrometry. In the 22 cases studied, heart blood citalopram concentrations ranged from 0.09 to 1.64 mg/L (n = 22, mean +/- SD = 0.51+/-0.43, median = 0.34); femoral blood concentrations ranged from 0.09 to 0.76 mg/L (n = 14, mean +/- SD = 0.34+/-0.23, median = 0.28); and urine concentrations ranged from 0.05 to 276.00 mg/L (n = 13). Liver was analyzed in three cases with citalopram concentrations ranging from 2.22 to 8.08 mg/kg. The average heart blood/femoral blood ratio was 1.26 (range 0.75 to 1.98, n = 14). In each case, the cause of death was not considered to be related to citalopram toxicity. These data may therefore provide a basis for establishing post mortem citalopram concentrations following therapeutic doses.",
"affiliations": "The Office of the Cuyahoga County Coroner, Cleveland, OH 44106, USA.",
"authors": "Jenkins|Amanda J|AJ|;Gubanich|Krista|K|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D015283:Citalopram",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1198",
"issue": "47(1)",
"journal": "Journal of forensic sciences",
"keywords": null,
"medline_ta": "J Forensic Sci",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001344:Autopsy; D015283:Citalopram; D005260:Female; D005554:Forensic Medicine; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D011180:Postmortem Changes; D012016:Reference Values; D017367:Serotonin Uptake Inhibitors; D013048:Specimen Handling",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "159-64",
"pmc": null,
"pmid": "12064644",
"pubdate": "2002-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disposition of citalopram in biological specimens from postmortem cases.",
"title_normalized": "disposition of citalopram in biological specimens from postmortem cases"
} | [
{
"companynumb": "US-ALLERGAN-2111081US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "020822",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CITALOPRAM HYDROBROMIDE ? BP"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugrecurrence": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "VERAPAMIL"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DIPHENHYDRAMINE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Postmortem blood drug level increased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Peritonitis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Pancreatitis acute",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Effusion",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Alcohol abuse",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "JENKINS A, GUBANICH K. DISPOSITION OF CITALOPRAM IN BIOLOGICAL SPECIMENS FROM POSTMORTEM CASES. JOURNAL OF FORENSIC SCIENCES. 2002?47(1):159?164",
"literaturereference_normalized": "disposition of citalopram in biological specimens from postmortem cases",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20210316",
"receivedate": "20210316",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19014324,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210420"
}
] |
{
"abstract": "BACKGROUND\nThe realization that attention-deficit/hyperactivity disorder (ADHD) often persists into adulthood has led to increased frequency of diagnosis and treatment in adults. Osmotic release oral system (OROS) methylpheni-date is a long-acting stimulant demonstrated to be effective in the treatment of children and adolescents with ADHD.\n\n\nMETHODS\nForty-seven adults entered and 41 completed this double-blind, placebo-controlled, crossover trial of OROS methylphenidate. Each double-blind arm lasted 4 weeks; data were collected from August 2004 through December 2005. Subjects met both DSM-IV-TR and Utah Criteria for ADHD in adults. Outcome measures included the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS), the adult ADHD-Rating Scale (ADHD-RS), and the Clinical Global Impressions-Improvement scale (CGI-I). At baseline, subjects were categorized as having significant emotional symptoms with the WRAADDS and/or significant oppositional-defiant symptoms using a self-report scale assessing the DSM-IV criteria for oppositional defiant disorder.\n\n\nRESULTS\n17% of the sample (N = 8) had ADHD alone, 38% (N = 18) had ADHD plus significant emotional symptoms, and 40% (N = 19) had ADHD with both significant emotional and oppositional symptoms. At a mean +/- SD dose of 64.0 +/- 23.3 (0.75 mg/kg), OROS methylphenidate proved superior to placebo for all clinical measures: total WRAADDS score decrease of 42% versus 13%, respectively, p < .001 and total ADHD-RS score decrease of 41% versus 14%, respectively, p = .003, plus the subscales addressing inattention, hyperactivity/ impulsivity, and emotional dysregulation.\n\n\nCONCLUSIONS\nOROS methylphenidate proved effective in treating adult ADHD. ADHD alone was relatively uncommon. Over 80% of our patients had ADHD with a combination of emotional and/or oppositional symptoms.",
"affiliations": "Mood Disorders Clinic, Department of Psychiatry, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA. fred.reimberr@hsc.utah.edu",
"authors": "Reimherr|Frederick W|FW|;Williams|Erika D|ED|;Strong|Robert E|RE|;Mestas|Ruth|R|;Soni|Poonam|P|;Marchant|Barrie K|BK|",
"chemical_list": "D000697:Central Nervous System Stimulants; D003692:Delayed-Action Preparations; D008774:Methylphenidate",
"country": "United States",
"delete": false,
"doi": "10.4088/jcp.v68n0113",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-6689",
"issue": "68(1)",
"journal": "The Journal of clinical psychiatry",
"keywords": null,
"medline_ta": "J Clin Psychiatry",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000342:Affective Symptoms; D001289:Attention Deficit Disorder with Hyperactivity; D019958:Attention Deficit and Disruptive Behavior Disorders; D000697:Central Nervous System Stimulants; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate; D008875:Middle Aged; D009995:Osmosis; D016896:Treatment Outcome",
"nlm_unique_id": "7801243",
"other_id": null,
"pages": "93-101",
"pmc": null,
"pmid": "17284136",
"pubdate": "2007-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A double-blind, placebo-controlled, crossover study of osmotic release oral system methylphenidate in adults with ADHD with assessment of oppositional and emotional dimensions of the disorder.",
"title_normalized": "a double blind placebo controlled crossover study of osmotic release oral system methylphenidate in adults with adhd with assessment of oppositional and emotional dimensions of the disorder"
} | [
{
"companynumb": "US-JNJFOC-20170915150",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "021121",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SUSTAINED RELEASE TABLETS",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ATTENTION DEFICIT/HYPERACTIVITY DISORDER",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "METHYLPHENIDATE HYDROCHLORIDE."
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Blood pressure diastolic increased",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Heart rate abnormal",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dry eye",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nasal dryness",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Decreased appetite",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Headache",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pain",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Electrocardiogram change",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Weight decreased",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Electrocardiogram QT prolonged",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Tension",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Agitation",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Anxiety",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Peripheral coldness",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood pressure systolic increased",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Urinary tract disorder",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dry mouth",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Insomnia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "REIMHERR FW, WILLIAMS ED, STRONG RE, MESTAS R, SONI P, MERCHANT BK. A DOUBLE-BLIND, PLACEBO-CONTROLLED, CROSSOVER STUDY OF OSMOTIC RELEASE ORAL SYSTEM METHYLPHENIDATE IN ADULTS WITH ADHD WITH ASSESSMENT OF OPPOSITIONAL AND EMOTIONAL DIMENSIONS OF THE DISORDER. J CLIN PSYCHIATRY JAN-2007;68(1):93-101.",
"literaturereference_normalized": "a double blind placebo controlled crossover study of osmotic release oral system methylphenidate in adults with adhd with assessment of oppositional and emotional dimensions of the disorder",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170920",
"receivedate": "20170920",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13993394,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20171128"
}
] |
{
"abstract": "Internal carotid artery dissection (ICAD) accounts for 25% of cerebrovascular accidents in young and middle-aged patients. Dissection occurs when the intimal wall of an artery is damaged as a result of trauma or defect. ICAD development after dental work is a relatively uncommon phenomenon. Our study highlights a rare presentation of ICAD that resulted from a direct lidocaine nerve block injection in a patient undergoing pulpotomy for a right maxillary second premolar tooth. We have described the case and reviewed the literature on this rare but potentially life-threatening phenomenon.",
"affiliations": "Internal Medicine, Staten Island University Hospital.;Pulmonary and Critical Care, Staten Island University Hospital.;Neurology, University of Missouri Columbia.;Pulmonary and Critical Care, Staten Island University Hospital.;Pulmonary and Critical Care, Staten Island University Hospital.",
"authors": "Narula|Naureen|N|;Siddiqui|Faraz|F|;Katyal|Nakul|N|;Avula|Akshay|A|;Chalhoub|Michel|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.2027",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.2027Internal MedicineNeurologyNeurosurgeryInternal Carotid Artery Dissection with Lidocaine Nerve Block Injection Trauma: A Rare Case Report Muacevic Alexander Adler John R Narula Naureen 1Siddiqui Faraz 2Katyal Nakul 3Avula Akshay 2Chalhoub Michel 2\n1 \nInternal Medicine, Staten Island University Hospital \n2 \nPulmonary and Critical Care, Staten Island University Hospital \n3 \nNeurology, University of Missouri Columbia \nNaureen Narula drnaureennarula@gmail.com5 1 2018 1 2018 10 1 e202713 12 2017 5 1 2018 Copyright © 2018, Narula et al.2018Narula et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/10208-internal-carotid-artery-dissection-with-lidocaine-nerve-block-injection-trauma-a-rare-case-reportInternal carotid artery dissection (ICAD) accounts for 25% of cerebrovascular accidents in young and middle-aged patients. Dissection occurs when the intimal wall of an artery is damaged as a result of trauma or defect. ICAD development after dental work is a relatively uncommon phenomenon. Our study highlights a rare presentation of ICAD that resulted from a direct lidocaine nerve block injection in a patient undergoing pulpotomy for a right maxillary second premolar tooth. We have described the case and reviewed the literature on this rare but potentially life-threatening phenomenon.\n\ninternal carotid artery dissectiondental traumaperiodontal infectioninjection traumaThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nInternal carotid artery dissection (ICAD) represents an important cause of cerebrovascular accidents in young and middle-aged patients [1]. About 25% of strokes in patients under the age of 45 are related to cervicocephalic artery dissections [2-3]. The median time to appearance of symptoms is four days; thus, the diagnosis can be delayed [2, 4]. The disease was first recognized by Dratz in 1947 when he reported a case of ICAD as a complication from a direct injection to the carotid artery [4]. Cervical arterial dissection occurs when the intimal wall of an artery is damaged as a result of trauma or defect. As blood fills the layers of the arterial wall, thrombi form, which can lead to stroke, pseudoaneurysm, vessel occlusion, and stroke.\n\nIn this study, we present a case of ICA dissection that resulted from a direct lidocaine nerve block injection in a patient undergoing pulpotomy for a right maxillary second premolar tooth. We describe the case and review the literature on this rare but potentially life-threatening phenomenon.\n\nCase presentation\nA 58-year-old female presented to the emergency department (ED) with severe occipital headache associated with right-sided neck pain and increased sleepiness of five days' duration. Her headache was reportedly 10/10 in intensity and was associated with nausea, drowsiness, and dizziness. She denied having a change in vision, hearing, or history of head or neck trauma. Her past medical history was significant for hypertension, atrial fibrillation, and dyslipidemia. Her medications consisted of Xarelto and she was treated with ablation in the past. Vital signs in ED showed a blood pressure (BP) of 206/98 mmHg, a temperature of 98°F, heart rate of 59 bpm, and a respiratory rate of 14/min. The examination was pertinent for right eye ptosis and right pupil constriction. She recalled that her symptoms started about a week ago when she received lidocaine injection prior to pulpotomy for her upper #5 tooth. Immediately after the procedure, she experienced a severe headache, profuse sweating, and shortness of breath. The dentist, therefore, was unable to complete the procedure and she was asked to follow-up after the symptoms resolved. After few days, she developed right-sided facial swelling and presented back to the ED where she underwent incision and drainage for a right-sided dental abscess. Antibiotic therapy was subsequently started. Two days later, she returned to the ED with above-mentioned chief complaints. Computed tomography (CT) head showed no acute changes. Magnetic resonance imaging (MRI) brain showed right distal ICA dissection with mild inflammatory type signal changes surrounding the carotid artery (Figure 1).