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"abstract": "Aim: Evaluation of the efficacy and safety of sofosbuvir/daclatasvir/ribavirin (SOF/DCV/RBV) in treating non-sustained virological responders (non-SVR12) to prior sofosbuvir-based therapy, in absence of RAS testing in mass treatment, and determination of the optimal timing to start re-treatment. Methods: Real-life prospective observational study included prior non-responders to 24-weeks SOF-RBV (n = 679, 67%) or 12-weeks SOF- RBV- PEG (n = 335, 33%). Patients were re-treated with daily SOF/DCV/RBV for 12 (n = 270) or 24 weeks (n = 744). The primary efficacy endpoint was SVR12. The primary safety endpoints were reported adverse events (AEs) from baseline to SVR12 time point. Results: We included 1,014 patients [age 52 ± 9 years, 58.48% men]. Cirrhosis was documented in 46.98% and 27.5% of SOF-RBV and SOF-RBV-PEG non-responders respectively. Overall, SVR12 was 90.6% [92.2% for 12 weeks therapy and 90.05% for 24 weeks therapy]. Mild AEs occurred in 5.13% (n=52) and 3.1% (n=32) discontinued treatment including eight on-treatment mortalities. Higher baseline FIB-4 and shorter interval before starting retreatment (<6 months) were independent predictors of non-SVR12 on multivariate regression analysis. Conclusion: SOF/DCV/RBV is an effective and safe treatment option for non-responders to prior sofosbuvir-based therapy. Six months interval before retreatment is optimal for achieving favorable SVR.",
"affiliations": "Endemic Medicine and Hepatology Department, Faculty of Medicine, Cairo University , Cairo , Egypt.;General Medicine, Hepatology and Gastroenterology Department, Faculty of Medicine, Ain Shams University , Cairo , Egypt.;Endemic Medicine and Hepatology Department, Faculty of Medicine, Cairo University , Cairo , Egypt.;Endemic Medicine and Hepatology Department, Faculty of Medicine, Cairo University , Cairo , Egypt.;Endemic Medicine and Hepatology Department, Faculty of Medicine, Cairo University , Cairo , Egypt.;Endemic Medicine and Hepatology Department, Faculty of Medicine, Cairo University , Cairo , Egypt.;NHTMRI , Cairo , Egypt.;Tropical Medicine Department, El- Fayoum University , Cairo , Egypt.;Hepatology-Internal Medicine Department, National Hepatology, and Tropical Medicine Research Institute , Cairo , Egypt.;Endemic Medicine Department, Faculty of Medicine, Helwan University , Cairo , Egypt.;Medical Research Division, National Research Center , Cairo , Egypt.;Tropical Medicine Department, Ain Shams University , Cairo , Egypt.;Endemic Medicine and Hepatology Department, Faculty of Medicine, Cairo University , Cairo , Egypt.;General Medicine, Hepatology and Gastroenterology Department, Faculty of Medicine, Ain Shams University , Cairo , Egypt.;Endemic Medicine and Hepatology Department, Faculty of Medicine, Cairo University , Cairo , Egypt.;Hepatology Department, National Liver Institute, Menoufiya University , Shebeen EL Kom , Egypt.",
"authors": "Darweesh|Samar K|SK|https://orcid.org/0000-0001-7428-4569;Elsaeed|Kadry|K|;Omar|Heba|H|https://orcid.org/0000-0002-9707-1141;El Raziky|Maissa|M|;Elakel|Wafaa|W|;Elserafy|Magdy|M|;Ismail|Sohier Ahmed|SA|;Gomaa|Ahmed A|AA|;Mehrez|Mai|M|;El Kassas|Mahamed|M|;Abdullah|Mohamed|M|;Shaker|Mohammed Kamal|MK|;Esmat|Gamal|G|;El Shazly|Yehia|Y|;Doss|Wahid|W|;Waked|Imam|I|",
"chemical_list": "D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D012254:Ribavirin; D014633:Valine; C549273:daclatasvir; D000069474:Sofosbuvir",
"country": "England",
"delete": false,
"doi": "10.1080/17474124.2019.1629287",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1747-4124",
"issue": "13(9)",
"journal": "Expert review of gastroenterology & hepatology",
"keywords": "Chronic HCV Genotype 4; Direct acting antivirals failure; daclatasvir; interval; ribavirin; safety; sofosbuvir; virologic response",
"medline_ta": "Expert Rev Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D002219:Carbamates; D004359:Drug Therapy, Combination; D005260:Female; D019698:Hepatitis C, Chronic; D006801:Humans; D007093:Imidazoles; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011759:Pyrrolidines; D019233:Retreatment; D012254:Ribavirin; D000069474:Sofosbuvir; D016896:Treatment Outcome; D014633:Valine",
"nlm_unique_id": "101278199",
"other_id": null,
"pages": "907-914",
"pmc": null,
"pmid": "31173527",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "High SVR rate following retreatment of non-sustained virological responders to sofosbuvir based anti-HCV therapies regardless of RAS testing: A real-life multicenter study.",
"title_normalized": "high svr rate following retreatment of non sustained virological responders to sofosbuvir based anti hcv therapies regardless of ras testing a real life multicenter study"
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"companynumb": "EG-KADMON PHARMACEUTICALS, LLC-KAD201908-000525",
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"actiondrug": "1",
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"activesubstancename": "DACLATASVIR"
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"abstract": "BACKGROUND The introduction of direct-acting antivirals (DAAs) has considerably improved therapeutic outcomes for patients with chronic hepatitis C virus (HCV) infections. The AMBER-CEE study aimed to assess real-world efficacy and safety of ombitasvir/paritaprevir/ritonavir/+ dasabuvir ±ribavirin (OBV/PTV/r/ +DSV±RBV) in the treatment of post-transplant recurrence of HCV infection. MATERIAL AND METHODS Liver transplant recipients with recurrent HCV genotype 1 infection, scheduled for OBV/PTV/r/+DSV±RBV according to therapeutic guidelines, were eligible. The primary efficacy endpoint was sustained virologic response (SVR) 12 weeks after the end of treatment (FU12). Clinical and laboratory adverse events (AEs) were recorded from baseline to FU12. RESULTS A total of 35 patients were included: 91.4% genotype 1b-infected, 94.3% treatment-experienced, and 77.1% at fibrosis stage ≥F2. SVR12 was achieved by all patients (35/35, 100%) including one patient with genotype 1a, one patient with detectable HCV RNA at the end of treatment, two patients with a history of first-generation DAA therapy, and two patients who prematurely discontinued the regimen. AEs were experienced by 22 patients (62.9%) and were mostly mild. No death, graft loss, or acute graft rejections were reported during the therapy. On-treatment hepatic decompensation occurred in three patients (8.6%). Anemia was observed in 29 patients (83.9%), with 21 (60%) requiring RBV dose reduction or discontinuation. CONCLUSIONS OBV/PTV/r/+DSV±RBV has excellent efficacy in post-transplant recurrence of HCV genotype 1-infection treated under real-world conditions. Excellent virologic outcomes were observed irrespective of prior treatment history or the degree of fibrosis, and AEs were mostly mild and transient.",
"affiliations": "Department of Transplantation Medicine and Nephrology, Medical University of Warsaw, Warsaw, Poland.;Department of Transplantation Medicine and Nephrology, Medical University of Warsaw, Warsaw, Poland.;Clinic of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland.;Clinic of Gastroenterology, Nephrourology and Surgery, Center of Hepatology, Gastroenterology and Dietetics, Vilnius University, Vilnius, Lithuania.;Department of Gastroenterology, Hepato-Pancreato-Biliary (HPB) Surgery and Transplantology, Military Medical Academy, Sofia, Bulgaria.;Department of Gastroenterology and Institute for Digestive Research, Lithuanian University, Kaunas, Lithuania.;Department of Hepatology, Riga East University Hospital, Infectology Center of Latvia, Latvian University, Faculty of Medicine, Riga, Latvia.;Clinic of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland.;ID Clinic, Mysłowice, Poland.;Department of Infectious Diseases and Hepatology, Faculty of Medicine, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland.;Chair and Department of Infectious Diseases, Karol Marcinkowski University of Medical Sciences, Poznań, Poland.;Department of Infectious and Liver Diseases, Medical University of Łódź, Łódź, Poland.;Division of Infectious Diseases and Hepatology, Faculty of Medicine and Dentistry, Wrocław Medical University, Wrocław, Poland.;Clinic of Gastroenterology, Nephrourology and Surgery, Center of Hepatology, Gastroenterology and Dietetics, Vilnius University, Vilnius, Lithuania.;Department of Gastroenterology, Hepato-Pancreato-Biliary (HPB) Surgery and Transplantology, Military Medical Academy, Sofia, Bulgaria.;Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, Poland.",
"authors": "Tronina|Olga|O|;Durlik|Magdalena|M|;Wawrzynowicz-Syczewska|Marta|M|;Buivydiene|Arida|A|;Katzarov|Krum|K|;Kupcinskas|Limas|L|;Tolmane|Ieva|I|;Karpińska|Ewa|E|;Pisula|Arkadiusz|A|;Karwowska|Kornelia Magdalena|KM|;Bolewska|Beata|B|;Jabłkowski|Maciej|M|;Rostkowska|Karolina|K|;Jakutiene|Jolita|J|;Simonova|Marieta|M|;Flisiak|Robert|R|",
"chemical_list": "D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D012254:Ribavirin; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir",
"country": "United States",
"delete": false,
"doi": "10.12659/aot.903535",
"fulltext": null,
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"issn_linking": "1425-9524",
"issue": "22()",
"journal": "Annals of transplantation",
"keywords": null,
"medline_ta": "Ann Transplant",
"mesh_terms": "D015081:2-Naphthylamine; D000328:Adult; D000368:Aged; D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D047029:Lactams, Macrocyclic; D016031:Liver Transplantation; D047028:Macrocyclic Compounds; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011392:Proline; D012254:Ribavirin; D019438:Ritonavir; D013449:Sulfonamides; D014498:Uracil; D014633:Valine",
"nlm_unique_id": "9802544",
"other_id": null,
"pages": "199-207",
"pmc": null,
"pmid": "28386057",
"pubdate": "2017-04-07",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Real-World Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir/+Dasabuvir±Ribavirin (OBV/PTV/r/+DSV±RBV) Therapy in Recurrent Hepatitis C Virus (HCV) Genotype 1 Infection Post-Liver Transplant: AMBER-CEE Study.",
"title_normalized": "real world safety and efficacy of ombitasvir paritaprevir ritonavir dasabuvir ribavirin obv ptv r dsv rbv therapy in recurrent hepatitis c virus hcv genotype 1 infection post liver transplant amber cee study"
} | [
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"companynumb": "PL-STRIDES ARCOLAB LIMITED-2017SP009972",
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"activesubstancename": "DASABUVIR"
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"abstract": "Osteoporotic fractures in elderly women are mainly due to postmenopausal bone loss but can sometimes be caused by a disabling haematological disease. We describe an 84-year-old woman suffering from multiple osteoporotic fractures as a manifestation of mast cell leukaemia. Mast cell leukaemia is a rare form of systemic mastocytosis with a poor prognosis and very few therapeutic options. Osteoporotic fractures have seldom been reported as its initial manifestation.",
"affiliations": "Department of Internal Medicine, Deventer Hospital, Deventer, the Netherlands.",
"authors": "de Boer|S E|SE|;Hoogenberg|K|K|;de Boer|N K|NK|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0300-2977",
"issue": "72(6)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007946:Leukemia, Mast-Cell; D008279:Magnetic Resonance Imaging; D058866:Osteoporotic Fractures",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "326-9",
"pmc": null,
"pmid": "25319858",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mast cell leukaemia presenting with multiple osteoporotic fractures in an elderly woman.",
"title_normalized": "mast cell leukaemia presenting with multiple osteoporotic fractures in an elderly woman"
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"companynumb": "PHHY2014NL091708",
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{
"abstract": "We report two cases which highlight the fact how poor communication leads to dangerously poor health outcome. We present the case of a 50-year-old woman recently diagnosed with rheumatoid arthritis from Southern Nepal presented to Patan hospital with multiple episodes of vomiting and oral ulcers following the intake of methotrexate every day for 11 days, who was managed in the intensive care unit. Similarly, we present a 40-year-old man with ileo-caecal tuberculosis who was prescribed with anti-tubercular therapy (ATT) and prednisolone, who failed to take ATT due to poor communication and presented to Patan Hospital with features of disseminated tuberculosis following intake of 2 weeks of prednisolone alone. These were events that could have been easily prevented with proper communication skills. Improvement of communication between doctors and patients is paramount so that life-threatening events like these could be avoided.",
"affiliations": "Department of Internal Medicine, Patan Academy of Health Sciences, Lalitpur, Nepal.;Department of Internal Medicine, Patan Academy of Health Sciences, Lalitpur, Nepal.;Department of Internal Medicine, Patan Academy of Health Sciences, Lalitpur, Nepal.;Department of Internal Medicine, Patan Academy of Health Sciences, Lalitpur, Nepal.;Department of Internal Medicine, Patan Academy of Health Sciences, Lalitpur, Nepal.",
"authors": "Tiwary|Abhishek|A|https://orcid.org/0000-0003-2669-738X;Rimal|Ajwani|A|;Paudyal|Buddhi|B|https://orcid.org/0000-0002-5119-4082;Sigdel|Keshav Raj|KR|;Basnyat|Buddha|B|https://orcid.org/0000-0002-1125-2743",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.12688/wellcomeopenres.15042.1",
"fulltext": "\n==== Front\nWellcome Open ResWellcome Open ResWellcome Open ResWellcome Open Research2398-502XF1000 Research Limited London, UK 10.12688/wellcomeopenres.15042.1Clinical Practice ArticleArticlesPoor communication by health care professionals may lead to life-threatening complications: examples from two case reports [version 1; peer review: 2 approved]\n\nTiwary Abhishek MethodologyWriting – Original Draft PreparationWriting – Review & Editinghttps://orcid.org/0000-0003-2669-738Xa1Rimal Ajwani ConceptualizationMethodologyWriting – Original Draft Preparation1Paudyal Buddhi ConceptualizationSupervisionWriting – Review & Editinghttps://orcid.org/0000-0002-5119-40821Sigdel Keshav Raj ConceptualizationSupervisionWriting – Review & Editing1Basnyat Buddha ConceptualizationMethodologyResourcesWriting – Review & Editinghttps://orcid.org/0000-0002-1125-274312\n1 Department of Internal Medicine, Patan Academy of Health Sciences, Lalitpur, Nepal\n2 Oxford University Clinical Research Unit, Patan hospital, Lalitpur, Nepala abhishektiwary@pahs.edu.npNo competing interests were disclosed.\n\n22 1 2019 2019 4 717 1 2019 Copyright: © 2019 Tiwary A et al.2019This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We report two cases which highlight the fact how poor communication leads to dangerously poor health outcome. We present the case of a 50-year-old woman recently diagnosed with rheumatoid arthritis from Southern Nepal presented to Patan hospital with multiple episodes of vomiting and oral ulcers following the intake of methotrexate every day for 11 days, who was managed in the intensive care unit. Similarly, we present a 40-year-old man with ileo-caecal tuberculosis who was prescribed with anti-tubercular therapy (ATT) and prednisolone, who failed to take ATT due to poor communication and presented to Patan Hospital with features of disseminated tuberculosis following intake of 2 weeks of prednisolone alone. These were events that could have been easily prevented with proper communication skills. Improvement of communication between doctors and patients is paramount so that life-threatening events like these could be avoided.\n\nCommunicationmethotrexatetuberculosisWellcome Trust106680This study was supported by the Wellcome Trust (106680).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n==== Body\nIntroduction\nCommunication refers to exchanging information with the help of different mediums, such as speaking, writing or body language\n1. It is of great importance in the field of medicine. Effective physician-patient communication is vital as it is related with favourable health outcomes such as increased patients satisfaction, compliance and overall health status\n2. A study in 2008 by Bartlett G\net al. concluded that communication problems with patients lead to increased preventable adverse effects which were mostly drug-related\n3. It has been estimated that 27% of medical malpractice is the result of the communication failures. Better communication can reduce medical errors and patient injury\n4. Poor communication can result in various negative outcomes, such as decreased adherence to treatment, patients dissatisfaction and inefficient use of resources\n5. The cases discussed here highlight the importance of proper communication, how such unfortunate events could have been prevented with good communication skills. The traditional medical education curriculum in South Asia usually focuses more on technical expertise than teaching communication skills. This fact has hindered the capacity of technically expert health professionals to effectively communicate with their patients regarding the disease and treatment approach\n6,\n7. Thus, a concerted effort needs to be made to improve the communication skills of health professionals in South Asia.\n\nCase reports\nCase 1\nA 50-year-old woman diagnosed with rheumatoid arthritis (RA) 3 weeks previously presented to Emergency Department of Patan Hospital in June of 2018 with complaints of multiple episodes of vomiting and oral ulcers for 5 days. She had a history of multiple joint pain for a year, for which she sought medical attention in New Delhi, India as her son used to work there. She visited New Delhi with her neighbour, and there was diagnosed with RA. As per the standard treatment of RA, her treating rheumatologist prescribed her 15 mg methotrexate once weekly and 5 mg folic acid twice weekly without emphasizing that methotrexate is to be taken weekly and not daily. The pharmacist also failed to stress the weekly dose schedule. Unfortunately, she consumed methotrexate 15 mg daily for 11 days. At 11th day, she presented with those above complaints to the National Medical College and Teaching Hospital near her home in Birgunj, in the southern plains of Nepal. There she was managed conservatively with folic acid and fluids for 2 days, then referred to our centre for further management. She had ongoing vomiting and her examination of the oral cavity revealed multiple erythematous and ulcerative lesions. Her total white blood cell count (WBC) was 2400/µl (normal range, 4000–11000/µl), with an absolute neutrophil count (ANC) of 1200/µl (normal range, 1500–8000/µl), haemoglobin of 9 g/dl (12–15 g/dl) and platelets of 84000/µl (150,000–450,000/µl). She was immediately admitted to the intensive care unit (ICU) for methotrexate toxicity (myelosuppression and mucositis). Her methotrexate was stopped and she was managed with leucovorin (15 mg once daily), GM-CSF (300 µg once daily) and nasogastric feeding as she was unable to eat anything because of the oral ulcers.\n\nAfter 3 days in the ICU, she was transferred to the ward, where treatment with leucovorin and GM-CSF was continued at the same dose. She was discharged after a total of 11 days of hospital stay when her blood counts came back to within the normal range (WBC, 12300/µl; ANC, 6888/µl). Her haemoglobin increased to 13 g/dl and her platelet reached 340,000/µl. Her oral lesions subsided, and she was able to feed orally. She was started back on the correct dosage of methotrexate (15 mg once weekly) and counselled about the disease, medications (dosage and adverse effects) and was advised to follow up in rheumatology clinic. She has been followed-up every 3 months since then, is in remission and is taking medications properly.\n\nCase 2\nA 40-year-old man from hills of Nepal presented to the emergency department of Patan Hospital in August 2018 with complaints of weakness in the right half of the body, deviation of the left side of the face and slurring of speech for 4 days. At 3 weeks prior to this, he had visited another tertiary level hospital in Kathmandu for pain in the lower abdomen and fever, where he was diagnosed as having ileo-cecal tuberculosis based on colonoscopy and biopsy with positive Ziehl-Neelson staining. He was then prescribed with antitubercular therapy (ATT) that included 3 tablets of Fixed dose combination consisting of isoniazid 75 mg, rifampicin 150 mg, pyrazinamide 400 mg and ethambutol 275 mg once daily and prednisolone 40 mg once daily. He was advised to take ATT from a health centre near his residence, whereas prednisolone was dispensed from the hospital pharmacy. Unfortunately, he just took prednisolone, but no ATT. As a result, he ended up in emergency with the aforementioned complaints. On evaluation, his chest x-ray showed features of pulmonary tuberculosis. Cerebral spinal Fluid (CSF) analysis was done which showed red blood cells (RBC) 200/µl (normal value, 0/µl), WBC 64/µl (normal range, 0–5/ µl), neutrophil 24%, lymphocytes 64%, protein 294 mg/dl (normal range, 15–45 mg/dl) and sugar 49 mg/dl (normal range, 50–80 mg/dl). Cerebrospinal fluid GeneXpert testing was positive for\nMycobacterium tuberculosis. He was then diagnosed as disseminated tuberculosis with meningeal involvement and was admitted to Patan Hospital with ATT (3 tablets of fixed-dose combination consisting of Isoniazid 75mg, Rifampicin 150 mg, Pyrazinamide 400 mg and Ethambutol 275mg once daily) and dexamethasone (6 mg three times a day) for 3 days. He was then discharged with ATT (same dose as above) and prednisolone (40 mg once daily) after proper counselling about the nature of the disease and site of availability of anti-tubercular drugs. He came in for follow-up after 2 weeks with improvement in the symptoms and has been taking all medications properly. \n\nDiscussion\nIn the discussed cases, the treating physicians had used the standard treatment protocol to best serve their patients. They used their medical knowledge in an appropriate manner to treat the disease condition, but proper communication with clear-cut emphasis on how and when to take the therapy, which is of utmost importance in achieving an overall positive health impact, was lacking. Had the doctors properly counselled and educated the patients regarding the disease, treatment options and the correct way of taking medications, these mishaps could have been prevented. Another major part of the communication involves the judgment of the doctor in figuring out how much the patient understood. As our patients were not literate, they could have explained about the disease and especially the weekly dosing of methotrexate and the availability and importance of ATT very clearly to the patient family. In South Asian countries like Nepal, the patient seldom is alone and therefore making things clear to the patient’s family is obviously a very important option that needs to be utilized to improve communication against the background of rampant illiteracy. In Nepal, only 48.6% of the population is literate; hence this fact needs to be kept in mind when explaining about diseases and prescribing drugs, especially regarding medicines that have dangerous side-effects\n8.\n\nIn Nepal, 25.2% population fall below the poverty line and 3.2% population are unemployed\n9. The young working generation have to leave their house for better employment opportunities, meaning they aren’t able to take care of their parents. In one of our cases, the son had to work in India for better employment opportunities and the patient came with her neighbour with whom the treating physician did not spend any time. It is possible that if the son had been there, he may well have been more concerned and asked more questions to the doctor. However, it is the responsibility of the health care professional to try to make sure the patient and their family have understood the matter clearly. There was also no caution mentioned by the pharmacy where the patient bought the medicine explaining the weekly (and not daily) dosing schedule of methotrexate. Hence there was failure of clear communication at various levels that led to this mishap.\n\nProblems in doctor‐patient communication have received little attention as a potential but a remediable cause of health hazards, especially in a setting like this one in South Asia. Communication during the medical interaction among the health practitioner and the patient has a pivotal role in creating a positive health impact that includes drug adherence, future decision making on the interventions and modifying the health behaviours of the patient. We consider the cost and the negative impact on the outcome of the health from poor communication, which includes non-adherence to drugs regimens that will increase the burden of the cost of the total drug therapy, poor health outcomes, and unnecessary treatment and investigations. Different measures need to be considered to improve the communication between doctors and patients which would improve the overall health outcome. The measures include providing communication skills training to health care professionals and regular evaluation of communication skills of these professionals by interviewing the patients after a consultation.\n\nConclusion\nClear communication is vital in the proper treatment of the patient especially against the background of rampant illiteracy in countries such as Nepal in South Asia. Poor Communication may lead to life-threatening complications, as in our patients. For better communication practice, proper communication training to health care professionals including pharmacists is paramount.\n\nConsent\nInformed consent for publication of their clinical details, in the form of a fingerprint, was obtained from the patients.\n\nData availability\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n10.21956/wellcomeopenres.16411.r36091Reviewer response for version 1 Allison Jill 1Refereehttps://orcid.org/0000-0003-0787-4555\n1 Division of Community Health and Humanities, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada\nCompeting interests: No competing interests were disclosed.\n\n12 8 2019 Copyright: © 2019 Allison J2019This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 1recommendationapprove\nThis article provides two cases where a lack of information and clear understanding of prescription medication contributed to morbidity and unnecessary suffering for the patients. The cases are linked to a lack of health professional engagement with the patient and failure to ensure full understanding of medication instructions. The cases and events surrounding are clearly described. The outcomes are also clearly described.\n\nThe clinical scenario is well described but it would be helpful to know what steps were taken with these two patients to prevent similar circumstances. There is no mention of what was done to educate and inform the patient or their families on discharge. Was there an interdisciplinary team involved to try to ensure the patient got sufficient information and how was their level of comprehension assessed?\n\nThere is a bit of repetition in the discussion and not many concrete suggestions for improving the skills of physicians in this area. Continuing medical education? Cultural competency teaching?\n\nThere are a few grammatical errors that could be corrected to improve the paper. \n\nOverall, an important concept for discussion and excellent examples of why the discussion must happen. \n\n\n\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.21956/wellcomeopenres.16411.r35794Reviewer response for version 1 Onta Sharad 12Referee\n1 Department of Community Medicine and Public Health, Institute of Medicine, Tribhuvan University, Kathmandu, Nepal\n2 Nepal Public Health Foundation, Kathmandu, Nepal\nCompeting interests: No competing interests were disclosed.\n\n2 7 2019 Copyright: © 2019 Onta S2019This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 1recommendationapprove\nIntroduction:\nThis section should focus on contextual facts about the central issue of the manuscript, communication in clinical practice in the present context. It is better to avoid assessment of the contents of the cases and conclusion with recommendation. \n\nThe statement “\nThe cases discussed here highlight the importance of proper communication, how such unfortunate events could have been prevented with good communication skills” indicates to the assessment of upcoming contents of the manuscript. It seems inappropriate in the introduction. (It better fits in the discussion).\n\nThe last phrase of this section “\nThus, a concerted effort needs to be made to improve the communication skills of health professionals in South Asia” carries a notion of recommendation, which seems premature for this section of the manuscript. (It can be moved to the conclusion).\n\nIt will be better to highlight the objective and rationale of presenting cases in this section. It provides the space for the authors to justify importance of communication in clinical practice.\n\n\nCases:\nAdequate exploration of the facts as the evidence of poor communication in health service/clinical practices and highlights of these facts (findings) are necessary in presentation of the cases for justification of explanations narrated in the section of discussion. The cases in the manuscript look weak, as the communication aspects are not adequately elaborated on. Elaboration of communication dimension in the case presentation is desirable and, hence, suggested.\n\nAs emphasized in the discussion section, and in the conclusion, of the manuscript, socio-economic characteristics of the service seekers are not clearly mentioned in the cases. Therefore, rationalization of importance of communication in the basis of these attributes is not well justifiable. \n\n \n\n\nDiscussion:\nThe discussion should further attempt to establish credible links between doctor-patient communication and implications seen in the discussed cases. Other potential causes for such implications should be excluded to the best possible extent.\n\n Few examples:\n\nIn case 1 – it should be explored in depth whether the attitude and faith of patients to recover earlier by getting medicine in more (frequently) quantity than prescribed dose could be the reason for this situation.\n\nIn case 2 – role of poor communication is not established clearly. Other possible reasons for not taking ATT like unavailability of medicines, distance to the health centres, and so on should be excluded to establish the role of communication. If prednisolone was the underlying cause of complication of the case, it should be analyzed, whether dispensing prednisolone alone without AT medicines to the patient was a right practice/protocol and correlate with the communication.\n\n \n\n\nConfidentiality:\nIn case 1 – name of the referring hospital as\nNational Medical College and Teaching Hospital is mentioned whereas in the case 2 – it is mentioned as\nanother tertiary level hospital in Kathmandu. It is better to maintain the consistency.\n\n \n\n\nConclusion:\nThe conclusion is not well based in facts of cases. The manuscript has justified the importance of communication (in Nepal) in the background of\nrampant illiteracy. However, literacy and other socio-economic status of the patients in both cases are not known.\n\n \n\n\nGeneral:\nLanguage could be improved.\n\nManuscript has addressed very relevant and useful issues. It should be considered for indexing after improvement incorporating all comments. \n\n \n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n==== Refs\n1 \nHornby A Deuter M :\nOxford advanced learner's dictionary of current English . Oxford: Oxford University Press,2015 \nReference Source\n\n2 \nOng LM de Haes JC Hoos AM :\nDoctor-patient communication: a review of the literature. \nSoc Sci Med. \n1995 ;40 (7 ):903 –918 .\n10.1016/0277-9536(94)00155-M \n7792630 \n3 \nBartlett G Blais R Tamblyn R :\nImpact of patient communication problems on the risk of preventable adverse events in acute care settings. \nCMAJ. \n2008 ;178 (12 ):1555 –1562 .\n10.1503/cmaj.070690 \n\n18519903 \n4 \nThe Doctor Weighs In :\nThe Impact of Poor Communication on Medical Errors . [online].2018 [Accessed 26 Oct. 2018].\nReference Source\n\n5 \nVermeir P Vandijck D Degroote S :\nCommunication in healthcare: a narrative review of the literature and practical recommendations. \nInt J Clin Pract. \n2015 ;69 (11 ):1257 –67 .\n10.1111/ijcp.12686 \n\n26147310 \n6 \nChoudhary A Gupta V :\nTeaching communications skills to medical students: Introducing the fine art of medical practice. \nInt J Appl Basic Med Res. \n2015 ;5 (Suppl 1 ):S41 –4 .\n10.4103/2229-516X.162273 \n\n26380210 \n7 \nFeinmann J :\nBrushing up on doctors' communication skills. \nLancet. \n2002 ;360 (9345 ):1572 .\n10.1016/S0140-6736(02)11592-3 \n12443603 \n8 \nWorldpopulationreview.com . [online].2018 [Accessed 26 Oct. 2018].\nReference Source\n\n9 \nAnon . [online].2018 [Accessed 26 Oct. 2018].\nReference Source\n\n",
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"keywords": "Communication; methotrexate; tuberculosis",
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"title": "Poor communication by health care professionals may lead to life-threatening complications: examples from two case reports.",
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"abstract": "SWOG S0800, a randomized open-label Phase II clinical trial, compared the combination of weekly nab-paclitaxel and bevacizumab followed by dose-dense doxorubicin and cyclophosphamide (AC) with nab-paclitaxel followed or preceded by AC as neoadjuvant treatment for HER2-negative locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). Patients were randomly allocated (2:1:1) to three neoadjuvant chemotherapy arms: (1) nab-paclitaxel with concurrent bevacizumab followed by AC; (2) nab-paclitaxel followed by AC; or (3) AC followed by nab-paclitaxel. The primary endpoint was pathologic complete response (pCR) with stratification by disease type (non-IBC LABC vs. IBC) and hormone receptor status (positive vs. negative). Overall survival (OS), event-free survival (EFS), and toxicity were secondary endpoints. Analyses were intent-to-treat comparing bevacizumab to the combined control arms. A total of 215 patients were accrued including 11 % with IBC and 32 % with triple-negative breast cancer (TNBC). The addition of bevacizumab significantly increased the pCR rate overall (36 vs. 21 %; p = 0.019) and in TNBC (59 vs. 29 %; p = 0.014), but not in hormone receptor-positive disease (24 vs. 18 %; p = 0.41). Sequence of administration of nab-paclitaxel and AC did not affect the pCR rate. While no significant differences in OS or EFS were seen, a trend favored the addition of bevacizumab for EFS (p = 0.06) in TNBC. Overall, Grade 3-4 adverse events did not differ substantially by treatment arm. The addition of bevacizumab to nab-paclitaxel prior to dose-dense AC neoadjuvant chemotherapy significantly improved the pCR rate compared to chemotherapy alone in patients with triple-negative LABC/IBC and was accompanied by a trend for improved EFS. This suggests reconsideration of the role of bevacizumab in high-risk triple-negative locally advanced breast cancer.",
"affiliations": "Division of Hematology-Oncology, Department of Internal Medicine, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX, USA. zeina.nahleh@ttuhsc.edu.;SWOG Statistical Center, Seattle, WA, USA.;University of Michigan, Ann Arbor, MI, USA.;University of Michigan, Ann Arbor, MI, USA.;Seattle Cancer Care Alliance, University of Washington, Seattle, WA, USA.;Women and Infants Hospital of Rhode Island and Warren Alpert Medical School of Brown University, Providence, RI, USA.;Genentech, Inc., San Francisco, CA, USA.;Hematology Oncology Consultants, Inc., Westerville, OH, USA.;Loma Linda University Cancer Center, Loma Linda, CA, USA.;Gibbs Cancer Center and Research Institute/Southeast Clinical Oncology Research (SCOR) Consortium NCORP/Upstate Carolina CCOP (previous), Spartanburg, SC, USA.;SWOG Statistical Center, Seattle, WA, USA.;Yale University, New Haven, CT, USA.;Arizona Cancer Center, Tucson, AZ, USA.;University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"authors": "Nahleh|Z A|ZA|0000-0002-2489-1501;Barlow|W E|WE|;Hayes|D F|DF|;Schott|A F|AF|;Gralow|J R|JR|;Sikov|W M|WM|;Perez|E A|EA|;Chennuru|S|S|;Mirshahidi|H R|HR|;Corso|S W|SW|;Lew|D L|DL|;Pusztai|L|L|;Livingston|R B|RB|;Hortobagyi|G N|GN|",
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"fulltext": "\n==== Front\nBreast Cancer Res TreatBreast Cancer Res. TreatBreast Cancer Research and Treatment0167-68061573-7217Springer US New York 388910.1007/s10549-016-3889-6Clinical TrialSWOG S0800 (NCI CDR0000636131): addition of bevacizumab to neoadjuvant nab-paclitaxel with dose-dense doxorubicin and cyclophosphamide improves pathologic complete response (pCR) rates in inflammatory or locally advanced breast cancer http://orcid.org/0000-0002-2489-1501Nahleh Z. A. zeina.nahleh@ttuhsc.edu 1Barlow W. E. 2Hayes D. F. 3Schott A. F. 3Gralow J. R. 4Sikov W. M. 5Perez E. A. 67Chennuru S. 89Mirshahidi H. R. 10Corso S. W. 11Lew D. L. 2Pusztai L. 12Livingston R. B. 13Hortobagyi G. N. 141 Division of Hematology-Oncology, Department of Internal Medicine, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX USA 2 SWOG Statistical Center, Seattle, WA USA 3 University of Michigan, Ann Arbor, MI USA 4 Seattle Cancer Care Alliance, University of Washington, Seattle, WA USA 5 Women and Infants Hospital of Rhode Island and Warren Alpert Medical School of Brown University, Providence, RI USA 6 Genentech, Inc., San Francisco, CA USA 7 Mayo Clinic, Jacksonville, FL USA 8 Hematology Oncology Consultants, Inc., Westerville, OH USA 9 Columbus NCI Community Oncology Research Program, Columbus, OH USA 10 Loma Linda University Cancer Center, Loma Linda, CA USA 11 Gibbs Cancer Center and Research Institute/Southeast Clinical Oncology Research (SCOR) Consortium NCORP/Upstate Carolina CCOP (previous), Spartanburg, SC USA 12 Yale University, New Haven, CT USA 13 Arizona Cancer Center, Tucson, AZ USA 14 University of Texas MD Anderson Cancer Center, Houston, TX USA 8 7 2016 8 7 2016 2016 158 485 495 23 6 2016 25 6 2016 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.SWOG S0800, a randomized open-label Phase II clinical trial, compared the combination of weekly nab-paclitaxel and bevacizumab followed by dose-dense doxorubicin and cyclophosphamide (AC) with nab-paclitaxel followed or preceded by AC as neoadjuvant treatment for HER2-negative locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). Patients were randomly allocated (2:1:1) to three neoadjuvant chemotherapy arms: (1) nab-paclitaxel with concurrent bevacizumab followed by AC; (2) nab-paclitaxel followed by AC; or (3) AC followed by nab-paclitaxel. The primary endpoint was pathologic complete response (pCR) with stratification by disease type (non-IBC LABC vs. IBC) and hormone receptor status (positive vs. negative). Overall survival (OS), event-free survival (EFS), and toxicity were secondary endpoints. Analyses were intent-to-treat comparing bevacizumab to the combined control arms. A total of 215 patients were accrued including 11 % with IBC and 32 % with triple-negative breast cancer (TNBC). The addition of bevacizumab significantly increased the pCR rate overall (36 vs. 21 %; p = 0.019) and in TNBC (59 vs. 29 %; p = 0.014), but not in hormone receptor-positive disease (24 vs. 18 %; p = 0.41). Sequence of administration of nab-paclitaxel and AC did not affect the pCR rate. While no significant differences in OS or EFS were seen, a trend favored the addition of bevacizumab for EFS (p = 0.06) in TNBC. Overall, Grade 3–4 adverse events did not differ substantially by treatment arm. The addition of bevacizumab to nab-paclitaxel prior to dose-dense AC neoadjuvant chemotherapy significantly improved the pCR rate compared to chemotherapy alone in patients with triple-negative LABC/IBC and was accompanied by a trend for improved EFS. This suggests reconsideration of the role of bevacizumab in high-risk triple-negative locally advanced breast cancer.\n\nKeywords\nBreast cancerLocally advancedInflammatoryBevacizumabNeoadjuvantNational Institutes of Health (US)CA180888, CA180819, CA180821, CA180835, CA180830, CA180846, CA180801, CA180834; NIH/NCI Community Oncology Research Program (NCORP) grants CA189954, CA189856, CA189971, CA189822, CA189952, CA189804, CA189817, CA189953, CA189858, CA189957, CA189872, CA189853; legacy NIH/NCI grants CA35119, CA52654, CA04919, CA37981, CA58416, CA16385http://dx.doi.org/10.13039/100004328Genentechhttp://dx.doi.org/10.13039/100004337RocheAbraxisissue-copyright-statement© Springer Science+Business Media New York 2016\n==== Body\nIntroduction\nLocally advanced breast cancer (LABC) was historically defined as cancers that were inoperable, T4 and/or advanced regional nodal disease at presentation, and had poor survival outcomes with locoregional therapy alone. However, the definition has expanded to include potentially operable tumors greater than 5 cm [1–3]. Inflammatory breast cancer (IBC) characterized by diffuse erythema or edema of the affected breast, with or without histologically confirmed involvement of the dermal lymphatics, is a highly aggressive form of LABC that has poor prognosis, with 10-year disease-free survival rates reported at 20–25 % [4]. Few randomized studies have targeted LABC and/or IBC and most large adjuvant and neoadjuvant trials exclude these patients. Anthracycline- and taxane-based neoadjuvant chemotherapy represents the standard of care for LABC. Pathologic complete response (pCR), commonly defined as the absence of residual invasive cancer in both the breast and axillary lymph nodes, has emerged as a surrogate endpoint for disease-free and overall survival, as the achievement of a pCR is associated with a favorable long-term prognosis in all breast cancer subtypes, while extensive residual disease predicts for poor outcomes, especially in triple-negative [estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) negative] and HER2-positive breast cancers [5–7].\n\nAngiogenesis is believed to play a significant role in LABC/IBC [8–12]. Bevacizumab is a recombinant, humanized, monoclonal antibody that binds and neutralizes the vascular endothelial growth factor A, thus acting as an antiangiogenic agent. Bevacizumab has activity in multiple advanced neoplasms, including breast cancer [12–17]. However, after initial enthusiasm over the combination of bevacizumab with chemotherapy in the metastatic setting, subsequent analyses suggested that bevacizumab produces more toxicity than benefit, and initial accelerated approval for the drug in this setting was subsequently withdrawn by the Food and Drug Administration (FDA) [18]. In addition, two prospective randomized trials failed to document benefit for the addition of bevacizumab to adjuvant chemotherapy in any subset of breast cancer patients [19, 20].\n\nHowever, in the initial metastatic trials, bevacizumab showed activity in some patients when administered with chemotherapy [21]. Despite suggestions that patients with ER/PgR-positive and those with triple-negative cancers may benefit from the addition of bevacizumab [25–28]; retrospective analyses have failed to identify predictive biomarkers that might permit more efficient use of this agent [22]. Therefore, in the current trial (SWOG0800-ClinicalTrials.gov NCT00856492), we prospectively examined whether neoadjuvant bevacizumab might be more active within selected intrinsic subtypes when administered with neoadjuvant chemotherapy. Furthermore, the vascular pruning hypothesis proposed by Jain suggests that antiangiogenesis might improve flow and oxygenation and enhance the delivery and proapoptotic effect of certain chemotherapy agents, in particular the taxanes [17, 23]. Thus, we considered whether the addition of bevacizumab to neoadjuvant weekly nab-paclitaxel followed by dose-dense doxorubicin and cyclophosphamide (“AC”) would increase the pCR rates in patients with HER2-negative LABC/IBC. Nab-paclitaxel was chosen as the taxane backbone based on several advantages compared to paclitaxel at the time of trial initiation, including increased intratumoral drug levels [24], albumin-mediated receptor transport of the drug via secreted protein acidic and rich in cysteine (SPARC)/osteonectin [25] overexpressed in around 55 % of primary breast tumors [26], specific receptor-mediated transport mechanisms due to overexpression of caveolin-1 and -2 in IBC [27], and antiangiogenic activity as well as synergistic activity with antiangiogenic agents [28, 29]. More recently, Nab-paclitaxel was shown to be more effective than conventional paclitaxel as part of a neoadjuvant regimen for patients with high-risk early breast cancer in a large German study, the GeparSepto [30]. This study found that 38 % of patients who received nab-paclitaxel during the randomized phase III trial achieved a pCR, compared with 29 % of participants who were given conventional paclitaxel, p < 0.001.\n\nPatients and methods\nPatient population and selection criteria\nEligible patients were women with biopsy-confirmed, previously untreated, clinical stage IIB to IIIC HER-2-negative breast carcinoma and known hormone receptor status. HER-2 status was determined locally according to the 2007 American Society of Clinical Oncology/College of American Pathology guidelines [31]. The clinical diagnosis of IBC (T4d) was based on AJCC cancer staging criteria. Patients had to have a Zubrod Performance Status of 0–2 and adequate hematologic, renal, and hepatic function. Patients over the age of 60 or with a history of hypertension were required to have a normal echocardiogram or multigated acquisition scan (MUGA). Patients were not permitted to have pre-existing peripheral neuropathy grade >2, be pregnant or nursing, or have a history of a cerebrovascular accident, transient ischemic attack, or cardiac event within 12 months prior to registration.\n\nTreatment plan\nFigure 1 illustrates the treatment schema. Patients were randomly assigned to Arm 1, 2, or 3 in a 2:1:1 ratio according to a dynamic allocation scheme based on two stratification factors (1) IBC vs. not and (2) hormone receptor-positive (ER/PgR+) vs. triple-negative breast cancer (TNBC).Fig. 1 Schema of randomized Phase II SWOG S0800 trial\n\n\n\nPatients randomized to treatment on Arm 1 (bevacizumab) received intravenous (IV) administration of nab-paclitaxel 100 mg/m2 IV weekly for 12 weeks (nP × 12) with IV bevacizumab 10 mg/kg every 2 weeks (six doses), followed by IV doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 with pegfilgrastim 6 mg subcutaneously every 2 weeks for six cycles (ddAC × 6). Patients randomized to Arm 2 received nP × 12 followed by ddAC × 6, and those randomized to Arm 3 received ddAC × 6 first followed by nP × 12, both without bevacizumab. The use of six cycles of AC was based on a similar therapy duration used in a parallel adjuvant SWOG study S0221 [32]. At the time when the study was initiated, the use of six cycles of doxorubicin and cyclophosphamide was common in breast cancer clinical trials [33, 34]. The ideal duration of adjuvant doxorubicin chemotherapy for patients with breast cancer, especially those with LABC, is not known. The results of the Cancer and Leukemia Group B trial 40101 conducted using a phase III factorial design, to define whether six cycles of a chemotherapy regimen are superior to four cycles, were not yet known [Shulman, 2014#5657]. The dose of nab-paclitaxel was chosen based on studies at the time showing that weekly administration of 100 mg/m2 nab-paclitaxel as single agent showed the same antitumor activity as 125 mg/m2, with the benefit of a more favorable toxicity profile in patients with advanced disease [35]. NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 was utilized for adverse event reporting and toxicity monitoring. The bevacizumab dose was never reduced, but treatment was held for uncontrolled hypertension or any grade 3 toxicity attributed to this agent and permanently discontinued for grade 3 hypertension not controlled medically. If the study treatment was interrupted for more than 3 consecutive weeks, the patient was taken off the study.\n\nSurgical management\nSurgery was performed within 3–6 weeks after completion of neoadjuvant chemotherapy. Patients with LABC who had an excellent clinical response could undergo breast-conserving surgery, but mastectomy was required for patients with IBC regardless of their response to treatment. Postneoadjuvant axillary staging was required for all patients. In clinical N0 patients, a sentinel node (SN) biopsy procedure was allowed; in patients who were still clinically node-positive and those with a positive SN biopsy, a full axillary lymph node dissection was required. Patients who progressed on study treatment were removed from protocol treatment. Postlumpectomy and postmastectomy standard breast radiation therapy (RT) was required irrespective of pathological response [36].\n\nPathologic evaluation\nPathologic response was determined by local pathologists who were instructed on the study definition of pCR. Surgical pathology reports were reviewed centrally for accuracy of coding by the study chair (Z.N.) without the knowledge of treatment assignment. pCR was defined as the absence of residual invasive disease with or without ductal carcinoma in situ (ypT0/isN0) in breast and axilla. Specific procedures were provided for evaluation of surgical specimens following neoadjuvant therapy (Appendix).\n\nStatistical analysis\nSWOG S0800 was a randomized Phase II trial comparing the experimental bevacizumab arm (Arm 1) with the control (no bevacizumab) arms (Arms 2 and 3). Accrual was expected to take 2 years with a planned follow-up of two additional years. Based on SWOG study S0012 with similar patients and similar chemotherapy backbone [37], we estimated that the control pCR rate would be 25 %, and that a sample size of 200 would allow detection of an increase of 15 % in pCR rate to 40 %. Power was 80 % (1-sided α = 0.10) for the primary comparison of bevacizumab versus no bevacizumab (collapsing over the two sequences). Dynamic balancing was used to adjust the randomization probabilities so that patient allocation was balanced within each stratum. Near the end of the trial an incorrect adjustment by SWOG programming staff disturbed the dynamic balancing allocation, causing more patients to be assigned to Arm 2 and fewer to Arm 3 than intended. However, this did not affect the primary comparison of pCR rates between bevacizumab versus no bevacizumab. Analysis was intent-to-treat of eligible patients which is the SWOG standard approach [38].\n\nThe secondary randomization of sequence between Arms 2 and 3 was conducted to allow study of the impact of potential predictive biomarkers such as SPARC proteins. There was no expectation of a difference in pCR due to the sequencing, and the primary statistical plan was to compare the intervention arm to the combined control arms. Predictive longitudinal biomarker studies are being conducted comparing all three arms and will be reported separately [39].\n\nOverall survival (OS) was a secondary endpoint defined as the time from registration to death due to any cause. We also analyzed event-free survival (EFS) starting at the time of registration. Events included progression prior to surgery, recurrence postsurgery, or death from any cause. Patients without an event were censored at the last known follow-up time. OS and EFS were analyzed using stratified log-rank tests and Cox regression.\n\nThe third objective was to explore for an interaction between bevacizumab and the stratification factors on pCR. A Cochran–Mantel–Haenszel test was performed for the primary analysis comparing pCR rates between the bevacizumab and no bevacizumab groups adjusting for the stratifying variables. We then used logistic regression to explore for an interaction of treatment with type of disease and ER/PgR status. The SWOG Data and Safety Monitoring Committee reviewed the study every 6 months for safety, but no interim analyses were planned or conducted.\n\nResults\nPatient characteristics\nBetween May 2010 and September 2012, 215 patients from SWOG member institutions were enrolled and randomized. Two patients were deemed ineligible due to clinical Stage IIA disease and two more withdrew consent leaving 211 patients for analysis. The final allocation of analyzable patients was 98, 62, and 51 in Arms 1, 2, and 3, respectively (Fig. 2).Fig. 2 Consort diagram for S0800\n\n\n\nBaseline characteristics of the patients and their tumors are provided in Table 1. The vast majority of the participants had non-inflammatory LABC (89 %), whereas only 11 % had IBC. Sixty-eight percent of tumors were ER/PgR+.Table 1 Demographic and disease characteristics at randomization\n\n\tArm 1\nBevacizumab\nNab-paclitaxel\nDD AC\tArms 2 and 3\nNo Bevacizumab\nNab-paclitaxel\nDD AC\tTotal\t\nRandomized\t99\t116\t215\t\nIneligible or withdrew consent\t1 (1.0 %)\t3 (2.6 %)\t4 (1.9 %)\t\nAnalyzed\t98\t113\t211\t\nAge median (range)\t51.7 (22–71)\t51.3 (31–75)\t51.5 (22–75)\t\nRace\t\t\t\t\n White\t70 (71.4 %)\t84 (74.3 %)\t154 (73.0 %)\t\n Black\t20 (20.4 %)\t18 (15.9 %)\t38 (18.0 %)\t\n Asian/Pacific Islander\t5 (5.1 %)\t6 (5.3 %)\t11 (5.2 %)\t\n Other/unknown\t3 (3.1 %)\t5 (4.4 %)\t8 (3.8 %)\t\nIBC or Non-IBC LABC\t\t\t\t\n IBC\t10 (10.2 %)\t14 (12.4 %)\t24 (11.4 %)\t\n Non-IBC LABC\t88 (89.8 %)\t99 (87.6 %)\t187 (88.6 %)\t\nHormone receptor status\t\t\t\t\n Positive: ER+ or PgR+\t66 (67.3 %)\t78 (69.0 %)\t144 (68.2 %)\t\n Negative: ER− and PR− (TNBC)\t32 (32.7 %)\t35 (31.0 %)\t67 (31.8 %)\t\nBreast cancer stage (1 missing)\t\t\t\t\n IIB\t35 (35.7 %)\t52 (46.4 %)\t87 (41.4 %)\t\n IIIA\t32 (32.6 %)\t30 (26.8 %)\t62 (29.5 %)\t\n IIIB\t29 (29.6 %)\t24 (21.4 %)\t53 (25.2 %)\t\n IIIC\t2 (2.0 %)\t6 (5.4 %)\t8 (3.8 %)\t\n\n\nPrimary outcome\nTable 2 shows pCR rates by randomized group and predefined patient subsets. Seventeen (8 %) patients had either no definitive surgery (n = 15) or an incomplete pathology report (n = 2), and were coded as no pCR in the intention-to-treat analyses. At the time of surgery, 135 (64 %) of the 211 patients had residual invasive disease (no pCR) and 59 (28 %) patients achieved a pCR. Overall, the pCR rate was significantly higher in patients who received bevacizumab 36 vs. 21 % for the non-bevacizumab arms; stratified p = 0.019). In ER/PgR+ disease (defined as >1 % expression by immunohistochemistry (IHC) stain), there was no statistically significant difference (bevacizumab 24 % vs. non-bevacizumab 18 %; p = 0.41), whereas the pCR rate was statistically superior with bevacizumab in TNBC (bevacizumab 59 % vs. non-bevacizumab 29 %; p = 0.014). In non-IBC, the overall pCR rate was 29 % with a higher rate in the patients treated with bevacizumab (36 vs. 22 %; p = 0.037). A higher pCR rate for bevacizumab-treated patients with IBC (30 vs. 14 %) was not statistically significant in this small patient subset (p = 0.61). In a multivariate logistic regression analysis, the increase in the pCR rate with bevacizumab was statistically significant (p = 0.023) adjusting for the type of disease (IBC vs. not; ER/PgR+ vs. TNBC) and neither significantly interacted with treatment (p = 0.62 and p = 0.19, respectively). In the non-bevacizumab arms, pCR rates did not differ by treatment sequence (Arm 2 23 %, Arm 3 20 %, p = 0.82), justifying merging these two control groups. Of the 195 patients who had surgery recorded after neoadjuvant therapy, 41 (21 %) had a lumpectomy rather than a mastectomy, which did not vary by treatment (bevacizumab 22 %; no bevacizumab 20 %; p = 0.86).Table 2 Primary outcome of pathological complete response (pCR) by randomized arm\n\n\tArm 1\nBevacizumab\nNab-paclitaxel\nDD AC\n\nN = 98\tArms 2 and 3\nNo Bevacizumab\nNab-paclitaxel\nDD AC\n\nN = 113\tTotal\t\nStatus at surgery postchemo\t\t\t\t\n No surgery/incomplete report\t7 (7.1 %)\t10 (8.9 %)\t17 (8.0 %)\t\n Residual disease\t56 (57.1 %)\t79 (69.9 %)\t135 (64.0 %)\t\n Pathological complete response\t35 (35.7 %)\t24 (21.2 %)\t59 (28.0 %)\t\nNumber with pCR (rates)\t\t\t\t\n Overall\t35/98 (35.7 %)\t24/113 (21.2 %)\t59/211 (28.0 %)\t\n IBC\t3/10 (30.0 %)\t2/14 (14.3 %)\t5/24 (20.8 %)\t\n Non-IBC LABC\t32/88 (36.4 %)\t22/99 (22.2 %)\t54/187 (28.9 %)\t\n ER/PgR-positive\t16/66 (24.2 %)\t14/78 (18.0 %)\t30/144 (20.8 %)\t\n TNBC\t19/32 (59.4 %)\t10/35 (28.6 %)\t29/67 (43.3 %)\t\n\n\nSecondary end points\nFigure 3a shows the Kaplan–Meier comparison of OS. Thus far, there have been 31 deaths with a median follow-up of about 3 years, with 3-year OS of 86 and 87 % for the bevacizumab and non-bevacizumab groups, for a hazard ratio (HR) of 0.84 (95 % CI 0.41–1.73, p = 0.64). When separated by hormone receptor status, there were no significant differences in OS between the bevacizumab and non-bevacizumab groups. The survival curves suggest a possible small benefit in the TNBC subset [Fig. 3b: HR = 0.49 (95 % CI 0.19–1.29), log-rank p = 0.14] but not in the ER/PgR+ subset (Fig. 3c: HR = 1.85 (95 % CI 0.58–5.85), log-rank p = 0.33), but the interaction of hormone receptor status and bevacizumab for OS was not statistically significant (p = 0.14). In a landmarked analysis starting at 6 months (i.e., after surgery), having a pCR was highly associated with subsequent OS for hormone receptor-negative disease (HR = 0.15; 95 % CI 0.03–0.63), but not for hormone receptor-positive disease (HR = 0.32; 95 % CI 0.04–2.50).Fig. 3 Overall survival. Time from randomization to death due to any cause. a Overall survival for all patients. b Overall survival for patients with triple-negative (ER− and PgR−) disease. c Overall survival for patients with ER+ or PgR+ disease\n\n\n\nEvent-free survival (EFS) also showed no significant difference by treatment (Fig. 4a: p = 0.71; HR = 0.89; 95 % CI 0.48–1.65). When separated by hormone receptor status, there were no significant differences for EFS, but in TNBC there was a trend favoring the bevacizumab arm [Fig. 4b: HR = 0.46 (95 % CI 0.20–1.05), log-rank p = 0.06] which was not seen in ER/PgR+ patients [Fig. 4c: HR = 2.20 (95 % CI 0.84–5.78), log-rank p = 0.10], and the interaction of treatment and receptor status was statistically significant for EFS (p = 0.028).Fig. 4 Event-free survival. Time from randomization to progression, recurrence, or death due to any cause. a Event-free survival for all patients. b Event-free survival for patients with triple-negative (ER− and PgR−) disease. c Event-free survival for patients with ER+ or PgR+ disease\n\n\n\nTreatment delivery and toxicity\nOverall, Grade 3/4 events were common and did not differ between the bevacizumab and non-bevacizumab arms (bevacizumab 67 %; non-bevacizumab 65 %) (Table 3). Grade 4 toxicities were seen in 19 (21 %) of patients in the bevacizumab arm (two with sepsis, one with respiratory failure, one with bilateral pulmonary emboli and deep vein thrombosis, and 17 with hematologic events that included anemia, febrile neutropenia, or thrombocytopenia). On the other hand, 20 (19 %) patients in the non-bevacizumab arm experienced Grade 4 events (one with heart failure, infectious enterocolitis, sepsis, and respiratory failure, one with dyspnea, one with Grade 4 anemia and hypercalcemia, one with anemia and febrile neutropenia, and 17 with other hematologic toxicities).Table 3 Serious adverse events (Grades 3 and 4) by treatment arm\n\n\tArm 1\nBevacizumab\nNab-paclitaxel\nDD AC\n\nN = 95\tArms 2 and 3\nNo Bevacizumab\nNab-paclitaxel\nDD AC\n\nN = 110\tTotal\t\nAny event\t64 (67 %)\t69 (63 %)\t133 (65 %)\t\nARDS\t1 (1 %)\t0 (0 %)\t1 (1 %)\t\nDiarrhea\t3 (3 %)\t2 (2 %)\t5 (2 %)\t\nDyspnea\t3 (3 %)\t1 (1 %)\t4 (2 %)\t\nEnterocolitis, infectious\t0 (0 %)\t2 (2 %)\t2 (1 %)\t\nHand foot syndrome\t1 (1 %)\t2 (2 %)\t3 (1 %)\t\nHeart failure\t0 (0 %)\t1 (1 %)\t1 (1 %)\t\nHematologic events (including anemia, febrile neutropenia, thrombocytopenia)\t44 (46 %)\t39 (35 %)\t83 (40 %)\t\nHypercalcemia\t0 (0 %)\t1 (1 %)\t1 (1 %)\t\nHypertension\t7 (7 %)\t3 (3 %)\t10 (5 %)\t\nNausea\t6 (6 %)\t9 (8 %)\t15 (7 %)\t\nPain\t2 (2 %)\t4 (4 %)\t6 (3 %)\t\nRespiratory failure\t1 (1 %)\t1 (1 %)\t2 (1 %)\t\nSepsis\t2 (2 %)\t1 (1 %)\t3 (1 %)\t\nThromboembolic event\t1 (1 %)\t2 (2 %)\t3 (1 %)\t\n\n\nDiscussion\nWe demonstrate that the addition of bevacizumab to neoadjuvant chemotherapy significantly increased the pCR rate in patients with LABC/IBC without significant additional toxicity, and that this increase was more pronounced in patients with TNBC. These data suggest that the addition of bevacizumab to anthracycline- and taxane-based chemotherapy enhances its cytotoxicity.\n\nThe addition of bevacizumab to chemotherapy in patients with metastatic breast cancer was initially approved by the FDA on the basis of improvements in response rate and PFS, but this approval was withdrawn when these studies failed to demonstrate improvement in OS [40], while the European Medicines Agency (EMA) has approved its use with paclitaxel and capecitabine. Meanwhile, four large randomized trials, in addition to S0800, have investigated the addition of bevacizumab to neoadjuvant chemotherapy for breast cancer [40–43]. All have reported a significant benefit with the addition of bevacizumab to anthracycline/taxane-based chemotherapy (Table 4). As in our trial, GeparQuinto, CALGB 40603, and ARTemis demonstrated a significant increase in the pCR rate in patients with TNBC, while NSABP B-40 demonstrated a higher pCR rate with bevacizumab in ER/PgR+ breast cancer but no statistically significant difference in TNBC.Table 4 Neoadjuvant bevacizumab trials in HER2-negative breast cancer\n\nTrial (definition of pCR)\tpCR\tDFS\tOS\t\nAll (%)\tER/PgR positive (%)\tER and PgR negative (%)\t\nS0800 (ypT0, ypTis, ypN0)\t\t\t\t3 years\t3 years\t\nBevacizumab\t36\t24\t59\tHR = 0.89\n\nP = 0.71\t86 %\t\nNo bevacizumab\t21\t18\t29\t\t87 %\t\nGeparQuinto [41] (ypT0, ypN0)\t\t\t\t3 years\t3 years\t\nBevacizumab\t18.4\t7.7\t39.9\t80.8 %\t90.7 %\t\nNo bevacizumab\t14.9\t7.8\t81.5\t81.5 %\t88.7 %\t\nArtemis [40] (ypT0, ypTis, ypN0)\t\t\t\tNot reported\tNot reported\t\nBevacizumab\t22.0\t6.0\t45.0\t\t\t\nNo bevacizumab\t17.0\t7.0\t31.0\t\t\t\nNSABP-B40 [44] (ypT0, any pN)\t\t\t\t5 years\t5 years\t\nBevacizumab\t34.5\t23.2\t51.1\tHR = 0.8\n\nP = 0.06\tHR = 0.65\n\nP = 0.004\t\nNo bevacizumab\t28.2\t15.1\t47.1\t\t\t\nCALGB 40603 [43] (ypT0, any pN)\t\t\t\tNot reported\tNot reported\t\nBevacizumab\tNA\tNA\t59\t\t\t\nNo Bevacizumab\tNA\tNA\t48\t\t\t\n\nER estrogen receptor, HR hazard ratio, pCR pathologic complete response, PGR progesterone receptor, TN triple negative, DFS disease-free survival, OS overall survival, NA not applicable\n\n\n\nOur EFS and OS results failed to demonstrate significant differences favoring the addition of bevacizumab for the overall study population, but in the relatively small (n = 67) TNBC subset, the EFS and OS hazard ratios trend in favor of the bevacizumab arm (HR 0.46, p = 0.06 and HR 0.49, p = 0.14), respectively, while the hazard ratios for these endpoints trend negatively in the larger ER/PGR+ population (HR 2.20, p = 0.10 and HR 1.85, p = 0.33, respectively). None of the neoadjuvant studies was powered to definitely demonstrate an EFS or OS benefit for the addition of bevacizumab, overall or in the TNBC population. The only study to show a survival benefit with bevacizumab was NSABP B-40, which was also the only one in which patients received bevacizumab in the adjuvant as well as the neoadjuvant settings; as with their pCR data, the survival benefit was seen only in the ER/PgR+ subset, and OS improvement was reported despite the absence of significant improvement in DFS [44]. The addition of bevacizumab also failed to improve DFS or OS in two sizable trials in the adjuvant setting [19, 20]; however, these trials were comprised largely of lower risk patients, and in E5103 the improvement in DFS with bevacizumab for TNBC approached significance (HR 0.77, 95 % CI 0.58–1.03).\n\nThese studies suggest that bevacizumab may be most helpful in patients with high-risk cancers, defined by both clinical stage and subtype. We have failed to identify any subset of breast cancer patients most likely to benefit from bevacizumab [22, 45]. In CALGB 40603, a randomized phase II limited to stage II-III TNBC, investigators studied how intrinsic subtype assigned by PAM50 and other gene signatures affected the impact of bevacizumab on pCR rates [46]. In basal-like cancers, the addition of bevacizumab significantly increased pCR in the breast (64 vs 45 %) and the breast/axilla (57 vs 43 %) rates, while paradoxically lowering pCR rates in relatively small (12.7 %) number of non-basal-like cancers, resulting in a significant interaction between subtype and bevacizumab-specific pCR benefit (p = 0.02). mRNA signatures for high proliferative rate, low estrogen signaling, and high TP53 mutation were also associated with greater pCR benefit with the addition of bevacizumab, suggesting that even within TNBC there are biologically defined patient subsets that may benefit differentially from this agent. Similar analyses are underway for S0800, and will be reported separately. If confirmed, these findings could suggest that identifying and excluding a biologically defined subset of ‘bevacizumab-resistant’ patients lead to positive DFS and OS results from studies of bevacizumab in the adjuvant or neoadjuvant settings.\n\nWe also hypothesize that bevacizumab may have had activity in our study because of the unique eligibility requirement for LABC/IBC. Several studies have shown that such extensive tumors with high levels of neoangiogenesis are more likely to benefit from the addition of bevacizumab to chemotherapy than early-stage cancers with lower levels of tumor vasculature [1, 8–11, 47]. Therefore, we propose that perhaps these patients are particularly susceptible to an antiangiogenic agent such as bevacizumab.\n\nOur study has several limitations. The power of a trial to detect survival improvement from (neo) adjuvant chemotherapy is influenced by the subtype composition of the accrued patients [48, 49]. Slightly more than two-thirds of our patients had ER/PgR+ cancers. Not only are these patients much less likely to achieve a pCR, they also have a better prognosis than TNBC and other more aggressive breast cancer subtypes. Nearly 80 % of our ER/PgR+ patients, across all treatment arms, were alive and free of disease recurrence at 4 years; EFS was only 50 % in TNBC patients assigned to the control arm, almost sufficient for demonstrating a significant benefit in a small cohort. Effective postneoadjuvant therapy, especially adjuvant endocrine therapy in ER/PgR+ cancers, improves outcomes in patients with residual disease and thus diminishes the impact of a more effective neoadjuvant regimen.\n\nIn summary, we find the trend favoring improvement in EFS in our high-risk TNBC subset encouraging and believing that the addition of bevacizumab to chemotherapy in the neoadjuvant setting for these patients warrants further investigation. While the role of bevacizumab remains uncertain due to the lack of OS improvement in several studies that included a high proportion of low- to moderate-risk patients, the consistent association between the addition of bevacizumab with higher response and pCR rates in metastatic and neoadjuvant trials is intriguing and underscores the importance of finding predictive biomarkers for this drug. Our results also suggest that it may worth re-evaluating the role of bevacizumab in locally advanced TNBC.\n\nAppendix: Surgical procedure\nIdentification of the tumor bed was done by placement of clips by core needle biopsy prior to treatment. However, in the absence of a clip, detailed information about the location (quadrant, clock face, distance from nipple) and the presence of any other identifiable features (e.g., calcifications) was required to identify the tumor bed. Axillary staging requirements were as noted previously. Also, a detailed procedure for evaluation of surgical specimens following neoadjuvant therapy was described. Specimens were oriented with sutures by the surgeon following removal. The surgeon and breast pathologist were required to confer to ensure optimal evaluation of the primary tumor site for possible pCR. (1) In cases showing significant clinical response, each specimen was inked using multiple colors to identify each face of the specimen and then sectioned into 3–5 mm slices. The sliced specimen was radiographed and a radiologist reviewed the films to determine the presence and extent of residual tumor. The pathologist examined the sliced specimen grossly to identify suspicious areas and noted their proximity to margins. The radiographic and pathological evaluation was discussed with the surgeon who decided whether additional margins should be obtained. Permanent paraffin sections of the suspicious areas and margins were obtained. The number of sections taken was based on the gross inspection, radiologic features, and size of the resection specimen. The entire radiographic abnormality as well as firm and suspicious-appearing breast tissue was submitted for histologic evaluation. In general, for non-palpable (clinical complete response) cases, at least 10–15 blocks were examined to assess the presence of residual microscopic disease; (2) in cases with residual palpable mass (partial clinical response or no response in the breast), the resection specimen was inked and sectioned into 3–5 mm slices. The pathologist examined the slices and determined the tumor size on gross evaluation and confirmed the tumor size by microscopic evaluation; (3) Evaluation of axillary lymph nodes regardless of response. All axillary lymph nodes were also carefully evaluated by serial gross sectioning. One or two representative histologic sections were evaluated for lymph nodes that contain grossly identifiable metastatic carcinoma. The lymph nodes that do not show grossly identifiable tumor were submitted for histologic evaluation in their entirety. One representative histologic section was evaluated per paraffin block.\n\nFunding\nThe work was supported in part by the National Institutes of Health (NIH)/National Cancer Institute (NCI)/National Clinical Trials Network (NCTN) grants CA180888, CA180819, CA180821, CA180835, CA180830, CA180846, CA180801, CA180834; NIH/NCI Community Oncology Research Program (NCORP) grants CA189954, CA189856, CA189971, CA189822, CA189952, CA189804, CA189817, CA189953, CA189858, CA189957, CA189872, CA189853; legacy NIH/NCI grants CA35119, CA52654, CA04919, CA37981, CA58416, CA16385; and in part by Genentech (Roche), Abraxis BioScience (Celgene), and Helomics™.\n\nCompliance with ethical standards\nConflicts of interest\nAll remaining authors have declared that they have no conflicts of interest to report.\n\nDisclosure\nEmployment: E. Perez: Genentech; Stock or other ownership: E. Perez: Genentech; D. Hayes: Oncimmune LLC, De Soto, KS, USA, and Inbiomotion, Barcelona, Spain; Consulting or advisory role: J. Gralow: Novartis, Roche/Genentech; G. Hortobagyi: Lilly USA, LLC, Celgene, Norvartis, Merck, Bayer and Peregrine Pharmaceuticals, Inc; H. Mirshahidi: Clovis Oncology, Boehringer; D. Hayes: Pfizer Global Advisory Board for pablociclib; W. Sikov: Abbvie, Celgene (uncompensated) Honoraria: L. Pusztai: Celgene; D. Hayes: Lecture/Honorarium as a Visiting Consultant for Lilly Oncology, Indianapolis, IN; W Sikov: Eisai, Celgen Research funding: J. Gralow: Novartis, Roche/Genentech; L. Pusztai/institution/clinical trial support: D. Hayes: Sponsored Clinical Research—Principle or co-Investigator: Merrimack Pharmaceuticals, Inc. (Parexel Intl Corp), Eli Lilly Company, Janssen R&D, LLC (Johnson & Johnson), Veridex (Johnson & Johnson), Puma Biotechnology, Inc., (subcontract Wash Univ St. Louis to Univ Mich), Pfizer, Astra Zeneca, Astra Zeneca; Travel, accommodations or expenses: L. Pusztai/self: Celgene Royalties: D. Hayes: Royalties from licensed technology: Janssen R&D, LLC (Johnson & Johnson); Patents: D. Hayes: Title: A method for predicting progression free and overall survival at each follow-up timepoint during therapy of metastatic breast cancer patients using circulating tumor cells. Filed 14 Mar 2005 with the European Patent Office, Netherlands. Application No./Patent No. 05725638.0-1223-US2005008602. Applicant/Proprietor: Immunicon Corporation. Dr. Daniel F. Hayes is designated as inventor/coinventor. Title: Diagnosis and Treatment of Breast Cancer. Patent No.: US 8,790,878 B2. Date of Patent: Jul. 29, 2014. Applicant Proprietor: University of Michigan. Dr. Daniel F. Hayes is designated as inventor/coinventor. Title: Circulating Tumor Cell Capturing Techniques and Devices. Patent No.: US 8,951,484 B2. Date of Patent: Feb. 10, 2015. Applicant Proprietor: University of Michigan. Dr. Daniel F. 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Sikov WM, Barry WT, Hoadley KA et al (2015) Impact of intrinsic subtype by PAM50 and other gene signatures on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NACT) plus/- carboplatin (Cb) or bevacizumab (Bev): CALGB 40603/150709 (Allianc). Cancer Res 75(9 Suppl):S4–05\n47. Tredan O Lacroix-Triki M Guiu S Angiogenesis and tumor microenvironment: bevacizumab in the breast cancer model Target Oncol 2015 10 189 198 10.1007/s11523-014-0334-9 25185646 \n48. Kaufmann M von Minckwitz G Mamounas EP Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer Ann Surg Oncol 2012 19 1508 1516 10.1245/s10434-011-2108-2 22193884 \n49. Korn EL Sachs MC McShane LM Statistical controversies in clinical research: assessing pathologic complete response as a trial-level surrogate end point for early-stage breast cancer Ann Oncol 2015 27 1 10 15 10.1093/annonc/mdv507 26489443\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0167-6806",
"issue": "158(3)",
"journal": "Breast cancer research and treatment",
"keywords": "Bevacizumab; Breast cancer; Inflammatory; Locally advanced; Neoadjuvant",
"medline_ta": "Breast Cancer Res Treat",
"mesh_terms": "D000328:Adult; D000368:Aged; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001943:Breast Neoplasms; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017239:Paclitaxel; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8111104",
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"pages": "485-95",
"pmc": null,
"pmid": "27393622",
"pubdate": "2016-08",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't; D052061:Research Support, N.I.H., Extramural",
"references": "16407877;25975632;11309294;12636887;26272770;21220618;16301832;23770008;16505422;16293862;21121833;17159189;21729988;25185646;15939715;23401453;21472137;25422488;9377574;22652232;8668675;12793894;17139244;12516032;24351399;16391297;11230499;11250736;22193884;21126687;22276820;22276821;22508812;9886175;20180029;18258987;18269774;16244790;18021479;23932548;26489443;16489089;25092775;21285431;12202663",
"title": "SWOG S0800 (NCI CDR0000636131): addition of bevacizumab to neoadjuvant nab-paclitaxel with dose-dense doxorubicin and cyclophosphamide improves pathologic complete response (pCR) rates in inflammatory or locally advanced breast cancer.",
"title_normalized": "swog s0800 nci cdr0000636131 addition of bevacizumab to neoadjuvant nab paclitaxel with dose dense doxorubicin and cyclophosphamide improves pathologic complete response pcr rates in inflammatory or locally advanced breast cancer"
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"abstract": "BACKGROUND\nA targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy.\n\n\nMETHODS\nPatients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety.\n\n\nRESULTS\nThree hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75-1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81-1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups.\n\n\nCONCLUSIONS\nBevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment.\nUMIN000002557.",
"affiliations": "Department of Surgery, Kansai Medical University Hirakata Hospital, Hirakata iwamoto@hirakata.kmu.ac.jp.;Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu.;Department of Gastroenterological Surgery, Osaka General Medical Center, Osaka.;Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto.;Department of Surgery, Fukuiken Saiseikai Hospital, Fukui.;Department of Surgery, Kansai Rosai Hospital, Amagasaki.;Department of Surgery, Osaka University, Suita.;Department of Gastroenterology, Chiba Cancer Center, Chiba.;Department of Radiology, Kobe Medical Center, Kobe.;Department of Integrated Medicine, Kagawa University, Kita.;Department of Surgery, Gifu Prefectural General Medical Center, Gifu.;Department of Surgery, Kitakyushu General Hospital, Kitakyusyu.;Second Department of Surgery, Hamamatsu University School of Medicine, Shizuoka.;Department of Medical Oncology, Nagoya Memorial Hospital, Nagoya.;Department of Surgery, Toho University Medical Center Sakura Hospital, Sakura.;Department of Chemotherapy, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo.;Department of Gastroenterological Surgery, Kumamoto University, Kumamoto.;Department of Biostatistics, School of Public Health, Graduate School of Medicine and Interfaculty Initiative in Information Studies, The University of Tokyo, Tokyo.;Tokai Central Hospital, Kagamihara.;Cancer Center, Aichi Medical University, Nagakute, Japan.",
"authors": "Iwamoto|S|S|;Takahashi|T|T|;Tamagawa|H|H|;Nakamura|M|M|;Munemoto|Y|Y|;Kato|T|T|;Hata|T|T|;Denda|T|T|;Morita|Y|Y|;Inukai|M|M|;Kunieda|K|K|;Nagata|N|N|;Kurachi|K|K|;Ina|K|K|;Ooshiro|M|M|;Shimoyama|T|T|;Baba|H|H|;Oba|K|K|;Sakamoto|J|J|;Mishima|H|H|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000068258:Bevacizumab; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdv197",
"fulltext": "\n==== Front\nAnn OncolAnn. OncolannoncannoncAnnals of Oncology0923-75341569-8041Oxford University Press 10.1093/annonc/mdv197mdv197Original ArticlesGastrointestinal TumorsFOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study† Iwamoto S. 1‡*Takahashi T. 2‡Tamagawa H. 3Nakamura M. 4Munemoto Y. 5Kato T. 6Hata T. 7Denda T. 8Morita Y. 9Inukai M. 10Kunieda K. 11Nagata N. 12Kurachi K. 13Ina K. 14Ooshiro M. 15Shimoyama T. 16Baba H. 17Oba K. 18Sakamoto J. 19Mishima H. 201 Department of Surgery, Kansai Medical University Hirakata Hospital, Hirakata2 Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu3 Department of Gastroenterological Surgery, Osaka General Medical Center, Osaka4 Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto5 Department of Surgery, Fukuiken Saiseikai Hospital, Fukui6 Department of Surgery, Kansai Rosai Hospital, Amagasaki7 Department of Surgery, Osaka University, Suita8 Department of Gastroenterology, Chiba Cancer Center, Chiba9 Department of Radiology, Kobe Medical Center, Kobe10 Department of Integrated Medicine, Kagawa University, Kita11 Department of Surgery, Gifu Prefectural General Medical Center, Gifu12 Department of Surgery, Kitakyushu General Hospital, Kitakyusyu13 Second Department of Surgery, Hamamatsu University School of Medicine, Shizuoka14 Department of Medical Oncology, Nagoya Memorial Hospital, Nagoya15 Department of Surgery, Toho University Medical Center Sakura Hospital, Sakura16 Department of Chemotherapy, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo17 Department of Gastroenterological Surgery, Kumamoto University, Kumamoto18 Department of Biostatistics, School of Public Health, Graduate School of Medicine and Interfaculty Initiative in Information Studies, The University of Tokyo, Tokyo19 Tokai Central Hospital, Kagamihara20 Cancer Center, Aichi Medical University, Nagakute, Japan* Correspondence to: Dr Shigeyoshi Iwamoto, Department of Surgery, Kansai Medical University Hirakata Hospital, Shinnmachi 2-3-1, Hirakata, Osaka 573-1010, Japan. Tel: +81-72-804-0101; E-mail: iwamoto@hirakata.kmu.ac.jp† Previously presented in part at the 2013 American Society of Clinical Oncology Annual Meeting, May 31–June 4, 2013, Chicago, IL.\n\n‡ Both authors contributed equally to this study.\n\n7 2015 23 4 2015 23 4 2015 26 7 1427 1433 18 2 2015 14 4 2015 15 4 2015 © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.2015This 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.comEAGLE was a randomized, multicenter phase III study which evaluated the superiority of bevacizumab 10 mg/kg plus FOLFIRI compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC previously treated with first-line bevacizumab plus an oxaliplatin-based regimen. The results suggest that the higher 10 mg/kg dose offers no clear clinical benefit compared with bevacizumab 5 mg/kg in this setting.\n\nBackground\nA targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy.\n\nPatients and methods\nPatients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety.\n\nResults\nThree hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75–1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81–1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups.\n\nConclusion\nBevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment.\n\nClinical trial identifier\nUMIN000002557.\n\nbevacizumabchemotherapymetastatic colorectal cancerdosesecond-line therapyrandomized controlled trialEpidemiological and Clinical Research Information Network (ECRIN; Kyoto, Japan)\n==== Body\nintroduction\nIn 2012, an estimated 1.3 million people had colorectal cancer, making it the third most common cancer worldwide [1]. In Japan, the incidence and mortality rates of colorectal cancer increased between 1958 and the mid-1990s, and have since stabilized or decreased slightly [2]. Based on data published in 2012, colorectal cancer is the third most common cause of death in women and the fourth most common cause of death in men in Japan [3].\n\nStandard chemotherapy combinations for the treatment of metastatic colorectal cancer (mCRC) are either 5-fluorouracil plus leucovorin combined with oxaliplatin (e.g. FOLFOX) or irinotecan (e.g. FOLFIRI) combined with a targeted agent directed against vascular endothelial growth factor (VEGF), epithelial growth factor receptor (EGFR), or multiple targets. Bevacizumab (Avastin®; Genentech), a recombinant, humanized monoclonal antibody directed against VEGF, is well established in the first-line treatment of mCRC [4, 5]. However, four questions regarding its continued use after disease progression remain: (i) Does continuous bevacizumab as second-line treatment offer any benefit? (ii) Is it preferable to treat with an anti-VEGF inhibitor or an anti-EGFR inhibitor? (iii) What is the optimal dose of bevacizumab?, and (iv) Which is the best anti-angiogenic agent?\n\nThe first question was answered by the ML18147 study, which showed that median overall survival (OS) was significantly prolonged with continuation of bevacizumab 5 mg/kg after progression compared with chemotherapy alone [6]. The second question was investigated in a randomized phase II study (SPIRITT), which reported similar efficacy with panitumumab plus FOLFIRI and bevacizumab plus FOLFIRI in patients with previously treated wild-type KRAS mCRC [7], although further trials are needed. The last two questions remain unanswered.\n\nRegarding the optimal dose of bevacizumab as second-line therapy, the E3200 study showed that bevacizumab 10 mg/kg biweekly plus chemotherapy improved median OS, compared with chemotherapy alone and bevacizumab alone, in bevacizumab-naive patients [8]; yet, a lower dose of 5 mg/kg biweekly was tested in the registration trials of bevacizumab as first-line therapy [4, 5]. Furthermore, there is some evidence that the effects of bevacizumab may be dose-related [9, 10].\n\nWe compared the efficacy and safety of bevacizumab 5 mg/kg plus FOLFIRI with that of bevacizumab 10 mg/kg plus FOLFIRI in the second-line setting in Japanese patients with mCRC following disease progression or toxicity with bevacizumab plus an oxaliplatin-based regimen (EAGLE study).\n\npatients and methods\nstudy design and patient selection\nThe EAGLE study was a randomized, multicenter, open-label, two-arm phase III study designed to evaluate the superiority of bevacizumab 10 mg/kg plus FOLFIRI compared with bevacizumab 5 mg/kg plus FOLFIRI as second-line therapy in patients with mCRC previously treated with first-line bevacizumab plus an oxaliplatin-based regimen. Patients were recruited in Japanese institutions. Written informed consent was obtained from all participating patients. The study was conducted in compliance with the 2008 Declaration of Helsinki and approved by institutional review boards. Details of the trial design have been published elsewhere [11]. The trial was registered on the University Hospital Medical Information Network (http://www.umin.ac.jp/ctr/; identifier: UMIN000002557).\n\nThe enrolled patients were randomized 1 : 1 at the data center (ECRIN Datacenter, Kyoto, Japan). Dynamic randomization was based on the minimization method with the following stratification factors: Eastern Cooperative Oncology Group (ECOG) performance status (0/1), number of metastatic organs (<2/≥2), reason for starting second-line treatment (disease progression/toxicity), early recurrence within 6 months from adjuvant chemotherapy (yes/no), and institution.\n\nEligibility criteria included patients with cytologically or histologically confirmed colorectal cancer, with disease progression or toxicity after receiving bevacizumab plus oxaliplatin-based therapy as first-line treatment of more than four cycles, 20 years of age or older, ECOG performance status of 0 or 1, life expectancy of 3 months or longer, and sufficient organ function. Patients who had received prior irinotecan treatment were not eligible.\n\ntreatment plan\nFOLFIRI plus bevacizumab consisted of bevacizumab 5 or 10 mg/kg as a 30-min infusion and l-leucovorin 200 mg/m2 as a 2-h infusion with concurrent irinotecan 150 mg/m2 as a 90-min infusion followed by bolus 5-fluorouracil 400 mg/m2 within 15 min and then a 46-h infusion of 5-fluorouracil 2400 mg/m2. Study treatment was given in 2-week cycles until disease progression, which was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1).\n\nDose reductions due to adverse events were allowed for 5-fluorouracil (bolus and infusion doses), irinotecan, and bevacizumab 10 mg/kg. 5-Fluorouracil and irinotecan doses were reduced on the occurrence of grade 4 neutropenia, grade 3 or 4 febrile neutropenia, grade 3 or 4 thrombocytopenia, and all non-hematological adverse events of grade 3 or higher. Bevacizumab 10 mg/kg was reduced in two steps (i.e. 7.5 and 5 mg/kg) on the occurrence of grade 2 hemorrhage, grade 2 or 3 proteinurea, grade 3 hypertension, and grade 3 or 4 hepatic toxicity. Study treatment was discontinued when the following adverse events occurred: grade 3 or 4 venous thrombosis, grade 2 or higher arterial thrombosis, posterior reversible encephalopathy syndrome, gastrointestinal perforation, and grade 3 allergic reactions. Dose reduction of bevacizumab was not allowed in the bevacizumab 5 mg/kg group.\n\nassessments\nDisease progression and the occurrence of new disease were monitored using abdominal radiography, abdominal computed tomography (CT) or magnetic resonance imaging, and thoracic CT every 8 weeks (RECIST 1.1), and by measuring levels of tumor markers (i.e. carcinoembryonic antigen [CEA] and carbohydrate antigen 19-9 [CA19-9]) every 4 weeks. Blood tests and monitoring for adverse events were conducted throughout the treatment period. The follow-up period was 1 year after registration of the last patient.\n\noutcomes\nThe primary end point was progression-free survival (PFS). The secondary end points included: OS, time from the start of first-line treatment until progression after the protocol treatment (second PFS), tumor response rate, time to treatment failure (TTF), and safety. PFS was defined as the time from the date of randomization to the first date of documented progression or death as a result of any cause. If no PFS event was observed, PFS was censored at the date of the last evaluable tumor assessment. OS was defined as the time from date of randomization to date of death due to any cause. TTF was defined as the time from the date of randomization to the date of each of the following, whichever occurred first: discontinuation of treatment, disease progression, or death from any cause. Response rate was assessed by using RECIST, version 1.1.\n\nToxicity was graded according to the National Cancer Institute Common Toxicity Criteria, version 3.0. In addition, dose intensity for the treatment period was calculated as the total cumulative dose divided by the duration of dosing (i.e. [start date of last cycle] – [start date of first cycle] + 14). Relative dose intensity was calculated as the dose intensity divided by the planned dose intensity, multiplied by 100. Planned dose intensities per cycle were 5 or 10 mg/kg for bevacizumab and 150 mg/m2 for irinotecan. If a patient continued study treatment, relative dose intensity was calculated using the latest treatment cycle as the last cycle.\n\nstatistical considerations\nThe median PFS of the bevacizumab 5 mg/kg group in this trial was assumed to be 5.0 months based on previous studies [8, 12], and prolongation of the median PFS to 7.0 months in the bevacizumab 10 mg/kg group was considered to be a clinically relevant increase (i.e. risk reduction of 30%). The required sample size to detect a 30% risk reduction with 90% power using a log-rank test with a two-sided significance level of 0.05 was 358 patients (330 events), assuming an accrual time of 2 years and a follow-up period of 1 year [13]. Taking some drop-outs into account, the total sample size was set at 370 patients.\n\nStatistical analysis was conducted in the full analysis set (modified intention-to-treat), which was as close as possible to the intention-to-treat principle of including all randomized subjects [14]. The full analysis set excluded patients who failed to satisfy major eligibility criteria based on the pre-randomization variable, patients without any post-randomization data, and those who withdrew consent. The safety evaluation was carried out in patients based on the actual treatment received (safety analysis set).\n\nTime-to-event end points were depicted by the Kaplan–Meier method and compared between groups using a stratified log-rank test (using all stratification factors, except for institute) at a two-sided significance level of 5%. A stratified Cox proportional hazards model was used to assess the hazard ratio with Wald-type 95% confidence intervals (CIs). Comparisons of response rates were conducted using the Fisher's exact test. Response rates were estimated with exact 95% CI. Subgroup analyses were also carried out in which the P-value for interaction was calculated with a Cox model including treatment group, baseline characteristics, and their interaction term. All analyses were carried out using SAS version 9.3.\n\nresults\npatients' characteristics\nA total of 387 patients were randomized between September 2009 and January 2012 from 100 institutions. The final follow-up of the study was on 28 September 2013. The median duration of follow-up was 394 (95% CI 344–432) days. Of the 369 patients included in the full analysis set, 181 patients were assigned to the bevacizumab 5 mg/kg group and 188 patients were assigned to the bevacizumab 10 mg/kg group. The number of patients included in the safety analysis set was 365, which excluded 4 patients who did not receive study treatment (5 mg/kg group, n = 1 and 10 mg/kg group, n = 3). A CONSORT flowchart is presented in supplementary Figure S1, available at Annals of Oncology online. Patient characteristics at baseline were well balanced between the two groups (Table 1). Time on first-line treatment (supplementary Figure S2, available at Annals of Oncology online) and the treatment-free interval between the end of first-line treatment and the start of second-line treatment (supplementary Figure S3, available at Annals of Oncology online) were similar in both treatment arms.\nTable 1. Baseline characteristics\n\n\tBevacizumab 5 mg/kg plus FOLFIRI (n = 181)\tBevacizumab 10 mg/kg plus FOLFIRI (n = 188)\t\nN\t%\tN\t%\t\nAge, years\t\n Median\t66\t65\t\n Range\t36–84\t31–88\t\nSex\t\n Male\t102\t56\t107\t57\t\n Female\t79\t44\t81\t43\t\nECOG performance status\t\n 0\t155\t86\t163\t87\t\n 1\t26\t14\t25\t13\t\nNo. of metastases\t\n <2\t84\t46\t84\t45\t\n ≥2\t97\t54\t104\t55\t\nReason for starting second-line treatment\t\n Progressive disease\t154\t85\t158\t84\t\n Toxicity\t27\t15\t30\t16\t\nTime to recurrence after adjuvant therapy\t\n ≤6 months\t23\t13\t25\t13\t\n >6 months\t158\t87\t163\t87\t\nPrimary cancer\t\n Colon\t115\t64\t104\t55\t\n Rectum\t66\t37\t84\t45\t\nCancer type\t\n Adenocarcinoma\t168\t93\t178\t95\t\n Other\t9\t5\t7\t4\t\n Unknown\t4\t2\t3\t2\t\nSite of metastases/recurrence\t\n Liver\t118\t65\t113\t60\t\n Lung\t75\t41\t88\t47\t\n Lymph nodes\t56\t31\t61\t32\t\n Peritoneum\t35\t19\t36\t19\t\n Othera\t25\t14\t28\t15\t\nFirst-line chemotherapy regimen\t\n mFOLFOX6\t105\t58\t110\t59\t\n XELOX\t27\t15\t36\t19\t\n Other\t49\t27\t42\t22\t\nResection status\t\n Resected\t153\t85\t149\t79\t\n Non-resected\t27\t15\t39\t21\t\nCycles of first-line oxaliplatin, n\t\n Median\t12\t12\t\n Range\t4–33\t4–30\t\nCycles of first-line bevacizumab, n\t\n Median\t15\t15\t\n Range\t4–54\t4–64\t\n\tn = 176\tn = 179\t\nCEA, ng/ml\t\n Median\t23.2\t18.2\t\n Range\t0.40–9279\t0.70–2049\t\n\tn = 175\tn = 178\t\nCA19-9, ng/ml\t\n Median\t38.3\t36.1\t\n Range\t0.60–48019\t0.10–50 000\t\n\tn = 181\tn = 186\t\nSum of target lesions,b mm\t\n Median\t50.0\t44.4\t\n Range\t4.40–254\t10–246\t\nPercentages may not add up to 100% because of rounding.\n\nCA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; ECOG, Eastern Cooperative Oncology Group; FOLFIRI, 5-fluorouracil/leucovorin plus irinotecan; mFOLFOX6, modified 5-fluorouracil/leucovorin plus oxaliplatin; XELOX, capecitabine plus oxaliplatin.\n\naData missing for one patient (bevacizumab 5 mg/kg plus FOLFIRI).\n\nbTarget lesions defined using RECIST, version 1.1.\n\n\n\ndose administration\nOne patients in each two groups, were treated with different bevacizumab doses to those allocated, i.e. one patient was treated with bevacizumab 10 mg/kg although they were in the 5 mg/kg group, and one patient received 5 mg/kg although they were in the 10 mg/kg group. After excluding these two patients, the median and mean relative dose intensity of bevacizumab was 82% and 80% in the 5 mg/kg group, and 80% and 77% in the 10 mg/kg group, respectively. The median and mean relative dose intensity of irinotecan was 78% and 76% in the 5 mg/kg group, and 73% and 72% in the 10 mg/kg group, respectively (supplementary Table S1, available at Annals of Oncology online).\n\nefficacy\nThe number of PFS events was 174 in the bevacizumab 5 mg/kg group and 176 in the bevacizumab 10 mg/kg group. As shown in Figure 1, the median PFS was 6.1 (95% CI 5.3–7.0) months in the bevacizumab 5 mg/kg group and 6.4 (95% CI 5.6–7.4) months in the bevacizumab 10 mg/kg group (hazard ratio, 0.95; 95% CI 0.75–1.21; log-rank P = 0.676). The median second PFS, defined as time from the start of the first-line treatment to progression after receiving the study treatment, was 17.4 (95% CI 16.1–19.4) months in the bevacizumab 5 mg/kg group and 17.6 (95% CI 16.0–18.9) months in the bevacizumab 10 mg/kg group (hazard ratio, 1.00; 95% CI 0.79–1.26; log-rank P = 0.976). The number of TTF events was 179 in the bevacizumab 5 mg/kg group and 188 in the bevacizumab 10 mg/kg group. Median TTF was 5.2 (95% CI 4.5–5.8) months in the bevacizumab 5 mg/kg group and 5.2 (95% CI 4.4–5.7) months in the bevacizumab 10 mg/kg group (hazard ratio, 1.01; 95% CI 0.81–1.25; log-rank P = 0.967). Response to treatment was similar in the two groups with partial responses reported in 20 patients (11%) in the bevacizumab 5 mg/kg group and 20 patients (11%) in the bevacizumab 10 mg/kg group (supplementary Table S2, available at Annals of Oncology online). The number of deaths was 126 and 133 in the bevacizumab 5 and 10 mg/kg groups, respectively. Median OS was 16.3 (95% CI 14.1–21.2) months in the bevacizumab 5 mg/kg group and 17.0 (95% CI 14.6–19.1) months in the bevacizumab 10 mg/kg group (hazard ratio, 1.08; 95% CI 0.75–1.57; log-rank P = 0.667), although follow-up of OS is ongoing.\nFigure 1. Progression-free survival (PFS).\n\n\n\nsafety\nA summary of all-grade and grade 3–5 adverse events is given in supplementary Table S3, available at Annals of Oncology online. The incidence of all-grade hematological and non-hematological adverse events was similar between the two treatment groups. Bevacizumab-related adverse events of grade 3 or greater, including hemorrhage or bleeding, were also similar between the two treatment groups. The reported incidence rates in the bevacizumab 5 versus 10 mg/kg groups were gastrointestinal hemorrhage 0.6% versus 0.0%, nasal hemorrhage 0.0% versus 0.5%, and hypertension 1.1%versus 1.6%, respectively. Treatment-related deaths occurred in 2 (1.1%) patients in each group (5 mg/kg group: aspiration pneumonia, n = 1; acute myocardial infarction, n = 1; 10 mg/kg group: interstitial lung disease, n = 1; unknown, n = 1).\n\nsubgroup analysis\nThe prespecified subgroup analysis of PFS is shown in supplementary Figure S4, available at Annals of Oncology online. Possible differences of treatment effect between the bevacizumab 5 and 10 mg/kg groups were observed for patients when analyzed according to tumor type, CEA level, or tumor size.\n\ndiscussion\nThe EAGLE study was designed to evaluate the superiority of bevacizumab 10 mg/kg plus FOLFIRI compared with bevacizumab 5 mg/kg plus FOLFIRI as second-line therapy in patients with mCRC previously treated with a first-line bevacizumab plus an oxaliplatin-based regimen. PFS, the primary study end point, was similar in both treatment groups with a hazard ratio of 0.95 (95% CI 0.75–1.21). Secondary efficacy outcomes, specifically second PFS, TTF, and tumor response rates, were also similar between the two treatment groups and were supportive of the primary result. Follow-up of OS is ongoing. The incidence of adverse events, including bevacizumab-related events, was similar in both groups. These findings suggest that a higher bevacizumab dose of 10 mg/kg offers no clear clinical benefit compared with a 5 mg/kg dose in this setting.\n\nThe reason why the higher bevacizumab dose was not more effective is unclear. Kabbinavar et al. [15] previously showed slightly improved efficacy with bevacizumab 5 mg/kg plus chemotherapy versus bevacizumab 10 mg/kg plus chemotherapy as first-line therapy in mCRC, although the study was small and there were imbalances favoring the low-dose group at randomization. It has, however, been shown that free serum VEGF concentrations drop below detectable limits with bevacizumab doses as low as 0.3 mg/kg [9], suggesting that higher doses may not be necessary for optimal activity in humans.\n\nOur data are consistent with the results from previous studies, which showed a beneficial effect of continued anti-VEGF treatment after first disease progression in patients with mCRC [6, 16]. In our study, the median PFS was 6.1 and 6.4 months in the bevacizumab 5 and 10 mg/kg groups, respectively. In the ML18147 study, patients who had received standard first-line bevacizumab-based therapy were randomly assigned to receive bevacizumab plus standard second-line chemotherapy or standard second-line chemotherapy alone after disease progression. The median PFS in the bevacizumab-treated group was 5.7 months [6]. In the VELOUR study, patients previously treated with an oxaliplatin-based regimen were randomly assigned to receive the anti-angiogenic agent aflibercept plus FOLFIRI or FOLFIRI alone [16]. A subgroup analysis of this study showed that the median PFS of patients who had been previously treated with bevacizumab was 6.7 months [17].\n\nThe profile of bevacizumab-related adverse events observed in our study was consistent with previous studies of bevacizumab in combination with FOLFIRI. No unknown toxicities were observed in the bevacizumab 10 mg/kg group of our study. A pooled analysis of 16 published studies which investigated bevacizumab plus FOLFIRI in mCRC reported weighted mean rates of grade 3–4 bevacizumab-related toxicities of 6% for hypertension, 9% for venous/arterial thromboembolic events, 2% for bleeding events, and 0.7% for proteinuria [18]. In our study, the reporting rates of grade ≥3 bevacizumab-related toxicities in the total safety population were 1% for hypertension, 1% for thrombosis venous events, 0.8% for thrombosis artery events, 0.5% for bleeding events, and 0.8% for proteinuria. The adverse events reporting rates in the present study were lower compared with previous studies, even with the higher bevacizumab dose of 10 mg/kg. The incidence of the adverse events in our study was more consistent with results from post-marketing surveillance conducted in Japan [19]. Possible reasons for the differences in the reporting rates between our study and other published studies could be due to differences in patient performance status, ethnicity, and/or standard medical practice/cancer care in Japan.\n\nWe conducted a subgroup analysis of PFS (supplementary Figure S4, available at Annals of Oncology online) to identify possible patient groups that might respond differently to the two bevacizumab doses. There was one strong interaction (tumor type) and two modest interactions (CEA level or tumor size) between treatment and subgroups. However, it is unclear why the higher dose was more effective in one subgroup, and the lower dose apparently better in the complementary subgroup. It is, therefore, likely that such findings are false-positives. They should be interpreted with caution, and need confirmation in other studies.\n\nThe EAGLE study was conducted only in centers in Japan. The generalizability of the study findings to other regions is unknown. The dose of irinotecan used in the FOLFIRI regimen (150 mg/m2) was the approved dose in Japan, but is slightly lower than that used in the USA and Europe (180 mg/m2), although, as discussed above, the median PFS durations in our study were similar to other recent studies in this setting.\n\nIn conclusion, bevacizumab 10 mg/kg plus FOLFIRI as second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC following first-line treatment with a bevacizumab-based regimen. No differences in safety profile were observed between the bevacizumab 5 and 10 mg/kg groups. If bevacizumab is continued after first-line therapy in mCRC, our data suggest that a dose of 5 mg/kg is appropriate to use as second-line treatment.\n\nfunding\nThis work was supported in part by the Epidemiological and Clinical Research Information Network (ECRIN; Kyoto, Japan). No grant number applied.\n\ndisclosure\nHonoraria: SI (Chugai, Merck KGaA); TT (Merck, Bristol-Myers Squibb, Taiho); MN (Chugai); TK (Chugai, Yakult); TD (Taiho, Eli Lilly Japan KK, Sanofi KK); HB (Chugai, Taiho, Takeda); and HM (Chugai, Takeda, Taiho, Ono, Yakult, Tsumura, Merck Serono, Bristol-Myers Squibb, Medicon). Speakers' bureau: TK (Yakult, Chugai, Taiho, Takeda, Merck Serono) and HM (Chugai, Takeda, Taiho, Ono, Yakult, Tsumura, Merck Serono, Bristol-Myers Squibb, Medicon). Research funding: HB (Chugai, Taiho, Takeda) and HM (Chugai, Takeda, Taiho, Daiichisankyo, Merck Serono, Bristol-Myers Squibb). All remaining authors have declared no conflicts of interest.\n\nSupplementary Material\nSupplementary Data\n acknowledgements\nWe thank all the patients, and participating investigators and ECRIN for organizing the study. Editorial assistance was provided by Miller Medical Communications funded by Chugai Pharmaceutical Co., Ltd.\n\nappendix\nIn addition to the investigators in the author list, we acknowledge the following investigators who also participated in this study: Shigeyoshi Iwamoto, Kansai Medical University Hirakata Hospital; Takao Takahashi, Gifu University Hospital; Hiroshi Tamagawa, Koichi Deguchi, Chu Matsuda, Shigeyoshi Higashi, Osaka General Medical Center; Masato Nakamura, Aizawa Hospital; Yoshinori Munemoto, FukuiKen Saiseikai Hospital; Takeshi Kato, Yasuhiro Miyake, Minoh City Hospital; Taishi Hata, Masakazu Miyake, Toyonaka Municipal Hospital; Hideyuki Mishima, National Hospital Organization Osaka National Hospital; Yoshitaka Morita, National Hospital Organization Kobe Medical Center; Tadamichi Denda, Chiba Cancer Center; Michio Inukai, Takashi Himoto, Kagawa University Faculty of Medicine; Chihiro Tanaka, Nobuhisa Matsuhashi, Kenichi Maeda, Gifu Prefectural General Medical Center; Akihiko Murata, Motoi Koyama, Yoshiyuki Sakamoto, Hirosaki University Hospital; Naoki Nagata, Kitakyushu General Hospital; Mitsuru Ohshiro, Toho University Sakura Medical Center; Kenji Ina, Nagoya Memorial Hospital; Kiyotaka Kurachi, Hamamatsu University School of Medicine; Yutaka Tsuruta, Yuji Miyamoto, Naoko Hayashi, Kotaro Hirashima, Yasuo Sakamoto, Kumamoto University Hospital; Tatsu Shimoyama, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital; Junichi Hasegawa, Junichi Nishimura, Hirotoshi Kin, Osaka Rosai Hospital; Ken Nakata, Rei Suzuki, Takeshi Kato, Kansai Rosai Hospital; Yasunori Emi, Saiseikai Fukuoka General Hospital; Fusao Ikeda, Saori Nakagawa, Nishi-Kobe Medical Center; Kouichi Taira, Shinya Tokunaga, Osaka City General Hospital; Takeshi Nagasaka, Okayama University Hospital; Takahiro Nishio, Saiseikai Noe Hospital; Shinya Kajiura, Ayumu Hosokawa, University of Toyama Hospital; Koji Nakajima, Hidetomo Matsumoto, University of Miyazaki Hospital; Takanori Matsui, Tomohiro Yamada, Aichi Cancer Center Aichi Hospital; Hirofumi Yamada, Kumi Hasegawa, Sekishindo Hospital; Hiroyuki Bando, Ishikawa Prefectural Central Hospital; Hisoka Kinoshita, Shoichi Kinugasa, Kozo Tsunemi, Hyogo Prefectural Kakogawa Medical Center; Hiroyuki Kayata, Yoshihiko Nakamoto, Kobe City Hospital Organization Kobe City Medical Center West Hospital; Tadashi Shigematsu, Saiseikai Shigaken Hospital; Tsuyoshi Takahashi, Saiseikai Yamaguchi Hospital; Masahiro Tsubaki, Masanori Fujita, Yuichi Ito, Dokkyo Medical University School of Medicine; Keisuke Uehara, Norifumi Ohashi, Nagoya Graduate School of Medicine; Satoshi Yuki, Hokkaido University Graduate School of Medicine; Shoichi Hazama, Michihisa Iida, Yuka Inoue, Yamaguchi University School of Medicine; Shigeyuki Ueshima, Noriko Nishiyama, Osaka Police Hospital; Masato Kano, Ken Yanagibashi, Otsu Municipal Hospital; Masaki Kitazono, Kagoshima University Medical and Dental Hospital; Koji Nishijima, Japanese Red Cross Kanazawa Hospital; Hideto Fujita, Kanazawa University Hospital; Hiroki Hashida, Medical Research Institute, Kitano Hospital; Hideto Sonoda, Akinori Egashira, Kyushu University Hospital; Shusaku Honma, Tomonori Morimoto, Kurashiki Central Hospital; Michiya Kobayashi, Ken Okamoto, Kochi University Hospital; Satoshi Tani, Kohnan Hospital; Keiichiro Ishibashi, Saitama Medical Center; Ryochi Fujii, Izumisano Municipal Hospital; Yoshihiro Shimizu, Daini Okamoto General Hospital; Keiji Koda, Atsushi Hirano, Teikyo University Chiba Medical Center; Norihisa Hanada, Izumi General Medical Center; Itsuro Terada, Toyama Prefectural Central Hospital; Nao Takano, Hiroshi Nakayama, National Hospital Organization Nagoya Medical Center; Masaki Kitazono, Tsutomu Kozono, Nanpuh Hospital; Masahiro Fujikawa, Nissay Hospital; Toshihiro Tanaka; Fukuoka University Hospital; Daisuke Minabe, Emi Inoue, Fujisawa City Hospital; Naoki Tomizawa, Maebashi Red Cross Hospital; Ichiro Matsuura, National Hospital Organization Minami Wakayama Medical Center; Hitoshi Inagaki, Yokoyama Hospital for Gastroenterological Diseases; Nobutaka Tanaka, Konan Kosei Hospital; Toshiaki Wada, Izumiotsu Municipal Hospital; Nobufumi Uchima, Urasoe General Hospital; Hiroaki Tanioka, Okayama Rosai Hospital; Masataka Oneyama, Kawasakisaiwai Hospital; Koji Matsui, Gifu Municipal Hospital; Ryuta Nishitani, Kyoto Katsura Hospital; Masumi Ichinose, Kusatsu General Hospital; Eiichiro Toyama, Kumamoto Saishunso National Hospital; Teruo Sasatomi, Kurume University Medical Center; Keitaro Hirai, Gunma University Hospital; Tadataka Hayashi, Hamamatsu Medical Center; Masami Yamauchi, Hiroshima Prefectural Hospital; Tatsuya Okuno, Kobe University Hospital; Takeshi Nakao, Saiseikai Chuwa Hospital; Eiji Toyota, Shiga Medical Center For Adults; Keisei Taku, Shizuoka General Hospital; Masashige Tendo, Kashiwara Municipal Hospital; Mutsumi Hukunaga, Sakai City Hospital; Naoto Koike, Seirei Sakura Citizen Hospital; Takeshi Kanbara, Chugoku Central Hospital; Kazuhiko Nakata, Chuno Kosei Hospital; Toshiyuki Enomoto, Toho University Sakura Medical Center; Masanori Nishioka, The University of Tokushima Hospital; Hiroaki Takeshita, Nagasaki University Hospital; Masaaki Ito, Noda Hospital; Ichio Hirota, Harasanshin Hospital; Takanori Watanabe, Japanese Red Cross Society Himeji Hospital; Koichi Nakagawa, Fukuyama Daiichi Hospital; Hiroshi Matsuoka, Fujita Health University Hospital; Eiji Oki, National Hospital Organization Beppu Medical Center; Hirokazu Oyamada, Matsushita Memorial Hospital; Michio Asano, Matsuda Hospital; Kenji Kobayashi, Matsunami General Hospital; Naoki Yamanaka, Yamaguchi Red Cross Hospital; Akihiro Toyokawa, Yodogawa Christian Hospital.\n==== Refs\nreferences\n1 Ferlay J , Soerjomataram I , Ervik M et al \nGLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 . Lyon, France : International Agency for Research on Cancer \n2013 . http://globocan.iarc.fr (10 February 2014, date last accessed ).\n2 Katanoda K , Matsuda T , Matsuda A et al \nAn updated report of the trends in cancer incidence and mortality in Japan . Jpn J Clin Oncol \n2013 ; 43 : 492 –507 .23493744 \n3 Cancer Statistics in Japan – 2012 . http://ganjoho.jp/data/professional/statistics/backnumber/2012/cancer_statistics_2012.pdf (10 February 2014, date last accessed ).\n4 Hurwitz H , Fehrenbacher L , Novotny W et al \nBevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer . N Engl J Med \n2004 ; 350 : 2335 –2342 .15175435 \n5 Saltz LB , Clarke S , Díaz-Rubio E et al \nBevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study . J Clin Oncol \n2008 ; 26 : 2013 –2019 .18421054 \n6 Bennouna J , Sastre J , Dirk A et al \nContinuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomized phase 3 trial . Lancet Oncol \n2013 ; 14 : 29 –37 .23168366 \n7 Cohn AL , Hecht JR , Dakhil SR et al \nSPIRITT (study 2006014): a randomized phase II study of FOLFIRI with either panitumumab or bevacizumab as second-line treatment in patients with wild-type KRAS metastatic colorectal cancer . J Clin Oncol \n2013 ; 31 : (suppl; abstr 3616) .\n8 Giantonio BJ , Catalano PJ , Meropol NJ et al \nBevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200 . J Clin Oncol \n2007 ; 25 : 1539 –1544 .17442997 \n9 Gordon MS , Margolin K , Talpaz M et al \nPhase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer . J Clin Oncol \n2001 ; 19 : 843 –850 .11157038 \n10 Johnson DH , Fehrenbacher L , Novotny WF et al \nRandomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer . J Clin Oncol \n2004 ; 22 : 2184 –2191 .15169807 \n11 Mishima H , Oba K , Sakamoto J et al \nFOLFIRI plus bevacizumab 5 mg/kg versus 10 mg/kg as second-line therapy in patients with metastatic colorectal cancer who have failed first-line bevacizumab plus oxaliplatin-based therapy: a randomized phase III study (EAGLE trial) . Jpn J Clin Oncol \n2012 ; 42 : 134 –138 .22167662 \n12 Bennouna J , Borg C , Delord JP et al \nBevacizumab combined with chemotherapy in the second-line treatment of metastatic colorectal cancer: results from the phase II BEVACOLOR study . Clin Colorectal Cancer \n2012 ; 11 : 38 –44 .21803002 \n13 Lakatos E , Lan KK \nA comparison of sample size methods for the logrank statistics . Stat Med \n1992 ; 11 : 179 –191 .1579757 \n14 ICH Steering Committee . Statistical Principles for Clinical Trials (E9) . Geneva, Switzerland : International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use \n1998 \nhttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/E9_Guideline.pdf (24 January 24 2014, date last accessed ).\n15 Kabbinavar F , Hurwitz HI , Fehrenbacher L et al \nPhase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer . J Clin Oncol \n2003 ; 21 : 60 –65 .12506171 \n16 Van Cutsem E , Tabernero J , Lakomy R et al \nAddition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen . J Clin Oncol \n2012 ; 30 : 3499 –3506 .22949147 \n17 Tabernero J , Van Cutsem E , Lakomý R et al \nAflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial . Eur J Cancer \n2014 ; 50 : 320 –331 .24140268 \n18 Petrelli F , Borgonovo K , Cabiddu M et al \nFOLFIRI-bevacizumab as first-line chemotherapy in 3500 patients with advanced colorectal cancer: a pooled analysis of 29 published trials . Clin Colorectal Cancer \n2013 ; 12 : 145 –151 .23763824 \n19 Hatake K , Shirao K et al , BV Appropriate Use Review Committee , Safety results from post-marketing surveillance (PMS) of bevacizumab (BV) in colorectal cancer patients (pts) in Japan In 2009 Gastrointestinal Cancers Symposium \n(abstr 485), San Francisco .\n\n",
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"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
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"title": "FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study.",
"title_normalized": "folfiri plus bevacizumab as second line therapy in patients with metastatic colorectal cancer after first line bevacizumab plus oxaliplatin based therapy the randomized phase iii eagle study"
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"abstract": "Pemphigus vulgaris is a rare autoimmune blistering disease of the skin and mucous membranes. The case reported presented unusually with dyspepsia that was not responsive to protein pump inhibitor (PPI) therapy. This progressed to severe dysphagia and odynophagia. An esophagogastroduodenoscopy showed extensive ulceration of the esophagus, and direct immunofluorescence of an esophageal biopsy showed bright intercellular staining with C3 and IgG, confirming the diagnosis of pemphigus vulgaris. Immunological remission was achieved after a number of courses of pulsed intravenous methylprednisolone and cyclophosphamide. The patient has remained in remission for 5 years, but has required regular dilation of esophageal strictures for symptom relief. During this period, a chronic lymphocytosis was incidentally noted on routine blood tests, and chronic lymphocytic leukaemia was diagnosed. It is essential to investigate PPI-resistant symptoms, dysphagia and odynophagia, as they may indicate a serious underlying cause.",
"affiliations": "East and North Hertfordshire NHS Trust, Stevenage, UK.;Lister Hospital, Stevenage, UK.",
"authors": "Al-Janabi|Ali|A|http://orcid.org/0000-0002-2094-0556;Greenfield|Simon|S|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D008775:Methylprednisolone",
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"mesh_terms": "D000368:Aged; D003520:Cyclophosphamide; D003680:Deglutition Disorders; D016145:Endoscopy, Digestive System; D004935:Esophageal Diseases; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008775:Methylprednisolone; D010392:Pemphigus; D014456:Ulcer",
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"pubdate": "2015-10-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22798740;12224704;12055666;16336615;14632796;7829142;14870982;22798741;15278072;7130483;2007666",
"title": "Pemphigus vulgaris: a rare cause of dysphagia.",
"title_normalized": "pemphigus vulgaris a rare cause of dysphagia"
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"companynumb": "GB-MYLANLABS-2016M1004965",
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... |
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"abstract": "Hereditary angioedema (HAE) is a rare inherited disorder characterized by sudden and unpredictable appearance of swelling. Surgical procedures, even minor ones, are known to precipitate an attack in these patients. C1 esterase inhibitor (C1-INH) therapy may be effective for short term prophylaxis in such situations. However, there is limited experience with short term prophylaxis in countries where C1-INH therapy is not available.\n\n\n\nTo report our experience of using short term prophylaxis for a dental procedure, a Cesarean section and a major hip surgery in one patient each with HAE in resource constrained settings.\n\n\n\nAll 3 patients were given FFP before and during the procedure. While the first (a 6-year-old girl) and third patient (a 60-year-old male) were already taking stanozolol and the dose was doubled 5 days before the surgery, the second patient (28-year-old woman) was not taking any prophylaxis and she was initiated on stanozolol on the day of Cesarean section. The first patient was also given additional FFP one day after the dental procedure. After the procedure, the dose of stanozolol was decreased to baseline in patient 1 and 3 while it was discontinued in patient 3. All 3 patients tolerated the procedures well and had no related episodes of angioedema.\n\n\n\nDental and other major surgical procedures in patients with HAE are known to precipitate an episode of angioedema. In countries where C1-INH therapy is not available, attenuated androgens and FFP may be used to prevent these episodes.",
"affiliations": "Allergy Immunology Unit Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Electronic address: ankurjindal11@gmail.com.;Allergy Immunology Unit Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Allergy Immunology Unit Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Allergy Immunology Unit Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Oral Health Sciences, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Obstetrics and Gynaecology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Orthopedics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Anesthesia, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Allergy Immunology Unit Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Allergy Immunology Unit Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Clinical Immunology, University College Hospitals, London and Addenbrooke's Hospital, Cambridge, UK.",
"authors": "Jindal|Ankur Kumar|AK|;Singh|Ankita|A|;Anjani|Gummadi|G|;Kaur|Anit|A|;Jaiswal|Manojkumar|M|;Chopra|Seema|S|;Saini|Uttam|U|;Mahajan|Shalvi|S|;Rawat|Amit|A|;Singh|Surjit|S|;Longhurst|Hilary|H|",
