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"abstract": "Torsades de Pointes (TdP) is a life-threatening ventricular arrhythmia that can be associated with metabolic abnormalities, exposure to arrhythmogenic medications, and congenital long-QT syndrome. This report describes a patient with ALL and multiple complications of therapy who developed TdP. The patient had no evidence of congenital long-QT syndrome, but a constellation of factors appears to have led to QT prolongation, ventricular ectopy, and TdP. Although the patient suffered cardiac arrest, rapid recognition of TdP and prompt defibrillation resulted in an excellent outcome.",
"affiliations": "Department of Pediatrics, Section of Pediatric Hematology/Oncology, University of Arizona Health Sciences Center, Tucson, Arizona 85724, USA. bagatell@peds.arizona.edu",
"authors": "Bagatell|Rochelle|R|;Hainstock|Michael|M|;Lowe|Merlin C|MC|;Barber|Brent J|BJ|;Samson|Ricardo A|RA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004573:Electrolytes",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.20712",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "49(7)",
"journal": "Pediatric blood & cancer",
"keywords": null,
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D016887:Cardiopulmonary Resuscitation; D004473:Ecthyma; D004562:Electrocardiography; D004573:Electrolytes; D005260:Female; D005500:Follow-Up Studies; D006323:Heart Arrest; D006801:Humans; D007674:Kidney Diseases; D008133:Long QT Syndrome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012074:Remission Induction; D016171:Torsades de Pointes; D016896:Treatment Outcome; D018879:Ventricular Premature Complexes",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "996-9",
"pmc": null,
"pmid": "16333840",
"pubdate": "2007-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The perfect storm: Torsades de Pointes in a child with leukemia.",
"title_normalized": "the perfect storm torsades de pointes in a child with leukemia"
} | [
{
"companynumb": "NVSC2020US067494",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLARITHROMYCIN"
},
"drugadditional": "3",
"d... |
{
"abstract": "Patients on dialysis often have secondary hyperparathyroidism (SHPT), a disorder associated with renal osteodystrophy, progressive vascular calcification, cardiovascular disease, and death. The objective of this retrospective observational study was to evaluate, in dialysis patients with SHPT, the impact of different levels of adherence to cinacalcet therapy on hospitalisations and direct healthcare costs charged to the Lombardy Regional Health Service (Italy).\nData recorded in the administrative databases on all citizens undergoing dialysis between 1 January 2011 and 31 December 2011 were selected. For the aim of this study, patients with SHPT already on dialysis in the first 6 months of 2009 who had been treated with cinacalcet for at least 365 days were selected and retrospectively analysed through to end of 2012. Healthcare resource utilisation, cinacalcet adherence, and costs for medication, hospitalisations, and diagnostic/therapeutic procedures were estimated.\nA total of 994 patients were identified (mean age 63.0 years, females 43.5%). The first patient tertile had an adherence to cinacalcet of <64.1%, whereas the third had an adherence of over 91.5%. Patients in the third adherence tertile experienced fewer all-causes hospitalisations than those in the first tertile (-19.2%; p=0.01423), fractures (-37.1%; p=0.59422), cardiovascular disease (-23.8%; p=0.04025), and sepsis (-32.3%; p=0.01386). The increase in costs for cinacalcet-adherent patients is almost completely offset by the reduction in costs for hospitalisations.\nThe results of the analysis suggest that there may be some correlation between a high level of cinacalcet adherence and a decrease in hospitalisations.",
"affiliations": "ProCure Solutions, Nembro, Italy.;Department of Health Sciences, Renal Division, University of Milan, San Paolo Hospital, Milan, Italy.;ProCure Solutions, Nembro, Italy.;Department of Health Sciences, Renal Division, University of Milan, San Paolo Hospital, Milan, Italy.;Lombardy Region, Regional Health Authority, Milan, Italy.;ProCure Solutions, Nembro, Italy.",
"authors": "Roggeri|Alessandro|A|;Conte|Ferruccio|F|;Rossi|Carlotta|C|;Cozzolino|Mario|M|;Zocchetti|Carlo|C|;Roggeri|Daniela Paola|DP|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.7573/dic.2020-1-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1740-4398",
"issue": "9()",
"journal": "Drugs in context",
"keywords": "SHPT; cinacalcet; costs; dialysis; therapeutic adherence",
"medline_ta": "Drugs Context",
"mesh_terms": null,
"nlm_unique_id": "101262187",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32273898",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "28615947;21454719;24516224;31587354;15322146;25048990;25404192;28499709;21988567;23121374;19734404;31088377;29346788;23133549;31141505;24516228;25028644;30675420;25710802;25851955;31807302;12830464;30223271;25918645;19732171;21372255;15689407;15071126",
"title": "Cinacalcet adherence in dialysis patients with secondary hyperparathyroidism in Lombardy Region: clinical implications and costs.",
"title_normalized": "cinacalcet adherence in dialysis patients with secondary hyperparathyroidism in lombardy region clinical implications and costs"
} | [
{
"companynumb": "IT-AMGEN-ITASP2019215080",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CINACALCET HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "We present a case of 48-year-old woman with relapsing remitting multiple sclerosis (MS), who switched disease modifying therapy from Copaxone to Fingolimod due to her clinical and radiological MS disease progression. Unexpectedly after 2.5 years of stable MS symptoms and liver function tests (LFTs), we noted deranged LFTs during routine testing. Additional investigations showed hepatitis C positivity, genotype 3. It is likely a case of hepatitis C reactivation secondary to prolonged immunosuppressive effects of Fingolimod. Although the increased risk of viral reactivation related to varicella zoster virus is known to occur with Fingolimod treatment, to our knowledge, this is only the second case of hepatitis C disease activity reported with Fingolimod treatment. We would like to raise the awareness of hepatitis C viral reactivation as a possible complication of prolonged immunosuppression with Fingolimod.",
"affiliations": "Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Salford, UK aram.aslanyan@doctors.org.uk.;Gastroenterology Department, Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, UK.;Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Salford, UK.;Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Salford, UK.",
"authors": "Aslanyan|Aram|A|;Anwar-Hashim|Zoheb|Z|;Siripurapu|Rekha|R|;Mihalova|Tatiana|T|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-238167",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(2)",
"journal": "BMJ case reports",
"keywords": "multiple sclerosis; neurology (drugs and medicines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D005260:Female; D000068876:Fingolimod Hydrochloride; D006526:Hepatitis C; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged; D009103:Multiple Sclerosis; D020529:Multiple Sclerosis, Relapsing-Remitting",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33637491",
"pubdate": "2021-02-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatitis C during disease modifying therapy with Fingolimod for Relapsing Remitting Multiple Sclerosis: diagnosis and treatment.",
"title_normalized": "hepatitis c during disease modifying therapy with fingolimod for relapsing remitting multiple sclerosis diagnosis and treatment"
} | [
{
"companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-304346",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FINGOLIMOD"
},
"drug... |
{
"abstract": "BACKGROUND\nLower gastrointestinal (GI) adverse events (LGAE) are common afflictions of patients undergoing stem cell transplantation (SCT). Unfortunately, the pathophysiology remains poorly characterized. Emerging data suggest a prominent role of intestinal microbiota; however, contributions of pathogenic gut microbiota such as Clostridium difficile are not well defined. We performed a genome-wide association study (GWAS) to investigate clinical and genetic factors associated with development of LGAE.\n\n\nMETHODS\nA total of 972 patients undergoing autologous SCT were graded for LGAE based on Common Terminology Criteria for Adverse Events (v 4.0). Germline DNA material was obtained from leukapharesis products and genotyped using Illumina(®) Whole Genome Genotyping Infinium chemistry and HumanOmni1-Quad Bead chips containing over 1.1 million single nucleotide polymorphisms (SNPs) (Illumina, San Diego, California, USA). Statistical models incorporating clinical factors, genetic factors, and a combination of clinical plus genetic factors were utilized to compare patients who developed severe LGAE (grade 2 or above) and others.\n\n\nRESULTS\nAmong 972 patients, 459 (47.2%) developed severe LGAE. Baseline hemoglobin and hematocrit, estimated glomerular filtration rate, β2-microglobulin, protocol type, and C. difficile infection (CDI) were associated with severe LGAE on univariate analysis, Genomic comparisons between groups did not reveal any SNPs associated with severe LGAE and neither did incorporation of genetic factors into the clinical model. In addition, 11 candidate SNPs associated with upper GI mucositis were evaluated, alongside clinical factors in a multivariate model. Only CDI was found to be associated with severe LGAE in all models.\n\n\nCONCLUSIONS\nCDI is a prominent factor in the development of LGAE in patients undergoing autologous SCT.",
"affiliations": "Division of Infectious Diseases, University of Cincinnati, Cincinnati, Ohio, USA.;University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;Department of Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;Department of Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.",
"authors": "Apewokin|S|S|http://orcid.org/0000-0002-3915-5814;Goodwin|J A|JA|;Lee|J Y|JY|;Erickson|S W|SW|;Sanathkumar|N|N|;Raj|V R|VR|;Zhou|D|D|;McKelvey|K D|KD|;Stephens|O|O|;Coleman|E A|EA|",
"chemical_list": "D005819:Genetic Markers",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12403",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "17(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Clostridium difficile; GI adverse events; GWAS; cancer; chemotherapy; stem cell transplant",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D016360:Clostridioides difficile; D003015:Clostridium Infections; D005260:Female; D005767:Gastrointestinal Diseases; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012720:Severity of Illness Index; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "566-73",
"pmc": null,
"pmid": "25988273",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Contribution of Clostridium difficile infection to the development of lower gastrointestinal adverse events during autologous stem cell transplantation.",
"title_normalized": "contribution of clostridium difficile infection to the development of lower gastrointestinal adverse events during autologous stem cell transplantation"
} | [
{
"companynumb": "US-CELGENE-USA-2015084503",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nWhile most cases of polymicrobial vertebral osteomyelitis are secondary to hematogenous seeding, direct inoculation during spinal surgery and contiguous spread from adjacent soft tissue are also potential routes whereby pathogens may infect the spine.\n\n\nMETHODS\nA 74 year-old man presented with an exacerbation of back pain after a fall. His past medical history included hepatocellular and oesophageal carcinoma. Three months earlier he had undergone an endoscopic biopsy of the oesophagus for routine follow-up of his oesophagus carcinoma. He also underwent a vertebroplasty due to suspected pathologic fracture. On admission to hospital, magnetic resonance imaging revealed an infiltrative process at the level of the 5th and 6th thoracic vertebrae. Blood cultures were positive for both Streptococcus mitis and Gemella morbillorum. During his course of antibiotic therapy he developed an abscess at the level of 8th thoracic vertebrae and culture of this abscess grew Candida albicans. He was treated with antibiotics and antifungal drugs and recovered fully.\n\n\nCONCLUSIONS\nVertebral osteomyelitis may be caused by direct spread following an oesophageal procedure. Microbiological diagnosis is essential to target the specific pathogen, especially in cases of polymicrobial infection.",
"affiliations": "Infectious Disease Service, Department of Medicine, Lausanne University Hospital (CHUV), Rue du Bugnon 46, CH-1011, Lausanne, Switzerland. aude.giger@chuv.ch.;Laboratory Medicine, Gasthuiszusters Antwerpen Hospital, Antwerpen, Belgium.;Infectious Disease Service, Department of Medicine, Lausanne University Hospital (CHUV), Rue du Bugnon 46, CH-1011, Lausanne, Switzerland.;Department of Medicine, Neuchâtel cantonal Hospital, Neuchâtel, Switzerland.;Center for Musculoskeletal Surgery, Charité University Medicine Berlin, Berlin, Germany.",
"authors": "Giger|Aude|A|;Yusuf|Erlangga|E|;Manuel|Oriol|O|;Clerc|Olivier|O|;Trampuz|Andrej|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000935:Antifungal Agents",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-016-1471-9",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 147110.1186/s12879-016-1471-9Case ReportPolymicrobial vertebral osteomyelitis after oesophageal biopsy: a case report Giger Aude aude.giger@chuv.ch Yusuf Erlangga Manuel Oriol Clerc Olivier Trampuz Andrej Infectious Disease Service, Department of Medicine, Lausanne University Hospital (CHUV), Rue du Bugnon 46, CH-1011 Lausanne, Switzerland Laboratory Medicine, Gasthuiszusters Antwerpen Hospital, Antwerpen, Belgium Department of Medicine, Neuchâtel cantonal Hospital, Neuchâtel, Switzerland Center for Musculoskeletal Surgery, Charité University Medicine Berlin, Berlin, Germany 31 3 2016 31 3 2016 2016 16 14118 12 2015 14 3 2016 © Giger et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nWhile most cases of polymicrobial vertebral osteomyelitis are secondary to hematogenous seeding, direct inoculation during spinal surgery and contiguous spread from adjacent soft tissue are also potential routes whereby pathogens may infect the spine.\n\nCase presentation\nA 74 year-old man presented with an exacerbation of back pain after a fall. His past medical history included hepatocellular and oesophageal carcinoma. Three months earlier he had undergone an endoscopic biopsy of the oesophagus for routine follow-up of his oesophagus carcinoma. He also underwent a vertebroplasty due to suspected pathologic fracture. On admission to hospital, magnetic resonance imaging revealed an infiltrative process at the level of the 5th and 6th thoracic vertebrae. Blood cultures were positive for both Streptococcus mitis and Gemella morbillorum. During his course of antibiotic therapy he developed an abscess at the level of 8th thoracic vertebrae and culture of this abscess grew Candida albicans. He was treated with antibiotics and antifungal drugs and recovered fully.\n\nConclusion\nVertebral osteomyelitis may be caused by direct spread following an oesophageal procedure. Microbiological diagnosis is essential to target the specific pathogen, especially in cases of polymicrobial infection.\n\nKeywords\nSpondylodiscitisPostinterventional osteomyelitisMixed infectionsInfectious Disease Unit (Prof. T. Calandra), CHUV, Lausanneissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nVertebral osteomyelitis, also known as spinal osteomyelitis, spondylodiscitis, septic discitis, or disk-space infection [1] is a rare disease; its incidence is estimated at 2.4 cases per 100,000 persons [2]. Most cases results from hematogenous seeding from a distant source such as the urinary tract, skin, infected vascular catheters, endocarditis, or bursitis/septic arthritis [3, 4]. Other routes of infection include direct external inoculation and spread from contiguous soft tissues. Predisposing factors include diabetes mellitus, advanced age, intravenous drug use, immunosuppression, malignancy, renal failure, and rheumatological disease [5]. Vertebral osteomyelitis is primarily a monomicrobial bacterial infection; predominant pathogens are Staphylococcus aureus, coagulase-negative staphylococci (in cases where a foreign body or hardware is present), streptococcal species and enterobacteriaceae [2]. Polymicrobial infections occur in less than 10 % of cases and are most likely to result from contiguous spread [6].\n\nWe describe here a unique case of polymicrobial vertebral osteomyelitis following an oesophageal biopsy which was originally misdiagnosed as a bone metastasis.\n\nCase presentation\nA 74 years old male was admitted to the internal medicine department due to an acute exacerbation of his chronic back pain following a fall in his bathroom the previous night. He also reported an involuntary weight loss of 15 kg. His past medical history included hepatocellular carcinoma four years ago and an epidermoid carcinoma of the upper oesophagus five years ago. Both types of carcinoma were considered in remission at the time of his admission to hospital. He had been on oral dexamethasone for 2 weeks for his back pain and sorafenib as maintenance chemotherapy for his oesophagus carcinoma.\n\nThe patient reported that his back pain had started three months before the current hospitalisation without history of trauma. A magnetic resonance imaging (MRI) scan was performed (Fig. 1) which demonstrated pathologic infiltrations of the 5th and 6th thoracic vertebra without involvement of the intervertebral disc, and associated with a fracture of the upper plate of the 6th thoracic vertebra. Bony metastasis with pathologic fracture was suspected and a transcutaneous vertebroplasty was performed by injecting high-viscosity polymethylmethacrylate cement. The bone biopsy taken prior to this procedure showed signs of acute and chronic osteomyelitis without sign of malignancy. The Gram stain did not reveal the presence of bacteria, and bacteria culture of the biopsy was negative.Fig. 1 Spine MRI shows fracture settlement of the sixth thoracic vertebra with infiltration from the fifth to the sixth thoracic vertebra\n\n\n\nOn physical examination at admission the patient appeared ill with a temperature of 38.3 °C. Auscultation of the heart and lungs was unremarkable. The 7th thoracic vertebra was painful on palpation. Laboratory tests revealed an increased C-reactive protein level (41 mg/l, normal: <10 mg/l) and an increased leukocyte count (20.3 G/l, normal: 4 to 10 G/l). Blood cultures grew Streptococcus mitis and Gemella morbillorum in 4 out of 6 bottles, both pathogens susceptible to clindamycin (MIC of 0.064 ug/ml for S.mitis and 0.094 ug/ml for G.morbillorum) and moxifloxacin (MIC of 0.25 ug/ml for S.mitis and 0.25 ug/ml for G.morbillorum).\n\nFurther information regarding the timeline of symptoms was obtained; his back pain started suddenly a few days after an endoscopic biopsy of the oesophagus had been performed, three months earlier, as follow-up for his oesophagus carcinoma. The oesophageal biopsy was negative. Thoracic and abdominal computed tomography (CT) scan images obtained one month before his admission showed no radiological signs of malignancy. This new information lead us to suspect of polymicrobial vertebral osteomyelitis by direct inoculation with a secondary bacteriemia due to recent bone sampling. Treatment with intravenous amoxicillin/clavulanate (2.2 g every 8 h) was initiated, and switched 48 h later to intravenous ceftriaxone (2 g once daily).\n\nA transthoracic echocardiogram was performed, and did not show any valvular abnormality. A CT scan of the chest revealed thickening of oesophageal wall with oedema, compatible with an oesophageal perforation. Accordingly, an oesophageal endoscopy was performed which demonstrated thickening of posterior oesophageal wall at the same level as the vertebroplasty. An MRI of the spine demonstrated an epidural abcess from the 3rd cervical to the 1st lumbar vertebra with minimal medullary compression (Fig. 2).Fig. 2 Spine MRI performed after Gadolinium intravenous contrast shows epidural posterior abscess from the third cervical (C3) to the first lumbar vertebra (L1). Medullary compression is seen without medullary suffering. Not well shown in this figure is abscess around the cement (fifth and sixth) thoracic vertebra\n\n\n\nNo surgical procedure was performed given the lack of neurological signs, and antibiotic treatment was continued. Clinical evolution was favourable and an MRI performed three weeks after initiation of antibiotic therapy showed regression of the epidural abscess (Fig. 3). Intravenous antibiotics were switched after six weeks to oral moxifloxacin (400 mg once daily), with a planned course of three months. Two days after initiation of oral antibiotic therapy the patient developed weakness of the right lower limb with progressive loss of sensation, extending to the left lower limb within 24 h. A CT of the spine revealed a new epidural abscess at the level of the 8th thoracic vertebra (Fig. 4). Intravenous ceftriaxone and metronidazole were reintroduced and a laminectomy at the 7th and 8th thoracic vertebra was immediately performed. The abscess was cultured and grew Candida albicans. Intravenous caspofungin was added and subsequently replaced by oral fluconazole (400 mg once daily) after two weeks. Metronidazole and ceftriaxone were switched to moxifloxacin after four weeks, and then to clindamycin due to a prolonged QT interval on the electrocardiogram. Therapy with clindamycin was maintained for three months and fluconazole for six months. The patient’s symptoms improved gradually, and an MRI performed twelve weeks after admission to our hospital revealed no residual abscess. At 6 month follow-up he had recovered almost fully, with only slight motor weakness of lower limbs.Fig. 3 Spine MRI shows improvement from earlier imaging, with decrease of epidural abcess and of medullary compression. Resolution of the abscess surrounding the site of cementoplasty as well as anterior abscess at the level of third thoracic to six thoracic and the soft tissue abcess\n\nFig. 4 Spine CT shows a block from the level of eight thoracic vertebrae due to an epidural posterior mass\n\n\n\nDiscussion\nWe describe a case of polymicrobial vertebral osteomyelitis initially misdiagnosed as a bony metastasis. This particular case is one of few cases of vertebral osteomyelitis that have been described after an oesophageal biopsy [7–10]. Cases of post-vertebroplasty osteomyelitis are also rare in the literature [11].\n\nWhen vertebral osteomyelitis is suspected, imaging of the spine followed by percutaneous bone biopsy should be performed. If polymicrobial osteomyelitis is suspected, a biopsy should be performed regardless of blood culture results [1] and immediate empirical antibiotic therapy should be initiated to cover the most common agents such as Staphylococci, Streptococci and enteric Gram negative bacilli (for example amoxicillin/clavulanate or a first or second generation cephalosporin, with or without vancomycin, depending on the local prevalence of MRSA). This may halt the progression of bony destruction and prevent the need for surgical treatment [12]. When vertebral collapse and spinal cord compression occur, surgical debridement and stabilisation should be combined with medical therapy to eradicate infection and resolve neurological deficits.\n\nWe hypothesize that the vertebral osteomyelitis in this case was likely caused by direct spread after oesophageal biopsy for two reasons: the posterior wall thickening seen at the time of the 2nd endoscopy at the same level as the vertebral infiltrate is consistent with a remote healed perforation. In addition, the polymicrobial flora, including Candida albicans, is suggestive of an upper gastrointestinal tract origin.\n\nCandidal infections are most commonly described in immunocompromised hosts (corticosteroids and sorafenib in this case) and in patients receiving prolonged courses of antibacterial therapy. In addition to direct spread from the oesophagus, Candida albicans may have been introduced during the vertebroplasty procedure or the Candidal infection may also have been a superinfection favoured by prolonged antibiotic therapy [13]. Vertebroplasty is, in general, a safe procedure but cases of osteomyelitis have been described [3, 4]. The cement used may have acted as a biofilm and could explain the slow progression of the infection.\n\nThere are several reasons for the delayed diagnosis of vertebral osteomyelitis in our patient. Firstly, due to patient’s past medical history, clinical presentation and MRI images, it was difficult to differentiate infection from neoplasia. Secondly, the recent vertebroplasty made performing a new bone biopsy difficult. Finally, the abscess did initially regress on MRI after three weeks of antibiotics, which was interpreted as an appropriate response to antibiotic therapy.\n\nConclusion\nIn conclusion, we present here an uncommon case of vertebral osteomyelitis after oesophageal biopsy. Because antibiotic therapy was directed to the pathogens found in the blood, Candida albicans was not suspected as the cause of a clinical relapse. In cases of polymicrobial vertebral osteomyelitis, we suggest performing a bone biopsy to appropriately target antibiotic therapy, and to systematically look for potential contiguous sources of infection.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nAG carried out the clinical follow up and draft the manuscript. EY and OM helped to draft the manuscript. OC and AT helped to draft the manuscript and supervised the clinical follow up. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe thank D. Richarme-Barthelet and S. Binaghi from the Department of Radiology for interpretation of the images, A. Rocca from the Department of Neurosurgery, and Dr Scott J Millington from the Department of Critical Care Medicine at the Ottawa Hospital/University of Ottawa for the language corrections.\n==== Refs\nReferences\n1. Zimmerli W Clinical practice. Vertebral osteomyelitis N Engl J Med 2010 362 1022 1029 10.1056/NEJMcp0910753 20237348 \n2. Grammatico L Baron S Rusch E Lepage B Surer N Desenclos JC Epidemiology of vertebral osteomyelitis (VO) in France: analysis of hospital-discharge data 2002–2003 Epidemiol Infect 2008 136 653 660 10.1017/S0950268807008850 17568478 \n3. McHenry MC Easley KA Locker GA Vertebral osteomyelitis: long-term outcome for 253 patients from 7 Cleveland-area hospitals Clin Infect Dis 2002 34 1342 1350 10.1086/340102 11981730 \n4. Cottle L Riordan T Infectious spondylodiscitis J Infect 2008 56 401 10.1016/j.jinf.2008.02.005 18442854 \n5. Gouliouris T Aliyu SH Brown NM Spondylodiscitis: update on diagnosis and management J Antimicrob Chemother 2010 65 11 24 10.1093/jac/dkq303 \n6. Mylona E Samarkos M Kakalou E Fanourgiakis P Skoutelis A Pyogenic vertebral osteomyelitis: a systematic review of clinical characteristics Semin Arthritis Rheum 2009 39 10 17 10.1016/j.semarthrit.2008.03.002 18550153 \n7. Mersol JV Kozarek RA Spine complications of stent placement Gastrointest Endosc 2002 55 241 10.1067/mge.2002.120812 11818932 \n8. Iannettoni MD Whyte RI Orringer MB Catastrophic complications of the cervical esophagogastric anastomosis J Thorac Cardiovasc Surg 1995 110 1493 1500 10.1016/S0022-5223(95)70072-2 7475201 \n9. Mecklenburg I Probst A Messmann H Esophagospinal Fistula with Spondylodiscitis and Meningitis after Esophagectomy with Gastric Pull-Up J Gastrointest Surg 2008 12 394 395 10.1007/s11605-007-0363-0 17955314 \n10. Radulovic D Vujotic L Cervical spinal epidural abscess after oesophagoscopy Eur Spine J 2013 22 Suppl 3 S369 S372 10.1007/s00586-012-2478-6 22918512 \n11. Walker DH Mummaneni P Rodts GE Jr Infected vertebroplasty. Report of two cases and review of the literature Neurosurg Focus 2004 17 10.3171/foc.2004.17.6.6 15636576 \n12. Wang YC Lee ST Candida vertebral osteomyelitis: a case report and review of the literature Chang Gung Med J 2001 24 810 815 11858398 \n13. Khazim RM Debnath UK Fares Y Candida albicans osteomyelitis of the spine: progressive clinical and radiological features and surgical management in three cases Eur Spine J 2006 15 1404 1410 10.1007/s00586-005-0038-z 16429290\n\n",
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"abstract": "Henoch-Schonlein purpura is vasculitis of small blood vessels characterized by deposits of IgA immune complexes and also non-thrombocytopenic purpura, abdominal pain, arthritis and renal involvement. It affects people of all ages, but most cases occur in children between 2 and 11 years old, more frequently in boys. The disease is much less common in adults, who often have a more severe course of the disease. The paper presents the case of a 38-year-old female patient with insidious course of the disease, initially dominant skin symptoms and joint pain without signs of inflammation. Symptoms of the disease were initially uncharacteristic and mild, and did not suggest severe and rapid course of the disease. The patient required hospitalization in several departments before final diagnosis of Henoch-Schonlein purpura. The patient was treated with corticosteroids and immunosuppression. Despite the rapid course of the disease, treatment was effective. The patient was discharged in good condition.",
"affiliations": "Department of Rheumatology, Voivodeship Hospital, Elbląg, Poland.;Clinical-Research Center, Elblag, Poland.;Clinical-Research Center, Elblag, Poland.;NZOZ Nasz Lekarz, Clinical Trials Office, Toruń, Poland.;University Hospital Nr 2 Dr. Jan Biziel, Bydgoszcz, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Poland.",
"authors": "Bielewicz-Zielińska|Agnieszka|A|;Górnikiewicz-Brzezicka|Bożena|B|;Brzezicki|Jan|J|;Rymko|Marcin|M|;Jeka|Sławomir|S|",
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"fulltext": "\n==== Front\nReumatologiaReumatologiaRUReumatologia0034-62332084-9834Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie 5400110.5114/reum.2015.54001Case ReportAtypical course of Henoch-Schonlein purpura in an adult patient Bielewicz-Zielińska Agnieszka 1Górnikiewicz-Brzezicka Bożena 2Brzezicki Jan 2Rymko Marcin 3Jeka Sławomir 41 Department of Rheumatology, Voivodeship Hospital, Elbląg, Poland2 Clinical-Research Center, Elblag, Poland3 NZOZ Nasz Lekarz, Clinical Trials Office, Toruń, Poland4 University Hospital Nr 2 Dr. Jan Biziel, Bydgoszcz, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, PolandAddress for correspondence: Agnieszka Bielewicz-Zielińska, Department of Rheumatology, Voivodeship Hospital, Elbląg, Poland. e-mail: agabielewicz@poczta.onet.pl21 9 2015 2015 53 4 225 229 22 6 2015 20 8 2015 Copyright © Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie 20152015This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.Henoch-Schonlein purpura is vasculitis of small blood vessels characterized by deposits of IgA immune complexes and also non-thrombocytopenic purpura, abdominal pain, arthritis and renal involvement. It affects people of all ages, but most cases occur in children between 2 and 11 years old, more frequently in boys. The disease is much less common in adults, who often have a more severe course of the disease. The paper presents the case of a 38-year-old female patient with insidious course of the disease, initially dominant skin symptoms and joint pain without signs of inflammation. Symptoms of the disease were initially uncharacteristic and mild, and did not suggest severe and rapid course of the disease. The patient required hospitalization in several departments before final diagnosis of Henoch-Schonlein purpura. The patient was treated with corticosteroids and immunosuppression. Despite the rapid course of the disease, treatment was effective. The patient was discharged in good condition.\n\narthritispurpuraimmunosuppression\n==== Body\nIntroduction\nHenoch-Schonlein purpura is small blood vessel vasculitis associated with deposits of IgA [1]. Peak incidence is at 4–5 years of age [1]. The disease in adults is associated with a much more severe course [2]. In the pathogenesis of the disease incorrect autoimmune reaction associated with exposure to exogenous antigens plays a major role [3]. The disease may begin with upper respiratory tract infection [4], often for several days preceding symptoms of the disease. Microorganisms occurring in relation with such an infection and Henoch-Schonlein purpura are the B-hemolytic streptococci, Mycobacterium tuberculosis, Escherichia coli, Mycoplasma pneumoniae, cytomegalovirus (CMV), Epstein-Barr virus (EBV), Varicella zoster virus (VZV), adenoviruses and parvoviruses [2]. Other factors initiating the disease are medication, insect bites, food and immunization [4]. In adult patients the clinical course and manifestation are not the same as in children [5]. Palpable purpura occurs in all pediatric patients.\n\nKidney changes occur in 10–50% of patients and are usually characterized by mild glomerulonephritis [4]. In adults, symptoms usually concern the skin and joints,and less frequently the first symptoms of disease are ailments of the intestines. Some studies have shown that kidney changes are more extensive and more severe in adults. Changes in heart muscle can occur in adults, but are rare in children [4]. Henoch-Schonlein purpura is differentiated from drug reactions, inflammation, bacterial endocarditis, leukocytoclastic vasculitis in the course of other diseases, and polyarteritis nodosa [6]. Some authors emphasize the relationship with cancer. In adults there have been described a few cases of the disease, accompanied by blood cancers [2], also with lupus nephritis and other forms of bleeding disorders, and rheumatic fever [7]. Diagnosis is based on clinical symptoms and histopathology of a skin sample. Kidney biopsy may be indicated only in case of proteinuria or hematuria, active urinary sediment, and renal dysfunction [8]. The are no specific laboratory tests, and diagnosis is generally based on the clinical presentation [6]. There is no specific treatment for Henoch-Schonlein purpura [9].\n\nCase report\nThe female, aged 38, noticed lesions of skin of lower legs, buttocks and upper limbs and lower leg swelling. Two days earlier there was left knee pain without swelling and redness. The patient has not suffered from chronic illnesses, and she reported duodenitis and Helicobacter pylori infection. She used only contraceptives. Three days late, she was admitted to the Dermatology Department for diagnosis of skin changes. In physical examination at admission purpura was found located within the lower legs, buttocks and upper limbs, as well as swelling of the lower legs and hands and left knee pain. Then the patients received dexamethasone – 4 mg 2 times a day and phenazolinum. During hospitalization, the patient had severe abdominal pain. In abdominal ultrasound examination there were no deviations besides a small amount of fluid in the small pelvis and fluid in Morison's pouch. The gynecological examination without deviation beyond a trace of fluid in the pelvis. After surgical consultation the patient was transferred to the Surgery Department, where exploratory laparoscopy was performed. Straw-filmy effusion was found in the minor pelvis, the appendix was unchanged, and genital organs were without any visible change. The last loop of small intestine infiltrated, inflamed thickened walls with raspberry spots, visible effusion under her serous membrane, intestine thickened and stiff. The patient was diagnosed with peritonitis, inflammation of the terminal ileum, and suspected Crohn's disease. Histopathological examination of fluid from the peritoneal cavity did not reveal tumor cells. Antibiotics were introduced – cefuroxime (intravenously 1500 mg three times a day), metronidazolum (intravenously 500 mg three times a day) and on the 10th day of hospitalization Mesalazinum (1500 mg two times a day) was added. After stabilizing the patient treatment was continued in the Department of Dermatology. Then, the patient reported the occurrence of loose stools, occasional vomiting and low-grade fever, joint pain and swelling of hands and ankles, as well as new purpuric changes in the mucous membranes of the mouth. On the 13th day of hospitalization chest pain occurred, so the patient was transferred to the Cardiology Division with suspected pulmonary embolism (D-dimers 4713, hsTroponina 0.0003). Angio-CT (computed tomography) revealed the presence of thrombi at the site of the intermediate artery bifurcation of the right lung and its branches. The patient was treated with anticoagulants – initially heparin 5000 IU bolus, followed by Enoxaparinum natricum 2 times a day 60 mg, yielding improvement of the patient.\n\nAfter rheumatological consultation the patient was transferred to the rheumatology division for further diagnosis. In the ward from the date of admission methylo-prednisolon orally was introduced, and at the same time methylprednisolone in a 500 mg dose in intravenous pulses for 3 days and one 250 mg pulse, then oral treatment at a dose of 48 mg/day was maintained, and mesalazinum was discontinued. Anticoagulation and antibiotic therapy were maintained.\n\nDuring hospitalization in the laboratory results there were observed increasing erythrocyturia 15–30 HPF, proteinuria to 697.8 mg/dl, protein loss 4.39 g/24 h, creatinine 0.55 mg/dl, hypokalemia 3.2 mmol/l, increasing leukocytosis to 34.46 K/UI likely post-steroid and/or in the course of the disease, erythrocytes 4.82 M/l, platelets 389,9 K/l, hemoglobin 13.3 g/dl, hematocrit of 40%, D-dimer 3453, ESR – 42, AST 65 U/l ALAT 45 U/l, CRP 63 mg/l, ANA at HEP-2 (anti-nuclear antibody screening using Hep-2 cells) titer of 1: 320, anti-cardiolipin IgA, IgM, IgG-negative, B2-glycoprotein antibodies IgM, IgG – negative, ANCA – negative, ASCA-IgA in normal range, IgG ASCA 12.03 (N < 10), anti-CCP 1.22 U/ml, TSH 2.23, fT3 – 3.77, fT4 – 22.9, total protein 4.94 g/dl, procalcitonin 0.18, 49.11% albumin, α1-globulins 6.14%, α2-globulins 12.78%, β1-globulins 10.01%, γ-globulins 14.55%, negative urine and blood cultures, throat-swab revealed normal flora.\n\nResults of chest X-ray were without deviations. The result of echocardiography (cardiac echocardiography) was within normal limits. Based on the clinical picture and laboratory results Henoch-Schonlein purpura was suspected. To complete the diagnosis a biopsy of skin and muscle was performed. In the obtained result of the histopathological examination, there were no vascular inflammatory changes. Waiting for the laboratory results, in tandem with steroid therapy, azathioprine therapy was included at a dose of 100 mg/day. In addition, the patient received perindopril 5 mg/day, furosemidum initially intravenously 80 mg 3 times a day, then reduced to 40 mg/day orally and spironolactone 25 mg/day, subcutaneous anticoagulant treatment was stopped, ASA (acetylsalicylic acid) 75 mg/day was started and analgesic paracetamol was administered if necessary. Gradual improvement of the patient's status was achieved. There was a reduction in proteinuria to 33.4 mg/dl, protein loss 1.53 g/24 h, CRP 6 mg /l, OB 12, AST 35 U/l, ALAT 42 U/l, leukocytes 27.6 K/µl.\n\nGradually improvement was observed in the patient, both clinically and in laboratory tests. The patient was discharged from the hospital in good general condition.\n\nDiscussion\nThe new nomenclature of the International Chapel Hill Consensus Conference 2012 classifies Henoch- Schonlein purpura as an immune complex small vessel vasculitis (IgA vasculitis) [8, 10–12].\n\nIncidence of Henoch-Schonlein purpura in children is 10.5–22/100,000 a year, and among adults is much lower (about 1.2/100,000 per year) [3]. The prognosis is good for children, worse in adults [3].\n\nAdults are much more likely to present joint pain and rapidly progressive glomerulonephritis. In our patient symptoms were preceded by a respiratory infection, initially not feverish. The first symptom was a sore knee without signs of inflammation, which did not arouse anxiety in the patient. Only the skin lesions prompted the patient to report to a doctor. One of the diagnostic criteria of Henoch-Schonlein purpura is a hemorrhagic palpable purpura located on the limbs and buttocks [10], as in this case and joints. Purpura is a constant symptom. Relapses of rashes are possible, and blisters and hemorrhagic necrosis may occur [6]. It occurs in 90% of cases [10]. In adults it is dominated by a symmetric erythematous rash appearing around the hydrostatic pressure dependent areas, i.e. the legs and buttocks [2]. An important element is the lack of disappearance of purpuric changes during the tribulation, resulting from the severity of inflammation [2]. The changes observed in vascular flow, which is included in the differential diagnosis, disappear during the tribulation [2]. Purpura was also differentiated from drug reactions; however, before the onset of symptoms the patient used drugs previously without complications. In order to exclude bacterial endocarditis echocardiography was performed, which showed no abnormalities.\n\nIgA vasculitis should also be distinguished from leukocytoclastic vasculitis occurring in the course of other diseases such as e.g. nodular arteritis: there are no neurological symptoms, hypertension, which occurred in the further course of the disease, the absence of HBsAg, and HCV antibody (HCV infection and HBV especially often coexist with above-mentioned vasculitis) [6].\n\nIn a study conducted in the years 1983–2000 in eleven French medical centers in 250 adult patients there were deaths observed in the course of cancer. Among these, 14% were caused by lung cancer, and 8% by a tumor of the gastrointestinal tract [5]. However, no evidence was found on the possibility of paraneoplastic origin of Schonlein-Henoch purpura [5]. In our patient there were no clinical data or evidence suggesting cancer. Also conducted tests excluded such a suspicion.\n\nA particularly important diagnostic tool is a skin biopsy. Leukocytoclastic inflammation is confirmed with the presence of deposits of IgA, complement component C3 and fibrinogen in vessels wall [2]. In our patient a biopsy of skin and muscle was performed and no deposits of IgA were found. Perhaps it was caused by late rheumatological diagnosis and already included treatment with corticosteroids.\n\nSymptoms of the gastrointestinal tract are common, particularly in children [12, 13]. Abdominal pain is the second most common symptom characteristic for the disease. It appears in 65–75% of patients. Usually it is located in the periumbilical area and is of colic character. Gastrointestinal bleeding is a consequence of hemorrhagic gastritis, duodenitis and enteritis [2]. In the case described, the patient had severe abdominal pain, initially without diarrhea, with no bleeding from the gastrointestinal tract. In abdominal ultrasonography and gynecological examination, apart from a small amount of fluid in the minor pelvis, no deviations from the norm were found.\n\nHowever, the severity of symptoms and the patient's condition required decisions to be made about surgical intervention and the implementation of laparoscopy. During the procedure there were revealed inflammatory changes mainly in the small intestine. In the course of the disease the small intestine is most often affected [14]. The suspicion of Crohn's disease arose. Therefore a blood sample was examined for ASCA antibody (anti-Saccharomyces cerevisiae), which occurs in 60% of patients with Crohn's disease. The presence of ASCA, both IgA and IgG, is specific for this disease [8]. In our patient ASCA IgA was negative, and IgG was slightly above normal. During the procedure, fluid was also collected from the peritoneal cavity, in which there was no presence of tumor cells.\n\nFurther symptoms that occurred in our patient were pain and swelling of joints of the hands and ankles and previously left knee pain without evidence of synovitis. Arthralgia affects 2/3 of patients. Typically, painful and/or swollen large joints are affected, mostly knee and ankle [13]. Arthritis resolves without complications [12]. This is yet another symptom that belongs to the diagnostic criteria of Henoch-Schonlein purpura. In this case, the patient reported pain in the chest, heart attack was excluded, but the angio-CT revealed a blood clot in an intermediate artery bifurcation of the right lung. Once applied anticoagulant therapy achieved improvement of the patient. The cardiac symptoms are not included in the diagnostic criteria of the disease because cardiac involvement occurs very rarely [2]. During hospitalization in the Department of Rheumatology a growing hematuria was observed, and proteinuria meeting the criteria of nephrotic syndrome.\n\nRenal involvement relates to 30% of cases of Henoch-Schonlein purpura in children and 60% in adults [14]. Renal involvement usually manifests itself a few days or weeks after the onset of systemic symptoms [15]. The most common manifestation is a segmental, focal glomerulonephritis, always associated with deposits of IgA in the mesangium. If symptoms are severe, renal biopsy should be performed, especially if daily protein loss is > 1 g or renal failure is progressing. The prevalence of chronic kidney disease in children is 18%, in adults 28% [16]. The main prognostic role is played by histopathology. The percentage of crescents, interstitial fibrosis, and subepithelial dense deposits correlates with a risk of chronic kidney disease.\n\nIn adults, the percentage of development of crescents is associated with an unfavorable course in less than 50% [16]. Adverse prognostic factors are assumed to be a high level of creatinine, proteinuria greater than 1 g/day, hypertension, proteinuria increase, vascular proliferation in biopsies, interstitial fibrosis, and renal tubular atrophy [17]. In the described patient, there was no increase in levels of creatinine, but poor prognostic factors were significant proteinuria and hypertension. In the patient renal biopsy was not performed due to the patient's severe condition and the need for quick implementation of treatment.\n\nHenoch-Schonlein purpura was diagnosed despite the lack of specific laboratory tests; it was based on the clinical picture and the diagnostic criteria of this disease. In mild purpura the treatment is symptomatic [3]. During the initial phase this is removal of foci of inflammation with antibiotics, while in the case of involvement of the gastrointestinal tract and/or joints it is glucocorticoids, and in nephritis, depending on the histopathology, it is steroids and cytotoxic drugs [6]. In refractory cases of renal changes intravenously cyclofosfamid pulsed for 6 months can be applied [17]. When no improvement occurs, plasmapheresis is used, dialysis or a kidney transplant [6]. In patients with contraindications to the use of immunosuppressive therapy (infections, old age) intravenous infusions of immunoglobulin can be considered.\n\nIn our patient, due to the rapid course of the disease, the serious patient condition, and multi-organ symptoms, it was decided immediately to use intravenous and oral corticosteroids. While waiting for the results of laboratory tests simultaneously with corticosteroids, treatment with azathioprine was started. In addition, the patient received pressure-lowering drugs, anticoagulants, and antibiotics. Gradual improvement was observed in the patient, both in clinical and in laboratory parameters [18].\n\nSummary\nIn summary, Henoch-Schonlein purpura, although more common in children, can also occur in adults. However, its progress in adults differs significantly from the disease occurring in children. It is an interdisciplinary disease, with rapid course, as shown in the described patient. It can cause diagnostic difficulties, and requires quick therapeutic decisions, even without a fully completed diagnosis, and the outcome is not always as successful as in the present case.\n\n\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1 Małecki R Staworska K Frankowski M Plamica Schönleina-Henocha o ciężkim przebiegu z zajęciem przewodu pokarmowego Reumatologia 2012 50 61 65 \n2 Wardyn K Życińska K Życiński K Plamica Schönleina-Henocha. Pierwotne układowe zapalenie naczyń 2004 Wrocław Wydawnictwo Medyczne Urban & Partner 284 288 \n3 Bujakowska O Saracyn M Kur-Zalewska J Dramatyczny przypadek plamicy Schönleina-Henocha u osoby dorosłej Reumatologia 2013 51 229 232 \n4 Fauci A Pazdur J Plamica Schönleina-Henocha. Harrison – Reumatologia Wyd 2012 Lublin II. Wydawnictwo Czelej 188 189 \n5 Pillebout E Thervet E Hill G Henoch-Schonlein purpura in adults: outcome and prognostic factors J Am Soc Nephrol 2002 13 1271 1278 11961015 \n6 Małdyk H Fiedorowicz-Fabrycy I Układowe zapalenie naczyń Reumatologia 2004 42 supl. 1 86 87 \n7 Romicka A Rostropowicz-Denisiewicz K Plamica Schonleina-Henocha Zarys reumatologii wieku rozwojowego 2010 Katowice Wydawnictwo Elamed 133 135 \n8 Zapalenie naczyń związane z IgA Interna Szczeklika 2014 Kraków Medycyna Praktyczna 1889 1890 \n9 Jaliman D Henoch-Schonlein Purpura 2013 7 12 2013 WebMD \n10 Maj J Reich A Baran E Pierwotne systemowe zapalenie naczyń. PSV Postępy Dermatologii i Alergologii 2004 21 247 254 \n11 Jennette JC Falk RJ Bacon PA 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides Arthritis Rheum 2013 65 1 11 23045170 \n12 Brogan P Elefherion D Dillon M Small vessel vasculitis Pediatr Nephrol 2010 25 1025 1035 19885685 \n13 Zaffarello M Fanos V Treatment-based literature of Henoch-Schonlein purpura nephritis in childhood Pediatr Nephrol 2009 24 1901 1911 19066976 \n14 Frigui M Lehiani D Konbae M Acute pancreatic as initial manifestation of adult Henoch-Schonlein purpura: raport of case and review of literature Eur J Gastroenteral Hepatol 2011 23 189 192 \n15 Zimmermann-Górska I Plamica Henocha-Schönleina Reumatologia kliniczna 2008 Warszawa Wydawnictwo Lekarskie PZWL 1019 1020 \n16 Rieu P Noel H Henoch-Schonlein nephritis in children and adults, morphological features and clinicopathological correlations Ann Med Interna 1999 150 151 159 \n17 López Meiller MJ Cavallasca JA Maliandi Mdel R Nasswetter GG Henoch-Schonlein purpura in adults Clinics 2008 63 273 276 18438584 \n18 Wiland P Madej M Zapalenie naczyń Przegląd Reumatologiczny 2007 3 5\n\n",
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"abstract": "Pulmonary actinomycosis reportedly forms 15% of all cases of actinomycosis, and pulmonary Actinomyces odontolyticus is particularly rare. A 60-year-old man with a hoarse voice was referred to our hospital. Lung squamous cell carcinoma was diagnosed at the clinical tumor-node-metastasis stage of cT2N2M0, and concurrent chemoradiotherapy was initiated. Further, a small cavity was also detected in the left upper lobe, but it was observed. During chemoradiotherapy, the small cavity lesion rapidly increased accompanying infiltration, and administration of short-term antibiotics did not improve the patient's condition. Bronchoscopy did not show any diagnostic results. Although a rapidly progressive malignant lesion could not be excluded and surgical management was considered, resection could not be performed because of the tight adhesion of the mass. Therefore, bronchoscopy was performed again, and the bronchial lavage culture showed a positive smear for the Actinomyces species. Further, using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), the bacteria was identified as A. odontolyticus. After long-term administration of amoxicillin, the lung cavity with infiltration gradually improved. To the best of our knowledge, there have been nine cases of pulmonary A. odontolyticus (excluding those with only empyema or pleural mass without lung lesions), which can occur in immunocompetent patients with persistent lung shadow. None of the cases showed drastic deterioration; therefore, the present case is the first to highlight that A. odontolyticus possibly produce drastically progressive lung cavity lesion. Further, repeated bronchoscopy and MALDI-TOF MS could help to diagnose pulmonary actinomycosis.",
"affiliations": "Department of Respiratory Medicine, Saiseikai-Noe Hospital, Osaka, Japan.;Department of Respiratory Medicine, Saiseikai-Noe Hospital, Osaka, Japan.;Department of Respiratory Medicine, Saiseikai-Noe Hospital, Osaka, Japan.;Department of Respiratory Medicine, Saiseikai-Noe Hospital, Osaka, Japan.;Department of Respiratory Medicine, Saiseikai-Noe Hospital, Osaka, Japan.;Department of Respiratory Medicine, Saiseikai-Noe Hospital, Osaka, Japan.;Department of Respiratory Medicine, Saiseikai-Noe Hospital, Osaka, Japan.",
"authors": "Matsumoto|Takeshi|T|;Kusakabe|Yusuke|Y|;Enomoto|Masamitsu|M|;Yamamoto|Naoki|N|;Aihara|Kensaku|K|;Yamaoka|Shinpachi|S|;Mishima|Michiaki|M|",
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"doi": "10.1016/j.rmcr.2019.100950",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(19)30209-610.1016/j.rmcr.2019.100950100950Case ReportDrastically progressive lung cavity lesion caused by Actinomyces odontolyticus in a patient undergoing chemoradiotherapy: A case report and literature review Matsumoto Takeshi mtakeshi@noe.saiseikai.or.jp∗Kusakabe Yusuke Enomoto Masamitsu Yamamoto Naoki Aihara Kensaku Yamaoka Shinpachi Mishima Michiaki Department of Respiratory Medicine, Saiseikai-Noe Hospital, Osaka, Japan∗ Corresponding author. Department of Respiratory Medicine, Saiseikai-Noe Hospital, 1-3-25 Furuichi, Jyoto-ku, Osaka, 536-0001, Japan. mtakeshi@noe.saiseikai.or.jp14 10 2019 2019 14 10 2019 28 1009507 7 2019 4 10 2019 12 10 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Pulmonary actinomycosis reportedly forms 15% of all cases of actinomycosis, and pulmonary Actinomyces odontolyticus is particularly rare. A 60-year-old man with a hoarse voice was referred to our hospital. Lung squamous cell carcinoma was diagnosed at the clinical tumor-node-metastasis stage of cT2N2M0, and concurrent chemoradiotherapy was initiated. Further, a small cavity was also detected in the left upper lobe, but it was observed. During chemoradiotherapy, the small cavity lesion rapidly increased accompanying infiltration, and administration of short-term antibiotics did not improve the patient's condition. Bronchoscopy did not show any diagnostic results. Although a rapidly progressive malignant lesion could not be excluded and surgical management was considered, resection could not be performed because of the tight adhesion of the mass. Therefore, bronchoscopy was performed again, and the bronchial lavage culture showed a positive smear for the Actinomyces species. Further, using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), the bacteria was identified as A. odontolyticus. After long-term administration of amoxicillin, the lung cavity with infiltration gradually improved. To the best of our knowledge, there have been nine cases of pulmonary A. odontolyticus (excluding those with only empyema or pleural mass without lung lesions), which can occur in immunocompetent patients with persistent lung shadow. None of the cases showed drastic deterioration; therefore, the present case is the first to highlight that A. odontolyticus possibly produce drastically progressive lung cavity lesion. Further, repeated bronchoscopy and MALDI-TOF MS could help to diagnose pulmonary actinomycosis.\n\nKeywords\nPulmonary actinomycosisImmunocompromisedBronchoscopyMatrix-assisted laser desorption/ionization time-of-flight mass spectrometry\n==== Body\n1 Introduction\nActinomyces species are anaerobic gram-positive rods. Actinomycosis has been reported worldwide. Recently, the incidence of all types of actinomycosis has markedly declined. Total 15% of all cases of actinomycosis are of pulmonary actinomycosis [1]. Pulmonary actinomycosis is rare, mainly owing to A. israelii and A. odontolyticus being particularly rare [[1], [2], [3]]. A. odontolyticus was first isolated from dental caries in 1958 and is a commensal organism found in the mouth [4]. Actinomycosis is difficult to diagnose using bronchoscopy or sputum culture [1], and in many patients, surgery is required for diagnosis [5]. In addition, usually, pulmonary actinomycosis gradually grows with air-space consolidation, adjacent pleural thickening, or cavitation in the lung field [6]; hence, pulmonary actinomycosis is not likely to be a disease with a rapidly progressive clinical course. Therefore, patients with progressive pulmonary disease can be misdiagnosed and consequently treated inappropriately. Here we report a case of drastically progressive lung cavity lesion caused by A. odontolyticus in a patient undergoing chemoradiotherapy and present a literature review.\n\n2 Case report\nA 60-year-old man with a hoarse voice was referred to our hospital. He did not have any medical history but had been smoking for 40 pack-years. His physical examination revealed no apparent abnormalities except for hoarse voice. Left vocal cord paralysis was discovered, and chest X-ray revealed a mass in the left hilum (Fig. 1a).Fig. 1 (a) Chest X-ray at the time of the patient's referral showing a mass in the left hilum. (b) The first bronchoscopy showing a mass with distended vessels in the left main bronchus that was identified as lung squamous cell carcinoma. (c, d) Positron emission tomography showing high uptake of fluorodeoxyglucose with mediastinal lymphadenopathy in the mass in the left main bronchus [maximum standardized uptake value (SUVmax) = 11.5]; however, minor uptake was observed in a small cavity in the left upper lobe (SUVmax = 1.9).\n\nFig. 1\n\nComputed tomography (CT) revealed a mass with mediastinal lymphadenopathy in the left main bronchus and a small cavity in the left upper lobe. Bronchoscopy revealed a mass with distended vessels in the left main bronchus (Fig. 1b), and the mass was revealed to be lung squamous cell carcinoma. Positron emission tomography revealed high uptake of fluorodeoxyglucose in the mass in the left main bronchus [maximum standardized uptake value (SUVmax) = 11.5]; however, minor uptake was observed in the lung cavity (SUVmax = 1.9) (Fig. 1c and d). The patient was diagnosed with lung squamous cell carcinoma at the clinical tumor-node-metastasis stage of cT2N2M0 (stage 3A). Concurrent chemoradiotherapy, i.e., chemotherapy comprising weekly carboplatin and paclitaxel combined with radiation therapy (60 Gy; 30 fractions), was initiated. A small cavity located in the left upper lobe was not included in the radiation field.\n\nDuring chemoradiotherapy, the small cavity lesion steadily increased (Fig. 2).Fig. 2 Clinical and radiological course.\n\nThe small cavity in the left upper field rapidly increased and gradually improved after long-term administration of antibiotics. Continuous arrows represent the points considered for CXR and dashed arrows represent those for CT shown below.\n\nABPC, ampicillin; ABPC/SBT, ampicillin/sulbactam; AMPC, amoxicillin; wCBDCA, weekly carboplatin; CT, computed tomography; CXR, chest X-ray; FBS, fiberoptic bronchoscopy; GRNX, garenoxacin; MEPM, meropenem; wPTX, weekly paclitaxel.\n\nFig. 2\n\nTwo weeks after chemoradiotherapy was initiated, CT revealed increased cavity wall thickness and new infiltration. Although the patient had no fever or purulent sputum, bacterial infection was assumed, and administration of antibiotics (ampicillin/sulbactam, 1.5 g every 6 h) was initiated. All sputum cultures for bacteria, including acid-fast bacteria, were negative, and chest X-ray obtained 5 days later revealed enlargement of the cavity under the administration of antibiotics.\n\nPhysical examination revealed no apparent abnormality, even in the oral cavity, and the following observations were noted: heart rate, 88 beats/min and regular; blood pressure level, 102/72 mmHg; oxygen saturation level, 97% on room air; and body temperature, 36.5 °C. Laboratory testing revealed a white blood cell count of 4800/mm3 with a neutrophil percentage of 70.9% and C-reactive protein level of 2.66 mg/dL. Procalcitonin level, interferon-gamma release assay findings, Mycobacterium avium complex-specific glycopeptidolipid core antigen antibody level, Aspergillus galactomannan antigen level, and β-d-glucan level were all within normal ranges. The second bronchoscopy was performed for diagnosis; although the mass in the left main bronchus identified as lung squamous cell carcinoma was diminished, there were no apparent findings indicating bacterial infection. However, garenoxacin, 400mg once daily, was administered owing to the rapid progression of the disease and the consideration of bacterial infection. The bronchial lavage culture was negative for bacteria, and the bronchial tissue showed no evidence of malignancy. Further, Mycobacterium szulgai was cultured; however, considering the clinical course, as described later, the organism was not considered to be the causative organism.\n\nAlthough the administration of garenoxacin was continued, the lung cavity with infiltration drastically increased (Fig. 2). Because the presence of a rapidly progressive malignant lesion could not be excluded, surgical management was considered for the diagnostic therapy. However, resection could not be performed because of the tight adhesion of the mass. Therefore, the third bronchoscopy was performed. The bronchial lavage culture showed a positive smear for the Actinomyces species, and using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS; MALDI Biotyper; BRUKER, Billerica, MA, USA), the bacteria was identified to be A. odontolyticus.\n\nBased on the antimicrobial susceptibility test results (minimum inhibitory concentration <0.125 μg/ml for ampicillin), ampicillin, 2 g every 6 h, was injected for 2 weeks followed by oral administration of amoxicillin, 500 mg t.i.d. The patient continued to receive treatment in the outpatient department. After chemoradiotherapy, the lung squamous cell carcinoma was treated using durvalumab. Continuous administration of durvalumab and amoxicillin for 4 months suppressed the lung squamous cell carcinoma and gradually improved the lung cavity with infiltration (Fig. 2).\n\n3 Discussion\nWe reported a drastically progressive lung cavity lesion caused by A. odontolyticus in a patient undergoing chemoradiotherapy. In this case, diagnosis of drastically progressive lung cavity lesion and its distinction from the diagnosis of rapidly progressive malignant tumor were difficult; however, repeated bronchoscopy and MALDI-TOF MS identified A. odontolyticus, which contributed to the appropriate treatment.\n\nOral insanitation, diabetes, and frequent alcohol consumption are reportedly the risk factors of pulmonary actinomycosis; however, no baseline diseases are found in 30% of them [7]. Of note, immunosuppression, such as that caused by acquired immune deficiency syndrome, cancer chemotherapy, or chronic steroid therapy, has not been reported as the risk factor for pulmonary actinomycosis [8,9]; however, underlying lung disease reportedly increases the prevalence of pulmonary actinomycosis [10]. Emphysema is reported to be associated with increased activity of proteolytic enzymes, which are activated because of inflammation and oxidative stress occurring in chronic obstructive pulmonary disease (COPD) [11]. Also, inflammation and chronic colonization of Haemophilus influenzae in sputum of patients with COPD were reported to be associated with the degree of emphysema and bronchiectasis on CT [12]. Therefore, in the present case, having emphysematous lesions might have predisposed the patients to bacterial infections, and these lesions possibly contributed to the infection by A. odontolyticus. Although the lung cavity lesion was not included in the radiation field, local immunosuppression might have affected the course of pulmonary actinomycosis because of the presence of lung squamous cell carcinoma and the administration of chemoradiotherapy.\n\nPulmonary actinomycosis is reportedly difficult to culture owing to the lack of culturing techniques, prevalence of previous antibiotic therapy in the patient, and bacterial overgrowth even when clinical suspicion is high, thereby resulting in a culture rate of <50% [1,9]. First, A. odontolyticus is part of the normal oropharyngeal flora, and positive sputum culture cannot establish the diagnosis of pulmonary actinomycosis [3]. Generally speaking, it is difficult to prevent the cross contamination of oral bacteria during bronchoscopy, and in this case, it was impossible to rule out coinfection by other bacteria in addition to A. odontolyticus. However, incubation of the bronchial lavage led to a significant number of A. odontolyticus colonies, and long-term administration of antibiotics was effective for treating the lung cavity lesion. Therefore, we believe that A. odontolyticus was the causative organism in this case. Pulmonary actinomycosis is most commonly misdiagnosed as a malignant disease or tuberculosis [13]; moreover, nocardiosis, histoplasmosis, blastomycosis, mixed anaerobic infections, bronchogenic carcinoma, lymphoma, mesothelioma, and pulmonary infarction are among the entities confused with pulmonary actinomycosis [14]. A quarter of cases were misdiagnosed as malignancy, and surgery was performed [1]. In the present case, although surgical resection was difficult, repeated bronchoscopy yielded the specimen. In addition, MALDI-TOF MS was effective in detecting the causative organism. Thus, MALDI-TOF MS would be a new tool for the diagnosis of this infectious disease [5,15].\n\nIn the present case, short-term administration of antibiotics could not improve the patient's condition; however, this does not necessarily indicate that the bacteria were resistant to the antibiotics. Infection caused by Actinomyces species is usually recommended to be treated using penicillin injection for 2–6 weeks followed by oral penicillin for 6–12 months [1,13]. In fact, in the present case, long-term administration of antibiotics improved the radiological findings.\n\nTo the best of our knowledge, there have been nine patients with pulmonary A. odontolyticus (excluding those with only empyema or pleural mass without lung lesions) [2,3,[16], [17], [18], [19], [20], [21], [22]]. A summary of the reported cases is presented in Table 1.Table 1 Summary of pulmonary Actinomyces odontolyticus (excluding those with only empyema or pleural mass without lung lesions).\n\nTable 1Authors\tAge (y), sex\tPresentation\tComorbidities or immunocompromised factors\tDiagnostic method\tAntibiotics for long-term administration\tOutcome\t\nTakiguchi et al. [3]\t64, female\tLung abscess\tPeriodontal disease\tPercutaneous needle aspiration\tSultamicillin tosilate\tRecovery\t\nBaron et al. [16]\t61, female\tLung abscess\tRheumatoid arthritis with prednisone therapy\tTransthoracic aspiration\tPenicillin\tRecovery\t\nDontfraid F et al. [17]\t52, female\tPneumonia with soft-tissue abscesses\tAlcoholism and periodontal disease\tCutaneous drainage\tAmoxicillin\tRecovery\t\nBassiri et al. [2]\t61, male\tPneumonia\tLung transplantation with prednisone, cyclosporine, and azathioprine\tBronchoscopy\tPenicillin\tRecovery\t\nIancu et al. [18]\t37, female\tLung abscess\tB cell lymphoma with prednisone therapy\tThoracotomy\tPenicillin and metronidazole\tDeceased\t\nVerrot et al. [19]\t52, female\tPneumonia\tBronchiectasis\tSurgery\tImipenem and minocycline\tRecovery\t\nSusaki et al. [20]\t51, male\tPneumonia\tDental caries\tSputum\tPenicillin\tRecovery\t\nGray et al. [21]\t11, female\tPneumonia\tBronchiectasis\tBronchoscopy\tPenicillin\tRecovery\t\nErro Iribarren et al. [22]\t43, male\tPneumonia\tBronchial asthma with omalizumab\tBronchoscopy\tAmoxicillin-clavulanic acid\tRecovery\t\nPresent case\t60, male\tPneumonia\tLung squamous cell carcinoma undergoing chemoradiotherapy\tBronchoscopy\tAmoxicillin\tRecovery\t\n\n\nConsidering the reported cases, an immunocompetent patient can also suffer from pulmonary A. odontolyticus. Aspiration of oropharyngeal or gastrointestinal secretions into the respiratory tract, or in rare cases, hematogenous dissemination due to disruption of the gastrointestinal tract mucosal barrier caused by periodontal disease, dental procedure, bacterial suppuration, surgery, or trauma is considered to cause pulmonary actinomycosis [1,13]. Although there was no apparent periodontal disease, dental caries, or Actinomyces bacteremia in the present case, similar cases have previously been reported [19,21]. Although one patient died likely due to lymphoma, pulmonary A. odontolyticus usually has a good prognosis. None of the cases, including immunocompromised ones, showed drastic deterioration. Therefore, the clinical course of the disease in our patient was rare; however, our case suggests that we should be aware that pulmonary A. odontolyticus could rapidly become exacerbated.\n\nIn conclusion, pulmonary A. odontolyticus is rare but can occur in immunocompetent patients with persistent lung shadow. Further, it should be noted that A. odontolyticus may produce drastically progressive lung cavity lesion. Repeated bronchoscopy and MALDI-TOF MS could help to diagnose pulmonary actinomycosis.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nPatient consent for publication\nConsent for publication has been obtained.\n\nDeclaration of competing interest\nThe authors have no conflict of interest.\n\nAcknowledgements\nThe authors thank T. Takuwa, A. Fukuda (Department of Thoracic Surgery, Saiseikai-Noe Hospital), M. Kamata, and Y. Itsuno (Department of Radiation Therapy, Saiseikai-Noe Hospital) for their clinical support. The authors also thank Enago (www.enago.jp) for the English language review.\n==== Refs\nReferences\n1 Mabeza G.F. Macfarlane J. Pulmonary actinomycosis Eur. Respir. J. 21 2003 545 551 12662015 \n2 Bassiri A.G. Girgis R.E. Theodore J. Actinomyces odontolyticus thoracopulmonary infections. Two cases in lung and heart-lung transplant recipients and a review of the literature Chest 109 1996 1109 1111 8635341 \n3 Takiguchi Y. Terano T. Hirai A. Lung abscess caused by actinomyces odontolyticus Intern. Med. 42 2003 723 725 12924500 \n4 Batty I. Actinomyces odontolyticus, a new species of actinomycete regularly isolated from deep carious dentine J. Pathol. Bacteriol. 75 1958 455 459 13576328 \n5 Valour F. Senechal A. Dupieux C. Karsenty J. Lustig S. Breton P. Actinomycosis: etiology, clinical features, diagnosis, treatment, and management Infect. Drug Resist. 7 2014 183 197 25045274 \n6 Kwong J.S. Muller N.L. Godwin J.D. Aberle D. Grymaloski M.R. Thoracic actinomycosis: Ct findings in eight patients Radiology 183 1992 189 192 1549670 \n7 Kobashi Y. Yoshida K. Miyashita N. Niki Y. Matsushima T. Thoracic actinomycosis with mainly pleural involvement J. Infect. Chemother. 10 2004 172 177 15290457 \n8 Chaudhry S.I. Greenspan J.S. Actinomycosis in HIV infection: a review of a rare complication Int. J. STD AIDS 11 2000 349 355 10872906 \n9 Bennhoff D.F. Actinomycosis: diagnostic and therapeutic considerations and a review of 32 cases The Laryngoscope 94 1984 1198 1217 6381942 \n10 Schaal K.P. Lee H.J. Actinomycete infections in humans--a review Gene 115 1992 201 211 1612438 \n11 Angelis N. Porpodis K. Zarogoulidis P. Spyratos D. Kioumis I. Papaiwannou A. Airway inflammation in chronic obstructive pulmonary disease J. Thorac. Dis. 6 Suppl 1 2014 S167 S172 24672691 \n12 Tufvesson E. Markstad H. Bozovic G. Ekberg M. Bjermer L. Inflammation and chronic colonization of haemophilus influenzae in sputum in COPD patients related to the degree of emphysema and bronchiectasis in high-resolution computed tomography Int. J. Chronic Obstr. Pulm. Dis. 12 2017 3211 3219 \n13 Smego R.A. Jr. Foglia G. Actinomycosis Clin. Infect. Dis. 26 1998 1255 1261 quiz 62-3 9636842 \n14 Ray P. Mandal J. Gautam V. Singh K. Gupta D. A case of pulmonary actinomycosis caused by actinomyces odontolyticus from India Indian J. Med. Res. 122 2005 547 548 16518008 \n15 Schubert S. Kostrzewa M. Maldi-tof ms in the microbiology laboratory: current trends Curr. Issues Mol. Biol. 23 2017 17 20 28504240 \n16 Baron E.J. Angevine J.M. Sundstrom W. Actinomycotic pulmonary abscess in an immunosuppressed patient Am. J. Clin. Pathol. 72 1979 637 639 495569 \n17 Dontfraid F. Ramphal R. Bilateral pulmonary infiltrates in association with disseminated actinomycosis Clin. Infect. Dis. 19 1994 143 145 7948516 \n18 Iancu D. Chua A. Schoch P.E. Cunha B.A. Actinomyces odontolyticus pulmonary infection Am. J. Med. 107 1999 293 294 \n19 Verrot D. Disdier P. Harle J.R. Peloux Y. Garbes L. Arnaud A. Pulmonary actinomycosis: caused by actinomyces odontolyticus? Rev. Med. Interne 14 1993 179 181 8378641 \n20 Susaki K. Bandoh S. Fujita J. Kanaji N. Ishii T. Kubo A. A case of pulmonary actinomycosis, who expectorated sulfur granules, caused by actinomyces odontolyticus and actinomyces meyeri Nihon Kokyuki Gakkai Zasshi 43 2005 231 235 15966370 \n21 Gray A. Do P. The case of the unwanted crystal: a case of pediatric pulmonary actinomyces odonolyticus Clin Case Rep 6 2018 1230 1231 29988629 \n22 Erro Iribarren M. Cisneros Serrano C. Rajas Naranjo O. Garcia Castillo E. Pulmonary actinomycosis in a patient with chronic eosinophilic pneumonia treated with omalizumab Arch. Bronconeumol. 54 2018 51 52 28720253\n\n",
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"title": "Drastically progressive lung cavity lesion caused by Actinomyces odontolyticus in a patient undergoing chemoradiotherapy: A case report and literature review.",
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"abstract": "Fusarium spp. causes infections mostly in patients with prolonged neutropenia. We describe the case of a disseminated Fusarium solani infection in a patient with acute myeloid leukemia which never reached complete remission during its clinical course. The patient had profound neutropenia and developed skin nodules and pneumonia in spite of posaconazole prophylaxis. F. solani was isolated from blood and skin biopsy, being identified from its morphology and by molecular methods. By broth dilution method, the strain was resistant to azoles, including voriconazole and posaconazole, and to echinocandins. MIC to amphotericin B was 4 mg/L. The patient initially seemed to benefit from therapy with voriconazole and amphotericin B, but, neutropenia perduring, his clinical condition deteriorated with fatal outcome. All efforts should be made to determine the correct diagnosis as soon as possible in a neutropenic patient and to treat this infection in a timely way, assuming pathogen susceptibility while tests of antimicrobial susceptibility are pending. A review of the most recent literature on invasive fungal infections is reported.",
"affiliations": "Department of DETO, University of Bari, Bari, Italy.;Department SMBNOS, University of Bari, Bari, Italy. rosa.monno@uniba.it.;Department DIM, University of Bari, Bari, Italy.;Department DIM, University of Bari, Bari, Italy.;Department of DETO, University of Bari, Bari, Italy.;Department of DETO, University of Bari, Bari, Italy.;Department SMBNOS, University of Bari, Bari, Italy.;Department SMBNOS, University of Bari, Bari, Italy.;Department of Biomedical Science for Health, University of Milan, Milan, Italy.;Department of DETO, University of Bari, Bari, Italy.",
"authors": "Delia|Mario|M|;Monno|Rosa|R|;Giannelli|Giorgia|G|;Ianora|Amato Antonio Stabile|AA|;Dalfino|Lidia|L|;Pastore|Domenico|D|;Capolongo|Carmen|C|;Calia|Carla|C|;Tortorano|Annamaria|A|;Specchia|Giorgina|G|",
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"title": "Fusariosis in a Patient with Acute Myeloid Leukemia: A Case Report and Review of the Literature.",
"title_normalized": "fusariosis in a patient with acute myeloid leukemia a case report and review of the literature"
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"abstract": "P. aeruginosa is a gram-negative bacterium present in nosocomial infections with high morbidity and mortality. This microorganism is frequently resistant to antibiotics, leading to clinical complications. In the present report, we described a clinical case of a patient with severe oral lesions caused by P. aeruginosa, which was refractory to antibiotics treatment and presented positive clinical outcomes after some sessions of antimicrobial photodynamic inactivation (API) mediated by methylene blue dye. We discuss the potential of API for P. aeruginosa refractory infections and possible resistance mechanisms of this microorganism to different API protocols.",
"affiliations": "Hospital Israelita Albert Einstein, Av. Albert Einstein, 627/520 São Paulo, São Paulo, CEP 05651-901, Brazil. Electronic address: fernanda.eduardo@einstein.br.;Hospital Israelita Albert Einstein, Av. Albert Einstein, 627/520 São Paulo, São Paulo, CEP 05651-901, Brazil. Electronic address: leticia.bezinelli@eisntein.br.;Hospital Israelita Albert Einstein, Av. Albert Einstein, 627/520 São Paulo, São Paulo, CEP 05651-901, Brazil; Pathology Department, School of Dentistry, University of São Paulo, Av. Professor Lineu Prestes 2227, CEP 05508-000, Brazil. Electronic address: marcella.gobbi@usp.br.;Hospital Israelita Albert Einstein, Av. Albert Einstein, 627/520 São Paulo, São Paulo, CEP 05651-901, Brazil. Electronic address: vanessa.montes@einstein.br.;Hospital Israelita Albert Einstein, Av. Albert Einstein, 627/520 São Paulo, São Paulo, CEP 05651-901, Brazil. Electronic address: maluffc@uol.com.br.;Pathology Department, School of Dentistry, University of São Paulo, Av. Professor Lineu Prestes 2227, CEP 05508-000, Brazil. Electronic address: lcorrea@usp.br.",
"authors": "Eduardo|F P|FP|;Bezinelli|L M|LM|;Gobbi|M F|MF|;Santos|V M|VM|;Maluf|F C|FC|;Corrêa|L|L|",
"chemical_list": "D000890:Anti-Infective Agents; D017319:Photosensitizing Agents; D008751:Methylene Blue",
"country": "Netherlands",
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"doi": "10.1016/j.pdpdt.2019.04.013",
"fulltext": null,
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"issn_linking": "1572-1000",
"issue": "26()",
"journal": "Photodiagnosis and photodynamic therapy",
"keywords": "Antimicrobial photodynamic inactivation; Methylene blue dye; Oral lesions; P. aeruginosa",
"medline_ta": "Photodiagnosis Photodyn Ther",
"mesh_terms": "D000328:Adult; D000890:Anti-Infective Agents; D005260:Female; D006801:Humans; D008751:Methylene Blue; D009059:Mouth Diseases; D010778:Photochemotherapy; D017319:Photosensitizing Agents; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa",
"nlm_unique_id": "101226123",
"other_id": null,
"pages": "284-286",
"pmc": null,
"pmid": "30991109",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe oral infection caused by Pseudomonas aeruginosa effectively treated with methylene blue-mediated photodynamic inactivation.",
"title_normalized": "severe oral infection caused by pseudomonas aeruginosa effectively treated with methylene blue mediated photodynamic inactivation"
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"companynumb": "BR-ACCORD-128244",
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"abstract": "BACKGROUND\nThere is an unmet medical need for simplified antiretroviral therapy regimens to improve patient's compliance and quality of life. The purpose of this study was to evaluate the efficacy and safety of a once-daily regimen with Tenofovir (TDF), Emtricitabine (FTC) and Nevirapine (NVP) for adult patients with HIV-1 infection.\n\n\nMETHODS\n70 patients were enrolled in a prospective, multicenter, non-randomized, single arm, open-label cohort study. Patients were either naive or had problems with their current ART and needed to be changed to another regimen. Daily drug dosage was 300 mg Tenofovir, 200mg Emtricitabine and 400 mg Nevirapine once daily. Follow-up was performed over 72 weeks.\n\n\nRESULTS\nAfter 72 weeks, the regimen was still continued by 52 patients (74,3%). Of these, 44 patients (84,6%) had a viral load below detection limit. The median viral load had decreased by 2,5 log and the median CD4 cell count had increased by 44,8%. Most side-effects occurred at an early stage during the study. Resistances were rare (only two resistances were considered as newly developed) and occurred rather late during the study.\n\n\nCONCLUSIONS\nA once-daily regimen of Tenofovir, Emtricitabine and Nevirapine is an attractive treatment option since it is safe, effective, and well tolerated.",
"affiliations": "Department of Dermatology, University of Heidelberg, Heidelberg, Germany. tanja.sehr@med.uni-heidelberg.de",
"authors": "Weberschock|T|T|;Gholam|P|P|;Hueter|E|E|;Flux|K|K|;|||;Hartmann|M|M|",
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"country": "England",
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"journal": "European journal of medical research",
"keywords": null,
"medline_ta": "Eur J Med Res",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents; D003841:Deoxycytidine; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D019829:Nevirapine; D063065:Organophosphonates; D011446:Prospective Studies; D000068698:Tenofovir; D016896:Treatment Outcome",
"nlm_unique_id": "9517857",
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"references": "17305925;18006524;16625606;10866231;12562035;10853971;16306032;15094269;14583852;11588505;15876285;11744832",
"title": "Long-term efficacy and safety of once-daily nevirapine in combination with tenofovir and emtricitabine in the treatment of HIV-infected patients: a 72-week prospective multicenter study (TENOR-trial).",
"title_normalized": "long term efficacy and safety of once daily nevirapine in combination with tenofovir and emtricitabine in the treatment of hiv infected patients a 72 week prospective multicenter study tenor trial"
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"abstract": "Cardiogenic pulmonary edema usually presents with characteristic clinical features and bilateral infiltrates on the chest radiograph. Rarely, pulmonary edema may manifest unilaterally, leading to a mistaken diagnosis of a primary lung pathology. We present a 30-year-old man who developed acute coronary syndrome following an overdose of alprazolam. He developed breathlessness with unilateral infiltrates on the chest radiograph. Echocardiography revealed regional wall motion abnormalities related to underlying ischemia and acute mitral regurgitation with an eccentric jet. Besides, he had significant impairment of left ventricular systolic function. His coronary angiogram revealed a slow-flow phenomenon in the right coronary and left anterior descending artery territories. Ischemia-related dysfunction of the posterolateral papillary muscle probably led to a floppy posterior mitral leaflet and an eccentrically directed regurgitant jet, leading to unilateral pulmonary edema. He was commenced on dual antiplatelet therapy, heparin infusion, atorvastatin, frusemide, and ramipril, following which he showed gradual clinical improvement along with resolution of the radiological infiltrates. His left ventricular function improved, and the mitral valve function normalized on echocardiography within a week.",
"affiliations": "Department of Critical Care Medicine, Narayana Multispecialty Hospital, Bengaluru, Karnataka, India.;Department of Critical Care Medicine, Narayana Multispecialty Hospital, Bengaluru, Karnataka, India.;Department of Critical Care Medicine, Narayana Multispecialty Hospital, Bengaluru, Karnataka, India.;Department of Critical Care Medicine, Narayana Multispecialty Hospital, Bengaluru, Karnataka, India.",
"authors": "Chacko|Jose|J|;Brar|Gagan|G|;Mundlapudi|Bhargav|B|;Kumar|Pradeep|P|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijccm.IJCCM_343_18",
"fulltext": "\n==== Front\nIndian J Crit Care MedIndian J Crit Care MedIJCCMIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine0972-52291998-359XMedknow Publications & Media Pvt Ltd India IJCCM-22-80610.4103/ijccm.IJCCM_343_18Case ReportPapillary Muscle Dysfunction Due to Coronary Slow-Flow Phenomenon Presenting with Acute Mitral Regurgitation and Unilateral Pulmonary Edema Chacko Jose Brar Gagan Mundlapudi Bhargav Kumar Pradeep Department of Critical Care Medicine, Narayana Multispecialty Hospital, Bengaluru, Karnataka, IndiaAddress for correspondence: Dr. Jose Chacko, Department of Critical Care Medicine, Narayana Multispecialty Hospital, Bengaluru, Karnataka, India. E-mail: chackojose@gmail.com11 2018 22 11 806 808 Copyright: © 2018 Indian Journal of Critical Care Medicine2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Cardiogenic pulmonary edema usually presents with characteristic clinical features and bilateral infiltrates on the chest radiograph. Rarely, pulmonary edema may manifest unilaterally, leading to a mistaken diagnosis of a primary lung pathology. We present a 30-year-old man who developed acute coronary syndrome following an overdose of alprazolam. He developed breathlessness with unilateral infiltrates on the chest radiograph. Echocardiography revealed regional wall motion abnormalities related to underlying ischemia and acute mitral regurgitation with an eccentric jet. Besides, he had significant impairment of left ventricular systolic function. His coronary angiogram revealed a slow-flow phenomenon in the right coronary and left anterior descending artery territories. Ischemia-related dysfunction of the posterolateral papillary muscle probably led to a floppy posterior mitral leaflet and an eccentrically directed regurgitant jet, leading to unilateral pulmonary edema. He was commenced on dual antiplatelet therapy, heparin infusion, atorvastatin, frusemide, and ramipril, following which he showed gradual clinical improvement along with resolution of the radiological infiltrates. His left ventricular function improved, and the mitral valve function normalized on echocardiography within a week.\n\nAcute coronary syndromecoronary slow-flow phenomenonpapillary muscle dysfunctionunilateral pulmonary edema\n==== Body\nINTRODUCTION\nAcute cardiogenic pulmonary edema usually presents with bilateral infiltrates on the chest radiograph described as a “butterfly shadow.”[1] Unilateral pulmonary edema (UPE) of cardiac origin is relatively rare and often misdiagnosed as primary respiratory disease leading to delay in the initiation of appropriate therapy.[2] We report a young man who presented with breathlessness and unilateral lung infiltrates following an overdose with alprazolam and review the literature on UPE of cardiac origin.\n\nCASE REPORT\nA 30-year-old man presented to our emergency department with breathlessness following an overdose with alprazolam. He had been evaluated earlier at another hospital, where he was found to be hypotensive. Ischemic changes were noted on electrocardiography (ECG); he was cardioverted as he was found to be in atrial fibrillation. Following this, he was transferred to our hospital.\n\nOn initial evaluation in our emergency department, he had mild dyspnea, with a respiratory rate of 32/min and oxygen saturation of 88% on room air. His heart rate was regular at 105/min with a blood pressure of 86/52 mm Hg. Systemic examination was otherwise unremarkable. He was administered supplemental oxygen, commenced on an infusion of noradrenaline, and transferred to the intensive care unit. His ECG performed earlier at the referring hospital, showed atrial fibrillation with ST-segment elevation in leads II and III, and ST-segment depression in leads V3–V4 [Figure 1]. A chest radiograph revealed diffuse infiltrates confined to the right lung fields, suggestive of UPE [Figure 2]. On transthoracic echocardiography, he had significant hypokinesia of the basal, inferoseptal, and basal posterior walls with impaired systolic function. Mitral regurgitation (MR) of moderate degree was also observed, with an eccentrically directed regurgitant jet [Figure 3]. The creatine kinase level was 23.3 ng/ml (normal range: 0–4.3 ng/ml) and the troponin-I level, 5.66 ng/ml (normal range: 0–0.02 ng/ml). Acute coronary syndrome with acute MR was suspected, and a coronary angiogram was carried out. Normal flows were noted in the left main and circumflex arteries. The right coronary artery was dominant with no stenotic lesion; however, a slow-flow pattern was observed. Slow flow was also observed in the left anterior descending artery. The flow rates were estimated using the corrected thrombolysis in myocardial infarction frame count as described previously by Gibson et al.[3]\n\nFigure 1 Electrocardiography showing ST-segment elevation in leads II and III and ST-segment depression in leads V3–V4\n\nFigure 2 Chest radiograph showing unilateral pulmonary edema on the right side\n\nFigure 3 Transthoracic echocardiogram. The arrow points to the eccentrically directed mitral regurgitant jet. LA: Left atrium; LV: Left ventricle\n\nBased on these findings, a diagnosis of the acute coronary syndrome with acute MR due to papillary muscle dysfunction was considered, and he was commenced on aspirin, clopidogrel, heparin infusion, ramipril, and frusemide. His breathlessness gradually improved and the infiltrates on the chest radiograph disappeared within a week. A repeat echocardiogram at this time showed improved left ventricular systolic function and the MR was no longer evident.\n\nDISCUSSION\nUPE may arise from cardiac or noncardiac causes. While bilateral pulmonary edema has typical clinical and radiographic features, UPE is relatively uncommon.[4] The presence of unilateral infiltrates on the chest radiograph may lead to a misdiagnosis of pneumonia and delay in the initiation of appropriate therapy.[2] Several noncardiac causes have been reported, including rapid lung reexpansion,[5] lying in the lateral position for prolonged periods,[6] fluid overload,[7] and following endobronchial intubation.[8] In a retrospective analysis of 869 patients with cardiogenic pulmonary edema, UPE was observed in 18 (2.1%) of patients and was associated with higher mortality compared to bilateral pulmonary edema. Severe MR was noted in all patients who presented with cardiogenic UPE in this study.[4]\n\nOur patient presented with features of acute coronary syndrome following an overdose of alprazolam. He had radiographic features of right-sided UPE. His initial ECG showed ST-segment elevation in the anterolateral leads. On transthoracic echocardiography, he had significant hypokinesia of the basal, inferoseptal, and basal posterior walls with impaired systolic function. Besides, he had a moderate degree of MR with an eccentric jet, resulting in right-sided pulmonary edema. Ischemia-related dysfunction of the posteromedial papillary muscle probably resulted in a floppy posterior mitral leaflet; the consequent eccentric regurgitant jet was directed toward the right pulmonary vein leading to right-sided pulmonary edema in our patient.\n\nUPE due to MR usually occurs on the right side,[4] as seen in our patient. The anatomical configuration of the mitral valve tends to direct a regurgitant jet toward the right pulmonary vein,[9] especially to the right superior pulmonary vein, leading to a predilection for edema formation in the right upper lobe.[10] Furthermore, the pulmonary capillary wedge pressure may be higher in the right upper lobe,[10] predisposing to the localization of edema to this area of the lung.\n\nBranches of the coronary arteries traverse the whole thickness of the myocardium before they reach the subendocardial layer to perfuse the papillary muscles, making them susceptible to ischemic insult.[11] The posteromedial papillary muscle is more vulnerable to ischemia-related dysfunction because of a single arterial supply by the posterior descending or the circumflex artery.[11] Papillary muscle dysfunction due to ischemia may be episodic and reversible.[12] Our patient probably developed transient impairment of left ventricular function and MR related to reversible papillary muscle dysfunction, which recovered completely within a few days.\n\nThe coronary angiogram in our patient did not reveal any stenotic lesion; however, a slow-flow phenomenon was observed in the right coronary and the left anterior descending arteries. The coronary slow flow phenomenon (CSFP) is a well-recognized cause of acute coronary syndromes, characterized by delayed opacification of the distal coronary arteries in the absence of epicardial occlusive disease.[1314] CSFP has been postulated to be due to underlying small vessel disease, endothelial dysfunction, inflammation, or due to anatomical factors, including tortuosity and branching.[14] Our patient had a right dominant coronary circulation, wherein the posterior descending branch arises from the right coronary artery. A CSFP involving the right coronary artery may have led to compromised flow in the posterior descending artery, resulting in ischemia and dysfunction of the posteromedial papillary muscle.\n\nOur patient presented with several unique features. He presented following an overdose with alprazolam. Subsequently, he developed acute coronary syndrome related to CSFP and developed UPE. He had ECG and echocardiographic evidence of acute coronary syndrome involving multiple territories, with impaired left ventricular function. The UPE was related to an eccentric MR jet due to papillary muscle dysfunction.\n\nCONCLUSION\nUPE is relatively rare and may occur due to MR with an eccentric jet. Acute MR with an eccentric jet may develop due to papillary muscle dysfunction, induced by CSFP. It is important to distinguish cardiogenic UPE from radiographic infiltrates arising from a primary lung pathology and initiate appropriate therapy without delay.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Gropper MA Wiener-Kronish JP Hashimoto S Acute cardiogenic pulmonary edema Clin Chest Med 1994 15 501 15 7982344 \n2 Choi HS Choi H Han S Kim HS Lee C Kim YY Pulmonary edema during pregnancy: Unilateral presentation is not rare Circ J 2002 66 623 6 12135127 \n3 Gibson CM Cannon CP Daley WL Dodge JT Jr Alexander B Jr Marble SJ TIMI frame count: A quantitative method of assessing coronary artery flow Circulation 1996 93 879 88 8598078 \n4 Attias D Mansencal N Auvert B Vieillard-Baron A Delos A Lacombe P Prevalence, characteristics, and outcomes of patients presenting with cardiogenic unilateral pulmonary edema Circulation 2010 122 1109 15 20805429 \n5 Murat A Arslan A Balci AE Re-expansion pulmonary edema Acta Radiol 2004 45 431 3 15323396 \n6 Leeming BW Gravitational edema of the lungs observed during assisted respiration Chest 1973 64 719 22 4586393 \n7 Balogun SA Balogun RA Acute unilateral pulmonary edema from dietary salt and water load: A case report and review of the literature Conn Med 2001 65 653 6 11766552 \n8 Kramer MR Melzer E Sprung CL Unilateral pulmonary edema after intubation of the right mainstem bronchus Crit Care Med 1989 17 472 4 2707019 \n9 Miyatake K Nimura Y Sakakibara H Kinoshita N Okamoto M Nagata S Localisation and direction of mitral regurgitant flow in mitral orifice studied with combined use of ultrasonic pulsed Doppler technique and two dimensional echocardiography Br Heart J 1982 48 449 58 7138708 \n10 Gurney JW Goodman LR Pulmonary edema localized in the right upper lobe accompanying mitral regurgitation Radiology 1989 171 397 9 2704804 \n11 Inoue T Iemura J Saga T Successful surgical treatment of mitral regurgitation for complete rupture of the anterior papillary muscle after acute myocardial infarction Jpn J Thorac Cardiovasc Surg 2003 51 565 8 14621026 \n12 Le Feuvre C Metzger JP Lachurie ML Georges JL Baubion N Vacheron A Treatment of severe mitral regurgitation caused by ischemic papillary muscle dysfunction: Indications for coronary angioplasty Am Heart J 1992 123 860 5 1549993 \n13 Beltrame JF Limaye SB Horowitz JD The coronary slow flow phenomenon – A new coronary microvascular disorder Cardiology 2002 97 197 202 12145474 \n14 Wang X Nie SP The coronary slow flow phenomenon: Characteristics, mechanisms and implications Cardiovasc Diagn Ther 2011 1 37 43 24282683\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0972-5229",
"issue": "22(11)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Acute coronary syndrome; coronary slow-flow phenomenon; papillary muscle dysfunction; unilateral pulmonary edema",
"medline_ta": "Indian J Crit Care Med",
"mesh_terms": null,
"nlm_unique_id": "101208863",
"other_id": null,
"pages": "806-808",
"pmc": null,
"pmid": "30598569",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports",
"references": "11766552;12135127;12145474;14621026;15323396;1549993;20805429;24282683;2704804;2707019;4586393;7138708;7982344;8598078",
"title": "Papillary Muscle Dysfunction Due to Coronary Slow-Flow Phenomenon Presenting with Acute Mitral Regurgitation and Unilateral Pulmonary Edema.",
"title_normalized": "papillary muscle dysfunction due to coronary slow flow phenomenon presenting with acute mitral regurgitation and unilateral pulmonary edema"
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"abstract": "SARS-CoV2, also known as COVID-19, is a specific strain of coronavirus that is responsible for an ongoing global pandemic. COVID-19 primarily targets the respiratory system via droplet transmission, causing symptoms similar to influenza, including fever, cough, and shortness of breath. It is now known to impact other organ systems, causing significant cardiovascular and gastrointestinal illness, among others.\nWe describe two cases of COVID-19 induced myocarditis presenting with cardiogenic shock. These cases highlight the importance of understanding the lethal cardiac complications of COVID-19 infection, as well as its presentation, diagnosis, pathophysiology, and potential treatment options. These two cases involve patients without underlying cardiovascular disease risk factors who experienced prolonged symptoms of COVID-19 infection. Both patients presented with cardiogenic shock more than one week after symptom onset and diagnosis. These cases demonstrate the late presentation of myocarditis and cardiogenic shock, treated with corticosteroids and inotropes, with subsequent recovery of cardiac function.\nThe cases highlight the importance of recognizing late presentation viral myocarditis secondary to COVID-19 infection, even in patients without underlying cardiac disease.",
"affiliations": "Department of Pulmonary & Critical Care, St. Luke's University Health Network, 709 Delaware Avenue, Bethlehem, PA 18015, USA.;Department of Pulmonary & Critical Care, St. Luke's University Health Network, 709 Delaware Avenue, Bethlehem, PA 18015, USA.;Department of Pulmonary & Critical Care, St. Luke's University Health Network, 709 Delaware Avenue, Bethlehem, PA 18015, USA.;Department of Anesthesiology & Critical Care, St. Luke's University Health Network, 709 Delaware Avenue, Bethlehem, PA 18015, USA.;Department of Pulmonary & Critical Care, St. Luke's University Health Network, 709 Delaware Avenue, Bethlehem, PA 18015, USA.;Department of Cardiology, Heart Failure, and Transplantation Cardiology, Atlantic Health System, Morristown, NJ, USA.",
"authors": "Purdy|Adam|A|0000-0002-7319-5668;Ido|Firas|F|;Sterner|Stacie|S|;Tesoriero|Eric|E|0000-0001-7950-6159;Matthews|Tokunbo|T|;Singh|Abhishek|A|0000-0001-9051-5435",
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"doi": "10.1093/ehjcr/ytab028",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n10.1093/ehjcr/ytab028\nytab028\nCase Series\nAcademicSubjects/MED00200\nMyocarditis in COVID-19 presenting with cardiogenic shock: a case series\nhttp://orcid.org/0000-0002-7319-5668\nPurdy Adam 1\nIdo Firas 1\nSterner Stacie 1\nhttp://orcid.org/0000-0001-7950-6159\nTesoriero Eric 2\nMatthews Tokunbo 1\nhttp://orcid.org/0000-0001-9051-5435\nSingh Abhishek 3\n1 Department of Pulmonary & Critical Care, St. Luke's University Health Network, 709 Delaware Avenue, Bethlehem, PA 18015, USA\n2 Department of Anesthesiology & Critical Care, St. Luke's University Health Network, 709 Delaware Avenue, Bethlehem, PA 18015, USA\n3 Department of Cardiology, Heart Failure, and Transplantation Cardiology, Atlantic Health System, Morristown, NJ, USA\nDias Andre Editor\nNikodem Rudzínski Piotr Editor\nBaghdasaryan Lilit Editor\nNgo Linh Editor\nChakir Mariame Editor\nCorresponding author. Tel: 484-526-3890, Email: adam.g.purdy@gmail.com\n2 2021\n16 2 2021\n16 2 2021\n5 2 ytab02816 1 2021\n26 10 2021\n19 8 2020\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nBackground\n\nSARS-CoV2, also known as COVID-19, is a specific strain of coronavirus that is responsible for an ongoing global pandemic. COVID-19 primarily targets the respiratory system via droplet transmission, causing symptoms similar to influenza, including fever, cough, and shortness of breath. It is now known to impact other organ systems, causing significant cardiovascular and gastrointestinal illness, among others.\n\nCase summary\n\nWe describe two cases of COVID-19 induced myocarditis presenting with cardiogenic shock. These cases highlight the importance of understanding the lethal cardiac complications of COVID-19 infection, as well as its presentation, diagnosis, pathophysiology, and potential treatment options. These two cases involve patients without underlying cardiovascular disease risk factors who experienced prolonged symptoms of COVID-19 infection. Both patients presented with cardiogenic shock more than one week after symptom onset and diagnosis. These cases demonstrate the late presentation of myocarditis and cardiogenic shock, treated with corticosteroids and inotropes, with subsequent recovery of cardiac function.\n\nDiscussion\n\nThe cases highlight the importance of recognizing late presentation viral myocarditis secondary to COVID-19 infection, even in patients without underlying cardiac disease.\n\nCOVID-19\nMyocarditis\nCase series\nCardiomyopathy\nShortness of breath\nCardiogenic shock\n==== Body\nLearning points\n\nCOVID-19 myocarditis is a late complication of COVID-19 infection, which may affect those without underlying cardiovascular disease.\n\nIt is imperative to be vigilant of late presentation cardiomyopathy and cardiogenic shock in patients diagnosed with COVID-19 infection, as mortality may be high without immediate support.\n\nIntroduction\n\nCOVID-19 virus is part of a large family of single positive-stranded, enveloped RNA viruses that initially presented in Wuhan, China in late 2019.1 It is an extremely contagious respiratory illness that has led to a debilitating global pandemic. Common symptoms include fever, cough, fatigue, shortness of breath, and loss of smell and taste, among others. While the majority of COVID-19 victims have mild illness, others may develop acute respiratory distress syndrome, intense cytokine storm, and septic shock, leading to multi-organ failure and death. The potential long-lasting effects of this deadly disease are yet to be determined, but detrimental cardiovascular injury has been described.2 Possible mechanisms for cardiac involvement include a cytokine storm affecting multiple organ systems, direct myocardial cell injury via angiotensin-converting enzyme 2 receptors, and myocardial oxygen supply/demand mismatch.3 These mechanisms of injury may lead to cardiac manifestations, such as myocarditis, heart failure, and arrhythmia. Those patients presenting with myocarditis should be identified rapidly to avoid progression to fulminant myocarditis, which is associated with higher mortality.4\n\nTimeline\n\nCase 1\t\t\n Five weeks prior to presentation\tInitial COVID-19 diagnosis, mild symptoms, treated with supportive therapy at home\t\n Hospital Day 1\tPresentation with cough, fever, shortness of breath, found to be in cardiogenic shock, started on milrinone therapy\t\n Hospital Day 2\tTransthoracic echocardiogram (TTE) with ejection fraction of 25% with diffuse hypokinesis and dilated right ventricle with reduced function\t\n Hospital Days 2–5\tTreated with corticosteroids, diuresis, and standard heart failure regime, repeat echocardiogram with improved ejection fraction of 50% on hospital Day 5\t\n Hospital Day 6–10\tWeaned off inotropes, transferred out of critical care\t\n Hospital Day 11\tDischarged from hospital\t\n Ten weeks after discharge\tRepeat TTE revealed improved ejection fraction of 60%\t\nCase 2\t\t\n Nine days prior to presentation\tInitial COVID-19 diagnosis, mild symptoms, treated with supportive therapy at home\t\n Hospital Day 1 (9 days after initial COVID-19 diagnosis)\tPresentation with worsening fatigue and shortness of breath, found to be in cardiogenic shock, started on inotropic therapy with milrinone\t\n Hospital Day 2\tTransthoracic echocardiogram with ejection fraction of 45%, diffuse hypokinesis, diastolic dysfunction, and moderate pericardial effusion\t\n Hospital Days 2–4\tTreated with corticosteroids, diuresis, and standard heart failure regime\t\n Hospital Days 5 and 6\tWeaned off inotropes, transferred out of critical care\t\n Hospital Day 7\tDischarged from hospital\t\n Six weeks after discharge\tRepeat TTE with ejection fraction of 55% and resolution of pericardial effusion\t\n\nCase presentation\n\nCase 1\n\nWe present the case of a 53-year-old African American male without significant past medical history who initially presented to the emergency room for evaluation of cough, fever, and shortness of breath. Five weeks prior, he had been diagnosed with COVID-19 and was treated with supportive therapy at home. In the emergency room, he was tachycardic and tachypnoeic with an oxygen saturation of 95% on 2 L/min nasal cannula. Distal pulses were 2+ and the patient was found to have cool extremities. His repeat COVID-19 nasopharyngeal polymerase chain reaction remained positive.\n\nSerologic analysis was remarkable for a creatinine of 3.11 mg/dL (RR 0.6–1.3 mg/dL), aspartate aminotransferase 64 U/L (RR 5–45 U/L), alanine aminotransferase 70 U/L (RR 12-78 U/L), alkaline phosphatase 149 U/L (RR 46–116 U/L), total bilirubin 2.60 mg/dL (RR 0.2–1.0 mg/dL), as well as a lactic acidosis of 2.5 mmol/L (RR 0.5–2.0 mmol/L) and D-dimer of 2.85 μg/mL (RR < 0.5 μg/mL). Troponin was noted to be 5.68 ng/mL (peaked at 5.98 ng/mL) (RR < 0.04 ng/mL) and N-terminal-pro B-type natriuretic peptide 53 205 pg/mL (RR < 125 pg/mL). Electrocardiogram revealed sinus tachycardia with J-point elevation in the inferolateral leads. Chest X-ray showed mild pulmonary vascular congestion, but was otherwise clear. The patient was empirically anticoagulated with heparin and given intravenous diuretics.\n\nHe was admitted to the intensive care unit with the presumptive diagnosis of COVID-19 induced cardiomyopathy. Upon arrival, his cardiac output and cardiac index by Fick were found to be 3.1 L/min (RR 4–8 L/min) and 1.3 L/min/m2 (RR 2.5–4 L/min/m2), respectively, as calculated by concurrent arterial and venous blood gas analysis. A central line was placed and given a low SCVO2 with progression to cardiogenic shock, he was initiated on milrinone therapy. A complete transthoracic echocardiogram (TTE) was obtained demonstrating an ejection fraction of 25% (normal > 55%) with diffuse hypokinesis and moderately dilated right ventricle with reduced right ventricular function (Figure 1, Video 1).\n\nHe was given pulse dose steroids with methylprednisolone 1 g for 3 days. He was also treated with empiric antibiotics, which were discontinued 2 days after admission, as no source of infection was found and blood cultures remained negative. He did complete a 7-day course of hydroxychloroquine for COVID-19 infection, which was recommended therapy early in the COVID-19 pandemic. He was started on isosorbide dinitrate, hydralazine, carvedilol, and eplerenone. Further aetiologies of cardiomyopathy were ruled out with negative antinuclear antibodies, rheumatoid factor, scleroderma panel, HIV, hepatitis panel, mononucleosis panel, lyme, cytomegalovirus PCR, babesia.\n\nRepeat TTE just 4 days after admission revealed an improved ejection fraction of 50%. IV steroids were tapered and given improvement in haemodynamics, he was weaned to room air and off inotropes. Inpatient left heart catheterization and cardiac magnetic resonance imaging (MRI) were deferred given the patient’s rapid improvement and low suspicion for ischaemic cardiomyopathy, as well as to limit further exposure to the virus. He was discharged on a heart failure regime, including aspirin, atorvastatin, isosorbide dinitrate, hydralazine, carvedilol, and eplerenone, as well as a prolonged prednisone taper. Repeat TTE 10 weeks after discharge showed an ejection fraction of 60% (Video 2).\n\nFigure 1 Transthoracic echocardiogram still and loop four-chamber view revealing an ejection fraction of 25% (normal > 55%) with diffuse hypokinesis, moderately dilated right ventricle, and reduced right ventricular function. Left ventricular internal diameter end diastole: 49 mm; left ventricular internal diameter end systole 46 mm (RR male 42–59 mm). Right ventricular internal diameter end diastole: 47 mm (RR 35–45 mm).\n\nCase 2\n\nWe present the case of a 30-year-old Caucasian female with past medical history of obesity who presented to the emergency department with complaints of fatigue and shortness of breath. She had been seen as an outpatient nine days prior, testing positive for COVID-19. On presentation, she was found to be tachycardic, tachypnoeic, and hypotensive with an oxygen saturation of 98% on room air. Physical exam was only remarkable for trace lower extremity oedema.\n\nLaboratory studies revealed lactic acidosis of 7.5 mmol/L (RR 0.5–2.0 mmol/L), troponin of 1.38 ng/mL (peak of 1.69 ng/mL) (RR < 0.04 ng/mL), NT-proBNP of 6022 pg/mL (RR < 125 pg/mL), and D-dimer of 1.05 μg/mL (RR < 0.5 μg/mL). Electrocardiogram showed sinus tachycardia with rate 140 b.p.m. Computed tomography chest showed patchy airspace disease, as well as a small pericardial effusion (Figure 2).\n\nShe was started on hydroxychloroquine, vitamin C, zinc, and atorvastatin. She was given empiric antibiotics and admitted to the intensive care unit. Transthoracic echocardiogram revealed an ejection fraction of 45% (normal > 55%) with moderate diffuse hypokinesis and a moderate pericardial effusion (Figure 3, Video 3). She was diagnosed with cardiogenic shock and was started on milrinone therapy and methylprednisolone.\n\nDuring admission, her haemodynamics improved and milrinone was subsequently weaned off. She completed seven days of hydroxychloroquine and 2 days of antibiotics. She was hospitalized for a total of 7 days and was discharged home on atorvastatin, vitamin D, metoprolol tartrate, and a prednisone taper. Six weeks after discharge, repeat TTE showed an improved ejection fraction of 55% and resolution of pericardial effusion (Supplementary material online, Video S4).\n\nFigure 2 Computed tomography chest (axial cut), depicting bilateral, peripheral-basal predominant ground-glass opacities, and small pericardial effusion.\n\nFigure 3 Transthoracic echocardiogram still and loop four-chamber revealing an ejection fraction of 45% (normal > 55%) with moderate diffuse hypokinesis, grade I diastolic dysfunction, and moderate pericardial effusion. Left ventricular internal diameter end diastole: 50 mm; left ventricular internal diameter end systole 37 mm (RR female 39–53 mm). Right ventricular internal diameter end diastole: 31 mm (RR 35–45 mm). Pericardial effusion 10 mm in size.\n\nDiscussion\n\nAlthough COVID-19 primarily targets the respiratory system, it has become increasingly associated with damage to other organs. In this case series, we discuss the cardiovascular effects of COVID-19 infection in two patients without prior cardiovascular disease. Both patients experienced worsening shortness of breath and continued fatigue after initial COVID-19 diagnosis, leading to their hospital presentations, at which time they were both found to be in cardiogenic shock.\n\nMyocarditis can be defined as an inflammatory disease of the heart causing myocardial injury without an ischaemic cause. The most common aetiology of myocarditis in the USA is viral. The pathophysiology of viral myocarditis is thought to be direct cell injury and T-lymphocyte mediated cytotoxicity, which can be augmented by a cytokine storm syndrome.5 Human coronaviruses prior to novel COVID-19 have been linked to myocarditis in all age groups, including MERS-CoV and SARS-CoV, both of which are closely linked to COVID-19. The specific pathophysiology of COVID-19 induced myocarditis is not well understood, but is thought to be closely related to its cell-entry mechanism. The virus enters human cells by binding its spike protein to the membrane protein angiotensin-converting enzyme 2 receptors, which can be found on ciliated columnar epithelial cells of the respiratory tract, type II pneumocytes, and cardiomyocytes.6\n\nClinical presentations of COVID-19 induced myocarditis can vary dramatically. Some patients may present with mild fatigue and dyspnoea, while others may present in fulminant cardiogenic shock, as was the case in these two patients. Typically, fulminant heart failure presents later in the course of viral infections, 2–3 weeks after contracting the disease. The early signs of fulminant myocarditis may resemble those of sepsis, but clues to suspect cardiac dysfunction include cold or mottled extremities, raised jugular venous pressure, peripheral oedema, and raised troponin and N-terminal pro-B-type natriuretic peptide levels. Electrocardiogram abnormalities can be seen in viral myocarditis, but these findings are not sensitive in detecting the disease and their absence is not exclusionary. The cardinal signs of myocarditis on echocardiogram are chamber dilation, increased wall thickness, and pericardial effusion, along with ventricular systolic dysfunction.7 Cardiovascular MRI, invasive catheterization, and endomyocardial biopsy may be considered for more definitive diagnosis, but are rarely required due to limited availability and their invasiveness.\n\nTreatment of COVID-19 induced myocarditis should follow cardiogenic shock protocol, including liberal use of inotropes and vasopressors.8 Depending on the severity of illness, patients may require mechanical circulatory support.\n\nLead author biography\n\nDr Adam Purdy is a pulmonary and critical care fellow at St. Luke’s University Hospital in Bethlehem, Pennsylvania. A graduate of the University of Delaware and St. George’s University School of Medicine, he completed his Internal Medicine training at Overlook Medical Center in New Jersey. Among others, his interests include critical care and undifferentiated shock.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\nConsent: The authors confirm that written consent for submission and publication of this case series including images and associated text has been obtained from both patients in line with COPE guidance.\n\nConflict of interest: none declared.\n\nFunding: none declared.\n\nSupplementary Material\n\nytab028_Supplementary_Data Click here for additional data file.\n==== Refs\nReferences\n\n1 WangD , HuB , HuC , ZhuF , LiuX , ZhangJ et al Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323 :1061–1069.32031570\n2 Basu-RayI , AlmaddahN , AdeboyeA , SoosM. Cardiac Manifestations of Coronavirus (COVID-19). StatPearls [Internet], U.S. National Library of Medicine. www.ncbi.nlm.nih.gov/books/NBK556152/ (23 April 2020).\n3 XiongTY , RedwoodS , PrendergastB , ChenM. Coronaviruses and the cardiovascular system: acute and long-term implications. Eur Heart J 2020;41 :1798–1800.32186331\n4 FungG , LuoH , QiuY , YangD , McManusB. Myocarditis. Circ Res 2016;118 :496–514.26846643\n5 SiripanthongB , NazarianS , MuserD , DeoR , SantangeliP , KhanjiM et al Recognizing COVID-19-related myocarditis: the possible pathophysiology and proposed guideline for diagnosis and management. Heart Rhythm 2020;17 :1463–1471.32387246\n6 HoffmannM , Kleine-WeberH , SchroederS , KrugerN , HerrlerT , ErichsenS et al SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181 :271–280.e8.32142651\n7 KociolRD , CooperLT , FangJC , MoslehiJ , PangP , SabeM , On behalf of the American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology et al Recognition and initial management of fulminant myocarditis: a scientific statement from the American Heart Association. Circulation 2020;141 :e69–e92.31902242\n8 SawalhaK , AbozenahM , KadadoA , BattishaA , Al-AkcharM , SalernoC et al Systematic review of COVID-19 related myocarditis: insights on management and outcome. Cardiovasc Revasc Med 2020;S1553-8389(20):30497–8.\n\n",
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"keywords": "COVID-19; Cardiogenic shock; Cardiomyopathy; Case series; Myocarditis; Shortness of breath",
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"title": "Myocarditis in COVID-19 presenting with cardiogenic shock: a case series.",
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"abstract": "Lactic acidosis is a rare and potentially lethal complication of metformin therapy. We present a case of a middle-aged diabetic man with metformin-induced acute lactic acidosis successfully managed with timely hemodialysis.",
"affiliations": "1Departments of Internal Medicine and 2Nephrology, New York Medical College-Metropolitan Hospital Center, New York, NY.",
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"abstract": "Chylothorax is rare in children. Only a few cases of tuberculosis (TB)-associated chylothorax have been reported. We present a child on standard four-drug TB treatment who presented with wheezing and a chylothorax. Bronchoscopy showed caseating lymph nodes, and rifampicin-resistant TB was identified from the bronchoalveolar lavage specimen. There was marked clinical and radiological improvement 1 month after starting multidrug-resistant (MDR) TB treatment and steroids. The association of chylothorax and MDR-TB has not been described in children. MDR-TB should be considered in children who fail adherent, empirically started drug-susceptible TB treatment.",
"affiliations": "Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, and Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.;Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, and Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.;Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, and Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.;Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, and Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.;Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, and Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.;Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, and Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.;Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, and Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.;Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, and Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.;Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, and Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.",
"authors": "McLaren|B|B|;Song|X|X|;Mate|E|E|;Jardine|C|C|;Mabaso|T|T|;Mammen|V|V|;Lala|S|S|;Dangor|Z|Z|;Verwey|C|C|",
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"doi": "10.7196/SARJ.2019.v25i3.237",
"fulltext": "\n==== Front\nAfr J Thorac Crit Care Med\nAfr J Thorac Crit Care Med\nAJTCCM\nPMCID\nAfrican Journal of Thoracic and Critical Care Medicine\n2617-0191\n2617-0205\nSouth African Medical Association Pretoria, South Africa\n\n10.7196/SARJ.2019.v25i3.237\nCase Report\nChylothorax in a child with rifampicin-resistant tuberculosis\nMcLaren B\nSong X\nMate E\nJardine C\nMabaso T\nMammen V\nLala S\nDangor Z\nVerwey C\nDepartment of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, and Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa\nCorrespondence: B McLaren - brittamclaren@gmail.com\nAuthor Contributions: BM: conception and design, acquisition of case information, research and interpretation, drafting the article, critical revision and final approval of the version to be published; XS: conception and design, acquisition of case information, research and interpretation; EM: conception and design, acquisition of case information, research and interpretation; CJ: acquisition of case information; TM: acquisition of case information; VM: acquisition of case information; SL: acquisition of case information, critical revision and final approval of the version to be published; ZD: conception and design, acquisition of case information, research and interpretation, drafting the article, critical revision and final approval of the version to be published; CV: conception and design, acquisition of case information, research and interpretation, drafting the article, critical revision and final approval of the version to be published, senior author.\n\nFunding: None.\n\nConflicts of interest: None.\n\n17 9 2019\n2019\n25 3 10.7196/SARJ.2019.v25i3.23705 2 2019\n2019\nMcLaren et al\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution - NonCommercial Works License (CC BY-NC 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nAbstract\n\nChylothorax is rare in children. Only a few cases of tuberculosis (TB)-associated chylothorax have been reported. We present a child on standard four-drug TB treatment who presented with wheezing and a chylothorax. Bronchoscopy showed caseating lymph nodes, and rifampicin-resistant TB was identified from the bronchoalveolar lavage specimen. There was marked clinical and radiological improvement 1 month after starting multidrug-resistant (MDR) TB treatment and steroids. The association of chylothorax and MDR-TB has not been described in children. MDR-TB should be considered in children who fail adherent, empirically started drug-susceptible TB treatment.\n\ndrug resistant tuberculosis\ntuberculosis\npaediatric tuberculosis\nendobronchial tuberculosis\nchylothorax\n==== Body\nBackground\n\nThe burden of pulmonary tuberculosis (PTB) is very high in subSaharan Africa, with a reported incidence of 500 per 100 000 population.[1] Children account for ~15% of the total tuberculosis (TB) burden in developing countries.[2] Culture-confirmed TB accounts for only 10 - 15% of children treated for TB.[3] This is a result of the paucibacillary nature of PTB in children, and the fact that specimens are often not obtained. Drug susceptibility testing can only be done if bacteriological confirmation is achieved. In settings with a high incidence of drug-resistant TB, drug resistance should be considered in children with clinically diagnosed TB who have not improved, or have progressively worsened, despite adequate first-line TB therapy. Although drug-resistant TB has not been reported to be more virulent than drug-susceptible TB,[4] the delay in identifying and treating these children may result in more advanced or disseminated disease.\n\nChylothorax is defined as a pleural effusion with triglyceride levels >110 mg/dL and the presence of chylomicrons.[5] It is hypothesised that TB lymph nodes erode through the thoracic duct, resulting in chylous fluid leaking into the thoracic space, of which only a few childhood cases have been reported. We describe a chylothorax in a child with rifampicin-resistant endobronchial TB.\n\nCase presentation\n\nAn HIV-exposed uninfected 20-month-old boy presented to Chris Hani Baragwanath Academic Hospital in Johannesburg, South Africa, with a 2-day history of shortness of breath, cough and noisy breathing. He had also experienced night sweats, fever and vomiting for a week. Two weeks prior to this presentation, he had been diagnosed with bacteriologically unconfirmed PTB at a primary healthcare clinic and was empirically started on a four-drug antituberculosis treatment regimen (rifampicin, isoniazid, pyrazinamide and ethambutol). The diagnosis was based on a chest X-ray (Fig. 1A) and a positive Mantoux test. His father (a household contact) had been diagnosed with PTB, and had been on first-line antituberculosis treatment for 4 months. The boy had had normal growth and development up to 1 year of age, but had subsequently lost weight, and fallen from a weight-for-height z-score +2 to the median over the preceding 8 months.\n\nOn admission, he was apyrexial, tachycardic and in moderate respiratory distress, with oxygen saturations of 97% in room air. He had marked chest wall indrawing and bilateral posterior cervical and axillary lymph nodes (<0.5 cm in diameter). He was clinically hyperinflated, with bilateral wheezing. The rest of his clinical examination was normal.\n\nCase management\n\nHe was diagnosed with viral bronchiolitis, and therefore a chest X-ray was not performed. He was started on oxygen and hypertonic saline nebulisation. He responded poorly to this initial treatment and was therefore started on oral corticosteroids and amoxicillin on day 2 of hospitalisation, and his first-line antituberculosis treatment was continued. Gastric aspirate samples for microscopy for acid-fast bacilli, Xpert MTB/RIF (Cepheid, USA) and culture for mycobacteria were negative.\n\nDuring his hospital admission period his wheezing persisted, and he remained in moderate respiratory distress. On the fifth day of admission, he developed percussion dullness and absent breath sounds over the right hemithorax.\n\nA chest X-ray at this point revealed a large right-sided pleural effusion (Fig. 1B). A computed tomography scan of the chest revealed hilar lymphadenopathy and a large right-sided pleural effusion. The thoracic duct could not be visualised. Diagnostic pleurocentesis confirmed a chylothorax. It was suspected that tuberculous lymph nodes had eroded the thoracic duct causing the chylothorax, and therefore a bronchoscopy was performed, which revealed caseating lymph nodes in the right main bronchus suggestive of TB, and 90% obstruction of the left main bronchus. The Xpert MTB/RIF (Cephaid, USA) test on a bronchoalveolar lavage specimen identified rifampicinresistant Mycobacterium tuberculosis. Gastric aspirates, pleural fluid and bronchoalveolar lavage samples were all smear-negative for acidfast bacilli and mycobacterial culture-negative.\n\nTreatment\n\nThe chylothorax was managed with a low-fat diet (with additional medium-chain triglycerides), therapeutic taps for worsening respiratory distress and an octreotide infusion. The boy was commenced on multidrug-resistant TB (MDR-TB) treatment (amikacin, levofloxicin, ethionamide, terizidone, pyrazinamide, ethambutol and high-dose isoniazid) and oral steroids.\n\nOutcomes and follow-up\n\nFor further management, he was transferred to a hospital dedicated to the care of MDR-TB patients. One month later, he showed marked clinical improvement, with almost complete radiological resolution of the chylothorax, and reduced hilar lymphadenopathy (Fig. 1C). The full case overview is shown in Fig. 2.\n\nDiscussion\n\nTo our knowledge, this is the first reported case of a chylothorax in a child with drug-resistant PTB. We suspect that this child had had endobronchial PTB that had not responded to first-line TB therapy, and progressed to large airway compression and infiltration of the thoracic duct, resulting in chylous fluid leaking into the pleural space. Other possibilities to consider would be paradoxical enlargement of lymph nodes from partial TB treatment, as oral steroids were not initiated at the initial presentation to the primary healthcare clinic.[6]\n\nIn children, congenital malformations of the lymphatic system are the most common medical cause of chylothorax, although infrequent outside the neonatal period.[5] Chylothorax due to malignancies is common in adults, but rare in children.[5] TB-associated chylothorax has been described, but this is limited to case reports. A PubMed search using the MeSH terms ‘tuberculosis’ and ‘chylothorax’ identified seven case reports of children with TB-associated chylothorax (age of presentation ranging from 4 months to 17 years).[7–12] In three of the cases, TB was bacteriologically confirmed on gastric aspirate samples, in one case on bronchioalveolar lavage and in two cases on pleural fluid. All cultures were susceptible to isoniazid and rifampicin. Most cases were associated with large TB perihilar lymphadenopathy. Our case differs in that the chylothorax was associated with drug-resistant TB. The delay in diagnosing drug-resistant TB and initiating appropriate second-line antituberculosis treatment may have led to progression of disease in this child, and this once again highlights the importance of vigorous contact screening, thorough clinical and microbiological investigation and initiation of appropriate antituberculosis treatment, as well as the implementation of a good follow-up plan for each case of TB.\n\nConclusion\n\nThis case highlights the difficulties in managing children diagnosed with unconfirmed TB, and the fact that drug-resistant TB must be considered in children who do not respond to conventional first-line TB treatment.\n\nAlthough endobronchial TB is common in children, severe disease resulting in bronchial obstruction and progression to invasion of other mediastinal structures such as the thoracic duct is infrequent.\n\nInformed consent to participate was obtained from the parents of the child presented in this case report. We thank the staff of Sizwe Tropical Disease Hospital, Johannesburg, for ongoing management of the case.\n\nFig. 1A Chest X-ray on diagnosis of unconfirmed tuberculosis at the local clinic 1 month prior to index presentation, demonstrating attenuation of the trachea and right and left main bronchus.\n\nFig. 1B Chest X-ray on day 5 of admission, demonstrating right pleural effusion.\n\nFig. 1C Chest X-ray after a month of rifampicin-resistant TB treatment, demonstrating radiological resolution of the chylothorax and loss of the attenuation of the trachea, right and left main bronchus.\n\nFig. 2 Case overview.\n\nMDR-TB = multidrug-resistant tuberculosis\n\nPTB = pulmonary tuberculosis\n\nPHC = primary healthcare clinic\n\nCT chest = computed tomography chest scan\n\nAFB = acid-fast bacilli\n\nMTB = Mycobacterium tuberculosis\n==== Refs\nReferences\n\n1 World Health Organization (WHO) Global tuberculosis report 2018 Geneva WHO 2018 (accessed 2 February 2019) https://www.who.int/tb/publications/global_report/en/\n2 Schaaf HS Marais BJ Whitelaw A Culture-confirmed childhood tuberculosis in Cape Town, South Africa: A review of 596 cases. BMC Infect Dis 2007 7 140 10.1186/1471-2334-7-140 18047651\n3 Marais BJ Pai M New approaches and emerging technologies in the diagnosis of childhood tuberculosis. Paediatr Respir Rev 2007 8 2 124 133 10.1016/j.prrv.2007.04.002 17574156\n4 Fauci AS NIAID Tuberculosis Working Group\nMultidrug-resistant and extensively drug-resistant tuberculosis: The National Institute of Allergy and Infectious Diseases Research agenda and recommendations for priority research. J Infect Dis NIAID 2008 197 11 1493 1498 10.1086/587904\n5 Soto-Martinez M Massie J Chylothorax: Diagnosis and management in children. Paediatr Respir Rev 2009 10 4 199 207 10.1016/j.prrv.2009.06.008 19879510\n6 Singh A Rahman H Kumar V An unusual case of paradoxical enlargement of lymph nodes during treatment of tuberculous lymphadenitis in immunocompetent patient and literature review. Am J Case Rep 2013 14 201 204 10.12659/ajcr.889013 23826468\n7 Grobbelaar M Andronikou S Goussard P Chylothorax as a complication of pulmonary tuberculosis in children. Pediatr Radiol 2008 38 2 224 226 10.1007/s00247-007-0634-7 17929008\n8 Rabie H Lomp A Goussard P Paradoxical tuberculosis associated immune reconstitution inflammatory syndrome presenting with chylous ascites and chylothorax in a HIV-1 infected child. J Trop Pediatr 2010 56 5 355 358 10.1093/tropej/fmp141 20100782\n9 Cakir E Gocmen B Uyan ZS An unusual case of chylothorax complicating childhood tuberculosis. Pediatr Pulmonol 2008 43 6 611 614 10.1002/ppul.20817 18433047\n10 Kim KJ Park DW Choi WS Simultaneous chylothorax and chylous ascites due to tuberculosis. Infect Chemother 2014 46 1 50 53 10.3947/ic.2014.46.1.50 24693471\n11 Gie RP Goussard P Kling S Unusual forms of intrathoracic tuberculosis in children and their management. Paediatr Respir Rev 2004 5 Suppl A S139 141 10.1016/s1526-0542(04)90026-7 14980259\n12 Kant S Verma SK Anand SC Development of bilateral chylothorax in a younger female secondary to tuberculosis. Lung India 2011 28 1 56 59 10.4103/0970-2113.76303 21654988\n\n",
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"issue": "25(3)",
"journal": "African journal of thoracic and critical care medicine",
"keywords": "chylothorax; drug resistant tuberculosis; endobronchial tuberculosis; paediatric tuberculosis; tuberculosis",
"medline_ta": "Afr J Thorac Crit Care Med",
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"title": "Chylothorax in a child with rifampicin-resistant tuberculosis.",
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"abstract": "Agent of choice for thrombolytic therapy (TT) in prosthetic valve thrombosis (PVT) is unknown. 84 mitral obstructive-PVT episodes treated with TT (43: Tenecteplase; 41: Streptokinase) were included in this prospective study. The incidence of primary end-point (CCS: complete clinical success, defined as complete or partial hemodynamic success with no complications or surgery) was 84.5% with recurrent PVT as a sole predictor. Bleeding and embolic manifestations were noted in 8.3% and 4.7% of episodes respectively. Tenecteplase use was associated with lower complication rate and a mitral EOA of <0.74 cm2 at presentation predicts the need for extended thrombolysis (accuracy, 78.6%).",
"affiliations": "Department of Cardiology, Kurnool Medical College and Hospital, Kurnool, India. Electronic address: drrxrk@gmail.com.;Department of Cardiology, Kurnool Medical College and Hospital, Kurnool, India.;Consultant, KIMS Hospital, Kurnool, Andhra Pradesh, India.",
"authors": "Kiran|G Ravi|GR|;Chandrasekhar|P|P|;Mohammad Ali|S|S|",