\n\nFigure 1 Magnetic Resonance Imaging (MRI) Brain\nMRI brain showing right distal internal carotid artery dissection. A notable dissection flap, along with mild inflammatory type signal changes, surrounding the carotid artery is seen (arrow).\n\nComputed tomography angiography (CTA) scan of the neck confirmed a dissection of the right internal carotid artery (ICA) at the C1-C2 level associated with infiltrative changes within the right carotid space (Figure 2).\n\nFigure 2 Computed Tomography Angiography (CTA) Neck \nCTA neck showing dissection of the right internal carotid artery at the C1-C2 level associated with infiltrative changes within the right carotid space\n\nShe was started on intravenous (IV) heparin. A blood pressure reduction goal of 25% per day was decided. IV heparin was continued for three days and later the anticoagulation was switched to Xarelto. During the course of hospitalization, her symptoms gradually improved. She was discharged home on Xarelto after 12 days of hospital stay and was encouraged to follow-up with vascular surgery, cardiology, and neurology on an outpatient basis.\n\nDiscussion\nIn this report, we have highlighted a rare presentation of ICAD that developed following a direct lidocaine injection trauma. We consider the possibility of a direct intraprocedural lidocaine injection needle-related internal carotid artery injury, as described by De Santis, et al. in a similar presentation [5]. The classical presentation of ICAD includes a triad of pain on one side of the head, face, or neck accompanied by a partial Horner's syndrome [6]. However, this classic triad is found in less than one-third of the patients; thus, in presence of any two elements of this triad, a diagnosis should be strongly suspected. Pain is usually the initial manifestation of ICAD [7]. The median time to appearance of other symptoms was usually around four days. Oculosympathetic palsy, consisting of miosis and ptosis, has long been recognized as a classical manifestation of ICAD but it is seen in less than half of the cases [8]. In our patient, symptoms developed after the anaesthetic block injection. There was no history of significant trauma, genetic predisposition, or other precipitating events; therefore, one can attribute that the ICAD developed secondary to the lidocaine injection trauma. Although the carotid neurovascular bundle anatomically is relatively distant from the anesthetic block target areas, there is always a possibility of an erroneous needle insertion more posteriorly and medially in the proximity of the neurovascular carotid bundle, causing an internal carotid artery injury [5]. Also, cervical hyperextension and fully opened mouth during the dental procedure can contribute to the development of ICAD as this position can compress the cervical internal carotid artery against upper cervical vertebra and facilitate the needle reaching the submandibular capsule. Furthermore, in cases of needle insertion behind the second molar level, it may reach the posterior border of the mylohyoid muscle and penetrate into the carotid triangle. Periodontal infection also contributes majorly in pathogenesis [9-10]. Infection is associated with secretion of inflammatory cytokines, free radicals, and proteases that can lead to vessel wall weakening and increased susceptibility for rupture [9-10]. Given all these circumstances, the possible role of direct injection trauma in ICAD development cannot be excluded. To prevent thromboembolic complications, anticoagulation with intravenous heparin, followed by oral warfarin, has been recommended for all patients with acute dissections of the carotid or vertebral artery, regardless of the type of symptoms, unless there are contraindications, such as an intracranial extension of the dissection [6]. Spontaneous ICA dissections usually have a favorable prognosis, with approximately 90% of cases resolving without serious sequelae [7].\n\nConclusions\nOur case highlights a rare presentation of ICAD resulting from a lidocaine nerve block injection trauma and now adds to the limited number of cases in the literature describing this uncommon phenomenon. ICAD development after dental work is a rare but potentially life-threatening clinical scenario; therefore, precaution should be taken in managing patients with periodontal infections to minimize the risk of arterial injury.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Intracranial atherosclerosis: current understanding and perspectives J Stroke Bang OY 27 35 16 2014 24741562 \n2 Ischemic stroke in patients under 45 Neurol Clin Bogousslavsky J Pierre P 113 124 10 1992 http://www.ncbi.nlm.nih.gov/pubmed/1556998 1556998 \n3 Incidence and outcome of cervical artery dissection: a population-based study Neurology Lee VH Brown RD Jr Mandrekar JN Mokri B 1809 1812 67 2006 17130413 \n4 Traumatic dissecting aneurysm of left internal carotid, anterior cerebral and middle cerebral arteries J Neuropathol Exp Neurol Dratz HM Woodhall B 286 291 6 1947 20254509 \n5 Internal carotid artery dissection after inferior alveolar nerve block for third molar dental care presented as hypoglossal nerve palsy Vasc Endovascular Surg De Santis F Martini G Thüringen P 591 595 46 2012 22914855 \n6 Spontaneous dissection of the carotid and vertebral arteries N Engl J Med Schievink WI 898 906 344 2001 11259724 \n7 Headache and neck pain in spontaneous internal carotid and vertebral artery dissections Neurology Silbert PL Mokri B Schievink WI 1517 1522 45 1995 7644051 \n8 Carotid artery dissection presenting as a painless Horner’s syndrome in a pilot: fit to fly? Aviat Space Environ Med Venketasubramanian N Singh J Hui F Lim MK 307 310 69 1998 https://www.ncbi.nlm.nih.gov/pubmed/?term=Aviat+Space+Environ+Med.+1998%2C+307%E2%80%93310 9549569 \n9 Association of cervical artery dissection with recent infection Arch Neurol Grau AJ Brandt T Buggle F 851 856 56 1999 10404987 \n10 Infection and the risk of spontaneous cervical artery dissection. A case-control study Stroke Guillon B Berthet K Benslamia L 0 81 34 2003\n\n",
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"literaturereference": "Rosenberg J.E., Ballman K.A., Halabi S., Atherton P.J., Mortazavi A., Sweeney C., et al.. Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance). J. Clin. Oncol.. 2021;39:22:2486-2496",
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{
"abstract": "Anaphylactoid reactions from blood contact with AN69 hemodialysis membrane in patients taking ACE inhibitors are well-known. Modified AN69 dialyzers (ST-AN69) were invented to create a membrane combining low thrombogenic properties with safety with ACE inhibitors. We report four patients taking ACE inhibitors that presented anaphylactoid reactions with ST-AN69.",
"affiliations": "Service de néphrologie, centre hospitalier universitaire de Sherbrooke, 12e avenue Nord, Sherbrooke, Quebec, Canada J1H 5N4.",
"authors": "Roux|Véronique D|VD|;Plaisance|Martin|M|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D008567:Membranes, Artificial; D004656:Enalapril; D002216:Captopril",
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"medline_ta": "Nephrol Ther",
"mesh_terms": "D000368:Aged; D000707:Anaphylaxis; D000806:Angiotensin-Converting Enzyme Inhibitors; D002216:Captopril; D004656:Enalapril; D004867:Equipment Design; D005260:Female; D006440:Hemofiltration; D006801:Humans; D006973:Hypertension; D007676:Kidney Failure, Chronic; D008297:Male; D008567:Membranes, Artificial; D008875:Middle Aged; D006435:Renal Dialysis",
"nlm_unique_id": "101248950",
"other_id": null,
"pages": "335-8",
"pmc": null,
"pmid": "18514054",
"pubdate": "2008-10",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Anaphylactoid reactions with the use of ST-AN69 dialysers in patients taking ACE inhibitors.",
"title_normalized": "anaphylactoid reactions with the use of st an69 dialysers in patients taking ace inhibitors"
} | [
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"literaturereference": "Roux VD, Plaisance M.. Anaphylactoid reactions with the use of ST-AN69 dialysers in patients taking ACE inhibitors.. NEPHROLOGIE AND THERAPEUTIQUE. 2008;4(5):335-338",
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{
"abstract": "Aminoglycoside-induced nephrotoxicity is not uncommon. Netilmicin being a member of gentamicin family has the advantage of being relatively free from ototoxicity and nephrotoxicity and is also prescribed for gentamicin resistant cases. In spite of these benefits with netilmicin, occasional development of symptomatic hypomagnesemia, hypocalcemia, and hypokalemia due to renal electrolyte wasting cannot be ruled out. Here we describe two cases of carpopedal spasm due to hypocalcemia following use of netilmicin.",
"affiliations": "Department of Pharmacology, Maharaja Krishna Chandra Gajapati Medical College and Hospital, Berhampur, Odisha, India.;Department of Urology, Maharaja Krishna Chandra Gajapati Medical College and Hospital, Berhampur, Odisha, India.;Department of Pharmacology, Maharaja Krishna Chandra Gajapati Medical College and Hospital, Berhampur, Odisha, India.",
"authors": "Ramani|Roja Y|RY|;Panigrahy|Benu|B|;Rath|Bandana|B|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0976-500X.136112",
"fulltext": "\n==== Front\nJ Pharmacol PharmacotherJ Pharmacol PharmacotherJPPJournal of Pharmacology & Pharmacotherapeutics0976-500X0976-5018Medknow Publications & Media Pvt Ltd India JPP-5-21110.4103/0976-500X.136112Case ReportNetilmicin-induced carpopedal spasm Ramani Roja Y. Panigrahy Benu 1Rath Bandana Department of Pharmacology, Maharaja Krishna Chandra Gajapati Medical College and Hospital, Berhampur, Odisha, India1 Department of Urology, Maharaja Krishna Chandra Gajapati Medical College and Hospital, Berhampur, Odisha, IndiaAddress for correspondence: Roja Y Ramani, Department of Pharmacology, Maharaja Krishna Chandra Gajapati Medical College, Berhampur, Orrisa - 760 004, India. E-mail: yrramani@gmail.comJul-Sep 2014 5 3 211 213 31 10 2013 30 11 2013 08 2 2014 Copyright: © Journal of Pharmacology and Pharmacotherapeutics2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Aminoglycoside-induced nephrotoxicity is not uncommon. Netilmicin being a member of gentamicin family has the advantage of being relatively free from ototoxicity and nephrotoxicity and is also prescribed for gentamicin resistant cases. In spite of these benefits with netilmicin, occasional development of symptomatic hypomagnesemia, hypocalcemia, and hypokalemia due to renal electrolyte wasting cannot be ruled out. Here we describe two cases of carpopedal spasm due to hypocalcemia following use of netilmicin.\n\nCarpopedal spasmhypocalcemianetilmicin\n==== Body\nINTRODUCTION\nNetilmicin, a semi-synthetic aminoglycoside, is highly effective against gram negative infections of the urinary tract (UTI), skin and skin structure (SSTI), and lower respiratory tract (RTI), as well as in intraabdominal infections and septicemia.[1] It has similar pharmacokinetic properties and dosage to that of gentamicin. Its major advantages are comparable or superior efficacy over other aminoglycosides, good clinical efficacy against gentamicin-resistant strains with relatively reduced ototoxicity and nephrotoxicity.[234] Hypocalcemia manifesting as carpopedal spasm with this drug has not been reported till date. Here we report two cases of carpopedal spasm following use of netilmicin prescribed for genitourinary surgery.\n\nCASE REPORTS\nCase 1\nA 12-year-old boy had to undergo operative procedure for epispadias and was on surgical prophylaxis with netilmicin 150 mg i.v. twice daily and ceftriaxone (500 mg) i.v twice daily. The boy received both the drugs for 3 days (six doses) following which he developed severe spasm of the feet and hands [Figures 1–3]. On observation the patient was irritable, there was flexion of the hands at the wrists and of the fingers at the metacarpophalangeal joints and extension of the fingers at the inter-phalangeal joints; the feet were dorsiflexed at the ankles and the toes plantar flexed. Immediate laboratory investigation revealed the following picture: Serum calcium 7.2 mg/dL (normal, 8.7-11 mg/dL), potassium 3.9 mmol/L (normal, 3.5-5.5 mmol/L), and sodium of 145 mmol/L (normal, 135-155 mmol/L), serum creatinine 3.0 mg/dL and serum albumin 3.4 g/dL (normal, 3.8-4.4 g/dL) with normal urine output. Total bilirubin, serum glutamic oxaloacetic transaminase (SGOT), and serum glutamic-pyruvic transaminase (SGPT) were also normal. Assuming that the patient developed drug-induced nonoliguric renal failure; both the drugs were withdrawn and the surgery postponed. The hypocalcemia was managed with i.v calcium gluconate. 24 h following this episode the laboratory investigations were repeated, which showed serum calcium 9.3 mg/dL, potassium, 3.9 mmol/L, sodium 144 mmol/L and serum albumin 4.2 g/dL [Table 1]. On recovery, the patient was discharged with oral calcium supplementation. After 4 weeks the surgery was planned. Netilmicin 300 mg once daily was given preoperatively for 1 day and continued postoperatively. But after 3 days (4 doses) postoperatively the patient developed the same features of carpopedal spasm with laboratory findings of hypocalcemia. On withdrawal of netilmicin and calcium supplementation the boy recovered.