"chemical_list": "D050718:Complement C1 Inhibitor Protein; D013197:Stanozolol",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.imbio.2020.152022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0171-2985",
"issue": "225(6)",
"journal": "Immunobiology",
"keywords": "Androgens; Fresh frozen plasma; Hereditary angioedema; Stanozolol; Tranexamic acid",
"medline_ta": "Immunobiology",
"mesh_terms": "D000328:Adult; D054179:Angioedemas, Hereditary; D002585:Cesarean Section; D050718:Complement C1 Inhibitor Protein; D003729:Dental Care; D019468:Disease Management; D005260:Female; D006801:Humans; D008297:Male; D019990:Perioperative Care; D011247:Pregnancy; D013197:Stanozolol",
"nlm_unique_id": "8002742",
"other_id": null,
"pages": "152022",
"pmc": null,
"pmid": "33197705",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful perioperative management of three patients with hereditary angioedema without C1 esterase inhibitor therapy: A developing country perspective.",
"title_normalized": "successful perioperative management of three patients with hereditary angioedema without c1 esterase inhibitor therapy a developing country perspective"
} | [
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"activesubstancename": "TRANEXAMIC ACID"
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"abstract": "Herein, we report a rare case of severe respiratory syncytial virus pneumonia after kidney transplant in a 46-year-old woman. The patient was diagnosed with end-stage renal disease and underwent living-donor kidney transplant. Direct flow cytometry crossmatch testing yielded positive results, and desensitization treatment with rituximab, plasmapheresis, and im-munoglobulin was performed before transplant. There were no complications. Five days after discharge, the patient was readmitted with a 2-day history of fever and diagnosed with bilateral pneumonia. The patient was placed on mechanical ventilation and given renal replacement therapy. Respiratory syncytial virus in the bronchial washings was detected via polymerase chain reaction. Broad-spectrum antibiotics, intravenous methylprednisolone, and immunoglobulin were admin-istered. Over-immunosuppression strategies, such as desensitization therapy, may result in severe respiratory syncytial virus pneumonia, even in kidney transplant recipients.",
"affiliations": "From the Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea.",
"authors": "Lee|Eun Song|ES|;Kim|Kyu Yeun|KY|;Jeong|Kye-Hwa|KH|;Lim|Jeong-Hoon|JH|;Jung|Hee-Yeon|HY|;Choi|Ji-Young|JY|;Cho|Jang-Hee|JH|;Park|Sun-Hee|SH|;Kim|Yong-Lim|YL|;Kim|Chan-Duck|CD|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D000069283:Rituximab",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2018.0252",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "18(4)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D003888:Desensitization, Immunologic; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D019520:Living Donors; D008875:Middle Aged; D009894:Opportunistic Infections; D010956:Plasmapheresis; D011024:Pneumonia, Viral; D018357:Respiratory Syncytial Virus Infections; D018113:Respiratory Syncytial Virus, Human; D000069283:Rituximab; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "515-518",
"pmc": null,
"pmid": "30968760",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Severe Respiratory Syncytial Virus Pneumonia in a Kidney Transplant Recipient With Desensitization: Case Report and Comprehensive Review of the Literature.",
"title_normalized": "severe respiratory syncytial virus pneumonia in a kidney transplant recipient with desensitization case report and comprehensive review of the literature"
} | [
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"companynumb": "KR-FRESENIUS KABI-FK202008921",
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"activesubstancename": "RITUXIMAB"
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{
"abstract": "BACKGROUND\nTo investigate the efficacy of posterior subtenon methylprednisolone acetate injection in treatment of refractory diffuse clinically significant diabetic macular edema (CSME).\n\n\nMETHODS\nIn a prospective, nonrandomized, interventional case series, 52 eyes were diagnosed with CSME and treated with at least two sessions of laser photocoagulation according to Early Treatment Diabetic Retinopathy Study guidelines. At least 3 months after laser therapy, eyes with a residual central macular thickness were offered posterior subtenon injection of 40 mg methylprednisolone acetate. Main outcome measures were visual acuity, macular thickness and intraocular pressure. Potential complications were monitored, including intraocular pressure response, cataract progression and scleral perforation.\n\n\nRESULTS\nMean baseline visual acuity (in logMAR) improved significantly (p = 0.003) from 0.8 +/- 0.36 to 0.6 +/- 0.41 at 3 months. Mean foveal thickness decreased from 388 +/- 78 mum at baseline to 231 +/- 40 mum after 3 months (p < 0.0001). Visual acuity improvement in eyes with CSME with extrafoveal hard exudates was significant (p = 0.0001), but not significant in eyes with CSME with subfoveal hard exudates (p = 0.32). Intraocular pressure increased from 14.7 +/- 2.0 mmHg (range, 12-18 mmHg) to a maximum value of 15.9 +/- 2.1 mmHg (range, 12-20 mmHg) during the follow-up period. Complications in two eyes developed focal conjunctival necrosis at the site of injection.\n\n\nCONCLUSIONS\nPosterior subtenon methylprednisolone acetate may improve early visual outcome in diffuse diabetic macular edema that fails to respond to conventional laser photocoagulation. Visual acuity improvement in eyes with CSME with extrafoveal hard exudates was significant; and this improvement is depends on location of hard exudates. Further study is needed to assess the long-term efficacy, safety, and retreatment.",
"affiliations": "Retina service, Department of Ophthalmology, Nikookari Hospital--Drug of applied research center, Tabriz University of Medical Sciences, Tabriz, Iran. javadzadehalireza@yahoo.com",
"authors": "Javadzadeh|Alireza|A|",
"chemical_list": "D000077555:Methylprednisolone Acetate; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1186/1471-2415-6-15",
"fulltext": "\n==== Front\nBMC OphthalmolBMC Ophthalmology1471-2415BioMed Central London 1471-2415-6-151659501110.1186/1471-2415-6-15Research ArticleThe effect of posterior subtenon methylprednisolone acetate in the refractory diabetic macular edema: a prospective nonrandomized interventional case series Javadzadeh Alireza 1javadzadehalireza@yahoo.com1 Retina service, Department of Ophthalmology, Nikookari Hospital – Drug of applied research center, Tabriz University of Medical Sciences, Tabriz, Iran2006 4 4 2006 6 15 15 6 1 2006 4 4 2006 Copyright © 2006 Javadzadeh; licensee BioMed Central Ltd.2006Javadzadeh; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nBackground\nTo investigate the efficacy of posterior subtenon methylprednisolone acetate injection in treatment of refractory diffuse clinically significant diabetic macular edema (CSME).\n\nMethods\nIn a prospective, nonrandomized, interventional case series, 52 eyes were diagnosed with CSME and treated with at least two sessions of laser photocoagulation according to Early Treatment Diabetic Retinopathy Study guidelines. At least 3 months after laser therapy, eyes with a residual central macular thickness were offered posterior subtenon injection of 40 mg methylprednisolone acetate. Main outcome measures were visual acuity, macular thickness and intraocular pressure. Potential complications were monitored, including intraocular pressure response, cataract progression and scleral perforation.\n\nResults\nMean baseline visual acuity (in logMAR) improved significantly (p = 0.003) from 0.8 ± 0.36 to 0.6 ± 0.41 at 3 months. Mean foveal thickness decreased from 388 ± 78 μm at baseline to 231 ± 40 μm after 3 months (p < 0.0001). Visual acuity improvement in eyes with CSME with extrafoveal hard exudates was significant (p = 0.0001), but not significant in eyes with CSME with subfoveal hard exudates (p = 0.32). Intraocular pressure increased from 14.7 ± 2.0 mmHg (range, 12–18 mmHg) to a maximum value of 15.9 ± 2.1 mmHg (range, 12–20 mmHg) during the follow-up period. Complications in two eyes developed focal conjunctival necrosis at the site of injection.\n\nConclusion\nPosterior subtenon methylprednisolone acetate may improve early visual outcome in diffuse diabetic macular edema that fails to respond to conventional laser photocoagulation. Visual acuity improvement in eyes with CSME with extrafoveal hard exudates was significant; and this improvement is depends on location of hard exudates. Further study is needed to assess the long-term efficacy, safety, and retreatment.\n==== Body\nBackground\nDiabetic retinopathy is the major cause of blindness in the United States in patients younger than 50 years of age, and macular edema is the leading cause of visual impairment in diabetic patients [1]. As might be expected, the prevalence of macular edema is directly related to the overall severity of the retinopathy and instruction, ranging from 3% among eyes with mild non proliferative diabetic retinopathy (NPDR) to 38% among eyes with moderate to severe NPDR and 71% among eyes with proliferative diabetic retinopathy [2].\n\nThe Early Treatment Diabetic Retinopathy Study (EDTRS) showed that laser photocoagulation has significant benefit for the treatment of localized clinically significant macular edema [3]. However, some clinical features are associated with poorer visual acuity outcomes after photocoagulation: diffuse macular edema with center involved, diffuse fluorescein leakage, macular ischemia (extensive perifoveal capillary nonperfusion), hard exudates deposits in the foveola, marked cystoid macular edema [4]. Diffuse and prolonged edema may fail to respond to laser photocoagulation or may returns after initial improvement [5-7]. Substantial subgroups of patients with refractory macular edema prompted interest in other treatment modalities, including pars plana vitrectomy [8], medical therapy with protein kinase C inhibitors [9], intravitreal injection of corticosteroids [9-11] or a sustained release intravitreal corticosteroid implant [9].\n\nSubtenon and retrobulbar injections of long acting corticosteroids have been used for treatment of cystoid macular edema (CME) secondary to uveitis [12,13] or intraocular surgeries [14]. Some studies showed acceptable results for intravitreal injection of triamcinolone acetonide, a corticosteroid suspension, in the treatment of uveitis and diabetic macular edema [9-11], [15,16]. Intravitreal injection has its potential complications and needs special setting to be done; also drug localization to the macula is important in obtaining maximum therapeutic effect [17].\n\nRecent studies showed that trans-tenon's retrobulbar infusion and posterior subtenon injection of the corticosteroids are effective in treating posterior inflammation and macular edema associated with uveitis [12,18] and intraocular surgeries [19]. Because of localization of drug in the macula, posterior subtenon and retrobulbar injections are equally effective in the treatment of CME [17]. The main advantage of posterior subtenon steroid injection is a prolonged effect due to a maximal local concentration of the drug that causes minimal systemic side effects [20]. The aim of the present study is to assess the effects of subtenon injection of methylprednisolone acetate in the management of persistent and refractory clinically significant diabetic macular edema.\n\nMethods\nIn a prospective, nonrandomized, interventional case series 52 eyes of 52 diabetic individuals were diagnosed with clinically significant macular edema (CSME) according to EDTRS criteria. Approval for the study was obtained from the ethical committee of Tabriz University of Medical Sciences which is in compliance with the Helsinki Declaration. All patients received a thorough explanation of the study design and aims, and were provided with written informed consent. All patients were evaluated and treated by retina specialist. Inclusion criteria were patients with type II diabetes, persistent diffuse CSME 3 months after at least 2 sessions of macular laser photocoagulation, visual acuity loss, and leakage shown by fluorescein angiography (Imagenet 2000, Topcon TRC50IX, Topcon Corp, Japan). Eyes with history of glaucoma, cataract extraction, or other intraocular surgery were excluded from the study. Eyes with an epiretinal membrane, posterior hyaloid traction, ischemic maculopathy, and diabetic papillopathy were also excluded. The risks and benefits of the procedure were discussed with each patient before injection, and all patients provided written informed consent. Baseline parameters were documented including best corrected visual acuity, central macular thickness, intraocular pressure (IOP) and lenticular status. The best-corrected visual acuity was determined from the Early Treatment Diabetic Retinopathy Study (EDTRS) chart and calculated as logarithm of minimal angle of resolution (logMAR). Central macular thickness was measured by optical coherence tomography (OCT2; Zeiss-Humphrey inc., Dublin, Ca). Optical coherence tomography (OCT) was performed by acquiring six radial scans, 6 mm long, centered in the fovea, and then analyzed with retinal map protocol. Intraocular pressure was measured by applanation tonometer. Systemic condition of the patients were under control (blood glucose, blood pressure, and general condition), and they were receiving oral hypoglycemic agents or insulin for glycemic control.\n\nAll patients underwent posterior subtenon capsule injection of methylprednisolone acetate. Topical tetracaine was applied to the ocular surface. A cotton-tipped applicator soaked in tetracaine was then placed over the superotemporal quadrant for 2 minutes as the patient looked inferonasally. The methyl prednisolone acetate suspension was then shaken and 1 cc (40 mg) was drawn into a tuberculin syringe using a 25-gauge, 0.5-inch long needle. The upper eyelid was lifted, and at the patient looked inferonasally, the 25-gauge needle was used to penetrate the posterior subtenon space. Before injection of the methyl prednisolone acetate, the needle was moved from side to side to check that the sclera was not engaged in the needle tip. A 40 mg injection of methyl prednisolone was then injected in the posterior subtenon space.\n\nLocation of hard exudates, detected by slit-lamp examination with a 78-diopter indirect lens, fundus photography and fluorescein angiography; and all of the eyes divided into two groups. Group 1 including of 30 eyes having refractory diffuse CSME with extrafoveal hard exudates; and group 2 including of 22 eyes having refractory diffuse CSME with subfoveal hard exudates. Response to treatment was monitored by snellen visual acuity and OCT. IOP was recorded at every visit. Potential corticosteroid-induced and injection-related complications were also observed. Patients were observed 1 week, 1 and 3 months after injection.\n\nAn ANOVA test was used to compare the Values before and after treatment. Any differences showing a p-value of less than or equal to 0.05 were considered to be statistically significant.\n\nResults\nThe study included 52 eyes of 52 patients. Mean age ± SD of the patients was 55 ± 7.6 years (median, 55 years; range, 40 to 68 years). There were 25 males (48%) and 27 females (52%). There was no statistically significant difference in age and gender distribution of the patients. All patients were in the stage of non proliferative diabetic retinopathy (NPDR) and had at least two sessions of MPC. Mean follow-up time ± SD was 3.6 ± 0.9 months (median, 3 months; range 3–5 months). The mean logMAR visual acuity significantly improved from 0.8 ± 0.36 at baseline to 0.6 ± 0.42 at 1 week, 0.6 ± 0.43 at 1 month, and 0.6 ± 0.41 at 3 months (Table 1). The mean foveal thickness decreased from 388 ± 78 μm at baseline to 264 ± 61 μm at 1 week, 230 ± 39 μm at 1 month, and 231 ± 40 μm at 3 months [Table 1].\n\nTable 1 Results of posterior subtenon methylprednisolone acetate injection for refractory diabetic macular edema.\n\n\tMean ± SD\t\t\n\t\t\t\n\tBefore injection\tAfter injection\tP-Value*\t\n\t\t\t\t\n\t\t1 week\t1 month\t3 months\t\t\nVA (logMAR)\t0.8 ± 0.36\t0.6 ± 0.42\t0.6 ± 0.43\t0.6 ± 0.41\t0.003\t\nCMT (μm)\t388 ± 78\t264 ± 61\t230 ± 39\t231 ± 40\t0.0001\t\nIOP (mmHg)\t14.7 ± 2.0\t15.9 ± 2.1\t15.7 ± 2.4\t15.3 ± 2.3\t0.043\t\nCMT = Central macular thickness; IOP = intraocular pressure; logMAR = logarithm of minimal angle of resolution; VA = visual acuity; *p < 0.05 is statistically significant\n\nThirty eyes had CSME with extrafoveal hard exudates, and 22 eyes had CSME with subfoveal hard exudates. In eyes with CSME with extrafoveal hard exudates, visual acuity improvement was significant in follow-up interval (p < 0.0001); although was not significant in eyes with CSME with subfoveal hard exudates (p = 0.32); Evaluation of visual acuity and retinal thickness in two groups was explored. There were statistically significant differences between baseline logMAR visual acuity and follow-up intervals in eyes with CSME with extrafoveal hard exudates (p < 0001), although in eyes with CSME with Subfoveal hard exudates were not statistically significant (p = 0.32); moreover macular thickness in two groups significantly decreased during the follow-up period (p < 0.0001, vs. p < 0.0001 respectively) [Table 2].\n\nTable 2 Results of posterior subtenon methylprednisolone acetate injection for refractory diabetic macular edema in two different groups.\n\n\tMean ± SD\t\t\n\t\t\t\n\tBefore injection\tAfter injection\tP-Value*\t\n\t\t\t\t\n\t\t1 week\t1 month\t3 months\t\t\nGroup 1(n = 30)\t\nVA (logMAR)\t0.6 ± 0.27\t0.3 ± 0.20\t0.3 ± 0.21\t0.3 ± 0.22\t0.0001\t\nCMT (μm)\t367 ± 65\t248 ± 44\t222 ± 35\t226 ± 40\t0.0001\t\nGroup 2(n = 22)\t\nVA (logMAR)\t1.1 ± 0.27\t1.0 ± 0.27\t1.0 ± 0.25\t1.0 ± 0.25\t0.32\t\nCMT (μm)\t417 ± 86\t286 ± 76\t241 ± 43\t238 ± 39\t0.0001\t\nCMT = central macular thickness; Group 1 = eyes having refractory diffuse CSME with extrafoveal hard exudates; Group 2 = eyes having refractory diffuse CSME with subfoveal hard exudates; logMAR = logarithm of minimal angle of resolution; VA = visual acuity; *p < 0.05 is statistically significant\n\nThe mean baseline IOP was 14.7 ± 2.0 mmHg (range 12–18 mmHg), and at 1 week, 1 month, and 3 months after injection were 15.9 ± 2.1 mmHg (range 12–20), 15.7 ± 2.4 mmHg (range 12–20), and 15.3 ± 2.3 mmHg (range 12–18) respectively [Table 1].\n\nIn our study there were not any significant complications such as ocular hypertension (IOP>21), globe rupture, or cataract formation. Two patients developed focal conjunctival injection and necrosis over the injection site that was treated with antibiotic drops.\n\nDiscussion\nMacular edema is the most frequent cause of visual impairment in patients with NPDR [21]. Vascular permeability, resulting in the leakage of fluid and plasma constituents, such as lipoproteins into the retina, leads to thickening of the retina [22]. When thickening involves or threatens the center of the fovea, there is a higher risk of visual loss. The EDTRS investigators classified macular edema by its severity. It was defined as clinically significant macular edema (CSME), if any of the following features were present: thickening of the retina at or within 500 microns of the center of the macula, hard exudates at or within 500 microns of the center of the macula, if associated with thickening of the adjacent retina (not residual hard exudates remaining after the disappearance of retinal thickening), or a zone or zones of retinal thickening 1 disc area or larger, and ultimately any part of which in 1 disc diameter of the center of the macula [3]. Site of hard exudates is one of the important factors for visual prognosis after resolution of macular edema being either subfoveal or extrafoveal.\n\nCorticosteroids have been used of their ability to inhibit the prostaglandin synthesis [10], and down regulate production of vascular endothelial growth factor (VEGF). Stabilization of blood retinal barrier (BRB) introduces a rationale for corticosteroid treatment of diabetic macular edema. Several studies showed the efficacy of intravitreal injection of corticosteroids in the management of diabetic macular edema [9-11]. Intravitreal injection is associated with rapid drug delivery to action site with maximal bioavailability, but has its complications. Recently trans-tenon's retrobulbar infusion and sub-tenon's injection of corticosteroids has been shown to be effective in the treatment of cystoid macular edema in patients with uveitis [12,15]. Subtenon injection of steroids in the treatment of uveitis was first reported in 1998 by Tanner et al [15]. It is a standard drug delivery method (with maximum concentration of drug in macula), which is used for treatment of chronic uveitis of posterior segment [13].\n\nIn retrospective, interventional case series, Chieh et al [23] treated 210 eyes with 1 or 4 mg of intravitreal triamcinolone acetonide for treatment of diffuse diabetic macular edema. They found a mean improvement in visual acuity from a median of 20/200 (mean logMAR, 0.92) at baseline to 20/80 (mean logMAR, 0.82) at 6 months. Mean intraocular pressure ± SD increased from 15.4 ± 3.4 mmHg to a maximal value of 20.4 ± 6.2 mmHg during the follow-up period. There were many complications, including culture-negative sterile endophthalmitis in six cases and cataract extraction in five eyes.\n\nIn prospective comparative, interventional case series, Jonas et al [11,24] studied 26 eyes injected with 25 mg of intravitreal triamcinolone acetonide for the treatment of diffuse diabetic macular edema. They showed that mean visual acuity ± SD improved significantly (p < 0.001) from 0.12 ± 0.08 at baseline to a maximum of 0.19 ± 0.14 during follow-up. Seventeen (81%) of 21 eyes with a follow-up of 1 month had improved visual acuity. Visual acuity did not change significantly in their control group. IOP also increased significantly (p < 0.001) and decreased significantly (p = 0.03) at the 5-month follow-up.\n\nThe main outcome measures of our study were best corrected visual acuity (by logMAR) and macular thickness (using OCT). Our results showed that, eyes had significant visual acuity improvement when compared with baseline as calculated by logMAR (p = 0.003), and also significant visual acuity improvement in eyes having CSME with extrafoveal hard exudates (p = 0.0001) but not significant in eyes having CSME with Subfoveal hard exudates (p = 0.32). In all eyes our results indicate that macular thickness significantly decreased between baseline and follow-up interval (p = 0.0001), and also significantly decreased in patients with CSME with extrafoveal and Subfoveal hard exudates (p = 0.0001 and, p = 0.0001) respectively [Table 2].\n\nOcular hypertension was not reported in this study. None of our patients had ocular complications of steroids, including development of cataract and glaucoma, prolonged healing of abrasions and epithelial defects [13]. Hemorrhage, globe perforation or perforation and extraocular muscle necrosis which are potential complications of injection itself was not reported in our study. In two patients developed focal conjunctival necrosis at the site of injection that was cured after 7–10 days of follow up with topical antibiotic.\n\nPosterior subtenon methylprednisolone acetate may improve diabetic macular edema, but visual acuity improvement may depend on location of hard exudates. According to the results obtained, in addition to those factors excluded in the subject selection, it is important in the treatment of diabetic patients having CSME with hard exudates; the exact location of the hard exudates should be considered carefully.\n\nConclusion\nThis method is associated with low potential complications related to intravitreal injections. However, long-term effects of posterior subtenon treatment are not clear. We believe further studies using a larger population with control will add valuable information to our results.\n\nCompeting interests\nThe author(s) declares that he has no competing interest.\n\nAuthors' contributions\nAJ contributed to designing, implementing, analyzing and writing the manuscript.\n\nPre-publication history\nThe pre-publication history for this paper can be accessed here:\n\n\n\nAcknowledgements\nThis research was supported by Research Vice-chancellery of Tabriz University of medical sciences. The author wishes to thank Dr. Hassan Argani and Dr. Amir Ghorbani Haghjoo for their assistance in data analysis.\n==== Refs\nKlein R Diabetic retinopathy Annu Rev Public Health 1996 17 137 158 8724221 10.1146/annurev.pu.17.050196.001033 \nKlein R Davis MD Moss SE Klein BE DeMetz DL The Wisconsin Epidemiologic Study of Diabetic Retinopathy. IV. Diabetic macular edema Ophthalmology 1984 91 1464 1474 6521986 \nEarly Treatment Diabetic retinopathy Study Research group. Photocoagulation for diabetic macular edema. Early Diabetic Retinopathy study report number 1 Arch Ophthalmol 1985 103 1796 1806 2866759 \nEarly Treatment Diabetic Retinopathy study research group. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Diabetic Retinopathy study report number 2 Ophthalmology 1987 94 761 774 3658348 \nFerris FL Patz A Macular edema. A complication of diabetic retinopathy Surv Ophthalmol 1984 452 461 6379946 10.1016/0039-6257(84)90227-3 \nBresnick GH Diabetic macular edema. A review Ophthalmology 1986 93 989 997 3531959 \nLee CM Olk RJ Modified grid laser photocoagulation for deafness macular edema. Long term visual results Ophthalmology 1991 98 1594 1602 1961650 \nOtani T Kishi S A controlled study of vitrectomy for diabetic macular edema Am J Ophthalmol 2002 134 214 219 12140028 10.1016/S0002-9394(02)01548-9 \nMartidis A Duker JS Greenberg PB Rogers AH Puliafito CA Reichel E Baumal C Intravitreal triamcinolone for refractory diabetic macular edema Ophthalmology 2002 109 920 927 11986098 10.1016/S0161-6420(02)00975-2 \nJonas JB Sofker A Intraocular injection of crystalline cortisone as adjunctive treatment for diabetic macular edema Arch Ophthalmol 2001 132 425 427 10.1016/S0002-9394(01)01010-8 \nJonas JB Kreissig I Sofker A Degenring RF Intravitreal injection of triamcinolone for diffuse macular edema Arch Ophthalmol 2003 121 57 61 12523885 10.1001/archopht.121.5.729 \nOkada AA Wakabayashi T Morimura Y Kavashara S Kojima E Asano Y Hida T Trans-tenon's retrobulbar triamcinolone infusion for the treatment of uveitis Br J Ophthalmol 2003 87 968 971 12881336 10.1136/bjo.87.8.968 \nAmerican Academy of Ophthalmology Liesegang TJ Intraocular inflammation and uveitis Basic and clinical science course 2001 San Francisco: American Academy of Ophthalmology 113 116 \nAmerican Academy of Ophthalmology Liesegang TJ Lens and cataract Basic and clinical science course 2001 San Francisco: American Academy of Ophthalmology 168 169 \nTanner V Kanski JJ Frith PA Posterior sub-tenon's triamcinolone injections in the treatment of uveitis Eye 1998 12 679 685 9850264 \nRiordan-Eva P Lightman S Orbital floor steroid injections in the treatment of uveitis Eye 1994 8 66 69 8013721 \nTolentino MJ Prenner JL Gendron EK Maguire AM Echographic localization of corticosteroid after retrobulbar injection Br J Ophthalmol 2001 85 626 627 11351972 10.1136/bjo.85.5.625b \nYoshikawa K Kotake S Ichiishi A Sasamoto Y Kosaka S Matsuda H Posterior sub-Tenon injections of repository corticosteroids in uveitis patients with cystoid macular edema Jpn J Ophthalmol 1995 39 71 76 7643487 \nThach AB Dugel PU Flindall RJ Sipperley JO Sneed SR A comparison of retrobulbar versus sub-Tenon's corticosteroid therapy for cystoid macular edema refractory to topical medication Ophthalmology 1997 104 2003 2008 9400758 \nLafranco Dafflon M Tran VT Guex-Crosier Y Herbort CP Posterior sub-Tenon's steroid injections for the treatment of posterior ocular inflammation: Indications, efficacy and side effects Graefes Arch Clin Exp Ophthalmol 1999 237 289 295 10208261 10.1007/s004170050235 \nHikichi T Fujio N Akiba J Azuma Y Takahashi M Yoshida A Association between the short-term medical history of diabetic macular edema and the vitreomacular relationship in type II diabetes mellitus Ophthalmology 1997 104 473 478 9082275 \nPelzek C Lim JI Diabetic macular edema: review and update Ophthalmol Clin North Am 2002 15 555 563 12515087 10.1016/S0896-1549(02)00043-3 \nChieh JJ Roth DB Liu M Belmont J Nelson M Regillo C Martidis A Intravitreal triamcinolone acetonide for diabetic macular edema Retina 2005 25 828 834 16205559 10.1097/00006982-200510000-00002 \nJonas JB Hayler JK Panda-Jonas S Intravitreal injection of crystalline cortisone as adjunctive treatment of proliferative vitreoretinopathy Br J Ophthalmol 2000 84 1064 1067 10966969 10.1136/bjo.84.9.1064\n\n",
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"mesh_terms": "D000328:Adult; D000368:Aged; D003238:Connective Tissue; D003930:Diabetic Retinopathy; D005123:Eye; D005260:Female; D006801:Humans; D007267:Injections; D017075:Laser Coagulation; D008269:Macular Edema; D008297:Male; D008775:Methylprednisolone; D000077555:Methylprednisolone Acetate; D008875:Middle Aged; D011446:Prospective Studies; D019233:Retreatment; D013997:Time Factors; D016896:Treatment Outcome; D014792:Visual Acuity",
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"title": "The effect of posterior subtenon methylprednisolone acetate in the refractory diabetic macular edema: a prospective nonrandomized interventional case series.",
"title_normalized": "the effect of posterior subtenon methylprednisolone acetate in the refractory diabetic macular edema a prospective nonrandomized interventional case series"
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"abstract": "With the increasing use of sodium-glucose cotransporter-2 inhibitors for type 2 diabetes and heart failure, clinicians need to understand how to treat euglycemic diabetic ketoacidosis (DKA), which is a potential side effect of the medication. The disease triad of euglycemic ketoacidosis, acute pancreatitis, and hypertriglyceridemia (HTG) has complex pathogenesis, and often the trigger of the triad is unknown. Here, we present an unusual case of euglycemic DKA in a transitioning transgender woman on canagliflozin who was treated with 10% dextrose and insulin infusions and apheresis. What makes our case unique is an added layer of complexity with her use of estrogen supplements contributing to HTG and gallstone formation, which could have set off the disease triad.",
"affiliations": "Internal Medicine, Rochester Regional Health, Rochester, USA.;Internal Medicine, Rochester Regional Health, Rochester, USA.;Internal Medicine, Rochester Regional Health, Rochester, USA.;Endocrinology, Diabetes and Metabolism, Johns Hopkins University, Baltimore, USA.",
"authors": "Tirthani|Ekta|E|;Said|Mina|M|;Neupane|Binita|B|;Quartuccio|Michael|M|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.16869\nEndocrinology/Diabetes/Metabolism\nInternal Medicine\nAn Unusual Case of the “Terrible Triad” in a Transgender Woman\nMuacevic Alexander\nAdler John R\nTirthani Ekta 1\nSaid Mina 1\nNeupane Binita 1\nQuartuccio Michael 23\n1 Internal Medicine, Rochester Regional Health, Rochester, USA\n2 Endocrinology, Diabetes and Metabolism, Johns Hopkins University, Baltimore, USA\n3 Endocrinology, Diabetes and Metabolism, Rochester Regional Health, Rochester, USA\nEkta Tirthani ekta.tirthani@rochesterregional.org\n4 8 2021\n8 2021\n13 8 e168694 8 2021\nCopyright © 2021, Tirthani et al.\n2021\nTirthani et al.\nhttps://creativecommons.org/licenses/by/3.0/ 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.\nThis article is available from https://www.cureus.com/articles/66562-an-unusual-case-of-the-terrible-triad-in-a-transgender-woman\nWith the increasing use of sodium-glucose cotransporter-2 inhibitors for type 2 diabetes and heart failure, clinicians need to understand how to treat euglycemic diabetic ketoacidosis (DKA), which is a potential side effect of the medication. The disease triad of euglycemic ketoacidosis, acute pancreatitis, and hypertriglyceridemia (HTG) has complex pathogenesis, and often the trigger of the triad is unknown. Here, we present an unusual case of euglycemic DKA in a transitioning transgender woman on canagliflozin who was treated with 10% dextrose and insulin infusions and apheresis. What makes our case unique is an added layer of complexity with her use of estrogen supplements contributing to HTG and gallstone formation, which could have set off the disease triad.\n\neuglycemic diabetic ketoacidosis\ncanagliflozin\nhypertriglyceridemia\nacute pancreatitis\nterrible triad of endocrinology\ntransgender\nestrogen supplements\ngallstone pancreatitis\nsglt2 inhibitors\ntransgender female\nThe 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\npmcIntroduction\n\nAlthough the “terrible triad” of acute pancreatitis (AP), hyperglycemic diabetic ketoacidosis (DKA), and hypertriglyceridemia (HTG) is rare, it has been well documented in the medical literature. With the increasing use of sodium-glucose cotransporter-2 (SGLT2) inhibitors in type 2 diabetes and heart failure, euglycemic DKA is on the rise. Therefore, it is important to know how to treat it. To date, the triad of euglycemic DKA, AP, and HTG has only been reported in two case reports in the medical literature with the use of dapagliflozin. In this case report, we describe an unusual case of euglycemic DKA, AP, and HTG in a transitioning male-to-female transgender woman on canagliflozin and estrogen supplements.\n\nCase presentation\n\nA 34-year-old transgender woman with a past medical history of type 2 diabetes, hyperlipidemia, and depression presented to the hospital with complaints of abdominal pain, poor appetite, and multiple episodes of nausea and vomiting for two days. The abdominal pain was located in the epigastrium, 8/10 in intensity, radiating to the back, and with no aggravating or relieving factors. She reported that the symptoms had started suddenly after she ate multiple cinnamon rolls and drank five glasses of milk, progressively worsening over two days. She denied any fevers, chills, dysuria, or diarrhea. She denied prior abdominal pain related to fatty foods and did not drink alcohol before the episode. Her medications included oral estradiol 2 mg three times daily, finasteride 5 mg daily, spironolactone 50 mg twice daily, canagliflozin 300 mg daily, metformin 1,000 mg twice daily, atorvastatin 20 mg daily, and lamotrigine 100 mg daily. She endorsed compliance with all her medications until her nausea set in two days prior. She did not have any recent surgeries or gender-affirming surgery. She vaped marijuana occasionally and drank four alcoholic drinks per week.\n\nOn arrival at the hospital, she felt dizzy, and her vital signs were: blood pressure 103/50 mmHg, respiratory rate 36 per minute with Kussmaul’s respiration, heart rate 136 beats per minute, temperature 97.7°F, and body mass index 31.3 kg/m2. On physical examination, she appeared weak and lethargic with a dry tongue. No abdominal distention or tenderness was noted, and Murphy’s sign was absent. Her blood work showed the abnormalities listed in Table 1.\n\nTable 1 Labs obtained on presentation to the hospital.\n\nLab test\tPatient’s labs\tNormal range\t\nWhite blood cell count\t27.8 × 103/µL\t4–11 × 103/ µL\t\nGlucose\t185 mg/dL\t65–100 mg/dL\t\nSodium\t128 mEq/L\t135–145 mEq/L\t\nChloride\t88 mEq/L\t98–108 mEq/L\t\nSerum bicarbonate\t<10 mEq/L\t22–30 mEq/L\t\nAnion gap\tNoncalculable (>25 mEq/L)\t4–16 mEq/L\t\nBeta-hydroxybutyrate\t7.36 mmol/L\t0.02–0.27 mmol/L\t\nLactic acid\t1.4 mmol/L\t0.4–2 mmol/L\t\nLipase\t116 U/L\t6–51 U/L\t\nTriglycerides\t2,142 mg/dl\t30–150 mg/dL\t\nVenous blood pH\t7.29\t7.32–7.42\t\nHemoglobin A1c\t9.6%\t<5.6%\t\nAspartate transaminase\t11 U/L\t7–37 U/L\t\nAlanine transaminase\t15 U/L\t10–49 U/L\t\nAlkaline phosphatase\t67 U/L\t46–116 U/L\t\n\nA CT scan of the abdomen showed an edematous pancreatic body and head with moderate surrounding peripancreatic inflammatory stranding and edema suggestive of AP. Gallstones without evidence of choledocholithiasis were also seen on the CT scan (Figure 1).\n\nFigure 1 CT scan of the abdomen.\n\nThe red arrow indicates the edematous pancreatic body and head with moderate surrounding peripancreatic inflammatory stranding and edema suggestive of acute pancreatitis. The blue arrow indicates a small gallstone visualized in the gallbladder.\n\nCT: computed tomography\n\nThe patient was diagnosed with an unusual “terrible triad” of AP, HTG, and euglycemic DKA in the setting of canagliflozin and estrogen use and was admitted to the medical intensive care unit. She was treated with boluses of normal saline, and empiric antibiotics with piperacillin/tazobactam were initiated as she met the criteria for sepsis, and her blood cultures were sent for testing. In addition, she was started on a modified DKA protocol with intravenous (IV) insulin along with 5% dextrose in normal saline. Blood sugars fell rapidly, and IV fluids were changed to 10% dextrose. She underwent apheresis to correct the HTG rapidly. Her triglycerides (TGs) fell to 491 mg/dL after the apheresis. It took almost two days for the anion gap to close, metabolic acidosis to resolve, and beta-hydroxybutyrate levels to return to the normal range. She was then transitioned to multiple daily injections of insulin with Lantus and Humalog. Her blood cultures returned negative, following which antibiotics were stopped. It was suspected that the leukocytosis was caused by hemoconcentration and stress.\n\nOnce the patient could tolerate an oral diet, fenofibrate 145 mg was started. Canagliflozin was removed from her medication list permanently. In addition, her estradiol was temporarily held until her follow-up appointment with her endocrinologist.\n\nDiscussion\n\nAccording to the 2021 Gallup survey data, approximately 0.6% of the U.S. population identifies as transgender, which is also supported by an extensive population study by Flores et al. in 2016 [1]. The ratio of transfeminine to transmasculine individuals is 1:1 [2]. Various formulations of supraphysiological doses of estrogen and antiandrogen therapy with finasteride, spironolactone, and cyproterone form the basis of hormonal therapy for transitioning male to female transgender individuals to maintain their secondary sexual characteristics [3,4]. Oral estrogens are notorious for causing AP due to the first-pass effect via portal circulation on hepatocytes. The proposed mechanism involves estrogen decreasing the activity of hepatocyte TG lipase and lipoprotein lipase and increasing the levels of very-low-density lipoprotein. This leads to increased TG-rich chylomicrons, which increase plasma viscosity, causing ischemia and damage to the pancreas [3,5]. Estrogen-induced AP in transgender individuals due to severe HTG has been reported in at least four cases in the medical literature thus far [3,6-8]. Hence, it is recommended that serum TGs should be routinely monitored in transfeminine patients on estrogen therapy, especially in those who have pre-existing HTG [8]. Estrogen also causes cholesterol supersaturation of bile which significantly increases the risk of developing cholesterol gallstones [9]. Freier et al. recently published a case of gallstone pancreatitis in a transgender woman taking estrogen supplements [10]. It is possible that in our patient, a transient obstruction with a gallstone may have contributed to AP, in addition to the more obvious HTG.\n\nSGLT2 inhibitors are being increasingly used for the treatment of type 2 diabetes, heart failure with reduced ejection fraction, and chronic kidney disease. Although once thought to be a rare adverse effect, several case reports have described SGLT2 inhibitor-related euglycemic DKA. In a systemic review and meta-analysis published by Colacci et al. in April 2021, which included >350,000 subjects, it was found that SGLT2 inhibitors were associated with twice the risk of DKA compared to placebo, with the absolute rate being approximately 1 per 1,000 person-years [11]. A multicentric cohort study conducted by Ata et al. showed that canagliflozin (which our patient was taking) carried the highest risk of euglycemic DKA with the highest medical intensive care admission rates [12]. However, there is no consensus regarding the blood glucose level that should be chosen as a cutoff to define euglycemic DKA. While some reports state blood glucose of < 200mg/dL fulfills the criteria for euglycemia, other reports have stated <250 mg/dL should be considered the cut-off, in addition to an increased anion gap (>12 mmol/L), metabolic acidosis (pH <7.3 and bicarbonate <15 mmol/L), and ketonemia or ketonuria [12,13]. In 2017, Burke et al. proposed that the triggers for DKA in patients on SGLT2 inhibitors included surgeries, noncompliance with medication, starvation, pregnancy, ketogenic diets, and dehydration. Euglycemic DKA is especially frequent in patients with long-standing diabetes with more than three months of use of SGLT2 inhibitors [13]. In addition, drug-induced pancreatitis is a rare side effect that has been reported with canagliflozin [14]. Although Gajjar et al. reported HTG due to SGLT2 inhibitor use, it was thought to be an incidental finding rather than true causation due to a lack of pathophysiologic evidence supporting this finding [15].\n\nThe “terrible triad” or the “enigmatic triad” of DKA, AP, and HTG is a rare but well-documented entity in the medical literature. Although the trigger is unknown in most cases, once the triad is activated, it has a “domino effect.” While some case reports have shown HTG (with serum TG levels >1,000 mg/dL) to be the trigger of AP which then causes DKA [16], in others, DKA has been suggested as the cause of the severe HTG and AP [17]. In the first case, circulating high serum TG levels are broken down to toxic free fatty acids by pancreatic lipase contributing to pancreatic cell injury with a subsequent insulin deficiency and DKA. In the second case, a primary insulin deficiency causes DKA with an excess of counterregulatory hormones and lipolysis with a decrease in the activity of the enzyme-lipoprotein lipase causing HTG and the resultant AP [8]. However, in a single case report, AP occurred even with mild-to-moderate HTG in a patient with diabetes [18]. Early treatment is recommended because HTG-triggered AP is associated with worse outcomes [19].\n\nTo date, two case reports have been reported in the medical literature describing an unusual “terrible triad” of euglycemic DKA, HTG, and AP with dapagliflozin, but not canagliflozin, though the pathogenesis is thought to be similar due to the class effect [20]. The pathogenesis of euglycemic DKA with canagliflozin use is shown in Figure 2.\n\nFigure 2 The proposed pathogenesis for the disease triad seen in our patient with the use of canagliflozin and estrogen supplements.\n\nThere are no specific guidelines for the treatment of euglycemic DKA, especially with concurrent HTG and AP, and it is generally directed by physician experience and reports of treatment success in the medical literature. Generally, the treatment of the disease triad starts by managing the euglycemic DKA with intensive fluid and electrolyte replacement, a continuous IV insulin drip with a concurrent dextrose infusion (up to 20%), and frequent blood glucose checks [8,13,16]. Although therapeutic plasma exchange or apheresis is often used for the management of severe HTG when available, overall, no significant difference has been seen with regular IV insulin therapy with the downside of increasing hospital costs and length of stays [8]. In our patient, we chose apheresis to initially lower the TGs due to the concern that the insulin infusion would take a longer time to correct the HTG as it was being given at a lower rate (0.05 U/kg/hour) than the standard DKA protocol (0.1 U/kg/hour) due to the fear of causing hypoglycemia in this patient with euglycemic DKA. A follow-up with endocrinology was recommended after the disease triad had resolved. Canagliflozin was permanently removed from the medication list and estradiol was held, with a plan for an outpatient cholecystectomy as gallstones may have contributed to the pathogenesis of the disease triad.\n\nConclusions\n\nEarly diagnosis and treatment of patients with euglycemic DKA, HTG, and AP are essential to stop the domino effect of these disease processes. Patients with the disease triad have significantly higher mortality than patients with just AP. Moreover, the fatality of DKA with the use of SGLT2 inhibitors is higher than that of DKA from other causes. Hence, a good understanding of this disease triad is important, especially in patients on medications such as canagliflozin and estrogen, which can trigger multiple arms of the triad and create a cascade of events like we saw in our patient.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 How many adults identify as transgender in the United States? 112016 Flores AR Herman JL Gates GJ Brown TN California, USA The Williams Institute 2016 https://williamsinstitute.law.ucla.edu/wp-content/uploads/Race-Ethnicity-Trans-Adults-US-Oct-2016.pdf\n2 Changes in size and demographic composition of transgender and gender non-binary population receiving care at integrated health systems Endocr Pract Zhang Q Rechler W Bradlyn A 390 395 27 2021 33678315\n3 A rare cause of acute pancreatitis in a transgender female J Investig Med High Impact Case Rep Shipley LC Steele DT Wilcox CM Burski CM 2324709620921333 8 2020\n4 Endocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab Hembree WC Cohen-Kettenis PT Gooren L 3869 3903 102 2017 https://doi.org/10.1210/jc.2017-01658 28945902\n5 Hypertriglyceridemia: an infrequent, difficult-to-predict, severe metabolic and vascular problem associated with estrogen administration Curr Vasc Pharmacol Whayne TF 254 261 18 2020 https://www.ingentaconnect.com/content/ben/cvp/2020/00000018/00000003/art00008 30843488\n6 Estrogen-induced pancreatitis: transgender females at risk Am J Hosp Med Goodwin N Nolan N Chinnakotla B 2018 2023 2 2018 30854402\n7 Estrogen-induced severe acute pancreatitis in a male JOP Perego E Scaini A Romano F Franciosi C Uggeri F 353 356 5 2004 https://pubmed.ncbi.nlm.nih.gov/15365202/ 15365202\n8 Lesson of the month: acute pancreatitis due to hypertriglyceridaemia in a transgender woman: a complication of high-dose oral oestrogen therapy? Clin Med (Lond) Hashmi A Smith EI Ciutac A Smith JC 228 230 21 2021 34001575\n9 New insights into the molecular mechanisms underlying effects of estrogen on cholesterol gallstone formation Biochim Biophys Acta Wang HH Liu M Clegg DJ Portincasa P Wang DQ 1037 1047 1791 2009 19589396\n10 Estrogen-induced gallstone pancreatitis in a transgender female [In Press] Am J Health Syst Pharm Freier E Kassel L Rand J Chinnakotla B 2021\n11 Sodium-glucose cotransporter-2 inhibitors and risk of diabetic ketoacidosis among adults with type 2 diabetes: a systematic review and meta-analysis [In Press] Can J Diabetes Colacci M Fralick J Odutayo A Fralick M 2021\n12 SGLT-2 inhibitors associated euglycemic and hyperglycemic DKA in a multicentric cohort Sci Rep Ata F Yousaf Z Khan AA 10293 11 2021 33986421\n13 Euglycemic diabetic ketoacidosis and sodium-glucose cotransporter-2 inhibitors: a focused review of pathophysiology, risk factors, and triggers Cureus Somagutta MR Agadi K Hange N 0 13 2021\n14 Canagliflozin-induced pancreatitis: a rare side effect of a new drug Ther Clin Risk Manag Chowdhary M Kabbani AA Chhabra A 991 994 11 2015 https://doi.org/10.2147/TCRM.S86641 26170677\n15 Euglycemic diabetic ketoacidosis in the setting of SGLT2 inhibitor use and hypertriglyceridemia: a case report and review of literature Cureus Gajjar K Luthra P 0 11 2019 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553675/\n16 Plasma exchange for the treatment of transient extreme hypertriglyceridemia associated with diabetic ketoacidosis and acute pancreatitis Eur J Case Rep Intern Med Donelli D Morini L Trenti C Santi R Arioli D Negri EA 853 5 2018\n17 Diabetic ketoacidosis and the domino effect Am J Case Rep Shaikh BH Sohaib M Alshantti R Barrera F Faridi FS Murvelashvili N 1342 1344 19 2018 30413682\n18 An enigmatic triad of acute pancreatitis, diabetic ketoacidosis and hypertriglyceridaemia: who is the culprit? BMJ Case Rep Mathuram Thiyagarajan U Ponnuswamy A Chung A 217272 12 2019\n19 Hypertriglyceridemia-induced pancreatitis: updated review of current treatment and preventive strategies Clin J Gastroenterol Rawla P Sunkara T Thandra KC Gaduputi V 441 448 11 2018 29923163\n20 Dapagliflozin-associated euglycemic diabetic ketoacidosis in a patient presenting with acute pancreatitis Case Rep Endocrinol Badwal K Tariq T Peirce D 6450563 2018 2018 30159178\n\n",
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"keywords": "acute pancreatitis; canagliflozin; estrogen supplements; euglycemic diabetic ketoacidosis; gallstone pancreatitis; hypertriglyceridemia; sglt2 inhibitors; terrible triad of endocrinology; transgender; transgender female",
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"title": "An Unusual Case of the \"Terrible Triad\" in a Transgender Woman.",
"title_normalized": "an unusual case of the terrible triad in a transgender woman"
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"abstract": "BACKGROUND\nInfectious complications are common during the postoperative course of a liver transplant recipient. Malaria, however, is a rare complication in such a setting.\n\n\nMETHODS\nWe report post-transplantation malaria causing elevation of liver enzymes in two recipients.\n\n\nRESULTS\nBoth patients who had undergone living donor liver transplantation showed elevated levels of liver enzymes and fever during the postoperative course. Investigations (including liver biopsy in one patient) were initially inconclusive in determining the cause of liver dysfunction. The diagnosis of malaria was established in both cases by peripheral blood smear. Liver function transiently worsened with antimalarial treatment but subsequently became normal.\n\n\nCONCLUSIONS\nThis report highlights the importance of excluding such uncommon causes of post-transplantation liver dysfunction, especially when either the recipient or the donor comes from a region endemic for malaria.",
"affiliations": "Department of Hepatobiliary Surgery and Liver Transplantation, Asian Centre for Liver Diseases and Transplantation, Gleneagles Hospital, Singapore. durgatosh@gmail.com",
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"mesh_terms": "D000368:Aged; D000818:Animals; D001706:Biopsy; D005260:Female; D006801:Humans; D008099:Liver; D016031:Liver Transplantation; D019520:Living Donors; D008288:Malaria; D008297:Male; D008875:Middle Aged; D010966:Plasmodium vivax; D000637:Transaminases; D005723:gamma-Glutamyltransferase",
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"title": "Malaria after living donor liver transplantation: report of two cases.",
"title_normalized": "malaria after living donor liver transplantation report of two cases"
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"abstract": "T-cell lymphoma (TCL) is resistant to conventional chemotherapy. We retrospectively evaluated the therapeutic efficiency and toxicity of gemcitabine, navelbine, and doxorubicin (GND) in patients with refractory or relapsed TCL. From 2002 to 2012, 69 patients with refractory or relapsed TCL received GND treatment in our hospital. The treatment protocol comprised gemcitabine (800 mg/m(2), group 1; 1000 mg/m(2), group 2) on days 1 and 8, navelbine (25 mg/m(2)) on day 1, and doxorubicin (20 mg/m(2)) on day 1, repeated every 3 weeks. The overall response rate (ORR) was 65.2%. The median overall survival (OS) was 36 months. The 5-year estimated OS rate was 32.4%. The GND regimen was well tolerated. Subgroup analysis demonstrated that the ORR and CR for group 1 were similar. A longer median OS was observed for group 1. Significant difference in grades 3-4 toxicities was observed between groups 1 and 2 (P = 0.035). Our study indicated that gemcitabine (800 mg/m(2)) on days 1 and 8 every 21 days was favorable for pretreated TCL patients.",
"affiliations": "Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tiyuanbei, Huanhuxi Road, Hexi District, Tianjin 300060, China.;Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tiyuanbei, Huanhuxi Road, Hexi District, Tianjin 300060, China.;Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tiyuanbei, Huanhuxi Road, Hexi District, Tianjin 300060, China.;Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tiyuanbei, Huanhuxi Road, Hexi District, Tianjin 300060, China.;Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tiyuanbei, Huanhuxi Road, Hexi District, Tianjin 300060, China.;Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tiyuanbei, Huanhuxi Road, Hexi District, Tianjin 300060, China.",
"authors": "Qian|Zhengzi|Z|;Song|Zheng|Z|;Zhang|Huilai|H|;Wang|Xianhuo|X|;Zhao|Jing|J|;Wang|Huaqing|H|",
"chemical_list": "D003841:Deoxycytidine; D014747:Vinblastine; D004317:Doxorubicin; C056507:gemcitabine; D000077235:Vinorelbine",
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"doi": "10.1155/2015/606752",
"fulltext": "\n==== Front\nBiomed Res IntBiomed Res IntBMRIBioMed Research International2314-61332314-6141Hindawi Publishing Corporation 10.1155/2015/606752Clinical StudyGemcitabine, Navelbine, and Doxorubicin as Treatment for Patients with Refractory or Relapsed T-Cell Lymphoma Qian Zhengzi Song Zheng Zhang Huilai Wang Xianhuo Zhao Jing Wang Huaqing \n*\nDepartment of Lymphoma, Sino-US Center for Lymphoma and Leukemia, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tiyuanbei, Huanhuxi Road, Hexi District, Tianjin 300060, China*Huaqing Wang: huaqingw@163.comAcademic Editor: Shiwu Zhang\n\n2015 19 3 2015 2015 60675225 6 2014 16 9 2014 Copyright © 2015 Zhengzi Qian 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.T-cell lymphoma (TCL) is resistant to conventional chemotherapy. We retrospectively evaluated the therapeutic efficiency and toxicity of gemcitabine, navelbine, and doxorubicin (GND) in patients with refractory or relapsed TCL. From 2002 to 2012, 69 patients with refractory or relapsed TCL received GND treatment in our hospital. The treatment protocol comprised gemcitabine (800 mg/m2, group 1; 1000 mg/m2, group 2) on days 1 and 8, navelbine (25 mg/m2) on day 1, and doxorubicin (20 mg/m2) on day 1, repeated every 3 weeks. The overall response rate (ORR) was 65.2%. The median overall survival (OS) was 36 months. The 5-year estimated OS rate was 32.4%. The GND regimen was well tolerated. Subgroup analysis demonstrated that the ORR and CR for group 1 were similar. A longer median OS was observed for group 1. Significant difference in grades 3-4 toxicities was observed between groups 1 and 2 (P = 0.035). Our study indicated that gemcitabine (800 mg/m2) on days 1 and 8 every 21 days was favorable for pretreated TCL patients.\n==== Body\n1. Introduction\nT-cell lymphoma (TCL) belongs to a group of malignant, clonal hyperplastic diseases that is derived from T lymphocytes, and it is characterized by high heterogeneity, strong invasiveness, and a prominent association with Epstein-Barr virus and human T-lymphotropic virus type 1 infections as well as with specific chromosome translocations. The treatment outcomes of patients with B-cell lymphoma (BCL) have improved due to great advancements in chemotherapy combined with molecular targeted agents such as rituximab. However, due to its highly aggressive features, including local tumor invasiveness in early-stage disease, the outcomes of TCL patients are generally worse with poor long-term survival (5-year overall survival (OS): 20–30%) [1]. In addition, owing to resistance to conventional chemotherapeutic agents such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like regimen, which is mediated by the expression of multidrug-resistance proteins, a substantial proportion of TCL patients develop refractory or relapsed disease. Although high-dose chemotherapy supported by autologous stem cell transplantation (ASCT) offers an advantage for some patients, the severe toxicities including cardiac and hematological adverse effects limit their widespread use. Even the introduction of novel drugs such as L-asparaginase cannot overcome the refractoriness completely. Therefore, additional trials and further studies are needed to develop safe and effective salvage chemotherapy regimens for patients with refractory or relapsed TCL.\n\nGemcitabine (2′,2′-difluoro-2′-deoxycytidine), which mainly acts on the synthesis phase of the cell cycle by inhibiting DNA synthesis, is a pyrimidine antimetabolite. It has been demonstrated that gemcitabine is one of the most effective agents when used either as a monotherapy agent or as part of a combination regimen for patients with relapsed or refractory Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) [1–3]. Of particular importance, the National Comprehensive Cancer Network has incorporated this nucleoside metabolic inhibitor into its clinical practice guidelines.\n\nGiven the encouraging outcomes of previous studies, we investigated the effectiveness, safety, and toxicity of gemcitabine, navelbine, and doxorubicin (GND) combination chemotherapy in patients with refractory or relapsed TCL.\n\n2. Patients and Methods\n2.1. Patients\nThe subjects of this retrospective study are patients with refractory or relapsed TCL, who received GND treatment between January 2002 and December 2012 in the Tianjin Medical University Cancer Hospital. Patients were eligible according to the following criteria: histological with immunohistochemical diagnosis of TCL from professional pathologists according to the Revised European-American Lymphoma classification [4] and available pathological reports; complete blood counts showing white blood cell (WBC) counts ≥4 × 109/L, platelet (PLT) counts ≥100 × 109/L, neutrophil counts ≥1.5 × 109/L, and hepatic and renal function tests demonstrating aspartate aminotransferase and alanine transaminase levels ≤35 U/L and serum creatinine ≤80 μmol/L at the beginning of the treatment; no abnormalities with electrocardiography (ECG); refractory or relapsed after conventional therapeutic approaches including chemotherapy and/or radiotherapy; and accumulated dose of doxorubicin ≤ 350 mg/m2 during the previous treatment. Exclusion criteria included a history of hepatitis B, hepatitis C, human immunodeficiency virus, uncontrolled infection or significant cardiac dysfunction, or central nervous system lymphoma at the time of GND administration. We collected the following clinical characteristics of enrolled patients retrospectively: patient demographics, time until relapse, histopathologic subtypes, Eastern Cooperative Oncology Group performance status, extent of disease involvement, Ann Arbor stage, International Prognostic Index, serum β2 microglobulin (β2-MG) levels, lactate dehydrogenase (LDH) levels, previous treatment regimens, deadline of the follow-up examination, and cause of death.\n\n2.2. Treatment Protocol\nFrom our archived clinical records, we established a cohort of 69 patients who received 2–6 cycles (median, 4 cycles) of the GND regimen every 3 weeks. All drugs were diluted in normal saline solution and administered through the subclavian vein. The treatment protocol consisted of gemcitabine (800 mg/m2 or 1000 mg/m2) on days 1 and 8, navelbine (25 mg/m2) on days 1 and 8, and doxorubicin (20 mg/m2) on day 1. In addition, 17 patients received local radiotherapy (36 Gy) for lymphoma masses after the completion of chemotherapy. Prophylactic 5-HT3 receptor antagonist (ramosetron and granisetron) and dexamethasone were administered routinely 30 minutes before every cycle. All patients were required to undergo a routine examination including physical examination, standard blood counts, liver and kidney function tests, urine routine analysis, and ECG on day 1 of each cycle. If the results showed no marked abnormalities, the subsequent cycle of chemotherapy was continued. Otherwise, patients whose WBC counts were <4 × 109/L and neutrophil counts were <1.5 × 109/L received recombinant human granulocyte colony-stimulating factor (G-CSF) at a dose of 100 μg/d and patients with PLT counts <100 × 109/L received thrombopoietin (TPO) at the discretion of the treating physician, resulting in a treatment delay for 3–7 days.\n\n2.3. Response Evaluation\nAll patients underwent a reevaluation with complete physical examination, laboratory tests, and previously positive radiographic examinations such as computed tomography (CT), magnetic resonance imaging, and positron emission tomography-CT imaging after every 2 cycles of the GND regimen. The tumor response was classified as complete remission (CR), unconfirmed complete remission (CRu), partial remission (PR), stable disease (SD), and progressive disease (PD), according to the International Workshop criteria for NHL [5]. The overall response rate (ORR) consists of CR, CRu, and PR. Adverse effects were also observed and graded from degree 1 to degree 4, according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Overall survival (OS) was measured from the first day of GND treatment to the date of death due to any cause or the date of the last follow-up visit (30 June 2013).\n\n2.4. Statistical Method\nThe SPSS software (Statistical Package for Social Science for Windows, version 17.0) for Windows was used for data analysis. Statistical significance was defined at P values < 0.05 by using a two-sided significance test. The survival rate was estimated and the survival curve was drawn simultaneously with the Kaplan-Meier method. Comparisons between response rates were performed by using the Chi-squared test (χ\n2-test). The median OS is shown with 95% confidence interval (CI) limits and estimators for 1-, 3-, and 5-year OS were determined concomitantly. To compare the potential association between variables and prognosis, the log-rank test was performed. Variables showing P values < 0.05 in univariate analyses were candidates for multivariate analysis, which was performed by using the Cox proportional hazard regression model.\n\n3. Results\n3.1. Patient Characteristics\nThe clinical characteristics of 69 patients that were retrieved from clinical and pathological reports are summarized in Table 1. First, patients were stratified into 2 groups according to the different doses of gemcitabine, which were administered at either 800 mg/m2 in group 1 (n = 49) or 1000 mg/m2 in group 2 (n = 20). The time until recurrence from the initial diagnosis was calculated, and a cut-off of 12 months [6] was used to distinguish early relapse (48 patients (37 from group 1; 11 from group 2)) from late relapse (21 patients (12 from group 1; 9 from group 2)). Among all patients, peripheral TCL-unspecified (PTCL-U) is the most common histopathologic subtype (59.4%) followed by extranodal natural killer/T-cell lymphoma (33.3%), anaplastic large cell lymphoma (4.4%), and subcutaneous panniculitis-like TCL (2.9%). There was a male preponderance (42/69) in the cohort, and the median age was 59 years (range, 10–80 years). A majority of patients experienced B-symptoms and splenomegaly (53.6% and 58.0%, resp.). At baseline, 31 patients were classified as stages I-II and 38 patients were classified as stages III-IV. Remarkably, most patients showed elevated β2-MG levels (56.5%), LDH levels (66.7%), and most frequently elevated lymphocyte counts (75.4%). The previous chemotherapy treatments included CHOP or CHOP-like regimens (COP, CHOEP, ECHOP, and CHOPT), Hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, and dexamethasone), DICE (dexamethasone, ifosfamide, carboplatin, and etoposide), and ICE (ifosfamide, carboplatin, and etoposide) with a median of 3 cycles (range, 2–6 cycles).\n\n3.2. Response to GND\n\nTable 2 demonstrates the clinical results of the two groups. Overall, objective responses to the GND regimen were obvious in 45 out of 69 evaluable patients with 20 patients achieving CR (29.0%) and 25 patients achieving PR (36.2%), resulting in an ORR of 65.2%. A total of 11 and 13 patients responded and developed SD (15.9%) or PD (18.9%), respectively. In addition, among 20 patients who achieved CR, 3 patients proceeded to receive ASCT and 5 patients received biotherapy. In subgroup analysis, the ORR was similar between patients from group 1 and group 2 (65.3% versus 65.0%, P = 0.981), although patients from group 1 achieved a higher CR rate than patients from group 2 (30.6% versus 25.0%, P = 0.641). Higher PR rates were observed in patients from group 2 versus group 1 (34.7% versus 40.0%, P = 0.677). There were no statistically significant response rate differences between the two different groups (by using χ\n2-test).\n\n3.3. Survival Analysis\nAt the cut-off date of the follow-up examination (30 June 2013), the median follow-up time was 3.5 years for all patients and 4 years for surviving patients (range, 0.5–11 years). The median OS was 36 months (range, 5–67 months; 95% CI: 25.314–46.686) among all patients. The median OS was higher for patients from group 1 compared to patients from group 2 (37 versus 23 months, resp.). According to the Kaplan-Meier analysis, the 1-, 3-, and 5-year estimated OS rates for the whole cohort were 71.7%, 47.3%, and 32.4%, respectively (Figure 1). Estimators for 1-year OS rates were similar between groups 1 and 2 (72.2% versus 70.3%, resp.). However, we observed significant differences for the 3- and 5-year OS rates between patients from groups 1 and 2 (53.1% versus 30.1% and 36.5% versus 20.1%, resp. (Figure 2)).\n\nAs shown in Table 1, univariate analysis identified 8 unfavorable prognostic factors for the 69 enrolled patients, including the time until recurrence (P = 0.021), B-symptoms (P = 0.014), bone marrow involvement (P = 0.000), splenomegaly (P = 0.010), disease stage (P = 0.004), lymphocyte counts (P = 0.005), β2-MG levels (P = 0.001), and LDH levels (P = 0.002). Moreover, multivariate Cox model analysis revealed that bone marrow involvement (P = 0.042; hazard ratio (HR): 3.816; 95% CI: 1.049–13.886), lymphocyte counts (P = 0.000; HR: 5.305; 95% CI: 2.100–13.403), and LDH levels (P = 0.018; HR: 2.538; 95% CI: 1.172–5.493) significantly influenced OS.\n\n3.4. Treatment Toxicities\nThe GND regimen was well tolerated with grade 3 or greater treatment-emergent adverse events occurring in less than one-third of all responding patients. Unexpectedly, a significant difference in grade 3 to 4 toxicities was present between groups 1 and 2 (16.3% versus 40%, P = 0.035, by using χ\n2-test). With regard to hematologic toxicities, which were more frequent relatively among all patients, grade 1 to 2 neutropenia or leukopenia was reported in 35 patients (50.7%), grade 1 to 2 anemia was noted in 23 patients (33.3%), and grade 1 to 2 thrombocytopenia was observed in 18 patients (26.1%). Grade 1 to 2 hematologic toxicities for group 2 patients were higher than those for group 1 patients. Table 3 displays the specific proportions for the different groups. Although 21.7% of patients (group 1: 16.3%; group 2: 35.0%) developed grade 3 to 4 neutropenia or leukopenia, no grade 3 to 4 anemia or thrombocytopenia was observed. By using G-CSF and TPO, these hematological toxicities were easily manageable and mostly of short duration (≤1 week). Only 1 patient from group 2 had a neutropenia-associated pulmonary infection and recovered after anti-infective therapy. Nonhematological toxicities included nausea, emesis, fatigue, fever, headache, decreased appetite, constipation, and temporary dysfunction of the liver and kidney; most of these were mild and reversed spontaneously. No patients presented with severe pulmonary toxicity, catarrh, rash, dyspnea, anaphylaxis, edema, or peripheral nerve toxicity. Treatment related deaths did not occur. Other adverse effects included fever, headache, and temporary dysfunction of the liver and kidney.\n\n4. Discussion\nTCL encompasses a heterogeneous group of diseases, altogether accounting for less than 15% of all NHLs worldwide. It is known for its aggressive biological behavior, low response rate to initial treatment accompanied with a high recurrence rate, and poor prognosis even for stage I to II disease. Previously, many advances have been made in the treatment of TCL. Unfortunately, initiatives that just mirrored the therapies used for BCL have not achieved promising outcomes in TCL patients, especially in cases with relapsed or refractory disease. Because of the disappointing responses and serious toxicities, few options remain for therapeutic approaches incorporating novel agents such as alemtuzumab, bortezomib, or L-asparaginase containing regimes [7–9]. In addition, there is a paucity of data and consensus from phase III trials concerning the treatment of pretreated TCL patients.\n\nGemcitabine, a novel nucleoside analogue that is activated by deoxycytidine kinase (dCK), has shown promising results in solid tumors such as nonsmall cell lung cancer and in pancreatic and ovarian cancers [10–12]. Notably, recent studies showed that gemcitabine alone and/or gemcitabine containing chemotherapies were also efficient in the treatment of HL and NHL, including heavily pretreated lymphoma [1–3, 9]. In a phase II study of 44 pretreated patients with mycosis fungoides or cutaneous peripheral PTCL-U, this agent presented an attractive treatment option with a surprisingly high RR of 70.5% [13]. Furthermore, Marchi et al. reported RR of 75% with gemcitabine monotherapy in a phase II study of 32 previously untreated cutaneous TCL patients, with 22% of patients achieving CR [14]. Bergman et al. explored the possible mechanisms in vitro and found that gemcitabine acts against various human malignant cells with a multidrug resistance (MDR) phenotype by circumventing MDR [15]. MDR, associated with cross-resistance to some natural toxin-related compounds, is characterized by the overexpression of drug efflux pumps such as P-glycoprotein and MDR-associated proteins 1–3, which may be a result of increased dCK activity and reduced deoxycytidine deaminase activity [16]. Therefore, MDR cells often presented with accumulated gemcitabine metabolism and sensitivity. This mechanism was related to the incorporation of gemcitabine into DNA and RNA, which in turn led to DNA damage [15].\n\nAccording to previous studies, the effectiveness of gemcitabine is demonstrated with satisfactory response rates and acceptable toxicities. However, there are very limited data available describing the efficacy and safety of gemcitabine combined with navelbine and specifically about doxorubicin as treatment for patients with refractory or relapsed TCL. In this report, we retrospectively analyzed a cohort of 69 patients with a range of pretreated TCL histology, who had received the gemcitabine-containing regimen, GND.\n\nThe ORR was 65.2%, including 29.0% of patients who achieved CR and a significant survival benefit (median OS: 36 months). Our observations are encouraging and comparable to other published salvage regimens such as ICE [17] and DHAP [18]. Even though those intensive regimens could achieve an ORR of 60–70% [17, 18], significant toxicities, especially serious complications related to myelosuppression, affected patients' survival. In contrast, mild bone marrow toxicity with GND was another significant advantage over other regimens, as only 15 patients (21.7%) developed grade 3 to 4 neutropenia or leukopenia. The incidence of grade 3 or 4 nonhematological toxicity was low, and severe pulmonary toxicity associated with gemcitabine [19] was not observed. In addition, these promising results were observed in a cohort of refractory or relapsed patients, many of which were characterized according to poor prognostic features such as early relapse [6], stages III-IV disease, elevated LDH and β2-MG levels, and elevated lymphocyte counts [20, 21].\n\nThe different outcomes may be due to the schedule or dose intensity of our study compared to historical reports. Grade 3 to 4 myelosuppression related toxicity as documented in the Royal Marsden Hospital experience [22] for CALGB 59804 was common (grade 3 to 4 neutropenia, 62% and 63%, separately) [3]. In addition, it is well established that navelbine and doxorubicin, which act on different parts of the cell cycle, play an important role in the management of malignant lymphomas, especially in the first-line treatment. Thus, the GND regimen did not contain alkylating agents such as ifosfamide and cyclophosphamide, which could increase the risk of secondary malignancies in patients with NHL [23].\n\nIn the further subgroups, in which gemcitabine was given at different doses, the OS and treatment-associated adverse events, particularly grade 3 to 4 toxicities (16.3% versus 40% in groups 1 and 2, resp., P = 0.035), were significantly different despite similar ORRs (65.3% versus 65% in groups 1 and 2, resp., P = 0.981). The outcome of our study indicates that gemcitabine at 800 mg/m2 on days 1 and 8 schedule repeated every 21 days was favorable for pretreated TCL patients.\n\n5. Conclusion\nIn summary, our retrospective analysis showed that the GND treatment regimen was effective and well tolerated by patients with refractory or relapsed TCL. When interpreting the outcome of our study, the limited number of cases should be kept in mind. Therefore, further prospective investigations that involve a larger number of patients will be helpful to confirm the advantages of the GND regime and elucidate its clinical significance intensively.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 The Kaplan-Meier estimate of overall survival (OS) for all patients.\n\nFigure 2 The Kaplan-Meier estimate of overall survival (OS) for groups 1 and 2.\n\nTable 1 Clinical characteristics and prognostic factors for overall survival (OS) of all patients.\n\nCharacteristics\tNumber of patients (%)\tUnivariate \tMultivariate\t\nGroup 1\tGroup 2\tTotal\t\nP value\t\nP value\tHR\t95% CI \t\nTotal \t49 (71%)\t20 (29%)\t69 (100%)\t \t \t \t \t\nRecurrent time \t \t \t \t0.021\t \t \t \t\n Early relapse\t37 (75.5%)\t11 (55%)\t48 (69.6%)\t \t \t \t \t\n Late relapse \t12 (24.5%)\t9 (45%)\t21 (30.4%)\t \t \t \t \t\nPathology\t \t \t \t \t \t \t \t\n PTCL-U\t28 (57.1%)\t13 (65%)\t41 (59.4%)\t \t \t \t \t\n NK/T\t18 (36.7%)\t5 (25%)\t23 (33.3%)\t \t \t \t \t\n Subcutaneous panniculitis-like\t2 (4.1%)\t0 (0%)\t2 (2.9%)\t \t \t \t \t\n T-cell lymphoma \t \t \t \t \t \t \t \t\n ALCL\t1 (2.1%)\t2 (10%)\t3 (4.4%)\t \t \t \t \t\nSex\t \t \t \t \t \t \t \t\n Male\t30 (61.2%)\t12 (60%)\t42 (60.9%)\t \t \t \t \t\n Female\t19 (38.8%)\t8 (40%)\t27 (39.1%)\t \t \t \t \t\nAge, years\t \t \t \t \t \t \t \t\n Median (range)\t50 (10–79)\t58 (19–80)\t59 (10–80)\t \t \t \t \t\n ≤60\t20 (40.8%)\t9 (45%)\t29 (42.0%)\t \t \t \t \t\n >60\t29 (59.2%)\t11 (55%)\t40 (58.0%)\t \t \t \t \t\nB-symptoms\t \t \t \t0.014\t \t \t \t\n Present\t27 (55.1%)\t10 (50%)\t37 (53.6%)\t \t \t \t \t\n Absent\t22 (44.9%)\t10 (50%)\t32 (46.4%)\t \t \t \t \t\nMarrow involvement \t \t \t \t0.000\t0.042\t3.816\t1.049–13.886\t\n Present\t9 (18.4%)\t5 (25%)\t14 (20.3%)\t \t \t \t \t\n Absent\t40 (81.6%)\t15 (75%)\t55 (79.7%)\t \t \t \t \t\nSplenomegaly\t \t \t \t0.010\t \t \t \t\n Present\t29 (59.2%)\t11 (55%)\t40 (58.0%)\t \t \t \t \t\n Absent\t20 (40.8%)\t9 (45%)\t29 (42.0%)\t \t \t \t \t\nECOG performance status\t \t \t \t \t \t \t \t\n 0-1\t19 (38.8%)\t8 (40%)\t27 (39.1%)\t \t \t \t \t\n 2\t26 (53.1%)\t11 (55%)\t37 (53.6%)\t \t \t \t \t\n ≥3\t4 (8.1%)\t1 (5%)\t5 (7.3%)\t \t \t \t \t\nStage\t \t \t \t0.004\t \t \t \t\n I-II\t24 (49.0%)\t7 (35%)\t31 (44.9%)\t \t \t \t \t\n III-IV\t25 (51.0%)\t13 (65%)\t38 (55.1%)\t \t \t \t \t\nIPI\t \t \t \t \t \t \t \t\n 0-1 (low-risk group)\t19 (38.8%)\t2 (10%)\t21 (30.4%)\t \t \t \t \t\n 2-3 (intermediate-risk group)\t25 (51.0%)\t14 (70%)\t39 (56.5%)\t \t \t \t \t\n 4-5 (high-risk group)\t5 (10.2%)\t4 (20%)\t9 (13.1%)\t \t \t \t \t\nLymphocyte counts\t \t \t \t0.005\t0.000\t5.305\t2.100–13.403\t\n ≥1 × 109/L \t36 (73.5%)\t16 (80%)\t52 (75.4%)\t \t \t \t \t\n <1 × 109/L\t13 (26.5%)\t4 (20%)\t17 (24.6%)\t \t \t \t \t\n\nβ2-MG\t \t \t \t0.001\t \t \t \t\n >Upper limit of normal\t26 (53.1%)\t13 (65%)\t39 (56.5%)\t \t \t \t \t\n Normal\t23 (46.9%)\t7 (35%)\t30 (43.5%)\t \t \t \t \t\nLDH\t \t \t \t0.002\t0.018\t2.538\t1.172–5.493\t\n >Upper limit of normal\t31 (63.3%)\t15 (75%)\t46 (66.7%)\t \t \t \t \t\n Normal\t18 (36.7%)\t5 (25%)\t23 (33.3%)\t \t \t \t \t\nPrevious therapeutic regimen\t \t \t \t \t \t \t \t\n Radiotherapy\t9 (18.4%)\t3 (15%)\t12 (17.4%)\t \t \t \t \t\n Chemotherapy\t29 (59.2%)\t13 (65%)\t42 (60.9%)\t \t \t \t \t\n Chemoradiotherapy \t11 (22.4%)\t4 (20%)\t15 (21.7%)\t \t \t \t \t\nPTCL-U: peripheral T-cell lymphoma-unspecified, NK/T: extranodal natural killer/T-cell lymphoma, ALCL: anaplastic large cell lymphoma, ECOG: Eastern Cooperative Oncology Group, LDH: lactate dehydrogenase, β2-MG: serum β2 microglobulin, IPI: International Prognostic Index, HR: hazard ratio, and 95% CI: 95% confidence interval. B-symptoms include unexplained fever over 38°C (100.4°F) for 1-2 weeks, unintentional weight loss of >10% of normal body weight over a period of 6 months or less, and drenching sweats, especially at night. IPI scores were calculated by summing the number of risk factors (age > 60 years, stage III/IV, involved extranodal sites > 1, ECOG performance status > 1, and elevated LDH levels). \n\nTable 2 The clinical results for the two groups.\n\nResponse \tNumber of patients (%)\t\nGroup 1 (n = 49)\tGroup 2 (n = 20)\tTotal (n = 69)\t\n\n\n\t\nCR\t15 (30.6%)\t5 (25%)\t20 (29.0%)\t\nPR\t17 (34.7%)\t8 (40%)\t25 (36.2%)\t\nORR (CR + PR)\t32 (65.3%)\t13 (65%)\t45 (65.2%)\t\nSD\t8 (16.3%)\t3 (15%)\t11 (15.9%)\t\nPD\t9 (18.4%)\t4 (20%)\t13 (18.9%)\t\nCR: complete response, PR: partial response, ORR: overall response rate, SD: stable disease, and PD: progressive disease.\n\nTable 3 Treatment-emergent adverse events for the two groups.\n\nTreatment toxicities\tNumber of patients (%)\t\nGroup 1 (n = 49)\tGroup 2 (n = 20)\tTotal (n = 69)\t\n\n\n\t\nGrades 1-2\t \t \t \t\n Neutropenia or leukopenia\t22 (44.9%)\t13 (65%)\t35 (50.7%)\t\n Anemia\t15 (30.6%)\t8 (40%)\t23 (33.3%)\t\n Thrombocytopenia\t11 (22.4%)\t7 (35%)\t18 (26.1%)\t\n Infection\t0\t1 (5%)\t1 (1.4%)\t\n Nausea or emesis\t25 (51.0%)\t9 (45%)\t34 (49.3%)\t\n Fatigue\t31 (63.3%)\t13 (65%)\t44 (63.8%)\t\n Constipation\t19 (38.8%)\t10 (50%)\t29 (42.2%)\t\n Others\t5 (10.2%)\t2 (10%)\t7 (10.1%)\t\nGrades 3-4\t \t \t \t\n Hematologic toxicities \t8 (16.3%)\t7 (35%)\t15 (21.7%)\t\n Nonhematological toxicities\t0\t1 (5%)\t1 (1.4%)\n==== Refs\n1 Zinzani P. L. Venturini F. Stefoni V. Gemcitabine as single agent in pretreated T-cell lymphoma patients: evaluation of the long-term outcome Annals of Oncology 2009 21 4 860 863 10.1093/annonc/mdp508 2-s2.0-77951964918 19887465 \n2 Bai B. Huang H.-Q. Cai Q.-Q. Promising long-term outcome of gemcitabine, vinorelbine, liposomal doxorubicin (GVD) in 14-day schedule as salvage regimen for patients with previously heavily treated Hodgkin's lymphoma and aggressive non-Hodgkin's lymphoma Medical Oncology 2013 30 1 p. 350 10.1007/s12032-012-0350-5 2-s2.0-84880614820 23329307 \n3 Bartlett N. L. Niedzwiecki D. Johnson J. L. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin's lymphoma: CALGB 59804 Annals of Oncology 2007 18 6 1071 1079 10.1093/annonc/mdm090 2-s2.0-34447320514 17426059 \n4 Pileri S. A. Leoncini L. Falini B. Revised European-American lymphoma classification Current Opinion in Oncology 1995 7 5 401 407 2-s2.0-0028979010 8541383 \n5 Cheson B. D. Pfistner B. Juweid M. E. Revised response criteria for malignant lymphoma Journal of Clinical Oncology 2007 25 5 579 586 10.1200/JCO.2006.09.2403 2-s2.0-33947496614 17242396 \n6 Guglielmi C. Gomez F. Philip T. Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the parma trial Journal of Clinical Oncology 1998 16 10 3264 3269 2-s2.0-0031757275 9779700 \n7 Kim S. J. Kim K. Park Y. Dose modification of alemtuzumab in combination with dexamethasone, cytarabine, and cisplatin in patients with relapsed or refractory peripheral T-cell lymphoma: analysis of efficacy and toxicity Investigational New Drugs 2012 30 1 368 375 10.1007/s10637-010-9523-2 2-s2.0-84856555122 20734108 \n8 Lee J. Suh C. Kang H. J. Phase I study of proteasome inhibitor bortezomib plus CHOP in patients with advanced, aggressive T-cell or NK/T-cell lymphoma Annals of Oncology 2008 19 12 2079 2083 10.1093/annonc/mdn431 2-s2.0-56749102974 18689866 \n9 Ahn H. K. Kim S. J. Hwang D. W. Gemcitabine alone and/or containing chemotherapy is efficient in refractory or relapsed NK/T-cell lymphoma Investigational New Drugs 2013 31 2 469 472 10.1007/s10637-012-9889-4 2-s2.0-84879549921 23108598 \n10 Manegold C. Bergman B. Chemaissani A. Single-agent gemeitabine versus cisplatln-etoposlde: early results of a randomised phase II study in locally advanced or metastatic non-small-cell lung cancer Annals of Oncology 1997 8 6 525 529 10.1023/A:1008207731111 2-s2.0-0031157857 9261520 \n11 Burris H. A. III Moore M. J. Andersen J. Improvements in survival and clinical benefit with gemcitabine as first- line therapy for patients with advanced pancreas cancer: a randomized trial Journal of Clinical Oncology 1997 15 6 2403 2413 2-s2.0-8244254377 9196156 \n12 Rose P. G. Mossbruger K. Fusco N. Smrekar M. Eaton S. Rodriguez M. Gemcitabine reverses cisplatin resistance: demonstration of activity in platinum- and multidrug-resistant ovarian and peritoneal carcinoma Gynecologic Oncology 2003 88 1 17 21 10.1006/gyno.2002.6850 2-s2.0-0037224987 12504621 \n13 Zinzani P. L. Baliva G. Magagnoli M. Gemcitabine treatment in pretreated cutaneous T-cell lymphoma: experience in 44 patients Journal of Clinical Oncology 2000 18 13 2603 2606 2-s2.0-0033934870 10893292 \n14 Marchi E. Alinari L. Tani M. Gemcitabine as frontline treatment for cutaneous T-cell lymphoma: phase II study of 32 patients Cancer 2005 104 11 2437 2441 10.1002/cncr.21449 2-s2.0-28044451294 16216001 \n15 Bergman A. M. Pinedo H. M. Talianidis I. Increased sensitivity to gemcitabine of P-glycoprotein and multidrug resistance-associated protein-overexpressing human cancer cell lines British Journal of Cancer 2003 88 12 1963 1970 10.1038/sj.bjc.6601011 2-s2.0-0038235998 12799644 \n16 Bergman A. M. Munch-Petersen B. Jensen P. B. Collateral sensitivity to gemcitabine (2′,2′-difluorodeoxycytidine) and cytosine arabinoside of daunorubicin- and VM-26-resistant variants of human small cell lung cancer cell lines Biochemical Pharmacology 2001 61 11 1401 1408 10.1016/S0006-2952(01)00627-X 2-s2.0-0035370527 11331076 \n17 Moskowitz C. H. Bertino J. R. Glassman J. R. Ifosfamide, carboplatin, and etoposide: a highly effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible patients with non-Hodgkin's lymphoma Journal of Clinical Oncology 1999 17 12 3776 3785 2-s2.0-0032761285 10577849 \n18 Velasquez W. S. Cabanillas F. Salvador P. Effective salvagae therapy for lymphoma with cisplatin in combination with high-dose ara-C and dexamethasone (DHAP) Blood 1988 71 1 117 122 2-s2.0-0023818185 3334893 \n19 Barlési F. Doddoli C. Gimenez C. Greillier L. Lima G. Kleisbauer J.-P. Acute pulmonary toxicity due to gemcitabine: a role for asbestos exposure? Revue des Maladies Respiratoires 2003 20 2, part 1 201 206 2-s2.0-0038798010 12844017 \n20 Castillo J. J. Morales D. Quinones P. Cotrina E. Desposorio C. Beltran B. Lymphopenia as a prognostic factor in patients with peripheral T-cell lymphoma, unspecified Leukemia and Lymphoma 2010 51 10 1822 1828 10.3109/10428194.2010.508189 2-s2.0-77957741520 20849388 \n21 Escalón M. P. Liu N. S. Yang Y. Prognostic factors and treatment of patients with T-cell non-Hodgkin lymphoma: the M. D. Anderson Cancer Center experience Cancer 2005 103 10 2091 2098 10.1002/cncr.20999 2-s2.0-18044383718 15816054 \n22 Arkenau H.-T. Chong G. Cunningham D. Gemcitabine, cisplatin and methylprednisolone for the treatment of patients with peripheral T-cell lymphoma: the Royal Marsden Hospital experience Haematologica 2007 92 2 271 272 10.3324/haematol.10737 2-s2.0-33947512466 17296587 \n23 Xu Y. Wang H. Zhou S. Risk of second malignant neoplasms after cyclophosphamide-based chemotherapy with or without radiotherapy for non-Hodgkin lymphoma Leukemia and Lymphoma 2013 54 7 1396 1404 10.3109/10428194.2012.743657 2-s2.0-84879335946 23101661\n\n",
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"nlm_unique_id": "101600173",
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"pmid": "25866797",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
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"title": "Gemcitabine, navelbine, and doxorubicin as treatment for patients with refractory or relapsed T-cell lymphoma.",
"title_normalized": "gemcitabine navelbine and doxorubicin as treatment for patients with refractory or relapsed t cell lymphoma"
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"companynumb": "CN-JNJFOC-20150419326",
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"abstract": "OBJECTIVE\nTo compare 3 different molecular techniques to detect the Mycobacterium tuberculosis genome in vitreous fluid of eyes with multifocal serpiginoid choroiditis (MSC).\n\n\nMETHODS\nProspective, interventional case series.\n\n\nMETHODS\nEleven patients (11 eyes) with active MSC in at least 1 eye underwent diagnostic pars plana vitrectomy (PPV) between October 2012 and December 2013.\n\n\nMETHODS\nVitreous fluid samples were subjected to multitargeted polymerase chain reaction (PCR) for a M. tuberculosis assay, the Gene Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA), and a line probe assay (GenoType MTBDRplus; Hain Lifescience, GmbH, Nehren, Germany). The samples with positive results were subjected to rpoB gene sequencing to demonstrate rifampicin resistance. The clinical details, digital fundus imaging, and treatment details and outcomes also were noted.\n\n\nMETHODS\nDetection of the M. tuberculosis genome and rifampicin resistance in the vitreous samples.\n\n\nRESULTS\nOf the 11 eyes subjected to PPV, the multitargeted PCR results for tuberculosis were positive for 10 eyes, the MTBDRplus assay results were positive in 6 eyes, and the Gene Xpert MTB/RIF assay results were positive in 4 eyes. Rifampicin resistance was detected in 3 eyes by rpoB gene sequencing, in 3 eyes by the MTBDRplus assay, and in 1 eye by the Gene Xpert MTB/RIF assay.\n\n\nCONCLUSIONS\nWe detected the M. tuberculosis genome in the vitreous fluid of eyes with MSC using 3 different molecular techniques. Rifampicin resistance was detected for the first time in eyes with MSC.",
"affiliations": "Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Microbiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India. Electronic address: dramodgupta@gmail.com.;Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Virology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Bureau of Health Laboratories, Jacksonville, Florida.",
"authors": "Bansal|Reema|R|;Sharma|Kusum|K|;Gupta|Amod|A|;Sharma|Aman|A|;Singh|Mini P|MP|;Gupta|Vishali|V|;Mulkutkar|Samyak|S|;Dogra|Mohit|M|;Dogra|Mangat R|MR|;Kamal|Shivali|S|;Sharma|Surya Parkash|SP|;Fiorella|Paul D|PD|",
"chemical_list": "D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D012293:Rifampin",
"country": "United States",
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"issn_linking": "0161-6420",
"issue": "122(4)",
"journal": "Ophthalmology",
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"medline_ta": "Ophthalmology",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D002833:Choroiditis; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D005260:Female; D005451:Fluorescein Angiography; D016680:Genome, Bacterial; D006801:Humans; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D000080364:Multifocal Choroiditis; D009169:Mycobacterium tuberculosis; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D012293:Rifampin; D018088:Tuberculosis, Multidrug-Resistant; D014392:Tuberculosis, Ocular; D014821:Vitrectomy; D014822:Vitreous Body; D055815:Young Adult",
"nlm_unique_id": "7802443",
"other_id": null,
"pages": "840-50",
"pmc": null,
"pmid": "25578256",
"pubdate": "2015-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Detection of Mycobacterium tuberculosis genome in vitreous fluid of eyes with multifocal serpiginoid choroiditis.",
"title_normalized": "detection of mycobacterium tuberculosis genome in vitreous fluid of eyes with multifocal serpiginoid choroiditis"
} | [
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"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2015-03310",
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"activesubstance": {
"activesubstancename": "PREDNISOLONE"
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{
"abstract": "The increasing prevalence of multi-drug resistant Gram-negative pathogens in intensive care units has led to the revival of colistin. Colistin had gone into disrepute in early 1970s because of numerous reports of adverse renal and neurological effects. The renewed interest in colistin has also revived the discussion about its toxicity. The neurotoxicity reported in literature is usually with higher doses of colistin. We present a case report of seizures in a critically ill-patient, possibly with low dose colistin. A 47-year-old hypertensive female with chronic kidney disease-5 with sepsis on colistimethate sodium 1 million units (80 mg), intravenous once daily, developed paresthesias and seizures on 12(th) day of therapy, which were subsequently controlled after withdrawl of the drug. To conclude, colistin should be considered as a cause of convulsions in critically ill-patients with renal failure, even when given in low dose and patient receiving intermittent hemodialysis, when other obvious causes have been ruled out. When possible, cessation of therapy may be considered.",
"affiliations": "Department of Critical Care, SPS Apollo Hospitals, Ludhiana, Punjab, India.;Department of Nephrology, SPS Apollo Hospitals, Ludhiana, Punjab, India.;Department of Critical Care, SPS Apollo Hospitals, Ludhiana, Punjab, India.;Department of Neurosciences, SPS Apollo Hospitals, Ludhiana, Punjab, India.;Department of Anaesthesia and Critical Care, SPS Apollo Hospitals, Ludhiana, Punjab, India.;Department of Anaesthesia and Critical Care, SPS Apollo Hospitals, Ludhiana, Punjab, India.",
"authors": "Sodhi|Kanwalpreet|K|;Kohli|Rahul|R|;Kaur|Basjinder|B|;Garg|Sidhartha|S|;Shrivastava|Anupam|A|;Kumar|Manender|M|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0970-9185.137282",
"fulltext": "\n==== Front\nJ Anaesthesiol Clin PharmacolJ Anaesthesiol Clin PharmacolJOACPJournal of Anaesthesiology, Clinical Pharmacology0970-91852231-2730Medknow Publications & Media Pvt Ltd India JOACP-30-41510.4103/0970-9185.137282Case ReportConvulsions in a critically ill patient on hemodialysis: Possible role of low dose colistin Sodhi Kanwalpreet Kohli Rahul 1Kaur Basjinder Garg Sidhartha 2Shrivastava Anupam 3Kumar Manender 3Department of Critical Care, SPS Apollo Hospitals, Ludhiana, Punjab, India1 Department of Nephrology, SPS Apollo Hospitals, Ludhiana, Punjab, India2 Department of Neurosciences, SPS Apollo Hospitals, Ludhiana, Punjab, India3 Department of Anaesthesia and Critical Care, SPS Apollo Hospitals, Ludhiana, Punjab, IndiaAddress for correspondence: Dr. Kanwalpreet Sodhi, Department of Critical Care, SPS Apollo Hospitals, Ludhiana, Punjab, India. E-mail: drkanwal2006@yahoo.comJul-Sep 2014 30 3 415 418 Copyright: © Journal of Anaesthesiology Clinical Pharmacology2014This 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.The increasing prevalence of multi-drug resistant Gram-negative pathogens in intensive care units has led to the revival of colistin. Colistin had gone into disrepute in early 1970s because of numerous reports of adverse renal and neurological effects. The renewed interest in colistin has also revived the discussion about its toxicity. The neurotoxicity reported in literature is usually with higher doses of colistin. We present a case report of seizures in a critically ill-patient, possibly with low dose colistin. A 47-year-old hypertensive female with chronic kidney disease-5 with sepsis on colistimethate sodium 1 million units (80 mg), intravenous once daily, developed paresthesias and seizures on 12th day of therapy, which were subsequently controlled after withdrawl of the drug. To conclude, colistin should be considered as a cause of convulsions in critically ill-patients with renal failure, even when given in low dose and patient receiving intermittent hemodialysis, when other obvious causes have been ruled out. When possible, cessation of therapy may be considered.\n\nColistincritically illintensive care unitneurotoxicityrenal failureseizures\n==== Body\nIntroduction\nThe increasing prevalence of multi-drug resistant (MDR) gram-negative pathogens in intensive care units (ICUs) and shortage of new antibiotics to combat them has led to the re-evaluation of colistin.[1] Colistin is a multicomponent polypeptide antibiotic, comprised of colistins A and B, which became available for clinical use in the 1960s.[2] It had gone into disrepute because of numerous reports of adverse renal and neurological effects.[13] The renewed interest into colistin has also revived the discussion about its toxicity. We present a case report of possible neurotoxicity with low dose colistin presenting as seizures in a critically ill patient.\n\nCase Report\nA 47-year-old known hypertensive female with chronic kidney disease-5 [CKD-5], on thrice weekly hemodialysis (HD), presented with cough with expectoration and breathlessness for 3-4 weeks and fever for 10 days. She was managed in an outside facility for 1 week on amlodipine, erythropoietin, imipenem, HD and other supportive care for CKD. On presentation, patient was conscious, well-oriented with a heart rate of 116 beats/min regular, non-invasive blood pressure of 108/66 mmHg, temperature of 100.2°F and respiratory rate of 34/min with accessory muscles being used. On chest examination, bilateral normal vesicular breath sounds were heard with decreased air entry and occasional coarse crepts in the right lower zone. Her laboratory workup on the day of admission and subsequently is shown in Table 1. Chest X-ray showed right lower lobe consolidation/collapse with pleural effusion. Blood and urine cultures were sent, which were sterile. She was managed in the medical intensive care unit on antibiotics and non-invasive ventilation. She was continued on injection imipenem 500 mg twice daily (BID), which she had already received for 2 days prior to admission. On the 3rd day of admission, the patient's clinical condition deteriorated with a significant rise in total leukocyte count (TLC) up to 28,600/mm3. Repeat blood cultures were sent and injection teicoplanin and injection caspofungin added empirically. Next day, a provisional report of gram-negative coccobacilli in blood was received, which was later confirmed to be Acinetobacter baumannii. Injection colistin in a dose of 1 million units (MU) (80 mg colistimethate sodium) intravenous (i/v) once daily (OD) following a loading dose of 2 MU was started. Her fever and TLC started decreasing gradually from the 7th day onward. Caspofungin was de-escalated on receiving culture reports and imipenem was stopped after 10 days of therapy. Patient continued to improve clinically with off and on low-grade fever. She was continued on almost alternate day HD.\n\nTable 1 Serial laboratory investigations\n\nOn the morning of 16th day of admission, patient had sudden onset of abnormal facial twitchings, which were mainly circumoral and initially limited to the neck. The seizures were controlled with short acting benzodiazepine in the form of injection midazolam 1 mg i/v stat. She was loaded with injection phenytoin 1 g i/v on neurologist's opinion, followed by 100 mg i/v BID. But in the same evening, patient had another episode of seizures, which were generalized tonic clonic and got relieved with injection midazolam 1 mg + 1 mg i/v bolus. Levirecetam 1 g i/v stat followed by 500 mg i/v BID was added by the neurophysician. Her laboratory workup reflected no acute metabolic derangements. Liver profile was normal. Neuroimaging of the brain (magnetic resonance imaging) and electroencephalography were normal. Nerve conduction velocity to rule out critical illness neuropathy was also done. To rule out meningitis as a cause for fever and seizures, lumbar puncture was performed and the cerebral spinal fluid (CSF) was found to be clear, with normal pressure and CSF biochemistry was within normal limits (CSF glucose = 56 mg/dl (corresponding Random Blood Sugar = 92), proteins = 37, TLC = nil).\n\nFurther search for any offending drug as a cause for seizures was made. Imipenem which is a potentially seizure inducing drug, was stopped around 1 week before the occurrence of focal seizures. Excluding all other possible causes, colistimethate which is a seizure-threshold lowering drug, was considered to be the sole possible causative agent for seizures. As the patient had improved clinically, colistin was stopped on the occurrence of seizures. Fresh blood cultures were sent after 48 h of stopping antibiotics, which were sterile. Patient had no recurrence of seizures at any point of time after stopping the drug. The antiepileptics were tapered after 1 week of starting the treatment. The patient was shifted to the ward and was finally discharged in a fair condition after 33 days of hospital stay.\n\nDiscussion\nAfter being abandoned in the 1970s because of reported nephrotoxicity and neurotoxicity, colistin is having a second life as a “salvage” treatment against multiresistant gram-negative bacteria (GNB).[14] Colistin belongs to the polymyxin class of cationic polypeptide antibiotics, composed of at least 30 different polymyxin compounds, mainly colistins A and B.[5] The mounting prevalence of MDR GNB worldwide has renewed interest into colistin, but it also has revived the discussion about its toxicity.[1] The incidence of colistin-associated nephrotoxicity and neurotoxicity in recent literature is low.[3] The reported adverse effects in older studies were usually observed with high doses of colistin.[456] Paradoxically, the present case report considers even low-dose colistin as a cause for focal and generalized tonic clonic seizures. In a known case of CKD with sepsis, multiple factors can lead on to seizures including metabolic derangements, dialysis disequilibrium syndrome, sepsis itself and concomitant drug therapy. In our patient, we had ruled out all possible causes of seizures on laboratory work-up and radiological studies. A potentially seizure inducing drug imipenem had been stopped 8 days prior to the episode of seizures. The plasma half-life of imipenem/cilastatin is approximately 1 h in a patient with a normal renal function, which may increase to more than 3 h with imipenem and 8.84-17 h with cilastatin in deranged renal function.[78] But both imipenem and cilastatin are cleared from the circulation by HD and half-lives are shortened.[8] Thus, it is highly unlikely to remain in circulation after three HD sessions which our patient had undergone after stopping imipenem. Hence seizures in our patient could not be attributed to imipenem. Dialysis disequilibrium can be another possibility in our patient, but usually it is more often seen when patients are undergoing their first HD. In our case, patient was already dialysis-dependent.\n\nNo clear-cut specifications on colistin dosage are available and colistin has been used in different doses in patients with normal or deranged renal function.[23] Colistin pharmacokinetics (PK) are expected to be dramatically altered in critically ill patients, because they are prone to large swings in distribution volume, fluctuations in renal clearance and variable protein binding.[259] Very limited information is available on the PKs of colistimethate and colistin in critically ill patients receiving renal replacement therapy. In renal failure, renal excretion of colistin methanesulfonate (CMS) is decreased resulting in higher conversion to colistin and prolongation of half-life.[9] But colistin is mainly excreted by non-renal mechanisms.[9] In a patient undergoing continuous venovenous hemodiafiltration (CVVH), conversion of CMS to colistin was rapid and terminal half-lives of CMS and colistin were 6.8 h and 7.5 h, respectively.[10] As our patient was also on alternate day HD and PK of colistin is unpredicted, the causal role of low-dose colistin with seizures in our patient could not be established with certainty. The removal of CMS and colistin by dialysis has yielded conflicting results in the literature.[29] Li et al. retrieved colistin and its CMS derivative from plasma and dialysis fluid during CVVH using high-performance liquid chromatography, suggesting that dose adjustment is smaller in these patients.[11] Sarria et al. failed to detect polymyxin B in the dialysate during CVVH; although, its presence in the plasma had been confirmed, suggesting that the drug is not dialyzable and therefore supplemental doses would not be necessary in patients subjected to dialysis.[12] However, it is quite likely that the daily dose of colistin might exert an important influence on adverse effects and numerous studies report that neurotoxicity increases strikingly with the mean daily dose administered and total cumulative dose.[134613] In one of the studies by Koch-Weser, neurological reactions rate reached 45% among patients who received over 400 mg/day of colistin.[3] Sabuda showed varying neurological signs and symptoms with a dose of colistin varying from 150 mg every 36 h to 125 mg every 6 h.[14] Another case report by Wahby described neurotoxicity with 170 mg BD colistin base within 5 days of initiation of treatment.[15] However, our patient was on a low dose colistimethate sodium 1 MU (80 mg) i/v OD based on the creatinine clearance (Cr Cl < 10 ml/min).[16] This was a very low dose as compared to other studies quoting neurotoxicity with colistin, even with deranged renal parameters.[346131415] From our review of literature, we could not find colistin neurotoxicity with dose lesser than this.\n\nColistin neurotoxicity may be associated with dizziness, muscle weakness, facial and peripheral paresthesia, partial deafness, visual disturbances, vertigo, confusion, hallucinations, seizures, ataxia and neuromuscular blockade, paresthesias being the most frequent.[1315] However, the most dreaded neurotoxic event is neuromuscular blockade presenting as a myasthenia-like syndrome or respiratory muscle paralysis producing apnea.[414] Diagnosis of neurotoxicity is mostly made on clinical grounds, making it difficult to discriminate from “critical illness polymyoneuropathy” in ICU patients.[4] The interaction of colistin with neurons having high lipid content has been postulated as a cause of neurotoxicity.[3] Other investigators have suggested a biphasic mechanism to explain the neurotoxic event; a short phase of competitive blockade between acetylcholine and polymyxins is followed by a prolonged phase of depolarization associated with calcium depletion.[1] Potential triggers of neurotoxicity are hypoxia, concomitant medication (muscle relaxants, narcotics, sedatives, anesthetic drugs and corticosteroids) and impaired renal function.[4] The female gender predisposition in neurotoxicity, has also been seen in our patient.[13]\n\nMild neurological complications of colistin such as paresthesias usually subside after prompt cessation of the offending drug.[117] We stopped colistin in our patient very next day of seizure episode and thereafter, there was no recurrence of seizures even on tapering off the epileptic drugs. For severe neurotoxicity, use of i/v calcium and choline-esterase inhibitors, e.g., neostigmine and edrophonium, have been recommended with conflicting results and in patients with coexisting renal failure, HD has also been indicated.[18]\n\nConclusion\nAlthough rare, but the toxicity potential of colistin should be kept in mind while prescribing the drug especially in critically ill-patients in ICUs, in whom colistin PK are expected to be dramatically altered. Colistin being a cause of seizures in this patient is not definitely proven, though highly probable. Colistin should be considered as a cause of convulsions in critically ill-patients with renal failure, even when given in low dose and patient receiving intermittent HD, when other obvious causes have been ruled out. When possible, cessation of therapy may be considered. Although considering the spectrum of colistin usage in ICU during recent times, it might not be possible to stop colistin altogether, Studies are required to determine if monitoring of serum colistin levels in ICU can prevent toxicity.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\n1 Falagas ME Kasiakou SK Toxicity of polymyxins: A systematic review of the evidence from old and recent studies Crit Care 2006 10 R27 16507149 \n2 Li J Nation RL Turnidge JD Milne RW Coulthard K Rayner CR Colistin: The re-emerging antibiotic for multidrugresistant gram-negative bacterial infections Lancet Infect Dis 2006 6 589 601 16931410 \n3 Koch-Weser J Sidel VW Federman EB Kanarek P Finer DC Eaton AE Adverse effects of sodium colistimethate. Manifestations and specific reaction rates during 317 courses of therapy Ann Intern Med 1970 72 857 68 5448745 \n4 Spapen H Jacobs R Van Gorp V Troubleyn J Honoré PM Renal and neurological side effects of colistin in critically ill patients Ann Intensive Care 2011 1 14 21906345 \n5 Couet W Grégoire N Marchand S Mimoz O Colistin pharmacokinetics: The fog is lifting Clin Microbiol Infect 2012 18 30 9 21988234 \n6 Pogue JM Lee J Marchaim D Yee V Zhao JJ Chopra T Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system Clin Infect Dis 2011 53 879 84 21900484 \n7 Somani P Freimer EH Gross ML Higgins JT Jr Pharmacokinetics of imipenem-cilastatin in patients with renal insufficiency undergoing continuous ambulatory peritoneal dialysis Antimicrob Agents Chemother 1988 32 530 4 3377464 \n8 Gibson TP Demetriades JL Bland JA Imipenem/cilastatin: Pharmacokinetic profile in renal insufficiency Am J Med 1985 78 54 61 3859216 \n9 Michalopoulos AS Falagas ME Colistin: Recent data on pharmacodynamics properties and clinical efficacy in critically ill patients Ann Intensive Care 2011 1 30 21906322 \n10 Li J Rayner CR Nation RL Deans R Boots R Widdecombe N Pharmacokinetics of colistin methanesulfonate and colistin in a critically ill patient receiving continuous venovenous hemodiafiltration Antimicrob Agents Chemother 2005 49 4814 5 16251342 \n11 Li J Rayner CR Nation RL Colistin-associated acute renal failure: Revisited South Med J 2005 98 1229 30 16440932 \n12 Sarria JC Angulo-Pernett F Kimbrough RC McVay CS Vidal AM Use of intravenous polymyxin B during continuous venovenous hemodialysis Eur J Clin Microbiol Infect Dis 2004 23 340 1 15007705 \n13 Hartzell JD Neff R Ake J Howard R Olson S Paolino K Nephrotoxicity associated with intravenous colistin (colistimethate sodium) treatment at a tertiary care medical center Clin Infect Dis 2009 48 1724 8 19438394 \n14 Sabuda DM Laupland K Pitout J Dalton B Rabin H Louie T Utilization of colistin for treatment of multidrug-resistant Pseudomonas aeruginosa Can J Infect Dis Med Microbiol 2008 19 413 8 19436571 \n15 Wahby K Chopra T Chandrasekar P Intravenous and inhalational colistin-induced respiratory failure Clin Infect Dis 2010 50 e38 40 20146630 \n16 Gilbert DN Moellering RC Jr Eliopoulos GM Chambers HF Saag MS The Sanford Guide to Antimicrobial Therapy 2011 2011 41st ed New Delhi B I Publications \n17 Linden PK Kusne S Coley K Fontes P Kramer DJ Paterson D Use of parenteral colistin for the treatment of serious infection due to antimicrobial-resistant Pseudomonas aeruginosa Clin Infect Dis 2003 37 e154 60 14614688 \n18 Gold GN Richardson AP Jr An unusual case of neuromuscular blockade seen with therapeutic blood levels of colistin methanesulfonate (Coly-Mycin) Am J Med 1966 41 316 21 5912305\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0970-9185",
"issue": "30(3)",
"journal": "Journal of anaesthesiology, clinical pharmacology",
"keywords": "Colistin; critically ill; intensive care unit; neurotoxicity; renal failure; seizures",
"medline_ta": "J Anaesthesiol Clin Pharmacol",
"mesh_terms": null,
"nlm_unique_id": "9516972",
"other_id": null,
"pages": "415-8",
"pmc": null,
"pmid": "25190957",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports",
"references": "19438394;21988234;14614688;16251342;16507149;16440932;3859216;21906345;5912305;5448745;21906382;3377464;15007705;16931410;21900484;19436571;20146630",
"title": "Convulsions in a critically ill patient on hemodialysis: Possible role of low dose colistin.",
"title_normalized": "convulsions in a critically ill patient on hemodialysis possible role of low dose colistin"
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"companynumb": "IN-PAR PHARMACEUTICAL, INC-2015SCPR014058",
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"abstract": "Repeated and prolonged episodes of central apnoea and hypoxia after receiving intravenous morphine for analgesia and ketamine for sedation.\n\n\n\nIntravenous morphine sulfate.\n\n\n\nPreviously healthy 12-year-old male with no history of sleep apnoea who presented with distal tibia and fibula fracture.\n\n\n\nPharmacogenomic testing revealed that the patient was homozygous for the T allele at the rs887829 SNP in UGT1A1, an enzyme involved in the metabolism of morphine. This polymorphism is a loss-of-function variant, leading to impaired metabolism of morphine.\n\n\n\nMorphine is metabolized by UDP-glucuronosyltransferase (UGT)-2B7 and UGT1A1 to form its major metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Our patient was a poor metabolizer through UGT1A1, likely leading to increased respiratory depression as morphine has greater respiratory depressant effects compared to its metabolites.\n\n\n\nWhen appropriate, physicians should enquire about prior receipt of opioids, in both the patient and family, to be better prepared for potential adverse reactions. In the patient with excessive sedation or respiratory depression to standard doses of morphine, genetic testing may be warranted, especially if there is a family or past history that supports a metabolic defect in morphine metabolism and/or excretion.",
"affiliations": "Division of Emergency Medicine, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.;Clinical Pharmacogenomics Service, Boston Children's Hospital, Boston, MA, USA.;Division of Emergency Medicine, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.;Division of Emergency Medicine, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.",
"authors": "Toce|Michael S|MS|0000-0002-7013-5432;Kim|Hyun|H|;Chung|Sarita|S|;Krauss|Baruch S|BS|",
"chemical_list": "D000701:Analgesics, Opioid; D009020:Morphine; C418331:UGT1A1 enzyme; D014453:Glucuronosyltransferase",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.13779",
"fulltext": null,
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"issn_linking": "0306-5251",
"issue": "85(1)",
"journal": "British journal of clinical pharmacology",
"keywords": "emergency medicine; genetic polymorphism; opioids; pain; pharmacogenomics",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D061605:Administration, Intravenous; D000701:Analgesics, Opioid; D001049:Apnea; D002648:Child; D005360:Fibula; D000069076:Fractures, Multiple; D014453:Glucuronosyltransferase; D006801:Humans; D000073658:Loss of Function Mutation; D008297:Male; D009020:Morphine; D010146:Pain; D000071185:Pharmacogenomic Testing; D020641:Polymorphism, Single Nucleotide; D013978:Tibial Fractures",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "258-262",
"pmc": null,
"pmid": "30421550",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15179405;19201064;27028535;29055038;15530129;12045153;8562297;28828486;30421550;10718775;17476361;23277092;26417955;3101549;18187562;29149325;4780184;1907362;29055034;11013440;9010622;29055040;27935268;244313;24703092;15791112;29055035",
"title": "Prolonged central apnoea after intravenous morphine administration in a 12-year-old male with a UGT1A1 loss-of-function polymorphism.",
"title_normalized": "prolonged central apnoea after intravenous morphine administration in a 12 year old male with a ugt1a1 loss of function polymorphism"
} | [
{
"companynumb": "US-MYLANLABS-2019M1006183",
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"activesubstancename": "KETAMINE"
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{
"abstract": "BACKGROUND\nThis retrospective review provides preliminary data regarding the safety and efficacy of olanzapine for chemotherapy-induced vomiting (CIV) control in children.\n\n\nMETHODS\nChildren <18 years old who received olanzapine for acute chemotherapy-induced nausea and vomiting (CINV) control from December 2010 to August 2013 at four institutions were identified. Patient characteristics, chemotherapy, antiemetic prophylaxis, olanzapine dosing, CIV control, liver function test results and adverse events were abstracted from the health record. Toxicity was graded using CTCAEv4.03.\n\n\nRESULTS\nSixty children (median age 13.2 years; range: 3.10-17.96) received olanzapine during 158 chemotherapy blocks. Olanzapine was most often (59%) initiated due to a history of poorly controlled CINV. The mean initial olanzapine dose was 0.1 mg/kg/dose (range: 0.026-0.256). Most children who received olanzapine beginning on the first day of the chemotherapy block experienced complete CIV control throughout the acute phase (83/128; 65%). There was no association between the olanzapine dose/kg and complete CIV control (OR 1.01; 95% CI: 0.999-1.020; P = 0.091). Sedation was reported in 7% of chemotherapy blocks and was significantly associated with increasing olanzapine dose (OR: 1.17; 95% CI: 1.08-1.27; P = 0.0001). Of the 25 chemotherapy blocks where ALT and/or AST were reported more than once, grade 1-3 elevations were observed in five. The mean weight change in 31 children who received olanzapine during more than one chemotherapy block was 0% (range: -22 to +18).\n\n\nCONCLUSIONS\nOlanzapine may be an important option to improve CIV control in children. Prospective controlled evaluation of olanzapine for CINV prophylaxis in children is warranted.",
"affiliations": "Department of Pharmacy, The Hospital for Sick Children, Toronto, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada.",
"authors": "Flank|Jacqueline|J|;Thackray|Jennifer|J|;Nielson|Danelle|D|;August|Amanda|A|;Schechter|Tal|T|;Alexander|Sarah|S|;Sung|Lillian|L|;Dupuis|L Lee|LL|",
"chemical_list": "D000932:Antiemetics; D000970:Antineoplastic Agents; D001569:Benzodiazepines; D000077152:Olanzapine",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25286",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "62(3)",
"journal": "Pediatric blood & cancer",
"keywords": "chemotherapy-induced vomiting; olanzapine; pediatric; supportive care",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000932:Antiemetics; D000970:Antineoplastic Agents; D001569:Benzodiazepines; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms; D000077152:Olanzapine; D012189:Retrospective Studies; D014839:Vomiting",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "496-501",
"pmc": null,
"pmid": "25328089",
"pubdate": "2015-03",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Olanzapine for treatment and prevention of acute chemotherapy-induced vomiting in children: a retrospective, multi-center review.",
"title_normalized": "olanzapine for treatment and prevention of acute chemotherapy induced vomiting in children a retrospective multi center review"
} | [
{
"companynumb": "CA-ALKEM LABORATORIES LIMITED-CA-ALKEM-2020-08493",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
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{
"abstract": "High-dose BEAM chemotherapy (BCNU, etoposide, Ara-C, and melphalan) followed by autologous hematopoietic stem cell transplantation is frequently used as consolidative therapy for patients with recurrent or refractory Hodgkin or non-Hodgkin lymphoma. The BEAM regimen has traditionally been administered over 6 days in the hospital, with patients remaining hospitalized until hematologic recovery and clinical stability. In an effort to reduce the length of hospitalization for these patients, our institution has transitioned from inpatient (IP) to outpatient (OP) administration of BEAM conditioning. Here, we report the results of an analysis of the feasibility, cost, complications, and outcomes for the initial group of patients who received OP BEAM compared to a prior cohort of patients who received IP BEAM. Patient and disease characteristics were comparable for the two cohorts, as were engraftment kinetics. Length of hospital stay was reduced by 6 days for the OP cohort (P < 0.001), resulting in a cost savings of more than $17,000 per patient. Fewer complications occurred in the OP cohort, including severe enteritis (P = 0.01), organ toxicities (P = 0.01), and infections (P = 0.04). Overall survival rate up to 3 years posttransplant was better for the OP cohort (P = 0.02), likely due to differences in posttransplant therapies. We conclude that OP administration of BEAM conditioning is safe and may offer significant advantages, including decreased length of hospitalization, reduced costs, decreased risks for severe toxicities and infectious complications, and likely improvement in patient satisfaction and quality of life.",
"affiliations": "James P Wilmot Cancer Institute and Department of Medicine, University of Rochester Medical Center, Rochester, New York.;James P Wilmot Cancer Institute and Department of Medicine, University of Rochester Medical Center, Rochester, New York.;James P Wilmot Cancer Institute and Department of Medicine, University of Rochester Medical Center, Rochester, New York.;James P Wilmot Cancer Institute and Department of Medicine, University of Rochester Medical Center, Rochester, New York.;James P Wilmot Cancer Institute and Department of Medicine, University of Rochester Medical Center, Rochester, New York.;James P Wilmot Cancer Institute and Department of Medicine, University of Rochester Medical Center, Rochester, New York.;James P Wilmot Cancer Institute and Department of Medicine, University of Rochester Medical Center, Rochester, New York.;James P Wilmot Cancer Institute and Department of Medicine, University of Rochester Medical Center, Rochester, New York.;James P Wilmot Cancer Institute and Department of Medicine, University of Rochester Medical Center, Rochester, New York.",