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"fulltext": "\n==== Front\nIndian Heart J\nIndian Heart J\nIndian Heart Journal\n0019-4832\n2213-3763\nElsevier\n\nS0019-4832(21)00046-8\n10.1016/j.ihj.2021.02.005\nResearch Brief\nClinical outcomes of patients with mitral prosthetic valve obstructive thrombosis treated with streptokinase or tenecteplase\nKiran G. Ravi drrxrk@gmail.com\na∗\nChandrasekhar P. a\nMohammad Ali S. b\na Department of Cardiology, Kurnool Medical College and Hospital, Kurnool, India\nb Consultant, KIMS Hospital, Kurnool, Andhra Pradesh, India\n∗ Corresponding author. Department of cardiology, Government general hospital, Kurnool, Andhra-pradesh, India. drrxrk@gmail.com\nMay-Jun 2021\n18 2 2021\n73 3 365368\n22 11 2020\n4 2 2021\n14 2 2021\n© 2021 Cardiological Society of India. Published by Elsevier B.V.\n2021\nCardiological Society of India\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nAgent of choice for thrombolytic therapy (TT) in prosthetic valve thrombosis (PVT) is unknown. 84 mitral obstructive-PVT episodes treated with TT (43: Tenecteplase; 41: Streptokinase) were included in this prospective study. The incidence of primary end-point (CCS: complete clinical success, defined as complete or partial hemodynamic success with no complications or surgery) was 84.5% with recurrent PVT as a sole predictor. Bleeding and embolic manifestations were noted in 8.3% and 4.7% of episodes respectively. Tenecteplase use was associated with lower complication rate and a mitral EOA of <0.74 cm2 at presentation predicts the need for extended thrombolysis (accuracy, 78.6%).\n\nKeywords\n\nProsthetic valve thrombosis\nStuck valve\nProsthetic valve\nThrombolytic therapy\nTenecteplase\nStreptokinase\nSystematic review\nAbbreviations\n\nTT, thrombolytic therapy\nSTK, Streptokinase\nTNT, Tenecteplase\nEOA, effective orifice area\nET, Extended thrombolysis\nO-PVT, obstructive prosthetic valve thrombosis\nTVG, Transvalvular gradient\nPHT, pressure half time\n==== Body\n1 Introduction\n\nSurgical valve replacement is currently the standard of care for the treatment of valvular heart disease. Prosthetic valve thrombosis (PVT) is a life-threatening complication with an average incidence of 1.8%–5.7% per patient-year.1,2 Latest guidelines had recommended treatment with either slow-infusion low-dose thrombolytic therapy (TT) or emergency surgery in patients with a left-sided mechanical obstructive (O)-PVT.3 Streptokinase (STK) and Urokinase are the only FDA approved agents for this purpose. However, many studies have shown that Tenecteplase (TNT) can also be used successfully by infusion4 as well as bolus5 for O-PVT.\n\n2 Methods\n\nThis was a single centre, prospective cohort study that was conducted after IEC approval. Mitral O-PVT was diagnosed by echocardiography6 and/or fluoroscopy.7 Trans-esophageal Echocardiography (TEE) was used only in selective cases where the diagnosis could not be confirmed on 2D trans-thoracic echocardiography (TTE).\n\nTTE Imaging was also carried out every 6 h and before changing treatment decisions. Patients are excluded, if they have contraindications to TT, severe ventricular dysfunction (LVEF <30%), severe unrepaired primary valvular pathology, associated with aortic or right sided O-PVT.\n\n2.1 Systemic thrombolysis\n\nPatients were thrombolysed with either TNT ([0.50 mg/kg]/24 per hour) or STK (30-min loading dose of 1,50,000–2,50,000 U, followed by 1,00,000 U/h) intravenous infusion. Choice of agent was based on the drug availability and at the discretion of treating physician. In any event of major thromboembolic or bleeding episode, TT is stopped.\n\nPatients who had complete hemodynamic response at any point during therapy or partial hemodynamic response even at the end of 48 h infusion, TT was stopped and were further managed with heparin. Patients with persistent hemodynamic instability were treated surgically.\n\n2.2 Adjuvant care\n\nHeparin was withheld during TT. Heparin (UFH) was infused at a rate of 1000 U/h (adjusted to maintain aPTT at 2.0–2.5 times the normal) for 48 h and later Inj. enoxaparin was administered at a dose of 1 mg/kg/SC twice daily. Overlapping acenocoumarol was started and dosage was adjusted until INR fell in range of 2.5–3.5.\n\nDuring in-hospital course patients were managed with diuretics, inotropes, vasopressors, ventilator (invasive/non-invasive) support were ever felt appropriate by the treating physician.\n\n2.3 Outcomes measures\n\nComposite of hemodynamic success (HS),8,9 embolic and bleeding manifestations were used to define clinical success (CS). Complete CS was defined as complete or partial HS with no surgery and/or bleeding and/or embolic features. Clinical failure was defined as death (due to any cause) and/or hemodynamic failure. Incidence of complete CS was the primary end-point and secondary end-points were the incidence of composite adverse events (death or surgery or embolic or bleeding episodes), duration of TT and duration of the hemodynamic support.\n\n2.4 Statistical analysis\n\nContinuous and categorical variables were reported as mean and number of observations (n), respectively. Multivariate regression analysis was performed to determine the predictors of in-hospital outcomes. Area under receiver operator characteristic (AUROC) curves were analysed for an optimal cut-off. A p < 0.05 was considered significant statistically. All the statistical analyses were performed using EZR® (3.5.2. R foundation).\n\n3 Results\n\nA total of 84 eligible mitral O-PVT episodes (15 recurrent) were included (62%, females) and all are breathless at presentation. Absence of therapeutic anticoagulation was the main risk factor. Mean mitral trans-valvular gradient (TVG) and effective orifice-area (EOA) were 25.5 ± 4.5 mmHg and 0.91 ± 0.27 cm2 respectively. 41 episodes were treated with STK.\n\nComplete HS and CS were achieved in 81% and 84.5% of episodes respectively. 2 patients needed surgery and 2 other patients died. Incidences of bleeding and embolic manifestations were 8.3% and 4.7% respectively. Mean duration of TT was 25.6 h (extended thrombolysis, ET in 16 episodes) and hemodynamic support was needed in 24 episodes (mean: 7.1 h), Table 1. In multivariate analysis, recurrent O-PVT was associated lower complete CS. Mitral EOA at presentation and TNT use were associated with duration of TT and hemodynamic support respectively. TNT was associated significantly lower composite adverse event rate, Table 2. A mitral EOA of <0.74 (AUROC: 0.74) predicts the need for ET with an accuracy of 78.6% (sensitivity and specificity of 75% and 79.4% respectively). Supplementary Figure 1.Table 1 Clinical presentation data, management and study outcomes.\n\nTable 1Variable\tVariable\t\nAge (years)\t41.1 ± 6.1\tSTK treated\t41 (48.8%)\t\nFemale\t52 (61.9%)\tExtended thrombolysis\t16 (19%)\t\ntilting disc\t59 (70.2%)\tHemodynamic support\t24 (28.5%)\t\nSH duration (days)\t6 ± 3.8\tLVEF (%)\t57 ± 4.9\t\nRecurrent\t15 (17.8%)\tmitral EOA (cm2)\t0.9 ± 0.27\t\nNYHA III\t72 (85.7%)\tTrans-mitral gradient (mmHg)\t25.5 ± 4.5\t\nOn aspirin prophylaxis\t16 (19%)\tClinical events with TT\t\nOn Penicillin prophylaxis\t44 (52.4%)\tBleeding\t7 (8.3%)\t\nDuration since surgery\t5.62 ± 3.7\tEmbolic manifestations\t5 (5.9%)\t\nINR\t1.4 ± 2.8\tdeath∗\t2 (2.4%)\t\nPlatelet count (104/dl)\t23 ± 4.9\tsurgery∗\t2 (2.4%)\t\n∗ SH: symptom onset to hospital presentation, STK: streptokinase. EOA: effective orifice area, LVEF: left ventricular ejection fraction, Bleed: as per ISTH criteria. ∗thrombolytic failure = 4 (4.8%). Surgery: both were STK pre treated - discharged uneventfully. TT: Thrombolytic therapy. Bleeding: 3 - gum bleeding (2: STK), 1 - hematuria (STK), 1 - surgical site bleeding (TNT) and 2 had major bleeding. Embolic: 3 patients had peripheral embolism (2: STK) and another 2 patents had stroke.\n\nTable 2 Incidence and Predictors of study outcomes∗.\n\nTable 2Outcomes\t\nprimary outcome\tN (%)\tSecondary outcomes\t\t\nComposite clinical\t71 (84.5%)\tComposite adverse events (N, %)\t13 (15.4%)\t\nsuccess\t\tDuration of TT (hours)\t25.6 ± 5.6\t\n\t\tDuration of hemodynamic support (hours)\t7.1 ± 3.5\t\nPredictors of in-hospital outcome\t\nComplete Clinical success: Univariate logistic regression\t\n\tβ\tOR\t95% CI\tp\t\nRecurrent PVT\t1.31\t2.88\t1.66–3.12\t0.03\t\nTNT (yes = 1)\t1.14\t3.14\t0.89–10.99\t0.08\t\nEOA\t1.17\t3.22\t0.40–25.9\t0.27\t\nSH interval\t0.12\t1.13\t0.87–1.46\t0.34\t\nTT duration\t0.09\t1.19\t0.78–1.66\t0.24\t\nComposite adverse events: Univariate logistic regression\t\n\tβ\tOR\t95% CI\tp\t\nTNT (yes = 1)\t−1.45\t0.23\t0.05–0.91\t0.03\t\nTT duration\t0.44\t1.44\t0.72–2.12\t0.19\t\nAspirin (yes = 1)\t−0.30\t0.74\t0.14–3.72\t0.71\t\nThrombolytic therapy duration: Univariate linear regression\t\n\tβ\tSE\tt\tp\t\nMitral EOA\t−8.54\t3.43\t−2.49\t0.01\t\nTNT\t−3.24\t1.39\t−1.66\t0.07\t\nHemodynamic support duration: Multivariate linear regression\t\n\tβ\tSE\tt\tp\t\nMitral EOA\t−4.66\t2.13\t−1.78\t0.09\t\nTNT\t−4.17\t1.12\t−2.11\t0.02\t\n^ Variables assessed are: Age; sex; Aspirin use; recurrent PVT; tilting disc; SH interval; TNT use; mitral TVG; mitral EOA; LVEF and TT duration (only relevant variables and significant in univariate analysis were presented). TT: thrombolytic therapy; EOA: effective orifice area; TVG: transvalvular gradient; TNT: Tenecteplase; SH: symptom onset to hospital, PVT: prosthetic valve thrombosis.\n\nbold: statistically significant.\n\n∗: provided at the foot notes of table\n\n4 Discussion\n\nYounger age, female predominance and sub-therapeutic INR in majority of O-PVT was seen; an epidemiology consistently demonstrated in studies from developing countries.10 We did not used TEE to quantify thrombus because, a sizeable proportion of study patients were not stable enough to perform a safe TEE at presentation. Recurrent PVT was associated with significantly lower success. Similar poor performance was published, where following TT, <50% of patients had complete gradient recovery with >1/3rd patients experiencing death.11 Lower mitral EOA may represent the higher thrombotic burden on leaflets and thus been associated with longer duration of TT. 4 systematic reviews on TT for PVT showed a complete success rate of about 70%–80%.12, 13, 14, 15 However, success might depend upon the valve position, definition of ’success’ used, size of obstructing thrombus, previous co-morbidities, nature of systemic TT used (76.6% with STK and 90% with TNT),. Among STK treated patients, 2 experienced major bleeding (massive hematemesis and other hemorrhagic stroke) and 1 had embolic stroke. There were no major bleeding episodes with TNT, but its use resulted in TIA in one patient. With STK, studies had documented an average bleeding and embolism rate of 8.5% and 6.5% respectively (6% each with TNT), Supplementary Table 1. Non-utilization of TEE for evaluating the thrombus burden and single centre nature with small sample were notable limitations.\n\n5 Conclusion\n\nIn left sided O-PVT systemic thrombolytic therapy (with streptokinase or tenecteplase) is associated with <5% failure rate. Recurrent PVT being associated with lower complete clinical success, thus patient education for proper drug compliance and follow-up is imperative. Compared to STK, TNT infusion is associated with statistically better safety profile and faster recovery, thus should be preferred. Lower mitral EOA (<0.74 cm2) at presentation predicts the need for extended thrombolysis with good accuracy (around 78%).\n\nDeclaration of competing interest\n\nAll authors have none to declare.\n\nAppendix A Supplementary data\n\nThe following are the Supplementary data to this article:Multimedia component 1\n\nMultimedia component 1\n\nfigs1 figs1\n\nAcknowledgements\n\nNone.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.ihj.2021.02.005.\n==== Refs\nReferences\n\n1 Hermans H. Vanassche T. Herijgers P. Antithrombotic therapy in patients with heart valve prostheses Cardiol Rev 21 1 2013 27 36 10.1097/CRD.0b013e3182638578 22695380\n2 Cevik C. Izgi C. Dechyapirom W. Treatment of prosthetic valve thrombosis: rationale for a prospective randomized clinical trial J Heart Valve Dis 19 2 2010 161 170 20369498\n3 Nishimura R.A. Otto C.M. Bonow R.O. AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines Circulation 135 25 2017 e1159 e1195 doi: 10.1161/CIR.0000000000000503 28298458\n4 Kathirvel D. Justin Paul G. Prathap Kumar G. Tenecteplase versus streptokinase thrombolytic therapy in patients with mitral prosthetic valve thrombosis Indian Heart J 70 4 2018 506 510 10.1016/j.ihj.2017.10.014 30170645\n5 Sharma V. Singh R. Mishra R. Arora A.P. Use of tenecteplase for left-sided prosthetic valve thrombosis J Assoc Phys India 60 2012 55 58\n6 Lancellotti P. Pibarot P. Chambers J. Recommendations for the imaging assessment of prosthetic heart valves: a report from the European association of cardiovascular imaging endorsed by the Chinese society of echocardiography, the inter-American society of echocardiography, and the Brazilian department of cardiovascular imaging Eur Heart J Cardiovasc Imaging 17 6 2016 589 590 10.1093/ehjci/jew025 27143783\n7 Montorsi P. De Bernardi F. Muratori M. Role of cine-fluoroscopy, transthoracic, and transesophageal echocardiography in patients with suspected prosthetic heart valve thrombosis Am J Cardiol 85 2000 58 64 10.1016/s0002-9149(99)00607-4 11078238\n8 Balasundaram R.P. Karthikeyan G. Kothari S.S. Fibrinolytic treatment for recurrent left sided prosthetic valve thrombosis Heart 91 6 2005 821 822 10.1136/hrt.2004.044123 15894790\n9 Schulman S. Kearon C. Subcommittee on control of anticoagulation of the scientific and standardization committee of the international society on thrombosis and haemostasis. Definition of major bleeding in clinical investigations of anti-hemostatic medicinal products in non-surgical patients J Thromb Haemostasis 3 2005 692 694 10.1111/j.1538-7836.2005.01204.x 15842354\n10 Hirachan A. Roka M. Prajapati D. Prosthetic valve thrombosis in a tertiary cardiac centre Nepal Heart J 14 2017 9 11\n11 Manjula M. Rangan Kapil Manjunath C.N. Clinical profile and outcome of recurrent prosthetic heart valve thrombosis in a tertiary care cardiology unit Indian Heart J 69 S2 2017 S1 28400032\n12 Castilho F.M. De Sousa M.R. Mendonça A.L. Thrombolytic therapy or surgery for valve prosthesis thrombosis: systematic review and meta-analysis J Thromb Haemostasis 12 2014 1218 1228 10.1111/jth.12577 24698327\n13 Reyes-Cerezo E. Jerjes-Sanchez C. Archondo-Arce T. Fibrinolytic therapy in left side-prosthetic valve acute thrombosis. In depth systematic review Arch Cardiol Mex 78 2008 309 317 18959020\n14 Huang G. Schaff H.V. Sundt T.M. Treatment of obstructive thrombosed prosthetic heart valve J Am Coll Cardiol 62 19 2013 Nov 5 1731 1736 10.1016/j.jacc.2013.07.075 23994405\n15 Karthikeyan G. Senguttuvan N.B. Joseph J. Urgent surgery compared with fibrinolytic therapy for the treatment of left-sided prosthetic heart valve thrombosis: a systematic review and meta-analysis of observational studies Eur Heart J 34 21 2013 1557 1566 10.1093/eurheartj/ehs486 23329151\n\n",
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"keywords": "Prosthetic valve; Prosthetic valve thrombosis; Streptokinase; Stuck valve; Systematic review; Tenecteplase; Thrombolytic therapy",
"medline_ta": "Indian Heart J",
"mesh_terms": "D005343:Fibrinolytic Agents; D006350:Heart Valve Prosthesis; D006801:Humans; D008943:Mitral Valve; D011446:Prospective Studies; D013300:Streptokinase; D000077785:Tenecteplase; D015912:Thrombolytic Therapy; D013927:Thrombosis; D016896:Treatment Outcome",
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"title": "Clinical outcomes of patients with mitral prosthetic valve obstructive thrombosis treated with streptokinase or tenecteplase.",
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"abstract": "Elderly patients with glioblastoma and an accumulation of negative prognostic factors have an extremely short survival. There is no consensus on the clinical management of these patients and many may escape histologically verified diagnosis. The primary aim of this study was to characterize this particular subgroup of patients with radiological glioblastoma diagnosis without histological verification. The secondary aim was to evaluate if oncological therapy was of benefit.\n\n\n\nBetween November 2012 and June 2016, all consecutive patients presenting with a suspected glioblastoma in the western region of Sweden were registered in a population-based study. Of the 378 patients, 131 (35%) met the inclusion criteria of the present study by typical radiological features of glioblastoma without histological verification.\n\n\n\nThe clinical characteristics of the 131 patients (72 men, 59 women) were: age ≥ 75 (n = 99, 76%), performance status according to Eastern Cooperative Oncology Group ≥ 2 (n = 93, 71%), significant comorbidity (n = 65, 50%) and multilobular tumors (n = 90, 69%). The overall median survival rate was 3.6 months. A subgroup of 44 patients (34%) received upfront treatment with temozolomide, with an overall radiological response rate of 34% and a median survival of 6.8 months, compared to 2.7 months for those receiving best supportive care only. Good performance status and temozolomide treatment were statistically significant favorable prognostic factors, while younger age was not.\n\n\n\nThirty-five percent of patients with a radiological diagnosis of glioblastoma in our region lacked histological diagnosis. Apart from high age and poor performance status, they had more severe comorbidities and extensive tumor spread. Even for this poor prognostic group upfront treatment with temozolomide was shown of benefit in a subgroup of patients. Our data illustrate the need of non-invasive diagnostic methods to guide optimal individualized therapy for patients considered too fragile for neurosurgical biopsy.",
"affiliations": "Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.;Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.;Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.;Sahlgrenska Cancer Center, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden.;Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden.;Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden.",
"authors": "Werlenius|Katja|K|0000-0003-1414-5588;Fekete|Boglarka|B|;Blomstrand|Malin|M|;Carén|Helena|H|;Jakola|Asgeir S|AS|;Rydenhag|Bertil|B|;Smits|Anja|A|",
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"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0228480PONE-D-19-29131Research ArticleMedicine and Health SciencesOncologyCancer TreatmentMedicine and Health SciencesDiagnostic MedicineMedicine and Health SciencesOncologyMedicine and Health SciencesDiagnostic MedicineCancer Detection and DiagnosisMedicine and Health SciencesOncologyCancer Detection and DiagnosisMedicine and Health SciencesGeriatricsPeople and PlacesPopulation GroupingsAge GroupsElderlyMedicine and Health SciencesDiagnostic MedicineDiagnostic RadiologyResearch and Analysis MethodsImaging TechniquesDiagnostic RadiologyMedicine and Health SciencesRadiology and ImagingDiagnostic RadiologyBiology and Life SciencesAnatomyHistologyMedicine and Health SciencesAnatomyHistologyPatterns of care and clinical outcome in assumed glioblastoma without tissue diagnosis: A population-based study of 131 consecutive patients Outcome in patients with glioblastoma without histological diagnosishttp://orcid.org/0000-0003-1414-5588Werlenius Katja ConceptualizationData curationFormal analysisInvestigationMethodologyValidationVisualizationWriting – original draftWriting – review & editing12*Fekete Boglarka Data curationInvestigationWriting – review & editing13Blomstrand Malin ConceptualizationMethodologyWriting – review & editing12Carén Helena SupervisionWriting – review & editing4Jakola Asgeir S. Formal analysisMethodologySupervisionWriting – review & editing35Rydenhag Bertil ConceptualizationData curationFunding acquisitionProject administrationSupervisionWriting – review & editing35Smits Anja ConceptualizationFormal analysisMethodologySupervisionWriting – original draftWriting – review & editing3671 \nDepartment of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden2 \nDepartment of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden3 \nDepartment of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden4 \nSahlgrenska Cancer Center, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden5 \nDepartment of Neurosurgery, Sahlgrenska University Hospital, Gothenburg, Sweden6 \nDepartment of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden7 \nDepartment of Neuroscience, Neurology, Uppsala University, Gothenburg, SwedenSherman Jonathan H EditorGeorge Washington University, UNITED STATESCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: katja.werlenius@vgregion.se13 2 2020 2020 15 2 e022848018 10 2019 15 1 2020 © 2020 Werlenius et al2020Werlenius 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.Background\nElderly patients with glioblastoma and an accumulation of negative prognostic factors have an extremely short survival. There is no consensus on the clinical management of these patients and many may escape histologically verified diagnosis. The primary aim of this study was to characterize this particular subgroup of patients with radiological glioblastoma diagnosis without histological verification. The secondary aim was to evaluate if oncological therapy was of benefit.\n\nMethods\nBetween November 2012 and June 2016, all consecutive patients presenting with a suspected glioblastoma in the western region of Sweden were registered in a population-based study. Of the 378 patients, 131 (35%) met the inclusion criteria of the present study by typical radiological features of glioblastoma without histological verification.\n\nResults\nThe clinical characteristics of the 131 patients (72 men, 59 women) were: age ≥ 75 (n = 99, 76%), performance status according to Eastern Cooperative Oncology Group ≥ 2 (n = 93, 71%), significant comorbidity (n = 65, 50%) and multilobular tumors (n = 90, 69%). The overall median survival rate was 3.6 months. A subgroup of 44 patients (34%) received upfront treatment with temozolomide, with an overall radiological response rate of 34% and a median survival of 6.8 months, compared to 2.7 months for those receiving best supportive care only. Good performance status and temozolomide treatment were statistically significant favorable prognostic factors, while younger age was not.\n\nConclusion\nThirty-five percent of patients with a radiological diagnosis of glioblastoma in our region lacked histological diagnosis. Apart from high age and poor performance status, they had more severe comorbidities and extensive tumor spread. Even for this poor prognostic group upfront treatment with temozolomide was shown of benefit in a subgroup of patients. Our data illustrate the need of non-invasive diagnostic methods to guide optimal individualized therapy for patients considered too fragile for neurosurgical biopsy.\n\nThis work received financial support from the Gothenburg Medical Society (KW), Regional FoU-support; #VGFOUREG-750851, BR), AFA Research Foundation (BR) and by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (#ALFGBG-717021, AS; #ALFGBG-716671, ASJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 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\nGlioblastoma (GBM) is the most common malignant brain tumor in adults, constituting 46% of malignant primary brain tumors [1]. The incidence of GBM is known to increase with age [2], and GBM rates have successively increased over the last decades in the ageing population [2–6]. Elderly patients with GBM more often present with poor performance status (PS) and significant comorbidities. At the same time, high age is amongst the strongest unfavorable prognostic factors for survival [7–11], and benefits of treatment are small compared to the younger population with GBM [10]. Furthermore, treatment seems to be tolerated worse amongst the elderly [12, 13]. A higher risk of postoperative complications in frail and elderly patients has been reported [14, 15], as well as shorter survival for those suffering from complications after surgery [14, 16].\n\nAs a consequence, elderly patients with an unambiguous radiological diagnosis of GBM and an accumulation of negative prognostic factors at disease presentation may receive best supportive care (BSC) without histological verification of tumor diagnosis [9, 17–19]. The exact proportion of this subgroup in the general GBM population is not well known, but numbers varying between 8–19% have been reported from national brain tumor registries [9, 17, 20, 21]. When taking the elderly population into consideration exclusively, the proportion of patients receiving BSC only has been reported as high as 44–75% [10, 17, 19, 22].\n\nIt is not clear whether there is a general underreporting of patients lacking histological tumor diagnosis or whether the variations in reported numbers represent true differences in clinical strategies between different centers and countries. In conclusion, the subgroup of elderly and fragile patients with GBM has largely gone unstudied. At the same time, these patients represent an important part of everyday clinical practice that can neither be ignored nor be expected to diminish over time.\n\nUntil recently, the Swedish Brain Tumor Registry included patients with histologically verified brain tumor diagnoses only. Thus, this registry cannot be used to study the particular subgroup of patients without tissue diagnosis. In our previous population-based study from the western region of Sweden, we found that 47% of all patients with a typical radiological diagnosis of GBM during 2004–2008 were not considered for diagnostic surgery [19]. As expected, the survival for this unfavorable prognostic subgroup of untreated GBM was extremely poor, with a median overall survival of only 3.2 months, illustrating the aggressive natural course of the disease.\n\nIn the present study, we characterized the subpopulation of patients with radiological diagnosis of GBM without histological verification during 2012–2016, with focus on clinical characteristics, patterns of care and outcome. We also evaluated if there has been a change in practice over time and if oncological treatment benefitted this poor prognostic group of patients.\n\nPatients and methods\nPatients\nBetween November 2012 and June 2016, all adult patients (≥ 18 years) presenting with a suspected radiological diagnosis of supratentorial GBM in the western health care region of Sweden (approx. 1.9 million inhabitants) were registered in a population-based consecutive study [23]. There is one single neurosurgical department serving the entire health care region, and no private health care for patients with brain tumors, assuring identification of all patients presenting with suspected GBM in the region during the study period.\n\nAll patients were discussed at the multidisciplinary neuro-oncological tumor board (MTB) at Sahlgrenska University Hospital, Gothenburg, and individual treatment recommendations were documented in the medical records and the meeting protocols.\n\nOf the in total 395 patients with radiological diagnosis of GBM registered in the data base, 148 patients were not recommended for surgery. The specific motivations to refrain from surgery (such as age, tumor location and spread, comorbidity, PS, previous histological diagnosis of lower-grade glioma or the individual wish of the patient) were documented. A retrospective review of the medical charts of these patients together with a re-evaluation of diagnostic imaging was performed for the purpose of this study. Following this evaluation, 131 patients (35%) met the inclusion criteria of the present study by typical radiological features of GBM without histological verification (Fig 1).\n\n10.1371/journal.pone.0228480.g001Fig 1 Flow chart illustrating the patient selection in the present study.\nClinical characteristics\nAll patients were followed for survival until death or the end of the study (30 June 2018). The following data were collected from medical records: date of diagnosis (i.e. date of the first brain scan showing typical features of GBM), type of diagnostic imaging, age at diagnosis, sex, tumor location, presenting symptoms, comorbidity, estimated PS according to Eastern Cooperative Oncology Group (ECOG) [24] at diagnosis, and treatment (supportive care or oncological treatment)). Multilobular tumors were defined as involving two or more cerebral lobes, multifocal as at least two separate contrast-enhancing lesions. Comorbidities were scored according to an adapted Charlson Comorbidity Index (CCI) [25], using the assigned weights for diseases modified by Schneeweiss [26]. Significant comorbidity was defined as a score of ≥ 2.\n\nFor patients receiving oncological treatment, the following additional data were registered: start- and stop-dates for oncological treatment, PS at follow-up, use of corticosteroids at start of treatment, type and number of oncological therapies, radiological response to treatment, clinical benefit and bone marrow toxicity (defined as platelets <100 x109/L or total white blood count <3.0 x109/L).\n\nStatistical analysis\nDescriptive statistics were used for patient characteristics and oncological treatment. Statistical calculations were performed using IBM SPSS Statistics version 25 (IBM cooperation, Armonk, NY, USA). Differences in distribution of clinical variables between the BSC group and the group of patients receiving oncological treatment were calculated by independent samples t-test for continuous variables and Fisher exact test for proportions. All p-values were two-sided. Survival was estimated by the Kaplan-Meier method and Log-rank test. A p-value of <0.05 was considered statistically significant.\n\nEthical review process\nApproval for inclusion of patients in the database was obtained by the Ethics committee (Regional Ethics Review Board, Dnr 559–12, date of approval 2012-08-15). For inclusion of patients (without histological diagnosis) in the present study, an amendment was submitted and approved (Regional Ethics Review Board, Dnr 505–18, date of approval 2018-05-30). For this particular part of the study, the ethics committee waived the requirements for informed consent based on the fact that all patients to be included were deceased at that time point. Patients’ medical records were obtained from the Sahlgrenska University Hospital, Gothenburg and analyzed during the time period May 2018—April 2019. All data were fully anonymized before they were accessed for the purpose of the study.\n\nResults\nPatient characteristics\nThe clinical characteristics of the 131 patients are listed in Table 1. As shown, the median age at diagnosis was 79.7 years (range 52.8–90.5). A total of 99 patients (76%) were ≥ 75 years, 72 men (55%) and 59 women (45%), with a male-to-female ratio of 1.22. At the time of diagnosis, 93 patients (71%) had PS ≥ 2. Sixty-five patients (50%) had significant comorbidity (CCI ≥ 2) and 90 patients (69%) had multilobular tumors. In 90% of cases, radiological diagnosis was based on MRI with contrast-enhancement, three patients (2%) had MRI or CT without contrast-enhancement, due to individual contraindications.\n\n10.1371/journal.pone.0228480.t001Table 1 Baseline characteristics of patients with radiological diagnosis of GBM without histological confirmation.\nVariable:\tNumber of patients (N = 131)\t\n\tN (%)\t\nAge at diagnosis:\t\t\n < 60 years\t5 (4)\t\n 60–74 years\t27 (21)\t\n ≥ 75 years\t99 (75)\t\nMedian age in years (range):\t79.7 (52.8–90.5)\t\nGender:\t\t\n Male\t72 (55)\t\n Female\t59 (45)\t\nPerformance status1:\t\t\n 0\t7 (5)\t\n 1\t31 (24)\t\n 2\t44 (34)\t\n 3\t32 (24)\t\n 4\t17 (13)\t\nTumor location:\t\t\n Right hemisphere\t46 (35)\t\n Left hemisphere\t41 (31)\t\n Bilateral\t44 (34)\t\nMultilobular tumor2:\t90 (69)\t\nMultifocal tumor3:\t49 (37)\t\nMethod of diagnosis:\t\t\n MRI with contrast\t118 (90)\t\n CT with contrast\t10 (8)\t\n MRI or CT without contrast\t3 (2)\t\nCharlson Comorbidity Index4:\t\t\n 0\t37 (28)\t\n 1\t29 (22)\t\n 2\t22 (17)\t\n 3\t21 (16)\t\n ≥4\t22 (17)\t\n1Performance status, according to ECOG, Eastern Cooperative Oncology Group/WHO,\n\n2Multilobular tumor, involving two or more cerebral lobes,\n\n3Multifocal tumor, defined as at least two separate contrast-enhancing lesions,\n\n4 Comorbidity according to adjusted Charlson Comorbidity index\n\nThe most common motivations for not recommending diagnostic surgery by the MTB were extensive tumor infiltration, together with high age, eloquent areas, poor PS, and/or significant comorbidities. In three cases, diagnostic surgery was recommended by the MTB but not performed due to the individual wish of the patient. For comparative reasons, the main clinical characteristics of the cohort of patients undergoing diagnostic surgery for GBM (n = 247) during the study period are presented in the supporting information (S1 Table).\n\nTreatment characteristics\nFifty-four of the 131 patients (41%) were seen by an oncologist in the outpatient setting, and a total of 45 patients (34%) received oncological treatment. The clinical characteristics for patients receiving treatment as compared to BSC are shown in Table 2. As illustrated, patients who received treatment were generally younger, had better PS, less comorbidities, and more often multifocal tumors, while there was no difference in gender or tumor location. The vast majority (93%) of the 45 patients receiving treatment had corticosteroids at baseline. TMZ as a single agent was the most common first line treatment (n = 44, 98%). In total, three patients received a short-course of radiotherapy. Five out of the seven patients receiving second line treatment received lomustine as a single agent, as depicted in Table 3.\n\n10.1371/journal.pone.0228480.t002Table 2 Clinical characteristics for patients with radiological GBM receiving oncological treatment vs best supportive care.\nVariable:\tNumber of patients (N = 131):\t\n\tOncological treatment N = 45 (34%)\tBest Supportive Care N = 86 (66%)\tp-value (χ2):\t\nN (%)\tN (%)\t\nAge at diagnosis:\t\t\t<0.0001*\t\n < 75 years\t24 (53)\t8 (9)\t\t\n ≥ 75 years\t21 (47)\t78 (91)\t\t\nMean age (years ± SD):\t72.7±8.0\t81.5±5.2\t<0.0001*\t\nGender:\t\t\t0.3\t\n Male\t22 (49)\t50 (58)\t\t\n Female\t23 (51)\t36 (42)\t\t\nPerformance status1:\t\t\t<0.0001*\t\n 0–1\t23 (51)\t15 (17)\t\t\n 2–4\t22 (49)\t71 (83)\t\t\nTumor location:\t\t\t0.8\t\n Unilateral\t28 (62)\t59 (69)\t\t\n Bilateral\t17 (38)\t27 (31)\t\t\nMultilobular2:\t29 (64)\t61 (71)\t0.4\t\nMultifocal3:\t22 (49)\t27 (31)\t0.05*\t\nComorbidity4:\t\t\t0.02*\t\n 0–1\t29 (64)\t37 (43)\t\t\n ≥ 2\t16 (36)\t49 (57)\t\t\nMedian survival in months (95% CI):\t6.8 (5.6–8.0)\t2.7 (2.4–3.1)\t<0.0001*\t\n1Performance status, according to ECOG,\n\n2Multilobular tumor, involving two or more cerebral lobes,\n\n3Multifocal tumor, defined as at least two separate contrast-enhancing lesions,\n\n4According to adjusted Charlson Comorbidity Index,\n\n*significant\n\n10.1371/journal.pone.0228480.t003Table 3 Treatment characteristics of patients without histopathological confirmation receiving oncological treatment.\n\tNumber of patients (N = 45):\t\nN (%)\t\nFirst line treatment:\t\t\n TMZ\t44 (98)\t\n Short course RT\t1 (2)\t\nAny second line treatment:\t7 (16)\t\nTreatment response TMZ:\t(N = 44)\t\n Radiological regression\t15 (34)\t\n Clinical benefit1\t19 (43)\t\nBone marrow toxicity2:\t10 (23)\t\n1As decided by stable (PS ≤ 2) or improved PS after 3 months,\n\n2White blood cell count <3.0x109/L or platelets <100x109/L\n\nResponse to treatment and toxicity\nThe overall radiological response rate to TMZ was 34%. Nineteen patients (43%) remained stable or improved in PS at three months after chemotherapy (see case illustration, Fig 2). Ten patients experienced bone marrow toxicity, defined as white blood cell count <3.0 x109/L or platelet count <100 x109/L (Table 3). Three patients experienced thrombocytopenia grade 3 according to CTCAE (Common Terminology Criteria for Adverse Events), with platelet count in the range of 25–49 x109/L. No grade 4 or 5 toxicities were observed.\n\n10.1371/journal.pone.0228480.g002Fig 2 Illustrative case report.\n73-year old patient who presented with confusion and change of personality. Diagnostic surgery was not considered suitable due to poor PS. The patient received palliative treatment with steroids and temozolomide, and responded radiologically and clinically, with improvement of cognition and performance status (PS 2 to PS 1), following three cycles of temozolomide treatment. The patient died 11.2 months after radiological diagnosis of glioblastoma.\n\nSurvival\nAt the end of the study all patients had died. The median total survival in the whole group (n = 131) was 3.6 months (95% CI, 2.8–4.3). Survival rate at 6 and 12 months was 27% and 5% respectively. The median survival for patients receiving oncological treatment was 6.8 months (95% CI, 5.6–8.0) compared to 2.7 months (95% CI, 2.4–3.1) for patients receiving BSC (Fig 3a–3c).\n\n10.1371/journal.pone.0228480.g003Fig 3 a. Overall survival for all patients with histologically unverified GBM. b. Survival stratified for performance status according to ECOG. c. Survival for patients receiving oncological treatment vs best supportive care only.\n\nPredictors of survival\nUnivariate analysis by log-rank test identified PS and oncological treatment as the only significant predictors of survival (PS, p < 0.0001; oncological treatment, p < 0.0001; Fig 3b and 3c). Age (as dichotomized parameter with cut-off at 75, and as continuous parameter using Cox-regression), comorbidity, gender, tumor location and multifocality did not have any significant impact on survival.\n\nRegression analysis with the aim to identify predictors of survival was not considered meaningful due to the strong association between the two variables PS and oncological treatment (Pearson Chi-Square p<0.0001), and this was considered a violation of the assumption of independence.\n\nDiscussion\nIn the present study we describe a poor prognostic subgroup of patients with radiological but not histologically verified GBM diagnosis. The median age of these patients was significantly higher (79.7 years) compared to the general population of GBM (64 years), as recently reported by the CBTRUS [1]. In addition to high age, the majority (71%) of patients had a poor PS at the time of diagnosis. Poor PS is a well-known risk factor associated with a shorter life expectancy [7, 8, 11, 12]. Apart from high age and poor PS, individual motivations for refraining from diagnostic surgery were severe comorbidities and extensive tumor spread.\n\nInterestingly, higher age was not associated with worse outcome in our study representing a selection of the very elderly GBM population. In contrast, we identified poor PS (ECOG ≥ 2) as a strong prognostic factor for shorter survival. Thus, for this selected subpopulation of GBM patients with poor outcome, PS was more important than factual age. We also found a less marked male predominance in our study compared to other reports [4]. This may be related to the fact that women in Sweden have a longer life-expectancy than men, but biological factors may also play a role in gender-related differences in the oldest age group.\n\nPrevious studies have shown that elderly patients are more likely to receive a GBM diagnosis without histological verification [3, 17, 20]. To our knowledge, the clinical characteristics and the outcome of this poor prognostic group have not been investigated earlier. As mentioned, the proportion of these patients in the general GBM population varies considerably between studies, suggesting differences in treatment strategies as well as in the registration of patients. In a previous population-based study from our own region during the time period 2004–2008, we found that 47% of patients lacked histological diagnosis [19], which is in line with a recent population-based British study of GBM patients aged >70 years [22]. In the present study, this proportion has decreased from 47% to 35%, while the median age of patients has increased to almost 80 years compared to 75 years in our previous cohort. These results indicate a shift in towards a more active policy for more fragile elderly patients with GBM in our region.\n\nAlthough it is not standard of care to give oncological treatment without tissue diagnosis, it can be argued that refraining from surgery in patients with such a short life expectancy will decrease the likelihood for receiving no tumor treatment at all. Particularly elderly patients with poor preoperative PS seem to be at risk for postoperative complications [7, 8, 12]. This is probably the reason why up to 34% of patients do not receive oncological treatment after diagnostic biopsy [19, 22]. An even higher number was reported in an Australian study of GBM in patients aged 80 or older, where only 6 out of 40 patients continued with postoperative radiotherapy or chemotherapy [27].\n\nStudies on elderly patients with GBM and poor PS are scarce, also because these patients are usually excluded from clinical trials. One important exception was provided by the French nonrandomized phase II trial evaluating the efficacy of TMZ in patients >70 years with newly diagnosed GBM and a poor postoperative PS [28]. More recently, a prospective phase III-study by Roa et al demonstrated that a one-week course of radiotherapy was non-inferior to a 3-week course of radiotherapy in elderly and/or frail patients [29].\n\nIn the present cohort, we used TMZ as a single agent instead of radiotherapy in almost all cases. Although not evidence-based, this strategy has been common practice in our region for elderly and frail patients with unknown MGMT methylation status and extensive tumor spread. Given the limited life expectancy of these patients, our experience is that the rapid start of TMZ treatment is an important advantage when waiting-time and hospitalization in connection with diagnostic surgery and radiotherapy can be detrimental, leaving no time left to benefit from treatment [14]. Indeed, we found that forgoing biopsy/resection reduced the waiting-time from radiological diagnosis to start of first oncological treatment by more than 50% (median of 28 days versus 59 days following diagnostic surgery) (S1 Table).\n\nSeveral trials support an active treatment of elderly GBM patients with good PS [30–33], and it is well-established that high age per se, without poor PS or significant comorbidities, is not a contraindication for active treatment. Keime-Guibert et al demonstrated that radiotherapy (50 Gy in 28 fractions) was superior to best supportive care (BSC) with a median survival of 7 months for patients receiving radiotherapy compared to 4 months in the group receiving BSC only, but there was no observed improvement of health-related quality of life during or after radiotherapy [30]. The Nordic trial showed that TMZ as a single agent and short course RT (34 Gy in 3.4 fractions) was superior to long course radiotherapy (60 Gy in 30 fractions) for patients > 70 years [31]. For patients with hypermethylated MGMT, TMZ alone rendered the longest median survival of 9.7 months. Median age at diagnosis in the Nordic trial was 70 years, and more than 75% had good PS (ECOG 0–1). Another important observation from this trial was that patients receiving TMZ alone generally reported better health-related quality of life than patients receiving radiotherapy [31].\n\nRecently, Perry et al demonstrated that the addition of TMZ to short course radiotherapy (40 Gy in 15 fractions) improved survival compared to radiotherapy alone [32]. This was particularly true for patients with hypermethylated MGMT, for whom median survival was 13.5 months compared to 7.7 months with radiotherapy alone. Interestingly, there was a survival benefit of 2.1 months, although not statistically significant (P = 0.055), for patients with unmethylated MGMT as well. The median age of the study population was 73 years, with almost 30% of the patients > 75 years old, and 77% with PS 0 or 1 [32].\n\nOur study showed a significant better survival for patients receiving oncological treatment compared to patients receiving BSC (6.8 vs 2.7 months). Obviously, no firm conclusions can be drawn since there was a strong selection bias for patients receiving treatment based on PS and age. The better outcome of the treated group is, however, consistent with the results of the previously mentioned French phase II trial, evaluating TMZ after surgery (biopsy 91%) in patients >70 years with newly diagnosed GBM and a poor postoperative PS. Median OS in the French trial was 6.2 months and 33% of the patients improved their functional status, demonstrating that elderly frail patient may benefit from TMZ alone [28]. A meta-analysis found TMZ to be non-inferior to radiotherapy for elderly patients, particularly for those with hypermethylated MGMT [34]. In another systematic review it was concluded that elderly patients with MGMT promotor methylated tumors who are not candidates for combined radiochemotherapy, are more likely to benefit from TMZ alone than radiotherapy [35]. In a longer perspective, these data strongly suggest that the old and frail GBM population would benefit from new non-invasive diagnostic methods prior to individual treatment decisions. Blood-based liquid biopsy has emerged as a promising resource not only for initial diagnosis but also for prognostic prediction, treatment planning and follow-up [36].\n\nAn obvious limitation of our study, which is intrinsic to the study design, is the lack of a definite GBM diagnosis confirmed by operation or autopsy, implying that some of the patients in the cohort might actually not have a GBM. However, for all 131 patients the clinical course of disease was in total agreement with GBM diagnosis.\n\nIt cannot be excluded that refraining from diagnostic surgery has limited the treatment options and thereby influenced the outcome of individual cases. As such, it is possible that some patients with better PS would have benefitted from surgery and a more active oncological treatment approach with combined radiation and chemotherapy. On the other hand, others may never have come to treatment due to postoperative complications and poor PS following surgical intervention.\n\nConclusions\nWe report that 35% of all patients with radiological diagnosis of GBM in the western region of Sweden lacked histological diagnosis. This group consisted mainly of elderly patients with poor PS, significant comorbidity and extensive tumor spread, and had a median survival of 3.6 months. The median survival in a subgroup of patients receiving single treatment with TMZ was 6.8 months compared to 2.7 months for those receiving best supportive care only. Our results suggest that even in this poor prognostic group upfront treatment with TMZ may be of benefit. Our data illustrate the need of novel non-invasive diagnostic methods for patients considered too fragile for neurosurgical biopsy to guide tailored therapy.\n\nSupporting information\nS1 Table Clinical characteristics of GBM patients in the western region of Sweden between November 2012 and June 2016.\n(DOCX)\n\nClick here for additional data file.\n\n S2 Table De-identified minimal data set of the study population.\n(DOCX)\n\nClick here for additional data file.\n\n We acknowledge Inger Nilsson, consultant neuro-radiologist, who kindly reviewed radiology, and the important work done by our research assistant Ünzüle Yildiz.\n==== Refs\nReferences\n1 Ostrom QT , Gittleman H , Fulop J , Liu M , Blanda R , Kromer C , et al\nCBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008–2012 . Neuro-oncology . 2015 ;17 \nSuppl 4 :iv1 –iv62 . 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Epub 2010/10/05. 10.1016/j.ijrobp.2010.06.012 \n20888136 \n9 Glaser SM , Dohopolski MJ , Balasubramani GK , Flickinger JC , Beriwal S . Glioblastoma multiforme (GBM) in the elderly: initial treatment strategy and overall survival . Journal of neuro-oncology . 2017 ;134 (1 ):107 –18 . Epub 2017/05/21. 10.1007/s11060-017-2493-x .28527010 \n10 Kita D , Ciernik IF , Vaccarella S , Franceschi S , Kleihues P , Lutolf UM , et al\nAge as a predictive factor in glioblastomas: population-based study . Neuroepidemiology . 2009 ;33 (1 ):17 –22 . Epub 2009/03/28. 10.1159/000210017 .19325245 \n11 Iwamoto FM , Cooper AR , Reiner AS , Nayak L , Abrey LE . Glioblastoma in the elderly: the Memorial Sloan-Kettering Cancer Center Experience (1997–2007) . Cancer . 2009 ;115 (16 ):3758 –66 . Epub 2009/06/02. 10.1002/cncr.24413 .19484785 \n12 Chaichana KL , Chaichana KK , Olivi A , Weingart JD , Bennett R , Brem H , et al\nSurgical outcomes for older patients with glioblastoma multiforme: preoperative factors associated with decreased survival. Clinical article . J Neurosurg . 2011 ;114 (3 ):587 –94 . Epub 2010/10/05. 10.3171/2010.8.JNS1081 \n20887095 \n13 Sijben AE , McIntyre JB , Roldan GB , Easaw JC , Yan E , Forsyth PA , et al\nToxicity from chemoradiotherapy in older patients with glioblastoma multiforme . Journal of neuro-oncology . 2008 ;89 (1 ):97 –103 . Epub 2008/04/10. 10.1007/s11060-008-9593-6 .18398569 \n14 Gulati S , Jakola AS , Nerland US , Weber C , Solheim O . The risk of getting worse: surgically acquired deficits, perioperative complications, and functional outcomes after primary resection of glioblastoma . World Neurosurg . 2011 ;76 (6 ):572 –9 . Epub 2012/01/19.22251506 \n15 Cloney M , D’Amico R , Lebovic , Nazarian M , Zacharia BE , Sisti MB , et al\nFrailty in Geriatric Glioblastoma Patients: A Predictor of Operative Morbidity and Outcome . World Neurosurg . 2016 ;89 :362 –7 . Epub 2016/01/18. 10.1016/j.wneu.2015.12.096 .26775233 \n16 McGirt MJ , Mukherjee D , Chaichana KL , Than KD , Weingart JD , Quinones-Hinojosa A . Association of surgically acquired motor and language deficits on overall survival after resection of glioblastoma multiforme . Neurosurgery . 2009 ;65 (3 ):463 –9 ; discussion 9–70. Epub 2009/08/19. 10.1227/01.NEU.0000349763.42238.E9 .19687690 \n17 Dressler EV , Liu M , Garcia CR , Dolecek TA , Pittman T , Huang B , et al\nPatterns and disparities of care in glioblastoma . Neuro-oncology practice . 2019 ;6 (1 ):37 –46 . Epub 2019/02/12. 10.1093/nop/npy014 \n30740232 \n18 Lorimer CF , Saran F , Chalmers AJ , Brock J . Glioblastoma in the elderly—How do we choose who to treat? \nJournal of geriatric oncology . 2016 ;7 (6 ):453 –6 . Epub 2016/08/02. 10.1016/j.jgo.2016.07.005 .27478132 \n19 Fekete B , Werlenius K , Orndal C , Rydenhag B . Prognostic factors for glioblastoma patients—a clinical population-based study . Acta Neurol Scand . 2016 ;133 (6 ):434 –41 . Epub 2015/09/12. 10.1111/ane.12481 .26358197 \n20 Gulati S , Jakola AS , Johannesen TB , Solheim O . Survival and treatment patterns of glioblastoma in the elderly: a population-based study . World Neurosurg . 2012 ;78 (5 ):518 –26 . Epub 2012/03/03. 10.1016/j.wneu.2011.12.008 .22381305 \n21 Ho VK , Reijneveld JC , Enting RH , Bienfait HP , Robe P , Baumert BG , et al\nChanging incidence and improved survival of gliomas . Eur J Cancer . 2014 ;50 (13 ):2309 –18 . 10.1016/j.ejca.2014.05.019 .24972545 \n22 Lorimer CF , Hanna C , Saran F , Chalmers A , Brock J . Challenges to Treating Older Glioblastoma Patients: the Influence of Clinical and Tumour Characteristics on Survival Outcomes . Clinical oncology (Royal College of Radiologists (Great Britain)) . 2017 ;29 (11 ):739 –47 . Epub 2017/08/16. 10.1016/j.clon.2017.05.010 .28807361 \n23 Fekete BWK , Carén H , Ozanne A , Rosengren L , Zetterberg H , Tisell M , et al\nThe Gothenburg population-based glioblastoma research database: Methodological aspects and potential impact . Neuro Neurosurg . 2019 , in press.\n24 Oken MM , Creech RH , Tormey DC , Horton J , Davis TE , McFadden ET , et al\nToxicity and response criteria of the Eastern Cooperative Oncology Group . American journal of clinical oncology . 1982 ;5 (6 ):649 –55 . Epub 1982/12/01. .7165009 \n25 Charlson ME , Pompei P , Ales KL , MacKenzie CR . A new method of classifying prognostic comorbidity in longitudinal studies: development and validation . Journal of chronic diseases . 1987 ;40 (5 ):373 –83 . Epub 1987/01/01. 10.1016/0021-9681(87)90171-8 .3558716 \n26 Schneeweiss S , Wang PS , Avorn J , Glynn RJ . Improved comorbidity adjustment for predicting mortality in Medicare populations . Health services research . 2003 ;38 (4 ):1103 –20 . Epub 2003/09/13. 10.1111/1475-6773.00165 \n12968819 \n27 Connon FV , Rosenthal MA , Drummond K . Glioblastoma multiforme in the very elderly . Neurosurgical review . 2016 ;39 (1 ):55 –60 ; discussion -1. Epub 2015/07/26. 10.1007/s10143-015-0652-0 .26208944 \n28 Gallego Perez-Larraya J , Ducray F , Chinot O , Catry-Thomas I , Taillandier L , Guillamo JS , et al\nTemozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: an ANOCEF phase II trial . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2011 ;29 (22 ):3050 –5 . Epub 2011/06/29. 10.1200/jco.2011.34.8086 .21709196 \n29 Roa W , Kepka L , Kumar N , Sinaika V , Matiello J , Lomidze D , et al\nInternational Atomic Energy Agency Randomized Phase III Study of Radiation Therapy in Elderly and/or Frail Patients With Newly Diagnosed Glioblastoma Multiforme . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2015 ;33 (35 ):4145 –50 . Epub 2015/09/24. 10.1200/jco.2015.62.6606 .26392096 \n30 Keime-Guibert F , Chinot O , Taillandier L , Cartalat-Carel S , Frenay M , Kantor G , et al\nRadiotherapy for glioblastoma in the elderly . N Engl J Med . 2007 ;356 (15 ):1527 –35 . Epub 2007/04/13. 10.1056/NEJMoa065901 .17429084 \n31 Malmström A , Grønberg BH , Marosi C , Stupp R , Frappaz D , Schultz H , et al\nTemozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial . The lancet oncology . 2012 ;13 (9 ):916 –26 . 10.1016/S1470-2045(12)70265-6 \n22877848 \n32 Perry JR , Laperriere N , O’Callaghan CJ , Brandes AA , Menten J , Phillips C , et al\nShort-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma . N Engl J Med . 2017 ;376 (11 ):1027 –37 . Epub 2017/03/16. 10.1056/NEJMoa1611977 .28296618 \n33 Wick W , Platten M , Meisner C , Felsberg J , Tabatabai G , Simon M , et al\nTemozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial . The Lancet Oncology . 2012 ;13 (7 ):707 –15 . Epub 2012/05/15. 10.1016/S1470-2045(12)70164-X .22578793 \n34 Yin AA , Cai S , Dong Y , Zhang LH , Liu BL , Cheng JX , et al\nA meta-analysis of temozolomide versus radiotherapy in elderly glioblastoma patients . Journal of neuro-oncology . 2014 ;116 (2 ):315 –24 . Epub 2013/11/02. 10.1007/s11060-013-1294-0 .24178440 \n35 Zarnett OJ , Sahgal A , Gosio J , Perry J , Berger MS , Chang S , et al\nTreatment of elderly patients with glioblastoma: a systematic evidence-based analysis . JAMA neurology . 2015 ;72 (5 ):589 –96 . Epub 2015/03/31. 10.1001/jamaneurol.2014.3739 .25822375 \n36 Saenz-Antonanzas A , Auzmendi-Iriarte J , Carrasco-Garcia E , Moreno-Cugnon L , Ruiz I , Villanua J , et al\nLiquid Biopsy in Glioblastoma: Opportunities, Applications and Challenges . Cancers (Basel) . 2019 ;11 (7 ). Epub 2019/07/10. 10.3390/cancers11070950 \n31284524\n\n",
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"issue": "15(2)",
"journal": "PloS one",
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"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D003581:Cytodiagnosis; D003937:Diagnosis, Differential; D005260:Female; D005909:Glioblastoma; D006801:Humans; D008297:Male; D059906:Neuroimaging; D010818:Practice Patterns, Physicians'; D011379:Prognosis; D011859:Radiography; D012189:Retrospective Studies; D015996:Survival Rate; D013548:Sweden; D016896:Treatment Outcome",
"nlm_unique_id": "101285081",
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"pmid": "32053655",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Patterns of care and clinical outcome in assumed glioblastoma without tissue diagnosis: A population-based study of 131 consecutive patients.",
"title_normalized": "patterns of care and clinical outcome in assumed glioblastoma without tissue diagnosis a population based study of 131 consecutive patients"
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"abstract": "Seven episodes of simultaneous severe systemic arterial hypotension and absolute or relative bradycardia were observed in five patients receiving either sublingual nitroglycerin (two patients) or intravenous nitroglycerin (three patients) within the first 24 hours of onset of symptoms of acute myocardial infarction. Left ventricular filling pressure, measured as pulmonary artery diastolic pressure, decreased simultaneously in all four patients in whom pulmonary artery pressures were monitored. No initial increase in heart rate was observed in any of the five patients prior to the development of bradycardia. Possible mechanisms producing simultaneous bradycardia and hypotension during nitroglycerin administration are considered. The patient studies emphasize the importance of careful hemodynamic monitoring during administration of sublingual or intravenous nitroglycerin to patients with acute myocardial infarction.",
"affiliations": null,
"authors": "Come|P C|PC|;Pitt|B|B|",
"chemical_list": "D005996:Nitroglycerin",
"country": "United States",
"delete": false,
"doi": "10.1161/01.cir.54.4.624",
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"issue": "54(4)",
"journal": "Circulation",
"keywords": null,
"medline_ta": "Circulation",
"mesh_terms": "D000368:Aged; D000787:Angina Pectoris; D001919:Bradycardia; D006801:Humans; D007022:Hypotension; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D005996:Nitroglycerin",
"nlm_unique_id": "0147763",
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"pubdate": "1976-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Nitroglycerin-induced severe hypotension and bradycardia in patients with acute myocardial infarction.",
"title_normalized": "nitroglycerin induced severe hypotension and bradycardia in patients with acute myocardial infarction"
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{
"companynumb": "US-PFIZER INC-2016468157",
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{
"abstract": "OBJECTIVE\nTolvaptan, vasopressin V2-receptor antagonist, has been used for patients with difficult-to-treat ascites in Japan. In this study, we conducted a genome-wide association study (GWAS) in the Japanese population to identify genetic variants associated with tolvaptan's efficacy for patients with hepatic ascites.\n\n\nMETHODS\nFrom 2014 through 2018, genomic DNA samples were obtained from 550 patients who were treated with tolvaptan. Of those, 80 cases (non-responder; increase of body weight [BW]) and 333 controls (responder; >1.5 kg decrease of BW) were included in the GWAS and replication study.\n\n\nRESULTS\nGenome-wide association study showed 5 candidate SNPs around the miR818, KIAA1109, and SVEP1 genes. After validation and performing a replication study, an SNP (rs2991364) located in the SVEP1 gene was found to have a significant genome-wide association (OR = 3.55, P = 2.01 × 10-8 ). Multivariate analyses showed that serum sodium (Na), blood urea nitrogen (BUN) and SVEP1 SNP were significantly associated with the response (OR = 0.92, P = .003; OR = 1.02, P = .02 and OR = 3.98, P = .000008, respectively). Based on a prediction model of logistic regression analysis in a population with the rs2991364 risk allele, the failure probability (=exp (score: 22.234 + BUN*0.077 + Na*-0.179) (1 + exp (score)) was determined for the detection of non-responders. Assuming a cutoff of failure probability at 38.6%, sensitivity was 84.4%, specificity was 70% and AUC was 0.774.\n\n\nCONCLUSIONS\nSVEP1 rs2991364 was identified as the specific SNP for the tolvaptan response. The prediction score (>38.6%) can identify tolvaptan non-responders and help to avoid a lengthy period of futile treatment.",
"affiliations": "Department of Gastroenterology, Nara Medical University, Nara, Japan.;Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.;Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan.;Division of Gastroenterology and Hepatology, Ootakanomori Hospital, Kashiwa, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan.;Department of Hepatology, Sapporo Kosei General Hospital, Hokkaido, Japan.;Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.;Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan.;Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan.;Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.;Department of Hepatology, Graduate School of Medicine, Osaka City University Osaka, Japan.;Clinical Research Center, Nagasaki Medical Center, Nagasaki, Japan.;Department of Gastroenterology, National Hospital Organization, Nagoya Medical Center, Nagoya, Japan.;Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Liver Center, Saga University, Saga, Japan.;Center for Translational Research, The Institute of Medical Science, the University of Tokyo, Tokyo, Japan.;Genome Medical Science Project (Toyama), National Center for Global Health and Medicine, Tokyo, Japan.;Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan.;Department of Gastroenterology, Nara Medical University, Nara, Japan.;Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.",
"authors": "Kawaratani|Hideto|H|https://orcid.org/0000-0002-4361-0592;Sawai|Hiromi|H|;Onishi|Masaya|M|;Kogiso|Tomomi|T|;Shimada|Noritomo|N|;Uojima|Haruki|H|https://orcid.org/0000-0003-1719-1352;Nakajima|Tomoaki|T|;Matsumoto|Naoki|N|;Ikejima|Kenichi|K|;Ishikawa|Toru|T|;Terai|Shuji|S|;Motoyama|Hiroyuki|H|;Komori|Atsumasa|A|;Hirashima|Noboru|N|;Saito|Satoru|S|;Eguchi|Yuichiro|Y|;Nojima|Masanori|M|;Kawai|Yosuke|Y|;Tateyama|Masakuni|M|;Yoshiji|Hitoshi|H|;Tanaka|Yasuhito|Y|https://orcid.org/0000-0002-2473-6966",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/liv.15022",
"fulltext": null,
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"issn_linking": "1478-3223",
"issue": null,
"journal": "Liver international : official journal of the International Association for the Study of the Liver",
"keywords": "Polydom; blood urine nitrogen (BUN); genome-wide association study (GWAS); hepatic ascites; liver cirrhosis; non-responder",
"medline_ta": "Liver Int",
"mesh_terms": null,
"nlm_unique_id": "101160857",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34309184",
"pubdate": "2021-07-26",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A genome-wide association study identifying SVEP1 variant as a predictor of response to tolvaptan for cirrhotic ascites.",
"title_normalized": "a genome wide association study identifying svep1 variant as a predictor of response to tolvaptan for cirrhotic ascites"
} | [
{
"companynumb": "JP-OTSUKA-2021_028732",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOLVAPTAN"
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"d... |
{
"abstract": "Background: We evaluated the efficacy and safety of gemcitabine in combination with erlotinib and S-1 for the treatment of advanced pancreatic cancer. Methods: Chemotherapy-naïve patients with pathologically-proven locally advanced, recurrent, or metastatic pancreatic adenocarcinoma were assessed for eligibility. Gemcitabine was administered at 1,000 mg/m2 intravenously on days 1 and 8, erlotinib was administered at 100 mg/day on days 1-21, and S-1 was administered at 60 mg/m2 on days 1-14 every 21 days and continued to a maximum of 8 cycles of treatment. Dose escalation of S-1 to 80 mg/m2 was permitted from the second cycle for pre-defined tolerable patients. Results: Thirty-seven patients (median age 61.5 years) were enrolled. A total of 140 cycles of chemotherapy were administered (median of 3.8; range 1-8 cycles). Toxicities were evaluated in 36 patients, and the responses were evaluated in 32 patients. Major grade 3/4 toxicities included neutropenia (25%), febrile neutropenia (2.8%), fatigue (22.2%), infection (8.3%), vomiting (5.6%), and mucositis (5.6%). The confirmed overall response rate was 12.5% [95% confidence interval (CI), 5.1-28.9%] and the disease control rate was 71.9% (95% CI, 56.8-86.3%). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. Conclusion: The combination of gemcitabine, erlotinib, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced pancreatic cancer.",
"affiliations": "Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeongigi-do, Korea.;Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeongigi-do, Korea.;Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeongigi-do, Korea.;Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeongigi-do, Korea.;Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea.;Department of Internal Medicine, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu, Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-do, Korea.;Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeongigi-do, Korea.;Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeongigi-do, Korea.;Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeongigi-do, Korea.;Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeongigi-do, Korea.;Department of General Surgery, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeongigi-do, Korea.;Departement of Radiology, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeongigi-do, Korea.;Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeongigi-do, Korea.",
"authors": "Han|Boram|B|;Kim|Bum Jun|BJ|;Kim|Hyeong Su|HS|;Choi|Dae Ro|DR|;Shim|Byoung Yong|BY|;Lee|Kyung Hee|KH|;Kim|Jin Won|JW|;Kim|Jung Han|JH|;Song|Hunho|H|;Kim|Jong Hyeok|JH|;Park|Choong Kee|CK|;Lee|Jung Woo|JW|;Kim|Min-Jeong|MJ|;Zang|Dae Young|DY|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.7150/jca.50514",
"fulltext": "\n==== Front\nJ Cancer\nJ Cancer\njca\nJournal of Cancer\n1837-9664\nIvyspring International Publisher Sydney\n\n10.7150/jca.50514\njcav12p0912\nResearch Paper\nA phase II study of gemcitabine, erlotinib and S-1 in patients with advanced pancreatic cancer\nHan Boram 1\nKim Bum Jun 1\nKim Hyeong Su 1\nChoi Dae Ro 1\nShim Byoung Yong 2\nLee Kyung Hee 3\nKim Jin Won 4\nKim Jung Han 1\nSong Hunho 1\nKim Jong Hyeok 1\nPark Choong Kee 1\nLee Jung Woo 5\nKim Min-Jeong 6\nZang Dae Young 1✉\n1 Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeongigi-do, Korea.\n2 Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea.\n3 Department of Internal Medicine, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu, Korea.\n4 Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-do, Korea.\n5 Department of General Surgery, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeongigi-do, Korea.\n6 Departement of Radiology, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeongigi-do, Korea.\n✉ Corresponding author: Dae Young Zang M.D., Ph.D. Division of Hematology-Oncology, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Republic of Korea. Tel: +82-31-380-3704, Fax: +82-31-380-1528, E-mail: fhdzang@hallym.or.kr.\nCompeting Interests: The authors have declared that no competing interest exists.\n\n2021\n1 1 2021\n12 3 912917\n9 7 2020\n1 11 2020\n© The author(s)\n2021\nThis is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.\nBackground: We evaluated the efficacy and safety of gemcitabine in combination with erlotinib and S-1 for the treatment of advanced pancreatic cancer.\n\nMethods: Chemotherapy-naïve patients with pathologically-proven locally advanced, recurrent, or metastatic pancreatic adenocarcinoma were assessed for eligibility. Gemcitabine was administered at 1,000 mg/m2 intravenously on days 1 and 8, erlotinib was administered at 100 mg/day on days 1-21, and S-1 was administered at 60 mg/m2 on days 1-14 every 21 days and continued to a maximum of 8 cycles of treatment. Dose escalation of S-1 to 80 mg/m2 was permitted from the second cycle for pre-defined tolerable patients.\n\nResults: Thirty-seven patients (median age 61.5 years) were enrolled. A total of 140 cycles of chemotherapy were administered (median of 3.8; range 1-8 cycles). Toxicities were evaluated in 36 patients, and the responses were evaluated in 32 patients. Major grade 3/4 toxicities included neutropenia (25%), febrile neutropenia (2.8%), fatigue (22.2%), infection (8.3%), vomiting (5.6%), and mucositis (5.6%). The confirmed overall response rate was 12.5% [95% confidence interval (CI), 5.1-28.9%] and the disease control rate was 71.9% (95% CI, 56.8-86.3%). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively.\n\nConclusion: The combination of gemcitabine, erlotinib, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced pancreatic cancer.\n\npancreatic neoplasms\ngemcitabine\nerlotinib\nS-1\nphase II study\n==== Body\nIntroduction\n\nPancreatic ductal adenocarcinoma (PDAC) is an intractable disease and is the 7th leading cause of global cancer deaths in industrialized countries 1. Because more than 80% of PDAC is locally advanced unresectable or metastatic at the time of diagnosis 2, the prognosis of PDAC patients is dismal with a 5-year relative survival rate of 11.4% 3. Although various types of targeted agents and immunotherapeutic agents are actively used in other cancers, cytotoxic chemotherapy remains the mainstream treatment for unresectable PDAC.\n\nFollowing the approval of gemcitabine by the US Food and Drug Administration in 1997 4, gemcitabine-based chemotherapy was considered the standard of care for patients with advanced PDAC for a decade. In the era of gemcitabine, various attempts were made simultaneously to find an optimal drug combination that could function synergistically with gemcitabine. A number of drugs, including cytotoxic agents 5-10 and targeted agents 11, 12, in combination with gemcitabine, were tested in large randomized clinical trials, but they failed to improve the efficacy.\n\nAmong the various drugs investigated, erlotinib, a small-molecule inhibitor of epidermal growth factor receptor, improved the efficacy of gemcitabine in a randomized phase III trial 13. In this study, erlotinib in combination with gemcitabine showed a small but statistically significant improvement in overall survival when compared to gemcitabine monotherapy (6.2 months vs. 5.9 months, p=0.038). S-1, an oral fluoropyrimidine derivative, was also studied as a combination partner of gemcitabine and has consistently shown promising results in terms of efficacy and safety in a series of phase II studies 14-18.\n\nAt the time this study was proposed and designed, gemcitabine plus erlotinib combination chemotherapy was approved as front-line chemotherapy for unresectable PDAC and was widely used globally. However, since the benefit of gemcitabine plus erlotinib in survival prolongation was too small, there has been a continuing need for new drugs or combination regimens for patients with PDAC. In this background, combination therapy with gemcitabine, erlotinib, and S-1 (GTS regimen) has been proposed as a novel front-line treatment for unresectable PDAC, and this study was conducted to demonstrate the efficacy and safety of this regimen.\n\nWith two combination regimens of FOLFIRINOX (a combination of oxaliplatin, folinic acid, irinotecan, and fluorouracil [5-FU]) 19 and albumin-bound paclitaxel/gemcitabine 20 currently accepted as front-line treatments and actively used in fit patients, the clinician's interest and possible range of application for our combination regimen will be limited. However, since GTS combination therapy has never been investigated in PDAC, it would be valuable to report and share efficacy and safety data.\n\nMethods\n\nPatient eligibility\n\nPatients were eligible for this study if they fulfilled all of the following criteria: (1) pathologically confirmed unresectable locally advanced, recurrent, or metastatic adenocarcinoma of the pancreas; (2) measurable disease, as defined using version 1.1 of the Response Evaluation Criteria In Solid Tumors (RECIST); (3) age ≥18 years; (4) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; (5) prior adjuvant chemotherapy without gemcitabine, erlotinib, or S-1 that had been completed >4 weeks before enrollment; (6) more than 4 weeks since completion of prior radiotherapy (measurable lesions are outside the radiation field); (7) adequate hematological, renal, and hepatic functions, as defined using an absolute neutrophil count of ≥1.5 × 109/L, a platelet count of ≥100 × 109/L, serum creatinine levels of ≤1.5 × upper limit of normal or creatinine clearance ≥50 mL/min, serum bilirubin ≤2× UNL, aspartate aminotransferase and alanine aminotransferase levels of ≤2.5×; and, (8) willingness to provide informed consent to participate in this study.\n\nPatients were excluded based on the following criteria: (1) a history of treatment with gemcitabine, erlotinib, or S-1 as adjuvant chemotherapy; (2) contraindication for any drug contained in the chemotherapy regimen; (3) central nervous system metastasis; (4) serious GI bleeding or obvious bowel obstruction; (5) other previous or concurrent malignancies within the last 5 years, with the exception of cured basal cell carcinoma of the skin or carcinoma in situ of the uterine cervix; (6) pregnant or lactating female patients; (7) sexually active and the partner is unwilling to practice contraception during the study; and (8) other clinically significant comorbid conditions, such as an active infection or severe cardiopulmonary dysfunction.\n\nTreatment and study design\n\nThe treatment consisted of intravenous administration of gemcitabine at 1,000 mg/m2 on days 1 and 8 every 3 weeks, continuously orally administered erlotinib at 100 mg/day, and orally administered S-1 at 30 mg/m2 twice daily on days 1-14 of each cycle. Patients with a body surface area of <1.25 m2 received 80 mg of S-1 daily, those with a body surface area of 1.25-1.5 m2 received 100 mg of S-1 daily, and those with a body surface area of ≥1.5 m2 received 120 mg of S-1 daily. Treatment was delivered as a 3-week cycle and repeated up to a maximum of 8 cycles of chemotherapy, or until disease progression, unacceptable toxicity, or the patient's refusal.\n\nThis trial was a prospective, single-arm phase II study evaluating combination chemotherapy with gemcitabine, erlotinib, and S-1 in previously untreated patients with unresectable locally advanced or metastatic pancreatic cancer. The primary endpoint was the confirmed objective response rate (ORR), and the secondary endpoints were median progression-free survival (PFS), median overall survival (OS), disease control rate (DCR), and toxicity profiles. The investigation was performed in accordance with the Declaration of Helsinki, and the protocol was approved by the institutional review boards of Hallym University Medical Center, Anyang-si, South Korea, and Asan Medical Center, Seoul, South Korea (protocol number: HMC-HO-GI-1201).\n\nDose modifications and dose intensity\n\nDose modifications were performed according to the study protocol. The next treatment cycle was initiated only when the neutrophil count was 1.5 × 109/L or greater and the platelet count was 100 × 109/L or greater. Treatment was delayed in the event of grade 3/4 nonhematologic toxicities until the toxicities were resolved to grade 1 or lower. The doses of gemcitabine and S-1 were reduced by 25% of the initial doses for related grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the second occurrence of the same grade 2 neutropenia and thrombocytopenia. The doses of gemcitabine were reduced by 50% of the initial doses for grade 4 thrombocytopenia, or for the second occurrence of the grade 3/4 neutropenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, or for the third occurrence of grade 3 neutropenia and thrombocytopenia. In the case of the second occurrence of grade 2 thrombocytopenia, grade 3/4 neutropenia, grade 3 febrile neutropenia, or the third occurrence of grade 2 neutropenia, erlotinib was omitted until recovery and then re-challenged. Treatment was discontinued if, despite the dose reduction, the same toxicity occurred for a fourth time at grade 2, a third time at grade 3, or a second time at grade 4 or any occurrence of life-threatening sepsis during treatment. In addition, if the toxicity had not improved to grade 0 or 1 after 3 weeks, the patient was withdrawn from the study. The dose reduction was maintained in subsequent cycles.\n\nTo evaluate a function of the drug and the frequency of administration, we calculated the relative dose intensity (RDI), which is expressed as the ratio of the administered amount of dose per time unit (mg/m2/week) to that of the originally planned dose.\n\nToxicity and response evaluation\n\nA physical examination with vital signs, complete blood cell counts with differentials, and blood chemistry tests were performed before every administration of gemcitabine in each subsequent cycle. Toxicity was evaluated and graded according to version 4.0 of the Common Terminology Criteria for Adverse Events of the National Cancer Institute. All of the patients who received at least one dose of treatment were included in the toxicity assessment. For the toxicity analysis, the data indicating the worst toxicity for each patient from all of the chemotherapy cycles were used. The proportion of patients who experienced adverse events was calculated by dividing the number of patients who experienced adverse events during the treatment period by the number of patients evaluable for safety analysis. Response to treatment according to RECIST version 1.1 was evaluated every 2 cycles. Patients with CR or PR required a confirmatory disease assessment at least 4 weeks later. PFS was defined as the interval from the date of treatment initiation to the first date of documented disease progression or death due to any cause. OS was defined as the interval from the date of treatment initiation to the date of death.\n\nStatistical analysis\n\nAccording to Simon's optimal two-stage design, 25 patients were required for enrollment to test the null hypothesis that the true ORR is 10% versus the alternative hypothesis that the true ORR is at least 30%, at a significance level of p<0.05 with a power of 80%. If two or more responses were observed among 15 patients in the first stage, the study was continued with 10 additional patients included. As the drop-out rate was assumed to be 10%, the number of patients necessary for recruitment into the study was calculated to be 28.\n\nDescriptive statistics were used to summarize the patients' characteristics, tumor responses, and safety events. The Kaplan-Meier method was used to estimate the median PFS and OS. All enrolled patients were included in an intent-to-treat analysis.\n\nResults\n\nPatient characteristics\n\nFrom October 2012 to May 2016, 37 patients who met the inclusion criteria were enrolled in this study. We exceeded the planned number of patients because several unexpected dropouts occurred early in the study and we allowed simultaneous registration of excess patients before the end of the study from multiple institutions. The reasons for dropout are explained below. The demographic and pathologic characteristics of the patients are described in Table 1. The median age was 61.5 years (range 35-88 years). Sixteen patients (43.2%) were male, and the majority of patients (73.0%) had an ECOG PS of 1. Twenty-six patients (70.3%) had metastatic disease, eight patients (21.6%) had recurrent pancreatic cancer after curative surgery, and three patients (8.1%) had locally advanced disease at the time of screening. The most common metastatic sites were distant lymph nodes (43.2%), the liver (43.2%), the lung (29.7%), and the peritoneum (27.0%).\n\nTreatment administration\n\nIn total, 140 treatment cycles were administered to 37 patients, with a median of 3.8 cycles (range 1-10 cycles) per patient. Five patients did not complete the first cycle of chemotherapy: two patients died (one patient died of cerebral infarction and one patient died of hepatic tumor rupture), two patients withdrew their informed consent, and one patient was lost to follow-up. Seven patients (18.9%) completed eight or more cycles of chemotherapy. Eleven patients (29.7%) required dose reductions or delays. The mean relative dose intensities (ratio of the dose received to the dose planned) of gemcitabine, S-1 for all of the cycles administered were 0.87 [95% confidence interval (CI) 0.81-0.93], and 0.92 (95% CI 0.87-0.96), respectively (Table 2).\n\nEfficacy\n\nOf the 37 patients, 32 were eligible for response evaluation. Five patients were not available for response evaluation: the detailed reasons for 5 patients who did not complete the first cycle are described in the 'Treatment administration' section. The tumor responses are summarized in Table 3. There were 4 partial responses, 19 cases of stable disease, and 9 cases of disease progression. All partial responses are confirmed in the following CT scan. The confirmed ORR was 12.5% (95% CI 5.1-28.9%) and the disease control rate was 71.9% (95% CI 56.8-86.3%). The median time to response was 1.4 months (95% CI 1.3-1.5 months) and the median duration of response was 7.4 months (95% CI 3.8-11.0 months).\n\nAt the time of analysis, 13 patients (35.1%) were still alive with a median follow-up duration of 12.9 months (95% CI 9.6-16.3 months). The median PFS was 3.7 months (95% CI 2.8-4.6 months) and the median OS was 6.7 months (95% CI 3.4-9.9 months; Figures 1 & 2).\n\nToxicities\n\nSafety was assessed in 36 patients on the basis of 139 cycles. One patient was lost to follow-up after receiving gemcitabine on day 1 of the first cycle, was excluded. One patient died suddenly of abdominal hemorrhage due to hepatic tumor rupture on day 3 of the first cycle. The adverse events are listed in Table 4. The most common grade 3/4 hematologic toxicity was neutropenia (25.0%). Febrile neutropenia developed in one patient (2.8%), who recovered without complications. Nonhematologic toxicities were usually mild and manageable. Grade 3 toxicities with a frequency of 5% or more included fatigue, infection, vomiting, and mucositis.\n\nDiscussion\n\nIn this study, the confirmed ORR of patients was 12.5%, which is slightly better than that of gemcitabine plus erlotinib 13 and is lower than the results of phase III studies of gemcitabine plus S-1 (GS) 21. The DCR was 71.9% (95% CI, 56.8-86.3%) and the median PFS and OS were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. The GTS regimen showed an acceptable toxicity profile in the safety analysis. Since, at this point, FOLFIRINOX and albumin-bound paclitaxel/gemcitabine are actively used as standard treatments; the implications of this result are thought to be limited.\n\n5-FU showed a marked synergistic cytotoxic effect with gemcitabine in pancreatic cancer cells in vitro 22 and S-1, which has an equivalent efficacy with a continuous 5-FU infusion in solid cancer, showed promising results in several phase II studies with an ORR of 28-48% 14-18. This study aimed to improve the efficacy of the existing treatment and to investigate a novel triple-combination regimen by adding S-1, which exhibits a synergistic effect with efficacy-proven gemcitabine plus erlotinib.\n\nWhile this study was in progress, the results of a phase III study (GEST study) comparing GS with gemcitabine alone were published 21. In this trial, despite the improvement in PFS and ORR, GS showed numerically longer OS compared to gemcitabine alone, but it was not statistically significant (10.1 months vs. 8.8 months, p=0.15). In the subgroup analysis of GEST study, GS was associated with significantly improved OS in locally advanced disease compared to metastatic disease. Furthermore, a pooled analysis of subsequent randomized studies comparing GS to gemcitabine alone also re-confirmed that GS showed better OS in locally advanced disease than metastatic disease (16.4 months vs. 11.8 months, HR 0.708, p=0.02) and supported the result of the subgroup analysis from the GEST study. Since most of the participants in this study had recurrent or metastatic disease rather than locally advanced disease, it is assumed that the differences in characteristics of the study population may lead to unsatisfactory results. In our study, the best response of all three patients with locally advanced disease was stable disease but it is difficult to determine statistical significance because the number of patients was too small.\n\nRecently, it was recommended that patients with locally advanced disease should be studied separately from those with metastatic disease because locally advanced and metastatic disease are considered to be two different clinical entities, each with distinctive clinical characteristics 23. Therefore, a study design with an appropriately selected population will be required to further clarify the efficacy of the GTS regimen.\n\nIn this study, the median age of the patients was >60 years, and 75% of the patients were symptomatic at the beginning of the study. More than half of the patients had two or more metastatic sites, and 45% and 13% of patients presented with liver metastasis and peritoneal metastasis, respectively. The patients' demographics in our study are relatively inferior to the conditions of other studies, and these differences may have influenced the outcome.\n\nRegarding the safety analysis, GTS showed a modest toxicity profile. Except for neutropenia (25%) and fatigue (22%), the incidence of all other G3 or 4 toxicity profiles did not exceed 10%, which was similar or relatively lower than that of gemcitabine plus erlotinib 13 and GS 21.\n\nConclusion\n\nIn conclusion, GTS did not show the expected efficacy outcome with a confirmed ORR of 12.5%. However, considering the meaningful effect that GS showed in locally advanced disease in a subsequent study and the modest safety profile that our study showed, there may be room to further investigate the GTS regimen depending on the profile of the patient.\n\nS-1 is sponsored by Jeil Pharmaceutical Co.,Ltd, Seoul, Korea.\n\nFunding\n\nThis research was supported by the Hallym University Research Fund (Protocol No. HMC-HO-GI-1201).\n\nFigure 1 Progression-free survival.\n\nFigure 2 Overall survival.\n\nTable 1 Patient characteristics (n=37)\n\nCharacteristics\tNo. of patients (%)\t\nAge, median (range)\t61.5 (35-88)\t\nGender\t\t\nMale\t16 (43.2%)\t\nFemale\t21 (56.8%)\t\nPerformance status (ECOG)\t\t\n0\t10 (27.0%)\t\n1\t27 (73.0%)\t\nLocation of primary tumor site\t\t\nHead\t9 (24.3%)\t\nBody\t7 (18.9%)\t\nTail\t9 (24.3%)\t\nDiffuse\t4 (10.8%)\t\nUnknown\t8 (21.6%)\t\nHistology\t\t\nWell differentiated\t5 (13.5%)\t\nModerately differentiated\t9 (24.3%)\t\nPoorly differentiated\t4 (10.8%)\t\nUndifferentiated\t1 (2.7%)\t\nUnknown\t18 (48.6%)\t\nDisease status at the time of screening\t\t\nLocally advanced\t3 (8.1%)\t\nMetastatic\t26 (70.3%)\t\nRecurrence after curative surgery\t8 (21.6%)\t\nMetastatic sites\t\t\nLymph node\t16 (43.2%)\t\nLiver\t16 (43.2%)\t\nLung\t11 (29.7%)\t\nPeritoneum\t10 (27.0%)\t\nOthers\t8 (21.6%)\t\nNo. of metastatic sites\t\t\n1\t14 (41.2%)\t\n2\t11 (32.4%)\t\n≥3\t9 (26.5%)\t\nECOG: Eastern Cooperative Oncology Group.\n\nTable 2 Duration of drug administration and dose intensity\n\nCriteria\t\t\nNo. of cycles\t140\t\nMedian cycles\t3.8 (1-8)\t\nNo. of patients with dose reduction\t11\t\nRelative dose intensity for gemcitabine, Mean (range)\t0.87 (0.81-0.93)\t\nRelative dose intensity for S-1, Mean (range)\t0.92 (0.87-0.96)\t\n\nTable 3 Treatment efficacy result\n\nResponse\tNo. of patients\t\nComplete response\t0\t\nPartial response\t4\t\nStable disease\t19\t\nProgressive disease\t9\t\nOverall response rate (Confirmed)\t12.5% (95% CI, 5.1-28.9%)\t\nDisease control rate\t71.9% (95% CI, 56.8-86.3%)\t\n\nTable 4 Incidence of grade 3/4 adverse events\n\nGrade 3/4 adverse events\tNumber of patients (%) (Total N=36)\t\nHematologic\t\t\nNeutropenia\t9 (25%)\t\nFebrile neutropenia\t1 (2.8%)\t\nThrombocytopenia\t1 (2.8%)\t\nNon-hematologic\t\t\nFatigue\t8 (22.2%)\t\nInfection\t3 (8.3%)\t\nVomiting\t2 (5.6%)\t\nMucositis\t2 (5.6%)\t\nNausea\t1 (2.8%)\t\nDiarrhea\t1 (2.8%)\t\nHepatopathy\t1 (2.8%)\t\nOthers\t4 (11.1%)\n==== Refs\n1 Bray F Ferlay J Soerjomataram I Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA: A Cancer Journal for Clinicians 2018 68 394 424 30207593\n2 Jemal A Bray F Center MM Global cancer statistics CA: A Cancer Journal for Clinicians 2011 61 69 90 21296855\n3 Jung K-W Won Y-J Kong H-J Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2016 Cancer Res Treat 2019 51 417 30 30913865\n4 Burris HA Moore MJ Andersen J Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial J Clin Oncol 1997 15 2403 13 9196156\n5 Berlin JD Catalano P Thomas JP Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297 J Clin Oncol 2020 20 3270 5\n6 Cunningham D Chau I Stocken DD Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer J Clin Oncol 2009 27 5513 8 19858379\n7 Heinemann V Quietzsch D Gieseler F Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer J Clin Oncol 2006 24 3946 52 16921047\n8 Louvet C Labianca R Hammel P Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial J Clin Oncol 2005 23 3509 16 15908661\n9 Oettle H Richards D Ramanathan RK A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer Ann Oncol 2005 16 1639 45 16087696\n10 Rocha Lima CM Green MR Rotche R Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate J Clin Oncol 2004 22 3776 83 15365074\n11 Philip PA Benedetti J Corless CL Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205 J Clin Oncol 2010 28 3605 10 20606093\n12 Kindler HL Niedzwiecki D Hollis D Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303) J Clin Oncol 2010 28 3617 22 20606091\n13 Moore MJ Goldstein D Hamm J Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group J Clin Oncol 2007 25 1960 6 17452677\n14 Nakamura K Yamaguchi T Ishihara T Phase II trial of oral S-1 combined with gemcitabine in metastatic pancreatic cancer Br J Cancer 2006 94 1575 9 16721372\n15 Lee G-W Kim HJ Ju J-H Phase II trial of S-1 in combination with gemcitabine for chemo-naïve patients with locally advanced or metastatic pancreatic cancer Cancer Chemother Pharmacol 2009 64 707 13 19151975\n16 Oh D-Y Cha Y Choi I-S A multicenter phase II study of gemcitabine and S-1 combination chemotherapy in patients with unresectable pancreatic cancer Cancer Chemother Pharmacol 2010 65 527 36 19578850\n17 Ozaka M Matsumura Y Ishii H Randomized phase II study of gemcitabine and S-1 combination versus gemcitabine alone in the treatment of unresectable advanced pancreatic cancer (Japan Clinical Cancer Research Organization PC-01 study) Cancer Chemother Pharmacol 2012 69 1197 204 22249272\n18 Song H Han B Park CK Phase II trial of gemcitabine and S-1 for patients with advanced pancreatic cancer Cancer Chemother Pharmacol 2013 72 845 52 23978987\n19 Conroy T Desseigne F Ychou M FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer New England Journal of Medicine 2011 364 1817 25\n20 Von Hoff DD Ervin T Arena FP Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine New England Journal of Medicine 2013 369 1691 703\n21 Ueno H Ioka T Ikeda M Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study J Clin Oncol 2013 31 1640 8 23547081\n22 Halloran CM Ghaneh P Shore S 5-Fluorouracil or gemcitabine combined with adenoviral-mediated reintroduction of p16INK4A greatly enhanced cytotoxicity in Panc-1 pancreatic adenocarcinoma cells J Gene Med 2004 6 514 25 15133762\n23 Philip PA Mooney M Jaffe D Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment J Clin Oncol 2009 27 5660 9 19858397\n\n",
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"issue": "12(3)",
"journal": "Journal of Cancer",
"keywords": "S-1; erlotinib; gemcitabine; pancreatic neoplasms; phase II study",
"medline_ta": "J Cancer",
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"title": "A phase II study of gemcitabine, erlotinib and S-1 in patients with advanced pancreatic cancer.",
"title_normalized": "a phase ii study of gemcitabine erlotinib and s 1 in patients with advanced pancreatic cancer"
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"abstract": "BACKGROUND\nNausea during pregnancy affects 80% of pregnant women and can severely affect women's functioning and quality of life. Women often have difficulty deciding whether to take anti-nausea medications due to concern about medication risks. This paper foregrounds U.S. women's voices as they share their experiences making decisions about anti-nausea medication use.\n\n\nMETHODS\nAs a pilot study, we conducted two focus groups including 20 women who had filled at least one prescription for an anti-nausea medication during pregnancy. Topics included deciding about and taking anti-nausea medications. Transcripts were analyzed by two medical anthropologists using an inductive or open coding approach.\n\n\nRESULTS\nWomen in our pilot study carefully considered whether to take anti-nausea medications. Most women preferred not to take medications, in general, but were willing to do so for severe symptoms. When considering medications, they expressed concerns about risks to fetal health. They considered information from internet research, their health care provider, and the experiences of friends and family. While some women in our study decided against taking medications, many did take a prescription medication, and they reported substantial improvement in their symptoms and sense of well-being.\n\n\nCONCLUSIONS\nWomen weighed various sources of evidence to assess the risks and benefits of taking anti-nausea medication and ultimately made a range of choices. More research is needed about the effectiveness and risks of anti-nausea medication, to help support women in their decision-making process, and also about the best methods to communicate scientific evidence to women.",
"affiliations": "Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA. Marlaine.S.Figueroagray@kp.org.;Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.;Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.;Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.",
"authors": "Figueroa Gray|Marlaine|M|http://orcid.org/0000-0003-1425-3968;Hsu|Clarissa|C|;Kiel|Linda|L|;Dublin|Sascha|S|",
"chemical_list": "D000932:Antiemetics; D017294:Ondansetron",
"country": "England",
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"doi": "10.1186/s12884-018-2093-6",
"fulltext": "\n==== Front\nBMC Pregnancy ChildbirthBMC Pregnancy ChildbirthBMC Pregnancy and Childbirth1471-2393BioMed Central London 209310.1186/s12884-018-2093-6Research ArticleGetting through the day: a pilot qualitative study of U.S. women’s experiences making decisions about anti-nausea medication during pregnancy http://orcid.org/0000-0003-1425-3968Figueroa Gray Marlaine 206-287-2620Marlaine.S.Figueroagray@kp.org 1Hsu Clarissa Clarissa.W.Hsu@kp.org 1Kiel Linda Linda.M.Kiel@kp.org 1Dublin Sascha Sascha.Dublin@kp.org 121 0000 0004 0615 7519grid.488833.cKaiser Permanente Washington Health Research Institute, Seattle, WA USA 2 0000000122986657grid.34477.33University of Washington Epidemiology Department, Seattle, WA USA 4 12 2018 4 12 2018 2018 18 47526 1 2018 16 11 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nNausea during pregnancy affects 80% of pregnant women and can severely affect women’s functioning and quality of life. Women often have difficulty deciding whether to take anti-nausea medications due to concern about medication risks. This paper foregrounds U.S. women’s voices as they share their experiences making decisions about anti-nausea medication use.\n\nMethods\nAs a pilot study, we conducted two focus groups including 20 women who had filled at least one prescription for an anti-nausea medication during pregnancy. Topics included deciding about and taking anti-nausea medications. Transcripts were analyzed by two medical anthropologists using an inductive or open coding approach.\n\nResults\nWomen in our pilot study carefully considered whether to take anti-nausea medications. Most women preferred not to take medications, in general, but were willing to do so for severe symptoms. When considering medications, they expressed concerns about risks to fetal health. They considered information from internet research, their health care provider, and the experiences of friends and family. While some women in our study decided against taking medications, many did take a prescription medication, and they reported substantial improvement in their symptoms and sense of well-being.\n\nConclusions\nWomen weighed various sources of evidence to assess the risks and benefits of taking anti-nausea medication and ultimately made a range of choices. More research is needed about the effectiveness and risks of anti-nausea medication, to help support women in their decision-making process, and also about the best methods to communicate scientific evidence to women.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12884-018-2093-6) contains supplementary material, which is available to authorized users.\n\nKeywords\nPregnancyNauseaVomitingMedicationAnti-emeticOndansetronQualitativeFocus groupDecision makingKaiser Permanente Washington Health Research Instituteissue-copyright-statement© The Author(s) 2018\n==== Body\nIntroduction\nAbout 80% of pregnant women experience nausea and/or vomiting during pregnancy—over 3 million women each year in the US [1, 2]. These symptoms can profoundly affect women’s lives. Consequences can include decreased ability to function at work and at home; depression; concern for the health of the baby; emergency department visits and hospitalizations; and significant economic burden [3–8]. Many women consider taking a medication for their symptoms. Yet this decision can be difficult because there is little evidence about the safety or effectiveness of most medications that are currently used to treat nausea and vomiting in pregnancy [9], as was concluded by a recent Cochrane review. Only one medication, Diclegis (doxylamine/pyridoxine) is currently approved by the US Food and Drug Administration (FDA) to treat nausea and vomiting during pregnancy; it is very expensive and often not covered by insurance. The most commonly used medication in the US, ondansetron, is not FDA-approved, but is currently used by about one in four pregnant women. Its safety remains controversial. Few relevant randomized clinical trials have been conducted, and most were very small and had very short follow up [9]. Thus, most of the evidence about these medications’ safety currently comes from retrospective epidemiologic studies. Two epidemiologic studies have suggested that ondansetron may increase the risk of birth defects [10, 11]; one found a higher risk of cleft lip/palate [10] while the other found higher risk of heart defects [11]. A third study found no association overall [12] but lacked power to examine individual birth defects. The findings of these studies have been questioned [13], and the role of ondansetron in treatment remains somewhat controversial [13–15]. Overall, because of inadequate evidence about medication safety in pregnancy [9], women with nausea and vomiting face a dilemma when making decisions about treatment. Little is known about women’s perspectives and decision-making process when confronting this difficult decision.\n\nSeveral studies have examined women’s experiences with nausea and vomiting in pregnancy, more broadly [16–20]. One study conducted focus groups with women and clinicians in Norway and found that women felt their experiences of nausea and vomiting were not taken seriously [17]. Pregnant women and clinicians were reluctant to consider medication use because of concerns about harm to the baby. In Norway, women and clinicians relied heavily on the option of graded sick leave (part-time work), which is less available in the US. A study in Canada interviewed women calling a telephone counseling line to learn about treatment options for nausea and vomiting in pregnancy; the authors found that despite detailed counseling about Diclegis (doxylamine and pyridoxine), a medication widely regarded as safe in pregnancy, many women remained fearful and continued to believe it caused birth defects [16]. This study took a quantitative approach, reporting survey results but not foregrounding women’s voices or providing details of their experience. Finally, Locock et al. conducted qualitative interviews with 73 women from the UK [18]. While this paper provides a rich and detailed view of women’s experiences with nausea and vomiting more broadly, little information was provided about women’s opinions and choices regarding medication use. No study has examined the perspectives of women in the US. The only study about women’s perspectives came from Norway [17], where attitudes and practices may be very different from the US because of greater access to paid sick leave and part-time work. This paper will examine the perspectives of U.S. women who chose to fill an anti-nausea medication prescription to understand how they made decisions about whether to take anti-nausea medication during pregnancy, including their attitudes regarding medication use, how they weighed risks, what evidence they considered, and their experiences using anti-nausea medication.\n\nMethods\nOverview\nThis pilot study was set within Kaiser Permanente Washington (KPWA), an integrated healthcare system in the northwestern United States with about 710,000 members and about 6000 births per year. Our study team conducted two focus groups with a total of twenty women who had filled at least one prescription for an anti-nausea medication during pregnancy. Our reporting of participant sampling, data collection, and data analysis follows the consolidated criteria for reporting qualitative research (COREQ) guidelines [21].\n\nSampling/recruitment\nWe used purposive sampling that focused on recruiting women living in the Seattle/Tacoma metropolitan area who were 18 years and older, who delivered a liveborn infant in 2015 or 2016, and who had filled at least one prescription for an anti-nausea medication during pregnancy (Table 1). Filling at least one prescription indicated to us that women experienced enough of a burden from nausea that they communicated with their provider about their symptoms and were likely to have actively considered the pros and cons of taking anti-nausea medication. Purposive sampling involves identifying individuals that have knowledge or experience with a phenomenon of interest and are willing to participate in research [22]. We excluded women with other serious health conditions during pregnancy (pregestational diabetes, cardiac disease, renal disease, liver disease, autoimmune disease, HIV, or a major psychiatric disorder) or adverse pregnancy outcomes such as stillbirth or major birth defects. KPWA electronic health records were used to identify women meeting these inclusion and exclusion criteria.Table 1 Participant Characteristics\n\nCharacteristic\tNumber (N = 20)\tPercent\t\nAge\t18–24\t2\t10%\t\n25–29\t5\t25%\t\n30–34\t5\t25%\t\n35–39\t7\t35%\t\n40–44\t1\t5%\t\nMedication used for nausea during pregnancy\tAny use of anti-nausea medication\t18\t90%\t\nAny use of Ondansetron\t12\t60%\t\nAny use of medication other than Ondansetron\t4\t20%\t\nDon’t Know/Can’t Remember which medication was taken\t2\t10%\t\nNo medication used\t2\t10%\t\nEmployment\tFull-time\t14\t70%\t\nPart-time\t1\t5%\t\nIn school/vocational training\t2\t10%\t\nHomemaker\t3\t15%\t\nMain Provider of Pregnancy Care\tObstetrician\t11\t55%\t\nFamily Practitioner\t3\t15%\t\nMidwife\t6\t30%\t\nMarital Status\tMarried/living with partner\t18\t90%\t\nNot married/not living with partner\t2\t10%\t\nEducation\tSome HSa, not a graduate\t1\t5%\t\nHSa graduate or GEDb\t1\t5%\t\nSome college/2 year degree\t4\t20%\t\nFour-year degree\t6\t30%\t\nMore than four year degree\t8\t40%\t\nRace\tWhite/Caucasian\t13\t65%\t\nBlack/African American\t1\t5%\t\nAsian\t3\t15%\t\nNative Hawaii/Pacific Islander\t1\t5%\t\nMore than one race\t2\t10%\t\nEthnicity\tHispanic or Latina\t0\t0%\t\nNot Hispanic or Latina\t20\t100%\t\nHome Ownership\tOwn\t12\t60%\t\nRent\t7\t35%\t\nLiving with friends/extended family\t1\t5%\t\nNumber of births\t1\t8\t40%\t\n2\t10\t50%\t\n3\t1\t5%\t\nMissing\t1\t5%\t\nahigh school\n\nbGeneral Educational Development (a series of tests available in the US that provide certification that the test taker has high school level academic skills)\n\n\n\nWe then mailed a recruitment letter to a random sample of 700 women from the eligible population. Women could call in to volunteer for focus groups. Within a week of sending the recruitment letters we began reaching out to potential participants by phone to invite them to participate and continued these calls until focus groups had been filled. In all, 20 women attended the focus groups.\n\nData collection\nThe focus group guide (themes represented by Table 2, and full guide available by supplemental attachment) was developed through an iterative process. We approached the design of the interview guide using a phenomenological perspective, which focuses on developing rich descriptions of lived experiences, in this case women’s experiences making decisions about medication use during pregnancy. The principal investigator (SD), an internist and pharmacoepidemiologist, drafted questions to elicit how women make decisions about medication use during pregnancy, and two team members who have doctorates in medical anthropology (MFG and CH) developed the guide with input from the entire team. Because this was a small pilot study, the guide was not pilot tested before use with our participants. The full.Table 2 Focus Group Questions/Themes – see Additional file 1 for complete focus group guide\n\nQuestion Type\tExamples\t\nBuilding Rapport\tWhat you would like us to call you?\nHow many children do you have?\t\nQuestions about women’s experience with nausea or vomiting in pregnancy.\tWe would like to go around and have you briefly describe how nausea during pregnancy affected your life.\t\nQuestions about women’s experience making decisions about how to treat nausea and vomiting in pregnancy.\tDid your doctor or midwife suggest any treatments? Did he or she offer to prescribe medications to treat your nausea/vomiting? (Vit B6, Unisom) What was the most important thing that you considered when deciding whether to take a medicine for nausea and/or vomiting in pregnancy?\t\nQuestions about women’s experiences with medications to treat nausea and vomiting in pregnancy\tNow let’s talk about your experience with medications. For those of you who took medication for nausea, can you describe your experience with medications? [Note –ask probing questions for each medication].For this kind of medication, what does effectiveness look like to you? For example, how would you know if an anti-nausea medication was working?\t\n\n\nA team member with advanced qualitative expertise (MFG) led the focus groups. Another team member with advanced qualitative expertise (CH) assisted with consenting, logistics, and scribing. A court reporter transcribed each 90-min discussion, and each discussion was also audio-recorded. Participants met each other and the facilitators for the first time when they arrived at the conference room in a KPWA clinic. Participants were given table tents and assigned a number which was used by the court reporter during transcription. Participants were asked a semi-structured series of questions (Table 2), and the facilitator asked probing questions to draw out topics of interest and clarify respondents’ comments. Participants responded to questions round-robin style in the beginning, but by the second question organic conversation developed. Transcripts were checked against the recording.\n\nData analysis\nWe used an inductive analysis approach [23], including an iterative code development process. The primary coder (MFG) drafted an initial “first cycle” code list [24]. Two team members (MFG, CH) then coded and compared one transcript. Codes were revised and code definitions and domains were clarified. The primary coder then reviewed and revised the coding for both transcripts using the final version of codes and domains [24]. In this small pilot study, data saturation was not a goal and was not discussed during analysis.\n\nNext, the full research team discussed key themes that provided insight into women’s experience deciding whether to take anti-nausea medication during pregnancy. Data were then extracted by code for all relevant codes and the first author reviewed these data again for subthemes and nuanced insights. The first author drafted a memo containing coded themes which was discussed with other team members and used to structure the findings presented in this article.\n\nResults\nFocus groups included twenty women (10 per group). Table 2 summarizes participant characteristics. Generally, they had high socioeconomic status (SES) as indicated by their educational status and the high rate of home ownership. Similar themes arose in each group.\n\nWomen’s general attitudes toward medication use during pregnancy\nWomen reported being very careful about what they consumed during pregnancy. Women described wanting to ingest only “natural” substances while pregnant and were concerned about the risks of pharmacological treatments to fetal health. They described the choice to take medication as one in which they weighed their comfort against their baby’s well-being, and the choices they made about medication use predominantly reflected what they understood as promoting the baby’s well-being. In general, women in our focus groups voiced a preference for not taking prescription medication during pregnancy, when possible.\n\nFocus Group 1, Participant 1: With my first kid, I was so natural and everything was smooth. So I wanted to do everything I did with the first kid, so the second would come out the same…[For my severe nausea] I asked my doctor what I could do, and she prescribed me some pills. I had them in my hand but the idea that it was a prescription just freaked me out and I didn’t want to put any foreign objects in my body. I don’t know what it’s going to do to the baby. [The nausea] was really bad, but I was scared for the baby. I was just going back and forth: pills, baby. [Participant makes hand motion to demonstrate weighing two options].\n\nFocus Group 1, Participant 2: Just like a lot of you, I don’t like to be on medication either. Actually, this was the first time I’ve ever actually taken medication being pregnant.\n\nPathways to prescription\nWhile participants were selected into our focus group because they had all filled a prescription for anti-nausea medication, their pathways to getting a prescription varied. Women who participated in our study described experiencing nausea during their first trimester, during which time prenatal visits with providers occur less frequently than later in pregnancy. We learned that decision-making about taking anti-nausea medication began before being given a prescription as women made choices about scheduling early appointments to discuss nausea or ask for help in dealing with nausea. Several women visited a provider in the first trimester for nausea and vomiting and were offered a prescription. Some women requested a prescription as a result of the severity of their symptoms and/or recommendations from friends and family members. Providers often initially recommended non-prescription treatment options such as over the counter vitamin B12 (pyridoxine) with or without doxylamine and then provided a prescription for a medication if the initial treatment approach did not provide relief (in keeping with current clinical guidelines) [15]. The prescription medication women most often talked about using was ondansetron (brand name Zofran).\n\nFocus Group 2, Participant 8: I asked my doctor [for the medication]. Back then, I was just worried all the time how my baby was going to survive, because I lost 15 pounds in a month.\n\nFocus Group 2, Participant 6: I didn’t even know to ask for the medicine until my friend who’s a doctor and his wife had had twins. He suggested it.\n\nSome of the participants did not discuss their nausea and vomiting with their providers because they thought their experience was a normal part of pregnancy. These women often did not get prescribed medication until later in their first trimester or when they ended up in the emergency department with dehydration.\n\nFocus Group 2, Participant 10: I never mentioned my nausea to my provider originally because I assumed this is what everybody goes through. I ended up getting it prescribed at Urgent Care because it got to that point.\n\nWeighing risks of medication\nRegardless of how they received their prescription, nearly all of the women gave serious consideration to the possible risks of taking medication. Women were primarily concerned about negative birth outcomes or long-term effects on their child’s health.\n\nFocus Group 2, Participant 10: I did fill it and I took it the one time and I got anxious about the side effects. I’m always concerned about taking medicine when pregnant, so I did look it up and I heard about the heart [defects] but also cleft lip. I was [worried about] risks that would affect him long-term. I was very anxious about anything affecting my baby. So I just kind of figured I’d get over [the nausea].\n\nSome women felt that their intense nausea interfered with their ability to function socially and professionally, and that this stress took a toll on their health and their baby’s health. For these women, nausea was disruptive and demoralizing. They described having to stop doing the things that they enjoyed as well as the things they needed to do such as care for their children. They thought that the benefit provided by the medication was worth the risk.\n\nFocus Group 1, Participant 7: I felt tired all the time, and I couldn’t focus at work. And it’s not good for my health and not good for my baby and just weighing the risk and the benefit for taking the nausea pill, I just think maybe it’s better, yeah, to take the medication.\n\nFocus group 1, Participant 6: You have to stand up all day, and you’re lifting [heavy items]. And I couldn’t take time to be sick. So I took the Ondansetron, which is what the doctor gave me and I just lived on it for, like, three months.\n\nFocus Group 2, Participant 9: The lowest point was I was at work, so nauseous, and then I had to ask the office manager, “Do you have an empty room so I can sleep?” I laid on the floor with my jacket. It was so sad. It was really sad.\n\nFocus group 2, Participant 7: Some days I had to miss school because I couldn’t get out of bed. I wasn’t eating. So I had to get on the pills to eat at school. Sometimes I had to go home from school because I couldn’t stomach watching everyone eat.\n\nFocus Group 2, Participant 3: I was taking public transportation and I had to stop because every time I would be on the bus I would throw up.\n\nOther women described not knowing when nausea and vomiting would occur and how this uncertainty limited their ability to move through their days. Treatment allowed them to regain their confidence and enjoy the experience of being pregnant.\n\nFocus Group 1, Participant 6: To me, there was so much stress and misery with not knowing what -- if you were going to be able to go to work or do I have to call out or can I go to the grocery store? I just wanted my pregnancy to have a -- to be jovial. I just wanted, like, an overall good juju with the pregnancy, so I just wanted there to be a happy spirit the whole time. So that to me was really important.\n\nWhat evidence matters to women\nWe sought to understand how women weighed and interpreted different kinds of evidence. Women got their information from a variety of sources. Many sought information by reviewing the published literature or consulting websites. Others were reassured by their doctors, by the length of time the drug has been on the market or by the experiences of their friends and family.\n\nFocus Group 1, Participant 7: I just looked up Wikipedia, and it said it was safe. I think it’s Class A or B, so it’s relatively safe. So I just decided to try it.\n\nFocus Group 2, Participant 4: For Zofran [ondansetron], there’s few studies, a handful, about heart defects in the baby, but I think that the percentage was from 0.8% or it could have happened anyway from 0.2%, so it wasn’t that much of a difference.\n\nTwo women were concerned about the lack of research on human fetuses or involving women like them (for instance, of the same racial or ethnic background).\n\nFocus Group 1, Participant 7: Whatever research they do they only do it on animals, not, like, real human babies. So just in the back of my mind I would always worry,\n\nFocus Group 1, Participant 1: There wasn’t, for me, I guess, enough research that said what it would do to my body. Are they testing on women that look like me, that are my size, my shape, my ethnicity? Is it really going to help me? And that’s what -- I’m just like -- I just can’t.\n\nOther women found their doctor’s reassurances to be sufficient evidence of safety.\n\nFocus Group 1, Participant 6: The doctor went to school for that. That’s their job. So if they say it’s okay, it’s okay. So I didn’t feel like if they were giving me it that there would be any huge risks associated.\n\nSome women considered the length of time the medication had been in use by pregnant women to be evidence of safety.\n\nFocus Group 1, Participant 4: Knowing that it had a long history of pregnant women taking it helped assure me that this is probably okay. If you’ve been having something prescribed for a couple decades [any risks] probably would have come out by then.\n\nOther women were influenced by the experiences of family, friends and acquaintances.\n\nFocus Group 1, Participant 11: I called my sister because she was the one who told me about it. She’s like, “I’ve used it for all of my pregnancies. They’re probably just trying to make some correlation, and there’s no [correlation].” -- So I was like, “Okay. That was reassuring enough for me.”\n\nOn the other hand, one woman whose friend had a baby with a birth defect decided not to take the medication.\n\nFocus Group 2, Participant 1: I didn’t end up taking the Zofran. One of my close girlfriends had a son [with] a clubfoot and a cleft lip because of it because she had to take so much of [the medication]. And the doctors told her it was because of that, so I was in a lot of fear of taking that.\n\nMedication experience\nThough two women in our groups decided not to take the medication after filling the prescription, a majority (18/20 or 90%) took their prescribed anti-nausea medication at least once. Many women reported that the benefits of the medication were significant, allowing them to regain their appetite and function throughout their day.\n\nFocus Group 1, Participant 2: My prescription was a saving grace. Once I actually took it and I was able to desire foods again, I was like, “Oh, I’m sold”. And I could literally get through the day.\n\nFocus Group 1, Participant 4: I was like, “This is my little miracle thing. It makes it go away, and I feel like I can function way better.”\n\nSome women considered the risks and either stopped taking the prescribed medication or never took it at all. They thought they could tolerate the physical discomfort, or they were concerned about negative effects on their child.\n\nFocus Group 2, Participant 10: I stopped taking it because it made me more scared for any possible risk or whatever, so I couldn’t do it. So I just lived in the pain because I couldn’t get over that.\n\nFinally, some women reported that their medication worked well, but they had to stop because of side effects such as severe constipation or hives.\n\nDiscussion\nThis study is the only qualitative study that specifically focuses on pregnant women’s experiences related to taking anti-nausea medication, something millions of women around the world do each year [2]. We explored how women made the decision to take anti-nausea medications and what evidence they considered when making that decision. As was previously reported [25], we found that nausea and vomiting during pregnancy can profoundly disrupt familial, social and professional roles and impact the happiness some women expect to be associated with pregnancy. These social and professional impacts were often as or more important to women in our study than the physical impacts of nausea and vomiting, and they played a significant role in women’s decisions. Women described how symptom relief from medications allowed them to take care of their children, commute to work, attend school, and perform their professional duties. Many women in our study who in general preferred to avoid medication use during pregnancy turned to pharmacological relief in this situation.\n\nIn other studies on this topic, some women described feeling that providers continued to disbelieve the severity of women’s symptoms and did not offer adequate early care to women [17, 20]. While our study did not reveal examples of providers not offering adequate care, we did find that KPWA clinicians were cautious about prescribing medication and typically began with vitamin supplements before offering prescriptions, which is consistent with clinical guidelines from national professional societies [15]. We noted two factors – this caution around prescribing and also the practice of not scheduling routine prenatal visits until fairly late in the first trimester—influenced whether women were prescribed medication to relieve their symptoms at the time when symptoms were most severe. This manuscript brings attention to a symptom that can negatively impact women’s quality of life, ability to function, ability to maintain social and professional roles, and their sense of self. Focusing attentive concern on a symptom which is often dismissed as a normal part of pregnancy can help providers give more patient-centered care to their pregnant patients.\n\nOur findings regarding the personal, professional and psychosocial impact of nausea and vomiting on women’s lives are consistent with previous work describing women’s experiences. Locock et al. [18] found that nausea and vomiting in pregnancy can be so severe that women experience a loss of self and “biographical disruption”, a loss of confidence in the body that leads to a loss of confidence in one’s self-identity [18, 25]. Because this disruption can be severe, women do want to find a way to maintain their sense of self-identity and often seek medication to help them manage their symptoms and return to feeling authentic and able to perform their social and professional roles. Our participants reported that symptom relief also allowed them to enjoy their pregnancy.\n\nOther researchers have found that pregnant women face the burden of weighing various types of evidence to assess risk to personal and fetal health [26]. When women in our study considered medication use, they drew on different kinds of evidence to weigh risks and benefits. As in our study, Baggley’s survey of 59 Canadian women found that women received medication information from a variety of sources, with a large majority receiving it from family and friends [16]. Baggley also noted that many women who had received evidence-based counseling about medication safety often did not feel convinced or reassured [16]. In our study, women found that personal experiences of friends and family were very powerful assurances. Understanding what kinds of information women consider as evidence of medication safety may be helpful to clinicians as they seek to convey information to women.\n\nStrengths and limitations\nThis study has several strengths. By recruiting women who had filled a prescription for medication and asking them specifically about medication use and decision-making, our study provides a unique perspective on how women make decisions about medication use for nausea and vomiting in pregnancy, what evidence they consider, and what benefits matter to them. We recruited women from an integrated health system which represents community-based practice, so they likely are more representative of the general population compared to patients from academic practice or a tertiary care setting. As far as we know, this is the only paper, either quantitative or qualitative, that has studied the experience of women taking anti-nausea medication during pregnancy.\n\nThis study also has limitations. By its nature, qualitative work is not expected to be generalizable to larger populations. We talked with a relatively small number of women who were predominantly white, married, and well educated. They might have had better access to resources to help them manage their nausea, as well as more flexibility in their work and care giving duties. Women with fewer resources might experience an even greater burden in managing the effects of their symptoms. There may be geographic variation in perspectives and experiences that we were not able to examine. Because this was a pilot study, we did not continue holding focus groups until we achieved data saturation, though emergent themes were consistent across the two groups. However, the consistency between our findings and previous work suggests that some of the themes we identified may prove applicable beyond this specific population.\n\nConclusion\nThis study provides much-needed information regarding women’s experiences with anti-nausea medication during pregnancy. Our study and prior studies have shown that many women want and need symptom relief to function at home and work. Women in our study had a wide range of perceptions about the potential risks of these medications. This heterogeneity may be partly due to the lack of rigorous evidence about whether these medications are safe in pregnancy. There is no meaningful information about risks available from randomized trials [9] and there is ongoing debate about the quality and findings of prior observational (epidemiologic) studies [13, 14].\n\nSome women in our study expressed a desire for greater information about risks and benefits of anti-nausea medication use during pregnancy, including about outcomes in diverse populations such as women from different racial and ethnic groups. Future research is needed to clarify the potential risks and effectiveness of widely used anti-nausea medications, including ondansetron, as was highlighted by a recent Cochrane systematic review [9]. More broadly, research is needed to find safe options for managing nausea and vomiting in pregnancy, and this research needs to include women with diverse backgrounds and characteristics.\n\nOur research also sheds light on how women interpret evidence and what kinds of information they find meaningful and compelling. Future qualitative research is needed to understand the ways in which women utilize knowledge and weigh evidence in their decision-making. Such research could help clinicians better understand how to communicate evidence to women in ways that are meaningful and helpful to them.\n\nAdditional file\n\nAdditional file 1: Supplementary Material for Reviewer Focus Group Guide. Pregnancy Perspectives - Focus Group Guide: Nausea and Medication Use. This is the guide given to focus group moderators to conduct the conversation for participants. It includes introductory information, questions to pose to the group, and additional probing questions to consider based on elicited conversations. (DOC 44 kb)\n\n \n\n\nAcknowledgements\nNot applicable.\n\nFunding\nThis exploratory pilot study was funded by Kaiser Permanente Washington Health Research Institute (KPWHRI) through an internal development grant. All study investigators and staff are employed by KPWHRI. Apart from the contributions of study investigators and staff, KPWHRI did not play a role in the design of the study or in the collection, analysis, and interpretation of the data, or in writing the manuscript.\n\nAvailability of data and materials\nFocus group guide themes are available in Table 2, and the full focus group guide is included as a Additional file 1. Availability of raw qualitative data not applicable.\n\nAuthors’ contributions\nAll authors have made substantive contributions to the study design, data collection, data analysis, and/or writing of this manuscript. MFG contributed to the study design, collected and analyzed the data and led the writing of the manuscript. CH contributed to the study design, collected and analyzed the data, and was a major contributor to the writing of the manuscript. LK supported data collection and performed the literature review. SD secured the grant, contributed to the study design, and was a major contributor to the writing of the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nStudy procedures were approved by the KPWA Human Subjects Review Committee, and written informed consent was provided by all participants (IRBNET 861491).\n\nConsent for publication\nParticipants consented to having quotations from discussion responses used in research publications with identifying information removed.\n\nCompeting interests\nNone of the authors of this manuscript have competing interests, either financial or non-financial.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Lacasse A, Rey E, Ferreira E, Morin C, Berard A. Epidemiology of nausea and vomiting of pregnancy: prevalence, severity, determinants, and the importance of race/ethnicity. BMC Pregnancy Childbirth. 2009;9(26) PMCID: PMC2713199.\n2. 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Smith C Crowther C Beilby J Dandeaux J The impact of nausea and vomiting on women: a burden of early pregnancy Aust N Z J Obstet Gynaecol 2000 40 397 401 10.1111/j.1479-828X.2000.tb01167.x 11194422 \n7. Miller F Nausea and vomiting in pregnancy: the problem of perception--is it really a disease? Am J Obstet Gynecol 2002 186 S182 S183 10.1067/mob.2002.122594 12011883 \n8. Piwko C Koren G Babashov V Vicente C Einarson TR Economic burden of nausea and vomiting of pregnancy in the USA J Popul Ther Clin Pharmacol 2013 20 e149 e160 23913638 \n9. Matthews A Haas DM O'Mathuna DP Dowswell T Interventions for nausea and vomiting in early pregnancy Cochrane Database Syst Rev 2015 9 CD007575 \n10. Anderka M Mitchell AA Louik C Werler MM Hernandez-Diaz S Rasmussen SA National Birth Defects Prevention S. medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects Birth Defects Res A Clin Mol Teratol 2012 94 22 30 10.1002/bdra.22865 22102545 \n11. Danielsson B Wikner BN Kallen B Use of ondansetron during pregnancy and congenital malformations in the infant Reprod Toxicol 2014 50 134 137 10.1016/j.reprotox.2014.10.017 25450422 \n12. Pasternak B Svanstrom H Hviid A Ondansetron in pregnancy and risk of adverse fetal outcomes N Engl J Med 2013 368 814 823 10.1056/NEJMoa1211035 23445092 \n13. Siminerio LL Bodnar LM Venkataramanan R Caritis SN Ondansetron use in pregnancy Obstet Gynecol 2016 127 873 877 10.1097/AOG.0000000000001375 27054931 \n14. Carstairs SD Ondansetron use in pregnancy and birth defects: a systematic review Obstet Gynecol 2016 127 878 883 10.1097/AOG.0000000000001388 27054939 \n15. American College of Obstetrics and Gynecology Practice Bulletin No. 153: Nausea and vomiting of pregnancy Obstet Gynecol 2015 126 e12 e24 10.1097/AOG.0000000000001048 26287788 \n16. Baggley A Navioz Y Maltepe C Koren G Einarson A Determinants of women's decision making on whether to treat nausea and vomiting of pregnancy pharmacologically J Midwifery Womens Health 2004 49 350 354 10.1016/j.jmwh.2004.03.011 15236716 \n17. Heitmann K Svendsen HC Sporsheim IH Holst L Nausea in pregnancy: attitudes among pregnant women and general practitioners on treatment and pregnancy care Scand J Prim Health Care 2016 34 13 20 10.3109/02813432.2015.1132894 26854395 \n18. Locock L Alexander J Rozmovits L Women's responses to nausea and vomiting in pregnancy Midwifery 2008 24 143 152 10.1016/j.midw.2006.12.001 17316935 \n19. O'Brien B Evans M White-McDonald E Isolation from “being alive”: coping with severe nausea and vomiting of pregnancy Nurs Res 2002 51 302 308 10.1097/00006199-200209000-00006 12352778 \n20. Power Z Thomson AM Waterman H Understanding the stigma of hyperemesis gravidarum: qualitative findings from an action research study Birth 2010 37 237 244 10.1111/j.1523-536X.2010.00411.x 20887540 \n21. Tong A Sainsbury P Craig J Consolidated criteria for reporting qualitative research (COREQ): a 32-item checklist for interviews and focus groups Int J Qual Health Care 2007 19 349 10.1093/intqhc/mzm042 17872937 \n22. Palinkas LA Horwitz SM Green CA Wisdom JP Duan N Hoagwood K Purposeful sampling for qualitative data collection and analysis in mixed method implementation research Admin Pol Ment Health 2015 42 5 533 544 10.1007/s10488-013-0528-y \n23. Bernard H Research methods in anthropology. 5 2011 Lanham, MD AltaMira Press \n24. Saldana J The coding manual for qualitative researchers. 2 2012 Los Angeles, CA SAGE Publications Ltd \n25. Bury M Chronic illness as biographical disruption Sociol Health Illn 1982 4 167 182 10.1111/1467-9566.ep11339939 10260456 \n26. Hallgrimsdottir HK Benner BE ‘Knowledge is power’: risk and the moral responsibilities of the expectant mother at the turn of the twentieth century Health Risk Soc 2014 16 7 21 10.1080/13698575.2013.866216\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2393",
"issue": "18(1)",
"journal": "BMC pregnancy and childbirth",
"keywords": "Anti-emetic; Decision making; Focus group; Medication; Nausea; Ondansetron; Pregnancy; Qualitative; Vomiting",
"medline_ta": "BMC Pregnancy Childbirth",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000932:Antiemetics; D003657:Decision Making; D005260:Female; D017144:Focus Groups; D006801:Humans; D048968:Morning Sickness; D017294:Ondansetron; D010865:Pilot Projects; D011247:Pregnancy; D036301:Qualitative Research; D018570:Risk Assessment; D012720:Severity of Illness Index; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "100967799",
"other_id": null,
"pages": "475",
"pmc": null,
"pmid": "30514332",
"pubdate": "2018-12-04",
"publication_types": "D016428:Journal Article",
"references": "27054931;20887540;26348534;17872937;17316935;15236716;24193818;2905299;22102545;26854395;26287788;23445092;12956841;19573237;12352778;11194422;25450422;10260456;23913638;12011883;26628289;10967171;27054939",
"title": "Getting through the day: a pilot qualitative study of U.S. women's experiences making decisions about anti-nausea medication during pregnancy.",
"title_normalized": "getting through the day a pilot qualitative study of u s women s experiences making decisions about anti nausea medication during pregnancy"
} | [
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"companynumb": "PHHY2018US187652",
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"activesubstancename": "ONDANSETRON HYDROCHLORIDE"