\n\nFigure 1 Carpal spasm (left hand)\n\nFigure 2 Carpal spasm (right hand)\n\nFigure 3 Flexed legs\n\nTable 1 Laboratory findings of netilmicininduced carpopedal spasm\n\nCase 2\nA 8-year-old boy diagnosed to be a case of hypospadias was given netilmicin 150 mg i.v. once daily as surgical prophylaxis for 2 days and was operated on the second day. Netilmicin in the same dose was continued postoperatively, but following the fifth dose, the child developed the characteristic features of tetany. Laboratory findings revealed low serum calcium (7.6 mg/dL), high serum creatinine (2.5 mg/dL) [Table 1]. Urine output was normal with serum electrolytes (Na+ and K+) within the normal range. Assuming that the reaction was due to hypocalcemia induced by netilmicin, it was withdrawn and supplemented with piperacillin + tazobactum. The child recovered following i.v. administration of calcium gluconate.\n\nDISCUSSION\nCarpopedal spasm (seen in tetany) is usually caused by low ionized serum calcium concentration, which causes increased excitability of peripheral nerves resulting in carpopedal spasm, convulsion, and stridor. The total serum calcium <8.5 mg/dL may be associated with tetany. We reported here two cases of carpopedal spasm caused by netilmicin.\n\nA dose dependent nephrotoxicity occurs with aminoglycoside therapy despite adequate fluid volume control and drug level monitoring. Renal electrolyte wasting is occasionally caused by symptomatic hypomagnesemia, hypocalcemia, and hypokalemia when treated with these drugs[5] but tetany has not been frequently reported except for a single report on paramomycin.[6] Several risk factors, like volume depletion, sepsis, liver and renal dysfunction, hypokalemia, hypomagnesemia, advanced age, prolonged therapy, type of aminoglycoside, time and frequency of dosing, an elevated serum aminoglycoside concentration, and interactions with other nephrotoxic drugs such as vancomycin, amphotericin B, piperacillin, cephalosporins, foscarnet, allopurinol, NSAIDs, inhibitors of angiotensin converting enzyme, cyclosporine, and cisplatin have been identified.[78] Among all aminoglycosides, netilmicin stands out clear because of its least toxicity and superior clinical efficacy, even in some resistant microorganisms.[39] Though studies show a clear benefit of the ceftriaxone-netilmicin combination,[10] their potential for interaction cannot be overlooked. Therefore netilmicin and ceftriaxone being nephrotoxic, both may be the suspects in the case report one. But it was also observed that, netilmicin prescribed alone in once daily dose later on (in case report one) and even half the dose (in case report two) also resulted in hypocalcemia and carpopedal spasm (tetany). In both the cases, laboratory findings with regard to serum electrolytes, urea, creatinine, albumin prior to administration of netilmicin were within normal range. Other causes of hypocalcemia like vitamin D deficiency, chronic renal failure, hypoparathyroidism were ruled out in both the cases. Another important point to be noted here that, though majority of patients in this hospital setup are being given netilmicin alone/netilmicin + ceftriaxone in combination, this type of adverse effects are seldom reported. Therefore netilmicin is probably the drug responsible for this rare adverse effect in these two cases (causality assessment using Naranjo's Adverse Drug Reaction probability score = score 7 and WHO-UMC causality assessment scale).\n\nCONCLUSION\nRecent studies have emphasized the role of calcium in aminoglycoside-induced renal failure.[11] Netilmicin has long been used both alone and in combination with ceftriaxone in the adult and pediatric population for the treatment of severe gram negative infections in hospital settings. Judicious use of such drugs is required to prevent untoward side effects like tetany and its associated disability. Identifying high risk patients and quick recognition of drug-induced injury with prompt cessation of the offending drug is the key to managing such cases before the injury causes permanent damage to the renal tissue.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Campoli-Richards DM Chaplin S Sayce RH Goa KL Netilmicin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use Drugs 1989 38 703 56 2689137 \n2 Panwalker AP Malow JB Zimelis VM Jackson GG Netilmicin: Clinical efficacy, tolerance, and toxicity Antimicrob Agents Chemother 1978 13 170 6 348092 \n3 Buckwold FJ Ronald AR Lank B Thompson L Fox L Harding GK Clinical efficacy and toxicity of netilmicin in the treatment of gram-negative infections Can Med Assoc J 1979 120 161 7 761144 \n4 Martínez-Salgado C López-Hernández FJ López-Novoa JM Glomerular nephrotoxicity of aminoglycosides: Review Toxicol Appl Pharmacol 2007 223 87 \n5 Elliott C Newman N Madan A Gentamicin effects on urinary electrolyte excretion in healthy subjects Clin Pharmacol Ther 2000 67 16 21 10668849 \n6 Thakur CP Tetany in kala azar patients treated with paromomycin Indian J Med Res 2008 127 489 93 18653914 \n7 Bertino JS Jr Booker LA Franck PA Jenkins PL Franck KR Nafziger AN Incidence of and significant risk factors for aminoglycoside-associated nephrotoxicity in patients dosed by using individualized pharmacokinetic monitoring J Infect Dis 1993 167 173 9 8418164 \n8 Verpooten GA Tulkens PM Molitoris BA Aminoglycosides and Vancomycin Clinical Nephrotoxins 2003 2nd ed Dordrecht, The Netherlands Kluwer Academic Publishers 151 62 \n9 Kumana CR Yuen KY Parenteral aminoglycoside therapy. Selection, administration and monitoring Drugs 1994 47 902 13 7521830 \n10 Fantin B Pangon B Potel G Vallois JM Caron F Bure A Ceftriaxone-netilmicin combination in single-daily-dose treatment of experimental escherichia coli endocarditis Antimicrob Agents Chemother 1989 33 767 70 2665645 \n11 Lortholary O Blanchet F Nochy D Heudes D Seta N Amirault P Effects of diltiazem on netilmicin-induced nephrotoxicity in rabbits Antimicrob Agents Chemother 1993 37 1790 8 8239586\n\n",
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"abstract": "Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are life-threatening conditions caused by drug reactions. There are multiple causative drugs and different risk factors associated with SJS/TEN.\nTo study the epidemiology of SJS/TEN and associated mortality rate in Qassim region, Saudi Arabia. Methodology. A retrospective chart review of all patients with the diagnosis of SJS/TEN who were admitted to King Fahad Specialist Hospital (KFSH) in Qassim region, Saudi Arabia, for the period between Jan 2014 to Jan 2019. The Careware information health system is used at KFSH, and patients were identified searching the diagnosis SJS/TEN.\nTotal of 10 patients with diagnosis of SJS/TEN were admitted to KFSH for the period from Jan 2014 to Jan 2019. Antibiotics were the culprit in 5 out of 10 patients. 9 out of 10 patients survived with good outcome. One patient with the diagnosis of TEN died, given extensive skin involvement complicated by sepsis.\nDespite the limitation of this study given small sample size, this is the first study of its kind that discusses the epidemiology of SJS/TEN in Saudi Arabia. We found the estimated incidence rate of SJS/TEN in Qassim region to be 7.6 cases per million person-years. Antibiotics and antiepileptics were the culprits in 8 out of 10 patients.",
"affiliations": "Qassim University, College of Medicine, Buraydah, Saudi Arabia.;Ministry of Health, KFSH, Dammam, Saudi Arabia.;Qassim University, College of Medicine, Buraydah, Saudi Arabia.;Qassim University, College of Medicine, Buraydah, Saudi Arabia.;Qassim University, College of Medicine, Buraydah, Saudi Arabia.;Qassim University, College of Medicine, Buraydah, Saudi Arabia.;Ministry of Health, KFSH, Dammam, Saudi Arabia.;Ministry of Health, KFSH, Dammam, Saudi Arabia.",
"authors": "Alajaji|Abdullah|A|https://orcid.org/0000-0002-5540-5465;Chandra Shekaran|Jagannath|J|;Mohammed Aldhabbah|Omar|O|;Alhindi|Hajar Abdullah|HA|;Almazyad|Nouf Salem|NS|;Aljutayli|Ziyad Abdulrahman|ZA|;Abaalkhail|Saleh|S|;Alfouzan|Saleh|S|",
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"doi": "10.1155/2020/7524726",
"fulltext": "\n==== Front\nDermatol Res Pract\nDermatol Res Pract\nDRP\nDermatology Research and Practice\n1687-6105 1687-6113 Hindawi \n\n10.1155/2020/7524726\nResearch Article\nToxic Epidermal Necrolysis (TEN)/Stevens-Johnson Syndrome (SJS) Epidemiology and Mortality Rate at King Fahad Specialist Hospital (KFSH) in Qassim Region of Saudi Arabia: A Retrospective Study\nhttps://orcid.org/0000-0002-5540-5465Alajaji Abdullah abdullahalajaji@qumed.edu.sa\n1\n Chandra Shekaran Jagannath \n2\n Mohammed Aldhabbah Omar \n1\n Alhindi Hajar Abdullah \n1\n Almazyad Nouf Salem \n1\n Aljutayli Ziyad Abdulrahman \n1\n Abaalkhail Saleh \n2\n Alfouzan Saleh \n2\n \n1Qassim University, College of Medicine, Buraydah, Saudi Arabia\n\n2Ministry of Health, KFSH, Dammam, Saudi Arabia\nAcademic Editor: Craig G. Burkhart\n\n\n2020 \n9 10 2020 \n2020 75247263 7 2020 13 9 2020 17 9 2020 Copyright © 2020 Abdullah Alajaji et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\n Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are life-threatening conditions caused by drug reactions. There are multiple causative drugs and different risk factors associated with SJS/TEN. \n\nObjectives\n To study the epidemiology of SJS/TEN and associated mortality rate in Qassim region, Saudi Arabia. Methodology. A retrospective chart review of all patients with the diagnosis of SJS/TEN who were admitted to King Fahad Specialist Hospital (KFSH) in Qassim region, Saudi Arabia, for the period between Jan 2014 to Jan 2019. The Careware information health system is used at KFSH, and patients were identified searching the diagnosis SJS/TEN. \n\nResults\n Total of 10 patients with diagnosis of SJS/TEN were admitted to KFSH for the period from Jan 2014 to Jan 2019. Antibiotics were the culprit in 5 out of 10 patients. 9 out of 10 patients survived with good outcome. One patient with the diagnosis of TEN died, given extensive skin involvement complicated by sepsis. \n\nConclusion\n Despite the limitation of this study given small sample size, this is the first study of its kind that discusses the epidemiology of SJS/TEN in Saudi Arabia. We found the estimated incidence rate of SJS/TEN in Qassim region to be 7.6 cases per million person-years. Antibiotics and antiepileptics were the culprits in 8 out of 10 patients.\n==== Body\n1. Introduction\nToxic epidermal necrolysis and Stevens-Johnson syndrome are acute inflammatory skin reactions [1]. SJS/TEN can affect any age group but is more prevalent in women, patients with HIV, and elderly. The global incidence rate of SJS/TEN is low [2].\n\nStudies showed increased incidence with age and the number of medications taken [3]. The onset is generally caused by exposure to a medication such as nonsteroidal anti-inflammatory agents, antibiotics, and anticonvulsants [3]. It generally presents with skin blistering and desquamation with involvement of mucosal surfaces.\n\nToxic epidermal necrolysis is the most serious type of drug-induced skin reactions and involves >30% body surface area (BSA). Stevens-Johnson syndrome involves <10% of BSA while Stevens-Johnson syndrome/toxic epidermal necrolysis overlap involves 10%–30% of BSA. Mucous membranes such as oral, genital, anal, nasal, and conjunctival mucosa are typically involved in toxic epidermal necrolysis and Stevens-Johnson syndrome. Toxic epidermal necrolysis is associated with 30%–50% mortality and long-term sequelae [3]. Treatment involves early cessation of causative medication, supportive care, and admission to burn unit if needed [1]. Specific treatment with immunosuppressive drugs or immunoglobulins showed conflicting results regarding outcomes, and it remains controversial [1, 2]. The disease mechanism is not fully understood, but it appears that there are immunological mechanisms, cytotoxic reactions, and delayed hypersensitivity that could be involved in the pathogenesis [1, 2].\n\nThe rationale of this study is to explore the epidemiology and mortality rate of SJS/TEN in Saudi Arabia. There is no published data about SJS/TEN epidemiology in Saudi Arabia or other gulf countries, and despite the small sample size, we hope that this study will shed some light on such an important topic and hopefully will encourage other researchers in the region to conduct a larger, multicenter study for better understanding of this life-threatening condition.\n\n2. Methodology\nA retrospective cohort study was conducted at King Fahad Specialist Hospital (KFSH) in Qassim region, Saudi Arabia. KFSH is a tertiary hospital with a capacity of 420 beds, and it is the largest hospital in Qassim region which has a population of 1.3 million and located in the center of Saudi Arabia. Prior to starting the study, the ethical approval was obtained from Qassim Local Research Ethics committee (QREC). The hospital uses Careware information health system, and we identified all study patients by searching the diagnosis SJS, TEN, or SJS/TEN spectrum for the period from Jan 2014 to Jan 2019 from all hospital services. Ten patients were identified who met the diagnosis of SJS, TEN, or SJS/TEN. We reviewed the following variables for each patient; age, gender, diagnosis, and year of the diagnosis, causative agents, treatment, duration of hospital stay, and survival outcome.\n\n3. Result\nWe identified 10 patients from KFSH hospital who met the diagnosis of SJS, TEN or SJS/TEN and were admitted between Jan 2014 to Jan 2019. Five patients were between 16 and 36 years old, three patients between 37 and 57 years old, and two patients were older than 57 years old. Six female patients and four were males.\n\nFour patients were diagnosed with SJS, and six patients were diagnosed with TEN.\n\nThe causative agent of SJS/TEN was amoxicillin/clavulanic acid in 3 patients and carbamazepine in 2 patients. The culprit medications for the remaining 5 patients were levetiracetam, acetaminophen, azithromycin, ciprofloxacin, and unknown OTC medication in one patient. Four patients received IVIG plus supportive treatment, two patients were treated by IVIG in addition to oral corticosteroid and supportive treatment, two patients were managed by corticosteroid plus supportive treatment, and remaining two patients were managed by supportive treatment only.