"authors": "Reid|Robin M|RM|;Baran|Andrea|A|;Friedberg|Jonathan W|JW|;Phillips|Gordon L|GL|;Liesveld|Jane L|JL|;Becker|Michael W|MW|;Wedow|Lucy|L|;Barr|Paul M|PM|;Milner|Laurie A|LA|",
"chemical_list": "D003561:Cytarabine; D011034:Podophyllotoxin; D008558:Melphalan; D002330:Carmustine",
"country": "United States",
"delete": false,
"doi": "10.1002/cam4.879",
"fulltext": "\n==== Front\nCancer MedCancer Med10.1002/(ISSN)2045-7634CAM4Cancer Medicine2045-7634John Wiley and Sons Inc. Hoboken 10.1002/cam4.879CAM4879Original ResearchClinical Cancer ResearchOriginal ResearchOutpatient administration of BEAM conditioning prior to autologous stem cell transplantation for lymphoma is safe, feasible, and cost‐effective Reid Robin M. \n1\n\n2\nBaran Andrea \n1\nFriedberg Jonathan W. \n1\nPhillips Gordon L. II\n1\n\n3\nLiesveld Jane L. \n1\nBecker Michael W. \n1\nWedow Lucy \n1\nBarr Paul M. \n1\nMilner Laurie A. laurie_milner@urmc.rochester.edu \n1\n\n4\n1 James P Wilmot Cancer Institute and Department of MedicineUniversity of Rochester Medical CenterRochesterNew York2 Rochester Regional HealthRochesterNew York3 Wake Forest Baptist HealthWinston‐SalemNorth Carolina4 Department of Pathology and Laboratory MedicineUniversity of Rochester Medical CenterRochesterNew York* Correspondence\n\nLaurie A. Milner, James P Wilmot Cancer Institute and Department of Medicine, University of Rochester Medical Center, 601 Elmwood Ave, Box 704, Rochester 14642, NY. Tel: 585‐275‐4099; Fax: 585‐276‐2596; E‐mail: laurie_milner@urmc.rochester.edu\n03 10 2016 11 2016 5 11 10.1002/cam4.2016.5.issue-113059 3067 24 3 2016 22 4 2016 27 7 2016 © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nHigh‐dose BEAM chemotherapy (BCNU, etoposide, Ara‐C, and melphalan) followed by autologous hematopoietic stem cell transplantation is frequently used as consolidative therapy for patients with recurrent or refractory Hodgkin or non‐Hodgkin lymphoma. The BEAM regimen has traditionally been administered over 6 days in the hospital, with patients remaining hospitalized until hematologic recovery and clinical stability. In an effort to reduce the length of hospitalization for these patients, our institution has transitioned from inpatient (IP) to outpatient (OP) administration of BEAM conditioning. Here, we report the results of an analysis of the feasibility, cost, complications, and outcomes for the initial group of patients who received OP BEAM compared to a prior cohort of patients who received IP BEAM. Patient and disease characteristics were comparable for the two cohorts, as were engraftment kinetics. Length of hospital stay was reduced by 6 days for the OP cohort (P < 0.001), resulting in a cost savings of more than $17,000 per patient. Fewer complications occurred in the OP cohort, including severe enteritis (P = 0.01), organ toxicities (P = 0.01), and infections (P = 0.04). Overall survival rate up to 3 years posttransplant was better for the OP cohort (P = 0.02), likely due to differences in posttransplant therapies. We conclude that OP administration of BEAM conditioning is safe and may offer significant advantages, including decreased length of hospitalization, reduced costs, decreased risks for severe toxicities and infectious complications, and likely improvement in patient satisfaction and quality of life.\n\nComplicationsconditioning chemotherapycoststem cell transplantation source-schema-version-number2.0component-idcam4879cover-dateNovember 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.8 mode:remove_FC converted:22.11.2016\n\nCancer Medicine \n2016 ; 5(11):3059 –3067\n==== Body\nIntroduction\nHigh‐dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) is standard consolidative treatment for patients with Hodgkin (HL) or non‐Hodgkin lymphoma (NHL) that persists or recurs following standard chemotherapy and/or radiation 1, 2, 3, 4, 5. The BEAM regimen (BCNU, etoposide [ETP], Ara‐C, and melphalan) is often utilized as the conditioning regimen and has traditionally been administered over 6 days in the hospital, with patients remaining hospitalized until hematologic recovery and clinical stability 6, 7, 8, 9. However, there is currently substantial interest in performing various aspects of stem cell transplantation (SCT) in outpatient (OP) settings and reports from multiple institutions suggest this can be done safely 10, 11, 12, 13. The feasibility of this approach, however, may depend on the facilities, infrastructure, and staffing of the institution, as well as the demographics of the patient population served 14, 15. The blood and marrow transplant (BMT) program at the JP Wilmot Cancer Institute (JPWCI) is the only comprehensive BMT program serving central New York State, a largely rural area of about 25 counties that comprises about half the square mileage of NY. In 2011, in an effort to reduce the length of hospitalization for patients undergoing ASCT for lymphoma, we transitioned from inpatient (IP) to OP administration of BEAM conditioning. We anticipated that this approach would not only result in significant cost savings and more efficient hospital bed utilization, but could also improve patient satisfaction and quality of life. In order to evaluate the impact of this approach at the JPWCI, we retrospectively evaluated the first 58 patients receiving OP BEAM and a comparable cohort of patients who received IP BEAM in the time immediately preceding the transition. This study describes the comparison between these two cohorts with respect to engraftment, length of hospital stay, toxicities, infectious complications, survival, and cost.\n\nPatients and Methods\nPatients\nFollowing Institutional Research Subjects Review Board approval, we performed a retrospective chart review on all 58 patients who received OP BEAM conditioning prior to ASCT for lymphoma from January 2011 through March 2014. There were no specific exclusions, although four patients enrolled on a clinical trial specifying administration of ETP and Ara‐C every 12 h were admitted to the hospital and thus excluded. We also reviewed charts of the 49 consecutive patients who received IP BEAM conditioning immediately prior to the transition to OP BEAM. These patients underwent ASCT from July 2008 through December 2010. In addition, 31 patients received IP BEAM during the concurrent OP BEAM time period due to lack of a caregiver or physician preference, these patients were reviewed separately.\n\nConditioning regimens\nPatients receiving IP BEAM were admitted the first day of conditioning, while those receiving OP BEAM were admitted prior to the stem cell infusion on day 0. All patients remained hospitalized until hematologic recovery and resolution of active medical issues.\n\nPatients receiving OP BEAM were required to stay within 30 min of the JPWCI and have a full‐time caregiver. Both patient and caregiver had to demonstrate an adequate level of comprehension regarding treatment plans and potential complications. Patients were evaluated by a nurse practitioner and an attending physician on the first day of conditioning and daily thereafter by either or both. During those visits, patients were directly queried about nausea, vomiting, diarrhea, infectious symptoms, and other issues, and were given a phone number for the SCT nurse practitioner should they have any problems after clinic hours. Laboratory monitoring included daily CBCs and chemistries.\n\nThe IP and OP BEAM regimens utilized the same chemotherapeutic agents at the same total doses, but on slightly different schedules, as depicted in Figure 1. The modifications for OP BEAM chemotherapy were initially made to facilitate outpatient administration; however, this has since become our standard regimen for IP BEAM as well.\n\nFigure 1 Inpatient and outpatient BEAM‐conditioning regimens. BCNU: carmustine; ETP: etoposide; Ara‐C: cytarabine. Chemotherapy drugs were dosed on 25% corrected ideal body weight: CIBW = IBW + [(0.25) × (Actual BW – IBW)], where IBW in kg = 50 (male) or 45.5 (female) + (2.3 × height in inches over 60 inches).\n\nSupportive care\nInstitutional guidelines for blood product support and symptom management were followed. Fluoroquinolone prophylaxis was started when the ANC dropped below 500/μL. Broad‐spectrum antibiotics were started for fevers and continued until neutrophil recovery or the completion of specific therapy if a pathogen was isolated. Viral prophylaxis with (val)acyclovir was started with conditioning and continued for 6 months posttransplant. Fluconazole for fungal prophylaxis was started with conditioning and given until engraftment.\n\nMethods and definitions\nPatients undergoing ASCT for lymphoma were identified by searching the Microsoft Access database used at our institution to track all patients undergoing SCT. Electronic medical records for each patient were then reviewed to confirm baseline demographic data and extract additional information. Pretransplant data acquired included specific diagnosis, disease status, lines of therapy received prior to transplant and response to each therapy, and comorbidity index as calculated by the Hematopoietic Cell Transplant‐Specific Comorbidity Index (HCT‐CI) 16. All patients underwent disease‐specific restaging studies prior to transplantation. A line of prior therapy was defined as a specific chemotherapy regimen or course of radiation prior to, but not including, conditioning.\n\nAll patients received mobilized peripheral blood stem cells. Times to neutrophil and platelet engraftment followed CIBMTR guidelines: for neutrophils, the first of ≥3 consecutive days with ANC ≥500/μL without growth factor support; for platelets, the first of ≥3 consecutive days with platelet count ≥20,000/μL without transfusion or, if the patient was transfused, 7 days following transfusion (if platelets remained ≥20,000). The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI‐CTCAE), version 4.03, was used to report toxicities and infections. Diagnosis of infection required a positive culture, molecular pathogen identification, or radiographic evidence of disease in the setting of corresponding signs and/or symptoms and the need for systemic antimicrobial therapy.\n\nCosts for OP and IP care were determined by review of financial records for lymphoma patients undergoing BEAM conditioning and ASCT. Average daily costs during OP BEAM and IP care were used to estimate cost savings for OP BEAM.\n\nStatistics\nContinuous variables were compared using the nonparametric Wilcoxon test, and were summarized by the median, minimum, and maximum. Categorical variables were compared using Fisher's exact test and were summarized by counts and proportions. Infection densities were compared using the exact binomial test. Overall survival (OS) was defined as the time from ASCT to the date of death from any cause and progression‐free survival (PFS) as the time from ASCT to date of relapse, progression, or death, whichever occurred first. The Kaplan–Meier method was used to estimate the distributions of OS and PFS. The log‐rank test was used to assess differences in survival between the cohorts. Hypothesis tests were two‐sided and conducted at the 0.05 level of significance. All analyses were conducted using SAS version 9.4 (SAS Institute, Inc.).\n\nResults\nPatient and disease characteristics\nAs shown in Table 1, patient demographics, specific diagnosis, disease status, prior therapy, and HCT‐CI were comparable for the OP and IP BEAM cohorts. Median follow‐up was slightly longer for the IP cohort (36.9 vs. 31.4 months).\n\nTable 1 Patient, disease, and treatment characteristics\n\n\n \n\tIP BEAM (N = 49)\tOP BEAM (N = 58)\t\nP value\t\nAge (years)\t\t\t0.83\t\nMedian\t59\t58\t\t\nRange\t16–74\t17–72\t\t\nGender\t\t\t0.69\t\nMale\t30 (61%)\t38 (66%)\t\t\nFemale\t19 (39%)\t20 (35%)\t\t\nDiagnosis\t\n \n\t\n \n\t0.92\t\nFollicular\t4 (8%)\t4 (7%)\t\t\nFL to DLBCL\t4 (8%)\t9 (16%)\t\t\nDLBCL\t11 (23%)\t15 (26%)\t\t\nMantle cell\t14 (29%)\t15 (26%)\t\t\nMarginal zone\t1 (2%)\t1 (2%)\t\t\nHodgkin\t11 (22%)\t9 (16%)\t\t\nOther\t4 (8%)\t5 (9%)\t\t\nDisease status\t\t\t0.69\t\nCR 1\t14 (29%)\t19 (33%)\t\t\nCR ≥2\t15 (30%)\t14 (24%)\t\t\nPR\t19 (39%)\t25 (43%)\t\t\nPD\t1 (2%)\t0\t\t\nLines of prior therapy\t\t\t0.23\t\n1\t11 (22%)\t9 (16%)\t \t\n2\t16 (33%)\t28 (48%)\t\t\n3\t14 (29%)\t17 (29%)\t\t\n>3\t8 (16%)\t4 (7%)\t\t\nHCT‐CI\t\t\t0.85\t\n0\t23 (47%)\t31 (54%)\t\t\n1\t9 (18%)\t10 (17%)\t\t\n2\t5 (10%)\t5 (9%)\t\t\n3\t8 (16%)\t5 (9%)\t\t\n4\t2 (4%)\t3 (5%)\t\t\n>4\t2 (4%)\t4 (7%)\t\t\nMedian follow‐up (months)\t36.9\t31.4\t\t\nRange\t1.8–88.5\t3.3–55.9\t\t\nIP, inpatient; OP, outpatient; FL, follicular lymphoma; DLBCL, diffuse large B‐cell lymphoma; CR, complete remission; PR, chemosensitive partial response; PD, persistent refractory disease; HCT‐CI, Hematopoietic Cell Transplant‐Specific Comorbidity Index.\n\nJohn Wiley & Sons, LtdCell dose, engraftment, and length of hospital stay\nCD34+ cell doses and times to engraftment were comparable for IP and OP BEAM (Table 2). Length of hospitalization was reduced by 6 days with OP BEAM. No OP BEAM patient required early admission for toxicity, symptom management, infection, or patient/family request; one patient was admitted on day ‐2 to utilize an available inpatient bed.\n\nTable 2 Transplant outcomes\n\n\tIP BEAM\tOP BEAM\t\nP value\t\nCD34+ cell dose (×106/kg)\t\nMedian\t4.18\t4.59\t0.72\t\nRange\t2–18.9\t2–16.8\t\t\nNeutrophil engraftment (day)\t\nMedian\t10\t10\t0.33\t\nRange\t7–22\t8–13\t\t\nPlatelet engraftment (day)\t\nMedian\t10\t11\t0.17\t\nRange\t0–19\t7–35\t\t\nLength of hospital stay (days)\t\nMedian\t18\t12\t<0.0001\t\nRange\t15–30\t10–28\t\t\nIP, inpatient; OP, outpatient.\n\nJohn Wiley & Sons, LtdToxicity\nTable 3 compares gastrointestinal (GI) and other organ toxicities experienced by patients receiving IP and OP BEAM. The JPWCI converted to an electronic medical record around the time of transition from IP to OP BEAM. Thus, details pertaining to GI or other toxicities were easier to quantitate for the OP BEAM cohort. Nonetheless, for the IP cohort, detailed discharge summaries that included stool volumes and documentation of other toxicities, as well as all laboratory, microbial, and radiographic information were available. Of note, with the exception of nausea/vomiting, no GI or other organ toxicities were recorded in either group prior to day 0.\n\nTable 3 Transplant‐related toxicities\n\n \tIP BEAMNumber of patients (%)\tOP BEAMNumber of patients (%)\t\nP value\t\n\t\nNausea/Vomiting\t\t\t0.29\t\nGrades 0–1\t32 (65%)\t44 (76%)\t\t\nGrades 2–3\t17 (35%)\t14 (24%)\t\t\nMucositis\t\t\t0.46\t\nGrades 0–1\t38 (78%)\t49 (85%)\t\t\nGrades 2–3\t11 (22%)\t9 (16%)\t\t\nDiarrhea/Enteritis\toverall P‐value\t\t0.004\t\nGrades 0–1\t25 (51%)\t43 (74%)\t0.02\t\nGrades 2–3\t18 (37%)\t15 (26%)\t0.29\t\nGrade 4\t6 (12%)\t0 (0%)\t0.01\t\nOrgan toxicity ≥ Grade 2\t\nNumber of patients\t14 (29%)\t5 (9%)\t0.01\t\nNumber of toxicities\t21\t6\t\t\nGrade 2\t9\t2\t\t\nGrade 3\t9\t4\t\t\nGrade 4\t3\t0\t\t\nNumber of toxicities/patient\t\t\t0.03\t\n0\t35\t53\t\t\n1\t9\t4\t\t\n2\t3\t1\t\t\n3\t2\t0\t\t\nTypes of organ toxicity (events)\t\nAfib\t4\t2\t\t\nCardiac\t5\t1\t\t\nPulmonary\t4\t1\t\t\nRenal\t3\t1\t\t\nHepatic\t4\t0\t\t\nCNS\t1\t1\t\t\nMICU transfer\t2 (3%)\t0\t\t\nIP, inpatient; OP, outpatient; Afib, atrial fibrillation; CNS, central nervous system; MICU, medical intensive care unit.\n\nJohn Wiley & Sons, LtdWhile the incidences of grades 2–3 nausea/vomiting and mucositis were comparable for IP and OP BEAM, the IP cohort experienced almost twice the incidence of severe enteritis. Furthermore, no OP BEAM patient developed grade 4 enteritis, whereas six IP BEAM patients suffered this degree of toxicity.\n\nCompared to OP BEAM, the IP cohort also had a significantly higher incidence of non‐GI organ toxicities, more severe organ toxicities, and more patients with multiorgan toxicities. Organ toxicities grade ≥2 are summarized in Table 3. There was no transplant‐related mortality for either cohort.\n\nShortly after implementation of OP BEAM, we changed our standard IP BEAM regimen to correspond to the OP regimen. In order to assess whether daily dosing of ETP and Ara‐C might result in less toxicity, we also reviewed charts on the patients receiving this BEAM regimen as inpatients during the same time period as our OP BEAM cohort. While the number of patients was low (N = 17), the toxicities appeared similar to the prior IP BEAM cohort; one patient had grade 4 enteritis and there were 10 organ toxicities ≥grade 2.\n\nInfections\nAs shown in Table 4, the incidence of neutropenic fever was similar for OP and IP BEAM. However, the incidence of infection (density) was significantly higher for the IP cohort (P = 0.04). One patient in the IP cohort developed varicella zoster on day ‐5; there were no other infections prior to day 0 in either cohort. The majority of infections were caused by common bacteria, with respiratory viruses being next most common. There was one case each of Mycobacterium avium, varicella zoster, hepatitis C reactivation, Streptomyces, and mold, all in the IP cohort.\n\nTable 4 Infections within 30 days of transplant\n\n\tIP BEAM\tOP BEAM\t\nP value\t\nNumber of patients (%)\t\nNeutropenic fever\t33 (67%)\t30 (52%)\t0.12\t\nInfection\t22 (45%)\t15 (26%)\t0.04\t\nIncidence of infection (density)a\n\t1.90\t0.98\t0.04\t\nNumber of infections\t\nAll infections\t28\t17\t\t\nTypes of infection\t\nBacteremia\t4\t3\t\t\nPneumonia\t4\t5\t\t\nUTI\t3\t3\t\t\nC. diff\t5\t5\t\t\nOther GI\t6\t1\t\t\nCellulitis\t4\t0\t\t\nOther\t2\t0\t\t\nIP, inpatient; OP, outpatient; UTI, urinary tract infection; C. diff, Clostridium difficile colitis; GI, gastrointestinal.\n\nOther GI: typhlitis, toxic megacolon, diverticulitis; other infections: hepatitis C, varicella zoster virus.\n\na Incidence of infection (density) = Number of infections/patient days × 100, where days = 30.\n\nJohn Wiley & Sons, LtdSurvival and posttransplant therapies\nAs secondary analyses, we reviewed time to relapse or progression, survival, and cause of death for all patients. As illustrated in Figure 2, the OS rate up to 3 years posttransplant appeared to be better for the OP than the IP BEAM cohort (P = 0.02) and there was a trend toward improved PFS in the OP cohort (P = 0.07). Speculating that differences in posttransplant therapies for the two cohorts might be responsible for the differences in survival, we evaluated posttransplant therapies for all patients (Table 5) and analyzed OS and PFS for HL and NHL subsets of IP and OP BEAM (Fig. 3). Analyses of the HL subsets suggested improved PFS for the OP BEAM cohort, but the differences were not statistically significant, likely due to the small numbers of patients. Analyses of the NHL subsets demonstrated a significant difference in OS (P = 0.02) and a trend toward improved PFS for the OP BEAM cohort.\n\nFigure 2 Kaplan–Meir plots demonstrating overall survival (A) and progression‐free survival (B) for inpatient and outpatient BEAM cohorts.\n\nTable 5 Posttransplant therapies\n\nA. Therapies prior to relapse/progression\t\n \tIP BEAM (N = 49)\tOP BEAM (N = 58)\t\nP value\t\nNumber of patients receiving:\t\nConsolidative radiation\t3\t10\t0.14\t\nRituximab maintenance\t2\t3\t \t\nBrentuximab vs placebo\t1\t2\t \t\nIntrathecal chemotherapy\t1\t0\t \t\n \tOverall P value\t\t0.33\t\nB. Initial therapy for relapse/progression occurring less than 18 months post‐ASCT\t\n \tIP BEAM (N = 16)\tOP BEAM (N = 15)\t\nP value\t\nNumber of patients receiving:\t\nChemotherapy\t5\t2\t \t\nNovel agent\t4\t11\t0.01\t\nRadiation\t1\t1\t \t\nNo therapy\t4\t1\t \t\nUnknown\t2\t0\t \t\n \tOverall P value\t\t0.06\t\nNumber of patients receiving the following novel agents:\t \t \t \t\nBrentuximab\t2\t2\t \t\nCarfilzomib + Vorinostat\t2\t1\t \t\nLenalidomide\t \t2\t \t\nBortezomib\t \t1\t \t\nPI3K inhibitor + Jak1 inhibitor\t \t2\t \t\nAmplimexon\t \t1\t \t\nIbrutinib\t \t1\t \t\nFostamatinib\t \t1\t \t\nIP, inpatient; OP, outpatient; ASCT, autologous stem cell transplantation; PI3K, phosphoinositide 3‐kinase; Jak, janus kinase.\n\nJohn Wiley & Sons, LtdFigure 3 Kaplan–Meir plots demonstrating overall survival and progression‐free survival for Hodgkin lymphoma (A) and non‐Hodgkin lymphoma (B) subsets of the inpatient and outpatient BEAM cohorts.\n\nWhile the differences in consolidative (pre‐relapse) posttransplant therapies were not statistically significant, five of the nine OP HL patients and none of the 11 IP HL patients received consolidative radiation (Table 5A). Since all of the patients were at least 18 months posttransplant, we compared first‐line therapies to treat relapses occurring within 18 months of transplant (Table 5B). This analysis revealed chemotherapy or no therapy being used more often in the IP cohort and novel therapies predominating in the OP cohort.\n\nCost\nExcluding the cost of chemotherapy drugs, the cost of inpatient care for lymphoma patients undergoing BEAM and ASCT was an average of $3300 per day, while the average daily cost for outpatient BEAM administration was $400. Therefore, based on a decrease in hospital stay by 6 days, we estimated a cost savings of about $17,400 per patient for OP BEAM.\n\nDiscussion\nThis cohort comparison between IP and OP administration of BEAM conditioning prior to ASCT for patients with lymphoma demonstrated that OP BEAM reduced the length of hospital stay and cost of treatment, and additionally was associated with lower rates of severe enteritis, organ toxicities, and infections. Although the study is limited by its retrospective nature, relatively small number of patients, and sequential time frames for the two cohorts, we conclude that at a minimum OP BEAM is feasible, safe, and cost‐effective.\n\nReports in the late 1990s first demonstrated the feasibility of OP ASCT for lymphoma 10, 17, 18. Outpatient care was generally restricted to patients having good performance scores and no significant comorbidities, and further to patients choosing to receive OP care 19. While those reports indicated that selected patients undergoing ASCT could be managed safely in an OP setting, the general applicability of the approach remained unclear and did not become widely utilized 20. Over the past decade, there has been resurgent interest in OP SCT and multiple centers have reported their experiences performing various aspects of ASCT in the OP setting 12, 13, 14, 21, 22, 23, 24, 25. While these reports are extremely variable in terms of patient selection and scope of outpatient management, there is a frequent emphasis on early posttransplant discharge 22, 23, 24, 25. In contrast, our model employs OP conditioning and IP posttransplant care, an approach that may offer certain advantages.\n\nThe BEAM regimen is generally well tolerated with regard to immediate side effects and none of our outpatients required early hospital admission for medical issues. We did not exclude patients based on age or comorbidity index and found OP BEAM to be safe, even for older patients and those with significant comorbidities. The current practice at our institution is for all lymphoma patients undergoing ASCT to receive BEAM conditioning in the OP department unless it is not possible to identify a suitable caregiver.\n\nThe decreased incidences of infections and organ toxicities we observed for OP BEAM are likely interrelated, as infections often predispose to organ dysfunction. It is also possible that the daily dosing of ETP and Ara‐C in OP BEAM resulted in less toxicity than the every 12 h schedule used for IP BEAM. However, the toxicity profile for the cohort of patients receiving the OP BEAM regimen as inpatients argues against this explanation. Of note, there was no evidence for reduced efficacy of the OP BEAM regimen. It also remains possible that the IP and OP cohorts differed in unmeasurable ways with respect to performance status, severity of comorbidities, or degree of prior toxicities from chemotherapy resulting in the IP cohort being more susceptible to complications.\n\nOthers have also reported reduced infection rates for SCT patients treated as outpatients. In a retrospective evaluation of 671 patients undergoing ASCT in IP and OP settings, McDiarmid and colleagues found significantly fewer infections in the OP cohort 21. Several factors that affect severity of illness, complication rates, and outcomes in hospitalized patients include nutritional status, degree of physical conditioning, sleep quality, and sense of emotional well‐being 26, 27. We speculate that these factors contributed to the differences in complications between our IP and OP BEAM cohorts. By staying active, eating and sleeping well, and remaining socially engaged during the 6 days of BEAM conditioning, the outpatients may have been physically and psychologically more resilient during the posttransplant period of pancytopenia and mucositis/enteritis.\n\nInfections and organ toxicities are responsible for significant morbidity and mortality associated with SCT and a decrease in these complications could impact SCT outcomes. In addition, the same physical and psychological factors that reduce complications may improve SCT outcomes. Thus, it is conceivable that OP conditioning contributed to the improved survival rates we observed for OP BEAM. However, given the sequential rather than concurrent time frames for the IP and OP cohorts, we presume the better survival rates for OP BEAM primarily reflect improved therapies for lymphoma in the more recent time period. In particular, the increased availability of novel, more directed therapies in recent years likely improved the OS of these patients. While the explanation for the trend toward improved PFS is less clear, it seems probable that improved therapies also impacted relapse rates following ASCT. For example, we suspect that posttransplant consolidative radiation and/or brentuximab for HL patients reduced the risk of relapse for this group, although the number of patients in our study was too small to demonstrate significant differences for these factors. It is also possible that the degree of disease control at the time of transplant was better for the more recent OP cohort even though we did not find significant differences in disease status or lines of prior therapy between the IP and OP cohorts.\n\nThere are obvious advantages to OP SCT, but there are also some potential drawbacks, and a single model is unlikely to fit every institution. Factors to consider include patient demographics, caregiver and housing support, and infrastructure and resources of the institution 15, 20. A variety of OP SCT models have been described by different institutions, most of which are based on early discharge posttransplant. While there is a consensus that OP approaches are generally safe and cost‐effective, the feasibility and cost savings vary greatly 13, 17, 24, 28, 29, 30. For many institutions, providing extensive OP services for complex patients during an unpredictable pancytopenic period may abrogate many of the benefits of OP SCT. For example, in a randomized study of early discharge post‐ASCT, Faucher and colleagues found that only 40% of patients were actually discharged early and many were readmitted, resulting in a 1‐day difference in hospital stay and a 6% cost savings 23.\n\nOutpatient BEAM has been extremely successful at our institution and has led to the implementation of several other OP‐conditioning regimens. This model of OP conditioning followed by IP posttransplant care facilitates planning for admissions, minimizes the need for additional personnel and resources, and optimizes cost savings. While the direct savings on cost of care for OP compared to IP BEAM is substantial, perhaps—from a global perspective—an even greater savings results from the reduction in resources consumed and the potential for more efficient hospital bed utilization. Most importantly, this general strategy is good for the overall medical and psychological care of these patients. In the future, as health care models continue to evolve, we need to be vigilant to assure that outpatient management of SCT patients remains excellent, that it improves the quality of life for patients and caregivers, and that cost savings for institutions are not simply shifted onto patients.\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\n1 \n\nLinch , D. C. \n, \nD. \nWinfield \n, \nA. H. \nGoldstone \n, \nD. \nMoir \n, \nB. \nHancock \n, \nA. \nMcMillan \n, et. al. 1993 \nDose intensification with autologous bone‐marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomized trial . Lancet \n341 :1051 –1054 .8096958 \n2 \n\nPhilip , T. \n, \nC. \nGuglielmi \n, \nA. \nHagenbeek \n, \nR. \nSomers \n, \nVan der Lelie \nH. \n, \nD. \nBron \n, et al. 1995 \nAutologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy‐sensitive non‐Hodgkin's lymphoma . N. Engl. J. 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C. \nLinch \n, \nM. \nTrneny \n, et al. 2010 \nSalvage regimens with autologous transplantation for relapsed large B‐cell lymphoma in the rituximab era . J. Clin. Oncol. \n28 :4184 –4190 .20660832 \n6 \n\nMills , W. \n, \nR. \nChopra \n, \nA. \nMcMillan \n, \nR. \nPearce \n, \nD. C. \nLinch \n, and \nA. H. \nGoldstone \n. 1995 \nBEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non‐Hodgkin's lymphoma . J. Clin. Oncol. \n13 :588 –595 .7884420 \n7 \n\nCaballero , M. D. \n, \nV. \nRubio \n, \nJ. \nRifon \n, \nI. \nHeras \n, \nR. \nGarcía‐Sanz \n, \nL. \nVázquez \n, et al. 1997 \nBEAM chemotherapy followed by autologous stem cell support in lymphoma patients: analysis of efficacy, toxicity and prognostic factors . Bone Marrow Transplant. \n20 :451 –458 .9313877 \n8 \n\nJo , J. C. \n, \nB. W. \nKang \n, \nG. \nJang \n, \nS. J. \nSym \n, \nS. S. \nLee \n, \nJ. E. \nKoo \n, et al. 2008 \nBEAC or BEAM high‐dose chemotherapy followed by autologous stem cell transplantation in non‐Hodgkin's lymphoma patients: comparative analysis of efficacy and toxicity . Ann. Hematol. \n87 :43 –48 .17710401 \n9 \n\nBan‐Hoefen , M. \n, \nJ. L. \nKelly \n, \nS. H. \nBernstein \n, \nJ. \nLiesveld \n, \nL. \nConstine \n, \nM. \nBecker \n, et al. 2012 \nHigh‐dose therapy and autologous stem cell transplant (HD‐ASCT) for transformed non‐Hodgkin lymphoma (NHL) in the rituximab era . Leuk. Lymphoma \n53 :830 –835 .22023518 \n10 \n\nWeaver , C. H. \n, \nL. \nSchwartzberg \n, \nB. \nZhen \n, \nM. \nMangum \n, \nR. \nLeff \n, \nK. \nTauer \n, et al. 1997 \nHigh‐dose chemotherapy and peripheral blood stem cell infusion in patients with non‐Hodgkin's lymphoma: results of outpatient treatment in community cancer centers . Bone Marrow Transplant. \n20 :753 –760 .9384477 \n11 \n\nGluck , S. \n, \nC. \ndes Rochers \n, \nC. \nCano \n, \nM. \nDorreen \n, \nC. \nGermond \n, \nK. \nGill \n, et al. 1997 \nHigh‐Dose Chemotherapy followed by autologous blood cell transplantation: a safe and effective outpatient approach . Bone Marrow Transplant. \n20 :431 –434 .9313874 \n12 \n\nLeger , C. \n, \nM. \nSabloff \n, \nS. \nMcDiarmid \n, \nI. \nBence‐Bruckler \n, \nH. \nAtkins \n, \nC. \nBredeson \n, et al. 2006 \nOutpatient autologous hematopoietic stem cell transplantation for patients with relapsed follicular lymphoma . Ann. Hematol. \n85 :723 –729 .16832675 \n13 \n\nHolbro , A. \n, \nI. \nAhmad \n, \nS. \nCohen \n, \nJ. \nRoy \n, \nS. \nLachance \n, \nM. \nChagnon \n, et al. 2013 \nSafety and cost‐effectiveness of outpatient autologous stem cell transplantation in patients with multiple myeloma . Biol. Blood Marrow Transplant. \n19 :547 –551 .23253556 \n14 \n\nGertz , M. A. \n, \nS. M. \nAnsell \n, \nD. \nDingli \n, \nA. \nDispenzieri \n, \nF. K. \nBuadi \n, \nM. A. \nElliott \n, et al. 2008 \nAutologous stem cell transplant in 716 patients with multiple myeloma: low treatment‐related mortality, feasibility of outpatient transplant, and effect of a multidisciplinary quality initiative . Mayo Clin. Proc. \n83 :1131 –1135 .18828972 \n15 \n\nMehta , J. \n, and \nF. L. \nDulley \n. 2009 \nOutpatient or inpatient stem cell transplantation: patria est ubicunqu est bene? \nLeuk. Lymphoma \n50 :3 –5 .19172493 \n16 \n\nSorror , M. L. \n, \nM. B. \nMaris \n, \nR. \nStorb \n, \nF. \nBaron \n, \nB. M. \nSandmaier \n, \nD. G. \nMaloney \n, et al. 2005 \nHematopoietic cell transplantation (HCT)‐specific comorbidity index: a new tool for risk assessment before allogeneic HCT . Blood \n106 :2912 –2919 .15994282 \n17 \n\nJagannath , S. \n, \nD. H. \nVesole \n, \nM. \nXhang \n, \nK. R. \nDesikan \n, \nN. \nCopeland \n, \nM. \nJagannath \n, et al. 1997 \nFeasibility and cost‐effectiveness of outpatient auto transplants in multiple myeloma . Bone Marrow Transplant. \n20 :445 –450 .9313876 \n18 \n\nSeropian , S. \n, \nR. \nNadkarni \n, \nA. P. \nJillella \n, \nE. \nSalloum \n, \nB. \nBurtness \n, \nG. L. \nHu \n, et al. 1999 \nNeutropenic infections in 100 patients with non‐Hodgkin's lymphoma or Hodgkin's disease treated with high‐dose BEAM chemotherapy and peripheral blood progenitor cell transplant: out‐patient treatment is a viable option . Bone Marrow Transplant. \n23 :599 –605 .10217191 \n19 \n\nMeisenberg , B. R. \n, \nK. \nFerran \n, \nK. \nHollenbach \n, \nT. \nBrehm \n, \nJ. \nJollon \n, and \nL. D. \nPiro \n. 1998 \nReduced charges and cost associated with outpatient autologous stem cell transplantation . Bone Marrow Transplant. \n21 :927 –932 .9613786 \n20 \n\nFrey , P. \n, \nT. \nStinson \n, \nA. \nSiston \n, \nS. J. \nKnight \n, \nE. \nFerdman \n, \nA. \nTraynor \n, et al. 2002 \nLack of caregivers limits use of outpatient hematopoietic stem cell transplant program . Bone Marrow Transplant. \n30 :741 –748 .12439696 \n21 \n\nMcDiarmid , S. \n, \nB. \nHutton \n, \nH. \nAtkins \n, \nI. \nBence‐Bruckler \n, \nC. \nBredeson \n, \nE. \nSabri \n, et al. 2010 \nPerforming allogeneic and autologous hematopoietic SCT in the outpatient setting: effects on infectious complications and early transplant outcomes . Bone Marrow Transplant. \n45 :1220 –1226 .19946343 \n22 \n\nAnastasia , A. \n, \nF. \nGiglio \n, \nR. \nMazza \n, \nB. \nSarina \n, \nE. \nTodisco \n, \nS. \nBramanti \n, et al. 2009 \nEarly discharge after high‐dose melphalan and peripheral blood stem cell reinfusion in patients with haematological and non‐haematological disease . Leuk. Lymphoma \n50 :80 –84 .19125385 \n23 \n\nScortechini , I. \n, \nM. \nMontanari \n, \nG. \nMancini \n, \nE. \nInglese \n, \nM. \nCalandrelli \n, \nM. \nChiarucci M \n, et al. 2014 \nConditioning regimen with BCNU, etoposide, cytarabine and melphalan plus amifostine for outpatient autologous stem cell transplant: feasibility and outcome in 97 patients with lymphoma . Leuk. Lymphoma \n55 :1657 –1660 .24024474 \n24 \n\nFaucher , C. \n, \nA. G. \nLe Corroller Soriano \n, \nB. \nEsterni \n, \nN. \nVey \n, \nA. M. \nStoppa \n, \nC. \nChabannon \n, et al. 2012 \nRandomized study of early hospital discharge following autologous blood SCT: medical outcomes and hospital costs . Bone Marrow Transplant. \n47 :549 –555 .21725375 \n25 \n\nFernandez‐aviles , F. \n, \nE. \nCarreras \n, \nA. \nUrbano‐Ispizua \n, \nM. \nRovira \n, \nC. \nMartínez \n, \nA. \nGaya \n, et al. 2006 \nCase‐Control comparison of at‐home to total hospital care for autologous stem‐cell transplantation for hematologic malignancies . J. Clin. Oncol. \n24 :4855 –4861 .17001069 \n26 \n\nKaplan , R. M. \n, \nJ. P. \nAnderson \n, \nA. W. \nWu \n, \nW. C. \nMathews \n, \nF. \nKozin \n, and \nD. \nOrenstein \n. 1989 \nThe Quality of Well‐being Scale . Med. Care \n27 :S27 –S43 .2921885 \n27 \n\nDe van der Schueren , M. \n, \nM. \nElia \n, \nL. \nGramlich \n, \nM. P. \nJohnson \n, \nS. L. \nLim \n, \nT. \nPhilipson \n, et al. 2014 \nClinical and economic outcomes of nutrition interventions across the continuum of care . Ann. NY Acad. Sci. \n1321 :20 –40 .25123208 \n28 \n\nRizzo , J. D. \n, \nG. B. \nVogelsand \n, \nS. \nKrumm \n, \nB. \nFrink \n, \nV. \nMock \n, and \nE. B. \nBass \n, et al. 1999 \nOutpatient‐based bone marrow transplantation for hematologic malignancies: cost saving or cost shifting? \nJ. Clin. Oncol. \n17 :2811 –2818 .10561357 \n29 \n\nStiff , P. \n\n2009 \nManaging hematopoietic stem‐cell transplant resources: the case for outpatient transplantation . Leuk. Lymphoma \n50 :6 –7 .19172494 \n30 \n\nPreussler , J. M. \n, \nE. M. \nDenzen \n, and \nN. \nMajhail \n. 2012 \nCosts and cost‐effectiveness of hematopoietic cell transplantation . Biol. Blood Marrow Transplant. \n18 :1620 –1628 .22484549\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "5(11)",
"journal": "Cancer medicine",
"keywords": "Complications; conditioning chemotherapy; cost; stem cell transplantation",
"medline_ta": "Cancer Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002330:Carmustine; D003131:Combined Modality Therapy; D003362:Cost-Benefit Analysis; D003561:Cytarabine; D005260:Female; D005500:Follow-Up Studies; D017048:Health Care Costs; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007239:Infections; D053208:Kaplan-Meier Estimate; D008223:Lymphoma; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D010045:Outpatients; D011034:Podophyllotoxin; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D055815:Young Adult",
"nlm_unique_id": "101595310",
"other_id": null,
"pages": "3059-3067",
"pmc": null,
"pmid": "27699999",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": "24024474;8096958;17710401;18828972;10217191;17001069;23253556;12439696;9313877;11464975;9313876;19946343;19172494;15994282;2921885;27699999;9313874;7884420;20660832;7477169;25123208;21725375;16832675;22484549;22023518;12086759;19172493;9384477;19125385;9613786;10561357",
"title": "Outpatient administration of BEAM conditioning prior to autologous stem cell transplantation for lymphoma is safe, feasible, and cost-effective.",
"title_normalized": "outpatient administration of beam conditioning prior to autologous stem cell transplantation for lymphoma is safe feasible and cost effective"
} | [
{
"companynumb": "US-CORDEN PHARMA LATINA S.P.A.-US-2017COR000038",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VALACYCLOVIR HYDROCHLORIDE"
},
... |
{
"abstract": "OBJECTIVE\nTo evaluate the effectiveness and toxicity of infliximab in patients with recalcitrant psoriatic arthritis (PsA).\n\n\nMETHODS\nPatients with treatment resistant PsA and at least six actively inflamed joints, who had failed to respond to at least two disease modifying agents, were included. Infliximab (5 mg/kg) was given at weeks 0, 2, 6, and every 6-8 weeks pending response. Clinical and laboratory measures included actively inflamed joint count (AJC), swollen joint count (SJC), psoriasis severity (PASI), HAQ, and SF-36. Response was defined as at least a 30% reduction in AJC and PASI. Differences from baseline were analysed using the signed rank test.\n\n\nRESULTS\nSixteen patients (12 male, 4 female), mean age 48 and disease duration 14 years, were included. At baseline the mean AJC was 22.5 and mean PASI 4.5. Eleven patients continued receiving methotrexate. The AJC did not show a statistically significant response. SJC improved significantly at week 54 (p = 0.01). The PASI improved significantly at weeks 14 (p = 0.001) and 30 (p = 0.002) and CRP was reduced significantly at week 30 (p = 0.02). The HAQ score improved at week 30 (p = 0.02). Six patients became positive for dsDNA without clinical features of a connective tissue disease. Six patients discontinued treatment owing to lack of efficacy (1) and toxicity (5). Other serious adverse events included: urticaria (3); thrombocytopenia (1); lower gastrointestinal bleeding (2); severe diarrhoea (2); serious infections (6). Raised transaminases, at least 1.5x normal, occurred in four patients.\n\n\nCONCLUSIONS\nIn refractory PsA, infliximab led to a marked improvement in psoriasis but modest response in joint disease. Toxicity and rate of treatment termination was high.",
"affiliations": "University of Toronto Psoriatic Arthritis Clinic, Toronto Western Hospital, Toronto, Canada.",
"authors": "Feletar|M|M|;Brockbank|J E|JE|;Schentag|C T|CT|;Lapp|V|V|;Gladman|D D|DD|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1136/ard.2003.006775",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4967",
"issue": "63(2)",
"journal": "Annals of the rheumatic diseases",
"keywords": null,
"medline_ta": "Ann Rheum Dis",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D015535:Arthritis, Psoriatic; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D000069285:Infliximab; D007596:Joints; D008099:Liver; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D012867:Skin; D016896:Treatment Outcome",
"nlm_unique_id": "0372355",
"other_id": null,
"pages": "156-61",
"pmc": null,
"pmid": "14722204",
"pubdate": "2004-02",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "10555027;12426660;12475006;10972371;11096166;11212159;11410193;11469469;357213;2206798;1828327;8076386;7934491;7586774;8587077;9058658;9058659;9712099;9714353;9751087;9891713;11830424;11830425;11867114;11920412;11955536;12011375;12020227;12022358;12046813;12063486;12353965;12382299;12421102",
"title": "Treatment of refractory psoriatic arthritis with infliximab: a 12 month observational study of 16 patients.",
"title_normalized": "treatment of refractory psoriatic arthritis with infliximab a 12 month observational study of 16 patients"
} | [
{
"companynumb": "CA-CELLTRION HEALTHCARE HUNGARY KFT-2017CA001515",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
... |
{
"abstract": "Patients with multiple myeloma often show skull bone involvement, although in most cases this is manifested as skull erosion and large masses develop only rarely. Here we report a patient who presented with a large cranial mass mimicking a subdural hematoma with calcification. The tumor shrunk with 37.5 Gy of focal irradiation in 15 fractions after biopsy. After irradiation the patient was treated with Bortezomib but died because of adverse events. The differential diagnosis of lenticular lesion of the skull and treatment strategy for large skull mass with myeloma cells are discussed.",
"affiliations": "Department of Neurosurgery, Saitama Medical University, Moroyama, Japan.;Department of Neurosurgery, Saitama Medical University, Moroyama, Japan.;Department of Neurosurgery, Saitama Medical University, Moroyama, Japan.;Department of Neurosurgery, Saitama Medical University, Moroyama, Japan.;Department of Neurosurgery, Saitama Medical University, Moroyama, Japan.",
"authors": "Fujimaki|Takamitsu|T|;Hirata|Sachiko|S|;Terano|Naruhiko|N|;Wakiya|Kenji|K|;Kobayashi|Masahito|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1055/s-0039-1697636",
"fulltext": "\n==== Front\nSurg J (N Y)Surg J (N Y)10.1055/s-00028781The Surgery Journal2378-51282378-5136Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. 10.1055/s-0039-16976361900014crCase ReportA Large Mass Mimicking Calcified Hematoma of the Skull Showing Involvement of Myeloma Cells and a Good Response to Irradiation Fujimaki Takamitsu MD, PhD1Hirata Sachiko MD1Terano Naruhiko MD1Wakiya Kenji MD, PhD1Kobayashi Masahito MD, PhD11 Department of Neurosurgery, Saitama Medical University, Moroyama, JapanAddress for correspondence Takamitsu Fujijmaki, MD, PhD Department of Neurosurgery, Saitama Medical University38 Morohongo, Moroyama, Saitama Pref. 350-0495Japantfujimak@saitama-med.ac.jp10 2019 18 10 2019 5 4 e159 e162 13 2 2019 07 8 2019 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,\ndistribution, and reproduction in any medium, provided the original work is properly cited.Patients with multiple myeloma often show skull bone involvement, although in most cases this is manifested as skull erosion and large masses develop only rarely. Here we report a patient who presented with a large cranial mass mimicking a subdural hematoma with calcification. The tumor shrunk with 37.5 Gy of focal irradiation in 15 fractions after biopsy. After irradiation the patient was treated with Bortezomib but died because of adverse events. The differential diagnosis of lenticular lesion of the skull and treatment strategy for large skull mass with myeloma cells are discussed.\n\nKeywords\nmyelomaskull masscalcified hematoma\n==== Body\nPatients with multiple myeloma often show skull bone involvement, although in most cases this is manifested as skull erosion,\n1\nand large masses develop only rarely.\n2\nHere we report a patient who presented with a large cranial mass mimicking a subdural hematoma with calcification. After biopsy, the local tumor was treated successfully by irradiation. The diagnostic procedures and treatment strategies for skull tumors, especially large plasmacytomas or myelomas, are discussed.\n\n\nCase Report\n\nA 75-year-old man was referred to our Saitama Medical University from a local hospital, where he had presented with gait disturbance and a computed tomography (CT) scan had demonstrated an extra-axial mass, suspected to be a calcified subdural or epidural hematoma. Three months previously, he had suffered a fall in the bathroom without any head trauma, and also had a history of knee joint inflammation. On admission, the findings of detailed neurological examinations were essentially normal, but the patient was unable to walk because of knee pain. A CT scan demonstrated a right frontal mass that compressed the frontal lobe, and calcifications at the border between the mass and the cortex (\nFig. 1\n). There were erosions of the skull overlying the mass, as well as elsewhere on the cranial vault (\nFig. 2\n). Myeloma with skull involvement was strongly suspected. Initial laboratory examinations revealed elevated serum levels of immunoglobulin G (4435 mg/dL) and immunoglobulin lambda chain (292.0 mg/L). Urinalysis was positive for Bence Jones protein (BJP). The tumor was well enhanced by gadolinium contrast, and a flow void with linear enhancement suggestive of large vessels within the tumor was demonstrated by magnetic resonance imaging (MRI) on admission. Some small skull lesions were also present (\nFigs. 3\nand\n4\n). Based on a preoperative diagnosis of myeloma skull invasion, biopsy of the tumor was performed in the area of the cortical bone defect. The tumor was hemorrhagic, but the bleeding was well controlled by bipolar coagulation and compression by cottonoid, since the surgery involved a limited field. Pathological examination of frozen and permanent sections confirmed the diagnosis of myeloma cell invasion (\nFig. 5\n). Local irradiation was started, and the patient was transferred to the Department to Hematology. After 37.5 Gy of irradiation in 15 fractions, the tumor showed marked shrinkage. During the irradiation, dexamethasone (20 mg × 4 days) was also administered. A systemic bone survey revealed erosion of the clavicle accompanied by pain, and therefore local irradiation of this lesion was also performed. After irradiation, bortezomib chemotherapy was started, but this led to disseminated intravascular coagulation and pneumonia as adverse events. Despite intensive treatment, the patient died 70 days after biopsy of the skull lesion. Autopsy was not performed.\n\n\nFig. 1 \nComputed tomography scan on admission (\nA\n). The mass is lenticular with marginal calcification. The tumor disappeared almost completely after 37.5 Gy of irradiation (\nB\n).\n\n\nFig. 2 \nThree-dimensional reconstruction based on the computed tomography scan through a bone window on admission, showing multiple punched-out lesions of the skull.\n\n\nFig. 3 \nMagnetic resonance imaging on admission. The mass showed iso-signal intensity in T1 (\nA\n), T2 (\nB\n), and diffusion-weighted images (\nC\n). The main mass was well enhanced by gadolinium (\nC\n), and multiple enhanced lesions were observed other than the main mass (arrows).\n\n\nFig. 4 \nMagnetic resonance imaging on admission showing the vasculature of the tumor. There was a flow void sign on the T2-weighted image (\nA\n) and this part was well enhanced with gadolinium (\nB\n).\n\n\nFig. 5 \nHistopathology of the biopsy specimen, showing massive proliferation of plasmacytoid cells (\nA\n), and immunohistochemistry showing positive staining for CD138 (\nB\n) and immunoglobulin lambda chain (\nC\n).\n\n\nDiscussion\n\nIntracranial lenticular or lens-shaped masses are not rare in the field of neurosurgery. Although epidural or subdural hematomas are the most frequent lesions, lenticular masses with calcification are relatively unusual. According to a PubMed search (113 papers, as of February 6, 2019), calcified subdural hematoma is the most frequent type. About 0.3 to 2.7% of chronic subdural hematomas have calcification.\n3\nCalcified epidural hematoma and calcified empyema are among the other entities that need to be considered in the differential diagnosis of calcified epidural hematoma. However, a previous review\n4\ndid not include plasmacytoma or a tumor mass composed of myeloma cells. The skull is one of the most frequent sites for myeloma cell invasion, and punched-out or lytic lesions are common. However, presentation in the form of a large mass is quite unusual,\n1\n2\n5\nand only a limited number of such cases have been reported.\n6\n7\nAlthough the present patient was referred to us with a tentative diagnosis of calcified hematoma, we suspected skull involvement of myeloma because multiple lytic skull lesions were present as well as the large mass. This prompted us to perform laboratory examinations for specific markers such as serum immunoglobulin and urinary BJP, to investigate the possibility of myeloma.\n\n\n\nWith regard to treatment, solitary plasmacytoma can be cured by surgery alone, but adjuvant therapy is mandatory for patients with multiple lesions. The tumors are rather hemorrhagic, and postoperative hemorrhagic complications have been reported.\n5\nHere, as MRI showed flow void signs and well-enhanced linear features within the tumor, suggestive of high-flow blood vessels, extensive surgical removal was considered to be risky. Biopsy confirmed the diagnosis of cranial involvement. The mass was almost completely resolved after local brain irradiation. Although the patient later died due to complications of chemotherapy after irradiation, our experience indicated that massive skull plasmacytoma can be well controlled with radiation therapy following biopsy to confirm the histology.\n\n\nConclusion\nLenticular lesions of the skull revealed by CT are not always hematomas, and skull involvement of plasmacytoma or myeloma should be borne in mind when the mass is accompanied by multiple lytic lesions. Biopsy followed by irradiation is able to control large invasive skull masses composed of myeloma cells.\n\nConflict of Interest None.\n==== Refs\nReferences\n1 Angtuaco E J Fassas A B Walker R Sethi R Barlogie B Multiple myeloma: clinical review and diagnostic imaging Radiology 2004 231 01 11 23 14990813 \n2 Colas L Caron S Cotten A Skull vault lesions: a review AJR Am J Roentgenol 2015 205 04 840 847 26397334 \n3 Pappamikail L Rato R Novais G Bernardo E Chronic calcified subdural hematoma: case report and review of the literature Surg Neurol Int 2013 4 21 23493910 \n4 Rahman A Haque M Bhandari P B Calcified chronic subdural haematoma BMJ Case Rep2012 . pii: bcr0120125499\n5 Zigouris A Drosos D Alexiou G A Primary plasmacytoma of the cranial vault: a case report Cases J 2009 2 9154 20062671 \n6 Bakar B Tekkok I H Plasmocytoma of the skull vault Turk Neurosurg 2012 22 01 95 98 22274978 \n7 Suyama K Nakamura M Yokoyama H Shimada M Kusano M [Multiple myeloma presenting as a mass lesion in the frontal bone. Case report] Neurol Med Chir (Tokyo) 1989 29 06 515 519 2479855\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2378-5128",
"issue": "5(4)",
"journal": "Surgery journal (New York, N.Y.)",
"keywords": "calcified hematoma; myeloma; skull mass",
"medline_ta": "Surg J (N Y)",
"mesh_terms": null,
"nlm_unique_id": "101695022",
"other_id": null,
"pages": "e159-e162",
"pmc": null,
"pmid": "31637287",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports",
"references": "2479855;14990813;20062671;23493910;22274978;26397334",
"title": "A Large Mass Mimicking Calcified Hematoma of the Skull Showing Involvement of Myeloma Cells and a Good Response to Irradiation.",
"title_normalized": "a large mass mimicking calcified hematoma of the skull showing involvement of myeloma cells and a good response to irradiation"
} | [
{
"companynumb": "JP-TAKEDA-2019TUS061293",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "Occult infection with hepatitis C virus (HCV) is defined as the presence of the HCV genome in either liver tissue or peripheral blood monocytes, despite constant negative results from tests for HCV RNA in serum. We investigated whether patients who maintained a sustained virologic response 12 weeks after therapy (SVR12) with direct-acting antiviral (DAA) agents for recurrent HCV infection after liver transplantation had occult HCV infections. We performed a prospective study of 134 patients with recurrent HCV infection after liver transplantation who were treated with DAAs, with or without ribavirin, from 2014 through 2016 (129 patients achieved an SVR12). In >10% of the patients who achieved SVR12 (n = 14), serum levels of aminotransferases did not normalize during or after DAA therapy, or they normalized transiently but then increased sharply after DAA therapy. Of these 14 patients, 9 were assessed for occult HCV infection by reverse transcription quantitative polymerase chain reaction. This analysis revealed that 55% of these patients (n = 5) had an occult infection, with the detection of negative strand viral genome, indicating viral replication. These findings indicate the presence of occult HCV infection in some patients with abnormal levels of serum aminotransferases, despite SVR12 to DAAs for HCV infection after liver transplantation.",
"affiliations": "Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California.;Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California.;Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California.;Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, Washington; Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.;Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California.;Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California.;Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California.;Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California.;Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.;Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, Washington; Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.;Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California. Electronic address: jkahn@usc.edu.;Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; Molecular Microbiology and Immunology, University of Southern California, Research Center for Liver Diseases, Los Angeles, California. Electronic address: saitotak@usc.edu.",
"authors": "Elmasry|Sandra|S|;Wadhwa|Sanya|S|;Bang|Bo-Ram|BR|;Cook|Linda|L|;Chopra|Shefali|S|;Kanel|Gary|G|;Kim|Brian|B|;Harper|Tammy|T|;Feng|Zongdi|Z|;Jerome|Keith R|KR|;Kahn|Jeffrey A|JA|;Saito|Takeshi|T|",
"chemical_list": "D000998:Antiviral Agents; D001562:Benzimidazoles; D002219:Carbamates; D005449:Fluorenes; D007093:Imidazoles; D011759:Pyrrolidines; D012367:RNA, Viral; C586541:ledipasvir; D012254:Ribavirin; D000069616:Simeprevir; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D014633:Valine; C549273:daclatasvir; D000069474:Sofosbuvir",
"country": "United States",
"delete": false,
"doi": "10.1053/j.gastro.2016.11.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-5085",
"issue": "152(3)",
"journal": "Gastroenterology",
"keywords": "Limit of Detection; Persistence; Treatment Outcome; Viral Hibernation",
"medline_ta": "Gastroenterology",
"mesh_terms": "D000410:Alanine Transaminase; D000998:Antiviral Agents; D001219:Aspartate Aminotransferases; D001562:Benzimidazoles; D002219:Carbamates; D004359:Drug Therapy, Combination; D005260:Female; D005449:Fluorenes; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D007093:Imidazoles; D057230:Limit of Detection; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011759:Pyrrolidines; D012367:RNA, Viral; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012254:Ribavirin; D000069616:Simeprevir; D000069474:Sofosbuvir; D000072230:Sustained Virologic Response; D014633:Valine; D019562:Viral Load; D014779:Virus Replication",
"nlm_unique_id": "0374630",
"other_id": null,
"pages": "550-553.e8",
"pmc": null,
"pmid": "27838287",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
"references": "19790147;21734024;27373513;10734027;15140984;24464209;19105211;10782918;19596234;26301494;14702147;14715313;25261839;16227280",
"title": "Detection of Occult Hepatitis C Virus Infection in Patients Who Achieved a Sustained Virologic Response to Direct-Acting Antiviral Agents for Recurrent Infection After Liver Transplantation.",
"title_normalized": "detection of occult hepatitis c virus infection in patients who achieved a sustained virologic response to direct acting antiviral agents for recurrent infection after liver transplantation"
} | [
{
"companynumb": "US-JNJFOC-20170214833",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SOFOSBUVIR"
},
"drugadditional": null,
... |
{
"abstract": "Levothyroxine (LT), T4, poisoning is rarely associated with a severe outcome. However, cases with significant complications have been reported. The aim of this study was to identify factors associated with symptoms of poisoning including late-onset symptoms. All enquiries to the Danish Poison Information Centre (DPIC) concerning LT poisoning between March 2007 and September 2012 were reviewed and the following parameters were recorded: age, dose, time from ingestion, multiple drug intake and symptoms. To evaluate the frequency of late-onset symptoms, a subgroup of patients without initial symptoms were contacted. A total of 181 patients were registered (112 children). Ingested LT dose ranged from 10 to 9000 mcg (median 275 mcg). A total of 29 of 181 (16%) patients were symptomatic at the time of enquiry, and there was no difference in ingested LT dose between asymptomatic and symptomatic patients, neither in children nor in adults (age 16-92 years) (p < 0.68 and p < 0.47, respectively). In total, 153 of 181 (85%) patients did not have symptoms of poisoning at the time of enquiry; however, in 9 of 21 (43%) patients, we were able to contact, late-onset symptoms existed. In none of the cases, hospital contact was needed and there were no reports of long-term sequelae. Acute LT poisoning often follows a benign course. The occurrence of symptoms appears not to be dose dependent. Late-onset symptoms seem to be common. However, all symptoms resolved spontaneously without need of medical care.",
"affiliations": "Department of Clinical Pharmacology and Toxicology, Copenhagen University Hospital, Bispebjerg, Denmark.;Department of Pharmacology, Aarhus University Hospital, Aarhus, Denmark.;Department of Clinical Pharmacology and Toxicology, Copenhagen University Hospital, Bispebjerg, Denmark.;Department of Clinical Pharmacology and Toxicology, Copenhagen University Hospital, Bispebjerg, Denmark.;Department of Clinical Pharmacology and Toxicology, Copenhagen University Hospital, Bispebjerg, Denmark.",
"authors": "Nygaard|Birgitte|B|;Saedder|Eva A|EA|;Dalhoff|Kim|K|;Wikkelsoe|Mette|M|;Jürgens|Gesche|G|",
"chemical_list": "D013974:Thyroxine",
"country": "England",
"delete": false,
"doi": "10.1111/bcpt.12401",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1742-7835",
"issue": "117(4)",
"journal": "Basic & clinical pharmacology & toxicology",
"keywords": null,
"medline_ta": "Basic Clin Pharmacol Toxicol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D003718:Denmark; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011039:Poison Control Centers; D011041:Poisoning; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013974:Thyroxine; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101208422",
"other_id": null,
"pages": "280-5",
"pmc": null,
"pmid": "25816846",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Levothyroxine Poisoning - Symptoms and Clinical Outcome.",
"title_normalized": "levothyroxine poisoning symptoms and clinical outcome"
} | [
{
"companynumb": "DK-MYLANLABS-2016M1001219",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo review experience with neutropenia related to low-dose methotrexate therapy in patients with psoriasis and rheumatoid arthritis.\n\n\nMETHODS\nRetrospective review of medical records.\n\n\nMETHODS\nA 509-bed Melbourne teaching hospital.\n\n\nMETHODS\nFive patients admitted in 1987 and 1988, with neutrophil counts of less than 1 x 10(9)/L, given low doses of methotrexate for psoriasis or rheumatoid arthritis.\n\n\nMETHODS\nDeath, or length of hospital admission.\n\n\nRESULTS\nFour patients were women, and one a man; three had been treated for psoriasis, and two for rheumatoid arthritis. Ages ranged from 56 to 91 years. The eldest patients, aged 77, 81 and 91 years, died. The other two were discharged after 43 and 48 days. Prior to or shortly after admission, four patients were treated with penicillin antibiotics which may have interfered with methotrexate excretion.\n\n\nCONCLUSIONS\nMethotrexate clearances (related to creatinine clearance rates and presumably low) were probably reduced sufficiently by concomitant therapy to result in neutropenia. Practitioners using methotrexate should be aware of drug interactions resulting in delayed methotrexate excretion. Blood counts should be monitored after changes in therapy, especially in patients with impaired renal function, such as the elderly.",
"affiliations": "Repatriation General Hospital, Heidelberg, VIC.",
"authors": "Mayall|B|B|;Poggi|G|G|;Parkin|J D|JD|",
"chemical_list": "D010406:Penicillins; D008727:Methotrexate",
"country": "Australia",
"delete": false,
"doi": "10.5694/j.1326-5377.1991.tb93847.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-729X",
"issue": "155(7)",
"journal": "The Medical journal of Australia",
"keywords": null,
"medline_ta": "Med J Aust",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009503:Neutropenia; D010406:Penicillins; D011565:Psoriasis; D012189:Retrospective Studies",
"nlm_unique_id": "0400714",
"other_id": null,
"pages": "480-4",
"pmc": null,
"pmid": "1921820",
"pubdate": "1991-10-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Neutropenia due to low-dose methotrexate therapy for psoriasis and rheumatoid arthritis may be fatal.",
"title_normalized": "neutropenia due to low dose methotrexate therapy for psoriasis and rheumatoid arthritis may be fatal"
} | [
{
"companynumb": "AU-ORION CORPORATION ORION PHARMA-21_00015215",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugaddi... |
{
"abstract": "To assess the efficacy of haploidentical hematopoietic stem cell transplantation (HSCT) in adult patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH), we retrospectively analyzed 30 cases that presented at our institution. At the time of HSCT, 20 patients (66.7%) had achieved a response after receiving HLH-94 or salvage therapies. All patients underwent myeloablative conditioning followed by peripheral blood HSCT from their related, haploidentical donors. Twenty-six patients (86.7%) achieved donor cell engraftment. Of these, 23 (88.5%) achieved complete chimerism and three (11.5%) demonstrated mixed chimerism. Reactivated EBV infection was found in 25 (96.2%). Acute graft-versus-host disease occurred in 18 (69.2%), with grade I-II in 11 patients and grade III-IV in seven. Chronic graft-versus-host disease occurred in six (23.1%). Nineteen patients survived until the end of follow-up. The three-year overall survival rate was 63.3%. Our results indicate that haploidentical HSCT is an effective treatment for adult patients with EBV-HLH.",
"affiliations": "a Department of Hematology , Beijing Friendship Hospital, Capital Medical University , Beijing , China.;a Department of Hematology , Beijing Friendship Hospital, Capital Medical University , Beijing , China.;a Department of Hematology , Beijing Friendship Hospital, Capital Medical University , Beijing , China.;a Department of Hematology , Beijing Friendship Hospital, Capital Medical University , Beijing , China.;a Department of Hematology , Beijing Friendship Hospital, Capital Medical University , Beijing , China.",
"authors": "Li|Zhihui|Z|;Wang|Yini|Y|;Wang|Jingshi|J|;Zhang|Jia|J|;Wang|Zhao|Z|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D007166:Immunosuppressive Agents; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2017.1330467",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "59(1)",
"journal": "Leukemia & lymphoma",
"keywords": "Epstein–Barr virus; Hemophagocytic lymphohistiocytosis; adult; allogeneic hematopoietic stem cell transplantation; haploidentical",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D002423:Cause of Death; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D004317:Doxorubicin; D020031:Epstein-Barr Virus Infections; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D007166:Immunosuppressive Agents; D019520:Living Donors; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D000069283:Rituximab; D018183:Transplantation Chimera; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014750:Vincristine; D014777:Virus Diseases; D055815:Young Adult",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "77-84",
"pmc": null,
"pmid": "28573910",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Haploidentical hematopoietic stem cell transplantation for adult patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis.",
"title_normalized": "haploidentical hematopoietic stem cell transplantation for adult patients with epstein barr virus associated hemophagocytic lymphohistiocytosis"
} | [
{
"companynumb": "CN-CORDEN PHARMA LATINA S.P.A.-CN-2017COR000227",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"d... |
{
"abstract": "There have been over 177 million cases of COVID-19 worldwide, many of whom could be organ donors. Concomitantly, there is an anticipated increase in the need for donor lungs due to expanding indications. Given that the respiratory tract is most commonly affected by COVID-19, there is an urgent need to develop donor assessment criteria while demonstrating safety and \"efficacy\" of lung donation following COVID-19 infection. Accordingly, we report an intentional transplant using lungs from a donor with recent, microbiologically confirmed, COVID-19 infection into a recipient suffering from COVID-19 induced ARDS and pulmonary fibrosis. In addition to the standard clinical assays, both donor and recipient lungs were analyzed using RNAscope, which confirmed that tissues were negative for SARS-CoV-2. Immunohistochemistry demonstrated colocalized KRT17+ basaloid-like epithelium and COL1A1+ fibroblasts, a marker suggestive of lung fibrosis in COVID-19 associated lung disease, in the explanted recipient lungs but absent in the donor lungs. We demonstrate that following a thorough assessment, lung donation following resolved COVID-19 infection is safe and feasible.",
"affiliations": "Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.;Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.;Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.;Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.;Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.;Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.;Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.;Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.;Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.;Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.;Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.",
"authors": "Querrey|Melissa|M|;Kurihara|Chitaru|C|;Manerikar|Adwaiy|A|;Garza-Castillon|Rafael|R|;Lysne|Jeffrey|J|;Tomic|Rade|R|;Budinger|Gr Scott|GS|;Kim|Samuel|S|;Lung|Kalvin|K|;Yeldandi|Anjana|A|;Bharat|Ankit|A|0000-0002-1248-0457",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.16777",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "21(12)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; donors and donation; lung transplantation/pulmonology; lung transplantation: living donor",
"medline_ta": "Am J Transplant",
"mesh_terms": null,
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "4073-4078",
"pmc": null,
"pmid": "34332512",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Lung donation following SARS-CoV-2 infection.",
"title_normalized": "lung donation following sars cov 2 infection"
} | [
{
"companynumb": "US-AMGEN-USASP2022003343",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Extensively drug-resistant (XDR) tuberculosis (TB) represents a serious and growing problem in both endemic and non-endemic countries. We describe a 2.5-year-old girl with XDR-pulmonary TB and an 18-month-old boy with pre-XDR-central nervous system TB. Patients received individualized treatment with second-line anti-TB agents based on genotypic and phenotypic drug susceptibility testing results. Both children achieved culture conversion 3 months and 1 month after treatment initiation, respectively. The child with XDR-pulmonary TB showed evidence of cure while treatment adverse events were managed without treatment interruption. The child with pre-XDR-central nervous system TB after 6-month hospitalization with multiple infectious complications had a dismal end due to hepatic insufficiency possibly related to anti-TB treatment. This is the first report of children with pre-XDR and XDR TB in Greece, emphasizing the public health dimensions and management complexity of XDR TB.",
"affiliations": "3rd Department of Pediatrics, School of Medicine, Aristotle University, Thessaloniki, Greece.",
"authors": "Katragkou|Aspasia|A|;Antachopoulos|Charalampos|C|;Hatziagorou|Elpis|E|;Sdougka|Maria|M|;Roilides|Emmanuel|E|;Tsanakas|John|J|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00431-012-1811-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-6199",
"issue": "172(4)",
"journal": "European journal of pediatrics",
"keywords": null,
"medline_ta": "Eur J Pediatr",
"mesh_terms": "D000995:Antitubercular Agents; D002675:Child, Preschool; D054908:Extensively Drug-Resistant Tuberculosis; D017809:Fatal Outcome; D005260:Female; D006115:Greece; D006801:Humans; D007223:Infant; D008297:Male; D020306:Tuberculosis, Central Nervous System; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "7603873",
"other_id": null,
"pages": "563-7",
"pmc": null,
"pmid": "22907397",
"pubdate": "2013-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22373593;19925960;15137548;21943844;19375159;20797644;19197080;22507870;14663461;20974784;22052896;18254003;21172673;18616396;22118883;14520140;19643501;20650053;16704040;19409848;17301295;20825317",
"title": "Drug-resistant tuberculosis in two children in Greece: report of the first extensively drug-resistant case.",
"title_normalized": "drug resistant tuberculosis in two children in greece report of the first extensively drug resistant case"
} | [
{
"companynumb": "ZA-ALKEM LABORATORIES LIMITED-ZA-ALKEM-2018-03725",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugad... |
{
"abstract": "In 3 patients, two women aged 88 and 82 and a man aged 76, the consciousness became disrupted due to a severe hyponatraemia, after a thiazide diuretic had been combined with another drug without laboratory control. After a change in medication, the laboratory values and the patients' conditions normalised. Severe hyponatraemia is a well known but rare complication of thiazide therapy. It has a significant mortality and morbidity rate. The risk is greater for elderly women. This effect on serum sodium can be enhanced by the use of other drugs like furosemide, carbamazepine, paroxetine and NSAIDs. That a patient uses a thiazide is sometimes overlooked when a combined preparation of other drugs is prescribed. Diuretic serum electrolytes should be monitored once treatment with thiazide has been started, especially in elderly patients taking other drugs.",
"affiliations": "Medisch Centrum Leeuwarden, afd. Interne Geneeskunde, Postbus 888, 8901 BR Leeuwarden.",
"authors": "Kalksma|R|R|;Leemhuis|M P|MP|",
"chemical_list": "D001581:Benzothiadiazines; D004232:Diuretics; D004573:Electrolytes; D049993:Sodium Chloride Symporter Inhibitors",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "146(33)",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001581:Benzothiadiazines; D004232:Diuretics; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004573:Electrolytes; D005260:Female; D006801:Humans; D007010:Hyponatremia; D008297:Male; D012307:Risk Factors; D012737:Sex Factors; D049993:Sodium Chloride Symporter Inhibitors",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": "1521-5",
"pmc": null,
"pmid": "12212496",
"pubdate": "2002-08-17",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Hyponatremia caused by thiazide diuretics: be aware of drug combinations which enhance this effect.",
"title_normalized": "hyponatremia caused by thiazide diuretics be aware of drug combinations which enhance this effect"
} | [
{
"companynumb": "NL-VALIDUS PHARMACEUTICALS LLC-NL-2021VAL000050",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OXAZEPAM"
},
"drugaddit... |
{
"abstract": "Reversible corpus callosum splenial (CCS) lesions are rare findings and usually detected incidentally. We presented a case of 15-year-old boy with a diagnoses of nephrotic syndrome. He was referred for neuropsychiatric symptoms following dose reduction on steroid treatment. Brain magnetic resonance imaging (MRI) revealed a focal lesion in the CCS, hyperintense on T2 and FLAIR and hypointense on T1 images with diffusion restriction on apparent diffusion coefficient map. Follow-up MRI 3 weeks later showed complete resolution of the lesion. It was probably result of focal intramyelinic edema due to excytotoxic mechanisms and/or arginine-vasopressin release.",
"affiliations": "Department of Radiology, School of Medicine, Bezmialem Vakif University, İstanbul, Turkey.",
"authors": "Aksu|Banu|B|;Kurtcan|Serpil|S|;Alkan|Alpay|A|;Aralasmak|Ayse|A|;Oktem|Faruk|F|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "United States",
"delete": false,
"doi": "10.1111/jon.12128",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1051-2284",
"issue": "25(3)",
"journal": "Journal of neuroimaging : official journal of the American Society of Neuroimaging",
"keywords": "Corpus callosum splenial lesion; diffusion weighted imaging; steroid",
"medline_ta": "J Neuroimaging",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D003337:Corpus Callosum; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009404:Nephrotic Syndrome; D011605:Psychoses, Substance-Induced; D016896:Treatment Outcome",
"nlm_unique_id": "9102705",
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"title": "Reversible corpus callosum splenial lesion due to steroid therapy.",
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"abstract": "One limitation of reduced-intensity preparative regimens is potential for graft failure. We have developed a regimen that targets CD4(+) lymphodepletion to ensure early and durable engraftment. The primary endpoint was achievement of ≥50% CD3(+) donor chimerism by day +28. Forty-two patients (median age, 53 years; range, 29 to 73 years) received pentostatin 4 mg/m(2) i.v. on days -28, -21, and -14 when the CD4(+) cell count was >100 cells/μL and on days -4 and -3 regardless of CD4(+) level. Rituximab 375 mg/m(2) was administered to patients with CD20(+) malignancies on days -21, -14, -7, +1, and +8. Busulfan 200 mg/m(2) i.v. was administered on days -4 and -2 at a dose to target a cumulative AUC dose of 16,000 (±10%) μmol·min/L. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus plus methotrexate in 86% of patients. Donors were matched-related (47%), matched unrelated (43%), or mismatched unrelated (10%). Chronic lymphocytic leukemia (45%) and follicular non-Hodgkin lymphoma (14%) were the most common diagnoses. Disease status at initiation of the preparative regimen was complete remission in 22%, partial response in 55%, and stable/progression in 24%. The median percent CD4(+) cell count decrease from baseline (day -28) was 52% to day -21, 66% to day -14, 62% to day -7, and 91% to day 0. At day +28, all 42 patients (100%) had ≥50% CD3(+) donor chimerism. No patient experienced graft failure. Overall response rate was 82% (complete remisson, 67%). The day +100 cumulative incidence of grade II-IV acute GVHD was 59% (grade III-IV acute GVHD, 19%), and the 2 year cumulative incidence of chronic GVHD was 69% (moderate/severe, 58%). Nonrelapse mortality was 2% at day +100 and 17% at 2 years. Two-year PFS was 55%, and OS was 68%. This regimen ensures durable engraftment, is effective against persistent disease, and results in relatively low mortality from causes other than relapse.",
"affiliations": "Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL 33612, USA. Mohamed.Kharfan-Dabaja@MOFFITT.org",
"authors": "Kharfan-Dabaja|Mohamed A|MA|;Anasetti|Claudio|C|;Fernandez|Hugo F|HF|;Perkins|Janelle|J|;Ochoa-Bayona|Jose L|JL|;Pidala|Joseph|J|;Perez|Lia E|LE|;Ayala|Ernesto|E|;Field|Teresa|T|;Alsina|Melissa|M|;Nishihori|Taiga|T|;Locke|Frederick|F|;Pinilla-Ibarz|Javier|J|;Tomblyn|Marcie|M|",
"chemical_list": "D000970:Antineoplastic Agents; D015649:Pentostatin; D002066:Busulfan",
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"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D002066:Busulfan; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes; D002908:Chronic Disease; D005260:Female; D006086:Graft vs Host Disease; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D015649:Pentostatin; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous",
"nlm_unique_id": "9600628",
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"references": "14990986;20925957;15994282;11091179;18411419;22143063;15090449;9446633;15226174;2434850;21130889;16338616;8342072;9160487;20102746;21151184;12393457;12652466;12720121;7581076;14551148;18216293;8003559;15073038;17242396;14673054;12374453;16609072;22689677;12374451;8471778;12877674;16549110;8558201;2265242;14501873;20083213;6355849;21246311;8167351;8652385;9192777",
"title": "Phase II study of CD4+-guided pentostatin lymphodepletion and pharmacokinetically targeted busulfan as conditioning for hematopoietic cell allografting.",
"title_normalized": "phase ii study of cd4 guided pentostatin lymphodepletion and pharmacokinetically targeted busulfan as conditioning for hematopoietic cell allografting"
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"abstract": "BACKGROUND\nThe use of extracorporeal membrane oxygenation (ECMO) is considered a risk factor for, or even a potential contraindication to, lung transplantation. However, only a few pediatric cases have been described thus far.\n\n\nMETHODS\nA 9-year-old boy with idiopathic pulmonary arterial hypertension developed cardiac arrest after the insertion of a central catheter. ECMO was used as a bridge to lung transplantation. However, after prolonged resuscitation, he developed medullary ischemia and medullary syndrome. After 6 weeks of ECMO and triple combination therapy for pulmonary hypertension, including continuous intravenous prostacyclin, he was weaned off support, and after 2 weeks, bilateral lung transplantation was performed. At 4 years post-transplant, he has minimal problems. The medullary syndrome has also alleviated. He is now back to school and can walk with aids.\n\n\nCONCLUSIONS\nIncreasing evidence supports the use of ECMO as a bridge to LT, reporting good outcomes. In the modern era of PAH therapy, it is feasible to use prolonged ECMO support as a bridge to lung transplant, with the aim of weaning off this support; however, its use requires more experience and knowledge of long-term outcomes.",
"affiliations": "Department of the Child and Adolescent, Children's University Hospital of Geneva, Geneva, Switzerland.;Department of the Child and Adolescent, Children's University Hospital of Geneva, Geneva, Switzerland.;Division of Pneumology, University Hospital of Geneva, Geneva, Switzerland.;Institute of Anesthesiology, University Hospital of Zurich, Zurich, Switzerland.;Institute of Anesthesiology, University Hospital of Zurich, Zurich, Switzerland.;Department of the Child and Adolescent, Children's University Hospital of Geneva, Geneva, Switzerland.;Department of the Child and Adolescent, Children's University Hospital of Geneva, Geneva, Switzerland.;Department of the Child and Adolescent, Children's University Hospital of Geneva, Geneva, Switzerland.;Department of the Child and Adolescent, Children's University Hospital of Geneva, Geneva, Switzerland.;Department of the Child and Adolescent, Children's University Hospital of Geneva, Geneva, Switzerland.;Department of the Child and Adolescent, Children's University Hospital of Geneva, Geneva, Switzerland.",
"authors": "Tissot|Cecile|C|;Habre|Walid|W|;Soccal|Paola|P|;Hug|Maja Isabel|MI|;Bettex|Dominique|D|;Pellegrini|Michel|M|;Aggoun|Yacine|Y|;Mornand|Anne|A|;Kalangos|Afksendyios|A|;Rimensberger|Peter|P|;Beghetti|Maurice|M|",
"chemical_list": null,
"country": "Iran",
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"doi": "10.5812/cardiovascmed.32545",
"fulltext": "\n==== Front\nRes Cardiovasc MedRes Cardiovasc Med10.5812/cardiovascmedKowsarResearch in Cardiovascular Medicine2251-95722251-9580Kowsar 10.5812/cardiovascmed.32545Case ReportSuccessful Lung Transplant After Prolonged Extracorporeal Membrane Oxygenation (ECMO) in a Child With Pulmonary Hypertension: A Case Report Tissot Cecile 1Habre Walid 1Soccal Paola 2Hug Maja Isabel 3Bettex Dominique 3Pellegrini Michel 1Aggoun Yacine 1Mornand Anne 1Kalangos Afksendyios 1Rimensberger Peter 1Beghetti Maurice 1*1 Department of the Child and Adolescent, Children’s University Hospital of Geneva, Geneva, Switzerland2 Division of Pneumology, University Hospital of Geneva, Geneva, Switzerland3 Institute of Anesthesiology, University Hospital of Zurich, Zurich, Switzerland* Corresponding author: Maurice Beghetti, Department of the Child and Adolescent, Children’s University Hospital of Geneva, Geneva, Switzerland. Tel: +41-223724580, Fax: +41-223824546, E-mail: maurice.beghetti@hcuge.ch16 7 2016 8 2016 5 3 e3254518 8 2015 23 10 2015 07 11 2015 Copyright © 2016, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences2016This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.Introduction\nThe use of extracorporeal membrane oxygenation (ECMO) is considered a risk factor for, or even a potential contraindication to, lung transplantation. However, only a few pediatric cases have been described thus far.\n\nCase Presentation\nA 9-year-old boy with idiopathic pulmonary arterial hypertension developed cardiac arrest after the insertion of a central catheter. ECMO was used as a bridge to lung transplantation. However, after prolonged resuscitation, he developed medullary ischemia and medullary syndrome. After 6 weeks of ECMO and triple combination therapy for pulmonary hypertension, including continuous intravenous prostacyclin, he was weaned off support, and after 2 weeks, bilateral lung transplantation was performed. At 4 years post-transplant, he has minimal problems. The medullary syndrome has also alleviated. He is now back to school and can walk with aids.\n\nConclusions\nIncreasing evidence supports the use of ECMO as a bridge to LT, reporting good outcomes. In the modern era of PAH therapy, it is feasible to use prolonged ECMO support as a bridge to lung transplant, with the aim of weaning off this support; however, its use requires more experience and knowledge of long-term outcomes.\n\nPediatricsHypertension, PulmonaryLung TransplantationExtracorporeal Membrane Oxygenation (ECMO)\n==== Body\n1. Introduction\nThe use of extracorporeal membrane oxygenation (ECMO) has, for a long time, been considered a risk factor for, or even a potential contraindication to, lung transplantation (LT). Although, recent progress has challenged this paradigm, controversy exists. The information of risks associated with ECMO is based on reports of individual case reports or small case series (1), but two large series published recently have reported ECMO as a feasible bridge to LT and with acceptable outcomes (2, 3). However, only a few pediatric cases have been reported thus far. Kirshbom et al. reported that long-term outcome is comparable to patients not being on assist devices after support with ECMO (4). Another report states that those children who can be weaned off ECMO support before LT may have an even better chance of survival (5). \n\n2. Case Presentation\nWe present the case of a 9-year-old boy who received prolonged ECMO support after suffering cardiac arrest and eventually underwent double LT successfully. The patient was diagnosed with idiopathic pulmonary arterial hypertension (PAH) at 4 years of age and was considered a non-responder to vasoreactivity testing. He had initially received sildenafil as part of a randomized controlled trial, with some beneficial effects. However, the family relocated. He was brought to our clinic at 7 years of age. Because of progression of symptoms (fatigue, dyspnea) and an unsatisfactory hemodynamic profile, bosentan was added to his therapy. After an initial improvement in response to the combination therapy, the child showed continuous deterioration. Echocardiography showed severe right ventricular (RV) dysfunction with massively dilated RV compressing the left ventricle. Prostacyclin treatment was suggested to the family, who preferred intravenous to subcutaneous prostacyclin administration.\n\nA Broviac® catheter was inserted to facilitate continuous prostacyclin infusion. Although we recommended insertion under local anesthesia, the family opted for general anesthesia (GA), even after receiving an explanation of the risks associated with GA. GA was administered using a mix of ketamine, etomidate, and midazolam for induction, along with sevoflurane and fentanyl for maintenance. Cardiac catheterization performed simultaneously showed a pulmonary arterial pressure of 170/126 mmHg (mean 140 mmHg), a systemic arterial pressure of 98/62 mmHg (mean 74 mmHg), right atrial pressure of 26 mmHg, and cardiac index of 1.8 L/min/× m2.\n\nA permanent catheter was inserted; the procedure was uneventful with stable hemodynamics. However, following extubation in the operating room, the child developed laryngospasm followed by a severe pulmonary hypertensive crisis that led to cardiac arrest, unresponsive to maximal cardiopulmonary resuscitation (CPR), including the use of inhaled nitric oxide.\n\nArterial blood gas analysis showed severe acidosis with pH 6.9, PCO2 5kPa, HCO3 6.9 mmol, BE -24.6 mmol/L, and lactate 15 mmol/L. Decision was taken to start ECMO. After femoral veno-arterial cannulation with retrograde perfusion of the femoral artery, ECMO was started 60 minutes after CPR had been initiated. Abdominal compression and head cooling were used during CPR to ensure brain oxygenation. Immediately after the initiation of ECMO, spontaneous cardiac activity was restored. \n\nECMO was first initiated as a bridge to LT. An atrioseptostomy was performed and intravenous prostacyclin was started to allow for potential weaning from the support when possible.\n\nThe patient developed several complications related to prolonged CPR: transient acute renal failure; left anterior leg compartment syndrome requiring emergency fasciotomy; and an unresolving anterior medullary syndrome at the level of L4 - L5 immediately after medullary ischemia, without evidence of brain damage on cerebral computed tomography. Spinal magnetic resonance imaging was not possible as the patient was on ECMO. After 2 days of CPR, the child was kept on mild sedation; he showed normal brain function but developed complete paraplegia. Evoked potentials of the lower limbs were absent, consistent with anterior medullary ischemia at the thoracic or lumbar level. Five days after the event, he showed absence of abdominal cutaneous and lower limb reflexes along with flask paraplegia. Proprioception was preserved. This sensori-motor dissociation was in favor of an anterior spinal cord ischemia.\n\nAfter a long discussion with the transplant team and the ethics committee, and because of the strong desire of the family to pursue LT despite the peripheral neurological damage, he was transferred to the national LT center on ECMO. After 5 weeks of the triple combination therapy including sildenafil, bosentan, and prostacyclin, he could be weaned off ECMO. He developed recurrent lung atelectasis, secondary to bronchial compression by the dilated pulmonary arteries that prevented extubation. A tracheostomy was therefore performed only 6 weeks after several unsuccessful attempts of extubation. He underwent successful LT 12 weeks after the event. Prophylactic ECMO support was used for 48 hours and thereafter was weaned off without starting any cardiotonic support. Ventilation was completely weaned off 25 days after LT. He was discharged 61 days post-LT to a secondary care hospital, which was close to his home, where a re-education program was initiated. Echocardiography showed progressive and rapid recovery of RV function.\n\nAt 4 years post-transplant, he has minimal problems. His medullary syndrome has partially alleviated, but the bladder dysfunction exists. He is back to school and can walk with aids!\n\n3. Discussion\nThis case is of interest for several reasons:\n\nProlonged ECMO support is feasible as a bridge to LT in children with end-stage cardiopulmonary disease, and even for idiopathic PAH. Recent evidence supports the use of this strategy, reporting good long-term outcome (1-3, 5-7). This case also illustrates that ECMO support may be weaned off with aggressive PAH therapy, including triple combination therapy and atrioseptostomy. Septostomy was performed as an emergency procedure and the communication was not sized. Sizing is indeed difficult, and relevant data in pediatrics are not available. Another possible approach would be to perform a Potts shunt for decompressing the RV, but because of scarce data available at the time of managing this case (no reports of patients on ECMO) (8), the procedure was considered high risk with the patient on ECMO. A current publication, nevertheless, suggests (9) that this approach merits consideration and further studies are required.\n\nRecently, Sitbon et al. have shown dramatic improvement with the triple combination therapy in severe PAH (10). A similar approach may be used for aggressively decreasing the RV afterload in patients after cardiac arrest, aiming to wean off ECMO if the patient is not receiving complete treatment for PAH. In the past few years, we have successfully used this approach in postoperative PAH after repair of congenital heart disease. The possibility of ECMO weaning may increase the potential success of LT, as reported by several groups (2, 5). ECMO can be used in conscious adults and children. In pediatric patients, ECMO requires the collaboration and an extremely good interaction with the patient, as was the case with our patient. This may not be always possible and would depend on the age and ability of the patient to collaborate. This strategy is of interest if prolonged circulatory support is necessary (6, 11). Finally, in our patient, double LT was performed despite a post-CPR medullary syndrome, The decision to transplant a patient with potential paraplegia remains a difficult decision and should be taken on case-by-case basis (12). Such a decision is indeed difficult and is taken on a case-by-case basis. \n\nOur patient was treated several years ago with sequential oral combination therapy, which was initiated because of continuous deterioration. A more aggressive approach is supported by current adult and pediatric data, but was not considered routine a few years ago. It must be remembered that at the time of treating our patient, no pediatric treatment had been approved for PAH, and therefore we used the sequential combination reported for adults (13).\n\nAnother learning from this case is that intravenous prostacyclin should probably be initiated before the insertion of the central catheter. Even though no controlled data are currently published to support this approach, we strongly suggest that patients with severe PAH (functional class 4) should first be stabilized using the triple combination therapy before GA or cardiac catheterization. Close surveillance after the procedure is another critical element in either intensive care or step-down units. GA has been reported to be a potential risk factor in pediatric PAH (14).\n\nOur group has previously described the possible use of hypnosis to insert the central line in this setting, but this was not an option available for our pediatric case (15).\n\nECMO support must be available in pediatric centers that manage patients requiring invasive procedures such as central catheter insertion or cardiac catheterization, i.e. procedures often performed under GA. ECMO may offer support to the patients as a bridge to LT when needed. \n\nAnother important learning is the high probability of recovery of severely impaired RV function in the setting of PAH once RV afterload is normalized. This has been already described in LT, and it allows for double LT and not heart-lung transplantation, but after pulmonary endarterectomy (16).\n\nIncreasing reports support the use of ECMO as a bridge to LT, with good post-transplant outcomes. In the modern era of PAH therapy, it is feasible to use prolonged ECMO as a bridge to LT in pediatric patients who suffer cardiac arrest, with the aim of weaning this support. However, it requires substantial experience and long-term results to support the treatment successfully offered to this single patient.\n\nAuthors’ Contribution:All authors have been involved in the treatment of this patient, have read the manuscript, made comments and suggestions, and have approved the final version. Cecile Tissot and Maurice Beghetti were in charge of the patient and wrote the report. Paola Soccal is the lung transplant person in Geneva. Maja Isabel Hug and Dominique Bettex were in charge of the patient at the transplant center and in charge of the immediate pre and post transplant care. Yacine Aggoun did perform the cardiac catheterization. Afksendyios Kalangos inserted the ECMO. Anne Mornand is the pediatric pneumologist and Peter Rimensberger is the pediatric intensivist. Walid Habre and Michel Pellegrini were the anesthetists in charge of\nthe patient.\n==== Refs\nReferences\n1 Javidfar J Bacchetta M Bridge to lung transplantation with extracorporeal membrane oxygenation support. Curr Opin Organ Transplant. 2012 17 5 496 502 10.1097/MOT.0b013e328357fa4f 22941324 \n2 Javidfar J Brodie D Iribarne A Jurado J Lavelle M Brenner K et al. Extracorporeal membrane oxygenation as a bridge to lung transplantation and recovery. J Thorac Cardiovasc Surg. 2012 144 3 716 21 10.1016/j.jtcvs.2012.05.040 22795457 \n3 Toyoda Y Bhama JK Shigemura N Zaldonis D Pilewski J Crespo M et al. Efficacy of extracorporeal membrane oxygenation as a bridge to lung transplantation. J Thorac Cardiovasc Surg. 2013 145 4 1065 70 10.1016/j.jtcvs.2012.12.067 23332185 \n4 Kirshbom PM Bridges ND Myung RJ Gaynor JW Clark BJ Spray TL Use of extracorporeal membrane oxygenation in pediatric thoracic organ transplantation. J Thorac Cardiovasc Surg. 2002 123 1 130 6 11782766 \n5 Puri V Epstein D Raithel SC Gandhi SK Sweet SC Faro A et al. Extracorporeal membrane oxygenation in pediatric lung transplantation. J Thorac Cardiovasc Surg. 2010 140 2 427 32 10.1016/j.jtcvs.2010.04.012 20538306 \n6 Fuehner T Kuehn C Hadem J Wiesner O Gottlieb J Tudorache I et al. Extracorporeal membrane oxygenation in awake patients as bridge to lung transplantation. Am J Respir Crit Care Med. 2012 185 7 763 8 10.1164/rccm.201109-1599OC 22268135 \n7 Lang G Taghavi S Aigner C Renyi-Vamos F Jaksch P Augustin V et al. Primary lung transplantation after bridge with extracorporeal membrane oxygenation: a plea for a shift in our paradigms for indications. Transplantation. 2012 93 7 729 36 10.1097/TP.0b013e318246f8e1 22415051 \n8 Blanc J Vouhe P Bonnet D Potts shunt in patients with pulmonary hypertension. N Engl J Med. 2004 350 6 623 10.1056/NEJM200402053500623 14762197 \n9 Baruteau A Belli E Boudjemline Y Laux D Levy M Simonneau G et al. Palliative Potts shunt for the treatment of children with drug-refractory pulmonary arterial hypertension: updated data from the first 24 patients. Eur J Cardiothorac Surg. 2015 47 3 e105 10 e32545 25475943 \n10 Sitbon O Jaïs X Savale L Cottin V Bergot E Macari EA et al. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Eur Respir J. 2014 43 6 1691 7 24627535 \n11 Wiesner O Hadem J Sommer W Kühn C Welte T Hoeper MM Extracorporeal membrane oxygenation in a nonintubated patient with acute respiratory distress syndrome. Eur Respir J. 2012 40 5 1296 8 22878882 \n12 Masson C Pruvo JP Meder JF Cordonnier C Touze E De La Sayette V et al. Spinal cord infarction: clinical and magnetic resonance imaging findings and short term outcome. J Neurol Neurosurg Psychiatry. 2004 75 10 1431 5 10.1136/jnnp.2003.031724 15377691 \n13 Galie N Humbert M Vachiery J Lang I Torbicki A Simonneau G et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the european society of cardiology (ESC) and the european respiratory society (ERS) endorsed by: association for european paediatric and congenital cardiology (AEPC), international society for heart and lung transplantation (ISHLT). Eur Heart J. 2015. 10.1093/eurheartj/ehv317 \n14 Shukla AC Almodovar MC Anesthesia considerations for children with pulmonary hypertension. Pediatr Crit Care Med. 2010 11 2 Suppl S70 3 10.1097/PCC.0b013e3181c76c6e 20216167 \n15 von Ungern-Sternberg BS Habre W Hypnosis as an alternative to avoid general anesthesia in a child with severe pulmonary arterial hypertension. Paediatr Anaesth. 2009 19 2 182 3 10.1111/j.1460-9592.2008.02800.x 19207914 \n16 Reesink HJ Marcus JT Tulevski ,I Jamieson S Kloek JJ Vonk Noordegraaf A et al. Reverse right ventricular remodeling after pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension: utility of magnetic resonance imaging to demonstrate restoration of the right ventricle. J Thorac Cardiovasc Surg. 2007 133 1 58 64 10.1016/j.jtcvs.2006.09.032 17198781\n\n",
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"issue": "5(3)",
"journal": "Research in cardiovascular medicine",
"keywords": "Extracorporeal Membrane Oxygenation (ECMO); Hypertension, Pulmonary; Lung Transplantation; Pediatrics",
"medline_ta": "Res Cardiovasc Med",
"mesh_terms": null,
"nlm_unique_id": "101608315",
"other_id": null,
"pages": "e32545",
"pmc": null,
"pmid": "27800456",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports",
"references": "11782766;15377691;22878882;25475943;23332185;14762197;22795457;22941324;17198781;20538306;24627535;22415051;22268135;26320113;20216167;19207914",
"title": "Successful Lung Transplant After Prolonged Extracorporeal Membrane Oxygenation (ECMO) in a Child With Pulmonary Hypertension: A Case Report.",
"title_normalized": "successful lung transplant after prolonged extracorporeal membrane oxygenation ecmo in a child with pulmonary hypertension a case report"
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"abstract": "BACKGROUND\nClinically hypomyopathic dermatomyositis is a rare disease that is important to recognize, investigate and treat early as it is associated with poor prognosis. In a proportion of patients, myositis specific antibodies could be negative, but with high clinical suspicion, myositis associated antibodies should be ordered. Anti-MDA-5 antibodies was reported in literature to be associated with severe and rapidly progressive interstitial lung disease, with few case reports of pneumothorax and/or pneumomediastinum.\n\n\nMETHODS\nA 49-year-old previously healthy lady, presented with a 6 week history of skin rash, photosensitivity, mouth ulcers, fatiguability, arthralgia and myalgia. She denied subjective weakness, respiratory symptoms or dysphagia. She had Raynaud's phenomenon affecting her fingers only. Initial examination showed synovitis in her hands with skin rash. Autoimmune screen was negative. She was started on hydroxychloroquine. 4 weeks later on follow-up, she developed proximal muscle pain, dysphagia, dyspnea and dry cough. Examination showed mild proximal muscle weakness and bi-basal crackles. She was admitted and extended myositis screen was sent. She had mild anemia, lymphopenia and neutropenia, normal inflammatory markers, liver and renal panels. Capillaroscopy showed pattern of systemic sclerosis. CT chest showed early ILD. Electromyography and MRI showed features of mild myositis. PFT showed muscle weakness with low DLCO. She was given intravenous steroid and Rituximab. As she continued to deteriorate, intravenous immunoglobulins and cyclophosphamide were given. There was a brief clinical response that was short-lived with increasing oxygen dependency necessitating transfer to the ICU. At this point, the extended myositis screen confirmed the presence of anti-MDA-5 antibodies. She commenced plasmapharesis and required intubation. Unfortunately, she developed multiple pneumothoraces, and was transferred urgently for ECMO. Subsequent immunosuppression included rituximab and tacrolimus. There was progression of her ILD and recurrent pneumothoraces and pneumomediastinum. Unfortunately, she passed away as a consequence of her disease.\n\n\nCONCLUSIONS\nThis case highlights a number of considerations in approaching patients with inflammatory myositis, particularly to pulmonary involvement. It is important to highlight the utility of extended myositis antibody testing in predicting disease phenotypes and its impact on therapeutic decisions. From a management perspective, aggressive immunosuppression should be considered with potential need of earlier utilization of ECMO.",
"affiliations": "Royal College of Physicians of Ireland, Rheumatology Department, Cork University Hospital, Wilton, Cork, Ireland, T12 DC4A. alqatarisafi@hotmail.com.;Rheumatology Department, Cork University Hospital, Wilton, Cork, Ireland.;Internal Medicine and Rheumatology Consultant Rheumatology Department, Cork University Hospital, Wilton, Cork, Ireland.;Rheumatology Department, Cork University Hospital, Wilton, Cork, Ireland.;Rheumatology Department, Cork University Hospital, Wilton, Cork, Ireland.",
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"fulltext": "\n==== Front\nBMC Pulm MedBMC Pulm MedBMC Pulmonary Medicine1471-2466BioMed Central London 62210.1186/s12890-018-0622-8Case ReportMDA-5 associated rapidly progressive interstitial lung disease with recurrent Pneumothoraces: a case report http://orcid.org/0000-0002-3994-8216Alqatari Safi 00353214922468alqatarisafi@hotmail.com 1Riddell Peter 00353214922468peterriddell@doctors.org.uk 2Harney Sinead 00353214922468Sinead.Harney@hse.ie 3Henry Michael 00353214922468michael.henry@hse.ie 2Murphy Grainne 00353214922468grainne.murphy4@hse.ie 21 0000 0004 0617 6269grid.411916.aRoyal College of Physicians of Ireland, Rheumatology Department, Cork University Hospital, Wilton, Cork Ireland T12 DC4A 2 0000 0004 0617 6269grid.411916.aRheumatology Department, Cork University Hospital, Wilton, Cork Ireland 3 0000 0004 0617 6269grid.411916.aInternal Medicine and Rheumatology Consultant Rheumatology Department, Cork University Hospital, Wilton, Cork Ireland 17 4 2018 17 4 2018 2018 18 5930 11 2017 9 4 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\nClinically hypomyopathic dermatomyositis is a rare disease that is important to recognize, investigate and treat early as it is associated with poor prognosis. In a proportion of patients, myositis specific antibodies could be negative, but with high clinical suspicion, myositis associated antibodies should be ordered. Anti-MDA-5 antibodies was reported in literature to be associated with severe and rapidly progressive interstitial lung disease, with few case reports of pneumothorax and/or pneumomediastinum.\n\nCase presentation\nA 49-year-old previously healthy lady, presented with a 6 week history of skin rash, photosensitivity, mouth ulcers, fatiguability, arthralgia and myalgia. She denied subjective weakness, respiratory symptoms or dysphagia. She had Raynaud’s phenomenon affecting her fingers only. Initial examination showed synovitis in her hands with skin rash. Autoimmune screen was negative. She was started on hydroxychloroquine. 4 weeks later on follow-up, she developed proximal muscle pain, dysphagia, dyspnea and dry cough. Examination showed mild proximal muscle weakness and bi-basal crackles. She was admitted and extended myositis screen was sent. She had mild anemia, lymphopenia and neutropenia, normal inflammatory markers, liver and renal panels. Capillaroscopy showed pattern of systemic sclerosis. CT chest showed early ILD. Electromyography and MRI showed features of mild myositis. PFT showed muscle weakness with low DLCO. She was given intravenous steroid and Rituximab. As she continued to deteriorate, intravenous immunoglobulins and cyclophosphamide were given. There was a brief clinical response that was short-lived with increasing oxygen dependency necessitating transfer to the ICU. At this point, the extended myositis screen confirmed the presence of anti-MDA-5 antibodies. She commenced plasmapharesis and required intubation. Unfortunately, she developed multiple pneumothoraces, and was transferred urgently for ECMO. Subsequent immunosuppression included rituximab and tacrolimus. There was progression of her ILD and recurrent pneumothoraces and pneumomediastinum. Unfortunately, she passed away as a consequence of her disease.\n\nConclusion\nThis case highlights a number of considerations in approaching patients with inflammatory myositis, particularly to pulmonary involvement. It is important to highlight the utility of extended myositis antibody testing in predicting disease phenotypes and its impact on therapeutic decisions. From a management perspective, aggressive immunosuppression should be considered with potential need of earlier utilization of ECMO.\n\nKeywords\nMyositisInterstitial lung diseaseMDA-5issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nClinically hypomyopathic DM is a rare disease that is important to recognize, investigate and treat early as it is associated with poor prognosis. In a proportion of patients, myositis specific antibodies are negative, but with high clinical suspicion, myositis associated antibodies should be ordered. Hypomyopathic dermatomyositis with positive anti-MDA-5 antibodies was reported in literature to be associated with severe and rapidly progressive interstitial lung disease. There are a limited number of case reports of associated pneumothorax and/or pneumomediastinum largely in an Asian population. We present a challenging case of rapidly progressive interstitial lung disease (ILD) and pneumothorax/pneumomediastinum in an Irish/Caucasian patient with hypomyopathic MDA-5 positive dermatomyositis.\n\nCase presentation\nA 49-year-old lady was referred to the rheumatology services with a 6-week history of an erythematous rash on her face, fingers and feet which was painful, desquamative and itchy. This was photosensitive in nature and accompanied by painful mouth ulcers. More recently she had noticed generalized myalgia, widespread joint pain especially in her small joints, easy fatiguability and malaise. She reported symptoms of Raynaud’s phenomenon on exposure to cold two years prior. She denied respiratory symptoms, dysphagia or odynophagia. Examination was remarkable for puffy fingers with polyarthritis (MCPs, PIPs, DIPs, wrists and toes), peri-ungual erythema and a desquamative rash. Power on initial presentation was normal and there were no clinical findings to suggest ILD. She was commenced on low dose prednisolone and hydroxychloroquine and serological testing was requested. A standard screen was negative (RF, ACPA, ANA, ENA, ANCA). She had no family history of autoimmune disorders.\n\nOver the ensuing 4 weeks she experienced a significant deterioration. She developed new progressive proximal muscle pain with no subjective weakness. She also reported dysphagia to solids as well as dyspnea on minimal exertion associated with a dry cough. Clinical examination revealed a mild proximal myopathy and end inspiratory bi-basal crackles. At that point, she was admitted for investigation and management including an extended myositis antibody panel. Results of her initial investigations are summarized in Table 1.Table 1 Results of blood tests\n\nTest\tResult\tTest\tResult\tTest\tResult\t\nWBCs\t2.25/ L (4.4–11.3/L)\tUrea\t2.4 mmol/L (2.8–8.4 mmol/L)\tUrinalysis\tNegative\t\nNeutrophils\t1.2/ L (1.4–6.6/L)\tCreatinine\t54 micromol/L (49–90 micromol/L)\tANA and ENA\tNegative\t\nLymphocytes\t0.6/ L (0.9–3.2/L)\tALT\t48 U/L (0–34 U/L)\tDsDNA\tNegative\t\nHemoglobin\t10.1 g/dl (11.7–15.9 g/dl)\tAST\t78 U/L (6–42 U/L)\tC3\t1.15 g/L (normal)\t\nPlatelets\t420,000/L (140–440 X10*9/L\tLDH\t1531 U/L (220–450 U/L)\tC4\t0.30 g/L (normal)\t\nESR\t7 mm (0–20 mm)\tCPK\t208 U/L (40–180 U/L)\tRF and Anti-CCP\tNegative\t\nCRP\t2 mg/L (0–10 mg/L)\tAlbumin\t25 g/L (35–52 g/L)\tANCA\tNegative\t\n\n\nEchocardiography was normal. Capillaroscopy showed early and active pattern of systemic sclerosis. CT chest showed early ILD in the form of non-specific interstitial pneumonia (NSIP) (Fig. 1a, b). Electromyography showed features of mild non-necrotic myopathy in the quadriceps muscles. MRI of bilateral humeri and femora showed features of myositis involving multiple muscle groups (Fig. 1c, d). PFT showed restrictive pattern with moderate DLCO reduction (DLCO 11.8 (predicted = 20), FEV1 1.7 L (predicted = 2.02), FVC 2.1 (predicted = 2.4), FEV//FVC = 80.95%).Fig. 1 Axial (a) and Coronal (b) CT (lung windows). Multifocal ground glass opacity progressing to consolidation in the dependent lungs. (d) Coronal STIR Pelvis: T2 hyperintensity in gluteal, quadriceps and adductor musculature in keeping with myositis. (e) Axial T2FS Upper limbs: Further oedema within trapezius, deltoid and rotator cuff musculature\n\n\n\nShe was commenced on methylprednisolone 500 mg intravenously for 3 days and received Day 1 Rituximab 1 g, with a plan to retreat on Day 14. Unfortunately, she developed a steroid-induced psychosis, necessitating a reduction in subsequent prednisolone dosing. Over the ensuing days she further deteriorated with radiological progression of her ILD. In the context of progressive dysphagia, she commenced IV Immunoglobulin and received cyclophosphamide (15 mg/kg). There was a brief clinical response following this combination but this was short-lived with increasing oxygen dependency necessitating transfer to the ICU for initial non-invasive ventilation. At this point, the extended myositis screen detected the presence of anti-MDA-5 antibodies confirming the diagnosis of hypomyopathic dermatomyositis. She commenced plasmapharesis for 5 days. She required intubation due to respiratory fatigue and increasing oxygen requirements. She developed multiple pneumothoraces, and due to ventilatory difficulties was transferred urgently for ECMO. Subsequent immunosuppression included day 14 rituximab and the addition of tacrolimus. Despite aggressive immunosuppression and prolonged ECMO therapy there was further progression of her interstitial lung disease, recurrent pneumothoraces and pneumomediastinum. Unfortunately, she passed away as a consequence of her disease.\n\nDiscussion and conclusion\nIdiopathic inflammatory myopathies (IIMs) are a heterogeneous group of diseases [polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM), necrotizing autoimmune myositis (NAIM)], characterized by myositis. Other organs such as the skin in DM and the lungs, heart, joints and gastrointestinal tract can be affected. Classification of IIMs is important as different phenotypes and serotypes are caused by different presentations, suggesting the need for targeted therapies [1]. Autoantibody testing has become crucial for the assessment of patients with IIM (as described by Betteridge and McHugh) [2].\n\nAuto-antibodies can be generally classified into myositis-associated and myositis-specific antibodies. The recognition of specific clinical phenotypes associated with individual antibodies has had significant clinical impact. Notable examples include the association of antibodies directed at TIF-1gamma with malignancy. Antisynthetase antibodies are strongly associated with ILD, especially non-Jo-1 (anti-PL-7 and anti-PL-12) where the association approaches 90–100% [3]. A rare form of ILD with a very poor prognosis, is strongly associated with CADM and the novel MDA- 5/anti-CADM-140 auto-antibody. A combination of anti-Jo-1 and anti-SSA/Ro antibodies also indicates severe pulmonary involvement [3].\n\nThe strong association between ILD and myositis has been recognized for many years and has led to the routine screening for ILD in individuals presenting with an inflammatory myopathy. Clinically amyopathic or hypomyopathic dermatomyositis however may initially present to a variety of specialties and ultimately this can lead to diagnostic delay. These individuals may present initially to respiratory services with symptoms and signs of ILD. The advent of EMA testing has suggested that particular antibodies segregate with propensity for ILD, such as PL-7 and PL-12. Interestingly these individuals who may present with imaging in keeping with established fibrosis may respond to immunosuppression [3]; highlighting the importance of requesting extended antibody testing, even in the absence of circulating anti-nuclear antibodies. In the case of MDA-5 antibodies in particular, ILD can be rapidly progressive and, as in the case discussed above, refractory to intensive immunosuppression, suggesting its valuable utility as a prognostic indicator of disease severity.\n\nIn our case, it is probably the high pressure from ventilatory support that caused the pneumothoraces but it is important to highlight an interesting and perhaps less recognized phenomenon, which is the potential for pneumothoraces and pneumomediastinum. Both can occur spontaneously as published in previous case reports/series [4]. The aetiopathogeneis is poorly understood but multiple theories have been proposed. These include the presence of raised intra-alveolar pressure which leads to rupture of previously damaged alveoli, or rupture of subpleural cyst(s) that developed from co-existing interstitial fibrosis. Another factor could be the presence of an underlying lung vasculitis, as DM is associated with inflammation of small blood vessels [4]. Many patients with rapidly progressive ILD and amyopathic myositis needed a combination of multiple immunosuppressives and steroids for a prolonged period (up to twelve months in some reports) highlighting the aggressive nature of ILD in this cohort.\n\nGiven the rarity of individuals with myositis associated antibodies, trials aiming to target a particular therapy by antibody type do not exist. Existing reports suggest that initial high dose steroids are the most common initial therapy used and perhaps the most effective medication in controlling acute disease. They are used in conjunction with a variety of additional immunosuppressives including cyclophosphamide, mycophenolate mofetil, ciclosporin and tacrolimus and biologic medication, commonly rituximab. Of note, rituximab offers dual benefit in treating accompanying myopathy and is also gaining increasing attention in treating ILD in the context of connective tissue disorders. Some studies suggested that the addition of tacrolimus improved the disease free survival of PM/DM as will as ILD. However, the number of patients involved in those studies were small [5].\n\nFinally, the impact of ECMO therapy merits discussion and particularly its role in reducing the risk of pneumothorax in this setting. In the case of rapidly progressive ILD associated with CADM, the use of ECMO should be considered early in the disease process, especially in potentially reversible conditions to avoid the need for mechanical ventilation [6].\n\nIn conclusion, this case highlights a number of critical considerations in approaching patients with inflammatory myositis, particularly in relation to associated pulmonary involvement. While ILD has long been recognized as a potential complication of myositis, the potential for ILD to be the prominent feature of presentation is now well described particularly in a subgroup of patients with little clinical evidence of myopathy. We wish to highlight the importance of clinical surveillance for the development of myopathy in individuals with amyopathic or hypomyopathic dermatomyositis; the utility of extended myositis antibody testing in predicting disease phenotypes and the potential impact on subsequent management in this cohort. Of particular significance, this case emphasized the importance of early consideration of ECMO to decrease the risk of pneumothorax/ mediastinum.\n\nAbbreviations\nACPAAnti-cetrullinated peptide antibody\n\nANAAnti-nuclear antibody\n\nANCAAnti-neutrophilic cytoplasmic antibody\n\nCADMClinically amyopathic dermatomyositis\n\nDIPsDistal inter-phalangeal joints\n\nDLCODiffusion carbon monoxide\n\nDMDermatomyositis\n\nECMOExtra-corporeal membrane oxygenation\n\nENAExtractable nuclear antibody\n\nFEV1Forced expiratory volume in 1 s\n\nFVCForced vital capacity\n\nIBMInclusion body myositis\n\nIIMsIdiopathic interstitial myopathies\n\nILDInterstitial lung disease\n\nMCPsMeta-carpo-phalangeal joints\n\nMDA-5melanoma differentiation-associated gene 5\n\nMRIMagnetic resonance imaging\n\nNAIMNecrotizing autoimmune myositis\n\nNSIPNon-specific interstitial pneumonia\n\nPFTPulmonary function test\n\nPIPsProximal inter-phalangeal joints\n\nAnti-PL-7Anti-Threonyl-tRNA Synthetase\n\nAnti-PL-12anti-alanyl-tRNA synthetase\n\nPMPolymyositis\n\nRFRheumatoid factor\n\nFunding\nWe received no funding to work on or publish this case report.\n\nAvailability of data and materials\nNot applicable. If you need any further information about this please contact the Rheumatology Department, Cork University Hospital at: Phone number: 00353214922468 or email: Margaret.murphy6@hse.ie.\n\nAuthors’ contributions\nSQ, PR wrote the manuscript of this case report including the case report and discussion. SH, MH and GM reviewed the manuscript and added to the discussion. All authors have read and agreed on the manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nConsent was obtained from the patient’s husband. He signed a consent form indicating that he is aware of this case report and the possibility of it being published (the patient unfortunately passed away).\n\nCompeting interests\nThere is no financial or non-financial conflict of interest with any person or organization.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Lundberg IE Miller FW Tjearnlund A Bottai M Diagnosis and classification of idiopathic inflammatory myopathies J Intern Med 2016 280 39 51 10.1111/joim.12524 27320359 \n2. Moghadam-Kia S Oddis CV Sato S Kuwana M Aggarwal R Anti–melanoma differentiation–associated gene 5 is associated with rapidly progressive lung disease and poor survival in US patients with Amyopathic and Myopathic dermatomyositis Arthritis Care & Research 2016 68 5 689 694 10.1002/acr.22728 26414240 \n3. Solomon J Swigris JJ Brown KK Myositis-related interstitial lung disease and antisynthetase syndrome J Bras Pneumol 2011 37 1 100 109 10.1590/S1806-37132011000100015 21390438 \n4. Bradley JD Spontaneous pneumomediastinum in adult dermatomyositis Ann Rheum Dis 1986 45 780 782 10.1136/ard.45.9.780 3767467 \n5. Kurita T, Yasuda S, Oba K, Odani T, Kono M, Kotaro O, et al. The efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis. Rheumatology. 2015, 54:39–44. 10.1093/rheumatology/keu166.\n6. MacLare G Combes A Bartlett RH Contemporary extracorporeal membrane oxygenation for adult respiratory failure: life support in the new era Intensive Care Med 2012 38 2 210 220 10.1007/s00134-011-2439-2 22147116\n\n",