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"abstract": "To report a case of linezolid-induced toxic optic neuropathy. Clinical examination and imaging are presented over a 4-month interval from initial presentation to subsequent follow-up of 4 months after discontinuation of linezolid. The patient was found to have optic neuropathy as demonstrated by clinical presentation and examination. Upon discontinuation of linezolid, the patient's visual acuity, visual fields, and color vision significantly improved. Linezolid has previously been reported to cause toxic optic neuropathy and retinopathy. We hereby describe a tuberculosis patient with linezolid-associated toxic optic neuropathy. Our report aims to describe the ocular side effects of linezolid use to enhance awareness.",
"affiliations": "Department of Ophthalmology, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.;Department of Ophthalmology, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.;Department of Ophthalmology, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.",
"authors": "Aljebreen|Meshaal A|MA|;Alotaibi|Abdulaziz K|AK|;Alrobaian|Malek|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000069349:Linezolid",
"country": "India",
"delete": false,
"doi": "10.4103/meajo.MEAJO_73_20",
"fulltext": "\n==== Front\nMiddle East Afr J Ophthalmol\nMiddle East Afr J Ophthalmol\nMEAJO\nMiddle East African Journal of Ophthalmology\n0974-9233\n0975-1599\nWolters Kluwer - Medknow India\n\nMEAJO-27-235\n10.4103/meajo.MEAJO_73_20\nCase Report\nLinezolid-Induced Toxic Optic Neuropathy\nAljebreen Meshaal A. 12\nAlotaibi Abdulaziz K. 12\nAlrobaian Malek 123\n1 Department of Ophthalmology, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia\n2 King Abdullah International Medical Research Center, Riyadh, Saudi Arabia\n3 Department of Ophthalmology, Ministry of the National Guard – Health Affairs, Riyadh, Saudi Arabia\nAddress for correspondence: Dr. Meshaal Ahmad Aljebreen, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Prince Mutib Ibn Abdullah Ibn Abdulaziz Road, Ar Rimayah, Riyadh 14611, Saudi Arabia. E-mail: aljebeen030@ksau-hs.edu.sa\nOct-Dec 2020\n19 1 2021\n27 4 235237\n07 3 2020\n13 3 2020\n15 12 2020\nCopyright: © 2021 Middle East African Journal of Ophthalmology\n2021\nThis is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nTo report a case of linezolid-induced toxic optic neuropathy. Clinical examination and imaging are presented over a 4-month interval from initial presentation to subsequent follow-up of 4 months after discontinuation of linezolid. The patient was found to have optic neuropathy as demonstrated by clinical presentation and examination. Upon discontinuation of linezolid, the patient's visual acuity, visual fields, and color vision significantly improved. Linezolid has previously been reported to cause toxic optic neuropathy and retinopathy. We hereby describe a tuberculosis patient with linezolid-associated toxic optic neuropathy. Our report aims to describe the ocular side effects of linezolid use to enhance awareness.\n\nKeywords:\n\nLinezolid\noptic neuropathy\ntoxic neuropathy\n==== Body\nIntroduction\n\nToxic optic neuropathy is a complex and multifactorial medical condition characterized by bilateral painless progressive visual impairment preceded by a change in color vision. It occurs secondary to exposure to a toxin that damages the optic nerve. Common etiologies known to cause toxicity are drugs (Ethambutol, Amiodarone, and Tamoxifen) and nutritional deficiencies (Vitamin B12, folate).[1] We report a case of bilateral toxic optic neuropathy in a 25-year-old male known to have extensive drug-resistant tuberculosis (XDR-TB) presented with bilateral sudden visual impairment after 5 months of linezolid use along with other anti-TB medications.\n\nCase Report\n\nA 25-year-old male was referred to ophthalmology from the infectious diseases department with a complaint of painless blurred vision in both eyes for a few days. He denied headache, proximal muscle ache, or recent trauma. Medical history showed that the patient was diagnosed with XDR-TB on treatment with INH (300 mg/day) for 1 month, ethionamide (500 mg/twice per day) for 3 months, clofazimine (100 mg/day), moxifloxacin (400 mg/day), linezolid (600 mg/twice per day), cyscloserin (750 mg/day), and bedaquiline and pyridoxine (80 mg/day) for the past 5 months. Ocular history was unremarkable. The dosage of linezolid was increased to 1200 mg 3 weeks before the presentation.\n\nOn examination, visual acuity was 20/200 in both eyes. The intraocular pressure was 17 mmHg in the right eye and 16 mmHg in the left eye. Ishihara color plate test revealed a decrease in color vision, mainly in the left eye (3 of 15 plates) while the right eye was (7 of 15 plates). Pupils were regular, round, and reactive without relative afferent pupillary defect. The anterior segment examination was unremarkable. Fundi showed blurred disk margins in both eyes with mild nasal elevation in the left eye. His visual field revealed ceco-central scotomas in both eyes [Figure 1]. Magnetic resonance imaging of the brain and orbit was unremarkable. Leber's hereditary optic neuropathy genetic testing was negative.\n\nFigure 1 Humphry visual field testing at the presentation which showed cecocentral scotomas in both eyes\n\nOut of the medications he is using, we concluded that the patient had a drug-induced toxic optic neuropathy secondary to a high dose of linezolid. Therefore, after informing the primary team, we suggested substituting linezolid with another alternative and they decided to stop linezolid and continue the rest of the medications. Subsequently, the patient reported improvement of vision 1-week post discontinuation of linezolid. Visual acuity improved to 20/60 in both eyes. However, color vision did not improve within the same period and inversely worsened in the right eye (5 of 15 plates). Three months after the presentation, visual acuity improved remarkably to 20/25 in the right eye and 20/28 in the left eye. Furthermore, color vision was fully restored in both eyes (15 of 15 plates). Furthermore, examination of fundi showed mild temporal disk pallor more prominent in the left eye. Visual field testing was unremarkable [Figure 2].\n\nFigure 2 Humphry visual field testing 3 months after linezolid cessation\n\nDiscussion\n\nLinezolid is a synthetic antibiotic that is used in the treatment of Gram-positive bacteria.[2] It belongs to the oxazolidinones group of antibiotics, which exert their action by blocking protein synthesis in bacterial cells. Linezolid has been used effectively in the treatment of multidrug-resistant TB as a second line.[2] While being effectively used in treating drug-resistant bacteria and such as numerous antibiotics, linezolid has been linked to side effects. These side effects can vary from mild headaches, nausea, diarrhea, and vomiting to potentially serious ones such as myelosuppression, serotonin syndrome, lactic acidosis, and peripheral neuropathy.\n\nThe possibility of experiencing side effects was linked to the dosage and duration of treatment, mainly when used for more than 2 weeks. Therefore, it requires weekly complete blood count monitoring and discontinuation when myelosuppression or neuropathy is suspected.[1] The main ocular side effect linked to linezolid use was optic neuropathy when used for more than 28 days that mandates frequent visual function monitoring. There were previous reports in the literature of changes in visual acuity or color vision, blurred vision, and visual field defects attributed to linezolid use.[34567891011121314]\n\nToxic optic neuropathy is a bilaterally symmetrical optic nerve disorder characterized by central or cecocentral scotomas and color vision impairment. The papillomacular bundle is frequently damaged due to its high demand for energy and the inability of mitochondria to generate enough adenosine triphosphate.[15] Frequent substances were linked to toxic optic neuropathy including chemotherapeutic agents, alcohols, antiarrhythmics, PDE inhibitors, heavy metals, antimalarials, and other antibiotics such as chloramphenicol, sulfonamides, isoniazid, ethambutol, and streptomycin.\n\nNutritional deficiencies can also result in toxic optic neuropathies, with Vitamin B and folic acid deficiencies being the most significant and related to alcohol use or bariatric surgery. In addition to optic neuropathy, linezolid has been associated with photoreceptor dysfunction.[1617] The photoreceptor dysfunction mechanism is attributed to mitochondrial dysfunction, causing an imbalance of free radical homeostasis resembling Leber's hereditary optic neuropathy.[16] A novel screening to prevent optic neuropathy has been proposed by Sean et al., based on the previously reported cases in which they recommend screening adult patients “within 1 month after initiating linezolid, followed by a subsequent evaluation every 30–60 days beginning 3 months from initiation.”[18] The primary treatment is the immediate cessation of linezolid with visual acuity improving first before color vision.[19]\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\nReferences\n\n1 Kesler A Pianka P Toxic optic neuropathy Curr Neurol Neurosci Rep 2003 3 410 4 12914684\n2 Who Expert Committee The Selection and Use of Essential Medicines WHO Technical Report Series 2015 Last accessed on 2020 Feb 24 31 Available from: https://apps.who.int/iris/bitstream/handle/10665/189763/9789241209946_eng.pdf; jsessionid=1A8F9E6BBB9BC6DB622EF371E6C6F4DC?sequence=1\n3 Rana P Roy V Ahmad J Drug-induced optic neuropathy in a case of extensively drug-resistant pulmonary tuberculosis J Basic Clin Physiol Pharmacol 2018 30 139 40 30173204\n4 Mehta S Das M Laxmeshwar C Jonckheere S Thi SS Isaakidis P Linezolid-associated optic neuropathy in drug-resistant tuberculosis patients in Mumbai, India PLoS One 2016 11 e0162138 27611434\n5 Ishii N Kinouchi R Inoue M Yoshida A Linezolid-induced optic neuropathy with a rare pathological change in the inner retina Int Ophthalmol 2016 36 761 6 26872906\n6 Libershteyn Y Ethambutol/linezolid toxic optic neuropathy Optom Vis Sci 2016 93 211 7 26636399\n7 Agrawal R Addison P Saihan Z Pefkianaki M Pavesio C Optic neuropathy secondary to Linezolid for multidrug-resistant mycobacterial spinal tuberculosis Ocul Immunol Inflamm 2015 23 90 2 24432953\n8 Xerri O Lemaire B Nasser G Rousseau-Huvey B Labetoulle M Rousseau A Severe linezolid-induced toxic optic neuropathy J Fr Ophtalmol 2015 38 e55 8 25637235\n9 Karuppannasamy D Raghuram A Sundar D Linezolid-induced optic neuropathy Indian J Ophthalmol 2014 62 497 500 24088636\n10 Chaitali P Suresh R Comment on linezolid induced optic neuropathy Indian J Ophthalmol 2015 63 75 6 25686072\n11 Han J Lee K Rhiu S Lee JB Han SH Linezolid-associated optic neuropathy in a patient with drug-resistant tuberculosis J Neuroophthalmol 2013 33 316 8 23912768\n12 Khadilkar SV Yadav RS Rajan S Linezolid optic neuropathy: Be careful and quick J Assoc Physicians India 2013 61 866 7 24974514\n13 Eisenack J Landau K Wildberger H Knecht P Linezolid-associated optic neuropathy? Klin Monbl Augenheilkd 2012 229 433 4 22496022\n14 Schecter GF Scott C True L Raftery A Flood J Mase S Linezolid in the treatment of multidrug-resistant tuberculosis Clin Infect Dis 2010 50 49 55 19947856\n15 De Vriese AS Coster RV Smet J Seneca S Lovering A Van Haute LL Linezolid-induced inhibition of mitochondrial protein synthesis Clin Infect Dis 2006 42 1111 7 16575728\n16 Grohmann SM Berman A Grassi MA Linezolid-induced photoreceptor dysfunction masquerading as autoimmune retinopathy Doc Ophthalmol 2020 140 77 82 31587118\n17 Park DH Park TK Ohn YH Park JS Chang JH Linezolid induced retinopathy Doc Ophthalmol 2015 131 237 44 26526593\n18 Dempsey SP Sickman A Slagle WS Case report: Linezolid optic neuropathy and proposed evidenced-based screening recommendation Optom Vis Sci 2018 95 468 74 29683987\n19 Sharma P Sharma R Toxic optic neuropathy Indian J Ophthalmol 2011 59 137 41 21350283\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0974-9233",
"issue": "27(4)",
"journal": "Middle East African journal of ophthalmology",
"keywords": "Linezolid; optic neuropathy; toxic neuropathy",
"medline_ta": "Middle East Afr J Ophthalmol",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D055253:Color Vision; D006801:Humans; D000069349:Linezolid; D008297:Male; D000081028:Toxic Optic Neuropathy; D018088:Tuberculosis, Multidrug-Resistant; D014792:Visual Acuity; D014794:Visual Fields",
"nlm_unique_id": "101521797",
"other_id": null,
"pages": "235-237",
"pmc": null,
"pmid": "33814822",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27611434;22496022;12914684;23912768;25637235;21350283;24974514;24088636;29683987;25686072;26636399;30173204;26526593;31587118;16575728;19947856;26872906;24432953",
"title": "Linezolid-Induced Toxic Optic Neuropathy.",
"title_normalized": "linezolid induced toxic optic neuropathy"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-03225",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
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"abstract": "Eosinophilic granulomatosis with polyangiitis (EGPA), which belongs to the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides, is characterized by eosinophil-rich granulomatous inflammation and small to medium-sized vessel vasculitis associated with bronchial asthma and eosinophilia. It sometimes causes severe organ damage, of which myocardial damage is one of the most important for determining the prognosis. A case of EGPA-associated myocarditis that was refractory to glucocorticoid therapy and responded successfully to rituximab (RTX) and mepolizumab (MPZ) combination therapy is presented. A 46-year-old woman was diagnosed with EGPA-associated myocarditis due to pre-existing asthma, eosinophilia, mononeuritis multiplex, and eosinophilic myocarditis by myocardial biopsy. Transthoracic echocardiography showed thickening of the cardiac wall, pericardial effusion, and left ventricular hypokinesis. Although the myocarditis was refractory to methylprednisolone pulse therapy followed by oral high-dose prednisolone, the disease activity reached remission with the successful tapering of glucocorticoid after initiation of the RTX and MPZ combination therapy. Combination therapy with RTX and MPZ can be a good treatment option for EGPA-associated myocarditis for which it is difficult to give intravenous cyclophosphamide due to cardiac dysfunction.",
"affiliations": "Department of Rheumatology, National Hospital Organization Yokohama Medical Center, Yokohama, Kanagawa, Japan.;Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.;Department of Rheumatology, National Hospital Organization Yokohama Medical Center, Yokohama, Kanagawa, Japan.;Department of Rheumatology, National Hospital Organization Yokohama Medical Center, Yokohama, Kanagawa, Japan.;Department of Rheumatology, National Hospital Organization Yokohama Medical Center, Yokohama, Kanagawa, Japan.",
"authors": "Higashitani|Kana|K|;Yoshimi|Ryusuke|R|;Sato|Yuichiro|Y|;Watanabe|Toshiyuki|T|;Ihata|Atsushi|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/mrcr/rxab022",
"fulltext": null,
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"issn_linking": "2472-5625",
"issue": null,
"journal": "Modern rheumatology case reports",
"keywords": "eosinophilic granulomatosis with polyangiitis (EGPA); eosinophilic myocarditis (EM); mepolizumab; mononeuritis multiplex; rituximab",
"medline_ta": "Mod Rheumatol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101761026",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34473835",
"pubdate": "2021-09-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rituximab and Mepolizumab Combination Therapy for Glucocorticoid-Resistant Myocarditis Related to Eosinophilic Granulomatosis With Polyangiitis.",
"title_normalized": "rituximab and mepolizumab combination therapy for glucocorticoid resistant myocarditis related to eosinophilic granulomatosis with polyangiitis"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2022-04122",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugad... |
{
"abstract": "BACKGROUND\nWe sought to assess the effectiveness and safety of adalimumab for the treatment of Crohn's disease (CD) in clinical practice.\n\n\nMETHODS\nDemographic, clinical, and treatment data were abstracted from the medical record. The primary outcome was clinical response to induction therapy with adalimumab for CD (complete, partial, or nonresponse).\n\n\nRESULTS\nIn all, 118 patients were prescribed adalimumab for CD between January 2003 and June 2007. All but five subjects (96%) had received prior infliximab and 50 were on systemic corticosteroids at the time of initial adalimumab dose (44%). A complete response was achieved in 53 patients and 20 patients had no response. The cumulative probability of any response (complete or partial) was 81.3% at 1 year. Dose escalation was required in 59 patients (1-year cumulative probability, 54.0%). Among patients with complete response, 18 lost response during follow-up (1-year cumulative probability, 21.4%). Among 50 patients on corticosteroids at baseline the median daily dose was 20 mg, which decreased to a median of 0 mg during treatment. Sixty-four patients (54%) experienced a total of 117 adverse events. Thirteen patients (11%) experienced 15 serious adverse events. Sixteen patients (14%) discontinued adalimumab due to an adverse event.\n\n\nCONCLUSIONS\nAdalimumab was both effective and well tolerated for the treatment of CD in this tertiary practice with a high prevalence of past infliximab exposure. This experience largely predates FDA approval of adalimumab for CD.",
"affiliations": "Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.",
"authors": "Swoger|Jason M|JM|;Loftus|Edward V|EV|;Tremaine|William J|WJ|;Faubion|William A|WA|;Pardi|Darrell S|DS|;Kane|Sunanda V|SV|;Hanson|Karen A|KA|;Harmsen|W Scott|WS|;Zinsmeister|Alan R|AR|;Sandborn|William J|WJ|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000069285:Infliximab; D000068879:Adalimumab",
"country": "England",
"delete": false,
"doi": "10.1002/ibd.21272",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0998",
"issue": "16(11)",
"journal": "Inflammatory bowel diseases",
"keywords": null,
"medline_ta": "Inflamm Bowel Dis",
"mesh_terms": "D000068879:Adalimumab; D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002986:Clinical Trials as Topic; D003424:Crohn Disease; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9508162",
"other_id": null,
"pages": "1912-21",
"pmc": null,
"pmid": "20848486",
"pubdate": "2010-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Adalimumab for Crohn's disease in clinical practice at Mayo clinic: the first 118 patients.",
"title_normalized": "adalimumab for crohn s disease in clinical practice at mayo clinic the first 118 patients"
} | [
{
"companynumb": "US-JNJFOC-20130611974",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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"drugadditional": null,
... |
{
"abstract": "Idiopathic central diabetes insipidus (DI) is a rare endocrine disorder that results from total or partial deficiency of vasopressin secretion. It is idiopathic when the cause is unknown, but in many cases, is associated with autoimmune disorders.\nWe present the case of a 44-year-old male with vitiligo and a family history of diabetes mellitus and thyroid disease. The patient presented with polydipsia and polyuria greater than 8 L/day. After water deprivation test, the patient was diagnosed with partial central diabetes insipidus. Contrast-enhanced pituitary magnetic resonance imaging showed decreased brightness of the neurohypophysis and normal thickness of the pituitary stalk. Because desmopressin was not initially available, the patient was managed with chlorpropamide, carbamazepine, and hydrochlorothiazide, and afterwards substituted. During his outpatient checkups, he presented many episodes of polyuria, the last after 13 years, with polyuria of up to 15 L associated with weight loss, and abnormal blood glucose levels; anti-GAD 65 and IA-2 antibodies were negative. He was subsequently diagnosed with diabetes mellitus and received metformin and insulin; this latter was suspended in subsequent check-ups due to hypoglycemic episodes.\nWe highlight the importance of treatment and adequate control of these pathologies, since they share similar clinical manifestations, can easily have electrolyte imbalance and represent a challenge for endocrinologists and internists.",
"affiliations": "Division of Endocrinology. Clínica Stella Maris, Lima, Perú.;National University of Trujillo, Faculty of Medicine, Trujillo, Perú.;Division of Endocrinology, Hospital Nacional Daniel Alcides Carrión, Lima, Perú.;Division of Endocrinology, Hospital Nacional Guillermo Almenara Irigoyen, Lima, Perú.;Division of Endocrinology, Hospital Nacional Guillermo Almenara Irigoyen, Lima, Perú.;Division of Endocrinology, Hospital Nacional Guillermo Almenara Irigoyen, Lima, Perú.;Division of Endocrinology, Hospital Nacional Guillermo Almenara Irigoyen, Lima, Perú.",
"authors": "Concepción-Zavaleta|Marcio José|MJ|;Marreros|Diego Martin Moreno|DMM|;Villasante|Eilhart Jorge García|EJG|;Plasencia-Dueñas|Esteban Alberto|EA|;Najarro|Sofia Ildefonso|SI|;Rojas|José Carrion|JC|;Acurio|Carmen Luisa Achahui|CLA|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": "10.22088/cjim.12.0.363",
"fulltext": "\n==== Front\nCaspian J Intern Med\nCaspian J Intern Med\nCJIM\nCaspian Journal of Internal Medicine\n2008-6164\n2008-6172\nBabol University of Medical Sciences Babol, Iran\n\n10.22088/cjim.12.0.363\nCase Report\nTherapeutic challenge: Unusual coexistence of idiopathic central diabetes insipidus and diabetes mellitus in a male with vitiligo\nConcepción-Zavaleta Marcio José MD 1\nMarreros Diego Martin Moreno MD 2\nVillasante Eilhart Jorge García MD 3\nPlasencia-Dueñas Esteban Alberto MD 4\nNajarro Sofia Ildefonso MD 5\nRojas José Carrion MD 5\nAcurio Carmen Luisa Achahui MD 5\n1 Division of Endocrinology. Clínica Stella Maris, Lima, Perú\n2 National University of Trujillo, Faculty of Medicine, Trujillo, Perú\n3 Division of Endocrinology, Hospital Nacional Daniel Alcides Carrión, Lima, Perú\n4 Division of Endocrinology, Hospital Nacional Guillermo Almenara Irigoyen, Lima, Perú\n5 Division of Endocrinology, Hospital Nacional Guillermo Almenara Irigoyen, Lima, Perú\n* Correspondence: Diego Martin Moreno Marreros, National University of Trujillo Faculty of Medicine. Trujillo, Perú. E-mail: diegomorenosud@hotmail.com, Tel: 0051950291202, Fax: 0051950291202\n2021\n12 Suppl 2 S363S367\n11 9 2020\n14 12 2020\n21 12 2020\nhttps://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground:\n\nIdiopathic central diabetes insipidus (DI) is a rare endocrine disorder that results from total or partial deficiency of vasopressin secretion. It is idiopathic when the cause is unknown, but in many cases, is associated with autoimmune disorders.\n\nCase presentation:\n\nWe present the case of a 44-year-old male with vitiligo and a family history of diabetes mellitus and thyroid disease. The patient presented with polydipsia and polyuria greater than 8 L/day. After water deprivation test, the patient was diagnosed with partial central diabetes insipidus. Contrast-enhanced pituitary magnetic resonance imaging showed decreased brightness of the neurohypophysis and normal thickness of the pituitary stalk. Because desmopressin was not initially available, the patient was managed with chlorpropamide, carbamazepine, and hydrochlorothiazide, and afterwards substituted. During his outpatient checkups, he presented many episodes of polyuria, the last after 13 years, with polyuria of up to 15 L associated with weight loss, and abnormal blood glucose levels; anti-GAD 65 and IA-2 antibodies were negative. He was subsequently diagnosed with diabetes mellitus and received metformin and insulin; this latter was suspended in subsequent check-ups due to hypoglycemic episodes.\n\nConclusion:\n\nWe highlight the importance of treatment and adequate control of these pathologies, since they share similar clinical manifestations, can easily have electrolyte imbalance and represent a challenge for endocrinologists and internists.\n\nKey Words\n\nCentral diabetes insipidus\nDiabetes mellitus\nWater deprivation test\nVitiligo.\n==== Body\npmcCentral diabetes insipidus is a rare disease of the hypothalamic-pituitary axis caused by deficiency of vasopressin synthesis in the hypothalamus, or a lack of secretion in the neurohypophysis (1, 2). The prevalence of central diabetes insipidus is 1 case for every 25,000 people, and the majority of cases are acquired, mainly as a result of craniopharyngioma and germ cell tumors (3). Nevertheless, the etiology remains unknown in 15%–50% of patients, in which the disease is classified as idiopathic (2, 3). The idiopathic form of diabetes insipidus is associated with the presence of autoantibodies against ADH-secreting neurons (AVPcAb), which are present in one third of the cases (4). Studies have shown that these autoantibodies are present in the serum of most patients with pituitary diseases (5). This form of diabetes is often accompanied by thyroid, rheumatologic, or dermatologic autoimmune disorders that increase the probability of immune etiology (1). Identification of AVPcAb and advances in imaging techniques have led to fewer reports of idiopathic (6). We present the case of a male patient with vitiligo, who initially developed idiopathic central diabetes insipidus and later diabetes mellitus, highlighting the challenge of treating and controlling both diseases at the same time.\n\nCase presentation\n\nA 44-year-old male patient diagnosed with vitiligo at 10 years old, came to the emergency department due to excessive thirst and polyuria of 8 to 10 L/day. The patient had a family history (father and 3 siblings) of type 2 diabetes mellitus and autoimmune hypothyroidism.\n\nHe was subsequently hospitalized in the endocrinology service with diagnosis of polydipsia-polyuria syndrome and high suspicion of diabetes insipidus. On physical examination the following were noted: Blood pressure, 110/70 mmHg; heart rate, 65 bpm; respiratory rate, 16 breaths per minute; body weight, 81 kg (178.5 lb); height, 170 cm; and BMI, 28 kg/m2.\n\nIn the preferential examination multiple irregular hypopigmented maculas were found in different parts of the body, compatible with vitiligo (figure 1).\n\nFigure 1 Clinical characteristics of the patient. Hypopigmented macular lesions on both forearms compatible with vitiligo\n\nAlso decreased the baresthesia and pallesthesia sensitivity in feet. The remainder of the examination was unremarkable. Biochemical and hormonal examinations revealed the following: serum Na, 141 mEq/l; serum K, 3.84 mEq/l; fasting blood glucose, 110 mg/dl; serum creatinine, 0.81 mg/dl; thyroid profile with free t4, 1.25 µg/dl (normal range: 0.8–1.7 µg/dl); TSH, 2,248 µUI/ml (normal range: 0.4–4 µUI/ml); antimicrosomal antibodies, 32.9 U/ml (normal range: <60 U/ml); and HbA1c at 6.2%.\n\nGiven the presumptive diagnosis of diabetes insipidus, the patient underwent a water deprivation test (Miller test), and after the subcutaneous administration of 5U vasopressin (desmopressin phase), he was subsequently diagnosed with partial central diabetes insipidus (table 1).\n\nTable 1 Results of the water deprivation test (Miller test)\n\n\t0 hours\t2 hours\t5 hours\t2 hours post Administration subcutaneously of 5U of vasopressin\t\nBody weight (Kg)\t82\t81\t79.4\n(↓ 3 %)\t78.9\t\nPlasma sodium (mEq/l)\t141\t144\t149\t148\t\nPlasma osmolarity (mOsm/Kg)\t302\t308\t318\t316\t\nUrinary osmolarity (mOsm/Kg)\t235\t242\t245\t281.2 (↑ 14.8 %)\t\nUrine Specific gravity\t1.002\t1.005\t1.007\t1.008\t\nUrination Volume (ml)\t0\t1730\t1600\t700\t\n\nTo identify the etiology, we requested a magnetic resonance imaging (MRI) of the pituitary with gadolinium (figure 2), which revealed the presence of two microadenomas (4×2 mm and 2×3 mm) in the posterolateral region of the adenohypophysis, a filiform neurohypophysis with decreased signal intensity, and normal thickness of the pituitary stalk. Likewise, due to blood glucose and HbA1c values, he was diagnosed with prediabetes.\n\nFigure 2 Magnetic resonance imaging of the pituitary gland. A. Sagittal view. Filiform neurohypophysis is observed with decrease intensity (white arrow) in the T1 sequence without contrast. B and C. Sagittal and coronal view. Two microadenomas of 4×2\n\nThe patient received initially pharmacological treatment based on chlorpropamide 100 mg QD, carbamazepine 200 mg TID and hydrochlorothiazide 25 mg QD, because desmopressin was not available at that time. In addition, it was recommended to limit the intake of foods rich in sodium and simple sugars, as well as to undertake regular physical activity and maintain an adequate state of hydration.\n\nThe patient had favorable response to the treatment, and was discharged with good tolerance and adherence to the medication. Ophthalmological and auditory evaluation was performed, and showed no abnormalities. However, during the outpatient controls, he had multiple episodes of polyuria requiring hospitalization, that were attributed to the decompensation of the underlying disease, the last being 13 years after diagnosis with polyuria of up to 15 L, which was associated with a weight loss of 10 kg, and strikingly, random blood sugar of 310 mg/dl. This was the last cause of hospitalization for glycemic management.\n\nBecause the patient had a family history of autoimmune hypothyroidism, as well as a personal history of vitiligo and idiopathic central diabetes insipidus by probable autoimmune etiology, we suspected a presentation pattern of latent autoimmune diabetes in adults (LADA 2). In line with this, we requested antibodies to glutamic acid decarboxylase 65 (GAD-65) and islet antigen 2 (IA-2) antibody, both of which were negative.\n\nConsequently, type 2 diabetes mellitus was diagnosed considering that the patient was overweight and had a family history. The results of the blood tests were obtained as follows: HbA1c was 8.2% and basal C-peptide was 0.32 nmol/l.\n\nGlycemia was controlled by administration of metformin 850 mg QD and progressive titration of the insulin dose until a schedule of insulin NPH 20 units in the morning and 10 units at night was established. During hospitalization, the drugs used for the management of diabetes insipidus were replaced by intranasal desmopressin 10 µg at night because this medication was already available in our country, with no adverse reactions.\n\nOne month later during his out-patient control, he reported two episodes of hypoglycemia and a result of fasting blood glucose of 83mg/dl, so we decided to withdraw insulin therapy. The next control in six months revealed serum sodium of 139 mEq/l, fasting blood glucose of 133 mg/dl, and HbA1c of 6.9%. Currently, the patient is asymptomatic and follows his out-patient controls by our service.\n\nDiscussion\n\nCentral diabetes insipidus (CDI) is a rare endocrine disorder, the basis of which is the total or partial absence of vasopressin; this is generally due to the destruction-degeneration of magnocellular neurons of the supraoptic and paraventricular nucleus in the hypothalamus, or alterations in their transport from the neurohypophysis to the circulation (1, 2). The typical clinical manifestations are polydipsia and polyuria, which in severe cases can cause serious neurological symptoms. Our patient presented with these typical symptoms, and as a result, a water deprivation test was performed. The laboratory parameters, and the increase of 14.8% in the urinary osmolarity after administering vasopressin, guided us to the diagnosis of partial central diabetes insipidus.\n\nOne of the challenges of CDI is to establish the etiology, which can either be of genetic origin due to mutations in the AVP gene locus or acquired. The latter being the most frequent etiology, in which tumors of the central nervous system (e.g., craniopharyngiomas, germinomas), postsurgical, post-traumatic states, and infections represent the main causes (3). It has been reported that the cause of disease for 15%–50% of these patients is unknown and they are included in the idiopathic classification (6). Numerous questions have been raised regarding the cause of idiopathic CDI, mainly highlighting a probable autoimmune origin. Pivonello et al. (12) described the presence of AVPcAb in 32.8% of the 64 patients with idiopathic CDI. The fact that AVPcAbs were recognized in only one third of such patients indicated that they are subject to early disappearance or that autoimmune T-cell local damage may have taken place (15); however, it cannot be ruled out that it may be an epiphenomenon. De Bellis et al. (11) studied the autoimmune cause and radiological characteristics in the pituitary MRI of 22 CDI patients, and reported that 68% of the patients had autoantibodies to AVPcAb in different titers; 7 of whom had thickening of the pituitary stalk. Furthermore, it was evidenced that all the patients presented loss of hyperintense signal of the neurohypophysis correlated to the vasopressin deficit expected of this disease.\n\nThe AVPcAb are generally not available in routine laboratories of our country and, if there is, in most cases their use is restricted for research. The consideration of this etiology is most suggestive in the presence of other concomitant autoimmune diseases, such as vitiligo described in this report (3). Patients with autoimmune CDI have an increased incidence of other organ-specific autoimmune endocrine disease, particularly thyroid disease (14). Furthermore, it has been proposed that vitiligo, together with the early onset of the disease and precise radiological changes at the level of the pituitary stalk, could explain the autoimmune origin of this disease with a probability of up to 99% (12). Nevertheless, the presence of AVPcAb has also been found in patients with Langerhans cell histiocytosis or germinomas which indicate that they are not exclusive markers for autoimmune etiology of central diabetes insipidus (11). The patient has a personal history of vitiligo since adolescence and a family history of autoimmune thyroiditis. In addition, the pituitary MRI demonstrated a decrease in the hyperintensity of the neurohypophysis and no thickening of the pituitary stalk, both of which are closely associated with autoimmune pituitary processes (13). However, the diagnostic sensitivity of lack of brightness in the neurohypophysis in cases of partial CDI is <60% (7). The adenomas described were irrelevant in the etiology in this disease, because they were small (microadenomas), non-invasive, and not secreting hormones, in fact non-functioning pituitary adenomas (NFPA). Additionally, data from Europe, North and South America have estimated the prevalence of clinically relevant NFPA to be 7 to 41.3 cases per 100,000 population (18).\n\nThere are multiple reports of the association between diabetes mellitus and diabetes insipidus in Wólfram syndrome, a neurodegenerative disease of recessive genetic origin, in which the main characteristics are type 1 diabetes, bilateral optic atrophy, and development of diabetes insipidus (8). However, this diagnosis is unlikely since the patient presented a normal ophthalmological and hearing examination, and the anti-GAD 65 and IA-2 antibodies were negative. Few cases have been reported where both pathologies coexist (9, 10), and in all of these, the diagnosis of diabetes mellitus was made before that of diabetes insipidus. In this way, to our knowledge, this is the first clinical case reported in which diagnosis of diabetes insipidus was made almost 13 years before than diabetes mellitus, and during this time the desmopressin, drug of choice for his treatment, was unavailable in our country.\n\nThe patient developed exacerbations in his symptoms that were attributed to irregular treatment and a lack of periodic control of the underlying disease; however, it was postulated that some episodes may have been due to increased blood glucose levels, secondary to lack of control of diabetes mellitus, not yet diagnosed, or by a poor diet control, which generated an increase in plasma osmolarity that could not be compensated by insufficient vasopressin and fluid intake. In addition, the patient used hydrochlorothiazide for more than ten years and it could contribute to the progression from pre-diabetes to diabetes. Zhang et al. established that the use of thiazide diuretics is significantly associated with higher blood glucose levels (16). The exact mechanism of hyperglycemia remains unknown, but it has been proposed that it may be related to increased insulin resistance, inhibition of glucose uptake, and decreased insulin release (17). Therefore, the better control of blood glucose was influenced by the withdrawal of hydrochlorothiazide. On the other hand, chlorpropamide, which is an effective antidiuretic agent for vasopressin-sensitive diabetes insipidus (19), also belongs to the family of first-generation sulfonylureas, so it could initially help to control diabetes mellitus. Chlorpropamide is no longer used for lowering blood glucose (20). Accordingly, the control of both pathologies requires achieving glycemic control and maintaining an adequate hydroelectrolytic and hydration state, for which treatment adherence is required.\n\nIn conclusion, the relevance of this case lies in the management and control of both pathologies together. This remains a medical challenge, since both share similar symptoms, can easily have electrolyte imbalance, and their coexistence is considered to be relatively rare.\n\nAcknowledgments\n\nNone\n\nFunding:\n\nThis case report did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nConflict of interest:\n\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nAuthor contributions:\n\nMarcio Jose Concepción-Zavaleta: Main writer, part of the treating team, case reviewer.\n\nDiego Martin Moreno Marreros: Case reviewer, translating, editing and preparing the manuscript.\n\nEilhart Jorge García Villasante: Part of the treating team, case reviewer.\n\nEsteban Alberto Plasencia-Dueñas: Part of the treating team, written contribution to body of text, and literature overview.\n\nSofia Ildefonso Najarro: Literature overview.\n\nJosé Carrion Rojas and Carmen Achahui Acurio: Part of the treating team, case reviewer.\n\nEthical Code:\n\nWe safeguard the integrity of our patient using an informed consent, we obtained the approval of the Hospital Ethics Committee, and follow the principles of Declaration of Helsinki.\n==== Refs\nReferences\n\n1 Babiker AM Al Jurayyan NA Al Jurayyan RN Al Gadi I Drop SL The Clinical pattern of Diabetes Insipidus in a large university hospital in the Middle East J Trop Pediatr 2015 61 100 105 25587001\n2 Arima H Azuma Y Morishita Y Hagiwara D Central diabetes insipidus Nagoya J Med Sci 2016 78 349 58 28008190\n3 Leroy C Karrouz W Douillard C Diabetes insipidus Ann Endocrinol (Paris) 2013 74 496 507 24286605\n4 Scherbaum WA Bottazzo GF Autoantibodies to vasopressin cells in idiopathic diabetes insipidus: evidence for an autoimmune variant Lancet 1983 1 897 901 6132221\n5 Kajita K Yasuda K Yamakita N Anti-pituitary antibodies in patients with hypopituitarism and their families: longitudinal observation Endocrinol Jpn 1991 38 121 9 1661231\n6 Almeida MQ Idiopathic central diabetes insipidus: the challenge remains Arq Bras Endocrinol Metabol 2010 54 251 2 20520953\n7 Fenske W Refardt J Chifu I A Copeptin-Based Approach in the Diagnosis of Diabetes Insipidus N Engl J Med 2018 379 428 39 30067922\n8 Pallotta MT Tascini G Crispoldi R et al Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives J Transl Med 2019 17 238\n9 Capatina C Ghinea A Dumitrascu A Poiana C Concurrent onset of type 2 diabetes mellitus and central diabetes insipidus in an adult male Int J Diabetes Dev Ctries 2016 36 393 6\n10 Paulose KP Padmakumar N Diabetes insipidus in a patient with diabetes mellitus J Assoc Physicians India 2002 50 1176 7 12516704\n11 De Bellis A Colao A Bizzarro A Longitudinal study of vasopressin-cell antibodies and of hypothalamic-pituitary region on magnetic resonance imaging in patients with autoimmune and idiopathic complete central diabetes insipidus J Clin Endocrinol Metab 2002 87 3825 9 12161517\n12 Pivonello R De Bellis A Faggiano A Central diabetes insipidus and autoimmunity: relationship between the occurrence of antibodies to arginine vasopressin-secreting cells and clinical, immunological, and radiological features in a large cohort of patients with central diabetes insipidus of known and unknown etiology J Clin Endocrinol Metab 2003 88 1629 36 12679449\n13 Imura H Nakao K Shimatsu A Lymphocytic infundibuloneurohypophysitis as a cause of central diabetes insipidus The N Engl J Med 1993 329 683 9 8345854\n14 Hannon M Thompson Ch Jameson J De Groot L Vasopressin, diabetes insipidus, and the syndrome of inappropriate antidiuretic hormone secretion Endocrinology: adult and pediatric 7th ed. Philadelphia Elsevier 2016 298\n15 Maghnie M Ghirardello S De Bellis A Idiopathic central diabetes insipidus in children and young adults is commonly associated with vasopressin-cell antibodies and markers of autoimmunity Clin Endocrinol 2006 65 470 8\n16 Zhang X Zhao Q Association of thiazide-type diuretics with glycemic changes in hypertensive patients: a systematic review and meta-analysis of randomized controlled clinical trials J Clin Hypertens (Greenwich) 2016 18 342 51 26395424\n17 Rehman A Setter S Vue M Drug-induced glucose alterations part 2: drug-induced hyperglycemia Diabetes Spectrum 2011 24 234 8\n18 Drummond JB Ribeiro-Oliveira A Soares BS Endotext [Internet] 2000 [Updated 2018 Nov 28] Available at: https://www.ncbi.nlm.nih.gov/books/NBK534880\n19 Cushard WG Jr Beauchamp CJ Martin ND Oral therapy of diabetes insipidus with chlorpropamide Calif Med 1971 115 1 5\n20 Sola D Rossi L Schianca GP Sulfonylureas and their use in clinical practice Arch Med Sci 2015 11 840 8 26322096\n\n",
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"issn_linking": "2008-6164",
"issue": "12(Suppl 2)",
"journal": "Caspian journal of internal medicine",
"keywords": "Central diabetes insipidus; Diabetes mellitus; Vitiligo.; Water deprivation test",
"medline_ta": "Caspian J Intern Med",
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"pages": "S363-S367",
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"pmid": "34760083",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "31337416;6132221;28008190;26322096;1661231;12161517;12516704;30067922;5563815;12679449;16984239;20520953;8345854;25587001;26395424;24286605",
"title": "Therapeutic challenge: Unusual coexistence of idiopathic central diabetes insipidus and diabetes mellitus in a male with vitiligo.",
"title_normalized": "therapeutic challenge unusual coexistence of idiopathic central diabetes insipidus and diabetes mellitus in a male with vitiligo"
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"abstract": "We characterized the metabolic profile of transgenic mice exhibiting enhanced muscle mass driven by increased mIGF-1 expression (MLC/mIGF-1). As expected, 6-month-old MLC/mIGF-1 mice were heavier than age-matched wild type (WT) mice (37.4 ± 0.3 versus 31.8 ± 0.6 g, resp.). MLC/mIGF-1 mice had higher respiratory quotient when compared to WT (0.9 ± 0.03 versus 0.74 ± 0.02, resp.) suggesting a preference for carbohydrate as the major fuel source. MLC/mIGF-1 mice had a higher rate of glucose disposal when compared to WT (3.25 ± 0.14 versus 2.39 ± 0.03%/min, resp.). The higher disposal rate correlated to ∼ 2-fold higher GLUT4 content in the extensor digitorum longus (EDL) muscle. Analysis of mRNA content for the glycolysis-related gene PFK-1 showed ∼ 3-fold upregulation in MLC/mIGF-1 animals. We also found a 50% downregulation of PGC1α mRNA levels in MLC/mIGF-1 mouse EDL muscle, suggesting less abundant mitochondria in this tissue. We found no difference in the expression of PPARα and PPARβ/δ, suggesting no modulation of key elements in oxidative metabolism. These data together suggest a shift in metabolism towards higher carbohydrate utilization, and that could explain the increased insulin sensitivity of hypertrophied skeletal muscle in MLC/mIGF-1 mice.",
"affiliations": "Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, 05508-000 São Paulo, SP, Brazil ; Centro de Ciências Naturais e Humanas (CCNH), Universidade Federal do ABC (UFABC), 09210-580 Santo André, SP, Brazil.;Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, 05508-000 São Paulo, SP, Brazil.;Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, 05508-000 São Paulo, SP, Brazil.;Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, 05508-000 São Paulo, SP, Brazil.;Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, 05508-000 São Paulo, SP, Brazil.;Biological and Health Science Center, Mackenzie Presbyterian University, 01302-907 São Paulo, SP, Brazil.;Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, 05508-000 São Paulo, SP, Brazil.;Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, 05508-000 São Paulo, SP, Brazil.;Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, 05508-000 São Paulo, SP, Brazil.;Institute Pasteur Cenci Bolognetti, DAHFMO, Unit of Histology and Medical Embryology, IIM, Sapienza University of Rome, 00161 Rome, Italy.;Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, 05508-000 São Paulo, SP, Brazil.",
"authors": "Christoffolete|Marcelo Augusto|MA|;Silva|William Jose|WJ|0000-0001-6969-3464;Ramos|Gracielle Vieira|GV|;Bento|Mirella Ribeiro|MR|;Costa|Monique Oliveira|MO|;Ribeiro|Miriam Oliveira|MO|;Okamoto|Maristela Mitiko|MM|;Lohmann|Tania Helena|TH|;Machado|Ubiratan Fabres|UF|;Musarò|Antonio|A|;Moriscot|Anselmo Sigari|AS|",
"chemical_list": "D051275:Glucose Transporter Type 4; D007328:Insulin; D009124:Muscle Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D047492:Peroxisome Proliferator-Activated Receptors; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; C495694:Slc2a4 protein, rat; D014157:Transcription Factors; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I",
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"doi": "10.1155/2015/282984",
"fulltext": "\n==== Front\nBiomed Res IntBiomed Res IntBMRIBioMed Research International2314-61332314-6141Hindawi Publishing Corporation 10.1155/2015/282984Research ArticleMuscle IGF-1-Induced Skeletal Muscle Hypertrophy Evokes Higher Insulin Sensitivity and Carbohydrate Use as Preferential Energy Substrate Christoffolete Marcelo Augusto \n1\n\n2\nhttp://orcid.org/0000-0001-6969-3464Silva William Jose \n1\nRamos Gracielle Vieira \n1\nBento Mirella Ribeiro \n1\nCosta Monique Oliveira \n1\nRibeiro Miriam Oliveira \n3\nOkamoto Maristela Mitiko \n4\nLohmann Tania Helena \n1\nMachado Ubiratan Fabres \n4\nMusarò Antonio \n5\nMoriscot Anselmo Sigari \n1\n\n*\n1Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, 05508-000 São Paulo, SP, Brazil2Centro de Ciências Naturais e Humanas (CCNH), Universidade Federal do ABC (UFABC), 09210-580 Santo André, SP, Brazil3Biological and Health Science Center, Mackenzie Presbyterian University, 01302-907 São Paulo, SP, Brazil4Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, 05508-000 São Paulo, SP, Brazil5Institute Pasteur Cenci Bolognetti, DAHFMO, Unit of Histology and Medical Embryology, IIM, Sapienza University of Rome, 00161 Rome, Italy*Anselmo Sigari Moriscot: moriscot@usp.brAcademic Editor: Pengjun Shi\n\n2015 4 2 2015 2015 2829845 11 2014 22 1 2015 Copyright © 2015 Marcelo Augusto Christoffolete 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.We characterized the metabolic profile of transgenic mice exhibiting enhanced muscle mass driven by increased mIGF-1 expression (MLC/mIGF-1). As expected, 6-month-old MLC/mIGF-1 mice were heavier than age-matched wild type (WT) mice (37.4 ± 0.3 versus 31.8 ± 0.6 g, resp.). MLC/mIGF-1 mice had higher respiratory quotient when compared to WT (0.9 ± 0.03 versus 0.74 ± 0.02, resp.) suggesting a preference for carbohydrate as the major fuel source. MLC/mIGF-1 mice had a higher rate of glucose disposal when compared to WT (3.25 ± 0.14 versus 2.39 ± 0.03%/min, resp.). The higher disposal rate correlated to ∼2-fold higher GLUT4 content in the extensor digitorum longus (EDL) muscle. Analysis of mRNA content for the glycolysis-related gene PFK-1 showed ∼3-fold upregulation in MLC/mIGF-1 animals. We also found a 50% downregulation of PGC1α mRNA levels in MLC/mIGF-1 mouse EDL muscle, suggesting less abundant mitochondria in this tissue. We found no difference in the expression of PPARα and PPARβ/δ, suggesting no modulation of key elements in oxidative metabolism. These data together suggest a shift in metabolism towards higher carbohydrate utilization, and that could explain the increased insulin sensitivity of hypertrophied skeletal muscle in MLC/mIGF-1 mice.\n==== Body\n1. Introduction\nOne of the remarkable features of skeletal muscle is the capacity to adapt its metabolic and functional properties in response to a wide range of external factors, including physical and neuron activity, change in hormone levels, and oxygen and nutrient supply [1]. However in several pathological conditions, skeletal muscle severely decreases this adaptive capacity, triggering alterations in its metabolic properties evolving to disease. In fact, insulin resistance (IR), obesity, high blood pressure, high fasting glucose or hyperglycemia, and lipid abnormalities are all conditions related to morphofunctional and metabolic changes in skeletal muscle [2].\n\nRecent evidences have shown that different therapeutic interventions can improve body composition and systemic metabolism [3]. Among these, physical activity has been considered in the therapeutic effects of exercise for type II diabetes (T2DM) and other metabolic syndromes [4], although regular physical activity as a therapeutic tool can be seriously assumed in only a fraction of the population, mainly due to motivational and physical limitations. From a metabolic point of view, however, it remains not well understood what molecular/cellular aspects of exercise should be mimicked and what type of muscle fiber is best targeted to improve metabolic dysfunction. Increased physical activity is usually achieved by exercise training, which can be divided into two major categories: endurance and resistance. It is well known that endurance training promotes metabolic alterations in skeletal muscle due to a shift in substrate preference as a consequence of fatty acid oxidative metabolism and muscle fiber type interconversion, resulting in a greater number of the slow twitch oxidative fibers [5]. In contrast, resistance training is known for its capacity to promote an increase in skeletal muscle mass (hypertrophy) and strength [6]. Nonetheless, the molecular factors linking skeletal muscle growth and metabolism still remain to be explored in detail. Among growth factors, the Insulin-like growth factor-1 (IGF-1) has been implicated in the control of both muscle mass and skeletal muscle homeostasis and its expression is significantly enhanced in response to exercise [7].\n\nIt has been previously reported that muscle restricted mIGF-1 transgene (MLC/mIGF-1) sustains muscle hypertrophy and regeneration in senescent skeletal muscle, enhances the recruitment of circulating stem cells in injured muscle [8], and counteracts muscle wasting in mdx dystrophic mice [9], improving muscle mass and strength and elevating pathways associated with muscle survival and regeneration. Although significant advances have been made with this genetic model, overall, the impact of manipulating skeletal muscle hypertrophic pathways upon whole body metabolism and glucose disposal is largely unknown.\n\nIn the present study, we investigated metabolic features of MLC/mIGF-1 mice, revealing an unexpected higher respiratory quotient at rest, an index of higher carbohydrate utilization. These animals also showed higher insulin sensitivity, in line with a preference for carbohydrate as the primary energy source. In addition we have detected increased GLUT4 protein levels in skeletal muscle. These findings reinforce the potential of manipulating IGF-1 triggered intracellular pathways as therapeutic tools in the treatment of insulin resistance and type II diabetes.\n\n2. Research Design and Methods\n2.1. Animals\nAll procedures described were performed in accordance with the guidelines of the committee on animal research at the Institute of Biomedical Sciences, University of São Paulo. Animals aged 4–6 months were obtained from our colony at the Department of Anatomy animal facility. Mice were housed at 21°C on a 12 h dark/light cycle (lights on 18:00 to 06:00 h) with free access to food and water. At the end of the experiments, animals were anesthetized with a ketamine/xylazine combination (100 mg/kg and 10 mg/kg b.w., resp.), tissues were harvested and euthanasia performed by exsanguination cardiac arrest. Our MLC/mIGF-1 mice inbred colony was expanded from two heterozygote males donated by Dr. Musarò [8].\n\n2.2. Genotyping\nApproximately 0.5 cm of mouse tail tip was excised and submitted to total DNA extraction according to a protocol previously described [10], with the following modifications; tail biopsies were digested overnight at 55°C with agitation in lysis buffer (100 mM Tris-HCl pH 8.5, 10 mM EDTA pH 8.0, 0.5% SDS, and 200 mM NaCl) supplemented with 10 μg Proteinase K (Invitrogen, Carlsbad, CA, USA). The resulting material was precipitated with isopropanol, washed in 70% ethanolandre-suspended in TE pH 8.0. Eighty nanograms of total genomic DNA was then submitted to conventional PCR. The reaction was carried out using a common sense primer targeting both mouse and rat MLC promoters (5′-GTGTCAAGGTTCTATTAGGCACTA-3′), and the presence of the transgenic gene was detected using a specific antisense primer targeting the mIGF-1 construct (5′-GAGCTGACTTTGTAGGCTTCA-3′); a positive control reaction was performed using a specific primer (5′-TGACCAAAACGATTCACCTG-3′) targeting the mouse MLC gene. Cycling conditions were 3 min at 95°C “hot start”, followed by 35 cycles at 95°C for 25 s, 60°C for 30 s, and 72°C for 60 s. The control amplicon consisted of ~300 bp fragment and the presence of the transgene was confirmed by identification of ~600 bp fragment, as determined by electrophoretic analysis.\n\n2.3. Muscle Mass Determination, Histochemical Analysis, and Measurement of Cross-Sectional Area\nAt the time of animal sacrifice, soleus and extensor digitorum longus (EDL) muscles were carefully dissected from both limbs. The muscle was weighted and cut in half; one segment was immersed in cold isopentane for 30 seconds, cooled in liquid nitrogen, and stored at −80°C for histochemistry; the other segment was snap frozen in liquid nitrogen and stored at −80°C for later analysis. EDL and soleus frozen muscles were cut into 10 μm cross-sections on a cryostat (CM3050; Leica, Nussloch, Germany) in order to determine the CSA of different fiber types by myofibrillar ATPase activity after alkaline (ATPase, pH 10.3) or acid preincubation (ATPase, pH 4.1) [11, 12]. The CSA (cross-sectional area) and relative total composition of each fiber type were obtained by measuring the CSAs of approximately 500 muscle fibers of each mouse (expressed as mean ± SEM) through image software Image Pro-Plus. The acquisition of the images was realized using a microscope (Nikon Eclipse TS100, Japan) equipped with a digital video camera and imaging software (NIS-Elements BR).\n\n2.4. Fasting Blood Cholesterol, Triglycerides and Glucose Concentrations, and Carcass Lipid Content\nAnimals were fasted for 8 h, with food being removed at 08:00 h and the test begun at 16:00 h. Cholesterol and triglycerides were determined in spectrophotometer by colorimetric method using a commercial KIT (Labtest Diagnóstica S/A, Lagoa Santa, MG, Brazil). Glucose was determined using specific test strips in an Accu-Chek meter (Roche Diagnostics GmbH, Mannheim, Germany). For carcass analysis, lipid extraction was performed as described [13] and body fat percentage was determined.\n\n2.5. Oxygen Consumption\nResting metabolic rate was estimated by determining oxygen consumption (VO2) in an open circuit respirometer (O2-10, Sable System, Las Vegas, NV, USA) [14, 15]. The measurements were conducted always in the afternoon (14:00–18:00 h) for 30 min at 25°C in animals fed ad libitum. The data were collected and evaluated by using the Sable Systems software. The results were expressed as milliliters of O2/min/grams of BW [16, 17].\n\n2.6. Insulin Tolerance Test (ITT) and kITT Determination\nFor ITT, animals were deprived of food for 2 h. Standard insulin diluted in saline was injected (0.125 U/kg) via the caudal vein. Blood glucose was measured with a glucometer (Accu-chek, Roche) at 0, 6, 9, 12, and 15 minutes after insulin injection. The constant rate for blood glucose disappearance (kITT) was calculated based on the linear regression of the Napierian logarithm of blood glucose concentrations [18].\n\n2.7. Real-Time Quantitative Polymerase Chain Reaction\nReal-time quantitative polymerase chain reaction (PCR) was performed on an ABI Prism 5700 sequence detection system (Applied Biosystems, Foster City, CA, USA) using SYBR Green (Applied Biosystems) following the instructions provided by the manufacturer. Thermal-cycling conditions for the real-time PCR were 50°C for 2 min, 95°C for 10 min, and then 40 cycles of 95°C for 15 s, 60°C for 25 s, and 72°C for 30 s. The internal control, Cyclophilin A (CycloA), was amplified in separate tubes. The data were collected semiquantitatively together with the cycle threshold reading of corresponding CycloA internal controls. Data from five to six determinations (mean ± SEM) are expressed in all experiments as fold changes relative to the control group which was arbitrarily set as one. Primers are available upon request.\n\n2.8. Western-Blot Analysis\nProtein extracts from tissue samples were obtained by ultrasonic membrane disruption in lysis buffer, containing Tris-HCl (pH 7.5) 100 mM, EDTA 10 mM, SDS 1%, NaF 100 mM, Na4PO2O7 10 mM, and sodium orthovanadate 10 mM, supplemented with protease inhibitor (Sigma). Protein concentration was determined by the Bradford method [19]. Fifty micrograms of total protein was loaded on a 12% SDS:acrylamide gel (SDS-PAGE) and separated by electrophoresis. Proteins were transferred to a nitrocellulose membrane in a semidry system and probed using a specific antibody for GLUT4 (1 : 1000; cat#2213; Cell Signaling) or GAPDH (1 : 1000; cat#2118; Cell Signaling) with incubation overnight at 4°C. Membrane was washed 15 min in TBS-T (Tween Tris-buffered saline solution) and incubated with secondary antibody goat anti-rabbit IgG (alkaline-phosphatase conjugated 1 : 1000; cat#D0487; Dako©, Glostrup, Denmark) for 1 hour at room temperature and posteriorly washed again for 15 min in TBS-T. Specific bands were visualized by enzymatic colorimetric NBT/BCIP (Roche, Mannheim, Germany).\n\n2.9. Data Analysis\nAll data obtained were analyzed using GraphPad Prism version 5.00.288 (GraphPad Software Inc. San Diego, CA, USA) and plotted as graphs. Data were submitted to Student's t-test to compare WT and MLC/mIGF-1 animals. All data are expressed as mean ± SEM.\n\n3. Results\nAs expected, MLC/mIGF-1 mice [8] presented a very selective and marked hypertrophy in the EDL muscle, which predominantly contains type II fast twitch fibers. This is supported by the 1.47-fold increment in wet weight in MLC/mIGF-1 EDL muscle (Figure 1(a)); on the other hand, no change in soleus wet weight was observed. Histochemical analysis clearly demonstrated an increase in incidence of fiber type IIb and decrease in the incidence of fiber type IIa/IId in the EDL of MLC/mIGF-1 animals when compared to WT animals (Figure 1(b)); on the other hand, the predominance of fiber types in the soleus muscle did not change (Figure 1(b)). We found that CSA of fiber types IIa/IId and IIb are increased in EDL muscle of MLC/mIGF-1 (Figures 1(c) and 1(d)) mice. Curiously, CSA of type IC/IIC and IIa fibers decreased in soleus muscle as compared to WT animals (Figures 1(c) and 1(d)). Because we have found increases in wet weight and CSA only in the EDL, we decided to proceed with further measurements exclusively in this muscle.\n\nAnalysis of biometric parameters of MLC/mIGF-1 mice revealed a very significant increase in body weight (37.4 ± 0.3 versus 31.8 ± 0.6 g, P < 0.0001, MLC/mIGF-1 and WT, resp., Table 1). This appears to be a major consequence of skeletal muscle hypertrophy, since there were no differences in fat mass and body fat composition (Table 1). Also, although MLC/mIGF-1 animals were heavier we did not find a difference in length between the two groups (Table 1). It was intuitive to assume that MLC/mIGF-1 mice would sustain greater skeletal muscle mass at the expense of higher food consumption. Nevertheless, we observed the same food intake per animal (not shown) in both groups and, more interestingly, lower food consumption in MLC/mIGF-1 mice compared to WT when corrected for body weight (Table 1). Because these data suggested increased metabolic efficiency in the MLC/mIGF-1 model, we decided to test this hypothesis by indirect calorimetry. Our next series of experiments showed a trend towards lower O2 consumption in MLC/mIGF-1 animals (Table 1). Although not significantly different, this trend was accompanied by a significantly higher respiratory quotient (RQ) (0.74 ± 0.02 versus 0.90 ± 0.03; P < 0.001 WT and MLC/mIGF-1 animals, resp.) (Table 1). According to the literature, these data strongly suggest higher oxidation of carbohydrates [16, 17], indicating increased utilization of carbohydrates as energy substrate in MLC/mIGF-1 mice.\n\nInterestingly, we did not find differences in total cholesterol, triglycerides, or fasting glucose (Table 1). Total epididymal fat, epididymal fat corrected for body weight and percentage of body fat determined by carcass analysis also showed no difference between WT and MLC/mIGF-1 mice (Table 1).\n\nSince the main metabolic difference observed between WT and MLC/mIGF-1 animals was a preference for carbohydrates as energy substrate, we determined insulin sensitivity in the animals by performing an ivITT. This test revealed a more pronounced curve of decay in MLC/mIGF-1 mice (Figure 2(a)). kITT determination from the ivITT showed a 2.4%/min and 3.25%/min rate of glucose disposal in WT and MLC/mIGF-1 animals, respectively, which represents a 35% increase in insulin-dependent glucose disposal in MLC/mIGF-1 mice (Figure 2(b)). The higher sensitivity to insulin in these animals was corroborated by higher levels of GLUT4 protein in EDL muscle (Figure 3), with ~2-fold upregulation in this tissue (P < 0.05) in comparison with WT groups.\n\nSince higher preference for carbohydrates was evident in the whole animal, we decided to investigate whether key genes involved in cell metabolism were affected in the EDL muscle. We found mRNA levels for PFK-1 (Phosphofructokinase 1), a rate-limiting enzyme in the glycolytic pathway [20], to be upregulated ~3-fold in EDL muscle of MLC/mIGF-1 mice compared to WT (Figure 4(a)). We also found mRNA for PGC1α, a key regulatory element in mitochondrion biogenesis [21], to be decreased by ~50% in EDL muscle of MLC/mIGF-1 mice compared to WT (Figure 4(b)).\n\nOn the other hand, fatty acid metabolism does not appear to be disturbed in EDL muscle of MLC/mIGF-1 mice, since the key regulatory elements, PPARβ/δ and PPARα [22, 23], were unaltered in these animals in comparison to WT (Figures 4(c) and 4(d)).\n\n4. Discussion\nIn the present study we have used a genetic model in which IGF1 is specifically expressed in fiber type II [8], allowing a better understanding of the specific hypertrophy of those upon metabolic profile.\n\nWe have observed quite unique features in MLC/mIGF-1 animal model, noteworthy, MLC/mIGF-1 animals presented relative lower food consumption despite higher muscle mass. Curiously, they have also a shift towards higher utilization of carbohydrate use as a fuel source, which is accompanied by increased insulin sensitivity. Although we have not specifically addressed the involved mechanisms, we reason that the higher whole body insulin sensitivity might be due to higher glucose uptake in type II skeletal muscle fibers, where the IGF-1 transgene is expressed. Indeed, this selective increased sensitivity was correlated with higher levels of GLUT4 protein in EDL suggesting that fast twitch muscles in IGF-1 transgenic animals have more capacity to uptake glucose. It has been described that mIGF-1 overexpression leads to increased activation of the PI3K/Akt/mTOR cascade [24, 25]. Since this cascade is involved in the regulation of GLUT4 expression, it could be a mechanism linking mIGF-1 and GLUT4 overexpression. Future studies are needed to better understand how GLUT4 levels are so highly elevated in MLC/mIGF-1 animals.\n\nA main outcome of the present study was the surprising finding that although the MLC/mIGF-1 animals clearly have increased muscle mass, no proportional increase in food intake was observed. In fact these animals consume, in absolute numbers, similar amount of food. Intriguingly, these animals have higher insulin sensitivity and higher carbohydrate utilization without requiring additional food intake or altered blood total cholesterol or triglycerides. Currently it is not clear why and how MLC/mIGF-1 animals can build more lean mass without more food intake. Possibilities include more efficient substrate gut absorption and less energy expenditure. A recently described myokine called irisin has been associated with activation of brown fat and consequently more energy expenditure in form of heat [26]. In addition, it has been shown that irisin expression is increased by PGC-1 alpha. Interestingly our results show that PGC-1 alpha expression is strongly reduced in MLC/mIGF-1 animals as compared to WT, raising the possibility that decreased activity of the PGC-1-irisin axis might be responsible for sparing the necessary fuel to build increased skeletal muscle in MLC/mIGF-1 animals.\n\nIt is currently not clear if the effects of IGF-1 increasing the use of carbohydrates observed in the present study are direct or rather a consequence of secondary changes in type II skeletal muscle fibers. It has been shown that exogenous administration of IGF1 to type 2 diabetes patients can improve insulin sensitivity [27]; therefore, a direct effect is possible. Another nonexclusive possibility involves secondary effects such as type II skeletal muscle fiber hypertrophy. In fact the MLC/mIGF1 animals have a consistent hypertrophy in those fibers and it has been shown that increased muscle mass can improve insulin sensitivity [28]. The metabolic consequence of increased insulin sensitivity in the MLC/mIGF1 animals could include resistance to the establishment of type II diabetes. Future studies submitting mIGF-1 hyperexpression animals to a long-term hypercaloric diet leading to increased body weight and also crossing these animals with ob/ob mice are warranted.\n\nTo our knowledge no studies systematically have addressed the effects of IGF1 upon fiber type shift. In our model we found a consistent shift in EDL towards a glycolytic profile. This effect might be mediated by decreasing the levels of PGC-1. It is well described that PGC-1 is a strong fiber type I inducer [29]. Another fiber type I inducer, the calciuneurin-NFATc1 axis, might be modulated by IGF1 increased levels [30]. Accordingly modulation of myogenin levels also remain as a possible mechanism since it has been shown to shift enzyme activity from glycolytic to oxidative metabolism [31].\n\nAlthough in the present study we have, as expected, detected hypertrophy of type II fibers (IIa/IId and IIb) in EDL muscle, intriguingly we have also seen a decrease in cross-sectional area in fibers IIa in soleus muscle. This unexpected finding might reveal a conditional hypertrophic effect of IGF1. For instance one might envisage that the fiber type I, which is the predominant fiber in this muscle, secretes a factor that can interfere with IGF1 hypertrophic action.\n\nIn conclusion, MLC/mIGF-1 mice have improved glucose homeostasis due to GLUT4-mediated higher insulin sensitivity. This improvement leads to a greater rate of carbohydrate utilization by the increased muscle, without interfering with other metabolic parameters.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFunding\nThis work was supported by FAPESP Grants nos. 2006/61523-7, 2006/59862-8, and 2012/22488-2 and CNPq Grant no. 301123/2010-1, PRIN, Telethon and ASI (to AM).\n\nFigure 1 (a) Wet weight of EDL and soleus muscles from WT (open bars) and MLC/mIGF-1 mice (filled bars). (b) Composition of each fiber type in EDL (type I, IIa/IId and IIb) and soleus (type I, IC/IIC and IIa) muscles from WT (open bars) and MLC/mIGF-1 mice (filled bars). (c) Cross-sectional area-CSA (μm2) of each fiber type in EDL and soleus muscles from WT (open bars) and MLC/mIGF-1 (filled bars) mice. (d) Serial cross-sections of the EDL and soleus muscles from WT and MLC/mIGF-1 mice muscle were submitted to histochemistry mATPase at pH 4.1 and 10.3. Data expressed as mean ± SEM. n = 4-5; *\nP < 0.05 versus WT muscles.\n\nFigure 2 Glucose disposal rate (a) and kITT values (b) for WT (open circles and solid line) and MLC/mIGF-1 animals (filled circles and dotted line). Data expressed as mean ± SEM. n = 5–7; *\nP < 0.001 versus WT.\n\nFigure 3 Representative western blot and densitometry of bands for GLUT4 protein expression in EDL muscle from WT (open bars) and MLC/mIGF-1 (filled bars) mice. Histogram represents the ratio of GLUT4:GAPDH densitometry values. Data are expressed as mean ± SEM. n = 4; *\nP < 0.05 versus WT.\n\nFigure 4 mRNA levels for (a) PFK-1, (b) PGC1α, (c) PPARα, and (d) PPARβ/δ in WT (open bars) and MLC/mIGF-1 (filled bars) mice. CycloA is an internal control. Data are expressed as mean ± SEM. n = 3–5; *\nP < 0.05 versus WT.\n\nTable 1 Biometric and metabolic parameters of wild type and MLC/mIGF-1 mice.\n\n \tWild type\tMLC/mIGF-1\t\nt-test\t\n \tMean\tSEM\t\nn\n\tMean\tSEM\t\nn\n\t\nBody weight (g)\t31.8\t0.6\t9\t37.4\t0.3\t6\t\nP < 0.0001\t\nAnimal length\t10.2\t0.05\t9\t10.4\t0.06\t6\tn.s.\t\nDaily food intake/body weight\t0.21\t0.007\t6\t0.18\t0.005\t6\t\nP < 0.05\t\nCholesterol (mg/dL)\t163\t1.4\t6\t166\t0.4\t6\tn.s.\t\nTriglycerides (mg/dL)\t118\t3.2\t6\t115\t5.3\t5\tn.s.\t\nGlucose (mg/dL)\t138\t9.7\t6\t150\t8.3\t6\tn.s.\t\nEpididymal WAT (g)\t0.4\t0.06\t9\t0.5\t0.05\t6\tn.s.\t\nEpididymal WAT/body weight\t1.2\t0.2\t9\t1.3\t0.1\t6\tn.s.\t\n% body fat\t4.7\t0.6\t5\t4.0\t0.6\t3\tn.s.\t\n\nO2 consumption (mL/min/kg)\t77.7\t6.3\t7\t67.2\t4.5\t7\tn.s.\t\nRespiratory quotient (RQ)\t0.74\t0.02\t7\t0.90\t0.03\t7\t\nP < 0.001\n==== Refs\n1 Miyabara E. H. Aoki M. S. Soares A. G. 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"mesh_terms": "D000818:Animals; D050260:Carbohydrate Metabolism; D051275:Glucose Transporter Type 4; D006984:Hypertrophy; D007328:Insulin; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria; D009124:Muscle Proteins; D018482:Muscle, Skeletal; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; D014157:Transcription Factors",
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"references": "7572227;15947969;4241609;22237023;12755;10938134;15157122;19646653;18355328;24867;3344216;15761233;16949353;16607124;10412986;19283669;17392536;11175789;18629230;12549594;10225962;16355022;22945298;16720625;942051;23805405;11927606;17876521;11828249;11715023;10433198",
"title": "Muscle IGF-1-induced skeletal muscle hypertrophy evokes higher insulin sensitivity and carbohydrate use as preferential energy substrate.",
"title_normalized": "muscle igf 1 induced skeletal muscle hypertrophy evokes higher insulin sensitivity and carbohydrate use as preferential energy substrate"
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"abstract": "Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for an ever-increasing number of cancers. However, their use has also led to the emergence of immune-related adverse events, such as ICI-induced inflammatory arthritis. A reproducible, reliable, and accessible modality is needed to assess and distinguish early ICI-induced inflammatory arthritis and help in management. Magnetic resonance imaging (MRI) of joints may be helpful for early diagnosis, guiding therapeutic decision-making, and identifying patients at high risk for erosive disease.\n\n\n\nTo assess the role of MRI of joints in patients with ICI-induced inflammatory arthritis.\n\n\n\nThis retrospective case series included patients enrolled at the National Institutes of Health Clinical Center in Bethesda, Maryland. Patients were evaluated by the rheumatology consultation service between December 27, 2016, and May 28, 2019. A retrospective health record review was performed to determine demographic characteristics, clinical characteristics of inflammatory arthritis and malignant tumors, and imaging findings. Inclusion criteria were patients who were enrolled on various institutional review board-approved protocols of ICIs, developed joint-related symptoms, and had MRI data for at least 1 joint. Data were analyzed from June 1, 2019, to September 1, 2019.\n\n\n\nUndergoing MRI of at least 1 joint.\n\n\n\nAll MRIs were reviewed for synovitis, tenosynovitis, bone marrow edema, and soft tissue conditions.\n\n\n\nA total of 8 patients (mean [SD] age, 58.8 [5.2] years; 6 women and 2 men) between the ages of 50 and 65 years who were undergoing ICI therapy for a variety of malignant tumors were included in this study. Only 1 patient was receiving combined ICI therapy. The results of 13 separate MRI examinations were reviewed. The most commonly performed MRIs were of the hands and wrists (9 MRIs), followed by knee examinations (3 MRIs). Tenosynovitis and synovitis were frequently seen in the hands and wrists. Bone marrow edema and erosions were also found in 3 patients, suggesting early damage. In larger joints (ie, knees and ankles), joint effusions and synovial thickening were characteristic. Most patients (5 patients) were treated with corticosteroids and had good responses. In patients with high-risk features on MRI imaging (eg, bone marrow edema, erosions), disease-modifying antirheumatic drug therapy was also discussed as a treatment option.\n\n\n\nThese findings suggest that advanced imaging may help to distinguish ICI-induced inflammatory arthritis from other causes of joint pain, aid in identifying patients at increased risk of joint damage, and provide utility in monitoring inflammatory arthritis treatment response in patients receiving ICI therapy.",
"affiliations": "Formerly Office of the Clinical Director, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland.;Office of the Clinical Director, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland.;Clinical Center, Radiology and Imaging Sciences, National Institutes of Health, Bethesda, Maryland.;Department of Internal Medicine, Alameda Health System, Oakland, California.;Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.;Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.;Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.;Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.;Office of the Clinical Director, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland.;Office of the Clinical Director, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland.;Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.;Intramural Research Program, Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland.;Office of the Clinical Director, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland.;Office of the Clinical Director, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland.",
"authors": "Subedi|Ananta|A|;Williams|Sandra G|SG|;Yao|Lawrence|L|;Maharjan|Suresh|S|;Strauss|Julius|J|;Sharon|Elad|E|;Thomas|Anish|A|;Apolo|Andrea B|AB|;Gourh|Pravitt|P|;Hasni|Sarfaraz A|SA|;Gulley|James L|JL|;Kaplan|Mariana J|MJ|;Katz|James D|JD|;Gupta|Sarthak|S|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological",
"country": "United States",
"delete": false,
"doi": "10.1001/jamanetworkopen.2020.0032",
"fulltext": "\n==== Front\nJAMA Netw Open\nJAMA Netw Open\nJAMA Netw Open\nJAMA Network Open\n2574-3805 American Medical Association \n\n10.1001/jamanetworkopen.2020.0032\nzoi200005\nResearch\nOriginal Investigation\nOnline Only\nOncology\nUse of Magnetic Resonance Imaging to Identify Immune Checkpoint Inhibitor–Induced Inflammatory Arthritis\nUse of Magnetic Resonance Imaging to Identify Immune Checkpoint Inhibitor–Induced Inflammatory ArthritisUse of Magnetic Resonance Imaging to Identify Immune Checkpoint Inhibitor–Induced Inflammatory ArthritisSubedi Ananta MD12 Williams Sandra G. MDPhD3 Yao Lawrence MD4 Maharjan Suresh MD5 Strauss Julius MD6 Sharon Elad MD7 Thomas Anish MD6 Apolo Andrea B. MD6 Gourh Pravitt MD3 Hasni Sarfaraz A. MD38 Gulley James L. MDPhD6 Kaplan Mariana J. MD8 Katz James D. MD3 Gupta Sarthak MD38 1 Formerly Office of the Clinical Director, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland\n2 WakeMed Physician Practices, Raleigh, North Carolina\n3 Office of the Clinical Director, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland\n4 Clinical Center, Radiology and Imaging Sciences, National Institutes of Health, Bethesda, Maryland\n5 Department of Internal Medicine, Alameda Health System, Oakland, California\n6 Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland\n7 Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland\n8 Intramural Research Program, Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland\nArticle Information\nAccepted for Publication: December 23, 2019.\n\nPublished: February 26, 2020. doi:10.1001/jamanetworkopen.2020.0032\n\nOpen Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Subedi A et al. JAMA Network Open.\n\nCorresponding Author: Sarthak Gupta, MD, Intramural Research Program, Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 10 Center Dr, Room 5-5521, Bethesda, MD 20892 (sarthak.gupta@nih.gov).Author Contributions: Dr Gupta had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Subedi and Williams contributed equally.\n\nConcept and design: Subedi, Williams, Sharon, Gourh, Gupta.\n\nAcquisition, analysis, or interpretation of data: Subedi, Williams, Yao, Maharjan, Strauss, Sharon, Thomas, Apolo, Hasni, Gulley, Kaplan, Katz, Gupta.\n\nDrafting of the manuscript: Subedi, Williams, Maharjan, Sharon, Apolo, Gupta.\n\nCritical revision of the manuscript for important intellectual content: All authors.\n\nAdministrative, technical, or material support: Yao, Strauss, Apolo, Gulley, Katz, Gupta.\n\nSupervision: Sharon, Apolo, Gourh, Hasni, Katz, Gupta.\n\nConflict of Interest Disclosures: Dr Yao reported serving on the voluntary staff of the Radiology and Imaging Sciences Department, Clinical Center, National Institutes of Health. No other disclosures were reported.\n\nFunding/Support: This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Center for Cancer Research, National Cancer Institute of the National Institutes of Health.\n\nRole of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.\n\n\n26 2 2020 \n2 2020 \n26 2 2020 \n3 2 e20003224 9 2019 23 12 2019 Copyright 2020 Subedi A et al. JAMA Network Open.This is an open access article distributed under the terms of the CC-BY License.jamanetwopen-3-e200032.pdfThis case series examines the use of magnetic resonance imaging to identify arthritis associated with use of immune checkpoint inhibitors in patients with cancer.\n\nKey Points\nQuestion\nCan magnetic resonance imaging assist with diagnosis and management of immune checkpoint inhibitor (ICI)–associated arthritis?\n\nFindings\nIn this case series of 8 patients with ICI-induced inflammatory arthritis, magnetic resonance imaging was used to identify synovitis and tenosynovitis as common features of ICI-induced inflammatory arthritis; erosive joint disease was less common but was also detected.\n\nMeaning\nThese findings suggest that magnetic resonance imaging may provide utility in distinguishing inflammatory arthritis from other causes of joint pain in patients receiving ICI therapy and identifying patients at increased risk of joint damage.\n\nImportance\nImmune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for an ever-increasing number of cancers. However, their use has also led to the emergence of immune-related adverse events, such as ICI-induced inflammatory arthritis. A reproducible, reliable, and accessible modality is needed to assess and distinguish early ICI-induced inflammatory arthritis and help in management. Magnetic resonance imaging (MRI) of joints may be helpful for early diagnosis, guiding therapeutic decision-making, and identifying patients at high risk for erosive disease.\n\nObjective\nTo assess the role of MRI of joints in patients with ICI-induced inflammatory arthritis.\n\nDesign, Setting, and Participants\nThis retrospective case series included patients enrolled at the National Institutes of Health Clinical Center in Bethesda, Maryland. Patients were evaluated by the rheumatology consultation service between December 27, 2016, and May 28, 2019. A retrospective health record review was performed to determine demographic characteristics, clinical characteristics of inflammatory arthritis and malignant tumors, and imaging findings. Inclusion criteria were patients who were enrolled on various institutional review board–approved protocols of ICIs, developed joint-related symptoms, and had MRI data for at least 1 joint. Data were analyzed from June 1, 2019, to September 1, 2019.\n\nExposures\nUndergoing MRI of at least 1 joint.\n\nMain Outcomes and Measures\nAll MRIs were reviewed for synovitis, tenosynovitis, bone marrow edema, and soft tissue conditions.\n\nResults\nA total of 8 patients (mean [SD] age, 58.8 [5.2] years; 6 women and 2 men) between the ages of 50 and 65 years who were undergoing ICI therapy for a variety of malignant tumors were included in this study. Only 1 patient was receiving combined ICI therapy. The results of 13 separate MRI examinations were reviewed. The most commonly performed MRIs were of the hands and wrists (9 MRIs), followed by knee examinations (3 MRIs). Tenosynovitis and synovitis were frequently seen in the hands and wrists. Bone marrow edema and erosions were also found in 3 patients, suggesting early damage. In larger joints (ie, knees and ankles), joint effusions and synovial thickening were characteristic. Most patients (5 patients) were treated with corticosteroids and had good responses. In patients with high-risk features on MRI imaging (eg, bone marrow edema, erosions), disease-modifying antirheumatic drug therapy was also discussed as a treatment option.\n\nConclusions and Relevance\nThese findings suggest that advanced imaging may help to distinguish ICI-induced inflammatory arthritis from other causes of joint pain, aid in identifying patients at increased risk of joint damage, and provide utility in monitoring inflammatory arthritis treatment response in patients receiving ICI therapy.\n==== Body\nIntroduction\nImmune checkpoint inhibitors (ICIs) first gained US Food and Drug Administration approval in 2011 after ipilimumab was found to be efficacious in metastatic melanoma.1 Since the approval of ipilimumab, ICIs have shown survival benefit in an increasing number of cancers. These therapies have demonstrated that the immune system can be effectively harnessed to aid in killing cancerous cells. However, their use has also led to the emergence of immune-related adverse events, such as ICI-induced inflammatory arthritis (ICI-IIA), which has been estimated to occur in approximately 2% of patients with cancer undergoing ICI treatments.2 Radiographic examinations are commonly performed as part of clinical evaluation; however, radiographs may not be useful during early phases of inflammatory arthritis (IA)3 and may only provide indirect information on synovial inflammation. Furthermore, radiographs have low sensitivity for early inflammatory bone involvement and damage. Indeed, despite evident clinical synovitis, patients who develop ICI-IIA typically only show evidence of degenerative changes on roentgenographs.4 Musculoskeletal ultrasonography may overcome some of these limitations, but its efficacy is operator-dependent and subject to significant variability in interpretation. In undifferentiated IA, magnetic resonance imaging (MRI) may detect factors associated with the progression to rheumatoid arthritis (RA).5 Magnetic resonance imaging findings of bone marrow edema, the combination of synovitis and erosions, and tenosynovitis are significant risk factors for RA progression.6 Additionally, MRI can be used to evaluate early changes in the joints and bones in patients with RA before such changes can be detected by other imaging modalities.7 Thus, we hypothesized that MRI may be useful to assess early arthritis related to ICI treatment. Anatomic localization of ICI-IIA with the use of MRI could also help in understanding the pathophysiological processes involved in this poorly characterized entity. We aimed to systematically evaluate MRI features of ICI-IIA in a cohort of patients with cancer who were undergoing other treatments at our center.\n\nMethods\nThis is a retrospective case series of patients who had given written informed consent and were enrolled in various other institutional review board–approved protocols at the National Institutes of Health Clinical Center in Bethesda, Maryland. All protocols required assessing the clinical activity and safety of immune checkpoint inhibitors, which forms the basis of the data used for this study. This report follows the reporting guideline for case series.8 All participants provided written consent to enroll in the respective institutional review board–approved protocols. Patients were evaluated by the rheumatology consultation service between December 27, 2016, and May 28, 2019. We reviewed the medical records of patients with ICI-IIA and identified patients who had undergone MRI evaluation of at least 1 joint as part of their clinical treatment at the onset of symptoms or presentation to our institute. These MRIs were performed for a variety of clinical indications, including exclusion of soft tissue injury or disease, evaluation for subclinical inflammation in patients whose physical findings of IA had resolved but who continued to experience joint pain, and evaluation for subclinical inflammation in a patient with physical examination findings consistent with chronic synovial thickening (ie, joints were swollen but neither warm nor tender). One MRI was also performed to evaluate a patient for progression of erosive disease. For anonymity, patients are identified as numbers between 1 and 8.\n\nAnalysis\nWith the exception of patients 3 and 7, all MRI examinations included contrast administration. All radiographs and MRIs were reviewed by a musculoskeletal (MSK) radiologist (L.Y.). The MRI assessments of IA included fat-suppressed T-weighted (or short tau inversion recovery sequences) and T1-weighted imaging, and intravenous contrast-enhanced, fat suppressed T1-weighted sequences. Magnetic resonance images were evaluated for the presence of erosion, marrow edema, arthrosis, effusion, synovitis, and tenosynovitis.9 Mean, median, and SD calculations were performed. Data were analyzed from June 1, 2019, to September 1, 2019.\n\nResults\nWe identified 8 patients (6 women and 2 men), between the ages of 50 and 65 years with mean (SD) age of 58.8 (5.2) years, who underwent MRI of the hands, wrists, knees, or ankles to evaluate MSK concerns that developed after the use of various ICIs (Table). The underlying cancer diagnoses among patients were variable. Joint symptoms started a median (range) duration of 10 (1-44) weeks after initiation of ICI treatment. All patients were undergoing ICI therapy at the time of initial evaluation by the rheumatology consultation service, with the exceptions of patient 4, who had stopped ICI therapy 6 months prior to evaluation, and patient 7, who had stopped ICI therapy 6 weeks prior to evaluation. Patients 3 and 8 were receiving ICI therapy at the time of imaging. The other patients had received their last dose of ICI therapy between 4 weeks and 6 months prior to imaging. On clinical evaluation by a rheumatology consultant, patients had minimal to moderate synovitis or tenosynovitis, and the joint concerns were determined to be clinically secondary to inflammatory disease rather than degenerative disease. Six patients had polyarticular symmetric arthritis, with predominant involvement of small joints, particularly of the wrist. Two patients (patients 6 and 7) had an oligoarticular pattern of joint involvement that affected a large joint.\n\nTable. Characteristics and MRI Findings of Patients With Immune Checkpoint Inhibitor Induced Inflammatory Arthritis\nPatient No./Sex\tPrimary Tumor\tICI\tICI Type\tPreexisting Joint Disease\tOnset of Symptoms, wka\tTime From Symptom Onset to MRI, wk\tAutoantibody Test Resultsb\tAcute Phase Reactantsc\tFindings\tAntitumor Response\tIA Management\t\nMSK Examination \tRadiographic\tMRI\t\n1/M\tKaposi sarcoma\tPembrolizumab\tAnti–PD-1\tTendinopathy (shoulder)\t2\t18\tNegative for RF, CCP, ENA, and ANA\tCRP = 13.3 mg/L; ESR = 51 mm/h\tDactylitis, limited passive to active ROM of shoulders, and synovitis in wrists, MCPs, and PIPs \tShoulders: AC joint OA; knee: small effusion; wrists, hands, and feet: unremarkable\tHand: tenosynovitis of bilateral flexor tendons (first though fourth)\tComplete \tICI therapy discontinued and high-dose corticosteroids (1 mg/kg) administered with slow taper\t\n2/M\tThyroid cancer\tPembrolizumab\tAnti–PD-1\tTendinopathy (shoulder), metastatic disease (pelvis)\t4\t1\tCCP >125; RF = 84; negative for ANA and ENA\tCRP = 270 mg/L; ESR = 127 mm/h\tShoulder IA (BL), left biceps tendinitis, first extensor compartment tenosynovitis, effusion in knees, and synovitis in elbows, wrists, PIPs, and knees;\tWrists and hands: Periarticular osteopenia and erosions; left shoulder: unremarkable; feet: degenerative changes\tHand: synovitis of fourth and fifth MCP joint, marginal erosions, and tenosynovitis of the extensor and flexor compartment; periarticular marginal bone marrow edema in carpals and metacarpals\tProgressive disease\tICI therapy held; good response to 20 mg/d for 2 wk followed by taper\t\n3/F\tUrothelial carcinoma\tNivolumab\tAnti–PD-1\tOA (hands and knees)\t16\t9\tNegative for RF, CCP, ENA, and ANA\tCRP = 6 mg/L; ESR = 57 mm/h\tBilateral first extensor compartment tenosynovitis and arthralgias of wrists, hands, shoulders, knees, and feet\tWrists and hands: degenerative changes\tHand: tenosynovitis of first and sixth extensor compartments\tStable disease\tICI therapy held briefly and high-dose acetaminophen and occupational therapy administered\t\n4/F\tCervical cancer\tNivolumab\tAnti–PD-1\tNone\t4\t80\tNegative for RF, CCP, ENA, and ANA\tCRP = 11.3 mg/L; ESR = 48 mm/h\tElbow contractures, restricted subtalar motion, swan neck deformities, effusion in knees, and synovitis in knees, MCPs, PIPs, and wrists\tWrists and hands: joint deformities and diffuse osteopenia; feet and ankles: periarticular osteopenia and bilateral pes planus\tHand: multifocal osseous erosions involving distal radius, distal ulna, carpal bones, and metacarpal bones, synovitis of intercarpal joints, tenosynovitis involving the flexor and extensor tendons at the wrist\tStable disease\tNSAIDs and intraarticular corticosteroids administered\t\n5/F\tColon cancer\tAvelumab\tAnti–PD-L1\tNone\t28\t16\tANA = 4.4 ELISA units; negative for dsDNA, ENA, RF, and CCP\tCRP = 10.7 mg/L; ESR = 38 mm/h\tEffusion in knees and synovitis in wrists, MCPs, PIPs, and knees\tNP\tHand: no erosions, tenosynovitis, or synovitis\tProgressive disease\tHeld ICI therapy, prednisone administered with taper, and ICI shortly thereafter discontinued given disease progression\t\n6/F\tPheochromocytoma\tNivolumab and ipilimumab\tAnti–PD-1 and anti–CTLA-4\tNone\t24\t2\tNegative for RF, CCP, ENA, and ANA\tCRP = 127 mg/L; ESR = 100 mm/h\tEffusion in knees and synovitis in knees and right wrist\tNP\tKnee: moderate effusion and diffuse thickening of synovium\tProgressive disease\tHeld ICI therapy and therapeutic arthrocentesis, intraarticular corticosteroids, and prednisone 20 mg administered followed by taper\t\n7/F\tCervical cancer\tBintrafusp alfa\tAnti–PD-L1 and TGF-βRII trap\tNone\t44\t24\tANA = 2.3 ELISA units; negative for RF and CCP\tCRP = 107 mg/L; ESR = 111 mm/h\tEffusion and synovitis in left ankle and knees\tBilateral knees: minimal degenerative changes; bilateral ankles: soft-tissue swelling\tAnkle: complex joint effusion, thickening of tibiotalar joint synovium, and peroneal tenosynovitis\tComplete \tICI stopped approximately 6 wk prior to symptom onset owing to another irAE, prednisone 20 mg administered, and methotrexate added given inability to wean steroids\t\n8/F\tLung cancer\tBintrafusp alfa\tAnti–PD-L1 and TGF-βRII trap\tSeronegative RA\t1\t13\tANA = 3 ELISA units; negative for RF, CCP, and ENA\tCRP = 8.4 mg/L; ESR = 62 mm/h\tAC joint warmth, TTP, first compartment tenosynovitis, and synovitis in wrists, MCPs, and PIPs\tHands and wrists: multifocal erosions; shoulders: unremarkable; knees: subtle narrowing of medial compartment on left side\tHand: erosions at the radial styloid and carpal bones; wrist: synovitis and tenosynovitis of the flexor and extensor tendons \tPartial \tICI continued and NSAIDs administered for IA\t\nAbbreviations: AC, acromioclavicular; ANA, antinuclear antibody; BL, bilateral; CCP, cyclic citrullinated peptide; CRP, C-reactive protein; CTLA-4, anti-cytotoxic T-lymphocyte-associated protein-4; dsDNA, double-stranded DNA; ENA, extractable nuclear antigen; ELISA, enzyme-linked immunosorbent assay; ESR, erythrocyte sedimentation rate; F, female; IA, inflammatory arthritis; ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; M, male; MCP, metacarpophalangeal; MRI, magnetic resonance imaging; MSK, musculoskeletal; NP, not performed; NSAID, nonsteroidal anti-inflammatory drug; OA, osteoarthritis; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand 1; PIP, proximal interphalangeal; RA, rheumatoid arthritis; RF, rheumatoid factor; ROM, range of motion; TGF-βRII, transforming growth factor β receptor II; TTP, tenderness to palpation.\n\nSI conversion factor: To convert CRP to nanomoles per liter, multiply by 9.524.\n\na Indicates the time between initiation of ICI therapy and the onset of MSK joint pain.\n\nb Laboratory thresholds for negative results: RF, less than 15 ELISA units; CCP, less than 20 ELISA units; ANA, less than 1 ELISA units; ENA, less than 20 ELISA units. Inflammatory markers were obtained at the time of initial rheumatologic evaluation.\n\nc Reference ranges for ESR, 0 to 25 mm/h; for CRP, 0 to 4.99 mg/L.\n\nPatient 6 presented with persistent unilateral involvement of the knee and subsequently developed contralateral knee and unilateral wrist inflammatory arthritis. This patient had an acute initial presentation of monoarthritis with elevated inflammatory markers (Table). On evaluation by the rheumatology consultation service, she underwent a knee joint aspiration, with synovial fluid consistent with IA, showing minimal red blood cells, elevated white blood cell count (45 000 cells/μL; to convert to ×109 per liter, multiply by 0.001) with preponderance of neutrophils (90%). No crystals were seen, and synovial fluid cultures were negative for aerobic, anaerobic, mycobacterial and fungal organisms.\n\nPatient 7 presented with inflammatory arthritis of the knees and ankles. Most patients (5 patients) also had prominent tenosynovitis. Consistent with other case series,10,11 symmetric polyarticular arthritis was seen more commonly in patients receiving ICI monotherapy (6 of 7 patients who received ICI monotherapy). Acute phase reactants and autoantibodies, including antinuclear, rheumatoid factor, and anti–cyclic citrullinated peptide antibodies were tested in all patients. Three patients (patients 5, 7, and 8) had a positive test results for antinuclear antibodies, and 1 patient (patient 2) had positive results for high-titer rheumatoid factor and anti–cyclic citrullinated peptide autoantibodies. Antinuclear antibody test results for patient 5 were positive for low-titer (1.1 enzyme-linked immunosorbent assay units) prior to starting ICI therapy. We did not have data on pre–ICI initiation autoantibody status for any other patient.\n\nMRI Findings\nOf 13 MRIS reviewed, the most commonly performed MRIs were of the hands and wrists (9 MRIs), followed by knee examinations (3 MRIs); 1 MRI was performed on a patient’s ankle. Magnetic resonance imaging findings of the small joints (eg, hands) included multicompartment tenosynovitis and bone marrow edema, whereas joint effusion and synovial thickening were observed in large joints (eg, knees and ankles) (Figure 1). Erosions were identified by MRI in 3 patients (patients 2, 4, and 8). Patient 2 did not have a history of IA, but MRI performed 4 weeks after onset of symptoms revealed synovitis, tenosynovitis, bone marrow edema, and erosions (Figure 2). This patient was also found to have elevated levels of anti–cyclic citrullinated peptide autoantibodies, characteristic of RA.\n\nFigure 1. Magnetic Resonance Image of the Knee and Ankle of an Individual With Cervical Cancer and Immune Checkpoint Inhibitor–Induced Inflammatory Arthritis (Patient 7)\nA, Sagittal fat-suppressed, proton density fast spin-echo image of the left knee depicts extensive, irregular synovial thickening (blue arrows) at the anterior and posterior aspects of the knee and bone marrow edema (asterisk). B, Sagittal image of the left ankle from a short tau inversion recovery sequence demonstrating synovial thickening at the tibiotalar joint (blue arrows), tenosynovitis (pink arrows), and periarticular bone marrow edema (asterisk).\n\nFigure 2. Magnetic Resonance Image of Bilateral Hands in an Individual With Thyroid Cancer With Inhibitor–Induced Inflammatory Arthritis (Patient 2)\nA, T1-weighted image of both hands reveals multiple marginal osseous erosions (pink arrows). B, Coronal maximum intensity projection image of both hands, generated from gadolinium contrast enhanced T1-weighted 3-dimensional gradient echo images, shows synovial enhancement at metacarpophalangeal, proximal interphalangeal and intercarpal joints (blue arrows), as well as tenosynovitis (pink arrows).\n\nAs reported previously,12 patient 4 developed arthritis 4 weeks after nivolumab initiation. Despite persistent IA, ICI was continued for 1 year owing to the patient’s apprehension of stopping ICI treatment or receiving systemic therapies for her symptoms, during which period she developed erosive disease with fixed joint deformities. This occurred prior to her clinical trial enrollment at National Institutes of Health. She was followed closely by the rheumatology consultation service for recurrence of IA after she was enrolled on a protocol for bintrafusp alfa, a bifunctional fusion protein composed of the extracellular domain of the transforming growth factor β receptor (TGF-βRII) to function as a TGF-β trap fused to a human IgG1 antibody, blocking programmed cell death ligand 1. Patient 4 had clinical evidence of mild IA but was reluctant to pursue systemic therapy. Follow-up MRI 6 months after initiation of therapy demonstrated persistent synovitis and tenosynovitis but did not demonstrate any new erosions or enlargement of existing erosions when compared with the MRI obtained at the initiation of treatment.\n\nPatient 8 had a history of seronegative RA and positive antinuclear antibody test results. Her arthritis had been in remission without therapy until she developed new onset of joint pain after the initiation of ICI; we do not have records regarding existence of erosions prior to the initiation of ICI therapy.\n\nManagement of ICI-IIA\nIn our cohort, ICI therapy was held or discontinued in all but 2 patients. The decisions to discontinue ICI therapy were made for several reasons. For patient 1, ICI therapy was discontinued because of MSK complications; this patient had experienced complete response to ICI therapy. For other patients, ICI therapy was discontinued for reasons including disease progression, infectious complications, and other immune-related adverse events. Three patients were treated successfully with nonsteroidal anti-inflammatory drugs or acetaminophen for systemic therapy; 1 of these patients also received intraarticular corticosteroids. The remaining 5 patients experienced complete resolution of their symptoms with various doses of oral prednisone (most patients received 20 mg daily as the initial dose) tapered over a median (range) duration of 5 (2-10) months. Only 1 patient (patient 7) required the addition of methotrexate, a disease modifying antirheumatic drug, which was self-discontinued after 6 months owing to resolution of symptoms. Given erosive disease identified on MRI, patients 2 and 4 were recommended disease modifying antirheumatic drug therapy. However, patient 2 developed serious infectious complications before this was initiated, and patient 4 was very reluctant to use systemic therapy given the perception that it might interfere with her cancer treatment.\n\nDiscussion\nThis case series found that MRI may be a valuable tool for evaluating ICI-IIA. There is limited evidence regarding the optimal disease assessment tools to distinguish ICI-induced arthralgias from other forms of IA. Physical and radiographic examinations are insensitive for early changes of IA. This could possibly explain the difference in the reported prevalence of arthralgias (from 1% up to 43%)13 vs only about 2% for ICI-IIA. Studies detailing the imaging findings of ICI-IIA are sparse. A 2018 study reported that use of radiography in 5 patients showed swelling in soft tissues and narrowing of joint spaces.14 In 2 of these patients, MRI demonstrated synovial hyperemia and hyperplasia with adjacent bone marrow edema.14 Other previously reported findings include joint effusion, tenosynovitis, and the presence of erosive arthritis in 1 patient.4,15 Another option for joint evaluation is MSK ultrasonography, which shows a variety of findings but is dependent on the availability of a trained and experienced operator.16\n\nIn patients with undifferentiated inflammatory arthritis, specific MRI findings, such as bone marrow edema, both synovitis and erosions, and flexor tenosynovitis, were associated with the development of RA.6 In a 2011 study,5 bone marrow edema detected on MRI of the metatarsophalangeal and wrist joints was associated with RA progression in 82% of patients with early undifferentiated arthritis. Once rheumatoid arthritis has been diagnosed, MRI is a sensitive test to detect early erosive changes.9 These studies all suggest that MRI may be a valuable tool for evaluating ICI-IIA.\n\nIn our study, we identified tenosynovitis and synovitis on MRI as common and early radiological features in ICI-IIA, even in patients with minimal symptoms. A subset of 6 patients presented symptoms associated with more aggressive forms IA, including bone marrow edema (3 patients) and osseous erosions (3 patients). The prevalence of erosive ICI-IIA is unknown, to our knowledge. Studies by Richter et al2 and Cappelli et al13 did not describe osseous erosions as a feature of ICI-IIA. However, in more recent studies, early erosive lesions have been detected by ultrasonography or MRI in a small subset of patients.4,15,16 Our findings suggest that erosions may be fairly common and underreported in the absence of sensitive tests, like MRI. Given these findings, it is possible that erosions can occur soon after the onset of symptoms, especially in patients with serologic test results positive for autoantibodies or patients who are partially treated and whose erosive ICI-IIA may represent a much more rapid, aggressive process than is seen in patients with RA.\n\nLimitations\nThis study has some limitations. Immune checkpoint inhibitor–induced inflammatory arthritis remains a rare and underrecognized entity that has only recently been described, and our small retrospective case series may limit the generalizability of the study. Also, owing to the heterogeneity of our patient population with respect to the types of cancer and the types of ICIs used, the associations of these variables were difficult to assess. Some patients were already using steroids before undergoing MRI evaluation, and this may have diminished the inflammatory changes on MRI in some of the patients, such as patients 1 and 5. While we did see inflammatory changes on evaluations of 2 patients (patients 3 and 7) who were not administered contrast owing to clinical contraindications, this may also have limited the extent of our findings. Patients in our cohort with autoantibodies offer an insight into the pathogenesis and evolution of this entity; however, because of the retrospective nature of this study, we were unable to assess pretreatment imaging or serologic test results in all the patients, so these are considerations for future prospective studies.\n\nConclusions\nThe findings of this case series suggest that MRI may be useful for early detection of erosive disease, as well as to help identify patients at high risk for erosive disease, and thus guide medical decision-making regarding management of ICI-IIA. This study supports the role of MRI as an important tool in the assessment of ICI-induced articular symptoms. A prospective study of MRI may be fruitful for understanding the pathophysiological processes and long-term clinical implications of this entity. Quantitative measurements through MRI in future studies could potentially help standardize the grading of this adverse event to guide treatment stratification, prevent prolonged exposure to high-dose systemic steroids, and allow early resumption of anticancer therapy.\n==== Refs\nReferences\n1 Hodi FS , O’Day SJ , McDermott DF , \nImproved survival with ipilimumab in patients with metastatic melanoma\n. N Engl J Med . 2010 ;363 (8 ):-. doi:10.1056/NEJMoa1003466 \n20525992 \n2 Richter MD , Crowson C , Kottschade LA , Finnes HD , Markovic SN , Thanarajasingam U \nRheumatic syndromes associated with immune checkpoint inhibitors: a single-center cohort of sixty-one patients\n. Arthritis Rheumatol . 2019 ;71 (3 ):468 -475\n. doi:10.1002/art.40745 \n30281202 \n3 van der Heijde DM , van Leeuwen MA , van Riel PL , \nBiannual radiographic assessments of hands and feet in a three-year prospective followup of patients with early rheumatoid arthritis\n. Arthritis Rheum . 1992 ;35 (1 ):26 -34\n. doi:10.1002/art.1780350105 \n1731813 \n4 Mooradian MJ , Nasrallah M , Gainor JF , \nMusculoskeletal rheumatic complications of immune checkpoint inhibitor therapy: A single center experience\n. Semin Arthritis Rheum . 2019 ;48 (6 ):1127 -1132\n. doi:10.1016/j.semarthrit.2018.10.012 30409415 \n5 Duer-Jensen A , Hørslev-Petersen K , Hetland ML , \nBone edema on magnetic resonance imaging is an independent predictor of rheumatoid arthritis development in patients with early undifferentiated arthritis\n. Arthritis Rheum . 2011 ;63 (8 ):2192 -2202\n. doi:10.1002/art.30396 \n21484772 \n6 Eshed I , Feist E , Althoff CE , \nTenosynovitis of the flexor tendons of the hand detected by MRI: an early indicator of rheumatoid arthritis\n. Rheumatology (Oxford) . 2009 ;48 (8 ):887 -891\n. doi:10.1093/rheumatology/kep136 19474128 \n7 Kleyer A , Krieter M , Oliveira I , \nHigh prevalence of tenosynovial inflammation before onset of rheumatoid arthritis and its link to progression to RA-A combined MRI/CT study\n. Semin Arthritis Rheum . 2016 ;46 (2 ):143 -150\n. doi:10.1016/j.semarthrit.2016.05.002 27342772 \n8 Kempen JH \nAppropriate use and reporting of uncontrolled case series in the medical literature\n. Am J Ophthalmol . 2011 ;151 (1 ):7 -10.e1, e1\n. doi:10.1016/j.ajo.2010.08.047 21163373 \n9 Østergaard M , Hansen M , Stoltenberg M , \nNew radiographic bone erosions in the wrists of patients with rheumatoid arthritis are detectable with magnetic resonance imaging a median of two years earlier\n. Arthritis Rheum . 2003 ;48 (8 ):2128 -2131\n. doi:10.1002/art.11076 \n12905465 \n10 Cappelli LC , Brahmer JR , Forde PM , \nClinical presentation of immune checkpoint inhibitor-induced inflammatory arthritis differs by immunotherapy regimen\n. Semin Arthritis Rheum . 2018 ;48 (3 ):553 -557\n. doi:10.1016/j.semarthrit.2018.02.011 \n29573850 \n11 Smith MH , Bass AR \nArthritis after cancer immunotherapy: symptom duration and treatment response\n. Arthritis Care Res (Hoboken) . 2019 ;71 (3 ):362 -366\n. doi:10.1002/acr.23467 \n29125905 \n12 Subedi A , Strauss J , Gupta S \nErosive deforming inflammatory arthritis in a patient with cervical adenocarcinoma\n. JAMA Oncol . 2019 . doi:10.1001/jamaoncol.2019.3140 \n31556909 \n13 Cappelli LC , Gutierrez AK , Bingham CO III, Shah AA \nRheumatic and musculoskeletal immune-related adverse events due to immune checkpoint inhibitors: a systematic review of the literature\n. Arthritis Care Res (Hoboken) . 2017 ;69 (11 ):1751 -1763\n. doi:10.1002/acr.23177 \n27998041 \n14 Mekki A , Dercle L , Lichtenstein P , \nDetection of immune-related adverse events by medical imaging in patients treated with anti-programmed cell death 1\n. Eur J Cancer . 2018 ;96 :91 -104\n. doi:10.1016/j.ejca.2018.03.006 29698933 \n15 Cappelli LC , Gutierrez AK , Baer AN , \nInflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab\n. Ann Rheum Dis . 2017 ;76 (1 ):43 -50\n. doi:10.1136/annrheumdis-2016-209595 \n27307501 \n16 Albayda J , Dein E , Shah AA , Bingham CO III, Cappelli L \nSonographic findings in inflammatory arthritis secondary to immune checkpoint inhibition: a case series\n. ACR Open Rheumatol . 2019 ;1 (5 ):303 -307\n. doi:10.1002/acr2.1026 \n31777806\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2574-3805",
"issue": "3(2)",
"journal": "JAMA network open",
"keywords": null,
"medline_ta": "JAMA Netw Open",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D001172:Arthritis, Rheumatoid; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007596:Joints; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D012189:Retrospective Studies",
"nlm_unique_id": "101729235",
"other_id": null,
"pages": "e200032",
"pmc": null,
"pmid": "32101306",
"pubdate": "2020-02-05",
"publication_types": "D016428:Journal Article; D052060:Research Support, N.I.H., Intramural",
"references": "27342772;27307501;20525992;29125905;19474128;21163373;21484772;30409415;27998041;31556909;1731813;29573850;12905465;30281202;29698933;31777806",
"title": "Use of Magnetic Resonance Imaging to Identify Immune Checkpoint Inhibitor-Induced Inflammatory Arthritis.",
"title_normalized": "use of magnetic resonance imaging to identify immune checkpoint inhibitor induced inflammatory arthritis"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-026898",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "The taxanes are chemotherapeutic agents that may, in rare cases, cause cystoid macular edema without leakage on fluorescein angiography. Two patients with evidence of taxane-related macular edema presented and were evaluated using novel en face optical coherence tomography (OCT) and OCT angiography (OCTA) imaging modalities. Although OCTA revealed no flow abnormalities in either patient, en face OCT revealed a striking bilateral symmetric cystic tessellation pattern.",
"affiliations": null,
"authors": "Sridhar|Jayanth|J|;Shahlaee|Abtin|A|;Ehmann|David|D|;Samara|Wasim A|WA|;Rahimy|Ehsan|E|;Ho|Allen C|AC|;Chiang|Allen|A|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.3928/23258160-20160126-12",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-8160",
"issue": "47(2)",
"journal": "Ophthalmic surgery, lasers & imaging retina",
"keywords": null,
"medline_ta": "Ophthalmic Surg Lasers Imaging Retina",
"mesh_terms": "D000368:Aged; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D008269:Macular Edema; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D010190:Pancreatic Neoplasms; D041623:Tomography, Optical Coherence; D014792:Visual Acuity",
"nlm_unique_id": "101599215",
"other_id": null,
"pages": "176-9",
"pmc": null,
"pmid": "26878452",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "En Face Optical Coherence Tomography and Optical Coherence Tomography Angiography Imaging of Taxane-Associated Cystoid Macular Edema.",
"title_normalized": "en face optical coherence tomography and optical coherence tomography angiography imaging of taxane associated cystoid macular edema"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0083740",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Cytomegalovirus (CMV) nephropathy may be seen in kidney transplant biopsy specimens. We report a CMV-negative patient who received a kidney transplant from a CMV-positive donor and subsequently developed CMV glomerulopathy and CMV-associated interstitial nephritis, as observed in 2 sequential kidney biopsies. The first biopsy specimen showed CMV-positive endothelial cells in glomerular capillaries and CMV-infected monocytes in glomerular capillary lumens. The second biopsy specimen showed CMV-positive cells in the interstitium with associated lymphoplasmacytic infiltrate and tubular injury, but no evidence of direct CMV infection in tubular epithelial cells. Moreover, the second biopsy specimen showed persistent monocytes with cytoplasmic viral particles within glomerular capillary loops by electron microscopy. Our case shows that CMV glomerulopathy can be caused by direct CMV infection of glomerular capillary endothelial cells. CMV-positive circulating monocytes may play an important role in the different histopathologic manifestations of CMV nephropathy in kidney transplant grafts.",
"affiliations": "Department of Medicine, Yale University School of Medicine, New Haven, CT.;Department of Medicine, Yale University School of Medicine, New Haven, CT.;Department of Pathology, Yale University School of Medicine, New Haven, CT. Electronic address: gilbert.moeckel@yale.edu.",
"authors": "Vichot|Alfred A|AA|;Formica|Richard N|RN|;Moeckel|Gilbert W|GW|",
"chemical_list": "D004279:DNA, Viral",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "63(3)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Transplant; cytomegalovirus (CMV) glomerulopathy; monocytes; tubular injury",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D001706:Biopsy; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004279:DNA, Viral; D003937:Diagnosis, Differential; D005500:Follow-Up Studies; D006801:Humans; D007668:Kidney; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial; D016133:Polymerase Chain Reaction",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "536-9",
"pmc": null,
"pmid": "24568687",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9921804;11807689;9041220;2850879;19414839;9355085;6295675;9349229;11274291;3009956;12201373;1965736;9142156;16406798;23194390;8023832;2821814;22483475;2833827;6264291",
"title": "Cytomegalovirus glomerulopathy and cytomegalovirus interstitial nephritis on sequential transplant kidney biopsies.",
"title_normalized": "cytomegalovirus glomerulopathy and cytomegalovirus interstitial nephritis on sequential transplant kidney biopsies"
} | [
{
"companynumb": "US-APOTEX-2017AP019423",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null... |
{
"abstract": "Ephenidine, diphenidine, and methoxphenidine belong to the family of diarylethylamines that are psychoactive substances derived from lefetamine (N, N-di-methyl-1,2-diphenylethylamine, also called L-SPA). These dissociative anesthetic compounds act as potent and selective N-methyl-d-aspartate receptor antagonists and were recently classified as narcotic drugs in France. The available data suggest a significant risk of psychic and somatic complications. To obtain more information, this retrospective study analyzed all spontaneous notifications of serious cases of ephenidine, diphenidine, and methoxphenidine abuse collected by the French Addictovigilance Network from 2012 to 2016 and classified them as proven, probable, and possible. For each case, age, sex, concomitantly ingested substances, pattern of abuse of psychoactive drugs, and related complications (scored using the poisoning severity score) were collected. Eighteen cases were identified (one in 2013, five in 2015, and 12 in 2016) in 16 men (median age: 31.5 years [IQR 25-75% 27-34]). Ephenidine, diphenidine, and methoxphenidine were involved in four, seven, and 11 cases, respectively. No case was considered proven, 16 cases were considered possible, and two probable due to polysubstance abuse (co-ingestion of other new psychoactive substances). The reported clinical complications were minor in five cases, moderate in six cases, and serious in four cases, and included psychiatric, neurologic, and cardiovascular problems. This analysis indicates that the number of reported cases progressively increased from 2012 to 2016 and mainly concerned methoxphenidine. The addictive potential of these substances seems highly probable; but further investigations are needed to limit their harmful effects.",
"affiliations": "Département de Pharmacologie Médicale et Toxicologie, Centre d'Addictovigilance, CHRU de Montpellier, 34294, Montpellier Cedex, France.;Département de Pharmacologie Médicale et Toxicologie, Centre d'Addictovigilance, CHRU de Montpellier, 34294, Montpellier Cedex, France.;Département de Pharmacologie Médicale et Toxicologie, Centre d'Addictovigilance, CHRU de Montpellier, 34294, Montpellier Cedex, France.;Département de Pharmacologie Médicale, Centre d'Addictovigilance, Nord-Pas-de-Calais, CHRU de Lille, 59037, Lille Cedex, France.;Département de Pharmacologie Clinique, Centre d'Addictovigilance, CHU de Nantes, 44093, Nantes Cedex 1, France.;Département de Pharmacologie Médicale, Centre d'Addictovigilance, CHU de Caen, 14033, Caen Cedex 9, France.;Centre d'Addictovigilance, Hôpital Central, CHRU de Nancy, 54035, Nancy Cedex, France.;ANSM Agence Nationale de Sécurité du Médicament et des Produits de Santé, 93285, Saint-Denis, France.;Département de Pharmacologie Médicale, Centre d'Addictovigilance, CHU de Grenoble, 38043, Grenoble Cedex 9, France.;Centre d'Addictovigilance de Lyon, CHU de Lyon, 69424, Lyon Cedex 03, France.;Département de Pharmacologie Médicale et Toxicologie, Centre d'Addictovigilance, CHRU de Montpellier, 34294, Montpellier Cedex, France.",
"authors": "Eiden|Céline|C|http://orcid.org/0000-0002-7839-9811;Leone-Burgos|Sarah|S|;Serre|Anaïs|A|;Carton|Louise|L|;Gerardin|Marie|M|;Le Boisselier|Reynald|R|;Gibaja|Valérie|V|;Monzon|Emilie|E|;Fouilhe|Nathalie|N|;Boucher|Alexandra|A|;Peyriere|Hélène|H|;|||",
"chemical_list": "D010627:Phenethylamines; D010880:Piperidines; D011619:Psychotropic Drugs; C000621156:ephenidine; C000595747:1-(1-(2-methoxyphenyl)-2-phenylethyl)piperidine; C000599677:diphenidine",
"country": "England",
"delete": false,
"doi": "10.1111/fcp.12395",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0767-3981",
"issue": "32(6)",
"journal": "Fundamental & clinical pharmacology",
"keywords": "diphenidine; ephenidine; methoxphenidine; recreational use; toxicity",
"medline_ta": "Fundam Clin Pharmacol",
"mesh_terms": "D000328:Adult; D005602:France; D006801:Humans; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D010627:Phenethylamines; D010880:Piperidines; D011619:Psychotropic Drugs; D012189:Retrospective Studies; D019966:Substance-Related Disorders; D055815:Young Adult",
"nlm_unique_id": "8710411",
"other_id": null,
"pages": "654-662",
"pmc": null,
"pmid": "29956843",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ephenidine, diphenidine, and methoxphenidine complications reported to the French Addictovigilance Network.",
"title_normalized": "ephenidine diphenidine and methoxphenidine complications reported to the french addictovigilance network"
} | [
{
"companynumb": "FR-LANNETT COMPANY, INC.-FR-2019LAN000115",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OXYCODONE HYDROCHLORIDE"
},
"... |
{
"abstract": "OBJECTIVE\nTo describe the first reported successful use of adjunctive linezolid bladder irrigation.\n\n\nMETHODS\nAn 89-year-old woman with 10% TBSA burns developed septic shock and anuric acute kidney insufficiency. She acquired a urinary tract infection caused by vancomycin-resistant Enterococcus faecium (VREfm). Based on clinical status, a linezolid bladder irrigation was initiated in addition to high-dose intravenous linezolid and demonstrated microbiological cure with 7 days of treatment.\n\n\nCONCLUSIONS\nLinezolid is primarily hepatically cleared and has no labeled indication for urinary tract infections. Anuria adds an additional complication of potentially reduced urinary drug concentrations. Bladder irrigation offers the benefit of achieving high local drug concentrations, but there are no data regarding such a route for linezolid. This case report is the first demonstrating the use, stability, safety, and efficacy of linezolid as a continuous bladder irrigation.\n\n\nCONCLUSIONS\nLinezolid use as a bladder irrigation may be a feasible route of administration in anuric, critically ill patients with VREfm and few antimicrobial options. Further studies are warranted.",
"affiliations": "Regional One Health, Memphis, TN, USA dmhill@regionalonehealth.org.;University of Tennessee Health Science Center College of Pharmacy, Memphis, TN, USA.;University of Tennessee Health Science Center College of Medicine, Memphis, TN, USA.",
"authors": "Hill|David M|DM|;Wood|G Christopher|GC|;Hickerson|William L|WL|",
"chemical_list": "D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D000069349:Linezolid",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028014563066",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "49(2)",
"journal": "The Annals of pharmacotherapy",
"keywords": "bladder irrigation; burns; linezolid; urinary tract infection; vancomycin-resistant Enterococcus",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000081:Acetamides; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D003428:Cross Infection; D016984:Enterococcus faecium; D017809:Fatal Outcome; D005260:Female; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D000069349:Linezolid; D023303:Oxazolidinones; D007507:Therapeutic Irrigation; D001743:Urinary Bladder; D014552:Urinary Tract Infections; D020713:Vancomycin Resistance",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "250-3",
"pmc": null,
"pmid": "25515867",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Linezolid bladder irrigation as adjunctive treatment for a vancomycin-resistant Enterococcus faecium catheter-associated urinary tract infection.",
"title_normalized": "linezolid bladder irrigation as adjunctive treatment for a vancomycin resistant enterococcus faecium catheter associated urinary tract infection"
} | [
{
"companynumb": "US-ACTAVIS-2015-14653",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "To report a case of extranodal natural killer/T-cell lymphoma (ENKTCL), nasal type metastatic to the space beneath the retinal pigment epithelium (RPE) with coincident paraneoplastic lymphoma-associated retinopathy.\nFindings of clinical and histopathologic examination are presented with differential diagnoses and a literature review.\nA 53-year-old man presented with bilateral blindness and had exudative retinal detachments overlying subretinal masses in both eyes. Flow cytometry of pericardial fluid revealed malignant T lymphocytes. After two cycles of chemotherapy, the patient was hospitalized and quickly expired. Autopsy revealed lymphoma involving the eyes, heart, right lung, and two subcarinal lymph nodes focally. Histopathologic examination of the eyes revealed intraocular metastases from ENKTCL, nasal type. Expression of CD3 and CD56, along with expression of Epstein-Barr virus by in situ hybridization, confirmed the diagnosis. Lymphomatous infiltrates were confined to the space beneath the neurosensory retina and between the RPE and the Bruch membrane, sparing the uveal tissue, similar to other metastatic T-cell lymphomas. Extensive RPE and photoreceptor loss in regions with and without underlying tumor was typical of a concurrent paraneoplastic lymphoma-associated retinopathy.\nPatients diagnosed with ENKTCL should be evaluated by an ophthalmologist, as ophthalmic involvement portends a poor prognosis.",
"affiliations": "Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, USA.;Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA.;Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA.",
"authors": "Thompson|Atalie C|AC|;McCall|Chad M|CM|;Proia|Alan D|AD|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000487268",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2296-4657",
"issue": "4(6)",
"journal": "Ocular oncology and pathology",
"keywords": "Extranodal natural killer/T-cell lymphoma, nasal type; Intraocular lymphoma; Lymphoma-associated retinopathy; Metastases; Sub-retinal pigment epithelium lymphoma",
"medline_ta": "Ocul Oncol Pathol",
"mesh_terms": null,
"nlm_unique_id": "101656139",
"other_id": null,
"pages": "388-394",
"pmc": null,
"pmid": "30574492",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports",
"references": "10571346;10604671;12208253;12414431;1318000;16019493;16360212;16912011;17064952;18438613;18501272;18790372;19168157;1967431;19882515;21228932;21958182;22323887;22681504;23232851;23715149;24317101;24672741;25154298;25811726;25835308;27680487;28275603;28503176;28619740;6608342;8188064;8387835;8540601;8608238;8640683",
"title": "Beneath the Retinal Pigment Epithelium: Histopathologic Findings in Metastatic Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type.",
"title_normalized": "beneath the retinal pigment epithelium histopathologic findings in metastatic extranodal natural killer t cell lymphoma nasal type"
} | [
{
"companynumb": "US-MYLANLABS-2018M1084633",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
"drugadditional": nul... |
{
"abstract": "A 78-year-old man with chronic hepatitis C underwent hepatectomy for hepatocellular carcinoma (HCC) 11 years prior to presentation. He was diagnosed with multiple intrahepatic recurrences of HCC with portal vein invasion and received hepatic arterial infusion chemotherapy (HAIC) with cisplatin. He developed abdominal pain, diarrhea, and blood-stained stool following treatment. Computed tomography revealed significant bowel wall thickening throughout the colon. Colonoscopy revealed reddish edematous mucosa with a reduced vascular pattern without ischemic changes. Conservative treatment with total parenteral nutrition improved his condition and his imaging findings. This is the first report of severe colitis following HAIC with cisplatin.",
"affiliations": "Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.",
"authors": "Yamamoto|Shumpei|S|;Onishi|Hideki|H|;Oyama|Atsushi|A|;Takaki|Akinobu|A|;Okada|Hiroyuki|H|",