\n\nOne out of the ten patients died and the remaining patients survived with good outcome (Table 1).\n\n4. Discussion\nSJS/TEN is an acute life-threatening condition typically caused by drug hypersensitivity [3]. There is no prior study that discussed the epidemiology of TEN/SJS in the kingdom of Saudi Arabia or other gulf countries. We compared our results with another epidemiological study in the Middle East that was conducted in Israel [4]. They reviewed 26 patients with SJS/TEN, and they found a higher percentage of patients with SJS compared with our results. 65% of total study patients had SJS compared with 40% of total patients in our study. There was no significant difference in demographics between the 2 studies. The mortality rate was 15% compared with 10% in our study (one death). Antiepileptic drugs were the most common causative drugs, while antibiotics in our study were more common [4].\n\nEpidemiology and incidence rate (IR) of SJS/TEN is a variable between different countries. A large observational study in the United Kingdom showed a TEN/SJS incidence ratio (IR) of 5.76 cases per million person-years in the UK [5]. Another epidemiological study in the United States showed IR of SJS/TEN of 12.7 cases per million person-years [6]. In our study, overall total number of person-years at risk in Qassim region was 1.3 million (Qassim population), and we estimated the IR to be 7.6 cases per million person-years.\n\nThe most commonly causative medications reported in the literature are antibiotics, anticonvulsants, allopurinol, and NSAID [3, 7, 8].\n\nThe gender distribution in our study was similar to published data in the literature [5, 9]. The mean age (SD) in this study sample was 38 ± (19.3). With regards to duration of hospital stay in this study, the average was 14.2 which is shorter than the average length of hospital stay reported by Chan et al. which was 20 days (range of 1–133 days) [10].\n\nAmong four patients in this study who received IVIG, one patient died which is comparable to the mortality rate reported in Israel 4 and was comparable to the mortality rate in Puerto Rico, USA, reported by Carrasquillo et al. who studied 30 patients with the diagnosis of SJS/TEN and found the mortality rate to be 12.5% [11].\n\nThe patient who died in our study was 35-year-old female, diagnosed with TEN with more than 90% skin involvement complicated by sepsis. There was a delay in her transfer from a nearby private hospital where she was managed by supportive care only with no other interventions.\n\nLimitations of this retrospective study include small sample size and the fact that it is a single center study. We also could not estimate the relative exposure to the culprit medications in the population, and this can affect the relative risk of those culprit medications in causing SJS/TEN.\n\nTo explore the epidemiology of this life-threatening condition in more depth in Saudi Arabia, we recommend a larger study sample with participation of multiple centers in Saudi Arabia.\n\n5. Conclusion\nDespite the limitation of this study given small sample size, this is the first study of its kind that discusses the epidemiology of SJS/TEN in Saudi Arabia. We found the estimated incidence rate of SJS/TEN to be 7.6 cases per million person-years. Antibiotics and antiepileptics were the culprits in 8 out of 10 patients.\n\nAcknowledgments\nThe authors would like to thank King Fahad Specialist Hospital administration for facilitating the process of the study.\n\nData Availability\nThe patient data used to support the findings of this study are included within the supplementary information file. Clinical data and demographics are available within the article.\n\nDisclosure\nThis research was not funded, and the cost will be divided between participants.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.\n\nSupplementary Materials\nSupplementary Materials Supplementary data contains clinical and demographic details of each patient and it includes the admission dates.\n\nClick here for additional data file.\n\n Table 1 The demographics, clinical characteristics, and outcome of study patients (N = 10).\n\n \tGender\tAge\tDiagnosis\tCulprit medication\tComorbidities\tLength of stay\tMortality outcome\t\nPatient no. 1\tFemale\t35\tTEN\tAmoxicillin/clavulanic acid\t—\t6 days\tDied\t\nPatient no. 2\tFemale\t16\tTEN\tAmoxicillin/Clavulanic acid\t—\t70 days\tAlive\t\nPatient no. 3\tMale\t42\tTEN\tAmoxicillin/Clavulanic acid\tBronchial asthma\t19 days\tAlive\t\nPatient no. 4\tFemale\t43\tSJS\tAcetaminophen\t—\t7 days\tAlive\t\nPatient no. 5\tMale\t17\tSJS\tUnknown drug\t—\t3 days\tAlive\t\nPatient no. 6\tMale\t26\tSJS\tAzithromycin\t—\t4 days\tAlive\t\nPatient no. 7\tFemale\t74\tSJS\tCiprofloxacin\tHTN, PE, CVA\t5 days\tAlive\t\nPatient no. 8\tFemale\t45\tTEN\tLevetiracetam\tEpilepsy, HTN, hypothyroidism, CVA\t6 days\tAlive\t\nPatient no. 9\tMale\t20\tTEN\tCarbamazepine\tEpilepsy\t14 days\tAlive\t\nPatient no. 10\tFemale\t62\tTEN\tCarbamazepine\tBronchial asthma, HTN\t8 days\tAlive\n==== Refs\n1 Gilbert M. Scherrer L. A. Efficacy and safety of cyclosporine in Stevens-Johnson syndrome and toxic epidermal necrolysis Dermatologic Therapy 2019 32 1 e12758 10.1111/dth.12758 2-s2.0-85055665477 \n2 Downey A. Jackson C. Harun N. Cooper A. Toxic epidermal necrolysis: review of pathogenesis and management Journal of the American Academy of Dermatology 2012 66 6 995 1003 10.1016/j.jaad.2011.09.029 2-s2.0-84861235187 22169256 \n3 Schwartz R. A. McDonough P. H. Lee B. W. Toxic epidermal necrolysis Journal of the American Academy of Dermatology 2013 69 2 187.e1 187.e16 10.1016/j.jaad.2013.05.002 2-s2.0-84880372333 23866879 \n4 Maggio N. Firer M. Zaid H. Causative drugs of Stevens-Johnson syndrome and toxic epidermal necrolysis in Israel The Journal of Clinical Pharmacology 2017 57 7 823 829 10.1002/jcph.873 2-s2.0-85012888036 28181259 \n5 Frey N. Jossi J. Bodmer M. The epidemiology of Stevens-Johnson syndrome and toxic epidermal necrolysis in the UK Journal of Investigative Dermatology 2017 137 6 1240 1247 10.1016/j.jid.2017.01.031 2-s2.0-85019946754 28202399 \n6 Hsu D. Y. Brieva J. Silverberg N. B. Silverberg J. I. Morbidity and mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis in United States adults Journal of Investigative Dermatology 2016 136 7 1387 1397 10.1016/j.jid.2016.03.023 2-s2.0-84992523193 27039263 \n7 Zhang A. J. Nygaard R. M. Endorf F. W. Hylwa S. A. Stevens‐Johnson syndrome and toxic epidermal necrolysis: retrospective review of 10‐year experience International Journal of Dermatology 2019 58 9 1069 1077 10.1111/ijd.14409 2-s2.0-85062363193 30825193 \n8 Yang L. Shou Y.-h. Li F. Zhu X.-h. Yang Y.-s. Xu J.-h. Retrospective study of 213 cases of Stevens-Johnson syndrome and toxic epidermal necrolysis from China Burns 2020 46 4 959 969 10.1016/j.burns.2019.10.008 31898979 \n9 Traikia C. Hua C. Le Cleach L. Individual‐ and hospital‐level factors associated with epidermal necrolysis mortality: a nationwide multilevel study, France, 2012–2016 British Journal of Dermatology 2020 182 4 900 906 10.1111/bjd.18294 2-s2.0-85071913668 31260078 \n10 Chan L. Cook D. K. A 10‐year retrospective cohort study of the management of toxic epidermal necrolysis and Stevens‐Johnson syndrome in a New South Wales state referral hospital from 2006 to 2016 International Journal of Dermatology 2019 58 10 1141 1147 10.1111/ijd.14426 2-s2.0-85063335107 30908601 \n11 Carrasquillo O. Y. Santiago‐Vazquez M. Cardona R. Cruz‐Manzano M. Figueroa L. D. Stevens‐Johnson syndrome and toxic epidermal necrolysis: a retrospective descriptive study International Journal of Dermatology 2019 58 11 1293 1299 10.1111/ijd.14493 2-s2.0-85067474720 31166019\n\n",
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{
"abstract": "Thrombopoietin (TPO) is the major regulator of megakaryopoiesis. Measurement of serum TPO levels may help distinguish between various causes of thrombocytopenia and predict treatment response to TPO receptor agonists. Serum TPO levels from 118 healthy volunteers and 88 patients with abnormal platelet counts were measured using a quantitative ELISA assay. The mean (range) TPO level in healthy volunteers was 39 (7-99) pg/mL. TPO values were correlated with the patient's diagnosis, platelet count, and response to TPO receptor agonists. 88 patients with history of consumptive thrombocytopenia (39) or hypoproliferative thrombocytopenia (49) were analyzed. Median (interquartile range) TPO level for consumptive thrombocytopenia patients was 63 (48-98) pg/mL with a corresponding median (interquartile range) platelet count of 73 (28-146) × 10(9) /L. In contrast, hypoproliferative thrombocytopenia patients had platelet counts [59 (30-117) × 10(9) /L] comparable with consumptive thrombocytopenia patients, but significantly higher serum TPO levels [706 (358-1546) pg/mL, P < 0.0001]. Analysis of 21 ITP patients treated with TPO receptor agonists demonstrated that a TPO level >95 pg/mL was associated with lack of clinical response (P < 0.002). TPO levels may have diagnostic utility in discriminating between patients with hypoproliferative and consumptive thrombocytopenia. Elevated TPO levels in ITP patients may predict a poor clinical response to treatment with TPO receptor agonists.",
"affiliations": "Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.",
"authors": "Makar|Robert S|RS|;Zhukov|Olga S|OS|;Sahud|Mervyn A|MA|;Kuter|David J|DJ|",
"chemical_list": "D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; C082218:MPL protein, human; D013926:Thrombopoietin; C488777:romiplostim; C520809:eltrombopag",
"country": "United States",
"delete": false,
"doi": "10.1002/ajh.23562",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-8609",
"issue": "88(12)",
"journal": "American journal of hematology",
"keywords": null,
"medline_ta": "Am J Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D016736:Antiphospholipid Syndrome; D001565:Benzoates; D001855:Bone Marrow Diseases; D004341:Drug Evaluation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D006834:Hydrazines; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic; D011720:Pyrazoles; D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D012189:Retrospective Studies; D016879:Salvage Therapy; D013921:Thrombocytopenia; D034061:Thrombopoiesis; D013926:Thrombopoietin",
"nlm_unique_id": "7610369",
"other_id": null,
"pages": "1041-4",
"pmc": null,
"pmid": "23913253",
"pubdate": "2013-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Thrombopoietin levels in patients with disorders of platelet production: diagnostic potential and utility in predicting response to TPO receptor agonists.",
"title_normalized": "thrombopoietin levels in patients with disorders of platelet production diagnostic potential and utility in predicting response to tpo receptor agonists"
} | [
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] |
{
"abstract": "Retinoid therapy has contributed to improved outcomes in neuroblastoma. Clinical trials of fenretinide report favorable toxicity and disease stabilization in patients with high risk (HR) neuroblastoma. Skeletal effects have been described with other retinoids, but not with fenretinide to date. Two patients with HR, metastatic, refractory neuroblastoma received protracted courses of oral fenretinide for more than 5 years' duration. Both developed premature long bone physeal closure, causing limb length discrepancies; their neuroblastoma remains in remission. The radiographic and clinical findings reported suggest these skeletal abnormalities may be a consequence of treatment with 13-cis-retinoic acid (13cisRA) followed by prolonged oral fenretinide exposure.",
"affiliations": "Department of Pediatrics, Stanford University School of Medicine, Stanford, California. asteine@stanford.edu.;Department of Radiology, University of California at San Francisco, San Francisco, California.;Department of Pediatrics, Division of Hematology/Oncology, Stanford University School of Medicine, Stanford, California.",
"authors": "Steineck|Angela|A|;MacKenzie|John D|JD|;Twist|Clare J|CJ|",
"chemical_list": "D000970:Antineoplastic Agents; D017313:Fenretinide; D015474:Isotretinoin",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26124",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "63(11)",
"journal": "Pediatric blood & cancer",
"keywords": "fenretinide; late-effects; neuroblastoma; pediatric oncology; premature physeal closure; skeletal toxicity",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000970:Antineoplastic Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D017313:Fenretinide; D006132:Growth Plate; D006801:Humans; D015474:Isotretinoin; D008297:Male; D009447:Neuroblastoma",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "2050-3",
"pmc": null,
"pmid": "27399265",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Premature physeal closure following 13-cis-retinoic acid and prolonged fenretinide administration in neuroblastoma.",
"title_normalized": "premature physeal closure following 13 cis retinoic acid and prolonged fenretinide administration in neuroblastoma"
} | [
{
"companynumb": "US-AKORN PHARMACEUTICALS-2016AKN00769",
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"drugdosagetext": "800 MG (2,475 MG/M^2/DAY), 3X/DAY FOR 7 DAYS",
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"drugindication": "NEUROBLASTOMA",
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"drugdosagetext": "CUMULATIVE DOSE: 13,440 MG/M^2, AFTER SIX COURSES",
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"drugindication": "NEUROBLASTOMA",
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"reaction": [