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"keywords": "Interstitial lung disease; MDA-5; Myositis",
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"mesh_terms": "D000888:Antibodies, Anti-Idiotypic; D003520:Cyclophosphamide; D003882:Dermatomyositis; D018450:Disease Progression; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D017563:Lung Diseases, Interstitial; D008875:Middle Aged; D011030:Pneumothorax; D000069283:Rituximab; D014057:Tomography, X-Ray Computed",
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"title": "MDA-5 associated rapidly progressive interstitial lung disease with recurrent Pneumothoraces: a case report.",
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"abstract": "The efficacy of rituximab for kidney disease, such as frequent relapsing nephrotic syndrome, has been reported recently. Herein, we report a case of a patient with acute kidney injury that was steroid-resistant nephrotic syndrome who responded to a single administration of low-dose rituximab. An 86-year-old Japanese woman with hypertension presented with severe peripheral edema within several days after onset. Due to the patient's age, renal biopsy was not performed, nephrotic syndrome was diagnosed and prednisolone was administered at 40 mg/day on the day after admission. However, anuria developed and hemodialysis was inevitably initiated on the 5th hospital day. The renal function did not recover, and the general condition gradually became aggravated. On the 50th hospital day, 100 mg rituximab was administered, which led to immediate depletion of CD20-positive cells. The urine volume gradually increased from 2-3 weeks after the rituximab administration, and the renal function recovered slightly. After 5 weeks, it became possible to wean the patient from dialysis, which had been applied for 3 months. Rituximab might be an option for the treatment of acute kidney injury due to steroid-resistant nephrotic syndrome.",
"affiliations": "Division of Nephrology, Kanto Rosai Hospital, 1-1 Kizukisumiyoshi-cho, Nakahara-ku, Kawasaki, 211-8510, Japan.;Division of Nephrology, Kanto Rosai Hospital, 1-1 Kizukisumiyoshi-cho, Nakahara-ku, Kawasaki, 211-8510, Japan. suda9682@yahoo.co.jp.;Division of Nephrology, Kanto Rosai Hospital, 1-1 Kizukisumiyoshi-cho, Nakahara-ku, Kawasaki, 211-8510, Japan.;Division of Nephrology, Kanto Rosai Hospital, 1-1 Kizukisumiyoshi-cho, Nakahara-ku, Kawasaki, 211-8510, Japan.;Division of Nephrology, Kanto Rosai Hospital, 1-1 Kizukisumiyoshi-cho, Nakahara-ku, Kawasaki, 211-8510, Japan.;Division of Nephrology, Kanto Rosai Hospital, 1-1 Kizukisumiyoshi-cho, Nakahara-ku, Kawasaki, 211-8510, Japan.;Division of Nephrology, Kanto Rosai Hospital, 1-1 Kizukisumiyoshi-cho, Nakahara-ku, Kawasaki, 211-8510, Japan.;Division of Nephrology, Kanto Rosai Hospital, 1-1 Kizukisumiyoshi-cho, Nakahara-ku, Kawasaki, 211-8510, Japan.;Division of Nephrology, Kanto Rosai Hospital, 1-1 Kizukisumiyoshi-cho, Nakahara-ku, Kawasaki, 211-8510, Japan.",
"authors": "Ashikaga|Eijin|E|;Uda|Susumu|S|;Kamata|Kazuhisa|K|;Shikida|Yasuto|Y|;Inoue|Takashi|T|;Kuno|Yoshihiro|Y|;Yao|Atsushi|A|;Nakamura|Mari|M|;Kai|Keiko|K|",
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"keywords": "Acute kidney injury; Rituximab; Steroid-resistant nephrotic syndrome",
"medline_ta": "CEN Case Rep",
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"other_id": null,
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"title": "Single low-dose rituximab for the treatment of steroid-resistant nephrotic syndrome with acute kidney injury.",
"title_normalized": "single low dose rituximab for the treatment of steroid resistant nephrotic syndrome with acute kidney injury"
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"abstract": "BACKGROUND\nThe Pipeline Embolisation Device with Shield technology (PED-Shield) is suggested to have reduced thrombogenicity. This reduced thrombogenicity may make it possible to use safely in the acute treatment of aneurysmal subarachnoid haemorrhage (aSAH) on single antiplatelet therapy (SAPT).\n\n\nOBJECTIVE\nTo evaluate the safety and efficacy of the off-label use of PED-Shield with SAPT for the acute treatment of aSAH.\n\n\nMETHODS\nPatients who underwent acute treatment of ruptured intracranial aneurysms with the PED-Shield with SAPT were retrospectively identified from prospectively maintained databases at three Australian neurointerventional centres. Patient demographics, aneurysm characteristics, clinical and imaging outcomes were reviewed.\n\n\nRESULTS\nFourteen patients were identified (12 women), median age 64 (IQR 21.5) years. Aneurysm morphology was saccular in seven, fusiform in five, and blister in two. Aneurysms arose from the anterior circulation in eight patients (57.1%). Six (42.9%) patients were poor grade (World Federation of Neurological Societies grade ≥IV) SAH. Median time to treatment was 1 (IQR 0.5) day. Complete or near complete aneurysm occlusion (Raymond-Roy <3) was achieved in 12 (85.7%) patients at the end of early-acute follow-up (median day 7 after SAH). Permanent, treatment-related morbidity occurred in one (7.1%) patient and one (7.1%) treatment-related death occurred. The use of a postoperative heparin infusion (n=5) was associated with a higher rate of all complications (80.0% vs 11.1%, p=0.023) and symptomatic complications (60% vs 0.0%, p=0.028). No symptomatic ischaemic or haemorrhagic complications were observed in the patients who did not receive a post-operative heparin infusion. Nine (64.3%) patients were functionally independent on discharge from the treatment centre.\n\n\nCONCLUSIONS\nThe PED-Shield may be safe to use in the acute treatment of ruptured intracranial aneurysms with SAPT. Further investigation with a formal treatment registry is needed.",
"affiliations": "Institute of Neurological Sciences, Prince of Wales Hospital, Randwick, New South Wales, Australia.;Institute of Neurological Sciences, Prince of Wales Hospital, Randwick, New South Wales, Australia.;Neurological Intervention and Imaging Service Western Australia (W.A.), Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.;Institute of Neurological Sciences, Prince of Wales Hospital, Randwick, New South Wales, Australia.",
"authors": "Manning|Nathan W|NW|http://orcid.org/0000-0002-9914-6311;Cheung|Andrew|A|http://orcid.org/0000-0003-2815-9198;Phillips|Timothy J|TJ|http://orcid.org/0000-0001-9023-5986;Wenderoth|Jason D|JD|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D006493:Heparin",
"country": "England",
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"doi": "10.1136/neurintsurg-2018-014363",
"fulltext": "\n==== Front\nJ Neurointerv SurgJ Neurointerv SurgneurintsurgjnisJournal of Neurointerventional Surgery1759-84781759-8486BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR neurintsurg-2018-01436310.1136/neurintsurg-2018-014363Hemorrhagic Stroke15061543Original researchPipeline shield with single antiplatelet therapy in aneurysmal subarachnoid haemorrhage: multicentre experience http://orcid.org/0000-0002-9914-6311Manning Nathan W 12345http://orcid.org/0000-0003-2815-9198Cheung Andrew 123http://orcid.org/0000-0001-9023-5986Phillips Timothy J 6Wenderoth Jason D 1234\n1 \nInstitute of Neurological Sciences, Prince of Wales Hospital, Randwick, New South Wales, Australia\n\n2 \nDepartment of Interventional Neuroradiology, Liverpool Hospital, Liverpool, New South Wales, Australia\n\n3 \nIngham Institute for Applied Medical Research, Sydney, New South Wales, Australia\n\n4 \nPrince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia\n\n5 \nFlorey Institute of Neuroscience, Parkville, Victoria, Australia\n\n6 \nNeurological Intervention and Imaging Service Western Australia (W.A.), Sir Charles Gairdner Hospital, Perth, Western Australia, Australia\nCorrespondence to Dr Nathan W Manning, Institute of Neurological Sciences, Prince of Wales Hospital, Randwick, NSW 2031, Australia; dr.nathan.manning@gmail.com7 2019 14 12 2018 11 7 694 698 21 8 2018 14 11 2018 19 11 2018 © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2019This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.Background\nThe Pipeline Embolisation Device with Shield technology (PED-Shield) is suggested to have reduced thrombogenicity. This reduced thrombogenicity may make it possible to use safely in the acute treatment of aneurysmal subarachnoid haemorrhage (aSAH) on single antiplatelet therapy (SAPT).\n\nObjective\nTo evaluate the safety and efficacy of the off-label use of PED-Shield with SAPT for the acute treatment of aSAH.\n\nMethods\nPatients who underwent acute treatment of ruptured intracranial aneurysms with the PED-Shield with SAPT were retrospectively identified from prospectively maintained databases at three Australian neurointerventional centres. Patient demographics, aneurysm characteristics, clinical and imaging outcomes were reviewed.\n\nResults\nFourteen patients were identified (12 women), median age 64 (IQR 21.5) years. Aneurysm morphology was saccular in seven, fusiform in five, and blister in two. Aneurysms arose from the anterior circulation in eight patients (57.1%). Six (42.9%) patients were poor grade (World Federation of Neurological Societies grade ≥IV) SAH. Median time to treatment was 1 (IQR 0.5) day. Complete or near complete aneurysm occlusion (Raymond-Roy <3) was achieved in 12 (85.7%) patients at the end of early-acute follow-up (median day 7 after SAH). Permanent, treatment-related morbidity occurred in one (7.1%) patient and one (7.1%) treatment-related death occurred. The use of a postoperative heparin infusion (n=5) was associated with a higher rate of all complications (80.0% vs 11.1%, p=0.023) and symptomatic complications (60% vs 0.0%, p=0.028). No symptomatic ischaemic or haemorrhagic complications were observed in the patients who did not receive a post-operative heparin infusion. Nine (64.3%) patients were functionally independent on discharge from the treatment centre.\n\nConclusion\nThe PED-Shield may be safe to use in the acute treatment of ruptured intracranial aneurysms with SAPT. Further investigation with a formal treatment registry is needed.\n\naneurysmhemorrhagestentstrokeplateletsspecial-featureunlocked\n==== Body\nIntroduction\nEndovascular management of ruptured intracranial aneurysms is well established.1 However, broad-necked saccular, fusiform or blister aneurysms pose specific challenges for conventional endovascular treatments. These aneurysms may also pose challenges for microsurgical clipping.2 Few options are available for the safe and effective treatment of this subpopulation of ruptured intracranial aneurysms. In these aneurysms, the use of stent-assisted coiling or flow diversion may be a viable treatment strategy.3 4 However, there is understandable resistance to the use of intravascular stents for subarachnoid haemorrhage, owing to the risks of thromboembolic and haemorrhagic complications.5 Dual antiplatelet therapy (DAPT) reduces the risk of the former at the cost of increasing the risk of the latter.6–8\n\nA surface modified flow-diverter stent, (Pipeline Flex with Shield Technology, Medtronic Neurovascular, Irvine, California, USA) has been introduced. The PED-Shield has 3 nm of phosphorylcholine covalently bound to the braid wires. Phosphorylcholine is a major constituent of red blood cell membranes and has been shown to reduce platelet adhesion and activation.9 The PED-Shield has demonstrated significantly reduced surface thrombus formation compared with the unmodified PED-Flex.10 These preliminary data suggest that it might be possible to use the PED-Shield off-label with single antiplatelet therapy (SAPT) in the acute treatment of ruptured intracranial aneurysms.\n\nPreviously, our group described the first successful example of the PED-Shield used for the acute treatment of a ruptured intracranial aneurysm with SAPT.11 We report here our further experience using this technique in a total of 14 cases across three centers. We discuss changes to our original approach and describe our current protocol as the basis for further investigation.\n\nMethods\nProspectively maintained databases at three Australian neurointerventional centers were retrospectively interrogated from July 2015 (corresponding to the release of PED-Shield) to September 2018. Patients with aneurysmal subarachnoid haemorrhage (aSAH) who underwent PED-Shield placement under aspirin cover within 5 days of ictus, either for flow diversion or stent-assisted coiling, were identified.\n\nAll patients underwent routine cerebral DSA, including three-dimensional (3D) rotational angiography, at the time of admission. The decision to offer endovascular therapy was based on consensus between the on-call neurointerventionist and the on-call open neurosurgeon on the day of admission. The dose and timing of aspirin therapy were at the discretion of the operator as was the use of intraoperative heparin and GPIIb/IIIa inhibitors as a one-off dose. Postoperative heparin infusion was allowed; however, the addition of a P2Y12 inhibitor or further GPIIb/IIIa inhibitor within the first 7 days postoperatively was considered treatment failure. Patients with a history of P2Y12 inhibitor use before surgery were excluded. The timing and modality of postoperative imaging were dependent on the operator’s preference and the clinical status of the patient. All patients were admitted to the intensive care unit after treatment.\n\nBasic patient demographic data—aneurysm size, location, number and size of PED-Shields used, use of coiling, clinical outcomes, and imaging data—were collected. Aneurysm occlusion was recorded with conventional DSA. A non-contrast CT brain scan was used to assess for evidence of ischaemia in the target vessel territory and perforator territory in the postoperative period within 7 days of ictus whenever possible. The follow-up period was defined as the first 7 days after SAH (early-acute), which avoids the peak vasospasm period potentially confounding results. After this point, the decision to withhold a P2Y12 inhibitor was reassessed based on the ongoing haemorrhage risk. Clinical outcomes were assessed at discharge from the treatment centre.\n\nDifferences between categorical variables were assessed using Fisher’s exact test and continuous variables with Wilcox rank sum test. Comparisons with a published meta-analysis of patients with aSAH treated with flow diverters while receiving DAPT12 were made with the t-test and Z-test for two populations. All statistical analysis was performed in RStudio (RStudio, Inc, Boston, Massachusetts, USA).\n\nResults\nBaseline patient and aneurysm characteristics\nFourteen patients were identified who fulfilled the selection criteria. The median age was 64 (IQR 21.5) years, and 12 patients (85.7%) were female. Three patients were current smokers, and a further patient had a smoking history. Three patients (21.4%) had a history of regular aspirin use before ictus. The median Fisher grade was IV. The median World Federation of Neurological Societies (WFNS) grade was 2.5 (42.9% WFNS ≥IV). Aneurysms were located in the anterior circulation in eight patients (57.1%). Aneurysm morphology was saccular in seven (50%), fusiform in five (35.7%) and blister in two (14.3%). The mean aneurysm size was 8.8 mm. Aneurysms involved the internal carotid artery-first segment of the middle cerebral artery (ICA-M1) in three (21.4%), the vertebral artery in three (14.3%), the posterior inferior cerebellar artery (PICA) in two (14.3%), and the A1/2 junction in two (14.3%) patients. Further aneurysms were located at the anterior communicating artery, the posterior communicating artery, the anterior choroidal artery, and the A2 artery in one patient each (table 1).\n\nTable 1 Baseline characteristics\n\nCharacteristics\tAll patients (n=14)\t\nAge (years)\t\t\n Median (IQR)\t64 (21.5)\t\nGender\t\t\n Female\t12\t\nSmoking history\t\n Current\t3\t\n Ex-smoker\t1\t\nCurrent aspirin\t3\t\nFisher grade\t\t\n Median\tIV\t\nWFNS grade\t\t\n Median\t2.5\t\n ≥IV\t6\t\nAneurysm size\t\t\n Median (IQR)\t7 (9.25) mm\t\n Mean\t8.8 mm\t\n >10 mm\t5\t\nAneurysm location\t\t\n Anterior circulation\t8\t\n ICA M1\t3\t\n VA\t3\t\n PICA\t2\t\n A1/2\t2\t\n AComA\t1\t\n PComA\t1\t\n AChA\t1\t\n A2\t1\t\nAneurysm morphology\t\t\n Saccular\t7\t\n Fusiform\t5\t\n Blister\t2\t\nA1/2, anterior cerebral artery first/second segment; AChA, anterior choroidal artery; AComA, anterior communicating artery; ICA, internal carotid artery; M1, middle cerebral artery, first segment; PICA, posterior inferior cerebellar artery; PComA, Posterior communicating artery; VA, vertebral artery; WFNS, World Federation of Neurological Societies.\n\nTreatment\nThe median time from ictus to treatment was 1 (IQR 0.5) day. External ventricular drains (EVDs) were placed before surgery in eight patients (57.1%). Two patients (14.3%) required an EVD within the first 7 days after treatment, and one patient (7.1%) was treated with serial lumbar puncture. Two patients (14.3%) were preloaded with aspirin, and two patients were loaded with aspirin immediately postoperatively. The remaining 10 (71.4%) patients were loaded intraoperatively at a dose of 500 mg IV in nine (64.3%) and 600 mg via nasogastric tube in one. Intraoperative heparin was administered in six patients (42.9%), and five of these had a postoperative heparin infusion. A single intraoperative IV dose of the GPIIb/IIIa inhibitor, abciximab, was administered in five patients (35.7%) at a median dose of 10 (IQR 4) mg. An average of 1.2 (SD 0.7) PED-Shield devices per patient were implanted. PED-Shield deployment was successful in all 14 patients. The devices were placed in the M1-ICA in five (35.7%) patients, the vertebral artery in four (28.6%) patients, and the A1/2 in two (14.3%) patients. Devices were placed in the posterior inferior cerebellar artery in one, the anterior communicating artery in one, and the A2 in another patient. Adjunctive coil embolization was performed in 12 (85.7%) patients. Immediate aneurysm occlusion (Raymond-Roy 1) was achieved in seven (50.0%) patients with three patients (21.4%) achieving almost total occlusion (Raymond-Roy 2). No instances of intraoperative stent thrombosis, platelet aggregation, or haemorrhage were identified, and no other operative complications were recorded (table 2).\n\nTable 2 Operative characteristics\n\nCharacteristics\tAll patients (n=14)\t\nTiming after SAH (day)\t\t\n Median (IQR)\t1 (0.5)\t\n Treated <48 hours after SAH\t11\t\nExtraventricular drain\t\t\n Before PED-Shield\t8\t\n After PED-Shield\t2\t\n Lumbar puncture\t1\t\nAspirin loading\t\t\n Preoperative\t2\t\n Intraoperative\t10\t\n Postoperative\t2\t\nHeparin\t\t\n Intraoperative\t6\t\n Postoperative infusion\t5\t\nNo PED-Shield\t\t\n Mean (SD)\t1.2 (0.7)\t\nPED-Shield placement\t\t\n M1 ICA\t5\t\n VA\t4\t\n A1–2\t2\t\n AComA\t1\t\n PICA\t1\t\n A2\t1\t\nCoil embolization\t12\t\nImmediate Raymond-Roy\t\t\n 1\t7\t\n 2\t3\t\n 3\t4\t\nIntraoperative complications\t0\t\nAComA, anterior communicating artery; ICA, internal carotid artery; PICA, posterior inferior cerebellar artery; SAH, subarachnoid hemorrhage; VA, vertebral artery.\n\nOutcomes\nAll patients underwent early follow-up imaging (median day 7 after SAH). Digital subtraction angiography (DSA) was used in 13 (92.9%) and CT angiography in the remaining patient. Complete stent thrombosis was identified in one (7.1%) patient at SAH day 2, PED-Shield day 1. This was treated successfully with endovascular thrombectomy. No further symptomatic ischaemic events were observed in the early-acute follow-up period. No asymptomatic stent occlusions were seen at follow-up imaging. No clinical or imaging evidence of perforator strokes was identified. Minor, non-flow-limiting platelet aggregation was noted on the PED-Shield of 2 (14.3 %) patients at follow-up imaging. These patients were judged to be at low risk of haemorrhagic complications or further intracranial procedures and treatment was started with a P2Y12 inhibitor without incident (SAH days 8–9). There was no association with smoking history (p=0.506), postoperative heparin infusion (p=1.0), or posterior circulation (p=0.473). No patients crossed-over to DAPT in the early-acute period (up to day 7 after SAH). Complete or near complete aneurysm occlusion (Raymond-Roy grades 1 and 2) was confirmed at early-acute follow-up imaging in 12 patients (85.7%). Aneurysmal rebleeding occurred in two (14.3%) patients in the early-acute period. This caused one death. The second patient made a full recovery. Both patients had unsecured aneurysms (Raymond-Roy 3) and received a heparin infusion postoperatively. Three patients died (21.4%) before acute hospital discharge, one patient from aneurysmal rebleeding and two from medical complications (hospital-acquired pneumonia). Mortality was associated with older patients (p=0.029).\n\nTreatment-related complications and antiplatelet protocol\nIn total, three symptomatic (21.4%) and two asymptomatic (14.3%) complications were observed. The permanent treatment-related morbidity was 7.1% and mortality 7.1%. The use of a heparin infusion postoperatively (first five patients) was associated with all complications combined (80.0% vs 11.1%, p=0.023) and symptomatic complications (60.0% vs 0.0%, p=0.028). In the patients who did not receive a postoperative heparin infusion one asymptomatic complication (11.1%, asymptomatic platelet aggregation at early-acute follow-up) occurred and no symptomatic complications. In the most recent five patients a twice daily aspirin dosing protocol has been used. No symptomatic or asymptomatic complications have been recorded in these patients (table 3).\n\nTable 3 Complications by postoperative antiplatelet protocol\n\nComplication\tPostoperative heparin+OD aspirin (n=5)\tOD aspirin (n=4)\tBD aspirin (n=5)\t\nHaemorrhagic\t2 (40%)\t0\t0\t\nIschaemic\t2 (40%)\t1 (25%)\t0\t\nSymptomatic\t3 (60%)*\t0\t0\t\nAll\t4 (80%)*\t1 (25%)\t0\t\nPostoperative heparin infusion run for 5–7 days with target APTT 40–60 s.\n\nBD aspirin, twice daily aspirin dosing 100–150 mg; OD aspirin, once daily aspirin dosing 100–150 mg.\n\n*Significant at p<0.05.\n\nComparison with the reference population\nThe meta-analysis of the use of flow diverters with DAPT in aSAH by Cagnazzo and colleagues was used as a reference population. This meta-analysis included 20 studies and 223 patients12 Our study included older patients (mean age 63.0 vs 53.3, p=0.038), more women (85.7% vs 34.0%, p<0.001), and more saccular aneurysms (50.0% vs 18.8%, p=0.005) than this reference population. Patients in our study were also treated more acutely than in the meta-analysis (mean number of days between SAH and treatment 1.4 vs 6.7, p<0.001), were more likely to have adjunctive coiling (85.7% vs 19.0%, p<0.001), and more likely to achieve immediate aneurysm occlusion or near occlusion (Raymond-Roy 1 and 2: 71.4% vs 32.0%, p=0.007). No statistically significant difference was seen between the two studies for stent thrombosis (7.1% vs 4.0%, p=0.342), permanent treatment-related morbidity (7.1% vs 7.0%, p=1.0), and treatment-related mortality (7.1% vs 4.5%, p=0.342) (tables 4 and 5).\n\nTable 4 Comparison of patient and aneurysm characteristics with those reported by Cagnazzo et al\n12\n\nCharacteristics\tCagnazzo et al\n\tPED-Shield SAPT\tP values\t\nProportion men\t66%\t14.3%\tp<0.001*\t\nMean age (years)\t53.3\t63.0\tp=0.038*\t\nWFNS grade IV and V\t26.9%\t42.9%\tp=0.215\t\nPosterior circulation aneurysms\t33.0%\t57.1%\tp=0.435\t\nProportion of aneurysms with saccular morphology\t18.8%\t50.0%\tp=0.005*\t\nMean no. of days between SAH and treatment\t6.7\t1.4\tp<0.001*\t\nProportion of patients receiving adjunctive coiling\t19.0%\t85.7%\tp<0.001*\t\nSAH, subarachnoid hemorrhage; SAPT, single antiplatelet therapy; WFNS, World Federation of Neurological Societies.\n\n*Statistically significant at p<0.05.\n\nTable 5 Comparison of outcomes with Cagnazzo et al\n\n\tCagnazzo et al\n\tPED-Shield SAPT\tP values\t\nImmediate Raymond-Roy 1 and 2\t32.0%\t71.4%\tp=0.007*\t\n% in stent thrombosis\t4.0%\t7.1%\tp=0.342\t\nPermanent treatment-related morbidity\t7.0%\t7.1%\tp=1.0\t\nTreatment-related mortality\t4.5%\t7.1%\tp=0.342\t\n*Statistically significant at p<0.05.\n\nDiscussion\nWe report here the operative, and early-acute outcomes in a series of aneurysmal subarachnoid haemorrhage patients with complex ruptured aneurysms treated acutely, off-label, with the PED-Shield device with SAPT. The data is limited, however, as the protocol has matured the rate of complications with the use of PED-Shield with SAPT has reduced. This technique requires further study, however, may provide a valid treatment option for complex ruptured aneurysms.\n\nThe International Subarachnoid Aneurysm Trial established endovascular surgery as a first-line treatment for ruptured intracranial aneurysms.13 However, specific morphologies, such as blister, fusiform, and wide-necked aneurysms pose significant challenges both for endovascular and open microsurgical treatment. In an elective setting, such aneurysms have been successfully treated using stent-assisted coiling techniques and flow diversion. However, the use of intravascular stents, and, in particular, the high metal-density flow diverters, requires the use of DAPT to prevent stent thrombosis and ischaemic complications. This, in turn, increases the risk and severity of haemorrhagic complications in patients with acutely ruptured aneurysms.8 The phosphorylcholine coating of the PED-Shield device has been shown to reduce platelet adhesion and activation.9 In animal studies, PED-Shield with SAPT showed both reduced thrombus formation and increased endothelialization compared with PED-Flex.10 14 Interestingly, in an ex vivo model, PED-Shield with SAPT had similar thrombogenicity to PED-Flex with DAPT.15 Therefore, there is experimental evidence to support the use of PED-Shield with SAPT in extreme circumstances.\n\nPrevious studies have reviewed stent-assisted coiling in the treatment of ruptured aneurysms with DAPT and reported an overall complication rate of ~10–45%. In these series, thromboembolic and haemorrhagic complications were relatively evenly distributed.16–20 A meta-analysis of the use of flow diverter stents with DAPT in aSAH has recently been perforemd by Cagnazzo et al.\n12 When our current study was compared to this meta-analysis, no statistically significant difference was seen in acute stent thrombosis, permanent morbidity, or mortality . Our patients were more likely to have saccular aneurysms, which were shown to have higher rates of haemorrhagic and ischaemic complications in the meta-analysis.12 In addition, patients in our study were treated significantly earlier and were more likely to achieve immediate aneurysm occlusion or near occlusion (see tables 4 and 5). This suggests at least a theoretical advantage of the current technique. Many operators prefer to delay aneurysm treatment when DAPT is required to minimise the need for additional intracranial procedures such as EVD placement. These preliminary results suggest this may not be necessary when using PED-Shield with SAPT. This may reduce the risk of aneurysm rebleeding before surgery. This early rebleed risk is unlikely to be completely identified in the retrospective case series which currently dominate the literature.\n\nLimitations\nOur study has several inherent limitations, which should be considered while interpreting the results. This is a multicenter, retrospective, observational study and, as such, has inherent selection bias. Selection bias is seen in the clinical severity of the patients studied and the complexity of the aneurysms. This bias is only natural given the lack of evidence surrounding the use of SAPT with PED-Shield. When this technique is used, patients should have no other viable alternatives. These data are considered preliminary and further investigation is necessary.\n\nProtocol advice\nThe small numbers in this study may preclude a detailed exploratory analysis; however, we can report our anecdotal experience and how our protocol has evolved. Whenever possible, we perform adjunctive aneurysm coiling to achieve acute aneurysm occlusion (Raymond-Roy 1). Initially, patients received both intraoperative heparin and a single dose of an intraoperative GPIIb/IIIa antagonist (abciximab). Both have now been replaced by intraoperative IV aspirin (500 mg). The postoperative heparin infusion was discontinued after the first five patients. This infusion has now been shown to have a statistically significant association with all complications. No symptomatic complications have been seen in the absence of postoperative heparin.\n\nRecently, the concept of accelerated platelet function recovery21 has prompted a change to aspirin 100–150 mg twice daily given that stressful states such as SAH may drive increased platelet turnover. Since switching to twice daily aspirin dosing (n=5) no symptomatic or asymptomatic complications have been seen. Routine DSA is performed at day ~7– 10 and the need to continue to withhold the second oral antiplatelet agent is reconsidered based on angiography and the patients' clinical state. See Figure 1 for illustrative cases.\n\nConclusion\nIn this small series, the PED-Shield has been used to treat acutely ruptured intracranial aneurysms with SAPT in a clinically severe patient population with complex aneurysms. These early results compare reasonably with previous treatment strategies and suggest the need for further investigation of this technique with a formal treatment registry.\n\nFigure 1 Illustrative cases. Ruptured right posterior inferior cerebellar artery (PICA) blister aneurysm (A–D). A balloon can be seen coming from the contralateral vertebral artery in the case of intraoperative rupture (A and C). The aneurysm is excluded at day 8 DSA with early vasospasm involving the PICA and vertebral artery (D). Ruptured giant, fusiform, left M1 aneurysm (E–H). Three-stent constructs deployed from distal M1 to the internal carotid artery with coiling. Proximal aneurysm body filling supplying posterior M2 (left intentionally) persists at the day 4 DSA (H). Ruptured fusiform A2 aneurysm (I–L). Single stent with adjunctive coiling. Aneurysm is completely excluded at day 8 DSA (L).\n\nContributors: NWM was responsible for concept and design. All authors acquired and analyzed data. The manuscript was prepared by NWM and all authors reviewed and made critical revisions to the manuscript.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: NWM, AC, TJP, and JDW have been paid proctors and consultants for Medtronic Neurovascular. Medtronic is a provider of educational grants to the Prince of Wales Hospital Foundation.\n\nPatient consent: Not required.\n\nEthics approval: University of NSW ethics board.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData sharing statement: Additional data may be available on request. Requests should be directed to the corresponding author.\n==== Refs\nReferences\n1 \nMolyneux AJ , Kerr RS , Yu LM , et al \nInternational subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion . Lancet \n2005 ;366 :809 –17 . 10.1016/S0140-6736(05)67214-5 \n16139655 \n2 \nOwen CM , Montemurro N , Lawton MT \nBlister neurysms of the internal carotid artery: microsurgical results and management strategy . Neurosurgery \n2017 ;80 :235 –47 . 10.1227/NEU.0000000000001259 \n28173470 \n3 \nLin N , Brouillard AM , Keigher KM , et al \nUtilization of Pipeline embolization device for treatment of ruptured intracranial aneurysms: US multicenter experience . J Neurointerv Surg \n2015 ;7 :808 –15 . 10.1136/neurintsurg-2014-011320 \n25230839 \n4 \nBodily KD , Cloft HJ , Lanzino G , et al \nStent-assisted coiling in acutely ruptured intracranial aneurysms: a qualitative, systematic review of the literature . AJNR Am J Neuroradiol \n2011 ;32 :1232 –6 . 10.3174/ajnr.A2478 \n21546464 \n5 \nChung J , Lim YC , Suh SH , et al \nStent-assisted coil embolization of ruptured wide-necked aneurysms in the acute period: incidence of and risk factors for periprocedural complications . J Neurosurg \n2014 ;121 :4 –11 . 10.3171/2014.4.JNS131662 \n24834945 \n6 \nKung DK , Policeni BA , Capuano AW , et al \nRisk of ventriculostomy-related hemorrhage in patients with acutely ruptured aneurysms treated using stent-assisted coiling . J Neurosurg \n2011 ;114 :1021 –7 . 10.3171/2010.9.JNS10445 \n20950080 \n7 \nMahaney KB , Chalouhi N , Viljoen S , et al \nRisk of hemorrhagic complication associated with ventriculoperitoneal shunt placement in aneurysmal subarachnoid hemorrhage patients on dual antiplatelet therapy . J Neurosurg \n2013 ;119 :937 –42 . 10.3171/2013.5.JNS122494 \n23808537 \n8 \nCagnazzo F , Di Carlo DT , Petrella G , et al \nVentriculostomy-related hemorrhage in patients on antiplatelet therapy for endovascular treatment of acutely ruptured intracranial aneurysms. A meta-analysis . Neurosurg Rev \n2018 \ndoi: 10.1007/s10143-018-0999-0. [Epub ahead of print]. \n10.1007/s10143-018-0999-0 \n\n9 \nCampbell EJ , O’Byrne V , Stratford PW , et al \nBiocompatible surfaces using methacryloylphosphorylcholine laurylmethacrylate copolymer . Asaio J \n1994 ;40 :M853 –7 . 10.1097/00002480-199407000-00118 \n8555634 \n10 \nMarosfoi M , Clarencon F , Langan ET , et al \nAcute thrombus formation on phosphorilcholine surface modified flow diverters . J Neurointerv Surg \n2018 ;10 :406 –11 . 10.1136/neurintsurg-2017-013175 \n28689183 \n11 \nChiu AH , Ramesh R , Wenderoth J , et al \nUse of aspirin as sole oral antiplatelet therapy in acute flow diversion for ruptured dissecting aneurysms . J Neurointerv Surg \n2017 ;9 :e18 \n10.1136/neurintsurg-2016-012657.rep \n27683754 \n12 \nCagnazzo F , di Carlo DT , Cappucci M , et al \nAcutely ruptured intracranial aneurysms treated with flow-diverter stents: a systematic review and meta-analysis . AJNR Am J Neuroradiol \n2018 ;39 :1669 –75 . 10.3174/ajnr.A5730 \n30049721 \n13 \nMolyneux A , Kerr R , Stratton I , et al \nInternational Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial . Lancet \n2002 ;360 :1267 –74 . 10.1016/S0140-6736(02)11314-6 \n12414200 \n14 \nMatsuda Y , Jang DK , Chung J , et al \nPreliminary outcomes of single antiplatelet therapy for surface-modified flow diverters in an animal model: analysis of neointimal development and thrombus formation using OCT . J Neurointerv Surg \n2018 :doi: 10.1136/neurintsurg-2018-013935 [Epub ahead of print 26 May 2018 ]. 10.1136/neurintsurg-2018-013935 \n\n15 \nHagen MW , Girdhar G , Wainwright J , et al \nThrombogenicity of flow diverters in an ex vivo shunt model: effect of phosphorylcholine surface modification . J Neurointerv Surg \n2017 ;9 :1006 –11 . 10.1136/neurintsurg-2016-012612 \n27799376 \n16 \nHo MJ , Göricke SL , Mummel P , et al \nStent-assisted treatment of ruptured intracranial aneurysms in the acute phase: a single center experience . eNeurologicalSci \n2018 ;10 :31 –6 . 10.1016/j.ensci.2018.01.001 \n29736426 \n17 \nYang P , Zhao K , Zhou Y , et al \nStent-assisted coil placement for the treatment of 211 acutely ruptured wide-necked intracranial aneurysms: a single-center 11-year experience . Radiology \n2015 ;276 :545 –52 . 10.1148/radiol.2015140974 \n25822469 \n18 \nCai K , Ji Q , Cao M , et al \nAssociation of different stenting procedures with symptomatic thromboembolic complications in stent-assisted coiling of ruptured wide-necked intracranial aneurysms . World Neurosurg \n2017 ;104 :824 –30 . 10.1016/j.wneu.2017.05.093 \n28552737 \n19 \nCohen JE , Gomori JM , Leker RR , et al \nStent and flow diverter assisted treatment of acutely ruptured brain aneurysms . J Neurointerv Surg \n2018 ;10 :851 –8 . 10.1136/neurintsurg-2017-013742 \n29778996 \n20 \nBechan RS , Sprengers ME , Majoie CB , et al \nStent-assisted coil embolization of intracranial aneurysms: complications in acutely ruptured versus unruptured aneurysms . AJNR Am J Neuroradiol \n2016 ;37 :502 –7 . 10.3174/ajnr.A4542 \n26405089 \n21 \nLordkipanidzé M , Harrison P \nAspirin twice a day keeps new COX-1 at bay . J Thromb Haemost \n2012 ;10 :1217 –9 . 10.1111/j.1538-7836.2012.04764.x \n22540218\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1759-8478",
"issue": "11(7)",
"journal": "Journal of neurointerventional surgery",
"keywords": "aneurysm; hemorrhage; platelets; stent; stroke",
"medline_ta": "J Neurointerv Surg",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017542:Aneurysm, Ruptured; D001315:Australia; D001807:Blood Vessel Prosthesis; D004621:Embolization, Therapeutic; D005260:Female; D006493:Heparin; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D011446:Prospective Studies; D012189:Retrospective Studies; D013345:Subarachnoid Hemorrhage; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101517079",
"other_id": null,
"pages": "694-698",
"pmc": null,
"pmid": "30552166",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "12414200;16139655;20950080;21546464;22540218;23808537;24834945;25230839;25822469;26405089;27683754;27799376;28173470;28552737;28689183;29736426;29778996;29804090;29968172;30049721;8555634",
"title": "Pipeline shield with single antiplatelet therapy in aneurysmal subarachnoid haemorrhage: multicentre experience.",
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"abstract": "A 20-month-old girl diagnosed with T-cell acute lymphoblastic leukemia was treated according to the Nordic NOPHO ALL2000 protocol. The patient developed severe immunosuppression and experienced life-threatening adenovirus infection, which was treated with ribavirin and cidofovir. α-fetoprotein was 20- to 30-fold elevated, and genetic analysis confirmed the diagnosis of ataxia telangiectasia. Despite receiving only 7 weeks of anti-leukemic therapy, she has stayed in first remission now 8 years after the diagnosis. We speculate that this could be because of increased chemosensitivity of ATM-mutated leukemic cells, adenovirus causing a direct oncolytic effect, and/or high levels of endogenous cortisol during her severe infection.",
"affiliations": "Rigshospitalet, University Hospital, Copenhagen, Denmark.",
"authors": "Hersby|Ditte S|DS|;Sehested|Astrid|A|;Kristensen|Kim|K|;Schmiegelow|Kjeld|K|",
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"issue": "37(2)",
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"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000256:Adenoviridae; D000258:Adenovirus Infections, Human; D000998:Antiviral Agents; D001260:Ataxia Telangiectasia; D005260:Female; D006801:Humans; D007223:Infant; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D012074:Remission Induction",
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"title": "T-cell ALL in ataxia telangiectasia cured with only 7 weeks of anti-leukemic therapy.",
"title_normalized": "t cell all in ataxia telangiectasia cured with only 7 weeks of anti leukemic therapy"
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"abstract": "Atopic dermatitis (AD) is one of the most common inflammatory skin diseases affecting children and adults. The intense pruritus and rash can be debilitating, significantly impairing quality of life. Until recently, treatment was largely nonspecific and, in severe disease, sometimes ineffective and/or fraught with many side effects. Now, multiple agents targeting specific disease pathways are available or in development. Two new therapies, crisaborole and dupilumab, have become available since 2016, and dupilumab has dramatically improved outcomes for adults with severe AD. This article provides an overview of AD, including strategies for differential diagnosis and assessment of disease severity to guide treatment selection. Key clinical trials for crisaborole and dupilumab are reviewed, and other targeted treatments now in development are summarized. Two cases, representing childhood-onset and adult-onset AD, are discussed to provide clinical context for diagnosis, severity assessment, and treatment selection and outcomes.",
"affiliations": "Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Ill. Electronic address: afishbein@luriechildrens.org.;Northwestern University Feinberg School of Medicine, Northwestern Medicine Multidisciplinary Eczema Center, Chicago, Ill.;The France Foundation, Old Lyme, Conn.;Division of Clinical Immunology and Allergy, Children's Hospital Los Angeles, Los Angeles, Calif; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, Calif.",
"authors": "Fishbein|Anna B|AB|;Silverberg|Jonathan I|JI|;Wilson|Eve J|EJ|;Ong|Peck Y|PY|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized",
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"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "Adult onset; Atopic dermatitis; Crisaborole; Differential diagnosis; Dupilumab; Eczema; Infant onset; Severity assessment",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D003876:Dermatitis, Atopic; D004485:Eczema; D006801:Humans; D011788:Quality of Life; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "101597220",
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"pages": "91-101",
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"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "30287309;15611432;10494710;24813298;30194992;9559883;192803;29906525;25584909;30972740;29305764;29153857;29864464;30234614;29273118;25179683;15131576;8765838;29121124;29089179;24696036;30025911;30598180;11168575;17352685;30439298;29063431;27690741;8389777;28071589;21414011;25017523;29063428;29353026;21970826;28583445;15381553;23374261;27417017;30962700;8277028;8752839;7918015;27525671;30069607;28478972;18620132;16669989;24813302;23636109;24290431;29676067;29410014;15209954;25482871;23245818;6128357;30838645;8040343;30466772;30554600;8435513",
"title": "Update on Atopic Dermatitis: Diagnosis, Severity Assessment, and Treatment Selection.",
"title_normalized": "update on atopic dermatitis diagnosis severity assessment and treatment selection"
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"abstract": "Insulinomas are rare, and even rarer in patients with end-stage renal disease (ESRD). Clear criteria for the biochemical diagnosis of insulinomas in patients with renal failure have not been established, and hypoglycemia is often attributed to the renal disease itself, frequently leading to a delay in diagnosis. We describe a case of a patient who presented with asymptomatic recurrent hypoglycemia during hemodialysis. Disease progression and biochemical testing strongly suggested an insulinoma. Computed tomography (CT) of the abdomen and pelvis, 111In-pentetreotide scintigraphy and endoscopic ultrasound did not localize a pancreatic tumor. A calcium stimulation test was performed while the patient was taking diazoxide due to severe hypoglycemia with fasting for a couple of hours without treatment. The test showed a marked increase in insulin after calcium infusion in the dorsal pancreatic artery, localizing the tumor to the body and tail of the gland. Exploratory surgery easily identified a tumor at the body of the pancreas and pathology confirmed an insulin-secreting pancreatic neuroendocrine tumor. On follow-up, there was resolution of the hypoglycemia. We review the challenges of diagnosing an insulinoma in ESRD and describe a successful intra-arterial calcium stimulation test done in an ESRD patient while continuing diazoxide.",
"affiliations": "Division of Endocrinology and Metabolism, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, CA, USA.;Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.;Division of Endocrinology and Metabolism, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, CA, USA.;Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.;Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, CA, USA.;Division of Endocrinology and Metabolism, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, CA, USA.",
"authors": "Kim|Stephanie|S|0000-0003-3317-822X;Conrad|Miles|M|;Chuang|Eunice|E|;Cai|Larry|L|;Masharani|Umesh|U|0000-0002-3269-804X;Murphy|Elizabeth J|EJ|0000-0001-7687-2831",
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"doi": "10.1210/jendso/bvaa185",
"fulltext": "\n==== Front\nJ Endocr Soc\nJ Endocr Soc\njes\nJournal of the Endocrine Society\n2472-1972\nOxford University Press US\n\n33381673\n10.1210/jendso/bvaa185\nbvaa185\nCase Reports\nAcademicSubjects/MED00250\nCalcium Stimulation Test for Insulinoma Localization in an End-stage Renal Disease Patient on Diazoxide\nhttp://orcid.org/0000-0003-3317-822X\nKim Stephanie 12stephaniekim410@gmail.com\n\nConrad Miles 3\nChuang Eunice 12\nCai Larry 3\nhttp://orcid.org/0000-0002-3269-804X\nMasharani Umesh 2\nhttp://orcid.org/0000-0001-7687-2831\nMurphy Elizabeth J 12\n1 Division of Endocrinology and Metabolism, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, CA, USA\n2 Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, CA, USA\n3 Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA\nCorrespondence: Stephanie Kim, MD, MPH, 400 Parnassus Ave A550, San Francisco, CA 94143. E-mail: stephaniekim410@gmail.com.\n01 2 2021\n27 11 2020\n27 11 2020\n5 2 bvaa18527 8 2020\n20 11 2020\n21 12 2020\n© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.\n2020\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nInsulinomas are rare, and even rarer in patients with end-stage renal disease (ESRD). Clear criteria for the biochemical diagnosis of insulinomas in patients with renal failure have not been established, and hypoglycemia is often attributed to the renal disease itself, frequently leading to a delay in diagnosis. We describe a case of a patient who presented with asymptomatic recurrent hypoglycemia during hemodialysis. Disease progression and biochemical testing strongly suggested an insulinoma. Computed tomography (CT) of the abdomen and pelvis, 111In-pentetreotide scintigraphy and endoscopic ultrasound did not localize a pancreatic tumor. A calcium stimulation test was performed while the patient was taking diazoxide due to severe hypoglycemia with fasting for a couple of hours without treatment. The test showed a marked increase in insulin after calcium infusion in the dorsal pancreatic artery, localizing the tumor to the body and tail of the gland. Exploratory surgery easily identified a tumor at the body of the pancreas and pathology confirmed an insulin-secreting pancreatic neuroendocrine tumor. On follow-up, there was resolution of the hypoglycemia. We review the challenges of diagnosing an insulinoma in ESRD and describe a successful intra-arterial calcium stimulation test done in an ESRD patient while continuing diazoxide.\n\ninsulinoma\ndiazoxide\ncalcium stimulation test\nend stage renal disease\n==== Body\nInsulinomas, while being the most common functioning islet cell tumors, are rare with an incidence of 4 per million persons [1]. They are exceedingly rare in patients with end-stage renal disease (ESRD), reported in just 7 patients, including 3 patients on hemodialysis and 1 patient on peritoneal dialysis [2–8]. Establishing the diagnosis of insulinoma is always challenging [9], and even more so in ESRD, where spontaneous hypoglycemia can be due to other factors, including decreased renal gluconeogenesis, impaired insulin clearance, decreased hepatic gluconeogenesis from uremia, an abnormal counter-regulatory hormone response, and malnutrition [2]. Hypoglycemia in ESRD is often attributed to these other causes, leading to missed or delayed diagnosis in cases of an insulinoma.\n\nOnce diagnosed, insulinomas are often difficult to localize. Several strategies exist for localizing difficult-to-find tumors, including intra-arterial calcium administration to arteries supplying the pancreas to stimulate insulin secretion from the tumor. Diazoxide, a potassium channel activator used to treat hyperinsulinemia, is usually discontinued during this testing so as not to suppress the insulin response to calcium. We report the first case of successful insulinoma localization from a calcium stimulation test performed in a patient with ESRD while continuing diazoxide.\n\nCase Report\n\nA 36-year-old man with ESRD due to systemic lupus erythematosus (SLE) and hypertension, on hemodialysis for 5 years, was referred to the San Francisco General Hospital Endocrine Clinic for recurrent hypoglycemia. During the previous 10 months, the patient was noted to have hypoglycemia on multiple occasions during hemodialysis with nonfasting serum blood glucoses (BG) ranging from 30 to 40 mg/dL. He denied symptoms other than weakness during these episodes. A cortisol level obtained during 1 instance of hypoglycemia (BG 34 mg/dL) was 14.7 mg/dL, which, given the degree of hypoglycemia, suggested possible adrenal insufficiency. His medications were benazepril 20 mg daily and cinacalcet 30 mg daily. He did have a history of prior prednisone use for many years for his SLE, but he had not been taking it for at least several months prior to presentation. There was no family history of endocrine disorders.\n\nThe patient was admitted to the hospital for a supervised fast. Physical examination was unremarkable. After 4.5 hours of fasting he became confused, diaphoretic, and irritable. Blood glucose was 27 mg/dL. Symptoms resolved with treatment of the hypoglycemia, thus establishing Whipple’s triad. When BG was 27 mg/dL, other labs included insulin 19.8 μU/mL (ref 3–25), C-peptide 7.6 ng/mL (ref 0.8–3.5), proinsulin 385.5 pmol/L (ref < 26.8), and beta-hydroxybutyrate 0.07 mmol/L (ref < 0.28). Sulfonylurea panel and insulin autoantibody were negative. These results are typically diagnostic of an insulinoma (criteria: BG < 55 mg/dL, insulin ≥ 3.0 μU/mL, C-peptide ≥ 0.6 ng/mL, proinsulin ≥ 5 pmol/L, and beta-hydroxybutyrate levels ≤ 2.7 mmol/L) [9]. However, in ESRD, endogenous glucose production, from both the kidney and liver, is reduced, contributing to fasting hypoglycemia. While insulin secretion should be quickly suppressed with hypoglycemia, because of delayed insulin clearance in ESRD, insulin concentrations can remain elevated and further contribute to hypoglycemia. Unfortunately, no clear diagnostic criteria exist for appropriate insulin suppression in ESRD. For our patient, given his ESRD and possible mild adrenal insufficiency (discussed below), the diagnosis of an insulinoma remained uncertain.\n\nDuring hospitalization the patient had a cosyntropin stimulation test that showed a precortisol level of 8.5 ug/dL, with an adrenocorticotropic hormone (ACTH) level of 55 pg/mL (ref 7–69 pg/mL; Siemens Immulite Assay; Siemens, Malvern, PA) and a postcortisol level of 15.8 ug/dL. This was deemed an insufficient response, especially in the setting of recurrent hypoglycemia. A 21-hydroxylase antibody test was negative and an abdominal computed tomography (CT) scan did not identify a pancreatic islet-cell tumor. He was therefore discharged home on hydrocortisone and diazoxide, with resolution of his hypoglycemic episodes. Repeat cosyntropin stimulation testing was performed on him as an outpatient 8 months later, with a precortisol level of 16.1 ug/dL and a postcortisol level of 20.3 ug/dL. It was presumed the patient had recovered from possible adrenal suppression from prior high-dose glucocorticoid use and hydrocortisone was subsequently discontinued. Further imaging with an octreotide scan and endoscopic ultrasound was performed and did not localize a pancreatic tumor. The patient refused referral for surgical exploration and did not follow-up further with endocrinology for several years.\n\nAs a side note, subsequent repeat ACTH several years later, again with the Siemens Immulite assay, was 236 pg/mL, with a corresponding cortisol of 16.8 ug/dL. This result was considered spurious given the cortisol and low clinical suspicion for adrenal insufficiency at the time. He had remained off prednisone and hydrocortisone. Subsequently, after it was reported that the Siemens Immulite ACTH assay could cause erroneously elevated results [10], this was rechecked using the Roche Cobas ACTH assay (Roche Diagnostics, Mannheim, Germany). The ACTH was actually borderline low at 5.4 pg/mL (ref 7.2–63.3 pg/mL), with a corresponding cortisol of 12.7. This suggests the original ACTH readings had been erroneously high and the patient may have initially had some degree of mild adrenal dysfunction due to his prior glucocorticoid use, which resolved with time.\n\nTwo years after his initial evaluation, the patient re-presented to the endocrine clinic with worsening hypoglycemia and frequent emergency room visits for nocturnal hypoglycemia with loss of consciousness. He also had a 50-pound weight gain due to eating and drinking soda every 4 hours. He had self-increased his diazoxide to 150 mg at night with minimal improvement in symptoms. Repeat endoscopic ultrasound and CT abdomen pelvis did not reveal a pancreatic lesion.\n\nTo localize the insulinoma, an intra-arterial calcium stimulation test was performed. Due to a hypoglycemic episode to 30 mg/dL while fasting in preparation for a CT scan, it was deemed unsafe to discontinue diazoxide during the calcium stimulation test. The patient fasted for 12 hours but took diazoxide 150 mg the night before and 50 mg on the morning of the procedure. The gastroduodenal, proper hepatic, superior mesenteric, and dorsal pancreatic arteries were catheterized with calcium gluconate bolused into each artery. Blood samples from the right hepatic vein were obtained at baseline and at 30, 60, 90, 120, and 150 seconds after injection. Notably, the majority of the blood supply to the body and tail of the pancreas was identified on angiography to originate from the dorsal pancreatic artery rather than branches from the splenic artery, as is more typically seen (Fig. 1). The results of the intra-arterial calcium stimulation showed a step-up in insulin from a baseline of 7.2 μU/L to a peak of 886.7 μU/L 90 seconds after injection of the dorsal pancreatic artery (Fig. 2). Injection in the other arteries showed no significant increase. The capillary BG decreased to 36 mg/dL with the surge in insulin. The patient reported tremors and diaphoresis and intravenous glucose (25 gm) was administered, with improvement in his symptoms. He was monitored postprocedure and his BG remained low at 44 mg/dL 4 hours later, likely due to the very high insulin level from the stimulation test and slow insulin clearance due to his renal failure. He was given an additional 25 grams of intravenous glucose and food, and his BG rose to 118 mg/dL. He refused to remain in the hospital and left against medical advice.\n\nFigure 1. Visceral arteriogram demonstrates the tip of the catheter in the dorsal pancreatic artery (long white arrow). In this patient, the dorsal pancreatic artery is the dominant supply to the neck and body of the pancreas via the pancreatica magna artery (short white arrow) and transverse pancreatic artery (black arrow). Contrast is seen refluxing in the splenic artery (asterisk), which does not show significant supply to the pancreas.\n\nFigure 2. Insulin in hepatic vein over time following arterial calcium gluconate stimulation.\n\nThe patient was referred to surgery for exploration and presumed resection of the distal pancreas. While awaiting surgery, whole body 68Gallium (68Ga)-DOTATATE (a radioconjugate with a high affinity to somatostatin receptor 2 positron emission tomography (PET)/CT scan [11]) became available under a research protocol. A radiotracer avid lesion was seen at the level of the body of the pancreas measuring 1.6 × 1.4 cm with a standardized uptake value of 32.2 (Fig. 3). Surgical laparoscopic exploration revealed an easily identifiable tumor situated directly over the body of the pancreas, and the patient underwent a distal pancreatectomy. Pathology showed a 1.9 × 1.2 × 1.2 cm well-differentiated tumor, with immunohistochemical staining positive for insulin, synaptophysin, chromogranin and a weak, patchy cytokeratin cocktail consistent with a low-grade insulin-secreting pancreatic neuroendocrine tumor. Postoperatively, the patient’s BG normalized with resolution of hypoglycemic symptoms and significant improvement in his quality of life. Notably, he lost 60 pounds 5 months postoperatively.\n\nFigure 3. Whole body 68Gallium (68Ga)-DOTATATE showing a radiotracer avid lesion at the level of the body of the pancreas measuring 1.6 × 1.4 cm, with a standardized uptake value (SUV) of 32.2 (red arrow).\n\nDiscussion\n\nSpontaneous hypoglycemia in ESRD is multifactorial and may occur due to reduced renal gluconeogenesis, decreased insulin clearance, reduced hepatic glucogenesis, impaired counterregulatory hormone response, diminished caloric intake, and the use of high glucose-containing dialysate during hemodialysis or peritoneal dialysis [2]. Thus, the diagnosis of endogenous hyperinsulinemia in the presence of ESRD is difficult and may be delayed without established criteria in this setting. Our patient had documented Whipple’s triad, though this can be seen in renal failure without the presence of an insulinoma. The clinical progression of his symptoms over several years with significant weight gain increased our suspicion for insulinoma. He initially responded well to diazoxide but 2 years later, re-presented with symptomatic hypoglycemia despite more aggressive diazoxide treatment.\n\nAs is common with insulinomas, initial localizing studies were negative. In these cases, an intra-arterial calcium stimulation test is reported to localize 88% to 100% of insulinomas to the correct region of the pancreas [11]. Understanding the arterial supply of the pancreas is important. Interestingly, in this case the patient displayed variable anatomy. His angiography showed no significant arterial supply to the pancreas from the splenic artery, which is normally the dominant blood supply to the body and tail of the pancreas. Rather, supply to this region appeared to originate from the dorsal pancreatic artery, which was selectively catheterized and bolused with calcium gluconate, along with the gastroduodenal, proper hepatic, and superior mesenteric arteries.\n\nIn pancreatic β-cells, glucose enters the cell and generates adenosine triphosphate (ATP), which closes the potassium ATP (KATP) channels. Cells are depolarized, voltage gated calcium channels open, and increased intracellular calcium leads to insulin release. Sulfonylureas bind to the KATP channels and also close them, thereby increasing insulin secretion. However, diazoxide opens the KATP channels, hyperpolarizing the cell, leading to the closure of voltage gated calcium channels, decreased intracellular calcium, and inhibition of insulin secretion. Thus, diazoxide is especially useful in the management of hyperinsulinism from an insulinoma [12]. However, in a patient undergoing a calcium stimulation test, calcium enters the pancreatic beta cells primarily through the voltage-activated calcium channels closed by diazoxide. In the presence of diazoxide, it would therefore be expected that insulinoma cells would be unresponsive to the increase in extracellular calcium. Accordingly, protocols for the calcium stimulation procedure dictate that diazoxide should be discontinued at the time of testing so as not to suppress insulin secretion.\n\nFor safety reasons, our patient was maintained on diazoxide, including on the morning of the test. This is the first report, to our knowledge, of a successful intra-arterial calcium stimulation test while continuing diazoxide treatment. Our patient showed marked elevation in insulin after calcium infusion into the dorsal pancreatic artery, localizing the tumor to the body and tail of the gland, which corresponded to the tumor location at surgery. A previous study reported a false-negative selective arterial calcium stimulation in a patient maintained on diazoxide, and repeat testing in the same patient after diazoxide was discontinued and localized the insulinoma [13]. The reason for success with diazoxide in 1 patient but not the other is likely due to underlying differences in the tumors. It was first observed over 30 years ago that there are striking differences in insulinoma responsiveness to diazoxide [14]. Different subtypes of insulinomas have been proposed with different postulated mechanisms responsible for dysregulated insulin secretion [15]. Therefore, we hypothesize the tumor in our patient was relatively unresponsive to diazoxide. Patients with diazoxide-unresponsive tumors also tended to have relatively higher proinsulin concentrations, as was the case in our patient [14]. Unresponsiveness to diazoxide is further supported by the severe hypoglycemia requiring frequent eating despite treatment. All of these factors may have allowed for successful arterial calcium stimulation, though future studies will be needed to determine how best to identify patients who can have successful tumor localization while still taking diazoxide.\n\nOf note, had it been available earlier, 68Ga-DOTATATE PET/CT would also have revealed the tumor location, forgoing the need for calcium stimulation. 68Ga-DOTATATE PET/CT identifies most insulinomas with better accuracy than CT, magnetic resonance imaging (MRI), ultrasound, and octreotide scintigraphy [16]. Therefore, while selective arterial secretagogue injection remains more accurate for regionalizing insulinomas [17], it may be used much less frequently. 111In-DTPA-exendin-4 SPECT/CT, used for glucagon-like-peptide-1 receptor imaging, is also known to be a more sensitive modality for the localization of insulinomas compared with traditional imaging methods.\n\nOur case highlights that in ESRD, there will be a significant risk for prolonged postprocedure hypoglycemia given a delay in clearance of the very high circulating insulin concentrations. In our patient, this hypoglycemia risk lasted at least 4 hours. Given he left against advice, we don’t know how much longer this may have lasted. Postprocedural-prolonged hypoglycemia in ESRD should be anticipated and patients should be monitored for many hours postprocedure. Consideration of overnight observation may be appropriate.\n\nThis case shows that while diazoxide is traditionally not used with an intra-arterial calcium stimulation test, it can be continued in some cases of severe hypoglycemia with successful results. Insulinoma in the setting of ESRD is rare and difficult to diagnosis, often leading to a delay in treatment. It is important to note that clearance of insulin after the calcium stimulation may be slow and patients need to be closely monitored for a prolonged period postprocedure to ensure that glucose levels are stable.\n\nAdditional Information\n\nDisclosure Summary: The authors have nothing to disclose.\n\nData Availability\n\nSome or all data generated or analyzed during this study are included in this published article or in the data repositories listed in References.\n==== Refs\nReferences\n\n1. Service FJ, McMahon MM, O’Brien PC, Ballard DJ Functioning insulinoma – incidence, recurrence, and long-term survival of patients: a 60-year study. Mayo Clin Proc. 1991;66 (7 ):711–719.1677058\n2. Basu A, Sheehan MT, Thompson GB, Service FJ Insulinoma in chronic renal failure: a case report. J Clin Endocrinol Metab. 2002;87 (11 ):4889–4891.12414845\n3. Foppiani L, Panarello S, Filauro M, et al Insulinoma and chronic kidney disease: an uncommon conundrum not to be overlooked. Clin Med Insights Endocrinol Diabetes. 2017;10 :1179551417742620.29200897\n4. Matas AJ, Simmons RL, Kjellstrand CM, Buselmeier TJ, Najarian JS Increased incidence of malignancy during chronic renal failure. Lancet. 1975;1 (7912 ):883–886.47534\n5. Pistrosch F, Büssemaker E, Gross P An old patient with end stage renal disease and sudden onset of confusion and lethargy. Nephrol Dial Transplant. 2006;21 (3 ):813–815.16390853\n6. Shaer AJ Management of hyperinsulinemia with diazoxide in an elderly hemodialysis patient. Nephron. 2001;89 (3 ):337–339.11598399\n7. Shimizu M, Suzuki K, Tsuchida K, Kojima M, Hiraishi H, Aso Y Insulinoma in a patient with chronic renal failure due to type 2 diabetes mellitus treated effectively with diazoxide. Intern Med. 2015;54 (6 ):621–625.25786453\n8. Jarrett RA, Block CA Peritoneal dialysis masking symptoms of an insulinoma uncovered during the perioperative period: a case report. South Med J. 2009;102 (2 ):214–215.19139696\n9. Okabayashi T, Shima Y, Sumiyoshi T, et al. Diagnosis and management of insulinoma. World J Gastroenterol. 2013;19 (6 ):829–837.23430217\n10. Greene LW, Geer EB, Page-Wilson G, Findling JW, Raff H Assay-specific spurious ACTH results lead to misdiagnosis, unnecessary testing, and surgical Misadventure-A case series. J Endocr Soc. 2019;3 (4 ):763–772.30963134\n11. Guettier JM, Kam A, Chang R, et al. Localization of insulinomas to regions of the pancreas by intraarterial calcium stimulation: the NIH experience. J Clin Endocrinol Metab. 2009;94 (4 ):1074–1080.19190102\n12. Graber AL, Porte D Jr, Williams RH Clinical use of diazoxide and mechanism for its hyperglycemic effects. Diabetes. 1966;15 (3 ):143–148.4286307\n13. Wiesli P, Brändle M, Schmid C, et al. Selective arterial calcium stimulation and hepatic venous sampling in the evaluation of hyperinsulinemic hypoglycemia: potential and limitations. J Vasc Interv Radiol. 2004;15 (11 ): 1251–1256.15525744\n14. Berger M, Bordi C, Cüppers HJ, et al. Functional and morphologic characterization of human insulinomas. Diabetes. 1983;32 (10 ):921–931.6311653\n15. Henquin JC, Nenquin M, Guiot Y, Rahier J, Sempoux C Human insulinomas show distinct patterns of insulin secretion in vitro. Diabetes. 2015;64 (10 ):3543–3553.26116696\n16. Nockel P, Babic B, Millo C, et al. Localization of insulinoma using 68Ga-DOTATATE PET/CT scan. J Clin Endocrinol Metab. 2017;102 (1 ):195–199.27805844\n17. Srirajaskanthan R, Kayani I, Quigley AM, Soh J, Caplin ME, Bomanji J The role of 68Ga-DOTATATE PET in patients with neuroendocrine tumors and negative or equivocal findings on 111In-DTPA-octreotide scintigraphy. J Nucl Med. 2010;51 (6 ):875–882.20484441\n\n",
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"keywords": "calcium stimulation test; diazoxide; end stage renal disease; insulinoma",
"medline_ta": "J Endocr Soc",
"mesh_terms": null,
"nlm_unique_id": "101697997",
"other_id": null,
"pages": "bvaa185",
"pmc": null,
"pmid": "33381673",
"pubdate": "2021-02-01",
"publication_types": "D002363:Case Reports",
"references": "20484441;11598399;1677058;25786453;4286307;19139696;23430217;6311653;15525744;27805844;12414845;29200897;26116696;16390853;19190102;47534;30963134",
"title": "Calcium Stimulation Test for Insulinoma Localization in an End-stage Renal Disease Patient on Diazoxide.",
"title_normalized": "calcium stimulation test for insulinoma localization in an end stage renal disease patient on diazoxide"
} | [
{
"companynumb": "US-TEVA-2021-US-1935758",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "Clinical trial results indicate that romidepsin, a histone deacetylase inhibitor, is a promising treatment in relapsed/refractory T-cell lymphomas (TCLs). This retrospective multicenter study was conducted in patients with relapsed/refractory TCL treated with romidepsin monotherapy through a Named Patient Program (NPP) in Italy. Principal endpoints were overall response rate (ORR), safety, and overall survival (OS). The ORR in 33 evaluable patients was 24.2% with an ORR in the cutaneous TCL of 35.7%. Global OS was 39.3% at 30 months. There were not any specific differences on hematological and extrahematological adverse events. Data from patients treated with romidepsin outside a controlled clinical trial give additional information about the clinical use, efficacy, and toxicity of the drug given to relapsed or refractory TCL patients in a real life context as TCLs are rare diseases and more information is needed. These findings suggest that romidepsin is effective and safe for heavily pretreated TCL patients.",
"affiliations": "a Institute of Hematology \"L. E A. Seràgnoli\", University of Bologna , Bologna , Italy ;;a Institute of Hematology \"L. E A. Seràgnoli\", University of Bologna , Bologna , Italy ;;b AOU Policlinico Federico II , Napoli , Italy ;;c A.O. SS Antonio E Biagio E Cesare Arrigo , Alessandria , Italy ;;d Centro Trapianti E Terapie Cellulari Azienda Ospedaliero-Universitaria , Udine , Italy ;;e Department of Hematology, Spedali Civili , Brescia , Italy ;;f UO Ematologia E Centro Trapianti, Ospedale Oncologico Di Riferimento Regionale \"Armando Businco\", Azienda Ospedaliera \"Brotzu\" , Cagliari , Italy ;;g Istituto Nazionale Dei Tumori, Università Di Milano , Milano , Italy ;;h Hematology Unit, Sant'andrea Hospital , Roma , Italy ;;i Natl Cancer Center \"Istituto Tumori Giovanni Paolo II IRCCS\" , Bari , Italy ;;j Oncohematology and Bone Marrow Unit, Oncology Department , La Maddalena , Palermo , Italy ;;k Department of Medical and Surgical Sciences , UNIMORE, AOU Policlinico , Modena , Italy ;;l Oncology and Hematology Department , IOM Istituto Oncologico Del Mediterraneo , Viagrande , Catania , Italy ;;m Hematology and BMT , Central Hospital , Bolzano , Italy ;;n Division of Hematology , San Giuseppe Moscati Hospital , Aversa, Caserta , Italy ;;o Division of Hematology , AOU Policlinico-Vittorio Emanuele , Catania , Italy ;;p Division of Hematology , Department of Translational Medicine Amedeo Avogadro University of Eastern Piedmont and Maggiore Hospital , Novara , Italy ;;q Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section , University of Bari , Bari , Italy ;;r Istituto Fiorentino Di Cura E Assistenza , Firenze , Italy ;;s Onco-Hematology, BMT Center Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico University of Milan , Milano , Italy ;;t Ospedale Di Circolo, Fondazione Macchi , University Hospital , Varese , Italy ;;u Hematology Department AOU Careggi , Firenze , Italy.;a Institute of Hematology \"L. E A. Seràgnoli\", University of Bologna , Bologna , Italy ;",
"authors": "Zinzani|Pier Luigi|PL|;Pellegrini|Cinzia|C|;Cerciello|Giuseppe|G|;Monaco|Federico|F|;Volpetti|Stefano|S|;Peli|Annalisa|A|;Angelucci|Emanuele|E|;Corradini|Paolo|P|;Cox|Maria Christina|MC|;Guarini|Attilio|A|;Musso|Maurizio|M|;Bresciani|Paola|P|;Amato|Gabriella|G|;Billio|Atto|A|;Caparrotti|Giuseppe|G|;Figuera|Amalia|A|;Nassi|Luca|L|;Gaudio|Francesco|F|;Grossi|Alberto|A|;Onida|Francesco|F|;Merli|Michele|M|;Rigacci|Luigi|L|;Argnani|Lisa|L|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; C087123:romidepsin",
"country": "United States",
"delete": false,
"doi": "10.3109/10428194.2015.1137292",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "57(10)",
"journal": "Leukemia & lymphoma",
"keywords": "Real life; T-cell lymphoma; refractory; relapsed; romidepsin",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D016399:Lymphoma, T-Cell; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012008:Recurrence; D019233:Retreatment; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "2370-4",
"pmc": null,
"pmid": "26732313",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Romidepsin in relapsed/refractory T-cell lymphomas: Italian experience and results of a named patient program.",
"title_normalized": "romidepsin in relapsed refractory t cell lymphomas italian experience and results of a named patient program"
} | [
{
"companynumb": "IT-CELGENE-ITA-2016011995",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ROMIDEPSIN"
},
"drugadditional": null,
... |
{
"abstract": "Objective: Perioperative chemotherapy can potentially downstage esophageal cancer, reducing the risk of early systemic dissemination. One recommended neoadjuvant regimen for managing gastroesophageal junction and esophageal cancer is docetaxel, cisplatin, and 5-fluorouracil (DCF). To address the high toxicity profile of DCF, modifications in dosages and treatment intervals have been studied. We integrated a modified DCF regimen (mDCF) into a multimodal treatment approach for non-metastatic esophageal cancer (nMEC). Retrospectively, we sought to describe our community experience of administrating neoadjuvant mDCF to patients with nMEC.Design: Patients diagnosed with nMEC between August 2008 and November 2017 and prescribed mDCF were identified for retrospective review. Outcomes of interest included disease-free survival (DFS), overall survival (OS), and hematologic toxicities. Analyses were performed using SAS 9.4.Results: Thirty patients met inclusion criteria with a median age of 64.9 years; 90% were male. The 2-year and 5-year DFS was 60.8% and 41.7%, respectively, for adenocarcinoma and 71.4% and 71.4% for squamous cell carcinoma (SCC). The 2-year and 5-year OS was 64.9% and 44.5%, respectively, for adenocarcinoma and 71.4% and 71.4% for SCC. Both DFS and OS decreased with increasing disease stage, histology (adenocarcinoma versus squamous), esophageal compared to esophagogastric-junction involvement, and without surgical intervention. Frequent toxicity grades for leukopenia and thrombocytopenia were Grades I and II.Conclusion: Using an mDCF regimen in combination with chemoradiation +/- surgical resection in a community setting appears to have an acceptable toxicity profile as well as DFS and OS outcomes compared to chemotherapeutic regimens reported in other similar studies.",
"affiliations": "Department of Hematology/Oncology, Marshfield Clinic-Weston Center, Weston, Wisconsin onitilo.adedayo@marshfieldclinic.org.;Wisconsin Surgical Outcomes Research Program, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.;Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.;Department of Hematology/Oncology, Marshfield Clinic-Weston Center, Weston, Wisconsin.;Department of Gastroenterology, Marshfield Clinic-Weston Center, Weston, Wisconsin.;Department of Hematology/Oncology, Marshfield Clinic-Weston Center, Weston, Wisconsin.;Cancer Care and Research Center, Marshfield Clinic Research Institute, Marshfield, Wisconsin.",
"authors": "Onitilo|Adedayo A|AA|;Stankowski-Drengler|Trista J|TJ|;Shiyanbola|Oyewale|O|;Engel|Jessica|J|;Tanimu|Sabo|S|;Fagbemi|Seth O|SO|;Li|Ya-Huei|YH|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.3121/cmr.2021.1573",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1539-4182",
"issue": "19(2)",
"journal": "Clinical medicine & research",
"keywords": "Community; Disease-free survival; Hematologic toxicities; Modified docetaxel, cisplatin, and fluorouracil; Non-metastatic esophageal cancer; Overall survival",
"medline_ta": "Clin Med Res",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D000077143:Docetaxel; D004938:Esophageal Neoplasms; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D012189:Retrospective Studies; D013274:Stomach Neoplasms; D043823:Taxoids",
"nlm_unique_id": "101175887",
"other_id": null,
"pages": "64-71",
"pmc": null,
"pmid": "33789952",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "29748347;17704421;27001629;25544126;25691612;30620402;29441562;21684205;26438119;29786848;27664261;10973385;28003586;23165781;17075117;31788647;22646630;7165009;29930885;19770374;22039085;21189380;9869669;15946974;26254683;28784312;18222210",
"title": "Modified Docetaxel, Cisplatin, and Fluorouracil (mDCF) as a Neoadjuvant Chemotherapy for Non-metastatic Esophageal Cancer (nMEC).",
"title_normalized": "modified docetaxel cisplatin and fluorouracil mdcf as a neoadjuvant chemotherapy for non metastatic esophageal cancer nmec"
} | [
{
"companynumb": "US-AMGEN-USASP2022027838",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": "4",
... |
{
"abstract": "OBJECTIVE\nDuring the past two decades, professional associations, accrediting bodies, and payors have made post-surgical pain treatment a high priority. In light of the disappointing findings in previous surveys, a survey was conducted to assess patient perceptions and characterize patient experiences/levels of satisfaction with post-surgical pain management.\n\n\nMETHODS\nSurvey included a random sample of US adults who had undergone surgery within 5 years from the survey date. Participants were asked about their concerns before surgery, severity of perioperative pain, pain treatments, perceptions about post-surgical pain and pain medications, and satisfaction with treatments they received.\n\n\nRESULTS\nOf the 300 participants, ∼86% experienced pain after surgery; of these, 75% had moderate/extreme pain during the immediate post-surgical period, with 74% still experiencing these levels of pain after discharge. Post-surgical pain was the most prominent pre-surgical patient concern, and nearly half reported they had high/very high anxiety levels about pain before surgery. Approximately 88% received analgesic medications to manage pain; of these, 80% experienced adverse effects and 39% reported moderate/severe pain even after receiving their first dose.\n\n\nCONCLUSIONS\nKey study limitations include the relatively small population size, potential for recall bias associated with the 14-month average time delay from surgery date to survey date, and the inability to account for influences of type of surgery and intraoperative anesthetic/analgesic use on survey results.\n\n\nCONCLUSIONS\nDespite heightened awareness and clinical advancements in pain management, there has been little improvement in post-surgical analgesia as measured by this survey of post-surgical patients.",
"affiliations": "Duke University Medical Center , Durham, NC , USA.",
"authors": "Gan|Tong J|TJ|;Habib|Ashraf S|AS|;Miller|Timothy E|TE|;White|William|W|;Apfelbaum|Jeffrey L|JL|",
"chemical_list": "D000700:Analgesics",
"country": "England",
"delete": false,
"doi": "10.1185/03007995.2013.860019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-7995",
"issue": "30(1)",
"journal": "Current medical research and opinion",
"keywords": null,
"medline_ta": "Curr Med Res Opin",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000698:Analgesia; D000700:Analgesics; D001007:Anxiety; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D059408:Pain Management; D010147:Pain Measurement; D010149:Pain, Postoperative; D017060:Patient Satisfaction; D013514:Surgical Procedures, Operative; D011795:Surveys and Questionnaires; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "0351014",
"other_id": null,
"pages": "149-60",
"pmc": null,
"pmid": "24237004",
"pubdate": "2014-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Incidence, patient satisfaction, and perceptions of post-surgical pain: results from a US national survey.",
"title_normalized": "incidence patient satisfaction and perceptions of post surgical pain results from a us national survey"
} | [
{
"companynumb": "US-JNJFOC-20140102858",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
"... |
{
"abstract": "Relapsed/refractory acute lymphoblastic leukemia poses a significant clinical challenge due to its poor prognosis, with survival rates of less than a year, even with novel therapies. Patients frequently experience toxicities from induction chemotherapy such as hepatotoxicity, which can limit therapeutic options upon relapse. Blinatumomab, a novel immunotherapy, has demonstrated excellent efficacy in relapsed/refractory acute lymphoblastic leukemia; however, there are limited data on use of this agent in patients with significant organ dysfunction. In this report, we describe the safe and effective use of blinatumomab in an adult patient with refractory Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia in the setting of severe hepatic dysfunction. Blinatumomab may represent a viable option to treat relapsed/refractory acute lymphoblastic leukemia in patients with significant hepatic dysfunction.",
"affiliations": "University of Michigan College of Pharmacy, Ann Arbor, MI, USA.;Department of Pharmacy Services and Clinical Sciences, Michigan Medicine, University of Michigan College of Pharmacy, Ann Arbor, MI, USA.;Division of Hematology/Oncology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, USA.;Department of Pharmacy Services and Clinical Sciences, Michigan Medicine, University of Michigan College of Pharmacy, Ann Arbor, MI, USA.",
"authors": "Robinson|Adam C|AC|;Marini|Bernard L|BL|;Pettit|Kristen M|KM|;Perissinotti|Anthony J|AJ|https://orcid.org/0000-0002-5205-1219",
"chemical_list": "D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; C510808:blinatumomab",
"country": "England",
"delete": false,
"doi": "10.1177/1078155219829534",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "26(1)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Acute lymphoblastic leukemia; acute leukemia; blinatumomab; hepatic dysfunction",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "200-205",
"pmc": null,
"pmid": "30760167",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful use of blinatumomab in a patient with acute lymphoblastic leukemia and severe hepatic dysfunction.",
"title_normalized": "successful use of blinatumomab in a patient with acute lymphoblastic leukemia and severe hepatic dysfunction"
} | [
{
"companynumb": "US-SERVIER-S20000674",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DAUNORUBICIN"
},
"drugadditional": "3",
... |
{
"abstract": "To determine whether a fraction of patients with primary CNS lymphoma (PCNSL) had been cured by systemic and intraventricular methotrexate- and cytarabine-based chemotherapy (Bonn protocol) after a very long-term follow-up of nearly 20 years.\n\n\n\nSixty-five patients (median age 62 years, range 27-75; median Karnofsky performance score 70, range 20-90) had been treated with systemic and intraventricular polychemotherapy without whole brain radiotherapy from September 1995 until December 2001. All patients still alive in 2019 were contacted and interviewed on their current life situation.\n\n\n\nMedian follow-up for surviving patients was 19.6 years (17.5-23.3 years). Out of 65 patients, 11 (17%) were still alive. Six of those never experienced any relapse. For the whole study population, median overall survival (OS) was 4.4 years (95% confidence interval [CI] 2.9-5.9); for patients ≤60 years, 11.0 years (95% CI 4.8-17.0). The 10-year OS rate for the entire cohort was 29% and the estimated 20-year OS rate was 19%. Four late relapses were observed after 9.8, 10.3, 13.3, and 21.0 years.\n\n\n\nAt a median follow-up of 19.6 years, 17% of patients were alive and free of tumor; however, even after response for decades, an inherent risk of relapse, either systemic or cerebral, characterizes the biology of PCNSL.\n\n\n\nThis work provides Class III evidence that PCNSL treatment with methotrexate-based polychemotherapy including intraventricular therapy is associated with long-term disease control in some patients.",
"affiliations": "From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany. sabine.seidel@kk-bochum.de.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.;From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.",
"authors": "Seidel|Sabine|S|;Pels|Hendrik|H|;Schlömer|Sabine|S|;Kowoll|Annika|A|;Fliessbach|Klaus|K|;Engert|Andreas|A|;Vogt-Schaden|Marlies|M|;Egerer|Gerlinde|G|;Reichmann|Heinz|H|;Schackert|Gabriele|G|;Kroschinsky|Frank|F|;Deckert|Martina|M|;Herrlinger|Ulrich|U|;Klockgether|Thomas|T|;Fimmers|Rolf|R|;Bode|Udo|U|;Schmidt-Wolf|Ingo G H|IGH|;Schlegel|Uwe|U|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0000000000010949",
"fulltext": "\n==== Front\nNeurology\nNeurology\nneurology\nneur\nneurology\nNEUROLOGY\nNeurology\n0028-3878\n1526-632X\nLippincott Williams & Wilkins Hagerstown, MD\n\n32989105\nNEUROLOGY2020095810\n10.1212/WNL.0000000000010949\n00010\n3\n19\n323\n214\n218\nArticle\nTwenty-year follow-up of a pilot/phase II trial on the Bonn protocol for primary CNS lymphoma\nSeidel Sabine MD\nPels Hendrik MD\nSchlömer Sabine PhD\nKowoll Annika MD\nFliessbach Klaus MD, PhD\nEngert Andreas MD\nVogt-Schaden Marlies MD\nEgerer Gerlinde MD\nReichmann Heinz MD, PhD\nSchackert Gabriele MD\nKroschinsky Frank MD\nDeckert Martina MD\nHerrlinger Ulrich MD\nKlockgether Thomas MD, PhD\nFimmers Rolf PhD\nBode Udo MD\nSchmidt-Wolf Ingo G.H. MD\nSchlegel Uwe MD\nFrom the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.\nCorrespondence Dr. Seidel sabine.seidel@kk-bochum.de\nGo to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was funded by Ruhr University Bochum.\n\n8 12 2020\n8 12 2020\n95 23 e3138e3144\n04 5 2020\n23 7 2020\nCopyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.\n2020\nAmerican Academy of Neurology\nThis is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nObjective\n\nTo determine whether a fraction of patients with primary CNS lymphoma (PCNSL) had been cured by systemic and intraventricular methotrexate- and cytarabine-based chemotherapy (Bonn protocol) after a very long-term follow-up of nearly 20 years.\n\nMethods\n\nSixty-five patients (median age 62 years, range 27–75; median Karnofsky performance score 70, range 20–90) had been treated with systemic and intraventricular polychemotherapy without whole brain radiotherapy from September 1995 until December 2001. All patients still alive in 2019 were contacted and interviewed on their current life situation.\n\nResults\n\nMedian follow-up for surviving patients was 19.6 years (17.5–23.3 years). Out of 65 patients, 11 (17%) were still alive. Six of those never experienced any relapse. For the whole study population, median overall survival (OS) was 4.4 years (95% confidence interval [CI] 2.9–5.9); for patients ≤60 years, 11.0 years (95% CI 4.8–17.0). The 10-year OS rate for the entire cohort was 29% and the estimated 20-year OS rate was 19%. Four late relapses were observed after 9.8, 10.3, 13.3, and 21.0 years.\n\nConclusion\n\nAt a median follow-up of 19.6 years, 17% of patients were alive and free of tumor; however, even after response for decades, an inherent risk of relapse, either systemic or cerebral, characterizes the biology of PCNSL.\n\nClassification of evidence\n\nThis work provides Class III evidence that PCNSL treatment with methotrexate-based polychemotherapy including intraventricular therapy is associated with long-term disease control in some patients.\n\nOPEN-ACCESSTRUE\nSTATUSONLINE-ONLY\n==== Body\nPrimary CNS lymphomas (PCNSLs) are highly aggressive diffuse large B-cell lymphomas with a worse prognosis than their systemic counterparts.1 In the past 2 decades, treatment developments in PCNSL focused on establishing effective radiation-free2–7 or reduced dose radiation8 protocols to avoid late cognitive decline after whole brain radiotherapy.9–13 For most of these trials, no long-term data are available. There is one study with a follow-up period of up to 23 years on 149 patients with PCNSL treated with intraarterial methotrexate after osmotic blood–brain barrier disruption (BBBD) that reported a median overall survival (OS) of 3.1 years, a 5-year OS rate of 41%, and an 8.5-year OS rate of 25%.7\n\nThe Bonn protocol was one of the first radiation-free protocols. It produced promising results that had been reported on in 2003 and 2010.14,15 In a multicenter pilot/phase II trial, 65 patients had been treated with high-dose methotrexate- and cytarabine-based systemic therapy in combination with intraventricular methotrexate, prednisolone, and Ara-C. Durable responses in a high fraction of patients were observed (median OS 54 months) without neurocognitive decline at long-term follow-up.15 For patients ≤60 years, median OS had not yet been reached after a median follow-up of 100 months with a survival rate at 100 months of 57%.15 According to these results, we concluded that the Bonn protocol might be curative for PCNSL in a fraction of patients, particularly in younger patients. We carried out this very long-term follow-up to further substantiate this assumption.\n\nMethods\n\nStudy procedures\n\nBetween September 1995 and December 2001, 65 patients had been enrolled in an multicenter pilot/phase II study evaluating a treatment protocol (Bonn protocol) including systemic and intraventricular therapy for PCNSL.14 Treatment consisted of systemic chemotherapy with 6 cycles of high-dose methotrexate (3–5 g/m2, cycles 1, 2, 4, and 5) and Ara-C (3 g/m2/d days 1–2, cycles 3 and 6) combined with vinca-alkaloids, ifosfamide, and cyclophosphamide. In addition, methotrexate, prednisolone, and Ara-C were administered via Ommaya reservoir in each cycle. The details of treatment, toxicity, and response were reported previously,14 as was data concerning favorable neurocognitive outcome for surviving patients at a median follow-up of 100 months.15\n\nCurrent information on actual survival and independence in daily living was collected by reviewing the archives of participating centers, by information received from treating general practitioners, by nonstandardized telephone interviews with patients themselves, or, if no information was available by the aforementioned methods, by a formal inquiry at the local registration office.\n\nStatistical analysis\n\nOS was calculated from the date of histologic diagnosis to death or last date of follow-up. Time to treatment failure (TTF) was defined as time from onset of treatment to disease progression or relapse, death from any cause, discontinuation of treatment because of any cause, or last date of follow-up. OS and TTF were estimated by the Kaplan-Meier method. Log-rank tests were used to compare survival between patient groups. The significance level was set at p < 0.05. A competing risk of death analysis was done comparing disease-related death and death for other reasons.\n\nStandard protocol approvals, registration, and patient consent\n\nThe ethics committees of the Faculties of Medicine of the Universities involved in treatment had approved the study. Written informed consent was obtained from all participants. The trial was conducted from 1995 to 2001 and had therefore not been registered by ClinicalTrials.gov.\n\nData availability\n\nAnonymized data can be shared by request from any qualified investigator.\n\nClassification of evidence\n\nThis work provides Class III evidence that treatment of PCNSL with methotrexate-based polychemotherapy including intraventricular therapy is efficient and is associated with long-term disease control in a fraction of patients (after a median follow-up of 19.6 years, 17% of patients were alive).\n\nResults\n\nPatient characteristics\n\nIn March 2019, a total of 65 patients was evaluated. Median age of all patients was 62 years (range 27–75 years) at first diagnosis, 30 of 65 patients were 60 years or younger, and 34 patients were male. Median Karnofsky Performance Scale score (KPS) was 70 (range 20–90). Sixteen patients (25%) had a KPS of ≤50 at first diagnosis. One of 65 patients had ocular involvement at first diagnosis. Intraventricular therapy was applied in 64 patients; 1 patient refused intraventricular treatment. Median follow-up for surviving patients was 19.6 years (range 17.5–23.3 years). One patient was lost to follow-up 21 years after first diagnosis (while reportedly alive and free of relapse). For 8 patients (12%), the cause of death was unknown.\n\nSurvival analysis\n\nMedian OS for all patients was 53 months (95% confidence interval [CI] 35–71 months), 5-year OS 43%, 10-year OS 29%, and the Kaplan-Meier survival estimate at 20 years 19%. Median OS for patients ≤60 years was 11 years (132 months, 95% CI 57–204 months), and for patients >60 years, 33 months (95% CI 19–47 months, p < 0.001; figure). For patients ≤60 years, the 5-year OS was 70%, 10-year OS 53%, and the estimated 20-year OS 39%. For patients >60 years 5-year OS was 23%, 10-year OS 9%, and the estimated 20-year OS 3%. Median TTF was 21 months (95% CI 6–36 months) for all patients. Median TTF for patients ≤60 years was 41 months (95% CI 7–75 months), and for patients >60 years, 5 months (95% CI 0–18 months, p < 0.001).\n\nFigure Overall survival according to age\n\nInitial response, response duration, and long-term survival\n\nOf the entire cohort of 65 patients, 37 showed CR, 6 partial response (PR), 12 progressive disease, and 6 early death (ED) (table 1). Four responses were not assessable after complete resection of tumor (2 patients) or treatment termination after 1 cycle according to the patient's (1 patient) or the participating center's (1 patient) decision. One patient with PR was irradiated after incomplete chemotherapy as a result of nephrotoxicity, 1 patient with PR discontinued chemotherapy and received no further treatment, and the other 4 patients with PR showed only minimal residual lymphoma on MRI after completion of treatment and no further therapy was applied (complete response unconfirmed according to current criteria16).\n\nTable 1 Whole study cohort (n = 65): initial response to treatment and characteristics of relapse\n\nExcluding patients with progressive disease and ED, in the remaining 47, a total of 36 documented first relapses occurred during follow-up (25 cerebral, 5 systemic, 1 systemic and cerebral, 5 ocular) after 5 months up to 251 months.\n\nAt follow-up in March 2019, 11 of 65 patients (17%) were still alive. Six of those never experienced a relapse. Five of 11 long-term survivors experienced first relapse (3 systemic, 1 cerebral, 1 ocular) after 7 up to 117 months and 3 patients also had second relapse (1 ocular, 2 cerebral) (table 2). Ten of 11 surviving patients were living at home at follow-up. One patient lived in a care facility after having had major cerebral ischemia. Three patients were still working. Five patients were retired but living independently at home (current age 72–80 years); 1 of these patients was the caregiver of his wife. For 2 patients, the current working status is unknown.\n\nTable 2 Course of disease of long-term survivors\n\nAll long-term survivors were 60 years or younger at first diagnosis (range 28–60 years). Seven of 11 patients were female. Eight of 11 patients had a KPS of ≤70 and 1 of 11 had a KPS of ≤50 at first diagnosis. For 9 patients, the initial lactate dehydrogenase (LDH) serum value was available and 1 had elevated LDH at first diagnosis. For 9 patients, CSF sample data were available. Four of 9 patients had elevated protein (>50 mg/dL) in CSF and 2 of 9 patients had lymphoma cells in CSF cytology. In 7 of 11 patients, deep brain structures were involved by the tumor. None of the 11 patients had ocular involvement at first diagnosis. For details on patient characteristics of long-term survivors, see also table 3.\n\nTable 3 Characteristics of long-term survivors (n = 11)\n\nLate relapses were observed in 4 patients after 9.8 (cerebral), 10.3 (systemic and cerebral), 13.3 (cerebral), and 21.0 (systemic) years (1 of these cases had already been published before17). Both patients with isolated cerebral relapses were treated with the Bonn protocol a second time, which again induced CR. The patient with systemic and cerebral relapse was treated with high-dose chemotherapy with autologous stem cell transplantation (HD-ASCT) and died from treatment-related complications (sepsis). The patient with systemic relapse after 21.0 years was treated in another hospital unaware of the PCNSL diagnosis 21 years before. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) was applied and the patient died from treatment-related complications (severe pneumonia).\n\nDiscussion\n\nThis analysis represents a very long-term follow-up of 65 patients with PCNSL, who had been treated within a pilot/phase II trial between 1995 and 2001. Results of the trial were published in 200314 and in 201015 with long-term disease control in about half of the younger patients (60 years and younger) after a median follow-up of 100 months.15 This very long-term follow-up after a median of 19.6 years for surviving patients shows that even after decades of complete response, relapses may occur. The possibility to compare our long-term data to those of other trials on chemotherapy alone,2 on chemotherapy with reduced dose radiation,8 or on HD-ASCT3–6 is limited, since these studies report on a median follow-up of 2.8–5.9 years. In our study, we observed very long-term survival in 12 patients (11 with documented follow-up and 1 lost to follow-up after 21 years when she was reportedly alive and disease free). Of the 11 patients with documented follow-up, 3 patients were still working, 5 patients were retired but living independently, 1 patient lived in a nursing facility after stroke, and for 2 patients the working status is unknown. No formal neuropsychological testing was done in this study for logistic reasons as patients were currently living in different places all over Germany. The 11 long-term survivors with documented follow-up were all 60 years or younger at first diagnosis; only the patient lost to follow-up with survival of more than 20 years was older than 60 years at diagnosis. Disregarding this single elderly patient, 6 of 11 long-term survivors never experienced relapse after a minimum of 18.2 years since first diagnosis. It is tempting to speculate that these 6 long-term survivors had actually been cured of PCNSL. However, we observed 4 late relapses after up to 21 years. This observation does not allow us to conclude that PCNSL can be considered cured after a definite time frame. Our results are in analogy to the results of a study on intraarterial methotrexate after osmotic BBBD in 149 patients, which also resulted in a small fraction of patients with long-term disease control with a follow-up period of up to 23 years (1982–2005, no range of follow-up was given). A median OS of 3.1 years was observed for all patients in this study: 5.2 years for patients <60 years of age and 2.2 years for patients ≥60 years. The 5-year OS rate was 41% and 8.5-year survival rate 25% for all patients. Patients <60 years had a 5-year OS rate of 52% and reportedly there was a plateau in the survival curve after 8.5 years. Relapses were observed also in this study after up to 9.7 years.7 These similar outcomes of 2 patient populations treated with different methotrexate-based protocols resulting in similar long-term results supports the hypothesis of an inherent risk of relapse in PCNSL due to the biology of the tumor itself rather than by the protocol applied. The question whether treatment protocols including HD-ASCT will lead to improved very long-term survival and to less risk of late relapse can only be answered when 20-year follow-up data on those trials3,5,6 will be available.\n\nWe cannot answer whether in late relapses the same B-cell clone is present as at first diagnosis, since none of our patients underwent biopsy at relapse. In a retrospective analysis on 378 patients with heterogenous first-line treatment, 10 patients relapsed after more than 5 years, with a median time to first relapse of 7.4 years (range 5.2–14.6). For 1 patient in this retrospective series, the persistence of the original PCNSL clone was histologically confirmed at cerebral relapse; for the other 2 patients for whom tissue was available, the investigation was uninformative.18 Other studies suggested that lymphoma cells in PCNSL at first diagnosis and at systemic or cerebral relapses have common precursor cells but also harbor unique somatic mutations.19,20\n\nWhile durable responses with the Bonn protocol had been achieved with an estimated 20-year survival rate of 19%, the protocol had been criticized because of an Ommaya reservoir infection rate of 19%.14 We continue to use a modified version of the Bonn protocol at our clinic and by postponement of intraventricular therapy until the beginning of the fourth treatment cycle at the start of consolidation reduced Ommaya reservoir infection rates of 9% were achieved.21\n\nStudy funding\n\nNo targeted funding reported.\n\nDisclosure\n\nDr. Seidel, Dr. Pels, Dr. Schlömer, Dr. Kowoll, Dr. Fliessbach, Dr. Engert, Dr. Vogt-Schaden, Dr. Egerer, Dr. Reichmann, and Dr. Schackert report no disclosures. Dr. Kroschinsky has received honoraria as a speaker and as an advisory board member from Roche and financial support for scientific investigations from Riemser. Dr. Deckert reports no disclosures. Dr. Herrlinger reports grants and personal fees from Roche; personal fees and nonfinancial support from Medac and Bristol-Myers Squibb; personal fees from Novocure, Janssen, Novartis, Daichii Sankyo, Riemser, Noxxon, AbbVie, and Bayer. Dr. Klockgether, Dr. Fimmers, Dr. Bode, and Dr. Schmidt-Wolf report no disclosures. Dr. Schlegel has received honoraria as a speaker from Novartis, GSK, medac, and as an advisory board member from Roche and Optune. Go to Neurology.org/N for full disclosures.\n\nAppendix Authors\n\nGlossary\n\nBBBD blood–brain barrier disruption\n\nCI confidence interval\n\nED early death\n\nHD-ASCT high-dose chemotherapy with autologous stem cell transplantation\n\nKPS Karnofsky Performance Scale\n\nLDH lactate dehydrogenase\n\nOS overall survival\n\nPCNSL primary CNS lymphoma\n\nPR partial response\n\nTTF time to treatment failure\n\nClass of Evidence: NPub.org/coe\n==== Refs\nReferences\n\n1. Grommes C , Rubenstein JL , DeAngelis LM , Ferreri AJM , Batchelor TT Comprehensive approach to diagnosis and treatment of newly diagnosed primary CNS lymphoma. Neuro Oncol 2018;21 :296–305.\n2. Rubenstein JL , His ED , Johnson JL , et al Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol 2013;31 :3061–3068.23569323\n3. Illerhaus G , Kasenda B , Ihorst G , et al High-dose chemotherapy with autologous haemopoietic stem cell transplantation for newly diagnosed primary CNS lymphoma: a prospective, single-arm, phase 2 trial. Lancet Haematol 2016;3 :e388–e397.27476790\n4. Omuro AMP , Correa DD , DeAngelis LM , et al R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood 2015;125 :1403–1410.25568347\n5. Ferreri AJM , Cwynarski K , Pulczynski E , et al Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. Lancet Haematol 2017;4 :e510–e523.29054815\n6. Houillier C , Taillandier L , Dureau S , et al Radiotherapy or autologous stem-cell transplantation for primary CNS lymphoma in patients 60 years of age and younger: results of the intergroup ANOCEF-GOELAMS randomized phase II PRECIS study. J Clin Oncol 2019;37 :823–833.30785830\n7. Angelov L , Doolittle ND , Kraemer DF , et al Blood-brain barrier disruption and intra-arterial methotrexate-based therapy for newly diagnosed primary CNS Lymphoma: a multi-institutional experience. J Clin Oncol 2009;27 :3503–3509.19451444\n8. Morris PG , Correa DD , Yahalom J , et al Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol 2013;31 :3971–3979.24101038\n9. Abrey LE , Yahalom JDL Long-term survival in primary CNS lymphoma. J Clin Oncol 1998;16 :859–863.9508166\n10. Fisher B , Seiferheld W , Schultz C , et al Secondary analysis of Radiation Therapy Oncology Group study (RTOG) 9310: an intergroup phase II combined modality treatment of primary central nervous system lymphoma. J Neurooncol 2005;74 :201–205.16193393\n11. O'Brien PC , Roos DE , Pratt G , et al Combined-modality therapy for primary central nervous system lymphoma: long-term data from a phase II multicenter study. Neuro Oncol 1999;1 :196–203.11554388\n12. Omuro AMP , Kim AK , Correa DD , et al Delayed neurotoxicity in primary central nervous system lymphoma. Arch Neurol 2005;62 :1595–1600.16216945\n13. Doolittle ND , Korfel A , Lubow MA , et al Long-term cognitive function, neuroimaging, and quality of life in primary CNS lymphoma. Neurology 2013;81 :84–92.23685932\n14. Pels H , Schmidt-Wolf IGH , Glasmacher A , et al Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 2003;21 :4489–4495.14597744\n15. Juergens A , Pels H , Rogowski S , et al Long-term survival with favorable cognitive outcome after chemotherapy in primary central nervous system lymphoma. Ann Neurol 2010;67 :182–189.20225195\n16. Küker W , Nägele T , Thiel E , Weller M , Herrlinger U Primary central nervous system lymphomas (PCNSL): MRI response criteria revised. Neurology 2005;65 :1129–1131.16217075\n17. Steinbeck JA , Stuplich M , Blasius E , et al Relapse of primary central nervous system lymphoma 13 years after high-dose methotrexate-based polychemotherapy. J Clin Neurosci 2011;18 :1554–1555.21868233\n18. Nayak L , Hedvat C , Rosenblum MK , Abrey LE , DeAngelis LM Late relapse in primary central nervous system lymphoma: clonal persistence. Neuro Oncol 2011;13 :525–529.21372070\n19. Pels H , Montesinos-Rongen M , Schaller C , et al Clonal evolution as pathogenetic mechanism in relapse of primary CNS lymphoma. Neurology 2004;63 :167–169.15249632\n20. Hattori K , Sakata-Yanagimoto M , Kusakabe M , et al Genetic evidence implies that primary and relapsed tumors arise from common precursor cells in primary central nervous system lymphoma. Cancer Sci 2019;110 :401–407.30353605\n21. Seidel S , Korfel A , Kowalski T , et al HDMTX-based induction therapy followed by consolidation with conventional systemic chemotherapy and intraventricular therapy (modified Bonn protocol) in primary CNS lymphoma: a monocentric retrospective analysis. Neurol Res Pract 2019;2 :1–9.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0028-3878",
"issue": "95(23)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D016543:Central Nervous System Neoplasms; D003561:Cytarabine; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007276:Injections, Intraventricular; D017567:Karnofsky Performance Status; D008223:Lymphoma; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D010865:Pilot Projects; D016019:Survival Analysis",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "e3138-e3144",
"pmc": null,
"pmid": "32989105",
"pubdate": "2020-12-08",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": "30353605;29054815;30785830;23569323;21372070;21868233;19451444;16216945;23685932;20225195;24101038;16217075;30418592;16193393;25568347;27476790;9508166;15249632;14597744",
"title": "Twenty-year follow-up of a pilot/phase II trial on the Bonn protocol for primary CNS lymphoma.",
"title_normalized": "twenty year follow up of a pilot phase ii trial on the bonn protocol for primary cns lymphoma"
} | [
{
"companynumb": "DE-MYLANLABS-2021M1039857",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "Psychogenic nonepileptic seizures may closely resemble epileptic seizures. Video EEG is an important tool in the diagnostic work-up to differentiate between seizures of neurological origin and nonepileptic events mimicking seizures. This article will review the case of a 30-year-old female presenting with a new onset of possible seizure activity and her stay in the epilepsy monitoring unit.",
"affiliations": "a Evokes, Inc. , Mason , Ohio.",
"authors": "Cantrell|Veronica|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/21646821.2016.1166028",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2164-6821",
"issue": "56(3)",
"journal": "The Neurodiagnostic journal",
"keywords": "Epilepsy; psychogenic nonepileptic seizures (PNES); seizure; semiology",
"medline_ta": "Neurodiagn J",
"mesh_terms": "D000328:Adult; D001526:Behavioral Symptoms; D004569:Electroencephalography; D004827:Epilepsy; D005260:Female; D006801:Humans; D012640:Seizures",
"nlm_unique_id": "101573167",
"other_id": null,
"pages": "165-177",
"pmc": null,
"pmid": "28436775",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Psychogenic Nonepileptic Seizures versus Epileptic Seizures: An Unusual Case Report.",
"title_normalized": "psychogenic nonepileptic seizures versus epileptic seizures an unusual case report"
} | [
{
"companynumb": "US-JNJFOC-20160930449",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GLIPIZIDE"
},
"drugadditional": "3",
"d... |
{
"abstract": "The addition of trastuzumab to chemotherapy regimen is the standard of care for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer; however, most patients eventually acquire trastuzumab resistance. Although some resistance mechanisms to trastuzumab-based regimens have been proposed, further understanding is required for developing therapeutic strategies to overcome the resistance. In the present work, we attempted to determine the possible resistance mechanism to trastuzumab in a patient with HER2-positive stage IV gastric adenocarcinoma. In this study, we first report the nucleotide change c.1899-1G>A at the intron 15 acceptor splice site promoting exon 16 deletion of HER2 as the potential mechanism of trastuzumab resistance in HER2-positive gastric adenocarcinoma. KEY POINTS: The combination of trastuzumab with chemotherapy is considered to be the standard therapy for HER2-positive advanced gastric cancer (GC), but most of the patients eventually acquire trastuzumab resistance. The mechanisms of resistance to trastuzumab in GC are poorly characterized. To the best of the authors' knowledge, this study is the first to implicate HER2 c.1899-1G>A, which results in exon 16 skpping, as the acquired resistance mechanism to trastuzumab in HER2-positive gastric adenocarcinoma. This work provides insights into the potential molecular mechanism of trastuzumab resistance, which is crucial in developing effective therapeutic strategies for HER2-positive GC patients refractory to trastuzumab.",
"affiliations": "Department of Medical Oncology, Changzheng Hospital, Shanghai, People's Republic of China.;Department of Medical Oncology, Changzheng Hospital, Shanghai, People's Republic of China.;Department of Medical Oncology, Changzheng Hospital, Shanghai, People's Republic of China.;Department of Internal Medicine, Qingyang People Hospital, Qingyang, Anhui, People's Republic of China.;Department of Medical Oncology, Changzheng Hospital, Shanghai, People's Republic of China.;Department of Medical Oncology, Changzheng Hospital, Shanghai, People's Republic of China.;Department of Medical Oncology, Changzheng Hospital, Shanghai, People's Republic of China.;Department of Medical Oncology, Changzheng Hospital, Shanghai, People's Republic of China.;Burning Rock Biotech, Guangzhou, People's Republic of China.;Burning Rock Biotech, Guangzhou, People's Republic of China.;Department of Medical Oncology, Changzheng Hospital, Shanghai, People's Republic of China.",
"authors": "Jiao|Xiao-Dong|XD|0000-0002-9663-8548;Liu|Ke|K|;Wu|Ying|Y|;Zhou|Xin-Cheng|XC|;Qin|Bao-Dong|BD|;Ling|Yan|Y|;Liu|Jun|J|;He|Xi|X|;Du|Haiwei|H|;Xiang|Jianxing|J|;Zang|Yuan-Sheng|YS|",
"chemical_list": "C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"country": "United States",
"delete": false,
"doi": "10.1002/onco.13799",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "26(9)",
"journal": "The oncologist",
"keywords": null,
"medline_ta": "Oncologist",
"mesh_terms": "D000230:Adenocarcinoma; D006801:Humans; D009154:Mutation; D018719:Receptor, ErbB-2; D013274:Stomach Neoplasms; D000068878:Trastuzumab",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "717-721",
"pmc": null,
"pmid": "33896090",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20728210;19671734;32727899;33214226;32050652;27578417;20721748;27641338;26693898;32208960;25838375;16077916;25164009;16601290;31557536;30837627;32469182",
"title": "HER2 Splice Site Mutation c.1899-1G>A as the Potential Acquired Resistance to Trastuzumab in a Patient with HER2-Positive Gastric Adenocarcinoma.",
"title_normalized": "her2 splice site mutation c 1899 1g a as the potential acquired resistance to trastuzumab in a patient with her2 positive gastric adenocarcinoma"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-341105",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"dru... |
{
"abstract": "This article reports on the treatment of a patient with nightmares who was treated with doxazosin of an alpha 1-adrenergic antagonists. A 71-year-old Japanese major depressive disorder (MDD) woman experienced nightmares after the coronavirus disease 2019 pandemic. She had nightmares about being chased by a coronavirus and catching the corona virus. After adding doxazosin 1 mg daily in the morning, her nightmares led to remission without side effects. We also had a rechallenge regimen with doxazosin. The nightmares ceased on the second night of the rechallenge and did not return with continued treatment. This case report suggests that doxazosin may be a useful therapeutic option to target nightmares in individuals with MDD.",
"affiliations": "Department of Psychiatry, School of Medicine, Fukuoka University, Nanakuma, Jyonan-ku, Fukuoka, Japan.",
"authors": "Hori|Hikaru|H|",
"chemical_list": "D058668:Adrenergic alpha-1 Receptor Antagonists; D017292:Doxazosin",
"country": "England",
"delete": false,
"doi": "10.1097/YIC.0000000000000364",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-1315",
"issue": "36(4)",
"journal": "International clinical psychopharmacology",
"keywords": null,
"medline_ta": "Int Clin Psychopharmacol",
"mesh_terms": "D058668:Adrenergic alpha-1 Receptor Antagonists; D000368:Aged; D000086382:COVID-19; D003865:Depressive Disorder, Major; D017292:Doxazosin; D004325:Dreams; D005260:Female; D006801:Humans; D000086402:SARS-CoV-2",
"nlm_unique_id": "8609061",
"other_id": null,
"pages": "221-223",
"pmc": null,
"pmid": "34030164",
"pubdate": "2021-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22851811;17414682;25944011;26439674;22819998;18447662;27828694;23846759;23123568;31855732;31972510;33012871;26644317;22777411;16268383;26835889",
"title": "Doxazosin improved COVID-19 associated nightmare in a patient with major depressive disorder: a case report with a positive rechallenge.",
"title_normalized": "doxazosin improved covid 19 associated nightmare in a patient with major depressive disorder a case report with a positive rechallenge"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-305958",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ESZOPICLONE"
},
"dru... |
{
"abstract": "Kounis Syndrome (KS) is the contemporary occurrence of Acute Coronary Syndromes (ACS) with an allergic or hypersensitivity reaction. This syndrome has been reported in association with a variety of drugs, food, insect stings, environmental exposures and medical conditions. Cases of KS seem to be more often encountered in everyday clinical practice than anticipated. It is believed that the lack of awareness of this association may lead to underreporting. We report a case of KS secondary to diclofenac intake.",
"affiliations": "Departamento de Anestesiologia, Hospital Pedro Hispano, Matosinhos, Portugal. Electronic address: mcatluis@hotmail.com.",
"authors": "Rodrigues|Maria Catarina Luís|MC|;Coelho|Daniela|D|;Granja|Cristina|C|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac",
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "63(5)",
"journal": "Brazilian journal of anesthesiology (Elsevier)",
"keywords": "Alergia; Anti-inflamatórios não Esteroides; COMPLICAÇÕES; DROGAS; Diclofenaco; Síndrome Coronariana Aguda",
"medline_ta": "Braz J Anesthesiol",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D004342:Drug Hypersensitivity; D006801:Humans; D008297:Male; D008875:Middle Aged; D013577:Syndrome",
"nlm_unique_id": "101624623",
"other_id": null,
"pages": "426-8",
"pmc": null,
"pmid": "24263049",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Drugs that may provoke Kounis syndrome.",
"title_normalized": "drugs that may provoke kounis syndrome"
} | [
{
"companynumb": "PT-ACTAVIS-2015-09649",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DICLOFENAC SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nDespite the frequency of oral involvement, there are unexpectedly few studies of either on the oral manifestations of pemphigus or their long-term management, and diagnostic delay in Dentistry is frequent.\n\n\nMETHODS\nWe have examined outcome of patients presenting with predominantly oral pemphigus vulgaris (PV). Ninety-eight subjects were followed up for 85.12 months and treated with systemic steroids: 48 of them received adjunctive therapy with azathioprine, 16 with rituximab, 13 with mycophenolate mofetil, three with immunoglobulin and one with dapsone.\n\n\nRESULTS\nClinical remission was achieved in 80 patients (84.21%); 39 of them were off therapy and 41 on therapy. Fifteen patients were not in remission, having been under systemic therapy for 72.16 months. Sixty-nine patients developed detectable adverse effects. Two fatal outcomes were recorded. Each additional year of steroid therapy ensured 47% chance of developing 1 or 2 side effects, and 64% chance of developing more than 3 (ORs 1.47, CI 1.162-1.903; ORs 1.64, CI 1.107-2.130, respectively).\n\n\nCONCLUSIONS\nIn one of the largest available cohort with the longest follow-up ever reported, we observed that the management remains need-based and patient-specific, still relying on systemic corticosteroids.",
"affiliations": "Department of Surgical Sciences, CIR-Dental School, University of Turin, Turin, Italy.;Department of Surgical Sciences, CIR-Dental School, University of Turin, Turin, Italy.;Department of Surgical Sciences, CIR-Dental School, University of Turin, Turin, Italy.;Dimeas, Politecnico of Turin, Turin, Italy.;Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco, Italy.;Department of Surgical Sciences, CIR-Dental School, University of Turin, Turin, Italy.;Department of Surgical Sciences, CIR-Dental School, University of Turin, Turin, Italy.;Center of Research of Immunopathology and Rare Diseases-Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.;Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco, Italy.;Center of Research of Immunopathology and Rare Diseases-Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.;Department of Oral Medicine, School of Dental Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.",
"authors": "Arduino|Paolo G|PG|https://orcid.org/0000-0002-8798-7834;Broccoletti|Roberto|R|;Carbone|Mario|M|;Gambino|Alessio|A|;Sciannameo|Veronica|V|;Conrotto|Davide|D|;Cabras|Marco|M|;Sciascia|Savino|S|;Ricceri|Fulvio|F|;Baldovino|Simone|S|;Carrozzo|Marco|M|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "Denmark",