"chemical_list": "D000970:Antineoplastic Agents; D002945:Cisplatin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.3340-19",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3148490910.2169/internalmedicine.3340-19Case ReportSevere Colitis Caused by Hepatic Arterial Infusion Chemotherapy with Cisplatin for Hepatocellular Carcinoma Yamamoto Shumpei 1Onishi Hideki 1Oyama Atsushi 1Takaki Akinobu 1Okada Hiroyuki 1\n1 Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, JapanCorrespondence to Dr. Shumpei Yamamoto, ysyunpei@hotmail.com\n\n3 9 2019 1 1 2020 59 1 69 75 14 5 2019 16 7 2019 Copyright © 2020 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 78-year-old man with chronic hepatitis C underwent hepatectomy for hepatocellular carcinoma (HCC) 11 years prior to presentation. He was diagnosed with multiple intrahepatic recurrences of HCC with portal vein invasion and received hepatic arterial infusion chemotherapy (HAIC) with cisplatin. He developed abdominal pain, diarrhea, and blood-stained stool following treatment. Computed tomography revealed significant bowel wall thickening throughout the colon. Colonoscopy revealed reddish edematous mucosa with a reduced vascular pattern without ischemic changes. Conservative treatment with total parenteral nutrition improved his condition and his imaging findings. This is the first report of severe colitis following HAIC with cisplatin. \n\ncolitishepatic arterial infusion chemotherapycisplatin\n==== Body\nIntroduction\nChemotherapy-induced gastrointestinal toxicity is a common complication in patients with cancer (1-7). Neutropenic enterocolitis, ischemic colitis, and pseudomembranous colitis are the specific types of colitis that are known complications of chemotherapy (3-8). In Japan, a fine-powder formulation of cisplatin is commonly used to administer hepatic arterial infusion chemotherapy (HAIC) for transcatheter arterial chemoembolization (TACE)-refractory hepatocellular carcinoma (HCC) (9,10). General chemotherapy with cisplatin may occasionally cause colitis (particularly neutropenic colitis) (6,8); however, no report has described colitis secondary to HAIC with cisplatin because the dosage of cisplatin used for HAIC is relatively small.\n\nWe herein report the first case of a patient with severe colitis that occurred secondary to HAIC with cisplatin. In this case, the colitis could not be classified into any specific type of chemotherapy-induced colitis. Although we were unable to accurately determine the pathomechanism contributing to colitis, improvement in the colonoscopic findings of edematous reddish mucosa and the immediate symptomatic improvement in the patient implicated allergic colitis as a contributor. This case emphasizes that physicians should consider colitis as a complication in patients developing abdominal pain after HAIC with cisplatin.\n\nCase Report\nA 78-year-old man with chronic hepatitis C was diagnosed with HCC affecting segment 8 and underwent hepatectomy 11 years prior to presentation. Intrahepatic recurrence was identified three years after resection. He reported a history of diabetes and acute myocardial infarction, appendectomy, and prostate cancer. Furthermore, he had been taking clopidogrel and low-dose aspirin. He underwent several sessions of radiofrequency ablation and TACE over eight years after the recurrence; however, ultrasonography and contrast-enhanced computed tomography (CECT) revealed multiple intrahepatic recurrences with portal vein invasion of the P5 branch (Fig. 1). Therefore, he was hospitalized and underwent the first session of hepatic arterial infusion (HAIC) using a fine-powder formulation of cisplatin (IA-callⓇ). Abdominal angiography revealed the thread and streaks sign at the P5 branch, which implied a vascularized tumor thrombus (Fig. 2a). CT hepatic arteriography in the early and delayed phases also showed HCC with a portal vein tumor thrombus of the P5 branch (Fig. 2b, c).\n\nFigure 1. Color Doppler ultrasonographic image showing a solid tumor in the portal vein (red arrowhead).\n\nFigure 2. (a) Hepatic angiography showing the thread and streaks sign, which implies a vascularized tumor thrombus (red arrowhead). (b) CT hepatic arteriography in the early phase showing multinodular recurrence of HCC with PVTT. A mass with ill-defined enhancement involving the P5 branch (red arrowhead). (c) CT hepatic arteriography showing PVTT on the P5 branch washed out in the delayed phase (red arrowhead). CT: computed tomography, HCC: hepatocellular carcinoma, PVTT: portal vein tumor thrombus\n\nHe was asymptomatic, and his vital signs were within the normal ranges. Laboratory investigations revealed an elevated serum alpha-fetoprotein level of 995 ng/mL and a des-γ-carboxy prothrombin level of 95 mAU/mL. His serum creatinine level was within the normal range; however, his serum albumin level and platelet count were reduced (Table 1). His liver function was categorized as Child-Pugh class B (7 points).\n\nTable 1. Laboratory Investigations.\n\nVariables\t\tValue\tUnit\t\tVariables\t\tValue\tUnit\t\tVariables\t\tValue\tUnit\t\nRBC\t\t264\t×104/μL\t\tCRP\t\t0.13\tmg/dL\t\tNa\t\t138\tmEq/L\t\nHb\t\t8.8\t%\t\tTP\t\t7.5\tg/dL\t\tK\t\t4.5\tmEq/L\t\nWBC\t\t3,590\t/μL\t\tAlbumin\t\t3.4\tg/dL\t\tCl\t\t104\tmEq/L\t\nNeut\t\t68.1\t%\t\tChE\t\t131\tIU/L\t\tCa\t\t8.8\tmg/dL\t\nEos\t\t0.9\t%\t\tT-BIL\t\t0.37\tmg/dL\t\t\t\t\t\t\nBaso\t\t0.1\t%\t\tAST\t\t29\tIU/L\t\tPT\t\t69\t%\t\nLymph\t\t25.1\t%\t\tALT\t\t14\tIU/L\t\t\t\t\t\t\nMono\t\t5.9\t%\t\tLDH\t\t221\tIU/L\t\tCEA\t\t2.31\tng/mL\t\nPLT\t\t9\t×104/μL\t\tALP\t\t187\tIU/L\t\tDCP\t\t95\tmAU/mL\t\n\t\t\t\t\tγ-GTP\t\t26\tIU/L\t\tAFP\t\t955\tng/mL\t\n\t\t\t\t\tUA\t\t4.2\tmg/dL\t\tAFP-L3\t\t75.1\t%\t\n\t\t\t\t\tCreatinine\t\t0.71\tmg/dL\t\tCA19-9\t\t21.5\tng/mL\t\n\t\t\t\t\tBUN\t\t14.9\tmg/dL\t\t\t\t\t\t\nRBC: red blood cell, Hb: hemoglobin, WBC: white blood cell, Neut: neutrophils, Eos: eosinophils, Baso: basophils, Lymph: lymphocytes, Mono: monocytes, PLT: platelet, CRP: C reactive protein, TP: total protein, Ch-E: cholinesterase, T-BIL: total-bilirubin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, UA: uric acid, BUN: blood urea nitrogen, PT: prothrombin time, CEA: carcinoembryonic antigen, DCP: des-γ-carboxy prothrombin, AFP: alfa-fetoprotein, AFP-L3: AFP lectin fraction, CA19-9: carbohydrate antigen 19-9\n\nHAIC was administered with 70 mg cisplatin based on his body surface area via the anterior branch of the right hepatic artery for over 30 minutes without any complications. Cisplatin was solubilized in saline at a concentration of 100 mg/70 mL without lipiodol. However, he developed abdominal pain the day following HAIC administration, with diarrhea on the third day and the passage of a small quantity of blood-stained stool on the sixth day. His white blood cell count and serum C-reactive protein levels gradually increased (Fig. 3). CECT performed on the sixth day showed significant bowel wall thickening between the cecum and the rectum with a disproportionate degree of fat stranding around the cecum and the sigmoid colon. An edematous gastric wall was also observed; however, the small bowel wall was normal (Fig. 4). No contrast failure was observed throughout the colon and the small bowel mucosa, and no arterial occlusion and venous thrombosis were detected. Colonoscopy performed on the seventh day showed reddish edematous mucosa with a reduced vascular pattern throughout the colon (Fig. 5). Although multiple erosions were observed, no ischemic changes were identified. The part of the terminal ileum that we could observe was normal. Laboratory investigations did not reveal neutropenia. Cytomegalovirus IgG/IgM and polymerase chain reaction tests showed negative results. Serum levels of beta-D glucan and procalcitonin were not elevated. Stool and blood cultures revealed negative results, and the Clostridium difficile toxin test also revealed negative results. Although the drug-induced lymphocyte stimulation test (DLST) for cisplatin showed a negative result, considering the patient's clinical course, we speculated that colitis might have occurred secondary to cisplatin administration.\n\nFigure 3. The clinical course of the patient described in the present case report.\n\nFigure 4. CECT showing significant bowel wall thickening between the cecum and the rectum (red arrowhead) without contrast failure or vascular thrombosis and also showing gastric wall thickening (yellow arrowhead). The small bowel wall did not show thickening (white arrowhead). Fat stranding is observed around the cecum and the sigmoid colon (red arrow). CECT: contrast-enhanced computed tomography\n\nFigure 5. Colonoscopic images showing reddish edematous mucosa with a reduced vascular pattern throughout the colon in the following segments: (a) the terminal ileum, (b) cecum, (c) transverse colon, (d) descending colon, (e) sigmoid colon, and (f) the rectum. Multiple slight erosions can be observed (arrow).\n\nHe received total parenteral nutrition (TPN) for bowel rest and was administered cefmetazole at a dose of 1 g twice a day to prevent bacterial translocation. He showed gradual improvement in symptoms and laboratory test parameters. CT performed on the 11th day revealed significant improvement in edematous mucosa between the transverse colon and the rectum. However, gastric wall thickening partially remained (Fig. 6). Colonoscopy performed on the 12th day also revealed improvement in the reddish edematous mucosa and the vascular pattern (Fig. 7). A histopathological examination of colonic biopsy specimens obtained from erosions showed lymphocytic infiltration and foamy histiocytes in the lamina propria; however, these findings could not confirm the cause of colitis. Oral intake was resumed on the 13th day, and his symptoms did not recur.\n\nFigure 6. (a) Residual bowel wall thickening and slight fat stranding are observed around the ascending colon (arrow). (b-d) CT images showing significant improvement in the edematous mucosa between the transverse colon and the rectum (arrowhead). Gastric wall thickening partially remained (yellow arrowhead). CT: computed tomography\n\nFigure 7. Colonoscopic images showing improvement in the reddish edematous mucosa and the vascular pattern throughout the colon.\n\nDiscussion\nTo our knowledge, this is the first case report that describes severe colitis secondary to the administration of HAIC with cisplatin. Although colitis was successfully treated conservatively with TPN for bowel rest, the edematous colonic mucosa throughout the colon and slightly blood-stained stool required close attention in this patient.\n\nAdvancements in chemotherapeutic regimens over the last decade have led to the use of several anticancer agents for HCC. HCC treatment guidelines proposed by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver recommend molecular-targeted therapy to treat advanced HCC (11,12); however, HAIC is also used in Asia as one of the most effective treatment strategies for advanced HCC, particularly in patients with portal vein invasion (13). Based on the Japanese Clinical Practice Guidelines for HCC, HAIC and molecular-targeted therapy are considered second-line treatments following TACE for advanced intrahepatic HCC (14). In Japan, IA-callⓇ (a platinum-based anticancer drug) is often used for HAIC in patients with TACE-refractory HCC (9,10). The cisplatin dosage administered is the primary factor affecting the development and the severity of adverse effects. The most common adverse effects of cisplatin used for HAIC are renal toxicity and cytopenia (15,16). Although general chemotherapy with cisplatin is known to occasionally cause colitis (particularly neutropenic colitis) (6,8), no report has described colitis secondary to HAIC with cisplatin because the dosage of cisplatin used for HAIC is relatively small.\n\nChemotherapy-induced gastrointestinal is a common complication observed in patients with cancer. Neutropenic enterocolitis, ischemic colitis, and pseudomembranous colitis are the specific types of colitis that occur as adverse effects of chemotherapy. Neutropenic colitis occurs in any patient with significant neutropenia, which commonly occurs during the third week after receiving cytotoxic chemotherapy (6,8,17). Ischemic colitis has been reported with the administration of docetaxel- or gemcitabine-containing regimens, which manifests as blood-stained stool and intestinal necrosis on a colonoscopic examination (3-5). Although pseudomembranous colitis is a well-known complication of antibiotic treatment, it is also a common complication in patients with cancer (18). In our case, the colonoscopic findings, which revealed edematous reddish mucosa without intestinal necrosis and pseudomembrane formation, were not consistent with ischemic or pseudomembranous colitis. Additionally, laboratory tests for C. difficile toxin revealed negative results, which excluded pseudomembranous colitis in this patient. Although a previous study reported that combination therapy using 5-fluorouracil (5FU) and cisplatin caused neutropenic colitis in a patient with head and neck cancer, neutropenia was not observed after the administration of cisplatin in our patient, so neutropenic colitis was also ruled out.\n\nIn our case, clopidogrel and low-dose aspirin, which the patient had been taking, may have contributed to the blood-stained stool due to the colitis. In fact, these drugs can sometimes cause colon mucosal disorders (19). However, the immediate improvement and lack of recurrence of colitis after short-term cessation of clopidogrel did not correspond with the clinical course of colitis caused by these drugs.\n\nIntestinal mucositis is a common adverse effect in patients with cancer undergoing combination chemotherapy using 5FU and irinotecan. Irinotecan and 5FU cause acute injury to the intestinal mucosa, which is a dose-limiting complication resulting in loss of epithelium (1,2). A study performed by Cappell et al., which described colonic toxicity secondary to administered drugs and chemicals, reported that 5-FU caused allergic and inflammatory colitis (20). In our case, both the improvement in the colonoscopic findings of edematous reddish mucosa as well as the immediate symptomatic improvement in the patient implicated allergic colitis as a possible etiopathogenetic contributor. Notably, cisplatin was not mentioned as a possible cause of allergic colitis in the study of Cappell et al., and no previous reports have implicated cisplatin as a possible cause of allergic colitis either.\n\nWe performed DLST for cisplatin to differentiate the allergic pathway; however, the test showed a negative result. Notably, Pichler et al. reported that a negative result with DLST could not exclude drug hypersensitivity because the DLST shows limited sensitivity (21). Therefore, we were unable to exclude the possibility of allergic colitis caused by cisplatin. In addition, the appearance and immediate improvement of gastric wall thickening concurrent with colitis sustained this allergic pathway. Unfortunately, we performed only colonoscopy and two biopsies from the rectum, and too few eosinophils were observed to allow for the determination of an allergic reaction. It is difficult to diagnose an allergic reaction by a biopsy because eosinophils are present even in normal physiologic states throughout the gastrointestinal tract. With respect to eosinophilic gastroenteritis, some studies have recommended multiple biopsies - at least four to five biopsies per site - from several sites, such as the stomach and small bowel mucosa (22,23). The discrepancy in the concentration of eosinophils between each part of the gastrointestinal mucosa must also be investigated. For the colon, Turner et al. reported that the concentration of eosinophils was higher in the right colon than in the left colon (24). Therefore, multiple biopsies from different parts of the colon are needed. Furthermore, gastroendoscopy and/or enteroscopy should have been performed to confirm thickening of the gastric wall and small bowel wall, as we were unable to assess these sufficiently.\n\nTable 2 shows the previous reports that have discussed chemotherapy-induced colitis, including those describing the use of cisplatin. Although early-onset colitis occurred in two previous patients, as well as in our patient two days after the administration of chemotherapy, ischemic mucosal changes in the colon were reported in these previous cases. Among the three patients with ischemic colitis that was attributed to the administration of docetaxel, gemcitabine and capecitabine, two showed a poor prognosis. Two cases of neutropenic colitis were reported in patients who received doublet chemotherapy. No reports have described severe colitis in patients who received chemotherapy with only cisplatin. Furthermore, allergic colitis without ischemia and neutropenia (as was observed in our patient) has never been reported.\n\nTable 2. Summary of Previous Literature.\n\nReference\tAge\tSex\tPrimary tumor\tDrug\tRoute\tTiming\tIschemic change\tNeutropenia\tDiagnose\tTreatment\tOutcome\t\n3)\t71\tmale\tbile-duct cancer\tGEM+CDDP\tdiv\t2 days\tyes\tno\tischemic colitis\tsurgery\tdeath\t\n4)\t72\tmale\tsalivary gland carcinoma\tDTX+CDDP\tIA\t2 days\tyes\tyes\tischemic colitis\tTPN\timproved\t\n4)\t51\tmale\tsalivary gland carcinoma\tDTX+CDDP\tIA\tunknown\tno\tno\tmucositis\tobserve\timproved\t\n5)\t45\tmale\tgastric cancer\tCAPE+CDDP\tdiv\t28 days\tyes\tno\tischemic colitis\tobserve\tdeath\t\n6)\t73\tmale\tSCLC\tIRI+CDDP\tdiv\t13 days\tno\tyes\tneutropenic colitis\tobserve\timproved\t\n7)\t58\tfemale\tgastric cancer\tDTX+CDDP+5FU\tdiv\t54 days\tno\tno\tcecal perforation\tsurgery\timproved\t\n8)\t60\tmale\thead and neck cancer\t5FU+CDDP\tdiv\t7 days\tunknown\tyes\tneutropenic colitis\tobserve\timproved\t\nDTX: docetaxel, CDDP: cisplatin, 5-FU: Fluorouracil, IRI: irinotecan, GEM: gemcitabine, CAPE: capecitabine, div: drip infusion in vein, IA: intra arterial infusion\n\nIn conclusion, HAIC with cisplatin alone for HCC caused severe colitis in the patient described in this report. Although the cause of this colitis could not be accurately identified, an allergic response was implicated as the most likely pathomechanism. Conservative treatment with TPN effectively treated the colitis in our patient. We emphasize that physicians should consider the possibility of colitis as an adverse effect of cisplatin administration for the prompt diagnosis and prevention of aggravation of colitis.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nRibeiro RA , Wanderley CW , Wong DV , et al \nIrinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives . Cancer Chemother Pharmacol \n78 : 881 -893 , 2016 .27590709 \n2. \nIkuno N , Soda H , Watanabe M , Oka M \nIrinotecan (CPT-11) and characteristic mucosal changes in the mouse ileum and cecum . J Natl Cancer Inst \n87 : 1876 -1883 , 1995 .7494232 \n3. \nOsumi H , Ozaka M , Ishii H , Sasahira N \nSevere ischemic colitis after treatment of bile-duct cancer using gemcitabine and cisplatin . Jpn J Clin Oncol \n45 : 402 -403 , 2015 .25821231 \n4. \nMaruya S , Namba A , Matsubara A , et al \nSalivary gland carcinoma treated with concomitant chemoradiation with intraarterial cisplatin and docetaxel . Int J Clin Oncol \n11 : 403 -406 , 2006 .17058139 \n5. \nCetin B , Buyukberber S , Senturk S , Guzel E , Coskun U , Benekli M \nIschemic colitis after capecitabine plus cisplatin treatment in advanced gastric cancer . J Thromb Thrombolysis \n31 : 503 -506 , 2011 .21069429 \n6. \nJi EH , Kim YM , Kim SJ , et al \nA case of typhlitis developed after chemotherapy with irinotecan and Cisplatin in a patient with small cell lung carcinoma . Tuberc Respir Dis (Seoul) \n73 : 288 -291 , 2012 .23236322 \n7. \nColucci G , Thaler W , Dejaco H , Marsoner H , Grones A \nColonic rupture in a patient on combination chemotherapy for metastasized carcinoma of the esophagogastric junction. Case report and review of the literature . Onkologie \n28 : 204 -206 , 2005 .15840969 \n8. \nPetruzzelli GJ , Johnson JT , de Vries EJ \nNeutropenic enterocolitis. A new complication of head and neck cancer chemotherapy . Arch Otolaryngol Head Neck Surg \n116 : 209 -211 , 1990 .2297418 \n9. \nHatanaka T , Kakizaki S , Shimada Y , et al \nEarly decreases in alpha-fetoprotein and des-gamma-carboxy prothrombin predict the antitumor effects of hepatic transarterial infusion chemotherapy with cisplatin (CDDP) powder in patients with advanced hepatocellular carcinoma . Intern Med \n55 : 2163 -2171 , 2016 .27522991 \n10. \nIwasa S , Ikeda M , Okusaka T , et al \nTranscatheter arterial infusion chemotherapy with a fine-powder formulation of cisplatin for advanced hepatocellular carcinoma refractory to transcatheter arterial chemoembolization . Jpn J Clin Oncol \n41 : 770 -775 , 2011 .21459893 \n11. \nHeimbach JK , Kulik LM , Finn RS , et al \nAASLD guidelines for the treatment of hepatocellular carcinoma . Hepatology \n67 : 358 -380 , 2018 .28130846 \n12. \nEuropean Association for the Study of the Liver \nElectronic address eee, European Association for the Study of the L. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma . J Hepatol \n69 : 182 -236 , 2018 .29628281 \n13. \nKudo M , Ueshima K , Yokosuka O , et al \nSorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial . Lancet Gastroenterol Hepatol \n3 : 424 -432 , 2018 .29631810 \n14. \nKokudo N , Hasegawa K , Akahane M , et al \nEvidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2013 update (3rd JSH-HCC Guidelines) . Hepatol Res \n45 , 2015 .\n15. \nHiguchi K , Yanagawa T \nEvaluating dose of cisplatin responsible for causing nephrotoxicity . PLoS One \n14 : e0215757 , 2019 .31022233 \n16. \nAstolfi L , Ghiselli S , Guaran V , et al \nCorrelation of adverse effects of cisplatin administration in patients affected by solid tumours: a retrospective evaluation . Oncol Rep \n29 : 1285 -1292 , 2013 .23404427 \n17. \nBow EJ , Meddings JB \nIntestinal mucosal dysfunction and infection during remission-induction therapy for acute myeloid leukaemia . Leukemia \n20 : 2087 -2092 , 2006 .17082779 \n18. \nAng P , Cheong WK , Khoo KS \nPseudomembranous colitis in a patient treated with paclitaxel for carcinoma of the breast: a case report . Ann Acad Med Singapore \n29 : 132 -134 , 2000 .10748982 \n19. \nOhkusa T , Terai T , Abe S , et al \nColonic mucosal lesions associated with long-term administration of non-steroidal anti-inflammatory drugs . Aliment Pharmacol Ther \n24 : 88 -95 , 2007 .\n20. \nCappell MS \nColonic toxicity of administered drugs and chemicals . Am J Gastroenterol \n99 : 1175 -1190 , 2004 .15180742 \n21. \nPichler WJ , Tilch J \nThe lymphocyte transformation test in the diagnosis of drug hypersensitivity . Allergy \n59 : 809 -820 , 2004 .15230812 \n22. \nLeinbach GE , Rubin CE \nEosinophilic gastroenteritis: a simple reaction to food allergens? \nGastroenterology \n59 : 874 -889 , 1970 .5486274 \n23. \nKatz AJ , Goldman H , Grand RJ \nGastric mucosal biopsy in eosinophilic (allergic) gastroenteritis . Gastroenterology \n73 : 705 -709 , 1977 .892374 \n24. \nTurner KO , Sinkre RA , Neumann WL , Genta RM \nPrimary colonic eosinophilia and eosinophilic colitis in adults . Am J Surg Pathol \n41 : 225 -233 , 2017 .27792062\n\n",
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"issue": "59(1)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "cisplatin; colitis; hepatic arterial infusion chemotherapy",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000792:Angiography; D000970:Antineoplastic Agents; D006528:Carcinoma, Hepatocellular; D002945:Cisplatin; D003092:Colitis; D003113:Colonoscopy; D000072226:Computed Tomography Angiography; D000072700:Conservative Treatment; D006498:Hepatectomy; D006499:Hepatic Artery; D006801:Humans; D007261:Infusions, Intra-Arterial; D008113:Liver Neoplasms; D008297:Male; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D010289:Parenteral Nutrition, Total; D011169:Portal Vein; D012720:Severity of Illness Index",
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"pages": "69-75",
"pmc": null,
"pmid": "31484909",
"pubdate": "2020-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27590709;25625806;2297418;10748982;7494232;17082779;27792062;892374;29628281;15230812;15840969;5486274;31022233;25821231;23236322;29631810;17058139;28130846;21069429;15180742;23404427;27522991;21459893",
"title": "Severe Colitis Caused by Hepatic Arterial Infusion Chemotherapy with Cisplatin for Hepatocellular Carcinoma.",
"title_normalized": "severe colitis caused by hepatic arterial infusion chemotherapy with cisplatin for hepatocellular carcinoma"
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"abstract": "In the area of multiple myeloma (MM) therapy, proteasome inhibitors (PI) have emerged with promising responses both in the first- and second-line setting. Carfilzomib (CFZ) is a second-generation, selective PI approved in 2012 for the treatment of relapsed/refractory multiple myeloma (RRMM) in patients who received 2 prior therapies or have evidence of disease progression within 60 days of completion of last therapy. Its safety profile reported adverse events (AEs) ranging from drug-related AEs (nausea and vomiting), hematologic AEs (neutropenia and thrombocytopenia), and nonhematologic AEs (electrolyte imbalances). As CFZ use is gaining popularity, various hematological, renal, cardiovascular, pulmonary, and neurological toxicities have been reported. We are presenting this case to describe a rare occurrence of tumor lysis syndrome (TLS) with the use of this novel targeted therapy.",
"affiliations": "Department of Internal Medicine, Northwell Health Staten Island University Hospital, Staten Island, NY, USA.;Department of Hematology and Oncology, Northwell Health Staten Island University Hospital, Staten Island, NY, USA.;Department of Hematology and Oncology, Northwell Health Staten Island University Hospital, Staten Island, NY, USA.",
"authors": "Sandy|El Bitar|EB|https://orcid.org/0000-0002-2625-9171;Weerasinghe|Chanudi|C|;Terjanian|Terenig|T|",
"chemical_list": "D000970:Antineoplastic Agents; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib",
"country": "United States",
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"issue": "33(2)",
"journal": "Journal of pharmacy practice",
"keywords": "adverse events; carfilzomib; multiple myeloma; proteasome inhibitor; tumor lysis syndrome",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D006801:Humans; D008297:Male; D009101:Multiple Myeloma; D009325:Nausea; D009503:Neutropenia; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D013921:Thrombocytopenia; D015275:Tumor Lysis Syndrome; D014839:Vomiting; D014882:Water-Electrolyte Balance",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "213-216",
"pmc": null,
"pmid": "30278813",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Carfilzomib Induced Tumor Lysis Syndrome and Other Adverse Events.",
"title_normalized": "carfilzomib induced tumor lysis syndrome and other adverse events"
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"abstract": "This paper presents the case of a young girl with idiopathic pulmonary hypertension, who developed signs of severe heart failure within a short period of time. Pharmacotherapy with sildenafil and bosentan (among other drugs) was ineffective. Heart catheterization revealed suprasystemic pressure in the pulmonary artery. At the age of 7.5 years, the patient underwent a surgical Potts shunt (namely, a direct side-by-side anastomosis from the left pulmonary artery to the descending aorta). The procedure resulted in a significant improvement of the clinical, echocardiographic, and biochemical parameters, which persists after one and a half years of follow-up. After the surgery, pharmacotherapy with bosentan was gradually discontinued.",
"affiliations": "Clinical Department of Congenital Heart Diseases and Pediatric Cardiology, Medical University of Silesia, Silesian Center for Heart Diseases in Zabrze, Poland.;Clinical Department of Congenital Heart Diseases and Pediatric Cardiology, Medical University of Silesia, Silesian Center for Heart Diseases in Zabrze, Poland.;Clinical Department of Congenital Heart Diseases and Pediatric Cardiology, Medical University of Silesia, Silesian Center for Heart Diseases in Zabrze, Poland.;Clinical Department of Congenital Heart Diseases and Pediatric Cardiology, Medical University of Silesia, Silesian Center for Heart Diseases in Zabrze, Poland.;Department of Anesthesiology and Intensive Care, University Children's Hospital, Krakow, Poland.;Clinic of Cardiac Surgery, University Children's Hospital, Krakow, Poland.;Clinical Department of Congenital Heart Diseases and Pediatric Cardiology, Medical University of Silesia, Silesian Center for Heart Diseases in Zabrze, Poland.",
"authors": "Fiszer|Roland|R|;Karwot|Blandyna|B|;Chodór|Beata|B|;Szkutnik|Małgorzata|M|;Kobylarz|Krzysztof|K|;Skalski|Janusz|J|;Białkowski|Jacek|J|",
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"doi": "10.5114/kitp.2015.52864",
"fulltext": "\n==== Front\nKardiochir Torakochirurgia PolKardiochir Torakochirurgia PolKITPKardiochirurgia i Torakochirurgia Polska = Polish Journal of Cardio-Thoracic Surgery1731-55301897-4252Termedia Publishing House 2548010.5114/kitp.2015.52864Case ReportsPotts’ shunt in a child with idiopathic pulmonary arterial hypertension – one-and-a-half year observation Fiszer Roland 1Karwot Blandyna 1Chodór Beata 1Szkutnik Małgorzata 1Kobylarz Krzysztof 2Skalski Janusz 3Białkowski Jacek 11 Clinical Department of Congenital Heart Diseases and Pediatric Cardiology, Medical University of Silesia, Silesian Center for Heart Diseases in Zabrze, Poland2 Department of Anesthesiology and Intensive Care, University Children's Hospital, Krakow, Poland3 Clinic of Cardiac Surgery, University Children's Hospital, Krakow, PolandAddress for correspondence: Prof. Jacek Białkowski, Clinical Department of Congenital Heart Diseases and Pediatric Cardiology, Silesian Center for Heart Diseases in Zabrze, 9 M. Skłodowskiej-Curie St., 41-800 Zabrze, Poland. phone: +48 32 271 34 01. e-mail: jabi_med@poczta.onet.pl30 6 2015 6 2015 12 2 170 172 25 7 2014 10 8 2014 07 11 2014 Copyright © 20152015This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License, permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.This paper presents the case of a young girl with idiopathic pulmonary hypertension, who developed signs of severe heart failure within a short period of time. Pharmacotherapy with sildenafil and bosentan (among other drugs) was ineffective. Heart catheterization revealed suprasystemic pressure in the pulmonary artery. At the age of 7.5 years, the patient underwent a surgical Potts shunt (namely, a direct side-by-side anastomosis from the left pulmonary artery to the descending aorta). The procedure resulted in a significant improvement of the clinical, echocardiographic, and biochemical parameters, which persists after one and a half years of follow-up. After the surgery, pharmacotherapy with bosentan was gradually discontinued.\n\nW pracy opisano przypadek dziewczynki, u której w krótkim czasie rozwinął się obraz ciężkiej postępującej niewydolności krążenia spowodowanej pierwotnym nadciśnieniem płucnym. Farmakoterapia, m.in. sildenafilem i bozentanem, była nieefektywna. W przeprowadzonym cewnikowaniu serca stwierdzono suprasystemowe ciśnienie w tętnicy płucnej. Gdy dziecko miało 7,5 roku, wykonano chirurgiczne zespolenie Pottsa (połączenie pomiędzy lewą tętnicą płucną a aortą zstępującą), uzyskując poprawę parametrów klinicznych, echokardiograficznych oraz biochemicznych, która utrzymuje się półtora roku po zabiegu. Po zabiegu stopniowo wycofano się z farmakoterapii bozentanem.\n\nidiopathic pulmonary hypertensionPotts’ procedure\n==== Body\nIntroduction\nIdiopathic pulmonary hypertension (IPH) is a very rare disease with poor prognosis, especially in children. Its effects include the development of suprasystemic pressure in the pulmonary artery (PA), a very significant dilatation of the right ventricle (RV), as well as a number of consequent physiopathological changes, including RV compression on the left ventricle (LV), causing recurrent spells of unconsciousness and sudden death. According to one American register, the time of survival from the moment of diagnosis in children with IPH was 10 months and in adults 2.8 years [1]. The prevalence of IPH has been estimated at approximately 2 cases per million [2]. Recently, a number of new agents have been introduced to IPH therapy, but they offer only short-term improvement [3].\n\nOn the other hand, it has been known for a long time that the prognosis for Eisenmenger's syndrome caused by pulmonary hypertension with right-to-left shunt (e.g., in non-operated heart defects such as patent ductus arteriosus or ventricular septal defect) is much better, and the time of survival is estimated at 40-60 years [4]. In 2004, Blanc et al. proposed a novel strategy for the treatment of IPH in children by performing the long-known Potts shunt (i.e., anastomosing the left pulmonary artery with the descending aorta) [5]. There are few publications on the subject [5, 6]. The present report describes the case of a child with severe IPH, in whom a successful Potts shunt was performed; the good outcome of the surgery was confirmed by 1.5 years of follow-up.\n\nCase study\nThe girl (G1, T1, natural birth in the 34th week of gestation, birth weight 2690 g, Apgar score 8/9) was admitted to the clinic at the age of 6 years due to quickly increasing exercise intolerance, chest pain, and a single episode of loss of consciousness; her medical history included frequent respiratory tract infections before the age of 3 years, which later subsided. The child could not participate in school activities and was recommended to take part in an individual education program. Initially, based on non-invasive examinations, the cardiac clinic suspected primary pulmonary hypertension; the patient was administered sildenafil, l-arginine, and captopril (the parents did not consent to cardiac catheterization at the time). Physical examination performed at admission to the clinic established the patient's weight as 22 kg (35th-65th percentile) and height as 120 cm (35th-65th percentile). The child was in a severe general condition (she exhibited fatigue even during light exercises – NYHA III/IV), showing signs of heart failure, clear dyspnea, as well as tachypnea (36 breaths per minute) and tachycardia (130-140 bpm). O2 saturation was 94%. The result of the patient's 6-minute walk test (6MWT) was 215 m (Borg scale result – 5). Moreover, a systolic murmur (1-2/6 at the base of the 2nd left intercostal space) and a diastolic murmur (1/4 in the 4th left intercostal space) were present. The liver was enlarged by 3 cm. Electrocardiography and echocardiography revealed: enlargement of the right atrium and ventricle, presence of fluid in the pericardial sac, signs of right ventricular compression on the left ventricle, and signs of pulmonary hypertension (PulmAT increased to 48 ms). Doppler echocardiography also demonstrated significant pulmonary regurgitation (+ + +) and tricuspid regurgitation (+ + /+ + +). Posterior-anterior chest X-ray examination revealed wide, vascular hila and significantly enlarged cardiac silhouette with full waist; the cardiothoracic ratio was 0.71. Ventilation-perfusion scintigraphy excluded pulmonary embolization, and NMR excluded left ventricular noncompaction and arrhythmogenic right ventricular dysplasia (ARVD), revealing great enlargement of the right ventricle, significant widening of the trunk of the pulmonary artery and its two branches, as well as displacement of the left ventricle compressed by the right ventricle. Cardiac catheterization revealed suprasystemic pressure in the pulmonary artery (invasive measurement of pulmonary artery pressure: 125/70/91 mmHg, noninvasive cuff measurement of aortic pressure: 81/47/64 mmHg). The attempt to place the catheter in the peripheral branch of the pulmonary artery ended in a pulmonary hypertensive crisis with bradycardia and a drop of O2 saturation to 30%. The circulation was only stabilized after a period of continuous intravenous infusion of amrinone. The serum concentration of NT-proBNP during this time was 13,433 pg/ml. Bosentan was added to the therapy at the initial dose of 2 × 31 mg (later increased to 2 × 62 mg). Despite the employed treatment, the patient's condition continued to deteriorate. On December 12, 2012, during a cardiac surgery consultation with Prof. M. Zembala, the child was qualified for a Potts procedure. Several days later, the patient suffered from a severe respiratory tract infection which was managed with antibiotic therapy. On January 1, 2013, the planned surgery was performed at the Clinic of Pediatric Cardiac Surgery (headed by Prof. J. Skalski) of the University Children's Hospital in Kraków. Pre- and post-operatively, the patient received intravenous infusion of Flolan (prostaglandin meant to reduce the pressure in the pulmonary artery). The postoperative course was complicated by an incident of circulatory insufficiency with the presence of fluid in the left pleural cavity, requiring a period of underwater drainage. At two weeks after the procedure, the child was referred from Krakow to our center. Oxygen saturation measured with pulse oximetry was 78% (lower extremities) and 96% (upper extremities). The patient still suffers from thrombocytopenia and remains under the supervision of an outpatient pediatric hematology clinic in Zabrze (Prof. Z Szczepański). At present (1.5 years after the procedure), the girl feels well (NYHA class I/II); she has returned to school; her liver is no longer palpable under the costal margin. No further episodes of syncope have been observed. According to her parents, the girl's exercise tolerance has increased; her height has increased by 8 cm and her weight by 5 kg (body mass = 27 kg, 35th-65th percentile; height = 128 cm, 15th percentile). In comparison to preoperative examinations, the patient's echocardiogram indicates improved proportions of the ventricular cavities (LV dimensions in the lower range of normal; the right ventricle is smaller, but still larger than LV in apical 4-chamber view) as well as reduced tricuspid regurgitation (+/ + +) and pulmonary regurgitation (+ +) without fluid in the pericardial sac. The diameter of the Potts shunt was established at 6 mm by the latest echocardiographic examination; the maximal gradient through the anastomosis was established at 14 mmHg. The new result of 6MWT was 472 m, and the result of NT-proBNP was 1000 pg/ml. At approximately 1 year after the procedure, the treatment with bosentan was gradually discontinued; the patient currently receives only sildenafil and acenocoumarol.\n\nDiscussion\nThe treatment options for IPH are limited. Although pharmacotherapy with state-of-the-art pulmonary vasodilators – endothelin-1 receptor antagonists (bosentan), phosphodiesterase type 5 inhibitors (sildenafil), and intravenous prostacyclins (epoprostenol) constitutes an interesting treatment option resulting in improved prognosis [7], the long-term efficacy of these agents in the treatment of IPH is relatively low [3]. These observations are in accord with the case study presented above, as our patient's condition continued to deteriorate despite the intensification of pharmacological therapy (combined therapy with sildenafil and bosentan). Idiopathic pulmonary hypertension can also be treated with balloon atrioseptostomy and pulmonary transplantation, but both these methods are known to have significant limitations.\n\nThe idea to use Potts’ shunt in the treatment of IPH [5] is based on the observations of the physiopathology of Eisenmenger's syndrome and patent ductus arteriosus. Right-to-left shunt between the left pulmonary artery and the descending aorta (as is the case with the Potts procedure) prevents the desaturation of the CNS and coronary circulation and the occurrence of paradoxical embolisms in the CNS. Concurrently, right ventricular afterload is improved, and the suprasystemic pressure in the pulmonary artery becomes equal to that in the aorta. Left ventricular function is unburdened, and LV ejection fraction improves. Recently, Baruteau et al. [6] presented a series of 8 children with IPH from 6 cardiology centers in France (median age: 8 years) who were treated with Potts’ procedure. All the children were in NYHA class IV, and 6 suffered from episodes of loss of consciousness. The mean time of postoperative follow-up was approximately 5 years. Two patients, in whom pharmacological treatment with state-of-the-art pulmonary vasodilators was discontinued in the early postoperative period, died on the 11th and 13th day after the surgery due to hypertensive crises (postoperative mortality: 25%). No long-term mortality was noted in this group. These observations indicate that the aforementioned agents should be discontinued gradually at a later time after the surgery, as was the case with our patient.\n\nPotts’ shunt can also be created using interventional catheterization [8]. Four patients were treated in this manner. A retrograde puncture of the left pulmonary artery from the descending aorta was made; after the creation of a veno-arterial loop, a covered stent was introduced into the puncture site. The procedure was successful in 3 patients, two of whom survived. One of the patients died during the procedure due to massive bleeding into the chest; another died shortly after the procedure due to multiple organ dysfunction syndrome. In view of these results, the application of this method appears limited and reserved for carefully selected cases.\n\nIn conclusion, palliative Potts’ shunt constitutes a new and interesting therapeutic alternative to lung transplantation. The method offers a chance to prolong the life of children with idiopathic pulmonary hypertension and to improve its quality.\n\nDislocure\nAuthors report no conflict of interest.\n==== Refs\nReferences\n1 D'Alonzo GE Barst RJ Ayers SM Bergofsky EH Brundage BH Detre KM Fishman AP Goldring RM Groves BM Kernis JT Levy PS Pietra GP Reid LM Reeves JT Rich S Vreim CE Williams GW Wu M Survival in patients with primary pulmonary hypertension. Results from a national prospective registry Ann Intern Med 1991 115 343 349 1863023 \n2 Rubin LJ Primary pulmonary hypertension N Engl J Med 1997 336 111 117 8988890 \n3 van Loon RL Roofthooft MT Delhaas T van Osch-Gevers M ten Harkel AD Strengers JL Backx A Hillege HL Berger RM Outcome of pediatric patients with pulmonary arterial hypertension in the era of new medical therapies Am J Cardiol 2010 106 117 124 20609658 \n4 Diller GP Dimopoulos K Broberg CS Kaya MG Naghotra US Uebing A Harries C Goktekin O Gibbs JS Gatzoulis MA Presentation, survival prospects, and predictors of death in Eisenmenger syndrome: acombined retrospective and case-control study Eur Heart J 2006 27 1737 1742 16793921 \n5 Blanc J Vouhe P Bonnet D Potts shunt in patients with pulmonary hypertension N Engl J Med 2004 350 623 14762197 \n6 Baruteau AE Serraf A Lévy M Petit J Bonnet D Jais X Vouhé P Simonneau G Belli E Humbert M Potts shunt in children with idiopathic pulmonary arterial hypertension: long-term results Ann Thorac Surg 2012 94 817 824 22704329 \n7 McLaughlin VV Archer SL Badesch DB Barst RJ Farber HW Lindner JR Mathier MA McGoon MD Park MH Rosenson RS Rubin LJ Tapson VF Varga J Harrington RA Anderson JL Bates ER Bridges CR Eisenberg MJ Ferrari VA Grines CL Hlatky MA Jacobs AK Kaul S Lichtenberg RC Lindner JR Moliterno DJ Mukherjee D Pohost GM Rosenson RS Schofield RS Shubrooks SJ Stein JH Tracy CM Weitz HH Wesley DJ ACCF/AHA. ACCF/AHA 2009 expert consensus document on pulmonaryhypertension: a report of the American College of Cardiology FoundationTask Force on Expert Consensus Documents and the American HeartAssociation: developed in collaboration with the American College ofChest Physicians, American Thoracic Society, Inc., and the PulmonaryHypertension Association Circulation 2009 119 2250 2294 19332472 \n8 Esch JJ Shah PB Cockrill BA Farber HW Landzberg MJ Mehra MR Mullen MP Opotowsky AR Waxman AB Lock JE Marshall AC Transcatheter Potts shunt creation in patients with severe pulmonary arterial hypertension: Initial clinical experience J Heart Lung Transplant 2013 32 381 387 23415728\n\n",
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"issue": "12(2)",
"journal": "Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery",
"keywords": "Potts’ procedure; idiopathic pulmonary hypertension",
"medline_ta": "Kardiochir Torakochirurgia Pol",
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"pages": "170-2",
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"pubdate": "2015-06",
"publication_types": "D002363:Case Reports",
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"title": "Potts' shunt in a child with idiopathic pulmonary arterial hypertension - one-and-a-half year observation.",
"title_normalized": "potts shunt in a child with idiopathic pulmonary arterial hypertension one and a half year observation"
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"abstract": "OBJECTIVE\nThe study aims to describe the management of a case of life-threatening yew (Taxus baccata) intoxication.\n\n\nBACKGROUND\nThe needles of the yew tree contain highly cardiotoxic taxines. Intoxication with taxines, typically as part of suicide attempts, may lead to potentially lethal arrhythmias which often require prolonged cardiopulmonary resuscitation and other supportive measures. No specific therapy has been described. In some cases, extracorporeal life support has been used.\n\n\nMETHODS\nAfter an attempted suicide with yew needles and out-of-hospital cardiac arrest, a female adolescent was resuscitated for 6 hours according to Advanced Cardiovascular Life Support guidelines. Complex ventricular tachycardias were treated by repeated direct current shocks and broad complex bradycardia managed with transvenous cardiac pacing. Antiarrhythmic drugs (amiodarone, lidocaine), magnesium sulfate, and supportive measures (intravenous lipids, sodium bicarbonate) were provided. The arrhythmias finally resolved, and the patient did not show any significant neurological or cardiac short-term sequelae after 24 hours.\n\n\nRESULTS\nThe authors describe the successful management of a case of severe taxine intoxication by prolonged conventional advanced cardiac life support lasting for more than 6 hours.\n\n\nCONCLUSIONS\nIn life-threatening yew intoxication, prolonged cardiopulmonary resuscitation is absolutely essential owing to the long duration of the cardiotoxic action of taxines and can lead to an outcome without cardiac or neurological sequelae.",
"affiliations": "From the Division of Pediatric Intensive Care and Pulmonology.;Division of Emergency Care, University Children's Hospital Basel (UKBB).;Division of Emergency Care, University Children's Hospital Basel (UKBB).;Division of Emergency Care, University Children's Hospital Basel (UKBB).;Department of Anesthesiology and Intensive Care Medicine.;Department of Cardiac Surgery.;Division of Anesthesia.;Department of Cardiology, University Hospital Basel.;Division of Pediatric Cardiology, University Children's Hospital Basel (UKBB), Switzerland.",
"authors": "Zutter|Andreas|A|;Hauri|Kathrin|K|;Evers|Katrina S|KS|;Uhde|Sabine|S|;Fassl|Jens|J|;Reuthebuch|Oliver Tobias|OT|;Berset|Andreas|A|;Kühne|Michael|M|;Donner|Birgit C|BC|",
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"mesh_terms": "D000293:Adolescent; D000889:Anti-Arrhythmia Agents; D001145:Arrhythmias, Cardiac; D001919:Bradycardia; D016887:Cardiopulmonary Resuscitation; D004435:Eating; D004554:Electric Countershock; D005260:Female; D006801:Humans; D058687:Out-of-Hospital Cardiac Arrest; D018515:Plant Leaves; D010939:Plant Poisoning; D013406:Suicide, Attempted; D017180:Tachycardia, Ventricular; D020946:Taxus; D016896:Treatment Outcome",
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"title": "\"Chaotic Arrhythmia\" During Successful Resuscitation After Ingestion of Yew (Taxus baccata) Needles.",
"title_normalized": "chaotic arrhythmia during successful resuscitation after ingestion of yew taxus baccata needles"
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"abstract": "Recent clinical trials revealed that both immune checkpoint inhibitors (ICI) and BRAF/MEK inhibitors significantly prolonged survival in melanoma patients when used for both advanced stage disease and postoperative adjuvant therapy. Although BRAF/MEK inhibitors are associated with a higher objective response rate than ICI, most patients relapse during treatment. However, progression patterns during treatment with BRAF/MEK inhibitors have not been extensively investigated. Here, we retrospectively collected the data of melanoma patients initially treated with BRAF/MEK inhibitors or anti-programmed death 1 (PD-1) antibody monotherapy at the University of Tsukuba Hospital and compared their results. The χ2 -test revealed that frequency of brain metastasis (BM) development was significantly higher in cases treated with BRAF/MEK inhibitors compared with those with anti-PD-1 antibody monotherapy. In addition, BM-free survival in cases treated with BRAF/MEK inhibitors was significantly shorter than those treated with anti-PD-1 antibody monotherapy. Our results indicate that BM development during treatment with BRAF/MEK inhibitors may be more frequent than anti-PD-1 antibody monotherapy, even though the extracranial metastases are well controlled. Therefore, we recommend frequent brain examinations during treatment with BRAF/MEK inhibitors to detect BM at an early stage and to promptly administrate ICI with local radiation therapy.",
"affiliations": "Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.",
"authors": "Nakamura|Yoshiyuki|Y|https://orcid.org/0000-0003-0166-2658;Ishitsuka|Yosuke|Y|https://orcid.org/0000-0002-1733-5427;Tanaka|Ryota|R|;Okiyama|Naoko|N|https://orcid.org/0000-0002-5398-0773;Watanabe|Rei|R|https://orcid.org/0000-0001-8254-9176;Saito|Akimasa|A|https://orcid.org/0000-0001-9001-6126;Furuta|Junichi|J|;Fujisawa|Yasuhiro|Y|https://orcid.org/0000-0003-3010-8496",
"chemical_list": "D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases",
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"medline_ta": "J Dermatol",
"mesh_terms": "D001932:Brain Neoplasms; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases; D009364:Neoplasm Recurrence, Local; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D012189:Retrospective Studies",
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"title": "Frequent brain metastases during treatment with BRAF/MEK inhibitors: A retrospective single institutional study.",
"title_normalized": "frequent brain metastases during treatment with braf mek inhibitors a retrospective single institutional study"
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"abstract": "Herein, we describe a case of early belatacept conversion in a human immunodeficiency virus (HIV)-positive kidney transplant recipient in an effort to improve suboptimal graft function and avoid drug interactions following anti-thymocyte globulin (ATG) administration. We observed improvement in renal function without HIV disease progression or opportunistic infections. Donor-specific antibodies appeared shortly after conversion but cleared without intervention. This case highlights belatacept as a means to improve renal function and avoid significant drug interactions even following ATG induction.",
"affiliations": "Department of Pharmacy, Houston Methodist Hospital, Houston, TX, USA.;Department of Pharmacy, Houston Methodist Hospital, Houston, TX, USA.;Department of Nephrology, Austin Kidney Associates, Austin, TX, USA.;Department of Surgery, Houston Methodist Hospital, Houston, TX, USA.;Department of Pharmacy, University of Houston College of Pharmacy, Houston, TX, USA.;Department of Nephrology, Baylor College of Medicine, Houston, TX, USA.;Department of Surgery, Houston Methodist Hospital, Houston, TX, USA.",
"authors": "Kuten|Samantha A|SA|http://orcid.org/0000-0002-8994-0968;Patel|Samir J|SJ|;Baru|Ashvin|A|;Gaber|A Osama|AO|;Crutchley|Rustin D|RD|;Ramanathan|Venkataraman|V|;Knight|Richard J|RJ|",
"chemical_list": "D019380:Anti-HIV Agents; D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D000069594:Abatacept",
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"issue": "19(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "HIV; belatacept; human immunodeficiency virus; kidney transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000069594:Abatacept; D019380:Anti-HIV Agents; D000961:Antilymphocyte Serum; D015658:HIV Infections; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Belatacept conversion in an HIV-positive kidney transplant recipient following anti-thymocyte globulin induction.",
"title_normalized": "belatacept conversion in an hiv positive kidney transplant recipient following anti thymocyte globulin induction"
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"abstract": "Lateral pelvic sidewall lymph nodes (PSW LN) may be involved in up to 24% of locoregionally advanced rectal cancers. PSW LN are not resected in total mesorectal excision (TME), and no standard of care regarding the management of PSW LN exists in the United States. We assessed our institutional experience of preoperative radiation therapy (RT) boost to clinically involved PSW LN that were not planned for resection.\nData from all patients with rectal adenocarcinoma treated between 2006 and 2018 were reviewed to identify those who received a cumulative dose of >50.4 Gy to suspicious PSW LN during neoadjuvant chemoradiation therapy (nCRT). Demographic, cancer characteristic, treatment, and toxicity data were derived from the chart.\nOf a total of 261 patients, 12 patients met the inclusion criteria. The median age was 47.5 years, and 83% of patients were men. All patients had T3/4 disease, 17% of patients had N1b disease and the remainder had N2 disease, and 33% had M1 disease (all ≤2 metastases). Seventy-five percent of patients had moderately or poorly differentiated histology. The mean distance from the anal verge was 4.85 cm (range, 2-8.9 cm), and 58% had ≥2 PSW LN with an average short axis diameter of 1.11 cm (range, 0.4-3.2 cm). Boost doses ranged from 53.48 Gy to 60.2 Gy in 27 to 30 fractions (1.8-2.15 Gy/fraction). The median follow-up time was 18 months. One patient who received concurrent capecitabine and irinotecan had grade 3 perineal dermatitis and anemia during nCRT. The median hospitalization time for TME was 6.5 days. Within 90 days of TME, 1 patient required surgical exploration for perineal wound breakdown, and another required a blood transfusion for anemia. At the time of the last follow up, 75% of patients were alive. Local control at 12 months was 90%.\nRT dose escalation to nonresected PSW LN during nCRT was well tolerated with a low risk of acute toxicity and perioperative complications and has a high rate of local control at 12 months. RT boost warrants further study in patients with clinically involved nonresected PSW LN.",
"affiliations": "Department of Radiation Oncology, Seattle, Washington.;Department of Radiation Oncology, Seattle, Washington.;Department of Radiation Oncology, Seattle, Washington.;Department of Medicine, Seattle, Washington.;Department of Surgery, University of Washington School of Medicine, Seattle, Washington.;National Comprehensive Cancer Network, Plymouth Meeting, Pennsylvania.;Department of Radiation Oncology, Seattle, Washington.",
"authors": "Hartvigson|Pehr E|PE|;Apisarnthanarax|Smith|S|;Schaub|Stephanie|S|;Cohen|Stacey|S|;Bernier|Greta|G|;Koh|Wui-Jin|WJ|;Kim|Edward Y|EY|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.adro.2019.03.007",
"fulltext": "\n==== Front\nAdv Radiat OncolAdv Radiat OncolAdvances in Radiation Oncology2452-1094Elsevier S2452-1094(19)30037-510.1016/j.adro.2019.03.007Gastrointestinal CancerRadiation Therapy Dose Escalation to Clinically Involved Pelvic Sidewall Lymph Nodes in Locally Advanced Rectal Cancer Hartvigson Pehr E. MDpehrh@uw.eduab∗Apisarnthanarax Smith MDaSchaub Stephanie MDaCohen Stacey MDcBernier Greta MDdKoh Wui-Jin MDeKim Edward Y. MDaa Department of Radiation Oncology, Seattle, Washingtonb Department of Radiation Medicine, Oregon Health and Science University, Portland, Oregonc Department of Medicine, Seattle, Washingtond Department of Surgery, University of Washington School of Medicine, Seattle, Washingtone National Comprehensive Cancer Network, Plymouth Meeting, Pennsylvania∗ Corresponding author. Department of Radiation Oncology, University of Washington Medical Center 2, 1959 NE Pacific Street, Box 356043, Seattle, WA 98195. pehrh@uw.edu01 4 2019 Jul-Sep 2019 01 4 2019 4 3 478 486 15 10 2018 24 2 2019 20 3 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nLateral pelvic sidewall lymph nodes (PSW LN) may be involved in up to 24% of locoregionally advanced rectal cancers. PSW LN are not resected in total mesorectal excision (TME), and no standard of care regarding the management of PSW LN exists in the United States. We assessed our institutional experience of preoperative radiation therapy (RT) boost to clinically involved PSW LN that were not planned for resection.\n\nMethods and materials\nData from all patients with rectal adenocarcinoma treated between 2006 and 2018 were reviewed to identify those who received a cumulative dose of >50.4 Gy to suspicious PSW LN during neoadjuvant chemoradiation therapy (nCRT). Demographic, cancer characteristic, treatment, and toxicity data were derived from the chart.\n\nResults\nOf a total of 261 patients, 12 patients met the inclusion criteria. The median age was 47.5 years, and 83% of patients were men. All patients had T3/4 disease, 17% of patients had N1b disease and the remainder had N2 disease, and 33% had M1 disease (all ≤2 metastases). Seventy-five percent of patients had moderately or poorly differentiated histology. The mean distance from the anal verge was 4.85 cm (range, 2-8.9 cm), and 58% had ≥2 PSW LN with an average short axis diameter of 1.11 cm (range, 0.4-3.2 cm). Boost doses ranged from 53.48 Gy to 60.2 Gy in 27 to 30 fractions (1.8-2.15 Gy/fraction). The median follow-up time was 18 months. One patient who received concurrent capecitabine and irinotecan had grade 3 perineal dermatitis and anemia during nCRT. The median hospitalization time for TME was 6.5 days. Within 90 days of TME, 1 patient required surgical exploration for perineal wound breakdown, and another required a blood transfusion for anemia. At the time of the last follow up, 75% of patients were alive. Local control at 12 months was 90%.\n\nConclusions\nRT dose escalation to nonresected PSW LN during nCRT was well tolerated with a low risk of acute toxicity and perioperative complications and has a high rate of local control at 12 months. RT boost warrants further study in patients with clinically involved nonresected PSW LN.\n==== Body\nIntroduction\nColorectal cancer is the third most common cancer in the United States1 with approximately 40,000 new cases annually. A large surgical series suggested that the prevalence of pelvic sidewall lymph node involvement (PSW LNI) is approximately 15% and may be up to 24% in patients with positive perirectal lymph nodes.2, 3 PSW LNI is associated with a higher risk of locoregional recurrence and poorer overall survival.2 The current standard of surgical care in North America and Europe is total mesorectal excision (TME). However, PSW LN are not routinely resected with TME and represent an important potential source of locoregional failure.\n\nLateral pelvic lymph node dissection (LLND) with TME is the standard of care in Japan.4 However, owing to increased morbidity with LLND observed in early studies, poorer prognosis associated with PSW LNI, and a previous lack of randomized data demonstrating a benefit to extended surgery, LLND was largely abandoned in the West.5 A Japanese phase 3 trial showed that TME was not noninferior to TME + LLND.6 However, patients who underwent TME + LLND had a significantly increased operation time, blood loss, and trend toward increased grade 3 to 4 adverse events.7 Neoadjuvant chemoradiation therapy (nCRT) followed by TME remains the accepted standard therapy for stage II to III rectal adenocarcinomas in North America and Europe.8, 9, 10, 11\n\nAt the present time, there is no accepted standard of care to manage clinically involved PSW LN, and most patients in the West receive nCRT and TME without LLND. An alternative option to intensify local therapy without extending surgical resection margins is increasing the radiation dose to clinically involved or at-risk nodes during nCRT. However, the safety of radiation therapy (RT) boost needs to be established, and no published patient data exist on RT boost safety or efficacy to PSW LN in patients with rectal cancer.\n\nHerein, we assess our institutional experience with preoperative RT boost (sequential or simultaneously integrated) to clinically involved PSW LN that were not planned to undergo resection.\n\nMethods and Materials\nData from all patients with International Classification of Diseases 9 or 10 diagnosis codes for rectal cancer who were treated at our RT department between 2006 and 2018 were reviewed, including patients who had biopsy-proven rectal adenocarcinoma and received a RT boost to a cumulative dose of >50.4 Gy to clinically suspicious PSW LN during nCRT. Clinical suspicion was primarily based on lymph node size (short axis >0.5 cm) but ultimately determined by a multidisciplinary tumor board. Patient charts that met these criteria were further reviewed for demographic, cancer characteristic, treatment, and toxicity (severity retrospectively graded per the Common Terminology Criteria for Adverse Events, version 4.0) data. Patients whose PSW LN received a cumulative dose of ≤50.4 Gy, short-course nCRT, or whose histology was something other than adenocarcinoma were excluded. PSW LN included lymph nodes in the following areas: obturator, sidewall, internal or external iliac region, and common iliac region. Dosimetry data was obtained from treatment planning and oncology information systems. No predefined protocol for RT boost target volume delineation existed.\n\nThe primary endpoint was to retrospectively determine the rate of grade 3 to 4 adverse events during neoadjuvant therapy. Adverse events during neoadjuvant therapy were determined by reviewing all available radiation and medical oncology notes. Intraoperative events were determined by reading all operative notes. Immediate postoperative complications were assessed by reviewing all hospital discharge notes. Postoperative adverse events were determined by a review of all available medical notes. Charts were evaluated to determine if any unplanned hospital admissions occurred, in which case admission and discharge notes were reviewed to evaluate whether the admission was related to complications of treatment. Each chart was reviewed through to the most recent follow up to detect documentation of adverse events. Survival, control, and follow-up rates were calculated from the date of the diagnostic biopsy. Local control was defined as no evidence of growth of the lymph node(s) treated with an RT boost on imaging. Locoregional control was defined as no evidence of new pelvic disease or progression in size of treated unresected pelvic disease on imaging. This study was approved by our institutional review board (IRB ID: STUDY00003900).\n\nResults\nBetween 2006 and 2018, a total of 261 patients with rectal cancer of all stages were treated, 12 of whom received a RT boost of >50.4 Gy during nCRT for clinically involved PSW LN. Patient demographics and treatment course information are summarized for each patient in Tables 1 and 2. Ten patients were men (83%), and the median age was 47.5 years (range, 32-76 years). Two-thirds of patients had clinical T3 disease, and the remaining patients had T4 disease. Two patients (17%) had cN1b lymph node involvement, and 10 patients (83%) had N2 disease. One-third of patients had distant metastatic disease (M1) with ≤2 metastases. Two patients had well differentiated adenocarcinoma (17%), but most had moderately or poorly differentiated malignancy (50% and 25%, respectively), and 1 patient's pathology test results did not include tumor grade. Three patients (25%) had ≥3 clinically involved PSW LN, and the remainder of patients had <3. The mean PSW LN short axis was 1.11 cm (range, 0.4-3.2 cm). The lymph nodes of 1 patient with a short axis of <0.5 cm were clinically suspected by the tumor board based on radiographic morphology and the number of lymph nodes. The average PSW LN long axis was 1.49 cm (range, 0.7-3.7 cm). The mean distance of the rectal primaries from the anal verge was 4.85 cm (range, 2-8.9 cm).Table 1 Patient demographics, treatment course\n\nCase no.\tAge at Dx\tSex\tRace\tECOG PS\tcT\tcN\tcM\tNo. PSW LNI\tLeast dimension PSW LN (cm)\tGreatest dimension PSW LN (cm)\tNeo-adjuvant chemo\tNo. cycles\tTotal Dose (cGy)\t\n1\t32\tM\tAsian\t0\tT3\tN2b\tM0\t3+\t1.3\t\tFOLFOX∗\t8∗\t6020\t\n2\t50\tM\tWhite\t1\tT4b\tN2NOS\tM1a\t1\t1\t1\tFOLFOX\t12\t6020\t\n3\t57\tM\tAsian\t0\tT4b\tN1b\tM0\t3+\t0.8\t1.4\t\t\t6020\t\n4\t45\tM\tLatino\t0\tT3\tN1b\tM1b\t2\t0.9\t1.6\tFOLFOX\t4\t5600\t\n5\t34\tM\tWhite\t0\tT4a\tN2NOS\tM1a\t2\t0.6\t0.9\tFOLFOX\t5\t5600\t\n6\t53\tM\tWhite\t0\tT3\tN2b\tM0\t3+\t0.4\t0.8\t\t\t5460\t\n7\t35\tF\tWhite\t0\tT3\tN2a\tM0\t1\t3.2\t3.7\t\t\t5404\t\n8\t76\tM\tWhite\t1\tT3\tN2a\tM0\t1\t1.3\t1.4\t\t\t5400\t\n9\t38\tM\tWhite\t0\tT3\tN2a\tM0\t1\t0.8\t\t\t\t5400\t\n10\t43\tF\tWhite\t1\tT4\tN2\tM0\t2\t1\t1.4\tOther†\t†\t5400\t\n11\t60\tM\tWhite\t0\tT3\tN2a\tM0\t1\t0.6\t0.7\t\t\t5400\t\n12\t56\tM\tWhite\t1\tT3\tN2a\tM1a\t2\t1.4\t2\tFOLFOX\t11\t5348\t\nAbbreviations: ECOG PS = Eastern Collaborative Oncology Group performance status; FOLFOX = leucovorin, 5-fluorouracil, and oxaliplatin; LN = lymph node; LNI = lymph node involvement; nCRT = neoadjuvant chemoradiation therapy; PLND = pelvic lymph node dissection; PSW = pelvic side wall.\n\n∗ This patient received nCRT first, followed by consolidative neoadjuvant FOLFOX. The other patients were administered induction systemic therapy, followed by nCRT before surgery.\n\n† Complex regimen at an outside institution included capecitabine, erlotinib, bevacizumab, and naturopathic supplements, then capecitabine with oxaliplatin + bevacizumab, then cetuximab, before starting nCRT with concurrent capecitabine with irinotecan. The exact number of cycles of induction therapy could not be determined.\n\nTable 2 Surgical and adjuvant therapy characteristics\n\nCase No.\tDays from neoadjuvant therapy to surgery\tSurgery details\tIORT (cGy)\tDays from surgery to discharge\tAdjuvant chemotherapy\tNo. cycles\t\n1\t15\tTotal proctocolectomy\t1000\t12\t\t\t\n2\tNo surgery\tNo surgery\t\t\tCAPIRI + Bev∗\t11∗\t\n3\t66\tLAR, robot-assisted\t\t26\tFOLFOX\t12\t\n4\t58\tAPR, robot-assisted\t\t3\t\t\t\n5\t35\tLAR, laparoscopic\t\t6\tFOLFOX\t6\t\n6\tLost to follow-up\tLost to follow-up\t\t\t\t\t\n7\t58\tAPR, robot-assisted\t1000\t5\tFOLFOX\t7\t\n8\t98\tAPR, robot-assisted\t\t7\t\t\t\n9\t105\tLAR, robot-assisted\t\t12\tCAPOX\t5\t\n10\t36\tTPE, posterior vaginectomy, PLND\t\t10\tCAPIRI\t8\t\n11\t62\tAPR, robot-assisted\t\t4\tFOLFOX\t8\t\n12\t56\tLAR\t\t3\tCapecitabine\t4\t\nAbbreviations: APR = abdominoperineal resection; Bev = bevacizumab; CAPIRI = capecitabine + irinotecan; cM = clinical metastasis classification; FOLFOX = leucovorin, 5-fluorouracil, and oxaliplatin; IORT = intraoperative radiation therapy; LAR = low anterior resection; PLND = pelvic lymph node dissection; TPE = total pelvic exenteration.\n\n∗ Patient had progression of extra-pelvic disease, and subsequently received multiple lines of palliative chemotherapy after CAPIRI with bevacizumab.\n\n\n\nNeoadjuvant therapy for each patient is summarized in Table 1. Five patients (42%) received induction chemotherapy before starting nCRT. Another patient received consolidative systemic therapy after nCRT before his surgery. Most patients received 5-fluorouracil/oxaliplatin-based systemic therapy. The average number of completed neoadjuvant cycles was 8 (range, 4-12 completed cycles). All patients received concurrent capecitabine with RT. One patient received capecitabine and irinotecan during nCRT. Two patients (17%) received sequential boosts at 1.8 Gy per fraction, and the other patients were treated with a simultaneous, integrated, boost technique using intensity modulated RT (IMRT) with fractional doses >1.8 Gy (range, 1.91-2.15 Gy/fraction). These doses were selected on the basis of the clinical judgment of the treating radiation oncologist, and often, the limiting factors were proximity to the bowel and overall size of the boost volume with typically lower doses per fraction used for larger boost volumes.\n\nRepresentative images from a patient planned with a simultaneous integrated boost to 60.2 Gy are shown in the Figure 1. Seven patients (58%) were treated to a cumulative dose of >54 Gy, and 25% of patients received 60.2 Gy in 28 fractions. Table 3 lists pertinent dose-volume histogram data for key organs at risk. Generally, the small bowel dose was kept acceptably low with low percent volumes at 50 Gy and 45 Gy, and the absolute volumes of the small bowel at these doses were low in all patients for whom there was information available. The bladder and femoral head doses were low (Table 3). Table 4 outlines the target volume doses. The average planning target volume (PTV) was 217.6 cc (range, 27.8-865.1 cc). Tables 3 and 4 show that ample PTV coverage for the RT boost targets was achieved in all patients. RT boost target volumes were variably defined with 1 of 2 methods typically used: clinical target volume consisting of the extra-mesorectal lymph node region that contains the clinically involved lymph node contoured with a 5 to 7 mm margin from clinical target volume to PTV or gross tumor volume of individual extra-mesorectal lymph nodes contoured with a 7 to 10 mm margin from the gross tumor volume directly to the PTV. Table 5 outlines the dose constraints for contoured volumes, including the small bowel. Two plans used the term “bowel”, and were reviewed including both the small and large bowels. Dose constraints were available for all patients except patient 10. The sacral plexus was not contoured.Figure 1 Representative images from radiation therapy boost plan for case number 1 (axial and coronal views).\n\nTable 3 Organ at risk dose-volume histogram and PTV boost coverage data\n\nCase No.\tRectum\tSmall bowel\tBladder\tFemoral heads\tPTV boost\t\nMax point (cGy)\tV50 (%)\tV45 (%)\tV45 (cc)\tMax point (cGy)\tV45 (%)\tV30 (%)\tMax point (cGy)\tV45 (%)\tMax point (cGy)\tD98%\tD95%\t\n1\t6018\t0\t5\t29\t5109\t23\t96\t5469\t0\t4096\t90\t100\t\n2\t6027\t0\t16\t57\t5141\t32\t98\t5750\t0\t4234\t99\t100\t\n3\t5535\t0\t5\t26\t5002\t25\t72\t5525\t0\t4781\t90.4\t99\t\n4\tN/a\t0\t4\t16\t5051\t13\t46\t5419\t0\t4087\t99\t100\t\n5\t5864\t0\t7\t18\t5150\t36\t93\t5520\t0\t4502\t100\t100\t\n6\t5855\t5\t9\t63\t5638\t44\t79\t5350\t0\t4164\t100\t100\t\n7\t5767\t3\t22\t30\t5369\t20\t76\t5675\t10\t5196\t95\t100\t\n8\t5670\t0\t0\t0\t4775\t35\t57\t5691\t0\t4639\t100\t100\t\n9\t5445\t15\t20\t113\t5556\t21\t57\t5225\t0\t3707\t99\t100\t\n10∗\t5768\t\t\t\t5839\t\t\t5992\t\t5812\t\t\t\n11\t5492\t0\t2\t8\t5170\t23\t49\t5482\t0\t4119\t100\t100\t\n12\tN/a\t0\t16\t16\t4795\t31\t80\t5658\t0\t4022\t100\t100\t\nAbbreviations: max = maximum; N/A = not applicable; PTV = planning target volume.\n\nThe maximum point dose is a pixel dose. Not applicable means this structure was not contoured.\n\n∗ Unable to retrieve patient's plan in the treatment planning system, and the maximum point doses were found on plan print-outs in the oncology information system. Of note, this patient's small bowel dose point is from a contour that included both the large and small bowels as a single bowel contour volume.\n\nTable 4 Target volumes and doses\n\nCase no.\tCumulative total dose (cGy)\tPlanned fractions\tGTV rectal volume (cc)\tGTV LN volume (cc)\tPTV boost volume (cc)\tMinimum dose to PTV boost (cGy)\tMax dose to PTV boost (cGy)\tMean dose to PTV boost (cGy)\t\n1\t6020\t28\t153.8\t16.7\t92.2\t5637\t6453\t6097\t\n2\t6020\t28\t61.7\t4.5\t27.8\t5812\t6197\t6081\t\n3\t6020\t28\t137.2\t3.1\t55.3\t5474\t6287\t6056\t\n4\t5600\t28\t271.3\t11\t33\t5338\t5922\t5744\t\n5\t5600\t28\t79.3\t4.3\t87.2\t5496\t6000\t5710\t\n6\t5460\t28\t124.5\t6\t274\t5450\t5855\t5648\t\n7\t5404\t28\t49.3\t0.6\t745.7\t4950\t5885\t5495\t\n8\t5400\t30\t71.7\t8\t865.1\t4870\t5785\t5571\t\n9\t5400\t27\t94.3\t2.9\t76.6\t5178\t5810\t5480\t\n10\t5400\t30\t145.7\t6.4\tNR\t2097\t6140\t5587\t\n11\t5400\t27\t50.4\t1.4\t32.4\t5432\t5649\t5535\t\n12\t5348\t28\t50.3\t4.2\t104.6\t5217\t5725\t5513\t\nAbbreviations: GTV = gross target volume; LN = lymph node; NR = not reported; PTV = planning target volume.\n\nTable 5 Small bowel dose constraints\n\nVolume name\tMax dose\tRelative volume constraint\tAbsolute volume constraint\tPatients treated with constraints\t\nDose\tLimit\tVolume (%)\tDose\tLimit\tVolume (cc)\t\nSmall bowel\t5150\t\t\t\t\t\t\t1, 2, 3, 8\t\n\t5300\t\t\t\t\t\t\t6\t\n\t5400\t\t\t\t\t\t\t7, 11\t\n\t\t4000\t≤\t40\t\t\t\t6\t\n\t\t4000\t<\t25\t\t\t\t11\t\n\t\t4500\t<\t25\t\t\t\t6\t\n\t\t5000\t<\t10\t\t\t\t11\t\n\t\t\t\t\t1500\t<\t120\t9\t\n\t\t\t\t\t3500\t<\t150\t3, 7, 8, 11\t\n\t\t\t\t\t4000\t<\t150\t1, 2, 7\t\n\t\t\t\t\t4000\t<\t70\t3, 7, 8\t\n\t\t\t\t\t4500\t<\t195\t9\t\n\t\t\t\t\t4500\t<\t100\t1, 2, 3, 5\t\n\t\t\t\t\t4500\t<\t90\t7\t\n\t\t\t\t\t4500\t<\t35\t3, 7, 8\t\n\t\t\t\t\t5000\t<\t10\t5\t\n\t\t\t\t\t5040\t<\t10\t7\t\nBowel∗\t5150\t\t\t\t\t\t\t4, 12\t\n\t\t\t\t\t2500\t<\t185\t4\t\n\t\t\t\t\t3000\t<\t155\t4\t\n\t\t\t\t\t3500\t<\t40\t4\t\n\t\t\t\t\t3500\t<\t150\t12\t\n\t\t\t\t\t4000\t<\t70\t12\t\n\t\t\t\t\t4000\t<\t30\t4\t\n\t\t\t\t\t4500\t<\t35\t12\t\nDose is in units of cGy. No organ at risk constraint documentation could be found for patient 10.\n\n∗ Volume included both the small and large bowels.\n\n\n\nTable 6 summarizes the toxicity experienced during treatment for patients who received ≥14 fractions of nCRT. Patient 6 transferred care to another institution after 13 fractions, and outside treatment records were not available for review. The patient's death date was obtained from public records. The majority of patients tolerated treatment well. One patient (8%) received capecitabine + irinotecan-based nCRT and experienced grade 3 dermatitis and anemia, which required a blood transfusion. The maximum treatment break during nCRT was 3 days.Table 6 Adverse events of patients completing ≥14 fractions of RT boost\n\nCase no.\tPre-nCRT chemotherapy\tnCRT with RT boost\tPost-nCRT preoperative chemotherapy\tIntraoperative, immediate postoperative, and 90-day surgical complications\t\nGrade\tDetails\tRT break (days)\tGrade\tDetails\tAdverse events\tIntraoperative\tImmediate postoperative\tSurgery to discharge (days)\t90 day\t\n1\t\t\t1\t1\tAnoproctitis\tNo\tNo\tPre-sacral abscess\t12\tSymptomatic anemia, out-patient transfusion\t\n2\t3;3\tNeuropathy; mucositis\t0\t1\tHand foot syndrome\t--\t--\t--\t--\t--\t\n3\t\t\t3\t2\tAllergic reaction to capecitabine\t--\tNo\tSBO managed non-operatively\t26\tNo\t\n4\t\t\t1\t1\tDiarrhea\t--\tNo\tNo\t3\tNo\t\n5\t\t\t3\t1\tDiarrhea\t--\tNo\tBilateral lower extremity sensory neuropathy\t6\tNo\t\n7\t\t\t3\t1\tAnoproctitis\t--\tNo\tNo\t5\tNo\t\n8\t\t\t0\t1\tAnoproctitis\t--\tNo\tIschemic colostomy requiring revision\t7\tPerineal wound breakdown requiring surgery\t\n9\t\t\t0\t1\tAnoproctitis\t--\tNo\tPostop ileus with prolonged NGT use\t12\tNo\t\n10\t\tDisease progression\t0\t3;3\tPerineal dermatitis; anemia\t--\tDVT found intra-op\tNo\t10\tNo\t\n11\t\t\t2\t1\tAnoproctitis\t--\tNo\tNo\t4\tNo\t\n12\t3\tHand foot syndrome\t1\t2\tHand foot syndrome\t--\tNo\tNo\t3\tNo\t\nAbbreviations: DVT = deep vein thrombosis; nCRT = neoadjuvant chemoradiation therapy; NGT = nasogastric tube; RT = radiation therapy; SBO = small bowel obstruction.\n\n“Immediate postoperative” is defined as the time from surgery to hospital discharge.\n\n-- indicates not applicable (ie, patient did not have post-nCRT pre-operative chemotherapy, surgery, etc.)\n\n\n\nOf the 12 patients who received ≥14 fractions, 1 patient transferred care and was lost to follow up, and 1 patient developed distant progression of disease and did not undergo a resection. For the 10 patients who received TME, the median time from whichever the neoadjuvant therapy last preceded surgery (nCRT or consolidative chemotherapy) was 58 days (range, 15-105 days). One patient had a combined operation with gynecologic oncologists who performed PSW LN dissection in addition to the TME performed by the patient's colorectal surgeon and was found to be ypN0. Eight of 10 patients who underwent TME were ypN0.\n\nTwo patients received intraoperative RT (IORT) boosts of 10 Gy electrons to either the anticipated close margins or unresectable lymph node areas. Patient 1 developed a presacral abscess during admission for surgery 7 days after surgery. The IORT boost was to the anterior pelvic wall margin. One patient was discovered during surgery to have an asymptomatic deep vein thrombosis, but otherwise no intraoperative complications were reported. Immediate postoperative complications (ie, before discharge from admission for surgery) were seen in 5 patients: Pre-sacral abscess, small bowel obstruction managed without surgery, bilateral lower extremity sensory neuropathy, ischemic colostomy that requires revision, and postoperative ileus with prolonged nasogastric tube use. The median number of days from surgery to discharge was 6.5 (range, 3-26 days). Within 90 days of surgery, 2 patients had complications, with 1 patient who had perineal wound breakdown that required a surgical revision in the setting of chronic steroid therapy and another patient who had symptomatic anemia that was managed with an outpatient transfusion. The same patient with chronic steroid therapy who had a perineal wound breakdown within 90 days also had a challenging body habitus that required the presence of 2 attending surgeons at the time of the resection. The patient underwent several subsequent admissions >90 days after surgery for recurrent wound infections and ultimately died of sepsis from a pelvic abscess 16 months after surgery. The patient received a sequential RT boost to a total dose of 54 Gy.\n\nAfter TME, 7 of 10 resected patients received adjuvant systemic therapy (Table 2). The average number of completed adjuvant cycles was 6.4 (range, 3-12 completed cycles). One patient underwent a metastasectomy for 2 pulmonary metastases. The median follow-up time was 18 months (range, 5-63 months). Median overall survival was not yet reached, but 9 patients (75%) were alive at the time of the last follow up, including 2 patients who were alive with the disease. The 1-year overall survival rate was 91.7%, and the median locoregional progression-free survival (ie, any progression in the pelvis) was 16 months (range, 8-22 months). After excluding 1 patient who transferred care after 13 fractions and another patient who received a PSW LN dissection along with the TME, local control of PSW LN at 12 months was 90% and locoregional control was 80%.\n\nOne patient had progression of disease in an unresected PSW LN that received an RT boost, and another patient had a locoregional recurrence in a new PSW LN contralateral to the originally clinically involved and RT boosted PSW LN (boosted LN remained controlled).\n\nDiscussion\nOur case series of 12 patients with locally advanced rectal adenocarcinoma with clinically involved PSW LN who were not planned to undergo LLND suggests that RT boosts >50.4 Gy and up to 60.2 Gy in 28 fractions, using daily doses up to 2.15 Gy per fraction, are well tolerated during neoadjuvant therapy and associated with high rates of short-term local control and no detected increased risk of intraoperative complications. To the best of our knowledge, this is the first report of various radiation dose-escalation schemes in patients with clinically involved PSW LN and suggests that further research into the safety and efficacy of RT boost for PSW LN involvement is merited.\n\nPSW LN are an important contributor to locoregional failure and death in patients with rectal cancer.2, 12, 13 One approach to mitigate the risks associated with PSW LNI includes extending the surgical margins to include the pelvic sidewall. LLND has been largely abandoned by Western colorectal surgeons,5, 14 but widely adopted and undergone considerable refinement in Japan and Korea, including the development of nerve-sparing techniques15 and robotic surgery.16 In 2017, Fujita et al6 published the results of the Japan Clinical Oncology Group trial 0212, a large, prospective, randomized trial of 701 patients with stage 2-3 rectal cancer with PSW LN measuring ≤1 cm who were randomized to TME + LLND versus TME alone cohorts. The 5-year relapse-free survival rates were 73.4% versus 73.3%, respectively, with a hazard ratio (HR) of 1.07 (90.9% confidence interval [CI], 0.84-1.36). Despite the extraordinary numerical similarity, this study did not find TME to be noninferior to TME + LLND (P-value for noninferiority = .0547), and supported TME + LLND as standard of care in Japan. The 5-year overall survival rate was also similar between TME + LLND and TME at 92.6% versus 90.2%, respectively (HR: 1.25; 95% CI, 0.85-1.84). A significant difference was observed in local recurrence, favoring TME + LLND (7% vs 13%; P = .02). No neoadjuvant radiation or chemoradiation was used, and adjuvant RT was rarely used.\n\nAlthough TME + LLND appears to be effective and its technique much improved, concerns about intraoperative complications and adverse events remain. Patients who underwent TME + LLND versus TME had significantly longer operative times (360 vs 254 minutes; P < .0001) and blood loss (576 vs 337 ml; P < .0001).7 There was a nonsignificant trend toward higher grade 3-4 complications with TME + LLND (22% vs 16%; P = .07).7 These concerns, combined with local control benefits observed in trials that incorporate neoadjuvant therapy, have driven interest to explore the efficacy of neoadjuvant therapy and address suspected PSW LNI.\n\nNo prospective randomized trials have compared nCRT + TME with TME + LLND. A matched analysis17 of patients who were randomized in a Dutch rectal trial9 between TME and short-course RT followed by TME (RT + TME) compared with the Tokyo National Cancer Center Hospital database of patients treated with LLND found similar rates of local recurrence between RT + TME versus LLND (5.8% vs 6.9%; HR: 1.0; 95% CI, 0.6-1.8), which suggests that preoperative RT may be able to successfully treat PSW LNI. nCRT has become an accepted part in the management of stage II-III rectal cancers, and several retrospective reports have been published exploring its incorporation into treatment paradigms with or without LLND.18, 19, 20 All studies used standard nCRT to 45 Gy with rectal primary 5.4 Gy boosts. These papers found locoregional failure rates of 8% to 12%, of which 40% to 83% were PSW LN recurrences. Recently Ogura et al21 published the results of a large international retrospective study of >1200 patients with clinical T3-4 low rectal primaries who underwent surgery. A 19.5% rate of lateral lymph node recurrence at 5 years after surgery was observed in patients with pelvic sidewall lymph nodes of a ≥0.7 cm short axis diameter who underwent nCRT (both short and long course were included) followed by TME. These combined findings demonstrate that pelvic sidewall failure remains a clinically important concern in the nCRT era.\n\nA key question is whether intensifying RT to enlarged PSW LN during nCRT can supplant LLND. If so, which is less toxic, intensified neoadjuvant therapy or extended surgical resection? Other studies investigated various combinations of systemic-dosed chemotherapy, chemoradiotherapy, and TME for stage II-III rectal cancers and demonstrated variable rates of complete pathologic response. One study suggested a pathologic complete response rate as high as 27%, with 47% of all patients studied achieving >90% pathologic response.22 These results suggest that RT may provide adequate local control for some patients, but a question remains whether RT dose intensification would improve pathologic response rates. Our case series is too small and the follow-up time too short to accurately characterize local and locoregional control rates.\n\nWhether RT boosts increase the risk of immediate and delayed postoperative complications remains unclear. One patient (patient 8) experienced significant wound complications, including an ischemic colostomy site that required colostomy revision in the immediate postoperative setting and multiple episodes of wound breakdown and abscess formation. The patient ultimately died of sepsis from a perineal abscess 16 months after surgery. This patient had the largest PTV boost volume (865.1 cc), which included the entire mesorectum and right obturator lymph node bed. Of note, this patient was treated with a sequential IMRT-based boost to one of the lowest overall doses in the series (54 Gy in 30 fractions at 1.8 Gy/fraction). Perhaps a dose-volume interaction with toxicity was responsible for increased late toxicity; however, the next largest PTV boost volume was 745.7 cc in patient 7, who was treated to a cumulative dose of 54.04 Gy in 28 fractions at 1.93 Gy per fraction using a simultaneous integrated boost with IMRT. This patient did not have any grade 2+ early or late adverse effects from treatment. Neither patient 7 or 8 had neoadjuvant systemic therapy. Patient 7 had higher doses to all organs at risk compared with patient 8 (Table 3) and received a 10 Gy intraoperative electron boost and 7 cycles of adjuvant FOLFOX. Patient 8 received no additional therapy, except for nCRT and TME. Patient 8 may have had other health factors placing him at a greater risk for wound complications, including chronic systemic steroid therapy. Indeed, other comorbidities, including body habitus and anatomy, necessitated the presence of 2 experienced attending colorectal surgeons for the TME.\n\nAnother patient (patient 1) developed a presacral abscess 7 days after resection, which required a drain for source control. The patient was ultimately discharged 12 days after surgery and received an IORT boost to the anterior pelvic wall for a close margin. The other patient who received an IORT boost did not have any postoperative complications. Too few patients received IORT to determine how much contributed to toxicity. However, the presacral abscess may be considered a potential immediate postoperative complication of RT.\n\nThis case series is subject to the shortcomings of retrospective data. Adverse events and their severity were abstracted from available documentation, and no prospectively recorded patient reported outcomes were obtained; thus, adverse events may be underreported and their true severity not represented accurately. The number of patients included in this study is small, and target delineation for RT boost was variable, which limited generalizable conclusions about survival and tumor control. Similarly, because patients were analyzed in a retrospective manner, determining how well these patients represent all patients with clinically suspicious PSW LN is difficult.\n\nWe are unable to definitively answer the critical question of whether an RT boost increases peri-and postoperative complications or improves local control. A prospective phase 1/2 trial is needed to answer these questions and under consideration at our institution.\n\nConclusions\nOur data are hypothesis-generating and suggest that an integrated RT boost up to 60.2 Gy in 28 fractions may be well tolerated. This approach is worthy of further exploration in prospective trials. As interest in augmenting neoadjuvant therapy in stage II-III rectal cancer increases, determining the safety and efficacy of definitive chemoradiotherapy to clinically involved extra-mesorectal lymph nodes is important.\n\nSources of support: This work had no specific funding.\n\nDisclosures: The authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n1 Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2017 CA Cancer J Clin 67 2017 7 30 28055103 \n2 Sugihara K. Kobayashi H. Kato T. Indication and benefit of pelvic sidewall dissection for rectal cancer Dis Colon Rectum 49 2006 1663 1672 17041749 \n3 Kinugasa T. Akagi Y. Ochi T. Lateral lymph-node dissection for rectal cancer: Meta-analysis of all 944 cases undergoing surgery during 1975-2004 Anticancer Res 33 2013 2921 2927 23780981 \n4 Watanabe T. Muro K. Ajioka Y. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer Int J Clin Oncol 23 2018 1 34 28349281 \n5 Koch M. Kienle P. Antolovic D. Buchler M.W. Weitz J. Is the lateral lymph node compartment relevant? Recent Results Cancer Res 165 2005 40 45 15865019 \n6 Fujita S. Mizusawa J. Kanemitsu Y. Mesorectal excision with or without lateral lymph node dissection for clinical stage II/III lower rectal cancer (JCOG0212): A multicenter, randomized controlled, noninferiority trial Ann Surg 266 2017 201 207 28288057 \n7 Fujita S. Akasu T. Mizusawa J. Postoperative morbidity and mortality after mesorectal excision with and without lateral lymph node dissection for clinical stage II or stage III lower rectal cancer (JCOG0212): Results from a multicentre, randomised controlled, non-inferiority trial Lancet Oncol 13 2012 616 621 22591948 \n8 Sauer R. Becker H. Hohenberger W. Preoperative versus postoperative chemoradiotherapy for rectal cancer N Engl J Med 351 2004 1731 1740 15496622 \n9 Kapiteijn E. Marijnen C.A.M. Nagtegaal I.D. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer N Engl J Med 345 2001 638 646 11547717 \n10 Swedish Rectal Cancer Trial Cedermark B. Dahlberg M. Glimelius B. Improved survival with preoperative radiotherapy in resectable rectal cancer N Engl J Med 336 1997 980 987 9091798 \n11 Folkesson J. Birgisson H. Pahlman L. Cedermark B. Glimelius B. Gunnarsson U. Swedish rectal cancer trial: Long lasting benefits from radiotherapy on survival and local recurrence rate J Clin Oncol 23 2005 5644 5650 16110023 \n12 Group M.S. Shihab O.C. Taylor F. Relevance of magnetic resonance imaging-detected pelvic sidewall lymph node involvement in rectal cancer Br J Surg 98 2011 1798 1804 21928408 \n13 Yano H. Moran B.J. The incidence of lateral pelvic side-wall nodal involvement in low rectal cancer may be similar in Japan and the West Br J Surg 95 2008 33 49 18165939 \n14 Georgiou P. Tan E. Gouvas N. Extended lymphadenectomy versus conventional surgery for rectal cancer: A meta-analysis Lancet Oncol 10 2009 1053 1062 19767239 \n15 Sugihara K. Moriya Y. Akasu T. Fujita S. Pelvic autonomic nerve preservation for patients with rectal carcinoma Cancer 78 1996 1871 1880 8909305 \n16 Park J.A. Choi G.S. Park J.S. Park S.Y. Initial clinical experience with robotic lateral pelvic lymph node dissection for advanced rectal cancer J Korean Soc Coloproctol 28 2012 265 270 23185707 \n17 Kusters M. Beets G.L. van de Velde C.J. A comparison between the treatment of low rectal cancer in Japan and the Netherlands, focusing on the patterns of local recurrence Ann Surg 249 2009 229 235 19212175 \n18 Kim T.H. Jeong S.Y. Choi D.H. Lateral lymph node metastasis is a major cause of locoregional recurrence in rectal cancer treated with preoperative chemoradiotherapy and curative resection Ann Surg Oncol 15 2008 729 737 18057989 \n19 Kim T.G. Park W. Choi D.H. Factors associated with lateral pelvic recurrence after curative resection following neoadjuvant chemoradiotherapy in rectal cancer patients Int J Colorectal Dis 29 2014 193 200 24322736 \n20 Lim S.B. Yu C.S. Kim C.W. Clinical implication of additional selective lateral lymph node excision in patients with locally advanced rectal cancer who underwent preoperative chemoradiotherapy Int J Colorectal Dis 28 2013 1667 1674 23943283 \n21 Ogura A. Konishi T. Cunningham C. Neoadjuvant (chemo)radiotherapy with total mesorectal excision only is not sufficient to prevent lateral local recurrence in enlarged nodes: Results of the multicenter lateral node study of patients with low cT3/4 rectal cancer J Clin Oncol 37 2019 33 43 30403572 \n22 Cercek A. Goodman K.A. Hajj C. Neoadjuvant chemotherapy first, followed by chemoradiation and then surgery, in the management of locally advanced rectal cancer J Natl Compr Canc Netw 12 2014 513 519 24717570\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "4(3)",
"journal": "Advances in radiation oncology",
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"medline_ta": "Adv Radiat Oncol",
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"title": "Radiation Therapy Dose Escalation to Clinically Involved Pelvic Sidewall Lymph Nodes in Locally Advanced Rectal Cancer.",
"title_normalized": "radiation therapy dose escalation to clinically involved pelvic sidewall lymph nodes in locally advanced rectal cancer"
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"abstract": "We performed an autopsy on a patient with systemic sclerosis who developed uncontrollable pulmonary hypertension due to pulmonary tumour thrombotic microangiopathy (PTTM) caused by gastric carcinoma. The case was of a 62-year-old woman with systemic sclerosis who was admitted to the intensive care unit (ICU) with severe pulmonary hypertension accompanied by respiratory insufficiency. Pulmonary hypertension could not be controlled despite aggressive medical treatment including vasodilators. Approximately 10 days after admission, a unilateral pleural effusion developed. Thoracentesis was performed, and cytology examination of the pleural fluid revealed carcinomatous pleurisy. Because of the presence of a known gastric carcinoma, PTTM was clinically diagnosed. Although chemotherapy was administered, she died 33 days after ICU admission. An autopsy revealed diffuse fibrocellular intimal thickening of the peripheral pulmonary arterioles, which indicated PTTM. In patients with connective tissue disease complicated with pulmonary hypertension, it is necessary to differentiate not only pulmonary arterial hypertension but also other pathological conditions such as PTTM.",
"affiliations": "The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.;The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.;The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.;The Department of Pathology and Oncology, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.;The Department of Pathology, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.;The Department of Pathology, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.;Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.;Department of Respiratory Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.;Department of Respiratory Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.;The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.",
"authors": "Yamauchi|Yusuke|Y|;Nakano|Kazuhisa|K|;Miyagawa|Ippei|I|;Inaba|Yuna|Y|;Nawata|Aya|A|;Sato|Naoko|N|;Kumei|Shinsuke|S|;Kawanami|Toshinori|T|;Yatera|Kazuhiro|K|;Tanaka|Yoshiya|Y|",
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"country": "England",
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"doi": "10.1080/24725625.2019.1690767",
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"issn_linking": "2472-5625",
"issue": "4(1)",
"journal": "Modern rheumatology case reports",
"keywords": "PTTM; autopsy; gastric cancer; pulmonary hypertension; systemic sclerosis",
"medline_ta": "Mod Rheumatol Case Rep",
"mesh_terms": "D001344:Autopsy; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D008175:Lung Neoplasms; D008875:Middle Aged; D012595:Scleroderma, Systemic; D013274:Stomach Neoplasms; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "101761026",
"other_id": null,
"pages": "56-62",
"pmc": null,
"pmid": "33086979",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An autopsy case of a patient with systemic sclerosis who developed marked pulmonary hypertension because of pulmonary tumor thrombotic microangiopathy caused by gastric carcinoma.",
"title_normalized": "an autopsy case of a patient with systemic sclerosis who developed marked pulmonary hypertension because of pulmonary tumor thrombotic microangiopathy caused by gastric carcinoma"
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"abstract": "Proton pump inhibitors (PPIs) are the mainstay of therapy for all gastric acid related diseases and are commonly used in current clinical practice. Although widely regarded as safe, PPIs have been associated with a variety of adverse effects, including hypomagnesaemia. The postulated mechanism of PPI-related hypomagnesaemia involves inhibition of intestinal magnesium absorption via transient receptor potential melastin (TRPM) 6 and 7 cation channels. PPIinduced hypomagnesaemia (PPIH) has become a well recognized phenomenon since it was first reported in 2006. Clinical concerns arise from growing number of case reports presenting PPIH as a consequence of long-term PPI use, with more than 30 cases published to date. In this article, we report 2 cases of PPIH associated with the use of pantoprazole. Both patients presented with severe hypomagnesaemia and hypocalcaemia. One of them had associated hypokalemia and cardiac arrhythmia. A casual relation with PPIs postulated and supported by resolution of electrolyte abnormalities after discontinuation of PPIs.",
"affiliations": "Department of Medicine, Hospital Melaka, Malaysia.;Department of Medicine, Hospital Melaka, Malaysia.",
"authors": "Tai|Yong Ting|YT|;Tong|Chin Vong|CV|",
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"country": "Thailand",
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"doi": "10.15605/jafes.035.01.18",
"fulltext": "\n==== Front\nJ ASEAN Fed Endocr Soc\nJ ASEAN Fed Endocr Soc\nJAFES\nJournal of the ASEAN Federation of Endocrine Societies\n0857-1074 2308-118X Journal of the ASEAN Federation of Endocrine Societies \n\nJAFES-35-1-109\n10.15605/jafes.035.01.18\nCase Report\nThe Perilous PPI: Proton Pump Inhibitor as a Cause of Clinically Significant Hypomagnesaemia\nTai Yong Ting Tong Chin Vong Department of Medicine, Hospital Melaka, Malaysia\nCorresponding author: Yong Ting Tai, MD Department of Medicine, Hospital Melaka Jalan Mufti Haji Khalil, 75400, Melaka, Malaysia. Tel. No.: +6062892344. Fax No.: +6062827501. E-mail: yongting_1120@yahoo.com. ORCiD: https://orcid.org/0000-0002-5304-925X\n20 4 2020 \n2020 \n35 1 109 113\n05 1 2020 26 2 2020 © 2020 Journal of the ASEAN Federation of Endocrine Societies2020This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International.Proton pump inhibitors (PPIs) are the mainstay of therapy for all gastric acid related diseases and are commonly used in current clinical practice. Although widely regarded as safe, PPIs have been associated with a variety of adverse effects, including hypomagnesaemia. The postulated mechanism of PPI-related hypomagnesaemia involves inhibition of intestinal magnesium absorption via transient receptor potential melastin (TRPM) 6 and 7 cation channels. PPIinduced hypomagnesaemia (PPIH) has become a well recognized phenomenon since it was first reported in 2006. Clinical concerns arise from growing number of case reports presenting PPIH as a consequence of long-term PPI use, with more than 30 cases published to date.\n\nIn this article, we report 2 cases of PPIH associated with the use of pantoprazole. Both patients presented with severe hypomagnesaemia and hypocalcaemia. One of them had associated hypokalemia and cardiac arrhythmia. A casual relation with PPIs postulated and supported by resolution of electrolyte abnormalities after discontinuation of PPIs.\n\nProton pump inhibitorshypomagnesaemiahypocalcaemiahypokalemia\n==== Body\nINTRODUCTION\nProton pump inhibitors (PPIs) are the mainstay of therapy for all gastric acid related diseases and are commonly used in current clinical practice. Although widely regarded as safe, PPIs have been associated with a variety of adverse effects including interstitial nephritis, pneumonia, Clostridium difficile-associated diarrhea, vitamin B12 deficiency, osteoporosis and fractures.1 More recently, long-term use of PPIs has been suggested as a potential cause of hypomagnesaemia2 Magnesium is the second most abundant intracellular cation and its homeostasis is intricately regulated by intestinal absorption and renal excretion. The postulated mechanism of PPI-related hypomagnesaemia involves inhibition of intestinal magnesium absorption via transient receptor potential melastin (TRPM) 6 and 7 cation channels.3,4 Severe hypomagnesaemia can be associated with malignant cardiac arrhythmias, tetany, generalized seizures, and other metabolic disturbances such as hypokalemia and hypocalcaemia.5\n\nPPI-induced hypomagnesaemia (PPIH) has become a well recognized phenomenon since it was first reported in 2006.6 Clinical concerns arise from growing number of case reports presenting PPIH as a consequence of longterm PPI use, with more than 30 cases published to date.6-22 In 2011, United States Food and Drug Administration released a safety concern on PPIs, stating that it may cause hypomagnesaemia if taken for prolonged periods of time.23 This announcement alerted healthcare professionals to the risk of hypomagnesaemia among chronic PPI users, with the consideration of obtaining baseline and regular follow-up serum magnesium concentrations over time. In this article, we report 2 cases of PPIH associated with the use of pantoprazole.\n\nCASE 1\nPatient 1 was a 59-year-old female with a background history of diabetes mellitus and hypertension. Her medications included perindopril, amlodipine, metformin and gliclazide. She was diagnosed with pulmonary tuberculosis one month prior to admission (PTA), having presented with 3-month history of fever, cough and constitutional symptoms. She was started on antituberculosis treatment. Unfortunately, she developed epigastric pain and vomiting and was started on pantoprazole a month later. She requested at-own-risk discharge from hospital on two days after starting the PPI.\n\nThree days later, she was admitted again due to persistent vomiting and epigastric pain. On her 1st hospital day (HD) she developed an episode of narrow-complex tachycardia with prolonged QTc and went into respiratory distress. She required intubation and was transferred to the intensive care unit. Her blood investigations showed multiple electrolyte abnormalities, including hypomagnesaemia, hypocalcaemia, hypophosphatemia and hypokalemia. She was given multiple doses of parenteral magnesium sulfate, calcium gluconate and potassium chloride to correct those deficiencies. However, the serum magnesium, potassium and calcium levels failed to return to normal despite multiple corrections given.\n\nOn the 3rd HD, pantoprazole was discontinued. Thereafter, the serum levels of magnesium, potassium and calcium started to respond to the IV corrections and slowly returned to normal. (Table 1 and Figure 1). Unfortunately, the patient developed hospital-acquired pneumonia and succumbed to septicemia two weeks later.\n\nTable 1 Patient 1 blood investigations\n\nDate\tBaseline\tOn pantoprazole\tPantoprazole discontinued\t\n27/8/17\t19/9/17\t20/9/17\t21/9/17\t22/9/17\t24/9/17\t27/9/17\t29/9/17\t\nCorrected calcium (2.18-2.6 mmol/L)\t2.22\t1.5\t1.5\t1.46\t2.0\t2.02\t1.96\t2.26\t\nMagnesium (0.53-1.11 mmol/L)\t0.75\t0.35\t–\t0.74\t0.85\t0.78\t0.74\t0.65\t\nPhosphate (0.78-1.65 mmol/L)\t0.83\t0.7\t0.48\t0.12\t0.66\t0.86\t1.01\t0.57\t\nPotassium (3.5-5.1 mmol/L)\t4.6\t3.0\t3.3\t3.6\t4.1\t4\t3.3\t4.4\t\niPTH:\t7.45 pmol/L\t(1.58-6.03)\t\t\t\t\t\t\t\n24 hour urine calcium:\t0.15 mmol/24hour\t(2.5-7.5)\t\t\t\t\t\t\t\n24 hour urine magnesium:\t3.4 mmol/24 hour\t(4.0-5.0)\t\t\t\t\t\t\t\nTotal 25-hydroxyVitamin D:\t46.94 nmol/L\t(<25 Deficient)\t\t\t\t\t\t\t\n\t\t(25-75 Insufficient)\t\t\t\t\t\t\t\n\t\t(75-250 Sufficient)\t\t\t\t\t\t\t\n\t\t(>250 Possible intoxication)\t\t\t\t\t\t\t\nFigure 1 Course of laboratory parameters over time in patient 1.\n\nCASE 2\nPatient 2 is a 71-year-old female. She had underlying diabetes mellitus, hypertension, chronic kidney disease (CKD) stage V (not on renal replacement therapy) and bilateral knee osteoarthritis. She was diagnosed with peptic ulcer disease in 5 months PTA after an episode of upper gastrointestinal bleeding. She was prescribed pantoprazole since that admission. On the day of admission, she presented with lethargy and bilateral hand numbness. Blood investigations showed she had severe hypocalcaemia and hypomagnesaemia. Her pantoprazole was withheld on her 2nd HD and substituted with oral ranitidine. She was given a few intravenous calcium and magnesium corrections. Her serum magnesium and calcium levels slowly returned to near normal levels after the pantoprazole was discontinued (Table 2 and Figure 2). She was discharged on her 6th HD with oral calcium carbonate supplement. When she followed up one month later, her blood magnesium and calcium levels had normalized. Vitamin D level was not available due to reagent shortage.\n\nTable 2 Patient 2 blood investigations\n\nDate\tPantoprazole dis continued\t\n11/9/18\t13/9/18\t14/9/18\t15/9/18\t16/9/18\t17/9/18\t17 /10/ 18\t\nCorrected calcium (2.18-2.6 mmol/L)\t1.35\t1.54\t1.63\t1.73\t1.91\t1.96\t2.29\t\nMagnesium (0.53-1.11 mmol/L)\t0.42\t0.48\t0.53\t0.46\t0.52\t0.77\t0.81\t\nPhosphate (0.78-1.65 mmol/L)\t1.47\t1.44\t1.33\t1.58\t1.63\t1.58\t–\t\nPotassium (3.5-5.1 mmol/L)\t4.3\t–\t–\t4.4\t4.6\t4.6\t–\t\niPTH: 22.78 pmol/L (1.58-6.03)\n\nFigure 2 Course of laboratory parameters over time in patient 2.\n\nDISCUSSION\nWe describe two adult patients presenting with severe hypomagnesaemia and hypocalcaemia while using PPIs. Patient 1 developed hypomagnesaemia and hypocalcaemia after short-term use of pantoprazole of 7 days while patient 2 experienced the same side effects after 4 months. This is consistent with the findings in a systematic review published by Hess et al, in which the time to onset of hypomagnesaemia is highly variable and ranged from 14 days up to 13 years (mean 5.5 years).7 This finding suggests that serum magnesium and calcium levels should be frequently monitored in patients taking PPIs, regardless of the duration of medication given.\n\nRecent studies postulated that the potential mechanism for PPIH is not due to renal magnesium wasting, but rather decreased gastrointestinal absorption, evidenced by reduced urinary excretion of magnesium in the setting of PPIH.6-9 Few recent mechanistic studies which have focused on the potential effect of PPI use on the TRMP6 transporter, the main pathway of magnesium absorption in the intestine, supports the above clinical observations. TRPM6 activity is regulated by intracellular magnesium along with pH.24,25 A more acidic environment will increase TRPM6 activity. PPI therapy decreases gastric acid secretion, increasing lumen pH, and therefore decreases TRPM6 activity, which results in decreased intestinal magnesium absorption.26-28 Our patient 1 showed similar pattern, in which during the hypomagnesaemia state, the urine excretion of magnesium was reduced to conserve magnesium. For patient 2, unfortunately, no 24-hour urine magnesium was sent.\n\nHypomagnesaemia is commonly asymptomatic and the most common signs of magnesium deficiency are hypokalemia and hypocalcaemia. Patients with symptomatic hypomagnesaemia will most commonly present with neuromuscular irritability or cardiac arrhythmia29 as was the case with our patient 1 who presented with a narrow complex tachycardia with prolonged QT.\n\nAs mentioned above, the most classical sign of severe hypomagnesaemia is hypocalcaemia. Adequate amount of magnesium is essential for vitamin D and calcium homeostasis30 and function of the parathyroid glands. Magnesium deficiency affects the function of phosphatidylinositol system and adenylate cyclase activity in parathyroid glands and in target tissues.31-36 As a result, this will lead to:\n\nReduced secretion of parathyroid hormone (PTH), leading to reduced bone resorption, reduced intestinal calcium absorption, and increased renal calcium loss. Collectively, these will lead to hypocalcaemia.\n\nReduced target tissue sensitivity to PTH. When bone and kidney tissues are resistant to PTH, PTH mediated 1α-hydroxylation of vitamin D decreases.37 This will lead to a decrease in intestinal absorption of calcium and result in hypocalcaemia.\n\nIn patient 1, we noted magnesium-dependent PTH suppression with development of transient hypoparathyroidism and severe hypocalcaemia (the iPTH level 7.45 pmol/L is only mildly increased, which is inappropriate in the setting of severe hypocalcaemia in patient 1). After the magnesium level was corrected, hypocalcemia in patient 1 slowly resolved. This confirmed that hypomagnesaemia is the cause of the transient hypoparathyroidism and hypocalcaemia in patient 1. On the other hand, in patient 2, the iPTH level was high (22.78 pmol/L) instead of low. Patient 2 had CKD stage 5, she might have concurrent secondary hyperparathyroidism due to CKD and therefore the iPTH level was elevated.\n\nPatient 1 was noted to have concurrent vitamin D deficiency. This is not an uncommon finding among Malaysian women as the prevalence of vitamin D deficiency is high in Malaysia.38 Concurrent vitamin D deficiency in patient 1 could also be contributing to her hypocalcaemia. For patient 2, unfortunately no vitamin D level was sent.\n\nHypokalemia is a common event in patients with hypomagnesaemia, occurring in 40 to 60 percent of cases.39 Hypomagnesaemia is associated with a reduction in intracellular magnesium concentration, which may then lead to a decline in adenosine triphosphate (ATP) activity. This decline removes the ATP inhibition of potassium (ROMK) channels, leading to an increase in the number of these channels. The uninhibited potassium channels will therefore increase potassium secretion from the cell into the lumen in the cells of the thick ascending limb and cortical collecting tubule, and cause renal potassium wasting and eventually lead to hypokalemia.40-42 As a result, hypokalemia is resistant to potassium supplement and can be treated only by correcting the magnesium deficit. In patient 1, the hypokalemia was initially resistant to potassium correction. After pantoprazole was discontinued and the magnesium deficit corrected, the potassium level normalized. In patient 2, no hypokalemia was noted, possibly because patient 2 had advanced chronic kidney disease with reduced kidney excretion of potassium, which neutralized the hypokalemia caused by magnesium deficiency.\n\nThe treatment of PPIH is similar to that of other forms of hypomagnesaemia, in which parenteral magnesium is indicated in severe hypomagnesaemia. However, intravenous magnesium replacement is only partially effective and provides only short-term relief, while PPI therapy is maintained. This is because PPI-induced blockade in magnesium absorption cannot be overcome by magnesium supplement alone. The struggle to reverse the hypomagnesaemia in these 2 patients while still on pantoprazole improved after pantoprazole was discontinued. This finding is consistent with previous case reports and systematic review.6-22 The only effective way to reverse PPIH is discontinuation of PPIs.\n\nPPIH is observed for all currently available PPIs and appear to be a class effect. Discontinuation of PPIs leads to fast recovery from PPIH. However, it reappears invariably when rechallenged with the same or a different PPI. Fortunately, it does not occur with other acid suppressants such as H2 receptor antagonists (H2RA)6-22 as seen in patient 2. Her pantoprazole was substituted with ranitidine. During her clinic follow up a month later, her magnesium and calcium levels remained normal. Therefore, in patients with gastric acid related disease that is complicated with PPIH, H2RA should be considered and we should avoid rechallenge with the same or a different PPI.\n\nThe prevalence of PPI-induced hypomagnesaemia is not known. Case reports and case series to date only represent the tip of the iceberg. Symptoms of hypomagnesaemia are either non-specific or could be misinterpreted. Therefore, proper identification and treatment of PPIH mainly rests on 3 principles:\n\nThe need for long-term PPI therapy in patients should be kept under regular review.\n\nIf PPI therapy is required on a long-term basis, serum magnesium monitoring should be performed on a regular basis. If PPIH develops, discontinuation of PPIs, supported by magnesium supplement, will lead to rapid normalization of serum magnesium.\n\nPatients with PPIH can avoid hypomagnesaemia by using alternative acid suppressants. Therefore, H2RA should be considered in the event of PPIH.\n\nCONCLUSION\nIn conclusion, known risks of long-term PPI administration must be considered in clinical practice and judicious use of PPIs is important to avoid potentially fatal complications.\n\nAcknowledgment\nThe authors thank the Director General of Health Malaysia for his permission to publish this article.\n\nEthical Consideration\nEthical clearance has been obtained by the authors. The Chief Health Director of Malaysia has approved the publication of the manuscript. The manuscript will also be submitted to the Scientific Unit of Communication and Distribution, the National Institute after its publication.\n\nStatement of Authorship\nAll authors certified fulfillment of ICMJE authorship criteria.\n\nAuthor Disclosure\nThe authors declared no conflict of interest.\n\nFunding Source\nNone.\n\n\nAuthors are required to accomplish, sign and submit scanned copies of the JAFES Author Form consisting of: (1) Authorship Certification, that authors contributed substantially to the work, that the manuscript has been read and approved by all authors, and that the requirements for authorship have been met by each author; (2) the Author Declaration, that the article represents original material that is not being considered for publication or has not been published or accepted for publication elsewhere, that the article does not infringe or violate any copyrights or intellectual property rights, and that no references have been made to predatory/suspected predatory journals; (3) the Author Contribution Disclosure, which lists the specific contributions of authors; and (4) the Author Publishing Agreement which retains author copyright, grants publishing and distribution rights to JAFES, and allows JAFES to apply and enforce an Attribution-Non-Commercial Creative Commons user license. Authors are also required to accomplish, sign, and submit the signed ICMJE form for Disclosure of Potential Conflicts of Interest. For original articles, authors are required to submit a scanned copy of the Ethics Review Approval of their research as well as registration in trial registries as appropriate. For manuscripts reporting data from studies involving animals, authors are required to submit a scanned copy of the Institutional Animal Care and Use Committee approval. For Case Reports or Series, and Images in Endocrinology, consent forms, are required for the publication of information about patients; otherwise, appropriate ethical clearance has been obtained from the institutional review board. Articles and any other material published in the JAFES represent the work of the author(s) and should not be construed to reflect the opinions of the Editors or the Publisher.\n==== Refs\nReferences\n1 Kinoshita Y , Ishimura N , Ishihara S \nAdvantages and disadvantages of long-term proton pump inhibitor use\n. J Neurogastroenterol Motil . 2018 ;24 (2 ):182 –96\n. PMID: PMCID: \n10.5056/jnm18001 .29605975 \n2 Famularo G , Gasbarrone L , Minisola G \nHypomagnesaemia and proton-pump inhibitors\n. Expert Opin Drug Saf . 2013 ;12 (5 ):709 -16\n. PMID: 10.1517/14740338.2013.809062 .23808631 \n3 Schlingmann KP , Waldegger S , Konrad M , Chubanov V , Gudermann T \nTRPM6 and TRPM7–Gatekeepers of human magnesium metabolism\n. Biochim Biophys Acta . 2007 ;1772 (8 ): 813 –21\n. PMID: 10.1016/j.bbadis.2007.03.009 .17481860 \n4 William JH , Danziger J \nProton-pump inhibitor-induced hypomagnesaemia: Current research and proposed mechanisms\n. World J Nephrol . 2016 ;5 (2 ): 152 -7\n. PMID: PMCID: \n10.5527/wjn.v5.i2.152 .26981439 \n5 Weisinger JR , Bellorin-Font E \nMagnesium and phosphorus\n. Lancet . 1998 ;352 (9125 ):391 –6\n . PMID: 10.1016/S0140-6736(97)10535-9 .9717944 \n6 Epstein M , McGrath S , Law F \nProton-pump inhibitors and hypomagnesemic hypoparathyroidism\n. N Engl J Med . 2006 ;355 (17 ): 1834 -6\n. PMID: 10.1056/NEJMc066308 .17065651 \n7 Hess MW , Hoenderop JG , Bindels RJ , Drenth JP \nSystematic review: Hypomagnesaemia induced by proton pump inhibition\n. Aliment Pharmacol Ther . 2012 ;36 (5 ):405 –13\n. PMID: 10.1111/j.1365-2036.2012.05201.x .22762246 \n8 Cundy T , Dissanayake A \nSevere hypomagnesaemia in long-term users of proton-pump inhibitors\n. Clin Endocrinol (Oxf) . 2008 ;69 (2 ):338 –41\n. PMID: https://doi/org/10.1111/j.1365-2265.2008.03194.x.18221401 \n9 Hoorn EJ , van der Hoek J , de Man RA , Kuipers EJ , Bolwerk C , Zietse R \nA case series of proton pump inhibitor-induced hypomagnesaemia\n. Am J Kidney Dis . 2010 ;56 (1 ):112 -6\n. PMID: 10.1053/j.ajkd.2009.11.019 .20189276 \n10 Fernández-Fernández FJ , Sesma P , Caínzos-Romero T , FerreiraGonzález L \nIntermittent use of pantoprazole and famotidine in severe hypomagnesaemia due to omeprazole\n. Neth J Med . 2010 ;68 (10 ):329 –30\n. PMID : .21071783 \n11 Shabajee N , Lamb EJ , Sturgess I , Sumathipala RW \nOmeprazole and refractory hypomagnesaemia\n. BMJ . 2008 ;337 :a425 . PMID: PMCID: \n10.1136/bmj.39505.738981.BE .18617497 \n12 Arulanantham N , Anderson M , Gittoes N , Ferner RE \nA 63-year-old man with hypomagnesaemia and seizures\n. Clin Med (Lond) . 2011 ;11 (6 ):591 –3\n. PMID: 10.7861/clinmedicine.11-6-591 .22268316 \n13 Famularo G , Minisola G , Bravi MC , Colucci P , Gasbarrone L \nTetany, hypomagnesaemia, and proton-pump inhibitors\n. Am J Med . 2012 ; 125 (10 ):e7 –8\n. PMID: 10.1016/j.amjmed.2012.04.027 .22800870 \n14 Broeren M , Geerdink E , Vader HL , van den Wall Bake AW \nHypomagnesaemia induced by several proton-pump inhibitors\n. Ann Intern . 2009 ; 151 (10 ): 755 –6\n. PMID: 10.7326/0003-4819-151-10-200911170-00016 .19920278 \n15 Mackay JD , Bladon PT \nHypomagnesaemia due to proton-pump inhibitor therapy: A clinical case series\n. QJM . 2010 ;103 (6 ): 387 –95\n. PMID: 10.1093/qjmed/hcq021 .20378675 \n16 Kuipers MT , Thang HD , Arntzenius AB \nHypomagnesaemia due to use of proton pump inhibitors-A review\n. Neth J Med \n2009 ; 67 :169 -72\n. PMID: .19581665 \n17 Furlanetto TW , Faulhaber GAM \nHypomagnesaemia and proton pump inhibitors: Below the tip of the iceberg\n. Arch Intern Med . 2011 ; 171 (15 ): 1391 –2\n. PMID: 10.1001/archinternmed.2011.199 21555654 \n18 Matsuyama J , Tsuji K , Doyama H , Kim F , Takeda Y , et al \nHypomagnesaemia associated with a Proton Pump Inhibitor\n. Intern Med . 2012 ; 51 (16 ): 2231 –4\n. PMID: 10.2169/internalmedicine.51.7748 .22892510 \n19 Gandhi NY , Sharif WK , Chadha S , Shakher J \nA patient on longterm proton pump inhibitors develops sudden seizures and encephalopathy: An unusual presentation of hypomagnesaemia\n. Case Rep Gastrointest Med . 2012 ; 2012 :632721 . PMID: PMCID: \n10.1155/2012/632721 .23213582 \n20 Egshatyan LV \nFunctional hypoparathyroidism secondary to magnesium deficiency in long-term users of proton pump inhibitor: case report\n. Osteopo Bone Dis . 2017 ; 20 (3 ):102 -7\n. 10.14341/osteo20173102-107 .\n21 François M , Lévy-Bohbot N , Caron J , Durlach V \nChronic use of proton-pump inhibitors associated with giardiasis: A rare cause of hypomagnesemic hypoparathyroidism?\n\nAnn Endocrinol (Paris) . 2008 ;69 (5 ):446 –8\n. PMID: 10.1016/j.ando.2008.03.003 .18614153 \n22 Regolisti G , Cabassi A , Parenti E , Maggiore U , Fiaccadori E \nSevere hypomagnesaemia during long-term treatment with a proton pump inhibitor\n. Am J Kidney Dis . 2010 ;56 (1 ):168 –74\n. PMID: 10.1053/j.ajkd.2010.03.013 .20493607 \n23 FDA Drug Safety Communication: Low magnesium levels can be associated with long-term use of proton pump inhibitor drugs (PPIs) . Available from URL: https://www.fda.gov/drugs/drugsafety/ucm245011.htm. Accessed on December 18, 2018 .\n24 Voets T , Nilius B , Hoefs S , et al \nTRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption\n. J Biol Chem . 2004 ;279 (1 ):19 -25\n. PMID: 10.1074/jbc.M311201200 .14576148 \n25 Thébault S , Cao G , Venselaar H , Xi Q , Bindels RJ , Hoenderop JG \nRole of the alpha-kinase domain in transient receptor potential melastatin 6 channel and regulation by intracellular ATP\n. J Biol Chem . 2008 ;283 (29 ):19999 -20007\n. PMID: 10.1074/jbc.M800167200 .18490453 \n26 Lameris AL , Hess MW , van Kruijsbergen I , Hoenderop JG , Bindels RJ \nOmeprazole enhances the colonic expression of the Mg(2+) transporter TRPM6\n. Pflugers Arch . 2013 ;465 (11 ):1613 -20\n. PMID: 10.1007/s00424-013-1306-0 .23756852 \n27 Li M , Du J , Jiang J , Ratzan W , Su LT , Runnels LW , Yue L \nMolecular determinants of Mg2+ and Ca2+ permeability and pH sensitivity in TRPM6 and TRPM7\n. J Biol Chem . 2007 ;282 (35 ): 25817 -30\n. PMID: PMCID: \n10.1074/jbc.M608972200 .17599911 \n28 Groenestege WM , Hoenderop JG , van den Heuvel L , Knoers N , Bindels RJ \nThe epithelial Mg2+ channel transient receptor potential melastatin 6 is regulated by dietary Mg2+ content and estrogens\n. J Am Soc Nephrol \n2006 ;17 (4 ):1035 -43\n. PMID: 10.1681/ASN.2005070700 .16524949 \n29 Agus ZS \nHypomagnesemia\n. J Am Soc Nephrol . 1999 ;10 (7 ):1616 -22\n. PMID: .10405219 \n30 Deng X , Song Y , Manson JE , et al \nMagnesium, vitamin D status and mortality: Results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III\n. BMC Med . 2013 ;11 :187 . PMID: PMCID: \n10.1186/1741-7015-11-187 .23981518 \n31 Litosch I \nG protein regulation of phospholipase C activity in a membrane-solubilized system occurs through a Mg2(+)- and time dependent mechanism\n. J Biol Chem . 1991 ; 266 (8 ):4764 -71\n. PMID: .2002026 \n32 Northup JK , Smigel MD , Gilman AG \nThe guanine nucleotide activating site of the regulatory component of adenylate cyclase. Identification by ligand binding\n. J. Biol. Chem . 1982 ;257 (19 ): 11416 -23\n. PMID: .6288684 \n33 Volpe P , Alderson-Lang BH , Nickols GA \nRegulation of inositol 1,4,5-trisphosphate-induced Ca2+ release. I. Effect of Mg2+\n. Am J Physiol . 1990 ;258 (6 Pt 1 ): C1077 -85\n. 10.1152/ajpcell.1990.258.6.C1077 .2360619 \n34 Rude RK , Oldham SB , Sharp CF Jr., Singer FR \nParathyroid hormone secretion in magnesium deficiency\n. J Clin Endocrinol Metab . 1978 ;47 (4 ):800 -6\n. PMID: 10.1210/jcem-47-4-800 .263326 \n35 Freitag JJ , Martin KJ , Conrades MB , et al \nEvidence for skeletal resistance to parathyroid hormone in magnesium deficiency\n. J Clin Invest .1979 ;64 (5 ):1238 -44\n. PMID: PMCID: 10.1172/JCI109578 .227929 \n36 Rude RK , Oldham SB , Singer FR \nFunctional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency\n. Clin Endocrinol (Oxf) . 1976 ;5 (3 ):209 –24\n. PMID: 10.1111/j.1365-2265.1976.tb01947.x .182417 \n37 Fatemi S , Ryzen E , Flores J , Endres DB , Rude RK \nEffect of experimental human magnesium depletion on parathyroid hormone secretion and 1,25-dihydroxyvitamin D metabolism\n. J Clin Endocrinol Metabol . 1991 ;73 (5 ):1067 –72\n. PMID: 10.1210/jcem-73-5-1067 .1939521 \n38 Rahman SA , Chee WS , Yassin Z , Chan SP \nVitamin D status among postmenopausal Malaysian women\n. Asia Pac J Clin Nutr . 2004 ;13 (3 ):255 -60\n. PMID: .15331337 \n39 Whang R , Ryder KW \nFrequency of hypomagnesaemia and hypermagnesemia. Requested vs routine\n. JAMA . 1990 ; 263 (22 ): 3063 -4\n. PMID: .2342219 \n40 Huang CL , Kuo E \nMechanism of hypokalemia in magnesium deficiency\n. J Am Soc Nephrol . 2007 ; 18 (10 ): 2649 -52\n. PMID: 10.1681/ASN.2007070792 .17804670 \n41 Nichols CG , Ho K , Hebert S \nMg(2+)-dependent inward rectification of ROMK1 potassium channels expressed in Xenopus oocytes\n. J Physiol . 1994 \n5 ; 476 (3 ): 399 -409\n. PMID: PMCID: \n10.1113/jphysiol.1994.sp02014 .8057249 \n42 Yang L , Frindt G , Palmer LG \nMagnesium modulates ROMK channel-mediated potassium secretion\n. J Am Soc Nephrol . 2010 ;21 (12 ):2109 -16\n. PMID: PMCID: \n10.1681/ASN.2010060617 .21030597\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0857-1074",
"issue": "35(1)",
"journal": "Journal of the ASEAN Federation of Endocrine Societies",
"keywords": "Proton pump inhibitors; hypocalcaemia; hypokalemia; hypomagnesaemia",
"medline_ta": "J ASEAN Fed Endocr Soc",
"mesh_terms": null,
"nlm_unique_id": "8608483",
"other_id": null,
"pages": "109-113",
"pmc": null,
"pmid": "33442177",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "263326;22762246;1939521;227929;10405219;21071783;16524949;2002026;22268316;2360619;22892510;14576148;18614153;19920278;18617497;19581665;2342219;18490453;9717944;6288684;22800870;26981439;23981518;20378675;8057249;15331337;17481860;18221401;20189276;182417;17065651;20493607;29605975;23808631;23213582;23756852;21030597;21555654;17599911;17804670",
"title": "The Perilous PPI: Proton Pump Inhibitor as a Cause of Clinically Significant Hypomagnesaemia.",
"title_normalized": "the perilous ppi proton pump inhibitor as a cause of clinically significant hypomagnesaemia"
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"companynumb": "MY-PFIZER INC-2020300900",
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"occurcountry": "MY",
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"actiondrug": "1",
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"activesubstancename": "PANTOPRAZOLE"
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"abstract": "We previously reported that low-dose methotrexate (MTX) was associated with an increased risk of pulmonary adverse events (AEs) in a large randomized, placebo-controlled trial. Herein, we report details on the predictors and severity of pulmonary AEs.\n\n\n\nWe conducted a prespecified analysis of pulmonary AEs in the Cardiovascular Inflammation Reduction Trial. Adults with known cardiovascular disease and diabetes/metabolic syndrome were randomly allocated to receive low-dose MTX (target dose 15-20 mg/week) or placebo after a 6-8-week open-label run-in phase in which all patients received low-dose MTX. Individuals with systemic inflammatory diseases were excluded. Pulmonary AEs were adjudicated in a blinded manner. We described severe pulmonary AEs and examined associations of baseline characteristics with pulmonary AEs in patients receiving low-dose MTX.\n\n\n\nA total of 2,391 subjects were randomized to receive low-dose MTX and 2,395 to receive placebo. There were 13 severe pulmonary AEs (0.5%) and 7 cases of possible pneumonitis (0.3%) in the low-dose MTX group, compared to 8 (0.3%) and 1 (<0.1%), respectively, in the placebo group. Among those randomized to receive low-dose MTX, risk factors for any pulmonary AE included female sex (hazard ratio [HR] 1.69 versus male sex [95% confidence interval (95% CI) 1.16-2.45]), white race (HR 2.35 versus other race [95% CI 1.03-5.36]), and insulin use (HR 1.60 versus non-use [95% CI 1.11-2.30]). The only risk factor for severe pulmonary AEs was older age at baseline (HR 1.09 per year increase [95% CI 1.02-1.16]).\n\n\n\nIn this large placebo-controlled trial, pulmonary AEs, including possible pneumonitis, were uncommon but were more likely to occur in those randomized to receive low-dose MTX. White race, older age, male sex, and insulin use were associated with an increased risk of pulmonary AEs in those receiving low-dose MTX.",
"affiliations": "Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.;Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.;Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.;Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.;Brigham and Women's Hospital, Boston, Massachusetts.;Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.;Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.",
"authors": "Sparks|Jeffrey A|JA|0000-0002-5556-4618;Dellaripa|Paul F|PF|;Glynn|Robert J|RJ|;Paynter|Nina P|NP|;Xu|Chang|C|;Ridker|Paul M|PM|;Solomon|Daniel H|DH|0000-0001-8202-5428",
"chemical_list": "D007166:Immunosuppressive Agents; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1002/art.41452",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2326-5191",
"issue": "72(12)",
"journal": "Arthritis & rheumatology (Hoboken, N.J.)",
"keywords": null,
"medline_ta": "Arthritis Rheumatol",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D002318:Cardiovascular Diseases; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007249:Inflammation; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D011014:Pneumonia; D012307:Risk Factors; D012737:Sex Factors",
"nlm_unique_id": "101623795",
"other_id": null,
"pages": "2065-2071",
"pmc": null,
"pmid": "32741143",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "32066146;3913775;25800216;28284844;24757133;31075163;30415610;21638023;3325643;9273826;12355475;9336418;12355476;1734901;25770113",
"title": "Pulmonary Adverse Events in Patients Receiving Low-Dose Methotrexate in the Randomized, Double-Blind, Placebo-Controlled Cardiovascular Inflammation Reduction Trial.",
"title_normalized": "pulmonary adverse events in patients receiving low dose methotrexate in the randomized double blind placebo controlled cardiovascular inflammation reduction trial"
} | [
{
"companynumb": "US-MYLANLABS-2021M1010784",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FOLIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "•An ovarian clear cell carcinoma patient showed malignant pericardial and pleural effusion.•She subsequently experienced pulmonary embolism due to cancer progression.•Pericardial and pleural effusion were successfully treated using bevacizumab.",
"affiliations": "Department of Obstetrics and Gynecology, Hyogo College of Medicine, Japan.;Department of Obstetrics and Gynecology, Hyogo College of Medicine, Japan.;Division of Coronary Heart Disease, Department of Internal Medicine, Hyogo College of Medicine, Japan.;Department of Thoracic Oncology, Hyogo College of Medicine, Japan.;Department of Obstetrics and Gynecology, Hyogo College of Medicine, Japan.",
"authors": "Ueda|Tomoko|T|;Tsubamoto|Hiroshi|H|;Eguchi|Akiyo|A|;Terada|Takayuki|T|;Shibahara|Hiroaki|H|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.gore.2016.01.006",
"fulltext": "\n==== Front\nGynecol Oncol RepGynecol Oncol RepGynecologic Oncology Reports2352-5789Elsevier S2352-5789(16)30006-610.1016/j.gore.2016.01.006Case ReportBevacizumab helped resolve pericardial and pleural effusion that was associated with malignant ovarian clear cell carcinoma Ueda Tomoko aTsubamoto Hiroshi tsuba@hyo-med.ac.jpa⁎Eguchi Akiyo bTerada Takayuki cShibahara Hiroaki aa Department of Obstetrics and Gynecology, Hyogo College of Medicine, Japanb Division of Coronary Heart Disease, Department of Internal Medicine, Hyogo College of Medicine, Japanc Department of Thoracic Oncology, Hyogo College of Medicine, Japan⁎ Corresponding author at: Department of Obstetrics and Gynecology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya-shi, Hyogo Prefecture 663-8501, Japan.Department of Obstetrics and GynecologyHyogo College of Medicine1-1 Mukogawa-choNishinomiya-shiHyogo Prefecture663-8501Japan tsuba@hyo-med.ac.jp02 2 2016 4 2016 02 2 2016 16 11 13 14 12 2015 21 1 2016 29 1 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• An ovarian clear cell carcinoma patient showed malignant pericardial and pleural effusion.\n\n• She subsequently experienced pulmonary embolism due to cancer progression.\n\n• Pericardial and pleural effusion were successfully treated using bevacizumab.\n\n\n\nKeywords\nPericardial effusionTamponadePleural effusionOvarian cancerClear cell carcinomaBevacizumab\n==== Body\n1 Introduction\nPericardial effusion is an uncommon fatal complication of advanced or recurrent ovarian cancer. Dauplat et al. reported that its incidence was 2.4%, and all 6 patients in that series also had pleural effusion (Dauplat et al., 1987). A PubMed search reveals 12 case reports of cardiac tamponade that was associated with ovarian carcinoma, and the median overall survival (OS) among these cases was < 2 months (Feferkorn et al., 2014). In this report, we describe a patient with ovarian clear cell carcinoma who ultimately developed pericardial and pleural effusion, which were successfully managed using bevacizumab (Bev). To our best knowledge, this is the first report of using Bev to treat pericardial effusion that was associated with ovarian cancer.\n\n2 Case report\nA 52-year-old nulliparous woman initially visited our hospital with an ovarian tumor of 19 cm in diameter in 2010. After primary debulking surgery, she was diagnosed with stage IC ovarian clear cell carcinoma with positive cytology of ascites and the rupture of the left ovarian tumor during surgery. She underwent 6 cycles of adjuvant chemotherapy with paclitaxel and carboplatin. Three years later, she developed multiple lung metastases (maximum diameter: 20 mm) and subsequently underwent 6 cycles of paclitaxel and carboplatin, which resulted in complete remission. However, she developed malignant ascites with lung metastases (maximum diameter: 10 mm) and deep vein thrombosis after 14 months. We initiated treatment using warfarin and she underwent 2 cycles of carboplatin therapy, which induced anaphylaxis, and then underwent 3 cycles of pegylated liposomal doxorubicin (40 mg/m2), which induced interstitial pneumonia. Although the interstitial pneumonia improved with prednisolone treatment, she subsequently presented with minor chest pain, a cough, and dyspnea in February 2015 (Fig. 1).\n\nHer blood pressure and heart rate were normal at the February 2015 presentation, although computed tomography (CT) revealed lung metastases (maximum diameter: 11 mm), minor right-side pleural effusion, and pericardial effusion. Echocardiography revealed an echo-free space of 20 mm and diastolic collapse of the right atrium. We performed pericardiocentesis, drained 700 mL of bloody fluid, and performed cytology, which revealed clear cell adenocarcinoma. The patient refused combination chemotherapy with Bev due to the risk of gastrointestinal perforation (GIP), and underwent 3 months of weekly treatment with paclitaxel (wPTX, 80 mg/m2). Unfortunately, she developed a cough and dyspnea due to the right-side pleural effusion, and refused hospitalization for talc pleurodesis; therefore, we performed outpatient thoracocentesis. The interval between thoracocentesis was reduced, and she received an oral etoposide (50 mg daily). However, she required weekly thoracocentesis, and her dyspnea was exaggerated. Her oxygen saturation was 82–86% in room air, with a blood pressure of 119/75 mm Hg and a heart rate of 124 bpm.\n\nIn May 2015, the patient was admitted to our emergency department, where echocardiography revealed 25 mm of pericardial effusion and diastolic collapse of the right atrium and ventricle. Her oxygen saturation improved to 95% with an oxygen mask. As CT revealed pulmonary embolism, despite her use of warfarin, we decided to place an inferior vena cava filter, and administered heparin in addition to the warfarin. The patient exhibited bilateral pleural effusion and pericardial effusion (Fig. 2), and her Eastern Cooperative Oncology Group performance status (PS) was 3. Furthermore, she had mild ascites, underwent right-side thoracocentesis, and 1450 mL of bloody pleural effusion was drained, although her dyspnea and cough persisted. Her symptoms improved after 750 mL of pericardial effusion was drained via pericardiocentesis, and she agreed to receive Bev therapy. After intravenous administration of 15 mg/kg of Bev, she was discharged. After 3 weeks, chest radiography and echocardiography revealed no increase of pleural or pericardial effusion, and her PS was improved to 1. She began a combination regimen of Bev (15 mg/kg, triweekly) and wPTX (80 mg/m2). She has not required pericardiocentesis or thoracocentesis for 18 weeks after the initiation of Bev therapy.\n\n3 Discussion\nMalignant pericardial effusion or cardiac tamponade reduces patients' quality of life and can lead to a life-threatening condition. Approximately one-half of these cases are comprised of patients with lung cancer and breast cancer, and when malignant cells are detected in the pericardial effusion, the patients' median OS is 7.3 months (Gornik et al., 2005). This is consistent with the findings from the 12 cases of patients with ovarian cancer. In addition to repeated pericardiocentesis, various treatments have been reported, such as surgical or percutaneous balloon pericardiostomy, sclerotherapy, intrapericardial chemotherapy, and radiation therapy (Gornik et al., 2005). In the present case, we treated the patient using anticoagulation therapy for the pulmonary embolism and deep vein thrombosis, which was likely due to the activation of her clear cell carcinoma (Matsuura et al., 2007). Unfortunately, the surgical or invasive approach increases the risk of bleeding, and sclerotherapy increases the risk of constrictive pericarditis, although Petersen et al. have reported successfully treating a patient with ovarian cancer using intrapericardial administration of thiotepa (Petersen et al., 2009). Chen et al. have recently reported intrapericardial administration of Bev for a patient with lung cancer and pericardial effusion (Chen et al., 2015). Although most cases of malignant pericardial effusion or cardiac tamponade with advanced or recurrent ovarian cancer exhibit pleural effusion (Dauplat et al., 1987), local treatment appears to provide minimal benefit.\n\nThe etiology of pericardial effusion appears similar to that of malignant effusion in the peritoneal and pleural cavities via metastases to the serosal membranes. Furthermore, vascular endothelial growth factor (VEGF)-A is considered a key molecule in the development of malignant ascites and pleural effusion. In this context, Bev is a human monoclonal antibody to VEGF-A that preclinical and clinical studies have demonstrated and is effective for controlling malignant ascites in ovarian cancer, and pleural effusion in lung cancer (Pujade-Lauraine et al., 2014, Bradshaw et al., 2013). At the last hospitalization in the present case (May 2015), our patient complained of dyspnea and exhibited tachycardia, hypoxia, pulmonary embolism, and pericardial and pleural effusion. Anticoagulation therapy and placement of an inferior vena cava filter for her acute pulmonary embolism, and drainage of the pleural effusion via thoracocentesis, did not resolve her dyspnea. However, drainage of the pericardial effusion and Bev monotherapy improved her dyspnea and cough, which resulted in her discharge and a sustained response for 3 weeks. She then underwent combination therapy using Bev and wPTX, did not require pericardiocentesis or thoracocentesis, and was not hospitalized for > 4 months. Therefore, we believe that the Bev therapy helped relieve her symptoms and improve her quality of life during the late stage of ovarian cancer.\n\nThe patient in the present case was not classified as platinum-resistant, although she had a history of anaphylaxis to platinum. She experienced interstitial pneumonia that was induced by pegylated liposomal doxorubicin, and did not respond to wPTX and etoposide. The patient initially refused Bev therapy, as GIP is a known adverse effect of this therapy. Cannistra et al. have reported that the incidence of GIP is only 11.4% and that the number of previous regimens is a risk factor (Cannistra et al., 2007). Furthermore, the AURELIA trial (a randomized phase 3 trial) evaluated patients with platinum-resistant ovarian cancer, and reported that the incidence of GIP was only 2.2% among Bev-treated patients, although that study excluded patients with a history of ≥ 3 previous regimens (Pujade-Lauraine et al., 2014). In contrast, other reports have denied any relationship between the number of previous regimens and the incidence of GIP.\n\nWhen the patient eventually decided to accept Bev therapy, we initially administered it as a monotherapy, as she had complained of weakness. The patient was subsequently discharged, and received a combination of Bev and wPTX in our outpatient clinic once her condition had improved. A recent retrospective study that compared Bev monotherapy and combination chemotherapy revealed that the combination chemotherapy provided longer OS (hazard ratio: 0.51, p < 0.01) in the multivariate analysis, with similar adverse events for both treatments (Fuh et al., 2015). Furthermore, analysis according to chemotherapy in the AURELIA trial revealed that wPTX and Bev were a promising combination. In the present case, the patient's cancer progressed after she had received wPTX monotherapy, although it has remained stable during the treatment using Bev and wPTX.\n\nIn conclusion, pericardial effusion or cardiac tamponade is a rare, but fatal, complication of ovarian cancer. Furthermore, patients with pericardial effusion can also experience pleural effusion. Given the poor prognosis that is associated with malignant pericardial effusion, symptom relief and cancer stabilization are the main goals of treatment, and the efficacy and mild toxicities of Bev may indicate that it is a promising treatment.\n\nDisclosure\nWritten informed consent for this report was obtained from the patient. The authors have no conflicts of interest to declare.\n\nFig. 1 Treatment course for a patient with ovarian clear cell carcinoma (December 2014 to November 2015). PLD, pegylated liposomal doxorubicin at 40 mg/m2 every 28 days; wPTX, weekly paclitaxel at 80 mg/m2; VP-16, 50 mg of oral etoposide daily; Bev, 15 mg/kg of bevacizumab; Bev + wPTX, 15 mg/kg of bevacizumab every 21 days and weekly paclitaxel at 80 mg/m2; PE, pulmonary embolization.\n\nFig. 2 Computed tomography and echocardiography findings. (A) Computed tomography reveals bilateral pleural effusion. (B) An echocardiogram reveals pericardial effusion (width: 32.9 mm). The patient underwent treatment with bevacizumab (15 mg/kg, every 21 days) after thoracocentesis and pericardiocentesis.\n==== Refs\nReferences\nBradshaw M. Mansfield A. Peikert T. The role of vascular endothelial growth factor in the pathogenesis, diagnosis and treatment of malignant pleural effusion Curr. Oncol. Rep. 15 2013 207 216 23568600 \nCannistra S.A. Matulonis U.A. Penson R.T. Hambleton J. Dupont J. Mackey H. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer J. Clin. Oncol. 25 2007 5180 5186 18024865 \nChen D. Zhang Y. Shi F. Li M. Zhu H. Kong L. Yu J. Sustained response of malignant pericardial effusion to intrapericardial bevacizumab in an advanced lung cancer patient: a case report and literature review Onco Targets Ther. 8 2015 2767 2770 26491350 \nDauplat J. Hacker N.F. Nieberg R.K. Berek J.S. Rose T.P. Sagae S. Distant metastases in epithelial ovarian carcinoma Cancer 60 1987 1561 1566 3621129 \nFeferkorn I. Shai A. Gemer O. Auslender R. Lavie O. The natural history of pericardial tamponade secondary to recurrent ovarian carcinoma — a case report and review of the literature Gynecol. Oncol. Rep. 10 2014 53 55 26082940 \nFuh K.C. Secord A.A. Bevis K.S. Huh W. ElNaggar A. Blansit K. Comparison of bevacizumab alone or with chemotherapy in recurrent ovarian cancer patients Gynecol. Oncol. 2015 (Epub ahead of print) \nGornik H.L. Gerhard-Herman M. Beckman J.A. Abnormal cytology predicts poor prognosis in cancer patients with pericardial effusion J. Clin. Oncol. 23 2005 5211 5216 16051963 \nMatsuura Y. Robertson G. Marsden D.E. Kim S.N. Gebski V. Hacker N.F. Thromboembolic complications in patients with clear cell carcinoma of the ovary Gynecol. Oncol. 104 2 2007 Feb 406 410 17014897 \nPetersen E.E. Shamshirsaz A.A. Brennan T.M. Demetroulis E.M. Goodheart M.J. Malignant pericardial effusion with cardiac tamponade in ovarian adenocarcinoma Arch. Gynecol. Obstet. 280 2009 675 678 19225795 \nPujade-Lauraine E. Hilpert F. Weber B. Reuss A. Poveda A. Kristensen G. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial J. Clin. Oncol. 32 2014 1302 1308 24637997\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-5789",