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"reactionmeddraversionpt": "19.1",
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},
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"reactionoutcome": "1"
}
],
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},
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"literaturereference": "STEINECK A, MACKENZIE JD, TWIST CJ. PREMATURE PHYSEAL CLOSURE FOLLOWING 13-CIS-RETINOIC ACID AND PROLONGED FENRETINIDE ADMINISTRATION IN NEUROBLASTOMA. PEDIATR BLOOD CANCER (DOI: 10.1002/PBC.26124). 2016;63:2050-2053",
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] |
{
"abstract": "Gilteritinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor that has shown efficacy in patients with refractory or recurrent adult acute myeloid leukemia (AML) with FLT3 mutations. However, there are limited data for pediatric patients treated with this drug. Herein, we report the clinical courses of two children with FLT3-mutated recurrent AML who received gilteritinib. Case 1: An 11-year-old boy with secondary relapsed AML presented with an FLT3 internal tandem duplication (ITD) since the first recurrence. One week after gilteritinib initiation, blasts, which had comprised 90% of the white blood cells before treatment, almost disappeared from the peripheral blood without tumor lysis syndrome. The patient developed multiple adverse effects and died from the disease 2.5 months after gilteritinib initiation. Case 2: A 12-year-old girl diagnosed with AML was positive for FLT3 ITD. She received gilteritinib during her first relapse post-stem cell transplantation. After the drug was administered, the recipient cell counts increased, as determined by molecular tests (i.e., FISH), whereas microscopically, there was a complete response for 5 months with good performance status. Gilteritinib treatment in children with FLT3-mutated recurrent AML is feasible and effective. As a patient experienced several adverse effects with gilteritinib treatment, clinical trials are required to determine the appropriate pediatric dose of this medication.",
"affiliations": "Department of Hematology/Oncology, Saitama Children's Medical Center.;Department of Hematology/Oncology, Saitama Children's Medical Center.;Department of Hematology/Oncology, Saitama Children's Medical Center.;Department of Hematology/Oncology, Saitama Children's Medical Center.;Department of Hematology/Oncology, Saitama Children's Medical Center.;Department of Hematology/Oncology, Saitama Children's Medical Center.;Department of Hematology/Oncology, Saitama Children's Medical Center.;Department of Hematology/Oncology, Saitama Children's Medical Center.;Department of Hematology/Oncology, Saitama Children's Medical Center.;Department of Hematology/Oncology, Saitama Children's Medical Center.;Department of Hematology/Oncology, Saitama Children's Medical Center.;Department of Hematology/Oncology, Saitama Children's Medical Center.;Department of Hematology/Oncology, Saitama Children's Medical Center.;Department of Hematology/Oncology, Saitama Children's Medical Center.;Department of Hematology/Oncology, Saitama Children's Medical Center.",
"authors": "Fukuoka|Kohei|K|;Tsumura|Yusuke|Y|;Noguchi|Jun|J|;Sugawa|Masahiro|M|;Takaki|Torataro|T|;Hiraki|Takamasa|T|;Inoue|Kyohei|K|;Mitani|Yuichi|Y|;Tomita|Osamu|O|;Oshima|Koichi|K|;Yanagi|Masato|M|;Isobe|Kiyotaka|K|;Mori|Makiko|M|;Arakawa|Yuki|Y|;Koh|Katsuyoshi|K|",
"chemical_list": "D000814:Aniline Compounds; D011719:Pyrazines; C000609080:gilteritinib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.61.322",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "61(4)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "FLT3 internal tandem duplication; Gilteritinib; NUP98-NSD1 fusion; Pediatric acute myeloid leukemia",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000814:Aniline Compounds; D002648:Child; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009154:Mutation; D011719:Pyrazines; D012008:Recurrence; D051941:fms-Like Tyrosine Kinase 3",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "322-326",
"pmc": null,
"pmid": "32378574",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gilteritinib for pediatric FLT3 internal tandem duplication-positive recurrent acute myeloid leukemia.",
"title_normalized": "gilteritinib for pediatric flt3 internal tandem duplication positive recurrent acute myeloid leukemia"
} | [
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{
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"reactionmeddraversionpt": "24.0",
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{
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},
{
"reactionmeddrapt": "Hepatic function abnormal",
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"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "24.0",
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},
{
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},
{
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},
{
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{
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},
{
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{
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},
{
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{
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{
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},
{
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},
{
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{
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}
},
"primarysource": {
"literaturereference": "FUKUOKA K, TSUMURA Y, NOGUCHI J, SUGAWA M, TAKAKI T, HIRAKI T, ET AL.. GILTERITINIB FOR PEDIATRIC FLT3 INTERNAL TANDEM DUPLICATION?POSITIVE RECURRENT ACUTE MYELOID LEUKEMIA. THE JAPANESE JOURNAL OF CLINICAL HEMATOLOGY. 2020?61(4):322?6",
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"reactionmeddraversionpt": "23.1",
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},
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"reactionoutcome": "2"
},
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "2"
},
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "3"
},
{
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "2"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20181210"
}
},
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"literaturereference": "FUKUOKA K, TSUMURA Y, NOGUCHI J, SUGAWA M, TAKAKI T, HIRAKI T, ET AL.. GILTERITINIB FOR PEDIATRIC FLT3 INTERNAL TANDEM DUPLICATION?POSITIVE RECURRENT ACUTE MYELOID LEUKEMIA. [RINSHO KETSUEKI] THE JAPANESE JOURNAL OF CLINICAL HEMATOLOGY. 2020?61(4):322?6",
"literaturereference_normalized": "gilteritinib for pediatric flt3 internal tandem duplication positive recurrent acute myeloid leukemia",
"qualification": "2",
"reportercountry": "JP"
},
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"receiptdate": "20210304",
"receivedate": "20181231",
"receiver": {
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"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 15776225,
"safetyreportversion": 11,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
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"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20210419"
}
] |
{
"abstract": "Background: Streptococcal Toxic Shock Syndrome (STSS) is a serious condition that can arise from streptococcal postpartum endometritis. It is associated with a substantial increase in mortality rate and can rarely result in multiorgan infarction. Early recognition plays a vital role in patients' outcome. Objective: To report a case of complicated STSS and review the literature for previous case reports of streptococcal postpartum endometritis to determine if STSS diagnostic criteria (published by the Centers for Disease Control and Prevention) were fulfilled. Case presentation: This is a 41-year-old woman who presented 5 days after an uncomplicated vaginal delivery with endometritis complicated by invasive group A β-hemolytic streptococcus (GAS) infection and confirmed toxic shock syndrome. The patient was initially admitted to the critical care unit due to hemodynamic compromise requiring intravenous (IV) fluids, IV antibiotic therapy with penicillin and clindamycin, and IV immunoglobulin therapy. The patient subsequently developed multi-organ infarctions, acute respiratory distress syndrome requiring noninvasive respiratory support, and severe reactive arthritis. Literature review revealed 15 case reports of GAS postpartum endometritis, five met criteria for confirmed STSS. One patient died from severe septic shock leading to cardiopulmonary arrest. Thirteen out of 15 cases of postpartum endometritis occurred after uncomplicated vaginal delivery. Conclusion: STSS is a serious and possibly fatal medical condition that requires early diagnosis and treatment to prevent poor patient outcomes and death. Careful consideration to the patient's postpartum clinical presentation with the implementation of an intradisciplinary approach should be utilized.",
"affiliations": "Department of Internal Medicine, University of Alabama Huntsville Regional Campus , Huntsville, AL, USA.;Department of Internal Medicine, University of Alabama Huntsville Regional Campus , Huntsville, AL, USA.;Department of Pharmacy, Huntsville Hospital , Huntsville, AL, USA.;Department of Internal Medicine, University of Alabama Huntsville Regional Campus , Huntsville, AL, USA.;Department of Internal Medicine, University of Alabama Huntsville Regional Campus , Huntsville, AL, USA.",
"authors": "Riad|Mariam|M|https://orcid.org/0000-0001-5245-8724;Thottacherry|Elizabeth|E|https://orcid.org/0000-0003-0896-3760;Crawley|Christina|C|;Phillip-Abraham|Nessy|N|;Ibrahim|Farrah|F|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.1080/00325481.2020.1760031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0032-5481",
"issue": "132(6)",
"journal": "Postgraduate medicine",
"keywords": "Group A streptococcus; endometritis; renal infarction; spleen infarction; toxic shock syndrome",
"medline_ta": "Postgrad Med",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D016918:Arthritis, Reactive; D004716:Endometritis; D005260:Female; D005440:Fluid Therapy; D006801:Humans; D007668:Kidney; D010102:Oxygen Inhalation Therapy; D011645:Puerperal Infection; D012128:Respiratory Distress Syndrome; D012772:Shock, Septic; D013159:Splenic Infarction; D013290:Streptococcal Infections; D013297:Streptococcus pyogenes; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "0401147",
"other_id": null,
"pages": "526-531",
"pmc": null,
"pmid": "32379557",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Invasive Group A streptococcal postpartum endometritis associated with multi-organ infarctions: an uncommon case presentation and literature review.",
"title_normalized": "invasive group a streptococcal postpartum endometritis associated with multi organ infarctions an uncommon case presentation and literature review"
} | [
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"literaturereference_normalized": "invasive group a streptococcal postpartum endometritis associated with multi organ infarctions an uncommon case presentation and literature review",
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] |
{
"abstract": "Fingolimod, an immunomodulatory agent, is used for the treatment of relapsing-remitting multiple sclerosis (RRMS). Fingolimod-associated macular edema (FAME) is a known complication with an incidence of 0.4%. The current recommendation for treatment of FAME is cessation of fingolimod. There are few case reports with management of FAME with steroid eye drops.\nA 38-year-old Caucasian female patient with history of relapsing-remitting multiple sclerosis (RRMS) and treated with fingolimod developed Fingolimod-associated macular edema (FAME). Nevertheless, FAME was successfully treated with nonsteroidal anti-inflammatory eye drops without discontinuation of fingolimod.\nFAME may be managed with non-steroidal eye drops without discontinuation of fingolimod in appropriate patient monitored with close follow up.",
"affiliations": "1University of Minnesota, Minneapolis, MN USA.;VitreoRetinal Surgery, PA, 7760 France Ave S, Suite 310, Minneapolis, MN USA.;3Department of Neurology, University of Minnesota, MMC 295, 12-181 Phillips Wangensteen Building, 516 Delaware St. SE, Minneapolis, MN 55455 USA.;3Department of Neurology, University of Minnesota, MMC 295, 12-181 Phillips Wangensteen Building, 516 Delaware St. SE, Minneapolis, MN 55455 USA.;Minneapolis Clinic of Neurology, 4225 Golden Valley Road, Golden Valley, MN 55422 USA.",
"authors": "Husmann|Rachel|R|;Davies|John B|JB|;Ghannam|Malik|M|;Berry|Brent|B|;Kelkar|Praful|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12948-020-00119-4",