"delete": false,
"doi": "10.1111/jop.12847",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0904-2512",
"issue": "48(5)",
"journal": "Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology",
"keywords": "oral manifestation; pemphigus vulgaris; treatment and adverse effects",
"medline_ta": "J Oral Pathol Med",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D057210:Delayed Diagnosis; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D009059:Mouth Diseases; D010392:Pemphigus; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8911934",
"other_id": null,
"pages": "406-412",
"pmc": null,
"pmid": "30860627",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term evaluation of pemphigus vulgaris: A retrospective consideration of 98 patients treated in an oral medicine unit in north-west Italy.",
"title_normalized": "long term evaluation of pemphigus vulgaris a retrospective consideration of 98 patients treated in an oral medicine unit in north west italy"
} | [
{
"companynumb": "PHHY2019IT131198",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "BACKGROUND\nPart B of the modified Magrath regimen (IVAC) +/- rituximab (R) is recommended as standalone therapy by national guidelines for management of relapsed/refractory Burkitt lymphoma, and is used in other non-Hodgkin lymphomas (NHL). Activity of IVAC in B-cell NHL, particularly with R, and its toxicity remain incompletely described.\n\n\nMETHODS\nWe reviewed patients with relapsed/refractory B-cell NHL treated with IVAC +/- R between 2004 and 2019 at Memorial Sloan Kettering Cancer Center to assess efficacy and toxicity.\n\n\nRESULTS\nAmong 54 eligible patients (median 2 prior lines of therapy), 76% had diffuse large B-cell lymphoma; 30% had central nervous system involvement at IVAC initiation. Objective response rate was 48%. At median 22-month follow-up, median progression-free and overall survival were 3.1 months and 4.9 months, respectively. Grade ≥ 3 anemia (93%), neutropenia (94%), and thrombocytopenia (100%; all grade 4) were common. Febrile neutropenia occurred in 65% and did not appear to be influenced by use of antimicrobial or granulocyte colony stimulating factor prophylaxis. Mortality was attributed to treatment in 19% of evaluable patients.\n\n\nCONCLUSIONS\nThe clinical efficacy and utility of IVAC +/- R remain unclear. However, its profound hematologic toxicity and life-threatening complications despite prophylactic measures warrant careful consideration of alternatives.",
"affiliations": "Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address: buegem@mskcc.org.;Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.",
"authors": "Buege|Michael J|MJ|;Dao|Phuong H|PH|;Drill|Esther|E|;LeVoir|Andréa|A|;Pak|Terry|T|;Peterson|Tim J|TJ|;Straus|David J|DJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2021.07.024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "21(12)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Chemotherapy; Diffuse large B-cell lymphoma; Drug toxicity; Prophylaxis; Retrospective study",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": null,
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "873-878",
"pmc": null,
"pmid": "34413005",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": "28774879;15160953;32451711;16288806;23446093;25258344;25816933;32453640",
"title": "IVAC With or Without Rituximab for Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas: Real-World Experience in the Modern Era.",
"title_normalized": "ivac with or without rituximab for relapsed or refractory b cell non hodgkin lymphomas real world experience in the modern era"
} | [
{
"companynumb": "US-ROCHE-2897917",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Patients with certain types of allergic reactions to medication may safely receive the culprit medication through an elaborate allergy procedure called a drug desensitization. Nurses play a key role in this process which is only performed when a certain medication is absolutely indicated as optimal therapy. Nurses are instrumental in the planning stages of drug desensitizations for coordination of interdisciplinary care and anticipation of adverse effects. Thus, it is paramount that nurses performing this procedure understand the mechanism of desensitizations and have access to the resources needed to safely complete these procedures in pediatric patients.\n\n\n\nExcellence in nursing clinical acumen and a detailed order set are essential to patient safety during dug desensitization. With the following methodology and coordination by nursing, we have had great success at Children's Hospital Los Angeles in over one hundred drug desensitizations in pediatric patients which allowed them to received first line therapies. We have created order sets from published references and years of clinical experience. The nursing care of adult patients undergoing drug desensitization procedures is well described in the literature but few resources exist for pediatric nurses. There is paucity of published nursing resources for pediatric drug desensitizations. Repeated PubMed searches for \"pediatric drug desensitizations\" in 2019-2020, revealed only one recent reference geared toward physicians.\n\n\n\nWith appropriate training, staffing, and coordination, drug desensitizations can be safely performed in pediatric patients with close observation by a multi-disciplinary team. The bedside nurse has a pivotal role as coordinator and clinician for these high-risk resource-intensive procedures.",
"affiliations": "Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Heath System, Los Angeles, California, USA.;Clinical Immunology and Allergy, Children's Hospital Los Angeles, Los Angeles, California, USA.;Clinical Immunology and Allergy, Children's Hospital Los Angeles, Los Angeles, California, USA.",
"authors": "Herr|Sarah|S|0000-0003-4219-9380;Ferdman|Ronald|R|0000-0001-5744-0427;Braskett|Melinda|M|0000-0002-6042-939X",
"chemical_list": "D004364:Pharmaceutical Preparations",
"country": "United States",
"delete": false,
"doi": "10.1111/jspn.12322",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1539-0136",
"issue": "26(2)",
"journal": "Journal for specialists in pediatric nursing : JSPN",
"keywords": "allergy; case study; children; clinic; documentation; drug desensitization; hospital; nursing; out-patient; pediatric",
"medline_ta": "J Spec Pediatr Nurs",
"mesh_terms": "D002648:Child; D003888:Desensitization, Immunologic; D004342:Drug Hypersensitivity; D006801:Humans; D004364:Pharmaceutical Preparations",
"nlm_unique_id": "101142025",
"other_id": null,
"pages": "e12322",
"pmc": null,
"pmid": "33378570",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safe administration of drug desensitizations in pediatric patients.",
"title_normalized": "safe administration of drug desensitizations in pediatric patients"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-305795",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FAMOTIDINE"
},
"drug... |
{
"abstract": "Internet-facilitated self-diagnosis and treatment is becoming more prevalent, putting individuals at risk of toxicity when drugs are acquired without medical oversight. We report a patient with delusional parasitosis who consumed veterinary albendazole purchased on the Internet, leading to pancytopenia, transaminase elevation, and alopecia. A 53-year-old man was sent to the emergency department (ED) by his gastroenterologist because of abnormal laboratory results. The patient had chronic abdominal pain and believed he was infected with parasites. He purchased two bottles of veterinary-grade albendazole on the Internet, and over the 3 weeks before his ED visit, he consumed 113.6 g of albendazole (a normal maximal daily dose is 800 mg). Five days before admission, he noticed hair loss and a rash on his face. His examination was notable for significant scalp hair loss and hyperpigmentation along the jaw line. Laboratory studies were remarkable for pancytopenia (most notably a white blood cell count (WBC) of 0.4 × 103 cells/mm3, with an absolute neutrophil count (ANC) of 0 × 103 cells/mm3) and transaminase elevation (aspartate aminotransferase [AST] 268 IU/L, alanine aminotransferase [ALT] 89 IU/L). He developed a fever and was treated with antibiotics and colony-stimulating factors for presumed neutropenic bacteremia. Over the course of 1 week, his hepatic function normalized and his ANC increased to 3,000 × 103 cells/mm3. Serial albendazole and albendazole sulfoxide concentrations were measured in serum and urine by liquid chromatography-quadruple time-of-flight mass spectrometry. On day 2, his serum concentrations were 20.7 ng/mL and 4,257.7 ng/mL for albendazole and albendazole sulfoxide, respectively. A typical peak therapeutic concentration for albendazole sulfoxide occuring at 2-5 hours post-ingestion is 220-1,580 ng/mL. Known adverse effects of albendazole include alopecia, transaminase elevation, and neutropenia. Pancytopenia leading to death from septic shock is reported. In our patient, prolonged use of high-dose albendazole resulted in a significant body burden of albendazole and albendazole sulfoxide, leading to pancytopenia, transaminase elevation, and alopecia. He recovered with supportive therapy.",
"affiliations": "Division of Emergency Medicine, Department of Medicine, Western University, Ontario, Canada.;New York University School of Medicine, New York, New York.;Clinical Toxicology and Environmental Biomonitoring Laboratory, University of California San Francisco, San Francisco, California.;Department of Pharmacy, New York University Langone Health, New York, New York.;Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, New York University School of Medicine, New York, New York.;Clinical Toxicology and Environmental Biomonitoring Laboratory, University of California San Francisco, San Francisco, California.;Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, New York University School of Medicine, New York, New York.",
"authors": "Riggan|Morgan A A|MAA|;Perreault|Gabriel|G|;Wen|Anita|A|;Raco|Veronica|V|;Vassallo|Susi|S|;Gerona|Roy|R|;Hoffman|Robert S|RS|",
"chemical_list": "D000871:Anthelmintics; D015766:Albendazole; C027186:albendazole sulfoxide",
"country": "United States",
"delete": false,
"doi": "10.4269/ajtmh.19-0198",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9637",
"issue": "102(1)",
"journal": "The American journal of tropical medicine and hygiene",
"keywords": null,
"medline_ta": "Am J Trop Med Hyg",
"mesh_terms": "D015766:Albendazole; D000505:Alopecia; D000871:Anthelmintics; D062787:Drug Overdose; D006801:Humans; D008297:Male; D008875:Middle Aged; D010198:Pancytopenia",
"nlm_unique_id": "0370507",
"other_id": null,
"pages": "177-179",
"pmc": null,
"pmid": "31701853",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18955802;22890344;2513680;15772324;8813106;15463313;12469331;26157077;12745134;11474247;24423162",
"title": "Case Report: Analytically Confirmed Severe Albenzadole Overdose Presenting with Alopecia and Pancytopenia.",
"title_normalized": "case report analytically confirmed severe albenzadole overdose presenting with alopecia and pancytopenia"
} | [
{
"companynumb": "CA-AMGEN-CANSP2020021263",
"fulfillexpeditecriteria": "2",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Twenty patients with stage III and IV diffuse well-differentiated lymphocytic lymphoma were treated with combination chemotherapy consisting of BCNU, cyclophosphamide, vincristine, melphalan and prednisone (M-2). Treatment was given every 5 weeks for 11 cycles in responding patients. The median age of the patients was 62 years (range 45-76). There were 12 complete remissions and 6 partial remissions for an overall response rate of 90%. The median duration of remission was 24 months (range 12-79 months) and was identical for complete responders and partial responders. All but 2 responding patients have been subsequently retreated for relapse. The median survival was 84 months (range 1-108 months). Myelosuppression was mild. Nausea/vomiting, neuropathy, alopecia and gastrointestinal symptoms from prednisone were seen in the minority of patients. One patient expired from sepsis/neutropenia during the first cycle of therapy. The M-2 protocol produces effective remissions in diffuse well-differentiated lymphocytic lymphoma. The relapse and survival pattern are similar to the results achieved with other chemotherapy regimens in low-grade lymphoma.",
"affiliations": "Department of Medicine, Maine Medical Center, Portland.",
"authors": "Case|D C|DC|;Boyd|M|M|;Hayes|D M|DM|;Dorsk|B M|BM|",
"chemical_list": "D014750:Vincristine; D003520:Cyclophosphamide; D008558:Melphalan; D002330:Carmustine; D011241:Prednisone",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000226656",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-2414",
"issue": "45(6)",
"journal": "Oncology",
"keywords": null,
"medline_ta": "Oncology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002330:Carmustine; D003520:Cyclophosphamide; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008558:Melphalan; D008875:Middle Aged; D011241:Prednisone; D014750:Vincristine",
"nlm_unique_id": "0135054",
"other_id": null,
"pages": "417-20",
"pmc": null,
"pmid": "3054672",
"pubdate": "1988",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Diffuse well-differentiated lymphocytic lymphoma: chemotherapy with BCNU, cyclophosphamide, vincristine, melphalan and prednisone.",
"title_normalized": "diffuse well differentiated lymphocytic lymphoma chemotherapy with bcnu cyclophosphamide vincristine melphalan and prednisone"
} | [
{
"companynumb": "US-PFIZER INC-2021194947",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "We present a patient with an angiosarcoma in an arteriovenous fistula and we reviewed current treatments for angiosarcomas. We extended the systematic review by Oskrochi et al. on this topic in 2015, using the same search query. We searched systematically OVID, EMBASE and PubMed from April 2015 until January 2020 with the aim to update the state of the art in managing this rare but serious condition. We retrieved 12 new case reports about 11 unique patients. Mean age was 61.5 ± 11 years. Six arteriovenous fistulas had failed spontaneously. Two fistulas were operatively closed post-transplant. Nine patients (81.8%) were receiving ongoing immunosuppressive therapy. Pain and growing lesions, mass or swelling were the most frequent symptoms. Angiosarcoma mostly presents with a nonspecific clinical picture of pain, growing lesions and swelling of a previously normal arteriovenous fistula. Amputation of the limb was most frequently conducted as treatment in localized disease. Treatment of systemic disease included supportive care, chemotherapy, especially with paclitaxel and change of immunosuppressive regimen. Metastasized angiosarcoma has a very poor prognosis. Classical chemotherapy has rather low response rates. There is limited data supporting treatment of angiosarcomas with tyrosine kinase inhibitors or immunotherapy. Further comparative research is needed.",
"affiliations": "Renal Division, Ghent University Hospital, Ghent, Belgium.;Renal Division, Ghent University Hospital, Ghent, Belgium.;Department of Thoracovascular Surgery, ASZ Aalst, Aalst, Belgium.;Renal Division, Ghent University Hospital, Ghent, Belgium.",
"authors": "Van Acker|Paulien|P|0000-0001-7915-1810;Veys|Nic|N|;Speybrouck|Sabrina|S|;Van Biesen|Wim|W|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.1111/hdi.12873",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1492-7535",
"issue": "24(4)",
"journal": "Hemodialysis international. International Symposium on Home Hemodialysis",
"keywords": "Angiosarcoma; arteriovenous fistula; case report; immunotherapy; targeted therapy",
"medline_ta": "Hemodial Int",
"mesh_terms": "D001164:Arteriovenous Fistula; D001166:Arteriovenous Shunt, Surgical; D005260:Female; D006394:Hemangiosarcoma; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011379:Prognosis",
"nlm_unique_id": "101093910",
"other_id": null,
"pages": "431-438",
"pmc": null,
"pmid": "32954648",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Angiosarcoma in an arteriovenous fistula after kidney transplantation: Case report and review of treatment options.",
"title_normalized": "angiosarcoma in an arteriovenous fistula after kidney transplantation case report and review of treatment options"
} | [
{
"companynumb": "PHHY2019GR095876",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "We herein report a 38-year-old woman with breast cancer who developed Pneumocystis jirovecii pneumonia (PCP) during neoadjuvant dose-dense chemotherapy combined with dexamethasone as antiemetic therapy. Chest computed tomography showed bilateral ground-glass opacities and consolidation. The serum β-D-glucan levels were elevated, and P. jirovecii DNA was detected from the bronchoalveolar lavage fluid by polymerase chain reaction. Her clinical findings improved with trimethoprim/sulfamethoxazole and adjunctive steroid therapy. Clinicians must be mindful of the manifestations of PCP in non-human immunodeficiency virus (HIV)-infected immunocompromised patients and include the possibility of PCP in the differential diagnosis when confronted with breast cancer on dose-dense chemotherapy showing diffuse lung disease.",
"affiliations": "Division of Respiratory Medicine, Iwata City Hospital, Japan.;Division of Respiratory Medicine, Iwata City Hospital, Japan.;Division of Respiratory Medicine, Iwata City Hospital, Japan.;Division of Respiratory Medicine, Iwata City Hospital, Japan.;Division of Respiratory Medicine, Iwata City Hospital, Japan.;Division of Respiratory Medicine, Iwata City Hospital, Japan.;Division of Respiratory Medicine, Iwata City Hospital, Japan.;Division of Respiratory Medicine, Iwata City Hospital, Japan.;Division of Respiratory Medicine, Iwata City Hospital, Japan.;Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Japan.",
"authors": "Watanabe|Hirofumi|H|;Kitahara|Yoshihiro|Y|;Murakami|Yurina|Y|;Nihashi|Fumiya|F|;Matsushima|Sayomi|S|;Eifuku|Tatsuru|T|;Uto|Tomohiro|T|;Sato|Jun|J|;Imokawa|Shiro|S|;Suda|Takafumi|T|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.3907-19",
"fulltext": "\n==== Front\nIntern Med\nIntern. Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n31839658\n10.2169/internalmedicine.3907-19\nCase Report\nPneumocystis jirovecii Pneumonia in a Patient with Breast Cancer Receiving Neoadjuvant Dose-dense Chemotherapy\nWatanabe Hirofumi 1 Kitahara Yoshihiro 1 Murakami Yurina 1 Nihashi Fumiya 1 Matsushima Sayomi 1 Eifuku Tatsuru 1 Uto Tomohiro 1 Sato Jun 1 Imokawa Shiro 1 Suda Takafumi 2 \n1 Division of Respiratory Medicine, Iwata City Hospital, Japan\n\n2 Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Japan\nCorrespondence to Dr. Hirofumi Watanabe, h-watanabe@i.shizuoka-pho.jp\n\n\n13 12 2019 \n1 4 2020 \n59 7 987 990\n7 9 2019 30 10 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/).We herein report a 38-year-old woman with breast cancer who developed Pneumocystis jirovecii pneumonia (PCP) during neoadjuvant dose-dense chemotherapy combined with dexamethasone as antiemetic therapy. Chest computed tomography showed bilateral ground-glass opacities and consolidation. The serum β-D-glucan levels were elevated, and P. jirovecii DNA was detected from the bronchoalveolar lavage fluid by polymerase chain reaction. Her clinical findings improved with trimethoprim/sulfamethoxazole and adjunctive steroid therapy. Clinicians must be mindful of the manifestations of PCP in non-human immunodeficiency virus (HIV)-infected immunocompromised patients and include the possibility of PCP in the differential diagnosis when confronted with breast cancer on dose-dense chemotherapy showing diffuse lung disease. \n\nchest CTdexamethasoneβ-D-glucanbronchoalveolar lavagedrug-induced pneumonitis\n==== Body\nIntroduction\n\nPneumocystis jirovecii pneumonia (PCP) is a potentially life-threatening fungal infection in immunocompromised individuals (1). Recently, its incidence has been increasing in patients not infected with human immunodeficiency virus (HIV). The typical chest computed tomography (CT) findings of PCP are symmetric, upper lobe-predominant ground-glass opacities with peripheral sparing (2,3); however, other less common manifestations are more frequently seen in non-HIV-infected patients, such as consolidation, architectural distortion, and nodules (2,3). These CT findings are non-specific, and differential diagnoses may include drug-induced pneumonitis, underlying disease involving the lungs, pulmonary haemorrhaging, or other opportunistic infections.\n\nWe herein report a case of PCP in a patient undergoing neoadjuvant dose-dense adriamycin/cyclophosphamide (AC) chemotherapy for breast cancer whose clinical findings resembled those of drug-induced pneumonitis.\n\nCase Report\nA 38-year-old woman was admitted to our hospital because of a 3-day history of a fever and dyspnoea. She had been previously diagnosed with stage IIB breast cancer. She had been treated with a neoadjuvant dose-dense regimen of chemotherapy consisting of dexamethasone 12 mg, adriamycin 60 mg/m2, and cyclophosphamide 600 mg/m2 on day 1, pegfilgrastim on day 2, and dexamethasone 4 mg on days 2-4. The cycle repeated every two weeks. She received 4 courses of treatment, and the total doses of dexamethasone was 96 mg. After the treatment, she received docetaxel (70 mg/m2 every 3 weeks), which had been initiated 7 days prior to her presentation at the hospital - the patient reported that the low-grade fever and dyspnoea on exertion had begun 4 days after the start of docetaxel.\n\nThe patient was a never-smoker. At presentation, she appeared ill, and her vital signs were as follows: body temperature 37.8℃, blood pressure 99/66 mmHg, heart rate 110 beats/min, respiratory rate 20 breaths/min, and O2 saturation (SpO2) 90% in room air. Fine crackles were audible on both of her lungs. Laboratory examinations showed the following: partial pressure of oxygen (PaO2) 57.8 torr on room air, white blood cell count 27,500 cells/mm3 (80.0% neutrophils, 2.0% lymphocytes), and C-reactive protein (CRP) 13.8 mg/dL. Krebs von den Lungen (KL)-6 and brain natriuretic peptide levels were within the normal range (402 U/mL and <5.8 pg/mL, respectively). The serum β-D-glucan level was found to be slightly elevated (48.5 pg/mL) on the second hospital day. HIV antibody was negative, as were serum Candida, Aspergillus, and cytomegalovirus antigens.\n\nChest X-ray showed bilateral diffuse infiltration, and chest CT revealed bilateral ground-glass opacities and airspace consolidation (Fig. 1a, 2). On the first hospital day, bronchoalveolar lavage (BAL) was performed. An analysis of the BAL fluid (BALF) revealed a total cell count of 2.75×105/mL (lymphocytes 41.7%, neutrophils 16.0%, eosinophils 0.3%) with no malignant cells or pathogenic organisms detected.\n\nFigure 1. (a) Chest X-ray findings on admission, showing bilateral diffuse infiltration predominantly in the lower lobes. (b) Chest X-ray findings after treatment with methylprednisolone (1,000 mg per day for 3 days), showing marked resolution of infiltration shadows. (c) Chest X-ray findings 4 days after switching to oral prednisolone, showing slightly worsening infiltration in the right lower lobes.\n\nFigure 2. Chest computed tomography images on admission, showing bilateral diffuse ground-glass opacities and consolidation with transverse parenchymal bands, which cross the broncho-vascular bundle.\n\nBased on these findings, the patient received systemic corticosteroid therapy with intravenous methylprednisolone (1,000 mg/day for 3 days) followed by oral prednisolone at 0.5 mg/kg/day (25 mg/day) under a presumptive diagnosis of drug-induced pneumonitis. After methylprednisolone was started, her symptoms, SpO2, and chest X-ray findings improved (Fig. 1b), and her CRP decreased to 2.56 mg/dL. However, on day 4 of oral prednisolone, she again developed a fever up to 39.3℃. At this time, her CRP level was elevated (6.32 mg/dL), and the chest X-ray findings were slightly worse than before (Fig. 1c). The serum β-D-glucan level was 47.5 pg/mL. SpO2 was reduced from 98% to 95% on room air. On day 7 of her admission, polymerase chain reaction (PCR) of her earlier BALF specimen was positive for P. jirovecii DNA. Lymphocyte stimulation tests (LSTs) with peripheral blood for docetaxel, adriamycin, and cyclophosphamide and with BALF for docetaxel were all negative. Based on these new findings, we diagnosed her with PCP and prescribed trimethoprim /sulfamethoxazole (TMP/SMX, 15 mg/kg/day).\n\nThe steroid dose was increased to 60 mg/day because of her respiratory failure on admission. Treatment with TMP/SMX continued for 12 days, during which the patient's clinical symptoms and chest CT findings improved (Fig. 3) and the serum β-D-glucan level decreased to 8.96 pg/mL. Prednisolone was gradually tapered off over two months. Because of adverse events with TMP/SMX, PCP prophylaxis was initiated with atovaquone and continued until prednisolone cessation. After treatment of PCP, total mastectomy for breast cancer was performed.\n\nFigure 3. Chest computed tomography findings after treatment with trimethoprim/sulfamethoxazole and a steroid, showing the marked resolution of ground-glass opacities and consolidation.\n\nDiscussion\nA definite diagnosis of PCP can be difficult in non-HIV-infected patients. P. jirovecii does not grow in vitro; therefore, the definite diagnosis of PCP generally relies on the visualization of cysts or trophic forms in respiratory samples by microscopy, using various stains and immunofluorescence methods (1,4); however, a microscopy-based diagnosis is difficult in non-HIV-infected patients (1,4), in whom the fungal burden is low (5). PCR can detect very low levels of Pneumocystis DNA, but it cannot distinguish PCP from asymptomatic Pneumocystis colonization (4). β-D-glucan is derived from the cell wall of several fungi, including P. jirovecii, and has been reported to be useful in the diagnosis of PCP (4,6). In our case, PCR of the BALF was positive for P. jirovecii, and serum β-D-glucan levels were elevated. Furthermore, the patient's clinical symptoms and laboratory and imaging findings improved following treatment with TMP/SMX and adjunctive steroid therapy. These clinical findings and outcomes are consistent with PCP and support our diagnosis of PCP.\n\nNon-HIV-infected immunocompromised patients are at risk for the development of PCP, but estimated incidence rates of PCP have been reported to be low in solid tumours, including breast cancer (7). However, the use of corticosteroids in chemotherapy regimens has been consistently reported as a major risk factor (8). Recently, there have been isolated reports of PCP in patients on dose-dense AC chemotherapy for early breast cancer (9-11). In the dose-dense AC regimen, these agents are administered on an every-two-weeks schedule, while in the standard AC regimen, they are administered on an every-three-weeks schedule. The authors speculated that the dose-dense regimen and dose/time threshold anti-emetic corticosteroids contributed to the development of PCP in their patients (9-11). The majority of patients received 4 cycles of this regimen, and the median time from the start of chemotherapy to the PCP diagnosis was 64 days. The average dose of corticosteroids was 16 mg prednisone equivalent/day over the course of their approximately 56-day-long AC chemotherapy course (9). Our patient had also received 4 courses of this regimen with 11 mg prednisolone equivalent/day prior to the diagnosis of PCP. The time from the start of chemotherapy to the diagnosis of PCP was 65 days, which was similar to the median time previously reported (9-11). Because this infection was not observed in patients receiving a standard cumulative steroid dose over 12 weeks in a non-dose-dense AC regimen, as Waks mentioned (9), we speculate that the anti-emetic steroid dose/time threshold in the dose-dense AC regimen was linked to the development of PCP in our case.\n\nP. jirovecii interacts with lung epithelial cells and immune cells in the lower respiratory tract, resulting in inflammation and causing significant respiratory impairment (1). Corticosteroids exert an anti-inflammatory effect, and there are some reports that, in combination with specific anti-Pneumocystis therapy, adjunctive corticosteroid therapy may reduce the morbidity and mortality in non-HIV-infected as well as in HIV-infected patients with PCP (12-14). Although only temporarily, our patient's symptoms and chest X-ray findings improved with steroid treatment before the start of TMP/SMX, likely because of its anti-inflammatory effect. Notably, in our patient, the chest CT findings showed consolidations superimposed on ground-glass opacities, which resembled those of drug-induced pneumonitis (15). As mentioned above, β-D-glucan has been reported to be useful in the diagnosis of PCP, but a uniformly accepted cut-off value has yet to be determined. Based on these findings, as a presumptive diagnosis, we suspected drug-induced pneumonitis over PCP on admission. Furthermore, after the diagnosis of PCP, the steroid dose was increased to 60 mg/day in addition to treatment with TMP/SMX because she had respiratory failure on admission. It is therefore difficult to completely rule out the contribution of drug-induced pneumonitis due to docetaxel, cyclophosphamide, or adriamycin.\n\nA variety of predisposing conditions and drug therapies have been implicated in the development of PCP in non-HIV-infected patients. Accordingly, the risk assessment for PCP may be more complex than was previously thought. Clinicians should be aware that dose-dense AC treatment for breast cancer carries a risk of PCP. Further investigations are needed to clarify whether or not reducing corticosteroids used as anti-emetic medication with chemotherapy and providing concomitant PCP prophylaxis helps reduce the risk for this infection-associated complication.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nWe thank Eleanor Scharf, MSc(A) for editing a draft of this manuscript.\n==== Refs\n1. \nThomas CF Jr, Limper AH \nPneumocystis pneumonia\n. N Engl J Med \n350 : 2487 -2498\n, 2004 .15190141 \n2. \nTasaka S , Tokuda H , Sakai F , et al \nComparison of clinical and radiological features of pneumocystis pneumonia between malignancy cases and acquired immunodeficiency syndrome cases: a multicenter study\n. Intern Med \n49 : 273 -281\n, 2010 .20154431 \n3. \nKanne JP , Yandow DR , Meyer CA \nPneumocystis jiroveci pneumonia: high-resolution CT findings in patients with and without HIV infection\n. AJR Am J Roentgenol \n198 : 555 -561\n, 2012 .\n4. \nSalzer HJF , Schäfer G , Hoenigl M , et al \nClinical, diagnostic, and treatment disparities between HIV-infected and non-HIV-infected immunocompromised patients with Pneumocystis jirovecii pneumonia\n. Respiration \n96 : 52 -65\n, 2018 .29635251 \n5. \nLimper AH , Offord KP , Smith TF , Martin II WJ \nPneumocystis carinii pneumonia. Differences in lung parasite number and inflammation in patients with and without AIDS\n. Am Rev Respir Dis \n140 : 1204 -1209\n, 1989 .2817582 \n6. \nTasaka S , Hasegawa N , Kobayashi S , et al \nSerum indicators for the diagnosis of pneumocystis pneumonia\n. Chest \n131 : 1173 -1180\n, 2007 .17426225 \n7. \nFillatre P , Decaux O , Jouneau S , et al \nIncidence of Pneumocystis jiroveci pneumonia among groups at risk in HIV-negative patients\n. Am J Med \n127 : 1242.e11 -1242.e17\n, 2014 .\n8. \nYale SH , Limper AH \nPneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated Illnesses and prior corticosteroid therapy\n. Mayo Clin Proc \n71 : 5 -13\n, 1996 .8538233 \n9. \nWaks AG , Tolaney SM , Galar A , et al \nPneumocystis jiroveci pneumonia (PCP) in patients receiving neoadjuvant and adjuvant anthracycline-based chemotherapy for breast cancer: incidence and risk factors\n. Breast Cancer Res Treat \n154 : 359 -367\n, 2015 .26420402 \n10. \nTolaney SM , Partridge AH , Sheib RG , Burstein HJ , Winer EP \nPneumocystis carinii pneumonia during dose-dense chemotherapy for breast cancer\n. J Clin Oncol \n24 : 5330 -5331\n, 2006 .17114668 \n11. \nKhoo C , Gilchrist J , Williamson JP , Paul M , Kefford R \nPneumocystis jirovecii in a patient on dose-dense chemotherapy for early breast cancer\n. Respirol Case Rep \n7 : e00459 , 2019 .31312456 \n12. \nInoue N , Fushimi K \nAdjunctive corticosteroids decreased the risk of mortality of non-HIV pneumocystis pneumonia\n. Int J Infect Dis \n79 : 109 -115\n, 2019 .30529109 \n13. \nPareja JG , Garland R , Koziel H \nUse of adjunctive corticosteroids in severe adult non-HIV Pneumocystis carinii pneumonia\n. Chest \n113 : 1215 -1224\n, 1998 .9596297 \n14. \nNational Institutes of Health-University of California Expert Panel for Corticosteroids as Adjunctive Therapy for Pneumocystis Pneumonia .\nConsensus statement on the use of corticosteroids as adjunctive therapy for pneumocystis pneumonia in the acquired immunodeficiency syndrome\n. N Engl J Med \n323 : 1500 -1504\n, 1990 .2136587 \n15. \nRossi SE , Erasmus JJ , McAdams HP , Sporn TA , Goodman PC \nPulmonary drug toxicity: radiologic and pathologic manifestations\n. Radiographics \n20 : 1245 -1259\n, 2000 .10992015\n\n",
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"keywords": "bronchoalveolar lavage; chest CT; dexamethasone; drug-induced pneumonitis; β-D-glucan",
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"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D020360:Neoadjuvant Therapy; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D016896:Treatment Outcome",
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"title": "Pneumocystis jirovecii Pneumonia in a Patient with Breast Cancer Receiving Neoadjuvant Dose-dense Chemotherapy.",
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"abstract": "Remdesivir has seen extensive use during the coronavirus disease-2019 pandemic given its clinically proven efficacy against severe acute respiratory syndrome coronavirus type 2. There has been little cited regarding adverse effects. Here we present the case of a patient with marked sinus bradycardia that began acutely on initiation of remdesivir and resolved almost immediately on cessation of the drug. (Level of Difficulty: Beginner.).",
"affiliations": "Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey.;Department of Cardiology, Rutgers New Jersey Medical School, Newark, New Jersey.;Department of Cardiology, Rutgers New Jersey Medical School, Newark, New Jersey.;Department of Infectious Disease, Rutgers New Jersey Medical School, Newark, New Jersey.;Department of Infectious Disease, Rutgers New Jersey Medical School, Newark, New Jersey.;Department of Medicine-Pediatrics, Rutgers New Jersey Medical School, Newark, New Jersey.;Department of Medicine-Pediatrics, Rutgers New Jersey Medical School, Newark, New Jersey.;Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey.",
"authors": "Gubitosa|James C|JC|;Kakar|Parul|P|;Gerula|Christine|C|;Nossa|Hernando|H|;Finkel|Diana|D|;Wong|Kristin|K|;Khatri|Megna|M|;Ali|Hasan|H|",
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"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(20)31100-1\n10.1016/j.jaccas.2020.08.025\nCase Report\nClinical Case\nMarked Sinus Bradycardia Associated With Remdesivir in COVID-19\nA Case and Literature Review\nGubitosa James C. DO james.gubitosa@gmail.com\njg838@njms.rutgers.edu\n@dr_gubi\na∗\nKakar Parul MD b\nGerula Christine MD b\nNossa Hernando MD c\nFinkel Diana MD c\nWong Kristin MD d\nKhatri Megna MD d\nAli Hasan DO a\na Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey\nb Department of Cardiology, Rutgers New Jersey Medical School, Newark, New Jersey\nc Department of Infectious Disease, Rutgers New Jersey Medical School, Newark, New Jersey\nd Department of Medicine-Pediatrics, Rutgers New Jersey Medical School, Newark, New Jersey\n∗ Address for correspondence: Dr. James C. Gubitosa, Department of Medicine, Rutgers New Jersey Medical School, 185 S. Orange Avenue, Newark, New Jersey 07103. james.gubitosa@gmail.comjg838@njms.rutgers.edu@dr_gubi\n28 10 2020\n18 11 2020\n28 10 2020\n2 14 22602264\n5 8 2020\n11 8 2020\n14 8 2020\n© 2020 The Authors\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nRemdesivir has seen extensive use during the coronavirus disease-2019 pandemic given its clinically proven efficacy against severe acute respiratory syndrome coronavirus type 2. There has been little cited regarding adverse effects. Here we present the case of a patient with marked sinus bradycardia that began acutely on initiation of remdesivir and resolved almost immediately on cessation of the drug. (Level of Difficulty: Beginner.)\n\nGraphical abstract\n\nKey Words\n\nbradycardia\ncancer\ncardiovascular disease\nchest pain\nelectrocardiogram\nelectrophysiology\nlethargy\nphysical examination\nshortness of breath\nAbbreviations and Acronyms\n\nAV, atrioventricular\nCOVID-19, coronavirus disease-2019\nECG, electrocardiogram\nh-mtRNAP, human mitochondrial RNA polymerase\nLBBB, left bundle branch block\n==== Body\nHistory of Presentation\n\nA 54-year-old woman with a medical history notable for left bundle branch block (LBBB) of unknown origin, hypertension, and B-cell lymphoma being treated with lenalidomide and rituximab presented with a 3-week duration of worsening shortness of breath, fevers, and chills. On presentation she was febrile to 102.7°F, with other vital signs remaining within normal limits and oxygen saturations maintained at 95% on room air. Physical examination demonstrated bilateral diffuse expiratory wheezing.Learning Objectives\n\n• To be aware of a possible rare adverse effect of remdesivir.\n\n• To understand the importance of assessing for ECG changes in patients with COVID-19.\n\n• To be vigilant for cardiac complications of COVID-19 (and its therapy) in patients with underlying cardiovascular disease.\n\nPast Medical History\n\nHer past medical history included LBBB, hypertension, and B-cell lymphoma.\n\nInvestigations\n\nLaboratory test results were significant for the following: lymphopenia; ferritin, 1,125 ng/ml; lactate dehydrogenase, 324 U/l; aspartate transaminase, 58 U/l; and alanine transaminase, 58 U/l. The chest radiograph demonstrated new bilateral pulmonary infiltrates superimposed on pre-existing pulmonary nodules from her B-cell lymphoma. Computed tomography of the chest with contrast enhancement was performed to rule out pulmonary embolism. The scan demonstrated new ground-glass opacities present in addition to advanced lung infiltration from B-cell lymphoma. The electrocardiogram (ECG) demonstrated mild QRS complex widening from baseline (168 ms from 150 ms) (Figure 1). She was subsequently found to be positive for coronavirus disease-2019 (COVID-19) by real-time polymerase chain reaction. The patient’s last cycle of rituximab was several weeks before admission, and lenalidomide was held on the day of her admission.Figure 1 Admission Electrocardiogram Before, Remdesivir Administration, Demonstrates Normal Sinus Rhythm and Chronic Left Bundle Branch Block\n\nManagement\n\nOxygen delivered through a nasal cannula at 2 l/min resolved the patient’s sensation of dyspnea. Remdesivir was started on day 2 of her hospitalization, starting with a loading dose of 200 mg and proceeding with 100 mg daily for 5 additional days. Within 24 h, the patient was noted to be in sinus bradycardia to 38 beats/min on telemetry monitoring (baseline heart rate 60 to 70 beats/min). Other vital signs remained normal. Cardiac enzyme test results were negative. Her medications were monitored, and no known pro-bradycardic, arrhythmogenic, or cardiotoxic agents were identified. Her bradycardia was attributed to COVID-19 at the time. The patient also exhibited chronotropic responsiveness, and the decision was made to monitor the patient cautiously. In the following 2 days, her sinus bradycardia persisted, with her heart rate decreasing to 34 beats/min. She began to complain of dizziness and progressive, persistent crushing chest pressure accompanied by associated shortness of breath. Blood pressure had decreased, and she was now hypotensive. Cardiac enzyme test results remained negative. Subsequent ECG demonstrated sinus bradycardia and QRS complex widening to 170 ms (Figure 2). The decision was made to discontinue remdesivir and administer atropine at the bedside. Over the following days, the patient’s heart rate returned to her baseline of 60 to 70 beats/min, and her QRS complex decreased to 168 ms (Figure 3). Chest pressure and dizziness rapidly resolved as well.Figure 2 Electrocardiogram During Remdesivir Treatment Demonstrates Sinus Bradycardia, Chronic Left Bundle Branch Block, Worsening QRS Complex Widening, and QTc Interval Prolongation\n\nFigure 3 Electrocardiogram After Withdrawal of Remdesivir Demonstrates Normal Sinus Rhythm and Chronic Left Bundle Branch Block, With Resolution of QRS Complex Widening and QTc Interval Prolongation\n\nDiscussion\n\nRemdesivir is a nucleoside analogue prodrug. Its triphosphorylated form resembles adenosine triphosphate, and it is used as a substrate of several viral RNA-dependent RNA polymerases, which it then subsequently inhibits. It demonstrates in vivo and in vitro activity against nonsegmented negative-sense RNA viruses, including the Filoviridae, Paramyxoviridae, Pneumoviridae, and Coronaviridae (Middle East respiratory syndrome coronavirus, severe acute respiratory syndrome coronavirus, severe acute respiratory syndrome coronavirus type 2) families (1). In vitro, remdesivir is a substrate of cytochrome P 450 (CYP) 2C8, CYP2D6, and CYP3A4, as well as organic anion transporting polypeptide 1B1 (OATP1B1) and P-glycoprotein (P-gp) transporters. It inhibits CYP3A4, OATP1B1, OATP1B3, bile salt export pump (BSEP), multidrug resistance protein 4 (MRP4), and sodium and taurocholate cotransporting polypeptide (NTCP). Inactive ingredients within the remdesivir injection include sulfobutylether-β-cyclodextrin sodium salt (SBECD) and water and may include hydrochloric acid and/or sodium hydroxide for pH adjustment (2).\n\nDespite the emergent and widespread use of remdesivir during the COVID-19 pandemic, little information exists regarding the drug’s cardiac side effects. During the Ebola pandemic of 2016, a randomized controlled trial of various antiviral agents including remdesivir was performed on 673 subjects. One incident of hypotension and cardiac arrest that occurred during transfusion of the loading dose of remdesivir was recorded (3). In the initial compassionate use trial of remdesivir in COVID-19 (n = 53), hypertension developed in 8 patients, and atrial fibrillation developed in 6 patients. This study was limited in that it did not have a control group (4). A subsequent randomized controlled trial of 233 patients cited 1 patient with cardiac arrest during remdesivir therapy and none noted in the placebo group (5). The ACTT-1 (Adaptive COVID-19 Treatment Trial) demonstrated a 1.1% incidence of cardiac arrest in the experimental group compared with 1.0% in the control group, as well as a 4% incidence of serious atrial fibrillation (2% control) (6).\n\nDespite the rare incidence of cardiac side effects of remdesivir, a possible mechanism exists on review of existing literature. The inherent safety and efficacy of remdesivir, like that many other antiviral nucleotide analogues, partly depend on its affinity for viral RNA polymerase compared with human mitochondrial RNA polymerase (h-mtRNAP). In studies performed during the Ebola pandemic, remdesivir was found to have an affinity for viral polymerases >500 times that of h-mtRNAP (7). Although this affinity for viral RNA polymerase over h-mtRNAP is significant, the possibility of h-mtRNAP involvement and subsequent mitochondrial dysfunction is still plausible, with drug-induced mitochondrial dysfunction from other agents being a well-known cause of observed cardiotoxicity (8).\n\nIt is known that the endogenous nucleoside adenosine has intrinsic electrophysiological properties, given its use as an antiarrhythmic drug. Specifically, adenosine is most commonly used in atrioventricular (AV) nodal inhibition in the setting of supraventricular tachycardias and works by binding to the A1 receptor on cardiac cells, thereby causing a cascade of changes that blocks AV nodal conduction (9). Given remdesivir’s status as a nucleoside analogue that resembles adenosine triphosphate, investigation into expression of similar effects on the AV node may be warranted. A theoretical partial affinity for the A1 receptor may explain the transient QRS complex prolongation observed in our patient. The other components of the remdesivir injection (SBECD, water, and small amounts of hydrochloric acid or sodium hydroxide) are not known to cause clinically evident cardiac dysfunction.\n\nDuring her hospitalization, our patient was not given any other medications known to cause cardiac dysfunction. She did have some underlying form of cardiovascular disease in the form of a chronic LBBB of unknown origin, however. An echocardiogram performed 2 years earlier demonstrated an ejection fraction of 64% with no other significant abnormality. A nuclear stress test the following year demonstrated a fixed defect in the anteroseptal segments that was thought to be the result of overlying breast tissue, otherwise without abnormality.\n\nFollow-Up\n\nThe patient had an unremarkable hospital course after discontinuation of the remdesivir and was discharged home with outpatient follow up. In clinic a month after discharge, it was confirmed that her bradycardia, chest pain, and dizziness had not returned.\n\nConclusions\n\nAlthough the data from remdesivir’s initial use indicate a clear clinical benefit for most patients, little information exists on the drug’s potential side effects, specifically those effects on the cardiovascular system. The presence of bradycardia in our patient that began briskly with the administration of remdesivir and subsided immediately after its discontinuation raises significant suspicion that remdesivir was the causative factor. Further surveillance and research are needed to assess for possible mechanisms of cardiotoxicity in the general population, as well as in patients with underlying cardiovascular disease. It is our hope that these data will increase the overall safety and efficacy of remdesivir, to the global benefit of all who receive it.\n\nAuthor Disclosures\n\nThe authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Case Reportsauthor instructions page.\n==== Refs\nReferences\n\n1 Gordon C.J. Tchesnokov E.P. Woolner E. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency J Biol Chem 295 2020 6785 6797 32284326\n2 Gilead Sciences Remdesivir [package insert] 2020 U.S. Food and Drug Administration\n3 Mulangu S. Dodd L.E. Davey R.T. A randomized, controlled trial of Ebola virus disease therapeutics N Engl J Med 381 2019 2293 2303 31774950\n4 Grein J. Ohmagari N. Shin D. Compassionate use of remdesivir for patients with severe Covid-19 N Engl J Med 382 2020 2327 2336 32275812\n5 Wang Y. Zhang D. Du G. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial Lancet 395 2020 1569 1578 32423584\n6 Beigel J.H. Tomashek K.M. Dodd L.E. Remdesivir for the treatment of Covid-19 — preliminary report N Engl J Med 383 2020 994 32649078\n7 Tchesnokov E.P. Feng J.Y. Porter D.P. Götte M. Mechanism of inhibition of Ebola virus RNA-dependent RNA polymerase by remdesivir Viruses 11 2019 326\n8 Varga Z.V. Ferdinandy P. Liaudet L. Pacher P. Drug-induced mitochondrial dysfunction and cardiotoxicity Am J Physiol Heart Circ Physiol 309 2015 H1453 H1467 26386112\n9 Zipes D.P. Libby P. Bonow R.O. Mann D.L. Tomaselli G.F. Braunwald E. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine 11th edition 2018 Elsevier/Saunders Philadelphia, PA\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "2(14)",
"journal": "JACC. Case reports",
"keywords": "AV, atrioventricular; COVID-19, coronavirus disease-2019; ECG, electrocardiogram; LBBB, left bundle branch block; bradycardia; cancer; cardiovascular disease; chest pain; electrocardiogram; electrophysiology; h-mtRNAP, human mitochondrial RNA polymerase; lethargy; physical examination; shortness of breath",
"medline_ta": "JACC Case Rep",
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"pubdate": "2020-11-18",
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"title": "Marked Sinus Bradycardia Associated With Remdesivir in COVID-19: A Case and Literature Review.",
"title_normalized": "marked sinus bradycardia associated with remdesivir in covid 19 a case and literature review"
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"abstract": "Gastrointestinal stromal tumours (GISTs) are the most common digestive mesenchymal tumours, whose prognosis has been revolutionised by targeted therapies such as oral imatinib. Abdomen compartment syndrome (ACS) is associated with mortality superior to 50% in adults. ACS has never been reported to date in patients with GIST. Specific anticancer treatment in critically ill patients in intensive care unit (ICU) remains a matter of debate given the high mortality rate. Here, we report the case of a 58-year-old woman with ACS related to a 40-cm huge GIST and multi-organ failure requiring mechanical ventilation, vasopressive support and haemodialysis. She was treated in emergency with imatinib via the naso-gastric tube (day 1), then at day 3 by decompressive laparotomy and \"open abdomen\" without any tumour removal. Imaging after 11 days imatinib showed objective tumour response. Because of improvement of multi-organ dysfunctions, the laparotomy was closed at day 14, and the resuscitation procedures were progressively stopped. After discharge from hospital, she survived nearly two years. This is the first case of successful treatment of cancer-associated ACS by targeted therapy and decompressive laparotomy. Imatinib in critically ill patients with GIST may be successful even in presence of multi-organ failure.",
"affiliations": "Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, CNRS UMR725, Institut Paoli-Calmettes, Marseille, France.;Department of Surgery, Institut Paoli-Calmettes, Marseille, France.;Department of Pathology, Institut Paoli-Calmettes, Marseille, France.;Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, CNRS UMR725, Institut Paoli-Calmettes, Marseille, France.;Unit of Intensive Care, Institut Paoli-Calmettes, Marseille, France.;Unit of Intensive Care, Institut Paoli-Calmettes, Marseille, France.;Unit of Intensive Care, Institut Paoli-Calmettes, Marseille, France.;Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, CNRS UMR725, Institut Paoli-Calmettes, Marseille, France.;Department of Radiology, Institut Paoli-Calmettes, Marseille, France.;Unit of Intensive Care, Institut Paoli-Calmettes, Marseille, France.;Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, CNRS UMR725, Institut Paoli-Calmettes, Marseille, France.",
"authors": "Bertucci|Alexandre|A|;Guiramand|Jérôme|J|;Mescam|Lena|L|;Monneur|Audrey|A|;Bisbal|Magali|M|;Chow-Chine|Laurent|L|;Sannini|Antoine|A|;Perrot|Delphine|D|;De Luca|Valéria|V|;Mokart|Djamel|D|;Bertucci|François|F|",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000502338cro-0012-0644Case ReportSuccessful Imatinib Treatment of an Abdominal Compartment Syndrome due to Huge Gastrointestinal Stromal Tumour Bertucci Alexandre aGuiramand Jérôme bMescam Lena cMonneur Audrey aBisbal Magali dChow-Chine Laurent dSannini Antoine dPerrot Delphine aDe Luca Valéria eMokart Djamel dBertucci François a*aDepartment of Medical Oncology, Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, CNRS UMR725, Institut Paoli-Calmettes, Marseille, FrancebDepartment of Surgery, Institut Paoli-Calmettes, Marseille, FrancecDepartment of Pathology, Institut Paoli-Calmettes, Marseille, FrancedUnit of Intensive Care, Institut Paoli-Calmettes, Marseille, FranceeDepartment of Radiology, Institut Paoli-Calmettes, Marseille, France*Professor François Bertucci, Department of Medical Oncology, Institut Paoli-Calmettes, 232 Bd de Sainte-Marguerite, FR–13009 Marseille (France), E-Mail bertuccif@ipc.unicancer.frMay-Aug 2019 13 8 2019 13 8 2019 12 2 644 649 23 7 2019 23 7 2019 2019 Copyright © 2019 by S. Karger AG, Basel2019This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Gastrointestinal stromal tumours (GISTs) are the most common digestive mesenchymal tumours, whose prognosis has been revolutionised by targeted therapies such as oral imatinib. Abdomen compartment syndrome (ACS) is associated with mortality superior to 50% in adults. ACS has never been reported to date in patients with GIST. Specific anticancer treatment in critically ill patients in intensive care unit (ICU) remains a matter of debate given the high mortality rate. Here, we report the case of a 58-year-old woman with ACS related to a 40-cm huge GIST and multi-organ failure requiring mechanical ventilation, vasopressive support and haemodialysis. She was treated in emergency with imatinib via the naso-gastric tube (day 1), then at day 3 by decompressive laparotomy and “open abdomen” without any tumour removal. Imaging after 11 days imatinib showed objective tumour response. Because of improvement of multi-organ dysfunctions, the laparotomy was closed at day 14, and the resuscitation procedures were progressively stopped. After discharge from hospital, she survived nearly two years. This is the first case of successful treatment of cancer-associated ACS by targeted therapy and decompressive laparotomy. Imatinib in critically ill patients with GIST may be successful even in presence of multi-organ failure.\n\nKeywords\nAbdominal compartment syndromeGISTImatinibIntensive care\n==== Body\nIntroduction\nAbdominal compartment syndrome (ACS) is defined by systemic dysfunction associated with sustained increased intra-abdominal pressure (IAP) more than 20 mm Hg [1]. Mortality is higher than 90% without treatment and early detection is crucial for obtaining the best therapeutic results. Primary and secondary ACSs are triggered by a condition located in and out of the abdomino-pelvic cavity respectively. The main consequences of ACS include hemodynamic, respiratory and renal dysfunctions. When ACS is due to intra-abdominal tumor, the only effective treatment is abdominal decompression with surgical resection. However, the prognosis is very poor and ∼50% of adult patients die in acute phase [2].\n\nGastrointestinal stromal tumors (GISTs) are the most common digestive mesenchymal tumours [3]. They mainly develop in stomach (60%) and jejunum/ileum (30%), but can occur anywhere along the gastrointestinal tract and peritoneum. The most frequent metastatic sites are liver and peritoneum. GISTs are characterised by activating gain-of-function mutations of KIT or PDGFRA oncogenes. The successful development of targeted therapies directed against KIT and PDGFRA receptors (imatinib, sunitinib, regorafenib) has revolutionized the treatment of advanced stages. The main abdominal complications of GIST are bleeding, intestinal obstruction, rupture, and peritonitis. To our knowledge, a GIST-associated ACS has never been reported in literature.\n\nWe present here a case of patient with huge GIST with ACS successfully treated in intensive care unit (ICU) by both decompressive laparotomy and imatinib without any initial tumor resection.\n\nCase Presentation\nA 59-year-old woman, without particular history, consulted her general practitioner in December 2016 after one week with asthenia, abdominal pain and increase of abdominal perimeter. The thoraco-abdomino-pelvic (TAP) computed tomography (CT)-scan showed a huge abdominal solid mass of likely mesenteric origin. She was transferred to our institution on December 25, 2016.\n\nClinically, her weight was stable and WHO performance status (PS) was equal to 1. The physical examination found an increase of abdominal volume without obvious palpable mass. The laboratory tests showed inflammatory syndrome, moderate anicteric cholestasis, and elevated lactate dehydrogenase. A new CT-scan revealed the intra-abdominal mass of 26 × 21 × 41 cm, occupying the whole abdominal cavity, heterogeneous before and after iodine injection, associated with low abundance ascite (Fig. 1A). Gastric endoscopy-ultrasound-guided tumor biopsies revealed tumour cells with morphological and immunohistochemical criteria evoking GIST. The diagnosis was confirmed by the presence of a KIT exon 11 mutation.\n\nNine days after hospitalization, the patient displayed acute respiratory failure with hypercapnia and hypoxemia, justifying her transfer to our ICU and mechanic ventilation. The ratio of partial pressure arterial oxygen and fraction of inspired oxygen (P/F ratio) was 190 with 70% FiO2, positive end-expiratory pressure (PEEP) at 10, and thoraco-pulmonary compliance was 30 mL/cm H2O. A few hours after, hemodynamic instability and acute renal failure occurred, requiring vasopressive support and establishment of hemodialysis. The IAP measured using intravesical catheter was high, equal to 22 mm Hg evoking ACS. Imatinib was immediately started via the nasogastric tube at high dose of 800 mg/day (day 1, D1). Despite initiation of other therapeutic measures of intra-abdominal hypertension, the IAP increased to 25 mm Hg at D3 and organ dysfunctions were getting worse, leading to practice an emergency decompressive laparotomy via a transversal incision. After surgery, the “open abdomen” was left open and managed with a Vacuum-Assisted Closure (VAC)-type dressing (Fig. 2). The IAP rapidly decreased to 7 mm Hg. However, evolution was marked by hemorrhagic ascites requiring transfusion and albumin perfusion, and by acute pulmonary edema with weight gain of 15 Kg in one week. A CT-scan done at D12 imatinib treatment showed a decrease of the tumor size (22×20×36 cm) and density (13 Hounsfield Units, HU; Fig. 1B), suggesting efficiency of imatinib.\n\nThen, the multi-organ dysfunctions improved. The laparotomy was closed (skin plan only) at D14, and the resuscitation procedures were progressively stopped: in all, the patient stayed 11 days with open abdomen, and received 28 days of mechanic ventilation, 19 days of non-invasive ventilation, 15 days of hemodialysis, and 8 days of vasopressive support. After 8 weeks in the ICU, she was transferred into the Department of Medical Oncology. A CT-scan showed further tumor regression (Fig. 1C) in size (21 × 19 × 35 cm) and density (10 HU). The clinical status continued to improve. The patient was discharged home on March 2017 with a standard imatinib dose (400 mg/d), 11 weeks after hospital admission. During several successive follow-up visits, she fared very well with a PS equal to 0. On CT-scan, the tumor regression continued on June and October 2017 (Fig. 1D). On November 2017, after 10 months of imatinib, the disease progressed and imatinib dose was increased to 800 mg/d. However, after 3 months, the disease worsened: imatinib was relayed by sunitinib during 5 months, then by regorafenib. On November 2018, the patient died from further disease progression, nearly two years after initial diagnosis.\n\nDiscussion\nSince the 2000s, ACS is recognized as a well-defined clinical entity [1]. Primary ACS may be due to decreased abdominal wall compliance after abdominal surgery for example, to increased intra-luminal contents in case of ileus or gastric distension for example, or to increased intra-abdominal contents in case of acute pancreatitis, intra-abdominal infection, intra-abdominal or retroperitoneal tumors for example. In our case, the cause was a huge 40-cm GIST, the origin of which could not be clearly defined, either peritoneal or digestive with huge peritoneal metastasis. To our knowledge, this is the first case of GIST-associated ACS reported in literature. The other cancer-associated ACS published in the English literature include Wilm's tumor, neuroblastoma, benign and malignant ovarian tumors, prostate and rectal cancers, rhabdomyosarcoma, and Burkitt lymphoma [4, 5, 6, 7, 8, 9, 10].\n\nThe diagnosis was based on the detection of increased IAP combined with appearance of multi-organ failure, renal, hemodynamic, and respiratory. IAP was measured using the transvesical method that is the standard method [1]. Despite initiation of adequate medical treatment, the situation worsened, and decompressive laparotomy was required. Such surgical procedure, crucial in case of failure of conservative medical treatment, reduces the mortality by between 16 and 37% [11]. During laparotomy, the peritoneal cavity is opened and left open: “open abdomen” presents several clinical challenges, and diverse solutions preventing complications have been developed, including the method of wound aspiration by creating negative pressure that we used. This method allows to eliminate secretions, protects the viscera and avoids the lateral musculo-aponeurotic retraction. Our patient did not experience severe complication during the 11 days of “open abdomen” and the bedside dressing changes in the ICU, as previously reported [12]. The aim of decompressive laparotomy in ACS is both to release the IAP and to treat the underlying disease. In our case, and by contrast to the other cancer-associated ACS reported in literature [4, 5, 7, 8, 9, 10], no surgical removal of tumor was done because of the huge tumor size. The specific treatment was based on imatinib tablets taken via the naso-gastric tube during the mechanic ventilation. In emergency and before having the tumor mutational status, we gave a double dose of imatinib to increase the probability of tumor response in the eventuality of KIT exon 9 mutation [13]. Treatment was quickly efficient, both clinically with improvement of ACS and radiologically on CT-scan done at D11. Efficiency was favored by the presence of a KIT exon 11 mutation, known to be sensitive to imatinib [3]. Thanks to decrease in tumor size and density, the ACS was resolved and the abdomen could be closed 11 days after laparotomy. To our knowledge, such successful treatment of cancer-associated ACS by targeted therapy has never been described. There is one similar recent report of ACS successfully treated with chemotherapy for a Burkitt lymphoma [6]. During the course, the 42-year patient required mechanical ventilation and developed several organ failures. After laparotomy, abdomen was left open, and the patient received systemic R-CHOP chemotherapy, allowing tumor response, weaning from vasopressor and respiratory support, and of abdomen closure 18 days after laparotomy.\n\nIn conclusion, we report the first case of successful treatment of cancer-associated ACS by targeted therapy and decompressive laparotomy without any tumor removal. At a time when the prognosis of critically ill cancer patients has improved over the past decades and specific anticancer treatments such as chemotherapy and targeted therapy are under assessment in the ICU [14, 15], our case underlines that efficient oral target therapy for a life-threatening malignancy-related complication may be life-saving even in presence of multi-organ dysfunction.\n\nStatement of Ethics\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nDisclosure Statement\nThe authors declare that they have no competing interests.\n\nFunding Sources\nNone.\n\nAuthor Contributions\nConceptualization: FB. Data collection and interpretation: all authors. Manuscript writing: AB, DM and FB. Approval of the article: all authors.\n\nAcknowledgments\nOur work is supported by Institut Paoli-Calmettes. We thank our patient who kindly gave her consent for this publication.\n\nFig. 1 CT-scan aspects of GIST before and during imatinib treatment. Transversal (up), and coronal (bottom) planes of TAP CT-scan at four successive times. Before imatinib treatment (December 26, 2016): see the huge mass with necrotic center occupying the whole peritoneal cavity from diaphragm to pelvis. Tumor density is 45 HU (Hounsfield Units). Almost no viscera is visible. After 12 days imatinib (January 16, 2017), objective tumor response is visible in term of size and density. The tumor response further improved after 8 weeks imatinib (March 7, 2017), and was maximal after 10 months (October 3, 2017).\n\nFig. 2 “Open abdomen” after decompressive laparotomy. Photographs taken during the ICU hospitalization. The tumor is visible through the transversal incision. After surgery, the “open abdomen” was managed with a Vacuum-Assisted Closure (VAC)-type dressing and bedside dressing changes in the ICU.\n==== Refs\nReferences\n1 Wu CE Tzen CY Wang SY Yeh CN Clinical Diagnosis of Gastrointestinal Stromal Tumor (GIST): From the Molecular Genetic Point of View Cancers (Basel) 2019 5 11 (5) 679 \n2 Kirkpatrick AW Roberts DJ De Waele J Jaeschke R Malbrain ML De Keulenaer B Pediatric Guidelines Sub-Committee for the World Society of the Abdominal Compartment Syndrome Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the World Society of the Abdominal Compartment Syndrome Intensive Care Med 2013 7 39 (7) 1190 206 23673399 \n3 Van Damme L De Waele JJ Effect of decompressive laparotomy on organ function in patients with abdominal compartment syndrome: a systematic review and meta-analysis Crit Care 2018 7 22 (1) 179 30045753 \n4 Casali PG Abecassis N Aro HT Bauer S Biagini R Bielack S Gastrointestinal stromal tumours: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up Annals of Oncology 2018 10 29 (Supplement_4) iv267 iv267 30188977 \n5 Ahn J Odom SR Saillant N Ojeifo OA Abramson Z Gupta A Capillary leak syndrome and abdominal compartment syndrome from occult rectal malignancy Am Surg 2012 11 78 (11) E443 5 23089411 \n6 Chung PH Wong KK Lan LC Tam PK Abdominal compartment syndrome after open biopsy in a child with bilateral Wilms' tumour Hong Kong Med J 2009 4 15 (2) 136 8 19342740 \n7 Egyed E Heiss MM Wappler F Sakka SG Successful treatment of abdominal compartment syndrome with chemotherapy in a patient with a newly diagnosed Burkitt lymphoma J Crit Care 2019 6 51 26 8 30710879 \n8 Gurel A Acute kidney injury due to abdominal compartment syndrome caused by duodenal metastases of prostate cancer Clin Case Rep 2015 7 3 (7) 629 31 26273457 \n9 Le-Xiang Z Yao-Hao W Na L Rong-Lin Q Jia-Jia Z Wen-Li J Analysis of treatment of large abdominal malignancies in children complicated with abdominal compartment syndrome: report of six cases Medicine (Baltimore) 2017 4 96 (17) e6705 28445278 \n10 Matinyan N Saltanov A Martynov L Kazantsev A Anesthesia management of a 20-month-old patient with giant unilateral wilms tumor Case Rep Anesthesiol 2015 2015 487219 25815216 \n11 Sabri N Athavale R Abdominal compartment syndrome: a rare complication of an ovarian tumour J Obstet Gynaecol 2013 10 33 (7) 744 5 24127973 \n12 Muresan M Muresan S Brinzaniuc K Voidazan S Sala D Jimborean O How much does decompressive laparotomy reduce the mortality rate in primary abdominal compartment syndrome?: A single-center prospective study on 66 patients Medicine (Baltimore) 2017 2 96 (5) e6006 28151898 \n13 Seternes A Fasting S Klepstad P Mo S Dahl T Björck M Bedside dressing changes for open abdomen in the intensive care unit is safe and time and staff efficient Crit Care 2016 5 20 (1) 164 27233244 \n14 Gronchi A Blay JY Trent JC The role of high-dose imatinib in the management of patients with gastrointestinal stromal tumor Cancer 2010 4 116 (8) 1847 58 20166214 \n15 Azoulay E Schellongowski P Darmon M Bauer PR Benoit D Depuydt P The Intensive Care Medicine research agenda on critically ill oncology and hematology patients Intensive Care Med 2017 9 43 (9) 1366 82 28725926\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "12(2)",
"journal": "Case reports in oncology",
"keywords": "Abdominal compartment syndrome; GIST; Imatinib; Intensive care",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "644-649",
"pmc": null,
"pmid": "31572153",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "28151898;28445278;30188977;19342740;23089411;24127973;27233244;23673399;26273457;28725926;30045753;30710879;20166214;31100836;25815216",
"title": "Successful Imatinib Treatment of an Abdominal Compartment Syndrome due to Huge Gastrointestinal Stromal Tumour.",
"title_normalized": "successful imatinib treatment of an abdominal compartment syndrome due to huge gastrointestinal stromal tumour"
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"companynumb": "FR-SHILPA MEDICARE LIMITED-SML-FR-2019-00215",
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"activesubstancename": "IMATINIB"
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"abstract": "<sec id=\"st1\"> <title>SETTING</title> Niger National Tuberculosis Programme. </sec> <sec id=\"st2\"> <title>OBJECTIVE</title> To describe the outcomes and adverse events (AEs) in a cohort of adults, children and adolescents with multidrug-resistant tuberculosis (MDR-TB) who were treated with the 'short-course regimen'. </sec> <sec id=\"st3\"> <title>DESIGN</title> The regimen comprised an intensive phase of 4-6 months with kanamycin, medium-high dose of isoniazid and prothionamide, and high doses of gatifloxacin, clofazimine, ethambutol and pyrazinamide throughout. Sixty-five patients were treated with a regimen of 12-14 months and 55 patients with a regimen of 9-11 months. </sec> <sec id=\"st4\"> <title>RESULTS</title> Of the 120 patients evaluated, 110 (92%) were adults (median age 31 years) and 10 (8%) were children or adolescents (median age 17 years). The treatment success rate was respectively 88% and 83% with the 9-month regimen, and 90% and 75% with the 12-month regimen in adults and children/adolescents. Initial resistance to ethambutol and prothionamide did not affect treatment success rates but resistance to fluoroquinolones did, although this was not statistically significant. Vomiting was the most frequently encountered AE, followed by ototoxicity and hepatotoxicity. AEs experienced were mild or moderate in severity in most patients, and did not lead to treatment interruption. </sec> <sec id=\"st5\"> <title>CONCLUSION</title> These results confirm the programmatic effectiveness and tolerability of the shorter regimen in second-line drug-naïve patients. </sec>.",
"affiliations": "Damien Foundation, Niamey, Niger.;Damien Foundation, Brussels, Belgium.;Damien Foundation, Niamey, Niger.;Médecins Sans Frontières, Nairobi, Kenya.;Damien Foundation, Niamey, Niger.;Damien Foundation, Niamey, Niger.;Institute of Tropical Medicine, Antwerp.;Médecins Sans Frontières, Luxembourg.;Damien Foundation, Niamey, Niger, International Union Against Tuberculosis and Lung Disease, Paris, France.",
"authors": "Harouna|S H|SH|;Ortuno-Gutierrez|N|N|;Souleymane|M B|MB|;Kizito|W|W|;Morou|S|S|;Boukary|I|I|;Zolfo|M|M|;Benedetti|G|G|;Piubello|A|A|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "France",
"delete": false,
"doi": "10.5588/ijtld.17.0871",
"fulltext": null,
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"issn_linking": "1027-3719",
"issue": "23(5)",
"journal": "The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease",
"keywords": null,
"medline_ta": "Int J Tuberc Lung Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000995:Antitubercular Agents; D002648:Child; D015331:Cohort Studies; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009313:National Health Programs; D009548:Niger; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant; D055815:Young Adult",
"nlm_unique_id": "9706389",
"other_id": null,
"pages": "625-630",
"pmc": null,
"pmid": "31097073",
"pubdate": "2019-05-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Short-course treatment outcomes and adverse events in adults and children-adolescents with MDR-TB in Niger.",
"title_normalized": "short course treatment outcomes and adverse events in adults and children adolescents with mdr tb in niger"
} | [
{
"companynumb": "PHHY2019NE141282",
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"activesubstancename": "ETHAMBUTOL HYDROCHLORIDE"
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... |
{
"abstract": "We present herein a patient with rocuronium anaphylaxis, which had been identified using skin test, underwent conventional coronary artery bypass surgery without any neuromuscular blocking agent. Immobility was achieved with sedatives and analgesics.",
"affiliations": "Department of Cardiovascular Surgery, Toyohashi Municipal Hospital, Toyohashi, Japan.",
"authors": "Toyama|Masashi|M|;Abe|Tomonobu|T|;Nakayama|Masato|M|;Takahashi|Tetsuyuki|T|;Shiba|Tomoka|T|;Nakajima|Chihiro|C|",
"chemical_list": "D009466:Neuromuscular Blocking Agents",
"country": "Japan",
"delete": false,
"doi": null,
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"issn_linking": "0021-5252",
"issue": "71(2)",
"journal": "Kyobu geka. The Japanese journal of thoracic surgery",
"keywords": null,
"medline_ta": "Kyobu Geka",
"mesh_terms": "D000368:Aged; D000707:Anaphylaxis; D000072226:Computed Tomography Angiography; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease; D006801:Humans; D008297:Male; D009466:Neuromuscular Blocking Agents",
"nlm_unique_id": "0413533",
"other_id": null,
"pages": "115-119",
"pmc": null,
"pmid": "29483465",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Coronary Artery Bypass Surgery for the Patient with a History of Anaphylaxis due to Neuromuscular Blocking Agent ; Report of a Case.",
"title_normalized": "coronary artery bypass surgery for the patient with a history of anaphylaxis due to neuromuscular blocking agent report of a case"
} | [
{
"companynumb": "JP-FRESENIUS KABI-FK201808067",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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"activesubstance": {
"activesubstancename": "ROCURONIUM BROMIDE"
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{
"abstract": "BACKGROUND\nOptimal dosing of vancomycin in morbidly obese patients (>100 kg and at least 140% of their ideal body weight) has not been determined. Conventional dosing strategies have led to the observation of supratherapeutic trough concentrations (>20 mcg/mL).\n\n\nOBJECTIVE\nTo evaluate the effectiveness of a new vancomycin dosing protocol in morbidly obese patients in achieving therapeutic trough concentrations between 10 and 20 mcg/mL and to determine patient-specific factors influencing the trough concentration attained.\n\n\nMETHODS\nA single-center, retrospective chart review included morbidly obese adult patients with a pharmacy-to-dose vancomycin consult and at least 1 trough concentration obtained at steady state. Patients were excluded if they had a creatinine clearance (CrCl) less than 35 mL/min or unstable renal function, were not dosed according to the revised protocol, or received vancomycin prior to initiation of the protocol.\n\n\nRESULTS\nOf the 48 patients included, 17 (35.4%) achieved a therapeutic vancomycin trough concentration. Subtherapeutic concentrations (<10 mcg/mL) were observed in 27 patients (56.3%) and supratherapeutic concentrations were observed in 4 (8.3%) patients. Age less than 45 years and CrCl greater than 100 mL/min were associated with subtherapeutic trough concentrations.\n\n\nCONCLUSIONS\nThis study demonstrates that the revised vancomycin dosing protocol led to the attainment of therapeutic trough concentrations in 35.4% of patients. The majority had subtherapeutic concentrations, which increases the risk of treatment failures and resistance. Further study is needed to determine the optimal dosing strategy in this patient population.",
"affiliations": "Critical Care Pharmacy Specialist, Carolinas Healthcare System , Charlotte, North Carolina.;Medical ICU Clinical Pharmacy Specialist, Carolinas Medical Center, Charlotte, North Carolina; Assistant Professor of Pharmacy, Wingate University School of Pharmacy, Wingate, North Carolina.;Statistician, Dickson Advanced Analytics Group, Carolinas Healthcare System , Charlotte, North Carolina.;Director of Biostatistics, Carolinas Healthcare System, Charlotte , North Carolina.;Infectious Diseases and Antimicrobial Stewardship Clinical Pharmacy Specialist, Carolinas Medical Center, Charlotte , North Carolina .",
"authors": "Kosmisky|Desiree E|DE|;Griffiths|Carrie L|CL|;Templin|Megan A|MA|;Norton|James|J|;Martin|Kelly E|KE|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1310/hpj5009-789",
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"issue": "50(9)",
"journal": "Hospital pharmacy",
"keywords": "dosing; obesity; therapeutic drug monitoring; vancomycin",
"medline_ta": "Hosp Pharm",
"mesh_terms": null,
"nlm_unique_id": "0043175",
"other_id": null,
"pages": "789-97",
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"pubdate": "2015-10",
"publication_types": "D016428:Journal Article",
"references": "1244564;14727222;15573054;17692725;18227177;18929686;19106348;21130609;21208910;21411801;22610026;23165462;6219616;7081978;7846752;8010319;8460912;9860149",
"title": "Evaluation of a New Vancomycin Dosing Protocol in Morbidly Obese Patients.",
"title_normalized": "evaluation of a new vancomycin dosing protocol in morbidly obese patients"
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{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2016-03948",
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"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
... |
{
"abstract": "Satoyoshi syndrome is a multisystemic rare disease of unknown etiology, although an autoimmune basis is presumed. Its main symptoms are: painful muscle spasms, diarrhea, alopecia and skeletal abnormalities. Clinical course without treatment may result in serious disability or death. A review of treatment and its response is still pending.\n\n\n\nSixty-four cases of Satoyoshi syndrome were published between 1967 and 2018. 47 cases described the treatment administered. Drugs used can be divided into two main groups of treatment: muscle relaxants/anticonvulsants, and corticosteroids/immunosuppressants. Dantrolene improved muscle symptoms in 13 out of 15 cases, but not any other symptoms of the disease. Other muscle relaxants or anticonvulsant drugs showed little or no effect. 28 out of 30 cases responded to a regimen that included costicosteroids. Other immunosuppressive drugs including cyclosporine, mycophenolate mofetil, azathioprine, methotrexate, tacrolimus and cyclophosphamide were used to decrease corticosteroid dose or improve efficacy. Immunoglobulin therapy was used in nine patients and four of them obtained a favorable response.\n\n\n\nCorticosteroids was the most widely treatment employed with the best results in Satoyoshi syndrome. Further studies are needed to determine optimal dose and duration of corticosteroids as well as the role of other immunosuppressants and immunoglobulin therapy. Genetic or autoimmune markers will be useful to guide future therapies.",
"affiliations": "Department of Internal Medicine, Hospital General de Villarrobledo, Villarrobledo, Spain.;Research Department, Neuropsychopharmacology Unit, Complejo Hospitalario Universitario de Albacete, Albacete, Spain. carlosd@sescam.jccm.es.;Department of Internal Medicine, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.",
"authors": "Solís-García Del Pozo|Julián|J|;de Cabo|Carlos|C|0000-0002-2144-0107;Solera|Javier|J|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000927:Anticonvulsants; D007166:Immunosuppressive Agents; D003620:Dantrolene",
"country": "England",
"delete": false,
"doi": "10.1186/s13023-019-1120-7",
"fulltext": "\n==== Front\nOrphanet J Rare DisOrphanet J Rare DisOrphanet Journal of Rare Diseases1750-1172BioMed Central London 112010.1186/s13023-019-1120-7ReviewTreatment of Satoyoshi syndrome: a systematic review Solís-García del Pozo Julián julianeloysolis@gmail.com 1http://orcid.org/0000-0002-2144-0107de Cabo Carlos carlosd@sescam.jccm.es 25Solera Javier solera53@gmail.com 341 Department of Internal Medicine, Hospital General de Villarrobledo, Villarrobledo, Spain 2 0000 0000 9321 9781grid.411839.6Research Department, Neuropsychopharmacology Unit, Complejo Hospitalario Universitario de Albacete, Albacete, Spain 3 0000 0000 9321 9781grid.411839.6Department of Internal Medicine, Complejo Hospitalario Universitario de Albacete, Albacete, Spain 4 0000 0001 2194 2329grid.8048.4Department of Medical Sciences, Falculty of Medicine, Universidad de Castilla – La Mancha, Albacete, Spain 5 0000 0004 0506 8127grid.411094.9Hospital General Universitario de Albacete, Unidad de Neuropsicofarmacología, Edificio de Investigación, 3ª planta, c/ Hermanos Falcó, 37, E-02008 Albacete, Spain 19 6 2019 19 6 2019 2019 14 1463 4 2019 7 6 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nSatoyoshi syndrome is a multisystemic rare disease of unknown etiology, although an autoimmune basis is presumed. Its main symptoms are: painful muscle spasms, diarrhea, alopecia and skeletal abnormalities. Clinical course without treatment may result in serious disability or death. A review of treatment and its response is still pending.\n\nResults\nSixty-four cases of Satoyoshi syndrome were published between 1967 and 2018. 47 cases described the treatment administered. Drugs used can be divided into two main groups of treatment: muscle relaxants/anticonvulsants, and corticosteroids/immunosuppressants. Dantrolene improved muscle symptoms in 13 out of 15 cases, but not any other symptoms of the disease. Other muscle relaxants or anticonvulsant drugs showed little or no effect. 28 out of 30 cases responded to a regimen that included costicosteroids. Other immunosuppressive drugs including cyclosporine, mycophenolate mofetil, azathioprine, methotrexate, tacrolimus and cyclophosphamide were used to decrease corticosteroid dose or improve efficacy. Immunoglobulin therapy was used in nine patients and four of them obtained a favorable response.\n\nConclusion\nCorticosteroids was the most widely treatment employed with the best results in Satoyoshi syndrome. Further studies are needed to determine optimal dose and duration of corticosteroids as well as the role of other immunosuppressants and immunoglobulin therapy. Genetic or autoimmune markers will be useful to guide future therapies.\n\nKeywords\nAlopeciaCorticosteroidsDantroleneDiarrheaImmunoglobulin therapyMuscle spasmsRare diseasesSatoyoshi syndromeissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nSatoyoshi syndrome (SS) (ORPHA 3130), also called komuragaeri disease, is a rare disorder with fewer than 70 cases reported in the medical literature. It is a multisystem disease presenting with progressive painful muscle spasms, diarrhea, endocrinopathy, alopecia, and skeletal abnormalities [1]. An autoimmune basis is likely through association with other autoimmune conditions: the presence of autoantibodies, and successful treatment of symptoms with immunosuppressants [2, 3].\n\nThe first two SS patients were described by Satoyoshi and Yamada in 1967 [4]. These authors employed multiple drugs including acetazolamide, magnesium sulfate, dexamethasone, prednisolone, diazepam, phenobarbital, diphenylhydantoin, quinine sulfate, chlorpromazine and others [4]. Despite these treatments, they failed to control muscle spasms in their patients. Eleven years later, in 1978, Satoyoshi reported 15 patients with this syndrome (including again the two first ones from 1967 [4]), most of them young women [1]. Of these 15 patients, five died, and the evolution was towards a disabling condition in the remaining patients due to failure of treatment. Since then, the existing reviews have focused on some of the manifestations of the disease [5–7], but a review of treatment and prognosis of this syndrome has not yet been carried out.\n\nThe first treatments for SS were aimed primarily to alleviate the painful and incapacitating intermittent muscle spasms. Muscle relaxants and antiepileptic drugs were used by different authors with limited results [3, 8, 9]. In the last 30 years, the drugs used for SS can be divided into two main groups of treatment: i) muscle relaxants and anticonvulsants, and ii) corticosteroids and immunosuppressants. Other treatments such as nutritional support, hormonal treatments or orthopedic surgery and rehabilitation were necessary in some cases. In the present article, we performed a systematic review of the treatment of SS.\n\nMaterial and methods\nSearch strategy and inclusion of cases\nAll published cases of Satoyoshi syndrome were reviewed. For this purpose, a MEDLINE, Web of Knowledge (WOS), and Scopus search was performed using the keywords “Satoyoshi syndrome” or “Komuragaeri disease” with no limit for the year of publication or language. All records found up to December 2018 were included. The lists of references from the articles found by electronic search were also reviewed to identify additional records. We also reviewed the references from works cited on OMIM [10], ORPHANET [11] and Rare Diseases NIH [12] websites. All articles that reported SS cases were included.\n\nBoth the literature search and the inclusion of case reports were carried out by two of the authors. In case of disagreement between them, the final decision was reached after discussion among all the authors.\n\nThe searches in MEDLINE, Scopus and WOS searches yielded 45, 63 and 53 articles, respectively. Twelve additional works were retrieved from reviewing the bibliographies from the articles previously found. A total of 64 cases of Satoyoshi syndrome were identified from 53 published articles (Fig. 1).Fig. 1 Flow chart illustrating case selection strategy [13–31]\n\n\n\nData extraction\nThe following data were extracted from each of the selected cases:Clinical and epidemiological characteristics: age, age at onset of symptoms and delay of diagnosis, sex, country of origin, symptoms and sings, and presence of other associated diseases.\n\nTreatments received including muscle relaxants, antiepileptic drugs, corticosteroids, other immunosuppressants such as azathioprine, methotrexate, mycophenolate, tacrolimus, immunoglobulin therapy or a combination of these drugs. Duration of treatment and response were also recorded.\n\nOutcomes: time of follow-up, mortality and sequelae.\n\n\n\nThe improvement of muscle spasms was recorded following the authors’ descriptions. This improvement was usually reported as the ability to perform the activities of daily living without significant interference from muscular symptoms. In the same way, the improvement or remission of alopecia and digestive symptoms was recorded according to the clinical case report. Usually, improvement of alopecia was considered as the regrowth of hair in the areas where it had fallen. Remission of digestive symptoms was usually described as the disappearance of diarrhea or signs of malabsorption along with weight gain. Non-response to treatment was defined as either no significant change in any of the symptoms of the disease according to the authors, or the death of the patient due to the disease. Death was considered related to SS if it was not possible to attribute it to a different cause. The time until the improvement occurred and the duration of the response were recorded if available.\n\nData analysis\nData from each one of the cases were stored in an Excel database. A descriptive analysis was made after verification of the database. Qualitative data were described using frequency and percentage. Quantitative data were described as the mean ± standard deviation. Median and range were used in the case of non-normal variables.\n\nResults\nForty-seven out of the 64 total cases (73%) were women and 28 cases (43%) were Japanese patients, although cases of SS have been reported in other parts of the world. The age at diagnosis ranged from 5 to 65 years with a median of 16 years and with a mean of 20.3 ± 12.4 years. The average diagnostic delay was 7.5 years. Age at onset of symptoms ranged from 1 to 46 years with a median of 11 years and a mean of 13.02 ± 9.1 years. Only 13% cases of Satoyoshi syndrome were adult-onset.\n\nAll published cases had intermittent painful muscle spasms, and all had some degree of alopecia. Alopecia became universalis in 63% of cases. 37 cases (58%) had digestive alterations, mainly diarrhea. Skeletal alterations were described in 22 cases (34%) of which in 4 cases had dental occlusion problems. In 23 patients (38.3%) the presence of autoantibodies in different combinations was detected. Symptoms were progressive until onset of treatment and 7 patients died (11%). Out of the 64 patients detected, 47 [1–3, 5, 6, 8, 9, 32–68] had data on the individualized treatment administered, and in two other cases the treatment is not reported individually [4]. Seven articles described complementary data of these 49 patients [1, 69–74]. The treatment was not reported in the remaining 15 patients [1, 40, 75, 76]. There were no differences in their initial clinical characteristics between the the group of 47 SS patients whose treatment was reported and the rest of patients with SS (15 patients) whose treatment was not described in the publications (Table 1).Table 1 Initial clinical characteristics of all SS patients included in this review, the 47 patients whose treatment was described and the 30 patients treated with corticosteroids\n\n\tAll patients N = 64\tPatients where treatment was specified N = 47\tPatients treated with corticosteroids N = 30\t\nAge of onset\t13.02 ± 9.08\t14.19 ± 10.35\t13.80 ± 10.32\t\nFemale sex\t47/64 (73%)\t35/47 (74%)\t23/30 (77%)\t\nMuscle manifestations\t100%\t100%\t100%\t\nAlopecia\t100%\t100%\t100%\t\nAlopecia universalis\t40/64 (63%)\t25/47 (53%)\t17/30 (57%)\t\nDiarrhea\t37/64 (58%)\t26/47 (55%)\t17/30 (57%)\t\nWeight loss, low weight or growth retardation\t33/64 (52%)\t23/47 (49%)\t14/30 (47%)\t\nSkeletal alterations\t22/64 (34%)\t16/47 (34%)\t10/30 (33%)\t\nAmenorrhea\t23/47 (49%)\t15/35 (43%)\t9/23 (39%)\t\nANA +\t17/64 (27%)\t17/47 (36%)\t13/30 (43%)\t\nOther autoantibodies\t15/64 (23%)\t15/47 (32%)\t11/30 (37%)\t\nDeaths\t7 (11%)\t2 (4%)\t0 (0%)\t\n\n\nIn addition to pharmacological treatment, patients with SS have received other therapies including orthopedic surgery, rehabilitation, or nutritional treatments. However, this review will focus mainly on the pharmacological treatment.\n\nAnticonvulsant drugs\nPhenytoin and carbamazepine were the main anticonvulsant drugs used in patients with SS (Table 2). Seven patients received treatment with phenytoin [5, 32–37]. In 4 cases phenytoin was used as the first option in combination with corticosteroids [5, 33–35]. Baclofen was also used in one of these four cases [33]. When reported, the dose administered ranged from 100 mg [34] to 200 mg daily [5, 35]. Overall, 3 out of the seven patients (42%) who received a phenytoin-containing regimen improved with this therapy [5, 34, 35], although all three cases also received treatment with corticosteroids.Table 2 Non-immunosuppresive drugs used in the therapy of SS patients\n\nDrug\tNumber of times used\tMonotherapy as initial treatment\tAs initial treatment in combination with other drugs\tAs second or further-line treatment option\tImprovement\tNo improvement\tChange of treatment\tComments\t\nDantrolene\t15\t9\t4\t2\t13\t2\t3\tDantrolene improved muscular symptoms but no other manifestations. It was used as a first option in combination with corticosteroids in two cases [6, 46] and in another case with immunoglobulin therapy [47], although, subsequently, immunoglobulin therapy was replaced by corticosteroids. Although improvement was recorded in 13 patients, such improvement only lasted for a short time in one of them, which led to the change in treatment [32]. In another case, the treatment was changed to immunoglobulin therapy because dantrolene is not a radical treatment [3]. For one of the cases that did not respond adequately, a change of treatment was not recorded in the article [45].\t\nCarbamacepine/Oxcarbacepine\t9\t1\t7\t1\t4\t5\t5\tIn two cases carbamazepine was combined with corticosteroids [2, 41]. In five cases, the treatment was changed due to lack of effectiveness [9, 32, 40, 42, 70]. In one of them, it was necessary to use botulinum toxin to control masticatory spasms [32]. In another of these cases, authors stated that carbamazepine, phenobarbital, quinine sulfate, and chlorpromazine were tested during hospitalization and they were not effective for spasms [40]. In one case, carbamazepine was used with gabapentin without result [70].\t\nPhenitoin\t7\t0\t4\t3\t3\t4\t1\tIn the 3 SS patients in whom there was an improvement, phenitoin was the first option in combination with corticosteroids [5, 34, 35]. In another patient, it was combined with blaclofen and prednisone without response [33]. In one case, phenytoin was used as a second option and no satisfactory response was obtained. But after several treatment options, phenytoin was maintained combined with corticoids and mycophenolate [37]. In another case, phenytoin was used as second option treatment with carbamazepine, but it was not effective [32]. Averianov reported its use, but without effectiveness [36].\t\nBaclofen\t3\t1\t2\t0\t0\t3\t3\tIt has been used as a first option treatment only in one SS patient [50]. In another patient, multiple muscle relaxants and anticonvulsants were used without satisfactory results [42]. Baclofen was used in combination with phenytoin and prednisone in another patient [33]. In none of the cases the treatment had a good clinical response.\t\nClotiapine and biperidene\t1\t1\t0\t0\t0\t1\t1\tIt was not effective [51].\t\nClonazepam\t3\t0\t2\t1\t0\t3\t3\tClonazepam was used in combination with carbamazepine without improvement [9] and the SS patient required changing treatment to dantrolene. Clonazepam was used in a patient adding it to dantrolene, but it was necessary to change treatment to phenytoin and carbamazepine [32]. In one patient clonazepam was used together with several other drugs such as dantrolene, carbamazepine or diazepam [42].\t\nTetrazepam\t1\t0\t1\t0\t1\t0\t0\tTetrazepam in combination with carbamazepine improved spasms in a patient with SS [39].\t\nOtilonium bromide\t1\t0\t1\t0\t1\t0\t0\tIt was used in combination with carbamazepine with disappearance of spasms and diarrhea [38]\t\nPhenobarbital\t1\t0\t0\t1\t0\t1\t1\tPhenobarbital was used in a SS patient who was also receiving carbamazepine, quinine sulfate and chlorpromazine treatment. But it was not effective either [40].\t\nQuinine sulfate\t1\t0\t0\t1\t0\t1\t1\tQuinine sulfate was used in a patient who was also receiving carbamazepine, phenobarbital and chlorpromazine treatment. But it was not effective either [40].\t\nChlorpromazine\t1\t0\t0\t1\t0\t1\t0\tChlorpromazine was used in a patient who was also receiving carbamazepine, quinine sulfate and phenobarbital treatment. But it was not effective either [40].\t\nAcetazolamide\t1\t0\t0\t1\t1\t0\t0\tAcetazolamide improved muscle symptoms in a patient [36]. It was used in this patient after thioridazine, haloperidol and phenytoin were unsuccessful.\t\nNeostigmine\t1\t0\t1\t0\t1\t0\t0\tNeostigmine was used in combination with traditional Chinese medicine in a patient with myasthenia. The authors stated that she remained stable after 8 months of follow-up [40].\t\nBotulinum toxin\t3\t0\t1\t2\t3\t0\t1\tBotulinum toxin was used together with corticosteroids in a patient as a primary therapy. Treatment was changed by adding azathioprine [59]. In one case, botulinum toxin was added to the treatment to control masticatory spasms [47]. In another case, it was used after several previous treatments with dantrolene, diazepam, clonazepam, phenytoin and carbamazepine [32].\t\nAmitriptilin\t1\t0\t1\t0\t1\t0\t0\tAmitriptilin was used in combination with corticosteroids as a maintenance therapy [61].\t\nThioridazine\t1\t1\t0\t0\t0\t1\t1\t[36]\t\nHaloperidol\t1\t0\t0\t1\t0\t1\t1\t[36]\t\nDiazepam\t2\t1\t0\t1\t1\t1\t1\tIt was combined with several other treatments such as immunoglobulin therapy, cyclophosphamide and azatioprine [51]. Although this patient improved, it is difficult to attribute her improvement to diazepam. In another patient diazepam was used together with multiple muscle relaxants and anticonvulsants without satisfactory results [42].\t\nMidazolam\t1\t1\t0\t0\t0\t1\t0\tThe patient developed a neuroleptic malignant syndrome after the onset of iv midazolam and died [52].\t\n\n\nCarbamazepine (or oxcarbazepine) were used in 9 patients with SS [2, 9, 32, 38–42, 70]. In two of them, it was used in combination with corticosteroids [2, 41]. Other drugs used in conjunction with carbamazepine as the first treatment option were otilonium bromide [38], tetrazepam [39], and clonazepam [9]. The dose was reported in four cases [2, 9, 39, 42], and ranged from 200 mg [2] to 600 mg daily [9]. Overall, 4 out of the nine patients treated with carbamazepine improved (44%) [2, 38, 39, 41], although in two of them carbamazepine was used in conjunction with corticosteroids [2, 41]. Phenobarbital was used in a patient after the failure of treatment with carbamazepine, but this treatment was not effective either [40].\n\nMuscle relaxants\nThe cases where the use of this type of drug has been reported for SS are shown in Table 2. The most frequently used drug in this group was dantrolene (15 cases) [1, 3, 6, 8, 9, 32, 33, 42–49]. Dantrolene is a muscle relaxant that disrupts calcium release from the sarcoplasmic reticulum in the skeletal muscle [77]. It has been used as a specific drug to treat malignant hyperthermia [78]. In 7 out of 13 cases of SS dantrolene dose was reported and ranged from 25 [48] to 200 mg daily [33]. Dantrolene was able to improve muscle symptoms in 13 out of 15 (87%) SS cases [1, 3, 6, 8, 9, 32, 33, 43, 44, 46–49] but it proved to be ineffective for the improvement of the other clinical manifestations of SS. In three out of the 13 cases it was used in association with corticosteroids or immunoglobulin therapy [6, 46, 47], which makes it difficult to assess the effect of dantrolene by itself.\n\nBaclofen is a gamma-aminobutyric acid derivative that acts as a muscle relaxant mainly by disrupting polysynaptic and monosynaptic reflexes at the spinal cord level [77]. It was used in three patients with SS [33, 42, 50] without improvement in any of them.\n\nBenzodiazepines\nBenzodiazepines were used on seven occasions: Clonazepam in 3 patients, diazepam in 2 patients, tetrazepam in 1 patient and midazolam in 1 patient. Clonazepam was always used in combination [9, 32, 42] with either carbamazepine [9], dantrolene [32], or, in one patient, with several drugs such as dantrolene, carbamazepine or diazepam [42]. None of these patients experienced clinical improvement.\n\nDiazepam was used in combination in two patients. One patient received treatment with diazepam and other muscle relaxants without adequate response [42]. Another adult patient received treatment with diazepam in combination with other therapies such as immunoglobulin therapy and cyclophosphamide, with improvement [51].\n\nTetrazepam 50 mg daily was used in a 21-year-old patient along with carbamazepine 300 mg daily, with an improvement of spasms [39]. Adachi et al. [52] treated a patient with intravenous midazolam. This patient developed a malignant neuroleptic syndrome and died. The authors warned that careful attention should be paid when midazolam is used in SS.\n\nSystemic corticosteroids\nSystemic corticosteroids are the most widely used drugs for the treatment of SS (Table 3). Out of the 47 analyzed cases, 30 were treated with systemic corticosteroids [2, 5, 6, 33–35, 37, 41, 42, 46, 47, 50, 51, 53–67]. In 22 cases the initial therapeutic regimen included corticosteroids, in 8 patients as monotherapy [53–58, 61, 63] and in 14 as combined treatment [2, 5, 6, 33–35, 37, 41, 46, 59, 60, 67]. In the remaining eight patients, corticosteroids were used after therapeutic failure of other treatments [42, 47, 50, 51, 62, 64–66].Table 3 Corticosteroids and immunossuppresants drugs used in SS patients\n\nDrug\tNumber of times used\tMonotherapy as initial treatment\tIn combination with other drugs as initial treatment\tAs second or other treatment option\tImprovement\tNot improvement\tChange of treatment\tComments\t\nSystemic corticosteroids\t30\t8\t14\t8\t28\t2\t4\tIn one case the treatment was changed to dantrolene for lack of efficacy [33]. In a case that had been previously treated with carbamazepine and otilonium bromide, systemic corticosteroids were prescribed for alopecia. However, treatment was interrupted a month later due to the appearance of adverse effects [13]. In one case, corticosteroids showed improvement of short duration and the treatment was changed [37]. In another case, a single pulse of corticosteroid diminished the frequency of muscle spasms during two weeks, but therapy was changed to cyclophosphamide and subsequently to azathioprine [51].\t\nCorticosteroids have been combined with other immunosuppressants in 7 cases. In 5 patients as initial treatment [5, 37, 60, 67] and in two patients after other treatments [50, 62]. Corticosteroids were combined with immunoglobulin therapy in two patients, [60, 67] with mycophenolate mofetil in one patient [37], with cyclosporin in two patients reported by Rudnicka [5], with methotrexate in one patient [62] and with tacrolimus in another patient [50]. Other immunosuppressants have been used in combination to low doses of corticosterois, such as methotrexate [63], azathioprine [59]. Corticosteroids have also been used in combination with other drugs such as baclofen [33], phenytoin [5, 33–35], dantrolene [6, 46], carbamazepine [2, 41] and botulinum toxin [59]. In one patient initially treated with corticosteroids in monotherapy, amitriptyline was added later [61].\t\nImmunoglobulin therapy\t9\t1\t3\t5\t4\t5\t6\tIn one case, immunoglobulin therapy was used alone as a first option without improvement [64]. In two cases, immunoglobulin therapy was used in combination with corticosteroids [60, 67]. In one case, it was used as a first option in combination with dantrolene, but treatment was changed to pulsed treatment of methylprednisolone together with dantrolene [47]. In another case, immunoglobulin therapy was used as a second option after short-term improvement with corticoids and mycophenolate mofetil, with no response [37]. In another patient they were also used as second option treatment together with diazepam [51]. Endo used them as a second option with effect for 2 months and then changing to corticoids [50]. Arita used it as second option treatment after dantrolene with satisfactory response [3]. The treatment with immunoglobulin therapy was changed in six cases [37, 47, 50, 51, 64, 69]\t\nCyclosporin\t2\t0\t2\t0\t2\t0\t0\tIn one of the cases, both alopecia and spasms improved. In the other case, improvement of spasms was achieved, but it was less effective for alopecia [5]\t\nMycophenolate mofetil\t1\t0\t1\t0\t1\t0\t1\tThe initial treatment in this patient was with corticosteroids and mycophenolate mofetil. Later phenytoin was added. Treatment was changed due to short-term improvement. The treatment was changed to immunoglobulin without response, and subsequently, to plasmapheresis (5 cycles) with improvement in pain and cramps. Later this same case was treated with a combination of phenytoin, mycophenolate and corticosteroids [37], thus it can be deduced that mycophenolate and corticosteroids adminstarion was maintained throughout the course of the treatment.\t\nAzathioprine\t2\t0\t0\t2\t2\t0\t0\tIt was used after treatment with both botulinum toxin and corticosteroids to help lower the dose of corticosteroids [59]. In another case it was used after multiple treatments [51]\t\nPlasmapheresis\t1\t0\t0\t1\t1\t0\t0\tIt was used after short-term improvement with both corticosteroids and mycophenolate mofetil as the first option, and failure of immunoglobulin therapy as a second option. After plasmapheresis (5 cycles) the patient improved in pain and cramps [37]\t\nMethotrexate\t2\t0\t0\t2\t2\t0\t0\tIn one case it was used together with prednisone [62], and in another case it was added to corticosteroids due to loss of effect [63]\t\nTacrolimus\t1\t0\t0\t1\t1\t0\t0\tIt was used together with corticosteroids after trying other treatments [50]\t\nCyclophosphamide\t1\t0\t0\t1\t0\t1\t1\tIt was used together with diazepam after trying other treatments, and was later changed to azathioprine [51]\t\n\n\nIn 16 cases corticosteroids were employed in combination with other drugs. In 9 cases, corticosteroids were used together with muscle relaxants or anticonvulsants: 3 patients with phenytoin [5, 34, 35], two patients with dantrolene [6, 46], two patients with carbamazepine [2, 41], one patient with botulinum toxin [59], and one patient with phenytoin and baclofen [33]. In the 7 other patients, corticosteroids were used in combination with other immunosuppressants: two patients with cyclosporin [5], one patient with mycophenolate mofetil [37], one patient with methotrexate [62] and two patients with immunoglobulin therapy [60, 67] and one patient with tacrolimus [50].\n\nIn another two cases, immunosuppressants were subsequently used to lower the dose of corticosteroids in two patients (methotrexate in one patient [63] and azathioprine in another one patient [59]).\n\nThe corticosteroid drugs used were prednisone (12 patients) [2, 5, 33, 41, 55, 56, 59–62, 64], prednisolone (12 patients) [6, 34, 35, 37, 42, 50, 54, 58, 63, 65–67],methylprednisolone (6 patients) [37, 42, 46, 47, 50, 51] and triamcinolone (in one case) [5]. Two additional patients were treated with corticosteroids without specifying the drug used [53, 57]. In five patients, methylprednisolone was administered as intravenous boluses at a high dose [42, 46, 50, 51, 63] during a period of 3 days that could be extended for up to 4–6 weeks [63]. The doses of oral corticosteroids ranged from 2 mg / kg / day of prednisolone [65] to 0.3 mg / kg / day of prednisone [5], with subsequent dose reductions.\n\nTaken together, 28 out of 30 patients (93%) responded to a regimen that included corticosteroids. The optimal treatment duration could not be clearly determined, since in most of the published clinical cases the follow-up time was limited. That notwithstanding, improvement was reported at two or more years of follow-up [35, 46].\n\nOther immunosuppressive drugs\nOther immunosuppressive drugs including cyclosporine, mycophenolate mofetil, azathioprine, methotrexate, tacrolimus and cyclophosphamide, were used in 9 cases for the treatment of SS. In eight patients they were used in combination with corticosteroids. Table 3 reports the number of times these drugs have been tested in the treatment of SS.\n\nCyclosporine at a dose of 50 mg daily was used in two patients (two mg/kg/day in one of the patients and 3.33 mg/kg/day in the other) in combination with prednisone [5]. Both patients showed improvement of the spasms and only one of them had an improvement in alopecia.\n\nAzathioprine was also used in two cases. In one of them, azathioprine was used in monotherapy after having tried other treatment options that included clotiapine, biperiden, cyclophosphamide, diazepam, immunoglobulin therapy and a 3-day cycle of high doses of methylprednisolone [51]. In the other case, azathioprine was prescribed to lower corticosteroid doses due to side effects [59].\n\nMethotrexate was another drug from this group that was used for two patients. In an adult patient it was used at a dose of 7.5 mg weekly together with 30 mg daily of prednisone, resulting in improvement of all symptoms within weeks, excepting alopecia [62]. In the other case (a 14-year-old girl), methotrexate was added to corticosteroids at a dose of 10 mg/m2 once a week to enhance effects, and reduce the dose of corticosteroids [63].\n\nMycophenolate mofetil was used in a 30-year-old patient [37], originally together with corticosteroids. After an initial response, the patient worsened and treatment with phenytoin was added. Because of the poor control of symptoms, treatment with immunoglobulin therapy was tried, but also without success. Later plasmapheresis was prescribed (5 cycles), improving cramps and pain. As a maintenance treatment, the patient continued with corticoids, mycophenolate, and phenytoin.\n\nIntravenous human immunoglobulin therapy\nImmunoglobulin therapy was used in 9 cases [3, 37, 47, 50, 51, 60, 64, 67, 69] and it was the second most frequently used immunosuppressive treatment after corticosteroids. In 4 cases, treatment with immunoglobulin therapy was part of the initial treatment of patients with SS [47, 60, 64, 67]. Only in one case immunoglobulin therapy was used in monotherapy as the first therapeutic option, but no improvement of the patient was achieved [64]. In 3 other patients, immunoglobulin therapy was used as initial treatment in combination with either corticosteroids (2 patients) [60, 67] or dantrolene (1 patient) [47]. In five patients they were not used as part of the initial treatment regimens [3, 37, 50, 51, 69]. In one of these cases immunoglobulin therapy were added after treating the patient with corticoids, mycophenolate mofetil and phenytoin, without showing efficacy [37]. Another case was an adult woman in whom immunoglobulin therapy were a second treatment option in combination with diazepam [51]. In this patient, the effect of a 5-days cycle of immunoglobulin therapy was beneficial in the improvement of muscular spasms for 6–8 weeks. After 2 cycles, immunoglobulin therapy was stopped and changed to cyclophosphamide, as her medical insurance company was unwilling to pay for additional immunoglobulin therapy cycles. In three other patients, immunoglobulin therapy were used as monotherapy after having tested dantrolene (1 patient) [3] and baclofen (1 patient) [50] or carbamacepine and gabapentin (1 patient) [69, 70]. In the first two cases, both patients improved but in one of the cases the improvement was brief, and treatment changed to corticoids [50]. The third patient did not improve [69]. In summary, only 4 out of the 9 patients treated with immunoglobulin therapy, obtained some degree of favorable response (44%).\n\nOther treatments\nBotulinum toxin was employed in three patients for controlling masticatory muscle spasms [32, 47, 59]. In one of them, botulinum toxin was used injected into both masseter muscles to control the trismus as a first treatment option together with systemic corticosteroids [59]. Merello et al. reported the use of botulinum toxin because of poor control of spasms with other treatments such as dantrolene, diazepam, clonazepam, phenytoin and carbamazepine [32].\n\nMuscle massage together with analgesics such as paracetamol, did not achieve any improvement [65]. Techniques of traditional Chinese medicine were used together with neostigmine in a patient with SS and myasthenia. The authors reported that after 8 months the patient was stable [40].\n\nTopical corticosteroid treatment was tested in three patients with alopecia, without beneficial results [5, 13, 64]. There is only one case reporting a response to diphencyprone, a drug used for alopecia areata [13]. Kamat et al. reported a patient who started treatment with minoxidil followed by topical steroids after he began losing hair on his scalp. Despite this treatment, he continued experiencing hair loss on his scalp [64]. Another patient reported by Ashalata et al., tried the treatment with minoxidil before the diagnosis was made, but without favorable result [35]. In one case, UVB rays were used to try to improve alopecia, but also without result [13].\n\nFor the control of diarrhea, a diet with restriction of simple carbohydrates was tried without results [2]. In another case with significant digestive manifestations, parenteral hyperalimentation was administered with weight improvement but without resolution of diarrhea, amenorrhea or alopecia [68]. Subsequently, this patient suffered episodes of recurrent pancreatitis attributed to stenosis of the duodenal papilla due to fibrosis of the duodenal mucosa. Gastrojejunostomy, percutaneous enterostomy, and percutaneous cholangiostomy were performed. The patient died a few months later due to sepsis [68]. This patient did not received therapy with corticosteroids or immunosuppressants.\n\nIn one case, the authors comment that treatment with estradiol and norgestrel was started to achieve regular menstrual cycles as well as breast development [63]. Growth hormone was also used to achieve greater growth [38]. In some patients, orthopedic surgery was necessary due to skeletal alterations [35, 65, 73].\n\nPrognosis\nSince the introduction of corticosteroids in the treatment, the prognosis of patients with Satoyoshi syndrome has improved. We found seven patients who died due to SS in the literature search [1, 52, 68]. Five out of these seven cases were described by Satoyoshi in 1978 [1]. The two other cases were those described by Nagahama et al. [68] and by Adachi et al. [52]. The first one was a patient with digestive manifestations and lesions compatible with cystic gastroenteritis. He died due to sepsis after suffering several episodes of recurrent pancreatitis and undergoing biliary and gastrojejunal surgery. The second case died as a consequence of a neuroleptic malignant syndrome after the start of treatment with intravenous midazolam. Only two one of the seven cases who died could have received corticoids at some point.\n\nRegarding the clinical manifestations of the syndrome, as already mentioned, muscular symptons improve in most cases with corticoids or dantrolene and the patient was able to carry on with a normal life with little interference from symptoms [2, 6, 35, 41, 61, 65, 73]. A smaller percentage of patients was able to recover from alopecia. Although hair regrowth was reported in some cases, complete full hair recovery was rare [2, 5, 6, 35, 41, 61, 65, 73]. Digestive symptoms also responded to treatment with steroids, with disappearance of diarrhea [2, 41, 46]. Menstruation also reappeared in many of the patients [35, 41, 66, 73].\n\nDiscussion\nOur review suggests that the best treatment for SS was corticosteroids administration. These drugs have been the primary treatment that has allowed an improvement in the prognosis of this disease. This improvement in prognosis is reflected in the fact that after the cases reported by Satoyoshi, mortality has been nil in the cases that received corticoid treatment. However, the appropriate duration of treatment, best corticosteroids dose, or the indication and time to add other immunosuppressive drugs, are still unknown. Other immunosuppressive drugs have been scarcely used, and most of the times they were administered in association with corticosteroids to reduce their dose or avoid adverse effects. Thus, it is not currently known whether their addition to corticosteroids allows increasing the efficacy of the treatment. Anticonvulsants and muscle relaxants were widely used in the first patients described [32, 33, 42, 49]. These drugs have not shown to be effective. In general, patients that improved with these drugs also received therapy with corticosteroids [2, 5, 34, 35, 41, 46, 47], therefore making difficult to assess the actual improvement of symptoms they cause. Only dantrolene showed efficacy in controlling muscle manifestations, but it failed to improve other symptoms of SS. Also, the management of SS includes not only pharmacological treatment but also other therapeutic approaches such as splints, botulinum toxin, dental procedures, surgery and orthopedic therapies and rehabilitation.\n\nAmong the limitations of this review are that it is based on case reports with a small number of patients, sometimes with an incomplete description and with a short follow-up. As with other rare diseases, there are no treatment guidelines or recommendations based on comparative studies. However, the review of the literature points towards a combination of immunosuppressant drugs based on corticosteroids. In addition, because only a few patients have been followed in the long-term, it is not possible to make recommendations about the duration of therapy or the rate of reduction of corticosteroids over time. On the other hand, the recorded response to treatment in SS patients was mainly clinical. There are no biological markers to predict or monitor the effect due to the medication.\n\nClinical experience supports the probable association between autoimmunity and Satoyoshi syndrome. In the next years, it is likely that further research may determine the role of specific autoantibodies in the pathogenesis and help the management of Satoyoshi syndrome. The discovery of the presence of antibodies against brain [75, 79] and gastrointestinal tissue [75] by means of western blot, opens a way to identify specific autoantibodies related to the pathogenesis of this syndrome which may become a diagnostic tool in the future.\n\nOn the other hand, the study of familial aggregation and possible genetic component of this disease is hampered by a lack of reports on the descendants of affected patients. The fact that amenorrhea or uterine hypoplasia are among the possible manifestations in women with SS make it difficult for these patients to have offspring. The association of SS with an autosomal recessive inheritance pattern [62] opens a new avenue of research in this field.\n\nAnother challenge is to achieve the collaboration among the different specialists who have treated SS patients, and particularly, the creation of an international registry of SS cases. Data from this future international registry should help to correlate the genetic and autoimmune information with the clinical characteristics and response to treatment.\n\nConclusions\nSatoyoshi syndrome is a rare disease with characteristic manifestations that make its clinical diagnosis easy if it is suspected. Since its description in the decade of the 60s, a multitude of drugs have been tested for its treatment. Our review suggests that the best treatment for SS was corticosteroids administration. Corticosteroids were the most widely used type of drugs (with different regimens, dosages and formulations), with the best results. However the differences in treatments, impaired follow-up data and small number of cases prevents any definitive conclusions. The use of corticosteroids and immunosuppressants has improved prognosis significantly. Other than corticosteroids and immunosuppressants, the drug that obtained the best response in the control of muscle spasms was dantrolene. This drug can be used in conjunction with corticosteroids or other immunosuppressants, although it has failed to show effect in non-muscular manifestations.\n\nPending issues are: the optimal treatment duration to achieve a sustained response with minimal side effects, the optimal dose of corticosteroids to be used, or whether the use of high dose intravenous boluses of corticosteroids every 4 to 6 weeks is better than daily oral doses. It is not clear either whether the combined use with methotrexate, azathioprine or cyclosporine is an alternative that will allow reducing or suspending corticoid treatment after a certain period of time.\n\nSS is a complex and multisystemic disease. The approach to patients must be individualized according to the patient’s manifestations, requiring a multidisciplinary team for their management. As it happens in other rare diseases, only data sharing and coordinated research among different clinical and research groups can lead to results that improve the clinical management of SS patients.\n\nAbbreviations\nSSSatoyoshi Syndrome\n\nWOSWeb of Science\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\nJS, JSGP and CdC conceived and designed the work. JSGP and CdC did the literature search and collected data. JSGP, CdC and JS revised and analyzed data. JSGP, CdC and JS drafted and revised the final manuscript and approved the submitted version.\n\nAuthors’ information\nCdC: https://orcid.org/0000-0002-2144-0107\n\nJSGP: https://orcid.org/0000-0002-8361-2090\n\nJS: https://orcid.org/0000-0001-9517-3083\n\nFunding\nThis paper was not funded.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.\n==== Refs\nReferences\n1. 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McKinley K Harati Y Fishman M Parke J Barroso A Satoyoshi syndrome without malabsorption or response to immunosuppression Ann Neurol 1991 30 2 264 \n34. Mukhopadhyay D Ghosh A Mukhopadhyay M Satoyoshi Syndrome Indian Pediatr 2011 48 729 731 21992906 \n35. Ashalatha R Kishore A Sarada C Nair MD Satoyoshi syndrome Neurol India 2004 52 94 95 15069249 \n36. Aver’ianov IN Vodolagin VD Logunova LV LIa L Positive therapeutic effect of diacarb in the syndrome of progressive muscle spasms, alopecia and diarrhea (Satoyoshi syndrome) Zh Nevropatol Psikhiatr Im S S Korsakova 1984 84 1623 1627 6524180 \n37. Aghoram R Srijithesh PR Kannoth S Adult-onset Satoyoshi syndrome and response to plasmapheresis Ann Indian Acad Neurol 2016 19 1 131 133 27011647 \n38. Merino de Paz N Rodriguez-Martin M Contreras Ferrer P Pestana Eliche M Noda Cabrera A Satoyoshi Syndrome: a cause of alopecia Universalis in association with neurologic and bony abnormalities Pediatr Dermatol 2013 30 e22 e24 22612551 \n39. Venegas-Vega CA Rivera-Vega MR Cuevas-Covarrubias S Orozco J Kofman-Alfaro S Satoyoshi syndrome with unusual skeletal abnormalities and parental consanguinity Am J Med Genet Part A 2009 149A 2448 2451 19839037 \n40. De-Xin W Hui-di F Three cases of recurrent generalized muscle spasm in China Jap J Med 1985 24 263 268 4068361 \n41. Li J Peng D Jiang T Avivi-Arber L Satoyoshi syndrome with progressive orofacial manifestations: a case history report Int J Prosthodont 2017 30 163 167 28267828 \n42. Kuru S Riku S Nakayabu M Kobayashi Y Ieda T A case of 'syndrome of progressive muslce spasm, alopecia, and diarrhea (Satoyoshi)' treated with steroid pulse therapy Clinical Neurology 1992 32 6 612 615 1424340 \n43. Matsumura T, Yokoe M, Shinno S. [A case of Satoyoshi syndrome complicating marginal gingivitis of the mandible and dislocation of the temporomandibular joint]. Japanese. PubMed PMID: 12710092.\n44. Ikegawa S Nagano A Nakamura K Kurokawa T A case of Satoyoshi’s Syndrome J Pediatr Orthop 1993 13 793 796 8245211 \n45. Matsuo N Fujioka M Tsuchiya Y Cho H Nagai T Kumagai M Multiple metaphyseal lesions in a child with a syndrome of progressive muscle cramps, alopecia and stunted growth (Satoyoshi disease) Radiation Medicine - Medical Imaging and Radiation Oncology 1983 1 205 207 \n46. Ishii K Furusho K Tamaoka A Morishita Y Lymphocytic colitis in Satoyoshi Syndrome South Med J 2010 103 591 20710153 \n47. Rosales, RL; Banzon, JE. Painful muscle spasms, twisting, and loose stools: what a combination in an adolescent girl!. Movement disorders: unforgettable cases and lessons from the bedside. ISBN: 978-1-9362-8728-4. 2013. 217–221.\n48. Satoh A Yoshimura T Mori M Tsujihata M Takamori M A case of generalized Komuragaeri disease complicating myasthenia gravis Clin Neurol 1982 22 251 257 \n49. Inoue K General muscle crapms (Komuragaeri disease) and its intestinal absortion Clin Neurol 1976 20 699 705 \n50. Endo K Yamamoto T Nakamura K Hoshi A Yamanoi T Watanabe A Homma M Improvement of Satoyoshi syndrome with tacrolimus and corticosteroids Neurology. 2003 60 12 2014 2015 12821760 \n51. Asherson RA Giampaolo D Strimling M A case of adult-onset Satoyoshi syndrome with gastric ulceration and eosinophilic enteritis Nat Clin Pract Rheumatol 2008 4 439 444 18607399 \n52. Adachi H Riku S Fujishiro K Kuru S A case of Satoyoshi syndrome with symptoms resembling neuroleptic malignant syndrome Rinsho Shinkeigaku 1998 38 7 637 640 9868307 \n53. Mani V George R Satoyoshi syndrome - a case report from India Pediatr Dermatol 2017 00 1 3 \n54. Sharpe A Mahadasu S Manda P Meneni D Satoyoshi syndrome in pregnancy Eur J Obstet Gynecol Reprod Biol 2016 199 215 216 26947175 \n55. Drost G Verrips A van Engelen BG Stegeman DF Zwarts MJ Involuntary painful muscle contractions in Satoyoshi syndrome: a surface electromyographic study Mov Disord 2006 21 11 2015 2018 16972238 \n56. Ehlayel MS Lacassie Y Satoyoshi Syndrome: an unusual postnatal multisystemic disorder Am J Med Genet 1995 57 620 625 7573141 \n57. Yamagata T Miyao M Momoi M Matsumoto S Yanagisawa M A case of generalized komuragaeri disease (Satoyoshi disease) treated with glucocorticoid Clin Neurol. 1991 31 79 83 \n58. Ezgu FS Tumer L Serdaroglu A Hasanoglu A Cansu A Hirfanoglu T Dalgic B The co-existence of Satoyoshi syndrome and myoadenylate deaminase deficiency J Inherit Metab Dis 2005 28 253 \n59. Montanaro VVA Hora TF Couto CM Ribas FD Adult-onset Satoyoshi syndrome in a young male Neuromuscul Disord 2017 27 382 338 28215594 \n60. Dhamija R Renaud DL Pittock SJ McKeon A Lachance DH Nickels KC Wirrell EC Kuntz NL King MD Lennon VA Neuronal voltage-gated Potassium Channel complex autoimmunity in children Pediatr Neurol 2011 44 275 281 21397169 \n61. Cecchin CR Félix TM Magalhães RB Furlanetto TW Satoyoshi Syndrome in a Caucasian girl improved with glucocorticoids Am J Med Genet A 2003 118A 52 54 12605441 \n62. Solera J Álvarez S Botet J de Cabo C A newly homozygous variant in ZNF808: a possible candidate gene for Satoyoshi Syndrome? J Neurol Sci 2017 379 226 228 28716247 \n63. Heger S Kuester RM Volk R Stephani U Sippell WG Satoyoshi syndrome: a rare multisystemic disorder requiring systemic and symptomatic treatment Brain Dev 2006 28 300 304 16478652 \n64. Kamat D Petry L Berry S A case of Satoyoshi Syndrome: a multisystem disorder Clin Pediatr (Phila) 2003 42 745 748 14601924 \n65. Wisuthsarewong W Likitmaskul S Manonukul J Satoyoshi syndrome Pediatr Dermatol 2001 18 406 410 11737686 \n66. Oyama M Imaizumi T Mitsuhashi Y Kondo S Satoyoshi syndrome Arch Dermatol 1999 135 91 92 9923791 \n67. Son KR JH KK Kim BJ Kim SJ Ma JS A case of Satoyoshi syndrome presented with progressive muscular spasm and alopecia J Korean Pediatr Soc 2002 45 1165 1169 \n68. NagahamaT YK Oishi T Iwashita A Hirai F Yao T Matsui T Takaki Y GI manifestations of Satoyoshi’s syndrome Gastrointest Endosc 2006 64 143 145 16813828 \n69. Solera J Rallo B Herranz AS Pardal JM Martin-del Rio R de Cabo C High glycine levels in the cerebrospinal fluid in Satoyoshi syndrome J Neurol Sci 2015 357 1–2 312 313 26190524 \n70. Pardal-Fernández JM Solera-Santos J Iniesta-López I Rodríguez-Vázquez M Satoyoshi's syndrome related muscle spasms: functional study Rev Neurol (Paris) 2012 168 3 291 295 22100320 \n71. Li J Jiang T Feng HL A case report of dental abnormality and prosthetic treatment of Satoyoshi syndrome Zhonghua Kou Qiang Yi Xue Za Zhi 2008 43 4 213 215 18846940 \n72. Drost G Verrips A Hooijkaas H Zwarts M Glutamic acid decarboxylase antibodies in Satoyoshi syndrome Ann Neurol 2004 55 3 450 451 14991831 \n73. Haymon M Willis RB Ehlayel MS Lacassie Y Radiological and orthopedic abnormalities in Satoyoshi syndrome Pediatr Radiol 1997 27 5 415 418 9133353 \n74. Satoh A Tsujihata M Yoshimura T Mori M Nagataki S Myasthenia gravis associated with Satoyoshi syndrome: muscle cramps, alopecia, and diarrhea Neurology. 1983 33 9 1209 1211 6684258 \n75. Matsuura E Matsuyama W Sameshima T Arimura K Satoyoshi syndrome has antibody against brain and gastrointestinal tissue Muscle Nerve 2007 36 3 400 403 17405137 \n76. Itahara K Oyama K Ohara Y Kobayashi K Tsumuraya K Iijima K Nakamura S Rikimaru S Gastroscopic findings of a patient with recurrent muscle spasm of central origin (Satoyoshi) Clin Neurol 1976 20 126 128 \n77. See S Ginzburg R Skeletal muscle relaxants Pharmacotherapy. 2008 28 2 207 213 18225966 \n78. Rosenberg H Pollock N Schiemann A Bulger T Stowell K Malignant hyperthermia: a review Orphanet J Rare Dis 2015 10 93 26238698 \n79. Endo K Kumagai T Nakahara T Nakamura K Shimizu M Watanabe A A novel autoantibody associated with Satoyoshi syndrome Neuroimmunology (Tokyo) 2001 9 102 103\n\n",