"issue": "16()",
"journal": "Gynecologic oncology reports",
"keywords": "Bevacizumab; Clear cell carcinoma; Ovarian cancer; Pericardial effusion; Pleural effusion; Tamponade",
"medline_ta": "Gynecol Oncol Rep",
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"pages": "11-3",
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"pmid": "27331128",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports",
"references": "26144600;26491350;17014897;24637997;23568600;19225795;16051963;3621129;26082940;18024865",
"title": "Bevacizumab helped resolve pericardial and pleural effusion that was associated with malignant ovarian clear cell carcinoma.",
"title_normalized": "bevacizumab helped resolve pericardial and pleural effusion that was associated with malignant ovarian clear cell carcinoma"
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"abstract": "Recurrence of anti-glomerular basement membrane (anti-GBM) glomerulonephritis in the kidney graft is a rare event, described in limited reports. The aim of this study was to evaluate, in a large cohort of patients with long follow-up, the risk of recurrence of anti-GBM disease, the risk factors associated with clinical recurrence, and the long-term patient and graft survival.\nThis was a multicenter retrospective study. Inclusion criteria were patients with anti-GBM glomerulonephritis who underwent transplantation of a kidney between 1977 and 2015. Exclusion criteria were systemic vasculitis, lupus erythematosus, and cryoglobulinemia. Recurrence was defined as reappearance of clinical signs of glomerulonephritis along with histological signs of proliferative glomerulonephritis and linear IgG staining on kidney biopsy, with or without anti-GBM antibodies.\nA total of 53 patients were included. Recurrence of anti-GBM glomerulonephritis in a first kidney transplant occurred in only 1 patient 5 years after transplantation (a prevalence rate of 1.9%) in the context of cessation of immunosuppressive drugs, and resulted in graft loss due to recurrence. Linear IgG staining on kidney biopsy in the absence of histological signs of proliferative glomerulonephritis was observed in 4 patients, in the context of cellular rejection. Patient survival was 100%, 94%, and 89% at 5, 10, and 15 years, respectively. Death-censored first-graft survival rates were 88%, 83%, and 79% at 5, 10, and 15 years, respectively.\nThe recurrence rate of anti-GBM glomerulonephritis after transplantation is very low but is associated with graft loss. The long-term patient and graft survival rates are excellent.",
"affiliations": "Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.;Division of Nephrology, Katholieke Universiteit Leuven, Leuven, Belgium.;Renal Division, Ghent University Hospital, Ghent, Belgium.;Division of Nephrology, Centre Hospitalier Universitaire Sart-Tilman, Liège, Belgium.;Division of Nephrology, Vrije Universiteit Brussel, Brussels, Belgium.;Division of Nephrology, Universitair Ziekenhuis Antwerpen, Antwerpen, Belgium.;Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.;Division of Nephrology, Katholieke Universiteit Leuven, Leuven, Belgium.;Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.;Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.;Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.;Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.;Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.;Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.;Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.;Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.",
"authors": "Coche|Sophie|S|;Sprangers|Ben|B|;Van Laecke|Steven|S|;Weekers|Laurent|L|;De Meyer|Vicky|V|;Hellemans|Rachel|R|;Castanares|Diego|D|;Ameye|Heleen|H|;Goffin|Eric|E|;Demoulin|Nathalie|N|;Gillion|Valentine|V|;Mourad|Michel|M|;Darius|Tom|T|;Buemi|Antoine|A|;Devresse|Arnaud|A|;Kanaan|Nada|N|",
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"doi": "10.1016/j.ekir.2021.04.011",
"fulltext": "\n==== Front\nKidney Int Rep\nKidney Int Rep\nKidney International Reports\n2468-0249\nElsevier\n\nS2468-0249(21)01093-7\n10.1016/j.ekir.2021.04.011\nClinical Research\nRecurrence and Outcome of Anti−Glomerular Basement Membrane Glomerulonephritis After Kidney Transplantation\nCoche Sophie 1\nSprangers Ben MD 23\nVan Laecke Steven 4\nWeekers Laurent 5\nDe Meyer Vicky 6\nHellemans Rachel 7\nCastanares Diego 8\nAmeye Heleen 2\nGoffin Eric 18\nDemoulin Nathalie 18\nGillion Valentine 18\nMourad Michel 89\nDarius Tom 89\nBuemi Antoine 89\nDevresse Arnaud 18\nKanaan Nada nada.kanaan@uclouvain.be\n18∗\n1 Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium\n2 Division of Nephrology, Katholieke Universiteit Leuven, Leuven, Belgium\n3 Department of Microbiology, Immunology and Transplantation, Laboratory of Molecular Immunology, Rega Institute, KU Leuven, Leuven, Belgium\n4 Renal Division, Ghent University Hospital, Ghent, Belgium\n5 Division of Nephrology, Centre Hospitalier Universitaire Sart-Tilman, Liège, Belgium\n6 Division of Nephrology, Vrije Universiteit Brussel, Brussels, Belgium\n7 Division of Nephrology, Universitair Ziekenhuis Antwerpen, Antwerpen, Belgium\n8 Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium\n9 Department of Abdominal Surgery and Transplantation, Cliniques Universitaires Saint-Luc, Brussels, Belgium\n∗ Correspondence: Nada Kanaan, Cliniques Universitaires Saint-Luc, Avenue Hippocrate, 10, 1200 Brussels, Belgium. nada.kanaan@uclouvain.be\n28 4 2021\n7 2021\n28 4 2021\n6 7 18881894\n27 1 2021\n6 4 2021\n12 4 2021\n© 2021 International Society of Nephrology. Published by Elsevier Inc.\n2021\nInternational Society of Nephrology\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nIntroduction\n\nRecurrence of anti-glomerular basement membrane (anti-GBM) glomerulonephritis in the kidney graft is a rare event, described in limited reports. The aim of this study was to evaluate, in a large cohort of patients with long follow-up, the risk of recurrence of anti-GBM disease, the risk factors associated with clinical recurrence, and the long-term patient and graft survival.\n\nMethods\n\nThis was a multicenter retrospective study. Inclusion criteria were patients with anti-GBM glomerulonephritis who underwent transplantation of a kidney between 1977 and 2015. Exclusion criteria were systemic vasculitis, lupus erythematosus, and cryoglobulinemia. Recurrence was defined as reappearance of clinical signs of glomerulonephritis along with histological signs of proliferative glomerulonephritis and linear IgG staining on kidney biopsy, with or without anti-GBM antibodies.\n\nResults\n\nA total of 53 patients were included. Recurrence of anti-GBM glomerulonephritis in a first kidney transplant occurred in only 1 patient 5 years after transplantation (a prevalence rate of 1.9%) in the context of cessation of immunosuppressive drugs, and resulted in graft loss due to recurrence. Linear IgG staining on kidney biopsy in the absence of histological signs of proliferative glomerulonephritis was observed in 4 patients, in the context of cellular rejection. Patient survival was 100%, 94%, and 89% at 5, 10, and 15 years, respectively. Death-censored first-graft survival rates were 88%, 83%, and 79% at 5, 10, and 15 years, respectively.\n\nConclusion\n\nThe recurrence rate of anti-GBM glomerulonephritis after transplantation is very low but is associated with graft loss. The long-term patient and graft survival rates are excellent.\n\nKeywords\n\nanti-glomerular basement membrane glomerulonephritis\nrecurrence\nrenal transplantation\nsurvival\n==== Body\nAnti-glomerular basement membrane (anti-GBM) disease is a rare small-vessel vasculitis mediated by circulating autoantibodies directed predominantly against the noncollagenous domain of the α3 chain of type IV collagen, found in both glomerular and alveolar basement membranes.1 In most patients (>90%), anti-GBM disease leads to rapidly progressive glomerulonephritis. Kidney biopsy samples usually show crescentic glomerulonephritis on light microscopy, and immunofluorescence reveals the pathognomonic linear deposition of IgG along the glomerular capillaries (although rarely, the antibody may be of the IgA or IgM type).2 Concomitant alveolar hemorrhage affects 20% to 60% of patients.3 Serologic testing for anti-GBM antibodies allows a rapid diagnosis of the disease, but false-negative results may occur in patients with low antibody titers or for technical reasons related to antigen testing.4\n\nEarly diagnosis, plasma exchange therapy, and immunosuppressive agents have improved the once extremely poor outcome of the disease. However, it remains a rare cause of kidney failure (KF), accounting for less than 1% of all patients with KF5 and requiring dialysis at presentation in approximately half of the patients.6 For those with KF, transplantation is the best option. Recurrence of symptomatic anti-GBM disease in the kidney graft is a rare event. Few cases have been reported in the literature,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and although 1 registry study reported 14% of graft failure resulting from disease recurrence 2 decades ago, another more recent registry study found that only 3% of patients developed biopsy-proven recurrent anti-GBM disease after transplantation.5,13 A recent single-center cohort study from the United States reported a recurrence rate of 3.8%, without providing, however, any information regarding the context and clinical presentation of recurrence.17\n\nThe aim of this study was to evaluate, in a multicenter, national, large cohort of patients with an extended follow-up and detailed data collection, the risk of recurrence of anti-GBM disease and graft loss caused by recurrence. We also analyzed the complications and the long-term patient and graft survival.\n\nMaterials and Methods\n\nStudy Population\n\nPatients who underwent transplantion with a kidney for anti-GBM disease were considered for inclusion in 6 academic Belgian transplant centers (Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels; Ghent University Hospital, Ghent; University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven; University Hospital Antwerp, Antwerp; Université de Liège, Liège; Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel, Brussels). Inclusion criteria were as follows: (i) a history of anti-GBM disease, defined as a (sub)acute glomerulonephrititis (hematuria, proteinuria, increased creatinine) in the presence of a characteristic kidney biopsy result (proliferative extracapillary glomerulonephritis with linear deposits of IgG along the glomerular capillaries on kidney biopsy sample) and/or circulating anti-GBM antibodies; and (ii) a kidney transplantation between 1 January 1977 and 31 December 2015. Patients with systemic vasculitis (except antineutrophil cytoplasmic antibodies [ANCA]), lupus erythematosus, and cryoglobulinemia were excluded.\n\nAdherence to the Declaration of Helsinki and informed consent were respected. The study was approved by the Biomedical Ethics Committee of the Université Catholique de Louvain (Brussels, Belgium) and by the ethics committee of each center.\n\nDefinitions\n\nClinical recurrence was defined as reappearance of signs of glomerulonephritis (hematuria, proteinuria, and increased creatinine), along with histological signs of proliferative glomerulonephritis and linear IgG staining on kidney biopsy, with or without anti-GBM antibodies in a patient with previously documented disappearance of anti-GBM antibodies. Immunohistological recurrence in the graft was defined as linear IgG staining on kidney biopsy in the absence of histologic signs of proliferative glomerulonephritis.\n\nRejection was defined as treated biopsy-proven acute rejection. Pulmonary involvement was defined as proven alveolar hemorrhage on chest computed tomography or bronchoscopy with bronchoalveolar lavage.\n\nStatistical Analysis\n\nAnalyses were conducted using SPSS 25 software (IBM SPSS Statistics for Windows, Version 21.0; IBM Corporation, Armonk, NY) and graphed with GraphPad Prism 8.0 (GraphPad Software, La Jolla, CA). Continuous variables were expressed as mean ± SD or as median with 25th and 75th percentiles. Categorical variables were reported as counts and percentages. Analysis of progression to graft loss or mortality was estimated using the Kaplan−Meier method. Survival curves were computed with the same method.\n\nResults\n\nPatient Characteristics at Diagnosis of Anti-GBM Disease\n\nThe clinical records of 60 patients with a diagnosis of anti-GBM disease were analyzed. Seven patients were excluded because they did not meet the inclusion criteria. In all, 53 patients who underwent transplantation between 1977 and 2015 were included (Table 1). Of these 53 patients, 39 had biopsy-proven IgG linear staining and 48 had anti-GBM antibodies at diagnosis, associated with antineutrophil cytoplasmic antibodies positivity in 4 patients. The human leucocyte antigen (HLA) HLA-DR15(2) risk allele, which is associated with genetic susceptibility, was present in 70% of all included patients. Pulmonary involvement was present in less than 25% of patients. Therapy combining plasmapheresis, cyclophosphamide, and corticosteroids was predominant. All patients had to start dialysis within a mean time of 2 months (SD, 13 months).Table 1 Demographic characteristics of patients with anti-GBM−mediated glomerulonephritis at initial diagnosis (n = 53)\n\nSex ratio male/female, n (%)\t27 (51) /26(49)\t\nCaucasian, n (%)\t53 (100)\t\nAge at diagnosis, yr, median (P25−P75)\t40 (25−56)\t\nTrigger, n (%)\t\n Smoking\t14 (26)\t\n Organic\t5 (9)\t\n Herbicide\t1 (2)\t\n Infection\t14 (27)\t\n None identified\t22 (41)\t\nHLA typing (n = 51), n (%)\t\n DR15(2)\t37 (70)\t\n DR1\t3 (6)\t\n DR4\t21 (40)\t\n DR7\t10 (19)\t\nPulmonary involvement (n = 47), n (%)\t12 (23)\t\nin smokers (n = 14), n (%)\t6 (43)\t\nSerology\t\t\n Anti-GBM antibodies, n (%)\t48 (91)\t\n ANCA positivity\t4/36\t\n Low C3\t3/33\t\nTreatment, n (%)\t\t\n Plasmapheresis\t34 (64)\t\n Corticosteroids\t47 (89)\t\n Cyclophosphamide\t37 (70)\t\n Azathioprine\t5 (9)\t\nDialysis, n (%)\t53 (100)\t\n Age at ESRD, yr, median (P25−P75)\t41 (10-72)\t\n Modality (n = 52), n (HD/PD/HD+PD)\t44/1/7\t\n Time on dialysis, mo, median (P25−P75)\t23 (18-38)\t\nTime from diagnosis to ESRD, mo, mean (SD)\t21 (13)\t\nANCA, antineutrophil cytoplasmic antibodies; ESRD, end-stage renal disease; HD, hemodialysis; HLA, human leucocyte antigen; PD, peritoneal dialysis; P25− P75, 25th to 75th percentile.\n\nPatient Characteristics at Transplantation\n\nA total of 53 patients underwent a first kidney transplantation for anti-GBM disease (Table 2). The median age at transplantation was 43 years (range, 27−59 years). Anti-GBM serology at the time of first kidney transplantation was available in 43 of these patients, and none was positive. Median time between anti-GBM disappearance and first kidney transplantation was 15 months (range, 8−31 months). The most frequent maintenance therapy (n = 35) was a combination of calcineurin inhibitor, mycophenolate mofetil, and corticosteroids.Table 2 Demographic characteristics of patients with anti-GBM−mediated glomerulonephritis at first kidney transplantation\n\nAge, yr, median (P25−P75)\t43 (27-59)\t\nAnti-GBM antibodies (n = 43)\t0\t\nTime between anti-GBM disappearance and kidney transplantation, mo, median (P25−P75)\t15 (8-31)\t\nDonor deceased/living, n (%)\t44 (83)/9 (17)\t\nImmunosuppressive regimen\t\t\n Induction (n = 46), n (%)\t28 (61)\t\n Maintenance, n (%)\t\t\n Calcineurin inhibitors\t50 (96)\t\n mTOR inhibitors\t4 (8)\t\n MMF\t37 (71)\t\n AZA\t13 (25)\t\n Corticosteroids\t52 (100)\t\nAZA, azathioprine; GBM, glomerular basement membrane; MMF, mycophenolate mofetil; mTOR, mechanistic target of rapamycin; P25−P75, 25th−75th percentile.\n\nRecurrence of Anti-GBM\n\nA total of 33 allograft biopsies were performed during follow-up. Of these 33 biopsies, the search for IgG staining was available in 19 biopsy samples: 1 patient had clinical recurrence, whereas 4 had only immunohistological recurrence.\n\nClinical Recurrence\n\nClinical recurrence occurred in only 1 recipient after a first kidney transplantation (n = 53), representing a prevalence rate of 1.9%. Our group reported this case in 1998.12 This patient was a 33-year-old woman who was diagnosed with anti-GBM glomerulonephritis at age 24 years when she presented with subacute kidney failure requiring dialysis. There was no lung involvement. Intravenous methylprednisolone followed by oral prednisolone and oral azathioprine failed to improve renal function. She received a kidney transplant from a deceased donor 26 months later. Circulating anti-GBM antibodies had been consistently negative for 14 months. The postoperative immunosuppressive regimen included an induction therapy with anti-thymocyte globulins and a maintenance immunosuppressive regimen with cyclosporine, azathioprine, and prednisolone. Graft tolerance was excellent during the next 5 years. Circulating anti-GBM antibodies were repeatedly negative, and microscopic hematuria was observed intermittently in the absence of proteinuria. Sixty-eight months after transplantation, she stopped her immunosuppressive treatment in the context of social and financial problems, and was admitted 1 month later with severe acute kidney injury, proteinuria, and microhematuria. Recurrence of anti-GBM nephritis was diagnosed based on the reappearance of circulating anti-GBM antibodies and crescentic glomerulonephritis with strong linear staining for IgG along the GBM. The kidney biopsy sample also showed signs of both acute and chronic graft rejection, with acute interstitial inflammation with tubulitis and tubulointerstitial fibrosis. The patient had no pulmonary involvement. Maintenance hemodialysis was required despite treatment with intravenous cyclophosphamide and methylprednisolone. Except for stopping immunosuppressive treatment, no environmental trigger (such as cigarette smoking, hydrocarbon solvents, organic solvents, and herbicides) or infection episode was identified. She carried the HLA DR15(2) allele, which is associated with an increased susceptibility to the development of anti-GBM antibodies.\n\nImmunohistological Recurrence\n\nImmunohistological recurrence with IgG linear deposits was documented in 4 of the 19 first grafts in which a kidney biopsy sample with IgG staining (IF/IHC) was available. The indications for biopsy in these patients were an increased creatinine in 3 patients and per protocol in 1 patient.\n\nPatient 1 underwent biopsy per protocol 3 months after transplantation and had a borderline acute rejection along with strong linear IgG deposits. Anti-GBM antibodies were negative. He was treated with transient increased oral methylprednisolone. Seven years later, he presented with increased creatinine. A kidney biopsy sample showed transplant glomerulopathy, with no linear IgG deposits and negative C4d. He lost his graft function within 1 month.\n\nPatient 2 underwent biopsy 4 years after transplantation for increased creatinine. Acute vascular rejection and weak linear IgG deposits were observed. Anti-GBM antibodies were not tested. Kidney graft was lost within days.\n\nPatient 3 underwent biopsy for increased creatinine 3 months after transplantation. The biopsy showed a moderate to severe acute cellular rejection and weak linear IgG deposits. She was treated with corticosteroids and anti-thymocyte globulin. Anti-GBM antibody titer was not available at the time of the biopsy, but was negative 2 weeks later and repeatedly thereafter. A second biopsy sample 3 weeks later showed persistent severe acute cellular rejection, but no linear IgG deposits. The kidney graft was lost within weeks.\n\nPatient 4 presented with an acute rise in creatinine (2.1 mg/dl, rising from 1.08 mg/dl) and slight proteinuria (0.48 g/d) without hematuria, 7 weeks after transplantation. Circulating anti-GBM antibodies were weakly positive (despite being negative for 14 months before transplantation). The graft biopsy showed borderline acute cellular rejection, no glomerular lesion, but weak linear glomerular deposits of IgG. The patient was treated with intravenous methylprednisolone, with stabilization of her serum creatinine. Circulating anti-GBM antibodies were thereafter repeatedly negative. Twenty-two years after kidney transplantation, she is alive with stable graft function and absence of hematuria. She also displayed the HLA DR15(2) risk allele.\n\nPosttransplantation Outcomes of Patients Receiving Transplants for Anti-GBM Disease\n\nThe median posttransplantation patient follow-up period was 122 months (range, 60−213 months) (Table 3). Patient survival was excellent: 100% at 5 years, 94% at 10 years, and 89% at 15 years (Figure 1). Three patients died: 1 of a hemorrhagic stroke, 1 of a small cell lung carcinoma, and 1 of infection, 80, 124, and 153 months after transplantation, respectively. The overall death-censored first graft survival rates were 88%, 83%, and 79% at 5, 10, and 15 years respectively (Figure 1). Sixteen first grafts were lost for the following reasons: rejection (n = 12), recurrence (n = 1), infection (n = 1), renal vein thrombosis (n = 1), and cause unknown (n = 1). Twenty-two patients (43%) had a treated biopsy-proven acute rejection. The reason for the graft biopsy is known in 12 of these patients. Eleven biopsies were performed for an increased serum creatinine, and 1 was performed per protocol.Table 3 Post-transplantation outcomes of patients who underwent transplantation for anti-GBM disease (except for recurrence)\n\nAcute rejection, n (%)\t22 (43)\t\nComplications, n (%)\t\t\n Cardiac\t13 (25)\t\n Hypertension\t39 (74)\t\n Neoplasia\t14 (27)\t\n NODAT\t9 (17)\t\n Infection\t37 (70)\t\nLoss of first graft, n (%)\t\t\n Rejection\t12 (23)\t\n Recurrence\t1 (1,9)\t\n Renal vein thrombosis\t1 (1,9)\t\n Infection\t1 (1,9)\t\n NA\t1 (1,9)\t\nDeath, n (%)\t3 (5,7)\t\nKidney re-transplanted for second/third time, n\t7/1\t\nFollow-up, mo, median (P25−P75)\t122 (60−213)\t\nNA, not available; NODAT, new-onset diabetes after transplantation; P25−P75, 25th−75th percentile.\n\nFigure 1 Kaplan−Meier curve. Patient survival and death-censored first graft survival after kidney transplantation for anti−glomerular basement membrane (GBM) glomerulonephritis.\n\nPosttransplantation complications included high blood pressure (n = 39), infections (n = 37), neoplasia (n = 14), cardiovascular disease (n = 13), and new-onset diabetes after transplantation (n = 9). Seven patients underwent transplantation 2 times and 1 patient 3 times.\n\nEvolution of Second and Third Transplantations\n\nSeven patients underwent transplantation for a second time (their first grafts were lost from rejection [n = 5], venous thrombosis [n = 1], and unknown reason [n = 1]). Two patients lost their second graft (1 from rejection and the second from venous thrombosis). One patient underwent a third transplantation, with a still-functional graft at last follow-up. There was no recurrence of their primary kidney disease.\n\nDiscussion\n\nIn this multicenter analysis, we reviewed the outcome of 53 patients who underwent kidney transplantation for anti-GBM disease and were followed up for a median of 10 years. We found that clinical recurrence occurred in only 1 patient, a prevalence rate of 1.9%. Recurrence led to graft loss. Patient survival and overall death-censored first graft survival rates were excellent: 100%, 94%, 89%, and 88%, 83% and 79% at 5, 10, and 15 years, respectively.\n\nClinical recurrence of anti-GBM disease after transplantation was considered non-negligible in early reports. A study in 1973 reported recurrent glomerulonephritis in more than half of the patients who had undergone transplantation for anti-GBM disease. Graft loss from recurrence was noted in 40% of the patients.8 In 1999, an analysis of the European Renal Association and European Dialysis and Transplant Association (ERA-EDTA) registry reported 14% graft failure was recorded as resulting from anti-GBM disease recurrence.13 A few case reports have described recurrence of anti-GBM disease after kidney transplantation. Seven case reports, including the one describing our patient, pointed to the risk of recurrence of glomerulonephritis.7,10−12,14−16 In 2013, the Australian and New Zealand Dialysis and Transplantation (ANZDATA) registry reported biopsy-proven recurrence of the disease in 6 of 224 patients transplanted for anti-GBM disease between 1963 and 2010 (2.7%) leading to graft failure in 2 cases.5 Very recently, a single-center cohort study reported a recurrence rate of 3.8%.17 In line with these recent publications, we found a clinical recurrence of 1.9% for anti-GBM disease after transplantation.\n\nRisk factors for recurrence of anti-GBM glomerulonephritis that emerge from the literature, including our patient, are the presence of anti-GBM antibodies before transplantation and low-dose or no immunosuppressive therapy. Indeed, recurrence occurred in 2 patients who had circulating anti-GBM antibodies before transplantation,2,15 leading the Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group to recommend a period of at least 6 months’ sustained seronegativity before undertaking kidney transplantation.18 Of 4 other patients, 2 were not taking any immunosuppressive agent: 1 patient because he received a kidney from an identical twin10 and 1 patient because of immunosuppression therapy cessation,12 and 2 patients because they were on low-dose bi-therapy immunosuppression including cyclosporine and prednisone only.11,14 This underlines that potent maintenance immunosuppressive therapy is important in suppressing disease activity and maintaining a negative titer of negative anti-GBM antibodies. With cessation or reduction of immunosuppression, not only can the disease reactivate with production of anti-GBM antibodies, but rejection can also occur, causing graft injuries that could reveal an epitope normally hidden from the immune system, and precipitating anti-GBM antibody formation/reactivation.19 Genetic susceptibility, including HLA allele, could also be associated with disease recurrence.20\n\nThe incidence of recurrent linear IgG staining in the kidney allograft reached 50% in historical series when transplantation was performed in the presence of anti-GBM antibodies. Only a quarter of these patients developed clinical anti-GBM disease.3 In our cohort, biopsies were performed for increased creatinine and per protocol in some patients. Linear IgG deposits were observed concomitant to acute or borderline rejection. Unlike the classical clinical recurrence associated with anti-GBM antibodies reappearance, these linear IgG deposits are observed without other glomerular lesions or crescents in the absence or presence of weak titer of antibodies. A possible explanation could be that rejection unveils normally hidden antigens or that low immunosuppression favors disease reactivation with anti-GBM antibody production. Nevertheless, restoring adequate immunosuppression in case histological lesions are not yet severe could prevent further progression of glomerular lesions.\n\nPatient and graft survival were excellent in our cohort. Patient survival was 100%, 94%, and 89% at 5, 10, and 15 years, respectively. The 10-year patient survival is better than the one reported by Tang et al. in the ANZDATA registry (86%),5 and is comparable to that in a cohort of patients who underwent kidney transplantation for Henoch−Schönlein purpura nephritis over approximately the same time period (95%).21 Three patients died of cardiovascular disease, malignancy, and infection, the classical causes of mortality in transplant recipients. Our 10-year graft survival was 83%, much better than the 63% reported by the ANZDATA registry and the 65% reported in the cohort with Henoch−Schönlein purpura nephritis. Unlike a registry study, our study allows an in-depth analysis of patient outcomes during an extended follow-up period.\n\nWe acknowledge the limitations of this study. It is a retrospective study with a relatively limited number of patients and no systematic biopsies of the kidney graft. Nevertheless, it is the largest reported cohort study to include patients with this rare disease. Moreover, it gathers patients from a small country with a homogeneous population and detailed data collection, including individual therapy management, laboratory values, and renal histopathology. This allowed us a thorough analysis of recurrence, whereas recent reports mentioned recurrence without further detail. Also, follow-up was very long, allowing a good appreciation of disease evolution.\n\nIn conclusion, we found that patient and first graft survival rates after kidney transplantation for anti-GBM disease were excellent. The clinical recurrence rate of anti-GBM disease after transplantation is very low (1.9%) and is associated with graft loss. Delaying transplantation until circulating anti-GBM antibodies have disappeared and maintaining adequate immunosuppression decreases the likelihood of recurrence, which nevertheless should be considered in case of clinical signs.\n\nDisclosure\n\nAll the authors declare no competing interests. SVL reports non-financial support from Travel fee and congress registration Astellas, personal fees from Advisory board GSK, outside the submitted work.\n\nAcknowledgments\n\nFunding was provided to BS, a senior clinical investigator of The Research Foundation Flanders (F.W.O.) (1842919N).\n==== Refs\nReferences\n\n1 Greco A. Rizzo M.I. De V.A. Goodpasture’s syndrome: a clinical update Autoimmun Rev 14 2015 246 253 25462583\n2 Borza D.B. Chedid M.F. Colon S. Recurrent Goodpasture’s disease secondary to a monoclonal IgA1-kappa antibody autoreactive with the alpha1/alpha2 chains of type IV collagen Am J Kidney Dis 45 2005 397 406 15685519\n3 McAdoo S.P. Pusey C.D. Anti-glomerular basement membrane disease Clin J Am Soc Nephrol 12 2017 1162 1172 28515156\n4 Salama A.D. Dougan T. Levy J.B. Goodpasture’s disease in the absence of circulating anti-glomerular basement membrane antibodies as detected by standard techniques Am J Kidney Dis 39 2002 1162 1167 12046026\n5 Tang W. McDonald S.P. Hawley C.M. Anti-glomerular basement membrane antibody disease is an uncommon cause of end-stage renal disease Kidney Int 83 2013 503 510 23254902\n6 Levy J.B. Turner A.N. Rees A.J. Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression Ann Intern Med 134 2001 1033 1042 11388816\n7 Beleil O.M. Coburn J.W. Shinaberger J.H. Recurrent glomerulonephritis due to anti-glomerular basement membrane-antibodies in two successive allografts Clin Nephrol 1 1973 377 380 4594999\n8 Wilson C.B. Dixon F.J. Anti-glomerular basement membrane antibody-induced glomerulonephritis Kidney Int 3 1973 74 89 4571918\n9 McPhaul J.J. Jr. Lordon R.E. Thompson A.L. Jr. Nephritogenic immunopathologic mechanisms and human renal transplants: the problem of recurrent glomerulonephritis Kidney Int 10 1976 135 138 787616\n10 Almkuist R.D. Buckalew V.M. Jr. Hirszel P. Recurrence of anti-glomerular basement membrane antibody mediated glomerulonephritis in an isograft Clin Immunol Immunopathol 18 1981 54 60 7460397\n11 Trpkov K. Abdulkareem F. Jim K. Recurrence of anti-GBM antibody disease twelve years after transplantation associated with de novo IgA nephropathy Clin Nephrol 49 1998 124 128 9524784\n12 Fonck C. Loute G. Cosyns J.P. Recurrent fulminant anti-glomerular basement membrane nephritis at a 7-year interval Am J Kidney Dis 32 1998 323 327 9708621\n13 Briggs J.D. Jones E. Recurrence of glomerulonephritis following renal transplantation. Scientific Advisory Board of the ERA-EDTA Registry. European Renal Association−European Dialysis and Transplant Association Nephrol Dial Transplant 14 1999 564 565 10193799\n14 Khandelwal M. McCormick B.B. Lajoie G. Recurrence of anti-GBM disease 8 years after renal transplantation Nephrol Dial Transplant 19 2004 491 494 14736982\n15 Sauter M. Schmid H. Anders H.J. Loss of a renal graft due to recurrence of anti-GBM disease despite rituximab therapy Clin Transplant 23 2009 132 136 19087095\n16 Thibaud V. Rioux-Leclercq N. Vigneau C. Recurrence of Goodpasture syndrome without circulating anti-glomerular basement membrane antibodies after kidney transplant, a case report BMC Nephrol 20 2019 6 30621605\n17 Singh T. Kharadjian A.B. Astor B.C. Long-term outcomes in kidney transplant recipients with end-satge renal disease due to anti-glomerular basement membrane disease Clin Transplant 35 2021 e14179 33259076\n18 Kidney Disease: Improving Global Outcomes KDIGO clinical practice guideline for glomerulonephritis Kidney Int Suppl 2 2012 139 274\n19 Pusey C.D. Anti-glomerular basement membrane disease Kidney Int 64 2003 1535 1550 12969182\n20 Phelps R.G. Rees A.J. The HLA complex in Goodpasture’s disease: a model for analyzing susceptibility to autoimmunity Kidney Int 56 1999 1638 1653 10571772\n21 Kanaan N. Mourad G. Thervet E. Recurrence and graft loss after kidney transplantation for Henoch–Schönlein purpura nephritis: a multicenter analysis Clin J Am Soc 6 2011 1768 1772\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2468-0249",
"issue": "6(7)",
"journal": "Kidney international reports",
"keywords": "anti-glomerular basement membrane glomerulonephritis; recurrence; renal transplantation; survival",
"medline_ta": "Kidney Int Rep",
"mesh_terms": null,
"nlm_unique_id": "101684752",
"other_id": null,
"pages": "1888-1894",
"pmc": null,
"pmid": "34307983",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": "21734091;12969182;30621605;14736982;33259076;9524784;10193799;11388816;4571918;12046026;10571772;787616;4594999;28515156;19087095;9708621;25462583;7460397;15685519;23254902",
"title": "Recurrence and Outcome of Anti-Glomerular Basement Membrane Glomerulonephritis After Kidney Transplantation.",
"title_normalized": "recurrence and outcome of anti glomerular basement membrane glomerulonephritis after kidney transplantation"
} | [
{
"companynumb": "BE-LUPIN PHARMACEUTICALS INC.-2021-21262",
"fulfillexpeditecriteria": "2",
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"actiondrug": "6",
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"activesubstancename": "METHYLPREDNISOLONE"
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{
"abstract": "Patients with congenital thrombocytopenia have an increased risk of developing myeloid neoplasms. In these cases, the morphologic distinction between disease at baseline and at progression is challenging. This report analyzes clinicopathologic features of congenital thrombocytopenia with long-term follow-up at one referral center. Records from the last 20 years were searched for cases of congenital thrombocytopenia with bone marrow biopsies and peripheral blood smears. The clinical, morphologic, immunophenotypic, and molecular features were analyzed. Six adult and two pediatric patients were identified (six male, two female). Age range at first biopsy was 1-47 (median, 31) years. Underlying diseases included thrombocytopenia-absent radius syndrome, congenital thrombocytopenia with radial-ulnar synostosis, MYH9-related disorder, shortened telomere syndrome, congenital thrombocytopenia with ANKRD26 mutation, and familial platelet disorder with predisposition to acute myeloid leukemia. Four patients had myelodysplastic/myeloproliferative neoplasm-like marrow changes such as hypercellularity, increased myeloid to erythroid ratio, numerous micromegakaryocytes (highlighted by CD42b), and marrow fibrosis. Two patients had marrow hypoplasia and two had unremarkable marrow morphology. Three patients-all in the myelodysplastic/myeloproliferative neoplasm-like group-developed disease progression characterized by erythroid and myeloid dysplasia, elevated bone marrow blasts, and new cytogenetic abnormalities. Unlike non-familial myeloid neoplasms, congenital thrombocytopenia patients in the myelodysplastic/myeloproliferative neoplasm-like group had a long and indolent clinical course (average age at disease progression, 47 years). In summary, three distinct morphologic types of congenital thrombocytopenia were identified: a hyperplastic myelodysplastic/myeloproliferative neoplasm-like group, a hypoplastic bone marrow failure-like group, and a group with relatively normal marrow morphology. Emergence of cytogenetic abnormalities and dysplasia in non-megakaryocyte lineages correlated with disease progression.",
"affiliations": "Department of Pathology and Laboratory Medicine, New York-Presbyterian Hospital Weill Cornell Medicine, New York, NY, USA.;Department of Pediatrics and Medicine, New York-Presbyterian Hospital Weill Cornell Medicine, New York, NY, USA.;Department of Pathology and Laboratory Medicine, New York-Presbyterian Hospital Weill Cornell Medicine, New York, NY, USA.;Department of Pathology and Laboratory Medicine, New York-Presbyterian Hospital Weill Cornell Medicine, New York, NY, USA.;Department of Pediatrics and Medicine, New York-Presbyterian Hospital Weill Cornell Medicine, New York, NY, USA.;Department of Pathology and Laboratory Medicine, New York-Presbyterian Hospital Weill Cornell Medicine, New York, NY, USA.;Department of Pathology and Laboratory Medicine, New York-Presbyterian Hospital Weill Cornell Medicine, New York, NY, USA.",
"authors": "Tsang|Hamilton C|HC|;Bussel|James B|JB|;Mathew|Susan|S|;Liu|Yen-Chun|YC|;Imahiyerobo|Allison A|AA|;Orazi|Attilio|A|;Geyer|Julia T|JT|",
"chemical_list": "C583630:ANKRD26 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D009687:Nuclear Proteins; D018995:Myosin Heavy Chains",
"country": "United States",
"delete": false,
"doi": "10.1038/modpathol.2016.218",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0893-3952",
"issue": "30(4)",
"journal": "Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc",
"keywords": null,
"medline_ta": "Mod Pathol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001853:Bone Marrow; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains; D009687:Nuclear Proteins; D012189:Retrospective Studies; D013921:Thrombocytopenia; D055815:Young Adult",
"nlm_unique_id": "8806605",
"other_id": null,
"pages": "486-498",
"pmc": null,
"pmid": "28059092",
"pubdate": "2017-04",
"publication_types": "D016428:Journal Article",
"references": "12676774;27365488;24325356;19028006;22886561;15239405;8219187;17910625;21343560;20091385;15477207;11590545;23926458;17475912;19571318;19946261;20619386;21148331;19357394;11776386;23023736;25581430;12161364;16227975;21841770;23732052;15561694;16276527;15814878;21606161;21467542;15497094;21282718;20844233;12847322;3056062;22736231;18166807;24553179;18024606;11442476;18723428;24325359;27112265;24618731;23690288;24628296;24030261;22898599;26224646;19351959;12792306",
"title": "Bone marrow morphology and disease progression in congenital thrombocytopenia: a detailed clinicopathologic and genetic study of eight cases.",
"title_normalized": "bone marrow morphology and disease progression in congenital thrombocytopenia a detailed clinicopathologic and genetic study of eight cases"
} | [
{
"companynumb": "US-AMGEN-USASP2018037528",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": ... |
{
"abstract": "The differential diagnosis of acute abdominal complaints is challenging in Crohn's disease. This is particularly true in patients in remission induced by biological therapy. In addition to the acute relapse of Crohn's disease, other common causes, such as acute appendicitis exhibiting similar and often atypical course, should be taken into consideration irrespective of the age. An ileocecal flare-up is unlikely to occur in patients with perianal Crohn's disease in remission induced by infliximab even if laboratory and radiological findings point towards this diagnosis. We report the case of a middle-aged woman in remission induced by infliximab who developed acute abdominal symptoms due to perforated appendicitis. Orv Hetil. 2018; 159(10): 405-409.",
"affiliations": "Transzlációs Medicina Intézet, Pécsi Tudományegyetem, Általános Orvostudományi Kar Pécs, Szigeti út 12., 7624.;Klinikai Központ, Radiológiai Klinika, Pécsi Tudományegyetem, Általános Orvostudományi Kar Pécs.;Patológiai Intézet, Pécsi Tudományegyetem, Általános Orvostudományi Kar Pécs.;Klinikai Központ, Sebészeti Klinika, Pécsi Tudományegyetem, Általános Orvostudományi Kar Pécs.;Klinikai Központ, I. Belgyógyászati Klinika, Gasztroenterológiai Tanszék, Pécsi Tudományegyetem, Általános Orvostudományi Kar Pécs.;Klinikai Központ, I. Belgyógyászati Klinika, Gasztroenterológiai Tanszék, Pécsi Tudományegyetem, Általános Orvostudományi Kar Pécs.",
"authors": "Szakács|Zsolt|Z|;Faluhelyi|Nándor|N|;Fincsur|András|A|;Papp|András|A|;Vincze|Áron|Á|;Bajor|Judit|J|",
"chemical_list": "D005765:Gastrointestinal Agents; D000069285:Infliximab",
"country": "Hungary",
"delete": false,
"doi": "10.1556/650.2018.30982",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-6002",
"issue": "159(10)",
"journal": "Orvosi hetilap",
"keywords": "Crohn-betegség; Crohn’s disease; appendicitis; biological therapy; biológiai terápia",
"medline_ta": "Orv Hetil",
"mesh_terms": "D000208:Acute Disease; D001064:Appendicitis; D003424:Crohn Disease; D003937:Diagnosis, Differential; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "0376412",
"other_id": null,
"pages": "405-409",
"pmc": null,
"pmid": "29504422",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Acute appendicitis in a patient with perianal Crohn's disease receiving infliximab.",
"title_normalized": "acute appendicitis in a patient with perianal crohn s disease receiving infliximab"
} | [
{
"companynumb": "HU-JNJFOC-20180326816",
"fulfillexpeditecriteria": "1",
"occurcountry": "HU",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of gastrointestinal tract. GISTs range from benign indolent neoplasms to highly malignant sarcomas. Gain-of-function mutations of tyrosine kinase receptors, KIT or PDGFRA, have been identified in most GISTs. In this study, we report 36 GIST patients whose tumors had homozygous KIT exon 11 mutations detected by direct sequencing of PCR products. Loss of heterozygosity in KIT locus and other chromosome 4 loci were documented in majority of these tumors. However, fluorescence in situ hybridization with KIT locus-specific probe and chromosome 4 centromeric enumeration probe showed no evidence of KIT hemizygosity in a majority of analyzed cases. These findings are consistent with duplication of chromosome 4 with KIT mutant allele. Homozygous KIT exon 11 mutations were found in 33 primary tumors and 7 metastatic lesions. In two cases, shift from heterozygosity to homozygosity was documented during tumor progression being present in metastases, but not in primary tumors. Among primary GISTs, there were 16 gastric, 18 intestinal and 2 from unknown locations. An average primary tumor size was 12 cm and average mitotic activity 32/50 HPFs. Out of 32 tumors 29 (90.6%) with complete clinicopathologic data were diagnosed as sarcomas with more than 50% risk of metastatic disease, and 26 of 29 patients with follow-up had metastases or died of disease. An average survival time among pre-imatinib patients, who died of the disease was 33.4 months. Based on these findings, we conclude that presence of homozygous KIT exon 11 mutations is associated with malignant course of disease and should be considered an adverse prognostic marker in GISTs.",
"affiliations": "Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA. lasota@afip.osd.mil",
"authors": "Lasota|Jerzy|J|;vel Dobosz|Anna Jerzak|AJ|;Wasag|Bartosz|B|;Wozniak|Agnieszka|A|;Kraszewska|Ewa|E|;Michej|Wanda|W|;Ptaszynski|Konrad|K|;Rutkowski|Piotr|P|;Sarlomo-Rikala|Maarit|M|;Steigen|Sonja E|SE|;Schneider-Stock|Regine|R|;Stachura|Jerzy|J|;Chosia|Maria|M|;Ogun|Gabriel|G|;Ruka|Wlodzimierz|W|;Siedlecki|Janusz A|JA|;Miettinen|Markku|M|",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit",
"country": "United States",
"delete": false,
"doi": "10.1038/labinvest.3700628",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0023-6837",
"issue": "87(10)",
"journal": "Laboratory investigation; a journal of technical methods and pathology",
"keywords": null,
"medline_ta": "Lab Invest",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001549:Benzamides; D005091:Exons; D005260:Female; D046152:Gastrointestinal Stromal Tumors; D006720:Homozygote; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010879:Piperazines; D019009:Proto-Oncogene Proteins c-kit; D011743:Pyrimidines; D018570:Risk Assessment",
"nlm_unique_id": "0376617",
"other_id": null,
"pages": "1029-41",
"pmc": null,
"pmid": "17632543",
"pubdate": "2007-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Presence of homozygous KIT exon 11 mutations is strongly associated with malignant clinical behavior in gastrointestinal stromal tumors.",
"title_normalized": "presence of homozygous kit exon 11 mutations is strongly associated with malignant clinical behavior in gastrointestinal stromal tumors"
} | [
{
"companynumb": "NVSC2019US079441",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": "3",
... |
{
"abstract": "Hailey-Hailey disease is an adult-onset skin condition characterized by lesions in the intertriginous regions of the body. The lesions can be pruritic, painful, and associated with physical and social impairment.\n\n\n\nWe present a case of psoriasiform Hailey-Hailey disease in a 60-year-old white woman who exhibited erythematous psoriasiform plaques in many areas of her body. The patient's condition was successfully treated with a twice-daily regimen of doxycycline, mometasone, and clindamycin.\n\n\n\nIt is important to recognize this variant of Hailey-Hailey disease so it can be diagnosed and treated promptly. Hailey-Hailey disease can be treated with topical corticosteroids and antibiotics and usually is associated with a positive prognosis.",
"affiliations": "Medical Student at Boston University School of Medicine in MA. jni@bu.edu.;Resident in the Department of Dermatology at Indiana University in Indianapolis. katgilbe@iupui.edu.;Resident in the Department of Dermatology at Emory University in Atlanta, GA: ivie.manalo@gmail.com.;Dermatologist at the Los Angeles Medical Center in CA. jashinwu@gmail.com.",
"authors": "Ni|Jonathan|J|;Gilbert|Kathleen E|KE|;Manalo|Ivie F|IF|;Wu|Jashin J|JJ|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.7812/TPP/17-016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1552-5767",
"issue": "22()",
"journal": "The Permanente journal",
"keywords": null,
"medline_ta": "Perm J",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D008875:Middle Aged; D016506:Pemphigus, Benign Familial; D011565:Psoriasis; D016896:Treatment Outcome",
"nlm_unique_id": "9800474",
"other_id": null,
"pages": "17-016",
"pmc": null,
"pmid": "29236657",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10615129;1554604",
"title": "Psoriasiform Hailey-Hailey Disease Presenting as Erythematous Psoriasiform Plaques Throughout the Body: A Case Report.",
"title_normalized": "psoriasiform hailey hailey disease presenting as erythematous psoriasiform plaques throughout the body a case report"
} | [
{
"companynumb": "US-APOTEX-2018AP019259",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
... |
{
"abstract": "The Capgras syndrome (CS) is a rare psychiatric disorder. CS is classified as a delusional misidentification syndrome. Initially, CS was described in paranoid schizophrenia and schizoaffective disorders. CS has also been reported in neurodegenerative diseases such as Alzheimer's disease and Lewy body dementia. To date, there are very few descriptions of the occurrence of CS in idiopathic Parkinson's disease (PD), with or without dementia. Considering the recent observation of two new cases in PD patients, a systematic overview of the literature published between 1976 and 2016 reporting CS in PD was conducted. The purpose of this article is to examine the phenomenon in people with PD with and without dementia, the psychopathologic context in which it happened, the role played by the dopaminergic medications and to define useful therapeutic strategies. Our CS cases occurred in two elderly patients with advanced PD and cognitive impairment, respectively, after an acute stressor event and after an increase of the total daily dose of levodopa. In light of our observations and the cases reported in the literature, we argue that CS is an acute or subacute psychotic disorder occurring mostly in PD with dementia. Besides, the increase in brain dopamine levels induced by acute stressful events and/or dopamine-enhancing medications should be considered as a possible causal mechanism of CS in patients with advanced stages of PD and cognitive decline.",
"affiliations": "Department of Neurology, Movement Disorders Center, Policlinico Universitario Monserrato, University of Cagliari, SS 554 Bivio per Sestu, Monserrato, 09042, Cagliari, Italy.;Department of Neurology, Movement Disorders Center, Policlinico Universitario Monserrato, University of Cagliari, SS 554 Bivio per Sestu, Monserrato, 09042, Cagliari, Italy. mario.meloni@hotmail.it.;Department of Neurology, Movement Disorders Center, Policlinico Universitario Monserrato, University of Cagliari, SS 554 Bivio per Sestu, Monserrato, 09042, Cagliari, Italy.;Department of Neurology, Movement Disorders Center, Policlinico Universitario Monserrato, University of Cagliari, SS 554 Bivio per Sestu, Monserrato, 09042, Cagliari, Italy.;Department of Neurology, Movement Disorders Center, Policlinico Universitario Monserrato, University of Cagliari, SS 554 Bivio per Sestu, Monserrato, 09042, Cagliari, Italy.;Department of Neurology, Movement Disorders Center, Policlinico Universitario Monserrato, University of Cagliari, SS 554 Bivio per Sestu, Monserrato, 09042, Cagliari, Italy.;Department of Neurology, Movement Disorders Center, Policlinico Universitario Monserrato, University of Cagliari, SS 554 Bivio per Sestu, Monserrato, 09042, Cagliari, Italy.;Department of Neurology, Movement Disorders Center, Policlinico Universitario Monserrato, University of Cagliari, SS 554 Bivio per Sestu, Monserrato, 09042, Cagliari, Italy.;Department of Neurology, Movement Disorders Center, Policlinico Universitario Monserrato, University of Cagliari, SS 554 Bivio per Sestu, Monserrato, 09042, Cagliari, Italy.",
"authors": "Cannas|Antonino|A|;Meloni|Mario|M|;Mascia|Marcello Mario|MM|;Solla|Paolo|P|;Cocco|Luigi|L|;Muroni|Antonella|A|;Floris|Gianluca|G|;Di Stefano|Francesca|F|;Marrosu|Francesco|F|",
"chemical_list": "D015259:Dopamine Agents",
"country": "Italy",
"delete": false,
"doi": "10.1007/s10072-016-2765-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-1874",
"issue": "38(2)",
"journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology",
"keywords": "Capgras syndrome; Delusional misidentification syndromes; Dementia; Parkinson’s disease; Parkinson’s psychosis",
"medline_ta": "Neurol Sci",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D002194:Capgras Syndrome; D060825:Cognitive Dysfunction; D015259:Dopamine Agents; D005264:Femoral Fractures; D006801:Humans; D008297:Male; D010300:Parkinson Disease",
"nlm_unique_id": "100959175",
"other_id": null,
"pages": "225-231",
"pmc": null,
"pmid": "27848117",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "20385373;7480431;17957215;16122573;24812655;7846237;16362848;23636466;608663;17266092;2709017;27086263;25093788;7796146;15633849;12426417;20686153;2380157;943070;949230;12076726;19853006;19196939;18525289;23680417;25886646;25309399;23211760;571979;26037875;19650368;2084656;26554328;23446145;21801840;22450637;20945171;9107057;4056277;23064228;60643;4691312;12489921;26078747;2289104;23345220;11596786;9608408;7326542",
"title": "Capgras syndrome in Parkinson's disease: two new cases and literature review.",
"title_normalized": "capgras syndrome in parkinson s disease two new cases and literature review"
} | [
{
"companynumb": "IT-ACCORD-048747",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationn... |
{
"abstract": "We aimed to evaluate the comparative risk of hospitalized infection among patients with rheumatoid arthritis (RA) who initiated abatacept versus a tumor necrosis factor inhibitor (TNFi).\n\n\n\nUsing claims data from Truven MarketScan database (2006-2015), we identified patients with RA ages ≥18 years with ≥2 RA diagnoses who initiated treatment with abatacept or a TNFi. The primary outcome was a composite end point of any hospitalized infection. Secondary outcomes included bacterial infection, herpes zoster, and infections affecting different organ systems. We performed 1:1 propensity score (PS) matching between the groups in order to control for baseline confounders. We estimated incidence rates (IRs) and hazard ratios (HRs) with 95% confidence intervals (95% CIs) for hospitalized infection.\n\n\n\nWe identified 11,248 PS-matched pairs of patients who initiated treatment with abatacept and TNFi with a median age of 56 years (83% were women). The IR per 1,000 person-years for any hospitalized infection was 37 among patients who initiated treatment with abatacept and 47 in those who initiated treatment with TNFi. The HR for the risk of any hospitalized infection associated with abatacept versus TNFi was 0.78 (95% CI 0.64-0.95) and remained lower when compared to infliximab (HR 0.63 [95% CI 0.47-0.85]), while no significant difference was seen when compared to adalimumab and etanercept. The risk of secondary outcomes was lower for abatacept for pulmonary infections, and similar to TNFi for the remaining outcomes.\n\n\n\nIn this large cohort of patients with RA who initiated treatment with abatacept or TNFi as a first- or second-line biologic agent, we found a lower risk of hospitalized infection after initiating abatacept versus TNFi, which was driven mostly by infliximab.",
"affiliations": "Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.;Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.;Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.;Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.",
"authors": "Chen|Sarah K|SK|0000-0002-8206-597X;Liao|Katherine P|KP|0000-0002-4797-3200;Liu|Jun|J|;Kim|Seoyoung C|SC|0000-0002-2517-3579",
"chemical_list": "D018501:Antirheumatic Agents; D000079424:Tumor Necrosis Factor Inhibitors; D000069594:Abatacept",
"country": "United States",
"delete": false,
"doi": "10.1002/acr.23824",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2151-464X",
"issue": "72(1)",
"journal": "Arthritis care & research",
"keywords": null,
"medline_ta": "Arthritis Care Res (Hoboken)",
"mesh_terms": "D000069594:Abatacept; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001424:Bacterial Infections; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007297:Inpatients; D008297:Male; D008875:Middle Aged; D057216:Propensity Score; D012189:Retrospective Studies; D012307:Risk Factors; D000079424:Tumor Necrosis Factor Inhibitors; D014481:United States",
"nlm_unique_id": "101518086",
"other_id": null,
"pages": "9-17",
"pmc": null,
"pmid": "30570833",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "25086079;15757918;12815076;18717997;29750409;20398273;24470378;21586439;21921094;25880932;22887849;12355475;21288960;23453683;7640345;21208778;17346615;18834713;21704234;17530704;8109596;21345216;23221586;16255017;16162882;18203761;12355476;16960927;12915155;19224750;25201241;16947384;16884970;18260176;11961039;27113415;9826720;26315675;12709536;16785475;25708920;3718563",
"title": "Risk of Hospitalized Infection and Initiation of Abatacept Versus Tumor Necrosis Factor Inhibitors Among Patients With Rheumatoid Arthritis: A Propensity Score-Matched Cohort Study.",
"title_normalized": "risk of hospitalized infection and initiation of abatacept versus tumor necrosis factor inhibitors among patients with rheumatoid arthritis a propensity score matched cohort study"
} | [
{
"companynumb": "US-JNJFOC-20200140421",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
},
"drugadditional": null,
... |
{
"abstract": "Systemic karyomegaly is a distinct disorder characterized by progressive renal failure and enlarged, bizarre renal tubular epithelial cells. We report the first case of systemic karyomegaly with primary pulmonary presentation and present the first detailed characterization of the karyomegalic cells in lung tissue. A 33-year-old woman was evaluated for chronic and progressive restrictive lung disease, ultimately necessitating single-lung transplantation. Her post-transplant course was marked by graft dysfunction, respiratory decline and renal failure culminating in her death 97 days post-transplant. At autopsy, karyomegalic cells were identified in her kidneys, prompting a careful examination of her native lung and other tissue. Karyomegalic cells were identified in the alveolar epithelium and airway walls. Viral studies were negative. DNA ploidy studies revealed an abnormal ploidy status of the karyomegalic cells. The identification and characterization of systemic karyomegaly with symptomatic lung involvement expands the differential diagnosis for relatively young patients presenting with interstitial lung disease.",
"affiliations": "Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA.",
"authors": "Tagliente|Damian J|DJ|;Voss|Jesse S|JS|;Peters|Steve G|SG|;Aubry|Marie Christine|MC|;Cornell|Lynn D|LD|;Maleszewski|Joseph J|JJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0046-8177",
"issue": "45(1)",
"journal": "Human pathology",
"keywords": "Interstitial lung disease; Karyomegalic interstitial nephritis; Systemic karyomegaly",
"medline_ta": "Hum Pathol",
"mesh_terms": "D000328:Adult; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007674:Kidney Diseases; D017563:Lung Diseases, Interstitial; D016040:Lung Transplantation; D011003:Ploidies",
"nlm_unique_id": "9421547",
"other_id": null,
"pages": "180-4",
"pmc": null,
"pmid": "24047724",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Systemic karyomegaly with primary pulmonary presentation.",
"title_normalized": "systemic karyomegaly with primary pulmonary presentation"
} | [
{
"companynumb": "PHHY2015US028898",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"dru... |
{
"abstract": "We present the case of a 60-year-old woman with Brugada syndrome, permanent type 1 electrocardiographic pattern, who had previously received an implantable cardioverter-defibrillator. She suffered frequent syncopal episodes and multiple appropriate shocks (around five per month) due to polymorphic ventricular tachycardia/ventricular fibrillation, refractory to quinidine therapy. Combined epicardial and endocardial electroanatomical mapping was performed with a view to substrate ablation. An area of abnormal fractionated electrograms, lasting up to 370 ms and up to 216 ms after the end of the surface QRS, was identified in the epicardium in the lower anterior part of the right ventricular outflow tract. Extensive epicardial ablation of this area, which eliminated the fractionated electrograms, led to the disappearance of the Brugada electrocardiographic pattern six weeks after ablation. Despite discontinuation of quinidine, no further ventricular arrhythmias occurred during follow-up, which is still of short duration.",
"affiliations": "Unidade de Arritmologia Invasiva, Serviço de Cardiologia, Hospital de Santa Maria, Centro Hospitalar de Lisboa Norte, Lisboa, Portugal; Clínica Universitária de Cardiologia, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal. Electronic address: cortezdias@yahoo.com.;Unidade de Arritmologia Invasiva, Serviço de Cardiologia, Hospital de Santa Maria, Centro Hospitalar de Lisboa Norte, Lisboa, Portugal; Clínica Universitária de Cardiologia, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.;Unidade de Arritmologia Invasiva, Serviço de Cardiologia, Hospital de Santa Maria, Centro Hospitalar de Lisboa Norte, Lisboa, Portugal; Serviço de Cardiologia, Hospital Distrital de Santarém, Santarém, Portugal.;Unidade de Arritmologia Invasiva, Serviço de Cardiologia, Hospital de Santa Maria, Centro Hospitalar de Lisboa Norte, Lisboa, Portugal.;Unidade de Arritmologia Invasiva, Serviço de Cardiologia, Hospital de Santa Maria, Centro Hospitalar de Lisboa Norte, Lisboa, Portugal.;Unidade de Arritmologia Invasiva, Serviço de Cardiologia, Hospital de Santa Maria, Centro Hospitalar de Lisboa Norte, Lisboa, Portugal; Clínica Universitária de Cardiologia, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.;Unidade de Arritmologia Invasiva, Serviço de Cardiologia, Hospital de Santa Maria, Centro Hospitalar de Lisboa Norte, Lisboa, Portugal; Clínica Universitária de Cardiologia, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.",
"authors": "Cortez-Dias|Nuno|N|;Plácido|Rui|R|;Marta|Liliana|L|;Bernardes|Ana|A|;Sobral|Sílvia|S|;Carpinteiro|Luís|L|;de Sousa|João|J|",
"chemical_list": null,
"country": "Portugal",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0870-2551",
"issue": "33(5)",
"journal": "Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology",
"keywords": "Ablação epicárdica; Ablação por cateter; Brugada syndrome; Catheter ablation; Electrophysiology; Eletrofisiologia; Epicardial ablation; Mapeamento; Mapping; Síndrome de Brugada",
"medline_ta": "Rev Port Cardiol",
"mesh_terms": "D053840:Brugada Syndrome; D017115:Catheter Ablation; D005260:Female; D006801:Humans; D008875:Middle Aged; D010496:Pericardium; D014693:Ventricular Fibrillation",
"nlm_unique_id": "8710716",
"other_id": null,
"pages": "305.e1-7",
"pmc": null,
"pmid": "24931179",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Epicardial ablation for prevention of ventricular fibrillation in a patient with Brugada syndrome.",
"title_normalized": "epicardial ablation for prevention of ventricular fibrillation in a patient with brugada syndrome"
} | [
{
"companynumb": "PT-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-112075",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "QUINIDINE"
},
"druga... |
{
"abstract": "BACKGROUND\nPost-transplant focal segmental glomerulosclerosis (FSGS) is associated with renal allograft loss. Currently, optimal treatment remains controversial.\n\n\nMETHODS\nThe aim of our study was to examine the efficacy and safety of therapeutic plasma exchange (TPE), and rituximab (RTX), in the management of post-transplant FSGS. The treatment protocol consisted of RTX and monthly cycles of 5 plasma exchanges for 6 months. We treated 10 transplant recipients with biopsy-proven post-transplant FSGS. Lastly, we compared the studied group to a historic control group of nine patients with post-transplant FSGS.\n\n\nRESULTS\n9 out of 10 patients achieved remission after the conclusion of treatment (4 complete and 5 partial), while 1 patient did not respond to treatment. During the follow-up period, there was one graft loss and one patient died while in remission from unrelated complications. There was a significant reduction in mean uPCR between diagnosis (517.4 ± 524.2 mg/mmol) and last follow-up (87 ± 121.6 mg/mmol) in the patients with sustained remission (p = 0.026). There was no significant decline in eGFR in the eight relapse-free responders at the end of follow-up. (54.4 ± 16.7 from 49.8 ± 20.4 ml/min) (p = 0.6) An increased response rate to the combined TPE and RTX treatment was demonstrated, when compared to a historic control group of nine patients with post-transplant FSGS, as only five out of nine patients achieved remission (two complete and three partial) in that group.\n\n\nCONCLUSIONS\nIn this study, treatment with TPE and RTX appears to be safe, well tolerated and effective in the management of patients with post-transplant FSGS.",
"affiliations": "Imperial College Kidney and Transplant Centre, London, UK. k.koutroutsos@windowslive.com.;Imperial College Kidney and Transplant Centre, London, UK.;Department of Histopathology, Imperial Healthcare NHS Trust, London, UK.;Department of Histopathology, Imperial Healthcare NHS Trust, London, UK.;Department of Histopathology, Imperial Healthcare NHS Trust, London, UK.;Department of Histopathology, Imperial Healthcare NHS Trust, London, UK.;Imperial College Kidney and Transplant Centre, London, UK.;Imperial College Kidney and Transplant Centre, London, UK.;Imperial College Kidney and Transplant Centre, London, UK.",
"authors": "Koutroutsos|Konstantinos|K|http://orcid.org/0000-0002-2103-9823;Charif|Rawya|R|;Moran|Linda|L|;Moss|Jill|J|;Cook|Terence|T|;Roufosse|Candice|C|;Pusey|Charles|C|;Taube|David|D|;Loucaidou|Marina|M|",
"chemical_list": "D007155:Immunologic Factors; D000069283:Rituximab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10157-019-01690-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1342-1751",
"issue": "23(5)",
"journal": "Clinical and experimental nephrology",
"keywords": "Focal segmental glomerulosclerosis; Rituximab; Therapeutic plasma exchange; Transplantation",
"medline_ta": "Clin Exp Nephrol",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D007155:Immunologic Factors; D007668:Kidney; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010951:Plasma Exchange; D011183:Postoperative Complications; D012189:Retrospective Studies; D000069283:Rituximab; D055815:Young Adult",
"nlm_unique_id": "9709923",
"other_id": null,
"pages": "700-709",
"pmc": null,
"pmid": "30637591",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": "14750104;21068142;2980843;15888021;16939521;21030574;11158232;27797890;12110738;8259160;21486614;17181660;19715934;20637013;19875378;3051560;19344432;16303004;15866644;3558619;19153775;15071769;16672715;22174985;3719858;2652683;27043407;4966699;22187987;15659563;11044217;21804539;23842190;24061480;23465123;16045739;25273097;3489448;19020006;12427125;23138488;25500737",
"title": "Successful management of post-transplant focal segmental glomerulosclerosis with therapeutic plasma exchange and rituximab.",
"title_normalized": "successful management of post transplant focal segmental glomerulosclerosis with therapeutic plasma exchange and rituximab"
} | [
{
"companynumb": "GB-ROCHE-2254733",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"druga... |
{
"abstract": "Primary Epstein-Barr virus infection in children typically presents as infectious mononucleosis and in immunocompetent individuals severe pneumonitis proves to be a rare complication. Chronic active Epstein-Barr virus infection (CAEBV) is associated with multiple life-threatening conditions, including interstitial lung disease with fibrosis and lymphoid and lymphohistiocytic infiltrations. We report on a pediatric patient in whom CAEBV resulted in severe pneumopathy with a fatal outcome.",
"affiliations": "ola@malwa.com.pl.",
"authors": "Szczawińska-Popłonyk|Aleksandra|A|;Jończyk-Potoczna|Katarzyna|K|;Ossowska|Lidia|L|;Bręborowicz|Anna|A|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5603/PiAP.2014.0046",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0867-7077",
"issue": "82(4)",
"journal": "Pneumonologia i alergologia polska",
"keywords": null,
"medline_ta": "Pneumonol Alergol Pol",
"mesh_terms": "D000293:Adolescent; D002908:Chronic Disease; D020031:Epstein-Barr Virus Infections; D017809:Fatal Outcome; D006801:Humans; D007153:Immunologic Deficiency Syndromes; D008171:Lung Diseases; D008297:Male",
"nlm_unique_id": "9302892",
"other_id": null,
"pages": "364-7",
"pmc": null,
"pmid": "24964240",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal pulmonary complications in an immunodeficient child with chronic active Epstein-Barr virus infection.",
"title_normalized": "fatal pulmonary complications in an immunodeficient child with chronic active epstein barr virus infection"
} | [
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"companynumb": "PL-BAXTER-2014BAX051498",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
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"drugadditional": nu... |
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"abstract": "Coagulopathy of coronavirus disease 2019 is largely described as hypercoagulability, yet both thrombotic and hemorrhagic complications occur. Although therapeutic and prophylactic anticoagulant interventions have been recommended, empiric use of antifactor medications (heparin/enoxaparin) may result in hemorrhagic complications, including death. Furthermore, traditional (antifactor) anticoagulation does not address the impact of overactive platelets in coronavirus disease 2019. The primary aim was to evaluate if algorithm-guided thromboelastography with platelet mapping could better characterize an individual's coronavirus disease 2019-relatedcoagulopathic state and, secondarily, improve outcomes.\nCoronavirus disease 2019 patients (n = 100), receiving thromboelastography with platelet mapping assay upon admission to an 800-bed tertiary-care hospital, were followed prospectively by a hospital-based thromboelastography team. Treating clinicians were provided with the option of using a pre-established algorithm for anticoagulation, including follow-up thromboelastography with platelet mapping assays. Two groups evolved: 1) patients managed by thromboelastography with platelet mapping algorithm (algorithm-guided-thromboelastography); 2) those treated without thromboelastography with platelet mapping protocols (non-algorithm-guided). Outcomes included thrombotic/hemorrhagic complications, pulmonary failure, need for mechanical ventilation, acute kidney injury, dialysis requirement, and nonsurvival.\nStandard-of-care therapy with or without algorithm-guided-thromboelastography support.\nAlthough d-dimer, C-reactive protein, and ferritin were elevated significantly in critically ill (nonsurvivors, acute kidney injury, pulmonary failure), they did not distinguish between coagulopathic and noncoagulopathic patients. Platelet hyperactivity (maximum amplitude-arachidonic acid/adenosine diphosphate > 50 min), with or without thrombocytosis, was associated with thrombotic/ischemic complications, whereas severe thrombocytopenia (platelet count < 100,000/μL) was uniformly fatal. Hemorrhagic complications were observed with decreased factor activity (reaction time > 8 min). Non-algorithm-guided patients had increased risk for subsequent mechanical ventilation (relative risk = 10.9; p < 0.0001), acute kidney injury (relative risk = 2.3; p = 0.0017), dialysis (relative risk = 7.8; p < 0.0001), and death (relative risk = 7.7; p < 0.0001), with 17 of 28 non-algorithm-guided patients (60.7%) dying versus four algorithm-guided-thromboelastography patients (5.6%) (p < 0.0001). Thromboelastography with platelet mapping-guided antiplatelet treatment decreased mortality 82% (p = 0.0002), whereas non-algorithm-guided (compared with algorithm-guided-thromboelastography) use of antifactor therapy (heparin/enoxaparin) resulted in 10.3-fold increased mortality risk (p = 0.0001).\nThromboelastography with platelet mapping better characterizes the spectrum of coronavirus disease 2019 coagulation-related abnormalities and may guide more tailored, patient-specific therapies in those infected with coronavirus disease 2019.",
"affiliations": "Division of Transplantation, Memorial Regional Hospital, Hollywood, FL.;Emergency Department, Memorial Regional Hospital, Hollywood, FL.;Pharmacy, Memorial Regional Hospital, Hollywood, FL.;Division of Trauma/Acute Care/Critical Care Surgery, Memorial Regional Hospital, Hollywood, FL.;Division of Transplantation, Memorial Regional Hospital, Hollywood, FL.;Department of Surgery, Division of Trauma/Acute Care/Critical Care Surgery, Bariatric Surgery, University of Texas Southwestern Medical Center, Dallas, TX.;Memorial Hospital West, Pembroke Pines, FL.;Division of Trauma/Acute Care/Critical Care Surgery, Memorial Regional Hospital, Hollywood, FL.;Division of Transplantation, Memorial Regional Hospital, Hollywood, FL.;Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL.;Emergency Department, Memorial Regional Hospital, Hollywood, FL.;Pharmacy, Memorial Regional Hospital, Hollywood, FL.;Division of Trauma/Acute Care/Critical Care Surgery, Memorial Regional Hospital, Hollywood, FL.;Division of Trauma/Acute Care/Critical Care Surgery, Memorial Regional Hospital, Hollywood, FL.;Division of Transplantation, Memorial Regional Hospital, Hollywood, FL.;Division of Transplantation, Memorial Regional Hospital, Hollywood, FL.;Division of Transplantation, Memorial Regional Hospital, Hollywood, FL.;Division of Trauma/Acute Care/Critical Care Surgery, Memorial Regional Hospital, Hollywood, FL.;Emergency Department, Memorial Regional Hospital, Hollywood, FL.;Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI.;Metropolitan Emergency Medical Services Medical Directors Alliance, Dallas, TX.",
"authors": "Hranjec|Tjasa|T|;Estreicher|Michael|M|;Rogers|Bradley|B|;Kohler|Lisa|L|;Solomon|Rachele|R|;Hennessy|Sara|S|;Cibulas|Megan|M|;Hurst|Deborah|D|;Hegazy|Mohamed|M|;Lee|Jieun|J|;Perez|Donny|D|;Doctor|Norman|N|;Kiffin|Chauniqua|C|;Pigneri|Danielle|D|;LaGuardia|Heather|H|;Shaw|Kathryn|K|;Arenas|Juan|J|;Rosenthal|Andrew|A|;Katz|Randy S|RS|;Sawyer|Robert G|RG|;Pepe|Paul E|PE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/CCE.0000000000000287",
"fulltext": "\n==== Front\nCrit Care Explor\nCrit Care Explor\nCC9\nCritical Care Explorations\n2639-8028 Lippincott Williams & Wilkins Hagerstown, MD \n\n00030\n10.1097/CCE.0000000000000287\nObservational Study\nIntegral Use of Thromboelastography With Platelet Mapping to Guide Appropriate Treatment, Avoid Complications, and Improve Survival of Patients With Coronavirus Disease 2019–Related Coagulopathy\nHranjec Tjasa MD, FACS12 Estreicher Michael MD3 Rogers ; Bradley PharmD4 Kohler Lisa PharmD2 Solomon ; Rachele MPH1 Hennessy ; Sara MD, FACS5 Cibulas ; Megan MD6 Hurst ; Deborah RN2 Hegazy ; Mohamed MD1 Lee Jieun BS7 Perez ; Donny DO3 Doctor ; Norman PharmD4 Kiffin Chauniqua MD, FACS2 Pigneri Danielle MD2 LaGuardia ; Heather MD1 Shaw ; Kathryn MD1 Arenas Juan MD, FACS1 Rosenthal Andrew MD, FACS2 Katz ; Randy S. DO3 Sawyer ; Robert G. MD, FACS8 Pepe ;Paul E. MD, MPH910 1 Division of Transplantation, Memorial Regional Hospital, Hollywood, FL.\n2 Division of Trauma/Acute Care/Critical Care Surgery, Memorial Regional Hospital, Hollywood, FL.\n3 Emergency Department, Memorial Regional Hospital, Hollywood, FL.\n4 Pharmacy, Memorial Regional Hospital, Hollywood, FL.\n5 Department of Surgery, Division of Trauma/Acute Care/Critical Care Surgery, Bariatric Surgery, University of Texas Southwestern Medical Center, Dallas, TX.\n6 Memorial Hospital West, Pembroke Pines, FL.\n7 Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL.\n8 Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI.\n9 Metropolitan Emergency Medical Services Medical Directors Alliance, Dallas, TX.\n10 Department of Management, Policy and Community Health, University of Texas Health Sciences Center, School of Public Health, Houston, TX.\nFor information regarding this article, E-mail: tjasa.hranjec@gmail.com\n21 12 2020 \n12 2020 \n2 12 e0287Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.2020This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Objectives:\nCoagulopathy of coronavirus disease 2019 is largely described as hypercoagulability, yet both thrombotic and hemorrhagic complications occur. Although therapeutic and prophylactic anticoagulant interventions have been recommended, empiric use of antifactor medications (heparin/enoxaparin) may result in hemorrhagic complications, including death. Furthermore, traditional (antifactor) anticoagulation does not address the impact of overactive platelets in coronavirus disease 2019. The primary aim was to evaluate if algorithm-guided thromboelastography with platelet mapping could better characterize an individual’s coronavirus disease 2019-relatedcoagulopathic state and, secondarily, improve outcomes.\n\nDesign, Setting, and Patients:\nCoronavirus disease 2019 patients (n = 100), receiving thromboelastography with platelet mapping assay upon admission to an 800-bed tertiary-care hospital, were followed prospectively by a hospital-based thromboelastography team. Treating clinicians were provided with the option of using a pre-established algorithm for anticoagulation, including follow-up thromboelastography with platelet mapping assays. Two groups evolved: 1) patients managed by thromboelastography with platelet mapping algorithm (algorithm-guided-thromboelastography); 2) those treated without thromboelastography with platelet mapping protocols (non-algorithm-guided). Outcomes included thrombotic/hemorrhagic complications, pulmonary failure, need for mechanical ventilation, acute kidney injury, dialysis requirement, and nonsurvival.\n\nInterventions:\nStandard-of-care therapy with or without algorithm-guided-thromboelastography support.\n\nMeasurements and Main Results:\nAlthough d-dimer, C-reactive protein, and ferritin were elevated significantly in critically ill (nonsurvivors, acute kidney injury, pulmonary failure), they did not distinguish between coagulopathic and noncoagulopathic patients. Platelet hyperactivity (maximum amplitude-arachidonic acid/adenosine diphosphate > 50 min), with or without thrombocytosis, was associated with thrombotic/ischemic complications, whereas severe thrombocytopenia (platelet count < 100,000/μL) was uniformly fatal. Hemorrhagic complications were observed with decreased factor activity (reaction time > 8 min). Non-algorithm-guided patients had increased risk for subsequent mechanical ventilation (relative risk = 10.9; p < 0.0001), acute kidney injury (relative risk = 2.3; p = 0.0017), dialysis (relative risk = 7.8; p < 0.0001), and death (relative risk = 7.7; p < 0.0001), with 17 of 28 non-algorithm-guided patients (60.7%) dying versus four algorithm-guided-thromboelastography patients (5.6%) (p < 0.0001). Thromboelastography with platelet mapping–guided antiplatelet treatment decreased mortality 82% (p = 0.0002), whereas non-algorithm-guided (compared with algorithm-guided-thromboelastography) use of antifactor therapy (heparin/enoxaparin) resulted in 10.3-fold increased mortality risk (p = 0.0001).\n\nConclusions:\nThromboelastography with platelet mapping better characterizes the spectrum of coronavirus disease 2019 coagulation-related abnormalities and may guide more tailored, patient-specific therapies in those infected with coronavirus disease 2019.\n\nCOVID-19 anticoagulationCOVID-19 coagulopathyplatelet hyperactivityplatelet mappingTEG-PMthromboelastrographyOPEN-ACCESSTRUE\n==== Body\nSignificant infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may lead to development of coagulopathy, most typically a hypercoagulable state (1). This concern has led to empiric or pre-emptive treatment with anticoagulants (1). However, in addition to thrombotic conditions, coronavirus disease 2019 (COVID-19) patients may develop hemorrhagic complications, which have been underrecognized or inadequately emphasized in prior studies (1–5). Although most autopsy reports describe a high frequency of venous/arterial thromboemboli or microthrombi associated with pulmonary failure (PF) and acute kidney injury (AKI), some patients do present with manifestations of cerebrovascular, gastrointestinal, and/or pulmonary bleeding (3–7). Under these circumstances, incorrect anticoagulation therapy might be harmful. Early characterization of patient-specific coagulopathy may not only avoid iatrogenic incidents but may also improve outcomes, especially when considering that COVID-19 coagulopathy can insidiously lead to respiratory and renal complications, disseminated intravascular coagulation (DIC), and death (8, 9).\n\nMarked elevation in coagulation-related markers such as d-dimer, C-reactive protein (CRP), and fibrin degradation products (FDPs) are typically found among those with isolated thromboses, encouraging a similar diagnostic approach when evaluating coagulopathic complications seen in patients with COVID-19 (9–11). However, d-dimer, CRP, and FDP can also indicate a marked inflammatory state and, together with conventional coagulation tests (CCTs)—prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR), do not reflect the complexities of COVID-19 coagulopathy (8, 12, 13). Most importantly, these laboratory variables do not characterize the significant and multifaceted platelet activity abnormalities of COVID-19 (14, 15). Studies have now identified altered platelet gene expression leading to increased platelet aggregation and hypercoagulability (14, 15). Overall, the various components of COVID-19 coagulopathy, thrombotic or hemorrhagic, still need to be characterized better, and, in turn, COVID-19 coagulopathy remains a complex diagnostic and treatment challenge.\n\nThromboelastography (TEG), being a whole blood assay, is a more inclusive technology that evaluates the overall contribution of blood cells, platelets, and plasma during clot formation by mimicking in vivo coagulation processes (16–18). TEG can measure profound hemostatic derangements, and it identifies key dysfunctional components, from the initiation phase of blood clotting to the fibrinolysis phase (1, 12, 13, 16–21). Accordingly, TEG could be considered another useful tool in the current pandemic (1, 18, 21). Moreover, recognizing the frequent platelet abnormalities in COVID-19, platelet mapping (PM) can be added as an adjunct to TEG, particularly as platelet aggregation and microthrombi formation have now become key clinical concerns (14). However, clinical data are lacking with regard to characterization of platelet dysfunction and particularly when using TEG with platelet mapping (TEG-PM). Considering its potential advantages, TEG-PM might be able to better guide treatment of patients with identified platelet dysfunction (22, 23).\n\nMost important, it is not known if TEG-PM can better identify an individual’s coagulopathic state and, in turn, better guide treatment. We hypothesized that: 1) TEG-PM could become a facile tool for improved characterization of patient-specific COVID-19 coagulopathy, 2) TEG-PM would more accurately delineate the platelet-related contribution to any COVID-19 coagulopathy, and 3) TEG-PM-guided therapy intended to target patient-specific dysfunctional blood components will not only help to avoid iatrogenic complications but also likely lead to improved patient outcomes.\n\nMETHODS\nParticipants and Design\nOver a 5-month period during the SARS-CoV-2 pandemic, patients (age 18 years or older) admitted to an 800-bed tertiary care facility with a confirmed diagnosis of COVID-19 were entered into the study. Per routine, in addition to the standard work-up, during the emergency department evaluation, patients with hypoxemia (oxygen saturation < 92% on room air) received coagulopathy evaluation using TEG-PM. The hospital-based Thromboelastography Task Force (TTF) prospectively followed 100 patients meeting these criteria to assist with the application and interpretation of initial and on-going TEG findings. TTF members provided treating clinicians with the option of using pre-established (pre-COVID) TEG-PM protocols/algorithms for managing coagulopathy, both thrombotic and hemorrhagic. As a part of the TEG-PM algorithm, TEG-PM was repeated every 48–72 hours or with any significant clinical deterioration (e.g. worsening hypoxemia, cardiac arrhythmia, escalation of care). Although the TTF could be consulted for TEG interpretation and anticoagulant suggestions, the primary team made all final therapeutic decisions.\n\nAll study patients were followed and observed throughout their hospital course to evaluate the following: 1) the accuracy of TEG readings as interpreted or reported by the attending clinician of record, 2) any noted justifications for medication adjustments, and 3) relevant laboratory and clinical data with eventual outcomes. Patient charts were also abstracted and reviewed for demographics, medical history, hospital course, and imaging interpretations, both prospectively and in retrospective fashion, when necessary to complete the data collection. Inflammatory markers as well as at-home or in-hospital use of anticoagulants were noted, including antifactor (e.g., warfarin, heparin, enoxaparin, argatroban, or rivaroxaban) and antiplatelet medications (e.g., aspirin, clopidogrel, or ticagrelor).\n\nThe study was approved by the Memorial Healthcare Institutional Review Board with waiver of consent.\n\nInterventions\nThe hospital’s multidisciplinary TTF team had been an established entity prior to the COVID-19 crisis. Comprised of cross-specialty physicians, pharmacists, laboratory staff, and registered nurses, the team had constructed both hypo- (Appendix 1, Supplemental Digital Content 1, http://links.lww.com/CCX/A430) and hypercoagulable (Fig. 1) TEG treatment algorithms for various applicable conditions in order to aid treating clinicians in choosing appropriate anticoagulant therapies. When patients were identified as medication nonresponders, alternate treatments were suggested by the algorithm in order to create the most comprehensive, individualized approach to treating patients’ hypercoagulability. Per routine, most patients received an initial prophylactic dose of enoxaparin or heparin at the time of admission.\n\nFigure 1. Thromboelastography (TEG)–guided venous thromboembolism (VTE) prophylaxis in a setting of a hypercoagulable TEG. AA = arachidonic acid, ADP = adenosine phosphate, COVID-19 = coronavirus disease 2019, MA = maximum amplitude, R = reaction time, SQ = subcutaneous.\n\nIdentification of Coagulopathy Based on TEG-PM\nThe processing device used was TEG 5000 Thrombelastograph Hemostasis Analyzer (manufactured by Haemonetics, Boston, MA), with PM employed to specifically assess activation of the platelet’s cyclooxygenase 1 (maximum amplitude [MA]-arachidonic acid [AA]) and P2Y12 pathways (MA-adenosine diphosphate [ADP]). Additional Methodological Details (Supplemental Digital Content 2, http://links.lww.com/CCX/A429), which contain specific information regarding hyper-, hypo-, and normocoagulable TEG variables, are appended as an online supplement (24–26).\n\nFollow-up TEG-PM assays were clinician ordered and collected every 48–72 hours when possible. The treating clinicians could contact the TTF at any time to assist in TEG interpretations and for guidance with the treatment algorithm, taking into consideration that coagulation status can be an ever-changing dynamic, often varying with patient’s clinical condition. Again, final diagnostic and therapeutic decisions, including the ordering and use of the TEG algorithm, were made by the primary treating clinicians.\n\nCategorization of Patients\nAlthough many clinicians used the TEG algorithm and consulted the TTF for on-going TEG support, not all practitioners chose to follow the proscribed TEG-guided approach. As a result, two groups evolved allowing for a de facto comparative analysis: (1) the algorithm-guided (AG)-TEG group which included patients managed by TEG algorithm and (2) the non-AG group which was managed without those protocols. Patients in the non-AG group received prophylaxis or treatment doses of anticoagulants (heparin, enoxaparin and other antifactor medications) based on clinical judgment. Nevertheless, once identified by the initial TEG in the emergency department, all 100 patients were followed to discharge.\n\nMain Outcomes Analyzed\nIn addition to the demographic, historical, TEG-PM, and clinical laboratory data, patients were monitored for therapies initiated, their general clinical course, and significant clinical decision-making. Specific study outcomes included rates of PF and need for mechanical ventilation (MV), ICU admission and length of stay (LOS), AKI and need for dialysis, and the rates of survival/mortality.\n\nStatistical Analysis\nUnivariate comparison was performed using Student t test and Wilcoxon rank sum test for continuous variables. Paired continuous data was analyzed using paired t test. Categorical data were evaluated using chi-square or Fisher exact test, depending on the sample size. Relative risk of mortality was also calculated. All statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC).\n\nRESULTS\nAmong the 100 patients studied, ages ranged from 32 to 91 years, and 67% were male, 46.5% African American, 29.3% Hispanic. At presentation, 78% had fever, 79% respiratory symptoms (cough and/or dyspnea), and 21% gastrointestinal symptoms (abdominal pain, diarrhea, nausea, vomiting, constipation). Past medical history included hypertension (55%), diabetes (38%), hyperlipidemia (33%), remote history of smoking (17%), chronic obstructive pulmonary disease or asthma (9%), and smoking prior to hospitalization (2%). Following admission, one third of all patients were transferred to the ICU for closer monitoring, and 37% were diagnosed with AKI, 8% required dialysis, whereas 21% were intubated and ultimately succumbed to COVID-19.\n\nOn initial presentation, TEG-PM was balanced (e.g. contained normal variables) in 38% of the patients; however, TEG factors fluctuated throughout the hospital course paralleling clinical progression and medication adjustments. Ultimately, 72 patients were categorized as having followed TEG algorithms (AG-TEG group), whereas 28 patients were included in the non-AG group for whom anticoagulation was managed independent of TEG variables.\n\nTable 1 provides comparison demographics for AG-TEG versus non-AG patients. Overall, the two groups were comparable. The AG-TEG group had more male patients and fewer patients with hypertension history, but there were no significant differences in home use of antifactor and/or antiplatelet anticoagulants or the number of non-AG and AG-TEG patients who required initial/early ICU (within 48 hours) admission or MV (Table 1).\n\nTABLE 1. Demographics of Patients With Algorithm-Guided (AG)-Thromboelastography and Non-AG-Guided Care\n\nComparative Characteristics\tNon-AG (n = 28)\t%\tAG-TEG (n = 72)\t%\t\nAge\t\t\t\t\t\n Mean ± se\t64.4 ± 2.9\t\t59.8 ± 1.8\t\t\n Median (IQR)\t66 (61–77)\t\t60 (46–70)\t\t\nGender, n\t\t\t\t\t\n Male\t13\t46.4\t54\t75.0\t\nRace, n\t\t\t\t\t\n Caucasian\t6\t22.2\t14\t19.4\t\n African American\t14\t51.9\t32\t44.4\t\n Hispanic\t5\t18.5\t24\t33.3\t\n Asian\t1\t3.7\t1\t1.4\t\n Native American\t1\t3.7\t1\t1.4\t\nMedical history\t\t\t\t\t\n Body mass index\t\t\t\t\t\n Mean ± se\t33.9 ± 1.6\t\t30.9 ± 1.0\t\t\n Median (IQR)\t32.6 (30–36)\t\t28.8 (25–34)\t\t\n Coronary artery disease/congestive heart failure\t3\t10.7\t11\t15.3\t\n Myocardial infarction\t0\t0.0\t6\t6.9\t\n Cardiac arrhythmia\t4\t14.3\t5\t6.9\t\n Hyperlipidemia\t7\t25.0\t26\t36.1\t\n Hypertension\t20\t71.4\t35\t48.6\t\n Diabetes mellitus\t15\t53.6\t23\t31.9\t\n Asthma/chronic obstructive pulmonary disease\t2\t7.1\t7\t9.7\t\n Smoking (current)\t1\t3.6\t1\t1.4\t\n Smoking (past)\t6\t21.4\t11\t15.3\t\n Malignancy\t3\t10.7\t5\t6.9\t\n Chronic renal disease\t5\t17.9\t8\t11.1\t\n Hemodialysis\t3\t10.7\t4\t5.6\t\n Deep venous thrombosis/pulmonary embolus\t1\t3.6\t4\t5.6\t\n Steroids/immunosuppression\t0\t0.0\t3\t4.2\t\nHome anticoagulant use\t8\t28.6\t21\t29.3\t\n Full anticoagulant (antifactor)\t3\t10.7\t4\t5.6\t\n Antiplatelet\t6\t21.4\t18\t25.0\t\nInitial admission\t\t\t\t\t\n Initial noncoagulopathic TEG\t8\t28.6\t30\t41.7\t\n ICU (within 24 hr)\t7\t25.0\t15\t20.8\t\n Intubated (within 24 hr)\t2\t7.1\t1\t1.4\t\nAG = algorithm-guided, IQR = interquartile range, TEG = thromboelastography.\n\nFull anticoagulant (antifactor) includes medications like coumadin, apixaban, enoxaparin.\n\nInflammatory markers were associated with clinical deterioration, PF, AKI, and death (data not shown). d-dimer was significantly higher in non-AG patients, but ferritin and CRP were not significantly different between the two groups (Table 2). These markers reached peak measurements of varying levels within 1–4 days of maximal respiratory requirements, but they did not differentiate between coagulopathic and noncoagulopathic patients, making them less clinically applicable regarding the COVID-19 coagulation status.\n\nTABLE 2. Outcomes of Patients With Algorithm-Guided (AG)-Thromboelastography and Non-AG-Guided Care\n\nKey Findings\tNon-AG (n = 28)\t%\tAG-Thromboelastography (n = 72)\t%\tp\t\nHospital course\t\n Inflammatory markers\t\t\t\t\t\t\n d-dimer\t\t\t\t\t\t\n Mean ± se\t12.0 ± 2.0\t\t5.4 ± 0.9\t\t0.0012\t\n Median (IQR)\t8.7 (4–19)\t\t1.8 (1–6)\t\t0.0010\t\n C-reactive protein\t\t\t\t\t\t\n Mean ± se\t16.7 ± 1.3\t\t37.6 ± 23.4\t\t0.3755\t\n Median (IQR)\t16.5 (12–20)\t\t13.6 (8–18)\t\t0.0938\t\n Ferritin\t\t\t\t\t\t\n Mean ± se\t2,946.6 ± 710.6\t\t1,579.9 ± 257.8\t\t0.0797\t\n Median (IQR)\t1,728 (752–3,519)\t\t1,143 (624–1,934)\t\t0.0915\t\n Platelets\t\t\t\t\t\t\n Mean ± se\t393.2 ± 33.3\t\t404.0 ± 20.5\t\t0.7819\t\n Median (IQR)\t390.0 (277–470)\t\t372.5 (288–519)\t\t0.8572\t\n Treatment\t\t\t\t\t\t\n Remdesivir\t12\t42.9\t34\t47.2\t0.6941\t\n Tocilizumab\t10\t35.7\t18\t25.0\t0.2840\t\n Steroids\t23\t85.2\t39\t54.2\t0.0045\t\n Convalescent plasma\t13\t46.4\t25\t34.7\t0.2789\t\n Hospital (anticoagulant) administration\t\t\t\t\t\t\n Full anticoagulant (antifactor)\t19\t70.4\t26\t36.1\t0.0023\t\n Nonsurvivors\t12\t42.9\t3\t4.2\t< 0.0001\t\n Antiplatelet\t11\t39.3\t59\t81.9\t< 0.0001\t\n Nonsurvivors\t8\t28.6\t3\t4.3\t0.0005\t\nOutcomes\t\n Nonsurvivors\t17\t60.7\t4\t5.6\t< 0.0001\t\n Overall hospitalization\t\t\t\t\t\t\n ICU admission (all)\t19\t67.9\t21\t29.2\t0.0004\t\n Intubated (all)\t17\t60.7\t4\t5.6\t< 0.0001\t\n ICU LOS\t\t\t\t\t\t\n Mean ± se\t11.0 ± 3.3\t\t3.7 ± 1.1\t\t0.0456\t\n Median (IQR)\t8 (0–14)\t\t0 (0–7)\t\t0.0346\t\n Hospital LOS\t\t\t\t\t\t\n Mean ± se\t23.2 ± 3.1\t\t14.2 ± 1.3\t\t0.0122\t\n Median (IQR)\t18 (12–28)\t\t10.5 (6–17)\t\t0.0016\t\n Acute kidney injury\t17\t68.0\t20\t29.4\t0.0007\t\n Hemodialysis\t6\t22.2\t2\t2.8\t0.0017\t\nAG = algorithm-guided, IQR = interquartile range, LOS = length of stay.\n\nAntifactor (heparin, enoxaparin); antiplatelet (aspirin, clopidogrel, ticagrelor).\n\nMain Outcomes\nThe non-AG patients had prolonged LOS, increased frequency of eventual ICU admission, PF, MV, AKI, and dialysis. Compared with only four AG-TEG patients, 17 non-AG patients died (p < 0.0001) (Table 2). The non-AG group had a nearly 11-fold increased risk for MV (p < 0.0001), 2.3 for AKI (p = 0.0017), 7.8 for dialysis (p < 0.0001), and a 7.7-fold increased risk of death (p < 0.0001).\n\nComplications\nTable 3 demonstrates 18 representative coagulopathic TEG-PM assays from both groups, anticoagulation regimens used in those individuals and their associated complications (e.g. major bleeding, thrombosis, death). Ischemic complications were typically associated with platelet hyperactivity (MA-AA/ADP > 50 mm), even sometimes in the face of antiplatelet administration (medication nonresponders). Mild increases in MA-AA/ADP (> 60 mm) were associated with increased need for MV, whereas isolated thrombotic complications such as deep vein thrombosis (DVT), venothrombo-emboli (VTE), or ischemic strokes were seen with MA-AA/ADP greater than 70 mm. Platelets were often noted to rise during the time of clinical deterioration and worsening hypoxemia. Extreme thrombocytosis (> 500,000/µL) was not uniformly associated with worse outcomes, but rather, complications did parallel platelet hyperactivity (MA-AA/ADP > 50 mm).\n\nTABLE 3. Thromboelastography Variables in Patients With Severe Thrombotic and Hemorrhagic Complications, as Well as Death\n\nPatient\tComplications\tThromboelastography With Platelet Mapping Variables\tInflammatory Markers\tAnticoagulation Medications\t\nPlatelet Count (100,000/μL)\td-dimer\tC-Reactive Protein\tFerritin\tAntifactor\tAntiplatelet\t\nReaction Time\tAlpha Angle\tMA\tMA-Arachidonic Acid\tMA-Adenosine Diphosphate\tActivator F\tPercent of Lysis at 30 min\t\n\tIschemic complications\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nA\tPE\t5.4\t66.3\t64\t65\t69.0\t10.9\t3\t211\t27.1\t1.68\t316\tNone\tNone\t\nB\tPE\t5.5\t72.7\t76\t74\t73.7\t22.0\t4\t364\t> 30\t20.7\t240\tRivaroxaban 15 mg\tNone\t\nC\tPE\t4.8\t78.7\t77\t81\t79.3\t23.9\t10\t457\t1.03\t4.83\tNA\tNone\tNone\t\nD\tPE\t3.4\t72.0\t70\t77\t75.9\t28.0\t0\t434\t5.9\t6.45\t1,245\tEnoxaparin 60 mg BID\tNone\t\nE\tPE and bilateral deep vein thrombosis\t3.8\t78.5\t76\t78\t78.6\t24.0\t1\t306\t5.61\t11.4\t387\tEnoxaparin 60 mg BID\tNone\t\nF\tIschemic CVA\t3.2\t79.2\t79\t75\t81.4\tNA\t0\t587\t1.5\t1.31\t1,088\tNone\tAspirin 81 mg\t\nG\tIschemic CVA\t4.8\t77.0\t73\t73\t50.6\t19.0\t2\t535\tNA\tNA\t608\tNone\tClopidogrel 75 mg\t\nHa\tHemorrhagic, ischemic CVA\t9.8\t78.3\t86\t87\t87.3\t42.8\t0\t528\t2.8\t12.3\t787\tNone\tAspirin 81 mg/clopidogrel 75 mg\t\n\tBleeding complications\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nIa\tGl bleed, death\t9.2\t63.0\t62\t49\t46.8\t33.8\t0\t43\t> 30\t11.1\t1,054\tNone\tNone\t\nHa\tHemorrhagic, ischemic CVA\t9.8\t78.3\t86\t87\t87.3\t42.8\t0\t528\t2.8\t12.3\t787\tNone\tAspirin 81 mg/clopidogrel 75 mg\t\n\tDeath\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nIa\tGI bleed, death\t9.2\t63.0\t62\t49\t46.8\t33.8\t0\t43\t> 30\t11.1\t1,054\tNone\tNone\t\nJ\tDeath\t12.6\t53.4\t52\t10\t47.2\t7.0\t0\t162\t4.76\t< 0.29\t608\tEnoxaparin 100 BID\tNone\t\nK\tDeath\t40.5\t4.2\t10\t35\t43.3\t10.0\t0\t93\t> 30\t20.6\t752\tEnoxaparin 30 QD\tNone\t\nL\tDeath\t21.6\t17.3\t39\t31\t28.0\t27.3\t0\t128\t4.85\t9.49\t826\tEnoxaparin 40 BID\tAspirin 81 mg\t\nM\tDeath\t5.8\t78.3\t82\t43.1\t48.0\t40\t19\t469\t21.6\t8.7\t1,728\tEnoxaparin 90 BID\tAspirin 81 mg\t\nN\tDeath\t3.7\t77.2\t76\t53\t71.1\t25\t0\t273\t4.1\t5.9\t2,078\tHeparin 5,000 BID\tNone\t\nO\tDeath\t4.1\t76.2\t72\t56\t71.7\t31\t0\t48\t4\t9\tNA\tEnoxaparin 30 BID\tNone\t\nP\tDeath\t> 50\tNA\tNA\tNA\tNA\tNA\t100\t489\t1.97\t6.32\t700.5\tEnoxaparin 70 BID\tAspirin 81 mg\t\nR\tDeath\t10.5\t48.6\t60\t51\t46.7\t27\t0\t61\t0.76\t9.17\t1,173\tEnoxaparin 100 BID\tClopidogrel 75 mg\t\nQ\tDeath\t17.9\t61.3\t50\t11.0\t11.8\t11\t43\t111\t8.8\t3.8\t16,500\tEnoxaparin 60 QD\tAspirin 81 mg\t\nBID = twice daily, CVA = cerebrovascular accident, GI = gastrointestinal, MA = maximum amplitude, mg = miligrams, NA = not available, PE = pulmonary embolus, QD = once daily.\n\naPatients H and I are listed in two categories.\n\nBleeding complications were related to problems with clot initiation (reaction time [R] > 8 min), often in the setting of full antifactor anticoagulation. When prolonged R was combined with severe platelet hyperactivity (MA-AA/ADP > 80 mm), both ischemic and hemorrhagic complications cooccurred (Table 3, Patient F). However, a minimal increase in platelet function (MA-AA/ADP 50–60 mm) could also be balanced through decreased factor activity (R > 7), preventing complications.\n\nFor nonsurvivors, irreversible thrombocytopenia (< 100,000/µL) was an unmistakable sign of deterioration/death (Table 3, Patients I, K, R). When TEG variables were outside of their physiologic norm, death was more likely to occur (R > 10 min; percentage of lysis at 30 min [LY30] > 10%). Prolonged R (Table 3, Patients J, K, L, P, R, Q) or high LY30 (Table 3, Patients M, P, Q) denoted those with severe “hypocoagulability”. Conversely, uncorrected “hypercoagulability” of Patient N with persistently overactive platelets (MA-AA > 70 mm and ADP > 50 mm), early clot initiation (R < 4.5 min), and high activator F was also associated with patient demise.\n\nThromboelastography-Guided Anticoagulation\nAmong the 72 patients, who received TEG-guided anticoagulation (antifactor or antiplatelet) management, TEG-PM was typically repeated every 48–72 hours (90% of the time). Correction of TEG variables to R ~6 min and MA-AA/ADP less than 40–55 mm was associated with greatly improved survival, decreased rates of ICU admission, MV, and AKI (Table 2). In addition to proper characterization of coagulopathy, TEG-PM frequently identified antiplatelet nonresponders, requiring dose increase or substitution of medications. Overall, use of TEG-guided antiplatelet medications decreased mortality by 82% (p = 0.0002).\n\nPatients in the non-AG treatment group were more likely to have received full dose antifactor/anticoagulation with heparin or enoxaparin (Table 2). A total of 45 patients (both groups) received full (antifactor) anticoagulation; AG-TEG group followed TEG protocols for escalation and de-escalation of antifactor anticoagulation. Of the nonsurvivors, 12 (42.9%) were in the non-AG treatment group and three (4.2%) in the AG-TEG group, p < 0.0001. Accordingly, the non-AG use of antifactor treatment, without adjustments based on R, was associated with 10.3 times increased risk of mortality (p = 0.0001).\n\nA total of 10 patients with representative TEG-PM, before and after TEG-guided anticoagulation adjustment of anticoagulation medications are listed in Table 4. Increase in antifactor medications allowed for R prolongation in most cases, whereas antiplatelet medications decreased platelet activity (MA-AA/ADP). Of note, patients were often found to have inadequate platelet suppression with aspirin 81 mg alone. If incremental increase in aspirin dosage (162 or 325 mg) failed to show decreases in MA-AA or if MA-ADP remained extremely high (> 70 mm), clopidogrel or ticagrelor was added to the regimen.\n\nTABLE 4. Algorithm-Guided Treatment Using Antifactor (Heparin, Enoxaparin) and Antiplatelet (Aspirin, Clopidogrel) Medications; Comparison of 10 Before/After Thromboelastography With Platelet Mapping\n\n\tAnticoagulation Medications\t\tThromboelastography With Platelet Mapping Variables\tInflammatory Markers\t\nPatient No.\tAntifactor\tAntiplatelet\tTreatment\tReaction Time\tAlpha Angle\tMA\tMA-Adenosine Diphosphate\tMA-Arachidonic Acid\tLysis at 30 Min\tActivator F\td-dimer\tC-Reactive Protein\tFerritin\t\n1\tHeparin 5,000 BID\tNone\tInitial\t5.0\t73.8\t70\t68\t70.3\t0\t18\t0.96\t2.1\t986\t\nHeparin 5,000 BID\tAspirin 81 mg\tBased on TEG\t7.0\t68.3\t69\t67\t32.5\t0\t20\t1.1\t3.5\t1,516\t\n2\tNone\tNone\tInitial\t3.8\t80.2\t79\t66\t62.9\t1\t19.8\t2.1\t12\t816\t\nHeparin 5,000 BID\tAspirin 81 mg\tBased on TEG\t4.2\t78.1\t72\t74\t31.4\t3\t25.1\t1.7\t3.1\t524\t\n3\tNone\tNone\tInitial\t3.2\t79.2\t79\t75\t81.4\t0\t28\t1.5\t17\t1,089\t\nHeparin 5,000 BID\tAspirin 325 mg\tBased on TEG\t4.2\t77.1\t77\t76\t42.9\t0\t28\t4.3\t1.3\t1,256\t\n4\tEnoxaparin 40 QD\tAspirin 325 mg\tInitial\t5.9\t76.1\t80\t83\t84.3\t1\t26.9\t1.1\t2.5\t990\t\nEnoxaparin 40 BID\tAspirin 81 mg, clopidogrel 75 mg\tBased on TEG\t7.1\t69.7\t78\t77\t62.9\t0\t26\tNot available\t1.1\t829\t\n5\tNone\tNone\tInitial\t4.6\t75.3\t77\t86\t78.5\t0\t33\t4.7\t11\t1,639\t\nEnoxaparin 100 BID\tAspirin 81 mg\tBased on TEG\t7.2\t66\t72\t55\t57.1\t0\t19\t4.2\t6.8\t1,080\t\n6\tHeparin 5,000 TID\tNone\tInitial\t7.8\t78.3\t86\t87\t87.3\t0\t43\t2.8\t12.3\t787\t\nHeparin 5,000 TID\tAspirin 81 mg, clopidogrel 75 mg\tBased on TEG\t3.8\t80.4\t83\t40\t58.1\t0\t34\t1.2\t3.1\t284\t\n7\tEnoxaparin 40 QD\tClopidogrel 75 mg\tInitial\t4.7\t79\t81\t76\t82.9\t0\t35\t1.5\t15.8\t206\t\nEnoxaparin 40 QD\tAspirin 81 mg\tBased on TEG\t3.3\t78.9\t81\t77\t40\t0\t31\t3.5\t4.46\t150\t\n8\tEnoxaparin 40 QD\tNone\tInitial\t4.3\t74.9\t69\t78\t68.4\t2\t16\t1.89\t0.29\t124\t\nEnoxaparin 30 BID\tAspirin 81 mg\tBased on TEG\t4.7\t73.5\t69\t68\t49.3\t3\t15\t1.09\t0.19\t91\t\n9\tEnoxaparin 100 BID\tNone\tInitial\t5.1\t74.5\t71\t72\t76.5\t1\t19\t9.3\t4.2\t490\t\nEnoxaparin 80 BID\tAspirin 81 mg\tBased on TEG\t4.8\t75.4\t59\t38\t35\t0\t17\t2.96\t2.3\t274\t\n10\tEnoxaparin 40 QD\tNone\tInitial\t3.7\t77.2\t76\t53\t71.1\t0\t25\t4.05\t5.9\t2,079\t\nEnoxaparin 100 BID\tAspirin 81 mg, clopidogrel 75 mg\tBased on TEG\t4.5\t71.6\t68\t34\t24.7\t0\t12\t11.5\t3.5\t2,041\t\nBID = twice daily, MA = maximum amplitude, QD = once daily, R = reaction time, TEG = thromboelastography, TID = three times daily.\n\nDISCUSSION\nIn this study, TEG-PM is introduced as a more tailored, patient-specific approach to diagnosing COVID-19 coagulation abnormalities. TEG-PM better characterizes and emphasizes the spectrum of coagulopathic disorders and may indeed guide more appropriate, individualized therapies in patients infected with COVID-19.\n\nThe experience and results of this study have already led to an ever-increasing number of clinicians at the study’s institution to fully adopt the use of TEG-PM as a way to: 1) better characterize the specific coagulopathy found in any given COVID-19 patient, 2) more accurately delineate the underrecognized platelet contribution to any coagulopathy, and 3) better guide patient-specific anticoagulation management with the hope of improving patient outcomes.\n\nIt has been postulated that most signs and symptoms associated with COVID-19 are secondary to a coagulopathy (2, 27). Infected patients of all ages can present with arterial and venous thromboses (DVT and pulmonary emboli) and/or microthrombi causing PF and AKI, myocardial infarctions, ischemic and hemorrhagic strokes, or DIC and death (2, 5, 6, 27, 28). Coagulopathy is reported to carry an 11.5% mortality rate (9). The current study showed a significantly increased risk for MV and AKI in patients whose coagulopathy (as diagnosed by TEG-PM) did not resolve (Table 2) as well as a 7.7-fold increased risk of death (p = 0.0001).\n\nWith presenting symptoms and signs being highly variable and complications ranging from thrombotic to hemorrhagic, the diagnosis of coagulopathy remains difficult, yet of paramount importance. Based on our findings and those of others, a “hypercoagulable” state does not define the entire coagulopathic spectrum of COVID-19 (3, 7). Patient H (Table 3) presented with ischemic and hemorrhagic complications and was found to have prolonged R on TEG-PM in a setting of platelet hyperactivity. Overall, hemorrhagic complications were associated with factor inactivity and inability to initiate clot formation (R > 8 min), whereas ischemic complications occurred with platelet hyperactivity (MA-AA/ADP > 50 mm). Others proceeded to DIC and death with extremes of TEG variables (R > 10 min or LY30 > 10%), including primary fibrinolysis, previously noted to carry a 70–100% mortality rate in critically injured patients (29).\n\nAlthough inflammatory markers and CCTs have been associated with higher risk of coagulopathy in COVID-19 patients, they did not differentiate between coagulopathic and noncoagulopathic patients (9). Counterintuitively, prior studies have reported a 31% frequency of thrombosis in ICU patients when PT/PTT values were elevated (hazard ratio = 4.1) (2). Higher levels of CRP, d-dimer, FDPs, and prolonged PT/PTT were also found in COVID-19 nonsurvivors and among those with worsening respiratory failure, likely reflecting systemic inflammatory response (9, 11, 18). The current study did confirm that higher levels of d-dimer, CRP, and ferritin were associated with increased rates of PF, AKI, and mortality, but also demonstrated no change in PT/PTT/INR variables until demise was imminent (data not shown). In several studies, diagnosis of coagulopathy was only based on CCTs, anti-Xa, and inflammatory markers, rather than TEG (30–32). In this study, most patients received some form of antifactor prophylaxis at admission. However, use of prophylactic and/or therapeutic non-AG antifactor medications as compared to those guided by TEG-PM was associated with a 10.3-fold increased risk of mortality (p = 0.0001). One consideration is that coagulopathy of COVID-19 may include “hypocoagulability”, further exacerbated through administration of anticoagulants. Therefore, TEG guidance regarding antifactor medication administration may identify patients at risk for bleeding and further bridge the gap between survivors and non-survivors.\n\nA small number of studies have reported the use of TEG to identify hypercoagulability in COVID-19 patients, but the specific TEG-PM approach to manage platelets has not been described, despite the known complexities of platelet dysfunction as further demonstrated in this study (12, 22, 27, 33–36). Considering that platelets become hyperactive and have the ability to aggregate faster in COVID-19, TEG-PM appears to be a useful test to more optimally identify and characterize platelet dysfunction and, in turn, guide treatment (14, 36–40). In this study, corrected coagulopathy, largely platelet-related, was associated with what appeared to be markedly improved outcomes, including enhanced likelihood of survival.\n\nGiven the sheer volume of patients being diagnosed with COVID-19, it might not be feasible to perform TEG-PM testing in every confirmed COVID-19 patient. But based on these preliminary findings, high-risk patients with respiratory decline or other early organ failure should advisedly receive TEG-PM evaluation and, by all indications, the earlier the better. While use of TEG-PM emphasizes the tailoring of an individualized approach to care, management can be standardized to a large degree through pre-existing algorithms. Based on the preliminary results in this study, TEG-guided treatment appeared to make a significant difference compared with the cases in which TEG variables were not followed (40).\n\nThe main limitation of this study is that it remains observational in nature, rather than a randomized controlled trial testing TEG-guided management. Patients were followed prospectively in order to reliably capture all the data and document the clinical decisions regarding TEG-guided medication adjustments. However, the treating clinicians, regardless of their use of the TEG-PM algorithm and/or TTF support, were ultimately responsible for choosing patient’s anticoagulation management. Additionally, during the COVID-19 surge, the overwhelming demand for coagulopathy assessment using TEG-PM required the recruitment and training of multiple TTF teams. Only one team was involved with data-gathering, which may have led to an inadequate or biased sample size, although patients were randomly distributed among the TTF members. Also, although unrecognized confounding variables may have had an impact in this unadjusted exploratory analysis, the non-AG and AG-TEG groups overall appeared to be well-matched based on their demographics and admission criteria as seen in Table 1.\n\nAnother study limitation is that our patients were derived from one specific geographical and demographic setting, which is not large enough to represent the overall population of COVID-19 patients nor the many nuances of COVID-19 disease. Consequently, there is a potential selection bias that may limit the applicability of this study more broadly. Nevertheless, the hyper- and hypocoagulable algorithms created by the institutional TTF are of great value as a template and therefore should undergo external validation and additional testing with further evaluation in controlled trials.\n\nCONCLUSIONS\nAs confirmed by this study, COVID-19 coagulopathy has a multifaceted, chameleon spectrum of coagulopathy with platelet aberrations often playing a large role. Therefore, we recommended that patient-tailored diagnosis/characterization and treatment of COVID-19 coagulopathy should be based on a standardized algorithm employing TEG-PM. Although yet to be confirmed in other settings, the results here suggest that TEG-PM may be a mechanism to improve outcomes for COVID-19 patients, and, most importantly, it may reduce the risk of potential iatrogenic complications through indiscriminate use of anticoagulation medications. Most optimally, anticoagulant treatment should be tailored according to TEG-PM as some coagulopathic patients with COVID-19 are actually “hypocoagulable”, indicating a risk for bleeding, whereas many others have a significant platelet activity dysfunction that creates the “hypercoagulable” state. Some patients do not respond to first-line medications, and therefore, on-going TEG-PM assays and protocols are also indicated to guide the next steps in treatment (40).\n\nACKNOWLEDGMENTS\nThe Memorial Health System team expresses its deepest appreciation to the women and men in our healthcare system who continue to take on the inherent and ever-fatiguing risk of serving on the front lines of the severe COVID-19 pandemic in one the world’s busiest epicenters. All of us will be forever indebted to those team members for saving lives and for aiding and providing comfort to those afflicted. 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Tang N Li D Wang X \nAbnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.\n\nJ Thromb Haemost . 2020 ; 18 :844 –847\n32073213 \n10. Wu C Chen X Cai Y \nRisk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.\n\nJAMA Intern Med . 2020 ; 180 :934 –943\n32167524 \n11. Ling W: \nC-reactive protein levels in the early stage of COVID-19.\n\nMed Mal Infect . 2020 ; 50 :332 –334\n32243911 \n12. Kay AB Morris DS Collingridge DS \nPlatelet dysfunction on thromboelastogram is associated with severity of blunt traumatic brain injury.\n\nAm J Surg . 2019 ; 218 :1134 –1137\n31575420 \n13. Wang Z Li J Cao Q \nComparison between thromboelastography and conventional coagulation tests in surgical patients with localized prostate cancer.\n\nClin Appl Thromb Hemost . 2018 ; 24 :755 –763\n28870084 \n14. Manne BK Denorme F Middleton EA \nPlatelet gene expression and function in COVID-19 patients.\n\nBlood . 2020 ; 136 :1317 –1329\n32573711 \n15. Maatman TK Jalali F Feizpour C \nRoutine venous thromboembolism prophylaxis may be inadequate in the hypercoagulable state of severe coronavirus disease 2019.\n\nCrit Care Med . 2020 ; 48 :e783 –e790\n32459672 \n16. Tapia NM Chang A Norman M \nTEG-guided resuscitation is superior to standardized MTP resuscitation in massively transfused penetrating trauma patients.\n\nJ Trauma Acute Care Surg . 2013 ; 74 :378 –385\n23354228 \n17. Gonzalez E Moore EE Moore HB \nGoal-directed hemostatic resuscitation of trauma-induced coagulopathy: A pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays.\n\nAnn Surg . 2016 ; 263 :1051 –1059\n26720428 \n18. Panigada M Bottino N Tagliabue P \nHypercoagulability of COVID-19 patients in intensive care unit. A report of thromboelastography findings and other parameters of hemostasis.\n\nJ Thromb Haemost . 2020 ; 18 :1738 –1742\n32302438 \n19. Chau T Chan Y Patch D \nThrombelastographic changes and early rebleeding in cirrhotic patients with variceal bleeding.\n\nGut . 1998 ; 43 :267 –271\n10189856 \n20. De Pietri L Bianchini M Montalti R \nThrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: A randomized, controlled trial.\n\nHepatology . 2016 ; 63 :566 –573\n26340411 \n21. Wright FL Vogler TO Moore EE \nFibrinolysis shutdown correlates to thromboembolic events in severe COVID-19 infection.\n\nJ Am Coll of Surg . 2020 ; 231 :193 –203\n32422349 \n22. Helms J Tacquard C Severac F \nHigh risk of thrombosis in patients with severe SARS-CoV-2 infection: A multicenter prospective cohort study.\n\nIntensive Care Med . 2020 ; 46 :1089 –1098\n32367170 \n23. Liang C Yang Y He Z \nComparison between thromboelastography and the conventional coagulation test in detecting effects of antiplatelet agents after endovascular treatments in acute ischemic stroke patients: A STROBE-compliant study.\n\nMedicine . 2020 ; 99 :e19447 32150098 \n24. Le Quellec S Bordet J-C Negrier C \nComparison of current platelet functional tests for the assessment of aspirin and clopidogrel response.\n\nThromb Haemost . 2016 ; 116 :638 –650\n27440202 \n25. Chitlur M Sorensen B Rivard G \nStandardization of thromboelastography: A report from the TEG-ROTEM working group.\n\nHaemophilia . 2011 ; 17 :532 –537\n21323795 \n26. Bolliger D Seeberger MD Tanaka KA \nPrinciples and practice of thromboelastography in clinical coagulation management and transfusion practice.\n\nTransfus Med Rev . 2012 ; 26 :1 –13\n21872428 \n27. Hartmann J Murphy M Dias JD \nViscoelastic hemostatic assays: moving from the laboratory to the site of care—a review of established and emerging technologies.\n\nDiagnostics . 2020 ; 10 :118 \n28. Sakamoto Y Koami H Miike T: \nMonitoring the coagulation status of trauma patients with viscoelastic devices.\n\nJ Intensive Care . 2017 ; 5 :7 \n29. Barker EE Saini A Gazit AZ \nTEG Platelet mapping and impedance aggregometry to predict platelet transfusion during cardiopulmonary bypass in pediatric patients.\n\nFront Pediatr . 2019 ; 7 :509 31921722 \n30. Agarwal S Johnson RI Kirmani BH \nPre-and post-bypass platelet function testing with multiple electrode aggregometry and TEG platelet mapping in cardiac surgery.\n\nJ Cardiothorac Vasc Anesth . 2015 ; 29 :1272 –1276\n25987196 \n31. Yuriditsky E Horowitz JM Merchan C \nThromboelastography profiles of critically ill patients with coronavirus disease 2019.\n\nCrit Care Med . 2020 ; 48 :1319 –1326\n32618696 \n32. Dewitte A Lepreux S Villeneuve J \nBlood platelets and sepsis pathophysiology: A new therapeutic prospect in critical ill patients?\n\nAnn Intensive Care . 2017 ; 7 :115\n\n33. Liu X Li Z Liu S \nPotential therapeutic effects of dipyridamole in the severely ill patients with COVID-19.\n\nActa Pharm Sin B . 2020 ; 10 :1205 –1215\n32318327 \n34. Viecca M Radovanovic D Forleo GB \nEnhanced platelet inhibition treatment improves hypoxemia in patients with severe Covid-19 and hypercoagulability. A case control, proof of concept study.\n\nPharmacol Res . 2020 ; 158 :104950 32450344 \n35. Song J-C Wang G Zhang W \nChinese expert consensus on diagnosis and treatment of coagulation dysfunction in COVID-19.\n\nMil Med Res . 2020 ; 7 :19 32307014 \n36. Oxley TJ Mocco J Majidi S \nLarge-vessel stroke as a presenting feature of Covid-19 in the young.\n\nN Engl J Med . 2020 ; 382 :e60 32343504 \n37. Napolitano LM Cohen MJ Cotton BA \nTranexamic acid in trauma: How should we use it?\n\nJ Trauma Acute Care Surg . 2013 ; 74 :1575 –1586\n23694890 \n38. Stattin K Lipcsey M Andersson H \nInadequate prophylactic effect of low-molecular weight heparin in critically ill COVID-19 patients.\n\nJ Crit Care . 2020 ; 60 :249 –252\n32920503 \n39. Flaczyk A Rosovsky RP Reed CT \nComparison of published guidelines for management of coagulopathy and thrombosis in critically ill patients with COVID 19: Implications for clinical practice and future investigations.\n\nCrit Care . 2020 ; 24 :559 32938471 \n40. Nadkarni GN Lala A Bagiella E \nAnticoagulation, mortality, bleeding and pathology among patients hospitalized with COVID-19: A single health system study.\n\nJ Am Coll Cardiol . 2020 ; 76 :1815 –1826\n32860872\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2639-8028",
"issue": "2(12)",
"journal": "Critical care explorations",
"keywords": "COVID-19 anticoagulation; COVID-19 coagulopathy; TEG-PM; platelet hyperactivity; platelet mapping; thromboelastrography",
"medline_ta": "Crit Care Explor",
"mesh_terms": null,
"nlm_unique_id": "101746347",
"other_id": null,
"pages": "e0287",
"pmc": null,
"pmid": "33381763",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": "32450344;32150098;32307014;32302438;25987196;32228363;32098161;32437596;32860872;27440202;23354228;32073213;31921722;10189856;32322398;26340411;20008204;32374815;29192366;21323795;32367170;32243911;21872428;32327202;32573711;23694890;32938471;32618696;31575420;32422349;28870084;32291094;32167524;32459672;32318327;32920503;26720428;32501489;32343504",
"title": "Integral Use of Thromboelastography With Platelet Mapping to Guide Appropriate Treatment, Avoid Complications, and Improve Survival of Patients With Coronavirus Disease 2019-Related Coagulopathy.",
"title_normalized": "integral use of thromboelastography with platelet mapping to guide appropriate treatment avoid complications and improve survival of patients with coronavirus disease 2019 related coagulopathy"
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"abstract": "We report a case of a 39-year-old woman who presented to the emergency department (ED) with symptoms of pharyngitis and fever. Diagnosed with streptococcal pharyngitis, she received antibiotics and dexamethasone, and was discharged. Within 24 h she returned to the ED with signs and symptoms of an acute coronary syndrome; she was thus given β-blockers. Her coronary angiogram was normal. She developed cardiogenic shock with an ejection fraction (EF) of 10% and apical ballooning on echocardiography. Her condition improved with optimal medical therapy. Subsequent testing weeks later confirmed the presence of a pheochromocytoma. Following prazosin and an adrenalectomy, all her antihypertensive medications were weaned and her EF normalised. We believe the high-dose exogenous corticosteroids triggered a pheochromocytoma crisis. The concomitant use of β-blockers without preceding α blockade resulted in cardiovascular collapse. Pheochromocytoma crisis must be included in the differential diagnosis of any dramatic haemodynamic collapse after administration of exogenous corticosteroid or β-blockers.",
"affiliations": "Department of Internal Medicine/Division of Cardiology, University of Illinois College of Medicine at Peoria/OSF Saint Francis Medical Center, Peoria, Illinois, USA.;Department of Internal Medicine/Division of Cardiology, University of Illinois College of Medicine at Peoria/OSF Saint Francis Medical Center, Peoria, Illinois, USA.;Department of Internal Medicine/Division of Cardiology, University of Illinois College of Medicine at Peoria/OSF Saint Francis Medical Center, Peoria, Illinois, USA.;Department of Internal Medicine/Division of Cardiology, University of Illinois College of Medicine at Peoria/OSF Saint Francis Medical Center, Peoria, Illinois, USA.",
"authors": "Ibrahim|Majd|M|;Banga|Sandeep|S|;Venkatapuram|Suneetha|S|;Mungee|Sudhir|S|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000319:Adrenergic beta-Antagonists; D005938:Glucocorticoids; D003907:Dexamethasone",
"country": "England",
"delete": false,
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"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
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"mesh_terms": "D054058:Acute Coronary Syndrome; D000305:Adrenal Cortex Hormones; D000315:Adrenalectomy; D000319:Adrenergic beta-Antagonists; D000328:Adult; D003907:Dexamethasone; D003937:Diagnosis, Differential; D004305:Dose-Response Relationship, Drug; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D010612:Pharyngitis; D010673:Pheochromocytoma; D012770:Shock, Cardiogenic",
"nlm_unique_id": "101526291",
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"pages": null,
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"pmid": "25694646",
"pubdate": "2015-02-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16886958;21474192;18094670;18294473;12766539;9570034;15102960;19106400;2810691;12395363;3893809;16651478;23078863;17996552;19486873;21860721;484883;18299478;15703419",
"title": "Transient cardiogenic shock during a crisis of pheochromocytoma triggered by high-dose exogenous corticosteroids.",
"title_normalized": "transient cardiogenic shock during a crisis of pheochromocytoma triggered by high dose exogenous corticosteroids"
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"abstract": "Brentuximab vedotin is a CD30-antibody/drug conjugate which has demonstrated excellent response in treating CD30-positive mycosis fungoides (MF) and anaplastic large cell lymphoma (ALCL). In this report, we present a patient with CD30-negative MF refractory to multiple other lines of therapy who demonstrated a dramatic response to brentuximab. This paradoxical response may be due to inadequate detection of CD30 expression by immunohistochemical techniques. From this case we see that even in the setting of apparent CD30 negativity, brentuximab may be a viable treatment option for patients who require bridging to stem cell transplant or seek successful palliation. This case highlights the point that rigid inclusion criteria for MF trials without use of more sensitive techniques to confirm lack of CD30 expression may inappropriate.",
"affiliations": "Department of Dermatology, University of Minnesota, Minneapolis, Minnesota.;Department of Dermatology, University of Minnesota, Minneapolis, Minnesota.;Moffitt Cancer Center, Tampa, Florida.",
"authors": "Goyal|Amrita|A|0000-0003-3790-8242;Hordinsky|Maria|M|;Lazaryan|Aleksandr|A|",
"chemical_list": "D018796:Immunoconjugates; D017730:Ki-1 Antigen; D000079963:Brentuximab Vedotin",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.12835",
"fulltext": null,
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"issn_linking": "1396-0296",
"issue": "32(2)",
"journal": "Dermatologic therapy",
"keywords": "CD30; brentuximab; mycosis fungoides",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000369:Aged, 80 and over; D000079963:Brentuximab Vedotin; D006801:Humans; D018796:Immunoconjugates; D017730:Ki-1 Antigen; D008297:Male; D009182:Mycosis Fungoides; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e12835",
"pmc": null,
"pmid": "30659762",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Impressive response of CD30-negative, treatment-refractory mycosis fungoides to brentuximab vedotin.",
"title_normalized": "impressive response of cd30 negative treatment refractory mycosis fungoides to brentuximab vedotin"
} | [
{
"companynumb": "US-SEATTLE GENETICS-2019SGN00166",
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"activesubstancename": "BRENTUXIMAB VEDOTIN"
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"abstract": "We report two cases of bacteremia due to Clostridium difficile from two French hospitals. The first patient with previously diagnosed rectal carcinoma underwent courses of chemotherapy, and antimicrobial treatment, and survived the C. difficile bacteremia. The second patient with colon perforation and newly diagnosed lung cancer underwent antimicrobial treatment in an ICU but died shortly after the episode of C. difficile bacteremia. A review of the literature allowed the identification of 137 cases of bacteremia between July 1962 and November 2016. Advanced age, gastro-intestinal disruption, severe underlying diseases and antimicrobial exposure were the major risk factors for C. difficile bacteremia. Antimicrobial therapy was primarily based on metronidazole and/or vancomycin. The crude mortality rate was 35% (21/60).",
"affiliations": "AP-HP, HUEP (Assistance Publique - Hôpitaux de Paris, Hôpitaux Universitaires Est Parisien), Bacteriology Department, Paris, France.;UPMC, Univ Paris 06, GRC n°2 EPIDIFF, Paris, France.;AP-HP, la Pitié-Salpétrière Hospital, Bacteriology Department, Paris, France.;AP-HP, Tenon Hospital, Hepato-Gastro-Enterology Unit, Paris, France.;AP-HP, la Pitié-Salpétrière Hospital, Intensive Care Unit, Paris, France.;AP-HP, Tenon Hospital, Infection Diseases Unit, Paris, France.;AP-HP, Tenon Hospital, Hepato-Gastro-Enterology Unit, Paris, France.;AP-HP, HUEP (Assistance Publique - Hôpitaux de Paris, Hôpitaux Universitaires Est Parisien), Bacteriology Department, Paris, France.;UPMC, Univ Paris 06, GRC n°2 EPIDIFF, Paris, France.",