"fulltext": "\n==== Front\nClin Mol Allergy\nClin Mol Allergy\nClinical and Molecular Allergy : CMA\n1476-7961 BioMed Central London \n\n119\n10.1186/s12948-020-00119-4\nCase Report\nFingolimod-associated macular edema controlled with nepafenac non-steroidal anti-inflammatory opthalmologic applications\nHusmann Rachel schar178@umn.edu 1 Davies John B. johnbdavies@gmail.com 2 Ghannam Malik Mghannam@umn.edu 3 Berry Brent Brentb@umn.edu 3 Kelkar Praful praful.kelkar@mpls-clinic.com 4 1 grid.17635.360000000419368657University of Minnesota, Minneapolis, MN USA \n2 VitreoRetinal Surgery, PA, 7760 France Ave S, Suite 310, Minneapolis, MN USA \n3 grid.17635.360000000419368657Department of Neurology, University of Minnesota, MMC 295, 12-181 Phillips Wangensteen Building, 516 Delaware St. SE, Minneapolis, MN 55455 USA \n4 Minneapolis Clinic of Neurology, 4225 Golden Valley Road, Golden Valley, MN 55422 USA \n12 3 2020 \n12 3 2020 \n2020 \n18 33 1 2019 17 2 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nFingolimod, an immunomodulatory agent, is used for the treatment of relapsing–remitting multiple sclerosis (RRMS). Fingolimod-associated macular edema (FAME) is a known complication with an incidence of 0.4%. The current recommendation for treatment of FAME is cessation of fingolimod. There are few case reports with management of FAME with steroid eye drops.\n\nCase presentation\nA 38-year-old Caucasian female patient with history of relapsing–remitting multiple sclerosis (RRMS) and treated with fingolimod developed Fingolimod-associated macular edema (FAME). Nevertheless, FAME was successfully treated with nonsteroidal anti-inflammatory eye drops without discontinuation of fingolimod.\n\nConclusion\nFAME may be managed with non-steroidal eye drops without discontinuation of fingolimod in appropriate patient monitored with close follow up.\n\nKeywords\nMultiple sclerosisFingolimodRetinaMacular edemaNonsteroidal anti-inflammatory eye dropsissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nFingolimod, an immunomodulatory agent, is used for the treatment of relapsing–remitting multiple sclerosis (RRMS). Fingolimod-associated macular edema (FAME) is a known complication with an incidence of 0.4%. The current recommendation for treatment of FAME is cessation of fingolimod, which typically reverses its effects [1]. Nepafenac (brand NEVANAC) ophthalmic suspension is a nonsteroidal, anti-inflammatory prodrug indicated for the treatment of pain and inflammation associated with cataract surgery. It is dosed as one drop of NEVANAC ophthalmic suspension should be applied to the affected eye three-times-daily beginning 1 day usually and is usually prescribed in the setting of cataract surgery (for 2 weeks). The strength of formulation is in the sterile ophthalmic suspension: 0.1% 3 mL in a 4 mL bottle. Contraindications include hypersensitivity to any of the ingredients in the formula or to other non-steroidal anti-inflammatory drugs (NSAIDS). Other theoretically risk is similar to NSAIDs class including increased bleeding time due to interference with thrombocyte aggregation, delayed healing, corneal effects including keratitis. The most common adverse reactions (5 to 10%) are capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure, and sticky sensation. This case describes a 38-year old female with FAME successfully controlled with nonsteroidal anti-inflammatory drops without discontinuation of fingolimod. In the United States the use of nepafenac would be an off-label use of the medication in the purpose of treating FAME.\n\nCase presentation\nA 38-year-old Caucasian female with history of RRMS initiated fingolimod (0.5 mg QD) after experiencing significant disease progression with glatiramer acetate. Her baseline ophthalmologic examination was normal.\n\nSix months after commencing fingolimod, she developed decreased vision in the right eye and was referred to a retinal specialist for consultation. At the time of presentation, her best corrected visual acuity (BCVA) measured 20/25 in OD (right eye) and 20/20 in OS (left eye). Dilated exam showed mild macular edema (ME) and exudates in the right retina. The left retina was normal. Ocular coherence tomography (OCT) revealed moderate ME in the right macula and fluorescein angiography demonstrated corresponding leakage of dye. The left macula was anatomically and angiographically normal.\n\nManagement options for ME were discussed with the patient, including cessation of fingolimod versus starting a trial of nepafenac, a nonsteroidal anti-inflammatory drop. Since her multiple sclerosis was well-controlled with fingolimod, she was reluctant to discontinue this medication. Therefore, it was decided to continue fingolimod and start nepafenac ophthalmic drops (0.1% suspension three applications daily and one drop per application) in the right eye. The patient returned for follow-up 1 month later. Her BCVA improved to 20/20 in OD. Ophthalmologic examination and OCT showed that the ME had improved. The ME decreased over subsequent months and has resolved with ongoing nepafenac therapy. Additionally, her multiple sclerosis remains well-controlled on fingolimod with no relapses, disability, or change in MRI findings for 3 years. Look at Fig. 1.Fig. 1 1 Fundus at diagnosis of macular edema. The right eye has moderate ME with intraretinal exudates temporal to the fovea (1a). The left eye is normal (1b). 2 Fluorescein angiogram at presentation. The right eye has moderate leakage of fluorescein dye temporal to the fovea (2a). The left eye is normal (2b). 3 OCT of the right eye. The right eye at presentation. There is moderate cystoid ME and intraretinal exudates (3a). The right eye 1 month after initiating nepafenac treatment. There is a decrease in ME (3b). The right eye 2 years after initiating nepafenac treatment. The ME has essentially resolved with restoration of the normal foveal contour. There are minimal remaining intraretinal exudates (3c)\n\n\n\nDiscussion\nFingolimod was the first oral agent approved by the Food and Drug Administration (FDA) for the treatment of RRMS. Active metabolites of fingolimod bind to the sphinogosine-1-phosphate (S1P) receptor on lymphocytes resulting in internalization and degradation of the receptor. This action prevents lymphocytes from leaving secondary lymphoid organs, thus reducing the number of circulating lymphocytes available to participate in central nervous system autoimmune demyelination. In addition to modulating lymphocytes, the S1P receptor is responsible for regulating vascular permeability via interaction with the cytoskeleton and intracellular junctions. Disruption of the endothelial barrier in the retina may be implicated in the development of ME with use of fingolimod [1].\n\nData from clinical trials compiled by the FDA demonstrate the incidence of FAME to be 0.4% at the 0.5 mg dose with most cases occurring within 3–4 months of initiating treatment. The FDA recommends baseline ophthalmologic examination with repeated studies at 3–4 months. Should ME develop, resolution typically occurs after cessation of fingolimod [1].\n\nFor patients who develop fingolimod-associated ME, resolution typically occurs within 6 months following cessation of fingolimod, with 84% of patients in the pooled safety cohort having complete resolution [1, 2]. FAME was first realized not in ophthalmology or neurology patient populations but in renal transplant recipients who were treated with fingolimod as an immunosuppression agent during trials. Specifically, fingolimod at 2.5 mg/day or 5.0 mg/day, caused macular edema in 1.3% and 2.2% of patients, respectively [3]. Two trials, the TRANSFORMS and FREEDOMS trials subsequently utilized routine ophthalmic evaluation for fingolimod associated macular edema thereafter. The importance of these two studies with regard to FAME was that they found 0.2% incidence at a then lower FDA approval dosage of 0.5 mg/day. There are extensions of these trials ongoing on ophthalmic monitoring continues in both trials. Fingolimod discontinuation resulted in resolution of FAME and thus the studies mandated that should FAME develop the drug was to be discontinued. This has been incorporated into many clinical practices but leaves a problem for patients with severe demyelinating disease who have suboptimal response to other treatments. In these two trials, topical NSAIDs were occasionally prescribed by neurologists/ophthalmologists. There is minimal high level evidence to study this given that the incidence of FAME is low [4].\n\nPossible treatment options for ME include nonsteroidal anti-inflammatory drugs, corticosteroids, vascular endothelial growth factor antagonists, laser photocoagulation, and vitreoretinal surgery. However, only a few cases report successful treatment of ME in the setting of continued fingolimod use. Such cases describe use of topical or injected corticosteroids, which are associated with serious adverse effects, such as delayed healing, infection, elevated intraocular pressure, and cataracts [5–8]. In one case fingolimod was continued while FAME was persistent and not specifically treated [9].\n\nNepefanac topical application may result in the following adverse reactions: hypertension (≤ 4%), headache (≤ 4%), Nausea (≤ 4%), vomiting (≤ 4%), Decreased visual acuity (≤ 10%), increased intraocular pressure (≤ 10%), conjunctival edema (≤ 5%), corneal edema (≤ 5%), eye pain (≤ 5%), eye pruritus (≤ 5%), lacrimation (≤ 5%), ocular hyperemia (≤ 5%), photophobia (≤ 5%), vitreous detachment (≤ 5%), xerophthalmia (≤ 5%), Sinusitis (≤ 4%). Nepafenac carries the following contra-indications which should be discussed with the patient prior to administration: hypersensitivity should the patient have NSAID allergy documented [10, 11].\n\nThis report describes a case of FAME successfully treated with nonsteroidal anti-inflammatory drops without discontinuation of fingolimod. The patient’s ME resolved with ongoing treatment without evidence of side effects. This provides class IV evidence for safe management of FAME with nonsteroidal anti-inflammatory eye drops without discontinuation of fingolimod.\n\nConclusion\nFAME may be managed with non-steroidal eye drops without discontinuation of fingolimod in appropriate patient monitored with close follow up.\n\nAbbreviations\nFDAFood and Drug Administration\n\nS1PSphinogosine-1-phosphate\n\nRRMSRelapsing-remitting multiple sclerosis\n\nFAMEFingolimod-associated macular edema\n\nBCVABest corrected visual acuity\n\nMEMacular edema\n\nOCTOcular coherence tomography\n\nODOculus dexter\n\nOSOculus sinister\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors thank the patient who generously agreed to participate in this medical report.\n\nAuthors’ contributions\nRH, JBD and PK were responsible for the clinical management of the patient. RH, MG and BB were responsible of drafting and editing of the manuscript. All authors: critical revision of the manuscript for important intellectual content. All authors read and approved the final manuscript.\n\nFunding\nNot applicable\n\nAvailability of data and materials\nAll the data supporting our findings is contained within manuscript.\n\nEthics approval and consent to participate\nEthics committee approval was not applicable as the information was analyzed in a retrospective manner and had no effect on treatment.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Jain N Bhatti MT Fingolimod-associated macular edema: incidence, detection, and management Neurology 2012 78 672 680 10.1212/WNL.0b013e318248deea 22371414 \n2. Zarbin MA Jampol LM Jager RD Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis Ophthalmology 2013 120 7 1432 1439 10.1016/j.ophtha.2012.12.040 23531349 \n3. Tedesco-Silva H Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation Transplantation 2006 82 12 1689 1697 10.1097/01.tp.0000251718.95622.b3 17198261 \n4. Cohen JA Chun J Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis Ann Neurol 2011 69 5 759 777 10.1002/ana.22426 21520239 \n5. Thoo S Cugati S Lee A Chen C Successful treatment of fingolimod-associated macular edema with intravitreal triamcinolone with continued fingolimod use Mult Scler J 2015 21 249 251 10.1177/1352458514528759 \n6. Minuk A Belliveau MJ Almeida DR Dorrepaal SJ Gale JS Fingolimod-associated macular edema: resolution by sub-tenon injection of triamcinolone with continued fingolimod use JAMA Ophthalmol 2013 131 802 804 10.1001/jamaophthalmol.2013.2465 23599188 \n7. Chui J Herkes GK Chang A Management of fingolimod-associated macular edema JAMA Ophthalmol 2013 131 694 696 10.1001/jamaophthalmol.2013.47 23538612 \n8. Afshar AR Fernandes JK Patel RD Ksiazek SM Sheth VS Reder AT Hariprasad SM Cystoid macular edema associated with fingolimod use for multiple sclerosis JAMA Ophthalmol 2013 131 103 107 10.1001/jamaophthalmol.2013.570 23307220 \n9. Li V Kane J Chan HH Hall AJ Butzkueven H Continuing fingolimod after development of macular edema: a case report Neurol Neuroimmunol Neuroinflamm 2014 1 1 2 10.1212/NXI.0000000000000013 \n10. Nevanac (nepafenac) [prescribing information]. Fort Worth, TX: Alcon Laboratories, Inc; January 2019.\n11. Nevanac (nepafenac) [product monograph]. Dorval, Quebec, Canada; Novartis Pharmaceuticals Canada; January 2018.\n\n",
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"abstract": "Rituximab is a CD20 monoclonal antibody commonly used in the treatment of haematological malignancies. It causes lymphopenia with subsequent compromised humoral immunity resulting in an increased risk of infection. A number of infections and viral reactivations have been described as complicating Rituximab therapy. We report an apparently unique case of echovirus 9 (an enterovirus) infection causing an acute hepatitis and significant morbidity in an adult patient on maintenance treatment of Rituximab for follicular lymphoma. We also describe potential missed opportunities to employ more robust screening for viral infections which may have prevented delays in the appropriate treatment and thus may have altered the patient's clinical course. We also make suggestions for lowering the threshold of viral testing in similar patients in the future.",
"affiliations": "Worthing District General Hospital, Western Sussex Hospitals NHS Foundation Trust, Lyndhurst Road, Worthing BN11 2DH, UK.;Worthing District General Hospital, Western Sussex Hospitals NHS Foundation Trust, Lyndhurst Road, Worthing BN11 2DH, UK.;Worthing District General Hospital, Western Sussex Hospitals NHS Foundation Trust, Lyndhurst Road, Worthing BN11 2DH, UK.;Worthing District General Hospital, Western Sussex Hospitals NHS Foundation Trust, Lyndhurst Road, Worthing BN11 2DH, UK.",
"authors": "Morgan|Ceri|C|0000-0002-3404-0241;Thomson|S J|SJ|;Legg|Joanne|J|;Narat|Santosh|S|",