"fulltext_license": "CC BY",
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"issue": "14(1)",
"journal": "Orphanet journal of rare diseases",
"keywords": "Alopecia; Corticosteroids; Dantrolene; Diarrhea; Immunoglobulin therapy; Muscle spasms; Rare diseases; Satoyoshi syndrome",
"medline_ta": "Orphanet J Rare Dis",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000505:Alopecia; D000818:Animals; D000927:Anticonvulsants; D001842:Bone and Bones; D003620:Dantrolene; D003967:Diarrhea; D005260:Female; D006801:Humans; D007116:Immunization, Passive; D007166:Immunosuppressive Agents; D008297:Male; D035583:Rare Diseases; D013035:Spasm",
"nlm_unique_id": "101266602",
"other_id": null,
"pages": "146",
"pmc": null,
"pmid": "31217029",
"pubdate": "2019-06-19",
"publication_types": "D016428:Journal Article; D016454:Review",
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"title": "Treatment of Satoyoshi syndrome: a systematic review.",
"title_normalized": "treatment of satoyoshi syndrome a systematic review"
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"abstract": "BACKGROUND\nThe Centers of Disease Control and Prevention have declared prescription drug abuse an epidemic in the United States. However, demographic data correlating prescription-related deaths with actual prescriptions written is not well described. The purpose of this study is to compare toxicology reports on autopsy for prescription-related deaths with Prescription Drug Monitor Program (PDMP) data.\n\n\nMETHODS\nThis is a retrospective analysis comparing 2013 San Diego Medical Examiner data on 254 unintentional prescription-related deaths obtained for 12 months before death with data from the California PDMP. Data were analyzed on age, sex, whether there was information on the PDMP, types and quantities of prescribed medications, number of pharmacies and providers involved, and whether there was a match between the Medical Examiner toxicology report and data from the PDMP.\n\n\nRESULTS\nIn 2013, there were 254 unintentional prescription-related deaths; 186 patients (73%) had PDMP data 12 months before death. Ingesting prescription medications with illicit drugs, alcohol, and/or over-the-counter medications accounted for 40% of the unintentional deaths. Opioids were responsible for the majority of single medication deaths (36; 70.6%). The average number of prescriptions was 23.5 per patient, and the average patient used 3 pharmacies and had 4.5 providers. Chronic prescription use was found in 68.8% of patients with PDMP data.\n\n\nCONCLUSIONS\nThe PDMP data highlight important patterns that can provide valuable insight to clinicians making decisions regarding types and amounts of medications they prescribe. Although there is no guaranteed solution to prevent prescription-related deaths, PDMP data can be useful to prevent coprescribing and medication interaction and by following best clinical practices.",
"affiliations": "Department of Emergency Medicine, Scripps Mercy Hospital, San Diego, CA.;Keck School of Medicine, University of Southern California, Los Angeles, CA.;University of Arizona, Tucson, AZ.;San Diego County Medical Examiners Office, San Diego, CA.;Department of Emergency Medicine, University of California, San Diego, San Diego, CA.;Department of Emergency Medicine, University of California, San Diego, San Diego, CA.;Department of Emergency Medicine, University of California, San Diego, San Diego, CA. Electronic address: emcastillo@ucsd.edu.",
"authors": "Lev|Roneet|R|;Petro|Sean|S|;Lee|Oren|O|;Lucas|Jonathan|J|;Stuck|Amy|A|;Vilke|Gary M|GM|;Castillo|Edward M|EM|",
"chemical_list": "D055553:Prescription Drugs",
"country": "United States",
"delete": false,
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"issn_linking": "0735-6757",
"issue": "34(3)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D001344:Autopsy; D002140:California; D002423:Cause of Death; D003334:Coroners and Medical Examiners; D004347:Drug Interactions; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011041:Poisoning; D063487:Prescription Drug Misuse; D055553:Prescription Drugs; D012189:Retrospective Studies; D017678:Sex Distribution; D055815:Young Adult",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "510-4",
"pmc": null,
"pmid": "26778639",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A description of Medical Examiner prescription-related deaths and prescription drug monitoring program data.",
"title_normalized": "a description of medical examiner prescription related deaths and prescription drug monitoring program data"
} | [
{
"companynumb": "US-UCBSA-2016017490",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "ALPRAZOLAM"
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"... |
{
"abstract": "BACKGROUND\nTaxanes may partly mediate their effect in castration-resistant prostate cancer (CRPC) through disruption of androgen-receptor trafficking along microtubules. This raises the possibility of cross-resistance between androgen-directed agents and docetaxel.\n\n\nOBJECTIVE\nTo evaluate docetaxel efficacy after abiraterone treatment in CRPC patients.\n\n\nMETHODS\nThis was a single-institution, retrospective analysis in CRPC patients (N=119) who either received abiraterone before docetaxel (AD) (n=24) or did not receive abiraterone before docetaxel (docetaxel-only; n=95). Men initiated docetaxel between December 2007 (the date abiraterone was first used at our center) and May 2013.\n\n\nMETHODS\nThe primary efficacy end points were prostate-specific antigen progression-free survival (PSA-PFS) and clinical/radiographic progression-free survival (PFS) on docetaxel. Differences between groups were assessed using univariate and multivariable analyses.\n\n\nCONCLUSIONS\nMen in the AD group had a significantly higher risk for progression than those in the docetaxel-only group. Median PSA-PFS was 4.1 mo in the AD group and 6.7 mo in the docetaxel-only group (p=0.002). Median PFS was also shorter in the AD group (4.4 mo vs 7.6 mo; p=0.003). In multivariable analysis, prior abiraterone treatment remained an independent predictor of shorter PSA-PFS (hazard ratio [HR]: 3.48; 95% confidence interval [CI], 1.36-8.94; p=0.01) and PFS (HR: 3.62; 95% CI, 1.41-9.27; p=0.008). PSA declines ≥50% were less frequent in the AD group (38% vs 63%; p=0.02). The small size and retrospective nature of this study may have introduced bias.\n\n\nCONCLUSIONS\nMen receiving abiraterone before docetaxel were more likely to progress on docetaxel and less likely to achieve a PSA response than abiraterone-naïve patients. Cross-resistance between abiraterone and docetaxel may explain these findings; however, larger, more definitive studies are still needed to confirm this.\n\n\nRESULTS\nWe examined the efficacy of docetaxel in castration-resistant prostate cancer patients who either did or did not receive prior abiraterone. We found that men receiving abiraterone before docetaxel were less likely to achieve a PSA response and were more likely to progress sooner on docetaxel than abiraterone-untreated patients. This may be due to cross-resistance.",
"affiliations": "The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA. Electronic address: eantona1@jhmi.edu.",
"authors": "Schweizer|Michael T|MT|;Zhou|Xian C|XC|;Wang|Hao|H|;Bassi|Sunakshi|S|;Carducci|Michael A|MA|;Eisenberger|Mario A|MA|;Antonarakis|Emmanuel S|ES|",
"chemical_list": "D000736:Androstenes; D043823:Taxoids; D000077143:Docetaxel; C089740:abiraterone",
"country": "Switzerland",
"delete": false,
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"issn_linking": "0302-2838",
"issue": "66(4)",
"journal": "European urology",
"keywords": "Abiraterone; Activity; Docetaxel; Efficacy; Progression-free survival; Prostate cancer",
"medline_ta": "Eur Urol",
"mesh_terms": "D000368:Aged; D000736:Androstenes; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D015331:Cohort Studies; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D064129:Prostatic Neoplasms, Castration-Resistant; D012189:Retrospective Studies; D018570:Risk Assessment; D015996:Survival Rate; D043823:Taxoids; D016896:Treatment Outcome",
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"pages": "646-52",
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"publication_types": "D003160:Comparative Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
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"title": "The influence of prior abiraterone treatment on the clinical activity of docetaxel in men with metastatic castration-resistant prostate cancer.",
"title_normalized": "the influence of prior abiraterone treatment on the clinical activity of docetaxel in men with metastatic castration resistant prostate cancer"
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"abstract": "The proteasome inhibitor bortezomib is indicated for use in the treatment of multiple myeloma (MM) patients. The most common side effects are neurological and gastrointestinal, while severe pulmonary complications are rarely described. The present study reports the case of a 62-year-old man with immunoglobulin (Ig)G-type MM who was treated with bortezomib, thalidomide and dexamethasone. Subsequent to the administration of chemotherapy, the patient developed an acute respiratory distress syndrome. High-resolution computed tomography of the chest showed bilateral diffuse alveolar infiltrations and multiple subpleural lesions. A diagnosis of bortezomib-induced severe pulmonary complications was formed. Systemic corticosteroid therapy led to a rapid improvement in clinical conditions and radiological findings. In addition, the present study reviewed the characteristics, including medical history, clinical manifestations, treatment strategies and outcomes, of all 16 MM patients with bortezomib-induced severe pulmonary complications reported previously in Pubmed. It was indicated that patients who were male, of IgG type, with a relapse status and a previous history of auto-PBSCT had a higher possibility of developing bortezomib-induced severe pulmonary complications. Additionally, a relatively low dose rather than a high dose of corticosteroids could obtain a better outcome.",
"affiliations": "Intensive Care Unit, The Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang 310009, P.R. China.;Intensive Care Unit, The Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang 310009, P.R. China.;Intensive Care Unit, The Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang 310009, P.R. China.;Intensive Care Unit, The Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang 310009, P.R. China.",
"authors": "Li|Jingbo|J|;Chen|Shuda|S|;Hu|Yinghong|Y|;Cai|Jing|J|",
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"doi": "10.3892/ol.2016.4204",
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"issue": "11(3)",
"journal": "Oncology letters",
"keywords": "bortezomib; corticosteroids; multiple myeloma; pulmonary complications",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "2255-2260",
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"title": "Bortezomib-induced severe pulmonary complications in multiple myeloma: A case report and literature review.",
"title_normalized": "bortezomib induced severe pulmonary complications in multiple myeloma a case report and literature review"
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"abstract": "Non-Hodgkin lymphoma can occur concurrently with chronic phase-chronic myeloid leukemia (CML) at initial diagnosis. Combination treatment with second-generation tyrosine kinase inhibitors and rituximab-CHOP for patients newly diagnosed with CML and non-Hodgkin lymphoma is effective for both diseases. However, we found that this treatment combination may induce severe myelosuppression.",
"affiliations": "First Department of Internal Medicine Kansai Medical University Osaka 573-1010 Japan.;First Department of Internal Medicine Kansai Medical University Osaka 573-1010 Japan.;First Department of Internal Medicine Kansai Medical University Osaka 573-1010 Japan.;First Department of Internal Medicine Kansai Medical University Osaka 573-1010 Japan.;First Department of Internal Medicine Kansai Medical University Osaka 573-1010 Japan.;First Department of Internal Medicine Kansai Medical University Osaka 573-1010 Japan.;First Department of Internal Medicine Kansai Medical University Osaka 573-1010 Japan.;First Department of Internal Medicine Kansai Medical University Osaka 573-1010 Japan.;First Department of Internal Medicine Kansai Medical University Osaka 573-1010 Japan.;First Department of Internal Medicine Kansai Medical University Osaka 573-1010 Japan.;First Department of Internal Medicine Kansai Medical University Osaka 573-1010 Japan.",
"authors": "Takeyasu|Yuki|Y|;Satake|Atsushi|A|0000-0002-6007-6264;Azuma|Yoshiko|Y|;Tsubokura|Yukie|Y|;Yoshimura|Hideaki|H|;Hotta|Masaaki|M|;Nakanishi|Takahisa|T|;Fujita|Shinya|S|;Nakaya|Aya|A|;Ito|Tomoki|T|;Nomura|Shosaku|S|",
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"doi": "10.1002/ccr3.1253",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1253CCR31253Case ReportCase ReportsTyrosine kinase inhibitor and rituximab‐CHOP treatment for concurrent chronic myeloid leukemia and non‐Hodgkin lymphoma: a case report Y. Takeyasu et al.Takeyasu Yuki \n1\nSatake Atsushi http://orcid.org/0000-0002-6007-6264satakeat@hirakata.kmu.ac.jp \n1\nAzuma Yoshiko \n1\nTsubokura Yukie \n1\nYoshimura Hideaki \n1\nHotta Masaaki \n1\nNakanishi Takahisa \n1\nFujita Shinya \n1\nNakaya Aya \n1\nIto Tomoki \n1\nNomura Shosaku \n1\n\n1 \nFirst Department of Internal Medicine\nKansai Medical University\nOsaka\n573‐1010\nJapan\n* Correspondence\n\nAtsushi Satake, First Department of Internal Medicine, Kansai Medical University, 2‐5‐1 Shinmachi Hirakata city, Osaka 573‐1010, Japan. Tel: 072 804 2503; Fax: 072 804 2504; E‐mail: satakeat@hirakata.kmu.ac.jp\n02 11 2017 12 2017 5 12 10.1002/ccr3.2017.5.issue-122047 2050 19 7 2017 24 9 2017 05 10 2017 © 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nNon‐Hodgkin lymphoma can occur concurrently with chronic phase‐chronic myeloid leukemia (CML) at initial diagnosis. Combination treatment with second‐generation tyrosine kinase inhibitors and rituximab‐CHOP for patients newly diagnosed with CML and non‐Hodgkin lymphoma is effective for both diseases. However, we found that this treatment combination may induce severe myelosuppression.\n\nChronic myeloid leukemiamyelosuppressionnon‐Hodgkin lymphomaprimary mediastinal large B‐cell lymphomatyrosine kinase inhibitor source-schema-version-number2.0component-idccr31253cover-dateDecember 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.7 mode:remove_FC converted:05.12.2017\n\nClinical Case Reports \n2017 ; 5 (12 ): 2047 –2050\n==== Body\nIntroduction\nChronic myeloid leukemia (CML) is a clonal proliferative disorder of hematopoietic stem cells characterized by the Philadelphia (Ph) chromosome created by a reciprocal t(9:22) translocation, which transfers the Abelson (ABL) oncogene on chromosome 9 to the breakpoint cluster region (BCR) of chromosome 22, thus resulting in a fused BCR/ABL gene. The prognosis of CML has dramatically improved as the development of BCR‐ABL tyrosine kinase inhibitors (TKIs) 1. Although TKIs are unlikely to induce secondary malignancies 2, CML patients sometimes develop other malignancies because of their prolonged survival. However, coexistence of CML and another hematological malignancy at diagnosis is rarely observed. Moreover, the optimal treatment strategy for these patients in the second‐generation TKI (2nd TKI) era remains poorly understood. We describe a case of concurrent CML and NHL treated with 2nd TKI+rituximab‐CHOP (R‐CHOP) therapy.\n\nCase Report\nA 66‐year‐old woman diagnosed with leukocytosis and a mediastinal tumor was referred to our hospital for further investigation. Physical examination revealed significant splenomegaly (10 cm below the costal margin), but no enlarged superficial lymph nodes. Laboratory test findings were as follows: white blood cell count, 281.9 × 109/L (29% neutrophils, 0% lymphocytes, 1.5% monocytes, 7.0% basophiles, 4.5% myeloblasts, 35.0% myelocytes, and 9.5% metamyelocytes); hemoglobin, 9.5 g/dL; platelet count, 41.9 × 104/μL; lactic dehydrogenase, 833 U/L; and vitamin B12, >1500 pg/mL. Major BCR‐ABL mRNA transcripts were detected from peripheral blood via polymerase chain reaction. Bone marrow analysis showed marked hypercellularity with significant myeloid hyperplasia, while G‐band chromosome analysis showed a Ph‐chromosome translocation t(9;22) (q34;q11.2) in 100% of metaphases (20/20 cells) analyzed. The Sokal score was 1.686, indicating high risk. Computed tomography showed a tumor extending from the mediastinum to the right lung hilar region and bilateral pleural effusion. Therefore, she was diagnosed with CML; the mediastinal tumor was considered an extramedullary CML lesion. Dasatinib, which is applicable for chronic‐phase, accelerated‐phase, and blastic‐phase CML, was administered at a dose of 100 mg/day. Flow cytometric analysis of the pleural effusion did not indicate monoclonal abnormal leukocytes, while cytogenetic analysis of the fluid showed the Ph‐chromosome in 15% of metaphases (3/20 cells). Hematologic response was attained immediately; however, dyspnea owing to the increased pleural effusion emerged 5 weeks after the administration of dasatinib. Therefore, dasatinib was discontinued, and a diuretic drug was administered. Nevertheless, the pleural effusion worsened 2 weeks later. Dasatinib treatment was restarted at a dose of 50 mg/day. Subsequently, the patient underwent mediastinal tumor biopsy via video‐assisted thoracoscopic surgery. Histopathological examination showed focal and colonized proliferation of large lymphoid cells (Fig. 1A and B). Immunohistochemical analysis indicated these lymphocytes were CD3‐negative, CD20‐positive, and bcl‐6‐positive (Fig. 1C and D). Fluorescence in‐situ hybridization of the biopsy sample demonstrated the absence of the BCR/ABL fusion gene. 18F‐Fluorodeoxyglucose‐positron‐emission tomography/computed tomography demonstrated fluorodeoxyglucose accumulation (SUVmax 5.9) with lymphadenopathy in the cervical, mediastinal, hilar, and abdominal lymph nodes (Fig. 2). Finally, the patient was diagnosed with concurrent chronic‐phase CML (CP‐CML) and primary mediastinal large B‐cell lymphoma (PMBL).\n\nFigure 1 Histopathological images. Hematoxylin and eosin staining of the mediastinal tumor biopsy specimen (A, ×100) (B, ×400) revealed focal and colonized proliferation of large lymphoid cells. Immunohistochemical stains highlight that large lymphocytes are positive for CD 20 (C, ×400) and bcl‐6 (D, ×400). CD, cluster of differentiation; bcl‐6, B‐cell lymphoma 6.\n\nFigure 2 Imaging findings. (A) Computed tomography images at initial consultation. (B) FDG positron‐emission tomography images obtained before R‐CHOP. The image shows FDG accumulation in the cervical, mediastinal, hilar, and abdominal lymph nodes. FDG, 18F‐Fluorodeoxyglucose; R‐CHOP, Rituximab‐CHOP.\n\nThe patient was administered R‐CHOP therapy for the PMBL, and nilotinib (300 mg twice daily) for the CML to clear the pleural effusion. Grade 4 neutropenia occurred after the first cycle of nilotinib+R‐CHOP therapy. Furthermore, grade 4 thrombocytopenia and grade 3 anemia developed after the second cycle. Therefore, R‐CHOP therapy was discontinued owing to the prolonged severe myelosuppression. The third cycle of R‐CHOP, comprising of the same dosage as first and second cycles, was restarted 12 weeks after the previous cycle. Severe thrombocytopenia and anemia were not observed. There were no nonhematological adverse events during the treatment with nilotinib+R‐CHOP therapy. Complete remission of PMBL after six cycles of R‐CHOP was confirmed via 18F‐fluorodeoxyglucose–positron‐emission tomography/computed tomography. Disappearance of the BCR‐ABL fusion gene in peripheral blood was demonstrated via Fluorescence in‐situ hybridization analysis, 6 months after the initiation of TKI treatment, indicating a complete cytogenetic response. The BCR‐ABL mRNA transcript level in peripheral blood measured via quantitative reverse‐transcriptase polymerase chain reaction at 9 months after diagnosis revealed a major molecular response per international standards (Fig. 3).\n\nFigure 3 Clinical course from the initial consult in our hospital. Das, dasatinib; Nilo, nilotinib; R, rituximab; PT, platelet transfusion; RBC, red blood cell transfusion.\n\nDiscussion\nIn the present case, examination of the patient's bone marrow resulted in a diagnosis of CP‐CML, while the biopsy of the mediastinal tumor indicated that the PMBL originated from another clonal CML population. The patient received 2nd TKI+R‐CHOP and has achieved total remission from both diseases, despite severe myelosuppression.\n\nLittle is known about the clinical and genetic characteristics of B‐cell NHL with CML, and most of these cases have been reported before the TKI era 3, 4, 5. 2nd TKIs have shown remarkable efficacy for newly diagnosed CP‐CML 6, 7, 8, 9, 10; however, optimal approaches for patients with concurrent CML and NHL at diagnosis remains unclear.\n\nPleural effusions occurred more frequently in patients receiving dasatinib 1, 8, 10. Therefore, TKIs apart from dasatinib are commonly selected for patients at risk of developing pleural effusions. Until histopathological confirmatory diagnosis, we suspected that the mediastinal tumor with pleural effusion was an extramedullary lesion of CML, namely a blast crisis CML, hence, we had prescribed dasatinib treatment initially. Lymphopenia, neutropenia, and thrombocytopenia are common hematologic adverse events of nilotinib treatment in patients with newly diagnosed CP‐CML 1, 6, 7. Interestingly, these adverse events generally indicate a favorable profile. Moreover, as witnessed in our case, 2nd TKI+R‐CHOP therapy for patients with newly diagnosed CML and NHL may induce serious myelosuppression. The myelosuppression may have been caused by a small quantity of normal hematopoietic stem cells. After the achievement of a major molecular response and recovery from myelosuppression, our patient did not develop severe thrombocytopenia or anemia due to the nilotinib+R‐CHOP therapy. Therefore, if a patient with CML has achieved a good response, the efficacy of a combination of chemotherapy with another treatment may not be affected by hematologic toxicity. Secondary cancers that occur in a small percentage of patients with CML are mostly neoplasms of nonhematologic origin 2. The occurrence of NHL, mostly T‐cell lymphomas, with CML is less frequent 4. Identification of a B‐cell lymphoma at the time of CML diagnosis is even rarer, and in our case, Ph‐PMBL was identified in a patient with CP‐CML at diagnosis. PMBL is an aggressive lymphoma, which generally has a high SUVmax value with 18F‐Fluorodeoxyglucose–positron‐emission tomography/computed tomography; however, the SUVmax was lower than expected in our case. This might be associated with hyperglycemia as the patient had mild diabetes mellitus. There are some case reports in which patients have demonstrated concurrent CML and NHL at diagnosis 3, 5, 11. Nevertheless, to the best of our knowledge, no patient has received 2nd TKI and chemotherapy as an initial treatment. Furthermore, we believe that this is the first case of concurrent NHL and CP‐CML successfully treated with combination therapy consisting of 2nd TKI and R‐CHOP. The findings of the case also indicate that serious myelosuppression may be caused by this combination therapy early after its initiation.\n\nIn conclusion, NHL can occur concurrently with CP‐CML at initial diagnosis. Despite severe myelosuppression, treatment with 2nd TKI+R‐CHOP can be effective for patients with newly diagnosed CP‐CML and concurrent NHL. Optimal treatment strategies including the appropriate dose or timing of chemotherapy against the second malignancy should be elucidated for patients with CML receiving TKI therapy.\n\nConflict of Interest\nNone declared.\n\nAuthorship\nYT: hospitalization of the patient and data collection. AS: hospitalization and outpatient follow‐up, data analysis, and manuscript drafting. YA, YT, HY, MH, TN, SF, AN, TI, and SN: patient's hospitalization and manuscript review. SN: supervision of the case.\n==== Refs\nReferences\n1 \n\nJabbour , E. \n, and \nH. \nKantarjian \n. 2016 \nChronic myeloid leukemia: 2016 update on diagnosis, therapy, and monitoring . Am. J. Hematol. \n91 :252 –265 .26799612 \n2 \n\nVerma , D. \n, \nH. \nKantarjian \n, \nS. S. \nStrom \n, \nM. B. \nRios \n, \nE. \nJabbour \n, \nA. \nQuintas‐Cardama \n, et al. 2011 \nMalignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and other hematologic malignancies . Blood \n118 :4353 –4358 .21846902 \n3 \n\nAu , W. Y. \n, \nS. K. \nMa \n, \nT. S. \nWan \n, \nE. P. \nWang \n, \nT. C. \nLau \n, and \nY. L. \nKwong \n. 2003 \nConcurrent mediastinal B cell lymphoma and chronic myeloid leukemia with an unusually favorable response to chemotherapy . Leuk. Lymphoma \n44 :535 –538 .12688328 \n4 \n\nIchinohasama , R. \n, \nI. \nMiura \n, \nN. \nTakahashi \n, \nT. \nSugawara \n, \nE. \nTamate \n, \nK. \nEndoh \n, et al. 2000 \nPh‐negative non‐Hodgkin's lymphoma occurring in chronic phase of Ph‐positive chronic myelogenous leukemia is defined as a genetically different neoplasm from extramedullary localized blast crisis: report of two cases and review of the literature . Leukemia \n14 :169 –182 .10637493 \n5 \n\nZamecnikova , A. \n, \nA. \nVranovsky \n, and \nP. \nHlavcak \n. 2002 \nCoexistence of Philadelphia‐positive chronic granulocytic leukemia and diffuse large B‐cell lymphoma at initial diagnosis . Leuk. Lymphoma \n43 :429 –431 .11999582 \n6 \n\nSaglio , G. \n, \nD. W. \nKim \n, \nS. \nIssaragrisil \n, \nR. \nPasquini \n, \nR. E. \nClark \n, \nA. \nHochhaus \n, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia . N. Engl. J. Med. \n2010 ;362 :2251 –2252 \n20525993 \n7 \n\nHochhaus , A. \n, \nG. \nSaglio \n, \nT. P. \nHughes \n, \nR. A. \nLarson \n, \nD. W. \nKim \n, \nS. \nIssaragrisil \n, et al. 2016 \nLong‐term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5‐year update of the randomized ENESTnd trial . Leukemia \n30 :1044 –1054 .26837842 \n8 \n\nKantarjian , H. \n, \nN. P. \nShah \n, \nA. \nHochhaus \n, \nJ. \nCortes \n, \nS. \nShah \n, \nM. \nAyala \n, et al. 2010 \nDasatinib versus imatinib in newly diagnosed chronic‐phase chronic myeloid leukemia . N. Engl. J. Med. \n362 :2260 –2270 .20525995 \n9 \n\nCortes , J. E. \n, \nD. \nJones \n, and \nS. \nO'Brien \n. 2010 \nResults of dasatinib therapy in patients with early chronic‐phase chronic myeloid leukemia . J. Clin. Oncol. \n28 :398 –404 .20008620 \n10 \n\nJabbour , E. \n, \nH. M. \nKantarjian \n, \nG. \nSaglio \n, \nJ. L. \nSteegmann \n, \nN. P. \nShah \n, \nC. \nBoqué \n, et al. 2014 \nEarly response with dasatinib or imatinib in chronic myeloid leukemia: 3‐year follow‐up from a randomized phase 3 trial (DASISION) . Blood \n123 :494 –500 .24311723 \n11 \n\nAcar , H. \n, \nS. \nEcirli \n, \nF. \nGündoğan \n, \nO. \nBulay \n, and \nA. \nAcar \n. 1999 \nSimultaneous occurrence of chronic myelogenous leukemia and non‐Hodgkin lymphoma at diagnosis . Cancer Genet. Cytogenet. \n108 :171 –174 .9973949\n\n",
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"issn_linking": "2050-0904",
"issue": "5(12)",
"journal": "Clinical case reports",
"keywords": "Chronic myeloid leukemia; myelosuppression; non‐Hodgkin lymphoma; primary mediastinal large B‐cell lymphoma; tyrosine kinase inhibitor",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
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"pages": "2047-2050",
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"title": "Tyrosine kinase inhibitor and rituximab-CHOP treatment for concurrent chronic myeloid leukemia and non-Hodgkin lymphoma: a case report.",
"title_normalized": "tyrosine kinase inhibitor and rituximab chop treatment for concurrent chronic myeloid leukemia and non hodgkin lymphoma a case report"
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"abstract": "The aim of this study was to test the feasibility and utility of developing patient-derived orthotopic xenograft (PDOX) models for patients with malignant peripheral nerve sheath tumors (MPNSTs) to aid therapeutic interventions in real time.\nA sporadic relapsed MPNST developed in a 14-year-old boy was engrafted in mice, generating a PDOX model for use in co-clinical trials after informed consent. SNP-array and exome sequencing was performed on the relapsed tumor. Genomics, drug availability, and published literature guided PDOX treatments.\nA MPNST PDOX model was generated and expanded. Analysis of the patient's relapsed tumor revealed mutations in the MAPK1, EED, and CDK2NA/B genes. First, the PDOX model was treated with the same therapeutic regimen as received by the patient (everolimus and trametinib); after observing partial response, tumors were left to regrow. Regrown tumors were treated based on mutations (palbociclib and JQ1), drug availability, and published literature (nab-paclitaxel; bevacizumab; sorafenib plus doxorubicin; and gemcitabine plus docetaxel). The patient had a lung metastatic relapse and was treated according to PDOX results, first with nab-paclitaxel, second with sorafenib plus doxorubicin after progression, although a complete response was not achieved and multiple metastasectomies were performed. The patient is currently disease free 46 months after first relapse.\nOur results indicate the feasibility of generating MPNST-PDOX and genomic characterization to guide treatment in real time. Although the treatment responses observed in our model did not fully recapitulate the patient's response, this pilot study identify key aspects to improve our co-clinical testing approach in real time.",
"affiliations": "Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.;Pediatric Oncology Department, Hospital Sant Joan de Déu, Barcelona, Catalunya, Spain.;Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain.;Pediatric Oncology Department, Hospital Sant Joan de Déu, Barcelona, Catalunya, Spain.;Pediatric Oncology Department, Hospital Sant Joan de Déu, Barcelona, Catalunya, Spain.;Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.;CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Catalunya, Spain.;CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Catalunya, Spain.;CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Catalunya, Spain.;Programa d'Assessorament i Genètica Clínica, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain.;Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.;Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.;Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.;Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain.;Pediatric hand surgery and microsurgery, Hospital Sant Joan de Déu, Universitat de Barcelona, Spain.;Pediatric Surgical Oncology, Pediatric Surgery Department, Hospital Sant Joan de Déu, Universitat de Barcelona, Spain.;Pathology Department, Hospital Sant Joan de Déu, Barcelona, Spain.;Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain.;Procure Program, Catalan Institute of Oncology, Hospitalet de Llobregat (Barcelona) and CIBERONC, Av. Gran Via 199-203, Hospitalet de Llobregat, 08908, Spain.;Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL and CIBERONC, Av. Gran Via 199-203, Hospitalet de Llobregat, 08908, Spain.",
"authors": "Fernández-Rodríguez|Juana|J|;Morales La Madrid|Andrés|A|;Gel|Bernat|B|;Castañeda Heredia|Alicia|A|;Salvador|Héctor|H|;Martínez-Iniesta|María|M|;Moutinho|Catia|C|;Morata|Jordi|J|;Heyn|Holger|H|;Blanco|Ignacio|I|;Creus-Bachiller|Edgar|E|;Capella|Gabriel|G|;Farré|Lourdes|L|;Vidal|August|A|;Soldado|Francisco|F|;Krauel|Lucas|L|;Suñol|Mariona|M|;Serra|Eduard|E|;Villanueva|Alberto|A|;Lázaro|Conxi|C|https://orcid.org/0000-0002-7198-5906",
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"doi": "10.1177/1758835920929579",
"fulltext": "\n==== Front\nTher Adv Med Oncol\nTher Adv Med Oncol\nTAM\nsptam\nTherapeutic Advances in Medical Oncology\n1758-8340 1758-8359 SAGE Publications Sage UK: London, England \n\n10.1177/1758835920929579\n10.1177_1758835920929579\nOriginal Research\nUse of patient derived orthotopic xenograft models for real-time\ntherapy guidance in a pediatric sporadic malignant peripheral nerve sheath\ntumor\nFernández-Rodríguez Juana *Hereditary Cancer Program, Catalan Institute of\nOncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain\nProgram in Molecular Mechanisms and Experimental\nTherapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona,\nSpain\nCentro de Investigación Biomédica en Red de\nCáncer (CIBERONC), Spain\n Morales La Madrid Andrés *Pediatric Oncology Department, Hospital Sant\nJoan de Déu, Barcelona, Catalunya, Spain\n Gel Bernat Centro de Investigación Biomédica en Red de\nCáncer (CIBERONC), Spain\nHereditary Cancer Group, Germans Trias i Pujol\nResearch Institute (IGTP)-PMPPC; Can Ruti Campus, Badalona, Barcelona,\nSpain\n Castañeda Heredia Alicia Pediatric Oncology Department, Hospital Sant\nJoan de Déu, Barcelona, Catalunya, Spain\n Salvador Héctor Pediatric Oncology Department, Hospital Sant\nJoan de Déu, Barcelona, Catalunya, Spain\n Martínez-Iniesta María Program in Molecular Mechanisms and Experimental\nTherapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona,\nSpain\nProcure Program, Catalan Institute of Oncology,\nHospitalet de Llobregat, Barcelona, Spain\n Moutinho Catia CNAG-CRG, Centre for Genomic Regulation (CRG),\nBarcelona Institute of Science and Technology (BIST), Barcelona, Catalunya,\nSpain\n Morata Jordi CNAG-CRG, Centre for Genomic Regulation (CRG),\nBarcelona Institute of Science and Technology (BIST), Barcelona, Catalunya,\nSpain\n Heyn Holger CNAG-CRG, Centre for Genomic Regulation (CRG),\nBarcelona Institute of Science and Technology (BIST), Barcelona, Catalunya,\nSpain\n Blanco Ignacio Programa d’Assessorament i Genètica Clínica,\nHospital Universitari Germans Trias i Pujol, Badalona, Barcelona,\nSpain\n Creus-Bachiller Edgar Hereditary Cancer Program, Catalan Institute of\nOncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain\nProgram in Molecular Mechanisms and\nExperimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de\nLlobregat, Barcelona, Spain\n Capella Gabriel Hereditary Cancer Program, Catalan Institute of\nOncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain\nProgram in Molecular Mechanisms and\nExperimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de\nLlobregat, Barcelona, Spain\nCentro de Investigación Biomédica en Red de\nCáncer (CIBERONC), Spain\n Farré Lourdes Program in Molecular Mechanisms and\nExperimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de\nLlobregat, Barcelona, Spain\nProcure Program, Catalan Institute of Oncology,\nHospitalet de Llobregat, Barcelona, Spain\nInstitute Gonçalo Moniz. Fundaçao Oswaldo Cruz\n(FIOCRUZ), Brasil\n Vidal August Centro de Investigación Biomédica en Red de\nCáncer (CIBERONC), Spain\nDepartment of Pathology, Hospital Universitari\nde Bellvitge (IDIBELL), Barcelona, Spain\nXenopat S.L., Business Bioincubator, Bellvitge\nHealth Science Campus, Barcelona, Spain\n Soldado Francisco Pediatric hand surgery and microsurgery,\nHospital Sant Joan de Déu, Universitat de Barcelona, Spain\n Krauel Lucas Pediatric Surgical Oncology, Pediatric Surgery\nDepartment, Hospital Sant Joan de Déu, Universitat de Barcelona, Spain\n Suñol Mariona Pathology Department, Hospital Sant Joan de\nDéu, Barcelona, Spain\n Serra Eduard Centro de Investigación Biomédica en Red de\nCáncer (CIBERONC), Spain\nHereditary Cancer Group, Germans Trias i Pujol\nResearch Institute (IGTP)-PMPPC; Can Ruti Campus, Badalona, Barcelona,\nSpain\n Villanueva Alberto **Procure Program, Catalan Institute of Oncology,\nHospitalet de Llobregat (Barcelona) and CIBERONC, Av. Gran Via 199-203,\nHospitalet de Llobregat, 08908, Spain\nProgram in Molecular Mechanisms and\nExperimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de\nLlobregat, Barcelona, Spain\nXenopat S.L., Business Bioincubator, Bellvitge\nHealth Science Campus, 08907 L’Hospitalet de Llobregat, Barcelona,\nSpain\n https://orcid.org/0000-0002-7198-5906Lázaro Conxi **Hereditary Cancer Program, Catalan Institute of\nOncology, IDIBELL and CIBERONC, Av. Gran Via 199-203, Hospitalet de\nLlobregat, 08908, Spain\nProgram in Molecular Mechanisms and\nExperimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de\nLlobregat, Barcelona, Spain\nCentro de Investigación Biomédica en Red de\nCáncer (CIBERONC), Spain\n clazaro@iconcologia.netavillanueva@iconcologia.net* Both authors contributed equally to this manuscript and should be considered\nco-first authors\n\n** Both authors should be considered senior and corresponding authors\n\n\n3 7 2020 \n2020 \n12 175883592092957928 11 2019 1 5 2020 © The Author(s), 20202020SAGE Publications Ltd unless otherwise noted.\nManuscript content on this site is licensed under Creative Commons\nLicensesThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which\npermits non-commercial use, reproduction and distribution of the work\nwithout further permission provided the original work is attributed as\nspecified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Background:\nThe aim of this study was to test the feasibility and utility of developing\npatient-derived orthotopic xenograft (PDOX) models for patients with\nmalignant peripheral nerve sheath tumors (MPNSTs) to aid therapeutic\ninterventions in real time.\n\nPatient & Methods:\nA sporadic relapsed MPNST developed in a 14-year-old boy was engrafted in\nmice, generating a PDOX model for use in co-clinical trials after informed\nconsent. SNP-array and exome sequencing was performed on the relapsed tumor.\nGenomics, drug availability, and published literature guided PDOX\ntreatments.\n\nResults:\nA MPNST PDOX model was generated and expanded. Analysis of the patient’s\nrelapsed tumor revealed mutations in the MAPK1, EED, and\nCDK2NA/B genes. First, the PDOX model was treated with\nthe same therapeutic regimen as received by the patient (everolimus and\ntrametinib); after observing partial response, tumors were left to regrow.\nRegrown tumors were treated based on mutations (palbociclib and JQ1), drug\navailability, and published literature (nab-paclitaxel; bevacizumab;\nsorafenib plus doxorubicin; and gemcitabine plus docetaxel). The patient had\na lung metastatic relapse and was treated according to PDOX results, first\nwith nab-paclitaxel, second with sorafenib plus doxorubicin after\nprogression, although a complete response was not achieved and multiple\nmetastasectomies were performed. The patient is currently disease free\n46 months after first relapse.\n\nConclusion:\nOur results indicate the feasibility of generating MPNST-PDOX and genomic\ncharacterization to guide treatment in real time. Although the treatment\nresponses observed in our model did not fully recapitulate the patient’s\nresponse, this pilot study identify key aspects to improve our co-clinical\ntesting approach in real time.\n\nexome sequencingMPNSTPDOX modelpersonalized medicineSNP-arraytargeted drug treatmentcover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nMalignant peripheral nerve sheath tumors (MPNSTs) are aggressive, locally invasive\nsoft tissue sarcomas with a dismal prognosis, especially if complete surgical\nexcision cannot be achieved.1 Half of these tumors occur sporadically, whereas others appear in\nneurofibromatosis type 1 (NF1) patients.2,3 Focal radiotherapy is usually\nindicated, most importantly when margins remain affected after resection.4 Chemotherapy, including ifosfamide and doxorubicin, shows a modest response\nin a small percentage of patients.5,6 For unresectable, relapsed, and\nmetastatic patients, there are no effective therapies and enrollment in clinical\ntrials should be highly encouraged.\n\nMPNST cells contain hyperploid and highly rearranged genomes, with a low mutation\nburden and few recurrent alterations.7 These recurrent mutations basically consist of the loss of particular tumor\nsuppressor genes (TSGs). Lee et al. confirmed the implication of\nthese TSGs,8 and established a core signature that consists in the recurrent inactivation\nof NF1, CDKN2A/B, components of the polycomb repressive complex 2\n(EED and SUZ12), and TP53, a\ncore signature that has been consolidated by others.9,10 Interestingly, there are drugs\nthat target pathways activated due to the loss of these genes, such as MEK\ninhibitors (NF1 loss), CDK4/CDK6 inhibitors (loss of\nCDKN2A/B), and BRD4 inhibitors (PRC2 loss of function). Some of\nthese have been tested in pre-clinical or clinical contexts.11–13 Results, although promising,\nseem to indicate that the combination of different drugs will be required for an\neffective therapy of MPNSTs.14\n\nAdvances in the molecular characterization of MPNST have increased our understanding\nof the molecular pathways that underlie this entity, and have opened up a new window\nof opportunities in personalized medicine. However, no clinical trial has\ndemonstrated drug efficacy for unresectable MPNST, due partly to the low number of\npatients enrolled so far and the lack of a patient risk stratification\nsystem.2,3\n\nHerein, we present the case of an adolescent who developed a recurrent sporadic MPNST\nin which we tested the feasibility of using a patient derived orthotopic xenograft\n(PDOX) model and genomic characterization of the tumor to compile pre-clinical data\nin real time to guide the patient’s therapy.\n\nMethods\nPatient\nThe patient was a previously healthy 14-year-old boy diagnosed with a brachial\nplexus MPNST, who relapsed 15 months later. A fragment of fresh tissue from the\nrelapsed tumor was received for genomic analysis and PDOX generation. Informed\nconsent was obtained and covered comprehensive genomic characterization of\nprimary tumors from the patient as well as the development of mouse orthotopic\nanimal models for pre-clinical use. The study received IDIBELL IRB (#PR213/13)\nand IDIBELL Animal Ethic Experimentation Committee (CEEA-IDIBELL) (#9111)\napproval.\n\nGeneration of PDOX models\nSix-week-old male nude Harlan mice were used. A fragment of tumor\n(2–3 mm3) was engrafted in a single mouse (Passage 0) in the\nsciatic nerve (orthotopic engraftment) as previously described.15 Two months later, the tumor was expanded by resecting and engrafting into\nthe two legs of seven new mice (Passage 1). Tumor resection was performed,\nopening a subcutaneous pocket with surgical scissors, an incision was made in\nthe muscle to display and resect the MPNST. Animals were then sacrificed by\ncervical dislocation following the guidelines approved by our ethical committee.\nRepresentative fragments were either frozen in nitrogen or fixed in 10% buffered\nformalin and then processed for paraffin embedding.\n\nThe patient’s lung metastasis was implanted orthotopically in mice lungs.\nBriefly, mice were anesthetized with a continuous flow of 1–3% isoflurane/oxygen\nmixture (2 l/min) and subjected to right thoracotomy. Mice were situated in left\nlateral decubitus position, and a small transverse skin incision (∼5–8 mm) was\nmade in the right chest wall. Chest muscles were separated by a sharp\ndissection, and costal and intercostal muscles were exposed. An intercostal\nincision of 2–4 mm on the third or fourth rib on the chest wall was made and a\nsmall tumor piece of 2–4 mm3 was introduced into the chest cavity.\nThe tumor specimen was anchored to the lung surface with Prolene 7.0 suture.\nNext, the chest wall incision was closed with surgical staples, and, finally,\nchest muscles and skin were closed. Mice were inspected twice a week and\nmonitored for the presence of breathing problems.16 Seven months after engraftment, mice were sacrificed and tumors passed to\nanother animal.\n\nThe mouse experiments were approved by the campus Animal Ethics Committee and\ncomplied with AAALAC (Association for Assessment and Accreditation of Laboratory\nAnimal Care International) procedures.\n\nPre-clinical testing of drugs in PDOX models\nMimicking patient treatment in PDOX models\nWhen tumors reached a homogenous size of 500–1000 mm3 after a\nmonth of growth, mouse tumors at passage 1 showing homogenous growth\n(n = 6) were randomized into two groups: vehicle\n(n = 3) and combined trametinib plus everolimus group\n(n = 3) for 15 days. Mice were implanted with two\ntumors, one in each leg, and, after chemotherapy treatment, they were\nanesthetized and one tumor from each leg was resected while the other was\nallowed to regrow in live mice for 50 days. Subsequently, the regrowth\ntumors were engrafted in new nude mice to test new treatment schemes\n(Passage 2) (Table\n1, Supplemental Materials and methods file). After treatment\ninitiation, tumors were measured using a caliper every 2–3 days and tumor\nvolume was calculated using the formula v = (w2 l/2), where l is the longest diameter and w the width.15\n\nTable 1. Drug treatments in the PDOX mouse model.\n\nTreatment\tAdministration route\tDose (mg/kg)\tSolvent\tN° mice\tSchedule\t\nTrametinib\tOral\t1\t10% cremophor EL/10% PEG400\t3\tDaily\t\nEverolimus\tIntraperitoneal\t5\t2% DMSO/carboxymethylcellulose\t3\tDaily\t\nJQ1\tIntraperitoneal\t50\t5%DMSO/5% dextrose\t4\tDaily\t\nNab-paclitaxel&\tIntraperitoneal\t20\t50% ethanol/50% cremophor, diluted ¼ in saline\t4\tDaily\t\nBevacizumab\tIntraperitoneal\t5\tPBS\t3\tDaily\t\nPalbociclib\tOral\t150\t50 mM acetate buffer pH 4\t3\tDaily\t\nSorafenib\tOral\t60\t50% cremophor/50% ethanol\t3\tDaily\t\nDoxorubicin*\tIntraperitoneal\t8\tSaline\t3\tOne dose\t\nGemcitabine*\tIntraperitoneal\t90\tSaline\t3\tEvery 4 days\t\nDocetaxel*\tIntravenous\t15\tSaline\t3\tEvery 4 days\t\n* Obtained from our hospital pharmacy.\n\n& Nab-paclitaxel used is abraxane (the nano-particle of\nalbumin-bound paclitaxel).\n\nPBS, phosphate-buffered saline; PDOX, patient-derived orthotopic\nxenograft.\n\nWe administered all the diary compounds following a schedule of\n5-days-on/2-days off. Partial response is considered when treatment does not\ncompletely eliminate the tumor.\n\nTesting new treatments to guide future therapy\nConsidering the genomic alterations in the relapsed MPNST and bibliographic\ndata, we started new treatment tests on the regrown PDOX after everolimus\nand trametinib treatment (Passage 2). We selected monotherapy treatments\nwith bromodomain inhibitor JQ1 (PRC2 loss), palbociclib, a CDK4/6 inhibitor\n(CDKN2A/B loss), nab-paclitaxel, bevacizumab, and the\ncombination of sorafenib plus doxorubicin and gemcitabine plus docetaxel.\nThe treatments lasted 15 days, and, thereafter, tumors were allowed to\nregrow (Table\n1).\n\nHistological study\nRepresentative fragments of the tumors (human and PDOX) were fixed, dehydrated,\nand embedded in paraffin. Tissue sections (3 µm) were hematoxylin-eosin stained\nfor morphological analysis.\n\nDNA preparation, SNP-array analysis, and exome sequencing\nThe GentraPuragene Kit (Qiagen, Hilden, Germany) was used for DNA isolation.\nSNP-array was performed using HumanOmniExpress-24v1-1 Beadchip as previously described.15 Genomic plots were created with karyoploteR.17\n\nExome sequence capture and amplification was performed using Agilent SureSelect\nHuman All Exon kit (Agilent, Santa Clara, CA, USA) according to the\nmanufacturer’s instructions in the Centro Nacional de Análisis Genómico (CNAG).\nSequencing was performed in a HISeq2500 (Illumina, San Diego, CA, USA) with\npaired end 2x100 reads. We mapped the reads to the 1000 Genomes reference genome\n(hs37d5) using BWA MEM,18 and called variants using Strelka in germline mode.19 Variants were then normalized and annotated with annovar.20\n\nTable S1 in the\nsupplemental material depicts the genome characterization performed in each\nsample.\n\nWestern blot\nSamples for western blot were homogenized by a tissue lyser in\nradioimmunoprecipitation assay (RIPA) buffer containing complete protease\ninhibitor cocktail (Merck, Darmstadt, Germany) then centrifuged at\n10,000 × g for 10 min to remove cellular debris.\n\nEquivalent amounts of protein (20 µg) and the protein marker (NZYColour Protein\nMarker II, MB090, NZYtech, Lisbon, Portugal) were separated on 12% acrylamide\ngels (TGX Stain-Free™ FastCast™ Acrylamide kit; Bio-Rad, Hercules, CA, USA)\ngels. This technology contains trihalo compounds that react with tryptophan\nresidues in a UV-induced reaction to produce fluorescence that can be detected\nby the ChemiDoc imaging system. Total protein was detected using the ChemiDoc\nimager in the membrane after transfer onto nitrocellulose membranes. Membranes\nwere blocked for 1 h with bovine serum albumin (BSA) 5% and then incubated with\nprimary antibody [H3K27me from Cell Signaling (9733) at 1:1000 dilution in 5%\nBSA; Cell Signalling Technology, Beverly, MA, USA]. The membranes were incubated\nfor 1 h at room temperature with secondary antibody horseradish\nperoxidase-conjugated anti-rabbit (1:1000). Detection was conducted using\nSuperSignal West Femto chemiluminescent substrate kits (Pierce Biotechnology\nInc., Rockford, IL, USA) using the ChemiDoc imager.\n\nResults\nPatient description\nThe clinical history and evolution of the patient is summarized in Figure 1. Magnetic\nresonance imaging (MRI) revealed a large left brachial plexus tumor (Figure 2A) in a\n14-year-old boy. Surgery was performed achieving gross total resection.\nHistological review confirmed MPNST. The patient met no criteria for NF1.\nGermline testing for SMARCB1, NF1, CDKN2A, TP53, NF2, LZTR1, mTOR,\nMSH1, and MSH2 was negative. Upfront therapy\nincluded chemotherapy as per the International Society of\nPediatric Oncology (SIOP) non-rhabdomyosarcoma (RMS) protocol; arm C\n(ifosfamide, vincristine, and actinomycin D) plus doxorubicin, followed by\nconsolidation with focal radiotherapy (41 Grays). At the end of therapy, there\nwas no evidence of disease. However, 8 months later, two cervical masses were\ndetected (Figure 2B).\nWhole body FDG-PET/CT scan confirmed high metabolic activity in these two areas\nexclusively. A new, near total resection was achieved, and tumor relapse\nconfirmed. During surgery, tubes for brachytherapy were implanted. Fresh tissue\nwas used for PDOX generation and genomic analysis. External re-irradiation was\nadministered (normofractionated, total dose of 60 Grays). Based on pre-clinical data,21 and a clinical trial [ClinicalTrials.gov identifier: NCT03433183] where\nselumetinib was administered orally at a dose of 50 mg twice daily and sirolimus\nwas administered orally at a dose of 4 mg once daily with a cycle 1 day loading\ndose of 12 mg, each cycle is considered as 28 days,22 the patient was started on a regimen of everolimus and trametinib (Figure 1).\n\nFigure 1. Timeline summary.\n\nThe clinical evolution and treatment of the patient is represented above\nthe timeline arrow. Below is depicted the research activity performed.\nDiscontinuous purple rectangle indicates time patient was attended at\nHospital Sant Joan de Déu. Timeline is expressed in months.\n\nFigure 2. Images showing MPNST and relapses.\n\n(A) Magnetic resonance imaging for diagnostic purposes revealing a large\nleft brachial plexus tumor. The arrow points to the MPNST. (B) Neck and\nchest CT scan showing two nodes suspicious of local relapse. The arrow\npoints to one node. (C) CT scan showing new lung nodule suspicious of\nmetastatic relapse. The arrow points to a lung metastatic nodule.\n\nPDOX generation and treatment mimicking the patient’s drug scheme\nOur experience in generating MPNST PDOX facilitated a rapid establishment of this\npatient’s model in parallel with the patient’s treatment.15 We implanted a fragment of relapsed tumor in a single mouse (Passage 0)\nin the sciatic nerve. Tumor growth was palpable 2 months after implantation. To\ntry to better reproduce the patient’s treatment, PDOX mice were treated with\neverolimus and trametinib in order to submit tumor xenografts to the same drug\nselection pressure as the patient’s tumor. Since time is one of the key factors\nin real-time pre-clinical treatments, and a treatment of 15–21 days in mice is\nconsidered sufficient to evaluate the pharmacological response, mice were\ntreated for 15 consecutive days. At this point we observed a 35% tumor\nsize-weight reduction compared with the control group (Figure 3), indicative of tumor response.\nAfter that, we let the tumors regrow for 50 days in order to use these regrown\nPDOXs for implanting new animals, for new drug treatments. In total, 5 months\nwere necessary from the first tumor implantation until obtaining regrown PDOX\ntumors mirroring the patient’s treatment. Comparative analysis of the patient’s\nrelapsed tumor with the PDOX model using SNP-array and histology analyses\nconfirmed that the PDOX recapitulated human disease (Figure S1) as previously described.15,23,24 Overall, the genomic\nstructure of the PDOX after treatment greatly resembled the genomic structure of\nthe patient’s relapsed MPNST, although some small differences were observed such\nas the loss of chromosome 6q, already present in a subpopulation of the\npatient’s relapsed MPNST, or the amplification of chromosomes 8q and 17p\n(Figure S1B).\n\nFigure 3. PDOX response to trametinib + everolimus regimen.\n\nIn the left panel, results are plotted as the average of tumor volume at\ndifferent time points (days). In the right panel, the mean of the final\ntumor weight is plotted. Dashed grey areas denote time without\ntreatment.\n\nGenomic analysis\nConcomitant to PDOX development, SNP-array molecular karyotyping and exome\nsequencing was performed from the patient’s relapsed MPNST. SNP-array identified\na homozygous deletion in chromosome 11 involving the EED gene\n(Figure 4 and\nS2A), a component of the polycomb repressive complex 2 (PRC2).\nIn agreement with this, decreased levels of H3K27me3 were detected in this tumor\ncompared with another MPNST with wild-type PRC2 (Figure S2B). In addition, a homozygous deletion in chromosome 9\nwas also identified, affecting the CDKN2A and\nCDKN2B tumor suppressor genes (Figure 4). Some other homozygous\ndeletions were detected although they did not involve any other gene related\nwith MPNST to date and are now under further investigation (Table S2). Also, exome sequencing identified several genetic\nvariants (Table S3); MAPK1 variant c.241G>A\n(p.Glu81Lys) was predicted as pathogenic, potentially resulting in the\nactivation of the MAPK cascade.\n\nFigure 4. Molecular karyotyping by SNP-array analysis of the patient’s relapsed\nMPNST.\n\nHomozygous deletions encompassing the three last exons of\nEED (see Figure S2A for a detailed image) and the\nCDK2NA/B genes. Copy number variations are\nrepresented by a colored wide line under LRR (grey: 2n, yellow: > 2n\n(chromosomal gain); light green: 1n (heterozygous loss); dark green:\nhomozygous loss. LOH events are shown in blue.\n\nReal-time treatments in mice to guide clinical-treatment decisions\nConsidering the genomic alterations identified in the patient’s relapsed MPNST,\ndata from the literature, availability of drugs, and time constraints, we\ndesigned a treatment scheme for performing on the regrown PDOX after\neverolimus-trametinib (passage 2) consisting of monotherapies for: JQ1, a\nbromodomain inhibitor11; palbociclib, a CDK4/6 inhibitor25; nab-paclitaxel26; bevacizumab27; and the combinations of sorafenib plus doxorubicin15; and gemcitabine plus docetaxel.28 Treatments were performed in two separate experiments according to drug\navailability and time restrictions (Figure 5A and B). The highest tumor\nreduction was achieved with the sorafenib plus doxorubicin combination (71%),\nfollowed by nab-paclitaxel (67%) and palbociclib (57%) (Figure 5A and B). No significant\nhistological changes were found in residual regrown masses post-treatment\n(Figure S3). However, mice treated with sorafenib plus\ndoxorubicin suffered significant weight loss. For nab-paclitaxel, several mice\nwere re-treated with additional cycles, observing a clear stabilization of tumor\nsize (Figure 5A) without\nachieving original tumor size. Hence, nab-paclitaxel seemed to be a good first\noption in the case of tumor relapse. In summary, we needed 8 months, and two\nmouse passages to complete this personalized co-clinical trial (Figure 1).\n\nFigure 5. PDOX response to different drug treatment regimens.\n\nIn the left panels, results are plotted as the average of tumor volume at\ndifferent time points (days). In the right panels, the mean of the final\ntumor weight is plotted. (A), JQ1 and Nab-paclitaxel. (B) bevazicumab,\npalbociclib, sorafenib + doxorubicin and gemcitabine + docetaxel. Dashed\ngrey areas denote time without treatment.\n\nLung patient metastasis and treatment\nAfter 11 months of treatment with everolimus and trametinib, a CT scan showed the\nappearance of new lung nodules, suspicious of metastatic relapse (Figure 2C). An excised\nnodule confirmed lung metastasis. We opted to treat the patient with\nnab-paclitaxel, which exhibited the highest tumor response and lowest toxicity\nin PDOX pre-clinical data. We observed an initial disease stabilization, but\nlung metastasis progressed 4 months later and treatment was switched to\nsorafenib and doxorubicin (Figure 1). This combination was the most effective treatment in our\nMPNST PDOX model, but the lung nodule progressed further on this regimen.\nNotably, the number of metastatic lesions did not increase. In this clinical\nscenario, the patient underwent serial metastasectomies at another institution\nand is currently disease free 46 months after the first relapse. With the aim of\nrevealing new possibilities in the case of future tumor progression in the\npatient, the lung metastasis was implanted orthotopically in a new mouse, then\nthe lung metastatic PDOX was sequenced. Lung metastasis grew slowly in the PDOX\nmodel, and tumor amplification was not feasible for performing new real-time\ndrug tests (Figure S4A–B). Interestingly, histological analysis of the mouse\nlungs did not identify additional metastatic dissemination, only confined local\ngrowth (Figure S4 C–F).\n\nDiscussion\nWe tested here the feasibility of using PDOX models to guide therapeutic decisions in\nreal-time in a young patient with a relapsed MPNST. This patient’s relapse was\ntreated with a combination of MEK and mTOR inhibitors based on pre-clinical and\nclinical data [ClinicalTrials.gov identifier: NCT03433183].21,22 Accordingly,\nonce the MPNST PDOX model was established (3 months), the same treatment was\nadministered to the animals in order to emulate the potential molecular changes\noccurring in the patient’s tumor due to treatment. The time constraints of a\nco-clinical pilot study made it very difficult to generate treatment-resistant PDOX\nmodels, so we developed the closest model possible to the patient’s therapeutic\nscheme, while not compromising the collection of pre-clinical data during the\npatient’s treatment in real-time. According to the genomic analysis of the patient’s\nrelapsed tumor, published data, drug availability, and treatment possibilities, we\nfirst tested different monotherapy treatments and some co-treatments on regrown\nMPNST PDOX after trametinib and everolimus administration. Palbociclib (CDK4/6\ninhibitor) showed significant tumor size reduction, in agreement with results\npresented in sarcomas.25 JQ1 did not show the expected cytostatic effect observed previously\nin vivo,11 although a recent in vitro study indicated that, in human\nNF1-derived MPNST samples, BRD4 mRNA levels were not upregulated\nand that MPNST cell lines were relatively insensitive to the bromodomain inhibitor JQ1,29 being in agreement with our PDOX results in this patient. In our study, we\nobserved a significant tumor reduction, stabilizing tumor growth, when using\nnab-paclitaxel in monotherapy. Nab-paclitaxel, in combination with gemcitabine, has\nbeen described to produce a clinical benefit in 57% of patients with advanced\nsoft-tissue sarcomas,30 and is also now in a clinical trial [ClinicalTrials.gov identifier: NCT03524898].31 Moreover, the combination of sorafenib plus doxorubicin decreased tumor size\nas previously described.15 No clear response was observed when treating with bevacizumab alone or with\ngemcitabine plus docetaxel. The combination of these three compounds was described\nas well tolerated and with activity in very high risk sarcomas, and can be further\nexplored in future PDOX models.32 Interestingly, we completed our PDOX based-study 6 months before the disease\nprogressed in the patient.\n\nLung metastasis was identified in this patient after 11 months of\ntrametinib-everolimus treatment. Taking into consideration the PDOX results, we\ntreated the patient with nab-paclitaxel. We observed stable disease, but lung\nmetastasis progressed 4 months later. As a fourth line of treatment, sorafenib plus\ndoxorubicin was administered with acceptable tolerance. Although the rate of tumor\ngrowth was reduced and no further dissemination was identified, multiple\nmetastasectomies were performed to treat the patient.\n\nAs a future PDOX approach, it would be worthwhile to evaluate the efficacy and\ntoxicity of co-treatments, capturing the three different molecular alterations\nidentified in the patient’s tumor (MAPK1 activation, PRC2 and\nCDKN2A/B loss), some of which have previously been tested\npre-clinically,11,33,34 and clinically in cancer patients ([ClinicalTrials.gov\nidentifier: NCT03266159], [ClinicalTrials.gov identifier:NCT01841463])35,36 but we could\nnot do this due to time limitations. In addition, our patient did not present local\nrelapse, but lung metastasis and our PDOX model was not intended for modeling\nmetastasis. To obtain the metastatic model, the primary tumor needs to be removed\nand then wait for metastasis to occur, an approach difficult to achieve in real-time\nco-clinical studies. Another limitation is that our PDOX model does not fully mimic\nthe clinical course of the patient as the mice did not receive focal irradiation and\nbrachytherapy as did the patient after relapse resection. Whereas radiotherapy\ntreatments are frequent in clinical practice, they are difficult to implement in\nmice. Local irradiation is possible when the mouse is implanted in the sciatic\nnerve, but not in the lung. In order to optimize time and efforts, an ideal scenario\nwould be the combination of PDOX with other strategies based on in\nvitro development of tumoroids or HDRA assays (histoculture drug\nresponse assay) that could be faster and cheaper. However in vitro\nstudies do not obtain information regarding pharmacodynamic or pharmacokinetic\naspects since most of them depend on the route of administration and solvents used.\nFinally, it is important to note that relapsed MPNST is a condition with a grim\nprognosis. Therapies directed by pre-clinical experiments may raise ethical\nconsiderations, and short- and long-term toxicities should be discussed with the\npatient.\n\nConclusion\nIn summary, our work demonstrates the feasibility of achieving a combined approach\nthat includes the generation of PDOX models with the integration of genomic data\nused in real-time to guide critical clinical therapeutic decisions. However, the\nresults observed in our model did not exactly recapitulate the patient’s response.\nCertainly the time constraints of real-time pre-clinical studies greatly influence\nthe possibility of generating the best models to mimic the patient’s condition.\nHowever, the experience gained in this co-clinical pilot study could help us to\nbetter plan for a parallel modeling, to cover different potential scenarios, such as\nrelapse or metastasis.\n\nFuture and more accurate models and tumor characterization may reduce the gap between\nthe pre-clinical findings and patient outcomes. This could be achieved by\nimprovement in mimicking a patient’s real condition in PDOX (focal\nirradiation/brachytherapy and generation of a model with lung metastasis) as well as\nby enhancing genomic characterization by adding RNA sequencing and methylation data\nto our analysis that could provide a comprehensive variety of druggable targets to\nbe tested in these models.\n\nSupplemental Material\nSupplementary_material_and_methods – Supplemental material for Use of\npatient derived orthotopic xenograft models for real-time therapy guidance\nin a pediatric sporadic malignant peripheral nerve sheath tumor\nClick here for additional data file.\n\nSupplemental material, Supplementary_material_and_methods for Use of patient\nderived orthotopic xenograft models for real-time therapy guidance in a\npediatric sporadic malignant peripheral nerve sheath tumor by Juana\nFernández-Rodríguez, Andrés Morales La Madrid, Bernat Gel, Alicia Castañeda\nHeredia, Héctor Salvador, María Martínez-Iniesta, Catia Moutinho, Jordi Morata,\nHolger Heyn, Ignacio Blanco, Edgar Creus-Bachiller, Gabriel Capella, Lourdes\nFarré, August Vidal, Francisco Soldado, Lucas Krauel, Mariona Suñol, Eduard\nSerra, Alberto Villanueva and Conxi Lázaro in Therapeutic Advances in Medical\nOncology\n\n Table_S1 – Supplemental material for Use of patient derived orthotopic\nxenograft models for real-time therapy guidance in a pediatric sporadic\nmalignant peripheral nerve sheath tumor\nClick here for additional data file.\n\nSupplemental material, Table_S1 for Use of patient derived orthotopic xenograft\nmodels for real-time therapy guidance in a pediatric sporadic malignant\nperipheral nerve sheath tumor by Juana Fernández-Rodríguez, Andrés Morales La\nMadrid, Bernat Gel, Alicia Castañeda Heredia, Héctor Salvador, María\nMartínez-Iniesta, Catia Moutinho, Jordi Morata, Holger Heyn, Ignacio Blanco,\nEdgar Creus-Bachiller, Gabriel Capella, Lourdes Farré, August Vidal, Francisco\nSoldado, Lucas Krauel, Mariona Suñol, Eduard Serra, Alberto Villanueva and Conxi\nLázaro in Therapeutic Advances in Medical Oncology\n\n Table_S2 – Supplemental material for Use of patient derived orthotopic\nxenograft models for real-time therapy guidance in a pediatric sporadic\nmalignant peripheral nerve sheath tumor\nClick here for additional data file.\n\nSupplemental material, Table_S2 for Use of patient derived orthotopic xenograft\nmodels for real-time therapy guidance in a pediatric sporadic malignant\nperipheral nerve sheath tumor by Juana Fernández-Rodríguez, Andrés Morales La\nMadrid, Bernat Gel, Alicia Castañeda Heredia, Héctor Salvador, María\nMartínez-Iniesta, Catia Moutinho, Jordi Morata, Holger Heyn, Ignacio Blanco,\nEdgar Creus-Bachiller, Gabriel Capella, Lourdes Farré, August Vidal, Francisco\nSoldado, Lucas Krauel, Mariona Suñol, Eduard Serra, Alberto Villanueva and Conxi\nLázaro in Therapeutic Advances in Medical Oncology\n\n Table_S3 – Supplemental material for Use of patient derived orthotopic\nxenograft models for real-time therapy guidance in a pediatric sporadic\nmalignant peripheral nerve sheath tumor\nClick here for additional data file.\n\nSupplemental material, Table_S3 for Use of patient derived orthotopic xenograft\nmodels for real-time therapy guidance in a pediatric sporadic malignant\nperipheral nerve sheath tumor by Juana Fernández-Rodríguez, Andrés Morales La\nMadrid, Bernat Gel, Alicia Castañeda Heredia, Héctor Salvador, María\nMartínez-Iniesta, Catia Moutinho, Jordi Morata, Holger Heyn, Ignacio Blanco,\nEdgar Creus-Bachiller, Gabriel Capella, Lourdes Farré, August Vidal, Francisco\nSoldado, Lucas Krauel, Mariona Suñol, Eduard Serra, Alberto Villanueva and Conxi\nLázaro in Therapeutic Advances in Medical Oncology\n\n We thank CERCA Program/Generalitat de Catalunya for their institutional support. We\nthank all the patients and families with MPNST tumors. We would like to thank all\nSpanish Neurofibromatosis (NF) patients and NF associations for their continuing\nsupport and effort, in particular the Spanish Asociación de Afectados de\nNeurofibromatosis (AANF) and the Associació Catalana de les Neurofibromatosis\n(ACNefi). We also wish to thank the Catalan Institute of Oncology (ICO) and\nInstitute for Health Science Research Germans Trias i Pujol (IGTP) Hereditary Cancer\nProgram teams as well as the members of the Spanish CSUR of Phakomatoses.\n\nAuthor contributions statement: JFR, AM, AVLL, BG, and CL conceived and design the study. AC, HS, MMI, ECB, FS,\nIB, MS and LF were involved in data acquisition. JFR, CM, JM, LK, GC, AV, AVLL\nand HH worked on analysis and interpretation. JFR, AM, AV, CL, BG, and ES\nperformed the manuscript preparation. All authors revised the manuscript\ncritically and approved the final version to be published.\n\nFunding: The authors disclosed receipt of the following financial support for the\nresearch, authorship, and/or publication of this article: Contract grant\nsponsor: Supported by the Carlos III National Health Institute funded by FEDER\nfunds – a way to build Europe – [PI19/00553, PI16/00563; PI16/01898 and\nCIBERONC]; the Government of Catalonia [Pla estratègic de recerca i innovació en\nsalut (PERIS_MedPerCan and URDCat projects), 2017SGR1282 and 2017SGR496]; the\nFundación PROYECTO NEUROFIBROMATOSIS (FPNF), the Scientific Foundation\nAsociación Española Contra el Cáncer and Fundació La Marató de TV3. Xenopat S.L\n(www.xenopat.com) supported the cost of several experiments as a\nsocial corporate responsibility action. This study was performed without any\ncost/charge for the patient.\n\nConflict of interest statement: The authors declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nORCID iD: Conxi Lázaro \nhttps://orcid.org/0000-0002-7198-5906\n\nSupplemental material: Supplemental material for this article is available online.\n==== Refs\nReferences\n1. \nScaife CL Pisters PW \nCombined-modality treatment of localized soft\ntissue sarcomas of the extremities\n. Surg Oncol Clin\nN Am \n2003 ; 12 :\n355 –368\n.12916459 \n2. \nKim A Stewart DR Reilly KM , et al\nMalignant peripheral nerve\nsheath tumors state of the science: leveraging clinical and biological\ninsights into effective therapies\n. Sarcoma \n2017 ; 2017 :\n7429697 .28592921 \n3. \nReilly KM Kim A Blakely J , et al\nNeurofibromatosis type\n1-associated MPNST state of the science: outlining a research agenda for the\nfuture\n. J Natl Cancer Inst \n2017 ; 109 : djx124.\n4. \nStucky CC Johnson KN Gray RJ , et al\nMalignant peripheral nerve\nsheath tumors (MPNST): the mayo clinic experience\n.\nAnn Surg Oncol \n2012 ; 19 :\n878 –885\n.21861229 \n5. \nFerrari A Miceli R Rey A , et al\nNon-metastatic unresected\npaediatric non-rhabdomyosarcoma soft tissue sarcomas: results of a pooled\nanalysis from United States and European groups\n. Eur\nJ Cancer \n2011 ; 47 :\n724 –731\n.21145727 \n6. \nCarli M Ferrari A Mattke A , et al\nPediatric malignant\nperipheral nerve sheath tumor: the Italian and German soft tissue sarcoma\ncooperative group\n. J Clin Oncol \n2005 ; 23 :\n8422 –8430\n.16293873 \n7. \nLazar AJ McLellan MD Bailey MH , et al\nComprehensive and integrated\ngenomic characterization of adult soft tissue sarcomas\n.\nCell \n2017 ; 171 :\n950–965 e28 .\n8. \nLee W Teckie S Wiesner T , et al\nPRC2 is recurrently\ninactivated through EED or SUZ12 loss in malignant peripheral nerve sheath\ntumors\n. Nat Genet \n2014 ; 46 :\n1227 –1232\n.25240281 \n9. \nSohier P Luscan A Lloyd A , et al\nConfirmation of mutation\nlandscape of NF1-associated malignant peripheral nerve sheath\ntumors\n. Genes Chromosomes Cancer \n2017 ; 56 :\n421 –426\n.28124441 \n10. \nBrohl AS Kahen E Yoder SJ , et al\nThe genomic landscape of\nmalignant peripheral nerve sheath tumors: diverse drivers of Ras pathway\nactivation\n. Sci Rep \n2017 ; 7 : 14992 .29118384 \n11. \nDe Raedt T Beert E Pasmant E , et al\nPRC2 loss amplifies\nRas-driven transcription and confers sensitivity to BRD4-based\ntherapies\n. Nature \n2014 ; 514 :\n247 –251\n.25119042 \n12. \nJessen WJ Miller SJ Jousma E , et al\nMEK inhibition exhibits\nefficacy in human and mouse neurofibromatosis tumors\n.\nJ Clin Invest \n2013 ; 123 :\n340 –347\n.23221341 \n13. \nDombi E Baldwin A Marcus LJ , et al\nActivity of selumetinib in\nneurofibromatosis type 1-related plexiform neurofibromas\n.\nN Engl J Med \n2016 ; 375 :\n2550 –2560\n.28029918 \n14. \nKim A Pratilas CA \nThe promise of signal transduction in\ngenetically driven sarcomas of the nerve\n. Exp\nNeurol \n2018 ; 299 :\n317 –325\n.28859862 \n15. \nCastellsagué J Gel B Fernández-Rodríguez J , et al\nComprehensive establishment\nand characterization of orthoxenograft mouse models of malignant peripheral\nnerve sheath tumors for personalized medicine\n. EMBO\nMol Med \n2015 ; 7 :\n608 –627\n.25810463 \n16. \nAmbrogio C Carmona FJ Vidal A , et al\nModeling lung cancer\nevolution and preclinical response by orthotopic mouse\nallografts\n. Cancer Res \n2014 ; 74 :\n5978 –5988\n.25217522 \n17. \nGel B Serra E \nkaryoploteR: an R/Bioconductor package to plot\ncustomizable genomes displaying arbitrary data\n.\nBioinformatics \n2017 ; 33 :\n3088 –3090\n.28575171 \n18. \nLi H \nAligning sequence reads, clone sequences and\nassembly contigs with BWA-MEM\n. arXiv Preprint\narXiv:1303.3997 , 2013 .\n19. \nKim S Scheffler K Halpern AL , et al\nStrelka2: fast and accurate\ncalling of germline and somatic variants\n. Nat\nMethods \n2018 ; 15 :\n591 –594\n.30013048 \n20. \nWang K Li M Hakonarson H \nANNOVAR: functional annotation of genetic\nvariants from high-throughput sequencing data\n.\nNucleic Acids Res \n2010 ; 38 : e164 .20601685 \n21. \nWatson AL Anderson LK Greeley AD , et al\nCo-targeting the MAPK and\nPI3K/AKT/mTOR pathways in two genetically engineered mouse models of Schwann\ncell tumors reduces tumor grade and multiplicity\n.\nOncotarget \n2014 ; 5 :\n1502 –1514\n.24681606 \n22. \nClinicalTrials.gov. SARC031: MEK inhibitor selumetinib (AZD6244) in\ncombination with the mTOR inhibitor sirolimus for patients with malignant\nperipheral nerve sheath tumors , https://clinicaltrials.gov/ct2/show/NCT03433183?term=03433183&rank=1\n(2018 , accessed March\n2020 ).\n23. \nVidal A Muñoz C Guillén MJ , et al\nLurbinectedin (PM01183), a\nnew DNA minor groove binder, inhibits growth of orthotopic primary graft of\ncisplatin-resistant epithelial ovarian cancer\n. Clin\nCancer Res \n2012 ; 18 :\n5399 –5411\n.22896654 \n24. \nMoiola CP Lopez-Gil C Cabrera S , et al\nPatient-derived xenograft\nmodels for endometrial cancer research\n. Int J Mol\nSci \n2018 ; 19 : 2431 .\n25. \nPerez M Muñoz-Galván S Jiménez-García MP , et al\nEfficacy of CDK4 inhibition\nagainst sarcomas depends on their levels of CDK4 and p16ink4\nmRNA\n. Oncotarget \n2015 ; 6 :\n40557 –40574\n.26528855 \n26. \nApice G Pizzolorusso A Di Maio M , et al\nConfirmed activity and\ntolerability of weekly paclitaxel in the treatment of advanced\nangiosarcoma\n. Sarcoma \n2016 ; 2016 :\n6862090 .27019606 \n27. \nSomaiah N von Mehren M \nNew drugs and combinations for the treatment of\nsoft-tissue sarcoma: a review\n. Cancer Manag\nRes \n2012 ; 4 :\n397 –411\n.23226072 \n28. \nMaki RG \nGemcitabine and docetaxel in metastatic sarcoma:\npast, present, and future\n. Oncologist \n2007 ; 12 :\n999 –1006\n.17766660 \n29. \nAmirnasr A Verdijk RM van Kuijk PF , et al\nExpression and inhibition of\nBRD4, EZH2 and TOP2A in neurofibromas and malignant peripheral nerve sheath\ntumors\n. PLoS One \n2017 ; 12 :\ne0183155 .28813519 \n30. \nSonnenblick A Eleyan F Peretz T , et al\nGemcitabine in combination\nwith paclitaxel for advanced soft-tissue sarcomas\n.\nMol Clin Oncol \n2015 ; 3 :\n829 –832\n.26171190 \n31. \nClinicalTrials.gov. NAPAGE: NAb-PAclitaxel and GEmcitabine in Advanced\nSoft Tissue Sarcoma , https://clinicaltrials.gov/ct2/show/NCT03524898\n(2018 , accessed March\n2020 ).\n32. \nKuo C Kent PM Logan AD , et al\nDocetaxel, bevacizumab, and\ngemcitabine for very high risk sarcomas in adolescents and young adults: a\nsingle-center experience\n. Pediatr Blood\nCancer \n2017 ; 64 .27555087 \n33. \nBolin S Borgenvik A Persson CU , et al\nCombined BET bromodomain and\nCDK2 inhibition in MYC-driven medulloblastoma\n.\nOncogene \n2018 ; 37 :\n2850 –2862\n.29511348 \n34. \nLee MS Helms TL Feng N , et al\nEfficacy of the combination\nof MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal\ncancer models\n. Oncotarget \n2016 ; 7 :\n39595 –39608\n.27167191 \n35. \nClinicalTrials.gov. A dose escalation study to investigate the safety,\npharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of\nGSK525762 plus trametinib in subjects with solid tumors , https://clinicaltrials.gov/ct2/show/NCT03266159.\n(2017 , accessed March\n2020 ).\n36. \nClinicalTrials.gov. Study of an oral CDK inhibitor administered with an\noral BRAF inhibitor in patients with advanced or inoperable malignant\nmelanoma with BRAF mutation , https://clinicaltrials.gov/ct2/show/NCT01841463\n(2013 , accessed March\n2020 ).\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1758-8340",
"issue": "12()",
"journal": "Therapeutic advances in medical oncology",
"keywords": "MPNST; PDOX model; SNP-array; exome sequencing; personalized medicine; targeted drug treatment",
"medline_ta": "Ther Adv Med Oncol",
"mesh_terms": null,
"nlm_unique_id": "101510808",
"other_id": null,
"pages": "1758835920929579",
"pmc": null,
"pmid": "32670419",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "28124441;23221341;26171190;28029918;30126113;28859862;25810463;25119042;28221727;25240281;21145727;29118384;27019606;12916459;21861229;29117388;25217522;28575171;17766660;29100075;20601685;29511348;23226072;27167191;28813519;24681606;16293873;30013048;28592921;26528855;22896654",
"title": "Use of patient derived orthotopic xenograft models for real-time therapy guidance in a pediatric sporadic malignant peripheral nerve sheath tumor.",
"title_normalized": "use of patient derived orthotopic xenograft models for real time therapy guidance in a pediatric sporadic malignant peripheral nerve sheath tumor"
} | [
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"companynumb": "ES-CELGENEUS-ESP-20200704570",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
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... |
{
"abstract": "BACKGROUND\nIbrutinib, a Bruton's tyrosine kinase inhibitor has reformed the treatment of various B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. Although generally well tolerated, here we describe our institutional experience of unique adverse effects encountered with the use of ibrutinib in patients with B-cell lymphomas.\n\n\nMETHODS\nThis is a retrospective observational study done at a tertiary care facility, to evaluate adverse events in patients with B-cell malignancies on treatment with ibrutinib between 2014 and 2018. Further details including type of malignancy, cytogenetics, interventions for treatment of the side effect, and outcomes were obtained through electronic health record.\n\n\nMETHODS\nWe found 10 patients with unique adverse events related to ibrutinib. Among those, six had chronic lymphocytic leukemia, two had Waldenstrom's macroglobulinemia, and two had mantle cell lymphoma. The events included palindromic rheumatoid arthritis, diffuse spongiotic dermatitis, bullous pemphigoid, recurrent hemorrhagic stroke, peripheral neuropathy, recurrent paronychia, intramedullary fibrosis, recurrent joint pains, pulmonary aspergillosis, dyspnea with exacerbation of atrial fibrillation, and resolution of autoimmune hemolytic anemia.\n\n\nCONCLUSIONS\nOur case series illustrates the wide variety of unique events recognized in patients treated with ibrutinib, some of which required cessation and most had dose reduction of the treatment. Thus, stressing the importance of early identification and intervention for the events to avoid worsening of toxicity and inability to continue treatment in such patients.",
"affiliations": "1 Department of Internal Medicine, Allegheny Health Network, Pittsburgh, USA.;1 Department of Internal Medicine, Allegheny Health Network, Pittsburgh, USA.;1 Department of Internal Medicine, Allegheny Health Network, Pittsburgh, USA.;2 Hematology-Oncology, MD Anderson Cancer Center, USA.;3 Division of Hematology and Cellular Therapy, Allegheny Health Network, Pittsburgh, USA.;3 Division of Hematology and Cellular Therapy, Allegheny Health Network, Pittsburgh, USA.;3 Division of Hematology and Cellular Therapy, Allegheny Health Network, Pittsburgh, USA.",
"authors": "Shaikh|Hira|H|https://orcid.org/0000-0001-5604-4166;Khattab|Ahmed|A|;Faisal|Muhammad S|MS|;Chilkulwar|Abhishek|A|;Albrethsen|Mary|M|;Sadashiv|Santhosh|S|;Fazal|Salman|S|",
"chemical_list": "D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine",
"country": "England",
"delete": false,
"doi": "10.1177/1078155218788707",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(5)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "B-cell malignancies; Ibrutinib; adverse event; hematological malignancies; unique",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000225:Adenine; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D016393:Lymphoma, B-Cell; D020522:Lymphoma, Mantle-Cell; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012189:Retrospective Studies; D008258:Waldenstrom Macroglobulinemia",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1265-1270",
"pmc": null,
"pmid": "30045682",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Case series of unique adverse events related to the use of ibrutinib in patients with B-cell malignancies-A single institution experience and a review of literature.",
"title_normalized": "case series of unique adverse events related to the use of ibrutinib in patients with b cell malignancies a single institution experience and a review of literature"
} | [
{
"companynumb": "US-JNJFOC-20190740356",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBRUTINIB"
},
"drugadditional": "3",
"d... |
{
"abstract": "Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by skin and joint involvement. The disease may present with various joint pattern involvement, which sometimes may lead to joint destruction and deformity. Early diagnosis and treatment with disease-modifying anti-rheumatic drugs may prevent joint deformity. Recently there are many new treatment options including biologic drugs. Ustekinumab, an interleukin 12/23 inhibitor, has proven efficacy in the treatment of psoriatic arthritis. Like other biologic drugs (anti-TNF-α), there are contradictory data about the safety of ustekinumab and possible relationship with cancer development. Herein we report the development of chronic lymphocytic leukemia in a patient with PsA treated with ustekinumab.",
"affiliations": "Department of Hematology, University of Health Sciences, İzmir Bozyaka Training and Research Hospital, Turkey.;Department of Hematology, University of Health Sciences, İzmir Bozyaka Training and Research Hospital, Turkey.;Department of Dermatology,, University of Health Sciences, İzmir Bozyaka Training and Research Hospital, Turkey.;Department of Rheumatology, Faculty of Medicine, Istinye University, LIV Hospital, Istanbul, Turkey.",
"authors": "Gediz|Fusun|F|;Ugur|Mehmet Can|MC|;Turkmen|Meltem|M|;Kobak|Senol|S|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5114/reum.2021.102618",
"fulltext": "\n==== Front\nReumatologia\nReumatologia\nRU\nReumatologia\n0034-6233\n2084-9834\nNarodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie\n\n42983\n10.5114/reum.2021.102618\nCase-Based Review\nUstekinumab-induced chronic lymphocytic leukemia in a patient with psoriatic arthritis\nGediz Fusun 1\nUgur Mehmet Can 1\nTurkmen Meltem 2\nKobak Senol 3\n1 Department of Hematology, University of Health Sciences, İzmir Bozyaka Training and Research Hospital, Turkey\n2 Department of Dermatology,, University of Health Sciences, İzmir Bozyaka Training and Research Hospital, Turkey\n3 Department of Rheumatology, Faculty of Medicine, Istinye University, LIV Hospital, Istanbul, Turkey\nAddress for correspondence: Senol Kobak, Department of Rheumatology, Faculty of Medicine, Istinye University, LIV Hospital, Aşık Veysel Mah, Süleyman Demirel Cd.No: 1, 34517 Esenyurt/İstanbul, Turkey. e-mail: senolkobak@yahoo.com, ORCID: https://orcid.org/0000-0001-8270-640X\nFusun Gediz ORCID: https://orcid.org/0000-0003-3942-2035; Mehmet Can Ugur ORCID: https://orcid.org/0000-0002-5600-3169; Meltem Turkmen ORCID: https://orcid.org/0000-0003-1216-2253\n\n28 2 2021\n2021\n59 1 5861\n03 5 2020\n29 12 2020\nCopyright: © 2021 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie\n2021\nThis 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.\nPsoriatic arthritis (PsA) is a chronic inflammatory disease characterized by skin and joint involvement. The disease may present with various joint pattern involvement, which sometimes may lead to joint destruction and deformity. Early diagnosis and treatment with disease-modifying anti-rheumatic drugs may prevent joint deformity. Recently there are many new treatment options including biologic drugs. Ustekinumab, an interleukin 12/23 inhibitor, has proven efficacy in the treatment of psoriatic arthritis. Like other biologic drugs (anti-TNF-α), there are contradictory data about the safety of ustekinumab and possible relationship with cancer development.\n\nHerein we report the development of chronic lymphocytic leukemia in a patient with PsA treated with ustekinumab.\n\npsoriatic arthritis\nustekinumab\nchronic lymphocytic leukemia\n==== Body\nIntroduction\n\nPsoriatic arthritis (PsA) is a chronic inflammatory disease, mainly affecting the skin and musculoskeletal system [1]. Its incidence in the general population is reported to vary between 2 and 3% [2]. Environmental and genetic factors are considered to play a role in the etiology, although it is not fully known yet.\n\nThe mechanisms that are considered to be responsible for the immunopathogenesis of the disease include the activation of T cells, particularly in the skin and joints, causing the secretion of many pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin 17 (IL-17) and interleukin 12/23 (IL-12/23). Systemic treatment with disease-modifying antirheumatic drugs (DMARDs) is required to control the clinical findings and increase the quality of life [3].\n\nThe long-term use of conventional DMARDs such as methotrexate and cyclosporine is limited due to dose-related toxicity and secondary inefficacy. Recently, a clearer understanding of the pathogenesis of PsA and inflammatory cytokine pathways supported the development of biological therapies [4]. These therapeutic agents affect various steps in the immunopathogenesis of PsA, namely by inhibiting TNF-α, IL-17 and/or the IL-12/23 pathway.\n\nUstekinumab is a human IgG1к monoclonal antibody that blocks the biological activity of interleukin 12 and interleukin 23 by acting on T cells, natural killer cells and receptors on antigen presenting cells [5].\n\nInterleukin 12 and interleukin 23 are involved in the differentiation of Th1 and Th17 cells. Interleukin 12 is an inflammatory cytokine involved in both natural and adaptive immune responses and it consists of two subunits called p35 and p40 [6]. The efficacy and safety of ustekinumab in the treatment of psoriasis and psoriatic arthritis have been shown [7].\n\nHowever, some immune and paradoxical reactions due to use of ustekinumab have been reported [8]. One of the major concerns of ustekinumab use is their potential of increasing the risk of cancer development. The relationship between ustekinumab and malignancy is not clear yet.\n\nMaterial and methods\n\nWe analyzed studies reporting development of chronic lymphocytic leukemia due to ustekinumab use in psoriatic arthritis from PubMed and Google Scholar databases as key words using a combination of search terms such as: psoriatic arthritis, leukemia, and ustekinumab.\n\nUsing a combination of presented search terms, we undertook a systematic review of the literature for discussion and analysis of studies reporting ustekinumab related chronic lymphocytic leukemia and/or hematologic malignancy in psoriatic arthritis patients.\n\nCase description\n\nA 66-year-old male patient was referred to our Hematology Outpatient Clinic with complaints of fatigue, skin lesions and weight loss. According to the patient’s medical history he was followed up with PsA diagnosed until the year 2010 (Fig. 1).\n\nFig. 1 Psoriatic arthritis involvement and deformity of the hand joints.\n\nThe patient was treated with methotrexate (MTX) during the years 2010–2012 and thereafter with etanercept for his active psoriatic arthritis. In 2013 the etanercept was stopped because of secondary inefficacy and ustekinumab was started.\n\nTwo years later during ustekinumab treatment, the patient was admitted to the Hematology Outpatient Clinic because of complaints of fatigue, skin lesions, weight loss and abnormal findings of the blood tests.\n\nOn physical examination, skin lesions compatible with psoriasis were seen. The spleen and liver were not palpable. Auscultation revealed normal lung sounds, and a regular cardiac rhythm, with no murmurs.\n\nLaboratory test results were as follows: erythrocyte sedimentation rate (ESR): 45 mm/h, C-reactive protein (CRP): 12 mg/dl (normal range 0–5 mg/dl), leukocyte: 13 700/µl, lymphocyte: 6700/µl, Hb: 13.5 g/dl, Htc: 39.5%, Plt: 285,000/µl. Urinalysis, liver and kidney function tests were normal, and lactate dehydrogenase (LDH) was 183 U/l (normal range 1–140 U/l).\n\nPeripheral blood smear and bone marrow biopsy showed leukocytosis, with lymphocytes at a rate of 67%, where the majority were small and mature and some were of medium size.\n\nErythrocytes were normochromic normocytic and platelets were adequate in number, with normal distribution. Flow cytometric analysis was positive for CD5, CD19, CD20 and CD5+, CD19, which was consistent with stage 0 chronic lymphocytic leukemia (CLL).\n\nUstekinumab-related CLL was suspected and ustekinumab treatment was discontinued and low-dose corticosteroid and MTX was started for his PsA. The patient’s symptoms regressed; the fatigue and skin lesions disappeared almost totally.\n\nFollow-up laboratory test results were as follows: ESR: 25 mm/h, CRP: 3 mg/dl (normal range 0–5 mg/dl), leukocyte: 8300/µl, lymphocyte: 4700/µl , Hb: 14.5 g/dl, Htc: 39.4%, Plt: 292,000/µl, and LDH was 122 U/l (normal range 1–140 U/l). Peripheral blood smear showed normal cell distribution. The patient’s follow-up is ongoing at the hematology and rheumatology outpatient clinics.\n\nResults\n\nWe analyzed similar clinical problems in the literature. There have been only five case reports published in the literature regarding ustekinumab-related hematologic malignancy development. None of these cases reported the development of CLL due to ustekinumab use. Our study is the first report on this problem.\n\nDiscussion\n\nPsoriatic arthritis is a chronic inflammatory disease characterized by skin and joint involvement. The results of observational studies and a large-scale meta-analysis revealed that patients with psoriasis and PsA carry the risk of developing malignancies, including lymphoma and skin cancer such as melanoma [9]. Whether the risk of malignancy is related to the disease itself or to immunosuppressive systemic therapy is still controversial [10].\n\nIn recent years, biologic drugs have revolutionized the treatment of PsA and made significant clinical, laboratory and radiological remission possible. Interleukin 12 and interleukin 23 are among the cytokines playing a central role in regulation of the T cell immune response and have an important role in the pathogenesis of psoriatic arthritis.\n\nUstekinumab is an interleukin 12/23 antagonist which has proven efficacy in the treatment of psoriatic arthritis [11].\n\nThere are few and contradictory data about the relationship between ustekinumab and hematologic malignancy development (Table I).\n\nTable I Important reports in the literature regarding ustekinumab and hematologic malignancy\n\nPatient diagnosis\tPatient age/gender\tDisease duration (years)\tTreatment drugs before ustekinumab\tMalignancy type\tMalignancy diagnosis\tOutcome\tReferences\t\nPityriasis rubra pilaris\t50/female\t14 years\tCorticosteroids\tAnaplastic large T-cell lymphoma\tSkin biopsy\tGood\tHumme et al. [13]\t\nCrohn’s disease\t29/female\t8 years\tAzathioprine Corticosteroids Infliximab\tMalignant melanoma\tSkin biopsy\tGood\tEhmann et al. [14]\t\nCrohn’s disease\t29/female\t12 years\tAzathioprine Methotrexate Corticosteroids Vedolizumab\tAnaplastic large T-cell lymphoma\tInguinal lymph node\tGood\tSmeets et al. [16]\t\nPsoriasis\t68/male\t13 years\tEfalizumab Methotrexate\tMALT lymphoma\tGastric biopsy\tDied of cerebral infarction\tGonzález-Ramos et al. [17]\t\nPsoriatic arthritis\t66/male\t20 years\tMethotrexate Etanercept\tCLL\tBone marrow biopsy + FCA\tGood\tCurrent case\t\nCLL – chronic lymphocytic leukemia, FCA – flow cytometric analysis, MALT – mucosa-associated lymphoid tissue.\n\nFlorek et al. [12] reported various adverse events of 10 years of ustekinumab use in the postmarketing period. Among these events of importance are some malignancies such as B-cell lymphoma, epithelioid sarcoma, lung and thyroid cancer. This report’s strength is that it represents real-world data, contrary to randomized controlled trials.\n\nThus, it should be emphasized that these strong findings indicate a possible relationship between ustekinumab and malignancy, but not causality. Also there are some reports of ustekinumab-related hematologic malignancy in various diseases.\n\nHumme et al. [13] reported CD30-positive anaplastic large cell T-cell lymphoma under ustekinumab therapy for pityriasis rubra pilaris. The ustekinumab was stopped and the patient received CHOEP (cyclophosphamide, hydroxydaunorubicin, oncovin, etoposide, prednisone) chemotherapy.\n\nEhmann et al. [14] reported malignant melanoma during ustekinumab therapy of Crohn’s disease. Scherl et al. [15] reported some cases of malignancies of the prostate, thyroid and colon, while hematologic malignancy was not seen. Smeets et al. [16] reported anaplastic large T-cell lymphoma in a patient with Crohn’s disease during ustekinumab treatment. Treatment with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) was initiated. Unfortunately, the patient had a refractory lymphoma and proceeded to allogenic stem cell transplantation.\n\nGonzález-Ramos et al. [17] presented gastric mucosa-associated lymphoid tissue lymphoma in a patient with severe psoriasis receiving ustekinumab. The described patient received 19 sessions of radiation therapy, which resulted in complete remission of the disease. Chronic lymphocytic leukemia, as diagnosed in the presented case, has not been observed so far.\n\nOther studies found no significant relationship between ustekinumab and the risk of malignancy [18]. The contradictory results reported in the studies are explained with various reasons: patient selection, type and duration of disease, family history of malignancy and use of another immunosuppressive drugs.\n\nIt should be noted that a limitation of the analysis is still the relatively short time of using ustekinumab in the treatment of psoriatic arthritis.\n\nConclusions\n\nThis presentation reports occurrence of CLL in a patient with PsA treated with ustekinumab which may point to plausible time relation with use of this drug. However, this is only “possible” but not “certain” causality.\n\nSo, far there have been no unequivocal associations of ustekinumab with the development of malignancy in the available literature. At present, many studies and observations are inconsistent and the study groups are incomparable with each other.\n\nIn this subject further observations in real life studies and in the longer period of time are needed.\n\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n\n1 Gladman DD Antoni C Mease P Psoriatic arthritis: epidemiology, clinical features, course, and outcome Ann Rheum Dis 2005 64 Suppl 2 ii14 ii17 10.1136/ard.2004.032482 15708927\n2 Eder L Chandran V Shen H Incidence of arthritis in a prospective cohort of psoriatic patients Arthritis Care Res (Hoboken) 2011 63 619 622 10.1002/acr.20401 21452273\n3 Taylor W Gladman D Helliwell P CASPAR Study Group Classification criteria for psoriatic arthritis: development of new criteria from a large international study Arthritis Rheum 2006 54 2665 2673 10.1002/art.21972 16871531\n4 So A Inman RD An overview of biologic disease-modifying antirheumatic drugs in axial spondyloarthritis and psoriatic arthritis Best Pract Res Clin Rheumatol 2018 32 453 471 10.1016/j.berh.2018.12.002 31171315\n5 Weber J Keam SJ Ustekinumab BioDrugs 2009 23 53 61 10.2165/0042310-200925080-00002 19344192\n6 Trinchieri G Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity Annu Rev Immunol 1995 13 251 276 10.1146/annurev.iy.13.040195.001343 7612223\n7 Thibodaux RJ Triche MW Espinoza LR Ustekinumab for the treatment of psoriasis and psoriatic arthritis: a drug evaluation and literature review Expert Opin Biol Ther 2018 18 821 827 10.1080/14712598.2018.1492545 29949399\n8 Puig L Paradoxical Reactions: anti-tumor necrosis factor alpha agents, ustekinumab, secukinumab, ıxekizumab, and others Curr Probl Dermatol 2018 53 49 63 10.1159/000479475 29131037\n9 Fiorentino D Ho V Lebwohl MG Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry J Am Acad Dermatol 2017 77 845 854.e5 10.1016/j.jaad.2017.07.013 28893407\n10 Luo X Deng C Fei Y Malignancy development risk in psoriatic arthritis patients undergoing treatment: a systematic review and meta-analysis Semin Arthritis Rheum 2019 48 626 631 10.1016/j.semarthrit.2018.05.009 29929736\n11 Kavanaugh A Puig L Gottlieb AB Efficacy and safety of ustekinumab in psoriatic arthritis patients with peripheral arthritis and physician-reported spondylitis: post-hoc analyses from two phase III, multicentre, double-blind, placebo-controlled studies (PSUMMIT-1/PSUMMIT-2) Ann Rheum Dis 2016 75 1984 1988 10.1136/annrheumdis-2015-209068 27098404\n12 Florek AG Nardone B Thareja S Malignancies and ustekinumab: an analysis of the U.S. Food and Drug Administration Adverse Event Reporting System and the European Union Drug Regulating Authorities Pharmacovigilance database Br J Dermatol 2017 177 e220 e221 10.1111/bjd.15752 28646575\n13 Humme D Beyer M Röwert-Huber HJ CD30-positives anaplastisch großzelliges T-Zell-Lymphom unter immunsuppressiver Therapie einer Pityriasis rubra pilaris mit Ustekinumab Hautarzt 2013 64 190 194 10.1007/s00105-012-2526-5 23322178\n14 Ehmann LM Tillack-Schreiber C Brand S Wollenberg A Malignant melanoma during ustekinumab therapy of Crohn’s disease Inflamm Bowel Dis 2012 18 E199 E200 10.1002/ibd.21877 21987390\n15 Scherl EJ Kumar S Warren RU Review of the safety and efficacy of ustekinumab Therap Adv Gastroenterol 2010 3 321 328 10.1177/1756283X10374216\n16 Smeets FG Liedorp PR van der Poel M Anaplastic large cell T-cell lymphoma in a patient with severe therapy-refractory Crohn’s disease on long-standing ımmunosuppressive medication during ustekinumab treatment: a case report and review of the literature J Crohns Colitis 2019 13 1470 1473 10.1093/ecco-jcc/jjz084 31116402\n17 González-Ramos J Alonso-Pacheco ML Mayor-Ibarguren A Herranz-Pinto P Gastric mucosa-associated lymphoid tissue lymphoma in a patient with severe psoriasis receiving ustekinumab Actas Dermosifiliogr 2015 106 326 327 10.1016/j.ad.2014.05.010 25529464\n18 Greenspan A Marty-Ethgen P Fakharzadeh S Risk of malignancies associated with ustekinumab Br J Dermatol 2018 178 299 300 10.1111/bjd.16002 28940375\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0034-6233",
"issue": "59(1)",
"journal": "Reumatologia",
"keywords": "chronic lymphocytic leukemia; psoriatic arthritis; ustekinumab",
"medline_ta": "Reumatologia",
"mesh_terms": null,
"nlm_unique_id": "20130190R",
"other_id": null,
"pages": "58-61",
"pmc": null,
"pmid": "33707797",
"pubdate": "2021",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "27098404;28893407;31116402;31171315;28940375;7612223;16871531;19344192;25529464;23322178;29949399;28646575;21987390;21180612;29131037;29929736;21452273;15708927",
"title": "Ustekinumab-induced chronic lymphocytic leukemia in a patient with psoriatic arthritis.",
"title_normalized": "ustekinumab induced chronic lymphocytic leukemia in a patient with psoriatic arthritis"
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"abstract": "Dapagliflozin (Farxiga), is an SGLT-2 inhibitor commonly indicated for the treatment of diabetes mellitus type 2 (DM 2), heart failure, and chronic kidney disease. One rare side effect associated with SGLT-2 inhibitors is bacterial infection of the genitalia. There are several case reports highlighting the incidence of Fournier's gangrene (FG) in patients who take medications within this drug class. We report a case of FG in a diabetic patient on dapagliflozin who presented following scrotal hydrocelectomy for a large-volume hydrocele. The patient was urgently taken to the operating room for scrotal debridement and recovered well in the post-operative period.",
"affiliations": "PGY-4, Cleveland Clinic Akron General Urology Program, Akron, OH, 44307, USA.;NEOMED, Rootstown, OH, 44272, USA.;NEOMED, Rootstown, OH, 44272, USA.;PGY-5, Cleveland Clinic Akron General Urology Program, Akron, OH, 44307, USA.;Cleveland Clinic Akron General Urology Program, Akron, OH, 44307, USA.",
"authors": "Vargo|Ethan|E|;Leone|Giovanna|G|;Barat|Oren|O|;Yunker|Aaron|A|;Parekh|Neel|N|",
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"doi": "10.1016/j.eucr.2021.101834",
"fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420\nElsevier\n\nS2214-4420(21)00274-6\n10.1016/j.eucr.2021.101834\n101834\nInflammation and Infection\nA case of Fournier's gangrene following a large-volume hydrocelectomy in a diabetic patient managed with SGLT-2 inhibitor therapy\nVargo Ethan Vargoe614@gmail.com\na∗\nLeone Giovanna b\nBarat Oren b\nYunker Aaron c\nParekh Neel d\na PGY-4, Cleveland Clinic Akron General Urology Program, Akron, OH, 44307, USA\nb NEOMED, Rootstown, OH, 44272, USA\nc PGY-5, Cleveland Clinic Akron General Urology Program, Akron, OH, 44307, USA\nd Cleveland Clinic Akron General Urology Program, Akron, OH, 44307, USA\n∗ Corresponding author. Vargoe614@gmail.com\n05 9 2021\n11 2021\n05 9 2021\n39 10183424 8 2021\n1 9 2021\n3 9 2021\n© 2021 Published by Elsevier Inc.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nDapagliflozin (Farxiga), is an SGLT-2 inhibitor commonly indicated for the treatment of diabetes mellitus type 2 (DM 2), heart failure, and chronic kidney disease. One rare side effect associated with SGLT-2 inhibitors is bacterial infection of the genitalia. There are several case reports highlighting the incidence of Fournier's gangrene (FG) in patients who take medications within this drug class. We report a case of FG in a diabetic patient on dapagliflozin who presented following scrotal hydrocelectomy for a large-volume hydrocele. The patient was urgently taken to the operating room for scrotal debridement and recovered well in the post-operative period.\n\nKeywords\n\nFournier's gangrene\nLarge-volume hydrocelectomy\nSGLT-2 inhibitor\n==== Body\npmc1 Introduction\n\nIn 1883, Jean Alfred Fournier published a case series of five males who presented with similar symptoms manifesting as a gas-gangrene infection of the scrotum and penis.1 What would become known as Fournier's gangrene (FG), this infection requires broad spectrum antibiotics and urgent surgical intervention given its high mortality rate of 20–30%.2 Moreover, its incidence continues to rise due to an increased prevalence of diabetes mellitus (DM) – a well-known risk factor of FG.2 Drug classes like SGLT-2 inhibitors have emerged as effective treatments for DM 2. In 2018, however, a warning was released by the Food and Drug Administration (FDA) highlighting the relationship between this drug class and FG.3 There are case reports describing this association, but we report the first incidence of FG in a diabetic patient managed with an SGLT-2 inhibitor following large-volume hydrocelectomy.\n\n2 Case\n\nThe patient is a 64-year-old male with a history of DM 2 managed with dapagliflozin and metformin. Additionally, the patient endorsed a history of atrial fibrillation and coronary artery disease and was status post aortic valve replacement managed on aspirin and warfarin. He initially presented for evaluation of an enlarging, painful left hemiscrotum over the previous few years. Physical examination was consistent with a large left hydrocele and scrotal ultrasound confirmed the diagnosis. The patient elected to proceed to hydrocelectomy after understanding the risks and benefits to surgical intervention.\n\nPrior to surgery, the patient was transitioned off of coumadin via lovenox bridging. Surgery was without complications, and the patient was given antibiotics intraoperatively. The traditional hydrocelectomy approach was carried out, excising the excess sac and oversewing the edges of the remaining sac for hemostasis. A total of 1.1 L of fluid was evacuated from the hydrocele sac. A decision was made to leave a Jackson-Pratt (JP) drain. The patient was seen on post-operative day two and completed his lovenox bridge and re-started coumadin. Due to continued drainage, the JP drain was maintained until output was scant at two weeks. Following removal, serosanguinous output was appreciated from the old drain site during an office visit. Normal post-operative scrotal swelling was noted on physical exam. A wound culture of the drainage was obtained, and the patient was started on antibiotics.\n\nOn post-operative day 18, the patient presented to the emergency department with dark drainage from the JP site along with elevated glucose levels over the previous few days. Physical exam demonstrated erythema, blistering, and tenderness to palpation over the left hemiscrotum with a persistent and foul-smelling ooze from the old JP site. Subcutaneous crepitus in the scrotum was present. Computed tomography (CT) scan of the pelvis demonstrated an 8.5 x 7-cm fluid collection along with subcutaneous air within the midline of the patient's scrotum concerning for FG (Fig. 1). An international normalizing ratio (INR) value was found to be 5.3. The patient's INR was emergently reversed, he was started on broad-spectrum intravenous antibiotics, and a decision was made to urgently proceed to the operating room for scrotal exploration, hematoma evacuation, and FG debridement.Fig. 1 CT scan of the pelvis demonstrating subcutaneous air and heterogenous material within the scrotum concerning for FG.\n\nFig. 1\n\nIn the operating room, the patient was placed in the dorsal lithotomy position. After incising the scrotal skin, old clot was evacuated and several areas of necrotic tissue were debrided. The left testicle and spermatic cord appeared viable. The wound was irrigated and packed and the patient was transferred to the floor. The patient recovered well in the post-operative period and did not require any further debridements (Fig. 2). The SGLT-2 inhibitor was stopped, and he was re-started on his blood thinner. The patient was discharged from the hospital on post-operative day nine on intravenous antibiotics, and he ultimately underwent complex scrotoplasty two months after discharge (Fig. 3).Fig. 2 Viable scrotal and left testicular tissue three days following FG diagnosis and debridement in the operating room.\n\nFig. 2\n\nFig. 3 Patient's scrotum one month following complex scrotoplasty.\n\nFig. 3\n\n3 Discussion\n\nInfection is a common post-operative complication. According to a study that examined three surgical approaches for hydroceles, hematoma, pain, and infection were the top complications following hydrocelectomy.4 An infection rate of 0–4.5% was recorded amongst the three methods.4 While common wound infections were described in this study, only one case report in the literature describes the phenomenon of FG following routine hydrocelectomy, highlighting the rarity of this complication in this routine outpatient surgery.5\n\nBy 2020, just over 50 patients on SGLT-2 inhibitors had been diagnosed with FG and were reported by the FDA.3 Less than 10 case reports exist in the literature highlighting the incidence of FG in diabetic patients managed with SGLT-2 inhibitor therapy with the majority being managed on dapagliflozin3. None of these cases were diagnosed following a surgery.\n\nSeveral measures were taken in order to prevent post-operative complications in our patient. We elected to leave a drain due to the high-volume hydrocele. It has been reported that there is no relationship between drain placement and an increased risk of complications following hydrocelectomy.4 Appropriate measures were also taken peri-operatively to safely bridge the patient from a blood thinning standpoint in an attempt to reduce the risk of stroke and scrotal hematoma formation. We believe that a significant risk factor for FG development in our patient was the concurrent use of an SGLT-2 inhibitor. Our patient had been on SGLT-2 inhibitor therapy for one and a half years, falling well within the reported range of time for patients who develop FG while taking an SGLT-2 inhibitor.3 An exact mechanism accounting for FG incidence in patients on SGLT-2 inhibitors has not been established, and the relationship is unclear as many patients on this medication suffer from medical co-morbidities typically associated with FG.3 For this reason, more research must be conducted investigating the incidence of FG in those patients managed on SGLT-2 inhibitor therapy.\n\n4 Conclusions\n\nGiven the 2018 FDA warning regarding the possible relationship between SGLT-2 inhibitor therapy and FG, it is pertinent for the practicing urologist to be suspicious of FG in diabetic patients managed on these medications who present following scrotal surgery with infections of the genitalia.\n\nFinancial conflict of interest\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nDeclaration of competing interest\n\nNone.\n\nAcknowledgements\n\nNone.\n==== Refs\nReferences\n\n1 Fournier J.A. Gangrene foudroyante de la verge (overwhelming gangrene).Sem. Med. 1883 Dis Colon Rectum 31 1988 984 988 3063473\n2 Singh A. Ahmed K. Aydin A. Khan M.S. Dasgupta P. Fournier's gangrene. A clinical review Arch Ital Urol Androl 88 3 2016 157 164 27711086\n3 Ellegard L. Prytz M. Fournier's gangrene under SGLT-2 inhibitor therapy: a literature review and case report Int. J. Surg. Case Rep. 77 2020 692 694 33395875\n4 Tsai L. Millburn P.A. Cecil IV C.L. Lowry P.S. Hermans M.R. Comparison of recurrence and postoperative complications between 3 different techniques for surgical repair of idiopathic hydrocele J Urol 125 2019 239 242\n5 Al-Ali B.M. Popper H. Pummer K. A case of Fournier's gangrene after hydrocelectomy Cent. European J. Urol. 65 2 2012 92 93\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "39()",