"authors": "Doufair|Mouna|M|;Eckert|Catherine|C|;Drieux|Laurence|L|;Amani-Moibeni|Come|C|;Bodin|Liliane|L|;Denis|Michel|M|;Grange|Jean Didier|JD|;Arlet|Guillaume|G|;Barbut|Frédéric|F|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2017.03.012",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(17)30011-210.1016/j.idcr.2017.03.012Case ReportClostridium difficile bacteremia: Report of two cases in French hospitals and comprehensive review of the literature Doufair Mouna mounadoufair@yahoo.fra⁎Eckert Catherine bcDrieux Laurence dAmani-Moibeni Come eBodin Liliane fDenis Michel gGrange Jean Didier eArlet Guillaume aBarbut Frédéric bcha AP-HP, HUEP (Assistance Publique – Hôpitaux de Paris, Hôpitaux Universitaires Est Parisien), Bacteriology Department, Paris, Franceb UPMC, Univ Paris 06, GRC n°2 EPIDIFF, Paris, Francec AP-HP, Saint-Antoine Hospital, National Reference Laboratory for C. Difficile, Franced AP-HP, la Pitié-Salpétrière Hospital, Bacteriology Department, Paris, Francee AP-HP, Tenon Hospital, Hepato-Gastro-Enterology Unit, Paris, Francef AP-HP, la Pitié-Salpétrière Hospital, Intensive Care Unit, Paris, Franceg AP-HP, Tenon Hospital, Infection Diseases Unit, Paris, Franceh AP-HP, Saint-Antoine Hospital, UHLIN, Paris, France⁎ Corresponding author. mounadoufair@yahoo.fr28 3 2017 2017 28 3 2017 8 54 62 22 1 2017 5 3 2017 24 3 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report two cases of bacteremia due to Clostridium difficile from two French hospitals. The first patient with previously diagnosed rectal carcinoma underwent courses of chemotherapy, and antimicrobial treatment, and survived the C. difficile bacteremia. The second patient with colon perforation and newly diagnosed lung cancer underwent antimicrobial treatment in an ICU but died shortly after the episode of C. difficile bacteremia. A review of the literature allowed the identification of 137 cases of bacteremia between July 1962 and November 2016. Advanced age, gastro-intestinal disruption, severe underlying diseases and antimicrobial exposure were the major risk factors for C. difficile bacteremia. Antimicrobial therapy was primarily based on metronidazole and/or vancomycin. The crude mortality rate was 35% (21/60).\n\nKeywords\nClostridium difficile bacteremiaToxinTreatmentOutcome\n==== Body\nIntroduction\nClostridium difficile is an anaerobic gram-positive bacterium responsible for diarrhea. Spectrum of disease ranges from mild diarrhea to severe and complicated colitis, including pseudomembranous colitis, toxic megacolon and death [1], [2], [3]. C. difficile has been identified as the leading cause of healthcare-associated diarrhea among adults in industrialized countries. Increasing incidence of C. difficile infection (CDI) and large hospital outbreaks have been described worldwide [4], [5], [6], [7]. This trend is assumed to be due in part to the emergence and rapid spread of a highly virulent strain known as BI/NAP1/027 strain [8], [9], [10].\n\nThe main risk factors for CDI are antimicrobial exposure, prolonged hospitalization and age over 65 years. Severe underlying diseases are also commonly mentioned as predisposing situations to CDI developing. Any factors that disturb the host-microbiota homeostasis can promote C. difficile colonization and infection [11], [12], [13], [14], [15], [16], [17]. The most commonly incriminated antimicrobials are cephalosporins and fluoroquinolones but all antimicrobial classes are associated with a risk of CDI and the antimicrobial stewardship programmes may play a key role in CDI prevention [18], [19], [20], [21], [22], [23]. Metronidazole (MTZ), vancomycin (VA) and fidaxomicin (FDX) are the drugs of choice to treat CDI [24], [25].\n\nAlthough C. difficile-associated diarrhea incidence is increasing worldwide, extracolonic infections with C. difficile, including bacteremia (CDB), remain uncommon. The most commonly reported extraintestinal infections include abdominopelvic abscesses, peritoneal and pleural infections, visceral abscess, as well as bacteremia [26], [27], [28]. Here we report two cases of CDB in two French hospitals and give a review of the literature to comprehensively present the clinical features of CDB.\n\nCase report 1\nA 54-year-old man was admitted with severe sepsis to the hepato-gastro-enterology unit at Tenon University Hospital, Paris, France, on 10 July 2012. He was febrile and blood cultures were taken during the fever. His blood pressure was 87/55 mm Hg and his pulse rate 83 beats per min; the white blood cell count was 15,200/mm3 with 12,050/mm3 neutrophils; the hemoglobin level was 10.3 g/L and that of C-reactive protein was 276 mg/L; urinalysis was unremarkable. His medical history included a rectal adenocarcinoma diagnosed in June 2010. At that time, he underwent surgical resection of the rectosigmoid colon and of hepatic metastases followed by multiple courses of chemotherapy. Postoperatively, a colostomy bag was required. He also underwent radiation therapy. During that period, he had recurrent episodes of urinary tract infections treated with multiple courses of antimicrobials including cefixime, nitrofurantoin and amoxicillin-clavulanate. Five months prior to his admission in July 2012, he developed an abdominal abscess with iliac vein thrombosis that was treated with ceftazidime and MTZ and then with piperacillin-tazobactam and amikacin. In the month preceding his admission, he had sepsis due to extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli that was treated with imipenem.\n\nBlood cultures taken at admission grew an anaerobic gram-positive bacillus identified as C. difficile by mass spectrometry (Maldi-Tof, Bruker). A stool sample from the colostomy bag was examined for C. difficile a few days after the blood culture and was found to be positive. It also tested positive for glutamate dehydrogenase antigen (C DIFF Quick Chek® Alere™). A cytotoxicity assay using MRC-5 cells in order to detect free toxins was negative but culture of on selective TCCA (taurocholate, cycloserine, cefoxitin agar) was positive for toxigenic C. difficile. The bacteremia was treated with 500 mg intravenous MTZ every eight hours for three days. Repeated blood and stool cultures were negative and the treatment was switched to 500 mg oral MTZ every twelve hours for seventeen days. The patient recovered and was discharged to a palliative-care unit. C. difficile isolates from stool and blood cultures were sent to the National Reference Laboratory for C. difficile (Saint Antoine Hospital, Paris, France). Both isolates were toxigenic but did not produce the binary toxin. Their PCR ribotypes were identical, did not belong to the 25 most commonly identified PCR ribotypes (i.e., 070, 078/126, 002, 012, 029, 053, 075, 005, 018, 106, 131, 117, 003, 019, 046, 050, 014/020/077, 001, 015, 017, 023, 027, 056, 081 and 087) and were both susceptible to erythromycin, moxifloxacin, VA and MTZ.\n\nCase report 2\nA 62-year-old woman was admitted to Pitié-Salpêtrière University Hospital, Paris, France, on 26 June 2013 for fatigue, weight loss and arthralgia. On 27 June, computed tomography (CT) of the chest, abdomen and pelvis revealed a malignant lung lesion associated with pleural effusion and putative secondary cancerous lesions of liver, vertebrae and pelvis. Two days later, the patient was transferred to an intensive care unit because of acute respiratory distress syndrome due to massive pleural effusion and acute pneumonia. Antimicrobial treatment associating cefotaxime (1 g three times a day) and spiramycin (3 MIU twice a day) was initiated. On 5 July, the patient developed a distended abdomen and guarding of the left upper and lower quadrants, associated with tachypnea and mottled skin. Abdominal CT showed a pneumoperitoneum. During tomography, a perforation (1 cm) of the sigmoid colon was found and a left hemicolectomy and terminal colostomy were performed. No evidence of peritoneal carcinomatosis was found. Following the operation, the patient became hypotensive and required fluid resuscitation and vasopressor therapy and she was transferred to an intensive care unit.\n\nOn admission to the ICU, she had sepsis-induced tissue hypoperfusion with hypothermia (33.6 °C), tachycardia (heart rate, 110 beats per min), leucocytosis (19,000/mm3), hyperlactatemia (5.6 mmol/L), mottled skin of the lower limbs and cyanosis of the soles of the feet. She was initially given intravenous piperacillin-tazobactam (4 g three times a day); 24 h later, intravenous ciprofloxacin was added (400 mg twice a day). Peritoneal fluid cultures were positive with polymorphic flora and ESBL-producing E. coli. Blood cultures performed between 5 and 7 July were positive with Bacteroides fragilis and C. difficile. The C. difficile toxins A and B were detected with the enzyme immunoassay ImmunoCard® Toxins A&B test (Meridian Bioscience, Cincinnati, OH, USA) directly from colonies. The C. difficile isolate was resistant to moxifloxacin and erythromycin and was sent to the National Reference Laboratory for further investigations. Antimicrobial therapy was changed to imipenem (500 mg four times a day) and VA with a loading dose (1 g) followed by continuous infusion (1 g per day). On 10 July, a ventilator-associated pneumonia due to Stenotrophomonas maltophilia was diagnosed and treated with intravenous trimethoprim-sulfamethoxazole (400 mg twice a day) and ciprofloxacin (400 mg twice a day). Following five days of treatment with intravenous VA, the treatment was switched to oral MTZ (500 mg three times a day) for 5 additional days. On 21 July, the patient developed rectal ischemia, her general condition worsened and she died on 25 July. Stools collected 48 h before her death were positive for the toxigenic C. difficile strain of PCR ribotype 078/126. The strain was resistant to moxifloxacin and erythromycin but susceptible to VA and MTZ.\n\nSystematic review\nSearch strategy and selection criteria\nThe PubMed database was searched using the keywords “Clostridium difficile infection”; “extraintestinal C. difficile infection” (ECD); “Clostridium difficile bacteremia” (CDB); and C. difficile pathogenesis. Pertinent references included in some of the search results were also reviewed. Relevant articles and abstracts published in English; French and Japanese between 1962 (the first published CDB case) and November 2016 were selected. Among these articles; about 28 with descriptive cases of CDB and 10 other reports including other CDB cases were retrieved. The published reports were heterogeneous. The majority were published as case reports and the others were epidemiological or retrospective studies. The other main publications were related to CDB subject or to the particular features of Clostridium difficile pathogenesis. A single author (MD) reviewed the relevant articles and abstracts. A description of the patients’ clinical features; treatment and/or outcome was often lacking. The reported cases with missing clinical data about the analyzed parameter were not included in the statistical analysis.\n\nDescriptive statistics were used to determine the mean age and to summarize the distribution of CDB among the cohort of report cases in literature. Statistical analysis was performed using StatView software, version 5.0.0.0 (SAS Institute Inc). Categorical variables were compared using the chi-square test or two-tailed Fisher’s exact test where applicable. For all statistical comparisons, results were considered significant when the p value was <0.05.\n\nFrequency of CDB\nTo date, 137 CDB cases have been reported in the literature comprising 60 cases (including the 2 cases presented in this report) with detailed clinical patient characteristics. Most commonly reported information included age, sex, underlying diseases, toxinogenicity of the strain, antimicrobial therapy and clinical outcome. Apart from the 60 cases, 77 have been identified in epidemiological reports aiming at determining the incidence of CDB (Table 1, Table 2). The first case of CDB was described in 1962 in a 5-month-old male infant with a 3-week history of coryza, cough, and anorexia [29]. In 1975, Gorbach et al. reported one C. difficile isolate found among 2168 positive blood cultures (0.05%) in one general hospital over a 14-month period [30]. During a 10-year period (1985–1995), Wolf et al. identified three patients with CDB among 14 patients with ECD in a tertiary-care hospital [31]. Rechner et al. identified one isolate of C. difficile when retrospectively reviewing the blood cultures positive for Clostridium species in two teaching hospitals of ca. 300 and 200 beds, respectively, representing a total of 164,304 hospitalizations [32]. Garcia-Lechuz et al. reported two episodes of CDB during a 10-year period (1990–2000) in a large tertiary-care teaching hospital serving a population of approximately 650,000 with an average of 50,000 admissions per year [33]. This corresponds to an incidence of 0.4 cases per 100,000 admissions. Among 25 extraintestinal C. difficile infections recorded between 1988 and 2003, Zheng et al. found out two isolates from blood cultures but did not report clinical features [34]. Another epidemiological study covering a large Canadian health region (population 1.2 million) conducted over a six-year period (2000–2006) reported a CDB incidence of 0.08 per 100,000 residents per year [35]. This study reported a CDB prevalence of 5% among clostridial bacteremias, which is in line with that of 7% (3/42) reported by McGill et al. in England. In this latter study, the rate of CDB between 2004 and 2008 was estimated to be about 0.01% to 0.02% among a total of 320,371 bacteremias [36]. Thus, the National Health Protection Agency in the UK registered 62 CDB cases during 2003–2008 (range: 9–17 per annum) with a tendency for decreasing incidence (no CDB case was reported in the period 2008–2012 and 2010–2014) in England, Wales and Northern Ireland [37], [38], [39]. A recent retrospective medical record review conducted from January 1, 2004 through December 31, 2013 as a single-center experience exposed 40 ECD with 11C. difficile bloodstream infections identified among 6525 CDI cases [28]. Other cases have been reported as individual cases and are summarized in the present review (Table 2).Table 1 Epidemiology of C. difficile bacteremias reported in the literature.\n\nTable 1Period\tCountry\tNumber of CDB casesa\tIncidence\tReference\t\n1962–1969\tUSA\t3 Isolates/86 nonhistotoxic clostridial bacteremias (laboratory isolates)*\t0.4\t[42], [52]\t\n15 months\tUSA\t1 Blood culture isolate (Anaerobe study)*\t0.8\t[53]\t\n14 months\tUSA\t1 CDB/2168 bacteremias*\t0.9\t[30]\t\n1985–1995\tUSA\t3 CDB/14 ECD2\t0.3\t[31]\t\n1990–1997\tUSA\t1/164 304 hospitalizations*\t0.13\t[32]\t\n1990–2000\tSpain\t2 CDB/21 ECD (50 000 admissions/year)b\t0.2\t[33]\t\n1988–2003\tUSA\t2 Blood culture isolates/25 ECD*\t0.2\t[34]\t\n2000–2006\tCanada\t7 CDB/1.2 million residents*\t1\t[35]\t\n2004–2008\tUK\t62 CDB/320 371 bacteremias*\t9 to 17\t[36], [37]\t\n2008–2012\tUK\t0\t0\t[38]\t\n2010–2014\tUK\t0\t0\t[39]\t\n1989–2009\tTaiwan\t12 CDB/2 medical centersb,c\t0.6\t[43]\t\n2002–2012\tFinland\t2 CDB/31 ECDb\t0.2\t[54]\t\n2004–2013\tUSA\t11 CDB/40 ECD/6525 CDIb\t1.1\t[28]\t\n1962–2016\tAll countries\tTotal: 137 (the 58 published casesb, the two present casesb and 77* cases in other reports)\t\tPresent review\t\na CDB cases of each study or literature review when clearly mentioned in articles or reports.\n\nb Cases with clinical data reported in Table 2.\n\nc 1100-bed and 2800-bed tertiary-care hospitals in Taiwan.\n\n* Cases not available with clinical data but exposed in other reports in the reviewed literature.\n\nTable 2 Summary of the 58 well-documented C. difficile bacteremia cases (1962–2016) reviewed in this study and the present two cases.\n\nTable 2Age/sex.\tUnderlying conditions\tClinical presentation\tAntimicrobial exposure1\tStrain toxicity from blood/stool\tOther organisms in blood culture\tClinical management\tOutcome\tYear Reference\t\n5 months/M\tNone\tCough, coryza, anorexia\tNR\tNR/NR\tNone\tNR\tNR\t1962 [29]\t\n19 months/M\tPseudomembranous NEC, systemic carnitine deficiency (recurrent hypoglycemia and cirrhosis)\tFrequent sepsis, diarrhea, vomiting, peritonitis\tampicillin + gentamicin\tYes/NR\tNone\tNR\tDied\t1982 [40]\t\n68/M\tCirrhosis, chronic pancreatitis\tJaundice, ascites, encephalopathy, splenic abscess\tNone\tNR/NR2\tNone\tPenicillin G, DAT\tDied\t1983 [55]\t\nNeonate/M\tPrematurity, neonatal NEC\tFever, respiratory distress, abdominal distension, necrotic bowel, peritonitis\tAmpicillin + kanamycin\tYes3/NR\tS. epidermidis3 (contaminant)\tAmpicillin + kanamycin Surgery, DAT\tDied\t1984 [56]\t\n65/M\tArteritis of legs and gangrene\tDiarrhea and colitis 6th day, septicemia 10th day postoperative\tCefuroxime, vancomycin\tYes/No\tB. fragilis\tCefuroxime,MTZ\tRecovered\t1984 [57]\t\n35/F\tAML, neutropenia\tFever, abdominal pain, diarrhea\tCefotaxime + gentamicin\tYes/Yes\tBacteroides sp., Gr. D streptococci\tiv MTZ + oral VA\tDied\t1985 [58]\t\n69/F\tAcute lymphoblastic leukemia, chemotherapy corticosteroids\tAbdominal distension, peritonitis, toxic megacolon, bilateral psoas abscesses\tYes\tYes/Yes\tBacteroides sp., E.coli\tCloxacillin, Co, iv MTZ, ampicillin, gentamicin\tDied\t1985 [58]\t\n62/M\tHypertension, coronary surgery, appendectomy, cholecystectomy, aortofemoral bypass, C. difficile septicemia 5 months before\tFever, nausea, vomiting, left pleural effusion, splenic abscess\tPiperacillin, netilmicin\tNR/NR\tNone\tSplenectomy MTZ, cefoxitin\tRecovered\t1987 [59]\t\n39/M\tOropharynx cancer\tLeft mandible radionecrosis, hypotension, fever, acute diverticulitis\tNR\tYes/Yes\tE. coli, E. faecalis, B. vulgatus\tiv MTZ, iv and oral VA, pefloxacin\tRecovered\t1989 [47]\t\n85/F\tChronic pulmonary disease, heart failure, dementia, sinus bradycardia, ischemic attack, pneumonia\tRecurrent diarrhea, fever hypotension\tVA\tNR/Yes\tE. faecalis\tiv VA, gentamicin\tRecovered\t1995 [26]\t\n18/M\tNone\tTreated for exudative sore throat, fever, chills, abdominal pain, vomiting, diarrhea\tErythromycin, lincomycin\tNR/Yes\tNone\tOral VA\tRecovered\t1996 [60]\t\n78/M\tNone\tTrauma; pneumonia, fever, watery diarrhea\tOfloxacin, clindamycin, cefuroxime, amikacin\tNR/No\tNone\tOral and iv VA\tRecovered (died from nosocomial pneumonia)\t1996 [60]\t\n3/M\tThalassemia minor, 5 episodes of tonsillitis\tFever, odynophagia, acute pericarditis, pericardial effusion, mild GI signs\tAmoxicillin-clavulanic acid, cefixime, cefotaxime\tYes/NT\tNone\tiv VA\tDischarged\t1998 [61]\t\n17/M\tDuchenne muscular dystrophy\tIleus with small‐bowel obstruction\tYes\tNT/NT\tCandida parapsilosis\tNR\tRecovered\t1998 [31]\t\n33/F\tMetastatic cervical cancer\tPelvic abscesses, recto-vaginal fistula after radiotherapy\tYes\tNT/NT\tC. cadaveris, B. melaninogenicus, Fusobacterium species\tNR\tDied\t1998 [31]\t\n77/M\tSevere emphysema, corticosteroid therapy\tPerforated sigmoid diverticulum\tYes\tNT/NT\tEubacterium lentum\tNR\tDied\t1998 [31]\t\n66/M\tInfiltrating bladder cancer\tIntestinal invasion of the advanced bladder cancer, pyelonephritis\tNR\tNR/NT\tE. faecium, B.fragilis\tImipenem\tDied\t2001 [33]\t\n65/M\tObesity\tIschemic colitis after cardiac surgery, bacteremic peritonitis\tNR\tNR/NT\tE. faecium, B. ovatus\tCeftriaxone, ciprofloxacin\tDied\t2001 [33]\t\n66/M\tAML, immunodepression, chemotherapy\tFever, pancytopenia, anal margin abscess and diarrhea\tC3G+ FQ\tNR/NR\tNone\tOfloxacin, MTZ, abscess drainage\tRecovered\t2001 [62]\t\n69/F\t3rd degree burn injuries\tSkin operation, fever, abdominal pain and severe diarrhea\tCefazolin, flomoxef\tYes/Yes\tE. faecalis, E.casseliflavus\toral and iv VA\tRecovered\t2004 [63]\t\n50/M\tCrohn's disease with chemotherapy\tNausea, abdominal abscess, small-bowel obstruction, bowel surgery, jejunum adenocarcinoma\tAmpicillin/sulbactam + gentamicin\tNR/No\tNone\tPip-Taz\tRecovered\t2009 [45]\t\n40/F\tAML, Dermatomyositis, corticosteroid treatment\tFatigue, weight loss, fever, tachycardia\tYes, unknown antimicrobials\tNR/NT\tNone\tCefepime, MTZ, iv VA\tDied\t2009 [27]\t\n40/M\tAlcoholism, liver failure, bone marrow suppression, pancreatitis, and recurrent pneumonia.\tVomiting, diarrhea, abdominal pain, fever\tCephalexin\tNo4/NR\tStaphylococcus epidermidis (contaminant)\tCeftriaxone\tDischarged5\t2009 [46]\t\n\n\n\t\n1989–2009\tTaiwan, 12 patients [43]:\t\t\t\t\t\t\t\t\n69/F\tLiver cirrhosis\tNR (Dead on arrival)\tNR\tYes/NR\tNone\tNone\tDied\t2010\t\n38/M\tWilson’s disease\tAbdominal pain\tNR\tNo/NR\tNone\tCefmetazole\tDied\t2010\t\n65/F\tPerforated peptic ulcer\tFever, abdominal pain\tNR\tNR/NR\tNone\tMTZ\tDied\t2010\t\n58/M\tLiver cirrhosis\tFever, abdominal pain\tNR\tNo/NR\tNone\tMTZ\tRecovered\t2010\t\n12/M\tBiliary atresia, liver transplantation\tFever, dyspnea\tNR\tNo/NR\tNone\tPip-Taz, VA\tRecovered\t2010\t\n41/F\tPulmonary fibrosis\tFever, dyspnea\tNR\tNo/NR\tNone\tCeftazidime, gentamicin, VA\tRecovered\t2010\t\n45/M\tLiver cirrhosis\tAbdominal pain\tNR\tYes/NR\tCNS spp.\tCeftriaxone\tDied\t2010\t\n83/M\tNone\tGI bleeding, hypovolemic shock,\nfever, bloody stool\tNR\tNo/NR\tE. coli\tImipenem\tDied\t2010\t\n87/F\tCongestive heart failure, end-stage renal disease, pseudomembranous colitis\tBloody stool\tNR\tYes/NR\tP. aeruginosa, E.faecium, E. coli, ESBL-K. oxytoca\tVA, meropenem\tRecovered\t2010\t\n80/F\tLiver cirrhosis, pseudomembranous colitis\tBloody stool\tNR\tYes/NR\tCNS spp.\tMTZ\tRecovered\t2010\t\n66/F\tFemoral neck fracture (hip replacement with prosthetic infections), chronic kidney disease\tFever, lower GI bleeding, abdominal pain\tNR\tNo/NR\tE. cloacae\tDebridement cefepime, MTZ\tRecovered\t2010\t\n75/F\tLymphoma, biliary tract infection\tFever, chills, nausea, vomiting, abdominal pain\tNR\tNR/NR\tK. pneumoniae, C.perfringens\tCefepime, MTZ\tRecovered\t2010\t\n39/M\tAlcohol dependency\tJaundice, vomiting, fecal incontinence\tNone\tNR/NR\tNone\tCefuroxime, MTZ\tDischarged\t2011 [36]\t\n20/M\tJuvenile polyposis syndrome, elective subtotal colectomy\tUTI, small-bowel resection and end-ileostomy, CD ileitis\tCephradine, Pip-Taz\tNR/Yes\tNone\tOral VA, meropenem, iv MTZ\tDischarged\t2011 [36]\t\n67/M\tUlcerative colitis\tGI bleed\tNone\tNR/Yes\tNone\tNone\tDischarged\t2011 [36]\t\n39/F\tChronic hepatitis, chronic alcoholic liver disease\tMenorrhagia, spontaneous bruising, jaundice. 3rd week: fever, rectal bleed, varices, gastritis, breast abscess\tCefotaxime\tNR/NR\tNone\tMTZ + amoxicillin/clavulanic\tRecovered\t2011 [48]\t\n83/M\tCAD, chronic hemodialysis, diverticulitis and peptic ulcer disease\tFever, abdominal pain, nausea, vomiting, bleeding post gastrostomy tube placement\tAmikacin, VA, Pip-Taz\tYes/No\tNone\tMTZ\tRecovered\t2011 [49]\t\n39/M\tGastric adenocarcinoma, chemotherapy and chemoradiation\tAbdominal pain, vomiting and obstipation\tNone\tYes/NT\tCandida glabrata\tNR\tRecovered then discharged\t2011 [49]\t\n60/M\tMetastatic prostate cancer\tFever, abdominal pain, hematochezia, hydronephrosis, rectal stricture, loop ileostomy\tVA + meropenem, ticarcillin, piperacillin + MTZ\tNR/No\tNone\tNR\tDischarged\t2013 [64]\t\n72/F\tColon cancer with peritoneal carcinosis\tTumor resection, colon fistula to skin and bladder, diarrhea\tNR\tNR/NR\tB. fragilis\tNR\tDied\t2013 [54]\t\n69/M\tParaparesis, recurrent UTI\tIschemic colitis, diarrhea, operation for abdominal aneurysm\tYes for UTI\tNR/NR\tNone\tSurgery (Aneurysm prosthesis)\tRecovered\t2013 [54]\t\n57/M\tMantle cell lymphoma\tAbdominal pain, intra-abdominal tumor and cecum perforation\tNone\tNR/NR\tNone\tiv VA + MTZ\tRecovered then discharged\t2013 [65]\t\n\n\n\t\n2004–2013\tUSA, 11 patients:\t10/11 had diarrhea\tAll of them\t11NT/5Yes (10 stools tested)\t3 Monomicrobial\t1 ATB/10 surgery + ATB\t3 Died/8 Recovered\t2014 [28]\t\n88/F\tPeptic ulcer disease after partial gastrectomy\tC. difficile colitis, lower gastro-intestinal bleed\tYes\t\tB. fragilis, E. coli, P. aeruginosa\toral MTZ, iv cefepime, iv ciprofloxacin\tRecovered\t2014\t\n75/F\tSquamous cell carcinoma of mouth after resection\tCecal impaction and rupture after laparotomy\tYes\t\tCandida tropicalis\tAbdominal washouts, meropenem\tDied 17 days later\t2014\t\n46/F\tHepatic adenoma after resection\tAlcoholic hepatitis and ascites\tYes\t\tEnterococcus species, Candida species, Klebsiella species\tParacentesis, MTZ, cefepime\tRecovered\t2014\t\n41/F\tAlcohol abuse after inguinal hemia repair\tRecurrent groin cellulitis\tYes\t\tClostridium orbiscindens\tDebridement of groin infection, meropenem, linezolid\tRecovered\t2014\t\n47/F\tCrohn disease, multiple suicide attempts after self-stab to abdomen leading to liver laceration\tSelf-inflicted abdominal wounds, suspicion for factitious contamination\tYes\t\tEnterococcus species, Clostridium ramosum, Bacteroides species\tWound debridement Pip-Taz\tRecovered\t2014\t\n79/F\tColorectal cancer after resection, C. difficile colitis\tOvarian cyst after oophorectomy, postoperative confusion, ascites\tYes\t\tNone\tParacentesis, VA, Pip-Taz\tDied 7 days later\t2014\t\n80/F\tDiabetes mellitus, congestive heart failure, COPD, stroke\tDiverticulitis after laparotomy\tYes\t\tE. coli\tAbdominal washout, cefepime\tDied 6 days later\t2014\t\n51/F\tIleal neuroendocrine tumor, Crohn disease after ileal and sigmoid resection, C. difficile colitis\tAnastomotic breakdown and postoperative fever\tYes\t\tNone\tAnastomotic takedown, colostomy, washout, levofloxacin, MTZ\tRecovered\t2014\t\n35/M\tCongenital pancreatic duct abnormality after pancreatectomy, splenectomy, C. difficile colitis\tRecurrent polymicrobial bacteremia and skin abscesses\tYes\t\tBlautia coccoides, K. pneumoniae, E. coli\tSkin debridement meropenem, linezolid\tRecovered\t2014\t\n56/F\tCOPD, concurrent C. difficile colitis, small intestinal bowel obstruction after adhesiolysis\tAbdominal compartment syndrome, surgical wound infection\tYes\t\tNone\tWound debride, MTZ, VA\tRecovered\t2014\t\n27/F\tCrohn disease, recurrent C. difficile colitis\tPrevious right hemicolectomy and ileostomy\tYes\t\tCitrobacter species, Streptococcus anginosus\tAnastomotic takedown, washout, MTZ, VA, ertapenem\tRecovered\t2014\t\n40/M\tAlcohol liver disease\tAbdominal pain, vomiting, cirrhosis, gastrohepatic varices, colitis\tNone\tNR/Yes\tNone\tiv VA + Pip-Taz\tDied\t2015 [51]\t\nNeonate/NR\tNEC\tLarge bowel wall pneumatosis with out perforation\tNone\tNT/NT\tNone\tVA+ MTZ +gentamicin, Pip-Taz + MTZ\tRecovered\t2016 [66]\t\n54/M\tRectal adeno-carcinoma, colostomy, chemotherapy\tSevere sepsis\tImipenem\tYes/Yes\tNone\tiv and oral MTZ\tRecovered\tPresent Case 1\t\n62/F\tLung cancer with cancerous lesions of liver, vertebrae and pelvis\tColon perforation, hemicolectomy and end colostomy\tCefotaxime + spiramycin, Pip-Taz, ciprofloxacin\tYes/Yes\tB. fragilis\tiv VA, oral MTZ, other antimicrobials\tDied\tPresent Case 2\t\nNR (Not reported), NT (Not tested).\n\nCNS: Coagulase-negative Staphylococcus spp., DAT: diagnosis at autopsy, UTI: urinary tract infection, iv: intravenous, GI: gastrointestinal, NEC: Necrotizing enterocolitis, AML: Acute myeloid leukemia, CAD: Coronary artery disease, COPD: Chronic obstructive pulmonary disease, VA: Vancomycin, MTZ: Metronidazole, Co: Cotrimoxazole, Pip-Taz: Piperacillin − Tazobactam, C3G: Third cephalosporin generation, FQ: Fluoroquinolone, ATB: antibacterial.\n\n1 Antimicrobial exposure in the 3 months preceding CDB.\n\n2 Abscess toxin+.\n\n3 Heart Blood (Autopsy).\n\n4 A-B- Binary toxin+.\n\n5 Discharged: Home or hospice care.\n\n\n\nPatient characteristics\nAnalysis of the 58 cases described in the literature and of the two cases presented here showed that CDB affected male as well as female (33/59, [56%] and 26/59, [44%] respectively). Excluding two neonates, two infants (5 months and 19 months), and one 3-year-old child, the mean age (±standard deviation) was 56.1 ± 19.7 years (range, 12–88 years). Concerning infants or neonates, they may have inflammatory intestinal conditions favoring CDI [40], [41]. About 47% (28/60) of the described patients are over sixty and among them 35% (21/60) are between 60 and 79 years old. The data suggest that advanced age may be a risk factor for CDB (Fig. 1).Fig. 1 Distribution of the 60 recorded CDB cases according to age and sex. (*: 1 neonate with not reported sex by Bergamo et al.).\n\nFig. 1\n\nAnalysis of the data from the combined 60 cases showed that 93% (56/60) of patients had severe underlying diseases (e.g. colon carcinoma, liver cirrhosis, leukemia, cardiovascular disease), 85% (41/48) had abdominal setting (e.g. abdominal pain, diarrhea, bowel surgery, colitis), and 84% (36/43) had previous antibacterial treatment. Interestingly, only three patients (6%) presented diarrhea as the single abdominal symptom, 17% (8/48) developed this symptom with other abdominal disturbances, 62% (30/48) had abdominal signs without diarrhea and the others (7/48, [15%]) presented other clinical features (Table 3). The cases described in the recent experience of Gupta et al., not included in analysing proportions of CDB associated symptoms, were globally reported to have diarrhea for 10 patients of 11 and 3 of 11 with inflammatory bowel disease without specifying if the concerned patients presented other abdominal symptoms. Concerning diarrhea, there was a significant difference between Gupta et al. patients and the other literature cases (10/11, [91%] vs. 11/48, [23%]; p < 0.0001). However, there was no difference between Lee et al. series and the other literature cases with or without Gupta et al. cases (4/12 [33%] vs. 7/36 [19%]; p = 0.43, and 4/12 [33%] vs. 17/47 [36%] respectively; p = 1.0). These data show that CDB is not systematically associated with documented diarrhea while the presence of other abdominal symptoms was associated with bacteremia. Usually CDB was often preceded by gastrointestinal disorders (e.g. abdominal pain, enterocolitis or surgical and spontaneous disruption of the colon), or by previous exposure to cytotoxic drugs or antimicrobials.Table 3 Overview of the C. difficile toxinogenic status both in blood and in stools and its relationship with the clinical setting.\n\nTable 3Toxin status in Blood/Stools\tDiarrhea\tDiarrhea and abdominal signs\tAbdominal features\tOther symptoms\tNRa\tGupta et al. cases\tTotal\t\nYes/Yes\t–\t2\t3\t1\t–\t–\t6\t\nYes/No\t–\t1\t1\t–\t–\t–\t2\t\nYes/NR\t–\t1\t6\t–\t1\t–\t8\t\nNo/NR\t–\t1\t4\t2\t–\t–\t7\t\nNT/Yes\t1\t1\t3\t–\t–\t5\t10\t\nNT/No\t1\t–\t2\t–\t–\t5\t8\t\nNR, NT/NR, NT\t1\t2\t11\t4\t–\t1\t19\t\nTotal\t3\t8\t30\t7\t1\t11\t60\t\nNR (Not reported), NT (Not tested).\n\na One of Lee et al. cases: dead on arrival.\n\n\n\nIt may be assumed that the bowel is the primary site of clostridial colonization which may predispose C. difficile to spread by translocation or intestinal perforation [17], [42]. Indeed, monomicrobial CDB was present as frequently as CDB associated with additional pathogens to C. difficile (30/60, [50%]), which is similar to the 50% (6/12) of Lee et al. series, even if it has been reported that CDB were rather polymicrobial infections probably because of the small number of cases recorded at that time [27], [43], [44], [45]. In CDB, isolates other than C. difficile are often also from the gut flora. This indicates the ability of intestinal bacteria to translocate in patients with bowel damage. However, it is still unclear whether intestinal infection with C. difficile is the primary infection that promotes bacterial translocation or whether an underlying disease (e.g. colonic ischemia, intestinal tract disorders or disruption of mucosal barriers) is the initial step that facilitates bacteria dissemination. The use of proton pump inhibitor (PPIs) was not mentioned in the majority of published reports except in one recent study where 9 of 11 patients with CDB (82%) had received PPI for various indications [28].\n\nStrain toxin production\nThe potential of C. difficile isolates from blood to produce toxins A and B in vitro has been rarely investigated. Among the 23 CDB cases where the toxigenic status of blood strains was mentioned, 16 stains were toxigenic (70%) and 7 (30%) were non-toxigenic (Table 3). The direct detection of toxins in blood has never been reported. One bacteremia due to binary-toxin producing strain was reported by Elliott et al. [46].\n\nIn 26 of the 60 cases, the stools of patients with CDB were tested for C. difficile. In ten cases (38%) the isolate was non-toxigenic while in 16 cases (62%) it was toxigenic. Among the 16 patients with CDB due to a toxigenic strain isolated in blood, six had a toxigenic and two a non-toxigenic strain in their stools, the latter suggesting the presence of two different strains in the gut. It is still unknown whether toxigenic strains may translocate more easily into the blood than non-toxigenic strains. In addition, the rare patients who had only diarrhea, toxin is positive in stools as well as negative but the presence of abdominal symptoms with or without diarrhea appear more common with the presence of toxigenic strain. This data need to be further investigated.\n\nAbout a third of the reviewed cases have non documented toxin status for both blood and stool (19/60, 32%). In blood, most toxigenic status of isolated strains (37/60, 62%) was lacking, possibly due to the non-systematic toxin search in extra-intestinal samples. Indeed, stools were not tested in more than half of cases (34/60, 57%), which is perhaps likely due to the absence of diarrhea.\n\nTyping of strains isolated from blood culture has been rarely reported, probably because molecular typing was uncommon when CDB cases were described in the early 1990s. Gérard et al. characterized a serogroup C strain and McGill et al. reported two ribotype 106 strains and one ribotype 001 [36], [47]. Another case report detected a ribotype 106 from bacteremia and breast abscess [48]. One of two bacteremia cases recently reported by Hemminger et al. was due to the epidemic and hypervirulent NAP1 strain (027/BI, toxinotype III, binary toxin-positive), and the other was due to NAP-4 [49]. In the present series, Case 2 was due to a strain of ribotype 078/126 which is one of the ribotypes most frequently found in France [50]. So far, there is no evidence indicating that one specific ribotype may be more often responsible for CDB than another.\n\nMortality\nCDB-associated mortality rates vary among studies. The present comprehensive review indicates a crude mortality rate of 35% (n = 21/60) which is in line with the early reviews of Jacobs et al. and Libby et al. (20% [2/10], p = 0.48; 53% [8/15], p = 0.19 respectively), with that reported by Lee et al. (41.7%, 5/12, p = 0.75) and also similar to the recent study of Gupta et al. (27% [3/11], p = 0.74) [27], [28], [43], [44]. The latest review of Kazanji et al. concluded to the same rate (39%, p = 0.68) [51]. However, the mortality attributable to CDB remains difficult to assess because many patients with CDB have severe co-morbidities and underlying conditions.\n\nTreatment\nAntimicrobial therapy for CDB was highly variable and most of the time adapted to cover polymicrobial bacteremia. As CDB is a rare infection, there are no studies or specific guidelines for the appropriate therapy, but metronidazole (MTZ) and vancomycin (VA) are the commonly treatment options used to deal with CDB [27], [28], [43]. In CDB Case 1 we reported here, the patient was treated first with intravenous (IV) and then oral MTZ, and the septicemia rapidly resolved. Most commonly used treatments include VA or MTZ alone or in combination and in this review about 67% (35/52) had one of these two antimicrobials or both and eight patients had their therapeutic coverage not specified (Table 4). Treatment was usually started intravenously and continued orally. Sixteen patients were treated with MTZ (one IV and orally, one orally, not specified in the remaining cases), ten with VA (three IV, two orally and IV, one orally, four not specified) and nine with VA or MTZ sequentially or simultaneously (usually IV initially, then orally). These specific treatments against C. difficile were used alone or associated with other antimicrobials and surgery. MTZ and VA are usually associated with other antimicrobials with extended spectrum and against anaerobes according to the clinical setting. Of note, patients with MTZ, VA or both had a reduced rate of mortality than those with other antimicrobials (22% [6/27], 75% [6/8]; p = 0.011). The crude mortality rate in patients managed with associated medical and surgical therapy was 20% (7/35) compared to 59% (10/15) in those who did not receive antimicrobial therapy including MTZ or VA or both (p = 0.005). Therefore, management with medical therapy involving drugs against C. difficile appears to prevent death during CDB episode. Hence, the choice of treatment, the way the drugs are administered and the treatment duration may change but early patient management and antibacterial coverage may critically influence outcome.Table 4 Clinical management of the 60 patients with CDB and the crude rate of mortality.\n\nTable 4Medical Management\tMTZ or/and VA\tOther ATB\tOther ATB and Surgery\tSurgery alone\tNo therapy\tNRa\tTotala\t\n\tType\tCD therapy\tCD therapy and surgery\t\t\t\t\t\t\t\nNo. of patients (No. of death)\tMTZ\t5 (1)\t0\t8 (6)\t5 (2)\t2 (1)\t2 (1)\t8 (4)\t60 (21)*\t\nMTZ + ATB\t6 (1)\t5 (0)\t\nVA\t4 (0)\t0\t\nVA + ATB\t5 (1)\t1 (1)\t\nMTZ + VA\t2 (1)\t1 (0)\t\nMTZ + VA + ATB\t5 (2)\t1 (0)\t\n\n\n\t\nRate of mortality, p value\t\t22% (6/27)\t13% (1/8)\t75%\t40%\t50%\t50%\t50%\t35%*\t\n20% (7/35) vs. 62% (8/13), p = 0.012\t\n20% (7/35) vs. 60% (9/15), p = 0.009\t\n20% (7/35) vs. 59% (10/17), p = 0.005\t\nMTZ: Metronidazole, VA: Vancomycin, ATB: other antibacterial, CD therapy: C. difficile therapy (MTZ or/and VA), NR (Not reported).\n\na The case reported by Smith et al. with NR therapy and NR outcome status, accounted in mortality rate, did not change the conclusion. Surgery included all operations and other procedures used to resolve CDB and the implicated source of bacteria dissemination (e.g. abdominal washout, debridement).\n\n\n\nIn conclusion, CDB remains uncommon. It occurs mostly in patients with risk factors such as chronic underlying diseases, advanced age, coexisting gastrointestinal pathologic conditions and antimicrobial exposure. Outcome depends on various factors including early diagnosis, severity of the underlying conditions and antimicrobial therapy. MTZ and VA are the two drugs currently used to cover CDB. However, it is difficult to assess the most effective treatment since data on outcome are not systematically reported.\n\nContributors\nM. DOUFAIR, reviewed the literature, wrote the text and set figure and tables. F. BARBUT and C. ECKERT provided help and advices for writing. C. AMANI-MOIBENI and J-D. GRANGE wrote the case 1 whereas L. DRIEUX and L. BODIN wrote the second case. M. DENIS gave advices concerning clinical management.\n\nDeclaration of interests\nWe declare that we have no competing interests\n\nAcknowledgment\nWe thank Ekkehard COLLATZ for his help to manuscript correction.\n==== Refs\nReferences\n1 Kuipers E.J. Surawicz C.M. Clostridium difficile infection Lancet 371 2008 1486 1488 18456087 \n2 Goudarzi M. Seyedjavadi S.S. Goudarzi H. Mehdizadeh Aghdam E. Nazeri S. Clostridium difficile infection: epidemiology, pathogenesis, risk factors, and therapeutic options Scientifica 2014 2014 916826 24991448 \n3 Eckert C. Lalande V. Barbut F. Clostridium difficile colitis Rev Prat 65 2015 21 25 25842418 \n4 Eckert C. Barbut F. Clostridium-difficile-associated infections Méd Sci MS 26 2010 153 158 \n5 Magill S.S. Edwards J.R. Bamberg W. Multistate point-prevalence survey of health care-associated infections N Engl J Med 370 2014 1198 1208 24670166 \n6 Yamagishi Y. Mikamo H. 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Clostridium difficile bacteremia, Taiwan Emerg Infect Dis 16 2010 1204 1210 20678312 \n44 Jacobs A. Barnard K. Fishel R. Gradon J.D. Extracolonic manifestations of Clostridium difficile infections: presentation of 2 cases and review of the literature Medicine (Baltimore) 80 2001 88 101 11307591 \n45 Daruwala C. Mercogliano G. Newman G. Ingerman M.J. Bacteremia due to clostridium difficile: case report and review of the literature Clin Med Case Rep 2 2009 5 9 24179365 \n46 Elliott B. Reed R. Chang B.J. Riley T.V. Bacteremia with a large clostridial toxin-negative, binary toxin-positive strain of Clostridium difficile Anaerobe 15 2009 249 251 19723585 \n47 Gérard M. Defresne N. Van der Auwera P. Meunier F. Polymicrobial septicemia with Clostridium difficile in acute diverticulitis Eur J Clin Microbiol Infect Dis 8 1989 300 302 2497002 \n48 Durojaiye O. Gaur S. Alsaffar L. Bacteraemia and breast abscess: unusual extra-intestinal manifestations of Clostridium difficile infection J Med Microbiol 60 2011 378 380 21127155 \n49 Hemminger J. Balada-Llasat J.-M. Raczkowski M. Buckosh M. Pancholi P. Two case reports of Clostridium difficile bacteremia, one with the epidemic NAP-1 strain Infection 39 2011 371 373 21509425 \n50 Eckert C. Coignard B. Hebert M. Clinical and microbiological features of Clostridium difficile infections in France: the ICD-RAISIN 2009 national survey Méd Mal Infect 43 2013 67 74 23498135 \n51 Kazanji N. Gjeorgjievski M. Yadav S. Mertens A.N. Lauter C. Monomicrobial vs polymicrobial clostridium difficile bacteremia: a case report and review of the literature Am J Med 128 2015 e19 26 \n52 Alpern R.J. Dowell V.R. Nonhistotoxic clostridial bacteremia Am J Clin Pathol 55 1971 717 722 5572080 \n53 Ellner P.D. Granato P.A. May C.B. Recovery and identification of anaerobes: a system suitable for the routine clinical laboratory Appl Microbiol 26 1973 904 913 4588198 \n54 Mattila E. Arkkila P. Mattila P.S. Tarkka E. Tissari P. Anttila V.-J. Extraintestinal clostridium difficile infections Clin Infect Dis 57 2013 e148 153 23771984 \n55 Saginur R. Fogel R. Begin L. Cohen B. Mendelson J. Splenic abscess due to Clostridium difficile J Infect Dis 147 1983 1105 6854068 \n56 Genta V.M. Gilligan P.H. McCarthy L.R. Clostridium difficile peritonitis in a neonate. A case report Arch Pathol Lab Med 108 1984 82 83 6546347 \n57 Spencer R.C. Courtney S.P. Nicol C.D. Polymicrobial septicaemia due to Clostridium difficile and Bacteroides fragilis Br Med J Clin Res Ed 289 1984 531 532 \n58 Rampling A. Warren R.E. Bevan P.C. Hoggarth C.E. Swirsky D. Hayhoe F.G. Clostridium difficile in haematological malignancy J Clin Pathol 38 1985 445 451 3857233 \n59 Studemeister A.E. Beilke M.A. Kirmani N. Splenic abscess due to Clostridium difficile and Pseudomonas paucimobilis Am J Gastroenterol 82 1987 389 390 3565349 \n60 Byl B. Jacobs F. Struelens M.J. Thys J.P. Extraintestinal clostridium difficile infections Clin Infect Dis 22 1996 712 8729213 \n61 Cid A. Juncal A.R. Aguilera A. Regueiro B.J. González V. Clostridium difficile bacteremia in an immunocompetent child J Clin Microbiol 36 1998 1167 1168 9542965 \n62 Duthilly A. Blanckaert K. Thielemans B. Simon M. Cattoen C. [Clostridium difficile bacteremia] Presse Médicale Paris Fr 1983 30 2001 1825 1826 \n63 Nakamur I. Kunihiro M. Kato H. Bacteremia due to Clostridium difficile Kansenshōgaku Zasshi J Jpn Assoc Infect Dis 78 2004 1026 1030 \n64 Choi J.-L. Kim B.-R. Kim J.-E. A case of Clostridium difficile bacteremia in a patient with loop ileostomy Ann Lab Med 33 2013 200 202 23667848 \n65 Kaufman E. Liska D. Rubinshteyn V. Nandakumar G. 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"keywords": "Clostridium difficile bacteremia; Outcome; Toxin; Treatment",
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"publication_types": "D016428:Journal Article; D002363:Case Reports",
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"title": "Clostridium difficile bacteremia: Report of two cases in French hospitals and comprehensive review of the literature.",
"title_normalized": "clostridium difficile bacteremia report of two cases in french hospitals and comprehensive review of the literature"
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"abstract": "BACKGROUND\nMyasthenia gravis (MG) is an autoimmune neuromuscular disease whose treatment encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants. Kaposi's sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or immunosuppression, mainly corticosteroids.\n\n\nMETHODS\nWe present two cases of MG patients treated with oral steroids who developed KS. Patient 1 was diagnosed with three oral KS lesions. Prednisone was discontinued with lesion regression and stabilization, while azathioprine and pyridostigmine prompted control of MG. Patient 2 developed KS lesions on the trunk and lower limbs while taking prednisone and azathioprine. Steroid tapering was started but new oral and lymph nodal lesions appeared. Paclitaxel therapy was introduced and the patient experienced pulmonary embolism and developed sensitive neuropathy. Complete remission of KS lesions was achieved and maintained with azathioprine and pyridostigmine as MG medications.\n\n\nCONCLUSIONS\nKS is an uncommon but clinically relevant adverse event (AE) often induced by steroid therapy. It can be controlled by steroid withdrawal but could necessitate chemotherapy, which associates with further potential AEs. Skin evaluation should be performed in all patients with chronic steroid therapy. Steroid-sparing strategies, including new drugs, could reduce KS and other steroid-related comorbidities. HHV-8 testing should be considered before starting chronic immunosuppression.",
"affiliations": "Department of Neuroimmunology and Neuromuscular Diseases, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milano, Italy.;Department of Neuroimmunology and Neuromuscular Diseases, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milano, Italy.;Department of Neuroimmunology and Neuromuscular Diseases, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milano, Italy.;U.O. Dermatologia, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.;U.O. Dermatologia, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.;Department of Neuroimmunology and Neuromuscular Diseases, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milano, Italy.;Department of Neuroimmunology and Neuromuscular Diseases, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milano, Italy. renato.mantegazza@istituto-besta.it.",
"authors": "Frangiamore|Rita|R|;Giossi|Riccardo|R|https://orcid.org/0000-0002-7352-9445;Vanoli|Fiammetta|F|;Tourlaki|Athanasia|A|;Brambilla|Lucia|L|;Maggi|Lorenzo|L|https://orcid.org/0000-0002-0932-5173;Mantegazza|Renato|R|http://orcid.org/0000-0002-9810-5737",
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"country": "Italy",
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"doi": "10.1007/s10072-020-04971-9",
"fulltext": "\n==== Front\nNeurol Sci\nNeurol Sci\nNeurological Sciences\n1590-1874\n1590-3478\nSpringer International Publishing Cham\n\n33404862\n4971\n10.1007/s10072-020-04971-9\nBrief Communication\nIatrogenic Kaposi’s sarcoma in myasthenia gravis: learnings from two case reports\nFrangiamore Rita 1\nhttps://orcid.org/0000-0002-7352-9445\nGiossi Riccardo 12\nVanoli Fiammetta 13\nTourlaki Athanasia 4\nBrambilla Lucia 4\nhttps://orcid.org/0000-0002-0932-5173\nMaggi Lorenzo 1\nhttp://orcid.org/0000-0002-9810-5737\nMantegazza Renato renato.mantegazza@istituto-besta.it\n\n1\n1 grid.417894.7 0000 0001 0707 5492 Department of Neuroimmunology and Neuromuscular Diseases, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milano, Italy\n2 grid.4708.b 0000 0004 1757 2822 Department of Oncology and Onco-Hematology, Postgraduate School of Clinical Pharmacology and Toxicology, Università degli Studi di Milano, Milano, Italy\n3 grid.7841.a Neuromuscular and Rare Disease Center, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), SAPIENZA University, Sant’Andrea Hospital, Rome, Italy\n4 grid.414818.0 0000 0004 1757 8749 U.O. Dermatologia, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milano, Italy\n6 1 2021\n6 1 2021\n2021\n42 5 20812083\n13 10 2020\n5 12 2020\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 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/.\nIntroduction\n\nMyasthenia gravis (MG) is an autoimmune neuromuscular disease whose treatment encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants. Kaposi’s sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or immunosuppression, mainly corticosteroids.\n\nCase reports\n\nWe present two cases of MG patients treated with oral steroids who developed KS. Patient 1 was diagnosed with three oral KS lesions. Prednisone was discontinued with lesion regression and stabilization, while azathioprine and pyridostigmine prompted control of MG. Patient 2 developed KS lesions on the trunk and lower limbs while taking prednisone and azathioprine. Steroid tapering was started but new oral and lymph nodal lesions appeared. Paclitaxel therapy was introduced and the patient experienced pulmonary embolism and developed sensitive neuropathy. Complete remission of KS lesions was achieved and maintained with azathioprine and pyridostigmine as MG medications.\n\nConclusions\n\nKS is an uncommon but clinically relevant adverse event (AE) often induced by steroid therapy. It can be controlled by steroid withdrawal but could necessitate chemotherapy, which associates with further potential AEs. Skin evaluation should be performed in all patients with chronic steroid therapy. Steroid-sparing strategies, including new drugs, could reduce KS and other steroid-related comorbidities. HHV-8 testing should be considered before starting chronic immunosuppression.\n\nKeywords\n\nMyasthenia gravis\nKaposi’s sarcoma\nImmunosuppressive agents\nCorticosteroids\nCase report\nissue-copyright-statement© Fondazione Società Italiana di Neurologia 2021\n==== Body\nBackground\n\nMyasthenia gravis (MG) is an autoimmune disease mostly associated with anti-acetylcholine receptor (AChR) antibodies. The clinical hallmark is weakness worsened by exercise. Therapy encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants [1]. Kaposi’s sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or pharmacological immunosuppression, mainly corticosteroids [2]. Here, we describe two patients with MG who developed iatrogenic-KS (iKS). Both patients provided written informed consent.\n\nCase report\n\nPatient 1 is a male diagnosed with anti-AChR-positive generalized MG (gMG) without thymus involvement, at 83 years of age (March 2015). As pyridostigmine provided partial improvement, prednisone 50 mg/day was initiated 6 months after diagnosis, with benefit. Body weight was 80 kg, corresponding to a 0.63 mg/kg/day dose of prednisone. Steroid-induced diabetes developed; hence, azathioprine was initiated, and prednisone tapered to 5 mg/day (May 2016), corresponding to a 0.06 mg/kg/day dose of prednisone. Body weight remained stable and steroid therapy maintained at this dosage. In September 2017, the patient was referred to a dermatologist to assess a small violaceous and two bluish macules on the tongue and hard palate (Fig. 1a). Biopsy analyses revealed typical KS features. Serology tested negative for HIV and positive for HHV-8. Staging examinations for KS, including fecal occult blood test, esophagogastroduodenoscopy, abdomen ultrasound, and otolaryngologic examination were negative [3]. iKS diagnosis was made and steroid was discontinued. Follow-up at 3, 6, and 12 months confirmed the presence of the small nodule on the tongue, while the two macules had completely regressed. To date, the nodule remains stable and MG is controlled with pyridostigmine and azathioprine 100 mg/day.Fig. 1 Clinical images showing Kaposi’s sarcoma lesions. a One nodule and two macules (arrows) on the tongue in Patient 1; b angiomatous nodules, plaques, and edema on the lower limbs in Patient 2; voluminous tumor on the hard palate in Patient 2 c before and d after steroid interruption and paclitaxel chemotherapy. e Hematoxylin-eosin stain of a biopsy specimen from Patient 2 showed proliferation of spindle cells and numerous extravasated erythrocytes between dermal collagen bundles. f The spindle cells stained positively with HHV-8 latency-associated nuclear antigen (LNA)-1\n\nPatient 2 is a male diagnosed with anti-AChR-positive gMG at the age of 60 (October 2015), without thymus involvement. Pyridostigmine 60 mg four times daily (QID) and prednisone 65 mg/day were started. Body weight was 108 kg, corresponding to a 0.60 mg/kg/day dose of prednisone. In December 2015, azathioprine 150 mg/day was introduced and, due to limited efficacy, plasmapheresis was often used. Body weight was 100 kg, and prednisone 62.5 mg/day (0.63 mg/kg/day). In October 2016, the patient was referred to the dermatology department for numerous violaceous macules, plaques, and nodules on the lower limbs and reddish-purple plaques on the trunk. Bilateral ankle lymphoedema was present (Fig. 1b). A biopsy confirmed the diagnosis of KS, with serology positive for HHV-8 and negative for HIV. Staging examinations for KS were negative [3]. Whole blood count and biochemistry were normal. Patient body weight was 94 kg. MG therapy was prednisone 50 mg/day (0.53 mg/kg/day), azathioprine 150 mg/day, and pyridostigmine 90 mg QID. Upon iKS diagnosis, over the next 3 months, prednisone was tapered to 30 mg/day (0.32 mg/kg/day) and azathioprine was increased to 175 mg/day. Nevertheless, new KS lesions developed on the hard palate (Fig. 1c) and in left inguinal lymph nodes. Further lesions appeared on lower limbs and external ear during prednisone tapering to 5 mg/day. Thus, the patient stopped prednisone and started intravenous paclitaxel 100 mg/m2 weekly for 13 administrations with regression of all KS lesions (Fig. 1d). Five days after paclitaxel initiation, pulmonary embolism was detected and treated with enoxaparin with complete resolution. Moreover, the patient developed paclitaxel-induced axonal sensitive neuropathy. Three years after treatment, KS was still in remission, and MG symptoms were stable with azathioprine 200 mg/day plus pyridostigmine 60 mg QID.\n\nDiscussion\n\nPresented cases show the uncommon but clinically relevant adverse event of iKS, often induced by chronic steroid treatment. Notably, iKS generally occurs within the first 2 years of steroid treatment and about 8% of patients with iKS unrelated to organ transplants had MG [2]. iKS can be effectively controlled by steroid withdrawal (Patient 1). Additional chemotherapy is sometimes necessary, possibly causing additional severe comorbidities such as polyneuropathy and pulmonary embolism (Patient 2).\n\nOral corticosteroids are a cornerstone treatment in MG, though associated with relevant adverse events including iKS, interestingly even at low doses [2, 4, 5]. Notably, our patients received a maximum prednisone dose of 0.63 mg/kg/day. These doses are conformant to national recommendations of 0.75–1 mg/kg/day for initial gMG treatment, and even lower [6]. Patient 1 developed iKS when he was assuming 0.06 mg/kg/day of prednisone dose while being clinically stable for more than a year. Patient 2 developed iKS when he was slowly tapering prednisone (0.53 mg/kg/day) after the initial dose while being not clinically stable and often needing plasmaphereses.\n\niKS onset associates with immune-suppression through a direct effect on lymphangioendothelial cells, by downregulating the inhibition of endothelial cell growth [2]. It would be advisable to check for any suspicious skin or mucosal lesions, which are the most frequent localizations of iKS [2], in all patients on chronic corticosteroids. Moreover, considering the high seroprevalence of HHV-8 in regions such as the Mediterranean area (ranging 40 to 80%), it would be also advisable to test for HHV-8 to identify high-risk patients in which to possibly avoid corticosteroid treatment and to perform regular dermatologic assessments [7].\n\nReduction of iKS and other frequent steroid-related comorbidities might be achieved using new drugs, such as neonatal Fc receptor or complement inhibitors, which do not associate with reduced cellular immunity. As HHV-8 exploits the complement system to promote latent infection, targeting complement could be a useful therapeutic strategy but must be carefully investigated [8].\n\nAwareness of iKS as a consequence of chronic corticosteroid treatment should be fostered and screening for HHV-8 considered before starting chronic immunosuppression.\n\nAuthors’ contributions\n\nR.F. and R.G. equally contributed to paper conception, data acquisition and interpretation, and paper drafting. F.V. and A.T. contributed to data acquisition and interpretation, and paper drafting. L.B. contributed to data acquisition. L.M. and R.M. contributed to data acquisition and interpretation and revised the paper.\n\nCompliance with ethical standards\n\nConflicts of interest\n\nR.F. received support for congress participations from Argenx, Biogen, Catalyst, Merck, Momenta, Novartis, and Sanofi Genzyme. R.G. received support for congress participation from Mylan. F.V. received support for congress participations from Biogen, Kedrion, and Sanofi Genzyme. A.T. reports no competing interest. L.B. reports no competing interest. L.M. received honoraria for speaking and compensation for congress participations from Biogen and Sanofi Genzyme. R.M. received fees and honoraria for meeting, travel, and advisory board from Alexion, Argenx, Biomarin, Catalyst, Merck Serono, UCB.\n\nEthics approval\n\nThe Ethics Committee of Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta requires the patient consent for case reports publication.\n\nConsent for publication\n\nWritten informed consent for publication was received by the patients for the usage of anonymized clinical data and images.\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nRita Frangiamore and Riccardo Giossi contributed equally to this work.\n==== Refs\nReferences\n\n1. Gilhus NE Tzartos S Evoli A Myasthenia gravis Nat Rev Dis Prim 2019 5 1 19 10.1038/s41572-018-0051-2 30617281\n2. Brambilla L, Tourlaki A, Genovese G (2017) Iatrogenic Kaposi’s sarcoma: a retrospective cohort study in an Italian tertiary care centre. Clin Oncol 29:e165–e171. 10.1016/j.clon.2017.05.008\n3. Brambilla L, Genovese G, Berti E, Peris K, Rongioletti F, Micali G, Ayala F, Della Bella S, Mancuso R, Calzavara Pinton P, Tourlaki A (2020) Italian guidelines for the diagnosis and treatment of classic and iatrogenic Kaposi's sarcoma. G Ital Dermatol Venereol. 10.23736/S0392-0488.20.06703-6\n4. Brambilla L Esposito L Nazzaro G Tourlaki A Onset of Kaposi sarcoma and Merkel cell carcinoma during low-dose steroid therapy for rheumatic polymyalgia Clin Exp Dermatol 2017 42 702 704 10.1111/ced.13151 28598021\n5. Vincent T Moss K Colaco B Venables PJW Kaposi’s sarcoma in two patients following low-dose corticosteroid treatment for rheumatological disease Rheumatology 2000 39 1294 1296 10.1093/rheumatology/39.11.1294 11085817\n6. Evoli A Antonini G Antozzi C DiMuzio A Habetswallner F Iani C Inghilleri M Liguori R Mantegazza R Massa R Pegoraro E Ricciardi R Rodolico C Italian recommendations for the diagnosis and treatment of myasthenia gravis Neurol Sci 2019 40 1111 1124 10.1007/s10072-019-03746-1 30778878\n7. Minhas V Wood C Epidemiology and transmission of Kaposi’s sarcoma-associated herpesvirus Viruses 2014 6 4178 4194 10.3390/v6114178 25375883\n8. Dittmer DP Damania B Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy J Clin Invest 2016 126 3165 3175 10.1172/JCI84418 27584730\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1590-1874",
"issue": "42(5)",
"journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology",
"keywords": "Case report; Corticosteroids; Immunosuppressive agents; Kaposi’s sarcoma; Myasthenia gravis",
"medline_ta": "Neurol Sci",
"mesh_terms": "D019288:Herpesvirus 8, Human; D006801:Humans; D007049:Iatrogenic Disease; D007165:Immunosuppression Therapy; D009157:Myasthenia Gravis; D012514:Sarcoma, Kaposi",
"nlm_unique_id": "100959175",
"other_id": null,
"pages": "2081-2083",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Iatrogenic Kaposi's sarcoma in myasthenia gravis: learnings from two case reports.",
"title_normalized": "iatrogenic kaposi s sarcoma in myasthenia gravis learnings from two case reports"
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"abstract": "In non-small-cell lung cancer (NSCLC) refractory to standard therapy and which lacks well-known oncogenic drivers, genomic profiling can still identify genomic alterations that may suggest potential sensitivity to targeted therapy. PTEN mutation in NSCLC may be sensitizing to analogs of rapamycin such as everolimus or temsirolimus, but more investigation is needed. We report the case of a patient with metastatic NSCLC harboring a PTEN mutation as well as high tumor mutational burden and PD-L1 positivity with a durable response to temsirolimus, but refractory to a checkpoint inhibitor. Even in the event of failure of treatment with checkpoint inhibitors in the background of a case with a higher tumor mutational burden and PD-L1 positivity, targeting specific genomic alterations may still result in patient benefit.",
"affiliations": "Eastern Regional Medical Center, Cancer Treatment Centers of America, Philadelphia, PA, USA.;Foundation Medicine, Inc, Cambridge, MA, USA.;Foundation Medicine, Inc, Cambridge, MA, USA.;Foundation Medicine, Inc, Cambridge, MA, USA.;Foundation Medicine, Inc, Cambridge, MA, USA.;Foundation Medicine, Inc, Cambridge, MA, USA.;Eastern Regional Medical Center, Cancer Treatment Centers of America, Philadelphia, PA, USA.;Eastern Regional Medical Center, Cancer Treatment Centers of America, Philadelphia, PA, USA.",
"authors": "Parikh|Ankur R|AR|;Ali|Siraj M|SM|;Schrock|Alexa B|AB|;Albacker|Lee A|LA|;Miller|Vincent A|VA|;Stephens|Phil J|PJ|;Crilley|Pamela|P|;Markman|Maurie|M|",
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"fulltext": "\n==== Front\nLung Cancer (Auckl)Lung Cancer (Auckl)Lung Cancer: Targets and TherapyLung Cancer: Targets and Therapy1179-2728Dove Medical Press 10.2147/LCTT.S161738lctt-9-045Case ReportResponse to rapamycin analogs but not PD-1 inhibitors in PTEN-mutated metastatic non-small-cell lung cancer with high tumor mutational burden Parikh Ankur R 1Ali Siraj M 2Schrock Alexa B 2Albacker Lee A 2Miller Vincent A 2Stephens Phil J 2Crilley Pamela 1Markman Maurie 1\n1 Eastern Regional Medical Center, Cancer Treatment Centers of America, Philadelphia, PA, USA\n2 Foundation Medicine, Inc, Cambridge, MA, USACorrespondence: Ankur R Parikh, Eastern Regional Medical Center, Cancer Treatment Centers of America, 1331 E. Wyoming Avenue, Philadelphia, PA 19124, USA, Tel +1 215 537 7400, Email ankur.parikh@ctca-hope.com2018 18 5 2018 9 45 47 © 2018 Parikh et al. This work is published and licensed by Dove Medical Press Limited2018The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.In non-small-cell lung cancer (NSCLC) refractory to standard therapy and which lacks well-known oncogenic drivers, genomic profiling can still identify genomic alterations that may suggest potential sensitivity to targeted therapy. PTEN mutation in NSCLC may be sensitizing to analogs of rapamycin such as everolimus or temsirolimus, but more investigation is needed. We report the case of a patient with metastatic NSCLC harboring a PTEN mutation as well as high tumor mutational burden and PD-L1 positivity with a durable response to temsirolimus, but refractory to a checkpoint inhibitor. Even in the event of failure of treatment with checkpoint inhibitors in the background of a case with a higher tumor mutational burden and PD-L1 positivity, targeting specific genomic alterations may still result in patient benefit.\n\nVideo abstract\n\n\n\nKeywords\ngenomic profilingtemsirolimustargeted therapyimmunotherapy\n==== Body\nIntroduction\nLung cancer is one of the most common cancers diagnosed in the US. The 5-year survival upon diagnosis of stage IV lung cancer is 4%.1 Comprehensive genomic profiling is being used more frequently to help identify mutations in an individual patient’s non-small-cell lung cancer (NSCLC) to suggest benefit from targeted therapy or immunotherapy. We present the case of a patient with metastatic NSCLC found to harbor PTEN and STK11 alterations using comprehensive genomic profiling who responded to matched targeted therapy in the background of higher tumor mutational burden.\n\nCase history\nThe patient is a 62-year-old woman with a 60 pack-year smoking history who presented with stage IV lung adenocarcinoma in September 2012. She was found to have bilateral disease in her lungs, a right adrenal mass, and osseous metastasis. EGFR and ALK were queried by single gene molecular testing. The patient enrolled in a clinical trial and was treated with carboplatin, paclitaxel, and bevacizumab. She responded to therapy and was then placed on maintenance bevacizumab. She had disease progression in February 2013 and was treated with pemetrexed. Her disease progressed in November 2013, and so she was treated with docetaxel. Her computed tomography scans showed response at 3 months and 6 months; however, by 9 months, she had further disease progression including a new intracranial metastasis. She received stereotactic radiation to her intracranial metastasis in May 2014. She was then started on gemcitabine and found to have disease progression after 3 cycles.\n\nTo identify opportunities for possible benefit from targeted therapy, comprehensive genomic profiling (Foundation-One, Foundation Medicine, Inc., Cambridge, MA, USA) was performed on a biopsy of a right upper lobe lesion collected in December 2013, which revealed the following genomic alterations: PTEN D268fs*30, STK11 splice site 465-1G>T, p53 G293R, KEAP1 G480W, and LRP1B G528W, as well as tumor mutational burden of 18.9 mutations/megabase. On the basis of PTEN and STK11 alterations, the decision was made to treat the patient with weekly temsirolimus 25 mg IV weekly in analogy to dosing for advanced renal cell carcinoma. After 3 months of treatment, she showed significant clinical improvement in her breathing and overall functional status. Although her radiologic response was not formally evaluated by RECIST criteria, it was analogous to a robust partial response with significant reduction of a right lung mass and reduction of a pleural mass (Figure 1). She remained on treatment for almost 20 months until March 2016 when her scans showed disease progression with increase in size of right-sided lung mass as well as increase in pleural effusion. Her treatment was then changed to nivolumab, on which the disease progressed after 3 months. Treatment was changed to vinorelbine in July 2016 with partial response, but by January 2017, she had clinical and radiographic progression. Pleural fluid drained in January 2017 showed 80% PD-L1 expression by immunohistochemistry. She was then treated with pembrolizumab in February 2017, but after 2 cycles had further clinical and radiographic progression. The patient transferred to a hospice in March 2017 and passed away a month later.\n\nDiscussion\nThe exceptional response to a rapamycin analog in this patient and the underlying mechanism likely hinges on the mutations of PTEN and possibly, to a lesser extent, on STK11, which are both regulators of the downstream mTOR pathway, and the former is known to confer sensitivity to rapamycin analogs in vivo. Given that PTEN is a tumor suppressor, loss of heterozygosity (LOH) was queried on a research basis for both loci, but due to low sample purity could not be determined for either PTEN or STK11 (data not shown).\n\nLoss of function of PTEN, a lipid phosphatase, has long posited as being sensitizing to rapamycin due to ensuing hyperactivation of mTORC1.2 In particular, biallelic loss of function of PTEN should be more sensitizing than mutation of a single allele.2\n\nSTK11 is also upstream of mTOR, and loss of function alterations of STK11 also hyperactivate mTORC1, albeit through the intermediary of AMPK activity. However, in preclinical models of STK11-driven dysplasia and neoplasia, only some of these entities are rapamycin sensitive, such the polyps of juvenile polyposis and observation in PIN.3 Overall, whether STK11 alteration confers sensitivity to rapamycin analogs remains poorly understood.\n\nA significant limitation in this study is the inability to identify whether PTEN is under LOH, which would offer a compelling explanation for the efficacy of temsirolimus. The specimen purity did not permit LOH assessment, and no additional specimens were available including original sample (data not shown). Future investigation, whether on the basis of an exceptional responder to rapamycin analog like the patient here or in the context of clinical investigation where the therapeutic hypothesis is a similar question, should incorporate genomic assessment of both alleles of PTEN to help further explain the mechanism of the effect seen here. Studies of both temsirolimus and everolimus in unselected prostate cancer populations did not show an effect, but the latter trended toward some efficacy in a population with PTEN alteration.4,5\n\nOne aspect of note is the relatively high tumor mutational burden observed with high PD-L1 staining, but lack of durable response to checkpoint inhibitor. This failure increases the impact of observing a prolonged response to genomically matched targeted therapy for this patient.\n\nIn conclusion, the exceptional response observed here suggests that further assessment and investigation is warranted for PTEN status in NSCLC lacking known oncogenic drivers.\n\nThe authors apologize to all the investigators whose work cannot be cited here due to limitations of format. Written informed consent was provided by the patient to have the case details published.\n\nDisclosure\n\nABS, LAA, VAM, PJS, and SMA are employees of and have equity interest in Foundation Medicine Inc. The authors report no other conflicts of interest in this work.\n\nFigure 1 The top two images are from July 2014, and bottom two images are from October 2014 after 3 months of treatment with temsirolimus.\n\nNotes: There was a significant decrease in the size of the right upper lobe mass which abuts the major fissure. There was also marked improvement in the airspace consolidation involving the right lower lobe. Minimal amount of interstitial thickening remained within the right lower lobe. There was significant improvement in right pleural disease. There is no significant pleural effusion. A 1 cm right upper lobe pulmonary nodule had decreased in size. No significant mediastinal, axillary, or hilar lymphadenopathy was observed. No pericardial effusion was seen. Tiny nodules previously noted in the left lower lobe decreased in size.\n==== Refs\nReferences\n1 Siegel RL Miller KD Jemal A Cancer statistics, 2017 CA Cancer J Clin 2017 67 1 7 30 28055103 \n2 Neshat MS Mellinghoff IK Tran C Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR Proc Natl Acad Sci U S A 2001 98 18 10314 10319 11504908 \n3 Zhou W Marcus AI Vertino PM Dysregulation of mTOR activity through LKB1 inactivation Chin J Cancer 2013 32 8 427 433 23668926 \n4 Kruczek K Ratterman M Tolzien K Sulo S Lestingi TM Nabhan C A phase II study evaluating the toxicity and efficacy of single-agent temsirolimus in chemotherapy-naïve castration-resistant prostate cancer Br J Cancer 2013 109 7 1711 1716 24008662 \n5 Templeton AJ Dutoit V Cathomas R Phase 2 trial of single-agent everolimus in chemotherapy-naive patients with castration-resistant prostate cancer (SAKK 08/08) Eur Urol 2013 64 1 150 158 23582881\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-2728",
"issue": "9()",
"journal": "Lung Cancer (Auckland, N.Z.)",
"keywords": "genomic profiling; immunotherapy; targeted therapy; temsirolimus",
"medline_ta": "Lung Cancer (Auckl)",
"mesh_terms": null,
"nlm_unique_id": "101632521",
"other_id": null,
"pages": "45-47",
"pmc": null,
"pmid": "29844707",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "11504908;28055103;23668926;23582881;24008662",
"title": "Response to rapamycin analogs but not PD-1 inhibitors in PTEN-mutated metastatic non-small-cell lung cancer with high tumor mutational burden.",
"title_normalized": "response to rapamycin analogs but not pd 1 inhibitors in pten mutated metastatic non small cell lung cancer with high tumor mutational burden"
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"abstract": "Results of acute pulmonary vasodilator testing (AVT) and the outcome of medical therapy have not been described in patients with segmental pulmonary vascular disease (SPVD). We sought to compare the pulmonary vasodilatory effects of oxygen, oxygen with nitric oxide, and diltiazem, and to describe the clinical course of patients with SPVD and pulmonary hypertension. A retrospective review of 16 patients with pulmonary hypertension and SPVD involving 2-3 major lung segments who underwent AVT between January 2000 and December 2015 was performed. Baseline hemodynamic measurements were obtained with patients breathing ≤ 30% oxygen. AVT was performed using 100% oxygen, 100% oxygen with 20 ppm nitric oxide, 21-35% oxygen, and 21-35% oxygen with intravenous diltiazem. The events associated with their long-term care were described. Nine of 16 patients were acutely responsive during AVT using the Sitbon criteria. The change in mean pulmonary artery pressure with oxygen or oxygen with nitric oxide (19 ± 12 mmHg) was significantly greater than the change with diltiazem (7 ± 5 mmHg). Pulmonary vasodilator therapy was initiated or escalated after AVT in 12 patients. Five patients subsequently experienced a decrease in mean pulmonary artery pressure or normalization in B-type natriuretic peptide. Three patients experienced adverse events associated with therapy. The actuarial survival was 94% over a period of 1-20 years. This study suggests that AVT can be used to identify patients with SPVD who are reactive to oxygen, oxygen with nitric oxide, and diltiazem. Clinical improvement was temporally associated with pulmonary vasodilator therapy in some patients with few adverse effects.",
"affiliations": "Division of Pediatric Cardiology, Primary Children's Hospital, University of Utah, 81 North Mario Capecchi Drive, Salt Lake City, UT, 84113, USA. liezl.domingo@hsc.utah.edu.;Division of Pediatric Cardiology, Primary Children's Hospital, University of Utah, 81 North Mario Capecchi Drive, Salt Lake City, UT, 84113, USA.;Division of Pediatric Cardiology, Primary Children's Hospital, University of Utah, 81 North Mario Capecchi Drive, Salt Lake City, UT, 84113, USA.",
"authors": "Domingo|Liezl|L|http://orcid.org/0000-0002-6264-3138;Magdo|H Sonali|HS|;Day|Ronald W|RW|",
"chemical_list": "D014665:Vasodilator Agents; D009569:Nitric Oxide; D004110:Diltiazem; D010100:Oxygen",
"country": "United States",
"delete": false,
"doi": "10.1007/s00246-017-1780-9",
"fulltext": null,
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"issn_linking": "0172-0643",
"issue": "39(3)",
"journal": "Pediatric cardiology",
"keywords": "Acute pulmonary vasodilator testing; Pulmonary artery stenosis; Pulmonary hypertension; Pulmonary vein stenosis; Segmental pulmonary vascular disease",
"medline_ta": "Pediatr Cardiol",
"mesh_terms": "D000280:Administration, Inhalation; D061605:Administration, Intravenous; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004110:Diltiazem; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D007223:Infant; D008297:Male; D009569:Nitric Oxide; D010100:Oxygen; D011652:Pulmonary Circulation; D012189:Retrospective Studies; D014655:Vascular Resistance; D014664:Vasodilation; D014665:Vasodilator Agents",
"nlm_unique_id": "8003849",
"other_id": null,
"pages": "501-508",
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"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": "12170359;7810506;26707181;22891699;15289375;25099478;10069788;26458037;15657791;21763017;25172325;15939821;12560871;24355639;22086881;25992283;22073909",
"title": "Acute Pulmonary Vasodilator Testing and Long-Term Clinical Course in Segmental Pulmonary Vascular Disease.",
"title_normalized": "acute pulmonary vasodilator testing and long term clinical course in segmental pulmonary vascular disease"
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"abstract": "Glioblastoma multiforme is the most frequent primary brain tumor. The clinical course of glioblastoma is almost invariably fatal. Combined chemo-irradiation with temozolomide is currently the standard of care for newly diagnosed glioblastoma and concurrent Nivolumab, an anti-PD-1 monoclonal antibody is being studied for de novo glioblastoma. We present a 62-year old patient with glioblastoma, which was discovered during evaluation of sudden-onset moderate ataxia. Following craniotomy of the glial tumour he received chemo radiation. During this first-line treatment the patient participated in the CA209-548 phase III placebo controlled study investigating the addition of concurrent nivolumab. One month after the last administration of nivolumab after 60 weeks of study participation, magnetic resonance imaging scan showed progressive disease. Therefore stereotactic re-irradiation was given. Five days after completing radiation therapy and 50 days after his last nivolumab course he developed a mild diffuse generalized pruritic maculopapular exanthema. Skin biopsy was very indicative for a drug hypersensitivity reaction. The maculopapular rash and pruritus was successfully treated with moderate potency topical corticosteroids and prednisone. With the introduction of PD1/PD-L1 inhibitors and other immunotherapies tweaking the immune system to target cancer cells one can argue that once local radiation triggers a local immune mediated hypersensitivity reaction as seen in radiation recall dermatitis, the subsequent hypersensitivity reaction which would traditionally only be a local reaction is now possible to advance to more pronounced (systemic) reactions as seen in an abscopal effect. Therefore, we propose a combined name to coin this effect, the abscopal radiation recall phenomenon.",
"affiliations": "Department of Dermatology and Venerology, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Dermatology and Venerology, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.",
"authors": "van Seggelen|Wouter O|WO|;De Vos|Filip Y|FY|;Röckmann|Heike|H|;van Dijk|Marijke R|MR|;Verhoeff|Joost J C|JJC|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000504698",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1662-6575",
"issue": "12(3)",
"journal": "Case reports in oncology",
"keywords": "Abscopal effect; Glioblastoma; Nivolumab; Radiation recall",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "896-900",
"pmc": null,
"pmid": "31911775",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "18317586;19573801;30027278;13042090;11150363;28068177;15308095;29320654;16168567;15758009;26161407;27136138",
"title": "Occurrence of an Abscopal Radiation Recall Phenomenon in a Glioblastoma Patient Treated with Nivolumab and Re-Irradiation.",
"title_normalized": "occurrence of an abscopal radiation recall phenomenon in a glioblastoma patient treated with nivolumab and re irradiation"
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{
"abstract": "BACKGROUND\nThe presence of the levonorgestrel-releasing intrauterine system embedded within an ectopic pregnancy is a rare occurrence. Tubal migration of an intrauterine device is not well understood and has not been extensively studied in literature.\n\n\nMETHODS\nA 34-year-old African woman, para 1, gravida 2, presented with symptoms of ruptured ectopic pregnancy. She underwent a laparoscopy where a ruptured left ectopic pregnancy was found with a levonorgestrel-releasing intrauterine system inserted 2 years prior embedded within the tube. A left salpingectomy was performed with removal of the levonorgestrel-releasing intrauterine system. The patient recovered well and proceeded to have an intrauterine pregnancy 3 months later.\n\n\nCONCLUSIONS\nMigration of the levonorgestrel-releasing intrauterine system into the fallopian tube is a rare occurrence that is not well understood. In the case presented, levonorgestrel-releasing intrauterine system was found embedded within the fimbrial end of the left fallopian tube, which had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal intrauterine device to prevent complications.",
"affiliations": "Department of Obstetrics and Gynecology, Aga Khan University Hospital Nairobi, P.O. Box 30270-00100, Nairobi, Kenya. maksdot@gmail.com.;Department of Obstetrics and Gynecology, Aga Khan University Hospital Nairobi, P.O. Box 30270-00100, Nairobi, Kenya.;Department of Obstetrics and Gynecology, Aga Khan University Hospital Nairobi, P.O. Box 30270-00100, Nairobi, Kenya.",
"authors": "Makena|Dorothy|D|http://orcid.org/0000-0001-8254-8325;Gichere|Ingrid|I|;Warfa|Khadija|K|",
"chemical_list": "D016912:Levonorgestrel",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-021-02723-7",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2723\n10.1186/s13256-021-02723-7\nCase Report\nLevonorgestrel intrauterine system embedded within tubal ectopic pregnancy: a case report\nhttp://orcid.org/0000-0001-8254-8325\nMakena Dorothy maksdot@gmail.com\n\nGichere Ingrid\nWarfa Khadija\ngrid.411192.e 0000 0004 1756 6158 Department of Obstetrics and Gynecology, Aga Khan University Hospital Nairobi, P.O. Box 30270-00100, Nairobi, Kenya\n9 3 2021\n9 3 2021\n2021\n15 1073 6 2020\n9 2 2021\n© The Author(s) 2021\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nThe presence of the levonorgestrel-releasing intrauterine system embedded within an ectopic pregnancy is a rare occurrence. Tubal migration of an intrauterine device is not well understood and has not been extensively studied in literature.\n\nCase presentation\n\nA 34-year-old African woman, para 1, gravida 2, presented with symptoms of ruptured ectopic pregnancy. She underwent a laparoscopy where a ruptured left ectopic pregnancy was found with a levonorgestrel-releasing intrauterine system inserted 2 years prior embedded within the tube. A left salpingectomy was performed with removal of the levonorgestrel-releasing intrauterine system. The patient recovered well and proceeded to have an intrauterine pregnancy 3 months later.\n\nConclusion\n\nMigration of the levonorgestrel-releasing intrauterine system into the fallopian tube is a rare occurrence that is not well understood. In the case presented, levonorgestrel-releasing intrauterine system was found embedded within the fimbrial end of the left fallopian tube, which had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal intrauterine device to prevent complications.\n\nKeywords\n\nIUD\nMirena\nLevonorgestrel IUS\nEctopic pregnancy\nTubal migration\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nAn intrauterine contraceptive device (IUD) is a highly effective method of contraception [1]. Types of IUDs include the levonorgestrel releasing intrauterine system (LNG IUS), also commonly referred to as Mirena, and the copper IUD. They have a low failure rate of less than 1%, which is comparable to permanent sterilization [1]. The pearl index of the LNG IUS is 0.06 per 100 women years, while that of the copper IUD is 0.52 per 100 women years [2]. Even though the risk of ectopic pregnancy with IUDs is lower than with no contraception, if a pregnancy occurs with an IUD in situ, it is likely to be an ectopic pregnancy. The rate of ectopic pregnancy among LNG IUS users ranges from 0.02 to 0.2 per 100 women years, whereas the rate among copper IUD users ranges from 0.1 to 0.8 per 100 women years. In case of pregnancy, the risk of ectopic pregnancy is higher in LNG IUS users compared with copper IUD users (27% versus 15% respectively) [2]. Progesterone is known to cause ciliary dysfunction within the fallopian tube, subsequently predisposing LNG IUS users who conceive to ectopic pregnancy [3]. It is therefore important to rule out ectopic pregnancy in women with acute abdomen or positive pregnancy test among LNG IUS users [4]\n\nA correctly positioned IUD is located within 3 mm of the uterine fundus, with both arms extending to the cornua, a vertically oriented stem in the uterine body, and the strings protruding through the cervical os into the vaginal canal [5]. Suboptimally placed IUDs are at a higher risk of malposition or expulsion and associated symptoms [5]. Malposition of IUDs is a common complication of this method of contraception, with a reported rate of up to 10% [6]. Malposition of an IUD includes displacement, expulsion, rotation, or embedment. Migration of IUDs is, however, an uncommon occurrence, with most cases of migration reported to the colon and the urinary tract [7–9]. The fallopian tube is an uncommon location for migration and embedment [7]. Having an IUD embedded within a tubal ectopic pregnancy is an even rarer phenomenon.\n\nWe describe a case of a patient who presented with ruptured ectopic pregnancy and was found to have a LNG IUS embedded in the fimbrial end of the affected fallopian tube.\n\nCase presentation\n\nA 34-year-old African female, para 1, gravida 2, presented to the Accident and Emergency Department, having had symptoms of vomiting and abdominal pain for 3 days. The symptoms had worsened on the day of presentation to the hospital. She reported several episodes of vomiting with associated loose stools and abdominal fullness. She also had ongoing vaginal bleeding that had started 5 days prior to presentation.\n\nTwo years prior, the patient had an uncomplicated insertion of LNG IUS by an obstetrician/gynecologist at the 8-week visit following a normal vaginal delivery. She had a normal pap smear done at the time of insertion. One year following insertion, she had a desire to conceive and was scheduled for removal of the LNG IUS device. The strings could not be seen, and the device could not be retrieved with alligator forceps. The patient was therefore sent for a pelvic ultrasound to locate the lost IUD. The device was not seen on ultrasound. The patient was, however, lost to follow-up until presentation with symptoms of ruptured ectopic pregnancy. She had no preexisting conditions or previous surgery.\n\nOn physical examination she was in fair general condition and not pale. Her vital signs were a temperature of 37.6 °C, a blood pressure of 120/66 mmHg, pulse rate of 99 beats per minute, respiration rate of 18 breaths per minute, and oxygen saturation of 100% on room air. On abdominal examination she had tenderness on the left iliac fossa and suprapubic regions with absent bowel sounds. The rest of the systemic examination was normal. An impression of acute abdomen was made at this point. As initial treatment she was given intravenous fluids (Ringer’s lactate solution) 1-L bolus, as well as intravenous paracetamol and ondansetron for pain and vomiting, respectively.\n\nThe initial investigations included a full blood count, which revealed a normal hemoglobin level of 13.2 g/dl, slightly elevated white cell count of 12.28 × 109 cells/L, and normal platelet count of 314 × 109 cells/L. She had a beta human chorionic gonadotropin (Hcg) level of 7721 mIU/ml. Urinalysis showed leucocytes 2+, nitrite negative, and blood 2+. Transvaginal ultrasound showed a 2.1 cm × 1.8 cm echogenic mass with central cystic area on the left adnexa. It had no internal or peripheral vascularity. There was marked pelvic echogenic free fluid with low internal echoes extending to the Morrison’s pouch. The uterus was anteverted and normal in size and shape with an endometrial thickness of 5.5 mm. A 1.9 cm cystic lesion was seen in the right ovary, which was likely a corpus luteum cyst. There was no gestational sac or intrauterine device seen within the endometrial cavity (Fig. 1). These features indicated ruptured ectopic pregnancy.Fig. 1 Ultrasound image of an empty uterus. The arrow points to the endometrial lining measuring 5.5 mm\n\nThe diagnosis at this point was a ruptured left tubal ectopic pregnancy. The plan was to admit the patient for an emergency laparoscopy with possible left salpingectomy. The diagnosis and plan were explained to the patient, who signed an informed consent for the procedure. Group and cross match of one unit of packed red cells was ordered in case a transfusion would be required.\n\nThe laparoscopy was done under general anesthesia in the Lloyd–Davis position. Cohen’s uterine manipulator was placed. Veress insufflation was performed, followed by insertion of a 10-mm primary trocar at the umbilicus. Entry and operating pressures were 20 mmHg and 15 mmHg, respectively. Two secondary ports were inserted under vision, 5 mm in the right iliac fossa and 12 mm in the left iliac fossa. On primary survey, LNG IUS was found embedded at the fimbrial end of the left fallopian tube (Fig. 2). The LNG IUS was retrieved whole under vision through the 12-mm port (Fig. 3). There was hemoperitoneum of 700 ml (Fig. 2). A ruptured left ampullary ectopic pregnancy was identified by left salpingectomy using bipolar coagulation and scissors (Fig. 4). A corpus luteum cyst was found on the right ovary with normal right fallopian tube. Suction and peritoneal lavage were performed, and hemostasis was confirmed (Fig. 5). The specimen was retrieved through the 12-mm port and taken for histology. There was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal. All trocars were removed under vision.Fig. 2 Body of the embedded LNG IUS (indicated by arrow), which is seen protruding from the left tubal pregnancy with hemoperitoneum\n\nFig. 3 LNG IUS (indicated by arrow) being retrieved from the left tubal pregnancy\n\nFig. 4 Left salpingectomy (indicated by arrow) performed using bipolar coagulation\n\nFig. 5 Pelvic view after completion of the procedure confirming hemostasis. Arrow points to an empty pouch of Douglas\n\nThe postoperative recovery of the patient was unremarkable. She was debriefed about the surgery and discharged the following morning. She went home on oral paracetamol and diclofenac for pain relief.\n\nThe patient was reviewed in the gynecology outpatient clinic 2 weeks later. She was asymptomatic and doing well. Histology report confirmed left ectopic tubal gestation. She reported that she desired conception. Preconception counseling was done. She was put on daily folic acid (400 µg). The patient was advised to come to the hospital as soon as she missed a period or tested positive for pregnancy for an early pregnancy ultrasound to rule out another ectopic pregnancy. Three months later she presented at the early pregnancy clinic following 5 weeks of amenorrhea. A pelvic ultrasound was done that showed intrauterine pregnancy at 5 weeks gestation.\n\nDiscussion\n\nThe above case documents a rare occurrence of a ruptured ectopic pregnancy with the LNG IUS embedded within the affected fallopian tube.\n\nLevonorgestrel IUS (Mirena) is a safe, reversible, and highly effective contraceptive method [2]. It is known to have other therapeutic benefits such as reduction in menstrual bleeding, anemia, and dysmenorrhea, as well as management of endometrial hyperplasia [10]. In this patient, the use of the LNG IUS was purely for contraception purposes.\n\nEctopic pregnancies affect approximately 2% of all pregnancies. The most common presentation of an ectopic pregnancy is abdominal pain and abnormal uterine bleeding [11]. Even though the rate of ectopic pregnancy is lower in women using LNG IUS, if a pregnancy occurs while using this IUD, there is a high risk of it being an ectopic pregnancy [2]. Current IUD use is a known risk factor for ectopic pregnancy [12]. Other risk factors for ectopic pregnancy include pelvic inflammatory disease, previous tubal surgery, previous ectopic pregnancy, and smoking [12]. On examination, features of acute abdomen due to hemoperitoneum may be present [11, 12]. The patient in this case had a presentation suggestive of ectopic pregnancy with concurrent LNG IUS use as a risk factor. However, she had other unspecific presenting features of diarrhea, vomiting, and low-grade fever. It is important to note that some patients may be asymptomatic without specific risk factors for an ectopic pregnancy [12]\n\nOn the other hand, malposition of an IUD is one of its common complications, presenting with pelvic pain and bleeding or no symptoms [13]. Although malposition is associated with reduced contraceptive efficacy, this is mostly true for copper IUDs and not LNG IUS, which has local progesterone effects [6]. Malposition is diagnosed by ultrasound [13]. However, compared with copper IUDs, the LNG IUS is more likely to be missed by ultrasonography. LNG IUS is compounded with barium sulfate, which makes it radio opaque for X-ray recognition [14]. A plain X-ray can therefore be used as an adjunctive imaging modality in the case of a lost LNG IUS not seen on ultrasound [15]. The patient in this case had a lost LNG IUS not seen on ultrasound 1 year after insertion but was lost to follow-up for additional imaging.\n\nUterine perforation is uncommon, with an incidence of 1 in 1000 insertions. It is a serious complication of IUD use and is often asymptomatic [16]. There is increased risk of perforation if insertion is done less than 6 months postpartum or while breastfeeding. This period is associated with endometrial atrophy with accelerated uterine involution and hence has a high risk of perforation [6, 13]. The current patient was asymptomatic for malposition or perforation for 2 years prior to the ectopic pregnancy. The transvaginal ultrasound done at diagnosis of ectopic pregnancy did not visualize the device in the left adnexa. Her LNG IUS was inserted only 2 months postpartum while breastfeeding. This may have been a risk factor for possible unrecognized perforation.\n\nRoutine transvaginal ultrasound to monitor IUD position either immediately post insertion or after 6 weeks is not recommended without clinical suspicion of malposition according to de Kroon et al. [17]. It has been reported that IUDs take approximately 3 months to settle into their stable position. An initially malpositioned IUD can therefore assume the correct fundal position over time [18]. In asymptomatic women with uncomplicated IUD insertion, routine ultrasound lacks benefit over clinical evaluation with string check at 6 weeks [17]. The patient in this case was asymptomatic without complications at insertion. One year later, the LNG IUS device could not be seen on clinical examination nor on ultrasound.\n\nThe mechanism of device migration is not well understood, especially in the case of tubal migration. The fallopian tube is a rare site for dislocated IUD [19, 20]. This phenomenon has been described in few case reports. There are theories from case reports about the tubal migration of an IUD. The first possibility is placement of the device at the tubal ostium during insertion with subsequent migration into the tube due to uterine contractions and tubal peristalsis [21]. The other possibility is uterine perforation with migration of the device into the peritoneal cavity and subsequent perforation of a preexisting hydrosalpinx as described by Ozdemir et al. in a case report [19]. The patient in this case did not have any hydrosalpinx noted intraoperatively. Perforation can be due to either immediate traumatic perforation at insertion or delayed transmural migration [22, 23]. It is also possible that, following an unrecognized perforation, there was nestling of the IUD close to the fimbrial end of the fallopian tube, with the device being enveloped within the fimbria [7, 19]. This phenomenon could have occurred antecedent to conception of the ectopic pregnancy. In the patient in this case, there was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal.\n\nThe presence of an IUD within the fallopian tube is associated with an inflammatory reaction [19] interfering with tubal function and predisposing the patient to ectopic pregnancy. The tubal dysfunction is exacerbated by progesterone in the LNG IUS, which interferes with ciliary beating and tubal contractility [3]. It is possible that the embedment of LNG IUS at the fimbrial end of the fallopian tube occurred as a result of displacement from the proximal tube by the growing tubal pregnancy or its rupture.\n\nOnce an intraabdominal IUD is diagnosed, it should be removed whether it is symptomatic or not to avoid serious complications such as adhesion formation, bowel obstruction, and infertility [15, 19]. Laparoscopy is the surgical approach of choice as it is safe and effective. It provides good visualization to locate and remove a lost IUD [15]. In this case, the diagnosis of the LNG IUS within the fallopian tube and its removal were done laparoscopically.\n\nConclusion\n\nMigration of the LNG IUS into the fallopian tube is a rare occurrence that is not well understood. In the case presented, a LNG IUS was found embedded within the fimbrial end of the fallopian tube that had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal IUD to prevent complications. The patient made a good recovery and proceeded to have an intrauterine pregnancy 3 months later, as desired.\n\nAbbreviations\n\nIUD Intrauterine device\n\nLNG IUS Levonorgestrel intrauterine system\n\nAcknowledgements\n\nWe would like to thank the patient for her permission to publish this manuscript.\n\nAuthors’ contributions\n\nDM collected and analyzed the data and drafted the manuscript. IG and KW contributed to the manuscript writing and editing. All authors managed the patient and read and approved the final manuscript.\n\nFunding\n\nNone.\n\nAvailability of data and materials\n\nClinical data and complementary examinations are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of the case and any accompanying images. A copy of the consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Trussell J Contraceptive failure in the United States Contraception. 2011 83 5 397 404 10.1016/j.contraception.2011.01.021 21477680\n2. Heinemann K Reed S Moehner S Minh TD Comparative contraceptive effectiveness of levonorgestrel-releasing and copper intrauterine devices: the European Active Surveillance Study for Intrauterine Devices Contraception. 2015 91 4 280 283 10.1016/j.contraception.2015.01.011 25601350\n3. Paltieli Y Eibschitz I Ziskind G Ohel G Silbermann M Weichselbaum A High progesterone levels and ciliary dysfunction—a possible cause of ectopic pregnancy J Assist Reprod Genet. 2000 17 2 103 106 10.1023/A:1009465900824 10806589\n4. Graner S Mc Taggart J Nordstrom F Melander E Widenberg J Kopp KH Levonorgestrel intrauterine contraceptive systems (13.5 mg and 52 mg) and risk of ectopic pregnancy Acta Obstet Gynecol Scand. 2019 98 7 937 943 10.1111/aogs.13564 30737766\n5. Evans AT Szlachetka K Thornburg LL Ultrasound assessment of the intrauterine device Obstet Gynecol Clin North Am. 2019 46 4 661 681 10.1016/j.ogc.2019.07.005 31677748\n6. Braaten KP Benson CB Maurer R Goldberg AB Malpositioned intrauterine contraceptive devices: risk factors, outcomes, and future pregnancies Obstet Gynecol. 2011 118 5 1014 1020 10.1097/AOG.0b013e3182316308 22015868\n7. Goldbach AR Hava S Patel H Khan M IUD embedment in the fallopian tube: an unexpected location for a translocated IUD Radiol Case Rep. 2018 13 4 788 792 10.1016/j.radcr.2018.04.030 30002782\n8. Taras AR Kaufman JA Laparoscopic retrieval of intrauterine device perforating the sigmoid colon JSLS. 2010 14 3 453 455 10.4293/108680810X12924466006684 21333209\n9. Parent S Binette A Bureau YA Migration of an intrauterine system J Obstet Gynaecol Can. 2016 38 11 997 10.1016/j.jogc.2016.08.011 27969565\n10. Luukkainen T Toivonen J Levonorgestrel-releasing IUD as a method of contraception with therapeutic properties Contraception. 1995 52 5 269 276 10.1016/0010-7824(95)00210-2 8585882\n11. Alkatout I Honemeyer U Strauss A Tinelli A Malvasi A Jonat W Clinical diagnosis and treatment of ectopic pregnancy Obstet Gynecol Surv. 2013 68 8 571 581 10.1097/OGX.0b013e31829cdbeb 23921671\n12. Barnhart K Clinical practice. Ectopic pregnancy N Engl J Med. 2009 361 4 379 10.1056/NEJMcp0810384 19625718\n13. Benacerraf BR Shipp TD Bromley B Three-dimensional ultrasound detection of abnormally located intrauterine contraceptive devices which are a source of pelvic pain and abnormal bleeding Ultrasound Obstet Gynecol. 2009 34 1 110 115 10.1002/uog.6421 19565532\n14. Van Schoubroeck D Van Den Bosch T Mortelman P Timmerman D Sonographic determination of the position of a levonorgestrel intrauterine device Ultrasound Obstetr Gynecol 2009 33 1 121 124 10.1002/uog.6288\n15. Kho KA Chamsy DJ Perforated intraperitoneal intrauterine contraceptive devices: diagnosis, management, and clinical outcomes J Minim Invasive Gynecol. 2014 21 4 596 601 10.1016/j.jmig.2013.12.123 24462588\n16. Rowlands S Oloto E Horwell DH Intrauterine devices and risk of uterine perforation: current perspectives Open Access J Contracept. 2016 7 19 10.2147/OAJC.S85546 29386934\n17. de Kroon CD van Houwelingen JC Trimbos JB Jansen FW The value of transvaginal ultrasound to monitor the position of an intrauterine device after insertion. A technology assessment study Hum Reprod. 2003 18 11 2323 2327 10.1093/humrep/deg433 14585882\n18. Faundes D Perdigao A Faundes A Bahamondes L Petta C T-shaped IUDs accommodate in their position during the first 3 months after insertion Contraception. 2000 62 4 165 168 10.1016/S0010-7824(00)00167-0 11137069\n19. Özdemir S Özdemir S Cihangir N Görkemli H Emlik D Pyosalpinx caused by the tubal migration of an intrauterine device—a case report Eur J Contracept Reprod Health Care. 2008 13 3 320 322 10.1080/13625180802254563 18821466\n20. Tuncay Y Tuncay E Güzin K Öztürk D Omurcan C Yücel N Transuterine migration as a complication of intrauterine contraceptive devices: six case reports Eur J Contracept Reprod Health Care. 2004 9 3 194 200 10.1080/13625180400007165 15697109\n21. Sindos M Pisal N Setchell M Singer A Tubal migration: a rare complication of an intrauterine contraceptive device leading to formation of a hydrosalpinx Am J Obstet Gynecol 2003 188 4 1109 1110 10.1067/mob.2003.192 12712122\n22. Esposito JM Zarou DM Zarou GS A Dalkon Shield imbedded in a myoma: case report of an unusual displacement of an intrauterine contraceptive device Am J Obstet Gynecol 1973 117 4 578 581 10.1016/0002-9378(73)90128-2 4743363\n23. Ferguson CA Costescu D Jamieson MA Jong L Transmural migration and perforation of a levonorgestrel intrauterine system: a case report and review of the literature Contraception. 2016 93 1 81 86 10.1016/j.contraception.2015.08.019 26386445\n\n",
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"issn_linking": "1752-1947",
"issue": "15(1)",
"journal": "Journal of medical case reports",
"keywords": "Ectopic pregnancy; IUD; Levonorgestrel IUS; Mirena; Tubal migration",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000328:Adult; D005187:Fallopian Tubes; D005260:Female; D006801:Humans; D007436:Intrauterine Devices, Medicated; D016912:Levonorgestrel; D011247:Pregnancy; D011271:Pregnancy, Ectopic; D011274:Pregnancy, Tubal; D058994:Salpingectomy",
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"pages": "107",
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"pmid": "33685513",
"pubdate": "2021-03-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25601350;24462588;19565532;30002782;31677748;11137069;27969565;26386445;19111011;10806589;14585882;8585882;19625718;4743363;22015868;21477680;15697109;18821466;23921671;12712122;29386934;21333209;30737766",
"title": "Levonorgestrel intrauterine system embedded within tubal ectopic pregnancy: a case report.",
"title_normalized": "levonorgestrel intrauterine system embedded within tubal ectopic pregnancy a case report"
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"abstract": "Premature preterm rupture of membranes (PPROM) is reported to be associated with high rates of neonatal mortality and morbidity. Sildenafil has been used in infants with persistent pulmonary hypertension of newborn (PPHN) due to congenital diaphragmatic hernia (CDH) and bronchopulmonary dysplasia (BPD). Recently, Sildenafil has been evaluated as an alternative or adjunctive pulmonary vasodilator. This case report illustrates the use of early sildenafil for PPHN and right ventricular dysfunction in an unusual setting of lung and renal hypoplasia.\n\n\n\nA male infant was born at 37 weeks with a birth weight of 2840 g. Rupture of membranes developed at approximately 24 weeks of gestational age (GA). Bilateral small kidneys (< 2 standard deviations below average) were detected on ultrasound (US) examination at 30 weeks of gestation. The baby developed pneumothorax and pulmonary hypertensive crisis towards the end of the first day. An echocardiogram showed a dilated right ventricle, moderate right ventricular systolic dysfunction, hypoplastic pulmonary arteries and a large patent ductus arteriosus with bidirectional flow. The patient was sedated, paralyzed, and inhaled nitric oxide was administered to decrease the pulmonary resistance. In anticipation of persistent pulmonary hypertension due to the hypoplastic lungs and small calibre of pulmonary arteries, sildenafil was started on day of life (DOL) 5 at a dosage of 0.25 mg/kg/dose Q8H and gradually increased to 2 mg/kg/dose Q8H on DOL 9. The patient was finally extubated on DOL 7 and weaned off of non-invasive respiratory support on DOL 26. Sildenafil was gradually weaned beginning on DOL 21 and discontinued on DOL 48. Repeat echocardiogram assessment at 3 months showed complete resolution of PHT and right ventricular dilatation.\n\n\n\nWe describe the early use of sildenafil in treating pulmonary hypertension associated with lung and renal hypoplasia in a non-CDH patient. Following this treatment the patient made a full recovery from right ventricular dysfunction.",
"affiliations": "Department of Pediatrics, Carmel Medical Center, Haifa, Israel.;Department of Pediatrics, University of British Columbia, 1N16-4480 Oak Street, Vancouver, BC, V6H 3V4, Canada.;Department of Pediatrics, University of British Columbia, 1N16-4480 Oak Street, Vancouver, BC, V6H 3V4, Canada. jting2@cw.bc.ca.",
"authors": "Lavie-Nevo|Karen|K|;Harris|Kevin C|KC|;Ting|Joseph Y|JY|0000-0002-5246-8823",
"chemical_list": "D000959:Antihypertensive Agents; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate",
"country": "England",
"delete": false,
"doi": "10.1186/s12887-019-1801-3",
"fulltext": "\n==== Front\nBMC PediatrBMC PediatrBMC Pediatrics1471-2431BioMed Central London 180110.1186/s12887-019-1801-3Case ReportUse of sildenafil in an infant with persistent pulmonary hypertension secondary to lung and renal hypoplasia – a case report Lavie-Nevo Karen KarenLa@Clalit.org.il 1Harris Kevin C. kharris2@cw.bc.ca 2http://orcid.org/0000-0002-5246-8823Ting Joseph Y. +1(604)875-2136jting2@cw.bc.ca 21 grid.413469.dDepartment of Pediatrics, Carmel Medical Center, Haifa, Israel 2 0000 0001 2288 9830grid.17091.3eDepartment of Pediatrics, University of British Columbia, 1N16-4480 Oak Street, Vancouver, BC V6H 3V4 Canada 6 11 2019 6 11 2019 2019 19 4167 2 2019 24 10 2019 © The Author(s). 2019Open 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. 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\nPremature preterm rupture of membranes (PPROM) is reported to be associated with high rates of neonatal mortality and morbidity. Sildenafil has been used in infants with persistent pulmonary hypertension of newborn (PPHN) due to congenital diaphragmatic hernia (CDH) and bronchopulmonary dysplasia (BPD). Recently, Sildenafil has been evaluated as an alternative or adjunctive pulmonary vasodilator. This case report illustrates the use of early sildenafil for PPHN and right ventricular dysfunction in an unusual setting of lung and renal hypoplasia.\n\nCase presentation\nA male infant was born at 37 weeks with a birth weight of 2840 g. Rupture of membranes developed at approximately 24 weeks of gestational age (GA). Bilateral small kidneys (< 2 standard deviations below average) were detected on ultrasound (US) examination at 30 weeks of gestation. The baby developed pneumothorax and pulmonary hypertensive crisis towards the end of the first day. An echocardiogram showed a dilated right ventricle, moderate right ventricular systolic dysfunction, hypoplastic pulmonary arteries and a large patent ductus arteriosus with bidirectional flow. The patient was sedated, paralyzed, and inhaled nitric oxide was administered to decrease the pulmonary resistance. In anticipation of persistent pulmonary hypertension due to the hypoplastic lungs and small calibre of pulmonary arteries, sildenafil was started on day of life (DOL) 5 at a dosage of 0.25 mg/kg/dose Q8H and gradually increased to 2 mg/kg/dose Q8H on DOL 9. The patient was finally extubated on DOL 7 and weaned off of non-invasive respiratory support on DOL 26. Sildenafil was gradually weaned beginning on DOL 21 and discontinued on DOL 48. Repeat echocardiogram assessment at 3 months showed complete resolution of PHT and right ventricular dilatation.\n\nConclusions\nWe describe the early use of sildenafil in treating pulmonary hypertension associated with lung and renal hypoplasia in a non-CDH patient. Following this treatment the patient made a full recovery from right ventricular dysfunction.\n\nKeywords\nPulmonary hypertensionSildenafilLung hypoplasiaRenal hypoplasiaTargeted neonatal echocardiographyissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nMid-trimester PPROM with prolonged oligohydramnios remains a challenge for both obstetricians and neonatologists. Although survival rates have improved, morbidity remains common particularly due to pulmonary insufficiency and pulmonary hypertension [1]. Oligohydramnios due to second trimester PPROM or impaired foetal kidney development may cause pulmonary hypoplasia [2]. These newborns present with severe respiratory failure secondary to airway and vascular development abnormalities resulting in alveolar hypoplasia, pulmonary artery musculature hyperplasia, ventilation perfusion mismatch and often persistent pulmonary hypertension (PPHN) which may be partially reversible [3]. Contemporary neonatal intensive care strategies like the use of volume-targeted and high frequency ventilation, combined with early treatment of PPHN with inhaled nitric oxide (iNO), have contributed to recent improvement in outcomes. Sildenafil has been used in infants with PPHN due to congenital diaphragmatic hernia (CDH) and bronchopulmonary dysplasia (BPD) [4]. Recently, Sildenafil has been evaluated as an alternative or adjunctive pulmonary vasodilator in PPHN [5]. A Cochrane Data Base Systematic Review published in 2017 states that the therapeutic mainstay for PPHN consists of assisted ventilation and administration of iNO, however iNO is costly and approximately 30% of the patients fail to respond to iNO [6]. High concentrations of phosphodiesterases in the pulmonary vasculature have led to the use of phosphodiesterases inhibitors such as sildenafil. We describe a term infant with lung hypoplasia secondary to both mid-trimester PPROM and renal hypoplasia complicated by PPHN and right heart dysfunction. The infant was treated with iNO and a two-month course of sildenafil. The right heart function normalized before hospital discharge.\n\nCase presentation\nA male infant was born at 37 weeks with a birth weight of 2840 g. Rupture of the membranes developed at approximately 24 weeks of gestational age (GA), and serial ultrasounds (US) revealed progressively worsening oligohydramnios. Bilateral small kidneys (< 2 standard deviations below average) were detected on US examination at 30 weeks of gestation. Antenatal dexamethasone was given and the infant was delivered by caesarean section at 37 weeks GA due to severe oligohydramnios. He received intermittent positive pressure ventilation for a brief period and was then administered continuous positive airway pressure (CPAP). His Apgar scores were 5 at 1 min and 7 at 5 min. The infant developed right pneumothorax requiring chest needle compression shortly after admission into the neonatal intensive care unit (NICU). Empirical antibiotics were given followed by a negative culture. Towards the end of first day of life, there was re-accumulation of the right sided pneumothorax; a chest drain was inserted, and the patient was intubated and placed on a high frequency jet ventilator. He then developed multiple episodes of profound desaturations, increased pre- and post-ductal saturation differences (> 20%) and hypotension compatible with pulmonary hypertensive crisis. An echocardiogram showed a dilated right ventricle, moderate right ventricular systolic dysfunction, hypoplastic pulmonary arteries (2.8 mm bilaterally) and a large patent ductus arteriosus with bidirectional flow (Table 1). The patient was sedated, paralyzed, and inhaled nitric oxide was administered at 20 ppm to decrease the pulmonary resistance. FiO2 dropped from 100 to 21%, and oxygenation index decreased from 37 to 3.9 within 3 h. Low dose epinephrine at 0.05 micrograms/kg/min and alprostadil infusion at 0.005 μg/kg/min were added. Hydrocortisone was administered (up to 1 mg/kg/dose Q8H) for 4 days. In anticipation of persistent pulmonary hypertension due to the hypoplastic lungs and small calibre of pulmonary arteries, sildenafil was started on day of life (DOL) 5 at a dosage of 0.25 mg/kg/dose Q8H and gradually increased to 2 mg/kg/dose Q8H on DOL 9. Alprostadil infusion and iNO were weaned off on DOL 6 and DOL 7, respectively. The patient was finally extubated on DOL 7 and weaned off of non-invasive respiratory support on DOL 26. Despite the elevated serum creatinine (159umol/L on DOL 4), there were no significant fluid or electrolyte disturbances necessitating renal replacement therapy. Serial targeted neonatal echocardiograms (TNE) showed gradual improvement of the PPHN with time (Table 1). Sildenafil was gradually weaned beginning on DOL 21 and discontinued on DOL 48 (2 days before discharge). Repeat echocardiogram assessment at 3 months showed complete resolution of PHT and right ventricular dilatation. The infant is regularly followed up for growth and chronic renal disease.\nTable 1 Serial targeted neonatal echocardiography findings of the indexed baby\n\nEchocardiogram findings\t\n Days of life\tDay 2\tDay 3\tDay 5\tDay 8\tDay 48\t\n RV dilatation\tModerate\tModerate\tMild\tMild\tNo\t\n RV FAC (%)\t29\t57\t42\t52\t58\t\n TAPSE (cm)\t0.7\t0.7\t0.85\t0.9\tN/A\t\n PDA direction\tBidirectional\n\nL➔ R 70%\n\n\tR➔L\tBidirectional\n\nL➔ R 70%\n\n\tL➔R\tclosed\t\n LV FS (%)\t34\t29\t48\t47\tN/Aa\t\n LVO (ml/kg/min)\t70\t74\t151\t255\t287\t\nInterventions (at the time of echo)\t\n NO\t–\t+\t+\t–\t–\t\n PGE\t–\t–\t+\t–\t–\t\n Sildenafil\t–\t–\t+\t+\t+\t\nN/A Not available, RV Right ventricle, RVFAC Right ventricle fractional area change, TAPSE Tricuspid annular plane systolic excursion, PDA Patent ductus arteriosus, LV FS, Left ventricle fractional shortening, LVO Left ventricular output, NO Nitric oxide, PGE, Prostaglandin, LVEF Left ventricle ejection fraction, DOL Day of life\n\naN/A: not available; quantitative measurement of LVEF was not performed due to movement artefacts, although LV contractility was unremarkable on eye balling\n\n\n\nDiscussion and conclusions\nThe patient described in this report had PPROM before 25 weeks (prior to the saccular stage of lung development) with severe oligohydramnios and renal hypoplasia. He developed hypoxic respiratory failure and right ventricular dysfunction, secondary to lung hypoplasia and PPHN, and sildenafil was started to facilitate weaning of iNO. This report illustrated the use of early sildenafil for PPHN and right ventricular dysfunction in an unusual setting of lung hypoplasia unrelated to CDH condition (PPROM and renal hypoplasia).\n\nPulmonary hypoplasia secondary to second trimester PPROM and oligohydramnios presents a challenge to neonatal caregivers, although survival to discharge has improved substantially up to 70% in large series [2]. The pressure of the foetal lung fluid is essential for growth and morphogenesis of the developing lung, as normal transition to the saccular stage with the development of blood-gas interface requires the production of fluid by the foetal lung. Increased arteriolar muscularization, abnormal capillary formation, and thickening of the blood-gas barrier were demonstrated in autopsy samples from neonates with PPROM > 14 days [7].\n\nMost existing literature focuses on PPHN associated with pulmonary hypoplasia in the context of CDH [8–10]. NO is produced from the nitrogen of L-arginine and molecular oxygen by the endothelial nitric oxide synthase enzyme (eNOS) in vascular endothelial cells. NO diffuses through the endothelium to the vascular smooth muscle and activates soluble guanylyl cycles (sCG) leading to the production of cyclic guanyl monophosphate (cGMP) which activates the cGMP-dependent protein kinase or protein kinase G (PKG). PKG activates potassium channels and reduction of the influx of calcium which leads to vasodilatation [11, 12]. Thus, iNO induces pulmonary vasodilatation by increasing intracellular cyclic guanosine monophosphate (cGMP) concentrations [4]. Sildenafil is a potent and highly selective inhibitor of phosphodiesterase type 5 (PDE5) that reduces the degradation of cGMP, resulting in nitric oxide mediated vasodilatation [3]. It can be administered orally or intravenously. Its off-label use in term and premature infants with PPHN is increasing, with limited safety or efficacy data [13]. Currently, sildenafil is used for the following indications in neonates: (a) as an acute adjuvant to iNO in iNO-resistant PPHN or to facilitate weaning from iNO; (b) as an acute primary treatment of PPHN when iNO is not available or is contraindicated and (c) in the chronic primary treatment of pulmonary hypertension for conditions such as BPD and CDH to decrease right ventricular pressures and potentially improves right ventricular function over time [4].\n\nIn conclusion, we describe a single case with the early use of sildenafil to treat PPHN in a non-CDH patient, secondary to PPROM and lung & renal hypoplasia. Following this treatment, the patient made a full recovery. Further evidence is required to determine whether this treatment could be viable for all patients who present similar type of condition.\n\nAbbreviations\nBPDBronchopulmonary dysplasia\n\nCDHCongenital diaphragmatic hernia\n\ncGMPCyclic guanyl monophosphate\n\nCPAPContinuous positive airway pressure\n\nDOLDay of life\n\neNOSEndothelial nitric oxide synthase enzyme\n\nFACFractional area change\n\nFSFractional shortening\n\nGAGestational age\n\niNOInhaled nitric oxide\n\nLVLeft ventricle\n\nLVOLeft ventricular output\n\nNICUNeonatal intensive care unit\n\nNONitric oxide\n\nPDE5Phosphodiesterase type 5\n\nPGEProstaglandin\n\nPKGProtein kinase G\n\nPPHNPersistent pulmonary hypertension\n\nPPROMPreterm premature rupture of membrane\n\nRVRight ventricle\n\nsCGSoluble guanylyl cycles\n\nTAPSETricuspid annular plane systolic excursion\n\nTNETargeted neonatal echocardiography\n\nUSUltrasound\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nKL-N wrote the first draft of manuscript and contributed to the interpretation of data. KCH contributed to the first draft of manuscript, interpretation of data, critically reviewed the manuscript for intellectual content. JYT conceptualized the case report, contributed to the interpretation of data, and critically reviewed the manuscript for intellectual content. All authors read and approved the final manuscript as submitted.\n\nFunding\nThere are no financial relationships relevant to this article to disclose. Dr. Ting receives salary support from the Investigator Grant Award Program of British Columbia Children’s Hospital Research Institute. The funding agency had no role in the preparation for or decision to submit the manuscript for publication.\n\nAvailability of data and materials\nThe database used and analysed during the current case report are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nThe parents of the patient provided written informed consent for the publication of this case report.\n\nCompeting interests\nThe authors have no potential conflicts of interest to disclose. Dr. Ting is a member of the BMC Pediatrics Editorial Board.\n==== Refs\nReferences\n1. Williams O Hutchings G Hubinont C Pulmonary effects of prolonged Oligohydramnios following mid-trimester rupture of membranes – antenatal and postnatal management Neonatology 2012 101 83 90 10.1159/000329445 21934333 \n2. Everest NJ Jacobs SE Davis PG Begg L Rogerson S Outcomes following prolonged preterm premature rupture of the membranes Arch Dis Child Fetal Neonatal Ed 2008 93 3 F207 F211 10.1136/adc.2007.118711 17660215 \n3. Shah DM Kluckow M Early functional echocardiogram and inhaled nitric oxide: usefulness in managing neonates born following extreme preterm premature rupture of membranes (PPROM) J Paediatr Child Health 2011 47 6 340 345 10.1111/j.1440-1754.2010.01982.x 21309877 \n4. Lakshminrusimha S Mathew B Leach CL Pharmacologic strategies in neonatal pulmonary hypertension other than nitric oxide Semin Perinatol 2016 40 3 160 173 10.1053/j.semperi.2015.12.004 26778236 \n5. Al Omar S Salama H Al HM Effects of early adjunctive use of oral sildenafil and inhaled nitric oxide on the outcome of pulmonary hypertension in newborn infants. A feasibility study J Neonatal-Perinatal Med 2016 9 251 259 10.3233/NPM-16161 27589542 \n6. Kelly LE, Ohlsson A, Shah PS. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev. 2017;8:CD005494.\n7. Geary C Whitsett J Inhaled nitric oxide for oligohydramnios-induced pulmonary hypoplasia: a report of two cases and review of the literature J Perinatol 2002 22 1 82 85 10.1038/sj.jp.7210580 11840249 \n8. Chandrasekharan PK Rawat M Madappa R Congenital Diaphragmatic hernia-a review Matern Health Neonatol Pernatol 2017 3 6 10.1186/s40748-017-0045-1 \n9. Gien J Kinsella JP Management of pulmonary hypertension in infants with congenital diaphragmatic hernia J Perinatol 2016 36 Suppl 2 S28 S31 10.1038/jp.2016.46 27225962 \n10. Kumar VHS Dadiz R Koumoundouros J Response to pulmonary vasodilators in infants with congenital diaphragmatic hernia Pediatr Surg Int 2018 34 7 735 742 10.1007/s00383-018-4286-5 29808281 \n11. Pedersen Jonas Hedegaard Elise R. Simonsen Ulf Krüger Marcus Infanger Manfred Grimm Daniela Current and Future Treatments for Persistent Pulmonary Hypertension in the Newborn Basic & Clinical Pharmacology & Toxicology 2018 123 4 392 406 10.1111/bcpt.13051 29855164 \n12. Lai MY Chu SM Lakshminrusimha S Beyond the inhaled nitric oxide in persistent pulmonary hypertension of the newborn Pediatr Neonatol 2018 59 1 15 23 10.1016/j.pedneo.2016.09.011 28923474 \n13. Perez KM Laughon M Sildenafil in term and premature infants: a systematic review Clin Ther 2015 37 11 2598 2607 10.1016/j.clinthera.2015.07.019 26490498\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2431",
"issue": "19(1)",
"journal": "BMC pediatrics",
"keywords": "Lung hypoplasia; Pulmonary hypertension; Renal hypoplasia; Sildenafil; Targeted neonatal echocardiography",
"medline_ta": "BMC Pediatr",
"mesh_terms": "D000959:Antihypertensive Agents; D005322:Fetal Membranes, Premature Rupture; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007668:Kidney; D008168:Lung; D008297:Male; D010547:Persistent Fetal Circulation Syndrome; D000068677:Sildenafil Citrate; D014665:Vasodilator Agents",
"nlm_unique_id": "100967804",
"other_id": null,
"pages": "416",
"pmc": null,
"pmid": "31690278",
"pubdate": "2019-11-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21934333;28777888;11840249;27589542;27225962;21309877;29808281;26490498;28923474;17660215;28331629;29855164;26778236",
"title": "Use of sildenafil in an infant with persistent pulmonary hypertension secondary to lung and renal hypoplasia - a case report.",
"title_normalized": "use of sildenafil in an infant with persistent pulmonary hypertension secondary to lung and renal hypoplasia a case report"
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"abstract": "BACKGROUND\nUsing fluoroquinolone prophylaxis in pediatric neutropenic patients is a controversial issue due to the concern about emergence of resistant strains in addition to the lack of pediatric studies. This study was performed to assess the effectiveness of levofloxacin prophylaxis in pediatric patients during autologous stem cell transplantation.\n\n\nMETHODS\nThis was an observational study of pediatric patients who underwent autologous stem cell transplantation, comparing patients who received levofloxacin prophylaxis to historical controls.\n\n\nRESULTS\nA total of 96 patients were included (46 patients in the control group and 50 patients received levofloxacin). The median duration till onset of first fever was 11 d in the control group as compared to 15 d in patients who received levofloxacin (p ≤ 0.001). The incidence of infectious complications was higher in patients without levofloxacin (4/46) than those with levofloxacin (1/50). The median duration of empirical antibiotic use was 10 d in the levofloxacin group compared with 14 d in the control group (p < 0.001).\n\n\nCONCLUSIONS\nLevofloxacin prophylaxis delayed first spike of fever, decreased the incidence of septic complications, and shortened the duration of empiric antibiotic use, but its impact on emergence of resistant organisms should be closely monitored.",
"affiliations": "Pediatric Hematology/Oncology, National Cancer Institute, Cairo University, Cairo, Egypt.;Clinical Pharmacy, Children Cancer Hospital 57357, Cairo, Egypt.;Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt.;Pediatric Hematology/Oncology, National Cancer Institute, Cairo University, Cairo, Egypt.;Pediatric Hematology/Oncology, National Cancer Institute, Cairo University, Cairo, Egypt.",
"authors": "Hafez|Hanafy Ahmed|HA|;Yousif|Dalia|D|;Abbassi|Maggie|M|;Elborai|Yasser|Y|;Elhaddad|Alaa|A|",
"chemical_list": "D064704:Levofloxacin",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.12635",
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"issue": "29(12)",
"journal": "Clinical transplantation",
"keywords": "antibacterial prophylaxis; autologous; levofloxacin; stem cell transplantation",
"medline_ta": "Clin Transplant",
"mesh_terms": "D000293:Adolescent; D019072:Antibiotic Prophylaxis; D016470:Bacteremia; D002648:Child; D002675:Child, Preschool; D064147:Febrile Neutropenia; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D064704:Levofloxacin; D008297:Male; D011379:Prognosis; D012307:Risk Factors; D014182:Transplantation, Autologous",
"nlm_unique_id": "8710240",
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"publication_types": "D016428:Journal Article; D064888:Observational Study",
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"title": "Prophylactic levofloxacin in pediatric neutropenic patients during autologous hematopoietic stem cell transplantation.",
"title_normalized": "prophylactic levofloxacin in pediatric neutropenic patients during autologous hematopoietic stem cell transplantation"
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"abstract": "Splenectomy is a risk factor for serious pneumococcal disease like overwhelming post-splenectomy infection (OPSI). In healthy individuals with small spleen, fulminant pneumococcal infection similar to OPSI has been reported. Furthermore, it is reported that small spleen was associated with severe pneumococcal infection patients treated in an intensive care unit. However, the association between the small spleen and pneumococcal pneumonia was not investigated enough. We retrospectively analyzed patients with pneumococcal pneumonia who underwent computed tomography examination with measurement of the splenic volume at Harasanshin Hospital between 2004 and 2019. Data on their background characteristics, laboratory findings, and clinical courses were collected. 413 patients were included in the final analysis. The splenic volume was significantly lower in the moderate (P < 0.001), severe (P < 0.00005), and extremely severe (P < 0.001) pneumonia groups compared with the mild pneumonia group. Furthermore, the splenic volume was significantly lower in patients died within 30 days of pneumonia treatment (median of 73.49 versus 110.77 cm3, P < 0.005) or during hospitalization (median of 71.69 versus 111.01 cm3, P < 0.0005). Splenic volume <40 cm3 was significantly associated with mortality within 30 days and total hospital mortality as a risk factor in univariate analysis. Splenic volume <40 cm3 was an independent risk factor for mortality within 30 days (odds ratio: 5.0, 95% confidence interval: 1.2-21.1, P < 0.05) and total hospital mortality (odds ratio: 7.4, 95% confidence interval: 1.8-30.6, P < 0.01) in multivariate logistic regression analysis. These results suggest that small spleen is a risk factor for severity and mortality of pneumococcal pneumonia.",
"affiliations": "Division of Respiratory Medicine, Harasanshin Hospital, 1-8 Taihaku-cho, Hakata-ku, Fukuoka, 812-0033, Japan. Electronic address: satoshi.anai@gmail.com.;Division of Respiratory Medicine, Harasanshin Hospital, 1-8 Taihaku-cho, Hakata-ku, Fukuoka, 812-0033, Japan.;Division of Respiratory Medicine, Harasanshin Hospital, 1-8 Taihaku-cho, Hakata-ku, Fukuoka, 812-0033, Japan.;Division of Clinical Radiology, Harasanshin Hospital, 1-8 Taihaku-cho, Hakata-ku, Fukuoka, 812-0033, Japan.;Division of Respiratory Medicine, Harasanshin Hospital, 1-8 Taihaku-cho, Hakata-ku, Fukuoka, 812-0033, Japan.;Division of Respiratory Medicine, Harasanshin Hospital, 1-8 Taihaku-cho, Hakata-ku, Fukuoka, 812-0033, Japan.;Division of Clinical Radiology, Harasanshin Hospital, 1-8 Taihaku-cho, Hakata-ku, Fukuoka, 812-0033, Japan.;Division of Clinical Radiology, Harasanshin Hospital, 1-8 Taihaku-cho, Hakata-ku, Fukuoka, 812-0033, Japan.;Division of Respiratory Medicine, Harasanshin Hospital, 1-8 Taihaku-cho, Hakata-ku, Fukuoka, 812-0033, Japan.;Division of Respiratory Medicine, Harasanshin Hospital, 1-8 Taihaku-cho, Hakata-ku, Fukuoka, 812-0033, Japan.",
"authors": "Anai|Satoshi|S|;Ibusuki|Ritsu|R|;Takao|Tomoaki|T|;Okushima|Kazuhiro|K|;Sakurai|Yuko|Y|;Hisasue|Junko|J|;Furukawa|Tatsuya|T|;Shiraishi|Naotaka|N|;Takaki|Yoichi|Y|;Hara|Naohiko|N|",
"chemical_list": null,
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"issue": "26(9)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Hyposplenism; Pneumococcal pneumonia; SYNAPSE VINCENT; Splenic volume",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D006801:Humans; D011008:Pneumococcal Infections; D011018:Pneumonia, Pneumococcal; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013154:Spleen; D013156:Splenectomy",
"nlm_unique_id": "9608375",
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"pmid": "32376162",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Splenic volume in pneumococcal pneumonia patients is associated with disease severity and mortality.",
"title_normalized": "splenic volume in pneumococcal pneumonia patients is associated with disease severity and mortality"
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"companynumb": "JP-PFIZER INC-2020383685",
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"abstract": "Prenatally acquired human cytomegalovirus (HCMV) infection is the most frequent viral infection of newborns in developed countries. Virostatic therapy is accompanied by side effects and stepwise emergence of resistant virus variants. Different genotypic approaches show limited sensitivity in detecting on-growing minor resistant virus populations. Here, we demonstrate the superiority of pyrosequencing for the monitoring of mutant emergence. In a preterm baby born after 28 weeks of gestation and suffering from disseminated congenital HCMV infection, long-term control could not be achieved under ganciclovir/valganciclovir therapy and the infant died on the 113th day of life. Resistance-associated mutations in the HCMV UL97 gene were not detected by conventional DNA sequencing but postmortem pyrosequencing. Four different CMV variants carrying resistance-associated mutations each representing 11-17% of the total CMV population were found.",
"affiliations": "Department of Neonatology, Charité Universitätsmedizin, Berlin, Germany.",
"authors": "Kampmann|Susanne E|SE|;Schindele|Birgit|B|;Apelt|Luise|L|;Bührer|Christoph|C|;Garten|Lars|L|;Weizsaecker|Katharina|K|;Krüger|Detlev H|DH|;Ehlers|Bernhard|B|;Hofmann|Jörg|J|",
"chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D015774:Ganciclovir",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00430-010-0181-y",
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"issn_linking": "0300-8584",
"issue": "200(2)",
"journal": "Medical microbiology and immunology",
"keywords": null,
"medline_ta": "Med Microbiol Immunol",
"mesh_terms": "D000998:Antiviral Agents; D001344:Autopsy; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004279:DNA, Viral; D024882:Drug Resistance, Viral; D005260:Female; D015774:Ganciclovir; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases; D009154:Mutation; D017853:Phosphotransferases (Alcohol Group Acceptor); D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA",
"nlm_unique_id": "0314524",
"other_id": null,
"pages": "109-13",
"pmc": null,
"pmid": "21165648",
"pubdate": "2011-05",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": "18815745;10390260;20236864;10395867;16973841;10364600;19588102;271968;17468661;11156611;15728878;17537934;18383425;15482204;17872438;20876379;12915819;10745263",
"title": "Pyrosequencing allows the detection of emergent ganciclovir resistance mutations after HCMV infection.",
"title_normalized": "pyrosequencing allows the detection of emergent ganciclovir resistance mutations after hcmv infection"
} | [
{
"companynumb": "DE-AMGEN-DEUSP2017158407",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HUMAN CYTOMEGALOVIRUS IMMUNE GLOBULIN"
},
"dr... |
{
"abstract": "BACKGROUND\nBK viral nephropathy is an increasingly recognized cause of early allograft loss in kidney transplantation. This study aimed to determine whether a sirolimus (Sir)-based calcineurin inhibitor-sparing regimen is associated with a lower incidence of BK viremia.\n\n\nMETHODS\nThis was a single-center retrospective study. Patients were either on tacrolimus (Tac)-based or on Sir-based immunosuppression. Conversion from Tac to Sir occurred at or after 3 months if patients were <62 years of age, had calculated panel reactive antibodies of <20%, and did not have acute early rejection.\n\n\nRESULTS\nIncidence of clinically significant BK viremia was 17.9% in the Tac group and 4.3% in the Sir group. Cox regression multivariate analysis showed that male gender (hazard ratio [HR] = 2.87) and switch to Sir (HR = 0.333) impacted the incidence of BK viremia. Kaplan-Meier analysis showed a higher BK-free survival in the Sir group. A trend was seen toward shorter time to resolution of BK viremia and lower peak viremia in the Sir group. Patients on Sir had a higher estimated glomerular filtration rate at each time point; 34% of patients discontinued Sir because of side effects.\n\n\nCONCLUSIONS\nConversion to Sir-based maintenance immunosuppression at or about 3 months after kidney transplantation correlates with a lower incidence of BK viremia.",
"affiliations": "Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.",
"authors": "Tohme|F A|FA|;Kalil|R S|RS|;Thomas|C P|CP|",
"chemical_list": "D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12347",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "17(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "BK virus; calcineurin inhibitor sparing; kidney transplantation; sirolimus; tacrolimus",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D001739:BK Virus; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D015994:Incidence; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D027601:Polyomavirus Infections; D012189:Retrospective Studies; D020123:Sirolimus; D016559:Tacrolimus; D066027:Transplant Recipients; D014412:Tumor Virus Infections; D014766:Viremia",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "66-72",
"pmc": null,
"pmid": "25582442",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Conversion to a sirolimus-based regimen is associated with lower incidence of BK viremia in low-risk kidney transplant recipients.",
"title_normalized": "conversion to a sirolimus based regimen is associated with lower incidence of bk viremia in low risk kidney transplant recipients"
} | [
{
"companynumb": "US-APOTEX-2015AP007642",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null... |
{
"abstract": "Sexual side-effects are common among those using antipsychotic medication and may result in poor compliance and reduced quality of life. Retrograde ejaculation (RE) has been described occurring with a number of antipsychotic medications (thioridazine, risperidone, iloperidone and clozapine) but there are no guidelines regarding management of antipsychotic-associated RE. Imipramine has been suggested as a treatment for antipsychotic-associated RE in one small study of patients prescribed thioridazine and a case series of patients prescribed iloperidone. Quetiapine is a commonly used antipsychotic and is thought to be associated with less sexual side-effects relative to other antipsychotic medications. This case report describes a 25-year-old man with first episode psychosis who developed RE during treatment with quetiapine which improved with low-dose imipramine. This is the first description of RE occurring with quetiapine and successful treatment of quetiapine-associated RE with imipramine.",
"affiliations": "City and Hackney Centre for Mental Health, East London NHS Foundation Trust, London, UK.;John Howard Centre, East London NHS Foundation Trust, London, UK.",
"authors": "Roughley|Matthew|M|http://orcid.org/0000-0001-5095-4150;Lyall|Marc|M|",
"chemical_list": "D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate; D007099:Imipramine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-228539",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(8)",
"journal": "BMJ case reports",
"keywords": "pharmacology and therapeutics; psychiatry; psychotic disorders (incl schizophrenia); unwanted effects/adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D004542:Ejaculation; D006801:Humans; D007099:Imipramine; D008297:Male; D061686:Premature Ejaculation; D011618:Psychotic Disorders; D000069348:Quetiapine Fumarate; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31383672",
"pubdate": "2019-08-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21191308;11282707;26816751;15672600;25524544;10367237;7139590;25721311;8919429;18794656;16282833;20931406;22177462;18295343;15766299;8880656",
"title": "Retrograde ejaculation associated with quetiapine and treatment with low-dose imipramine.",
"title_normalized": "retrograde ejaculation associated with quetiapine and treatment with low dose imipramine"
} | [
{
"companynumb": "GB-ACCORD-151473",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"drugadditional": null,
"drug... |
{
"abstract": "To evaluate for evidence of systemic glucocorticoid absorption in cases of Fontan-associated protein-losing enteropathy (PLE) treated with enteral budesonide, we reviewed the charts of 27 patients with Fontan-associated PLE followed at Children's Hospital Colorado from 2005 to 2018. Cases were excluded for lack of budesonide thserapy or a treatment duration of less than 6 months. Charts were examined by two endocrinologists for review of prior biochemical endocrine evaluations, alterations in linear growth, and physical exam findings consistent with steroid excess. Twelve patients met inclusion criteria. Eight had prior documented cortisol screening. Three patients were tested while on treatment with a median fasting AM cortisol of 0.9 mcg/dL; two of these had a concomitantly measured ACTH, both below the detectable limit. Five patients were tested while weaning or having discontinued budesonide, with a median fasting AM cortisol of 9.1 mcg/dL. Eleven patients had decreases in height velocity associated with starting budesonide. Six patients had documentation of cushingoid features by an endocrinologist. In this cohort of children treated with budesonide for PLE following Fontan, clinical signs of systemic glucocorticoid absorption were frequent. Cortisol secretion was suppressed while on therapy, with adrenal recovery noted once budesonide was discontinued. Growth failure and cushingoid features were common findings. While these findings should be confirmed in larger cohorts, we recommend that the evaluation for systemic absorption of exogenous steroids be considered in patients treated with long-term enteral budesonide given the potential risk for adrenal crisis in times of physiologic stressors.",