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"fulltext": "\n==== Front\nCase Rep HematolCase Rep HematolCRIHEMCase Reports in Hematology2090-65602090-6579Hindawi Publishing Corporation 10.1155/2015/454890Case ReportA Case of Fulminant Hepatitis due to Echovirus 9 in a Patient on Maintenance Rituximab Therapy for Follicular Lymphoma http://orcid.org/0000-0002-3404-0241Morgan Ceri \n*\nThomson S. J. Legg Joanne Narat Santosh Worthing District General Hospital, Western Sussex Hospitals NHS Foundation Trust, Lyndhurst Road, Worthing BN11 2DH, UK*Ceri Morgan: cerimorgan@nhs.netAcademic Editor: Gandhi Damaj\n\n2015 28 5 2015 2015 4548904 1 2015 21 4 2015 11 5 2015 Copyright © 2015 Ceri Morgan et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Rituximab is a CD20 monoclonal antibody commonly used in the treatment of haematological malignancies. It causes lymphopenia with subsequent compromised humoral immunity resulting in an increased risk of infection. A number of infections and viral reactivations have been described as complicating Rituximab therapy. We report an apparently unique case of echovirus 9 (an enterovirus) infection causing an acute hepatitis and significant morbidity in an adult patient on maintenance treatment of Rituximab for follicular lymphoma. We also describe potential missed opportunities to employ more robust screening for viral infections which may have prevented delays in the appropriate treatment and thus may have altered the patient's clinical course. We also make suggestions for lowering the threshold of viral testing in similar patients in the future.\n==== Body\n1. Introduction\nWe report an apparently unique case of an echovirus 9 (an enterovirus) infection causing an acute hepatitis and significant morbidity in an adult patient on maintenance treatment of Rituximab for follicular lymphoma. Rituximab is a CD20 monoclonal antibody commonly used in the treatment of haematological malignancies [1]. It causes lymphopenia with subsequent compromised humoral immunity resulting in an increased risk of infection. A number of infections and viral reactivations have previously been documented to occur as a consequence of Rituximab treatment (including enterovirus meningoencephalitis and hepatitis B reactivation [2]) but no cases report an acute hepatitis as a direct consequence of enterovirus infection. We describe potential missed opportunities to employ more robust screening for viral infections which may have prevented delays in the appropriate treatment such as more timely use of immunoglobulin and Pleconaril or to possibly stop Rituximab maintenance steps which may have altered the patient's clinical course. We also make suggestions for lowering the threshold of viral testing in similar patients in the future.\n\n2. Case Report\nWe describe an apparently unique case of echovirus 9 (an enterovirus) infection causing an acute hepatitis in an adult patient on maintenance treatment of Rituximab for follicular lymphoma. The risk of viral reactivation in patients on Rituximab treatment is well established with several reported cases of reactivation of John Cunningham virus (a virus implicated in progressive multifocal leukoencephalopathy in immunocompromised patients) and hepatitis B infection in particular [1]. Echovirus 18 infection has been described as causing an acute hepatitis in a non-Hodgkin's lymphoma patient after stem cell transplant [3] and Rituximab associated enterovirus infections have previously been reported causing both meningoencephalitis and myocarditis [2, 4]. However this appears to be the first case of fulminant hepatitis attributed to enterovirus infection causing significant morbidity in an adult patient on maintenance Rituximab therapy.\n\nOur patient, a 70-year-old retired electrical engineer, fractured his hip after falling off his bicycle in February 2006. The X-ray of the hip showed an osteolytic lesion prompting a bone biopsy which demonstrated a low grade B cell lymphoma. A staging CT at the time stated there was no evidence of clinically significant lymphadenopathy and only moderate splenomegaly of 12.6 cm in diameter. The patient remained asymptomatic and a decision was made to “watch and wait.” Following an episode of left sided abdominal pain in January 2011, a CT demonstrated retroperitoneal lymphadenopathy and obstruction of the left ureter; there was also an increase in right axillary, mediastinal, left inguinal, and pelvic nodes. All other lymph nodes, specifically at the hepatic hilum, and spleen size remained stable. A lymph node biopsy from the left inguinal region demonstrated that the atypical lymphocytes were B cells (CD20 and CD79a positive). The atypical lymphocytes were also BCL2 and BCL6 positive and CD21 and CD23 positive highlighting expanded follicular dendritic cell meshwork consistent with low grade non-Hodgkin's follicular lymphoma. Treatment was commenced and the patient received a total of eight cycles of Rituximab and seven of CVP (cyclophosphamide, vincristine, and prednisolone). A posttreatment CT scan demonstrated a good partial response and he was therefore commenced on a two-year course of maintenance Rituximab on a three-month basis in the first instance in December 2011 at a dose of 750 mg, based on 375 mg per m2.\n\nA routine liver function test (LFT) in June 2012 demonstrated total bilirubin of 50 μmol/L (normal range <20 μmol/L), alkaline phosphatase of 453 u/L (normal <130 u/L), and alanine aminotransferase (ALT) of 966 u/L (normal <40 u/L) (Figure 1). Rituximab was therefore suspended following which the LFT panel normalised. A subsequent CT demonstrated no disease recurrence and he was recommenced on bimonthly Rituximab in November 2012 at the previous dose of 750 mg. The patient attended hospital twice in the subsequent months with low grade fevers and malaise, once treated with Amoxicillin for a UTI and on the second occasion diagnosed with suspected bronchitis. His LFTs during these consults were mildly deranged and a further aetiological liver screen was ordered (anti-nuclear antibodies, anti-mitochondrial antibodies, anti-smooth muscle antibodies, liver and kidney microsomal antibodies, and anti-neutrophil cytoplasmic antibody) and viral serology was ordered where CMV IgG was positive. All remaining serologies including EBV and hepatitis A, hepatitis B, and hepatitis C were negative. A HIV test was also negative.\n\nFurther assessment was triggered in January 2013 by ongoing weight loss and malaise. LFTs were bilirubin 20 μmol/L, ALP 543 u/L, and ALT 313 u/L and Rituximab was stopped. Shortly after this he presented with new onset confusion, fevers, and nausea. LFTs deteriorated again: bilirubin 75 μmol/L, ALP 652 u/L, and ALT 964 u/L. He was therefore admitted by the Haematology Team for further management as an inpatient. Repeat serologies for hepatitis A, hepatitis B, and hepatitis C were all negative as was PCR for CMV. Similarly, EBV and HSV PCR were also negative. Immunoglobulin levels were IgG 3.27 g/L (6–16 g/L), IgM <0.25 g/L (0.5–1.9 g/L), and IgA 0.50 g/L (0.8–2.8 g/L); unfortunately the patient did not have immunoglobulin levels done at any time prior to Rituximab therapy.\n\nThe patient deteriorated quickly in hospital and was treated with broad spectrum antimicrobials (piperacillin/tazobactam and gentamicin) due to fevers (39.8°C) and features of sepsis. An abdominal CT reported acute acalculous cholecystitis and antibiotics were continued; however both liver and renal function continued to deteriorate. INR at this stage was 1.9, APTT 1.7, fibrinogen 1.5 mcg/mL, platelets 56, C-reactive protein 69 mg/L, and creatinine 259 μmol/L.\n\nThe clinical picture progressed and he became more confused. In the context of acute jaundice and coagulopathy, concern was raised that this represented hepatic encephalopathy and, hence, acute liver failure. However, an arterial ammonia assay of 56.6 μmol/L (1–50 μmol/L) was not immediately supportive of that. Local hepatology opinion was sought and, due to his age, comorbidity, and apparent seronegative aetiology, he was not felt to be a transplant candidate. A plan was agreed to pursue supportive measures for his evolving multiorgan dysfunction and illness.\n\nOur patient continued spiking fevers of >38°C despite continued antibiotics and so an empirical trial of ganciclovir was commenced and a transjugular liver biopsy was performed. During this period, further real time viral PCR testing was performed on blood, and enterovirus RNA was detected at a “strong level.” This was later subspeciated as echovirus 9. Liver histology demonstrated predominantly lymphocytic inflammatory infiltration of the portal tracts with extension into the liver parenchyma and balloon degeneration of hepatocytes. There was also periodic acid-Schiff positive diastase resistant material in Kupffer cells. The report stated that this is a pattern described in disease states causing hepatocyte damage and necrosis. There was no evidence of cirrhosis, and the overall impression was that of an acute hepatitis (Figure 2). Echovirus 9 was also detected by PCR in the liver biopsy.\n\nOur patient was subsequently admitted to ICU due to rapidly deteriorating renal function and difficulty in maintaining fluid balance on the ward. Prior to admission to ICU, his ALT rose to its highest value of 3082 u/L; he was jaundiced, bilirubin of 134 μmol/L, and was hypoalbuminaemic, albumin of 22 g/L (35–50 g/L). A trial of intravenous immunoglobulin therapy (IV Ig) was commenced at 0.4 g/kg, a total dose of 2.4 g/kg being given. The authors are aware that this dose is slightly higher than the recommended total dose of 2.0 g/kg, but as the patient was in established renal failure requiring dialysis, it is not felt that this contributed to his renal failure. He was commenced on continuous venovenous haemofiltration due to progressive oligoanuric renal failure. His illness was further complicated by Clostridium difficile diarrhoea which was treated with oral vancomycin. He continued to suffer with agitation and confusion. An MRI brain reported mild inflammatory changes in the sphenoid sinus but no inflammatory changes in brain tissue. The possibility of an associated viral meningoencephalitis was postulated but a lumbar puncture was deferred due to coagulopathy and the multisystem nature of his condition.\n\nHe remained at the intensive care unit for a total of 17 days. Eventually renal and liver function was observed to improve and his requirements for organ support recovered. He was discharged to the ward where he completed a period of rehabilitation before being discharged. At follow-up, his memory has slowly improved although he does report being more forgetful. His follicular lymphoma remains in remission and he is not currently on any maintenance treatment. He is back playing golf twice a week but admits feeling more fatigued than he once did.\n\n3. Discussion\nEnteroviruses are single stranded positive sense RNA viruses that are transmitted via the faecal-oral route and have a peak transmission rate in the summer and autumn months. They are members of the Picornaviridae family and include the polioviruses, coxsackie A and coxsackie B, echoviruses, and the numbered enteroviruses. In immunocompromised adults, they are implicated in CNS disease [2] and they have been reported to cause sepsis and systemic infections in babies [5]. Treatment of enterovirus infections is reserved for encephalitis, myocarditis, neonatal infection, and B cell deficient hosts [6]. Previously the evidence for treating enteroviral, CNS infection in adults with immunoglobulin (IV Ig) alone in patients with compromised B cell response due to Rituximab maintenance is mixed, with one patient eventually dying after IV Ig of the infection [7] and another reporting a short lived improvement [1]. Our patient received IV Ig some two weeks into his stay and it is speculated that this may have been too late in affecting his clinical course. The drug Pleconaril which binds to the viral capsid and changes viral attachment and uncoating is unlicensed for use in enterovirus infection but has been used with some success in combination with IV Ig in CNS infection attributed to enterovirus infection in patients on maintenance Rituximab therapy [8].\n\nThe British Society of Haematology recommends that patients with follicular lymphoma have maintenance Rituximab after an appropriate induction regimen of chemotherapy [9]. The evidence base for this practice is robust with a recent meta-analysis demonstrating improved overall survival despite increased rates of infection in patients with relapsed follicular lymphoma but not untreated follicular lymphoma [10]. In individuals treated with Rituximab, it is their compromised humoral immunity that is thought to contribute to their vulnerability to viral infection. Rituximab is a chimeric monoclonal antibody directed against CD20 positive B cells. CD20 is expressed at all stages of B cell maturation with the exception of very early pre-B cell and mature plasma cell stages [11]. Rituximab causes profound B cell lymphopenia and can affect immunoglobulin levels up to 12 months after cessation of treatment [12]. An increase in grade 3 and grade 4 infections has been reported in meta-analysis of patients on maintenance Rituximab therapy but the rate of infections was not different whether it was given on 4-week, 6-week, 2-month, or 3-month basis [13].\n\nThere are several case reports of viral reactivation of hepatitis B and John Cunningham virus and resultant progressive multifocal leukoencephalopathy, the early features of which have some clinical resemblance to meningoencephalitis caused by enterovirus [2]. There are also reported cases of reactivation of CMV and infection of parvovirus B19, West Nile virus, and enterovirus as well as anecdotal cases of Pneumocystis jirovecii, Mycobacterium, and babesiosis [12, 13]. The clinical course and outcomes of these infections are often challenging as the compromised immunity leads to a more florid illness. This is also complicated by the low immunoglobulin levels present in some of these patients resulting in falsely negative serology testing, increasing our diagnostic dependence on more time consuming molecular techniques such as PCR. This may lead to delays in appropriate treatment.