"journal": "Urology case reports",
"keywords": "Fournier's gangrene; Large-volume hydrocelectomy; SGLT-2 inhibitor",
"medline_ta": "Urol Case Rep",
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"nlm_unique_id": "101626357",
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"pages": "101834",
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"pubdate": "2021-11",
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"title": "A case of Fournier's gangrene following a large-volume hydrocelectomy in a diabetic patient managed with SGLT-2 inhibitor therapy.",
"title_normalized": "a case of fournier s gangrene following a large volume hydrocelectomy in a diabetic patient managed with sglt 2 inhibitor therapy"
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{
"abstract": "Dapsone is recommended as a second line therapy in immune thrombocytopenia (ITP), but is underused because of its potential side effects. The medical charts of 42 ITP patients treated with dapsone (100 mg/day) were retrospectively reviewed in order to assess its efficacy and safety in daily clinical practice. The overall response rate was 54.8% (n = 22, with a complete response in 38.1%) with a median time to response of 29 days (24-41 days). Patients with complete response had shorter disease duration whereas no difference was observed between responders and non-responders regarding age, sex or previous treatments received. Importantly, after dapsone withdrawal, a sustained response was observed in 5 patients, representing 12% of the whole cohort. Twenty percent of patients (n = 8) relapsed on therapy after 8.1 (6.5-13.6) months. Side effects occurred in 31% (n = 13) of patients, and required dapsone withdrawal in 22% (n = 9) or dosage reduction in 10% (n = 4) of the cases. Side effects resolved in all but one case. Overall, these data support dapsone as an interesting second line therapy in ITP, with a good safety and efficacy profile at a low cost.",
"affiliations": "Université de Bourgogne Franche Comté, CHU Dijon Bourgogne, Service de Médecine Interne et Immunologie Clinique, Centre de Référence Constitutif des Cytopénies Auto-immunes de l'adulte, Dijon, France.;Université de Bourgogne Franche Comté, CHU Dijon Bourgogne, Service de Médecine Interne et Immunologie Clinique, Centre de Référence Constitutif des Cytopénies Auto-immunes de l'adulte, Dijon, France.;Université de Bourgogne Franche Comté, CHU Dijon Bourgogne, Service de Médecine Interne et Immunologie Clinique, Centre de Référence Constitutif des Cytopénies Auto-immunes de l'adulte, Dijon, France.;Université de Bourgogne Franche Comté, CHU Dijon Bourgogne, Service de Médecine Interne et Immunologie Clinique, Centre de Référence Constitutif des Cytopénies Auto-immunes de l'adulte, Dijon, France.;Université de Bourgogne Franche Comté, CHU Dijon Bourgogne, Service de Médecine Interne et Immunologie Clinique, Centre de Référence Constitutif des Cytopénies Auto-immunes de l'adulte, Dijon, France.;Université de Bourgogne Franche Comté, CHU Dijon Bourgogne, Service de Médecine Interne et Immunologie Clinique, Centre de Référence Constitutif des Cytopénies Auto-immunes de l'adulte, Dijon, France.;Université de Bourgogne Franche Comté, CHU Dijon Bourgogne, Service de Médecine Interne et Immunologie Clinique, Centre de Référence Constitutif des Cytopénies Auto-immunes de l'adulte, Dijon, France.;Université de Bourgogne Franche Comté, CHU Dijon Bourgogne, Service de Médecine Interne et Immunologie Clinique, Centre de Référence Constitutif des Cytopénies Auto-immunes de l'adulte, Dijon, France.",
"authors": "Estève|Clémentine|C|;Samson|Maxime|M|;Guilhem|Alexandre|A|;Nicolas|Barbara|B|;Leguy-Seguin|Vanessa|V|;Berthier|Sabine|S|;Bonnotte|Bernard|B|;Audia|Sylvain|S|http://orcid.org/0000-0003-1772-1392",
"chemical_list": "D003622:Dapsone",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0187296",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0187296PONE-D-17-32535Research ArticleEfficacy and safety of dapsone as second line therapy for adult immune thrombocytopenia: A retrospective study of 42 patients Dapsone in ITPEstève Clémentine Data curationFormal analysisSamson Maxime Data curationWriting – review & editingGuilhem Alexandre Data curationWriting – review & editingNicolas Barbara Data curationWriting – review & editingLeguy-Seguin Vanessa Data curationWriting – review & editingBerthier Sabine Data curationWriting – review & editingBonnotte Bernard ConceptualizationData curationFormal analysisValidationWriting – review & editinghttp://orcid.org/0000-0003-1772-1392Audia Sylvain ConceptualizationData curationFormal analysisMethodologySupervisionValidationWriting – original draftWriting – review & editing*Université de Bourgogne Franche Comté, CHU Dijon Bourgogne, Service de Médecine Interne et Immunologie Clinique, Centre de Référence Constitutif des Cytopénies Auto-immunes de l’adulte, Dijon, FranceKuwana Masataka EditorKeio University, JAPANCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: sylvain.audia@u-bourgogne.fr30 10 2017 2017 12 10 e01872965 9 2017 17 10 2017 © 2017 Estève et al2017Estève 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.Dapsone is recommended as a second line therapy in immune thrombocytopenia (ITP), but is underused because of its potential side effects. The medical charts of 42 ITP patients treated with dapsone (100 mg/day) were retrospectively reviewed in order to assess its efficacy and safety in daily clinical practice. The overall response rate was 54.8% (n = 22, with a complete response in 38.1%) with a median time to response of 29 days (24–41 days). Patients with complete response had shorter disease duration whereas no difference was observed between responders and non-responders regarding age, sex or previous treatments received. Importantly, after dapsone withdrawal, a sustained response was observed in 5 patients, representing 12% of the whole cohort. Twenty percent of patients (n = 8) relapsed on therapy after 8.1 (6.5–13.6) months. Side effects occurred in 31% (n = 13) of patients, and required dapsone withdrawal in 22% (n = 9) or dosage reduction in 10% (n = 4) of the cases. Side effects resolved in all but one case. Overall, these data support dapsone as an interesting second line therapy in ITP, with a good safety and efficacy profile at a low cost.\n\nThe authors received no specific funding for this work. Data AvailabilityThe data set has been summarized in a table that has been uploaded as a supporting information file.Data Availability\nThe data set has been summarized in a table that has been uploaded as a supporting information file.\n==== Body\nIntroduction\nImmune thrombocytopenia (ITP) is an autoimmune disorder leading to a low platelet count responsible for bleedings of variable severity. Treatments are recommended in case of bleeding symptoms and/or platelet count below 20x109/L. Steroids are used as first-line therapy, while intravenous immunoglobulins (IVIg) should be restricted to patients with severe bleeding symptoms [1–3]. Both steroids and IVIg offer high response rates, but relapses are common [1,2]. Rituximab is used as a second-line therapy with a response rate of 40% after one year follow-up, but only 20% after five years [4–6]. Of note, rituximab is expensive and could favour infections [7]. Hydroxychloroquine is usually used when antinuclear antibodies are positive, with a response rate of 60% [8]. Because of its side-effects, particularly virilization and liver cytolysis, danazol is less and less used [9,10]. Splenectomy is considered for chronic ITP, as it is the unique curative treatment with a long term response in 66–88% of patients, of whom only 15% will relapse [11,12]. Of note, long term infectious susceptibility following splenectomy requires prophylactic measures and patient education. Thrombopoietin receptor agonists (TPO-RA) have a response rate of 80%, with a suspensive effect, thus requiring long term treatment [13,14], although long-term response following their transient use have been observed in 15–30% [15–18]. Immunosuppressive drugs such as azathioprine, ciclosporine, cyclophosphamide or mycophenolate mofetil are dedicated to multirefractory patients [19].\n\nDapsone efficiency was first reported in the 90’s in ITP [20,21]. Since then, several studies confirmed its potential interest as second line therapy in ITP, with response rate ranging between 40–62% [10,22–26]. The mechanisms of action of dapsone remain unclear, but it has been postulated that haemolysis induced by dapsone might limit the phagocytosis of opsonized-platelets by diverting splenic macrophages [20,23].\n\nWe aimed to assess the efficacy and safety of dapsone in a retrospective monocentric study in adult ITP.\n\nMaterials and methods\nPatients\nMedical records of all patients registered in Dijon University Hospital Centre between January 2006 and August 2016 for thrombocytopenia according to the diagnosis-related group (DRG) medical information system (PMSI) were retrospectively reviewed. The study was approved by the institutional review board of the University Hospital of Dijon and the local ethics committee (Comité de Protection des Personnes Est I), who waived the requirement for informed consent.\n\nPatients with a diagnosis of ITP and treated with dapsone were selected. Demographic data (age, sex, weight, bleeding score [27] at dapsone introduction), dapsone-related side effects, previous treatments and their response were collected. The course of ITP was determined following the international criteria [28], i.e. newly diagnosed ITP (less than 3 months of evolution), persistent ITP (3–12 months) and chronic ITP (more than 12 months). Differential diagnoses for ITP were ruled out in all patients. Bone marrow examination was performed in patients older than 60, or in case of systemic symptoms, or when anaemia or leukopenia were present, as recommended [1,2, 3]. The following biological parameters were collected: screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency; the lowest platelet count within the 3 months prior to dapsone initiation, at response or after 4 weeks for non-responders, and at the time of the last response or the last follow-up; haemoglobin levels at dapsone initiation and at response, or after 4 weeks of treatments for non-responders.\n\nDefinition of response\nResponse was defined as an increase in platelet count over 30x109/L with at least a two-fold increase from the baseline in absence of bleedings, for at least 4 weeks. Partial response (PR) was considered when platelet count remain below 100x109/L, and complete response (CR) when platelet count was over 100x109/L. Non-response (NR) was considered when none of these criteria were achieved or when treatment was stopped because of side effects within the 4 weeks following its introduction. When another treatment (steroids or TPO-RA) was prescribed concomitantly with dapsone, only patients who had this treatment discontinued and maintained platelet counts over objectives were considered as responders. Patients lost to follow-up were considered as non-responders. Time to response was calculated from the day dapsone was initiated to the one of the first response was achieved. Duration of response was censored at the date of the last platelet count fulfilling response (PR or CR respectively) criteria.\n\nStatistics\nQuantitative values are reported as median (1st-3rd interquartile) and qualitative data as percentage. P-values were derived using Chi2 test and Mann-Whitney test for qualitative and quantitative values, respectively. Wilcoxon matched pairs test was used to compare platelet count before and after treatments. P<0.05 was considered significant. Statistical analyses were performed with STATATM Software (Stata Corporation).\n\nResults\nPatients\n124 patients with thrombocytopenia were identified from our records between January 2006 and August 2016, among which 108 had ITP (Fig 1). Sixteen patients were excluded because of platelet aggregates (n = 3), hypersplenism (n = 4), Epstein-Barr virus infection (n = 1), drug-induced thrombocytopenia due to rifampicin (n = 1), disseminated intravascular coagulation (n = 1) or because thrombocytopenia was related to other hematologic diseases (myelodysplastic syndrome (n = 2), myeloma (n = 1), lymphoma (n = 1), chronic myelomonocytic leukaemia (n = 1), aplastic anaemia (n = 1)). Among these 108 ITP patients, 46 patients were treated with dapsone, but 4 patients were excluded because of acute ITP that resolved in less than 3 months (n = 2) or missing data (n = 2).\n\n10.1371/journal.pone.0187296.g001Fig 1 Flowchart of the study.\nClinical characteristics of patients are summarized in Table 1. Patients were 49.2 years old (31.2–68.2) at diagnosis. The median age at dapsone initiation was 57.1 (34.4–72.2), and 12 patients (28.6%) were older than 75. The female/male ratio was 1.8 (27/15). 14 patients (33.3%) had newly diagnosed ITP, 9 (21.4%) had persistent ITP and 19 (45.2%) had chronic ITP. Most of the patients had primary ITP (n = 38, 90.5%). Secondary ITP was associated with antiphospholipid syndrome (n = 2), sicca syndrome (n = 1) or Graves' disease (n = 1). Patients received a median of 1 (1–2) treatment before dapsone, consistent with steroids in all but one patient. For this patient, dapsone was used as first line therapy without steroids, because of type 2 diabetes associated with non-severe thrombocytopenia. For the others, prednisone was used at 1 mg/kg/d for a short duration (3 to 4 weeks) with an abrupt discontinuation. Seven patients did not respond to this first line therapy, while the others (34 out of 41 patients, 82.9%) responded but relapsed after discontinuation. IVIg were used in 16 patients (38.1%), among which 13/16 (81.3%) achieved a transient response. A TPO-RA was used in 5 patients (11.9%) before or concomitantly with dapsone: only one patient did not respond. Rituximab was used prior to dapsone in 7 patients (16.7%): 5 did not respond, 1 relapsed after 4 years, 1 had a PR and finally underwent splenectomy with a late relapse after 8 years. Hydroxychloroquine and vincristine were inefficient in 1 and 2 cases respectively.\n\n10.1371/journal.pone.0187296.t001Table 1 Clinical characteristics of patients treated with dapsone.\n\tTotal\tResponders\tNon-responders\tp-value\t\nn = 42\tn = 23\tn = 19\t\nAge, years\t57.1 (34.4–77.2)\t61.1 (26.9–81.3)\t51.7 (37.7–67.5)\t0.63\t\nSex (F/M)\t27/15\t16/7\t11/8\t0.43\t\nPrimary ITP\t38 (90.5%)\t21 (91.3%)\t17 (89.5%)\t1.00\t\n Course of ITP, months\t8.8 (2–53.6)\t9.6 (1.6–49.9)\t7.5 (2.3–57.9)\t0.53\t\n Newly diagnosed\t14 (33.3%)\t9 (39.1%)\t5 (26.3%)\t0.38\t\n Persistent\t9 (21.4%)\t3 (13%)\t6 (31.6%)\t0.26\t\n Chronic\t19 (45.2%)\t11 (47.8%)\t8 (42.1%)\t0.71\t\nTreatments prior to dapsone, n\t1 (1–2)\t1 (1–2)\t1 (1–3)\t0.53\t\n Steroids\t41 (97.6%)\t23 (100%)\t18 (94.7%)\t\t\n IVIg\t16 (38.1%)\t7 (30.4%)\t9 (47.4%)\t\t\n Rituximab\t7 (16.7%)\t2 (8.7%)\t5 (26.3%)\t\t\n Splenectomy\t1 (2.4%)\t0 (0%)\t1 (5.3%)\t\t\n TPO receptor agonist\t5 (11.9%)\t2 (8.7%)\t3 (15.8%)\t\t\nBleeding score at dapsone initiation\t2 (0–5)\t4 (1–5)\t2 (0–5)\t0.25\t\nHaemoglobin level at dapsone initiation, g/dL\t13.9 (12.9–14.9)\t14 (13.3–15)\t13.3 (12.9–14.8)\t0.40\t\nNadir of platelet count within the 3 months prior dapsone initiation, x109/L\t14 (6–22)\t12 (6–24)\t14 (5–20)\t0.97\t\nSteroids at dapsone initiation\t23 (54.8%)\t14 (60.9%)\t9 (47.4%)\t0.38\t\nFollow-up, months\t67.6 (48.3–106.4)\t64.3 (25.3–91.6)\t76 (54.2–126.9)\t0.14\t\nThe lowest median platelet count within the 3 months prior to dapsone initiation was 14x109/L (6–22) and the bleeding score was 2 (0–5). Only 2 patients had a history of severe gastro-intestinal bleedings before dapsone initiation. Median follow-up was 67.6 months (49.5–105.2).\n\nDapsone was initiated at 100 mg/day for all but one patient, who had a CR with 100 mg 3 times a week. Dapsone was initiated in association with steroids in 54.8% (n = 23): prednisone was used at a median dose of 1 mg/kg/day and was discontinued after a median duration of 28 days (21–37.5). A TPO-RA was associated with dapsone in 4 cases: 2 did not respond to dapsone, 1 had a rash leading to dapsone withdrawal and the other maintained a CR after TPO-RA discontinuation.\n\nResponse to dapsone\nResponse rates on dapsone are reported in Table 2 and platelet counts are depicted in Fig 2. Dapsone was given for a median duration of 8.9 (5.1–19.8) months for responders and 1.5 (0.6–2.4) months for non-responders. Median time to response was 29 (24–41) days, with 52.2% (12) patients responding in less than 1 month and only 3 after 2 months (60, 69 and 85 days). Platelet count significantly rose from 12x109/L (6–25) to 119 (94–141) in responders (p<0.0001), but not in non-responders (14x109/L (5–20) vs. 20 (8–27), p = 0.6; Fig 2). Overall response rate was 54.8% (n = 23), with CR in 38.1% (n = 16) and PR in 16.7% (n = 7). The median duration of response was 7.5 (3.5–19.4) months. Of note, 7 patients were considered as non-responders because of side effects. For the remaining 12 non-responders, dapsone was stopped after a median of 1.9 months (1.6–3). When responders and non-responders were compared, no significant difference was found concerning demographic factors or ITP history. Notably, the proportions of responders were not significantly different between newly diagnosed (n = 9/14, 64.2%), persistent (n = 3/9, 33.3%) and chronic ITP (n = 11/19, 57.9%). However, patients with a CR had a shorter ITP duration before dapsone initiation compared to patients with PR (2.2 (1.2–18.7) vs. 49.9 (38.5–90.9) months, p = 0.009). Moreover, response duration was longer in case of CR (10.4 (4.2–21.3) vs. 3.9 (1.9–7.1) months; p = 0.05). Patients who received dapsone in association with steroids tended to have more CR than PR (75.0% vs. 28.6%, p = 0.066). Importantly, all patients who were treated with this combination interrupted steroids after a median duration of 28 days, and previously experienced a relapse after the discontinuation of a first course of steroids. Thus, the fact that the response attributed to dapsone was indeed due to steroids appeared unlikely. However, to rule out this hypothesis, the response rates of dapsone started as monotherapy were also considered: a response was achieved in 47.4% (n = 9/19 patients) with a CR in 21.1% (n = 4/19) and a PR in 26.3% (n = 5/19).\n\n10.1371/journal.pone.0187296.g002Fig 2 Platelet count before and after 4 weeks dapsone was started, in responders (n = 23) and non-responder patients (n = 19).\nP-value derived by Wilcoxon matched pairs test.\n\n10.1371/journal.pone.0187296.t002Table 2 Outcome on dapsone therapy.\n\tAll patients\tNon-responders\tResponders\tComplete response\tPartial response\tp-value *\t\n(n = 42)\t(n = 19)\t(n = 23)\t(n = 16)\t(n = 7)\t\nCourse of ITP at dapsone initiation, months\t8.8 (2–53.6)\t7.5 (2.3–57.9)\t9.6 (1.6–49.9)\t2.2 (1.2–18.7)\t49.9 (38.5–90.9)\t0.009\t\nCourse of ITP at dapsone initiation\t\t\t\t\t\t0.03\t\n Newly diagnosed, n (%)\t14\t5\t9\t9\t0\t\t\n Persistent, n (%)\t9\t6\t3\t2\t1\t\t\n Chronic, n (%)\t19\t8\t11\t5\t6\t\t\nTime to response, days\t29 (24–41)\t/\t29 (24–41)\t28.5 (24–44)\t32 (23–41)\t0.84\t\nResponse duration, months\t7.5 (3.5–19.4)\t/\t7.5 (3.5–19.4)\t10.4 (4.2–21.3)\t3.9 (1.9–7.5)\t0.05\t\nTreatment duration, months\t3.9 (1.6–9)\t1.5 (0.6–2.4)\t8.9 (5.1–19.8)\t12.1 (5.2–23)\t7.1 (2.5–8.9)\t0.08\t\nRelapse on dapsone therapy\t5 (11.9%)\t/\t5 (21.7%)\t2 (12.5%)\t3 (42.9%)\t\t\nTime to relapse, months\t8.1 (6.5–13.6)\t/\t8.1 (6.5–13.6)\t33.7 (20.9–46.4)\t6.5 (4.6–10.1)\t\t\nNumber of patients with sustained response (> 6 months) after dapsone cessation\t5 (11.9%)\t/\t5 (21.7%)\t4 (25%)\t1 (14.3%)\t\t\nFollow-up after dapsone cessation, months\t21.1 (12.6–29.5)\t/\t21.1 (12.6–29.5)\t21.1 (7.5–29.5)\t12.6\t\t\nSide effects\t13 (31%)\t7 (36.8%)\t6 (26.1%)\t3 (18.8%)\t3 (42.9%)\t\t\n Cutaneous toxicity\t5\t5\t0\t0\t0\t\t\n Methemoglobinemia\t4\t2\t2\t1\t1\t\t\n Withdrawal because of toxicity\t9\t7\t2\t0\t2\t\t\n Dosage adaptation because of toxicity\t4\t/\t4\t3\t1\t\t\nHaemoglobin level at dapsone initiation, g/dL\t13.9 (12.9–14.9)\t13.3 (12.9–14.8)\t14 (13.3–15)\t13.5 (12.8–14.2)\t15 (13.9–15.8)\t0.02\t\nDecrease in haemoglobin level, g/dL\t1.5 (0.6–2.1)\t1 (0.4–2)\t1.8 (0.9–2.5)\t1.5 (0.6–2)\t2.5 (2–2.9)\t0.02\t\n* Complete response versus partial response\n\nHaemoglobin level at dapsone initiation was 13.9 (12.9–14.9) g/dL, with a decrease in 1.5 (0.6–2.1) g/dL at response time. There was no significant difference in the decrease in haemoglobin level between responders and non-responders (1 (0.4–2) vs.1.8 (0.9–2.5) g/dL, respectively; p = 0.16).\n\nResponse to dapsone therapy is summarized in Fig 3. Among the 23 responders, a relapse occurred in 6 patients (26.2%). Five (21.7%) patients relapsed while on therapy, after 8.1 (6.5–13.6) months and received rituximab (n = 2) or underwent splenectomy (n = 2). One patient relapsed during dapsone tapering: a response was achieved after dapsone dosage was increased. Two other patients lost response at dapsone cessation but achieved response after dapsone was resumed.\n\n10.1371/journal.pone.0187296.g003Fig 3 Flowchart of dapsone-treated patients.\nFollow-up is given by median (1st-3rd interquartile).\n\nDapsone was definitively interrupted in 7 patients after 7.6 (5.1–15.7) months of response, after a progressive tapering for 3 patients. The reasons for dapsone cessation were side effects (n = 2) or desire of the patient to take off medication (n = 5). Two patients relapsed 3 and 3.5 months after dapsone cessation. Interestingly, a sustained response was observed in 5 patients (5/23 responders: 21.7%; 5/42 patients of the whole cohort: 14%) after a median follow-up of 21.1 (12.6–29.5) months. A CR was maintained in 3, while 2 switched to a PR. Among these 5 patients with sustained response after dapsone discontinuation, 3 had a newly diagnosed ITP and 2 a chronic ITP.\n\nTen patients were still responders under treatment after 5.9 (2.8–19.5) months. Dapsone dosage was tapered in 7 of them, in order to withdraw dapsone (n = 4) or because of side effects (n = 3). One patient was lost to follow-up after 4.2 months of response.\n\nRegarding the 19 non-responders, a response was achieved with rituximab in 8/11, with splenectomy in 3/5, with TPO-RA in 3/4, and with hydroxychloroquine in 1/2, while 3 patients had a platelet count allowing a wait and watch attitude.\n\nAs expected, responders to dapsone required less second line treatments (30%, 7/23) compared to non-responders (84%, 16/19) after a median follow-up of 67.6 (49.5–105.2) months. Rituximab was used in 17% of responders compared to 58% of non-responders; splenectomy was performed in 17% vs. 26% and TPO-RAs were used in 4% vs.21%, respectively, supporting dapsone as an interesting medication to spare the use of expensive drugs or radical treatment such as splenectomy.\n\nDapsone side-effects\nFifteen side effects were reported in 13 patients (31%), consistent with skin rash (n = 5), including sulfone syndrome (n = 2), methemoglobinemia (n = 4), neuropathy (n = 3), dyspnoea (n = 1), fatigue (n = 1) and diarrhoea (n = 1). Symptomatic anaemia or severe haemolysis was not observed. G6PD deficiency was screened in 36/42 patients (85.7%). There was no difference between patients with or without side effects, regarding age, ITP history, or the combination of steroids at dapsone initiation (Table 3). However, the proportion of women was higher in the group who experienced side effects (92.3% (12/13) vs. 51.7% (15/29), p = 0.015).\n\n10.1371/journal.pone.0187296.t003Table 3 Comparison of patients according to dapsone-related side effects.\n\tSide effects\tNo side effect\tp-value\t\n(n = 13)\t(n = 29)\t\nAge, years\t56 (44.5–60.8)\t62.7 (29.4–78.4)\t0.87\t\nSex ratio (F/M)\t12/1\t15/14\t0.015\t\nCourse of ITP, months\t7.2 (1.9–29.3)\t14.5 (2.1–62.7)\t0.23\t\nPrimary / Secondary ITP\t11/2\t27/2\t0.58\t\nNewly diagnosed ITP, n\t5 (38.5%)\t9 (31%)\t0.73\t\nPersistent ITP, n\t4 (30.8%)\t5 (17.2%)\t0.42\t\nChronic ITP, n\t4 (30.8%)\t15 (51.7%)\t0.21\t\nNumber of treatments prior to dapsone, n\t1 (1–2)\t2 (1–2)\t0.30\t\nSteroid therapy associated to dapsone, n\t8 (61.5%)\t15 (51.7%)\t0.56\t\nDue to side effects, dapsone was withdrawn in 9 patients and the dosage reduced in 4, leading to the resolution of all the side effects, except for one case (neuropathy), for which dapsone accountability was not formally demonstrated. One patient died of pneumonia, which was not related to dapsone.\n\nDiscussion\nThe characteristics of the population of this study are in accordance with previous reports on adult ITP with a median age of 57.1 years and a female predominance [29]. Dapsone was efficient in more than half of the patients (54.8%) with a CR achieved in more than one third (38.1%), irrespectively of the response to previous treatments and the course of ITP. These results are in line with literature, as summarized in Table 4, with a response rate ranging between 44.2% and 63.3%, and a CR in about 30% [20,22–26,30–34].\n\n10.1371/journal.pone.0187296.t004Table 4 Literature reports of dapsone in immune thrombocytopenia.\nStudy\tGodeau et al.\tDamodar et al.\tVancine et al.\tZaja et al.\tPatel et al.1\tCurrent study\t\nDesign\tProspective\tRetrospective\tRetrospective\tProspective\tRetrospective\tRetrospective\t\nNumber of patients (adults)\t66\t90 (55)\t52 (45)\t20 (20)\t38 (26)\t42 (42)\t\nAge, years\t48 (R)-43 (NR)\t20.6 (3–61)\t38 (13–78)\t51 (27–74)\t39.5 (20–68)\t57.1 (34.4–77.2)\t\nCourse of ITP at dapsone introduction, months\t52 (3–240)\t24.5 (6–132)\t5 (1–30)\t46 (2–274)\t-\t8.8 (2–53.6)\t\nPlatelet count before dapsone, x109/L\t23 (2–49)\t-\t-\t19\t10 (1–21)\t14 (6–22)\t\nAverage dose\t75–100 mg/day\t1–2 mg/kg/day\t100 mg/day\t100 mg/day\t1.57mg/kg/day\t33.3–100 mg/day\t\nOverall response\t33/66 (50%)2\t57/90 (63.3%)3\t23/52 (44.2%)3\t11/20 (55%)4\t12/26 (46.2%)4\t23/42 (54.8%)4\t\nComplete response\t13/66 (19.7%)\t44/90 (48.9%)\t-\t4/20 (20%)\t10/26 (38.5%)\t16/42 (38.1%)\t\nPartial response\t20/66 (30.3%)\t13/90 (14.4%)\t-\t7/20 (35%)\t2/26 (7.7%)\t7/42 (16.7%)\t\nTime to response, days\t21 (8–90)\t105 (30–270)\t-\t30 (15–60)\t59 (27–108)\t29 (24–41)\t\nResponse duration, months\t-\t-\t-\t42 (8–56)\t14.2 (1.9–36.1)\t7.5 (3.5–19.4)\t\nTreatment duration in responders, months\t-\t9 (PR)-12.5 (CR)\t9.7 (1–90.8)\t31 (8–56)\t5.3 (0.3–21.1)\t8.9 (5.7–19.8)\t\nRelapse on dapsone therapy\t1/33 (3%)\t-\t-\t0/11 (0%)\t0/12 (0%) 2/6 children\t6/23 (26.1%)\t\nSustained response after discontinuation (> 6 months) in responder patients\t1/33 (3%)\t27/57 (47.4%)\t15/23 (65.2%)\t1/11 (9.1%)\t2/12(16.7%)\t5/23 (21.7%)\t\nSide effects\t16/66 (24.2%)\t3/90 (3.3%)5\t12/52 (23.1%)\t2/20 (10%)\t5/38 (13.2%)\t13/42 (31%)\t\nWithdrawal due to toxicity\t7\t3\t2\t0\t2\t9\t\n1Study including adults and children, only adults are considered here\n\n2PR defined as platelet count > 50x109/L, CR as platelet count > 150x109/L\n\n3PR defined as platelet count > 50x109/L, CR as platelet count > 100x109/L\n\n4PR defined as platelet count > 30x109/L with at least a two-fold increase from baseline level, CR as platelet count > 100x109/L\n\n5Only severe side effects were reported\n\nRelapse during treatment or dapsone tapering was observed in 22%, which is in accordance with previous reports [23,24,26]. Of note, a response can usually be achieved after starting again dapsone or by increasing its dosage.\n\nMore surprisingly, a sustained response after dapsone discontinuation was observed in 5 out of 7 responders who interrupted dapsone, representing around 21% of the responders. Interestingly, the response lasted more than 6 months in 5 patients, among which 2 had a chronic ITP. Such a sustained response ranged between 3 and 65.2% of the responders in previous reports [23,24,26], which is probably due to the difference in follow-up and the fact that dapsone discontinuation was not proposed to all responders, as most of the studies had a retrospective design. These results need to be confirmed in prospective studies and should be emphasized to the one reported for rituximab, 20% after 5 years [6], or TPO-RA, 15–30% [13–18]. Whether dapsone has immunomodulatory properties remains to be demonstrated, but these results show its potential interest to avoid or to delay radical treatment such as splenectomy. To date, mechanisms of action of dapsone in ITP remain unclear. It has been postulated that haemolysis triggered by dapsone could divert splenic macrophages, thus decreasing the phagocytosis of auto-antibody-coated platelet. This hypothesis was supported by a higher decrease in haemoglobin level in responders [23], which was not confirmed in our study and others [22,24,25,32].\n\nThe median time to response was 29 days, which is in line with previous reports (21–59 days) [23,24,26], except for one study that reported a longer time to response (105 days) [22]. In our study, late responses were observed in only 3 patients and occurred between the second and third months. Hence, for clinical practice, the efficacy of dapsone should be evaluated after 1 to 2 months, keeping in mind that late response is rare. Obviously, because of its long time to response, dapsone cannot be considered as an emergency treatment.\n\nIn this study, side effects related to dapsone were observed in 31%. Cutaneous effects were the most frequent, with sulfone syndrome, that is indeed a DRESS (Drug Rash with Eosinophilia and Systemic Symptoms), occurring only in 2 cases. It has been suggested that the concomitant prescription of steroids decreases the intensity of cutaneous side effects during ITP [35] compared to what is observed in other situations. This was not confirmed in our study, probably due to the small size of the cohort. Increase in methemoglobinemia level was observed in 10% of our patients but was symptomatic in only 1 case. Because of its low occurrence, methemoglobinemia can be checked only in symptomatic patients, keeping in mind that the transient interruption of dapsone or the decrease of its dosage usually allows resolution of symptoms. Of note, side effects led to dapsone discontinuation in 21% of our patients and to dapsone tapering in 9.5%, with a resolution in all but one case. Indeed, one case of neuropathy persisted after dapsone discontinuation but the accountability for dapsone was not firmly confirmed. Overall, the frequency of side effects reported here is higher than previously described, with ranges between 3 to 25% (Table 4) [22–26].\n\nUnfortunately, no predictive factor of response to dapsone was identified. However, patients with ITP of short evolution had a higher rate of CR, which argues for the use of dapsone early in the course of ITP, notably for newly diagnosed or persistent ITP, which is in line with what was suggested in a previous report [26]. However, more than half of chronic ITP patients had a response to dapsone, supporting its use whatever the course of ITP. We did not confirm that a lower platelet count or a higher number of treatments received prior to dapsone were associated with non-response, contrary to what was previously reported [23,34].\n\nIn the past decade, new molecules such as rituximab and TPO-RA have improved the management of ITP. However, the cost of the long term use of these therapies can be very high and cheaper treatment options such as dapsone should be considered. The annual cost of dapsone is around 50 Euros, not considering biological exams, which should be compared to the one of TPO-RA that is around 26,000 Euros or to one course of intravenous rituximab (1000 mg, two weeks apart) that is approximatively 5,300 Euros, not considering hospitalization costs [10,36]. Even if medico-economic studies are lacking, dapsone appears as a cheaper option that should be tried whenever possible before using expensive drugs.\n\nConclusions\nOur results support the valuable place of dapsone as second line therapy in ITP with a response in about one half of the patients. Interestingly, a sustained response after its withdrawal can be observed, representing 5 out of our 23 responder patients. As expected, responders to dapsone will experience fewer treatments for ITP, thus decreasing the need for radical treatment such as splenectomy and for expensive therapies, which is of interest in the current economical context. However, side effects are frequent and reported in one quarter to one third of patients in retrospective studies. They are usually mild and resolved after dapsone tapering or discontinuation. Haemolysis is expected in all patients on treatment, and haemoglobin level should be checked during the first weeks of therapy and during any acute diseases that may precipitate anaemia, such as pulmonary diseases [26]. For this reason dapsone should be avoided in patients with severe pulmonary or cardiac diseases or with known haemolytic diseases. In that aim, screening for G6PD deficiency could be performed. Overall, prevention of major side effects mostly relies on patients’ education to recognize initial symptoms such as rash, fever, dyspnoea that require dapsone interruption and prompt medical assistance. Due to the time to response that is about one month, dapsone cannot be considered as an emergency therapy and its efficacy should not be assessed before one to two months. Of note, dapsone can be used in children [22,37] and can be maintained during pregnancy [38].\n\nSupporting information\nS1 Table Anonymized data set.\n(XLS)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Neunert C , Lim W , Crowther M , Cohen A , Solberg L Jr, Crowther MA (2011 ) The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia . Blood \n117 : 4190 –4207 . doi: 10.1182/blood-2010-08-302984 \n21325604 \n2 Provan D , Stasi R , Newland AC , Blanchette VS , Bolton-Maggs P , Bussel JB \net al (2010 ) International consensus report on the investigation and management of primary immune thrombocytopenia . Blood \n115 : 168 –186 . doi: 10.1182/blood-2009-06-225565 \n19846889 \n3 British Committee for Standards in Haematology General Haematology Task Force (2003 ) Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy . 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Haematologica \n98 : 875 –880 . doi: 10.3324/haematol.2012.075648 \n23144195 \n13 Bussel JB , Provan D , Shamsi T , Cheng G , Psaila B , Kovaleva L \net al (2009 ) Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial . Lancet \n373 : 641 –648 . doi: 10.1016/S0140-6736(09)60402-5 \n19231632 \n14 Kuter DJ , Bussel JB , Lyons RM , Pullarkat V , Gernsheimer TB , Senecal FM \net al (2008 ) Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial . Lancet \n371 : 395 –403 . doi: 10.1016/S0140-6736(08)60203-2 \n18242413 \n15 Gonzalez-Lopez TJ , Pascual C , Alvarez-Roman MT , Fernandez-Fuertes F , Sanchez-Gonzalez B , Caparros I \net al (2015 ) Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia . Am J Hematol \n90 : E40 –43 . doi: 10.1002/ajh.23900 \n25400215 \n16 Gonzalez-Lopez TJ , Sanchez-Gonzalez B , Pascual C , Arefi M , de Cabo E , Alonso A \net al (2015 ) Sustained response after discontinuation of short-and medium-term treatment with eltrombopag in patients with immune thrombocytopenia . Platelets \n26 : 83 –86 . doi: 10.3109/09537104.2013.870987 \n24499036 \n17 Mahevas M , Fain O , Ebbo M , Roudot-Thoraval F , Limal N , Khellaf M \net al (2014 ) The temporary use of thrombopoietin-receptor agonists may induce a prolonged remission in adult chronic immune thrombocytopenia. Results of a French observational study . Br J Haematol \n165 : 865 –869 . doi: 10.1111/bjh.12888 \n24725224 \n18 Newland A , Godeau B , Priego V , Viallard JF , Lopez Fernandez MF , Orejudos A \net al (2016 ) Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study . Br J Haematol \n172 : 262 –273 . doi: 10.1111/bjh.13827 \n26537623 \n19 Mahevas M , Gerfaud-Valentin M , Moulis G , Terriou L , Audia S , Guenin S \net al (2016 ) Characteristics, outcome, and response to therapy of multirefractory chronic immune thrombocytopenia . Blood \n128 : 1625 –1630 . doi: 10.1182/blood-2016-03-704734 \n27354722 \n20 Durand JM , Lefevre P , Hovette P , Mongin M , Soubeyrand J (1991 ) Dapsone for idiopathic autoimmune thrombocytopenic purpura in elderly patients . Br J Haematol \n78 : 459 –460 . 1873232 \n21 Moss C , Hamilton PJ (1988 ) Thrombocytopenia in systemic lupus erythematosus responsive to dapsone . BMJ \n297 : 266 \n3416146 \n22 Damodar S , Viswabandya A , George B , Mathews V , Chandy M , Srivastava A (2005 ) Dapsone for chronic idiopathic thrombocytopenic purpura in children and adults—a report on 90 patients . 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Rev Med Interne \n31 : 337 –344 . 20409619 \n31 Dutta TK , Goel A , Ghotekar LH , Hamide A , Badhe BA , Basu D (2001 ) Dapsone in treatment of chronic idiopathic thrombocytopenic purpura in adults . J Assoc Physicians India \n49 : 421 –425 . 11762611 \n32 Hernandez F , Linares M , Colomina P , Pastor E , Cervero A , Pérez A \net al (1995 ) Dapsone for refractory chronic idiopathic thrombocytopenic purpura . Br J Haematol \n90 : 473 –475 . 7794776 \n33 Le Louet H , Ruivart M , Bierling P , Duche JC , Godeau B (1999 ) Lack of relevance of the acetylator status on dapsone response in chronic autoimmune thrombocytopenic purpura . Am J Hematol \n62 : 251 –252 . 10589083 \n34 Godeau B , Oksenhendler E , Bierling P (1993 ) Dapsone for autoimmune thrombocytopenic purpura . Am J Hematol \n44 : 70 –72 . 8342569 \n35 Sauvetre G , MahEvas M , Limal N , Guillaud C , Khellaf M , Bierling P \net al (2015 ) Cutaneous rash and dapsone-induced hypersensitivity syndrome a common manifestation in adult immune thrombocytopenia. Presentation and outcome in 16 cases . Am J Hematol \n90 : E201 –202 . doi: 10.1002/ajh.24068 \n26120067 \n36 Rodrigo C , Gooneratne L (2013 ) Dapsone for primary immune thrombocytopenia in adults and children: an evidence-based review . J Thromb Haemost \n11 : 1946 –1953 . doi: 10.1111/jth.12371 \n23927583 \n37 Meeker ND , Goldsby R , Terrill KR , Delaney KS , Slayton WB (2003 ) Dapsone therapy for children with immune thrombocytopenic purpura . J Pediatr Hematol Oncol \n25 : 173 –175 . 12571474 \n38 Loustau V , Pourrat O , Mandelbrot L , Godeau B (2015 ) Immune thrombocytopenia and pregnancy: State of knowledge and unanswered questions . Rev Med Interne \n36 : 167 –172 . 25172779\n\n",
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"mesh_terms": "D000328:Adult; D003622:Dapsone; D006801:Humans; D016553:Purpura, Thrombocytopenic, Idiopathic; D012189:Retrospective Studies",
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"title": "Efficacy and safety of dapsone as second line therapy for adult immune thrombocytopenia: A retrospective study of 42 patients.",
"title_normalized": "efficacy and safety of dapsone as second line therapy for adult immune thrombocytopenia a retrospective study of 42 patients"
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"abstract": "Delayed post-hypoxic leukoencephalopathy (DPHL) is an uncommon, potentially under-recognized, cause of hypoxia induced white matter injury. It characteristically follows a biphasic course: After an initial phase of altered neurologic status a recovery occurs which is then followed by a recurring phase of neurologic deterioration, typically 2-4 weeks after the initial event. At this time white matter changes can be identified on MRI, which are the hallmark of DPHL. The characteristics and the typical MR-imaging signs of DPHL are discussed in this case report.",
"affiliations": "Department of Pediatric Radiology, University Hospital Leipzig, Leipzig, Germany.;Department of Neurology, University Hospital Leipzig, Leipzig, Germany.;Department of Neurology, University Hospital Leipzig, Leipzig, Germany.;Department of Neuroradiology, University Hospital Leipzig, Leipzig, Germany.;Department of Neuroradiology, University Hospital Leipzig, Leipzig, Germany.",
"authors": "Beeskow|Anne B|AB|;Oberstadt|Moritz|M|;Saur|Dorothee|D|;Hoffmann|Karl-Titus|KT|;Lobsien|Donald|D|",
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"doi": "10.3389/fneur.2018.00708",
"fulltext": "\n==== Front\nFront NeurolFront NeurolFront. Neurol.Frontiers in Neurology1664-2295Frontiers Media S.A. 10.3389/fneur.2018.00708NeurologyCase ReportDelayed Post-hypoxic Leukoencephalopathy (DPHL)—An Uncommon Variant of Hypoxic Brain Damage in Adults Beeskow Anne B. 1*Oberstadt Moritz 2Saur Dorothee 2Hoffmann Karl-Titus 3Lobsien Donald 31Department of Pediatric Radiology, University Hospital Leipzig, Leipzig, Germany2Department of Neurology, University Hospital Leipzig, Leipzig, Germany3Department of Neuroradiology, University Hospital Leipzig, Leipzig, GermanyEdited by: Rick Dijkhuizen, University Medical Center Utrecht, Netherlands\n\nReviewed by: Jens Fiehler, Universitätsklinikum Hamburg-Eppendorf, Germany; David Shprecher, Banner Sun Health Research Institute, United States\n\n*Correspondence: Anne B. Beeskow anne.beeskow@medizin.uni-leipzig.deThis article was submitted to Stroke, a section of the journal Frontiers in Neurology\n\n27 8 2018 2018 9 70811 4 2018 06 8 2018 Copyright © 2018 Beeskow, Oberstadt, Saur, Hoffmann and Lobsien.2018Beeskow, Oberstadt, Saur, Hoffmann and LobsienThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Delayed post-hypoxic leukoencephalopathy (DPHL) is an uncommon, potentially under-recognized, cause of hypoxia induced white matter injury. It characteristically follows a biphasic course: After an initial phase of altered neurologic status a recovery occurs which is then followed by a recurring phase of neurologic deterioration, typically 2–4 weeks after the initial event. At this time white matter changes can be identified on MRI, which are the hallmark of DPHL. The characteristics and the typical MR-imaging signs of DPHL are discussed in this case report.\n\ndelayed post-hypoxic leukoencephalopathyDPHLhypoxic brain damage in adultswhite matterischemianeuroradiologyCTMRI\n==== Body\nIntroduction\nDelayed post-hypoxic leukoencephalopathy (DPHL) is an uncommon, potentially under-recognized cause of hypoxia-induced white matter injury. DPHL typically occurs following a period of prolonged cerebral hypo-oxygenation, and follows a biphasic course. An initial period of altered mental status is followed by a dramatic recovery, often to initial baseline. Then, typically 2–4 weeks later, neurocognitive deterioration recurs (1). At this point in time, a characteristic leukoencephalopathy can be detected on MRI, which represents the diagnostic hallmark of DPHL.\n\nCase report\nA 51-year-old woman was found comatose and hypotonic in her home. The patient was resuscitated and intubated on site and admitted to an external hospital. An opiate antagonization, because of suspected opiate intoxication (she was on a treatment of for chronic pain syndrome with fentanyl patches), did not show any effect on the patient's consciousness. She had a past medical history of arterial hypertension, obesity, sleep apnea syndrome, and depression.\n\nA blood sample-laboratory analysis revealed rhabdomyolysis. Subsequently, the patient developed acute kidney- and liver failure, which led to immediate transfer to the intensive care unit of our hospital.\n\nOn neurological examination, the patient presented with coma, but did not show any focal neurologic impairment. An unenhanced computed tomography (CT) of the head showed almost symmetrical bilateral hypointensities of the globus pallidus (Figure 1). These changes were interpreted as of primarily hypoxic origin, possibly caused by carbon monoxide (CO) poisoning, although there were no anamnestic indications supporting this assumption. A spinal tap showed no pathological findings of the cerebrospinal fluid (CFS). Four days after the initial event, the patient clinically improved and was cleared for extubation. The neurological examination thereafter was discreet with no focal neurological deficits and her mental status returned to normal.\n\nFigure 1 Bilateral, hypodense basal ganglia necrosis in unenhanced CT (arrows); Philips Ingenuity 5 mm.\n\nMRI of the brain 3 weeks after hospitalization confirmed the bilateral lesions of the globus pallidus seen on CT, characterized by restricted diffusion and FLAIR-hyperintense signal changes (Figure 2). At this time no leukoencephalopathy could be detected. These findings were again interpreted as of post hypoxic origin.\n\nFigure 2 Bilateral basal ganglia necrosis with T2w hyperintense alterations (A) and hemoside deposits (B). These changes are diffusion-disturbed (C,D). 3 T Philips Ingenia, (A) FLAIR, (B) SWI, (C) b1000 image, (D) ADC map.\n\nApproximately 3 weeks after the initial event, the patient developed progressive neuropsychiatric symptoms. First, she attracted attention with odd behavior (e.g., urinating into the rubbish bin or other patients' beds) and phases of agitation. Within a few days, the disturbance in behavior turned into a clinical picture dominated by reduced psychomotor activity and apathy, finally progressing into mutism. In addition, a novel increase in muscle tone with generalized rigidity and spontaneous myoclonus was observed.\n\nA follow-up MRI-scan of the brain 5 weeks after the initial event showed, in addition to the known changes of the basal ganglia, a symmetrical, extensive increased FLAIR-signal with correlating marked diffusion restrictions of the white matter, primarily in the fronto-parietal regions of both hemispheres (Figure 3). The cortex remained spared from these changes. Neither the brain stem nor the cerebellum showed any pathological changes on MRI. In conjunction with the clinical course the changes were diagnosed as DPHL.\n\nFigure 3 Planar T2w hyperintense signal changes of the entire white matter (A) with diffusion restriction (B,C) 3 T Philips Ingenia, (A) FLAIR, (B) b1000 Figure, (C) ADC Map.\n\nA supportive therapy followed. During the course of the inpatient stay, the patient's impairment remained unchanged and she was released into early neurological rehabilitation about 6 weeks after the initial event. A follow up MRI nine months later showed a marked regression of the leukoencephalopathy with a remaining faint hyperintensity predominantly in the parietal white matter of both hemispheres and a complete regression of the diffusion restriction. A slight symmetrical enlargement of the ventricles could be seen indicating a mild atrophy (Figure 4).\n\nFigure 4 Slightly T2w hyperintense signal changes of the white matter (A) without diffusion restriction (B,C), Atophy of the parenchyma with slightly wider inner CSF. 3 T Philips Ingenia, (A) FLAIR, (B) b1000 Figure, (C) ADC Map. Overall there is a marked regression of the imaging findings.\n\nDiscussion\nDPHL is a rare and probably underrecognized form of hypoxic brain damage (1). The combination of the characteristic clinical symptoms and development and the imaging findings on cranial-MRI are key to establishing the diagnosis (1). After an initial hypoxic event with neurologic deterioration the patient typically improves until neurological deterioration reoccurs, about 3 weeks (2–40 days) after the initial event. Two forms of clinical manifestation, based on the leading symptoms during the second phase, are described (2, 3): An akinetic-mute form, as seen in our case, is clinically represented by bizarre behavior, faulty actions and psychomotor retardation progressing into mutism. The second form resembles symptoms of parkinsonism.\n\nThe typical imaging pattern of DPHL is best detected on MRI. After a latency of about 3 weeks new T2-hyperintense changes of the white matter can be seen, which are typically homogeneously configured and affect large areas of white matter of both hemispheres in a symmetric distribution. These areas typically show a marked diffusion restriction, often to the same extends as the T2-hyperintense lesions. Characteristically, the cortex and U-fibers, cerebellum and the brain stem are spared. Also, in most case series the diffusion restriction seen in DPHL seems to last substantially longer in comparison to the diffusion restriction seen in ischemic stroke (4). This pattern makes it possible to differentiate DPHL from competing diagnoses others than hypoxic brain damage, e.g., generalized brain edema after global hypoxia, toxic brain damage, as seen in heroin inhalation syndrome, metronidazole, or methotrexate induced leukoencephalopathy, as well as posterior reversible encephalopathy syndrome (PRES) (2). These diagnoses have in common that they typically show diffusion restrictions which extend beyond the white matter into the cortical rim.\n\nThere is no documentation of a contrast enhancement in cases of DPHL in the literature and this was also not seen in our case. In cases where MR-spectroscopy was performed, investigated areas showed a low N-acetylaspartate peak, indicating neurons loss, an increased choline peak as a consequence of the demyelination process, and an increased lactate peak was also described in DPHL patients, suggesting a shift from aerobic to anaerobic metabolism (5). However, the imaging findings most important for the diagnosis DPHL are the changes on T2 weighted and diffusion-weighted MR-images.\n\nThe pathomechanism of DPHL has not yet been fully understood. Myelin-sheath damage is suspected, which might be caused by a prolongation of moderate hypooxygenation, due to a dysfunction of the ATP-dependent enzyme that causes myelin secretion. Myelin secretion occurs every 19 to 22 days, which correlates with the delayed occurrence of symptoms of 2–40 days (on average 23 days) (1). Another explanation might be the delayed apoptosis of oligodendrocytes (6). DPHL is described mainly in the context of carbon monoxide intoxication (in up to 3% of the cases), however various other causes of hypoxia, such as drug overuse, cardiac arrest, strangling or seizures are reported to provoke DPHL as well (1, 4, 7).\n\nThe therapy is mainly supportive. The benefit of hyperbaric oxygen therapy in case of a DPHL with CO-intoxication is controversial (6). The prognosis of DPHL varies but is generally considered to be good, with a majority of patients who survived the second phase of deterioration showing significant recovery (2, 5). A complete neurological recovery was described in individual cases (8), however, lasting frontal-executive deficits in neuropsychological testing are common (5).\n\nIn conclusion, DPHL is a rare and probably underrecognized form of prolonged hypoxia progression and combination of the characteristic biphasic clinical course with bilateral MRI signal changes limited to the white matter are considered pathognomonic. However, due to the relatively late manifestation, the typical symptoms and imaging signs, it might be overlooked by the unaware clinician. To evaluate the course and impact of DPHL further, studies following patient's clinical development and imaging features after hypoxic events might be warranted.\n\nEthics statement\nThe written informed consent of the Patient is available.\n\nAuthor contributions\nAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.\n\nConflict of interest statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1. Zamora CA Nauen D Hynecek R Ilica AT Izbudak I Sair HI . Delayed posthypoxic leukoencephalopathy: a case series and review of the literature . Brain Behav . (2015 ) 5 :e00364 . 10.1002/brb3.364 26357591 \n2. Geraldo AF Silva C Neutel D Neto LL Albuquerque L . Delayed leukoencephalopathy after acute carbon monoxide intoxication . J Radiol Case Rep . (2014 ) 8 :1 -8 . 10.3941/jrcr.v8i5.1721 25426224 \n3. Hsiao C-L Kuo H-C Huang C-C . Delayed encephalopathy after carbon monoxide intoxication–long-term prognosis and correlation of clinical manifestations and neuroimages . Acta Neurol Taiwan (2004 ) 13 , 64 –70 . 15478677 \n4. Kim J Chang K-H Song IC Kim KH Kwon BJ Kim H-C . Delayed encephalopathy of acute carbon monoxide intoxication: diffusivity of cerebral white matter lesions . AJNR Am J Neuroradiol. (2003 ) 24 :1592 –7 . 13679276 \n5. Shprecher D Mehta L . The syndrome of delayed post-hypoxic leukoencephalopathy . Neurorehabilitation (2010 ) 26 :65 –72 . 20166270 \n6. Salazar R Dubow J . Delayed posthypoxic leukoencephalopathy following a morphine overdose . J Clin Neurosci . (2012 ) 19 :1060 –2 . 10.1016/j.jocn.2012.01.001 22555127 \n7. Choi IS . Delayed neurologic sequelae in carbon monoxide intoxication . Arch Neurol . (1983 ) 40 :433 –5 . 6860181 \n8. Molloy S Soh C Williams TL . Reversible delayed posthypoxic leukoencephalopathy . AJNR Am J Neuroradiol . (2006 ) 27 :1763 –5 . 16971632\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "9()",
"journal": "Frontiers in neurology",
"keywords": "CT; DPHL; MRI; delayed post-hypoxic leukoencephalopathy; hypoxic brain damage in adults; ischemia; neuroradiology; white matter",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "708",
"pmc": null,
"pmid": "30210433",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "16971632;20166270;15478677;26357591;13679276;22555127;6860181;25426224",
"title": "Delayed Post-hypoxic Leukoencephalopathy (DPHL)-An Uncommon Variant of Hypoxic Brain Damage in Adults.",
"title_normalized": "delayed post hypoxic leukoencephalopathy dphl an uncommon variant of hypoxic brain damage in adults"
} | [
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"companynumb": "DE-ELEFSEE PHARMACEUTICALS INTERNATIONAL-DE-2018WTD001206",
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"actiondrug": "5",
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"activesubstancename": "FENTANYL"
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... |
{
"abstract": "Cutaneous involvement in multiple myeloma is a very rare clinical problem. It occurs in less than 1% myeloma patients. Skin manifestation may be primary or secondary to MM. Primary involvement (PCP) according to the current WHO classification is one of the marginal zone lymphomas of the skin. PCP are characterized by significantly better prognosis than infiltrations secondary to MM. Skin manifestations require a thorough diagnosis to differentiate between myeloma-specific changes, MM-associated and non-specific skin disorders. Isolated primary infiltration can usually be successfully treated with radiation therapy or surgery. So far treatment of multiple and secondary to MM involvement are not satisfactory.",
"affiliations": null,
"authors": "Jurczyszyn|Artur|A|;Olszewska-Szopa|Magdalena|M|;Skotnicki|Aleksander B|AB|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": null,
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"issn_linking": "0033-2240",
"issue": "72(6)",
"journal": "Przeglad lekarski",
"keywords": null,
"medline_ta": "Przegl Lek",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D006801:Humans; D008875:Middle Aged; D009101:Multiple Myeloma; D011379:Prognosis; D012878:Skin Neoplasms",
"nlm_unique_id": "19840720R",
"other_id": null,
"pages": "325-9",
"pmc": null,
"pmid": "26817343",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Cutaneous involvement in multiple myeloma--case report and literature review.",
"title_normalized": "cutaneous involvement in multiple myeloma case report and literature review"
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{
"companynumb": "PL-CELGENE-POL-2015091293",
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"activesubstancename": "DEXAMETHASONE"
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{
"abstract": "OBJECTIVE\nTo evaluate the usefulness of the punctate pattern (PP) for the diagnosis and follow-up of patients with progressive multifocal leukoencephalopathy (PML).\n\n\nMETHODS\nA cohort of 20 consecutive patients with PML, related to natalizumab (NTZ) (n = 14) or not (n = 6), underwent 3T MRI (147 MRI examinations). MRI was available at presymptomatic (n = 9 patients), symptomatic (n = 15), immune reconstitution inflammatory syndrome (IRIS), and chronic stages (n = 20). A pathologic control group of patients without PML (n = 80), with clinically definitive multiple sclerosis or a clinically isolated syndrome suggestive of CNS demyelination, underwent the same MRI protocol. Number and appearance of punctate lesions were assessed by 3 blinded readers using T2-weighted, fluid-attenuated inversion recovery (FLAIR), and postcontrast T1-weighted images.\n\n\nRESULTS\nInterobserver agreement was good (κ = 0.79) (0.72-0.87). Of the 20 patients with PML, 18 had PP, including the 14 patients with NTZ-PML; none in the pathologic control group. Of the 9 presymptomatic patients with NTZ-PML, PP was observed in 7 (78% sensitive and 100% specific). Nonenhancing PP on T2-weighted/FLAIR images was detected in 13 patients with PML, exclusively at the presymptomatic or symptomatic stages (including 7 NTZ-PML), whereas enhancing PP occurred in 16 patients with PML, including 13 of the 14 patients with NTZ-PML at the IRIS stage.\n\n\nCONCLUSIONS\nPP is a highly specific feature of PML and may be the first imaging feature at the presymptomatic stage with potential implications in patient care.\n\n\nMETHODS\nThis study provides Class II evidence that a PP on MRI accurately identifies patients with NTZ-PML.",
"affiliations": "From the University of Lille, CHU Lille (J.H., C.D., O.O., V.D., A.L., J.P.P., P.V., X.L.), Lille, France; Departments of Neuroradiology (J.H., C.D., J.P.P., X.L.), Pathology (V.D.) and Neurology (O.O., A.L., P.V.), Hôpital Roger Salengro, Rue Emile Laine 59037 Lille, France; Department of Radiology (S.V.), Hôpital Saint Philibert, Lille, France; Department of Neuroradiology (J.H.), AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France; Faculty of Medicine (J.H.), Université Paris Est Créteil, Créteil, France; and Department of Radiology (M.Z.), Hôpital Saint Joseph, Paris, France. Jerome.hodel@gmail.com.;From the University of Lille, CHU Lille (J.H., C.D., O.O., V.D., A.L., J.P.P., P.V., X.L.), Lille, France; Departments of Neuroradiology (J.H., C.D., J.P.P., X.L.), Pathology (V.D.) and Neurology (O.O., A.L., P.V.), Hôpital Roger Salengro, Rue Emile Laine 59037 Lille, France; Department of Radiology (S.V.), Hôpital Saint Philibert, Lille, France; Department of Neuroradiology (J.H.), AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France; Faculty of Medicine (J.H.), Université Paris Est Créteil, Créteil, France; and Department of Radiology (M.Z.), Hôpital Saint Joseph, Paris, France.;From the University of Lille, CHU Lille (J.H., C.D., O.O., V.D., A.L., J.P.P., P.V., X.L.), Lille, France; Departments of Neuroradiology (J.H., C.D., J.P.P., X.L.), Pathology (V.D.) and Neurology (O.O., A.L., P.V.), Hôpital Roger Salengro, Rue Emile Laine 59037 Lille, France; Department of Radiology (S.V.), Hôpital Saint Philibert, Lille, France; Department of Neuroradiology (J.H.), AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France; Faculty of Medicine (J.H.), Université Paris Est Créteil, Créteil, France; and Department of Radiology (M.Z.), Hôpital Saint Joseph, Paris, France.;From the University of Lille, CHU Lille (J.H., C.D., O.O., V.D., A.L., J.P.P., P.V., X.L.), Lille, France; Departments of Neuroradiology (J.H., C.D., J.P.P., X.L.), Pathology (V.D.) and Neurology (O.O., A.L., P.V.), Hôpital Roger Salengro, Rue Emile Laine 59037 Lille, France; Department of Radiology (S.V.), Hôpital Saint Philibert, Lille, France; Department of Neuroradiology (J.H.), AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France; Faculty of Medicine (J.H.), Université Paris Est Créteil, Créteil, France; and Department of Radiology (M.Z.), Hôpital Saint Joseph, Paris, France.;From the University of Lille, CHU Lille (J.H., C.D., O.O., V.D., A.L., J.P.P., P.V., X.L.), Lille, France; Departments of Neuroradiology (J.H., C.D., J.P.P., X.L.), Pathology (V.D.) and Neurology (O.O., A.L., P.V.), Hôpital Roger Salengro, Rue Emile Laine 59037 Lille, France; Department of Radiology (S.V.), Hôpital Saint Philibert, Lille, France; Department of Neuroradiology (J.H.), AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France; Faculty of Medicine (J.H.), Université Paris Est Créteil, Créteil, France; and Department of Radiology (M.Z.), Hôpital Saint Joseph, Paris, France.;From the University of Lille, CHU Lille (J.H., C.D., O.O., V.D., A.L., J.P.P., P.V., X.L.), Lille, France; Departments of Neuroradiology (J.H., C.D., J.P.P., X.L.), Pathology (V.D.) and Neurology (O.O., A.L., P.V.), Hôpital Roger Salengro, Rue Emile Laine 59037 Lille, France; Department of Radiology (S.V.), Hôpital Saint Philibert, Lille, France; Department of Neuroradiology (J.H.), AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France; Faculty of Medicine (J.H.), Université Paris Est Créteil, Créteil, France; and Department of Radiology (M.Z.), Hôpital Saint Joseph, Paris, France.;From the University of Lille, CHU Lille (J.H., C.D., O.O., V.D., A.L., J.P.P., P.V., X.L.), Lille, France; Departments of Neuroradiology (J.H., C.D., J.P.P., X.L.), Pathology (V.D.) and Neurology (O.O., A.L., P.V.), Hôpital Roger Salengro, Rue Emile Laine 59037 Lille, France; Department of Radiology (S.V.), Hôpital Saint Philibert, Lille, France; Department of Neuroradiology (J.H.), AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France; Faculty of Medicine (J.H.), Université Paris Est Créteil, Créteil, France; and Department of Radiology (M.Z.), Hôpital Saint Joseph, Paris, France.;From the University of Lille, CHU Lille (J.H., C.D., O.O., V.D., A.L., J.P.P., P.V., X.L.), Lille, France; Departments of Neuroradiology (J.H., C.D., J.P.P., X.L.), Pathology (V.D.) and Neurology (O.O., A.L., P.V.), Hôpital Roger Salengro, Rue Emile Laine 59037 Lille, France; Department of Radiology (S.V.), Hôpital Saint Philibert, Lille, France; Department of Neuroradiology (J.H.), AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France; Faculty of Medicine (J.H.), Université Paris Est Créteil, Créteil, France; and Department of Radiology (M.Z.), Hôpital Saint Joseph, Paris, France.;From the University of Lille, CHU Lille (J.H., C.D., O.O., V.D., A.L., J.P.P., P.V., X.L.), Lille, France; Departments of Neuroradiology (J.H., C.D., J.P.P., X.L.), Pathology (V.D.) and Neurology (O.O., A.L., P.V.), Hôpital Roger Salengro, Rue Emile Laine 59037 Lille, France; Department of Radiology (S.V.), Hôpital Saint Philibert, Lille, France; Department of Neuroradiology (J.H.), AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France; Faculty of Medicine (J.H.), Université Paris Est Créteil, Créteil, France; and Department of Radiology (M.Z.), Hôpital Saint Joseph, Paris, France.;From the University of Lille, CHU Lille (J.H., C.D., O.O., V.D., A.L., J.P.P., P.V., X.L.), Lille, France; Departments of Neuroradiology (J.H., C.D., J.P.P., X.L.), Pathology (V.D.) and Neurology (O.O., A.L., P.V.), Hôpital Roger Salengro, Rue Emile Laine 59037 Lille, France; Department of Radiology (S.V.), Hôpital Saint Philibert, Lille, France; Department of Neuroradiology (J.H.), AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France; Faculty of Medicine (J.H.), Université Paris Est Créteil, Créteil, France; and Department of Radiology (M.Z.), Hôpital Saint Joseph, Paris, France.",
"authors": "Hodel|Jérôme|J|;Darchis|Christine|C|;Outteryck|Olivier|O|;Verclytte|Sébastien|S|;Deramecourt|Vincent|V|;Lacour|Arnaud|A|;Zins|Marc|M|;Pruvo|Jean-Pierre|JP|;Vermersch|Patrick|P|;Leclerc|Xavier|X|",
"chemical_list": "D004279:DNA, Viral; D007155:Immunologic Factors; D000069442:Natalizumab",
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0000000000002586",
"fulltext": null,
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"issn_linking": "0028-3878",
"issue": "86(16)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000328:Adult; D000359:Aftercare; D000368:Aged; D001921:Brain; D015331:Cohort Studies; D004279:DNA, Viral; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting; D000069442:Natalizumab; D015588:Observer Variation; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "1516-23",
"pmc": null,
"pmid": "27009257",
"pubdate": "2016-04-19",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Punctate pattern: A promising imaging marker for the diagnosis of natalizumab-associated PML.",
"title_normalized": "punctate pattern a promising imaging marker for the diagnosis of natalizumab associated pml"
} | [
{
"companynumb": "FR-BIOGEN-2013BI105799",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
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"activesubstancename": "MYCOPHENOLATE MOFETIL\\MYCOPHENOLATE MOFETIL HYDROCHLORIDE"
... |
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"abstract": "We present a case of diltiazem intoxication resulting in repeated asystole after the induction of anesthesia. A 39-year-old man was diagnosed as subarachnoid hemorrhage, and cerebral aneurysm clipping was scheduled on the next day. Electrocardiogram revealed normal sinus rhythm with complete right bundle branch block. Continuous intravenous administration of diltiazem, nicardipine and midazolam were started for intractable hypertension and tachycardia. In the operating room, electrocardiogram showed atrioventricular nodal rhythm. Nicardipine and midazolam were stopped and anesthesia was induced with thiamylal, fentanyl and vecuronium, and was maintained with sevoflurane. After tracheal intubation, the patient developed asystole, and cardiopulmonary resuscitation was provided immediately. Diltiazem was stopped. Cardiac rhythm was restored 8 min afterwards; however, asystole recurred six times. Temporary cardiac pacing was effective, and percutaneous cardiopulmonary support (PCPS), intraaortic balloon pumping (IABP), and continuous hemodiafiltration (CHDF) were initiated. The operation was canceled. On the next day, normal sinus rhythm was restored and the temporary pacing, PCPS, IABP, and CHDF were discontinued. Cerebral aneurysm was treated by endovascular coiling and the patient was discharged from the hospital without sequelae. This case illustrates asystole associated with diltiazem intoxication. It is necessary to consider this potential complication when diltiazem is used.",
"affiliations": "Department of Anesthesia, Shimada Municipal Hospital, Shimada 427-8502.",
"authors": "Kimura|Yuriko|Y|;Okamura|Makoto|M|;Harioka|Tokuya|T|;Hara|Tadashi|T|;Nakasato|Akane|A|;Ishiyama|Tadahiko|T|;Matsukawa|Takashi|T|",
"chemical_list": "D009529:Nicardipine; D004110:Diltiazem; D008874:Midazolam",
"country": "Japan",
"delete": false,
"doi": null,
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"issn_linking": "0021-4892",
"issue": "61(1)",
"journal": "Masui. The Japanese journal of anesthesiology",
"keywords": null,
"medline_ta": "Masui",
"mesh_terms": "D000328:Adult; D000758:Anesthesia; D004110:Diltiazem; D004347:Drug Interactions; D004621:Embolization, Therapeutic; D006323:Heart Arrest; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008874:Midazolam; D009529:Nicardipine; D019990:Perioperative Care; D013345:Subarachnoid Hemorrhage",
"nlm_unique_id": "0413707",
"other_id": null,
"pages": "104-7",
"pmc": null,
"pmid": "22338872",
"pubdate": "2012-01",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Suspected diltiazem intoxication resulting in repeated asystole after the induction of anesthesia.",
"title_normalized": "suspected diltiazem intoxication resulting in repeated asystole after the induction of anesthesia"
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{
"companynumb": "JP-RANBAXY-2012RR-55531",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NICARDIPINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo compare the efficacy of step-up and top-down infliximab therapy on patients with Crohn's disease (CD).\n\n\nMETHODS\nA prospective and open-label study was performed by the First Affiliated Hospital of SUN Yat-sen University during September 2007 to December 2010. Active CD patients who were refractory to steroid/immunomodulator or who were steroid-dependent were enrolled into step-up group. Active CD patients who had no steroid or immunomodulator therapy before were enrolled into top-down group. All patients were intravenously infused with infliximab of 5 mg/kg body weight in an induction regimen of 3 doses at week 0, 2 and 6, followed by maintenance dosing every 8 weeks beginning at week 14. The clinical and endoscopic follow up lasted 30 weeks. Clinical symptoms and mucosal healing status under endoscopy were evaluated by follow-up at week 10 and 30.\n\n\nRESULTS\nForty-one CD patients were enrolled, with 24 in step-up group and 17 in top-down group. There were significant differences in disease duration (P = 0.006), combination therapy (P < 0.001) and severity of disease (P = 0.011) in baseline between step-up and top-down groups. At week 10 and 30 during treatment, the clinical remission rates in step-up group were 45.8% (11/24) and 58.3% (14/24) respectively; the mucosal healing rates in step-up group were 33.3% (8/24) and 54.2% (13/24) respectively; the clinical remission rates in top-down group were 70.6% (12/17) and 82.4% (14/17) respectively; and the mucosal healing rates in top-down group were 35.3% (6/17) and 52.9% (9/17) respectively. No significant differences in clinical remission and mucosal healing rates at both week 10 and 30 were observed between the two groups. The prevalences of adverse events in step-up and top-down group were 41.7% (10/24) and 29.4% (5/17) respectively (P = 0.422).\n\n\nCONCLUSIONS\nBoth step-up and top-down infliximab therapy can induce remission in more than half of CD patients, while top-down therapy might be more beneficiary to symptom and endoscopic remission.",
"affiliations": "Department of Gastroenterology, SUN Yat-sen University, Guangzhou, China.",
"authors": "Xiao|Ying-lian|YL|;Chen|Bai-li|BL|;He|Yao|Y|;Gao|Xiang|X|;Huang|Mei-juan|MJ|;Hu|Pin-jin|PJ|;Chen|Min-hu|MH|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000069285:Infliximab",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0578-1426",
"issue": "51(2)",
"journal": "Zhonghua nei ke za zhi",
"keywords": null,
"medline_ta": "Zhonghua Nei Ke Za Zhi",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal; D003424:Crohn Disease; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "16210490R",
"other_id": null,
"pages": "100-3",
"pmc": null,
"pmid": "22490808",
"pubdate": "2012-02",
"publication_types": "D003160:Comparative Study; D018848:Controlled Clinical Trial; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "The clinical and endoscopic efficacy of step-up and top-down infliximab therapy in Crohn's disease.",
"title_normalized": "the clinical and endoscopic efficacy of step up and top down infliximab therapy in crohn s disease"
} | [
{
"companynumb": "CN-JNJFOC-20161008095",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nConcurrent chemoradiotherapy (CCRT) is the gold standard for limited-stage small-cell lung cancer (LS-SCLC); however, most patients inevitably experience relapse. We hypothesized consolidation amrubicin following CCRT to be a potential treatment for LS-SCLC.\n\n\nMETHODS\nAll enrolled patients were treated using induction CCRT consisting of four cycles of etoposide and cisplatin plus concurrent thoracic radiotherapy. Eligible patients then received three cycles of amrubicin as consolidation therapy (consolidation population). The primary endpoint was the 2-year progression-free survival rate in the consolidation population.\n\n\nRESULTS\nOf the 36 intention-to-treat patients, 28 (78%) received amrubicin and 24 (67%) completed all planned treatments. The 2-year progression-free survival rate and overall response rate were 35.7% and 86%, respectively. The median progression-free and overall survival were 14.3 and 60.9 months, respectively. There were no treatment-related deaths in the intention-to-treat population.\n\n\nCONCLUSIONS\nThis study was terminated due to slow patient accrual; however, this treatment strategy was feasible and demonstrated promising efficacy.",
"affiliations": "Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Respiratory Medicine, Kyoto Katsura Hospital, Kyoto, Japan.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Center for Integrated Medical Research, Hiroshima University Hospital, Hiroshima University, Hiroshima, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan ekim@kuhp.kyoto-u.ac.jp.",
"authors": "Yoshida|Hironori|H|;Nagai|Hiroki|H|;Sakamori|Yuichi|Y|;Ozasa|Hiroaki|H|;Nishimura|Takashi|T|;Tomii|Keisuke|K|;Hirai|Toyohiro|T|;Matsuo|Yukinori|Y|;Iizuka|Yusuke|Y|;Mizowaki|Takashi|T|;Yoshimura|Kenichi|K|;Kim|Young Hak|YH|",
"chemical_list": "D018943:Anthracyclines; D000970:Antineoplastic Agents; C055866:amrubicin",
"country": "Greece",
"delete": false,
"doi": "10.21873/invivo.11855",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0258-851X",
"issue": "34(2)",
"journal": "In vivo (Athens, Greece)",
"keywords": "LS-SCLC; amrubicin; chemoradiotherapy; consolidation",
"medline_ta": "In Vivo",
"mesh_terms": "D000368:Aged; D018943:Anthracyclines; D000970:Antineoplastic Agents; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D060830:Consolidation Chemotherapy; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D055752:Small Cell Lung Carcinoma; D016896:Treatment Outcome",
"nlm_unique_id": "8806809",
"other_id": null,
"pages": "897-902",
"pmc": null,
"pmid": "32111801",
"pubdate": "2020",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "9920950;24309370;17008692;25385727;11784874;1331787;9914793;12118018;19097774;28642008;26748638;30280641",
"title": "Phase II Study of Consolidation Amrubicin After Concurrent Chemoradiotherapy in Patients With Limited-stage Small-cell Lung Cancer.",
"title_normalized": "phase ii study of consolidation amrubicin after concurrent chemoradiotherapy in patients with limited stage small cell lung cancer"
} | [
{
"companynumb": "JP-HQ SPECIALTY-JP-2020INT000028",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RADIATION THERAPY"
},
"drugadditional"... |
{
"abstract": "We aimed to evaluate the impact of concurrent chemoradiotherapy (CCRT) on the survival of patients with squamous cell carcinoma of the temporal bone. We retrospectively analyzed the data of 13 consecutive patients who were treated by definitive radiation therapy (RT) or CCRT as the initial treatment between 1999 and 2012. There were 5 patients with stage II disease, 5 with stage III, and 3 with stage IV, as classified according to the University of Pittsburgh system. Among these, 2, 4, and 3 patients, respectively, were treated by CCRT; whereas the remaining (3 patients with stage II and 1 with stage III) were treated by RT alone. Median follow-up duration was 39 months (12-106 months) in all cases, and 61.5 months (17-70 months) in censored cases. The 5-year overall survival (OS) rates were 51 % in all patients, and 40, 100, and 0 % in patients with stage II, stage III, and stage IV disease, respectively. In patients with stage II and III disease, the 5-year OS rates were 80 % in the CCRT group and 50 % in the RT-alone group. We found better prognosis in patients with stage II and III disease who were treated by CCRT. Only 2 patients treated by CCRT experienced adverse events more than grade 3, which were neutropenia and dermatitis. There was no late adverse event of bony necrosis. Our study results indicate that CCRT is safe and very effective as a first-line treatment for stage II and III squamous cell carcinoma of the temporal bone.",
"affiliations": "Department of Head and Neck Surgery, Kanagawa Cancer Center, Yokohama, Japan. yousuke.kitani@gmail.com.;Department of Head and Neck Surgery, Kanagawa Cancer Center, Yokohama, Japan.;Department of Head and Neck Surgery, Kanagawa Cancer Center, Yokohama, Japan.;Department of Head and Neck Surgery, Kanagawa Cancer Center, Yokohama, Japan.;Department of Radiation Oncology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan.;Department of Radiation Oncology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan.;Department of Radiation Oncology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan.",
"authors": "Kitani|Yosuke|Y|;Kubota|Akira|A|;Furukawa|Madoka|M|;Sato|Kaname|K|;Nakayama|Yuko|Y|;Nonaka|Tetsuo|T|;Mizoguchi|Nobutaka|N|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00405-015-3616-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-4477",
"issue": "273(5)",
"journal": "European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery",
"keywords": "CCRT; Carcinoma of the temporal bone; Concurrent chemoradiotherapy; Definitive radiotherapy",
"medline_ta": "Eur Arch Otorhinolaryngol",
"mesh_terms": "D000368:Aged; D001859:Bone Neoplasms; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D016371:Cranial Irradiation; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009503:Neutropenia; D017063:Outcome Assessment, Health Care; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D013701:Temporal Bone",
"nlm_unique_id": "9002937",
"other_id": null,
"pages": "1293-8",
"pmc": null,
"pmid": "25822291",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": "11784271;10768432;1119983;17446002;16431060;2396807;6252880;10912706;20513031;10402528;24692266;2760515;16817330;21436754;2040835;22451818;3059809;7917206;9827809;19027512;8134137;6842060;3807618;8849792",
"title": "Primary definitive radiotherapy with or without chemotherapy for squamous cell carcinoma of the temporal bone.",
"title_normalized": "primary definitive radiotherapy with or without chemotherapy for squamous cell carcinoma of the temporal bone"
} | [
{
"companynumb": "JP-ACTAVIS-2016-10224",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nRamucirumab, a human Ig 1 monoclonal antibody against vascular endothelial growth factor receptor-2, in combination with paclitaxel is a second-line chemotherapy for patients with metastatic gastric cancer. Several reports have suggested that dose adjustments of cetuximab, an anti- epidermal growth factor receptor antibody, are not required in patients with renal impairment. However, the combination chemotherapy of ramucirumab and cytotoxic drug for hemodialysis (HD) patients has not been reported.\nA 65-year-old man on HD was diagnosed with gastric cancer and underwent a subtotal gastrectomy with D2 lymphadenectomy. Abdominal computed tomography (CT) was examined after completion of 8 cycles of adjuvant chemotherapy with capecitabine combination oxaliplatin.\n\n\nMETHODS\nThe patient was diagnosed with advanced gastric cancer at stage IIIb (pT3N2M0) 11 months ago. Unfortunately, 9 months after the start of adjuvant chemotherapy, multiple liver metastases from gastric cancer were found by abdominal CT.\n\n\nMETHODS\nHe began receiving weekly paclitaxel(80 mg/m2) and every 15-day ramucirumab (8 mg/kg). HD was performed next day after administration of chemotherapy and repeated 3 times a week.\n\n\nRESULTS\nHe was treated with ramucirumab without dose adjustment. The metastatic liver mass had a partial response, after 2 and 4 cycles of chemotherapy and had a stable disease up to 12 cycles of chemotherapy. No obvious adverse effect was observed during treatment. However, after 14 cycles chemotherapy, follow-up abdominal CT revealed progression disease of multiple liver metastasis and lymph nodes invasion.\n\n\nCONCLUSIONS\nThe paclitaxel chemotherapy with ramucirumab is effective and safe in HD patients with metastatic gastric cancer. As seen in patients with normal kidney function, ramucirumab can be safely administered without a dose reduction.",
"affiliations": "Department of Hematology-oncology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Republic of Korea.",
"authors": "Yang|Min Joo|MJ|0000-0002-3846-261;Choi|Young Jin|YJ|;Kim|Hyo Jeong|HJ|;Kim|Do Young|DY|;Seol|Young Mi|YM|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; C543333:ramucirumab; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000024795",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\n33607838\nMD-D-20-10531\n10.1097/MD.0000000000024795\n24795\n5700\nResearch Article\nClinical Case Report\nTreatment with Ramucirumab-paclitaxel in a metastatic gastric cancer patient undergoing hemodialysis\nA case report\nYang Min Joo MD\nChoi Young Jin MD, PhD\nKim Hyo Jeong MD, PhD\nKim Do Young MD, PhD\nSeol Young Mi MD, PhD ∗\nSaranathan. Maya\nDepartment of Hematology-oncology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Republic of Korea.\n∗ Correspondence: Young Mi Seol, Department of Hematology-oncology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, 179 Gudeok-ro, Seo-gu, Busan, 49421, Republic of Korea (e-mail: seol2100@hanmail.net).\n19 2 2021\n19 2 2021\n100 7 e2479511 11 2020\n20 1 2021\n29 1 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nRationale:\n\nRamucirumab, a human Ig 1 monoclonal antibody against vascular endothelial growth factor receptor-2, in combination with paclitaxel is a second-line chemotherapy for patients with metastatic gastric cancer. Several reports have suggested that dose adjustments of cetuximab, an anti- epidermal growth factor receptor antibody, are not required in patients with renal impairment. However, the combination chemotherapy of ramucirumab and cytotoxic drug for hemodialysis (HD) patients has not been reported.\n\nPatient concerns:\n\nA 65-year-old man on HD was diagnosed with gastric cancer and underwent a subtotal gastrectomy with D2 lymphadenectomy. Abdominal computed tomography (CT) was examined after completion of 8 cycles of adjuvant chemotherapy with capecitabine combination oxaliplatin.\n\nDiagnosis:\n\nThe patient was diagnosed with advanced gastric cancer at stage IIIb (pT3N2M0) 11 months ago. Unfortunately, 9 months after the start of adjuvant chemotherapy, multiple liver metastases from gastric cancer were found by abdominal CT.\n\nInterventions:\n\nHe began receiving weekly paclitaxel(80 mg/m2) and every 15-day ramucirumab (8 mg/kg). HD was performed next day after administration of chemotherapy and repeated 3 times a week.\n\nOutcomes:\n\nHe was treated with ramucirumab without dose adjustment. The metastatic liver mass had a partial response, after 2 and 4 cycles of chemotherapy and had a stable disease up to 12 cycles of chemotherapy. No obvious adverse effect was observed during treatment. However, after 14 cycles chemotherapy, follow-up abdominal CT revealed progression disease of multiple liver metastasis and lymph nodes invasion.\n\nLessons:\n\nThe paclitaxel chemotherapy with ramucirumab is effective and safe in HD patients with metastatic gastric cancer. As seen in patients with normal kidney function, ramucirumab can be safely administered without a dose reduction.\n\nKeywords\n\ngastric cancer\nhemodialysis\npaclitaxel\nramucirumab\nOPEN-ACCESSTRUE\n==== Body\npmc1 Introduction\n\nGastric cancer is the fifth most common cancer and the third leading cause of cancer-related death and high mortality.[1,2] Currently, chemotherapy based on a combination of fluoropyrimidines and platinum compounds is the standard treatment in first-line therapy.[3] Based on the result of a randomized phase III trials, ramucirumab monotherapy or in combination with paclitaxel was proven safe and effective for patients with metastatic gastric cancer progressed after a first-line of chemotherapy.[4,5]\n\nRamucirumab is a human IgG 1 monoclonal antibody against vascular endothelial growth factor receptor-2 that prevents ligand binding and receptor-mediated pathway activation in endothelial cells, resulting in the inhibition of angiogenesis.[6].\n\nHowever, there is no data on ramucirumab therapy in patients undergoing chronic hemodialysis (HD). We herein report the first case of a metastatic gastric cancer patient on HD who was successfully treated with ramucirumab combination paclitaxel.\n\n2 Case presentation\n\nA 65-year-old man was undergoing peritoneal dialysis for chronic renal failure due to Focal segmental glomerulosclerosis 5 years previously and had switched to HD 3 times weekly beginning 3 years previously. He also had coexisting diseases, including hypertension. He complained of melena and hematochezia, and endoscopy identified a Her-2-negative poorly differentiated adenocarcinoma in the gastric body. He underwent subtotal gastrectomy with D2 lymphadenectomy, which led to a diagnosis of stage IIIb (pT3N2M0) gastric adenocarcinoma.\n\nThe patient started receiving chemotherapy in our hospital from May 2018. Initially, he received adjuvant chemotherapy with capecitabine 500 mg/m2 (50% of the standard dose of 1000 mg/m2) combination oxaliplatin 65 mg/m2 (50% of the standard dose of 130 mg/m2) every 3weeks. Chemotherapy was administered in the morning and he received HD on same day in the afternoon.\n\nHowever, after completion of 8 cycles of chemotherapy, abdominal computed tomography (CT) examination revealed multiple liver metastasis. (Fig. 1) In Feb 2019, for progressed disease, second-line chemotherapy was started. At that time, his Eastern Cooperative Oncology Group performance status, body surface area, and body weight was 1, 1.59m2, and 57 kg, respectively. He began receiving weekly paclitaxel (80 mg/m2) and every 15-day ramucirumab (8 mg/kg). HD was performed next day after administration of chemotherapy and repeated 3 times a week. Because the patient had HD at another hospital, renal monitoring and drug trough levels monitoring could not be confirmed.\n\nFigure 1 Abdominal computed tomography showed mutiple targetoid masses in both lobe of the liver (arrow). The largest 1 is 2.4 cm in S6 subcapsular area (arrow head).\n\nOn day 1 after cycle 2 chemotherapy, he developed grade 3 neutropenia (according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0).[7] The dose of paclitaxel was reduced up to 75% from the next cycle. After cycle 2 and cycle 4 of chemotherapy, abdominal CT was done to confirm the effectiveness of chemotherapy (Fig. 2A, B). While the liver metastatic mass expanded to 24 mm in diameter at beginning of chemotherapy, the mass reduced to 18 mm after 2 cycles of chemotherapy and subcentimeter sized (3 mm) after 4 cycles of chemotherapy. According to the Response Evaluation Criteria in Solid Tumor guidelines, we evaluated the patient as having a partial response.\n\nFigure 2 Computed tomography images show the liver metastasis. (A) At the start of chemotherapy; (B) after 2 cycles; (C) after 4 cycles; (D) after 6 cycles; (E) after 9 cycles; and (F) after 12 cycles of chemotherapy. While the liver metastatic mass expanded to 24 mm in diameter at beginning of chemotherapy, the mass reduced to subcentimeter sized (3 mm) after 4 cycles of chemotherapy.\n\nFor the sixth course of chemotherapy, because he developed grade 3 neutropenia despite the 25% reduction in dose, we further reduced the dose of paclitaxel on 60% and paclitaxel was skipped on days 8 from the next cycle in November 2019. After that, his metastatic liver tumor showed a stable disease, (Fig. 2 C–F) and he received 8 cycles of chemotherapy at that dose.\n\nAfter cycle fourteen chemotherapy in July 2020, the progression of liver metastasis happened 16months after the second-line chemotherapy. Abdominal CT revealed progression disease of multiple liver metastasis and multiple small lymph nodes in the celiac axis, left gastric area, aortocaval area, left paraortic area. In August 2020, third-line chemotherapy was started with irinotecan (180 mg/m2). After cycle 1 chemotherapy, he was admitted to our department for neutropenic fever (ANC 80/uL), finally, he diagnosed enterocolitis and treated with antibiotics. After that, the third-line chemotherapy was stopped and he was received supportive care until October 2020. Since then, the patient has no longer visited our hospital.\n\n3 Discussion\n\nRecently, the phase 3 REGARD trial identified a new agent for second-line chemotherapy – ramucirumab, anti- vascular endothelial growth factor receptor-2 antibody.[4] Follow up phase 3 RAINBOW trial ramucirumab plus paclitaxel significant extended second-line overall survival (OS; medican 9.6 vs 7.4 months; hazard ratio [HR] = 0.807; P = .017) and progression-free survival (PFS; medican 4.4 vs 2.9 months; HR = 0.635; P < .0001) over placebo-paclitaxel.[5] Based on these results, we selected ramucirumab in combination with paclitaxel in second-line treatment for patients with advanced gastric cancer. Although the number of patients undergoing HD has been increasing to date, the guidelines for the management of chemotherapy in cancer patients undergoing HD have not yet been established. Renal dysfunction is not uncommon in cancer patients. However, patients with renal dysfunction are excluded from many clinical trials. Therefore, there is little data on the efficacy of all chemotherapy drugs in patients with renal impairment, and no recommendation for dosage and administration.\n\nTo the best of our knowledge, this is the first case of examining a combination of ramucirumab and paclitaxel for a patients undergoing HD.\n\nTable 1 lists the published cases involving therapy with antiepidermal growth factor receptor antibody (ie, cetuximab, panitumumab) or anti VEGF antibody (ie, bevacizumab) in patients receiving HD.[8–11]\n\nTable 1 Summary of data from previous case reports.\n\nCancer\tAge\tGender\tRegimen\tDose of anti-(V)EGFR antibody\tEfficacy\tAdverse events with anti-(V)EGFR antibody\tReference\t\nColorectal cancer\t65\tMale\tmFOLFOX6 and bevacizumab\tFull dose\tPartial response\tNot described\t[8]\t\nColorectal cancer\t71\tMale\tmFOLFOX6 and bevacizumab\tFull dose\tStable disease\tNot described\t[8]\t\nColorectal cancer\t71\tFemale\tmFOLFOX6 and bevacizumab\tFull dose\tProgressive disease\tNot described\t[8]\t\nColorectal cancer\t68\tMale\tCetuximab and irinotecan\tFull dose\tPartial response\tNot described\t[9]\t\nColorectal cancer\t66\tMale\tCetuximab monotherapy\tFull dose\tPartial response\tNot described\t[10]\t\nColorectal cancer\t62\tFemale\tmFOLFOX6 and panitumumab\tFull dose\tPartial response\tGrade 1 acneiform rash\t[11]\t\n\nThe administration of ramucirumab in patients with renal impairment has not yet been reported, but pharmacokinetic behavior appears similar to cetuximab. The previous cases HD cancer patients treated with cetuximab suggested its safety, efficacy and no necessity for dose reduction.[9,10] Another report analyzing the pharmacokinetics of cetuximab has shown that it can be safely used in patients with renal impairment without dose adjustment.[12]\n\nKobayashi et al[11] showed that chemotherapy with panitumumab, a fully human IgG2 monoclonal antibody against epidermal growth factor receptor, is safe and effective in cancer patient with chronic kidney disease on HD.\n\nLisa O’brien et al[13] reports about population pharmacokinetic meta-analysis of ramucirumab in cancer patients. This report showed that weight-normalized dosing regimen is appropriate for ramucirumab therapy, and dose adjustment was not required for patients with mild to moderate renal impairment or mild hepatic impairment. However, ramucirumab clearance in HD has not yet been analyzed.\n\nIn our case, ramucirumab was administered without a dose reduction and no side effects were observed. Although the mechanism is slightly different, ramucirumab can be safely used in patients with renal impairment, but further investigations involving drug clearance are required.\n\nIn terms of the efficacy of combined chemotherapy ramucirumab and paclitaxel, the mPFS and OS were 4.4 months and 9.6 months, respectively, in the RAINBOW trial.[5] For our patient, the PFS was about 17 months, so we believe that combination chemotherapy with ramucirumab and paclitaxel is effective for patient undergoing HD compared to previous reports.\n\nIn conclusion, combination chemotherapy with ramucirumab was safe and effective in patients with chronic kidney disease undergoing HD, similar to that seen in patients with normal renal function. However, it is necessary to determine the dosage and administration through additional pharmacodynamic therapy.\n\nAuthor contributions\n\nConceptualization: Min Joo Yang, Young Mi Seol, Young Jin Choi, Hyo Jeong Kim, Do Young Kim.\n\nInvestigation: Min Joo Yang, Hyo Jeong Kim, Do Young Kim.\n\nSupervision: Young Mi Seol, Young Jin Choi.\n\nWriting – original draft: Min Joo Yang.\n\nWriting – review & editing: Young Mi Seol.\n\nAbbreviations: CT = computed tomography, HD = hemodialysis.\n\nHow to cite this article: Yang MJ, Choi YJ, Kim HJ, Kim DY, Seol YM. Treatment with Ramucirumab-paclitaxel in a metastatic gastric cancer patient undergoing hemodialysis: A case report. Medicine. 2021;100:7(e24795).\n\nWritten informed consent was obtained from the patient for publication of the case details and accompanying images.\n\nWritten informed consent was obtained from the patient for publication of the case details and accompanying images. As this is a case report, ethics approval was not required for this document.\n\nThe authors have no funding and conflicts of interests to disclose.\n\nAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\n\nEGFR = epidermal growth factor receptor, VEGFR-2 = vascular endothelial growth factor receptor-2.\n==== Refs\nReferences\n\n[1] Bray F Ferlay J Soerjomataram I . Global Cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68 :394–424.30207593\n[2] Kanagavel D Fedyanin M Tryakin A . Second-line treatment of metastatic gastric cancer: current options and future directions. World J Gastroenterol 2015;21 :11621–35.26556991\n[3] Wagner AD Grothe W Haerting J . Chemotherapyin advanced gastric cancer: a systematic review and meta-analysis based onaggregate data. J Clin Oncol 2006;24 :2903–9.16782930\n[4] Fuchs CS Tomasek J Yong CJ . REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro- oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014;383 :31–9.24094768\n[5] Wilke H Muro K Van Cutsem E . RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 2014;15 :1224–35.25240821\n[6] Roviello G Petrioli R Marano L . Angiogenesis inhibitors in gastric and gastroesophageal junction cancer. Gastric Cancer 2016;19 :31–41.26329368\n[7] Common Terminology Criteria for Adverse Events v4.0-JCOG. Available at: http://www.jcog.jp/doctor/tool/ctcae v4.html.\n[8] Funasaka C Kanemasa Y Shimoyama T . Modified FOLFOX-6 plus bevacizumab chemotherapy for metastatic colorectal cancer in patients receiving hemodialysis: a report of three cases and review of the literature. Case Rep Oncol 2019;12 :657–65.31572155\n[9] Matsuda M Seyama Y Inada K . Third-line therapy in a patient with recurrent colon cancer undergoing hemodialysis. Gan To Kagaku Ryoho. Japanese Journal of Cancer and Chemotherapy 2013;40 :1397–400.24196079\n[10] Fontana E Pucci F Ardizzoni A . Colorectal cancer patient on maintenance dialysis successfully treated with cetuximab. Anticancer Drugs 2014;25 :120–2.24025565\n[11] Kobayashi M Endo S Hamano Y . Successful treatment with modified FOLFOX6 and panitumumab in cecal cancer patient undergoing hemodialysis. Intern Med 2016;55 :127–30.26781010\n[12] Krens LL Baas JM Verboom MC . Pharmacokinetics and safety of cetuximab in a patient with renal dysfunction. Cancer Chemother Pharmacol 2014;73 :1303–6.24705976\n[13] Lisa O’Brien Paul Westwood Ling Gao . Population pharmacokinetic meta-analysis of ramucirumab in cancer patients. Br J Clin Pharmacol 2017;83 :2741–51.28833321\n\n",
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"title": "Treatment with Ramucirumab-paclitaxel in a metastatic gastric cancer patient undergoing hemodialysis: A case report.",
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"abstract": "We experienced 3 adult patients with intractable focal epilepsy treated by levetiracetam (LEV) as polytherapy, who showed paradoxical effect (PE). Starting dose of LEV was small (62.5, 250 mg/day) and we gradually increased by less than 250 mg/day, every more than 2 weeks. Within 6 months after LEV was added, LEV of 750 to 1,000 mg/day brought reduction of seizure frequency. Serum concentration of LEV was 13.3 and 14.0 μg/ml. In order to obtain better seizure control, LEV was increased up to 1,000-2,500 mg/day (19.3-35.0 μg/ml) within one year, and they developed PE. They all showed increased habitual seizures, occurring in cluster. Once dose of LEV deceased down to what produced the maximum seizure suppression, all of the patients regained the better seizure control. It is most likely that at least in some patients like present 3 cases, PE of LEV may express U curve association between dose and effect and that it was only delineated by slow titration.",
"affiliations": "Department of Neurology, Kyoto University Graduate School of Medicine.;Department of Neurology, Kyoto University Graduate School of Medicine.;Department of Epilepsy, Movement Disorders and Physiology, Kyoto University Graduate School of Medicine.;Department of Neurology, Kyoto University Graduate School of Medicine.;Department of Epilepsy, Movement Disorders and Physiology, Kyoto University Graduate School of Medicine.;General Internal Medicine, Horikawa Hospital.;Department of Epilepsy, Movement Disorders and Physiology, Kyoto University Graduate School of Medicine.;Department of Neurology, Kyoto University Graduate School of Medicine.",
"authors": "Inoue|Takeshi|T|;Kobayashi|Katsuya|K|;Usami|Kiyohide|K|;Shimotake|Akihiro|A|;Inouchi|Morito|M|;Sakai|Tatsuya|T|;Ikeda|Akio|A|;Takahashi|Ryosuke|R|",
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"keywords": "antiepileptic drug; focal epilepsy; paradoxical effect; serum concentration",
"medline_ta": "Rinsho Shinkeigaku",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004569:Electroencephalography; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D008279:Magnetic Resonance Imaging; D008297:Male; D012640:Seizures; D016896:Treatment Outcome",
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"title": "Paradoxical effect of levetiracetam on seizure suppression: three cases showing U curve association between dose and effect.",
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"abstract": "A middle-aged woman was hospitalised for generalised, painful skin lesions 6 weeks after a successful double-lung transplant. She had end-stage lung disease associated with chronic obstructive pulmonary disease due to alpha-1 antitrypsin deficiency, and she had been treated with itraconazole for 16 months because of lung infection associated with Malbranchea spp. Results of a skin biopsy of the initial lesion on her arm showed non-specific dermal inflammation, presumably due to reactivation of the Malbranchea spp infection. Follow-up cervical lymph node biopsy and culture showed Coccidioides posadasii/C. immitis A detailed review of her travel history showed a 4-month stay in Arizona as a teenager that she barely remembered. Coccidioides spp were likely misidentified as Malbranchea spp owing to similar morphological characteristics. Dosages of immunosuppressive medications were reduced, and antifungal therapy was changed to posaconazole. Her skin lesions resolved.",
"affiliations": "Division of Infectious Diseases, Mayo Clinic, Jacksonville, Florida, USA.;University of Navarra, Pamplona, Navarra, Spain.;Division of Infectious Diseases, Mayo Clinic, Jacksonville, Florida, USA.;Division of Infectious Diseases, Mayo Clinic, Jacksonville, Florida, USA salvarez@mayo.edu.",
"authors": "Diaz|Mark Anthony|MA|;Bayo|Maria Luisa|ML|;Alvarez|Francisco|F|;Alvarez|Salvador|S|",
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"mesh_terms": "D000935:Antifungal Agents; D003047:Coccidioidomycosis; D003881:Dermatomycoses; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D016040:Lung Transplantation; D008875:Middle Aged; D014230:Triazoles",
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"title": "Coccidioides in lung transplant: case report.",
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"abstract": "Tumor lysis syndrome is rare in hepatocellular carcinoma (HCC), but it has been reported more frequently recently in response to treatments such as transcatheter arterial chemoembolization (TACE), radiofrequency thermal ablation (RFTA), and sorafenib. Tumor lysis syndrome induced by low-dose steroid appears to be very unusual in HCC. We report a patient with hepatitis-C-related liver cirrhosis and HCC in whom tumor lysis syndrome occurred due to low-dose steroid (10 mg of prednisolone). The patient was a 90-year-old male who presented at the emergency room of our hospital with general weakness and poor oral intake. He had started to take prednisolone to treat adrenal insufficiency 2 days previously. Laboratory results revealed hyperuricemia, hyperphosphatemia, and increased creatinine. These abnormalities fulfilled the criteria in the Cairo-Bishop definition of tumor lysis syndrome. Although the patient received adequate hydration, severe metabolic acidosis and acute kidney injury progressed unabated. He finally developed multiple organ failure, and died 3 days after admission. This was a case of tumor lysis syndrome caused by administration of low-dose steroid in a patient with HCC.",
"affiliations": "Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.",
"authors": "Kim|Jin Ok|JO|;Jun|Dae Won|DW|;Tae|Hye Jin|HJ|;Lee|Kang Nyeong|KN|;Lee|Hang Lak|HL|;Lee|Oh Young|OY|;Choi|Ho Soon|HS|;Yoon|Byung Chul|BC|;Hahm|Joon Soo|JS|",
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"fulltext": "\n==== Front\nClin Mol HepatolClin Mol HepatolCMHClinical and Molecular Hepatology2287-27282287-285XThe Korean Association for the Study of the Liver 10.3350/cmh.2015.21.1.85Case ReportLow-dose steroid-induced tumor lysis syndrome in a hepatocellular carcinoma patient Kim Jin Ok Jun Dae Won Tae Hye Jin Lee Kang Nyeong Lee Hang Lak Lee Oh Young Choi Ho Soon Yoon Byung Chul Hahm Joon Soo Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.Corresponding author: Dae Won Jun. Department of Internal Medicine, Hanyang University College of Medicine, 222 Wangsimni-ro, Seongdong-gu, Seoul 133-791, Korea. Tel: 82-2-2290-8338, Fax: 82-2-2298-9183, noshin@hanyang.ac.kr3 2015 25 3 2015 21 1 85 88 13 5 2013 23 7 2013 25 7 2013 Copyright © 2015 by The Korean Association for the Study of the Liver2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Tumor lysis syndrome is rare in hepatocellular carcinoma (HCC), but it has been reported more frequently recently in response to treatments such as transcatheter arterial chemoembolization (TACE), radiofrequency thermal ablation (RFTA), and sorafenib. Tumor lysis syndrome induced by low-dose steroid appears to be very unusual in HCC. We report a patient with hepatitis-C-related liver cirrhosis and HCC in whom tumor lysis syndrome occurred due to low-dose steroid (10 mg of prednisolone). The patient was a 90-year-old male who presented at the emergency room of our hospital with general weakness and poor oral intake. He had started to take prednisolone to treat adrenal insufficiency 2 days previously. Laboratory results revealed hyperuricemia, hyperphosphatemia, and increased creatinine. These abnormalities fulfilled the criteria in the Cairo-Bishop definition of tumor lysis syndrome. Although the patient received adequate hydration, severe metabolic acidosis and acute kidney injury progressed unabated. He finally developed multiple organ failure, and died 3 days after admission. This was a case of tumor lysis syndrome caused by administration of low-dose steroid in a patient with HCC.\n\nTumor lysis syndromeHepatocellular carcinomaSteroid\n==== Body\nINTRODUCTION\nTumor lysis syndrome is a potentially lethal oncologic emergency. It can occur in patients with extensive, rapidly growing, and chemosensitive malignancies such as hematologic malignancies.1,2 Massive lysis of tumor cells after effective treatment results in the release of intracellular substances into the bloodstream.3,4,5 Because large amounts of intracellular substances such as potassium, phosphate, and uric acid, etc. are released, the severe alteration of these metabolic profiles can have clinically toxic effects, including acute kidney injury, cardiac arrhythmias, seizures, and multiorgan failure that can finally result in death.6\n\nAlthough it most often happens in hematologic malignancies such as acute lymphocytic leukemia and Burkitt's lymphoma, tumor lysis syndrome has also been reported in various solid tumors, including lung and breast carcinomas.5,7,8,9 The syndrome is rare in hepatocellular carcinoma (HCC); about 8% of the cases of tumor lysis syndrome in solid tumors occur in HCC.5,10 Recently it has been increasingly reported after treatments such as transcatheter arterial chemoembolization (TACE), radiofrequency ablation, and sorafenib, etc.5,11,12,13,14 In HCC, tumor lysis syndrome induced by low dose steroid appears to be very unusual.\n\nHere, we report a case of tumor lysis syndrome occurring after administration of low dose steroid in a patient with HCC.\n\nCASE REPORT\nA 90-year-old male who presented with symptoms of general weakness and poor oral intake visited the emergency department of our hospital. He was diagnosed with hepatitis C-related liver cirrhosis and hepatocellular carcinoma (HCC) in our hospital. Abdominal computed tomography had been performed about one month previously and had revealed multiple viable HCCs in both lobes of the liver. Their largest diameter was 10.7 cm (Fig. 1). The patient's HCC was classified as stage B according to the Barcelona Clinic Cancer staging classification. He had undergone radio frequency thermal ablation (RFTA) once and TACE six times in our hospital. Two days ago he visited our outpatient clinic with symptoms such as general weakness, nausea, and vomiting. Because the symptoms had suggested adrenal insufficiency, he had been empirically administered prednisolone 10mg per day by the oral route for two days. ACTH stimulation test couldn't be performed at our outpatient clinic and the patient refused the test. Else he had been taking furosemide 20 mg, aldactone 50 mg a day. Before taking prednisolone, serum creatinine was 1.12 mg/dL, estimated glomerular filtration rate (eGFR) was 65 mL/min/1.73 m2, and his renal function had been well preserved considering his age.\n\nThe patient's vital signs were within normal limits at our emergency department. On physical examination, the abdomen was distended, without tenderness or rebound tenderness. A complete blood cell count showed mild leukocytosis with mild anemia: leukocytes, 14.4 × 103/µL; hemoglobin, 10.8 g/dL; and platelets, 180 × 103/µL. The following additional laboratory values were found: serum sodium, 145 mEq/L; potassium, 5.4 mEq/L; chloride 110 mEg/L; bicarbonate 24.0 mEq/L; total protein, 7.1 g/dL; albumin, 3.0 g/dL calcium, 8.7 mg/dL; inorganic phosphorus, 5.8 mg/dL. In addition, serum urea nitrogen level was 100.5 mg/dL, creatinine level was 3.00 mg/dL, eGFR was 21 mL/min/1.73 m2. AST was 310 U/L, ALT was 171 U/L, total bilirubin was 5.24 mg/dl, prothrombin time was 12.5 sec, α-fetoprotein (AFP) was 647.4 ng/mL. His Child-Turcotte-Pugh score was 9. Chest radiography revealed only an old tuberculosis lesion in the right upper lung zone. His electrocardiogram was normal. Because he had acute kidney damage, and adequate hydration could not correct it, hepatorenal syndrome was suspected. He was treated by intravenous hydration at first, and was also administered terlipressin and albumin.\n\nThough serum uric acid was 8.0 mg/dL about 6 months ago, the following day, serum uric acid increased to 18.3 mg/dL. Serum sodium was 146 mEq/L, potassium was 5.4 mEq/L, inorganic phosphorus was 6.2 mg/dL, calcium was 8.7 mg/dL, serum urea nitrogen level was 104.6 mg/dL, creatinine level was 2.90 mg/dL, and eGFR was 22 mL/min/1.73 m2. Though oliguria was not present, his urine output was lower than a day earlier. Hydration and treatment for hepatorenal syndrome were maintained.\n\nIn next day, he had severe metabolic acidosis and acute kidney injury. Multiple organ failure progressed steadily, and he expired three days after admission.\n\nDISCUSSION\nAlthough, tumor lysis syndrome is most commonly observed in chemosensitive malignancy, such as acute lymphocytic leukemia and Burkitt's lymphoma, it is rare in solid tumors.5,7 However recently it has been reported in various solid tumors, including lung and breast carcinomas.5,8,9 The most important risk factor for tumor lysis syndrome is tumor burden, which can easily result in autonecrosis and the release of intracellular substances. Other important risk factors are dehydration and preexisting renal insufficiency.15\n\nTumor lysis syndrome is still very rare in the treatment of HCC, and HCC contributes only about 8% of the cases of tumor lysis syndrome in solid tumors.10 Recently it has been increasingly reported after treatments such as transcatheter arterial chemoembolization (TACE), radiofrequency ablation and sorafenib, etc.5,11,12,13,14,16 Since Burney et al first observed the syndrome after TACE in two patients with HCC,17 occasional cases have been reported after TACE. Because sorafenib is now widely used in the treatment of advanced HCC, three cases of tumor lysis syndrome caused by treatment of HCC with sorafenib were recently reported.12,13,14 Cases have also been reported after treatments of HCC such as radiofrequency ablation, thalidomide, etc.11,18 As far as we know, low dose steroid-induced tumor lysis syndrome has not been previously reported.\n\nThe Cairo and Bishop definition of tumor lysis syndrome was proposed in 2004.4 It can be classified as a clinical and laboratory tumor lysis syndrome (Table 1).4 In the present case, the degree of abnormalities in his uric acid and phosphate fulfill the criteria of tumor lysis syndrome as defined by Cairo-Bishop. The criteria of clinical tumor lysis syndrome were also satisfied by his creatinine level. Because in the present case tumor lysis syndrome was misdiagnosed as hepatorenal syndrome, appropriate treatments such as hemodialysis and allopurinol were not performed, and only intravenous hydration was administered. The patient unfortunately expired three days after admission.\n\nSteroid induced tumor lysis syndrome occurs mainly in hematologic malignancies such as leukemia and lymphoma, and is rare in patients with solid tumors.\n\nSteroids are known to have lympholytic effects and are therefore widely used as components of combination chemotherapy protocols for hematologic malignancies. They act by inducing growth arrest and apoptosis. Although steroids are widely used, there are only a few case reports of tumor lysis syndrome in patients with malignancies treated solely with steroids.19,20 Therefore, empirical therapy with steroids should be avoided, especially in patients suspected of having large tumor burdens.19\n\nThe prognosis of tumor lysis syndrome caused in solid tumors is poor, with a high mortality rate. Prevention of the syndrome by treatments such as sufficient hydration, urine alkalization, and correction of metabolic disturbance, can be effective in patients with large solid tumor burdens or renal insufficiency.3,4,16 When steroid is administered to patients with large HCC or who are dehydrated, proper hydration before administering steroid is vital to prevent tumor lysis syndrome.\n\nIn conclusion, the development of treatments for HCC has increased the likelihood of tumor lysis syndrome. Low dose steroid can also cause the syndrome in patients with HCC. When administering steroid to HCC patients with large tumor burdens, or who are dehydrated, great care should be taken.\n\nConflicts of Interest: The authors have no conflicts to disclose.\n\nAbbreviations\nASTaspartate transaminase\n\nALTalanine transaminase\n\nAFPα-fetoprotein\n\neGFRestimated glomerular filtration rate\n\nHCChepatocellular carcinoma\n\nRFTAradiofrequency thermal ablation\n\nTACEtranscatheter arterial chemoembolization\n\nFigure 1 Abdominal computed tomography with enhancement performed about 1 month prior to this admission revealed multiple viable HCCs in both lobes of the liver. The largest of these tumors had a diameter of 10.7 cm (arrow head).\nTable 1 Cairo-Bishop definition of laboratory and clinical tumor lysis syndrome4\nTLS, tumor lysis syndrome; ULN, upper limit of normal.\n==== Refs\n1 Yarpuzlu AA A review of clinical and laboratory findings and treatment of tumor lysis syndrome Clin Chim Acta 2003 333 13 18 12809731 \n2 Darmon M Roumier M Azoulay E Acute tumor lysis syndrome: diagnosis and management Yearb Intensive Care Emerg Med 2009 819 827 \n3 Davidson MB Thakkar S Hix JK Bhandarkar ND Wong A Schreiber MJ Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome AM J Med 2004 116 546 554 15063817 \n4 Cairo MS Bishop M Tumour lysis syndrome: new therapeutic strategies and classification Br J Haematol 2004 127 3 11 15384972 \n5 Hsieh PM Hung KC Chen YS Tumor lysis syndrome after transarterial chemoembolization of hepatocellular carcinoma: case reports and literature review World J Gastroenterol 2009 15 4726 4728 19787837 \n6 Howard SC Jones DP Pui CH The tumor lysis syndrome N Engl J Med 2011 364 1844 1854 21561350 \n7 Cohen LF Balow JE Magrath IT Poplack DG Ziegler JL Acute tumor lysis syndrome: a review of 37 patients with Burkitt's lymphoma Am J Med 1980 68 486 491 7369230 \n8 Kalemkerian GP Darwish B Varterasian ML Tumor lysis syndrome in small cell carcinoma and other solid tumors Am J Med 1997 103 363 367 9375703 \n9 Rostom AY El-Hussainy G Kandil A Allam A Tumor lysis syndrome following hemi-body irradiation for metastatic breast cancer Ann Oncol 2000 11 1349 1351 11106126 \n10 Firwana BM Hasan R Hasan N Alahdab F Alnahhas I Hasan S Tumor lysis syndrome: a systematic review of case series and case reports Postgrad Med 2012 124 92 101 22437219 \n11 Lehner SG Gould JE Saad WE Brown DB Tumor lysis syndrome after radiofrequency ablation of hepatocellular carcinoma AJR Am J Roentgenol 2005 185 1307 1309 16247154 \n12 Shiozawa K Watanabe M Takenaka H Nagai H Ishii K Sakai K Tumor lysis syndrome after sorafenib for hepatocellular carcinoma: a case report Hepatogastroenterology 2010 57 688 690 21033210 \n13 Joshita S Yoshizawa K Sano K Kobayashi S Sekiguchi T Morita S A patient with advanced hepatocellular carcinoma treated with sorafenib tosylate showed massive tumor lysis with avoidance of tumor lysis syndrome Intern Med 2010 49 991 994 20519814 \n14 Huang WS Yang CH Sorafenib induced tumor lysis syndrome in an advanced hepatocellular carcinoma patient World J Gastroenterol 2009 15 4464 4466 19764104 \n15 Saini N Pyo Lee K Jha S Patel S Bonthu N Kansagra A Hyperuricemic Renal Failure in Nonhematologic Solid Tumors: A Case Report and Review of the Literature Case Rep Med 2012 314056 22693518 \n16 Huang WS Yang CH Sorafenib induced tumor lysis syndrome in an advanced hepatocellular carcinoma patient World J Gastroenterol 2009 15 4464 4466 19764104 \n17 Burney IA Acute tumor lysis syndrome after transcatheter chemoembolization of hepatocellular carcinoma South Med J 1998 91 467 470 9598857 \n18 Lee CC Wu YH Chung SH Chen WJ Acute tumor lysis syndrome after thalidomide therapy in advanced hepatocellular carcinoma Oncologist 2006 11 87 88 16401719 \n19 Chanimov M Koren-Michowitz M Cohen ML Pilipodi S Bahar M Tumor lysis syndrome induced by dexamethasone Anesthesiology 2006 105 633 634 16932011 \n20 Lerza R Botta M Barsotti B Schenone E Mencoboni M Bogliolo G Dexamethazone-induced acute tumor lysis syndrome in a T-cell malignant lymphoma Leuk Lymphoma 2002 43 1129 1132 12148896\n\n",
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"issue": "21(1)",
"journal": "Clinical and molecular hepatology",
"keywords": "Hepatocellular carcinoma; Steroid; Tumor lysis syndrome",
"medline_ta": "Clin Mol Hepatol",
"mesh_terms": "D058186:Acute Kidney Injury; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D003404:Creatinine; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D009536:Niacinamide; D010671:Phenylurea Compounds; D000077157:Sorafenib; D013256:Steroids; D014057:Tomography, X-Ray Computed; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "101586730",
"other_id": null,
"pages": "85-8",
"pmc": null,
"pmid": "25834806",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19764104;9598857;12148896;16401719;21033210;9375703;11106126;15063817;15384972;22437219;16247154;21561350;20519814;7369230;22693518;12809731;16932011;19787837",
"title": "Low-dose steroid-induced tumor lysis syndrome in a hepatocellular carcinoma patient.",
"title_normalized": "low dose steroid induced tumor lysis syndrome in a hepatocellular carcinoma patient"
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"abstract": "BACKGROUND\nProtease inhibitor (PI)-based highly active antiretroviral therapy (HAART) use in pregnancy has been associated with preterm deliveries in some observational studies.\n\n\nMETHODS\nHIV-infected, HAART-naive pregnant women with CD4+ counts ≥200 cells/mm(3) were randomized between 26 and 34 weeks gestation to lopinavir/ritonavir/zidovudine/lamivudine (PI group) or abacavir/zidovudine/lamivudine (NRTI group) in a clinical trial to prevent mother-to-child HIV transmission. Risk factors for preterm delivery (<37 weeks) and differences by randomization arm were evaluated for live infants by logistic regression.\n\n\nRESULTS\nPreterm delivery rates were higher among 267 women in the PI group than 263 women in the NRTI group (21.4% vs 11.8%, P = .003). PI-based HAART was the most significant risk factor for preterm delivery [odds ratio = 2.03, 95% confidence interval 1.26-3.27, P = .004]. Mean change in maternal body mass index (BMI) 1 month after HAART initiation was lower in the PI group (P < .001); however, this was not significantly associated with preterm delivery. Neither infant hospitalizations nor mortality through 6 months of life differed by maternal regimen.\n\n\nCONCLUSIONS\nPI-based HAART was associated with increased preterm delivery but not increased infant hospitalizations or mortality in a clinical trial setting. The association between PI use and lower increase in BMI in late pregnancy warrants further study.",