"affiliations": "Section of Endocrinology, Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, 13123 E 16th Ave, Box 265, Aurora, CO, 80045, USA. richard.roberts@childrenscolorado.org.;Section of Cardiology, Department of Pediatrics, Children's Hospital Colorado, The Heart Institute, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.;Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Colorado, The Digestive Health Institute, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.;Section of Endocrinology, Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, 13123 E 16th Ave, Box 265, Aurora, CO, 80045, USA.",
"authors": "Roberts|Richard Ogden|RO|http://orcid.org/0000-0001-9493-0978;Di Maria|Michael V|MV|http://orcid.org/0000-0003-0346-8517;Brigham|Dania|D|http://orcid.org/0000-0001-7868-8042;Hsu|Stephanie|S|http://orcid.org/0000-0002-6003-3600",
"chemical_list": "D005938:Glucocorticoids; D019819:Budesonide",
"country": "United States",
"delete": false,
"doi": "10.1007/s00246-019-02248-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-0643",
"issue": "41(2)",
"journal": "Pediatric cardiology",
"keywords": "Adrenal suppression; Budesonide; Fontan; Protein-losing enteropathy",
"medline_ta": "Pediatr Cardiol",
"mesh_terms": "D019819:Budesonide; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D018729:Fontan Procedure; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D011504:Protein-Losing Enteropathies; D012189:Retrospective Studies",
"nlm_unique_id": "8003849",
"other_id": null,
"pages": "241-250",
"pmc": null,
"pmid": "31707491",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article",
"references": "8800155;27157244;24523594;21784410;26222757;17242136;18377444;9605076;23695484;23251737;21660539;18178416;26430235;24889258;1892099;29184808;18334580;12686359;18036954;9467984;28761367;11994860;20172140",
"title": "Evidence of Systemic Absorption of Enteral Budesonide in Patients with Fontan-Associated Protein-Losing Enteropathy.",
"title_normalized": "evidence of systemic absorption of enteral budesonide in patients with fontan associated protein losing enteropathy"
} | [
{
"companynumb": "US-TEVA-2020-US-1236844",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUDESONIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Objective: Suspected idiosyncratic valproic acid-induced hepatotoxicity in a sickle cell patient with chronic migraines is reported. Case Summary: A 32-year-old female with a medical history significant for sickle cell anemia and cerebral palsy was admitted to an inpatient medicine service for moderate to severe right flank pain with worsening transaminitis and hyperbilirubinemia. The patient reported taking valproic acid for approximately 6 years for the prevention of chronic migraines. An extensive workup was inconclusive for an etiology of underlying liver disease for the presenting symptoms. Valproic acid was discontinued on hospitalization day 3, resulting in a rapid improvement of the signs and symptoms of hepatotoxicity. Discussion: Several mechanisms of idiopathic valproic acid-induced hepatotoxicity have been proposed, including the accumulation of hepatotoxic metabolites, induction of oxidative stress, and deficiency of l-carnitine. Drug-induced hepatotoxicity is typically confirmed following improvement on withdrawal of the suspected agent and exclusion of any underlying etiologies. For this particular patient case, the Council for International Organizations of Medical Sciences scale was also used to evaluate the probability of the hepatotoxicity being drug related. Objective causality assessment with this scale revealed a probable adverse drug event. Conclusion: Idiopathic valproic acid-induced hepatotoxicity was suspected in a 32-year-old female with a history of sickle cell anemia and cerebral palsy following improvement of transaminitis and abdominal pain on discontinuation of valproic acid therapy and exclusion of an underlying etiology. This case reveals the clinical significance of prompt pharmacist identification and management of the potential adverse drug event.",
"affiliations": "Penn Presbyterian Medical Center, Philadelphia, PA, USA.;University of the Sciences, Philadelphia, PA, USA.;Hospital of the University of Pennsylvania, Philadelphia, PA, USA.",
"authors": "Cimino|Christo|C|;Charneski|Lisa|L|;Kumar|Lisa|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/8755122514550490",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1549-4810",
"issue": "31(1)",
"journal": "The Journal of pharmacy technology : jPT : official publication of the Association of Pharmacy Technicians",
"keywords": "anticonvulsants; clinical toxicology; drug monitoring; hepatitis; hepatotoxicity; pharmacokinetics; sickle cell anemia; toxicity",
"medline_ta": "J Pharm Technol",
"mesh_terms": null,
"nlm_unique_id": "8504643",
"other_id": null,
"pages": "43-46",
"pmc": null,
"pmid": "34860915",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports",
"references": "17145692;6428980;15625224;17040368;8837953;11124828;19280426;8229110;8614514;23792104;12475192;11581089;10403231;22915484;21544855;21248613",
"title": "Idiosyncratic Valproic Acid-Induced Hepatotoxicity in a Sickle Cell Patient.",
"title_normalized": "idiosyncratic valproic acid induced hepatotoxicity in a sickle cell patient"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-98295",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DULOXETINE"
},
"drug... |
{
"abstract": "Despite the importance of pneumonia to public health, little is known about the composition of the lung microbiome during infectious diseases, such as pneumonia, and how it evolves during antibiotic therapy. To study the possible relation of the pulmonary microbiome to the severity and outcome of this respiratory disease, we analyzed the dynamics of the pathogen and the human lung microbiome during persistent infections caused by the bacterium Legionella pneumophila and their evolution during antimicrobial treatment. We collected 10 bronchoalveolar lavage fluid samples from three patients during long-term hospitalization due to pneumonia and performed a unique longitudinal study of the interkingdom microbiome, analyzing the samples for presence of bacteria, archaea, fungi, and protozoa by high-throughput Illumina sequencing of marker genes. The lung microbiome of the patients was characterized by a strong predominance of the pathogen, a low diversity of the bacterial fraction, and an increased presence of opportunistic microorganisms. The fungal fraction was more stable than the bacterial fraction. During long-term treatment, no genomic changes or antibiotic resistance-associated mutations that could explain the persistent infection occurred, according to whole-genome sequencing analyses of the pathogen. After antibiotic treatment, the microbiome did not recover rapidly but was mainly constituted of antibiotic-resistant species and enriched in bacteria, archaea, fungi, or protozoa associated with pathogenicity. The lung microbiome seems to contribute to nonresolving Legionella pneumonia, as it is strongly disturbed during infection and enriched in opportunistic and/or antibiotic-resistant bacteria and microorganisms, including fungi, archaea, and protozoa that are often associated with infections.IMPORTANCE The composition and dynamics of the lung microbiome during pneumonia are not known, although the lung microbiome might influence the severity and outcome of this infectious disease, similar to what was shown for the microbiome at other body sites. Here we report the findings of a comprehensive analysis of the lung microbiome composition of three patients with long-term pneumonia due to L. pneumophila and its evolution during antibiotic treatment. This work adds to our understanding of how the microbiome changes during disease and antibiotic treatment and points to microorganisms and their interactions that might be beneficial. In addition to bacteria and fungi, our analyses included archaea and eukaryotes (protozoa), showing that both are present in the pulmonary microbiota and that they might also play a role in the response to the microbiome disturbance.",
"affiliations": "Institut Pasteur, Biologie des Bactéries Intracellulaires, Paris, France.;CIRI, International Center for Infectiology Research, Legionella pathogenesis Team, Université de Lyon, Lyon, France.;Institut Pasteur, Biologie des Bactéries Intracellulaires, Paris, France.;CIRI, International Center for Infectiology Research, Legionella pathogenesis Team, Université de Lyon, Lyon, France.;Institut Pasteur, Biologie des Bactéries Intracellulaires, Paris, France cbuch@pasteur.fr.",
"authors": "Pérez-Cobas|Ana Elena|AE|0000-0002-3995-5571;Ginevra|Christophe|C|;Rusniok|Christophe|C|;Jarraud|Sophie|S|;Buchrieser|Carmen|C|0000-0003-3477-9190",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1128/mBio.00889-20",
"fulltext": "\n==== Front\nmBio\nmBio\nmbio\nmbio\nmBio\nmBio\n2150-7511 American Society for Microbiology 1752 N St., N.W., Washington, DC \n\n32430469\nmBio00889-20\n10.1128/mBio.00889-20\nResearch Article\nHost-Microbe Biology\nPersistent Legionnaires’ Disease and Associated Antibiotic Treatment Engender a Highly Disturbed Pulmonary Microbiome Enriched in Opportunistic Microorganisms\nLung Microbiome Evolution during PneumoniaPérez-Cobas et al.https://orcid.org/0000-0002-3995-5571Pérez-Cobas Ana Elena ab Ginevra Christophe cdefgh Rusniok Christophe ab Jarraud Sophie cdefgh https://orcid.org/0000-0003-3477-9190Buchrieser Carmen ab a Institut Pasteur, Biologie des Bactéries Intracellulaires, Paris, France\nb CNRS UMR 3525, Paris, France\nc CIRI, International Center for Infectiology Research, Legionella pathogenesis Team, Université de Lyon, Lyon, France\nd Inserm, U1111, Lyon, France\ne Ecole Normale Supérieure de Lyon, Lyon, France\nf Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France\ng CNRS, UMR5308, Lyon, France\nh Hospices Civils de Lyon, Centre National de Référence des Légionelles, Lyon, France\nFreitag Nancy E. EditorUniversity of Illinois at Chicago\n \nAddress correspondence to Carmen Buchrieser, cbuch@pasteur.fr.\n19 5 2020 \nMay-Jun 2020 \n11 3 e00889-2010 4 2020 23 4 2020 Copyright © 2020 Pérez-Cobas et al.2020Pérez-Cobas et al.This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.The composition and dynamics of the lung microbiome during pneumonia are not known, although the lung microbiome might influence the severity and outcome of this infectious disease, similar to what was shown for the microbiome at other body sites. Here we report the findings of a comprehensive analysis of the lung microbiome composition of three patients with long-term pneumonia due to L. pneumophila and its evolution during antibiotic treatment. This work adds to our understanding of how the microbiome changes during disease and antibiotic treatment and points to microorganisms and their interactions that might be beneficial. In addition to bacteria and fungi, our analyses included archaea and eukaryotes (protozoa), showing that both are present in the pulmonary microbiota and that they might also play a role in the response to the microbiome disturbance.\n\nABSTRACT\nDespite the importance of pneumonia to public health, little is known about the composition of the lung microbiome during infectious diseases, such as pneumonia, and how it evolves during antibiotic therapy. To study the possible relation of the pulmonary microbiome to the severity and outcome of this respiratory disease, we analyzed the dynamics of the pathogen and the human lung microbiome during persistent infections caused by the bacterium Legionella pneumophila and their evolution during antimicrobial treatment. We collected 10 bronchoalveolar lavage fluid samples from three patients during long-term hospitalization due to pneumonia and performed a unique longitudinal study of the interkingdom microbiome, analyzing the samples for presence of bacteria, archaea, fungi, and protozoa by high-throughput Illumina sequencing of marker genes. The lung microbiome of the patients was characterized by a strong predominance of the pathogen, a low diversity of the bacterial fraction, and an increased presence of opportunistic microorganisms. The fungal fraction was more stable than the bacterial fraction. During long-term treatment, no genomic changes or antibiotic resistance-associated mutations that could explain the persistent infection occurred, according to whole-genome sequencing analyses of the pathogen. After antibiotic treatment, the microbiome did not recover rapidly but was mainly constituted of antibiotic-resistant species and enriched in bacteria, archaea, fungi, or protozoa associated with pathogenicity. The lung microbiome seems to contribute to nonresolving Legionella pneumonia, as it is strongly disturbed during infection and enriched in opportunistic and/or antibiotic-resistant bacteria and microorganisms, including fungi, archaea, and protozoa that are often associated with infections.\n\nKEYWORDS\nLegionella pneumophilaantibiotic resistancepneumoniapulmonary microbiomeAgence Nationale de la Recherche (ANR)https://doi.org/10.13039/501100001665ANR-15-CE17-0014-03Buchrieser Carmen Agence Nationale de la Recherche (ANR)https://doi.org/10.13039/501100001665ANR-10-LABX-62-IBEIDBuchrieser Carmen Agence Nationale de la Recherche (ANR)https://doi.org/10.13039/501100001665ANR-15-CE17-0014-01Jarraud Sophie Agence Nationale de la Recherche (ANR)https://doi.org/10.13039/501100001665ANR-11-LABX-0048Jarraud Sophie cover-dateMay/June 2020\n==== Body\nINTRODUCTION\nHistorically, the lower airways were thought to be sterile unless they were infected. However, the culture-independent and high-throughput sequencing techniques that have been developed have revealed that the respiratory tract, like almost every mucosal surface in the human body, harbors a distinct microbiome composed of bacteria, fungi, and viruses (1–3). In 2016, the bacterial composition of the healthy lung was deeply characterized for the first time by analyzing bronchoalveolar lavage (BAL) fluid samples from healthy individuals. Two types of microbiome profiles (termed “pneumotypes”) were described (4). One of the pneumotypes, named supraglottic predominant taxa (SPT), was characterized by a high bacterial load and the presence of anaerobes, such as Prevotella and Veillonella, belonging to the phyla Bacteroides and Firmicutes, respectively, whereas the second pneumotype was called the background predominant taxa (BPT), as it presented a low biomass and consisted of bacteria that mainly belonged to the phylum Proteobacteria, such as Acidocella or Pseudomonas. Although analysis of the lung microbiome is a relatively new field and little is known about its role in human health, it was suggested that the lung microbiome participates in immune system functions, including immune cell maturation and inflammatory responses (2, 5). Segal and colleagues proposed that bacteria, such as Prevotella and Veillonella, that have been commonly identified in the lungs of healthy individuals or their products participate in the regulation of inflammation and are linked to the activation of the lung mucosal Th17 response (4).\n\nThe fungal microbiome of a healthy lung is mainly composed of environmental fungi belonging to the phyla Ascomycota and Basidiomycota, such as the Davidiellaceae, Eurotium, Eremothecium, and Cladosporium, while during disease, a higher abundance of pathogenic species belonging to the genera Aspergillus, Malassezia, or Candida is present (6). Commensal fungi, like bacteria, seem to participate in immune system stimulation, the inflammatory response, and protection against pathogens (5, 6). In contrast to the bacterial and fungal composition of the lung, which has started to be investigated better, the presence of eukaryotes, archaea, or viruses has been investigated very little.\n\nTo date, the majority of studies analyzing the lung microbiome in disease have focused on cystic fibrosis (7–9), asthma (10, 11), or chronic obstructive pulmonary disease (COPD) (12–14). These studies have shown that lung microbial dysbiosis is generally characterized by a microbiome enriched in pathogenic and opportunistic bacteria (such as certain Gammaproteobacteria) with a high biomass due to the overgrowth of pathogens and a low diversity because of the displacement of the normal members of the community (2, 5).\n\nAmong infectious diseases, acute lower respiratory tract infections are the leading cause of morbidity and mortality worldwide. Among these, pneumonia represents a clinical and economic burden and a major public health problem, particularly for children and the elderly. The bacterium Legionella pneumophila is one of the human pathogens (15) that can cause a severe pneumonia, called Legionnaires’ disease, which can be fatal in about 8% of the cases, despite timely and adequate therapy (16). However, Legionnaires’ disease is characterized by clinical polymorphism and variable severity. For example, in France, 98% of recognized patients with Legionnaires’ disease are hospitalized and 40% require admission to an intensive care unit (ICU), where the mortality rate remains high (>25% in ICUs) (17). Recently, Mizrahi and collaborators characterized the microbiome of nine sputum samples from patients with L. pneumophila infection, reporting a high abundance of Streptococcus bacteria and a low abundance of L. pneumophila bacteria (18). However, lung samples, like pulmonary lavage or tracheal aspirate samples, have not been analyzed yet.\n\nWe report the findings of a comprehensive analysis, performed by using high-throughput sequencing of marker genes, of the interkingdom (bacteria, archaea, and eukaryotes) lung microbiome of three patients with long-term pneumonia due to L. pneumophila and its evolution during antibiotic therapy.\n\nRESULTS\nLung samples that originated from patients and healthy individuals.\nThe medical histories of the three patients included in this study have been described as a case series of slowly resolving and nonresolving Legionnaires’ disease (19), and a detailed description of patient A’s clinical course has also been described (18). This retrospective research, conducted by the French National Reference Center for Legionella (2013 to 2017), reported several Legionnaires’ disease cases with persistent clinical symptoms, computed tomography (CT) scan abnormalities, and Legionella detection in lower respiratory tract specimens by culture and/or real-time (RT) PCR (18). Here, we analyzed the lung microbiome composition of three of the patients included in this previous study (19). Briefly, patient A (patient 3 in reference 19) was a 28-year-old immunocompetent man admitted to the hospital due to severe community-acquired pneumonia (CAP). For 5 days, he was treated with amoxicillin, as a Streptococcus pneumoniae infection was suspected. As the pneumonia got worse, this treatment was enlarged with amoxicillin-clavulanic acid and spiramycin and, later, with ceftriaxone, erythromycin, levofloxacin, and oseltamivir. Only at day 5 was L. pneumophila identified as the causative agent, and the treatment was switched to a combination of erythromycin and levofloxacin (19, 20) (Fig. 1A). Due to a suspicion of the presence of a lung abscess according to a thoracic computed tomography (CT) scan, rifampin was added at day 13. A second thoracic CT scan revealed a voluminous lung abscess at day 34, and Fusobacterium nucleatum was identified. Thus, metronidazole was added for 20 more days. The abscess was resected on day 42, and the patient recovered fully. We analyzed the microbiome composition of the BAL fluid samples taken at days 5, 14, 24, 34, and 42 postadmission as well as that of one sputum sample taken at day 4 postadmission and a biopsy sample taken during lung abscess removal at day 42 (Fig. 1A).\n\nFIG 1 History of the antibiotic treatments of the patients analyzed here. (A) Patient A; (B) patient B; (C) patient C. The colors indicate the antibiotic treatment, and the length of the colored block indicates the duration of treatment with each antibiotic. The numbers below the colored blocks indicate the days on which a sample was taken. The days on which BAL fluid samples were collected for analysis of the microbiome are marked with an asterisk. The percentage given below the timeline indicates the relative abundance of Legionella in the sample, as determined by qPCR.\n\nPatient B (patient 8 in reference 19), a 69-year-old immunocompromised woman, was hospitalized for Legionella-associated pneumonia and treated for 21 days with levofloxacin. After she had been free of symptoms for 37 days, she was rehospitalized for bilateral pulmonary consolidations and pleural effusion. A recurrent Legionella pneumonia was confirmed, and she was treated for 6 weeks with erythromycin, levofloxacin, and co-trimoxazole for a concomitant pneumocystosis (19). A sample was taken at the onset of treatment (day 0) and after 2.5 months (day 82) (Fig. 1B).\n\nPatient C (patient 10 in reference 19), a 76-year-old immunocompromised man, was sampled 109 days after the onset of the treatment, when the patient had fully recovered. The sample was taken 19 days after the end of antibiotic therapy. This BAL fluid sample (named sample C109) was negative for L. pneumophila, as confirmed by PCR (19) (Fig. 1C).\n\nTo compare the microbiomes of lungs with pneumonia with those of healthy lungs, we retrieved and reanalyzed the data for the lung microbiomes of 49 healthy individuals in our pipeline (4). The published data were obtained from BAL fluid samples and were characterized by sequencing the 16S rRNA gene (bacterial microbiome) (4). The persons defined to be healthy in this study did not present underlying lung diseases; had not been treated with antibiotics or steroids in the 3 months prior to sampling; had no cardiovascular, renal, or liver disease or diabetes mellitus; and did not have heavy alcohol use (more than six beers daily). They also did not present respiratory symptoms (cough, wheezing, or shortness of breath) before bronchoscopy (4).\n\nBAL fluid and sputum samples differ in microbiome composition.\nThe comparison of the BAL fluid sample taken on day 5 and the sputum sample taken on day 4 (patient A) identified Streptococcus (43%), Prevotella (13%), and Gemella (13%) to be the most abundant bacterial genera in the sputum sample, while Legionella represented only 3% of the total relative abundance (see Fig. S1A in the supplemental material). Interestingly, the fungal microbiome of both the sputum and the BAL fluid samples showed a high abundance of Ascomycota (40%) (Fig. S1B). In contrast, the BAL fluid sample showed a lower diversity and operational taxonomic unit (OTU) richness than the sputum sample, and more than 99% of the sequences belonged to Legionella (Fig. S1C). This reveals that, during pneumonia, the abundance of Legionella compared to that of other bacteria is low in sputum, while Legionella is very abundant in the BAL fluid samples, which represent the lung. Thus, the analysis of sputum samples and the analysis of BAL fluid samples are two approaches that might be coupled in analyzing the lung microbiome to have the best picture of the microbiomes in the upper and lower respiratory tract during disease.\n\n10.1128/mBio.00889-20.5FIG S1 Comparison of the microbiome composition of the BAL fluid and sputum samples and the bacterial alpha diversity of the microbiomes of patients A and B. For each sample, the estimated values and the error bars are shown. Download FIG S1, TIF file, 2.5 MB.\n\nCopyright © 2020 Pérez-Cobas et al.2020Pérez-Cobas et al.This content is distributed under the terms of the Creative Commons Attribution 4.0 International license. Legionella pneumophila strains isolated during infection and antimicrobial therapy show no specific resistance profile.\nIn a previous study, one L. pneumophila strain isolated at the start of hospitalization and one isolated at the end of hospitalization were analyzed (19). They did not exhibit phenotypic antibiotic resistance or have genomic mutations that could be related to antibiotic resistance (19). To follow the evolution of the pathogen in more detail, in the present study we performed whole-genome sequencing of 15 intermediate isolates recovered over the entire hospitalization period from patient A and 9 isolates (4 early isolates and 5 late isolates) recovered from patient B. Mapping of the corresponding genomes to those of the earliest isolates and a search for genes related to antibiotic resistance did not identify any genomic changes between the different isolates for either patient. Thus, L. pneumophila does not seem to evolve fast under antibiotic pressure, in line with our findings presented in a previous report, where we estimated a very low evolutionary rate of 0.71 single nucleotide polymorphism per genome per year for L. pneumophila strains (21). To further corroborate these results, long-read sequencing was performed for the first and the last isolates from patient A; however, this approach also did not identify any chromosomal rearrangements or recombination events, suggesting that the resistance of these isolates must be due to factors other than changes in their genome sequences.\n\nAntibiotic treatment leads to strong perturbations and the slow recovery of a healthy microbiome.\nLegionella dominated the bacterial composition of the BAL fluid samples of patients A and B during the first days of antibiotic treatment. For patient A, at the time of diagnosis, Legionella represented 99% of the bacteria identified in the lungs, and the Legionella bacteria stayed dominant until day 24, when they still represented 95% of the bacteria (Fig. 2A). Similarly, the microbiome of patient B was mainly composed of Legionella, representing 57% of the diversity at the beginning of treatment (Fig. 2B). After long-term antibiotic therapy, a substantial change in the microbiome composition of patients A (Fig. 2A) and B (Fig. 2B) occurred. Both patients showed a marked decrease in the relative abundance of Legionella (20% for patient A and 0.2% for patient B), indicating that the antibiotic treatment was efficient. Furthermore, the presence of bacteria commonly found in the lung microbiome of healthy individuals (5), such as Prevotella (from less than 1% during the first 24 days of therapy to about 50% at day 34) and Staphylococcus (11%) for patient A and Enterococcus (64%) and Staphylococcus (14%) for patient B, increased. Indeed, certain species of the genus Prevotella are resistant to different classes of antibiotics, including macrolides, which were included in the treatment (22). Furthermore, Prevotella was described to be a predominant taxon in healthy microbiomes (4), suggesting that the microbiome started to recover. The bacterial diversity of the microbiome of patient A collapsed due to the antibiotic treatment at about day 24, reaching the lowest values for all estimated metrics (Fig. S1C). For both patients, the community richness was higher at the end of the infection (Fig. S1C and D).\n\nFIG 2 Microbiome and mycobiome composition of the BAL fluid samples. (A and B) Bacterial composition of the BAL fluid samples from patient A (A) and patient B (B). The numbers on the y axes are percent abundance. (C) Number of total bacteria (patient A) estimated by qPCR of the 16S rRNA gene. (D) Correlation of the number of bacteria (CT of the 16S rRNA gene determined by qPCR) with the amount of Legionella (CT of the mip gene determined by qPCR) (patient A). The CT values for the mip gene were obtained from a clinical case study (20). (E and F) Fungal composition of the BAL fluid samples from patient A (E) and patient B (F).\n\nAnalysis of the evolution of the bacterial load of patient A showed a decrease in biomass during antibiotic treatment (Fig. 2C). During the first days of therapy, the load was very high (1010 to 1012 copies of the 16S rRNA gene), but after day 24 the load decreased significantly to 108 to 109 copies, probably due to the addition of rifampin at day 13 and/or to the time needed for the activity of the combination of a fluoroquinolone plus a macrolide (P = 0.002). The Pearson correlation test between the threshold cycle (CT) values of L. pneumophila and the total biomass (16S rRNA data) pointed to a significant positive correlation between the two (P = 0.04) (Fig. 2D). Thus, the lower biomass can be partially explained by the decrease in pathogen abundance due to therapy.\n\nDuring pneumonia and antibiotic therapy, the fungal microbiome is less disturbed.\nThe fungal composition of the BAL fluid samples of patients A (Fig. 2E) and B (Fig. 2F) was mainly composed of two phyla, Basidiomycota and Ascomycota. These are reported to be the most abundant phyla in the human respiratory tract (6). However, most of the OTUs could be classified only at the level of the phylum, suggesting that the true diversity of the fungi awaits characterization. The main genus identified was Candida (for patient A, 0.8 to 7%; for patient B, 65 to 99%). Despite the higher homogeneity of the fungal composition than the bacterial one, the richness and diversity of patient A decreased like those of the bacteria through the antibiotic treatment and started to recover by day 34 of treatment (Fig. S2A). For patient B, after several weeks of antibiotic treatment, the genus Candida constituted about 99% of the fungal microbiome composition, explaining why the diversity metrics were lower after therapy (Fig. S2B). The few studies that have analyzed the fungal microbiome have reported that in healthy people it consists predominantly of environmental organisms, such as Aspergillus or Cladosporium (23). This composition is clearly different from that of the fungal microbiome of the patients determined in the present study. The changes in the mycobiome during bacterial infection and antibiotic treatment suggest that the fungal and the bacterial communities interact ecologically in the lungs (i.e., cooperation, competition) and with the host immune system. Furthermore, infection and the associated antibiotic treatment change the healthy lung microbiome considerably and allow Candida species to occupy the niche, which is disturbed by the pathogen and the antibiotic treatment.\n\n10.1128/mBio.00889-20.6FIG S2 Fungal alpha diversity of the microbiomes of patients A and B. For each sample, the estimated values and the error bars are shown. Download FIG S2, TIF file, 2.7 MB.\n\nCopyright © 2020 Pérez-Cobas et al.2020Pérez-Cobas et al.This content is distributed under the terms of the Creative Commons Attribution 4.0 International license. Enrichment of the lung abscess with pathogenic microorganisms.\nThe microbial composition of the lung abscess was determined to be Legionella (38%), Prevotella (19%), Fusobacterium (15%), and Oribacterium (15%) (Fig. 3A). As expected, Legionella was more abundant in the lung abscess samples than in the BAL fluid samples. Also, anaerobic bacteria, such as Fusobacterium, Oribacterium, and Shuttleworthia, showed a higher abundance in the abscess, probably because the environment is more anoxic than that in other areas of the lungs. However, the diversity was lower in the abscess than in the BAL fluid samples (Fig. S1C). The fungal composition of the abscess (Fig. 3B) was dominated by Candida (50%) and other Ascomycota (20%), revealing enrichment of this phylum. The OTU richness was higher in the lung abscess than in the BAL fluid samples. However, the Shannon diversity index was lower, as only a few fungi were dominant (Fig. S2A).\n\nFIG 3 Comparison of the microbiome composition of the BAL fluid and abscess samples and the microbiome composition of patient C. (A) Bacterial composition. The taxonomy is based on the RDP. (B) Fungal composition. The taxonomy is based on the Warcup ITS training set. (C and D) Bacterial composition (C) and fungal composition (D) at 19 days after treatment. The numbers on the y axes are percent abundance.\n\nAfter long-term antibiotic treatment, the microbiome is enriched in Firmicutes.\nTo analyze the recovery of the microbiome after infection and long-term antibiotic treatment, we characterized the lung microbiome composition of patient C. The bacterial microbiome was enriched in Firmicutes, such as Streptococcus (20%), Veillonella (15%), and Enterococcus (10%), followed by Bacteroidetes: Prevotella (17%) (Fig. 3C). Prevotella and Veillonella are present in the lungs of healthy people, suggesting that the lung microbiome of this patient was in the restoration process (4). The fungal microbiome was mainly composed of Ascomycota (40%) and Basidiomycota (38%) (Fig. 3D). Similar to the samples from patient B, the evenness (Shannon diversity index = 4.9) and OTU richness (Chao 1 richness estimator = 2,348, number of OTUs = 990) after treatment for the samples from patient C were higher than those for the samples from patients A and B during infection.\n\nArchaea are part of the lung microbiota.\nAs it has been reported that archaea are present at all body sites, including the nose and lung (24), we analyzed our BAL fluid samples for archaea (Table S1A). Indeed, Methanobrevibacter, representing more than 50% of the archaeal diversity, was present in all samples (Table S1B). Patients A and C also carried other unclassified Euryarchaeota and Thermoprotei (Crenarchaeota), while in patient C, only archaea belonging to the genus Methanobrevibacter were identified. The closest species of the most abundant OTUs was Methanobrevibacter smithii, which was surprising, as it is described to be an anaerobic methane-producing archaeon. Thus, it is possible that there are anaerobic niches in the lung environment or that other bacteria present in the lung help this anaerobic archaeon to grow. Indeed, the aerobic culture of methanogenic archaea without an external source of hydrogen has been reported when Bacteroides thetaiotaomicron, which produces hydrogen, is present (25). Interestingly, methanogenic archaea have been associated with different diseases, suggesting that they may contribute to the disease under specific conditions and, thus, perhaps also to pneumonia (24).\n\n10.1128/mBio.00889-20.2TABLE S1 (A) Proportion of reads classified as bacteria or archaea for each sample. (B) Relative abundance of archaea present in the BAL fluid samples. (C) Relative abundance of protozoa in the BAL fluid samples. Download Table S1, DOCX file, 0.02 MB.\n\nCopyright © 2020 Pérez-Cobas et al.2020Pérez-Cobas et al.This content is distributed under the terms of the Creative Commons Attribution 4.0 International license. Legionella-related amoebae were identified in the human lungs.\nEnvironmental amoebae are the reservoir of Legionella, and amoebae infected with Legionella might be a vehicle of transmission. Inhaled infected protozoa may serve as cofactors in the pathogenesis of pulmonary disease (26). Thus, we analyzed the samples for the presence of the genus Acanthamoeba and the class Heterolobosea. A large proportion was identified to be unclassified eukaryotes, suggesting that considerable eukaryotic diversity is present in the lungs and remains to be described. Indeed, we identified Acanthamoeba castellanii (Table S1C) and Trichomonas tenax (Table S2), a protozoan commonly found in the human oral cavity but rarely associated with pulmonary infections (27). Acanthamoeba castellanii is an aquatic protozoan that is a natural host of Legionella and that may be important in the transmission of this pathogen, but it also could be part of a resident protozoan community in the lungs. However, further studies using various genus-specific primers and samples from healthy individuals need to be undertaken to answer this question.\n\n10.1128/mBio.00889-20.3TABLE S2 Relative abundance of eukaryotic sequences in the BAL fluid samples. Download Table S2, DOCX file, 0.02 MB.\n\nCopyright © 2020 Pérez-Cobas et al.2020Pérez-Cobas et al.This content is distributed under the terms of the Creative Commons Attribution 4.0 International license. The lung microbiome during infection and antimicrobial therapy is significantly different from a healthy microbiome.\nTo better understand the differences between the lung microbiome of healthy individuals and the one influenced by infection and antibiotic treatment, we compared the healthy microbiomes reported by Segal and colleagues in 2016 (4) with the microbiomes in our patients’ samples (Fig. S3). They analyzed bronchoalveolar lavage (BAL) fluid samples from healthy individuals. Two types of microbiome profiles (termed pneumotypes) were described (4). One of the pneumotypes, named supraglottic predominant taxa (SPT), was characterized by a high bacterial load and the presence of anaerobes, such as Prevotella and Veillonella, belonging to the phyla Bacteroidetes and Firmicutes, respectively. In contrast, the second pneumotype was called the background predominant taxa (BPT), as it presented a low biomass and consisted of bacteria that belonged mainly to the phylum Proteobacteria, such as Pseudomonas and Acidocella. The compositions of the microbiomes of healthy people and the ones of the patients were significantly different (adonis test, P = 0.004975). Clustering analyses grouped the microbiomes of the pneumonia patients separately from those of the healthy ones (Fig. 4A). Furthermore, the samples containing a high abundance of Legionella (patient A samples taken at days 5, 14, and 24 and the patient B sample taken at day 0) clustered together, while the microbiomes of samples taken after antibiotic treatment (patient A samples taken at days 34 and 42, the patient B sample taken at day 82, and patient C sample C109) were different.\n\nFIG 4 Comparison of the bacterial composition of healthy pneumotypes and Legionella-infected and antibiotic-treated BAL fluid samples. (A) Hierarchical clustering of all samples based on the bacterial composition. A hierarchical clustering analysis based on Bray-Curtis dissimilarity was used as a distance method. BPT (n = 32), background predominant taxa; SPT (n = 17), supraglottic predominant taxa; LEG (n = 4), BAL fluid samples from Legionella-infected patients (patient A samples were taken at days 5, 14, and 24; the patient B sample was taken at day 0); AB (n = 4), BAL fluid samples after antibiotic treatment (patient A samples were taken at days 34 and 42; the patient B sample was taken at day 82; the patient C sample was sample C109). (B) Comparison of the diversity between the two healthy pneumotypes (n = 49) and the pneumonia (n = 4) and antibiotic-treated (n = 4) samples. The diversity metrics Chao 1 richness estimator, the number of OTUs, and the Shannon diversity index were estimated for the three groups. Each box plot represents the distribution of values, including the median, minimum, maximum, first and third quartiles, and outliers.\n\n10.1128/mBio.00889-20.7FIG S3 Lung microbiome composition (SPT and BPT) of samples from healthy subjects and patients with pneumonia. Download FIG S3, TIF file, 2.7 MB.\n\nCopyright © 2020 Pérez-Cobas et al.2020Pérez-Cobas et al.This content is distributed under the terms of the Creative Commons Attribution 4.0 International license. When the healthy microbiome was statistically compared with that of the samples from the patients (disrupted microbiome), 34 families (most of them Proteobacteria) were significantly more abundant in the microbiomes of the healthy people (Table S3). The microbiomes of the pneumonia patients showed a high abundance of only five families: Legionellaceae, Staphylococcaceae, Streptococcaceae, Propionibacteriaceae, and Corynebacteriaceae. The most abundant OTUs were classified as L. pneumophila, a Staphylococcus sp., Streptococcus sanguinis, Cutibacterium acnes, and a Corynebacterium sp., respectively. Furthermore, diversity and richness were significantly lower in the samples from patients than in the ones from healthy people (P < 0.05) (Fig. 4B). The healthy microbiome showed a higher diversity and richness than the antibiotic-treated one (P > 0.05), indicating an intermediate state of diversity after therapy.\n\n10.1128/mBio.00889-20.4TABLE S3 Bacterial families identified to have statistically significantly different abundances between healthy subject and patient samples. Download Table S3, DOCX file, 0.02 MB.\n\nCopyright © 2020 Pérez-Cobas et al.2020Pérez-Cobas et al.This content is distributed under the terms of the Creative Commons Attribution 4.0 International license. Ecological interactions between bacterial and fungal communities in the human lungs.\nThe parallel changes in bacterial and fungal diversity observed in patient A led us to analyze possible interactions between the two microbial communities. To get insight into the ecology of these communities and their possible interactions, we used the Wilcoxon signed-rank test and compared the diversity metric distributions of both communities. Then, we established a correlation network for the microbiome and mycobiome and networks that were specific to each domain to identify putative associations between members of each community. Indeed, putative bacterium-bacterium, bacterium-fungus, and fungus-fungus interactions were identified. These interactions might be critical for the disease outcome and recovery after the cessation of antibiotic treatment (for details, see Text S1 and Fig. S4 and S5).\n\n10.1128/mBio.00889-20.1TEXT S1 Extended Material and Methods. Download Text S1, DOCX file, 0.03 MB.\n\nCopyright © 2020 Pérez-Cobas et al.2020Pérez-Cobas et al.This content is distributed under the terms of the Creative Commons Attribution 4.0 International license. 10.1128/mBio.00889-20.8FIG S4 Correlation of the diversity of the bacterial and fungal communities in the lungs. Download FIG S4, TIF file, 2.7 MB.\n\nCopyright © 2020 Pérez-Cobas et al.2020Pérez-Cobas et al.This content is distributed under the terms of the Creative Commons Attribution 4.0 International license. 10.1128/mBio.00889-20.9FIG S5 Correlation networks of taxa in the lung microbiome during pneumonia. Download FIG S5, TIF file, 2.8 MB.\n\nCopyright © 2020 Pérez-Cobas et al.2020Pérez-Cobas et al.This content is distributed under the terms of the Creative Commons Attribution 4.0 International license. DISCUSSION\nThis unique and comprehensive, longitudinal analysis of the interkingdom lung microbiome of patients suffering for several months from pneumonia due to L. pneumophila revealed that the pathogen strongly dominates the bacterial microbiome and that fungi, archaea, and eukaryotes are also present. The comparison with healthy lung microbiomes showed that the infection engenders a highly disturbed microbial community. During the first stage of the disease, the pathogen is highly abundant, outcompeting other bacteria in the microbiome, explaining the low diversity that we observed. Along this line, studies of lung infection by Pseudomonas aeruginosa or Mycoplasma pneumoniae showed a dominance of the pathogens in the microbiome (28–30). A low microbiome diversity has also been described for pneumonia in patients with HIV infection, cystic fibrosis (5, 28), or pulmonary tuberculosis (31, 32). Despite a low microbial diversity, absolute quantification of the bacteria present in the BAL fluid samples analyzed revealed a very high bacterial biomass during infection (up to 1011 bacteria per ml of BAL fluid) due to the high abundance of the pathogen. Thus, although the possibility of contamination derived from bronchoscopy and the saline solution cannot be excluded in this study, such contamination, if present, would significantly affect the results only for BAL fluid samples with lower bacterial loads (less than 8E+04 16S rRNA copies/ml), which was not the case in our study (33).\n\nOur detailed analyses of the genomes of different isolates of the pathogen collected during the entire hospitalization period suggested that the persistence of the infection was not due to changes in the DNA sequence leading to the antibiotic resistance of the bacterium, in agreement with phenotypic and genomic data published previously (19). Thus, the increased tolerance toward antibiotics observed in vivo might have been due to the upregulation of antibiotic efflux pumps or to the formation of L. pneumophila persisters (34, 35). Furthermore, other factors might have influenced the weak response of these individuals, including the presence of specific microorganisms from the lung community and their ecological interactions. The overabundance of opportunistic bacteria during infection and after antibiotic therapy indicates that they might contribute to the slower response to the disease, as certain opportunistic species may take advantage of the host inflammatory responses induced by infection. For example, we identified Streptococcus sanguinis to be associated with pneumonia caused by Legionella. Indeed, it has been shown that the generation of intra-alveolar catecholamines and inflammatory cytokines during lung infections alters the microbial growth conditions, thereby favoring specific bacterial groups, including Streptococcus (36). Also, the presence of S. sanguinis was identified in community-acquired streptococcal pneumonia (37). Furthermore, a retrospective study identified S. sanguinis to be associated with lung abscess development (38). In line with these reports, we identified S. sanguinis to be predominant in the examined abscess sample (40% of the relative abundance). Our results provide important information on the microbiome changes in pneumonia patients; however, it needs to be taken into account that the individuals analyzed here represent a particular group among Legionnaires’ disease patients, as they suffered from a long-term infection and an inadequate response to treatment. Thus, further studies of the lung microbiome composition of Legionnaires’ disease patients, including standard cases, will clarify whether this trend is maintained in all patients.\n\nVery little is known about the role of fungi in lung health and the response to infection. Here, we show that the mycobiome followed more stable dynamics than the microbiome during infection and antibiotic treatment, with Ascomycota and Basidiomycota being the most abundant phyla. However, the antibiotics promoted the presence of Candida, which is often associated with extensive antibiotic usage in hospitals (39). Interestingly, many differences between the mycobiomes of the three patients analyzed here and those of healthy individuals investigated in other studies were observed. In the fungal microbiome of the pneumonia patients, genera such as Candida or Malassezia were present, but the healthy lung microbiome was described as consisting of environmental fungi, such as Aspergillus and Cladosporium (23). Indeed, Candida species are known opportunistic pathogens that have been associated with different lung conditions, including cystic fibrosis (40) and lung transplantation (41). Moreover, Malassezia has been connected to asthma (42). Thus, these two genera seem to be typically present in diseased lungs. Furthermore, the identification of correlations between the diversity and the composition of the bacterial and fungal communities present in the lungs of the individuals analyzed here may suggest an ecological relationship between the two communities that could be key for restoration of the microbiome after the cessation of disease and antimicrobial therapy.\n\nInterestingly, archaea may also play a role in disease severity or outcome, as suggested by the presence of Methanobrevibacter smithii in all the patients. Methanogenic archaea have been associated with disease under specific conditions and, thus, perhaps also during pneumonia (24). This could be critical, since archaea are generally resistant to most antibiotics (43). Furthermore, we showed here that amoebae and other protozoans are present in the lungs. This might partly be because Legionella-infected amoebae were inhaled, but we identified different protozoa; thus, it seems that the lung microbiota also contains a community of protozoa. Acanthamoeba (identified in all the patients) is a natural host of Legionella that possibly plays a role in disease transmission. Interestingly, animal studies showed that certain Acanthamoeba species, such as A. castellanii or A. polyphaga, might also induce direct damage to the pulmonary parenchyma by causing pneumonitis (44). Furthermore, Trichomonas tenax, which was identified in the lung samples analyzed here, has also been described in pulmonary pathologies (27). Hence, environmental protozoa might play a role in the transmission and the severity of the pathology. The presence of amoeba in all patients analyzed here also supports the possibility that resident protozoa might be present in the human lung microbiome, as is the case in the gut (45) or the oral cavity (46). Indeed, free-living amoebae are commonly found in our air (47), and the isolation of amoebae from nasal passages and the pharynxes of humans has been reported (48). Whether the identified protozoa are part of the healthy microbiome or are particularly present in patients with Legionella-associated pneumonia or other diseases needs to be studied further. Thus, we show here that interkingdom interactions also need to be considered in the outcome of the infection and antibiotic therapies. Further large-scale studies are needed to identify markers of a healthy lung microbiome and to understand the time that it takes for a patient to recover a fully healthy lung microbiome.\n\nMATERIALS AND METHODS\nSample collection, Legionella detection, and DNA extraction.\nBronchoalveolar lavage (BAL) fluid samples (collected at 5, 14, 24, 34, and 42 days after hospital admission) and a sputum specimen (collected at day 4 after hospital admission) were collected from patient A, a sputum specimen was collected from patient B (at days 0 and 82 after hospital admission), and a sputum specimen was collected from patient C (at 109 days after hospital admission or 19 days after the end of therapy) during the hospitalization period. Furthermore, a biopsy specimen of the lung abscess of patient A (collected on day 42) was included (Fig. 1). All samples were stored at −80°C. DNA was extracted from 1 ml of BAL fluid using a PowerSoil DNA isolation kit (Mobio) following the manufacturer’s instructions. The presence of L. pneumophila in the samples was detected by diagnostic PCR using the primers and probes of the R-DiaLeg kit (Diagenode, Belgium), as detailed in Text S1 in the supplemental material.\n\nMicrobiome sequencing.\nWe analyzed the microbiome interkingdom diversity of all samples using primers for bacteria (16S rRNA Illumina sequencing standard primers), archaea (16S rRNA; primers 787F/1000R), fungi (internal transcribed spacer [ITS]; primers ITS1/ITs2), the genus Acanthamoeba (18S rRNA; primers JDP1/JDP2) (49), and the class Heterolobosea (18S rRNA; primers Vahl730F_C/R-1200) (50) (Text S1). The Illumina libraries were prepared following the manufacturer’s instructions. High-throughput sequencing was performed with a MiSeq Illumina sequencer (2 × 300 bp) by the Biomics Pole (Institute Pasteur).\n\nAnalysis of amplicon sequences.\nAnalysis of the microbiome data was done as detailed previously (51). Briefly, artefactual sequences, short reads (<50 bp), as well as sequences of low quality (quality score < 33) were discarded by using FASTX-Toolkit tools (http://hannonlab.cshl.edu/fastx_toolkit/index.html). The trimming of the sequences according to quality parameters was based on the PRINSEQ program (http://prinseq.sourceforge.net). Paired-end reads were joined by using the fastq-join script (https://expressionanalysis.github.io/ea-utils/). The Quantitative Insights into Microbial Ecology (QIIME) pipeline was used to discard chimeric sequences and to calculate the operational taxonomic units (OTUs) at 97% similarity. We selected the open-reference OTU picking method with the QIIME default taxonomy-training database. The taxonomic classification of the 16S rRNA and 18S rRNA reads was based on the Ribosomal Database Project (RDP) (52), and the ITS taxonomy was based on the Warcup ITS training set (53).\n\nStatistical analysis.\nWe estimated the microbial richness and diversity of the samples by calculating the total number of operational taxonomic units (OTUs), the Chao 1 richness estimator (54), and the Shannon diversity index (55). All analyses were based on the core diversity analysis script implemented in the QIIME pipeline (56). The 16S rRNA abundance table was rarefied at 60,000 reads per sample and the ITS abundance table was rarefied at 6,000 reads per sample, based on the sequencing effort. A hierarchical clustering analysis based on Bray-Curtis dissimilarity was applied to compare the microbial composition between samples. To statistically compare the diversity metrics between sample groups, we used the Wilcoxon signed-rank test implemented in the R program. Correlation analyses were based on the Pearson method. A multivariate analysis of variance based on dissimilarities (adonis test) to test the influence of external variables in explaining the differences in composition between different sample groups was used and was based on the Vegan package of the R program (57). Linear discriminant analysis (LDA) effect size (LEfSe) analysis was applied to identify the taxa characterizing the different sample groups (58).\n\nQuantification of bacterial load.\nQuantitative real-time PCR (qPCR), based on the 16S rRNA gene, was performed to quantify the total bacteria in samples from patient A and used forward primer 520F (5′-AYTGGGYDTAAAGNG-3′) and reverse primer 802R (5′-TACNVGGGTATCTAATCC-3′). Standard curves were estimated by using serial 10-fold dilutions of purified and quantified amplicons. The PCR mixture was prepared in a final volume of 20 μl by adding 10 μl of 5× SYBR green qPCR master mix (Applied Biosystems), 0.8 μl of primers (10 mM), 3.4 μl of H2O, and 5 μl of the DNA sample. The amplification was performed on a Bio-Rad CFX qPCR instrument using the following program: 95°C for 3 min, followed by 40 cycles of 95°C for 5 s, 55°C for 30 s, and 72°C for 1 s. All reactions, including negative controls, were run in triplicate.\n\nWhole-genome sequencing.\nTo analyze the intrapatient evolution of L. pneumophila, 17 L. pneumophila isolates recovered from patient A (at days 4, 5, 10, 13, 14 [2 isolates], 16, 22, 26, 29, 30, 31, 33, 34, 36, 39, and 42) and 11 isolates recovered from patient B (at days 0 [6 isolates] and 69 [5 isolates]) were sequenced on an Illumina Nextseq500 (150-bp paired-end) machine, and Pacific Bioscience sequencing was performed by GATC Biotech. The genomes were analyzed as detailed in Text S1.\n\nEthics approval and consent to participate.\nThe clinical sample collection of the Lyon University Hospital was declared to the French Ministry of Education and Research (number DC-2008-176), and written informed consent from the patients was obtained for this study.\n\nAvailability of data.\nAll sequences have been entered in the European Bioinformatics Institute database under project accession number PRJEB33790.\n\nThis article is a direct contribution from Carmen Buchrieser, a Fellow of the American Academy of Microbiology, who arranged for and secured reviews by Paul Edelstein, Univ. of Penn. Perelman School of Medicine; Olivier Neyrolles, IPBS CNRS UMR 5089; and Giuseppe D'Auria, Joint Unit of Research in Genomics and Health, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO) - Salud Pública.\n\nCitation Pérez-Cobas AE, Ginevra C, Rusniok C, Jarraud S, Buchrieser C. 2020. Persistent Legionnaires’ disease and associated antibiotic treatment engender a highly disturbed pulmonary microbiome enriched in opportunistic microorganisms. mBio 11:e00889-20. https://doi.org/10.1128/mBio.00889-20.\n\nACKNOWLEDGMENTS\nThis work was supported by the Institut Pasteur and the Agence National de Recherche (grant number ANR-15-CE17-0014-03 and grant number ANR-10-LABX-62-IBEID to C.B. and A.E.P.-C.). Work in the S.J. laboratory is financed by Santé Publique France and the Agence National de Recherche (grant number ANR-15-CE17-0014-01). C.G. and S.J. are part of the French Laboratory of Excellence project ECOFECT (grant number ANR-11-LABX-0048).\n\nWe thank the Institut Pasteur Biomics Pole (Christiane Bouchier and Laurence Ma) for sequencing of the samples reported in this study.\n\nA.E.P.-C. and C.G. contributed to the experimental processing, A.E.P.-C. and C.R. contributed to data analyses and interpretation, and S.J. contributed to sample collection and study design. The manuscript was written by A.E.P.-C. and C.B. with input from the coauthors. The project was conceived of, planned by, and supervised by C.B.\n==== Refs\nREFERENCES\n1. Dickson RP , Huffnagle GB \n2015 \nThe lung microbiome: new principles for respiratory bacteriology in health and disease\n. PLoS Pathog \n11 :e1004923. doi:10.1371/journal.ppat.1004923 .26158874 \n2. Huffnagle GB , Dickson RP , Lukacs NW \n2017 \nThe respiratory tract microbiome and lung inflammation: a two-way street\n. Mucosal Immunol \n10 :299 –306\n. doi:10.1038/mi.2016.108 .27966551 \n3. Man WH , de Steenhuijsen Piters WA , Bogaert D \n2017 \nThe microbiota of the respiratory tract: gatekeeper to respiratory health\n. Nat Rev Microbiol \n15 :259 –270\n. doi:10.1038/nrmicro.2017.14 .28316330 \n4. 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Genome Biol \n12 :R60 . doi:10.1186/gb-2011-12-6-r60 .21702898\n\n",
"fulltext_license": "CC BY",
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"issue": "11(3)",
"journal": "mBio",
"keywords": "Legionella pneumophila\n; antibiotic resistance; pneumonia; pulmonary microbiome",
"medline_ta": "mBio",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D001419:Bacteria; D001992:Bronchoalveolar Lavage Fluid; D004351:Drug Resistance; D056890:Eukaryota; D005260:Female; D005658:Fungi; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016952:Legionella pneumophila; D007877:Legionnaires' Disease; D008137:Longitudinal Studies; D008168:Lung; D008297:Male; D064307:Microbiota; D009894:Opportunistic Infections; D018410:Pneumonia, Bacterial; D000073336:Whole Genome Sequencing",
"nlm_unique_id": "101519231",
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"pages": null,
"pmc": null,
"pmid": "32430469",
"pubdate": "2020-05-19",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "9393834;9372668;22558432;23384395;25762787;30466159;22748132;18978136;31242293;21364979;28870496;22378558;30246806;28204479;27662900;22449586;24752365;5821845;31316955;28799901;26000957;26135861;26553774;25493970;27608937;24024497;25143582;22872870;26175772;28316330;29138298;31665066;30694508;11326011;23862082;28059171;25421702;27010812;28703097;27572644;27687858;26158874;23696621;31740681;22798321;22427533;25803243;27966551;27926431;24288368;21702898;30118374;31657966;20383131",
"title": "Persistent Legionnaires' Disease and Associated Antibiotic Treatment Engender a Highly Disturbed Pulmonary Microbiome Enriched in Opportunistic Microorganisms.",
"title_normalized": "persistent legionnaires disease and associated antibiotic treatment engender a highly disturbed pulmonary microbiome enriched in opportunistic microorganisms"
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"abstract": "Herein synchronous occurrence of Hodgkin lymphoma and secondary myelodysplastic syndrome in a 60 year old male patient with small cell lung cancer treated with combined chemotherapy (carboplatin and paclitaxel) and radiotherapy is presented. The objective of this report is to stress the importance of documenting and monitoring adverse drug reactions that arise from chemotherapy. After four years of treatment with the combined chemotherapy, the patient presented inguinal lymphadenopathy and enlarged lymph nodes and histopathology rapport was suggestive for plasmacytoid variant of Castleman disease. Three years later, biopsy of lymph node was performed and diagnosis of Hodgkin lymphoma - mixed cellularity has been established. Molecular analyses revealed presence of dominant monoclonal population of the immunoglobulin genes in the oligo/monoclonal background. Bone marrow biopsy findings suggested secondary myelodysplasia and revealed signs of hematopoietic cells dismaturation with signs of megaloblastic maturation of the erytropoetic lineage, appearance of ALIP (abnormal localization of immature precursors) in the myeloid lineage and dysplastic megakaryocytes. In addition, an increased level of polyclonal plasmacytes (lambda vs kappa was 60%:40%) was found. Hodgkin lymphoma and MDS occurring after 4 years of carboplatin/paclitaxel therapy might be contributed to the accumulation of alkylator-related DNA damage. This emphasize the need of outlining a monitoring plan regarding development of secondary leukemia and other malignant hematological proliferations should be outlined in the protocols.",
"affiliations": "Institute of preclinical and clinical pharmacology and toxicology, Faculty of Medicine, University \"Ss. Cyril and Methodius\" Skopje, Republic of Macedonia.;University Clinic of hematology, University \"Ss. Cyril and Methodius\" Skopje, Republic of Macedonia.;Department of clinical pharmacy, Faculty of Pharmacy, University \"Ss. Cyril and Methodius\" Skopje, Republic of Macedonia.;Institute of pathology, Faculty of Medicine, University \"Ss. Cyril and Methodius\" Skopje, Republic of Macedonia.",
"authors": "Petrusevska|Marija|M|;Stavridis|Irina Panovska|IP|;Mladenovska|Kristina|K|;Petrushevska|Gordana|G|",
"chemical_list": "D016190:Carboplatin; D017239:Paclitaxel",
"country": "North Macedonia",
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"issue": "38(3)",
"journal": "Prilozi (Makedonska akademija na naukite i umetnostite. Oddelenie za medicinski nauki)",
"keywords": "Castleman disease paclitaxel; Hodgkin lymphoma; MDS; carboplatin",
"medline_ta": "Pril (Makedon Akad Nauk Umet Odd Med Nauki)",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D001856:Bone Marrow Examination; D016190:Carboplatin; D006689:Hodgkin Disease; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D017239:Paclitaxel; D012307:Risk Factors; D055752:Small Cell Lung Carcinoma; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101677081",
"other_id": null,
"pages": "97-103",
"pmc": null,
"pmid": "29668470",
"pubdate": "2017-12-01",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Secondary Hodgkin Lymphoma and Myelodysplastic Syndrome (MDS) After Paclitaxel-Carboplatin Treatment in a Patient with Small Cell Lung Cancer.",
"title_normalized": "secondary hodgkin lymphoma and myelodysplastic syndrome mds after paclitaxel carboplatin treatment in a patient with small cell lung cancer"
} | [
{
"companynumb": "MK-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-216346",
"fulfillexpeditecriteria": "1",
"occurcountry": "MK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drug... |
{
"abstract": "Quetiapine is regarded as an effective and safe treatment for delirium. An 82-year-old man presented with a 1-week history of violent behavior and dizziness accompanied by weakness on the left side of his body. He was diagnosed with acute cerebral cortical infarction and delirium associated with alcohol abuse. After quetiapine treatment, he complained of fever and coughed up sputum, whereas his aggressive behavior improved. His symptoms persisted despite empirical antibiotic treatment. All diagnostic tests for infectious causes were negative. High-resolution computed tomography revealed bilateral consolidations and ground-glass opacities with predominantly peribronchial and subpleural distributions. The primary differential diagnosis was drug-associated interstitial lung disease, and therefore, we discontinued quetiapine and began methylprednisolone treatment. His symptoms and radiologic findings significantly improved after receiving steroid therapy. We propose that clinicians need to be aware of the possibility that quetiapine is associated with lung injury.",
"affiliations": "Division of Pulmonary Medicine, Department of Internal Medicine, The Armed Forced Capital Hospital, Bundang-gu, Seongnamsi, Korea.;Department of Neurology, Chungju Hospital, Konkuk University School of Medicine, Chungju, Korea.;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chungju Hospital, Konkuk University School of Medicine, Chungju, Korea.;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chungju Hospital, Konkuk University School of Medicine, Chungju, Korea. medicor@kku.ac.kr.",
"authors": "Kim|Se-Jin|SJ|;Han|Sang-Don|SD|;Lee|Jung Yeon|JY|;Chon|Gyu Rak|GR|",
"chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D005938:Glucocorticoids; D000069348:Quetiapine Fumarate; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.4187/respcare.02977",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-1324",
"issue": "59(10)",
"journal": "Respiratory care",
"keywords": "alcohol abuse; interstitial pneumonia; quetiapine",
"medline_ta": "Respir Care",
"mesh_terms": "D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D003693:Delirium; D003937:Diagnosis, Differential; D003987:Dibenzothiazepines; D005938:Glucocorticoids; D006801:Humans; D017563:Lung Diseases, Interstitial; D008297:Male; D008775:Methylprednisolone; D011595:Psychomotor Agitation; D000069348:Quetiapine Fumarate; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "7510357",
"other_id": null,
"pages": "e145-8",
"pmc": null,
"pmid": "24782551",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of drug-induced interstitial pneumonia potentially related to quetiapine (seroquel) therapy for behavioral and psychological symptoms.",
"title_normalized": "a case of drug induced interstitial pneumonia potentially related to quetiapine seroquel therapy for behavioral and psychological symptoms"
} | [
{
"companynumb": "KR-LUPIN PHARMACEUTICALS INC.-2015-03222",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OZAGREL"
},
"drugadditional":... |
{
"abstract": "Sorafenib is a multi-kinase inhibitor approved for the treatment of renal cell and hepatocellular carcinoma. Adverse cutaneous reactions are a very common side effect of the medication. We report the development of hidradenitis suppurativa (HS) in a patient after initiation of treatment with sorafenib. HS is marked by recurrent deep painful nodules, fluctuant abscesses, and draining sinus tracts most frequently occurring in the groin and axilla. To our knowledge, sorafenib-induced HS in the axillary and inguinal skin folds has not been previously reported.",
"affiliations": "2Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX. aohuen@mdanderson.org.",
"authors": "Morse|Daniel C|DC|;Chockalingam|Ramya|R|;Pye|Allison|A|;Huen|Auris|A|",
"chemical_list": "D000970:Antineoplastic Agents; D000077157:Sorafenib",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "25(6)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D001365:Axilla; D000069340:Deprescriptions; D017497:Hidradenitis Suppurativa; D006801:Humans; D008297:Male; D000077157:Sorafenib; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31329396",
"pubdate": "2019-06-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hidradenitis suppurativa associated with sorafenib initiation.",
"title_normalized": "hidradenitis suppurativa associated with sorafenib initiation"
} | [
{
"companynumb": "US-BAYER-2019-047487",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": null,
"d... |
{
"abstract": "A 69-year-old man received transurethral resection (TUR) ofbladder tumor. The histopathological diagnosis was urothelial carcinoma, high grade, pT1＋pTis. The surgical specimens obtained by second TUR showed no residual malignancy histopathologically. Intravesical Bacillus Calmette-Guerin (BCG) instillation therapy was initiated 2 months after the second TUR. He complained of lower abdominal pain and painful urination on the day following the second instillation of BCG. Computed tomography and cystography demonstrated rupture ofthe urinary bladder. During 2 weeks ofconservative treatment, the symptoms persisted. Then, open repair ofthe bladder was performed. Intravesical BCG therapy has been a widely accepted treatment for bladder cancer with high grade Ta and T1, and carcinoma in situ. In the present case, thinning ofthe bladder wall, delayed wound healing caused by 2 TURs, and abdominal pressure may have been the factors leading to the bladder rupture in addition to inflammation of the bladder due to BCG instillation. Although bladder rupture caused by intravesical BCG therapy has not been reported, we must be aware ofthe possibility ofthis rare condition, especially after 2 consecutive TURs.",
"affiliations": "The Department of Urology, Nara Prefecture General Medical Center.;The Department of Urology, Nara Prefecture General Medical Center.;The Department of Urology, Nara Prefecture General Medical Center.;The Department of Urology, Nara Prefecture General Medical Center.;The Department of Urology, Nara Medical University.;The Department of Urology, Nara Medical University.;The Department of Urology, Nara Prefecture General Medical Center.",
"authors": "Iemura|Yusuke|Y|;Fukui|Shinji|S|;Matsumura|Yoshiaki|Y|;Kagebayashi|Yoriaki|Y|;Toyoshima|Yuta|Y|;Inoue|Takeshi|T|;Samma|Shoji|S|",
"chemical_list": "D001500:BCG Vaccine",
"country": "Japan",
"delete": false,
"doi": "10.14989/ActaUrolJap_64_1_25",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-1994",
"issue": "64(1)",
"journal": "Hinyokika kiyo. Acta urologica Japonica",
"keywords": null,
"medline_ta": "Hinyokika Kiyo",
"mesh_terms": "D000283:Administration, Intravesical; D000368:Aged; D001500:BCG Vaccine; D006801:Humans; D008297:Male; D012421:Rupture; D001743:Urinary Bladder; D001749:Urinary Bladder Neoplasms; D013520:Urologic Surgical Procedures",
"nlm_unique_id": "0421145",
"other_id": null,
"pages": "25-28",
"pmc": null,
"pmid": "29471601",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bladder Rupture during Intravesical BCG Therapy : A Case Report.",
"title_normalized": "bladder rupture during intravesical bcg therapy a case report"
} | [
{
"companynumb": "JP-SA-2018SA184351",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN ANTIGEN, UNSPECIFIED SUBSTRAIN"
},
... |
{
"abstract": "5-Fluorouracil (5-FU) is an active chemoetheraputic agent in many malignancies, used both in the curative and metastatic setting. Therefore, the side effect profile of 5-FU is well-described and recognized. Here, we present a case of a 28-year-old male, who received 5-FU and carboplatin concurrently, with radiation, for esophageal carcinoma. On Day 3 of his 5-FU infusion, he developed simultaneous cardiac arrhythmias, renal dysfunction, and aphasia. Magnetic resonance imaging (MRI) of his brain revealed acute demyelination of the white matter corresponding to diffusion restriction, pointing toward a small vessel injury. The 5-FU infusion was promptly discontinued and stress dose steroids were administered. The patient's symptoms resolved rapidly with no residual effects. We believe this is the first case of multisystem, small-vessel, vasculopathy secondary to 5-FU. Early recognition and prompt discontinuation of the offending drug is essential for resolution of symptoms. Steroids, with their anti-inflammatory effects can aid in rapid recovery.",
"affiliations": "Department of Oncology, Aga Khan University Hospital, Karachi, Pakistan.",
"authors": "Zahid|Mohammad Faizan|MF|;Masood|Nehal|N|;Shabbir-Moosajee|Munira|M|",
"chemical_list": "D013256:Steroids; D016190:Carboplatin; D005472:Fluorouracil",
"country": "India",
"delete": false,
"doi": "10.4103/0973-1482.138130",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1998-4138",
"issue": "11(3)",
"journal": "Journal of cancer research and therapeutics",
"keywords": null,
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D000328:Adult; D001921:Brain; D016190:Carboplatin; D002277:Carcinoma; D003711:Demyelinating Diseases; D004938:Esophageal Neoplasms; D005472:Fluorouracil; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D011859:Radiography; D013256:Steroids",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "653",
"pmc": null,
"pmid": "26458637",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "5-Fluorouracil-induced vasculitic injury manifesting as a multiorgan dysfunction in a patient with esophageal carcinoma.",
"title_normalized": "5 fluorouracil induced vasculitic injury manifesting as a multiorgan dysfunction in a patient with esophageal carcinoma"
} | [
{
"companynumb": "PK-FRESENIUS KABI-FK201506280",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,... |
{
"abstract": "Acute undifferentiated leukemia (AUL) is a subtype of acute leukemias of ambiguous lineage. There is no standard treatment approach for AUL, although acute lymphoblastic leukemia-like regimens for induction therapy have been used. Additional data suggest that AUL may be better treated as acute myeloid leukemia (AML), given their similarities in genetic, cytogenetic, and gene expression patterns. Somatic mutations of IDH1 are found in 7% to 14% of patients with AML; however, the patient in this study was the first patient with IDH1-mutated AUL treated with ivosidenib. In this case, a woman aged 39 years was found to have anemia and thrombocytopenia after presenting to her primary care physician with fatigue, weight loss, and persistent infections. During further workup of the cytopenia, she was diagnosed with AUL and received 7+3 (daunorubicin, 60 mg/m2/d intravenously on days 1-3, and cytarabine, 100 mg/m2 24-hour continuous intravenous infusion on days 1-7) due to the presence of the IDH1 mutation. Bone marrow biopsy performed on day 14 of 7+3 showed persistent disease, and ivosidenib was initiated due to severe HLA alloimmunization (panel-reactive antibody, 100%) and significant bleeding complications. The patient achieved a complete morphologic and molecular remission on ivosidenib monotherapy despite critical bleeding complications during induction. Targeted therapy using ivosidenib may represent an encouraging therapeutic option in patients with AUL and IDH1 mutations. Additional evaluation of ivosidenib in this subgroup of patients with AUL is needed.",
"affiliations": "Division of Hematology, Department of Internal Medicine, and.;Division of Hematology, Department of Internal Medicine, and.;Department of Pathology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.;Division of Hematology, Department of Internal Medicine, and.;Division of Hematology, Department of Internal Medicine, and.;Division of Hematology, Department of Internal Medicine, and.",
"authors": "Patel|Sandipkumar H|SH|;Vasu|Sumithira|S|;Guo|Ling|L|;Lemaster|Olivia|O|;Byrd|John C|JC|;Walker|Alison|A|",
"chemical_list": "D014408:Biomarkers, Tumor; D011725:Pyridines; C000627630:ivosidenib; D005998:Glycine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1540-1405",
"issue": "18(1)",
"journal": "Journal of the National Comprehensive Cancer Network : JNCCN",
"keywords": null,
"medline_ta": "J Natl Compr Canc Netw",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D001706:Biopsy; D001853:Bone Marrow; D002454:Cell Differentiation; D005260:Female; D005998:Glycine; D006801:Humans; D015456:Leukemia, Biphenotypic, Acute; D011725:Pyridines; D012074:Remission Induction; D016896:Treatment Outcome",
"nlm_unique_id": "101162515",
"other_id": null,
"pages": "6-10",
"pmc": null,
"pmid": "31910380",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "2094323;30514800;27998706;21811096;28910610;3198552;22372202;29616841;23274355;30692099;27069254;8956868;20368543;29543066;28375741;23412561;29860938",
"title": "Molecular Complete Remission Following Ivosidenib in a Patient With an Acute Undifferentiated Leukemia.",
"title_normalized": "molecular complete remission following ivosidenib in a patient with an acute undifferentiated leukemia"
} | [
{
"companynumb": "US-AGIOS-2001US01621",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DAUNORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nUse of antiepileptic drugs in pregnancy is associated with congenital malformations and developmental delay. Previous studies have suggested that women who have had one child with a congenital malformation are at increased risk of having other children with malformations. We sought to confirm the magnitude of risk in a large cohort drawn from the United Kingdom Epilepsy and Pregnancy Register.\n\n\nMETHODS\nThe United Kingdom Epilepsy and Pregnancy Register is a prospective, observational registration and follow-up study set up to determine the relative safety of antiepileptic drugs in pregnancy. We have extracted data for those women who prospectively registered more than one pregnancy and calculated the recurrence risks for fetal malformations.\n\n\nRESULTS\nOutcome data were available for 1,534 pregnancies born to 719 mothers. For women whose first child had a congenital malformation there was a 16.8% risk of having another child with a congenital malformation, compared with 9.8% for women whose first child did not have a malformation (relative risk 1.73, 95% confidence interval [CI] 1.01-2.96). The risk for recurrence was 50% for women who had had two previous children with a congenital malformation. There was a trend toward a higher risk for recurrent malformations in pregnancies exposed to valproate (21.9%, relative risk 1.47, 95% CI 0.68-3.20) and topiramate (50%, relative risk 4.50, 95% CI 0.97-20.82), but not for other drugs such as carbamazepine and lamotrigine. Recurrence risks were also higher for pregnancies exposed to polytherapy regimens and for those where the dose of antiepileptic drug treatment had been increased after the first pregnancy.\n\n\nCONCLUSIONS\nWomen who have had a child with a malformation are at increased risk of having other children with malformations. This is in keeping with previous reports that have suggested that genetic influences may be one of the factors determining the teratogenic risk of antiepileptic drugs.",
"affiliations": "Neurology Department, Belfast Health and Social Care Trust, Royal Victoria Hospital, Belfast, United Kingdom.",
"authors": "Campbell|Ellen|E|;Devenney|Emma|E|;Morrow|Jim|J|;Russell|Aline|A|;Smithson|William Henry|WH|;Parsons|Linda|L|;Robertson|Iain|I|;Irwin|Beth|B|;Morrison|Patrick J|PJ|;Hunt|Stephen|S|;Craig|John|J|",
"chemical_list": "D000927:Anticonvulsants",
"country": "United States",
"delete": false,
"doi": "10.1111/epi.12001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-9580",
"issue": "54(1)",
"journal": "Epilepsia",
"keywords": null,
"medline_ta": "Epilepsia",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000927:Anticonvulsants; D005260:Female; D006801:Humans; D008297:Male; D010298:Parity; D011247:Pregnancy; D011248:Pregnancy Complications; D012008:Recurrence; D012042:Registries; D012307:Risk Factors; D006113:United Kingdom",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "165-71",
"pmc": null,
"pmid": "23167802",
"pubdate": "2013-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Recurrence risk of congenital malformations in infants exposed to antiepileptic drugs in utero.",
"title_normalized": "recurrence risk of congenital malformations in infants exposed to antiepileptic drugs in utero"
} | [
{
"companynumb": "GB-LUPIN PHARMACEUTICALS INC.-2017-00343",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional... |
{
"abstract": "Certain drugs are known to cause metabolic changes resulting in altered metabolic profiles. We report here a case where a combination of antiepileptic drugs resulted in a profile that mimicked a metabolic disorder. A 16month-old female child on antiepileptic drugs (valproate and topiramate) was suspected to have the inherited metabolic disorder, dihydrolipoamide dehydrogenase deficiency, based on clinical symptoms and metabolic profile showing hyperalaninemia, elevated branched-chain amino acids, and lactate-pyruvate ratio. Suspecting that the observed metabolic changes could have also arised from medication, current medication was weaned off and replaced with levetiracetam, clonazepam, and levocarnitine (supportive therapy). Metabolic profiling conducted after 47 days showed normal alanine, branched-chain amino acids, ornithine, and lactate-pyruvate ratio, suggesting that the earlier abnormalities could have been medication induced. We stress that metabolic changes resulting from chronic medication should be considered while interpreting a positive result when investigating an inherited metabolic disorder.",
"affiliations": "Department of Physical Medicine and Rehabilitation, National Institute for Empowerment of Persons with Multiple Disabilities, Muttukadu, Chennai, India.;Department of Physical Medicine and Rehabilitation, National Institute for Empowerment of Persons with Multiple Disabilities, Muttukadu, Chennai, India tomymampilly@gmail.com.;Department of Neurochemistry, National Institute of Mental Health and Neurosciences, Bangalore, India.;Department of Clinical Psychology, National Institute for Empowerment of Persons with Multiple Disabilities, Muttukadu, Chennai, India.;Department of Physical Medicine and Rehabilitation, National Institute for Empowerment of Persons with Multiple Disabilities, Muttukadu, Chennai, India.",
"authors": "Mampilly|George Tomy|GT|;Mampilly|Tomy Kochuvareed|TK|;Christopher|Rita|R|;Chandramohan|Neeradha|N|;Janaki|Vijayalakshmy|V|",
"chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D014635:Valproic Acid; D019289:Pyruvic Acid",
"country": "United States",
"delete": false,
"doi": "10.1177/0883073813477201",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-0738",
"issue": "29(6)",
"journal": "Journal of child neurology",
"keywords": "false positives; metabolic disorder; valproate",
"medline_ta": "J Child Neurol",
"mesh_terms": "D000927:Anticonvulsants; D005260:Female; D005632:Fructose; D006801:Humans; D007223:Infant; D008659:Metabolic Diseases; D019289:Pyruvic Acid; D000077236:Topiramate; D014635:Valproic Acid",
"nlm_unique_id": "8606714",
"other_id": null,
"pages": "833-6",
"pmc": null,
"pmid": "23439713",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Challenges in diagnosing a metabolic disorder: error of pyruvate metabolism or drug induced?",
"title_normalized": "challenges in diagnosing a metabolic disorder error of pyruvate metabolism or drug induced"
} | [
{
"companynumb": "IN-MYLAN-2014S1017775",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALPROATE SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "CGD is a rare primary immunodeficiency with high mortality rates when treated conventionally, especially for the X-chromosome-linked form. HSCT is the only curative therapy for CGD; however, haploidentical transplantation in CGD is rare. Here, we report a case of X-linked CGD treated successfully by haploidentical HSCT. The patient showed a positive result with full donor chimerism, good quality of life, and the absence of recurrent infectious diseases at follow-up (68 months). Thus, haploidentical HSCT may serve as an acceptable treatment approach for patients who have CGD, but no HLA-matched related or unrelated donor.",
"affiliations": "The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.;Shanghai Dao-Pei Hospital, Shanghai, China.;Shanghai Dao-Pei Hospital, Shanghai, China.;Shanghai Dao-Pei Hospital, Shanghai, China.;The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.",
"authors": "Zhou|Ling|L|;Dong|Lu-Jia|LJ|;Gao|Zhi-Yong|ZY|;Yu|Xin-Jian|XJ|;Lu|Dao-Pei|DP|",
"chemical_list": "D003520:Cyclophosphamide; D002066:Busulfan",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12861",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "21(1)",
"journal": "Pediatric transplantation",
"keywords": "X-linked chronic granulomatous disease; haploidentical; myeloablative conditioning",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D002066:Busulfan; D041321:Chromosomes, Human, X; D003520:Cyclophosphamide; D006105:Granulomatous Disease, Chronic; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D011788:Quality of Life; D019172:Transplantation Conditioning",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27885760",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Haploidentical hematopoietic stem cell transplantation for a case with X-linked chronic granulomatous disease.",
"title_normalized": "haploidentical hematopoietic stem cell transplantation for a case with x linked chronic granulomatous disease"
} | [
{
"companynumb": "CN-SA-2017SA034778",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
},
"drugadditio... |
{
"abstract": "To evaluate the efficacy and safety of sclerotherapy with sodium tetradecyl sulfate (STS) and bleomycin for treatment of venous malformations (VMs) of the oropharyngeal region.\n\n\n\nA retrospective study of 33 patients with 46 VMs of the buccal and pharyngolaryngeal cavity associated with impairment of eating, respiration, or elocution was performed. Individual lesions were divided based on their anterior or posterior location, using the base of the tongue as an anatomic landmark. Lesion size was estimated with the use of orthogonal measurements on magnetic resonance or ultrasound images before and after treatment to assess radiologic response. Sclerotherapy sessions were performed under ultrasound, fluoroscopic, and, if needed, endoscopic guidance. Clinical response was assessed with the use of the Manchester Orofacial Pain Disability Scale. Methods for airway management were also compiled.\n\n\n\nFollowing sclerotherapy, average VM diameter was reduced by 31.4% (P < .0001) on a per-patient basis and by 30.8% (P < .0001) on a per-lesion basis. The Manchester score improved by an average of 37.0% (P = .013). Four patients reported a worsening of symptoms, and 11 patients experienced symptomatic recurrence. Complications include pneumonia (5 patients) and urgent placement of a post-procedure tracheostomy (4 patients). Patients with posterior malformations experienced more complications (emergency tracheostomies in 4 and pneumonias in 4).\n\n\n\nSclerotherapy using STS is an efficient treatment for venous malformations of the buccal and pharyngolaryngeal cavity but can lead to significant complication for posterior lesions. Careful assessment of the airway is needed before treatment, and prophylactic tracheotomy should be considered in patients with posterior lesions.",
"affiliations": "Department of Radiology, Centre Hospitalier de l'Université de Montréal, Montréal H2X0C1, Québec, Canada.;Department of Radiology, Centre Hospitalier de l'Université de Montréal, Montréal H2X0C1, Québec, Canada.;Department of Radiology, Centre Hospitalier de l'Université de Montréal, Montréal H2X0C1, Québec, Canada.;Department of Radiology, Centre Hospitalier de l'Université de Montréal, Montréal H2X0C1, Québec, Canada.;Department of Radiology, Centre Hospitalier de l'Université de Montréal, Montréal H2X0C1, Québec, Canada.;Department of Surgery, Centre Hospitalier de l'Université de Montréal, Montréal H2X0C1, Québec, Canada.;Department of Medical Imaging, Sainte-Justine University Hospital, Montréal, Québec, Canada.;Department of Radiology, Centre Hospitalier de l'Université de Montréal, Montréal H2X0C1, Québec, Canada. Electronic address: gilles.soulez.chum@ssss.gouv.qc.ca.",
"authors": "Bourgouin|Patrick|P|;Thomas-Chaussé|Frédéric|F|;Gilbert|Patrick|P|;Giroux|Marie-France|MF|;Périgny|Sébastien|S|;Guertin|Louis|L|;Dubois|Josée|J|;Soulez|Gilles|G|",
"chemical_list": "D012597:Sclerosing Solutions; D001761:Bleomycin; D012981:Sodium Tetradecyl Sulfate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jvir.2017.12.028",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1051-0443",
"issue": "29(6)",
"journal": "Journal of vascular and interventional radiology : JVIR",
"keywords": null,
"medline_ta": "J Vasc Interv Radiol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D001761:Bleomycin; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009960:Oropharynx; D012189:Retrospective Studies; D012597:Sclerosing Solutions; D015911:Sclerotherapy; D012981:Sodium Tetradecyl Sulfate; D016896:Treatment Outcome; D054079:Vascular Malformations",
"nlm_unique_id": "9203369",
"other_id": null,
"pages": "809-815",
"pmc": null,
"pmid": "29628299",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effectiveness and Safety of Sclerotherapy for Treatment of Low-Flow Vascular Malformations of the Oropharyngeal Region.",
"title_normalized": "effectiveness and safety of sclerotherapy for treatment of low flow vascular malformations of the oropharyngeal region"
} | [
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"companynumb": "CA-MYLANLABS-2018M1045077",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
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"actiondrug": "6",
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"activesubstancename": "DEXAMETHASONE"
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{
"abstract": "Left ventricular assist devices (LVADs) are increasingly used for mechanical support of end-stage heart failure. Gastrointestinal bleeding (GIB) confers a significant morbidity in LVAD patients, with rates of up to 30% at 5 years. We assessed predictors of index and recurrent GIB (rGIB) in LVAD patients to risk stratify patients and evaluate if endoscopic approach and intervention at index GIB impacted rGIB.\nA retrospective chart review of all LVAD patients at our institution from 01/01/2006 to 31/10/2016 was completed. Predictors for index and recurrent GIB were analyzed. Multivariate logistic regression analysis was created using only statistically significant dependent variables and adjusted for demographic variables.\nA total of 77/214 (36%) patients developed GIB, and 38/214 (17.8%) developed rGIB. Destination therapy (P=0.01), longer duration of LVAD (P=0.03), and low albumin (<3.5 g/dL) (P<0.001) were associated with increased risk of index GIB. Charlson Comorbidity Index, heart failure etiology, and Medicare were predictors of index GIB on univariate analysis, but this was not seen on multivariate analysis. Performing an endoscopy with/without intervention, non- angioectasia lesions, and location of bleeding were not statistically significant predictors of rGIB. Longer duration of hospitalization appeared to be protective for rGIB on univariate analysis.\nIndex endoscopy and intervention is not associated with reduced risk of rGIB in LVAD patients. Several independent factors are associated with the risk of index GIB. Albumin is a potentially modifiable risk factor, and likely contributes to bleeding through poor nutrition. It is a surrogate marker for systemic illness, and may have pharmacologic implications.",
"affiliations": "Division of Gastroenterology and Hepatology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA (Benjamin Stern, Venkata S. Gorrepati, Deborah Bethards, Kofi Clarke).;Department of Internal Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA (Parth Maheshwari).;Division of Gastroenterology and Hepatology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA (Benjamin Stern, Venkata S. Gorrepati, Deborah Bethards, Kofi Clarke).;Division of Gastroenterology and Hepatology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA (Benjamin Stern, Venkata S. Gorrepati, Deborah Bethards, Kofi Clarke).;Division of Gastroenterology, University of California San Francisco Fresno, Fresno, CA, USA (Jayakrishna Chintanaboina).;Division of Cardiology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA (John Boehmer).;Division of Gastroenterology and Hepatology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA (Benjamin Stern, Venkata S. Gorrepati, Deborah Bethards, Kofi Clarke).",
"authors": "Stern|Benjamin|B|;Maheshwari|Parth|P|;Gorrepati|Venkata S|VS|;Bethards|Deborah|D|;Chintanaboina|Jayakrishna|J|;Boehmer|John|J|;Clarke|Kofi|K|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.20524/aog.2021.0656",
"fulltext": "\n==== Front\nAnn Gastroenterol\nAnn Gastroenterol\nAnnals of Gastroenterology\n1108-7471\n1792-7463\nHellenic Society of Gastroenterology Greece\n\nAnnGastroenterol-34-660\n10.20524/aog.2021.0656\nOriginal Article\nInitial endoscopic intervention is not associated with reduced risk of recurrent gastrointestinal bleeding in left ventricular assist device patients\nStern Benjamin a\nMaheshwari Parth b\nGorrepati Venkata S. a\nBethards Deborah a\nChintanaboina Jayakrishna c\nBoehmer John d\nClarke Kofi a\na Division of Gastroenterology and Hepatology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA (Benjamin Stern, Venkata S. Gorrepati, Deborah Bethards, Kofi Clarke)\nb Department of Internal Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA (Parth Maheshwari)\nc Division of Gastroenterology, University of California San Francisco Fresno, Fresno, CA, USA (Jayakrishna Chintanaboina)\nd Division of Cardiology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA (John Boehmer)\nCorrespondence to: Benjamin Stern, DO, 200 Campus Dr Suite 2400, Entrance 4, Hershey, PA 17033, USA, e-mail: bstern@pennstatehealth.psu.edu\nSep-Oct 2021\n12 7 2021\n34 5 660668\n23 6 2020\n23 9 2020\nCopyright: © Hellenic Society of Gastroenterology\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/3.0/ This 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.\nBackground\n\nLeft ventricular assist devices (LVADs) are increasingly used for mechanical support of end-stage heart failure. Gastrointestinal bleeding (GIB) confers a significant morbidity in LVAD patients, with rates of up to 30% at 5 years. We assessed predictors of index and recurrent GIB (rGIB) in LVAD patients to risk stratify patients and evaluate if endoscopic approach and intervention at index GIB impacted rGIB.\n\nMethods\n\nA retrospective chart review of all LVAD patients at our institution from 01/01/2006 to 31/10/2016 was completed. Predictors for index and recurrent GIB were analyzed. Multivariate logistic regression analysis was created using only statistically significant dependent variables and adjusted for demographic variables.\n\nResults\n\nA total of 77/214 (36%) patients developed GIB, and 38/214 (17.8%) developed rGIB. Destination therapy (P=0.01), longer duration of LVAD (P=0.03), and low albumin (<3.5 g/dL) (P<0.001) were associated with increased risk of index GIB. Charlson Comorbidity Index, heart failure etiology, and Medicare were predictors of index GIB on univariate analysis, but this was not seen on multivariate analysis. Performing an endoscopy with/without intervention, non- angioectasia lesions, and location of bleeding were not statistically significant predictors of rGIB. Longer duration of hospitalization appeared to be protective for rGIB on univariate analysis.\n\nConclusions\n\nIndex endoscopy and intervention is not associated with reduced risk of rGIB in LVAD patients. Several independent factors are associated with the risk of index GIB. Albumin is a potentially modifiable risk factor, and likely contributes to bleeding through poor nutrition. It is a surrogate marker for systemic illness, and may have pharmacologic implications.\n\nLeft ventricular assist device\ngastrointestinal bleeding\nendoscopy\nangioectasia\n==== Body\nIntroduction\n\nHeart failure (HF) affects over 6 million Americans and is associated with significant morbidity and mortality [1]. Surgical implantation of a mechanical pump, such as left ventricular assist device (LVAD) has become an increasingly common management option for end-stage HF. LVADs are used as either a bridge to transplant (BTT), or as destination therapy (DT) in patients not eligible for heart transplantation. As the number of HF patients continues to rise in parallel with an increase in indications for LVADs as destination therapy, the number of LVAD implantations has increased [2]. Gastrointestinal (GI) bleeding (GIB) remains the most common adverse event within this large population of patients, with bleeding rates up to 30% at 5 years [3-5]. GIB in LVAD patients does not appear associated with an increase in overall mortality but confers a significant morbidity and remains challenging to manage [6].\n\nAlthough GIB after initial hospitalization for LVAD implantation has been described along the entire GI tract, the optimal endoscopic approach to management is unclear [7-12]. LVAD patients have high incidence of arteriovenous malformation (AVM) or angioectatic bleeds (~50%) when a lesion is identified [13-15]. This is likely due to Heyde syndrome-type pathophysiology with cleavage of von Willebrand factor (vWF) as well as mucosal hypoxia and dysregulation of angiogenesis [13,16]. Up to 30% of these lesions are located in the small bowel (SB) which may be difficult to treat endoscopically and furthermore the lesions tend to recur [14,17]. This is an area of extensive and ongoing research. Several prior manuscripts have suggested a tailored algorithmic approach to this unique patient population, although the benefit of endoscopy in this population is unclear [10,18]. While video capsule endoscopy (VCE) appears safe in LVAD patients, a positive or negative VCE or any subsequent endoscopic intervention do not appear to decrease the rate of recurrent GIB (rGIB) [19]. The average cost of a traditional endoscopic workup of these patients is approximately $9,000 per event, is cumbersome to patients, and places a burden on the healthcare system [20].\n\nWe performed a comprehensive evaluation and characterization of predictors of index GIB and rGIB in LVAD patients. The primary goal was to identify predictors that help risk stratify patients and help guide informed consent pre-LVAD implantation for GIB. The secondary goal was to evaluate if endoscopic approach and/or treatment during index GIB impacts the risk of rGIB. In addition, we describe our experience with octreotide.\n\nPatients and methods\n\nBaseline data and definitions\n\nAn electronic medical record (EMR) chart review was completed on all patients with an LVAD device placed at a single academic tertiary-care center and documented in an institutional registry from 1st January 2006 to 31st October 2016. Institutional Review Board approval from Penn State University was obtained. All patients with LVADs aged ≥18 years old were included. Patients with incomplete data or total-artificial heart were excluded from the study. Data collected included demographics: age, date of death, sex, body mass index (characterized as underweight, normal, overweight, obese), insurance type (Medicare, Medicaid, self-pay, or private insurance), and smoking status (former, current, never). Other baseline data collected included etiology of HF (ischemic vs. non-ischemic), LVAD intent (BTT vs. DT), and history of GIB prior to LVAD implantation.\n\nGIB (index or rGIB) was defined as hospitalization for anemia not attributed to another cause. All patients had at least 1 g/dL decrease in hemoglobin. Baseline laboratory data was obtained from routine post-LVAD implantation outpatient visit laboratory data (typically 3-6 months post-operation). At our institution, all patients are anticoagulated post-operatively with at least warfarin with an initial goal therapeutic international normalized ratio (INR) of 2.0-3.0. Other medications, medical and/or endoscopic management determined by managing clinicians were recorded. All patients were admitted to cardiology division with gastroenterological consultation and the ability to perform bedside endoscopy.\n\nIndex GIB\n\nData documented at the time of index GIB included LVAD parameters (flow, speed, power, pulsatility index [only recorded for HeartMate™ devices]), duration of LVAD (months), LVAD device type (HeartMate IIÔ, HeartMate IIIÔ, HeartMate XVEÔ, HeartWareÔ, and “other” which included Pierce-Donachy VADÔ and Thoratec VADÔ), calculated Charlson Comorbidity Index (CCI) [22], echocardiogram findings (ejection fraction [EF] and right ventricular [RV] dysfunction [none, mild, moderate, severe]), presenting symptom (hematemesis, melena, hematochezia, “mixed” [e.g., maroon] stool, coffee-ground emesis, or hemoccult), number of packed red blood cells (pRBC) transfused, anticoagulation prior to index GIB (warfarin, aspirin, anti-platelet(s), and/or other anti-coagulant(s)), goal therapeutic INR (1.5-2.0, 2.0-2.5, 2.0-3.0, 2.5-3.5, 1.5-2.5, other, or n/a), change to anticoagulation (no change, discontinued anticoagulant/anti-platelet, decreased goal therapeutic INR), other medication use (proton pump inhibitor [PPI] and non-steroidal anti-inflammatory drugs [NSAID]), day(s) to endoscopy, and number of days hospitalized. Labs at index bleeding recorded included serum creatinine, platelet level, albumin, blood urea nitrogen, INR, hemoglobin, and bilirubin.\n\nEndoscopy and rGIB\n\nEndoscopic data collected during index and rGIB included location of bleeding (esophageal, gastric, proximal third of SB, middle third of SB, distal third of SB, colon, unknown), endoscopic approach (esophagogastric duodenoscopy [EGD], colonoscopy, EGD and colonoscopy, VCE ± other, push enteroscopy ± other, double-balloon enteroscopy ± other, none), lesion characteristic (ulcer, angioectasia, malignancy, other, unknown), endoscopic intervention (epinephrine injection, cauterization, hemostatic clip(s), dual therapy, none), failed endoscopy (including interventional radiology and/or surgery), days hospitalized for rGIB, and time to rGIB (months). Endoscopic approach included all endoscopic procedures completed during the course of a GIB (or rGIB) hospitalization and lesion characteristic was the first discovered lesion during that hospitalization.\n\nStatistical analysis\n\nUnivariate analysis was performed using all the above-mentioned predictors for index GIB and rGIB. For the purpose of comparison, Student’s t-test was used for continuous variables and chi-square for categorical variables. Multivariate logistic regression analysis was performed using statistically significant variables while adjusting for the demographic variables. All analyses were performed using SAS version 9.4 software (SAS Institute, Cary, NC); a P-value ≤0.05 was considered statistically significant.\n\nResults\n\nDemographic and other characteristics of patients with and without GIB are displayed in Table 1. Seventy-seven of 214 (36.0%) patients in our cohort experienced at least 1 episode of GIB (index GIB). Actuarial freedom from a GIB while censoring for transplant, explant or death was calculated and the incidence of GIB at 1 year was 27%, and then levels off thereafter (Fig. 1). On univariate analysis, destination therapy, Medicare insurance, longer duration of LVAD, ischemic cardiomyopathy, CCI, and albumin were significantly different in patients with and without GIB. The mean duration of LVAD for patients with GIB was 28.14 months vs. 18.12 for those without GIB (P<0.01). Comparing patients with and without GIB post-LVAD implantation, they appeared similar in terms of age distribution, sex, obesity, LVAD device type, LVAD parameters, goal therapeutic INR, anticoagulant use, history of GIB, echocardiogram findings, and medications (PPI or NSAID use).\n\nTable 1 Characteristics of study population vs. controls\n\nFigure 1 Actuarial survival from gastrointestinal bleeding\n\nOn multivariate analysis, LVAD as destination therapy (odds ratio [OR] 3.04, 95% confidence interval [CI] 1.3-7.0; P=0.01), longer duration of LVAD (OR 1.02, 95%CI 1.002-1.040; P=0.03), and low albumin (<3.5 g/dL) (OR 5.11, 95%CI 2.4-10.7; P<0.001) were found to be associated with increased risk of index GIB (Table 2).\n\nTable 2 Predictors of index GIB on multivariate analysis\n\nrGIB occurred in 38 patients (17.8% of all patients, 49.4% of index GIB patients). A second rGIB occurred in 19 patients (8.9% of all patients, 24.7% of index GIB patients), and a third rGIB in 11 patients (5.1% of all patients, and 14.3% of index GIB patients). Descriptive data including GIB location, lesion characteristic, endoscopic approach, and endoscopic intervention are shown in Table 3. The most common location for first, second, and third rGIB was “unknown”, endoscopic approach was EGD, and endoscopic intervention was “none”. The most common lesion on index and first rGIB was an angioectasia. The most common lesion was ulcer on second rGIB and “unknown” on the third rGIB.\n\nTable 3 Endoscopic description of index GIB and recurrent GIB\n\nTo better define predictors for first rGIB (second GIB event) a multivariate logistic regression analysis was performed. There were no statistically significant variables that influenced the occurrence of first rGIB. These include performing an endoscopy, performing an intervention during endoscopy, having a non-angioectasia lesion, location of bleeding, change to anticoagulation, duration of hospitalization, use of PPI, and presenting symptom. Longer duration of hospitalization appeared protective for rGIB on univariate analysis (Table 4).\n\nTable 4 Predictors of rGIB on univariate analysis\n\nSurvival was compared between the GIB group and control group over a 5-year period of time, censoring for explant or heart transplant. The GIB group and controls were compared on univariate analysis and any potential survival advantage for GIB group eventually matches the control group after 3 years (Fig. 2).\n\nFigure 2 Actuarial Survival of GIB vs. control group\n\nGIB, gastrointestinal bleeding\n\nDuring the last 3 years of the study period, octreotide was used to medically manage 4 patients with recurrent refractory GIB (Table 5). All 4 patients received octreotide 100 μg sub-Q b.i.d. for 4 weeks followed by 20 mg intra-muscularly every 4 weeks thereafter. All 4 patients were initially on aspirin 81 mg daily and warfarin with a therapeutic INR of 2.0-3.0. No other anti-platelet or anti-coagulant use was noted. These patients are included in the above data but had on average 6.5 GIB episodes prior to initiation of octreotide and required at a minimum EGD, colonoscopy, and VCE.\n\nTable 5 Use of octreotide for refractory recurrent GIB\n\nDiscussion\n\nGIB remains a major comorbidity in LVAD patients. More recently, management of GIB in this patient cohort has trended towards prevention and mitigation, with proper patient selection/education as well as post-operative medical management. Several studies and one meta-analysis evaluated the predictors of GIB in these patients with variable results [23-25]. A personalized GIB risk estimate score (Utah Score) has been purposed using independent risk factors for GIB in LVAD patients, although this has not been externally validated [26].\n\nOur sample size is similar to other academic tertiary-care centers in prior publications. The prevalence of GIB in our population is 36% and consistent with other studies. Our study is comprehensive and evaluated the impact of over 20 variables. We determined that only destination therapy, longer duration of LVAD, and low albumin were independent predictors of index GIB. As reported in other previous studies and in our study, univariate analysis noted CCI, ischemic cardiomyopathy, and Medicare to be predictors of index GIB but when weighted against other dependent variables and adjusted for demographics these factors do not remain independently associated with index GIB. Age has been identified by others as a predictor of GIB, and trended toward statistically significance (P=0.06) in our study. Age is associated with other variables that tend to tract with age (i.e., destination therapy) and may be a risk factor not captured in our sample.\n\nDestination therapy likely reflects a higher burden of comorbid disease in this population. Albumin (P<0.001) is the one potentially modifiable risk factor for these patients. Albumin likely contributes to bleeding through poor nutrition, is a surrogate marker for severe systemic illness, and may have potential pharmacologic implications. Hypoalbuminemia has been shown to be associated with GIB in other large studies as well [27]. The longer duration of LVAD in GIB group unfortunately represents a non-modifiable risk factor and may represent the unpredictable individual nature of GIB. Other studies have suggested that modification of LVAD device or parameters can alter GIB incidence, although in our study LVAD device type and LVAD parameters were not predictive of GIB [28]. Baseline anticoagulation/antiplatelet agent(s) or goal therapeutic INR were not associated with risk of GIB or rGIB between study population and controls.\n\nrGIB developed in nearly half of patients within an index GIB group (49.4%). Endoscopy did not reveal a source of bleeding in 23% of index GIB and 34% of 1st rGIB patients. “Unknown” was the most common location for all rGIB. Consistent with other studies these patients display a high rate of angioectasia lesions with the majority of bleeding located in the upper GI tract [29]. No statistically significant predictor of rGIB was noted within this heterogeneous group on multivariate analysis. One possible explanation for ulcers being the most common lesion on second rGIB rather than angioectasia could be explained by peptic ulcer disease from recurrent hospitalizations or iatrogenic from repeated endoscopic interventions. Changes to anticoagulation/antiplatelet agent(s) and changes to goal therapeutic INR were not associated with rGIB. This again emphasizes the challenges with non-modifiable risk factors in this particularly morbid population.\n\nAn important observation in our study is that endoscopic management was not associated with a decreased incidence of rGIB. Performing an endoscopy with/without intervention, non-angioectasia lesions, and location of bleeding were not statistically significant predictors of rGIB. Longer duration of hospitalization appeared to be protective for rGIB on univariate analysis. Previous studies reported that EGD may have the highest diagnostic yield or that early deep overtube-assisted enteroscopy may decrease the number of pRBC transfused. Since the vast majority of patients in our study did get endoscopy (~96%) for index GIB, it is difficult to conclude if these patients benefited. GI endoscopy is still recommended for clinically overt GIB with benefits of stopping acute bleeding and shortening hospitalization. While the ability to prevent rGIB did not exist in our study, it is difficult to determine if the predictive value of index endoscopic findings was helpful to risk stratify for future GIB. Given the predominance of angioectatic lesions, their pathophysiology, and distribution throughout the bowel, it is reasonable to hypothesize that endoscopic intervention may not be effective to decrease the risk of rGIB. For now, there does not appear to be any evidence that endoscopic management of these patients decreases the frequency of GIB or hospitalizations for GIB [18,21,30,31].\n\nMortality from GIB in LVAD patients has not been consistently reported in previous studies and was similar between GIB and control groups. This analysis is limited by the univariate methodology and its retrospective nature, as cohorts were not temporally matched. Interestingly, GIB tended to have a lower mortality at 1 year and this may reflect that more frequent hospitalizations increased medical optimization, which is lost over time. There has been a shift in focus on medical management on this unique population of patients [32]. There were 4 patients in our study population treated with octreotide for rGIB. Three-quarters of these patients responded to octreotide with a decreased frequency of GIB, similar to other studies. It should be noted that a small subset of LVAD patients (~5%), have refractory rGIB (≥4 GIB events) representing a particularly morbid population that may not have been captured in our study or previous reports.\n\nOur study is limited by being a retrospective chart review. In addition, the definition of GIB requiring hospitalization may have underestimated the true incidence of GIB and rGIB. Finally, the sample size may have not been significantly powered to identify other predictors.\n\nThis study highlights the heterogeneity and challenges in management of GIB and rGIB in LVAD patients. Shared decision making should be an important part of the discussion with patients undergoing destination therapy and or longer duration of LVAD, as these are non-modifiable risk factors. Albumin is strongly associated with the risk of index GIB and attempts should be made to focus on this parameter in the outpatient setting. While this is a retrospective, single-center study, endoscopic approach or intervention was not associated with the risk for rGIB. While not emphasized in the literature, this appears consistent with previously published research. Currently, there is not enough evidence to forgo endoscopy in patients with LVAD and GIB. Future prospective studies should evaluate the optimal endoscopic approach and intervention in this unique population. Medical management including non-pharmacologic and pharmacologic treatment options (e.g., thalidomide and octreotide) and novel approaches (e.g., omega-3 and angiotensin converting enzyme inhibitors/angiotensin receptor blockers) should be further evaluated [33-36].\n\nIn conclusion, destination therapy, longer duration of LVAD, and low albumin were independent predictors of index GIB in our study. In addition, endoscopy with/without intervention does not appear to affect the risk of rGIB. GIB and rGIB remain a significant comorbidity in patients with LVAD. Management remains a challenge for caregivers, is frustrating for patients, and places a significant burden on healthcare resources. Given the number of non-modifiable risk factors and heterogeneity of this population, future prospective studies should focus on exploring other treatment options for these patients.\n\nSummary Box\n\nWhat is already known:\n\nGastrointestinal bleeding (GIB) in left ventricular assist device (LVAD) patients is a major source of morbidity and challenging to treat\n\nSeveral non-modifiable risk factors have been identified\n\nGIB tends to occur along the entire gastrointestinal tract with angioectasia being the most common lesion identified\n\nThere is no consensus on the optimal approach to endoscopic intervention\n\nWhat the new findings are:\n\nEndoscopy during index GIB with or without intervention does not appear to affect the risk of recurrent GIB\n\nDestination therapy, longer duration of LVAD, and low albumin are predictors of index GIB\n\nManagement of recurrent GIB in this unique population should focus on medical management\n\nPenn State Health Milton S. Hershey Medical Center, Hershey, PA; University of California San Francisco Fresno, Fresno, CA, USA\n\nConflict of Interest: Dr Clarke has no relevant disclosures related to this project\n==== Refs\n1 Benjamin EJ Blaha MJ Chiuve SE Heart disease and stroke statistics-2017 update:a report from the American Heart Association Circulation 2017 135 e146 e603 28122885\n2 Feldmann C Chatterjee A Haverich A Schmitto JD Left ventricular assist devices - a state of the art review Adv Exp Med Biol 2018 1067 287 294 29532330\n3 Stulak JM Davis ME Haglund N Adverse events in contemporary continuous-flow left ventricular assist devices:a multi-institutional comparison shows significant differences J Thorac Cardiovasc Surg 2016 151 177 189 26545967\n4 Lopilato AC Doligalski CT Caldeira C Incidence and risk factor analysis for gastrointestinal bleeding and pump thrombosis in left ventricular assist device recipients Artif Organs 2015 39 939 944 25912789\n5 Aggarwal A Pant R Kumar S Incidence and management of gastrointestinal bleeding with continuous flow assist devices Ann Thorac Surg 2012 93 1534 1540 22541185\n6 Yandrapalli S Rochlani Y Harikrishnan P Hospitalizations for major bleeding and outcomes in patients with ventricular assist devices J Am Coll Cardiol 2018 71 962\n7 Imamura T Kinugawa K Uriel N Therapeutic strategy for gastrointestinal bleeding in patients with left ventricular assist device Circ J 2018 82 2931 2938 30369592\n8 Kim JH Brophy DF Shah KB Continuous-flow left ventricular assist device-related gastrointestinal bleeding Cardiol Clin 2018 36 519 529 30297069\n9 Kushnir VM Sharma S Ewald GA Evaluation of GI bleeding after implantation of left ventricular assist device Gastrointest Endosc 2012 75 973 979 22341716\n10 Cushing K Kushnir V Gastrointestinal bleeding following LVAD placement from top to bottom Dig Dis Sci 2016 61 1440 1447 27017225\n11 Singh G Albeldawi M Kalra SS Mehta PP Lopez R Vargo JJ Features of patients with gastrointestinal bleeding after implantation of ventricular assist devices Clin Gastroenterol Hepatol 2015 13 107 114.e1 24858705\n12 Harvey L Holley CT John R Gastrointestinal bleed after left ventricular assist device implantation:incidence, management, and prevention Ann Cardiothorac Surg 2014 3 475 479 25452907\n13 Kataria R Jorde UP Gastrointestinal bleeding during continuous-flow left ventricular assist device support:state of the field Cardiol Rev 2019 27 8 13 30520778\n14 Dakik HK McGhan AA Chiu ST The diagnostic yield of repeated endoscopic evaluation in patients with gastrointestinal bleeding and left ventricular assist devices Dig Dis Sci 2016 61 1603 1610 26809869\n15 Demirozu ZT Radovancevic R Hochman LF Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device J Heart Lung Transplant 2011 30 849 853 21530318\n16 Gurvits GE Fradkov E Bleeding with the artificial heart:gastrointestinal hemorrhage in CF-LVAD patients World J Gastroenterol 2017 23 3945 3953 28652649\n17 Al-Bawardy B Schettle SD Gorospe E Small bowel bleeding in patients with left ventricular assist device:outcomes of conservative therapy versus balloon-assisted enteroscopy Ann Gastroenterol 2018 31 692 697 30386119\n18 Elmunzer BJ Padhya KT Lewis JJ Endoscopic findings and clinical outcomes in ventricular assist device recipients with gastrointestinal bleeding Dig Dis Sci 2011 56 3241 3246 21792619\n19 Amornsawadwattana S Nassif M Raymer D LaRue S Chen CH Video capsule endoscopy in left ventricular assist device recipients with obscure gastrointestinal bleeding World J Gastroenterol 2016 22 4559 4566 27182165\n20 Hirose H Sarosiek K Cavarocchi NC Ad hoc cost analysis of the new gastrointestinal bleeding algorithm in patients with ventricular assist device ASAIO J 2014 60 351 352 24469295\n21 Sarosiek K Bogar L Conn MI O'Hare B Hirose H Cavarocchi NC An old problem with a new therapy:gastrointestinal bleeding in ventricular assist device patients and deep overtube-assisted enteroscopy ASAIO J 2013 59 384 389 23820277\n22 Charlson ME Pompei P Ales KL MacKenzie CR A new method of classifying prognostic comorbidity in longitudinal studies:development and validation J Chronic Dis 1987 40 373 383 3558716\n23 Draper KV Huang RJ Gerson LB GI bleeding in patients with continuous-flow left ventricular assist devices:a systematic review and meta-analysis Gastrointest Endosc 2014 80 435 446.e1 24975405\n24 Albeiruti R Chaudhary F Alqahtani F Kupec J Balla S Alkhouli M Incidence, predictors, and outcomes of gastrointestinal bleeding in patients admitted with ST-elevation myocardial infarction Am J Cardiol 2019 124 343 348 31182211\n25 Welden CV Truss W McGwin G Weber F Peter S Clinical predictors for repeat hospitalizations in left ventricular assist device (LVAD) patients with gastrointestinal bleeding Gastroenterology Res 2018 11 100 105 29707076\n26 Yin MY Ruckel S Kfoury AG Novel model to predict gastrointestinal bleeding during left ventricular assist device support Circ Heart Fail 2018 11 e005267 30571195\n27 Critsinelis AC Kurihara C Kawabori M Predictive value of preoperative serum albumin levels on outcomes in patients undergoing LVAD implantation J Card Surg 2018 33 469 478 29968261\n28 Wever-Pinzon O Selzman CH Drakos SG Pulsatility and the risk of nonsurgical bleeding in patients supported with the continuous-flow left ventricular assist device HeartMate II Circ Heart Fail 2013 6 517 526 23479562\n29 Thohan V Shi Y Rappelt M The association between novel clinical factors and gastrointestinal bleeding among patients supported with continuous-flow left ventricular assist device therapy J Card Surg 2019 34 453 462 31058372\n30 Meyer MM Young SD Sun B Azzouz M Firstenberg MS Endoscopic evaluation and management of gastrointestinal bleeding in patients with ventricular assist devices Gastroenterol Res Pract 2012 2012 630483 22474445\n31 Truss WD Weber F Pamboukian SV Tripathi A Peter S Early implementation of video capsule enteroscopy in patients with left ventricular assist devices and obscure gastrointestinal bleeding ASAIO J 2016 62 40 45 26501918\n32 Molina TL Krisl JC Donahue KR Varnado S Gastrointestinal bleeding in left ventricular assist device:octreotide and other treatment modalities ASAIO J 2018 64 433 439 29406356\n33 Ge ZZ Chen HM Gao YJ Efficacy of thalidomide for refractory gastrointestinal bleeding from vascular malformation Gastroenterology 2011 141 1629 1637 e1-e4 21784047\n34 Imamura T Nguyen A Rodgers D Omega-3 therapy is associated with reduced gastrointestinal bleeding in patients with continuous-flow left ventricular assist device Circ Heart Fail 2018 11 e005082 30354397\n35 Juricek C Imamura T Nguyen A Long-acting octreotide reduces the recurrence of gastrointestinal bleeding in patients with a continuous-flow left ventricular assist device J Card Fail 2018 24 249 254 29427603\n36 Converse MP Sobhanian M Taber DJ Houston BA Meadows HB Uber WE Effect of angiotensin II inhibitors on gastrointestinal bleeding in patients with left ventricular assist devices J Am Coll Cardiol 2019 73 1769 1778 30975293\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1108-7471",
"issue": "34(5)",
"journal": "Annals of gastroenterology",
"keywords": "Left ventricular assist device; angioectasia; endoscopy; gastrointestinal bleeding",
"medline_ta": "Ann Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101121847",
"other_id": null,
"pages": "660-668",
"pmc": null,
"pmid": "34475736",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "30975293;22541185;21784047;3558716;21530318;27182165;30354397;29707076;28122885;24469295;29968261;31058372;26809869;29532330;25912789;22341716;29406356;23479562;23820277;30297069;26501918;29427603;24858705;22474445;30520778;28652649;21792619;25452907;30386119;26545967;24975405;31182211;27017225;30369592;30571195",
"title": "Initial endoscopic intervention is not associated with reduced risk of recurrent gastrointestinal bleeding in left ventricular assist device patients.",
"title_normalized": "initial endoscopic intervention is not associated with reduced risk of recurrent gastrointestinal bleeding in left ventricular assist device patients"
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"abstract": "Gonadotropin-releasing hormone (GnRH) agonists, currently used in the treatment of advanced prostate cancer, have been described as a rare cause of pituitary apoplexy, a potentially life-threatening clinical condition. We report the case of a 69-year-old man with a known pituitary macroadenoma who was diagnosed with prostate cancer and started treatment with GnRH agonist leuprorelin (other hormones were not tested before treatment). Few minutes after drug administration, the patient presented with acute-onset severe headache, followed by left eye ptosis, diplopia and vomiting. Pituitary MRI revealed tumor enlargement and T1-hyperintense signal, compatible with recent bleeding sellar content. Laboratory endocrine workup was significant for low total testosterone. The patient was managed conservatively with high-dose steroids, and symptoms significantly improved. This case describes a rare phenomenon, pituitary apoplexy induced by GnRH agonist. We review the literature regarding this condition: the pathophysiological mechanism involved is not clearly established and several hypotheses have been proposed. Although uncommon, healthcare professionals and patients should be aware of this complication and recognize the signs, preventing a delay in diagnosis and treatment.\nPituitary apoplexy (PA) is a potentially life-threatening complication that can be caused by gonadotropin-releasing hormone agonist (GnRHa) administration for the treatment of advanced prostate cancer. This complication is rare but should be taken into account when using GnRHa, particularly in the setting of a known pre-existing pituitary adenoma. PA presents with classic clinical signs and symptoms that should be promptly recognized. Patients should be instructed to seek medical care if suspicious symptoms occur. Healthcare professionals should be aware of this complication, enabling its early recognition, adequate treatment and favorable outcome.",
"affiliations": "Department of Endocrinology, Hospital de Braga, Braga, Portugal.;Department of Endocrinology, Hospital de Braga, Braga, Portugal.;Department of Neurosurgery, Hospital de Braga, Braga, Portugal.;Department of Neurosurgery, Hospital de Braga, Braga, Portugal.;Department of Endocrinology, Hospital de Braga, Braga, Portugal.",
"authors": "Barbosa|Mariana|M|;Paredes|Sílvia|S|;Machado|Maria João|MJ|;Almeida|Rui|R|;Marques|Olinda|O|",