\n\nIn summary we have demonstrated a fulminant multisystem infection with severe hepatitis, features of liver failure, and associated acute renal failure due to echovirus 9 in direct relation to Rituximab therapy for a follicular lymphoma. In retrospect, the derangement in LFTs and febrile illness prior to his acute admission are likely to have been due to an evolving hepatitis and may have represented an opportunity for more robust screening for viral infection. It is also our impression that the associated features of confusion and disorientation may have been due to a coexistent meningoencephalitis for which enterovirus has also been historically implicated. A low threshold for comprehensive viral testing should be adopted in patients on Rituximab therapy who present with systemic symptoms, multisystem disorder, or more specifically abnormal liver function tests.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests with regard to the publication of this paper.\n\nFigure 1 Summary of biochemistry findings: the graph shows the clinical events prior to and during the patient's admission to hospital and the pattern observed in both liver and renal function.\n\nFigure 2 Histology findings: lymphocytic inflammatory infiltration of portal tracts, a finding suggestive of acute hepatitis.\n==== Refs\n1 Gea-Banacloche J. C. Rituximab-associated infections Seminars in Hematology 2010 47 2 187 198 10.1053/j.seminhematol.2010.01.002 2-s2.0-77950337482 20350666 \n2 Servais S. Caers J. Warling O. Enteroviral meningoencephalitis as complication of Rituximab therapy in a patient treated for diffuse large B-cell lymphoma British Journal of Haematology 2010 150 3 379 381 10.1111/j.1365-2141.2010.08202.x 2-s2.0-77954600464 20408837 \n3 Lefterova M. I. Rivetta C. George T. I. Pinsky B. A. Severe hepatitis associated with an echovirus 18 infection in an immune-compromised adult Journal of Clinical Microbiology 2013 51 2 684 687 10.1128/JCM.02405-12 2-s2.0-84873033161 23175267 \n4 Sellier-Leclerc A.-L. Belli E. Guérin V. Dorfmüller P. Deschênes G. Fulminant viral myocarditis after rituximab therapy in pediatric nephrotic syndrome Pediatric Nephrology 2013 28 9 1875 1879 10.1007/s00467-013-2485-9 2-s2.0-84881083944 23700173 \n5 Mandell G. L. Bennett J. E. Dolin R. Principles and Practice of Infectious Diseases 2010 7th Philadelphia, Pa, USA Churchill Livingston Elsevier \n6 Murk J. de Vries A. GeurtsvanKessel C. Persistent spiking fever in a child with acute myeloid leukemia and disseminated infection with enterovirus Journal of Clinical Virology 2014 61 3 453 455 10.1016/j.jcv.2014.09.006 25281281 \n7 Kiani-Alikhan S. Skoulidis F. Barroso A. Enterovirus infection of neuronal cells post-Rituximab British Journal of Haematology 2009 146 3 333 335 10.1111/j.1365-2141.2009.07748.x 2-s2.0-67650493506 19466969 \n8 Quartier P. Tournilhac O. Archimbaud C. Enteroviral meningoencephalitis after anti-CD20 (rituximab) treatment Clinical Infectious Diseases 2003 36 3 e47 e49 10.1086/345746 2-s2.0-0037318312 12539090 \n9 McNamara C. Davies J. Dyer M. Guidelines on the investigation and management of follicular lymphoma British Journal of Haematology 2012 156 4 446 467 10.1111/j.1365-2141.2011.08969.x 2-s2.0-84856266196 22211428 \n10 Vidal L. Gafter-Gvili A. Salles G. Rituximab maintenance for the treatment of patients with follicular lymphoma: an updated systematic review and meta-analysis of randomized trials Journal of the National Cancer Institute 2011 103 23 1799 1806 10.1093/jnci/djr418 2-s2.0-83255176958 22021664 \n11 Tridente G. Rituximab Adverse Events with Biomedicines 2014 Springer 351 368 10.1007/978-88-470-5313-7_35 \n12 Makatsori M. Kiani-Alikhan S. Manson A. L. Hypogammaglobulinaemia after rituximab treatment—incidence and outcomes QJM 2014 10.1093/qjmed/hcu094 \n13 Yang S. H. Hsu C. Cheng A. L. Kuo S. H. Anti-CD20 Monoclonal Antibodies and Associated Viral Hepatitis in Haematological Diseases 2014 http://www.wjgnet.com/2218-6204/pdf/v3/i2/29.doc\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6579",
"issue": "2015()",
"journal": "Case reports in hematology",
"keywords": null,
"medline_ta": "Case Rep Hematol",
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"nlm_unique_id": "101576456",
"other_id": null,
"pages": "454890",
"pmc": null,
"pmid": "26106492",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "20350666;12539090;22021664;23175267;20408837;22211428;25281281;19466969;23700173;24778295",
"title": "A Case of Fulminant Hepatitis due to Echovirus 9 in a Patient on Maintenance Rituximab Therapy for Follicular Lymphoma.",
"title_normalized": "a case of fulminant hepatitis due to echovirus 9 in a patient on maintenance rituximab therapy for follicular lymphoma"
} | [
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{
"drugrecuraction": "Alanine aminotransferase increased"
},
{
"drugrecuraction": "Blood bilirubin increased"
},
{
"drugrecuraction": "Blood alkaline phosphatase increased"
}
],
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},
{
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},
{
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},
{
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"reactionoutcome": "6"
},
{
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},
{
"reactionmeddrapt": "Hepatitis fulminant",
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},
{
"reactionmeddrapt": "Enterovirus infection",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood bilirubin increased",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Bronchitis",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood alkaline phosphatase increased",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Cytomegalovirus infection",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Meningoencephalitis viral",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Malaise",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "MORGAN C, THOMSON S, LEGG J AND NARAT S. A CASE OF FULMINANT HEPATITIS DUE TO ECHOVIRUS 9 IN A PATIENT ON MAINTENANCE RITUXIMAB THERAPY FOR FOLLICULAR LYMPHOMA. CASE REPORTS IN HEMATOLOGY 2015;:454890-.",
"literaturereference_normalized": "a case of fulminant hepatitis due to echovirus 9 in a patient on maintenance rituximab therapy for follicular lymphoma",
"qualification": "3",
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},
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"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20151125"
}
] |
{
"abstract": "BCR-ABL1-positive leukemias have historically been classified as either chronic myelogenous leukemia or Ph+ acute lymphoblastic leukemia. Recent analyses suggest there may be a wider range of subtypes. We report a patient with BCR-ABL1 fusion positive T-cell ALL with a previously undescribed cell distribution of the fusion gene. The examination of sorted cells by fluorescence in situ hybridization showed the BCR-ABL1 fusion in the malignant T cells and a subpopulation of the nonmalignant B cells, but not nonmalignant T cells or myeloid or CD34+ progenitor cells providing evidence that the fusion may have occurred in an early lymphoid progenitor.",
"affiliations": "Department of Pediatrics, College of Medicine-Jacksonville, University of Florida, Jacksonville, Florida.;Hematologics, Inc., Seattle, Washington.;Hematologics, Inc., Seattle, Washington.;Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.",
"authors": "Ragg|Susanne|S|0000-0002-8699-6608;Zehentner|Barbara K|BK|;Loken|Michael R|MR|;Croop|James M|JM|",
"chemical_list": "C581634:BCR-ABL1 fusion protein, human; D016044:Fusion Proteins, bcr-abl",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.27829",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "66(9)",
"journal": "Pediatric blood & cancer",
"keywords": "BCR-ABL1; T-cell ALL; discordant MRD",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D017403:In Situ Hybridization; D054503:Lymphoid Progenitor Cells; D008297:Male; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e27829",
"pmc": null,
"pmid": "31136068",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Evidence for BCR/ABL1-positive T-cell acute lymphoblastic leukemia arising in an early lymphoid progenitor cell.",
"title_normalized": "evidence for bcr abl1 positive t cell acute lymphoblastic leukemia arising in an early lymphoid progenitor cell"
} | [
{
"companynumb": "US-APOTEX-2019AP020293",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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{
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},
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}
],
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"patientonsetage": "13",
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"reaction": [
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Tumour lysis syndrome",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "RAGG S, ZEHENTNER BK, LOKEN MR, CROOP JM. EVIDENCE FOR BCR/ABL1-POSITIVE T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA ARISING IN AN EARLY LYMPHOID PROGENITOR CELL. DOI: 10.1002/PBC.27829. PEDIATRIC BLOOD AND CANCER. 2019?66:E27829",
"literaturereference_normalized": "evidence for bcr abl1 positive t cell acute lymphoblastic leukemia arising in an early lymphoid progenitor cell",
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},
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},
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"seriousnessother": 1,
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}
] |
{
"abstract": "Glycogenic hepatopathy (GH) is an underdiagnosed complication of uncontrolled type 1 diabetes mellitus (T1DM). It appears as an acute relapsing hepatitis with reversible transaminase elevations secondary to excessive hepatic glycogen accumulation. Patients are often asymptomatic but can present with abdominal pain, nausea and vomiting. Physical examination shows hepatomegaly without splenomegaly. GH is diagnosed by biopsy as it is clinically indistinguishable from non-alcoholic fatty liver disease (NAFLD), a more common cause of hepatic dysfunction in diabetics. Here we describe a case of GH in a patient with uncontrolled type 1 diabetes whose clinical course was complicated by drug-induced liver injury. The patient initially presented with diabetic ketoacidosis and had a mild transaminitis, thought to be due to NAFLD. She developed profound transaminase elevations while receiving treatment with newer antipsychotic medications for her bipolar disorder. Liver biopsy showed evidence of resolving glycogenic hepatopathy with signs of drug-induced liver injury. This case report reviews the pathology and pathogenesis of GH and reminds the clinician to keep GH within the differential diagnosis for severe transaminitis in a patient with type 1 diabetes mellitus.",
"affiliations": "Department of Medicine, Loyola University Stritch School of Medicine, Room 7612, 2160 S 1st Avenue, Maywood, IL, 60153, USA. valmiki.maharaj@lumc.edu.;Department of Medicine, Loyola University Stritch School of Medicine, Room 7612, 2160 S 1st Avenue, Maywood, IL, 60153, USA.;Department of Pathology, Loyola University Stritch School of Medicine, Room 7612, 2160 S 1st Avenue, Maywood, IL, 60153, USA.",
"authors": "Maharaj|Valmiki|V|;Fitz|Matthew|M|;Ding|Xianzdong|X|",
"chemical_list": "D014150:Antipsychotic Agents; D003986:Dibenzocycloheptenes; D006576:Heterocyclic Compounds, 4 or More Rings; D006003:Glycogen; C522667:asenapine",
"country": "United States",
"delete": false,
"doi": "10.1007/s11606-017-3996-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0884-8734",
"issue": "32(6)",
"journal": "Journal of general internal medicine",
"keywords": null,
"medline_ta": "J Gen Intern Med",
"mesh_terms": "D015746:Abdominal Pain; D014150:Antipsychotic Agents; D001706:Biopsy; D001714:Bipolar Disorder; D056486:Chemical and Drug Induced Liver Injury; D003922:Diabetes Mellitus, Type 1; D016883:Diabetic Ketoacidosis; D003937:Diagnosis, Differential; D003986:Dibenzocycloheptenes; D005260:Female; D006003:Glycogen; D006529:Hepatomegaly; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D008099:Liver; D008279:Magnetic Resonance Imaging; D055815:Young Adult",
"nlm_unique_id": "8605834",
"other_id": null,
"pages": "714-717",
"pmc": null,
"pmid": "28224373",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8982149;24330296;20009116;22700639;19957373;22673296;21651314;17220798;23428785;22675850;16625098",
"title": "Drug-Induced Liver Injury in the Setting of Glycogenic Hepatopathy.",
"title_normalized": "drug induced liver injury in the setting of glycogenic hepatopathy"
} | [
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},
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"medicinalproduct": "INSULIN GLARGINE"
},
{
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},
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"drugindication": "TYPE 1 DIABETES MELLITUS",
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}
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"reaction": [
{
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"reactionmeddraversionpt": "20.0",
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},
{
"reactionmeddrapt": "Drug ineffective",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood pH decreased",
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},
{
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},
{
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"reactionmeddraversionpt": "20.0",
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},
{
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},
{
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