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"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case Rep\nEndocrinol Diabetes Metab Case Rep\nEDM\nEndocrinology, Diabetes & Metabolism Case Reports\n2052-0573 Bioscientifica Ltd Bristol \n\n10.1530/EDM-20-0018\nEDM200018\nAdult\nMale\nWhite\nPortugal\nPituitary\nPituitary\nGnrh\nTestosterone\nPituitary Adenoma\nPituitary Apoplexy\nProstate Cancer\nHeadache\nDiplopia\nPtosis\nVomiting\nMRI\nTestosterone\nCT scan\nTSH\nProlactin\nCortisol\nC-reactive protein\nRadiotherapy\nLeuprolide acetate\nSteroids\nDexamethasone\nGlucocorticoids\nMethylprednisolone\nHydrocortisone\nUrology\nUnusual Effects of Medical Treatment\nUnusual Effects of Medical Treatment\nPituitary apoplexy induced by gonadotropin-releasing hormone agonist administration: a rare complication of prostate cancer treatment\nM Barbosa and othersRare complication of prostate cancer treatmentBarbosa Mariana 1 Paredes Sílvia 1 Machado Maria João 2 Almeida Rui 23 Marques Olinda 13 1 Department of Endocrinology, Hospital de Braga, Braga, Portugal\n2 Department of Neurosurgery, Hospital de Braga, Braga, Portugal\n3 Pituitary Consult, Hospital de Braga, Braga, Portugal\nCorrespondence should be addressed to M Barbosa; Email: marianamb013@gmail.com\n04 6 2020 \n2020 \n2020 20-001808 4 2020 06 5 2020 © 2020 The authors2020The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..Summary\nGonadotropin-releasing hormone (GnRH) agonists, currently used in the treatment of advanced prostate cancer, have been described as a rare cause of pituitary apoplexy, a potentially life-threatening clinical condition. We report the case of a 69-year-old man with a known pituitary macroadenoma who was diagnosed with prostate cancer and started treatment with GnRH agonist leuprorelin (other hormones were not tested before treatment). Few minutes after drug administration, the patient presented with acute-onset severe headache, followed by left eye ptosis, diplopia and vomiting. Pituitary MRI revealed tumor enlargement and T1-hyperintense signal, compatible with recent bleeding sellar content. Laboratory endocrine workup was significant for low total testosterone. The patient was managed conservatively with high-dose steroids, and symptoms significantly improved. This case describes a rare phenomenon, pituitary apoplexy induced by GnRH agonist. We review the literature regarding this condition: the pathophysiological mechanism involved is not clearly established and several hypotheses have been proposed. Although uncommon, healthcare professionals and patients should be aware of this complication and recognize the signs, preventing a delay in diagnosis and treatment.\n\nLearning points:\nPituitary apoplexy (PA) is a potentially life-threatening complication that can be caused by gonadotropin-releasing hormone agonist (GnRHa) administration for the treatment of advanced prostate cancer.\n\nThis complication is rare but should be taken into account when using GnRHa, particularly in the setting of a known pre-existing pituitary adenoma.\n\nPA presents with classic clinical signs and symptoms that should be promptly recognized.\n\nPatients should be instructed to seek medical care if suspicious symptoms occur.\n\nHealthcare professionals should be aware of this complication, enabling its early recognition, adequate treatment and favorable outcome.\n\nPatient Demographics\nAdultMaleWhitePortugalClinical Overview\nPituitaryPituitaryGNRHTestosteronePituitary adenomaPituitary apoplexyProstate cancerDiagnosis and Treatment\nHeadacheDiplopiaPtosisVomitingMRITestosteroneCT scanTSHProlactinCortisolC-reactive proteinRadiotherapyLeuprolide acetate SteroidsDexamethasoneGlucocorticoidsMethylprednisoloneHydrocortisoneRelated Disciplines\nUrologyPublication Details\nUnusual effects of medical treatmentJune2020\n==== Body\nBackground\nPituitary apoplexy (PA) is a potentially life-threatening clinical syndrome characterized by sudden onset of headache, vomiting, visual impairment and decreased consciousness, caused by bleeding and/or infarction of the pituitary gland, usually within a tumor (1). Androgen deprivation therapy, including gonadotropin-releasing hormone agonists (GnRHa), is administered as primary systemic therapy for regional or advanced prostate cancer and as neoadjuvant/concomitant/adjuvant therapy in combination with radiation in localized or locally advanced disease (2). GnRHa administration for prostate cancer has been reported to induce PA in patients with a concurrent pituitary adenoma, but there are only 21 cases described in the literature to date (3, 4, 5, 6, 7, 8, 9, 10). Although it is a rare complication, and since diagnosing PA requires high suspicion index, healthcare professionals should be aware of this association in order to enable an early recognition and adequate treatment.\n\nCase presentation\nA 69-year-old man with past medical history significant for diabetes, hypertension, dyslipidemia, Parkinson disease and cerebral falx meningioma had a pituitary macroadenoma (11.5 × 10.9 × 9 mm) incidentally detected in 2016 during workup for the meningioma – Fig. 1. An endocrinology evaluation was requested but the patient failed to attend and was lost to follow-up. He was diagnosed with prostate cancer in 2017 and underwent retropubic prostatectomy; two years later there was evidence of histologic prostate tumor progression and he started on a GnRHa – a s.c. injection of leuprorelin 45 mg every 6 months. A few minutes after the first injection, the patient presented with acute-onset severe persistent headache, followed by left eye ptosis 2 days later, diplopia and vomiting. He was observed by a neurosurgeon on the emergency department who confirmed left third cranial nerve palsy, with no other neurologic abnormalities. Remaining physical exam was unremarkable.\nFigure 1 Gadolinium-enhanced T1-weighted pituitary MRI images with sagittal (A) and coronal (B) sections showing macroadenoma before apoplexy.\n\n\n\n\nInvestigation\nHead CT with angiography showed pre-existing lesions: the tumor in the sellar region and the cerebral falx meningioma. Brain MRI was performed for further clarification and revealed sellar tumor enlargement and a heterogeneous T1-hyperintense signal, compatible with recent bleeding sellar content, with extension to the left cavernous sinus (Knosp grade II) – Fig. 2. Laboratory workup was significant for total testosterone 72.1 ng/dL (86.5–788.2), with no other relevant abnormalities on pituitary cell lines or blood electrolytes as the sample was collected after steroid administration - Table 1.\nFigure 2 Non-contrast T1-weighted sagittal section (A) and gadolinium-enhanced T1-weighted coronal section (B) of pituitary MRI at presentation demonstrating sellar tumor enlargement and heterogeneous hyperintense signal compatible with pituitary apoplexy.\n\n\nTable 1 Laboratory workup at admission(after steroids administration).\n\nLaboratory test\tResult\tReference range\t\nCortisol, µg/dL\t1.6\t4.3–22.4\t\nACTH, pg/mL\t10.8\t<46\t\nTSH, µUI/mL\t0.3\t0.4–3.7\t\nFT4, ng/dL\t0.9\t0.8–1.5\t\nProlactin, ng/mL\t0.5\t2.1–17.7\t\nGH, ng/mL\t0.8\t<3\t\nIGF-1, ng/mL\t147\t37–219\t\nFSH, mUI/mL\t3.5\t\t\nLH, mUI/mL\t4.3\t\t\nTT, ng/dL\t72.1\t86.5–788.2\t\nSodium, mmol/L\t139\t136–145\t\nPotassium, mmol/L\t3.8\t3.5–5.1\t\nCreatinine, mg/dL\t0.9\t0.7–1.2\t\nCRP, mg/L\t25\t<3\t\nACTH, adrenocorticotropic hormone; CRP, C-reactive protein; FSH, follicle-stimulating hormone; FT4, free thyroxine; GH, growth hormone; IGF-1, insulin-like growth factor-1; LH, luteinizing hormone; TSH, thyroid-stimulating hormone; TT, total testosterone.\n\n\n\n\nTreatment\nHigh-dose steroids – a 10 mg dexamethasone i.v. bolus followed by 5 mg of dexamethasone every 8 h – were started, with significant improvement of all clinical signs and symptoms, reason why the non-surgical approach was maintained. On discharge, the patient had complete resolution of the third nerve palsy, presenting with normal extraocular movements and no further headaches or vomiting. Dexamethasone was switched to methylprednisolone with tapering dose over 4 weeks and then replaced by hydrocortisone (15 mg/day).\n\nOutcome and follow-up\nAt two-month follow-up evaluation, the patient remained asymptomatic and biochemical workup revealed adrenocorticotrophic hormone 8.4 pg/mL (<46), cortisol 7.3 ug/dL (4.3–22.4) (sample collected 24 h after last hydrocortisone administration) and total testosterone 20 ng/dL (86.5–788.2), with no other biochemical remarks. He was maintained on hydrocortisone 15 mg/day. A pituitary MRI was performed 4 months later that revealed tumor volume reduction, with T1-isointense signal, but heterogeneous features reflecting different stages of previous bleeding and reduced extension to the left cavernous sinus (Knosp grade I) – Fig. 3. Meanwhile, he was started on radiation therapy for prostate cancer.\nFigure 3 Gadolinium-enhanced T1-weighted coronal pituitary MRI image showing tumor volume reduction and isointense signal 4 months after apoplexy.\n\n\n\n\nDiscussion\nProstate cancer is a prevalent disease, with an estimate of 174 650 new cases in the United States to be diagnosed in 2019, accounting for 20% of new cancer cases in men. Hormonal therapy including GnRHa is an important modality of treatment in selected cases (2). Increasing use of GnRHa therapy has revealed a rare adverse drug reaction, the development of apoplexy in a pre-existing pituitary adenoma. We report a case of PA occurring minutes after the administration of leuprorelin in a patient with prostate cancer and a previously diagnosed pituitary macroadenoma.\n\nThe first case recording this condition was reported by Ando et al. in 1995 and since then 20 other cases have been published (3, 4, 5, 6, 7, 8, 9, 10) – Table 2. Literature analysis of these reports revealed clinical features consistent with PA, highlighting pituitary MRI as the gold standard for diagnosis. Treatment decision on how to manage those patients – conservatively or with surgery – should be assessed by a multidisciplinary team (1). There are no randomized controlled trials and no evidence-based criteria to justify the clinical decision between a conservative approach and neurosurgical intervention. According to United Kingdom guidelines, patients with PA who are without any neuro-ophthalmic signs or mild and stable signs can be considered for conservative management with careful monitoring and frequent neurological assessments. On the other hand, patients with severely reduced visual acuity, severe and persistent or deteriorating visual field defects or deteriorating level of consciousness should be considered for surgical management (performed by an experienced pituitary surgeon and preferably within the first 7 days of symptoms onset). They emphasize that ocular paresis in the absence of visual field defects or reduced visual acuity is not in itself an indication for immediate surgery (resolution will typically occur within days or weeks) (1). Also, it is important to keep in mind that acute secondary adrenal insufficiency is seen in approximately two-thirds of patients with PA and is a major source of mortality. Therefore, initiating early glucocorticoid therapy is crucial in patients with PA and hemodynamic instability, altered consciousness level, reduced visual acuity, severe visual field defects or confirmed hypocortisolism. According to the literature, an i.v. bolus of hydrocortisone 100–200 mg is appropriate followed either by 2–4 mg/h continuous i.v. infusion or by 50–100 mg i.m. injection every 6 h (1). Dexamethasone is not favored as a glucocorticoid replacement option, although it may be used to reduce edema as part of nonsurgical strategy for PA treatment, as occurred in the case we report.\nTable 2 Summary of reported cases of pituitary apoplexy induced by gonadotropin-releasing hormone agonists.\n\nYear\tReference\tPatient age\tGnRH agonist, dose\tTime of onset\tSymptoms/signs\tPathological findings\tTreatment\t\n1995\t(11)\t83\tGoserelin, 3.6 mg\t9 days\tHeadache, nausea/vomiting, altered mentation, diplopia, fever and hyponatremia\t–\tMedical\t\n1995\t(12)\t78\tTriptorelin, 3.75 mg\ta few min\tHeadache, postural dizziness and left partial ophthalmoplegia\t–\tMedical\t\n1996\t(13)\t74\tLeuprolide, 7.5 mg\t15 min\tHeadache, nausea/vomiting, left ophthalmoplegia, altered mentation, generalized weakness and visual disturbances\tStain FSH +, LH +, GH +\tSurgical\t\n1997\t(14)\t62\tLeuprorelin, 3.75 mg\t4 days\tHeadache, left ophthalmoplegia and papilledema\tStain FSH +, LH +\tSurgical\t\n2001\t(15)\t67\tGoserelin, 3.6 mg\t4 h\tHeadache, nausea/vomiting, visual disturbances, altered mentation and hypertension\tStain FSH +, LH +\tSurgical\t\n2002\t(4)\t74\tLeuprolide, -\t–\tHeadache and nausea/vomiting\t–\tMedical\t\n2003\t(16)\t69\tLeuprolide, -\t<4 h\tHeadache, visual disturbances and diabetes insipidus\tStain FSH +\tSurgical\t\n2006\t(17)\t68\tGoserelin, 3.6 mg\t4–6 h\tHeadache, nausea/vomiting, altered mentation, diplopia and right ptosis\t–\tSurgical\t\n2006\t(18)\t61\tLeuprolide, 30 mg\ta few hours\tHeadache, nausea/vomiting, diplopia and ophthalmoplegia\tStain FSH +\tSurgical\t\n2006\t(19)\t70\tLeuprolide, 11.25 mg\t10 days\tVisual disturbances, diplopia and right ptosis\tStain FSH +\tSurgical\t\n2007\t(20)\t60\tLeuprolide, 22.5 mg\t4 hs\tHeadache, nausea/vomiting, altered mentation, visual disturbances, left ophthalmoplegia and diplopia\tStain LH +\tSurgical\t\n2010\t(5)\t71\tGoserelin, -\t8 weeks\tHeadache, nausea/vomiting and visual disturbances\tStain FSH +, LH +\tSurgical\t\n2010\t(10)\t60\tLeuprolide, -\ta few hours\tHeadache, left ophthalmoplegia and visual disturbances\tStain LH +\tSurgical\t\n2011\t(6)\t78\tGoserelin, 3.6 mg\t9 days\tHeadache, left ophthalmoplegia and visual disturbances\tStain FSH +\tSurgical\t\n2013\t(9)\t77\tLeuprorelin, 3.75 mg\ta few hours\tHeadache, nausea/vomiting and left ophthalmoplegia\t–\tSurgical\t\n2014\t(7)\t60\tLeuprolide, -\ta few hours\tHeadache, nausea/vomiting, diplopia and left ptosis\tStain LH +, TSH +\tSurgical\t\n2015\t(21).\t62\tLeuprolide, 11.25 mg\t10 min\tHeadache, nausea/vomiting and right ophthalmoplegia\tStain FSH +, LH +\tSurgical\t\n2015\t(8)\t77\tTriptorelin, 22.5 mg\t1 h\tHeadache, nausea/vomiting, diplopia and right ptosis\t–\tSurgical\t\n2016\t(22)\t67\tTriptorelin, -\t14 days\tHeadache and right ptosis\tStain FSH +, LH +\tSurgical\t\n2016\t(23)\t63\tLeuprolide, 11.25 mg\t3 days\tHeadache, visual disturbances and altered mentation\t–\tMedical\t\n2017\t(3)\t85\tLeuprolide, 45 mg\t4 h\tHeadache and nausea/vomiting\t–\tMedical\t\nFSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.\n\n\n\n\nReview of the documented cases evidenced a mean age of 69.8 years (ranging from 60 to 85 years) at the event time. The majority of reported cases (11) occurred with leuprolide, whereas goserelin was implicated in five cases, triptorelin in three cases and leuprorelin in tw cases. The most variable parameter was time of symptom onset, occurring within minutes to several days after GnRHa administration. In 13 cases, symptoms developed within hours; the remaining patients presented clinical features 3 to 14 days after the injection, and in one case delayed PA was diagnosed 8 weeks after treatment. Headache was the predominant symptom, described in 95.2% of cases (n = 20), followed by nausea/vomiting in 61.9% (n = 13), ophthalmoplegia and visual disturbances in 42.9% (n = 9), diplopia in 33.3% (n = 7) and altered mentation status in 28.6% (n = 6). Regarding treatment, surgical approach was conducted in 76.2% of cases (n = 16). As mentioned previously, while many patients with PA require surgical intervention, selected patients may be managed conservatively. In fact, our patient, despite the presence of a neuro-ophthalmic deficit, presented an excellent outcome with only medical treatment, possibly due to prompt evaluation and management. Histological findings with adenomatous tissue immunohistochemical staining were available in only 13 reports, all of them compatible with gonadotrophinomas (six positive for both luteinizing hormone (LH) and follicle-stimulating hormone (FSH), four positive for FSH and three positive for LH) (3, 4, 5, 6, 7, 8, 9, 10).\n\nThe exact pathophysiologic mechanism involved is this association is not clearly established. Multiple factors have been implicated in the increased risk of pituitary bleeding: larger size of the tumor, elevated intrasellar pressure and intrinsic vasculature abnormalities (9). Guerra et al. proposed a biphasic phenomenon, hypothesizing that PA induced by GnRHa can occur through an acute and a subacute phase (10). This concept of dual pathophysiology can reconcile the different features described in reported cases, especially concerning the timing of symptom onset. In cases where the condition occurred a few minutes or hours after drug administration (acute phase), a combination of cell degranulation/shrinking and metabolic hyperactivity in a poorly perfused adenomatous pituitary tissue (abnormal capillarity system) would explain the event. On the other hand, in the group of patients with a later start of symptoms (subacute phase), it was suggested that the stimulation of LH secretion leading to cell growth and protein synthesis could have an effect on tumor size and intrasellar pressure, promoting generalized ischemia and consequent bleeding (8, 10). Moreover, it has also been proposed that gonadotroph adenomas are the most common adenomas associated with the occurrence of PA. GnRHa binding to GnRH receptors on pituitary gonadotropin-secreting cells causes levels of LH and FSH to increase dramatically and this hormonal stimulation of gonadotrophs may be related to tumor growth, perpetuating tissue infarction (3). In fact, to our knowledge, only gonadotrophinomas were reported (both functioning and non-functioning (10)), despite co-staining for growth hormone (GH) in one case and thyroid-stimulating hormone (TSH) in another (3, 7).\n\nAttending to the frequency of pituitary adenomas in the general population and the widespread use of GnRHa in prevalent diseases such as prostate cancer, along with the fact that pre-treatment pituitary hormone tests or imaging evaluation are probably not cost-effective, it is essential to draw attention to this possible complication (7, 8). In patients with a known pituitary adenoma, Babbo et al. recommended a thorough clinical evaluation and discussion by a multidisciplinary team including endocrinologists and neurosurgeons: in macroadenomas, surgical resection of the tumor prior to GnRHa therapy may be appropriate (given the higher likelihood of apoplexy in larger tumors), while in microadenomas, it may be suitable to cautiously proceed with GnRHa therapy (7). Nonetheless, regardless of the presence or absence of a known pituitary adenoma, both physicians who prescribe these drugs and patients should be informed and vigilant to the warning, clinical signs and act accordingly.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\nWritten informed consent was obtained from the patient for publication of the submitted article and accompanying images.\n\nAuthor contribution statement\nAll authors contributed to the case report and were included in the medical team that assisted the patient. Material preparation, data collection and literature review were performed by Mariana Barbosa. The first draft of the manuscript was written by Mariana Barbosa and all authors commented on previous versions, read and approved the revised and final manuscript.\n==== Refs\nReferences\n1 Rajasekaran S Vanderpump M Baldeweg S Drake W Reddy N Lanyon M Markey A Plant G Powell M Sinha S , et al\nUK guidelines for the management of pituitary apoplexy\n. Clinical Endocrinology \n2011 \n74 \n9 –20\n. (10.1111/j.1365-2265.2010.03913.x )21044119 \n2 Mohler JL Antonarakis ES Armstrong AJ D’Amico AV Davis BJ Dorff T Eastham JA Enke CA Farrington TA Higanoet CS , et al\nProstate cancer, version 2.2019, NCCN Clinical Practice Guidelines in oncology\n. Journal of the National Comprehensive Cancer Network \n2019 \n17 \n479 –505\n. (10.6004/jnccn.2019.0023 )31085757 \n3 Tanios G Mungo NA Kapila A Bajaj K \nPituitary apoplexy: a rare complication of leuprolide therapy in prostate cancer treatment\n. BMJ Case Reports \n2017 (10.1136/bcr-2016-218514 )\n4 Spengos K Pavlopoulos C Grivas A \nPituitary haemorrhage after leuprolide therapy for prostatic cancer, clinically imitating acute subarachnoidal haemorrhage\n. Cerebrovascular Diseases \n2002 \n14 \n272 (10.1159/000065664 )12403969 \n5 Sinnadurai M Cherukuri RK Moses RG Nasser E \nDelayed pituitary apoplexy in patient with advanced prostate cancer treated with gonadotrophin-releasing hormone agonists\n. Journal of Clinical Neuroscience \n2010 \n17 \n1201 –1203\n. (10.1016/j.jocn.2010.01.012 )20605467 \n6 Ito Y \nUnexpected enlargement of clinically silent pituitary gonadotroph adenoma induced by goserelin acetate given as treatment for prostate cancer\n. International Journal of Urology \n2011 \n18 \n83 –84\n. (10.1111/j.1442-2042.2010.02676.x )21077963 \n7 Babbo A Kalapurakal GT Liu B Bajramovic S Chandler JP Garnett J Kalapurakal JA \nThe presence of a pituitary tumor in patients with prostate cancer is not a contraindication for leuprolide therapy\n. International Urology and Nephrology \n2014 \n46 \n1775 –1778\n. (10.1007/s11255-014-0708-z )24705727 \n8 Guerrero-Pérez F Marengo AP Planas-Vilaseca A Flores-Escobar V Villabona-Artero C \nPituitary apoplexy induced by triptorelin in patient with prostate cancer\n. Endocrinologia y Nutricion \n2015 \n62 \n411 –412\n. (10.1016/j.endonu.2015.05.005 )26184059 \n9 Huang TY Lin JP Lieu AS Chen YT Chen HS Jang MY Shen JT Wu WJ Huang SP Juan YS \nPituitary apoplexy induced by gonadotropin-releasing hormone agonists for treating prostate cancer-report of first Asian case\n. World Journal of Surgical Oncology \n2013 \n11 \n254 (10.1186/1477-7819-11-254 )24088191 \n10 Guerra Y Lacuesta E Marquez F Raksin PB Utset M Fogelfeld L \nApoplexy in non functioning pituitary adenoma after one dose of leuprolide as treatment for prostate cancer\n. Pituitary \n2010 \n13 \n54 –59\n. (10.1007/s11102-009-0202-2 )19842040 \n11 Ando S Hoshino T Mihara S \nPituitary apoplexy after goserelin\n. Lancet \n1995 \n345 \n458 (10.1016/s0140-6736(95)90443-3 )\n12 Chanson P Schaison G \nPituitary apoplexy caused by GnRH-agonist treatment revealing gonadotroph adenoma\n. Journal of Clinical Endocrinology & Metabolism \n1995 \n80 \n2267 –2278\n. (10.1210/jcem.80.7.7608291 )7608291 \n13 Morsi A Jamal S Silverberg JD \nPituitary apoplexy after leuprolide administration for carcinoma of the prostate\n. Clinical Endocrinology \n1996 \n44 \n121 –124\n. (10.1046/j.1365-2265.1996.644465.x )8706284 \n14 Reznik Y Chapon F Lahlou N Deboucher N Mahoudeau J \nPituitary apoplexy of a gonadotroph adenoma following gonadotrophin releasing hormone agonist therapy for prostatic cancer\n. Journal of Endocrinological Investigation \n1997 \n20 \n566 –568\n. (10.1007/BF03348020 )9413812 \n15 Eaton HJ Phillips PJ Hanieh A Cooper J Bolt J Torpy DJ \nRapid onset of pituitary apoplexy after goserelin implant for prostate cancer: need for heightened awareness\n. Internal Medicine Journal \n2001 \n31 \n313 –314\n. (10.1046/j.1445-5994.2001.00065.x )11512605 \n16 Hernandez Morin N Huet D Hautecouverture M \nTwo cases of non-functional gonadotroph adenoma pituitary apoplexy following GnRH-agonist treatment revealing gonadotroph adenoma and pseudopituitary apoplexy after GnRH administration\n. Annals of Endocrinology \n2003 \n64 \n227 –231\n.\n17 Błaut K Wiśniewski P Syrenicz A Sworczak K \nApoplexy of clinically silent pituitary adenoma during prostate Cancer treatment with LHRH analog\n. Neuro Endocrinology Letters \n2006 \n27 \n569 –572\n.17159826 \n18 Davis A , Goel S , Picolos M , Wang M & Lavis V. \nPituitary apoplexy after leuprolide\n. Pituitary \n2006 \n9 \n263 –265\n. (10.1007/s11102-006-8616-6 )16832587 \n19 Massoud W Paparel P Lopez J-G Perrin P Daumont M Ruffion A. \nDiscovery of a pituitary adenoma following treatment with a gonadotropin-releasing hormone agonist in a patient with prostate cancer\n. International Journal of Urology \n2006 \n13 \n87 –88\n. (10.1111/j.1365-2265.2010.03913.x )16448441 \n20 Hands KE Alvarez A Bruder J M. \nGonadotropin-releasing hormone agonist-induced pituitary apoplexy in treatment of prostate cancer: case report and review of literature\n. Endocrine Practice \n2007 \n13 \n642 –646\n. (10.4158/EP.13.6.642 )17954421 \n21 Sasagawa Y Tachibana O Nakagawa A Koya D Iizuka H. \nPituitary apoplexy following gonadotropin-releasing hormone agonist administration with gonadotropin-secreting pituitary adenoma\n. Journal of Clinical Neuroscience \n2015 \n22 \n601 –603\n (10.1016/j.jocn.2014.08.015 )25455737 \n22 Keane F Egan A M Navin P Brett F Dennedy MC \nGonadotropin-releasing hormone agonist-induced pituitary apoplexy\n. Endocrinology, Diabetes & Metabolism Case Reports \n2016 \n2016 \n160021 (10.1530/EDM-16-0021 )\n23 Fabiano AJ George S \nPituitary apoplexy after Initial Leuprolide injection. World Neurosurgery\n\n2016 \n95 \n616.e7 –616.e9\n. (10.1016/j.wneu.2016.08.091 )\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2052-0573",
"issue": "2020()",
"journal": "Endocrinology, diabetes & metabolism case reports",
"keywords": "2020; Adult; C-reactive protein; CT scan; Cortisol; Dexamethasone; Diplopia; GNRH; Glucocorticoids; Headache; Hydrocortisone; June; Leuprolide acetate ; MRI; Male; Methylprednisolone; Pituitary; Pituitary adenoma; Pituitary apoplexy; Portugal; Prolactin; Prostate cancer; Ptosis; Radiotherapy; Steroids; TSH; Testosterone; Unusual effects of medical treatment; Urology; Vomiting; White",
"medline_ta": "Endocrinol Diabetes Metab Case Rep",
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"nlm_unique_id": "101618943",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32554827",
"pubdate": "2020-06-04",
"publication_types": "D016428:Journal Article",
"references": "24705727;17954421;7608291;21077963;16832587;27586180;9413812;7853980;27284452;16448441;11512605;26184059;28710301;8706284;12403969;24088191;20605467;25455737;21044119;12910066;17159826;31085757;19842040",
"title": "Pituitary apoplexy induced by gonadotropin-releasing hormone agonist administration: a rare complication of prostate cancer treatment.",
"title_normalized": "pituitary apoplexy induced by gonadotropin releasing hormone agonist administration a rare complication of prostate cancer treatment"
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"abstract": "Introduction: Peritoneal carcinomatosis represents an advanced stage of tumor dissemination of abdominal cancers in general and colorectal cancer in particular. The only therapeutic methods currently available for the treatment of this pathology are systemic chemotherapy (palliative character) and cytoreductive surgery (CR) with intraperitoneal chemotherapy. After evaluation of evidence-based medical literature and current guide lines we can state that CR + HIPEC procedure is considered to be the treatment of choice in case of patients with peritoneal carcinomatosis of colorectal, ovarian and mucinous appendicular origin. Material and method: In the present study we prospectively analyzed the immediate postoperative results obtained in the first 50 patients that were treated by our team for peritoneal carcinomatosis of different origin. We described the protocol of selection, the patients characteristics that were included in our CR+HIPEC program and analyzed the complications and death rate. Results: From January 2015 till Dec 2018 we evaluated 98 patients with peritoneal carcinomatosis. From them, 51 received radical CR+HIPEC treatment, 33 were not suitable for surgery because of the exclusion criteria's and 15 had only exploratory laparotomies. In regard with the histopathological diagnosis, 30 patients had ovarian cancer and 19 had colorectal cancer or peritoneal pseudomixoma of appendicular origin. There was no 30 days postoperative mortality. The incidence of significant postoperative complications was 15%. Conclusions: Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy is a complex technique accompanied by an acceptable rate of complications and postoperative deaths, the results being optimized by a standardized perioperative management and patient selection. The initial results obtained by our team emphasize the feasibility of this procedure, with immediate good results, as a result of a standardization protocol of patient selection and perioperative care.",
"affiliations": null,
"authors": "Bartoş|Adrian|A|;Bartoş|Dana|D|;Raluca|Stoian|S|;Mitre|Călin|C|;Hadade|Adina|A|;Iancu|Ioana|I|;Cioltean|Cristian|C|;Iancu|Cornel|C|;Militaru|Claudia|C|;Părău|Angela|A|;Breazu|Caius|C|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1221-9118",
"issue": "114(2)",
"journal": "Chirurgia (Bucharest, Romania : 1990)",
"keywords": "colorectalcancer; hyperthermicintraperitonealchemotherapy; multiorganresections; ovariancancer; peritonealcarcinomatosis; pseudomyxomaperitonei",
"medline_ta": "Chirurgia (Bucur)",
"mesh_terms": "D000328:Adult; D000368:Aged; D001063:Appendiceal Neoplasms; D015179:Colorectal Neoplasms; D003131:Combined Modality Therapy; D065426:Cytoreduction Surgical Procedures; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms; D018579:Patient Selection; D010534:Peritoneal Neoplasms; D011446:Prospective Studies; D011553:Pseudomyxoma Peritonei; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9213031",
"other_id": null,
"pages": "222-233",
"pmc": null,
"pmid": "31060655",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for the Treatment of Peritoneal Carcinomatosis: Our Initial Experience.",
"title_normalized": "cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis our initial experience"
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"activesubstancename": "OXALIPLATIN"
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"abstract": "Pneumatosis intestinalis (PI) refers to the presence of gas within the wall of the small or large intestine. PI can be both asymptomatic and life-threatening. The patient was a 50-year-old man with previous cervical spine abscess and osteomyelitis post debridement 4 years ago, with a heroin abuse history. He presented with abdominal distension ongoing for 4 days and vomiting for 3 times with fluid content. Abdominal computed tomography revealed pneumatosis with pneumoretroperitoneum. A surgeon was contacted and antibiotic treatment was started. The patient was kept on nothing per os and intravenous fluid supply. A drainage tube was inserted into retroperitoneum space on the same day. Tracing back his history, our patient was discharged from the hospital recently with a diagnosis of superior mesenteric artery dyndrome (SMAS), hypersensitivity pneumonitis, and asbestosis with soft tissue pleural plaques and calcified pleural plaques. During the hospitalization period, hydrocortisone dexamethasone and methylprednisolone were prescribed for hypersensitivity pneumonitis. Steroid use and SMAS maybe the cause of PI. Finally, he was discharged 5 days later with a nasojejunal and drainage tubes and was arranged for OPD follow-up. PI can be asymptomatic or life-threatening, and patient management varies based on the clinical condition. Although in this case PI was found in the emergency department, a patient's past history of underlying disease and medication should be reviewed to find the most possible etiology.",
"affiliations": "Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.;Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: 990271@kmuh.org.tw.",
"authors": "Lee|Ching-I|CI|;Wu|Yen-Hung|YH|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D006854:Hydrocortisone; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2019.06.040",
"fulltext": null,
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"issn_linking": "0735-6757",
"issue": "37(10)",
"journal": "The American journal of emergency medicine",
"keywords": "Pneumatosis intestinalis; Pneumoretroperitoneum; Steroid; Superior mesenteric artery syndrome",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D006556:Heroin Dependence; D006801:Humans; D006854:Hydrocortisone; D008297:Male; D008487:Medical History Taking; D008775:Methylprednisolone; D008875:Middle Aged; D011006:Pneumatosis Cystoides Intestinalis; D011027:Pneumoperitoneum; D011860:Radiography, Abdominal; D013478:Superior Mesenteric Artery Syndrome; D016896:Treatment Outcome; D014839:Vomiting",
"nlm_unique_id": "8309942",
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"pmid": "31262624",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pneumatosis intestinalis and pneumoretroperitoneum post steroid use in a patient with superior mesenteric artery syndrome.",
"title_normalized": "pneumatosis intestinalis and pneumoretroperitoneum post steroid use in a patient with superior mesenteric artery syndrome"
} | [
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"companynumb": "TW-PFIZER INC-2019303331",
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"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
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{
"abstract": "OBJECTIVE\nHeparin-induced thrombocytopenia (HIT) is a rare but severe prothrombotic disorder of heparin treatment that leads to a decline in platelet count and thrombotic complications. If HIT is suspected, then heparin should be stopped and an alternative anticoagulant started. Fondaparinux is a factor Xa-inhibitor that is not FDA-approved for this condition, but preliminary experience in HIT patients has been reported in the literature. The present study describes an experience of anticoagulation management with fondaparinux in postoperative cardiac surgery patients.\n\n\nMETHODS\nRetrospective study.\n\n\nMETHODS\nTertiary hospital.\n\n\nMETHODS\nPatients who had undergone cardiac surgery from October 2009 to June 2012.\n\n\nMETHODS\nAfter HIT was suspected clinically, PaGIA and ELISA test were performed in all patients to diagnose HIT. In the patients included, anticoagulation was managed with a low dose of fondaparinux and daily monitoring of platelet count and anti-Xa level.\n\n\nRESULTS\nOf a total of 1,338 postoperative cardiac surgery patients, 15 patients were included (1.1%). Twelve of the 15 patients with HIT presented with renal failure and were under continuous renal replacement therapy. Two major bleeding events occurred during fondaparinux treatment, although platelet count and anti-Xa activity remained within the normal range. No thrombotic episodes were diagnosed.\n\n\nCONCLUSIONS\nWith daily monitoring of anti-Xa activity, fondaparinux appeared to be a good alternative to heparin in the study group; however, randomized clinical trials are needed to establish the safety and efficacy of this drug in critically ill, previously HIT patients.",
"affiliations": "Service of Anesthesiology, Post Operative Care Unit of Cardiac Surgery. Electronic address: vcegarra@santpau.cat.;Service of Anesthesiology, Post Operative Care Unit of Cardiac Surgery.;Service of Anesthesiology, Post Operative Care Unit of Cardiac Surgery.;Thrombosis and Haemostasis Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.;Service of Anesthesiology, Post Operative Care Unit of Cardiac Surgery.;Service of Anesthesiology, Post Operative Care Unit of Cardiac Surgery.;Service of Anesthesiology, Post Operative Care Unit of Cardiac Surgery.",
"authors": "Cegarra-Sanmartín|Virginia|V|;González-Rodríguez|Raúl|R|;Paniagua-Iglesias|Pilar|P|;Santamaría-Ortiz|Amparo|A|;Cueva|Luisa F|LF|;Galán-Serrano|Josefa|J|;Moral-García|M Victoria|MV|",
"chemical_list": "D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D011134:Polysaccharides; D005170:Factor X; D000077425:Fondaparinux",
"country": "United States",
"delete": false,
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"issue": "28(4)",
"journal": "Journal of cardiothoracic and vascular anesthesia",
"keywords": "HIT; HITT; cardiac surgery; fondaparinux; heparin-induced thrombocytopenia",
"medline_ta": "J Cardiothorac Vasc Anesth",
"mesh_terms": "D000328:Adult; D000368:Aged; D000925:Anticoagulants; D001777:Blood Coagulation; D006348:Cardiac Surgical Procedures; D004305:Dose-Response Relationship, Drug; D005170:Factor X; D005260:Female; D005500:Follow-Up Studies; D000077425:Fondaparinux; D006331:Heart Diseases; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D011134:Polysaccharides; D011183:Postoperative Complications; D012189:Retrospective Studies; D013921:Thrombocytopenia; D013927:Thrombosis; D016896:Treatment Outcome",
"nlm_unique_id": "9110208",
"other_id": null,
"pages": "1008-12",
"pmc": null,
"pmid": "24439171",
"pubdate": "2014-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Fondaparinux as a safe alternative for managing heparin-induced thrombocytopenia in postoperative cardiac surgery patients.",
"title_normalized": "fondaparinux as a safe alternative for managing heparin induced thrombocytopenia in postoperative cardiac surgery patients"
} | [
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"companynumb": "ES-ZYDUS-009480",
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"activesubstancename": "CLOPIDOGREL BISULFATE"
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... |
{
"abstract": "An aortic mural thrombus (AMT) on a non-atherosclerotic wall is a rare but important cause of arterial thromboembolism. We herein report two cases of AMT in the thoracic aorta. Both showed multiple hypercoagulable factors (case 1: protein S deficiency and positive finding of anti-cardiolipin antibody; case 2: protein C deficiency, gastric cancer, and cisplatin-based chemotherapy) and were successfully treated with anticoagulation. Hypercoagulable states, including malignancy, can influence the formation of AMT; therefore, the accurate assessment of a hypercoagulable condition is necessary when we encounter patients with AMT.",
"affiliations": "Department of Cardiology, Toyonaka Municipal Hospital, Japan.;Department of Cardiology, Toyonaka Municipal Hospital, Japan.;Department of Cardiology, Toyonaka Municipal Hospital, Japan.;Department of Cardiology, Toyonaka Municipal Hospital, Japan.",
"authors": "Yagyu|Takeshi|T|;Naito|Maiko|M|;Kumada|Masahiro|M|;Nakagawa|Tsutomu|T|",
"chemical_list": "D000925:Anticoagulants",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.0691-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3021010210.2169/internalmedicine.0691-17Case ReportAortic Mural Thrombus in the Non-atherosclerotic Aorta of Patients with Multiple Hypercoagulable Factors Yagyu Takeshi 1Naito Maiko 1Kumada Masahiro 1Nakagawa Tsutomu 1\n1 Department of Cardiology, Toyonaka Municipal Hospital, JapanCorrespondence to Dr. Takeshi Yagyu, ta.kc89@gmail.com\n\n12 9 2018 1 2 2019 58 3 381 385 20 12 2017 17 5 2018 Copyright © 2019 by The Japanese Society of Internal Medicine2019The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).An aortic mural thrombus (AMT) on a non-atherosclerotic wall is a rare but important cause of arterial thromboembolism. We herein report two cases of AMT in the thoracic aorta. Both showed multiple hypercoagulable factors (case 1: protein S deficiency and positive finding of anti-cardiolipin antibody; case 2: protein C deficiency, gastric cancer, and cisplatin-based chemotherapy) and were successfully treated with anticoagulation. Hypercoagulable states, including malignancy, can influence the formation of AMT; therefore, the accurate assessment of a hypercoagulable condition is necessary when we encounter patients with AMT.\n\naortic thrombusarterial embolismhypercoagulable disorderanticoagulant therapy\n==== Body\nIntroduction\nSystemic arterial thromboembolism, which can result in cerebral infarction, myocardial infarction, visceral ischemia, or limb ischemia, is a serious and sometimes life-threatening problem. Thrombi, in most cases of arterial thromboembolism, are considered to have cardiac origins, specifically from complications of atrial fibrillation and myocardial infarction (1). However, there are a few cases without such sources, often called “cryptogenic embolism” (2,3). With recent developments in imaging modalities, especially transesophageal echocardiography (TEE), the aorta has been considered a potential embolic source. When the aorta is suspected as the embolic source, complex atherosclerotic lesions are usually involved (3,4); however, mural thrombus on a normal or minimally atherosclerotic aorta has also been regarded as an unusual but possible cause of arterial thromboembolism (2,5). Furthermore, some hypercoagulable disorders have frequently been detected in cases of aortic mural thrombus (AMT) (5-9).\n\nAs its clinical features are not well-known, we herein report two cases of AMT in patients with multiple hypercoagulable factors.\n\nCase Reports\nCase 1\nA 50-year-old man who was a smoker with dyslipidemia presented to the emergency department due to sudden dysarthria and hand paralysis on the right side. There was asymmetry in the upper limb blood pressures: 135/87 mmHg on the left, unmeasurable on the right. He had sinus rhythm on his electrocardiogram, a normal left ventricular function, and no abnormal findings in the aortic or mitral valve on transthoracic echocardiography (TTE). Magnetic resonance imaging revealed acute cerebellar infarction, and contrast-enhanced computed tomography (CT) showed right subclavian artery occlusion and a low-density lesion on the thoracic aorta with minimal atherosclerosis (Fig. 1). We were unable to image the lesions detected by CT with TEE and TTE.\n\nFigure 1. Imaging findings of a 50-year-old man with sudden dysarthria and right-hand paralysis (Case 1). On admission, brain magnetic resonance imaging showed acute left cerebellar infarction on diffusion-weighted imaging (A, arrow). Contrast-enhanced computed tomography revealed an occluded right subclavian artery (B, arrow) and low-density lesion on the non-atherosclerotic aorta (C, arrow). Two weeks after anticoagulant therapy, the aortic lesion had disappeared (D).\n\nWe considered the lesion on the thoracic aorta to be a thrombus and started anticoagulant therapy (ACT) with intravenous unfractionated heparin. A laboratory examination on thrombophilia prior to ACT demonstrated low proteins S free antigen levels at <11% (normal range: 65-135%) and an activity of 21% (normal range: 60-150%). Furthermore, positive anti-cardiolipin antibody (IgG), a known antiphospholipid antibody, was detected at 20.9 units/mL (normal range: <10.0 units/mL), which was confirmed again 10 months later. Other coagulation parameters were within the normal ranges (Table 1, Case 1). Duplex ultrasonography showed no findings of deep venous thrombosis in the lower limbs.\n\nTable 1. Laboratory Data on Coagulation-fibrinolysis System.\n\nVariables\t\tReference\t\tCase 1\t\tCase 2\t\nPT (%)\t\t70-130\t\t93\t\t68\t\nPT (INR)\t\t0.9-1.3\t\t1.03\t\t1.21\t\nAPTT (s)\t\t25-37\t\t36\t\t25\t\nPlatelet (×104/mm3)\t\t12.0-38.0\t\t13.5\t\t6.4\t\nD-dimer (μg/mL)\t\t0-1.0\t\t0.6\t\t10.1\t\nAntithrombin III (mg/dL)\t\t23-34\t\t29.9\t\t29.6\t\nAntithrombin III (%)\t\t80-130\t\t105\t\t104\t\nProtein S free antigen (%)\t\t65-135\t\t<11\t\t69\t\nProtein S activity (%)\t\t60-150\t\t21\t\t71\t\nProtein C antigen (%)\t\t62-131\t\t125\t\t42\t\nProtein C activity (%)\t\t64-135\t\tN/A\t\t48\t\nAntiphospholipid antibody (unit/mL)\t\t<10.0\t\t20.9\t\t<8.0\t\nLupus anticoagulant (normalized ratio)\t\t<1.3\t\t1.14\t\t1.05\t\nPT: prothrombin time, INR: international normalized ratio, APTT: activated partial thromboplastin time\n\nTwo weeks after the initiation of ACT and following careful observation, contrast-enhanced CT confirmed the disappearance of the lesion in the aortic arch without any further embolic events. The laterality of the blood pressure was no longer noted. Eight months later, a follow-up imaging study showed no further embolic findings, and he claimed no further symptoms following oral ACT with warfarin.\n\nCase 2\nA 70-year-old man with gastric cancer (stage III) was undergoing chemotherapy prior to cancer surgery. After one course of chemotherapy with cisplatin, contrast-enhanced CT performed for a response evaluation revealed a low-density lesion on the thoracic aorta (Fig. 2A), which was not seen prior to the chemotherapy. There were no findings or symptoms that implied systemic embolism. Upon testing for thrombophilia, it was observed that the patient had low protein C antigen levels at 42% (normal range: 62-131%) and an activity of 48% (normal range: 64-135%). Other coagulation parameters were within the normal ranges. (Table 1, Case 2). With additional TEE, TTE, and duplex ultrasonography of the lower limbs, we were unable to confirm the findings detected by CT in the thoracic aorta, abnormal observations on the aortic valve, on the mitral valve, and in the deep veins of the legs. We also considered the lesion to be a thrombus and started ACT with intravenous unfractionated heparin.\n\nFigure 2. Imaging findings of a 70-year-old man with gastric cancer receiving cisplatin-based chemotherapy (Case 2). A low-density lesion on the aorta that had not been detected on previous imaging tests was noted on contrast-enhanced computed tomography after a course of chemotherapy (A, arrow). The lesion disappeared two months after anticoagulant therapy (B).\n\nOn follow-up CT two months later, we noted the disappearance of the filling defect on the thoracic aorta without any embolic clinical event (Fig. 2B). As the planned courses of chemotherapy with cisplatin were discontinued, he underwent gastric surgery. After successful surgery, we started oral chemotherapy with tegafur/gimeracil/oteracil and decided to discontinue the administration of warfarin due to concerns of anticoagulant instability during the chemotherapy. On follow-up after eight months without ACT, no recurrence of the thrombus was found on imaging tests.\n\nDiscussion\nAortic plaque instability is an important etiology of systemic embolism from non-cardiac sources and is usually caused by thrombus or cholesterol crystals, both of which arise from severe aortic atherosclerotic plaques (3,4). There is likely to be some overlap, but embolism by the former etiology tends to occur in single small or medium arteries, while the latter tends to cause damage to multiple tissues and organs by the occlusion of small arteries.\n\nAMT on a non-atherosclerotic wall, such as in our cases, is relatively rare. In a report of 10,671 consecutive autopsies, AMT in a normal aorta was found in 48 cases (0.45%); of them, 38 cases were found in the abdominal aorta, 1 in the thoracic aorta, and 9 in both the abdominal and thoracic aortas. Of the 48 cases, evidence of arterial embolism was found in 8 (17%) (2). In another report of 27,855 examinations of TEE for patients with recent arterial embolic events, mobile aortic thrombi in the aortic arch without obvious diffuse aortic atherosclerosis were detected in 23 cases (0.08%). Their mean age was younger (45 years) than that of patients with stroke from aortic atherosclerotic plaques or debris (>70 years) (5). Thus, AMT and thromboembolism are likely to form in relatively young patients. The former study showed the diagnostic value of TEE; however, in our cases, we were unable to acquire any images of the aortic thrombus by TEE. It should be noted that examinations with TEE are unable to provide useful evidence of the existence of AMT. Furthermore, the plasma D-dimer level, a useful marker for the diagnosis of venous thrombus, was not elevated in Case 1, suggesting that the plasma D-dimer level may provide little information on thrombus formation in the aorta.\n\nSeveral reports have stated that AMT is frequently associated with some hypercoagulable states, as shown in Table 2 (5-9). In a systematic review of 200 AMT patients from 98 articles, hypercoagulable disorders were detected in 49 patients (25%) (8). In another report of prospectively collected data from a single center, routine work-up on hypercoagulable states, including malignant diseases, in patients with AMT showed a high prevalence of 60% (6). The same report showed that malignant diseases were found less frequently than hypercoagulable disorders. Vascular thrombus and malignancy have been called “Trousseau's syndrome\" and has been well-known for some time (10). Recently, it has been reported that the risk of arterial thromboembolism in patients with cancer is quite high (11). Furthermore, with recent developments in chemotherapeutic agents for malignant diseases, cancer treatment has been discussed in relation to the occurrence of thrombosis (12). There have been several reports of AMT suspected to be related to chemotherapy, particularly in cisplatin-based chemotherapy, such as in Case 2 of this report (13,14). Regarding hypercoagulable states in our AMT cases, we confirmed protein S deficiency and positive anti-cardiolipin antibody in Case 1 and protein C deficiency, cancer, and a history of cisplatin-based chemotherapy in Case 2. Whether or not multiple thrombotic predispositions are related to the acceleration of AMT formation on a non-atherosclerotic aortic wall is unclear because we did not conduct specific tests to assess the coagulation activity or platelet function and no reports have described direct evidence of hypercoagulability in patients with AMT. We must cautiously assess the comorbidities associated with prothrombotic conditions, as various hypercoagulable states, including malignancy and chemotherapy, are often found in patients with AMT.\n\nTable 2. Reported Underlying Pathologies in Relation to Aortic Mural Thrombus.\n\nHypercoagulable factor\t\tCase 1\t\tCase 2\t\nEssential thrombocythemia\t\t\t\t\t\nProtein C deficiency\t\t\t\t●\t\nProtein S deficiency\t\t●\t\t\t\nAntithrombin III deficiency\t\t\t\t\t\nAntiphospholipid syndrome\t\t●\t\t\t\nHeparin-induced thrombocytopenia\t\t\t\t\t\nHyperhomocysteinemia\t\t\t\t\t\nCancer\t\t\t\t●\t\nChemotherapy\t\t\t\t●\t\nIatrogenic (e.g., IABP)\t\t\t\t\t\nAortic wall tumor\t\t\t\t\t\nBlunt aortic trauma\t\t\t\t\t\nDrug abuse\t\t\t\t\t\nIABP: intra-aortic balloon pump\n\nACT, surgical treatment, and endovascular treatment have been reported as effective strategies in the treatment for AMT; however, which strategy is the most appropriate remains unclear. As a primary treatment, ACT for patients without contraindications should be considered, as this approach has proven effective in eliminating aortic thrombi (9,15). Indeed, both patients in our report were treated with ACT alone and showed favorable outcomes. However, the appropriate duration of ACT is unclear. In Case 1, as two persistent hypercoagulable disorders were confirmed and the patient was able to tolerate ACT, we continued to treat him with anticoagulation therapy. In contrast, in Case 2, as two of three hypercoagulable factors were resolved (cancer and cisplatin-based chemotherapy) and the combination of oral chemotherapy and warfarin might have resulted in harmful drug interactions, inducing anticoagulant instability, we decided to discontinue ACT. As there is no consensus on how long ACT should be administered, we must consider the duration on a case-by-case basis.\n\nSurgical treatment, including thrombectomy and segmental aortic resection, is a very invasive strategy but is supported by a systematic review, which showed fewer recurrent embolic events in the surgically treated group than in the ACT group (8). In that study, the ACT group showed a significantly higher persistence or recurrence rates and higher major limb amputation rates than the surgical group. In addition, 25% of patients initially treated with ACT eventually required subsequent aortic surgery because of the recurrence of embolism or persistence of the thrombus. However, as surgical procedures on the aorta are associated with a high perioperative morbidity and mortality, ACT tends to be favored as the primary treatment in many cases. In a report, the authors recommend surgery for patients not responding to ACT (with thrombus resolution) after two weeks of therapeutic anticoagulation (15). Recently, several cases of AMT treated successfully with endovascular treatment have been reported (16,17). Although reports of treatment with stent grafts for AMT have been limited, favorable results may be reported in the future.\n\nConclusion\nAMT is a rare but important embolic source. In cases of mural thrombosis on a non-atherosclerotic aortic wall, we should consider underlying hypercoagulable disorders and concurrent malignancy and carefully select proper treatment depending on each situation.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Abbott WM , Maloney RD , McCabe CC , Lee CE , Wirthlin LS \nArterial embolism: a 44 year perspective . Am J Surg \n143 : 460 -464 , 1982 .7072911 \n2. Machleder HI , Takiff H , Lois JF , Holburt E \nAortic mural thrombus: An occult source of arterial thromboembolism . J Vasc Surg \n4 : 473 -478 , 1986 .3773130 \n3. Tunick PA , Kronzon I \nAtheromas of the thoracic aorta: clinical therapeutic update . J Am Coll Cardiol \n35 : 545 -554 , 2000 .10716454 \n4. Cassella CR , Jagoda A \nAtherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke . N Engl J Med \n334 : 1216 -1221 , 1996 .8606716 \n5. Laperche T , Laurian C , Roudaut R , Steg PG \nMobile thromboses of the aortic arch without aortic debris . Circulation \n96 : 288 -294 , 1997 .9236447 \n6. Verma H , Meda N , Vora S , George RK , Tripathi RK \nContemporary management of symptomatic primary aortic mural thrombus . J Vasc Surg \n60 : 1524 -1534 , 2014 .25256613 \n7. Tsilimparis N , Hanack U , Pisimisis G , Yousefi S , Wintzer C , Ruckert RI \nThrombus in the non-aneurysmal, non-atherosclerotic descending thoracic aorta - an unusual source of arterial embolism . Eur J Vasc Endovasc Surg \n41 : 450 -457 , 2011 .21145267 \n8. Fayad ZY , Semaan E , Fahoum B , Briggs M , Tortolani A , D'Ayala M \nAortic mural thrombus in the normal or minimally atherosclerotic aorta . Ann Vasc Surg \n27 : 282 -290 , 2013 .22929167 \n9. Bowdish ME , Weaver FA , Liebman HA , Rowe VL , Hood DB \nAnticoagulation is an effective treatment for aortic mural thrombi . J Vasc Surg \n36 : 713 -719 , 2002 .12368731 \n10. Varki A \nTrousseau's syndrome: multiple definitions and multiple mechanisms . Blood \n110 : 1723 -1729 , 2007 .17496204 \n11. Navi BB , Reiner AS , Kamel H , et al \nRisk of arterial thromboembolism in patients with cancer . J Am Coll Cardiol \n70 : 926 -938 , 2017 .28818202 \n12. Falanga A , Marchetti M \nAnticancer treatment and thrombosis . Thromb Res \n129 : 353 -359 , 2012 .22119391 \n13. Moore RA , Adel N , Riedel E , et al \nHigh incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: a large retrospective analysis . J Clin Oncol \n29 : 3466 -3473 , 2011 .21810688 \n14. Lee Y-G , Lee E , Kim I , et al \nCisplatin-based chemotherapy is a strong risk factor for thromboembolic events in small-cell lung cancer . Cancer Res Treat \n47 : 670 -675 , 2015 .25672586 \n15. Choukroun EM , Labrousse LM , Madonna FP , Deville C \nMobile thrombus of the thoracic aorta: diagnosis and treatment in 9 cases . Ann Vasc Surg \n16 : 714 -722 , 2002 .12417931 \n16. Fueglistaler P , Wolff T , Guerke L , Stierli P , Eugster T \nEndovascular stent graft for symptomatic mobile thrombus of the thoracic aorta . J Vasc Surg \n42 : 781 -783 , 2005 .16242568 \n17. Luebke T , Aleksic M , Brunkwall J \nEndovascular therapy of a symptomatic mobile thrombus of the thoracic aorta . Eur J Vasc Endovasc Surg \n36 : 550 -552 , 2008 .18722794\n\n",
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"issue": "58(3)",
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"keywords": "anticoagulant therapy; aortic thrombus; arterial embolism; hypercoagulable disorder",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001013:Aorta, Thoracic; D001018:Aortic Diseases; D006331:Heart Diseases; D006801:Humans; D008297:Male; D008875:Middle Aged; D013923:Thromboembolism; D013927:Thrombosis; D013997:Time Factors; D016896:Treatment Outcome",
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"title": "Aortic Mural Thrombus in the Non-atherosclerotic Aorta of Patients with Multiple Hypercoagulable Factors.",
"title_normalized": "aortic mural thrombus in the non atherosclerotic aorta of patients with multiple hypercoagulable factors"
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"abstract": "Venipuncture, the most frequently performed invasive medical procedure, is usually benign. Generally it produces only transitory mild discomfort. Venipuncture-induced neuropathic pain is hard to recognize at an early stage. Medical literature reviews show that there is not adequate medical knowledge about this important subject. The inciting incident in complex regional pain syndrome (CRPS) can often seem far too trivial to result in a condition with such severe pathophysiologic effects. The practicing physician has little information available to enable early recognition of the condition, initiation of multidisciplinary treatment modalities, and proper referral to pain specialists. We encountered a unique case of venipuncture-induced complex regional pain syndrome (CRPS). The patient is a 52-year-old school teacher with no significant past medical history, who presented initially to the Center of Pain Medicine with left upper extremity pain. The pain started while phlebotomy was performed in the patient's left antecubital area for routine blood check. The patient's pain did not improve with multiple medications, physical therapy, or several nerve blocks. The patient demonstrated all the signs and symptoms of chronic neuropathic pain of CRPS in the upper extremity with minimal response to the continuous pain management. We decided to proceed with cervical spinal cord nerve stimulation along with continuing other modalities. The patient responded to this combination. During the follow-up, we noticed that the patient's pain course was complicated by extension of the CRPS to her lower extremity. We will describe the course of treatment for the patient in this paper. In this paper we will discuss the electrical neuromodulation as an important modality in addition to the multidisciplinary pain management for a patient with venipuncture-induced chronic neuropathic pain.",
"affiliations": "Center of Pain Medicine, University of Iowa, 200 Hawkins Drive 5JPP, Iowa City, IA 52242, USA.;Department of Neurosurgery, University of Iowa, Iowa City, IA, USA.",
"authors": "Elahi|Foad|F|;Reddy|Chandan G|CG|",
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"doi": "10.1155/2014/613921",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2014/613921Case ReportVenipuncture-Induced Complex Regional Pain Syndrome: A Case Report and Review of the Literature Elahi Foad \n1\n*Reddy Chandan G. \n2\n1Center of Pain Medicine, University of Iowa, 200 Hawkins Drive 5JPP, Iowa City, IA 52242, USA2Department of Neurosurgery, University of Iowa, Iowa City, IA, USA*Foad Elahi: foad-elahi@uiowa.eduAcademic Editor: Di Lazzaro Vincenzo\n\n2014 19 8 2014 2014 61392129 5 2014 16 7 2014 8 8 2014 Copyright © 2014 F. Elahi and C. G. Reddy.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Venipuncture, the most frequently performed invasive medical procedure, is usually benign. Generally it produces only transitory mild discomfort. Venipuncture-induced neuropathic pain is hard to recognize at an early stage. Medical literature reviews show that there is not adequate medical knowledge about this important subject. The inciting incident in complex regional pain syndrome (CRPS) can often seem far too trivial to result in a condition with such severe pathophysiologic effects. The practicing physician has little information available to enable early recognition of the condition, initiation of multidisciplinary treatment modalities, and proper referral to pain specialists. We encountered a unique case of venipuncture-induced complex regional pain syndrome (CRPS). The patient is a 52-year-old school teacher with no significant past medical history, who presented initially to the Center of Pain Medicine with left upper extremity pain. The pain started while phlebotomy was performed in the patient's left antecubital area for routine blood check. The patient's pain did not improve with multiple medications, physical therapy, or several nerve blocks. The patient demonstrated all the signs and symptoms of chronic neuropathic pain of CRPS in the upper extremity with minimal response to the continuous pain management. We decided to proceed with cervical spinal cord nerve stimulation along with continuing other modalities. The patient responded to this combination. During the follow-up, we noticed that the patient's pain course was complicated by extension of the CRPS to her lower extremity. We will describe the course of treatment for the patient in this paper. In this paper we will discuss the electrical neuromodulation as an important modality in addition to the multidisciplinary pain management for a patient with venipuncture-induced chronic neuropathic pain.\n==== Body\n1. Introduction\nVenipuncture, the most frequently performed invasive medical procedure, is usually benign, producing only transitory mild discomfort. Several case series and individual patient reports document nerve injuries consequent to the procedure. While such injuries are reportedly rare (1 : 21,000–1 : 26,700) some can be severe with permanent residua, the most disturbing being chronic neuropathic pain, complex regional pain syndrome type 2 (CRPS-II), or causalgia. Venipuncture-induced CRPS-II/causalgia is, perhaps, the most paradigmatic human neuropathic pain that can follow acute nerve trauma [1].\n\nComplex regional pain syndrome (CRPS) is an enigmatic clinical condition characterized by various combinations of sensory, autonomic, and motor dysfunction. CRPS is diagnostically distinguished into two subtypes, CRPS-I (regional sympathetic dystrophy) which is triggered by a noxious event without known peripheral nerve injury, while CRPS-II (causalgia) is the result of known peripheral nerve injury.\n\nThe pain is continuous, not associated with a single nerve/dermatome, and is disproportionate in chronicity and/or severity to any potential inciting event. The syndrome shows variable progression over time. The pain is regional (not in a specific nerve territory or dermatome) and usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings. The resultant debilitating chronic pain affects the extremities and is associated with high rates of relapse [2].\n\nThe underlying pathophysiology remains controversial and poorly understood, with no evidence that the two subtypes differ in causative mechanisms. Over the past few years there have been increasing evidence and acceptance of a multifactorial etiology. The mechanisms include both peripheral and central sensitization, inflammation, sympathetic dysregulation, somatosensory cortex reorganization, genetic factors, and psychophysiologic interactions. Adding to the underlying complexity in diagnosing and treating CRPS, each patient's symptoms are likely a result of different combinations of mechanism that can change over time [3].\n\nOriginal International Association for the Study of Pain (Orlando) diagnostic criteria for complex regional pain syndrome include (1) the presence of an initiating noxious event or a cause of immobilization, (2) continuing pain, allodynia, or hyperalgesia with which the pain is disproportionate to any inciting event, (3) evidence of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of pain at some point in time, and (4) diagnosis that is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction.\n\nThe inciting incident in CRPS can often seem far too trivial to result in a condition with such severe pathophysiologic effects. Needlestick causing distal nerve injury has been shown to produce CRPS-like symptoms in rat models, which suggests that similar pathophysiologic mechanisms may contribute to the development of CRPS after venipuncture in humans [4]. In a Japanese study, between 2004 and 2008, venipunctures were performed with 133 cases of resultant persistent pain and 19 cases of neuropathic pain [5].\n\n2. Case Presentation\nA 52-year-old right handed female presented with a chief complaint of left arm and left hand pain. The patient's symptoms began after a phlebotomist had a difficult time obtaining blood draws from the patient's left antecubital region for a cholesterol test. The patient described that immediately following the needle insertion it felt like the patient was being “electrocuted.” A few days later the patient went to the doctor due to this ongoing pain. The patient developed a shooting, burning, and constant neuropathic pain. The pain was originally in the left thumb finger and gradually extended to the indicis and middle finger with the relatively rapid expansion of the entire hand up to the wrist and sharp radiating pain distally from the elbow. The pain was somewhat diffused and was most sensitive along all the dermatomes below the elbow. Due to the continuation of her pain and with no benefit from initial pain medications regimen, her pain specialists decided to do stellate ganglion block, epidural steroid injections, along with physical therapy, occupational therapy, and multiple combined pain medications. She never experienced a tolerable pain level during the use of her medications even in the highest permitted dose. The patient had tried gabapentin, tramadol, baclofen, amitriptyline, hydrocodone, nucynta, savella, and lyrica, as well as lidoderm patches for her symptoms.\n\nThe patient presented to the pain clinic with pain and rated the pain as 8 out of 10 on visual analog scale and stated that the pain was perceived constantly around moderate to severe. The patient reported a constant warm and burning sensation. The patient had difficulty falling asleep, as well as interrupted sleep due to change of position and inadvertent pressure on the left arm. The patient is right handed but due to pain was able to use the left arm for daily activities.\n\nThe patient did not complain of any associated neurological symptoms. However, the patient stated that she has become weaker in her left upper extremity secondary to the lack of use from the pain. The patient's other symptoms are associated with redness, bluish discoloration, temperature disparity amongst contralateral upper extremities, and allodynia.\n\nAfter one year since the inciting event and trial of multimodality treatment we decided to try dorsal spinal neuromodulation. During seven days of a spinal cord stimulation trial, the patient was able to perform many daily activities with reasonable pain control. The patient reported the pain between 2 and 3 on the visual analog scale during the trial period. The patient was deemed to be a candidate for permanent implantation of dorsal column stimulator. The patient underwent the implantation of 8-contact-compact-lead percutaneously sensor rechargeable battery (2 × 8 octad leads, model #3778-75 Medtronic Co.).\n\nOn a six-month follow-up, the patient reported left foot pain and discoloration. The patient's CRPS symptoms had now spread to involve the right lower extremity. We administered an aggressive course of physical therapy with desensitization techniques along with occasional lumbar sympathetic blocks and pain behavioral modifications techniques with multimodal medication management. The symptoms remained unresponsive and had been refractory to the multimodality management. The patient reported constant pain in the right leg with severity of 8 on visual analog scale. Gradually skin discoloration and nail changes along with hair loss on the right foot created a clear picture of CRPS. Interestingly, the patient reported great pain relief on the upper extremity by using a cervical spine stimulator. The patient was able to use the upper extremity for daily activities. The patient's right leg pain was greatly disabling and due to the unresponsive CRPS symptoms we decided to proceed with thoracic dorsal column stimulator placement after the patient demonstrated a great response to 7 days of the trial. A thoracic spinal cord stimulation implant was done via percutaneous placement of 2 × 8 octad leads (Medtronic Co.) (see (Figure 1)).\n\nWe did six-month follow-up after the patient's last surgery. The patient was 100% satisfied with the pain management result. We interrogated the spinal cord device. The patient was able to manage to go back to her school job using neuromodulation 100% of the time along with moderate consumption of gabapentin and tramadol. The patient rated her pain severity at both upper and lower extremities at a 2 on visual analog scale.\n\n3. Discussion\nIn this paper, we presented a severe and extreme case with venipuncture-induced CRPS. Pain is the chief reason why patients attend to doctors. The recognition of neuropathic pain after inadvertent injury to a nerve during operation should be straightforward. It is associated with disturbance of sensation and power and is expressed in the distribution of the nerve, remote from the site of operation. The recognition of neuropathic pain after a venipuncture is more difficult. Venipuncture, the most frequently performed invasive medical procedure, is usually benign. Generally it produces only transitory mild discomfort. Venipuncture-induced neuropathic pain is hard to recognize at early stage.\n\nThe injury may induce numbness or diffuse pins and needles through the injured limb for the first hour or two, or the pain from the multiple trials for venous access may mask the underlying nerve pain. On the other hand, neuropathic pain is sometimes so severe that the patient is scarcely aware of the injury. Spontaneous sensory symptoms which are usually painful, perceived in the limb, the hand, or the foot are significant and should not be overlooked.\n\nWe have been interested to hear patients describe their pain following accidental damage to the nerve. The exact timing of injury is well known to the patient.\n\nWe used the patient's description along with visual analog scale to document the patients' pain score during the follow-up. There is a vogue for measuring pain by visual analogue scales (VAS), a system which too often gives a spurious sense of objectivity. However, Kato et al. (2006) found a strong concordance between the VAS linear scale and the peripheral nerve injury scale [6].\n\nTherapies included analgesic, anti-inflammatory, tricyclic antidepressant, anticonvulsant medications, transcutaneous electrical nerve stimulation, nerve blocks, stellate ganglion blockades, and using chemical, thermal, or surgical sympathectomy.\n\nCRPS usually remains restricted to one limb, but it can spread to other body parts. CRPS in one limb may extend to another limb either as a result of a new trauma to a previously unaffected limb or because the syndrome spreads spontaneously. The severity of CRPS symptoms in the second limb may not differ significantly from that in the first limb. The mechanism underlying spontaneous spread of CRPS to other limbs is unclear. Venipuncture-induced CRPS patients raise many unanswerable questions regarding incidence, predisposition, and causation of disabling nerve injuries.\n\nConflict of Interests\nThe authors declare that there is no relevant conflict of interests. The authors at any time will receive no payment or services from a third party (government, commercial, private foundation, etc.) for any aspect of the submitted work (including but not limited to study design and paper preparation). There are no relationships, conditions, or circumstances that present a potential conflict of interests.\n\nFigure 1 In this X-ray picture you will see the cervical and thoracic leads.\n==== Refs\n1 Horowitz SH Venipuncture-induced causalgia: anatomic relations of upper extremity superficial veins and nerves, and clinical considerations Transfusion 2000 40 9 1036 1040 2-s2.0-0033812795 10988302 \n2 Hyatt KA Overview of complex regional pain syndrome and recent management using spinal cord stimulation The American Association of Nurse Anesthetists Journal 2010 78 3 208 212 2-s2.0-77953320014 \n3 Shah A Kirchner JS Complex regional pain syndrome Foot and Ankle Clinics 2011 16 2 351 366 2-s2.0-79956027637 21600455 \n4 Siegel SM Lee JW Oaklander AL Needlestick distal nerve injury in rats models symptoms of complex regional pain syndrome Anesthesia and Analgesia 2007 105 6 1820 1829 2-s2.0-36549066220 18042888 \n5 Kato J Araki H Kimura M Incidence and prognosis of persistent pain induced by venipuncture for blood sampling: an observational study over a 5-year period Pain Medicine 2012 13 12 1627 1630 2-s2.0-84871400069 22994390 \n6 Kato N Htut M Taggart M Carlstedt T Birch R The effects of operative delay on the relief of neuropathic pain after injury to the brachial plexus: a review of 148 cases Journal of Bone and Joint Surgery B 2006 88 6 756 759 2-s2.0-33745534840\n\n",
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"abstract": "Sinusitis is a serious infectious complication of allogeneic hematopoietic stem cell transplantation. Schizophyllum commune (S commune) is a common basidiomycete fungus that is rarely involved in human disease. We report herein a case of S commune sinusitis after allogeneic bone marrow transplantation. A 66-year-old man with myelodysplastic syndrome underwent allogeneic bone marrow transplantation and developed maxillary and ethmoid sinusitis. The sinusitis did not improve with liposomal amphotericin B after neutrophil engraftment, so we considered that surgical intervention was needed for the recovery of sinusitis. Endoscopic sinus surgery was performed. In the debridement tissue of paranasal mucosa, filamentous fungal elements were observed. Moreover, genetic analysis of the tissue revealed the presence of S commune. Schizophyllum commune should be recognized as a fungal pathogen that causes sinusitis after allogeneic hematopoietic stem cell transplantation. This case suggests the effectiveness of prompt surgical intervention with liposomal amphotericin B treatment for S commune sinusitis and the usefulness of genetic diagnosis for cases under antifungal treatment. (160 words).",
"affiliations": "Department of Medicine and Bioregulatory Science, Graduate School of Medical sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical sciences, Kyushu University, Fukuoka, Japan.;Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical sciences, Kyushu University, Fukuoka, Japan.",
"authors": "Narazaki|Taisuke|T|;Nakashima|Yasuhiro|Y|;Tsukamoto|Yasuhiro|Y|;Nishida|Ruriko|R|;Tsuda|Mariko|M|;Muta|Hiroki|H|;Kimura|Daisaku|D|;Masuda|Toru|T|;Takamatsu|Akiko|A|;Kohashi|Kenichi|K|;Murakami|Daisuke|D|;Shiratsuchi|Motoaki|M|https://orcid.org/0000-0002-0403-0122;Ogawa|Yoshihiro|Y|",
"chemical_list": "D000935:Antifungal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13205",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "22(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nSchizophyllum commune\n; bone marrow transplantation; nucleotide sequencing; sinusitis",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000368:Aged; D000666:Amphotericin B; D000935:Antifungal Agents; D016026:Bone Marrow Transplantation; D004724:Endoscopy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D009181:Mycoses; D009190:Myelodysplastic Syndromes; D012567:Schizophyllum; D012852:Sinusitis",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13205",
"pmc": null,
"pmid": "31674700",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Schizophyllum commune sinusitis after allogeneic bone marrow transplantation for myelodysplastic syndrome: A case report and literature review.",
"title_normalized": "schizophyllum commune sinusitis after allogeneic bone marrow transplantation for myelodysplastic syndrome a case report and literature review"
} | [
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{
"abstract": "Background Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in people with epilepsy. The pathogenesis of SUDEP is still unclear. The majority of SUDEP cases occur in intractable epilepsy, especially in the aftermath of a generalized tonic-clonic seizure. We report an atypical SUDEP case with infrequent seizures in frontal lobe epilepsy. Case Report A 14-year-old girl presented with a 13-year history of paroxysmal convulsions. She experienced three episodes within 6-10 months after birth. At 14 years old, she experienced an aggravated seizure, manifesting as unconsciousness, hyperventilation, and urinary incontinence. Electroencephalography showed spike-slow waves and slow waves with mixed asynchronized spike waves originating from the frontal lobe during the sleep stage. Transient outbreaks of spike-slow complex waves (1-2 s) were also noted in all leads. The diagnosis of frontal lobe epilepsy (generalized tonic-clonic seizures secondary to focal impaired awareness seizures and myoclonus) was made. Oral sodium valproate was prescribed. However, she suddenly died on her way to school 2 months later. Conclusion The causes of SUDEP are complicated, and frontal lobe epilepsy may be a potential risk factor. Early diagnosis and appropriate treatment of epileptic seizures, as well as close observation, should be emphasized.",
"affiliations": "1 Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Changchun, Jilin, China.;2 Department of Emergency, The First Hospital of Jilin University, Changchun, Jilin, China.;1 Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Changchun, Jilin, China.;1 Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Changchun, Jilin, China.",
"authors": "Zhang|Xinyue|X|;Sun|Lichao|L|;Cui|Li|L|;Lin|Weihong|W|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/0300060518762265",
"fulltext": "\n==== Front\nJ Int Med ResJ. Int. Med. ResIMRspimrThe Journal of International Medical Research0300-06051473-2300SAGE Publications Sage UK: London, England 2955723410.1177/030006051876226510.1177_0300060518762265Case ReportsSudden unexpected death in epilepsy in a 14-year-old girl: case report and literature review Zhang Xinyue 1Sun Lichao 2Cui Li 1Lin Weihong 1\n1 Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Changchun, Jilin, China\n2 Department of Emergency, The First Hospital of Jilin University, Changchun, Jilin, ChinaWeihong Lin, Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, Jilin 130021, China. Email: linweihong321@126.com20 3 2018 5 2018 46 5 2031 2036 17 10 2017 8 2 2018 © The Author(s) 20182018SAGE PublicationsCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Background\nSudden unexpected death in epilepsy (SUDEP) is the most common cause of death in people with epilepsy. The pathogenesis of SUDEP is still unclear. The majority of SUDEP cases occur in intractable epilepsy, especially in the aftermath of a generalized tonic-clonic seizure. We report an atypical SUDEP case with infrequent seizures in frontal lobe epilepsy.\n\nCase Report\nA 14-year-old girl presented with a 13-year history of paroxysmal convulsions. She experienced three episodes within 6–10 months after birth. At 14 years old, she experienced an aggravated seizure, manifesting as unconsciousness, hyperventilation, and urinary incontinence. Electroencephalography showed spike-slow waves and slow waves with mixed asynchronized spike waves originating from the frontal lobe during the sleep stage. Transient outbreaks of spike-slow complex waves (1–2 s) were also noted in all leads. The diagnosis of frontal lobe epilepsy (generalized tonic-clonic seizures secondary to focal impaired awareness seizures and myoclonus) was made. Oral sodium valproate was prescribed. However, she suddenly died on her way to school 2 months later.\n\nConclusion\nThe causes of SUDEP are complicated, and frontal lobe epilepsy may be a potential risk factor. Early diagnosis and appropriate treatment of epileptic seizures, as well as close observation, should be emphasized.\n\nSudden unexpected death in epilepsyfrontal lobe epilepsypediatric epilepsyelectroencephalogrampathogenesistonic-clonic seizure\n==== Body\nIntroduction\nSudden unexpected death in epilepsy (SUDEP) is defined as sudden, unexplained, nontraumatic (e.g., head injury), and nondrowning death in an individual with epilepsy, in which the autopsy discloses no toxicological or anatomical cause.1 The death may be witnessed or unwitnessed, and it may or may not occur after a seizure. SUDEP is the most common cause of death in patients suffering from epilepsy.2 The pathogenetic mechanisms underlying SUDEP have still not been fully determined, but possible risk factors include the following: 1) uncontrolled or frequent seizures; 2) generalized convulsive/tonic-clonic seizures; 3) seizures beginning at a young age; 4) long epileptic course; 5) missed doses of antiepileptic drugs; and 6) alcohol abuse.3–5 According to previous studies, the majority of SUDEP cases occur in intractable epilepsy, especially in the aftermath of a generalized tonic-clonic seizure.6 We report an atypical SUDEP case with infrequent seizures in frontal lobe epilepsy.\n\nCase report\nA 14-year-old girl presented with a 13-year history of afebrile convulsions. She experienced three episodes within 6–10 months after birth, manifesting as rolling eyes, body stiffness, and unconsciousness. Each seizure occurred during the daytime, lasted for several minutes, and spontaneously resolved. No antiepileptic drugs were used. At the age of 13 years, the convulsions relapsed, manifesting as turning of the eyes, asynchronous jerks of the limbs, and disturbance of consciousness. Prior to admission to our hospital, she experienced convulsions again, manifesting as unconsciousness, collapse, hyperventilation, and urinary incontinence. The previous medical history was unremarkable. There was no cardiac, pulmonary, or hepatorenal disease. A physical examination and brain magnetic resonance imaging showed no abnormalities. Electroencephalographic (EEG) monitoring for 24 h revealed spike-slow waves and slow waves with mixed asynchronized spike waves originating from the frontal lobe during the sleep stage, and there was also a tendency for slight generalization. Transient outbreaks of spike-slow complex waves (lasting for 1–2 s) were observed in all leads (Figure 1). Laboratory examinations, an electrocardiogram, and cardiac color ultrasound were all normal. The diagnosis of frontal lobe epilepsy (generalized tonic-clonic seizures secondary to focal impaired awareness seizures and myoclonus) was made. Oral sodium valproate with a dosage of 500 mg/day was prescribed, and no epileptic seizures were observed thereafter. However, 2 months later, our patient suddenly died on her way to school. The death was unwitnessed, and surveillance video showed that the girl fell over suddenly during walking with generalized tonic-clonic seizures, which manifested as four-limb convulsions, blood in the mouth, and urinary incontinence. No post-mortem examination was performed. The death was considered to be associated with SUDEP.\n\nFigure 1. Electroencephalogram of the patient\n\n(A) Electroencephalogram background activity showing a slightly generalized α rhythm and normal sleep stages. (B) Electroencephalogram showing irregular, high-amplitude, spike-slow, and sharp-slow waves originating from the frontal lobe. (C) Electroencephalogram showing transient outbreaks of spike-slow complex waves (lasting for 1–2 s) in all leads.\n\nThis study was approved by the Institutional Review Board and Ethics Committee of The First Hospital of Jilin University. Informed consent was obtained from the patient’s parents.\n\nDiscussion\nSUDEP has gained more attention recently, and it has been a hot focus of epilepsy research. There are six SUDEP subtypes that are classified according to the following diagnostic criteria.7 (1) Definite SUDEP is sudden, unexpected, nontraumatic, and nondrowning death of an individual with epilepsy, occurring in a safe situation, witnessed or unwitnessed, with or without a prior seizure. Status epilepticus can be excluded, and a post-mortem examination shows no specific cause of death. (2) Definite SUDEP plus satisfies the definition of definite SUDEP, as well as the possibility that a concomitant death-causing factor can be identified before or after death, the death may be caused by the combined effect of both conditions, or if post-mortem examination or direct observation of the death cannot identify a definitive cause of death. (3) Probable SUDEP/probable SUDEP plus satisfies the definition of definite SUDEP, but without post-mortem evidence. The individual dies unexpectedly in a healthy condition and in a safe situation, with no definite organic cause of death. 4) Possible SUDEP is defined as when there is a competing cause of death. 5) Near-SUDEP/near-SUDEP plus is defined as when an individual experiences cardiorespiratory arrest without any organic cause, surviving for more than 1 h after resuscitation. 6) Not SUDEP is defined as a definite cause of death rather than epilepsy. 7) Unclassified SUDEP is when information is incomplete, and thus case classification is impossible. In the current case, the girl suddenly fell over when she was walking on her way to school, and the circumstances were safe. There was no witness and no post-mortem examination was performed. This condition is consistent with probable SUDEP.\n\nAccording to previous reports, the risk factors of SUDEP are variable, including potential genetic predisposition, male sex, onset at a young age, frequent convulsive seizures, and multidrug therapy5. A recent study showed that the foremost and definitive risk factor of SUDEP is frequent, generalized tonic-clonic seizures. Individuals with three or more generalized tonic-clonic seizures per year have a 15-fold higher risk of SUDEP.8 SUDEP-associated risk factors with low evidence include the following: nocturnal epileptic seizures, use of antiepileptic drugs, use of lamotrigine in female patients, untreated with antiepileptic drugs, the number of antiepileptic drugs used overall, variable heart rate, extratemporal epilepsy, mental/intellectual deficiency, and use of anxiolytic drugs. Other potential risk factors of SUDEP with very low evidence or conflicting evidence are as follows: overall seizure frequency evaluated based on all seizure types, medically refractory epilepsy, uncontrolled seizures, monotherapy or polytherapy with antiepileptic drugs (carbamazepine, phenytoin, or sodium valproate), dosage of antiepileptic drugs (above, below, or within the reference range), onset age of epilepsy, structural lesion on magnetic resonance imaging, duration of epilepsy, use of psychotropic drugs, psychological disorders, idiopathic or localization-related epilepsy, pulmonary disorders, alcohol abuse, use of lamotrigine in patients with refractory epilepsy, frequent changes in antiepileptic drugs, monitoring of antiepileptic drugs, undergoing surgical resection, Engel scores following surgery for epilepsy, postictal EEG suppression, and use of a vagus nerve stimulator.8\n\nIn the present case, the girl was diagnosed with epilepsy 13 years ago. Despite the long history of epilepsy, seizures were rare (five times in total). According to the EEG characteristics, the diagnosis of frontal lobe convulsive epilepsy with myoclonus was made. In previous reports, researchers found that sleep-related hypermotor epilepsy (nocturnal frontal lobe epilepsy) was associated with SUDEP, with an incidence of 0.36 per 1000 person-years.9 These findings are inconsistent with the current case. Our patient had infrequent seizures, and the frontal lobe epilepsy attack occurred during the daytime. Therefore, there may be multiple complicated factors underlying the occurrence of SUDEP.\n\nThe pathogenesis of SUDEP is still debatable. There have been several theoretical hypotheses, including sinus bradycardia or cardiac arrest, respiratory depression, brain dysfunction, autonomic dysfunction, and abnormal central regulation.10,11 Sudden cardiac arrest and apnea have been considered as direct causes of SUDEP.7,12 However, some other researchers have proposed that respiratory and circulation dysfunction is caused by cerebral disturbances.13\n\nIn most cases, SUDEP occurs following generalized tonic-clonic seizures, suggesting that seizures may play a major role in SUDEP. The pathophysiology of SUDEP appears complex and may involve variable factors, such as loss of arousal, time of day, position of the patient during the seizures, intrinsic pulmonary and cardiac dysfunction, and genetic mutations that predispose patients with epilepsy to seizure-induced cardiorespiratory dysfunction.14 Impaired breathing is thought to play a critical role in SUDEP. When seizures spread to the amygdala from the forebrain sites, central apnea and O2 desaturation occur.15 In the current case, the cause of death was frontal lobe epilepsy. The frontal lobe, which accounts for the majority of the cerebral cortex, has extensive fiber connections with the temporal lobe and insular cortex.16 Therefore, we speculate that frontal lobe epilepsy may cause extensive disturbances in the cerebral cortex, eventually leading to cardiac arrest. However, the exact pathogenetic mechanisms still require further research.\n\nConclusion\nWe present a girl with frontal lobe epilepsy who succumbed to SUDEP. The causes of SUDEP are complicated, and frontal lobe epilepsy may be a potential risk factor of this condition. Early diagnosis and appropriate treatment of epileptic seizures, as well as close observation, should be highlighted.\n\nDeclaration of conflicting interest\nThe authors declare that there is no conflict of interest.\n\nFunding\nThis research received no specific grant from any funding agency in the public, commercial, or not for profit sectors.\n==== Refs\nReferences\n1 Nashef L. \nSudden unexpected death in epilepsy: terminology and definitions. \nEpilepsia \n1997 ; \n38 : S6 –S8 .\n2 Tu E Bagnall RD Duflou J et al \nPost-mortem review and genetic analysis of sudden unexpected death in epilepsy (SUDEP) cases. \nBrain Pathol \n2011 ; \n21 : 201 –208 .20875080 \n3 Devinsky O. \nSudden, unexpected death in epilepsy. \nN Engl J Med \n2011 ; \n365 : 1801 –1811 .22070477 \n4 Tomson T Nashef L Ryvlin P. \nSudden unexpected death in epilepsy: current knowledge and future directions. \nLancet Neurol \n2008 ; \n7 : 1021 –1031 .18805738 \n5 Nei M Hays R. \nSudden unexpected death in epilepsy. \nCurr Neurol Neurosci Rep \n2010 ; \n10 : 319 –326 .20446062 \n6 Shankar R Donner EJ McLean B et al. \nSudden unexpected death in epilepsy (SUDEP): what every neurologist should know . Epileptic Disord \n2017 ; \n19 : 1 –9 .28218059 \n7 Nashef L So EL Ryvlin P et al \nUnifying the definitions of sudden unexpected death in epilepsy. \nEpilepsia \n2012 ; \n53 : 227 –233 .22191982 \n8 Harden C Tomson T Gloss D et al \nPractice guideline summary: sudden unexpected death in epilepsy incidence rates and risk factors: report of the guideline development, dissemination, and implementation subcommittee of the American academy of neurology and the American epilepsy society . Neurology \n2017 ; \n88 : 1674 –1680 .28438841 \n9 Mostacci B Bisulli F Vignatelli L et al \nIncidence of sudden unexpected death in epilepsy in sleep-related hypermotor epilepsy, formerly named nocturnal frontal lobe epilepsy. \nSleep Med \n2017 ; \n29 : 98 .27915205 \n10 Shorvon S andTomson T. \nSudden unexpected death in epilepsy. \nLancet \n2011 ; \n378 : 2028 –2038 .21737136 \n11 Li J Ming Q andLin W. \nThe insula lobe and sudden unexpected death in epilepsy: a hypothesis. \nEpileptic Disord \n2017 ; \n19 : 10 –14 .28202427 \n12 Surges R Adjei P Kallis C et al \nPathologic cardiac repolarization in pharmacoresistant epilepsy and its potential role in sudden unexpected death in epilepsy: a case-control study. \nEpilepsia \n2010 ; \n51 : 233 –242 .19817816 \n13 Terra VC Cysneiros R Cavalheiro EA et al \nSudden unexpected death in epilepsy: from the lab to the clinic setting. \nEpilepsy Behav \n2013 ; \n26 : 415 –420 .23402930 \n14 Dlouhy BJ Gehlbach BK andRicherson GB. \nSudden unexpected death in epilepsy: basic mechanisms and clinical implications for prevention. \nJ Neurol Neurosurg Psychiatry . 2016 ; \n87 : 402 –413 .26979537 \n15 Dlouhy BJ Gehlbach BK Kreple CJ et al \nBreathing Inhibited When Seizures Spread to the Amygdala and upon Amygdala Stimulation. \nJ Neurosci \n2015 ; \n35 : 10281 –10289 .26180203 \n16 Mostacci B Bisulli F Vignatelli L et al \nIncidence of sudden unexpected death in nocturnal frontal lobe epilepsy: a cohort study. \nSleep Med \n2015 ; \n16 : 232 –236 .25600783\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0300-0605",
"issue": "46(5)",
"journal": "The Journal of international medical research",
"keywords": "Sudden unexpected death in epilepsy; electroencephalogram; frontal lobe epilepsy; pathogenesis; pediatric epilepsy; tonic-clonic seizure",
"medline_ta": "J Int Med Res",
"mesh_terms": "D000293:Adolescent; D004569:Electroencephalography; D004827:Epilepsy; D017809:Fatal Outcome; D005260:Female; D006801:Humans",
"nlm_unique_id": "0346411",
"other_id": null,
"pages": "2031-2036",
"pmc": null,
"pmid": "29557234",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
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"title": "Sudden unexpected death in epilepsy in a 14-year-old girl: case report and literature review.",
"title_normalized": "sudden unexpected death in epilepsy in a 14 year old girl case report and literature review"
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"abstract": "The mitogen-activated protein kinase pathway regulates cell growth and differentiation and is activated by BRAF mutations. BRAF mutations are present in about 40-50% of cutaneous melanomas. More than 90% of BRAF mutations are the V600E type. BRAF inhibitor (dabrafenib or vemurafenib) and MEK inhibitor (trametinib or cobimetinib) combination therapies are effective for BRAF-mutant advanced melanomas. A variety of side effects have been observed with combination therapy including pyrexia, fatigue, nausea, and vomiting. Rhabdomyolysis is one of the most severe adverse events, but it is very rare. Only two cases of rhabdomyolysis have been reported in clinical trials. A 41-year-old Japanese woman with cutaneous melanoma was started on a combination of dabrafenib and trametinib therapy after failure of immune checkpoint therapy. One month later, she complained of myalgia and fatigue and was shifted to our hospital. She was diagnosed with trametinib-induced rhabdomyolysis and showed improvement only with a high volume of fluid infusion. We stopped combination therapy, but there were no useful treatment options for her. After resuming dabrafenib, followed by trametinib, she did not have any problems. This is the first case of a patient with metastatic cutaneous melanoma who could recommence combination therapy after trametinib-associated rhabdomyolysis. We assume that not all patients experience recurrence of rhabdomyolysis in trametinib-induced rhabdomyolysis. As few cases have been reported, more information is needed. We have to evaluate safety carefully if rechallenging combination therapy.",
"affiliations": "Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.",
"authors": "Muto|Yusuke|Y|;Ng|William|W|;Namikawa|Kenjiro|K|;Takahashi|Akira|A|;Tsutsumida|Arata|A|;Nishida|Makiko|M|;Yamazaki|Naoya|N|",
"chemical_list": "D007093:Imidazoles; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C561627:dabrafenib",
"country": "England",
"delete": false,
"doi": "10.1097/CMR.0000000000000424",
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"issn_linking": "0960-8931",
"issue": "28(2)",
"journal": "Melanoma research",
"keywords": null,
"medline_ta": "Melanoma Res",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D007093:Imidazoles; D008545:Melanoma; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; D012206:Rhabdomyolysis; D012878:Skin Neoplasms",
"nlm_unique_id": "9109623",
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"pages": "151-154",
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"pmid": "29356791",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Success of rechallenging dabrafenib and trametinib combination therapy after trametinib-induced rhabdomyolysis: a case report.",
"title_normalized": "success of rechallenging dabrafenib and trametinib combination therapy after trametinib induced rhabdomyolysis a case report"
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"activesubstancename": "TRAMETINIB DIMETHYL SULFOXIDE"
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"abstract": "OBJECTIVE\nGastric perforation is a rare condition with high mortality rates in preterm infants. The aim of this retrospective study was to define the risk factors and prognosis in very low birth weight (VLBW) infants with gastric perforations.\n\n\nMETHODS\nVLBW infants with a diagnosis of gastric perforation between 2012 and 2016 were included. The data including birth weight, gestational age, gender, risk factors, time and location of the perforation and prognosis were recorded.\n\n\nRESULTS\nA total of eight infants were identified. The median gestational age and birth weight of the infants were 26 weeks and 860 g, respectively. Five were male and 6 (75%) had a diagnosis of hemodynamically significant patent ductus arteriosus (PDA), early sepsis, persistent hypotension, and drug administration (paracetamol, ibuprofen). The main clinical finding was abdominal distension and pneumoperitoneum was detected in all infants. The median diagnosis was 6 days of life. The median perforation size was 2.5 cm and curvature major and anterior wall were the most common locations. The mortality rate was 62.5%.\n\n\nCONCLUSIONS\nMale gender, chorioamnionitis, early sepsis, asphyxia, hemodynamic PDA, persistent hypotension, ibuprofen and paracetamol usage, and orogastric catheter administration were the main risk factors for gastric perforations in VLBW infants.",
"affiliations": "Department of Neonatology, Kanuni Sultan Suleyman Training and Research Hospital, Turgut Ozal Caddesi No:1 34303 Altınsehir, Kucukcekmece, Istanbul, Turkey.;Department of Neonatology, Kanuni Sultan Suleyman Training and Research Hospital, Turgut Ozal Caddesi No:1 34303 Altınsehir, Kucukcekmece, Istanbul, Turkey.;Department of Neonatology, Kanuni Sultan Suleyman Training and Research Hospital, Turgut Ozal Caddesi No:1 34303 Altınsehir, Kucukcekmece, Istanbul, Turkey. drmerih@yahoo.com.;Department of Neonatology, Kanuni Sultan Suleyman Training and Research Hospital, Turgut Ozal Caddesi No:1 34303 Altınsehir, Kucukcekmece, Istanbul, Turkey.",
"authors": "Babayigit|Aslan|A|;Ozaydın|Seyithan|S|;Cetinkaya|Merih|M|;Sander|Serdar|S|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D007052:Ibuprofen",
"country": "Germany",
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"doi": "10.1007/s00383-017-4205-1",
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"issue": "34(1)",
"journal": "Pediatric surgery international",
"keywords": "Gastric perforation; Newborn; Preterm infant; Very low birth weight",
"medline_ta": "Pediatr Surg Int",
"mesh_terms": "D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D001238:Asphyxia Neonatorum; D002821:Chorioamnionitis; D004374:Ductus Arteriosus, Patent; D005260:Female; D006801:Humans; D007022:Hypotension; D007052:Ibuprofen; D007231:Infant, Newborn; D007234:Infant, Premature; D019102:Infant, Very Low Birth Weight; D008297:Male; D011027:Pneumoperitoneum; D011247:Pregnancy; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D018805:Sepsis; D012737:Sex Factors; D013275:Stomach Rupture; D014421:Turkey",
"nlm_unique_id": "8609169",
"other_id": null,
"pages": "79-84",
"pmc": null,
"pmid": "29079904",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": "26023450;23742621;28477387;27696212;12774146;14999537;22929145;21980855;22009207;25957026;25278658;17875089;3081865;26388893;1403517;10917298",
"title": "Neonatal gastric perforations in very low birth weight infants: a single center experience and review of the literature.",
"title_normalized": "neonatal gastric perforations in very low birth weight infants a single center experience and review of the literature"
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"companynumb": "TR-VISTAPHARM, INC.-VER201801-000214",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN\\HYDROCODONE"
},
"dr... |
{
"abstract": "BACKGROUND\nFerumoxytol, an \"off-label\" contrast agent, allows for better cardiac MRI quality as compared with gadolinium-based contrast agents. However, hypotension has been reported with the use of ferumoxytol for indications other than cardiac MRI. The purpose of our investigation was to evaluate the safety of ferumoxytol in children undergoing general anaesthesia for cardiac MRI.\n\n\nMETHODS\nMedical records of children undergoing general anaesthesia for cardiac MRI were reviewed. Baseline demographic and medical characteristics, as well as imaging and anaesthetic duration and technique, were collected. The incidence of hypotension or other adverse events', need for vasoactive support, or airway intervention throughout the anaesthetic, was recorded.\n\n\nRESULTS\nA total of 95 patients were identified, 61 received ferumoxytol and 34 received gadolinium. There were no significant differences between groups with respect to age, weight, or baseline blood pressure. The incidence of low blood pressure - systolic or mean - after contrast administration did not differ between groups, and there was no difference in sustained hypotension or use of vasopressors between groups. One patient who received ferumoxytol had possible anaphylaxis. The image acquisition time (45 versus 68 min, p=0.002) and anaesthesia duration (100 versus 132 min, p=0.02) were shorter in the ferumoxytol group.\n\n\nCONCLUSIONS\nTransient low blood pressure was common in children undergoing cardiac MRI with anaesthesia, but the incidence of hypotension did not differ between ferumoxytol and gadolinium groups. The use of ferumoxytol was associated with significantly shorter scan time and anaesthesia duration, as well as a decreased need for airway intervention.",
"affiliations": "1Lucile Packard Children's Hospital Heart Center,Stanford University School of Medicine,Palo Alto,CA,USA.;1Lucile Packard Children's Hospital Heart Center,Stanford University School of Medicine,Palo Alto,CA,USA.;1Lucile Packard Children's Hospital Heart Center,Stanford University School of Medicine,Palo Alto,CA,USA.;1Lucile Packard Children's Hospital Heart Center,Stanford University School of Medicine,Palo Alto,CA,USA.;1Lucile Packard Children's Hospital Heart Center,Stanford University School of Medicine,Palo Alto,CA,USA.;1Lucile Packard Children's Hospital Heart Center,Stanford University School of Medicine,Palo Alto,CA,USA.",
"authors": "Wise-Faberowski|Lisa|L|;Velasquez|Nathalia|N|;Chan|Frandics|F|;Vasanawala|Shreyas|S|;McElhinney|Doff B|DB|;Ramamoorthy|Chandra|C|",
"chemical_list": "D003287:Contrast Media; D005682:Gadolinium; D052203:Ferrosoferric Oxide",
"country": "England",
"delete": false,
"doi": "10.1017/S1047951118000306",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1047-9511",
"issue": "28(7)",
"journal": "Cardiology in the young",
"keywords": "MRI; cardiac; ferumoxytol; paediatric",
"medline_ta": "Cardiol Young",
"mesh_terms": "D000768:Anesthesia, General; D001794:Blood Pressure; D002648:Child; D002675:Child, Preschool; D003287:Contrast Media; D052203:Ferrosoferric Oxide; D005682:Gadolinium; D006330:Heart Defects, Congenital; D006801:Humans; D007022:Hypotension; D007223:Infant; D016015:Logistic Models; D008279:Magnetic Resonance Imaging; D056687:Off-Label Use; D061214:Patient Safety; D012189:Retrospective Studies",
"nlm_unique_id": "9200019",
"other_id": null,
"pages": "916-921",
"pmc": null,
"pmid": "29848399",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety of ferumoxytol in children undergoing cardiac MRI under general anaesthesia.",
"title_normalized": "safety of ferumoxytol in children undergoing cardiac mri under general anaesthesia"
} | [
{
"companynumb": "US-AMAG PHARMACEUTICALS, INC.-AMAG201802880",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FERUMOXYTOL NON-STOICHIOMETRIC MAGNETITE"
... |
{
"abstract": "Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.",
"affiliations": "Loma Linda University Medical Center, Loma Linda, CA, USA.;Loma Linda University Medical Center, Loma Linda, CA, USA.;Loma Linda University Medical Center, Loma Linda, CA, USA.",
"authors": "De Vera|Jerome|J|0000-0002-4970-5525;Kim|Hyungjin Ben|HB|;Sakr|Antoine E|AE|",
"chemical_list": "D000930:Antidiarrheals; D008139:Loperamide",
"country": "United States",
"delete": false,
"doi": "10.1177/2324709621990768",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n33533290\n10.1177/2324709621990768\n10.1177_2324709621990768\nCase Report\nA Case Report of Loperamide-Induced Ventricular Storm\nhttps://orcid.org/0000-0002-4970-5525De Vera Jerome DO1 Kim Hyungjin Ben DO1 Sakr Antoine E. MD1 1 Loma Linda University Medical Center, Loma Linda, CA, USA\nJerome De Vera, DO, Loma Linda University Medical Center Department of Internal Medicine, 11234 Anderson Street, MC 1503, Loma Linda, CA 92350, USA. Email: jedevera@llu.edu\n3 2 2021 \nJan-Dec 2021 \n9 232470962199076814 10 2020 11 12 2020 31 12 2020 © 2021 American Federation for Medical Research2021American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide’s mechanisms for causing toxicity as well as how to appropriately treat its complications.\n\nventricular tachycardiaventricular fibrillationcardioversiontachycardiaelectrophysiologyelectrocardiogramelectrical stormcover-dateJanuary-December 2021typesetterts1\n==== Body\nIntroduction\nLoperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1\n\nWith the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2\n\nIn addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.\n\nCase Report\nA 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.\n\nOn presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.\n\nFigure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.\n\nFigure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.\n\nPreliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.\n\nAfter cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.\n\nFigure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.\n\nSeveral hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.\n\nAfter 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).\n\nFigure 4. Sinus bradycardia after anti-arrhythmics.\n\nThe final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.\n\nDiscussion\nLoperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1\n\nDespite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6\n\nIn addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9\n\nLoperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9\n\nTreating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7\n\nAs for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.\n\nAmiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.\n\nConclusion\nLoperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).\n\nInformed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.\n\nORCID iD: Jerome De Vera \nhttps://orcid.org/0000-0002-4970-5525\n==== Refs\nReferences\n1 \nPowell JW Presnell SE \nLoperamide as a potential drug of abuse and misuse: fatal overdoses at the Medical University of South Carolina\n. J Forensic Sci . 2019 ;64 :1726 -1730\n. doi:10.1111/1556-4029.14115 31219627 \n2 \nUS Food and Drug Administration . FDA Drug Safety Communication: FDA warns about serious heart problems with high doses of the antidiarrheal medicine loperamide (Imodium), including from abuse and misuse\n. Published January 29, 2018. Accessed March 22, 2020 \nhttps://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-serious-heart-problems-high-doses-antidiarrheal\n3 \nTeigeler T Stahura H Alimohammad R , et al\nElectrocardiographic changes in loperamide toxicity: case report and review of literature\n. J Cardiovasc Electrophysiol . 2019 ;30 :2618 -2626\n. doi:10.1111/jce.14129 31432581 \n4 \nLee VR Vera A Alexander A , et al\nLoperamide misuse to avoid opioid withdrawal and to achieve a euphoric effect: high doses and high risk\n. Clin Toxicol (Phila) . 2019 ;57 :175 -180\n. doi:10.1080/15563650.2018.1510128 30585509 \n5 \nRiaz IB Khan MS Kamal MU , et al\nDysrhythmias associated with substitutive use of loperamide: a systematic review\n. Am J Ther . 2019 ;26 :e170 -e182\n. doi:10.1097/MJT.0000000000000585 28594339 \n6 \nEggleston W Marraffa JM Stork CM , et al\nNotes from the field: cardiac dysrhythmias after loperamide abuse—New York, 2008-2016\n. MMWR Morb Mortal Wkly Rep . 2016 ;65 :1276 -1277\n. doi:10.15585/mmwr.mm6545a7 27855148 \n7 \nEggleston W Palmer R Dubé PA Thornton S , et al\nLoperamide toxicity: recommendations for patient monitoring and management\n. Clin Toxicol (Phila) . 2020 ;58 :355 -359\n. doi:10.1080/15563650.2019.1681443 31684751 \n8 \nDeWitt CR Waksman JC \nPharmacology, pathophysiology and management of calcium channel blocker and blocker toxicity\n. Toxicol Rev . 2004 ;23 :223 -238\n. doi:10.2165/00139709-200423040-00003 15898828 \n9 \nUpadhyay A Bodar V Malekzadegan M , et al\nLoperamide induced life threatening ventricular arrhythmia\n. Case Rep Cardiol . 2016 ;2016 :5040176 . doi:10.1155/2016/5040176 27547470 \n10 \nSuarez K \nSoproterenol suppresses recurrent torsades de pointes in a patient with long QT syndrome type 2\n. HeartRhythm Case Rep . 2018 ;4 :576 -579\n. doi:10.1016/j.hrcr.2018.08.01 30581736\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2324-7096",
"issue": "9()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "cardioversion; electrical storm; electrocardiogram; electrophysiology; tachycardia; ventricular fibrillation; ventricular tachycardia",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000328:Adult; D000930:Antidiarrheals; D066126:Cardiotoxicity; D005260:Female; D006801:Humans; D008133:Long QT Syndrome; D008139:Loperamide; D016171:Torsades de Pointes",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709621990768",
"pmc": null,
"pmid": "33533290",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30581736;31432581;30585509;28594339;31219627;31684751;27547470;15898828;27855148",
"title": "A Case Report of Loperamide-Induced Ventricular Storm.",
"title_normalized": "a case report of loperamide induced ventricular storm"
} | [
{
"companynumb": "US-B.BRAUN MEDICAL INC.-2108235",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM BICARBONATE"
},
"drugadditional... |
{
"abstract": "SAPHO syndrome, namely Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis, is a rare autoinflammatory chronic disease presenting with non-infectious inflammatory osteitis, sterile joint inflammation and skin manifestations, including palmoplantar pustulosis and severe acne. The case of a 15-year-old boy affected by SAPHO syndrome and hidradenitis suppurativa (HS) is presented and discussed. Coexistence of these two diseases may represent a therapeutic challenge and this case confirms literature data reporting the efficacy of the combination of methotrexate and adalimumab in SAPHO complicated by HS.",
"affiliations": "Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Centro per le malattie autoinfiammatorie ed immunodeficienze, Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.",
"authors": "Genovese|G|G|https://orcid.org/0000-0002-7636-958X;Caorsi|R|R|;Moltrasio|C|C|;Marzano|A V|AV|https://orcid.org/0000-0002-8160-4169",
"chemical_list": "D000893:Anti-Inflammatory Agents; D003879:Dermatologic Agents; D000068879:Adalimumab; D011241:Prednisone; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1111/jdv.15849",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0926-9959",
"issue": "33 Suppl 6()",
"journal": "Journal of the European Academy of Dermatology and Venereology : JEADV",
"keywords": null,
"medline_ta": "J Eur Acad Dermatol Venereol",
"mesh_terms": "D020083:Acquired Hyperostosis Syndrome; D000068879:Adalimumab; D000293:Adolescent; D000893:Anti-Inflammatory Agents; D003879:Dermatologic Agents; D017497:Hidradenitis Suppurativa; D006801:Humans; D008297:Male; D008727:Methotrexate; D011241:Prednisone",
"nlm_unique_id": "9216037",
"other_id": null,
"pages": "40-41",
"pmc": null,
"pmid": "31535768",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of co-existent SAPHO syndrome and hidradenitis suppurativa with adalimumab and methotrexate.",
"title_normalized": "successful treatment of co existent sapho syndrome and hidradenitis suppurativa with adalimumab and methotrexate"
} | [
{
"companynumb": "IT-AMGEN-ITASP2019158420",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "Pseudomyxoma peritonei (PMP) is a rare disease characterized by mucinous ascites and widespread peritoneal implants. It usually originates from the rupture of an adenoma/adenocarcinoma of the appendix. Although this tumor is only superficially invasive and does not metastasize, it could be a fatal disease. Extra-abdominal spread of PMP is an unusual occurrence with few reports in medical literature.\n\n\n\nA 50-year-old man was diagnosed with PMP according to the findings of thorax and abdomen CT scan and cytologic and histological examinations. The radiological exam showed irregular thickening on the surface of left diaphragmatic and parietal pleura.\n\n\n\nFirst, cytoreductive surgery associated with hyperthermic intraperitoneal chemotherapy (HIPEC) for the abdominal disease was performed. Histopathological examination confirmed the diagnosis of low grade PMP. The radiological evaluation performed 5 months later showed a dimensional increase in pleural nodules. The treatment consisted of an extensive intrathoracic cytoreductive surgery in combination with pressurized intra-thoracic aerosol chemotherapy (PITAC). Postoperative course was uneventful.\n\n\n\nPMP with pleural extension is a rare phenomenon and carries an unfavourable prognosis. Due to the rarity of this presentation, its correct treatment is still unclear. We present a therapeutic approach to be applied in selected patients.",
"affiliations": "Unit of Surgical Oncology, Candiolo Cancer Institute, IRCCS - FPO, Candiolo, Italy manuela.robella@ircc.it.;Unit of Surgical Oncology, Candiolo Cancer Institute, IRCCS - FPO, Candiolo, Italy.;Unit of Surgical Oncology, Candiolo Cancer Institute, IRCCS - FPO, Candiolo, Italy.;Department of Thoracic Surgery, AOU Città della Salute e della Scienza di Torino - University of Torino, Turin, Italy.;Unit of Surgical Oncology, Candiolo Cancer Institute, IRCCS - FPO, Candiolo, Italy.",
"authors": "Robella|Manuela|M|;Vaira|Marco|M|;Borsano|Alice|A|;Mossetti|Claudio|C|;DE Simone|Michele|M|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.12305",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "38(2)",
"journal": "Anticancer research",
"keywords": "PITAC; Pseudomyxoma Peritonei; locoregional chemotherapy",
"medline_ta": "Anticancer Res",
"mesh_terms": "D003131:Combined Modality Therapy; D000529:Complementary Therapies; D065426:Cytoreduction Surgical Procedures; D006801:Humans; D006979:Hyperthermia, Induced; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D010534:Peritoneal Neoplasms; D010997:Pleural Neoplasms; D011379:Prognosis; D011553:Pseudomyxoma Peritonei",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "929-932",
"pmc": null,
"pmid": "29374723",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Low-dose Pressurized Intrathoracic Aerosol Chemotherapy (PITAC) as an Alternative Therapy for Pleuropulmonary Involvement in Pseudomyxoma Peritonei.",
"title_normalized": "low dose pressurized intrathoracic aerosol chemotherapy pitac as an alternative therapy for pleuropulmonary involvement in pseudomyxoma peritonei"
} | [
{
"companynumb": "IT-MYLANLABS-2018M1050808",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Cutaneous T cell lymphoma is a heterogeneous group of lymphoproliferative disorders with different clinical behavior and prognosis in which malignant T cells accumulate in the skin. In the relapsed/refractory stage, treatment strategy varies depending on clinical perspective. We retrospectively evaluated advanced stage relapse or refractory mycosis fungoides and Sezary syndrome patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our hospital. The overall response rate was 25%, while the disease progressed and relapsed after transplant in 38% of patients. Allo-HSCT may be a reasonable treatment option in the relapsed/refractory stage.",
"affiliations": "BMT Unit, Department of Hematology, Cebeci Hospital, School of Medicine, Ankara University, Dikimevi, 06590, Ankara, Turkey. erdenatilla@gmail.com.;BMT Unit, Department of Hematology, Cebeci Hospital, School of Medicine, Ankara University, Dikimevi, 06590, Ankara, Turkey.;BMT Unit, Department of Hematology, Cebeci Hospital, School of Medicine, Ankara University, Dikimevi, 06590, Ankara, Turkey.;BMT Unit, Department of Hematology, Cebeci Hospital, School of Medicine, Ankara University, Dikimevi, 06590, Ankara, Turkey.;BMT Unit, Department of Hematology, Cebeci Hospital, School of Medicine, Ankara University, Dikimevi, 06590, Ankara, Turkey.;BMT Unit, Department of Hematology, Cebeci Hospital, School of Medicine, Ankara University, Dikimevi, 06590, Ankara, Turkey.;Department of Dermatology, School of Medicine, Ankara University, Ankara, Turkey.;BMT Unit, Department of Hematology, Cebeci Hospital, School of Medicine, Ankara University, Dikimevi, 06590, Ankara, Turkey.;BMT Unit, Department of Hematology, Cebeci Hospital, School of Medicine, Ankara University, Dikimevi, 06590, Ankara, Turkey.;BMT Unit, Department of Hematology, Cebeci Hospital, School of Medicine, Ankara University, Dikimevi, 06590, Ankara, Turkey.",
"authors": "Atilla|Erden|E|;Atilla|Pinar Ataca|PA|;Bozdag|Sinem Civriz|SC|;Yuksel|Meltem Kurt|MK|;Toprak|Selami Kocak|SK|;Topcuoglu|Pervin|P|;Akay|Bengu Nisa|BN|;Sanli|Hatice|H|;Gurman|Gunhan|G|;Ozcan|Muhit|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-017-2245-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "106(3)",
"journal": "International journal of hematology",
"keywords": "Allogeneic hematopoietic stem cell transplantation; Mycosis fungoides; Sezary syndrome",
"medline_ta": "Int J Hematol",
"mesh_terms": "D064591:Allografts; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009182:Mycosis Fungoides; D009364:Neoplasm Recurrence, Local; D012189:Retrospective Studies; D012751:Sezary Syndrome; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "426-430",
"pmc": null,
"pmid": "28466385",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": "17339420;19589488;25458083;25154828;15286686;15692063;21576639;20697072;24213148;23478054;25068422;20351328;18176611",
"title": "Allogeneic hematopoietic stem cell transplantation for refractory mycosis fungoides (MF) and Sezary syndrome (SS).",
"title_normalized": "allogeneic hematopoietic stem cell transplantation for refractory mycosis fungoides mf and sezary syndrome ss"
} | [
{
"companynumb": "PHHY2017TR066267",
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"patient": {
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{
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"activesubstance": {
"activesubstancename": "METHOTREXATE"
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"drugadditional": null,
"dr... |
{
"abstract": "Docetaxel (Taxotere(®)) is an agent that is indicated for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer. In recent years, docetaxel-related interstitial lung disease (ILD) has been reported in several case series studies. The onset of ILD occurred ~10-20 days (median time: 18 days) after docetaxel administration. Here, we reported the case of a patient who had pulmonary toxicity of ILD within 3 days after using a relatively low-dose docetaxel administration. Although some articles have described patients who progressed to respiratory failure and needed intubation, this patient responded well to steroid treatment and discontinued docetaxel administration.",
"affiliations": "Division of Chest Medicine, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.;Division of Chest Medicine, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.;Division of Chest Medicine, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.",
"authors": "Wang|Chung-Jen|CJ|;Chang|Hou-Tai|HT|;Chang|Cheng-Yu|CY|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/TCRM.S90488",
"fulltext": "\n==== Front\nTher Clin Risk ManagTher Clin Risk ManagTherapeutics and Clinical Risk ManagementTherapeutics and Clinical Risk Management1176-63361178-203XDove Medical Press 10.2147/TCRM.S90488tcrm-11-1813Case ReportDocetaxel-related interstitial pneumonitis Wang Chung-Jen Chang Hou-Tai Chang Cheng-Yu Division of Chest Medicine, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, TaiwanCorrespondence: Cheng-Yu Chang, Division of Chest Medicine, Department of Internal Medicine, Far Eastern Memorial Hospital, No 21, Section 2, Nanya S Road, Banciao District, New Taipei City 220, Taiwan, Tel +886 2 8966 7000 ext 88252, Fax +886 2 7738 0708, Email koala2716@hotmail.com2015 09 12 2015 11 1813 1816 © 2015 Wang et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2015The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Docetaxel (Taxotere®) is an agent that is indicated for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer. In recent years, docetaxel-related interstitial lung disease (ILD) has been reported in several case series studies. The onset of ILD occurred ~10–20 days (median time: 18 days) after docetaxel administration. Here, we reported the case of a patient who had pulmonary toxicity of ILD within 3 days after using a relatively low-dose docetaxel administration. Although some articles have described patients who progressed to respiratory failure and needed intubation, this patient responded well to steroid treatment and discontinued docetaxel administration.\n\nKeywords\ndocetaxelinterstitial lung disease\n==== Body\nCase report\nA 47-year-old male smoker presented with chronic cough and dyspnea for 2 months. The chest X-ray (Figure 1A) and chest computed tomography (CT) showed right lower lung tumor and lobulated effusion (Figure 1B), and the lung window showed no interstitial lesion (Figure 1C). Pathological immunostaining was positive for p63 and CK7 and negative for CK20 and TTF-1, which indicated squamous cell carcinoma. After a series of studies, including brain CT and whole body bone scan, the cancer was classified as cT4 (9.87 cm) N3M0, stage IIIb, due to multiple enlarged lymph nodes in the retrocaval, prevascular, bilateral lower paratracheal, subcarinal, and right interlobar regions. He received chemotherapy with docetaxel (30 mg/m2, day 1) after premedication with intravenous dexamethasone (10 mg). He developed severe cough and progressive dyspnea 3 days after administration. He had no systemic inflammatory or infection symptoms at the time. In room air, the arterial blood gas analysis revealed: pH, 7.362; partial pressure of carbon dioxide, 40.3 mmHg; partial pressure of oxygen, 44.6 mmHg; and bicarbonate (HCO3) level, 23.4 mmol/L. The serum examination showed no leukocytosis or neutropenia. The chest X-ray revealed diffused interstitial infiltrates (Figure 2A), and chest CT showed diffuse ground glass opacities at bilateral lung fields and nonsegmental predominance of lung opacity without prominent hilum engorgement (Figure 2B). The patient had no heart disease history and fair urine output. The cardiac echography showed good left ventricular ejection fraction (74%). The fluid overload or cardiogenic edema was less likely.\n\nUnder the impression of interstitial lung disease (ILD), steroid (intravenous methylprednisolone, 2 mg/kg) and broad spectrum antibiotics were prescribed. We tapered the steroid gradually within 14 days of treatment. The clinical symptoms, chest X-ray (Figure 3A), and chest CT (Figure 3B) showed significant improvement after treatment. He also received serological tests, sputum culture, blood culture, Legionella pneumophila, Mycoplasma pneumoniae, Chlamydophila pneumonia, influenza virus A and B, and autoimmune profile examinations, and all tests showed negative findings. Written informed consent was obtained by the patient. Permission of case report publication from the Ethics Review Committee of the Far Eastern Memorial Hospital was also sought.\n\nDiscussion\nAmong previously published cases of docetaxel-related interstitial pneumonitis, this is the first to describe a patient who developed acute pulmonary toxicity within 3 days after administration of low-dose docetaxel (30 mg/m2). Taxanes are known to cause proliferation of cytotoxic T-cells, leading to a hypersensitivity type of lung damage, or might cause direct pulmonary damage through reactive oxygen metabolites. According to our report, low-dose docetaxel treatment was less toxic but not an effective prevention method of lung damage. The physicians should be aware of the possibility of interstitial pneumonitis by the patient’s symptoms and daily physical examination after administration of taxanes.\n\nThe acute pulmonary toxicity of ILD after docetaxel administration is an uncommon adverse event in patients with cancer.1 Approximately 4.6% of patients experience pulmonary toxicity induced by triweekly conventional-dose docetaxel monotherapy (75 mg/m2).2,3 Pneumonitis in most cases occurred after two cycles with a conventional dose.3 The incidence of pulmonary toxicity is more related to the docetaxel delivery schedule than the dose, that is, a weekly schedule leads to lower myelosuppression but more pneumonitis than triweekly administration.4 Moreover, the largest published series of docetaxel-related interstitial pneumonitis reported 18 different cases of a total of 392 patients with metastatic non-small-cell lung cancer treated with docetaxel. The time from the last docetaxel administration to the onset of toxicity findings on the chest radiograph was approximately 10–20 days (median time: 18 days).5\n\nAlthough docetaxel-related side effects are rare, the mortality rate is high. The overall mortality rate due to drug-associated interstitial fibrosis, estimated based on published case reports, appears to be ~40%, with 12 deaths among 30 cases in which mortality data were available.2 This result was also seen in another literature review, which summarizes a total of 31 cases of taxane-induced pneumonitis, in which 35% needed ventilator support, and the mortality rate was 42% in the whole group; those in need of intubation had a mortality rate of 82%.6\n\nThe treatment of choice is administration of systemic glucocorticoid therapy in selected patients in whom an infectious etiology was excluded with appropriate cultures. The patient is usually treated with prednisolone 40–60 mg/day for 2–3 weeks; 60–240 mg/day may be used in patients who have impending respiratory failure, along with a slow and careful tapering-off period.7\n\nAlthough the occurrence of docetaxel-related ILD is rare, it will lead to respiratory failure if treatment is delayed. ILD responds well to steroid treatment and discontinuation of docetaxel administration. Our case indicates the acute pulmonary toxicity of ILD when administering docetaxel.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Before chemotherapy.\n\nNotes: (A) A chest X-ray shows right lower lung consolidation and pleural effusion (black arrow). (B) A chest CT shows a soft tissue mass measured as 98.7×87.4×82.7 mm3 in the right lower lung field (white arrow) with central necrosis and lobulated pleural effusion (white arrow head). (C) A chest CT shows no interstitial lung disease or lymphangitis carcinomatosis.\n\nAbbreviation: CT, computed tomography.\n\nFigure 2 3 days later following chemotherapy.\n\nNotes: (A) A chest X-ray shows increased interstitial lung markings bilaterally; the implanted port was placed at the right subclavian vein. (B) A chest CT shows diffuse ground glass opacity at the bilateral lung fields.\n\nAbbreviation: CT, computed tomography.\n\nFigure 3 After steroid administration.\n\nNotes: (A) A chest X-ray shows no obviously increased lung marking, and the implanted port was placed at the right subclavian vein. (B) The repeated chest CT shows marked improvement in ground glass opacity.\n\nAbbreviations: CT, computed tomography; L, left side.\n==== Refs\nReferences\n1 Eivind S Gunhild H Karsten G Lethal pneumonitis after docetaxel chemotherapy: case report and review of the literature Acta Oncol 2013 52 1034 1038 23244676 \n2 Read WL Mortimer JE Picus J Severe interstitial pneumonitis associated with docetaxel administration Cancer 2002 94 847 853 11857321 \n3 Wang GS Yang KY Perng RP Life-threatening hypersensitivity pneumonitis induced by docetacel (taxotere) Br J Cancer 2001 85 1247 1250 11720456 \n4 Chen YM Shih JF Perng RP Tsai CM Whang-Peng J A randomized trial of different docetaxel schedules in non-small cell lung cancer patients who failed previous platinum-based chemotherapy Chest 2006 129 1031 1038 16608954 \n5 Tamiya A Naito T Miura S Interstitial lung disease associated with docetaxel in patients with advanced non-small cell lung cancer Anticancer Res 2012 32 1103 1106 22399640 \n6 Nagata S Ueda N Yoshida Y Matsuda H Maehara Y Severe interstitial pneumonitis associated with the administration of taxanes J Infect Chemother 2010 16 340 344 20354889 \n7 Khan A McNally D Tutschka PJ Bilgrami S Paclitaxel-induced acute bilateral pneumonitis Ann Pharmacother 1997 31 1471 9416383\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6336",
"issue": "11()",
"journal": "Therapeutics and clinical risk management",
"keywords": "docetaxel; interstitial lung disease",
"medline_ta": "Ther Clin Risk Manag",
"mesh_terms": null,
"nlm_unique_id": "101253281",
"other_id": null,
"pages": "1813-6",
"pmc": null,
"pmid": "26677333",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "11720456;23244676;22399640;9416383;16608954;20354889;11857321",
"title": "Docetaxel-related interstitial pneumonitis.",
"title_normalized": "docetaxel related interstitial pneumonitis"
} | [
{
"companynumb": "TW-PFIZER INC-2015473030",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "Deutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients' symptoms with Huntington's disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer's claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.",
"affiliations": "Emergency Medicine, Wayne State University School of Medicine, Detroit, USA.;Emergency Medicine, Wayne State University Detroit Medical Center, Detroit, USA.;Emergency Medicine, Wayne State University Detroit Medical Center, Detroit, USA.",
"authors": "Obadeyi|Oluseyi|O|;Paxton|James H|JH|;Kouyoumjian|Sarkis|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.12886",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.12886\nEmergency Medicine\nNeurology\nOther\nBenign Presentation Following Massive Deutetrabenazine Overdose\nMuacevic Alexander Adler John R Obadeyi Oluseyi 1 Paxton James H 2 Kouyoumjian Sarkis 2 \n1 \nEmergency Medicine, Wayne State University School of Medicine, Detroit, USA \n\n2 \nEmergency Medicine, Wayne State University Detroit Medical Center, Detroit, USA \n\nOluseyi Obadeyi sobadeyi@gmail.com\n24 1 2021 \n1 2021 \n13 1 e1288624 1 2021 Copyright © 2021, Obadeyi et al.2021Obadeyi 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/49130-benign-presentation-following-massive-deutetrabenazine-overdoseDeutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, which acts by blocking dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has also been shown to improve patients’ symptoms with Huntington’s disease-induced chorea. We present the case of a 59-year-old woman with a history of TD, who presented to the emergency department following massive DTBZ ingestion. The relative paucity of other overdose symptoms further supports the manufacturer’s claims of a low side effect profile for this drug in overdose. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be aware of the potential side effect of DTBZ overdose, in addition to other known side effects of this novel drug.\n\ndeutetrabenazineoverdosetoxicologyside effectstoxicitytardive dyskinesiaThe 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\nDeutetrabenazine (DTBZ) (Austedo®) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor that blocks dopamine release and other monoamines from neuronal vesicles. Although this drug is considered the first-line treatment for tardive dyskinesia (TD), VMAT2 inhibition has been shown to improve patients’ symptoms with Huntington’s disease (HD)-induced chorea [1]. TDs are involuntary movements of the tongue, lips, face, trunk, or extremities associated with and often attributed to long-term use of dopaminergic antagonist medications [1]. The unique movements of TD are repetitive, purposeless, and involuntary and can often cause functional impairment. We present the case of a 59-year-old woman with a history of TD, who presented to the Emergency Department (ED) following massive DTBZ ingestion. The patient had an benign course.\n\nCase presentation\nA 59-year-old female with a history of hypertension, type 2 diabetes, hypothyroidism, TD, Parkinson’s disease, schizophrenia, bipolar disorder, and ischemic stroke presented to the ED with her daughter for DTBZ overdose. Her daughter stated that the patient ingested 20 tablets of 12 mg DTBZ (Table 1) approximately more than eight hours before presenting to the ED. She denied wanting to hurt herself and having any history of a suicide attempt. Our patient stated that she took the medication because she thought it was a pain medication that would relieve a left lower extremity pain that she sustained from hitting her left lower leg on a bed frame. She admitted to feeling depressed, and her only complaint was that she felt drowsy. She had no other symptoms or complaints. The patient denied headache, tinnitus, nausea, vomiting, chest pain, shortness of breath, or any other symptoms.\n\nHer vital signs on arrival revealed a temperature of 98.8°F, blood pressure of 162/104 mmHg, heart rate of 74 beats per minute, respiration of 20 breaths per minute, and oxygen saturation (SpO2) of 96% on room air. Physical examination revealed an alert and oriented female who was in no acute distress. She had clear bilateral lung sounds, non-labored respirations with a regular heart rate, and rhythm. Aside from tremors noted on her right hand, she had unremarkable sensory, strength, and deep tendon reflexes in all extremities.\n\nTable 1 Patient’s outpatient medications prior to overdose presentation\nMg: milligrams, mCg: microgram, Cap: capsule\n\nDrug\tDose\t\nAspirin\t81 mg by mouth, daily\t\nAtorvastatin\t40 mg by mouth, daily\t\nCarvedilol\t12.5 mg by mouth, twice daily\t\nClopidogrel\t75 mg by mouth, daily\t\nDeutetrabenazine\t12 mg by mouth, daily\t\nDocusate\tOne Cap 100 mg by mouth, twice daily\t\nHydralazine\t75 mg by mouth, three times daily\t\nLevothyroxine\t125 mCg by mouth, daily\t\nNifedipine\tTab 90 mg by mouth, daily\t\nQuetiapine\tTab 50 mg by mouth, before bed\t\nElectrocardiogram demonstrated normal sinus rhythm. She had a narrowed anion gap, and her complete blood count and electrolyte levels were within normal limits. Her urine drug screen for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, methadone, and opiates was negative.\n\nThe toxicology service was consulted and recommended 23 hours of telemetry observation to monitor for QT prolongation. The patient had an uneventful overnight course. The next morning, her orofacial TD was present, and neurology was consulted. Neurology recommended psychiatry consult to evaluate for suicidal ideation and outpatient follow-up to discuss the resumption of DTBZ. From a medical standpoint, the patient had an unremarkable hospital course. She was medically cleared by the neurology and inpatient team on day two of her admission. She was admitted for three days, and her length of stay was prolonged because she reported to the psychiatry team that she would like to be placed in a group home facility instead of living with her daughter at home. The patient was finally discharged home with her daughter after changing her mind about desiring a group home placement.\n\nDiscussion\nBefore the introduction of VMAT2 inhibitors, TD was believed to be an irreversible side effect of dopamine antagonism. Neuroleptics and antiemetic dopamine blocking agents cause TD as a side effect of their clinical use. First- and second-generation antipsychotic treatments have been linked with a 5.5% and 3.9% yearly incidence rate of TD development, respectively [1]. Although the pathophysiology of TD development is poorly understood, it is thought to involve the upregulation and sensitization of the dopamine D2 receptor as a result of the prolonged blockade [2].\n\nDTBZ functions as a reversible VMAT2 inhibitor. The US Drug Administration (FDA) approved it in August 2017 for the treatment of TD in adults. The medication is also approved to treat HD-induced chorea and Tourette syndrome [3-5]. Tetrabenazine (TBZ) is the archetype VMAT2 inhibitor and was used for decades to manage hyperkinetic movement disorders before developing other VMAT2 inhibitors like DTBZ and valbenazine (Ingrezza®). The substandard pharmacokinetic profile and lack of FDA approval other than its use for HD chorea limited the use of TBZ in the US. Valbenazine and DTBZ addressed some of the deleterious pharmacokinetic profile of TBZ. Although TBZ and DTBZ are structurally similar, the substitution of deuterium for hydrogen in strategic locations of TBZ resulted in a compound with better pharmacokinetics and safety profile [6-8]. At approximately half the dose of TBZ, DTBZ offers a comparable total exposure time with a longer half-life and at a lower maximum serum concentration [8].\n\nAlthough it is safer than TBZ, DTBZ still has the potential to cause serious side effects. A 12-week trial examining patients with HD revealed that somnolence was the most common dose-limiting side effect of DTBZ [9]. The other adverse effects noted in TD patients include nasopharyngitis, insomnia, depression, and akathisia [3,9]. DTBZ can induce QT prolongation in patients who are CYP2D6 poor metabolizers or consuming a potent CYP2D6 inhibitor. DTBZ also has the potential to cause hyperprolactinemia and neuroleptic malignant syndrome (NMS) [3]. Patients with NMS present with fever, muscle rigidity, and altered mental status with autonomic changes. The novelty of DTBZ demonstrates the lack of sufficient information on the potential signs and symptoms of DTBZ overdose.\n\nIn this case, the patient had no significant adverse effect from a substantial DTBZ consumption at the time of initial presentation. DTBZ for the management of TD appears to be well-tolerated. The recommended starting dose of DTBZ for the management of TD is 6 mg/day, and it can be titrated up to a recommended maximum dose of 48 mg per day. Previous studies started DTBZ at 12 mg/day (6 mg twice daily) with weekly titration of 6 mg/day for up to six weeks until the maximum 48 mg per day or adequate TD control was reached, barring the occurrence of a severe side effect [7]. Due to the ability of TBZ to cause QT interval prolongation, it is recommended that patients at risk of developing QT prolongation have their QT interval assessed before and after increasing their total dose above 24 mg per day [3].\n\nThe diagnosis of DTBZ overdose can only be made through history taking and clinical presentation. Management of DTBZ overdose includes discontinuation of DTBZ, symptomatic treatment, and medical monitoring. DTBZ metabolites are primarily metabolized by CYP2D6 and virtually eliminated renally [3]. Although she had ingested ten times her prescribed daily dose of DTBZ, the patient described in this case report had a mild symptom. The only symptom that she complained of was somnolence, which is the most common adverse effect of DTBZ in patients [3,7,9]. The reported half-life of the active metabolites of DTBZ is nine to ten hours [3]. Considering the substantial amount of DTBZ the patient ingested, a noteworthy observation was that the patient’s orofacial TD manifested the following morning after her admission 24 hours after DTBZ ingestion.\n\nConclusions\nDTBZ overall has an excellent safety profile with tolerable side effects when utilized for the management of TD. Because of its novelty, limited studies have investigated the potential clinical presentation of DTBZ poisoning. Our patient had a mild symptom following massive DTBZ ingestion. Although DTBZ demonstrates an excellent safety profile, emergency physicians should be conscious of its potential to cause fetal abnormalities like QT prolongation and NMS. Consultation with a medical toxicologist and heart monitoring for QT prolongation is recommended.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n1 Tardive dyskinesia prevalence in the period of second-generation antipsychotic use: a meta-analysis J Clin Psychiatry Carbon M Hsieh C-H Kane JM Correll CU 264 278 78 2017 \n2 An update on tardive dyskinesia: from phenomenology to treatment Tremor Other Hyperkinet Mov Waln O Jankovic J 1 11 3 2013 \n3 AUSTEDO (deutetrabenazine) tablets, for oral use. Prescribing information August Teva Pharmaceuticals North Wales, PA 2017. 2017 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209885lbl.pdf \n4 INGREZZA (valbenazine) capsules, for oral use. Prescribing information April Neurocrine Biosciences San Diego, CA 2017 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209241lbl.pdf. \n5 Deutetrabenazine in tics associated with Tourette syndrome Tremor Other Hyperkinet Mov Jankovic J Jimenez-Shahed J Budman C Coffey B Murphy T Shprecher D Stamler D 422 6 2016 \n6 Dopamine depleters in the treatment of hyperkinetic movement disorders Expert Opin Pharmacother Jankovic J 2461 2470 17 2016 27819145 \n7 Randomized controlled trial of deutetrabenazine for tardive dyskinesia: the ARM-TD study Neurology Fernandez HH Factor SA Hauser RA 2003 2010 88 2017 28446646 \n8 The pharmacokinetics of extended release SD-809, a deuterium-substituted analogue of tetrabenazine Mov Disord Stamler D Brown F Bradbury M 765 28 2013 https://adisinsight.springer.com/trials/700235244 \n9 Effect of deutetrabenazine on chorea among patients with Huntington Disease: a randomized clinical trial JAMA Frank S Testa CM Stamler D 40 50 316 2016 27380342\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(1)",
"journal": "Cureus",
"keywords": "deutetrabenazine; overdose; side effects; tardive dyskinesia; toxicity; toxicology",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e12886",
"pmc": null,
"pmid": "33633914",
"pubdate": "2021-01-24",
"publication_types": "D002363:Case Reports",
"references": "27380342;27819145;27917309;23858394;28446646;28146614",
"title": "Benign Presentation Following Massive Deutetrabenazine Overdose.",
"title_normalized": "benign presentation following massive deutetrabenazine overdose"
} | [
{
"companynumb": "US-TEVA-2021-US-1885079",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drugadditional": null,
... |
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