"affiliations": "Departments of Internal Medicine and Pediatrics, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. kpowis@partners.org",
"authors": "Powis|Kathleen M|KM|;Kitch|Douglas|D|;Ogwu|Anthony|A|;Hughes|Michael D|MD|;Lockman|Shahin|S|;Leidner|Jean|J|;van Widenfelt|Erik|E|;Moffat|Claire|C|;Moyo|Sikhulile|S|;Makhema|Joseph|J|;Essex|Max|M|;Shapiro|Roger L|RL|",
"chemical_list": "D019380:Anti-HIV Agents; D011480:Protease Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1093/infdis/jir307",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1899",
"issue": "204(4)",
"journal": "The Journal of infectious diseases",
"keywords": null,
"medline_ta": "J Infect Dis",
"mesh_terms": "D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D005260:Female; D015658:HIV Infections; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011256:Pregnancy Outcome; D047928:Premature Birth; D011480:Protease Inhibitors; D012307:Risk Factors",
"nlm_unique_id": "0413675",
"other_id": null,
"pages": "506-14",
"pmc": null,
"pmid": "21791651",
"pubdate": "2011-08-15",
"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": "15752534;20574524;17314523;12640195;17117021;20554983;12351559;20196653;11398741;10930154;19708170;20716250;16556647;20196654;16586354;19730269;18177778;8558295;10548643;17299724;19483516",
"title": "Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy.",
"title_normalized": "increased risk of preterm delivery among hiv infected women randomized to protease versus nucleoside reverse transcriptase inhibitor based haart during pregnancy"
} | [
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP009372",
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"activesubstancename": "LOPINAVIR\\RITONAVIR"
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"abstract": "We report a case of tacrolimus vascular toxicity found on a protocol biopsy shortly after a deceased donor renal transplantation. The patient was immunologically high-risk and acute antibody-mediated rejection during post-transplant dialysis phase was suspected on the protocol biopsy. Although the patient was stable after treatment of rejection, a further examination showed a very rare but specific side-effect of tacrolimus. It is sometimes difficult to make a differential diagnosis during postoperative dialysis period among AMR, primary non-functioning, drug toxicity, infection or just prolonged recovery from the damage of a long agonal phase on the non-heart beating donor. Although the possibilities of coexistence of rejection or other causes such as infection have not been completely excluded, it is important to be aware of this unusual side effect of tacrolimus.",
"affiliations": "Departments of Surgery, Yonago-city, Tottori, Japan.;Departments of Urology, Yonago-city, Tottori, Japan.;Departments of Surgery, Yonago-city, Tottori, Japan.;Departments of Surgery, Yonago-city, Tottori, Japan.;Departments of Surgery, Yonago-city, Tottori, Japan.;Departments of Surgery, Yonago-city, Tottori, Japan.;Departments of Urology, Yonago-city, Tottori, Japan.;Departments of Internal Medicine, Yonago-city, Tottori, Japan.;Departments of Pathology, Yonago Medical Center, Yonago-city, Tottori, Japan.;Departments of Surgery, Yonago-city, Tottori, Japan.",
"authors": "Sugitani|Atsushi|A|;Takahashi|Chihiro|C|;Naka|Takuji|T|;Hisamitsu|Kazunori|K|;Yamamoto|Osamu|O|;Taniguchi|Kenjiro|K|;Kobayashi|Naoto|N|;Kimura|Mari|M|;Yoshida|Haruhiko|H|;Hamazoe|Ryuichi|R|",
"chemical_list": "D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "Australia",
"delete": false,
"doi": "10.1111/nep.12783",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1320-5358",
"issue": "21 Suppl 1()",
"journal": "Nephrology (Carlton, Vic.)",
"keywords": "acute antibody-mediated rejection; non-heart beating donor; protocol biopsy; renal transplantation; tacrolimus toxicity",
"medline_ta": "Nephrology (Carlton)",
"mesh_terms": "D064591:Allografts; D001160:Arterioles; D001706:Biopsy; D065095:Calcineurin Inhibitors; D003937:Diagnosis, Differential; D003951:Diagnostic Errors; D006084:Graft Rejection; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents; D007668:Kidney; D016030:Kidney Transplantation; D008297:Male; D011237:Predictive Value of Tests; D016559:Tacrolimus; D016896:Treatment Outcome; D014652:Vascular Diseases; D055815:Young Adult",
"nlm_unique_id": "9615568",
"other_id": null,
"pages": "60-2",
"pmc": null,
"pmid": "27004749",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unusual case of tacrolimus vascular toxicity after deceased donor renal transplantation.",
"title_normalized": "unusual case of tacrolimus vascular toxicity after deceased donor renal transplantation"
} | [
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"companynumb": "PHHY2016JP087825",
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"occurcountry": "JP",
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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{
"abstract": "Eating disorders, like binge eating, have a strong association with schizophrenia. Illness characteristics like disordered eating, cognition, and behavior can lead to eating disorders. Previous research highlighted the neurobiological structural similarity and the role of hormonal factors, like hypocretin, in the etiology of eating disorders in schizophrenia. Modifying the obesogenic environment by adapting healthy eating styles has been effective in reducing binging episodes. Antipsychotic medications also have a role in altering eating patterns that result in binge eating disorder. Adolescents with psychosis have a higher incidence of eating disorders. Here, we present an elderly female with schizophrenia who had obesogenic behaviors along with binge eating disorder. Interestingly, the patient had atypical age of onset and presentation and no psychopathological symptoms as a reason for binging.",
"affiliations": "Department of Psychiatry, Aarupadai Veedu Medical College and Hospital, Puducherry, India.",
"authors": "Veeraraghavan|Vishnupriya|V|https://orcid.org/0000-0001-6279-5556",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.7570/jomes20096",
"fulltext": "\n==== Front\nJ Obes Metab Syndr\nJ Obes Metab Syndr\nJournal of Obesity & Metabolic Syndrome\n2508-6235\n2508-7576\nKorean Society for the Study of Obesity\n\n33820877\n10.7570/jomes20096\njomes-30-2-184\nCase Report\nObesogenic Behavior and Binge Eating Disorder in an Elderly Female with Schizophrenia\nhttps://orcid.org/0000-0001-6279-5556\nVeeraraghavan Vishnupriya *\nDepartment of Psychiatry, Aarupadai Veedu Medical College and Hospital, Puducherry, India\n* Corresponding author Vishnupriya Veeraraghavan, https://orcid.org/0000-0001-6279-5556, Department of Psychiatry, Aarupadai Veedu Medical College and Hospital,, No. 22, Moolakulam, Puducherry 605010, India, Tel: +91-9499942564, Fax: +91-9499942564, E-mail: vishnu27raghav@gmail.com\n30 6 2021\n05 4 2021\n05 4 2021\n30 2 184187\n22 9 2020\n31 10 2020\n18 3 2021\nCopyright © 2021 Korean Society for the Study of Obesity\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nEating disorders, like binge eating, have a strong association with schizophrenia. Illness characteristics like disordered eating, cognition, and behavior can lead to eating disorders. Previous research highlighted the neurobiological structural similarity and the role of hormonal factors, like hypocretin, in the etiology of eating disorders in schizophrenia. Modifying the obesogenic environment by adapting healthy eating styles has been effective in reducing binging episodes. Antipsychotic medications also have a role in altering eating patterns that result in binge eating disorder. Adolescents with psychosis have a higher incidence of eating disorders. Here, we present an elderly female with schizophrenia who had obesogenic behaviors along with binge eating disorder. Interestingly, the patient had atypical age of onset and presentation and no psychopathological symptoms as a reason for binging.\n\nObesity\nSchizophrenia\nBinge-eating disorder\nSerotonin reuptake inhibitors\n==== Body\nINTRODUCTION\n\nObesogenic behaviors refer to a spectrum of eating behaviors that include “inability to leave food behind,” “anger when people comment on their eating,” “craving for food,” and “night eating.”1 Binge eating disorder is characterized by consumption of large amounts of food in a relatively short time period at least once a week for 3 months and is accompanied by a sensation of losing control over eating behavior. Furthermore, binge eating disorder is accompanied by eating more rapidly than normal, eating until uncomfortably full, eating large amounts of food when not feeling hungry, eating alone because of being embarrassed by how much one is eating, and feeling disgusted with oneself after overeating.2 An episode of binge eating is defined as “eating, in a discrete period of time, an amount of food that is definitely larger than most of the people would eat in a similar period of time under similar circumstances” according to the Diagnostic and Statistical Manual.2 The discrete period of time is usually considered 2 hours, and lack of control over eating behaviors is commonly observed in these patients. Moreover, binge eating disorder is not associated with regular use of inappropriate compensatory behaviors like purging.3\n\nOne study showed that 16% of people with schizophrenia had binge eating disorder,4 and in China, Japan, Africa, and Latin America, binge eating disorder had the highest prevalence among all eating disorders, although no cases were reported in India.5 In India, the most common psychiatric comorbidity (50%) observed in patients with an eating disorder was depression.5 Here, we present an interesting case of schizophrenia in a patient whose psychotic features were under control, but her eating habits were worrisome and prompted consultation.\n\nCASE REPORT\n\nA 63-year-old female was brought by her husband and son to the psychiatry outpatient department with the complaint of excessive eating for the previous 6 months. Her past medical history included type 2 diabetes mellitus for the past 10 years. Her diet consisted of the following South Indian food items along with curd: (1) dosas: 20–25 per day; 3 every 2 waking hours and once or twice during the nighttime; approximate calories, 2,000–2,500 per day; (2) chapathi: 20–25 per day; 3 every 2 waking hours and once or twice during the nighttime; approximate calories, 1,800–2,000 per day; and (3) cooked rice with sambar: 7–8 bowls per day; 1 every 3 hours and once during the nighttime; approximate calories, 1,500–1,700 per day.\n\nShe had been diagnosed with schizophrenia 20 years previously and was on irregular treatment. For the past 2.5 years, she had used risperidone 4 mg and amisulpride 50 mg tablets by mouth to help control her abnormal behavior. Six months before presentation, her eating patterns changed, and she started to consume more food than usual. Furthermore, she began to eat at night, one or two episodes, which hampered her sleep. When her family members tried to restrict her food intake, she became excessively irritable and quarrelsome. She commented that she could not control her hunger and did not experience satiety, even after consuming large amounts of food. She did not attribute her symptoms to any thought or perceptual disturbance.\n\nShe was admitted to the psychiatric ward. On examination, she did not have any focal neurological signs or symptoms, and no repetitive behaviors, abnormal behaviors, or any other frontal release signs were observed. Her weight was 90 kg. Her body mass index was 35 kg/m2. Complete blood count, serum electrolytes, and tests for liver and renal function were all within normal limits. Her glycosylated hemoglobin level demonstrated good glycemic control. Neuroimaging magnetic resonance imaging (MRI) revealed cortical atrophic changes and lacunar infarcts. Thyroid function test and serum vitamin B12 level were normal. The following psychological scales were administered: (1) Mini Mental State Examination score was 27/30, (2) Brief Psychiatric Rating Scale score was 35, and (3) Binge Eating Scale score was 28.\n\nA neurologist, whose opinion was sought in view of the atrophic changes and lacunar infarcts on MRI, advised tablet aspirin/atorvastatin 75/10 mg and considered the atrophic changes age-related and incidental as there were no symptoms of forgetfulness or any abnormal movements. A medical gastroenterologist advised serotonergic agents for mitigating her hunger. She was started on capsule fluoxetine 20 mg once daily and tablet topiramate 25 mg at night, and tablet risperidone was cross tapered with tablet aripiprazole 10 mg at night. Recording and maintenance of a diet chart were required for supervision of the patient’s diet. Dietary restrictions of reduced quantity of single meals and increased duration between meals (from 2 hours to 4 hours) were practiced. After 2 weeks of treatment, her meal frequency decreased to 4–5 times a day, and the quantity of food per meal was reduced. Her feelings of suspiciousness reduced, and she would only occasionally report it.\n\nHowever, she was not able to manage her hunger at times and would demand food. So, the dosage of fluoxetine was increased to 40 mg and topiramate was increased to 50 mg. After 10 days, her meal frequency decreased to 3–4 meals per day, and the nighttime eating stopped completely. Her feeling of hunger and demanding food also stopped. She experienced a weight loss of 2.5 kg. She was discharged with the following medications: 40 mg fluoxetine, 50 mg topiramate, and 10 mg aripiprazole. At a follow-up visit 3 weeks later, did not complain of excessive hunger or nighttime eating. She had lost another 1.5 kg of weight. The fluoxetine and topiramate were slowly tapered and stopped, and her family members were educated regarding the need for good glycemic control and physical activity. Informed consent was obtained from the patient. Ethical committee waiver off was obtained from the institution as it is a case report.\n\nDISCUSSION\n\nObesogenic behavior in the elderly is associated with increased risk of cardiometabolic syndrome, dementia, and impaired quality of life.6 Previous study by Sharma7 revealed that physical activity in obese elderly individuals can prevent the onset of dementia. Despite a growing interest in weight gain and metabolic disorders in individuals with schizophrenia, evaluation of eating disorders and obesogenic behavior remains underexplored.8 Previous researchers have highlighted the role of olanzapine and clozapine in inducing eating disorders,9 whereas our patient developed a disordered eating habit while using risperidone. Antipsychotics antagonize histamine H1, serotonin 2A/2C (5-hydroxytryptamine [5-HT]2A/C), and dopamine D1/D2/D3 receptors as well as adrenergic and muscarinic receptors. Serotonergic and muscarinic receptor antagonism has been implied in disruption of insulin homeostasis and can lead to antipsychotic-induced weight gain.10 The serotonergic system is involved in antipsychotic-induced binge eating because both drugs affect serotonergic neurotransmission as an antagonist with high affinity for all 5-HT2 receptor subtypes and the 5-HT6 receptor. Altered 5-HT physiology, seen in patients treated with antipsychotics, predisposes patients to this abnormal eating behavior.11 Our patient was receiving an antipsychotic and is considered a case of antipsychotic-induced eating disorder.12 An obesogenic environment can be changed by “modifying the food delivery” and “adjusting the offered food,”11 which was successful in our patient. Previous studies in patients with eating disorders have shown structural changes, like cortical atrophy, especially in the inferior frontal regions.13 Our patient had cortical atrophy without any memory deficits. Previous studies suggest that 5-HT (serotonin) neurotransmission leads to reduced eating behavior, whereas reduced 5-HT activity precipitates compulsive or binge eating. Hence, serotonin reuptake inhibitors (SRIs) can be used to control binge eating by increasing serotonergic neurotransmission.14 Theories postulate that stimulation of the lateral hypothalamus by glutamate and glutamate agonists, including kainite or AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) agonists, causes a rapid increase in food intake.15 Topiramate is an antagonist at kainite and AMPA glutamate receptors and helps in reducing binging.16 Few randomized trials highlighted that topiramate produces a significant weight loss of 6–8 kg over a period of 24 weeks, with improvement in lipid parameters, glycemic control, and blood pressure. Topiramate also augments the effects of cognitive behavioral therapy in patients with binge eating.17 Topiramate can be used as monotherapy or in combination with phentermine for weight loss.18 Selective SRIs, like fluoxetine, were found to reduce binge episodes.19 Atypical antipsychotics, like aripiprazole, when combined with SRIs also were effective in reducing binge episodes.20 Finally, previous studies described underreporting of dietary calorie intake as a common feature in obese individuals, but this was not found in our patient.\n\nThis report described a case of binge eating disorder in a patient with schizophrenia who was on antipsychotics. In India, there is an alarming increase of obesity. For patients with a high degree of body dissatisfaction, psychoeducation in the form of diet therapy and moderate calorie restrictions must be encouraged by the treating physician, for both patients and their family members. Weight loss before binge stabilization and attempts to exclude certain food items should be discouraged.20 Based on our case report and previous studies in obese individuals, we suggest that asking about eating behavior is more reliable than asking about quantity of food consumed. This distinguishes eating disorders and food addiction from other substance addictions and dependence disorders.\n\nCONFLICTS OF INTEREST\n\nThe author declares no conflict of interest.\n==== Refs\nREFERENCES\n\n1 Aronoff J 1992 Eat to live light [Internet] Live Light Available from: https://www.myjanee.com/livelight/eat/plates.htm cited 2021 Mar 18\n2 American Psychiatric Association 2013 Diagnostic and statistical manual of mental disorders (DSM-5) 5th ed American Psychiatric Association Arlington (VA) 10.1176/appi.books.9780890425596\n3 Cooper Z Fairburn CG 2003 Refining the definition of binge eating disorder and nonpurging bulimia nervosa Int J Eat Disord 34 Suppl S89 95 10.1002/eat.10208 12900989\n4 Ramacciotti CE Paoli RA Catena M Ciapparelli A Dell'Osso L Schulte F 2004 Schizophrenia and binge-eating disorders J Clin Psychiatry 65 1016 7 10.4088/JCP.v65n0720a 15291693\n5 Vaidyanathan S Kuppili PP Menon V 2019 Eating disorders: an overview of indian research Indian J Psychol Med 41 311 7 10.4103/IJPSYM.IJPSYM_461_18 31391662\n6 Janssen I Mark AE 2007 Elevated body mass index and mortality risk in the elderly Obes Rev 8 41 59 10.1111/j.1467-789X.2006.00248.x 17212795\n7 Sharma AM 2011 Physicians' calling patients on excess weight may provide reality check and increase desire to lose weight in overweight and obese individuals Evid Based Med 16 176 7 10.1136/ebmed-2011-04-0010 21856640\n8 Kouidrat Y Amad A Lalau JD Loas G 2014 Eating disorders in schizophrenia: implications for research and management Schizophr Res Treatment 2014 791573 10.1155/2014/791573 25485152\n9 Brömel T Blum WF Ziegler A Schulz E Bender M Fleischhaker C 1998 Serum leptin levels increase rapidly after initiation of clozapine therapy Mol Psychiatry 3 76 80 10.1038/sj.mp.4000352 9491817\n10 Raben AT Marshe VS Chintoh A Gorbovskaya I Müller DJ Hahn MK 2018 The complex relationship between antipsychotic-induced weight gain and therapeutic benefits: a systematic review and implications for treatment Front Neurosci 11 741 10.3389/fnins.2017.00741 29403343\n11 Kluge M Schuld A Himmerich H Dalal M Schacht A Wehmeier PM 2007 Clozapine and olanzapine are associated with food craving and binge eating: results from a randomized double-blind study J Clin Psychopharmacol 27 662 6 10.1097/jcp.0b013e31815a8872 18004133\n12 Milano W Capasso A 2019 Psychopharmacological options in the multidisciplinary and multidimensional treatment of eating disorders Open Neurol J 13 22 31 10.2174/1874205X01913010022\n13 Looijmans A Stiekema AP Bruggeman R van der Meer L Stolk RP Schoevers RA 2017 Changing the obesogenic environment to improve cardiometabolic health in residential patients with a severe mental illness: cluster randomised controlled trial Br J Psychiatry 211 296 303 10.1192/bjp.bp.117.199315 28982656\n14 Donnelly B Touyz S Hay P Burton A Russell J Caterson I 2018 Neuroimaging in bulimia nervosa and binge eating disorder: a systematic review J Eat Disord 6 3 10.1186/s40337-018-0187-1 29468065\n15 Blundell JE 1986 Serotonin manipulations and the structure of feeding behaviour Appetite 7 Suppl 39 56 10.1016/S0195-6663(86)80051-4 3527061\n16 Stanley BG Ha LH Spears LC Dee MG 2nd 1993 Lateral hypothalamic injections of glutamate, kainic acid, D,L-alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid or N-methyl-D-aspartic acid rapidly elicit intense transient eating in rats Brain Res 613 88 95 10.1016/0006-8993(93)90458-Y 7688643\n17 Bray GA Hollander P Klein S Kushner R Levy B Fitchet M 2003 A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity Obes Res 11 722 33 10.1038/oby.2003.102 12805393\n18 Kim BY Kang SM Kang JH Kim KK Kim B Kim SJ 2020 Current long-term pharmacotherapies for the management of obesity J Obes Metab Syndr 29 99 109 10.7570/jomes20010 32378399\n19 Claudino AM de Oliveira IR Appolinario JC Cordás TA Duchesne M Sichieri R 2007 Double-blind, randomized, placebo-controlled trial of topiramate plus cognitive-behavior therapy in binge-eating disorder J Clin Psychiatry 68 1324 32 10.4088/JCP.v68n0901 17915969\n20 McElroy SL Guerdjikova AI Mori N O'Melia AM 2012 Pharmacological management of binge eating disorder: current and emerging treatment options Ther Clin Risk Manag 8 219 41 10.2147/TCRM.S25574 22654518\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2508-6235",
"issue": "30(2)",
"journal": "Journal of obesity & metabolic syndrome",
"keywords": "Binge-eating disorder; Obesity; Schizophrenia; Serotonin reuptake inhibitors",
"medline_ta": "J Obes Metab Syndr",
"mesh_terms": null,
"nlm_unique_id": "101704724",
"other_id": null,
"pages": "184-187",
"pmc": null,
"pmid": "33820877",
"pubdate": "2021-06-30",
"publication_types": "D002363:Case Reports",
"references": "29468065;18004133;29403343;17915969;7688643;22654518;12805393;32378399;3527061;28982656;25485152;17212795;9491817;21856640;15291693;31391662;12900989",
"title": "Obesogenic Behavior and Binge Eating Disorder in an Elderly Female with Schizophrenia.",
"title_normalized": "obesogenic behavior and binge eating disorder in an elderly female with schizophrenia"
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{
"abstract": "BACKGROUND\nHepatitis E virus infection usually causes an acute and self-resolving hepatitis. In areas where chronic hepatitis B virus infection is prevalent, acute hepatitis E virus superinfection on chronic hepatitis B virus infection occurs sporadically. In recent years, however, chronic hepatitis E virus infection has been recognized in patients under immunosuppressant therapy. To the best of our knowledge, cases involving patients with chronic hepatitis E virus and hepatitis B virus dual infection have never been reported.\n\n\nMETHODS\nA 47-year-old Taiwanese woman who was a renal transplant recipient with chronic hepatitis B virus infection was under immunosuppressant and antiviral treatment. An episode of hepatitis B exacerbation developed due to withdrawal of antiviral treatment against advice, but the flare subsided following antiviral re-treatments. However, an episode of hepatitis exacerbation developed following removal of the renal graft because of graft failure. During the hepatitis flare, she was still under successful antiviral suppression against hepatitis B virus, while her serum samples were positive for hepatitis E virus RNA. Following the hepatitis flare, seroclearance of hepatitis B virus surface antigen developed. From then on, she was under regular hemodialysis. Five years later, another episode of mild hepatitis exacerbation occurred again with positive serum hepatitis E virus RNA. Tracing back the longitudinal serum samples, serum hepatitis E virus RNA was persistently positive throughout the course. This patient was thus recognized to have chronic hepatitis E virus and hepatitis B virus dual infection with intermittent hepatitis E exacerbations.\n\n\nCONCLUSIONS\nIn areas where chronic hepatitis B virus infection is prevalent, chronic hepatitis E virus coinfection can occur in organ transplant recipients receiving immunosuppressant. Intermittent hepatitis E exacerbations may develop, interfering with the status of hepatitis B virus infection.",
"affiliations": "Liver Research Center, Chang Gung Memorial Hospital, 5, Fu-Shin Street, Kuei-Shan District, Taoyuan, Taiwan. chautingy@gmail.com.;Department of Cognitive Science, College of Letters and Science, University of California Los Angeles, Los Angeles, USA.;Liver Research Center, Chang Gung Memorial Hospital, 5, Fu-Shin Street, Kuei-Shan District, Taoyuan, Taiwan.;Department of Urology and Renal Transplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan.",
"authors": "Yeh|Chau-Ting|CT|http://orcid.org/0000-0001-7376-275X;Yeh|Christopher Sung-Huan|CS|;Chu|Yu-De|YD|;Chiang|Yang-Jen|YJ|",
"chemical_list": "D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D007166:Immunosuppressive Agents; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; C053001:adefovir; D000225:Adenine; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-018-1586-2",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 158610.1186/s13256-018-1586-2Case ReportSeroclearance of hepatitis B surface antigen following hepatitis E exacerbation on chronic hepatitis E and B dual infection in a renal transplant recipient: a case report http://orcid.org/0000-0001-7376-275XYeh Chau-Ting chautingy@gmail.com 1Yeh Christopher Sung-Huan chrisyeh75@gmail.com 2Chu Yu-De yudechu19871003@gmail.com 1Chiang Yang-Jen zorro@cgmh.org.tw 31 Liver Research Center, Chang Gung Memorial Hospital, 5, Fu-Shin Street, Kuei-Shan District, Taoyuan, Taiwan 2 0000 0000 9632 6718grid.19006.3eDepartment of Cognitive Science, College of Letters and Science, University of California Los Angeles, Los Angeles, USA 3 Department of Urology and Renal Transplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan 28 2 2018 28 2 2018 2018 12 5029 8 2017 27 1 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\nHepatitis E virus infection usually causes an acute and self-resolving hepatitis. In areas where chronic hepatitis B virus infection is prevalent, acute hepatitis E virus superinfection on chronic hepatitis B virus infection occurs sporadically. In recent years, however, chronic hepatitis E virus infection has been recognized in patients under immunosuppressant therapy. To the best of our knowledge, cases involving patients with chronic hepatitis E virus and hepatitis B virus dual infection have never been reported.\n\nCase presentation\nA 47-year-old Taiwanese woman who was a renal transplant recipient with chronic hepatitis B virus infection was under immunosuppressant and antiviral treatment. An episode of hepatitis B exacerbation developed due to withdrawal of antiviral treatment against advice, but the flare subsided following antiviral re-treatments. However, an episode of hepatitis exacerbation developed following removal of the renal graft because of graft failure. During the hepatitis flare, she was still under successful antiviral suppression against hepatitis B virus, while her serum samples were positive for hepatitis E virus RNA. Following the hepatitis flare, seroclearance of hepatitis B virus surface antigen developed. From then on, she was under regular hemodialysis. Five years later, another episode of mild hepatitis exacerbation occurred again with positive serum hepatitis E virus RNA. Tracing back the longitudinal serum samples, serum hepatitis E virus RNA was persistently positive throughout the course. This patient was thus recognized to have chronic hepatitis E virus and hepatitis B virus dual infection with intermittent hepatitis E exacerbations.\n\nConclusions\nIn areas where chronic hepatitis B virus infection is prevalent, chronic hepatitis E virus coinfection can occur in organ transplant recipients receiving immunosuppressant. Intermittent hepatitis E exacerbations may develop, interfering with the status of hepatitis B virus infection.\n\nKeywords\nHepatitis BHepatitis ECoinfectionhttp://dx.doi.org/10.13039/501100005795Chang Gung Memorial Hospital, LinkouCRRPG3F0051 and CRRPG3E0101Yeh Chau-Ting issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nChronic hepatitis E virus (HEV) infection has been reported in immunocompromised patients [1]. In Asia, where hepatitis B virus (HBV) infection is highly prevalent, acute HEV superinfection on chronic HBV infection could occur sporadically. However, patients with dual chronic HEV and HBV infection have never been documented. Here, we reported a renal transplant recipient, who had dual chronic HEV and HBV infection. Interestingly, following an episode of acute hepatitis E exacerbation, seroclearance of HBV surface antigen (HBsAg) developed and our patient achieved a “functional cure” for chronic HBV infection.\n\nCase presentation\nA 47-year-old Taiwanese woman, a housewife, who was an HBV carrier, had received renal transplantation in 2002 and was treated with an immunosuppressant. Lamivudine was provided to maintain virological suppression for HBV. She was referred to the Liver Clinic of Chang Gung Memorial Hospital in January 2004 due to elevated HBV DNA levels (31.2 × 106 copies/mL). She denied major systemic diseases other than chronic hepatitis B and renal disease. No documented hereditary diseases or psychological disorders in her family were noted. She had an average socioeconomic status. On physical examination, she appeared normal with no icteric sclera, no hepatosplenomegaly, no spider nevi, and no caput medusae. She was positive for HBsAg, negative for HBV e antigen (HBeAg), and positive for anti-HBe antibody. No clinical evidence of liver cirrhosis was noted. Genotypic analysis revealed genotype B, precore stop codon G1896A mutation (+), basal core promoter mutation (−), and rtM204V/rtL180M mutation (+). She was switched to adefovir monotherapy and HBV DNA declined rapidly (Fig. 1, lower panel). HBV DNA became undetectable in August 2007. She stopped antiviral treatment in February 2008 against advice. However, relapse of viremia (29.3 × 106 copies/mL) developed and she was treated with lamivudine again for no detectable genotypic resistance (insurance coverage policy), but switched to adefovir shortly afterwards because of emergence of rtM204V/rtL180M mutants accompanied by a mild hepatitis flare: alanine transaminase (ALT) 49 U/L. From then on, maintained suppression of HBV DNA was achieved. HBV DNA was undetectable since March 2010. The flares in 2004 and late 2008 were considered flares of hepatitis B because of the accompanied elevations of HBV DNA levels with normalization of ALT after suppression of HBV DNA.Fig. 1 Clinical course of our patient with dual chronic hepatitis E and B infection. Upper panel Hepatitis E virus RNA was detected by reverse transcription-polymerase chain reaction followed by southern Blot analysis (top). Lanes 1–4, hepatitis E virus RNA detected from serum samples obtained from various time-points (arrows). Changes of alanine transaminase (orange circles and line), bilirubin (grey), alpha-fetoprotein (blue), and creatinine (green) along the course are depicted. Positive (solid horizontal bar) status of hepatitis E virus RNA; hepatitis C virus RNA and hepatitis B virus surface antigen are shown. Lower panel Changes of hepatitis B virus DNA along the course. Solid squares, positive hepatitis B virus DNA; green squares, hepatitis B virus DNA undetectable. Time-points to detect the rtM204V mutation are marked by arrows. Bottom, the periods of time when lamivudine or adefovir were given (solid horizontal bars). All serological and molecular virology assays are described in our previous publications [6, 7]. ADV adefovir, AFP alpha-fetoprotein, ALT alanine transaminase, BIL bilirubin, Cr creatinine, GR graft removed, HBsAg hepatitis B virus surface antigen, HBV hepatitis B virus, HCV hepatitis C virus, H/D hemodialysis, HEV hepatitis E virus, LAM lamivudine, P positive hybridization control\n\n\n\nOur patient suffered from graft rejection after renal transplantation and was treated with immunosuppressant drugs, including tacrolimus (3 mg/day), mycophenolate mofetil (500 mg twice a day), and prednisolone (10 mg/day). Her creatinine levels were between 3 and 4 mg/dL initially, but gradually elevated to 10 mg/dL despite increasing dosage of immunosuppressants. In January 2010, obstruction of graft ureter was found and hemodialysis resumed. Immunosuppressants were withdrawn and an episode of hepatitis flare occurred with ALT elevation to 251 U/L. After normalization of ALT, the renal graft was removed by operation. No HBV DNA elevation was detected before and during the flare. Throughout the flare, HBV DNA was suppressed to less than 104 copies/mL by adefovir. No known hepatotoxic drug was in use during this period. Anti-hepatitis C virus (HCV) antibody was positive since January 2008 but HCV RNA was negative throughout the clinical course. IgM anti-hepatitis A virus antibody, anti-hepatitis D virus (HDV) antibody, and HDV RNA were all tested negative. Subsequently, HEV RNA was found to be positive by reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analysis (Fig. 1, upper panel). Sequence analysis revealed genotype 3. Positive HEV RNA could be traced back to January 2005 but before that it was negative. Strikingly, seroclearance of HBsAg occurred in July 2010. Before this flare, the quantitative level of HBsAg was 25,000 IU/mL. It remained negative thereafter and adefovir was stopped in January 2014 with no subsequent virological relapse. Another episode of ALT elevation (to 73 U/L) was found during October to November 2014 with no positive hepatitis A to D markers. HEV RNA continued to be positive (final check was performed in January 2016). IgG anti-HEV was positive. Ribavirin was not given because of the low hemoglobin level in this patient who received hemodialysis. Anti-HBs antibody was negative throughout the course.\n\nDiscussion\nChronic HBV infection is highly prevalent in Asia. Therefore, acute but self-resolving HEV superinfection on chronic HBV infection can occur sporadically [2, 3]. Because chronic HEV infection can develop in patients under immunosuppressants, dual chronic HEV and HBV infection should be found in patients receiving organ transplantation, especially in an HBV endemic area. Here we identified a renal transplant recipient with chronic dual HEV and HBV infection. In this reported case of a patient, the dual chronic hepatitis infection was mostly asymptomatic during the clinical course. At that time, HBV infection was controlled by either lamivudine or adefovir monotherapy (if resistance developed), but not by add-on therapy because of high cost of adefovir. In this patient, HBV DNA could be suppressed to a low or undetectable level. The actual cause of hepatitis exacerbation preceded by HEV RNA elevation in January 2010 was unknown. A previous study showed that calcineurin inhibitors promoted HEV replication but mycophenolic acid inhibited HEV replication [4]. A disproportionate increase of the two immunosuppressants during graft rejection could result in fluctuating levels of HEV replication. On the other hand, withdrawal of immunosuppressant agents could increase host immune responses, and partly contribute to the exacerbation. No other causes of hepatitis could be identified other than HEV-related hepatitis flare. It is inspiring to find that HBsAg seroclearance could develop following a HEV-related hepatitis flare. Current clinical trials for new anti-HBV therapies are following a strategy similar to this scenario, where patients were under antiviral treatment to suppress HBV DNA and a novel immune-related agent or a new strategy to perturb immune responses was applied to induce seroclearance of HBsAg. Seroclearance of HBsAg was considered a “functional cure” for HBV infection [5]. It is worth noting that HEV-induced immune response can result in HBsAg clearance.\n\nA second episode of mild hepatitis E exacerbation developed 5 years after the removal of the renal graft and withdrawal of immunosuppressant. Our patient was under regular hemodialysis at that time and remained persistently positive for serum HEV RNA.\n\nConclusions\nThis case report revealed that chronic dual HEV and HBV infection could occur in areas where hepatitis B is prevalent. Hepatitis exacerbations of HEV were noted, resulting in seroclearance of HBsAg. Serum HEV RNA persisted even after immunosuppressant was stopped, while our patient was under hemodialysis.\n\nAbbreviations\nALTAlanine transaminase\n\nHBeAgHepatitis B virus e antigen\n\nHBsAgHepatitis B virus surface antigen\n\nHBVHepatitis B virus\n\nHCVHepatitis C virus\n\nHDVHepatitis D virus\n\nHEVHepatitis E virus\n\nRT-PCRReverse transcription-polymerase chain reaction\n\nAcknowledgements\nThe authors thank all members in Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan for helpful discussion and technical assistance.\n\nFunding\nThis study was supported by grants from Chang Gung Medical Research Program (CRRPG3F0051 and CRRPG3E0101).\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nAuthors’ contributions\nCTY and CSHY carried out the literature research, manuscript preparation, and were the main moderators of the manuscript. Y-DC revised the manuscript. CTY and YJC collected and interpreted all clinical data of the patient. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nWritten consent was obtained from the patient for all serological assays. Anonymous case report was conducted in accordance with the requirement of Chang-Gung Memorial Hospital Ethics Committee.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Fujiwara S Yokokawa Y Morino K Hayasaka K Kawabata M Shimizu T Chronic hepatitis E: a review of the literature J Viral Hepat 2014 21 2 78 89 10.1111/jvh.12156 24383921 \n2. Singh NJ Kumari A Catanzaro R Marotta F Prevalence of hepatitis E and hepatitis B dual infection in North India (Delhi) Acta Bio Medica Atenei Parmensis 2013 83 3 197 201 \n3. Hoan NX Tong HV Hecht N Sy BT Marcinek P Meyer CG Song le H Toan NL Kurreck J Kremsner PG Hepatitis E Virus Superinfection and Clinical Progression in Hepatitis B Patients EBioMedicine 2015 2 12 2080 2086 10.1016/j.ebiom.2015.11.020 \n4. Wang Y Zhou X Debing Y Chen K Van Der Laan LJ Neyts J Janssen HL Metselaar HJ Peppelenbosch MP Pan Q Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis E virus Gastroenterology 2014 146 7 1775 1783 10.1053/j.gastro.2014.02.036 24582714 \n5. Liang TJ Block TM McMahon BJ Ghany MG Urban S Guo JT Locarnini S Zoulim F Chang KM Lok AS Present and future therapies of hepatitis B: From discovery to cure Hepatology 2015 62 6 1893 1908 10.1002/hep.28025 26239691 \n6. Yeh CT Tsao ML Detection of serum anti-NV-F antibodies in the convalescent phase of severe hepatitis in patients positive for tissue NV-F antigen and novel virus-like particles J Med Virol 2015 87 10 1727 1736 10.1002/jmv.24224 25873412 \n7. Lai MW Lin TY Tsao KC Huang CG Hsiao MJ Liang KH Yeh CT Increased seroprevalence of HBV DNA with mutations in the s gene among individuals greater than 18 years old after complete vaccination Gastroenterology 2012 143 2 400 407 10.1053/j.gastro.2012.05.002 22580098\n\n",
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"title": "Seroclearance of hepatitis B surface antigen following hepatitis E exacerbation on chronic hepatitis E and B dual infection in a renal transplant recipient: a case report.",
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"abstract": "Reportedly, a high plasma concentration of lamotrigine plays a role in the development of lamotrigine-related rash. The relationship between plasma concentrations of lamotrigine at week 2 and the lamotrigine-related rash was prospectively studied in 84 patients (22 males and 62 females) with treatment-resistant depressive disorder during an 8-week treatment of lamotrigine augmentation.\n\n\n\nEighty-four depressed patients with an insufficient response to at least 3 psychotropics, including antidepressants, mood stabilizers, and atypical antipsychotics, were included. The diagnoses were major depressive disorder (n = 39), bipolar I disorder (n = 10), and bipolar II disorder (n = 35). The final doses of lamotrigine were 100 mg/d for 57 subjects who were not taking valproate and 75 mg/d for 27 subjects taking valproate. Blood sampling was performed at week 2. Lamotrigine plasma concentrations were measured using high-performance liquid chromatography. The development of lamotrigine-related rash was assessed during the 8-week treatment.\n\n\n\nSix females developed lamotrigine-related rash. The mean plasma lamotrigine concentrations at week 2 were significantly (P = 0.009) higher in the rash group (4.81 ± 1.23 μmol/L) than in the nonrash group (3.35 ± 1.39 μmol/L). Receiver-operating characteristic analysis indicated that a plasma lamotrigine concentration of 4.38 μmol/L or greater at week 2 was significantly (P < 0.0001) predictive of lamotrigine-related rash. The proportion of patients with a lamotrigine concentration of 4.38 μmol/L or greater was significantly divided by the cutoff point into the rash group and the nonrash group (5/1 versus 13/65, P = 0.001).\n\n\n\nThis study suggests that a high plasma lamotrigine concentration during week 2 is a risk factor for lamotrigine-related rash and a plasma lamotrigine concentration of 4.38 μmol/L may be a considered a threshold for rash in treatment-resistant depressive disorder.",
"affiliations": "Departments of Hospital Pharmacy; and.;Neuropsychiatry, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.;Neuropsychiatry, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.;Neuropsychiatry, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.;Neuropsychiatry, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.;Neuropsychiatry, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.;Neuropsychiatry, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.",
"authors": "Suzuki|Takeshi|T|;Mihara|Kazuo|K|;Nagai|Goyo|G|;Kagawa|Shoko|S|;Nakamura|Akifumi|A|;Nemoto|Kenji|K|;Kondo|Tsuyoshi|T|",
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"title": "A High Plasma Lamotrigine Concentration at Week 2 as a Risk Factor for Lamotrigine-Related Rash.",
"title_normalized": "a high plasma lamotrigine concentration at week 2 as a risk factor for lamotrigine related rash"
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"abstract": "Tamsulosin in a widely used drug in urology practice in treating lower urinary tract symptoms of benign prostatic hyperplasia, distal ureteral stones, and ureteral stent-related symptoms. Ischemic priapism is a rare but serious adverse effect of tamsulosin. We report two cases of tamsulosin-induced priapism and reviewed available literature citing priapism as a complication of tamsulosin. We also reviewed the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database to identify reported cases of tamsulosin-induced priapism. First patient was a 61-year-old African American male with paraplegia of 30-year duration. He developed priapism after taking first dose of tamsulosin for lower urinary tract symptoms. He presented with 18 hours of painful erection and was treated with aspiration and irrigation, followed by phenylephrine injection. The patient maintained potency after treatment. The second patient was a 24-year-old male who received tamsulosin in the emergency department as medical expulsive therapy for 11 mm distal ureteral stone. Since he had intractable pain, he underwent emergency primary ureteroscopy with laser lithotripsy as definitive treatment of his ureteral calculus. He developed intraoperative priapism that subsided postoperatively. However, he was discharged with tamsulosin to reduce stent-related urinary symptoms. He returned back to the emergency department after 3 days with persistent priapism for 3 days and needed penoscrotal corporeal decompression to treat his priapism. At 6 weeks follow-up visit, the patient has lost his potency. Although there were only 4 case reports on review of the literature, we were able to identify 46 cases reported in the U.S. FAERS database. Priapism can be an adverse reaction to tamsulosin. Providers and patients should be aware about this complication to ensure early seeking of management to avoid devastating outcomes, particularly in young patients when tamsulosin is given as medical expulsive therapy for ureteral stone and stent-related symptoms.",
"affiliations": "Department of Urology, University of Miami Miller School of Medicine, Miami, Florida, USA.;Department of Urology, University of Miami Miller School of Medicine, Miami, Florida, USA.;Department of Urology, University of Miami Miller School of Medicine, Miami, Florida, USA.",
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"abstract": "Infective endocarditis is a potentially lethal infection, which predominantly affects the atrioventricular valves. Rapid identification and management is critical to reduce morbidity and mortality in this patient population. Herein, we present a case of a 24-year-old man with Leuconostoc species infective endocarditis of the aortic valve. Disease course was complicated by several septic emboli to the brain, central retinal artery, and spleen. This case serves to remind clinicians that Leuconostoc species, which are typically not pathogenic to human species, can cause infective endocarditis in individuals with a history of intravenous drug use. <Learning objective: It is crucial that clinicians maintain a high index of suspicion in high-risk patients for infective endocarditis with Leuconostoc species, especially in the setting of positive blood cultures with group viridans streptococcus resistant to penicillin. Although cases of penicillin resistant group viridans streptococci have been reported, it is not common and merits further review. Leuconostoc is a Gram-positive ovoid cocci that is intrinsically vancomycin-resistant and is typically non-pathogenic to the human species.>.",
"affiliations": "Department of Medicine, Kettering Medical Center, Kettering, OH, USA.;Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Department of Medicine, Kettering Medical Center, Kettering, OH, USA.",
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"title": "Leuconostoc species endocarditis in an intravenous drug user.",
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"abstract": "Benzodiazepine withdrawal-induced catatonia is a rare phenomenon in the adult population and has never been reported in a pediatric patient. We present a 9-year-old boy who exhibited catatonia symptoms following discontinuation of a midazolam infusion in the pediatric intensive care unit. The pediatric anesthesia acute pain team was consulted. When the patient's altered mental status could not otherwise be explained, benzodiazepine withdrawal-induced catatonia was considered. A dose of 2 mg intravenous lorazepam was given and the patient's symptoms dramatically improved within 5 minutes of administration. The patient was successfully treated with an oral diazepam taper.",
"affiliations": "From the Departments of *Anesthesiology; †Pharmacy: Clinical and Administrative Sciences; and ‡Pediatrics, Critical Care, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.",
"authors": "Duncan-Azadi|Cassandra R|CR|;Johnson|Peter N|PN|;Gormley|Andrew|A|",
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"title": "Case Report of Midazolam Withdrawal-Induced Catatonia in a 9-Year-Old Patient.",
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"abstract": "Erythrodermic psoriasis is a severe type of psoriasis associated with comorbidities and high mortality. Patients with erythrodermic psoriasis need hospitalization and systemic treatment. Conventional drugs and biologic agents may not manage to control refractory and complicated erythrodermic psoriasis resulting from treatment failure. Ustekinumab, a human monoclonal antibody against interleukin-12 and 23, seems to be an effective therapeutic option in erythrodermic psoriasis whenever other therapies have failed.",
"affiliations": "2nd Department of Dermatology and Venereology, Attikon University General Hospital, University of Athens, Medical School, Athens, Greece.",
"authors": "Koutsoukou|Xanthippe-Argyro|XA|;Papadavid|Evangelia|E|;Theodoropoulos|Konstantinos|K|;Rigopoulos|Dimitris|D|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D003879:Dermatologic Agents; D000069549:Ustekinumab",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.12131",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "27(5)",
"journal": "Dermatologic therapy",
"keywords": "erythrodermic psoriasis; sepsis; ustekinumab",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D003873:Dermatitis, Exfoliative; D003879:Dermatologic Agents; D005260:Female; D006801:Humans; D008875:Middle Aged; D011565:Psoriasis; D012074:Remission Induction; D012720:Severity of Illness Index; D012867:Skin; D013997:Time Factors; D016896:Treatment Outcome; D000069549:Ustekinumab",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "257-9",
"pmc": null,
"pmid": "24813816",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ustekinumab in severe complicated erythrodermic psoriasis: rapid clearing, safety, and sustained remission.",
"title_normalized": "ustekinumab in severe complicated erythrodermic psoriasis rapid clearing safety and sustained remission"
} | [
{
"companynumb": "US-JNJFOC-20140510992",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "USTEKINUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Mitomycin (MMC) has been associated with a variety of complications, including corneoscleral melt. We report the successful repair of a scleral melt with a partial thickness autologous scleral graft of the scleral melting. A 55-year-old male patient underwent pterygium resection surgery and intraoperative MMC application. The patient developed a deep melting area that almost reached the choroid layer at the nasal sclera. We repaired scleral defect with a partial thickness autologous scleral graft. Closure of an MMC-associated scleral melting area with an autologous partial thickness scleral graft is an effective and easy-to-use method.",
"affiliations": "Department of Ophthalmology, Medical Faculty, Inonu University, 44 280, Malatya, Turkey. drnihatpolat@gmail.com.",
"authors": "Polat|Nihat|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1007/s40123-014-0026-7",
"fulltext": "\n==== Front\nOphthalmol Ther\nOphthalmol Ther\nOphthalmology and Therapy\n2193-8245\n2193-6528\nSpringer Healthcare Heidelberg\n\n26\n10.1007/s40123-014-0026-7\nCase Report\nUse of an Autologous Lamellar Scleral Graft to Repair a Scleral Melt After Mitomycin Application\nPolat Nihat drnihatpolat@gmail.com\n\nDepartment of Ophthalmology, Medical Faculty, Inonu University, 44 280 Malatya, Turkey\n22 11 2014\n22 11 2014\n12 2014\n3 1-2 7376\n20 9 2014\n© The Author(s) 2014\nMitomycin (MMC) has been associated with a variety of complications, including corneoscleral melt. We report the successful repair of a scleral melt with a partial thickness autologous scleral graft of the scleral melting. A 55-year-old male patient underwent pterygium resection surgery and intraoperative MMC application. The patient developed a deep melting area that almost reached the choroid layer at the nasal sclera. We repaired scleral defect with a partial thickness autologous scleral graft. Closure of an MMC-associated scleral melting area with an autologous partial thickness scleral graft is an effective and easy-to-use method.\n\nElectronic supplementary material\n\nThe online version of this article (doi:10.1007/s40123-014-0026-7) contains supplementary material, which is available to authorized users.\n\nKeywords\n\nAutologous\nMitomycin\nScleral graft\nScleral melting\nissue-copyright-statement© Springer Healthcare 2014\n==== Body\nIntroduction\n\nMitomycin (MMC) application has been shown to be effective in preventing recurrence in pterygium surgery [1, 2]. MMC is an alkylating agent that reduces pterygium recurrence by inhibiting fibrovascular growth and has been demonstrated to be a useful adjunct for this surgery [3]. Unfortunately, MMC has also been to be associated with a variety of complications, including corneoscleral melt [3]. The scleral defect must be covered with donor tissue to prevent subsequent infection or perforation in such cases. The materials used for this complication include preserved sclera, cornea, pericardium, dura or amniotic membrane [4]. We report the successful repair with a partial thickness autologous scleral graft of the scleral melting that developed in a patient who underwent pterygium surgery with MMC.\n\nCase\n\nA 55-year-old male patient underwent pterygium resection surgery and intraoperative MMC application at an external center for the pterygium in his right eye, 6 months ago. The patient developed a deep melting area that almost reached the choroid underlying the nasal sclera during follow-up and was referred to our clinic. The examination revealed full visual acuity bilaterally with normal biomicroscopy and retinal findings in the left eye. A scleral melt area with a diameter of 0.5–0.75 cm and extending almost to the choroid except for a thin membrane was present approximately 1 cm away from the limbus at the nasal section of the right eye. Normal vascularization was severely decreased in the defect starting from the limbus (Fig. 1). It was decided to close the defect as the area was open to trauma.Fig. 1 Pre-operative appearance of the sclera melt in the right eye after pterygium resection surgery and intraoperative mitomycin\n\nThe conjunctiva in the defect region of the right eye was dissected under retrobulbar anesthesia. The edges of the scleral defect were trimmed with a crescent knife to ensure donor tissue as the graft site would adhere easily. In the same eye, the conjunctiva and Tenon’s capsule in the upper temporal region were then dissected. A partial thickness scleral graft about 0.75–1.00 cm and suitable for the defect region in size was then removed from the upper temporal region with a 45° surgical knife. Dissection was performed with utmost care in order not to create scleromalacia in the area. The Tenon’s capsule and conjunctiva in the region where the graft was taken were primarily closed with 8-0 vicryl. The removed graft was placed in the appropriate position so as to close the defect region and sutured with 8-0 vicryl. The Tenon’s capsule and conjunctival tissue at the site of the sclera defect were freed with blunt dissection and sutured with 8-0 vicryl so as to close the entire defect region. There were no complications and surgery was ended with a subconjunctival gentamicin and dexamethasone injection. Postoperatively moxifloxacin, one drop, five times a day and florometolon, one drop, four times a day were started and the patient was monitored. The patient had no symptoms except for minimal stinging at the postoperative first week. On examination, the conjunctiva was hyperemic, the graft intact, the sutures unharmed, visual acuity full, and the intraocular pressure and retinal findings normal. No complication was observed in the postoperative first month. The visual acuity was full, and the intraocular pressure and retinal findings were normal. The patient had no symptoms and the drops were stopped. In the third postoperative month it was seen that the defect had completely healed and was well covered by a vascular conjunctiva. The region providing the graft had also healed without any complication. The visual acuity was full, and the intraocular pressure and retinal findings were normal (Fig. 2).Fig. 2 Post-operative appearance of the autologous lamellar scleral graft bed at 3 months\n\nInformed consent was obtained from the patient for being included in the study.\n\nDiscussion\n\nMMC is used in many areas such as glaucoma and pterygium surgery. MMC can cause serious problems in tissues such as the cornea and sclera if used for a longer duration than usual or not sufficiently irrigated and removed afterwards [3]. Our patient was operated on in an external center so we did not know which MMC regimen had been employed. Severe damage occurred in the nasal region, affecting the conjunctiva, Tenon’s capsule and sclera of our case with sclera melting almost to the choroid. In such cases, the choroid can be ruptured by minimal trauma to the eye, leading to vitreous loss and the risk of infection, including endophthalmitis. Amniotic membrane, fascia lata, pericardium, dura mater, and corneal or scleral grafts can be used to repair the defect [4, 5]. A scleral graft has been used to treat perforated corneal ulcer, scleral melting, or scleromalacia as it is strong, flexible, easy to handle, and can be placed on host sclera [6–8]. A scleral graft can also be used in the cosmetic closure of an Ota nevus [9]. The scleral graft can be obtained from another donor or from the patient’s same or the other eye [8]. We preferred partial thickness autologous sclera because a relatively small graft was required, removal of sclera from the temporal site was straightforward and there was no risk of rejection using this approach. The upper temporal region was preferred as a site distant from the earlier MMC exposure, where scleral removal is easy. However, excessively deep incisions during removal of the graft may lead to choroidal and retinal damage or cause later staphyloma formation. Scleral perforation under the suture is another significant complication that may occur. The repair did not cause any preoperative or postoperative complications in our case.\n\nIn conclusion, closure of an MMC-associated scleral melting area with an autologous partial thickness scleral graft is an effective and easy-to-use method.\n\nElectronic supplementary material\n\nSupplementary material 1 (PDF 199 kb)\n\nNo funding or sponsorship was received for this study or publication of this article. The author meets the ICMJE criteria for authorship for this manuscript, takes responsibility for the integrity of the work as a whole, and has given final approval for the version to be published.\n\nConflict of interest\n\nNihat Polat declares no conflict of interest.\n\nCompliance with ethics guidelines\n\nInformed consent was obtained from all patients for being included in the study.\n\nOpen Access\n\nThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.\n==== Refs\nReferences\n\n1. Segev F Jaeger-Roshu S Gefen-Carmi N Assia EI Combined mitomycin C application and free flap conjunctival autograft in pterygium surgery Cornea 2003 22 7 598 603 10.1097/00003226-200310000-00003 14508255\n2. Hirst LW Mitomycin C in the treatment of pterygium Clin Exp Ophthalmol 2006 34 3 197 198 10.1111/j.1442-9071.2006.01195.x\n3. Rubinfeld RS Pfister RR Stein RM Serious complications of topical mitomycin-C after pterygium surgery Ophthalmology 1992 99 11 1647 1654 10.1016/S0161-6420(92)31749-X 1454338\n4. Prydal JI Use of an autologous lamellar scleral graft to repair corneal perforation Br J Ophthalmol 2006 90 924 925 10.1136/bjo.2006.092726 16782960\n5. Ti SE Tan DTH Tectonic corneal lamellar grafting for severe scleral melting after pterygium surgery Ophthalmology 2003 110 1126 1136 10.1016/S0161-6420(03)00260-4 12799236\n6. Levartovsky S Springer A Leiba H Marcovich AL Pollack A Homologous scleral graft for corneal perforation in a child Cornea 2008 27 230 231 10.1097/ICO.0b013e31815a510e 18216584\n7. Oh JH Kim JC Repair of scleromalacia using preserved scleral graft with amniotic membrane transplantation Cornea 2003 22 288 293 10.1097/00003226-200305000-00002 12792468\n8. Sangwan VS Jain V Gupta P Structural and functional outcome of scleral patch graft Eye 2007 21 930 935 10.1038/sj.eye.6702344 16601740\n9. Cho BJ Kwon JW Han YK Kim JH Wee WR Lee JH Cosmetic improvement of nevus of Ota by scleral allograft overlay Can J Ophthalmol 2011 46 5 428 430 10.1016/j.jcjo.2011.07.006 21995987\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": null,
"issue": "3(1-2)",
"journal": "Ophthalmology and therapy",
"keywords": "Autologous; Mitomycin; Scleral graft; Scleral melting",
"medline_ta": "Ophthalmol Ther",
"mesh_terms": null,
"nlm_unique_id": "101634502",
"other_id": null,
"pages": "73-6",
"pmc": null,
"pmid": "25416161",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article",
"references": "16601740;12792468;18216584;21995987;16671897;16782960;14508255;1454338;12799236",
"title": "Use of an Autologous Lamellar Scleral Graft to Repair a Scleral Melt After Mitomycin Application.",
"title_normalized": "use of an autologous lamellar scleral graft to repair a scleral melt after mitomycin application"
} | [
{
"companynumb": "TR-ACCORD-027493",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MITOMYCIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "We present this unusual case of cisplatin-induced acute myocardial infarction in a patient with no organic coronary artery disease (CAD), receiving chemoradiation for small cell lung cancer. Patient developed symptoms of acute coronary syndrome after receiving two cycles of cisplatin and etoposide. The possible mechanism of vasospasm induced by cisplatin, in the background of thoracic radiation and hypomagnesemia, is discussed in this case report.",
"affiliations": "Department of Radiotherapy, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, Karnataka, India.",
"authors": "Rao|Arpitha S|AS|;Kumar|Rishabh|R|;Narayanan|Geeta S|GS|",
"chemical_list": "D000970:Antineoplastic Agents; D002945:Cisplatin",
"country": "India",
"delete": false,
"doi": "10.4103/0973-1482.157320",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1998-4138",
"issue": "11(4)",
"journal": "Journal of cancer research and therapeutics",
"keywords": null,
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D000970:Antineoplastic Agents; D018288:Carcinoma, Small Cell; D059248:Chemoradiotherapy; D002945:Cisplatin; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D011379:Prognosis",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "983-5",
"pmc": null,
"pmid": "26881563",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "A rare case of cisplatin-induced acute myocardial infarction in a patient receiving chemoradiation for lung cancer.",
"title_normalized": "a rare case of cisplatin induced acute myocardial infarction in a patient receiving chemoradiation for lung cancer"
} | [
{
"companynumb": "IN-HQ SPECIALTY-IN-2016INT000309",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Chronic hepatitis C virus (HCV) infection and autoimmune disorders show a complex interplay, with HCV often being identified as the trigger of autoimmune phenomena or diseases. While there is evidence of successful HCV treatment with direct-acting antivirals (DAA) in patients with concomitant HCV and autoimmune hepatitis (AIH), there are also sparse reports of AIH developing during, or following, DAA treatment. Here we report a case of a patient with suspected concomitant HCV and AIH who underwent liver biopsy but showed no histological hallmarks of autoimmunity. The patient later developed a hepatitic flare following DAA-induced viral clearance, and a second liver biopsy showed features compatible with AIH. Response to corticosteroid and azathioprine treatment was seen. This reports demonstrates that patients with features of auto-reactivity and HCV after DAA-induced viral clearance require careful follow-up.",
"affiliations": "Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Italy; IRCCS-Ospedale Policlinico San Martino, Genoa, Italy.;Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Italy; IRCCS-Ospedale Policlinico San Martino, Genoa, Italy.;Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Italy; IRCCS-Ospedale Policlinico San Martino, Genoa, Italy.;Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Italy; IRCCS-Ospedale Policlinico San Martino, Genoa, Italy.;Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Italy; IRCCS-Ospedale Policlinico San Martino, Genoa, Italy.;Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Italy; IRCCS-Ospedale Policlinico San Martino, Genoa, Italy.;Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Italy; IRCCS-Ospedale Policlinico San Martino, Genoa, Italy. Electronic address: egiannini@unige.it.",
"authors": "Cacciato|Valentina|V|;Casagrande|Edoardo|E|;Bodini|Giorgia|G|;Furnari|Manuele|M|;Marabotto|Elisa|E|;Grillo|Federica|F|;Giannini|Edoardo G|EG|",
"chemical_list": "C541116:ACTA2 protein, human; D000199:Actins; D000974:Antibodies, Antinuclear; D000998:Antiviral Agents; D002219:Carbamates; D004338:Drug Combinations; D005938:Glucocorticoids; D006576:Heterocyclic Compounds, 4 or More Rings; D007166:Immunosuppressive Agents; C000611331:sofosbuvir-velpatasvir drug combination; D011239:Prednisolone; D001379:Azathioprine; D000069474:Sofosbuvir",
"country": "Mexico",
"delete": false,
"doi": "10.1016/j.aohep.2019.11.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1665-2681",
"issue": "19(2)",
"journal": "Annals of hepatology",
"keywords": "Autoimmunity; Direct acting antivirals; Sustained virological response; Treatment",
"medline_ta": "Ann Hepatol",
"mesh_terms": "D000199:Actins; D000368:Aged; D000974:Antibodies, Antinuclear; D000998:Antiviral Agents; D001379:Azathioprine; D001706:Biopsy; D002219:Carbamates; D004338:Drug Combinations; D005938:Glucocorticoids; D019698:Hepatitis C, Chronic; D019693:Hepatitis, Autoimmune; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D011239:Prednisolone; D000069474:Sofosbuvir; D016896:Treatment Outcome",
"nlm_unique_id": "101155885",
"other_id": null,
"pages": "222-225",
"pmc": null,
"pmid": "32029393",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Eradication of hepatitis C virus infection disclosing a previously hidden, underlying autoimmune hepatitis: Autoimmune hepatitis and HCV.",
"title_normalized": "eradication of hepatitis c virus infection disclosing a previously hidden underlying autoimmune hepatitis autoimmune hepatitis and hcv"
} | [
{
"companynumb": "IT-GILEAD-2021-0517803",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SOFOSBUVIR\\VELPATASVIR"
},
"drugadditional": nu... |
{
"abstract": "Aim of this study was to estimate the prevalence of cerebrospinal fluid (CSF)/Plasma HIV-1 RNA discordance in virologically suppressed individuals presenting with incident neurologic symptoms.In this retrospective cohort study conducted between March 1, 2009, and March 1, 2017, HIV-1 infected adults exposed to atleast 12 months of antiretroviral therapy (ART) and having plasma viral load (VL) <1000 copies/mL (virologically suppressed) were included. Among these, individuals presenting with neurologic symptoms during follow-up were assessed for CSF/Plasma HIV-1 RNA discordance by measuring HIV-1 RNA in collected plasma and CSF samples. CSF/plasma HIV-1 RNA discordance was defined as either detectable CSF HIV-1 RNA (VL > 20 copies/mL) with an undetectable plasma RNA (complete viral suppression, VL ≤20 copies/mL) or CSF HIV-1 RNA ≥ 0.5 log10 higher than plasma RNA when plasma VL was between 20 and 1000 copies/mL (low-level viremia, LLV).Out of 1584 virologically suppressed patients, 71 (4.4%) presented with incident neurologic symptoms. Twenty out of 71 (28.2%) patients were diagnosed with CSF/Plasma HIV-1 discordance. Median plasma and CSF VL in patients with discordance was 120 [interquartile range (IQR): <20 to 332.5] and 4250 (IQR: 2550.0- 9615.0) copies/mL, respectively. All 9 individuals in which CSF HIV-1 genotypic resistance testing was done showed mutations that would compromise efficacy of prescribed ART regimen. Prevalence of CSF/plasma HIV-1 RNA discordance was higher among neurologically symptomatic patients with plasma LLV as compared with those with complete viral suppression (70% vs 11.8%, P < .001). The risk of discordance was also greater in patients who received protease inhibitor (PI) containing ART (P < .001) and those on ART regimens with central nervous system (CNS) penetration effectiveness (CPE) value <6 (P = .006).CSF/plasma HIV-1 RNA discordance indicates replication of HIV-1 that has adapted to the CNS or has developed antiretroviral drug resistance. Larger studies should be performed to study incidence of discordance in India. This will help in managing patients presenting with neurologic symptoms on suppressive ART with appropriate neuroeffective therapy.",
"affiliations": "Department of Medicine, Ruby Hall Clinic Department of Medicine, Poona Hospital Department of Medicine, Noble Hospital Precision Diagnostics and Biosciences, Pune Department of Dermatology, Ashwini Sahakari Rugnalaya, Solapur Department of Medicine, Apex Hospital, Kolhapur GeneOmbio Technologies Private Limited, Pune, Maharashtra, India.",
"authors": "Dravid|Ameet N|AN|;Natrajan|Kartik|K|;Kulkarni|Milind M|MM|;Saraf|Chinmay K|CK|;Mahajan|Uma S|US|;Kore|Sachin D|SD|;Rathod|Niranjan M|NM|;Mahajan|Umakant S|US|;Wadia|Rustom S|RS|",
"chemical_list": "D019380:Anti-HIV Agents; D012367:RNA, Viral",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000009969",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29465595MD-D-17-0705310.1097/MD.0000000000009969099694850Research ArticleObservational StudyDiscordant CSF/plasma HIV-1 RNA in individuals on virologically suppressive antiretroviral therapy in Western India Dravid Ameet N. MDabc∗Natrajan Kartik MBBSbKulkarni Milind M. MBBSaSaraf Chinmay K. MDdMahajan Uma S. M.ScdKore Sachin D. MDeRathod Niranjan M. MDfMahajan Umakant S. B.M.TechgWadia Rustom S. MDaShang. Liang a Department of Medicine, Ruby Hall Clinicb Department of Medicine, Poona Hospitalc Department of Medicine, Noble Hospitald Precision Diagnostics and Biosciences, Punee Department of Dermatology, Ashwini Sahakari Rugnalaya, Solapurf Department of Medicine, Apex Hospital, Kolhapurg GeneOmbio Technologies Private Limited, Pune, Maharashtra, India.∗ Correspondence: Ameet N. Dravid, Ruby Hall Clinic, 40, Sassoon Road, Pune 411004, Maharashtra, India. (e-mail: ameet.dravid@gmail.com).2 2018 23 2 2018 97 8 e996913 11 2017 5 1 2018 30 1 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nAim of this study was to estimate the prevalence of cerebrospinal fluid (CSF)/Plasma HIV-1 RNA discordance in virologically suppressed individuals presenting with incident neurologic symptoms.\n\nIn this retrospective cohort study conducted between March 1, 2009, and March 1, 2017, HIV-1 infected adults exposed to atleast 12 months of antiretroviral therapy (ART) and having plasma viral load (VL) <1000 copies/mL (virologically suppressed) were included. Among these, individuals presenting with neurologic symptoms during follow-up were assessed for CSF/Plasma HIV-1 RNA discordance by measuring HIV-1 RNA in collected plasma and CSF samples. CSF/plasma HIV-1 RNA discordance was defined as either detectable CSF HIV-1 RNA (VL > 20 copies/mL) with an undetectable plasma RNA (complete viral suppression, VL ≤20 copies/mL) or CSF HIV-1 RNA ≥ 0.5 log10 higher than plasma RNA when plasma VL was between 20 and 1000 copies/mL (low-level viremia, LLV).\n\nOut of 1584 virologically suppressed patients, 71 (4.4%) presented with incident neurologic symptoms. Twenty out of 71 (28.2%) patients were diagnosed with CSF/Plasma HIV-1 discordance. Median plasma and CSF VL in patients with discordance was 120 [interquartile range (IQR): <20 to 332.5] and 4250 (IQR: 2550.0– 9615.0) copies/mL, respectively. All 9 individuals in which CSF HIV-1 genotypic resistance testing was done showed mutations that would compromise efficacy of prescribed ART regimen. Prevalence of CSF/plasma HIV-1 RNA discordance was higher among neurologically symptomatic patients with plasma LLV as compared with those with complete viral suppression (70% vs 11.8%, P < .001). The risk of discordance was also greater in patients who received protease inhibitor (PI) containing ART (P < .001) and those on ART regimens with central nervous system (CNS) penetration effectiveness (CPE) value <6 (P = .006).\n\nCSF/plasma HIV-1 RNA discordance indicates replication of HIV-1 that has adapted to the CNS or has developed antiretroviral drug resistance. Larger studies should be performed to study incidence of discordance in India. This will help in managing patients presenting with neurologic symptoms on suppressive ART with appropriate neuroeffective therapy.\n\nKeywords\nantiretroviral therapy (ART)CNS penetration effectiveness (CPE) scoreCSF/plasma HIV-1 RNA discordanceHIV encephalopathylow-level viremia (LLV)nadir CD4 countprotease inhibitorsOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nThe central nervous system (CNS) is a reservoir for HIV, which is established very early during the course of HIV infection.[1,2] With the advent of potent antiretroviral therapy (ART), virologic suppression is achieved in plasma and cerebrospinal fluid (CSF)[3,4] and the incidence of HIV-1 associated dementia has declined dramatically.[5] However, milder forms of HIV associated neurocognitive disorders persist in 25% to 50% people with chronic HIV-1 infection.[5] Episodes of severe neurologic impairment developing in patients on virologically suppressive ART have also been reported.[6,7] One reason for this could be the limited distribution of ART drugs into CNS due to restriction at the blood–brain and blood–CSF barriers. If the concentrations of ART drugs in the CNS are subtherapeutic, HIV-1 could replicate at low levels, leading to viral neurotoxicity, chronic sustained immune activation, and evolution of drug-resistant CNS HIV.[8–10] Persistent HIV-1 RNA in CSF with or without neurologic symptoms in spite of well controlled plasma HIV-1 RNA (CSF/Plasma HIV-1 RNA discordance) has been reported from Europe and North America.[11–16] Independent evolution of drug resistant CNS HIV has also been described.[17,18] However, there are sparse data on neurosymptomatic CSF/plasma HIV-1 discordance from countries outside these regions, such as India. The prevalence of CSF/plasma HIV-1 discordance is estimated at 12% to 21% among adults undergoing clinically indicated lumbar punctures (LPs).[14,15] The objective of this study was to estimate the prevalence of CSF/Plasma HIV-1 RNA discordance in virologically suppressed Indian patients presenting with incident neurologic symptoms and associated risk factors.\n\n2 Materials and methods\n2.1 Study design\nThis was a retrospective cohort study conducted between March 1, 2009, and March 1, 2017, at 3 private, tertiary-level hospitals and research centers in Pune, Western India (Ruby Hall Clinic, Poona Hospital, and Noble Hospital).\n\n2.2 Settings and patient characteristics\nAll 3 private hospitals provide clinical care, diagnostic, and treatment services. The patients are followed regularly on the basis of their clinical presentations and treatment duration. The demographic, clinical, and laboratory data were abstracted from the electronic records of the hospital database. The approval for data analysis was obtained from the Ethics Committees of all 3 hospitals. We retrospectively compiled data of all patients who had at least 12 months of stable ART and plasma HIV-1 viral load (VL) <1000 copies/mL, a level that is considered to be virologically suppressed as per WHO ART guidelines.[19] Among these, individuals presenting with neurologic symptoms during follow-up such as imbalance during walking, memory and speech disturbance, intractable headache, pain and sensory disruption, seizures, partial or complete paralysis of limb, and loss of control over bladder and bowel were identified and their inpatient case files were studied. Laboratory and imaging data including routine biochemical investigations, CD4 count, CSF studies, and magnetic resonance imaging (MRI, GE 1.5 Tesla Signa model in 2 hospitals and Phillips 1.5 Tesla model in 1 hospital) were abstracted for analysis. Follow-up data of each patient were censored at the time of development of neurologic symptoms or loss of virologic suppression (plasma VL on ART > 1000 copies/mL) or loss to follow-up or completion of cohort duration or death of patient.\n\n2.3 Diagnosis and clinical management\nCriteria used to diagnose common neurologic conditions in our cohort were as follows:1) CNS tuberculosis (TB): CSF automated liquid TB culture, CSF TB real-time polymerase chain reaction (PCR) assay (Xpert MTB/RIF, Cepheid, USA), and MR imaging.\n\n2) Cerebral toxoplasmosis and progressive multifocal leucoencephalopathy (PML): MR imaging, stereotactic brain biopsy, and CSF JC virus DNA in case of PML.\n\n3) Cryptococcal meningoencephalitis: CSF Cryptococcal antigen and CSF fungal culture.\n\n4) HIV encephalopathy (HIV-E): MR imaging and the absence of other diagnoses.\n\n5) Viral encephalitis such as herpes simplex virus (HSV) and Varicella zoster virus (VZV): MR imaging and CSF PCR for viral DNA.\n\n6) Neurosyphilis: CSF WBC count of 20 cells/μL or greater and a reactive CSF venereal disease research laboratory test.\n\n7) Cerebrovascular diseases: MR imaging.\n\n\n\nIn patients admitted with neurologic symptoms, paired plasma and CSF samples were collected for HIV-1 RNA estimation as a standard of care at all 3 hospitals. HIV RNA was measured by real-time PCR [NucliSENS Easy Q real-time nucleic acid sequence based amplification (NASBA); BioMérieux, France, detection limit -20 to 10,000,000 copies/ml]. Patients presenting with neurologic symptoms were further classified into those with complete plasma viral suppression (PVL <20 copies/mL) and those with low-level viremia (LLV; PVL: 20–1000 copies/mL) as per their latest plasma VL values. CSF/Plasma HIV-1 RNA discordance was defined as either detectable CSF HIV RNA (CSF VL > 20 copies/mL) with an undetectable plasma RNA (plasma VL ≤20 copies/mL) or CSF HIV RNA ≥ 0.5 log10 higher than plasma RNA when plasma VL was between 20 and 1000 copies/mL.[14] In a subset of patients with discordance, CSF HIV-1 genotypic resistance testing was performed. Protease, reverse transcriptase (RT), and integrase genes were sequenced using an automated population-based full sequence analyser (ABI 3130 Genetic Analyser; PE Applied Biosystems, minimum detection limit for successful sequencing - 1000 copies/mL). Resistance testing was not attempted in the plasma virus in view of low VL and cost constraints. Effectiveness of ART in CNS was determined by applying the revised CNS penetration effectiveness score 2010 to current suppressive ART regimen.[20] CPE score was calculated by assigning a predefined number of points to each component of ART regimen. Among neurologically symptomatic individuals, those showing CSF/Plasma HIV-1 RNA discordance were taken as cases and the rest were controls.\n\n2.4 Statistical methods\nBaseline characteristics for continuous variables were summarized using median and interquartile range (IQR), and for noncontinuous variables using frequency and percentages. Continuous variables were compared using a median test. Categorical variables were compared using Chi-square test and Fishers exact test. Incidence of neurologic disease and corresponding 95% confidence intervals (CIs) were estimated. All analyses were performed using STATA version 12.1 (Statacorp LLC, Texas).\n\n3 Results\nOne thousand five hundred eighty-four virologically suppressed HIV-1 infected adults (35.7% females) with 7139.17 person-years of follow-up on suppressive ART were included in the study (Fig. 1). Median age was 39 years (IQR = 33.0, 46.0), median pre-ART CD4 count was 174.5 (IQR = 83.0–257.0) cells/mm3, and median nadir CD4 count was 156 (IQR = 75.0–241.0) cells/mm3. About 31.9% patients had a history of TB before starting ART. A total of 133 neurologic conditions were reported in 107 (6.8%) patients before starting ART. The most commonly reported baseline neurologic conditions were CNS TB (42/107), HIV encephalopathy (24/107), Cryptococcal meningitis (20/107), CNS toxoplasmosis (21/107), and PML (6/107). Median duration of follow-up since HIV diagnosis was 62 (IQR = 36.0–90.0) months, median duration of ART was 56 (IQR = 32.0–84.0) months, and median duration of viral suppression was 50 (IQR = 26.0–74.0) months. Non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing [2 nucleoside reverse transcriptase inhibitors (NRTIs) and 1 NNRTI] and protease inhibitor (PI)-containing regimens (2 NRTIs and 1 ritonavir-boosted (PI) or 1 boosted PI with integrase inhibitor) were prescribed to 1218 (76.9%) and 360 (22.7%) patients, respectively. Tenofovir with either Emtricitabine or Lamivudine was the most commonly used NRTI backbone. Efavirenz was the most common NNRTI and ritonavir-boosted Atazanavir (ATV/r) the most common PI used in our cohort. One thousand four hundred forty of 1584 (90.9%) patients had complete viral suppression, while 144 of 1584 (9.1%) had LLV at the time of latest plasma VL estimation. Seventy-eight of 1218 (6.4%) and 66 of 360 (18.3%) patients on NNRTI and PI-based therapy had LLV, respectively. Median CPE score of ART regimen was 6 (IQR = 6.0–7.0). Two percent patients were on ART regimens with CPE <6.\n\nFigure 1 Flow chart depicting identification of individuals with neurosymptomatic CSF/Plasma HIV-1 RNA discordance in Pune cohort. CSF = cerebrospinal fluid.\n\n3.1 Incident neurological symptoms\nOf the 1584 virologically suppressed individuals, 71 (4.4%) patients had neurologic symptoms during follow-up and required inpatient care (Fig. 1). Fifty-five of 71 (77.5%) patients were diagnosed to have an incident neurologic disease [7.71 (95% CI): 5.920–10.043] episodes per 1000 person-years]. HIV encephalopathy (HIV-E), CNS TB, and cerebrovascular disease (ischemic stroke or intracranial hemorrhage) were the most common incident neurologic diseases (Fig. 2). On basis of clinical findings, biochemical investigations, neuroimaging, and CSF studies, there was no significant neurologic diagnosis in 16 patients. About 71.8% patients with incident neurologic symptoms had complete viral suppression, while 28.2% had LLV.\n\nFigure 2 Incident neurologic disease (n = 55). Cerebrovascular disease includes clinical conditions such as ischemic stroke, hemorrhagic stroke, and intracranial bleed. Metabolic encephalopathy includes clinical conditions such as hepatic encephalopathy, uremic encephalopathy, septic encephalopathy, and hyponatremic encephalopathy. X axis – Neurologic diagnosis. Y axis – Total number of patients. HIV-E = HIV encephalopathy, NHL = non-Hodgkin lymphoma.\n\n3.2 CSF/plasma HIV-1 RNA discordance\nTwenty of 71 (28.2%) patients with neurologic symptoms had CSF/Plasma HIV-1 RNA discordance (12 men and 8 women). Demographic data of patients with and without discordance have been elucidated in Table 1. Imbalance during walking, forgetfulness, and tremor of hands were the most common presenting symptoms of patients presenting with discordance. Twelve of 20 (60%) had subacute onset of symptoms. Eight of 20 (40%) patients presented with acute symptoms such as seizures or altered level of consciousness. Median duration of follow-up since HIV diagnosis in patients with discordance was 74 (IQR: 37.0–109.0) months, median duration of ART was 73 (IQR: 31.0–108.0) months, and median duration of viral suppression was 25 (IQR: 19.0–38.0) months. Except for 1 case, all individuals with CSF/plasma HIV discordance were on PI-containing ART. Median nadir CD4 count and median CD4 count at the time of discordance was 54.5 (IQR: 29.0–102.3) cells/mm3 and 352 (IQR: 200.3–505.8) cells/mm3, respectively. Median plasma and CSF VL in patients with CSF/plasma HIV discordance was 120 (IQR: <20 to 332.5) and 4250 (IQR: 2550.0–9615.0) copies/mL, respectively (Table 2). Abnormal CSF studies (high CSF protein, abnormal CSF glucose, or lymphocytic pleocytosis) were found in 18 of 20 (95.0%) patients. Median CSF protein was 97.5 mg/dL (IQR: 80.25–107.75), median CSF sugar was 54 mg/dL (IQR: 45.75–56.50), and median CSF cell count was 18 cells/mm3 (IQR: 10.0–35.0). Most common MRI findings in patients with CSF/plasma HIV discordance were generalized cerebral atrophy and asymmetrical, nonenhancing periventricular white matter hyperintensities on T2 and FLAIR images. Three patients had HIV-related meningoencephalitis on MRI. CSF samples from 11 of 20 (55%) patients underwent sequencing for the detection of HIV-1 resistance-associated mutations (RAMs). Two samples could not be amplified. All 9 samples tested showed RAMs that reduced efficacy of 1 or more antiretroviral drugs from current ART regimen. The most common CSF mutation in RT gene was M184 V/I, which was seen in all 9 samples. Thymidine analog mutations (TAMs) were present in 7 cases (77.78%), most commonly T215Y/V/F, K219E/Q, or D67N/T (Table 2). The most common NNRTI mutations were Y181C and K103N/S, which were present in 5 samples each. The most common major PI mutations were V82A and I50L, which were present in 2 patients each.[21,22] One sample showed presence of N155H mutation in the integrase gene.[22] Triple class resistance (resistance to NRTI, NNRTI, and PI drugs) was seen in 5 (55.6%) CSF samples (patient number 5, 6, 10, 11, and 16, Table 2). In the remaining 4 samples (patient number 3, 12, 17, and 20, Table 2), NRTI and NNRTI resistance was seen in CNS virus. All cases of discordance were seen in patients presenting with HIV-E. There was no case of secondary CSF escape, defined as discordant CSF and plasma HIV-1 RNA levels in the context of a new infection, in our cohort.\n\nTable 1 Factors associated with neurosymptomatic CSF/plasma HIV-1 RNA discordance.\n\nTable 2 CD4+-T-cell counts, plasma, and CSF HIV-1 viral loads in individuals with CSF/Plasma HIV-1 RNA discordance.\n\n3.3 Factors associated with neurosymptomatic CSF plasma HIV-1 RNA discordance\nResults presented in Table 1 summarize that neurosymptomatic CSF/plasma HIV-1 RNA discordance was not associated with age, gender, presence of baseline TB, baseline brain disease, nadir CD4 count, and duration of ART regimen. Prevalence of CSF/plasma HIV-1 RNA discordance was higher among neurologically symptomatic patients with plasma LLV than those with complete viral suppression (70% vs 11.8%, P < .001). The risk of neurosymptomatic CSF/plasma HIV-1 discordance was greater in patients who received PI-containing ART (P < .001). Individuals who took ART regimens with CPE values <6 were more likely to develop discordance (P = .006).\n\n4 Discussion\nThis study reports prevalence of neurosymptomatic CSF/Plasma HIV-1 RNA discordance in virologically suppressed adults in western India. Incident neurologic deterioration requiring hospitalization was an uncommon but significant event in our patients on virologically suppressive ART. Of the 71 patients who developed neurologic symptoms during the period of observation, 20 (28.2%) had CSF/Plasma HIV-1 RNA discordance.\n\n4.1 CSF/plasma HIV-1 RNA discordance\nThis entity also known as CSF HIV escape was first described by Canestri et al,[11] followed by a second case series by Peluso et al.[13] Recently, cases of CSF/Plasma HIV-1 discordance have been described by Nightingale et al[15] and Mukerji et al[16] In addition, there have been multiple individual case reports[6,7,23–29] of CSF/Plasma HIV-1 discordance. To the best of our knowledge, our study is one of the first reports of a large number of neurosymptomatic CSF/plasma HIV-1 discordance cases from a resource-limited setting. As compared to the reported case series,[11,13] we have described episodes of discordance as a part of incident neurologic disease, developing in patients on suppressive ART. Published case reports of symptomatic CSF/plasma HIV discordance described patients taking PI monotherapy or ART regimens, which are no longer recommended.[11,27–29] In our series, all cases of CSF/plasma HIV-1 discordance occurred among patients taking WHO-recommended triple-drug NNRTI or PI-containing regimens.[19] In our case series, we have studied CSF/plasma HIV-1 discordance in patients with plasma VL <1000 copies/mL (LLV or complete viral suppression), while other studies have included patients with complete viral suppression, plasma LLV, and high-level viremia (plasma VL >1000 copies/mL).[15,16]\n\nMechanisms of CSF/plasma HIV discordance remain poorly defined. One hypothesis suggests that discordance can be seen in individuals who fail to show durable viral suppression on ART. In such individuals, drug-resistant plasma HIV secondarily infects the CNS and subsequent replication of CNS HIV leads to discordance.[30] Another hypothesis is that more advanced immune suppression (as estimated by a low nadir CD4+ T-cell count) eases HIV entry into the CNS. In the CNS, HIV productively replicates within perivascular macrophages and microglia (M tropic HIV). The administration of ART drugs that reach higher concentrations in the CNS better suppress viral replication in these cells, although integrated provirus persists. Suboptimal adherence to ART or switch to drugs with lower distribution into the CNS allows the neurologic reservoir of HIV to replicate at low levels. Suboptimal CNS penetration of ART and multidrug-resistant CNS HIV leads to compartmentalized infection, which manifests in its severest form as HIV encephalopathy.[30,31] However, in our study, we did not find an association between nadir CD4 count and neurosymptomatic CSF/plasma HIV-1 discordance (P = .47).\n\n4.2 Presence of plasma LLV and CSF/Plasma HIV-1 RNA discordance\nOur results showed a higher prevalence of CSF/plasma HIV-1 RNA discordance among neurologically symptomatic patients with plasma LLV as compared with those with complete viral suppression (70% vs 11.8%, P < .001). This finding was also seen in a study conducted by Nightingale et al[15] and could signify suboptimal suppression in both plasma and CSF. Intermittent or persistent plasma LLV occurs in up to a quarter of ART-treated patients.[32] Persistent plasma LLV between 50 and 999 copies/mL is associated with an increased risk of virologic failure.[33] Accumulation of resistance mutations during LLV[34] may increase risk of neurovirulence. Definition of virologic suppression used for patients in our cohort[19] is different from that used in resource rich settings[35] (plasma VL < 1000 copies/mL as compared with plasma VL < 200 copies/mL). This leads to a higher prevalence of plasma LLV in our cohort, especially among patients on PI-based therapy (18.3% vs 6.4% in patients on NNRTI-based therapy, P < .001). Plasma LLV does not warrant optimization of ART in India as it does in resource-rich settings. This could be the reason for higher prevalence of CSF/Plasma HIV-1 RNA discordance seen in our cohort compared with earlier studies (28.2% vs 12–21%).[14,15] The treatment options for individuals with plasma LLV and neurosymptomatic CSF/plasma HIV-1 discordance must include strict adherence to ART to prevent plasma and CSF blips, complete suppression of plasma VL by changing ART regimen as per resistance testing report, and use of regimens with better CNS penetrability (CPE score of ≥6), in order to prevent loss of neurocognitive functions.\n\n4.3 ART regimen and CSF/Plasma HIV-1 RNA discordance\nUse of PI-based ART was associated with increased prevalence of neurosymptomatic CSF/Plasma HIV-1 discordance. In the present study, except for 1 case, all individuals with CSF/plasma HIV-1 discordance were on PI-containing ART. Out of 360 individuals who were on PI-based ART in our cohort, 19 (5.27%) developed neurosymptomatic CSF/Plasma HIV-1 discordance. Out of 43 patients who developed incident neurologic symptoms on PI-based ART, 19 (44.2%) had CSF/Plasma HIV-1 discordance (Table 1). As per the ART guidelines of WHO and Indian National AIDS Control Organization (NACO),[36] PI-containing regimens (2 NRTI and 1 boosted PI or 1 boosted PI with 1 integrase inhibitor) are recommended as second-line treatment of HIV infected adults when NNRTI regimens (2NRTIs and 1 NNRTI) fail to suppress plasma VL. ATV/r is the preferred PI used in India, while boosted darunavir is preferred in resource-rich settings.[35] ATV/r has subtherapeutic concentrations in CSF in a substantial proportion of adults and, accordingly, a low CPE value.[37] The combination of CNS-compartmentalized HIV that may contain drug-resistant HIV archived during failed first-line therapy and subtherapeutic concentrations of ATV/r or another PI during second-line therapy could lead to functional dual or monotherapy. Among 9 patients undergoing CSF genotypic resistance testing in our cohort, 5 samples had triple-class resistance effectively leading to no active drug for viral suppression in the CNS compartment. In remaining 4 samples, NRTI and NNRTI resistance led to functional PI monotherapy in CNS compartment. Studies have shown a higher CSF HIV replication in patients taking double-boosted PI regimens, supporting possible functional monotherapy in the CNS.[38] As PIs are substrates for drug efflux transporters that are expressed on brain microvascular endothelial cells and ependymal cells of choroid plexus, their concentrations in CNS can be subtherapeutic.[39] These results supports the inference that shifting to a PI such as darunavir that has better CNS penetration than atazanavir[40] and superior efficacy against triple-class resistant virus than lopinavir[41] may reduce the risk of CSF/plasma HIV-1 RNA discordance.\n\n4.4 CPE score and CSF/Plasma HIV-1 RNA discordance\nThe CPE method attempts to estimate the efficacy of ART drugs in the CNS. In cohort studies, higher CPE values, indicating better estimated efficacy of an ART regimen in the CNS, correlate with lower CSF HIV RNA.[42] Evidence linking use of neuroactive ART regimens (regimens with higher CPE score) with improvement in cognitive performance,[43–45] lower incidence of CSF/Plasma HIV-1 discordance,[14,15] and prevention of multidrug-resistant CNS HIV[46,47] has been mixed. However, our results show that using ART regimens with better CPE values (≥6) were beneficial, being associated with a lower prevalence of neurosymptomatic CSF/plasma HIV-1 discordance. As per the Mind Exchange Consensus Report, patients presenting with worsening cognitive impairment and detectable CSF HIV should consider modifying their ART regimen as per the CPE method provided other risk factors (e.g., poor adherence to medication, virologic drug resistance, and comorbidities) have been addressed.[48] An “adjusted” CPE score has been proposed as a more relevant score in CSF/plasma HIV-1 discordance, as it takes into account resistance profiles for the calculation of CNS ART effectiveness.[13] All 9 cases with genotyping from CSF isolates had mutations that would result in resistance to at least 1 prescribed ART drug, resulting in a lower “adjusted” CPE score.\n\nOur study has several limitations. First, as for all retrospective studies, some episodes of incident neurologic disease may be unreported leading to measurement bias and underestimation of prevalence of CSF discordance. Second, milder neurologic symptoms such as headache may not have triggered LP and measurement of CSF HIV-1 RNA, leading to unaccounted cases of mildly symptomatic CSF discordance. Third, neuropsychological testing for cognitive impairment was not performed at baseline or follow-up in our cohort and hence milder forms of HIV-associated neurocognitive disease[49] could not be identified and CSF discordance in these patients could not be studied. Screening for functional impairment[48] and mood disorders[50] was not performed as well. Fourth, patients were classified into LLV and complete viral suppression on the basis of latest plasma VL record. Longitudinal analysis of VLs to identify patients with intermittent LLV, persistent LLV, and durable suppression was not done. Some patients with intermittent LLV could have been classified as complete viral suppression as a result. Fifth, genotypic HIV-1 resistance testing of CNS virus was not performed for all patients with CSF/plasma HIV-1 discordance. In spite of these limitations, our cases of neurosymptomatic CSF/plasma HIV-1 RNA discordance clearly demonstrate that HIV persistence in the brain remains a concern among patients on virologically suppressive ART in India.\n\n5 Conclusion\nCSF/plasma HIV-1 RNA discordance remains understudied in low-income settings such as India despite a substantial HIV burden. Identification of these cases in our cohort will help bridge that gap and add to the growing body of literature on this uncommon but increasingly significant topic. These cases clearly illustrate that physicians in resource-limited settings such as India should perform CSF HIV-1 VL analysis in patients who develop neurologic symptoms while on PI-based ART with well-controlled plasma HIV. Association of CSF/plasma HIV-1 discordance with use of PI-containing ART and ART regimens with CPE score <6 should prompt use of newer PIs such as ritonavir-boosted darunavir and integrase inhibitors that have limited availability in resource-limited settings such as India. Higher prevalence of CSF/plasma HIV-1 RNA discordance among neurologically symptomatic patients with plasma LLV further strengthens the case for maintaining complete viral suppression on ART.\n\nAbbreviations: CNS = central nervous system, CSF = cerebrospinal fluid, HIV-E = HIV encephalopathy, NNRTI = nonnucleoside reverse transcriptase inhibitor, NRTI = nucleoside reverse transcriptase inhibitor, PI = protease inhibitor, PVL = plasma viral load, RNA = Ribonucleic acid.\n\nAuthorship: Manisha Ghate [National AIDS research institute (NARI), Pune, India] edited the manuscript for nonintellectual content.\n\nThe approval for the study was obtained from the Ethics Committees of Ruby Hall Clinic, Poona Hospital, and Noble Hospital, Pune, India.\n\nDr Ameet Dravid received payment from Cipla, Hetero, Emcure, Merck Sharpe, and Dome (MSD) and Aurobindo pharmaceuticals for educational presentation and travel expenses and payment from Mylan for board membership on scientific advisory board. 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Ann Neurol \n2010 ;67 :699 –714 .20517932 \n[32] Doyle T Geretti AM \nLow-level viraemia on HAART: significance and management . Curr Opin Infect Dis \n2012 ;25 :17 –25 .22156900 \n[33] Laprise C de Pokomandy A Baril JG \nVirologic failure following persistent low-level viremia in a cohort of HIV-positive patients: results from 12 years of observation . Clin Infect Dis \n2013 ;57 :1489 –96 .23946221 \n[34] Mackie NE Phillips AN Kaye S \nAntiretroviral drug resistance in HIV-1-infected patients with low-level viremia . J Infect Dis \n2010 ;201 :1303 –7 .20350161 \n[35] Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 15, 2016 .\n[36] National AIDS Control Organization (NACO), Ministry of Health and Family Welfare, Government of India, Policy and guidelines. National Guidelines on Second-line and Alternative First-line ART for Adults and Adolescents. May 2013. Available at: www.naco.gov.in/documents/policy-guidelines. Accessed December 15, 2016 .\n[37] Best BM Letendre SL Brigid E \nLow atazanavir concentrations in cerebrospinal fluid . AIDS \n2009 ;23 :83 –7 .19050389 \n[38] Donath M Wolf T Stürmer M \nHIV-1 replication in central nervous system increases over time on only protease inhibitor therapy . Med Microbiol Immunol \n2016 ;205 :575 –83 .27469377 \n[39] Kim RB Fromm MF Wandel C \nThe drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors . J Clin Invest \n1998 ;101 :289 –94 .9435299 \n[40] Calcagno A Simiele M Alberione MC \nCerebrospinal fluid inhibitory quotients of antiretroviral drugs in HIV infected patients are associated with compartmental viral control . Clin Infect Dis \n2015 ;60 :311 –7 .25281609 \n[41] Deeks ED \nDarunavir: a review of its use in the management of HIV-1 infection . Drugs \n2014 ;74 :99 –125 .24338166 \n[42] Letendre S Marquie-Beck J Capparelli E \nValidation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system . Arch Neurol \n2008 ;65 :65 –70 .18195140 \n[43] Garvey L Winston A Walsh J \nAntiretroviral therapy CNS penetration and HIV-1–associated CNS disease . Neurology \n2011 ;76 :693 –700 .21339496 \n[44] Ellis RJ Letendre S Vaida F \nRandomized trial of central nervous system-targeted antiretrovirals for HIV-associated neurocognitive disorder . Clin Infect Dis \n2014 ;58 :1015 –22 .24352352 \n[45] Vassallo M Durant J Biscay V \nCan high central nervous system penetrating antiretroviral regimens protect against the onset of HIV-associated neurocognitive disorders? \nAIDS \n2014 ;28 :493 –501 .24472743 \n[46] Antinori A Perno CF Giancola ML \nEfficacy of cerebrospinal fluid (CSF)-penetrating antiretroviral drugs against HIV in the neurological compartment: different patterns of phenotypic resistance in CSF and plasma . Clin Infect Dis \n2005 ;41 :1787 –93 .16288405 \n[47] Vissers M Stelma FF Koopmans PP \nCould differential virological characteristics account for ongoing viral replication and insidious damage of the brain during HIV 1 infection of the central nervous system? \nJ Clin Virol \n2010 ;49 :231 –8 .20833583 \n[48] Mind Exchange Working Group . Assessment, diagnosis, and treatment of HIV-associated neurocognitive disorder: a consensus report of the mind exchange program . Clin Infect DisV 56 \n2013 ;1004 –17 .\n[49] Antinori A Arendt G Becker JT \nUpdated research nosology for HIV-associated neurocognitive disorders . Neurology \n2007 ;69 :1789 –99 .17914061 \n[50] Savard J Laberge B Gauthier JG \nScreening clinical depression in HIV-seropositive patients using the Hospital Anxiety and Depression Scale . AIDS Behav \n1999 ;3 :167 –75 .\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "97(8)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D002493:Central Nervous System Diseases; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D007194:India; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D012367:RNA, Viral; D012189:Retrospective Studies; D019562:Viral Load; D014766:Viremia",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e9969",
"pmc": null,
"pmid": "29465595",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article",
"references": "22156215;26713503;17914061;27295036;27469377;21998185;9435299;23946221;22522289;22551810;24338166;25281609;18195140;20100092;20833583;21658774;19424052;25096495;10669367;16218168;16288405;21504362;22614889;14523776;20350161;23344463;25316020;20516524;21339496;24472743;19050389;10997399;10880317;25860317;24352352;23737348;23175555;21135382;27194435;20517932;19564723;21050119;25156113;15731227;28328546;22156900",
"title": "Discordant CSF/plasma HIV-1 RNA in individuals on virologically suppressive antiretroviral therapy in Western India.",
"title_normalized": "discordant csf plasma hiv 1 rna in individuals on virologically suppressive antiretroviral therapy in western india"
} | [
{
"companynumb": "IN-GLAXOSMITHKLINE-IN2018056700",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE"
},
"drug... |
{
"abstract": "The use of short-acting agents, such as clonidine, for hypertensive urgency has been shown to worsen outcomes and, therefore, should be avoided in the office.\n\n\n\nThe primary objective was to achieve decreased rates of clonidine orders for immediate treatment of asymptomatic hypertension in the office. The secondary objective was to determine if reduced use leads to a decline in poor outcomes.\n\n\n\nThis was an observational cohort study evaluating a protocol and algorithm developed by clinical pharmacists on the appropriate management of hypertensive urgencies. The protocol included the provision of avoiding short-acting antihypertensives (ie, clonidine). Preintervention and postintervention reports were generated to determine the number of times clonidine was ordered in the office. Electronic health charts were also reviewed for documentation of poor outcomes related to clonidine administration within 1 week of the hypertensive urgency visit date.\n\n\n\nIn the preintervention cohort, 106 (17.4%) orders of clonidine were captured compared with 73 (10.6%) in the postintervention group (P = 0.001). Of the patients who were administered clonidine, 7 patients in the preintervention group were advised to go to the emergency department (ED) for additional hypertensive management, 2 of whom were subsequently hospitalized; 9 patients were advised to go to the ED in the postintervention group, and no patient was subsequently hospitalized. No adverse effects were documented from in-office clonidine administration in either cohort of patients.\n\n\n\nThe hypertensive urgency protocol and education reduced the number of clonidine orders and hospital admissions. The increase in ED referrals needs further assessment.",
"affiliations": "St John's University College of Pharmacy and Health Sciences, Queens, NY, USA Institute for Family Health, New York, NY, USA chimc@stjohns.edu.;Minneapolis VA Health Care System, Minneapolis, MN, USA.;St John's University College of Pharmacy and Health Sciences, Queens, NY, USA Institute for Family Health, New York, NY, USA.",
"authors": "Chim|Christine|C|;Dimitropoulos|Erica|E|;Ginzburg|Regina|R|",
"chemical_list": "D000959:Antihypertensive Agents; D003000:Clonidine",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028016644756",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "50(7)",
"journal": "The Annals of pharmacotherapy",
"keywords": "disease management; hypertension; medication safety; quality assurance; α-adrenergic blockers",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000465:Algorithms; D000959:Antihypertensive Agents; D003000:Clonidine; D015331:Cohort Studies; D004363:Drug Utilization; D004632:Emergency Medical Services; D004638:Emergency Treatment; D005260:Female; D019983:Guideline Adherence; D006760:Hospitalization; D006801:Humans; D006973:Hypertension; D008297:Male; D011050:Policy Making; D017410:Practice Guidelines as Topic",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "548-54",
"pmc": null,
"pmid": "27083919",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Implementing a Policy and Protocol on Managing Patients With Hypertensive Urgencies.",
"title_normalized": "implementing a policy and protocol on managing patients with hypertensive urgencies"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-52063BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONIDINE HYDROCHLORIDE"
... |
{
"abstract": "Long-acting injectable (LAI)antipsychotics are often used in psychosis to assist with medication compliance and relapse prevention, although the weight gain and metabolic effects in young people are yet to be examined. This study examined the long-term effects of aripiprazole and paliperidone in LAI formulation on weight gain and metabolic parameters in young people with early episode psychosis.\n\n\n\nWeight gain and other metabolic effects of aripiprazole and paliperidone in LAI formulation were examined in 59 young people with early episode psychosis over a 12-month period. Changes in outcome measurements were examined at baseline and 3 monthly intervals.\n\n\n\nThe results showed that both aripiprazole and paliperidone were associated with time-dependent increases in weight. At 12 months, weight increased by an average of 7% (6 kg) with both aripiprazole and paliperidone relative to the baseline, and the percentage of overweight or obese people increased from 33% to 60%. There was no advantage of aripiprazole compared to paliperidone with regards to weight change, although aripiprazole was associated with lower triglycerides and prolactin levels.\n\n\n\nBoth LAI medications were associated with substantial weight increases over time. These results build on emerging evidence showing that aripiprazole is not weight neutral in young people. Our recommendation is that weight-management programs should be offered from the start of medication initiation.",
"affiliations": "Black Swan Health, headspace Early Psychosis, Perth, Western Australia, Australia.;Black Swan Health, Perth, Western Australia, Australia.;Black Swan Health, headspace Early Psychosis, Perth, Western Australia, Australia.;Black Swan Health, headspace Early Psychosis, Perth, Western Australia, Australia.;Black Swan Health, headspace Early Psychosis, Perth, Western Australia, Australia.;Black Swan Health, headspace Early Psychosis, Perth, Western Australia, Australia.;Black Swan Health, headspace Early Psychosis, Perth, Western Australia, Australia.;Black Swan Health, headspace Early Psychosis, Perth, Western Australia, Australia.",
"authors": "Shymko|Gordon|G|;Grace|Terina|T|;Jolly|Nicole|N|;Dobson|Louise|L|;Hacking|Daniel|D|;Parmar|Arti|A|;Kapi|Puanna|P|;Waters|Flavie|F|0000-0001-5570-2040",
"chemical_list": "D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D000068180:Aripiprazole; D000068882:Paliperidone Palmitate",
"country": "Australia",
"delete": false,
"doi": "10.1111/eip.13013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1751-7885",
"issue": "15(4)",
"journal": "Early intervention in psychiatry",
"keywords": "Second generation antipsychotic medication; adolescents; weight gain; youth mental health",
"medline_ta": "Early Interv Psychiatry",
"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D003692:Delayed-Action Preparations; D006801:Humans; D000068882:Paliperidone Palmitate; D011618:Psychotic Disorders; D012559:Schizophrenia; D015430:Weight Gain",
"nlm_unique_id": "101320027",
"other_id": null,
"pages": "787-793",
"pmc": null,
"pmid": "32715655",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Weight gain and metabolic screening in young people with early psychosis on long acting injectable antipsychotic medication (aripiprazole vs paliperidone).",
"title_normalized": "weight gain and metabolic screening in young people with early psychosis on long acting injectable antipsychotic medication aripiprazole vs paliperidone"
} | [
{
"companynumb": "AU-OTSUKA-2020_018758",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nRespiratory syncytial virus (RSV) causes serious respiratory tract infections in lung transplant (LTx) recipients, is associated with development of bronchiolitis obliterans syndrome, and has no proven effective therapy. We evaluated the efficacy, safety, and cost-effectiveness of oral ribavirin for the treatment of RSV infection after LTx.\n\n\nMETHODS\nBetween December 2011 and May 2014, 52 LTx recipients developed 56 episodes of symptomatic RSV infection, which was diagnosed by positive RSV polymerase chain reaction on nasopharyngeal swabs. An intravenous (IV) loading dose of ribavirin (33 mg/kg) was given in 52 of 56 episodes; an equivalent oral loading dose was given in 2 episodes. Oral ribavirin (20 mg/kg/day) was given by day 2 in 53 of 56 episodes. Median duration of therapy was 8 days (range 6-31 days).\n\n\nRESULTS\nMean forced expiratory volume in 1 sec decreased from 2.38 ± 0.78 liters to 2.07 ± 0.85 liters (p < 0.001) at presentation, recovered to 2.26 ± 0.82 liters at cessation of ribavirin, and was maintained at 2.31 ± 0.81 liters within 3 months. New-onset bronchiolitis obliterans syndrome developed in 1 of 38 patients (2.6%) at 3 months. Anemia worsened in 23 episodes, and de novo anemia developed in 5 episodes. Mean hemoglobin decreased from 118 ± 16 g/liter to 113 ± 21 g/liter (p = 0.015). There were 4 late deaths. Compared with IV therapy, mean drug cost saving was US $6,035 per episode, and mean inpatient bed days was reduced by 6.7 days (p < 0.001).\n\n\nCONCLUSIONS\nTo our knowledge, we report the largest series of LTx recipients treated with oral ribavirin for RSV. Oral ribavirin appears to be an effective, well-tolerated alternative to IV or inhaled ribavirin; provides considerable cost savings and reduces length of hospital stay. Potential long-term benefits in preventing development of chronic lung allograft dysfunction are yet to be determined.",
"affiliations": "Department of Pharmacy; Lung Transplant Unit. Electronic address: fay.burrows@svha.org.au.;Department of Pharmacy; Lung Transplant Unit.;Lung Transplant Unit.;Department of Microbiology and Clinical Infectious Diseases, St. Vincent's Hospital, Sydney, New South Wales, Australia.;Lung Transplant Unit.;Lung Transplant Unit.;Lung Transplant Unit.;Lung Transplant Unit.",
"authors": "Burrows|Fay S|FS|;Carlos|Lilibeth M|LM|;Benzimra|Mark|M|;Marriott|Deborah J E|DJ|;Havryk|Adrian P|AP|;Plit|Marshall L|ML|;Malouf|Monique A|MA|;Glanville|Allan R|AR|",
"chemical_list": "D000998:Antiviral Agents; D012254:Ribavirin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-2498",
"issue": "34(7)",
"journal": "The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation",
"keywords": "CLAD; Lung transplantation; RSV; ribavirin",
"medline_ta": "J Heart Lung Transplant",
"mesh_terms": "D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D003362:Cost-Benefit Analysis; D016527:Drug Costs; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D018357:Respiratory Syncytial Virus Infections; D012189:Retrospective Studies; D012254:Ribavirin; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9102703",
"other_id": null,
"pages": "958-62",
"pmc": null,
"pmid": "25753833",
"pubdate": "2015-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Oral ribavirin for respiratory syncytial virus infection after lung transplantation: Efficacy and cost-efficiency.",
"title_normalized": "oral ribavirin for respiratory syncytial virus infection after lung transplantation efficacy and cost efficiency"
} | [
{
"companynumb": "AU-ROCHE-1220390",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "We present a case of a pediatric patient who developed recurarization after a cardiac catheterization procedure. Intraoperative neuromuscular blockade was achieved with 2 doses of rocuronium, and the blockade was reversed with a bolus dose of sugammadex at the end of the procedure. While recovering in the pediatric cardiac intensive care unit, the patient developed respiratory failure and a decline in the train-of-four response. The patient fully recovered after receiving a second dose of sugammadex.",
"affiliations": "From the Department of Anesthesiology, Division of Pediatric Cardiac Anesthesiology, Ochsner Clinic, New Orleans, Louisiana.",
"authors": "Carollo|Dominic S|DS|;White|William M|WM|",
"chemical_list": "D000077122:Sugammadex; D000077123:Rocuronium",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000001023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "13(6)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D055191:Delayed Emergence from Anesthesia; D005260:Female; D006801:Humans; D007223:Infant; D019148:Neuromuscular Blockade; D011184:Postoperative Period; D012131:Respiratory Insufficiency; D000077123:Rocuronium; D000077122:Sugammadex",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "204-205",
"pmc": null,
"pmid": "30985317",
"pubdate": "2019-09-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Postoperative Recurarization in a Pediatric Patient After Sugammadex Reversal of Rocuronium-Induced Neuromuscular Blockade: A Case Report.",
"title_normalized": "postoperative recurarization in a pediatric patient after sugammadex reversal of rocuronium induced neuromuscular blockade a case report"
} | [
{
"companynumb": "US-TEVA-2021-US-1874797",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SEVOFLURANE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nA painful maxillary sinus metastasis in previously irradiated tissue required palliation.\n\n\nMETHODS\nLesion was treated by computed tomography-guided palladium103 implantation as an outpatient procedure; the lesion and its attendant facial pain and swelling resolved completely.\n\n\nCONCLUSIONS\nComputed tomography-guided permanent seed brachytherapy is a novel, rapid, effective, and low resource cost method of treating paranasal malignancy.",
"affiliations": "Radiation Oncology, Mission Regional Medical Center, Mission Viejo, California. Electronic address: drdoggett@nocancer.com.;Thoracic Surgery, Mission Regional Medical Center, Mission Viejo, California.;Interventional Radiology, Mission Regional Medical Center, Mission Viejo, California.;Interventional Radiology, Mission Regional Medical Center, Mission Viejo, California.",
"authors": "Doggett|Stephen|S|;Chino|Shigeru|S|;Lempert|Todd|T|;Sidhar|Kunal|K|",
"chemical_list": "D011868:Radioisotopes; D010165:Palladium; C000615531:Palladium-103",
"country": "United States",
"delete": false,
"doi": "10.1016/j.prro.2018.01.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1879-8500",
"issue": "8(4)",
"journal": "Practical radiation oncology",
"keywords": null,
"medline_ta": "Pract Radiat Oncol",
"mesh_terms": "D001918:Brachytherapy; D005145:Face; D005260:Female; D006801:Humans; D008875:Middle Aged; D010165:Palladium; D010255:Paranasal Sinus Neoplasms; D011868:Radioisotopes; D011879:Radiotherapy Dosage; D061089:Radiotherapy, Image-Guided; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101558279",
"other_id": null,
"pages": "e221-e223",
"pmc": null,
"pmid": "29778742",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of paranasal sinus metastasis by percutaneous CT-guided permanent seed brachytherapy.",
"title_normalized": "management of paranasal sinus metastasis by percutaneous ct guided permanent seed brachytherapy"
} | [
{
"companynumb": "US-009507513-1807USA002009",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of a 25-year-old pregnant woman diagnosed with a large, unresectable retroperitoneal synovial sarcoma. Successful neoadjuvant treatment with doxorubicin plus ifosfamide prepartum and continuing postpartum resulted in significant disease response allowing for later tumor resection. Following the first prepartum chemotherapy cycle, a decreased amniotic fluid index was noted, representing a potential complication of chemotherapy. Induction of labor was performed at 33 weeks gestation with excellent outcome in the newborn. This case highlights the complex medical decision-making process in the setting of cancer diagnosed during pregnancy, balancing oncologic and obstetric concerns, and to our knowledge is only the second reported case of synovial sarcoma treated with neoadjuvant cytotoxic chemotherapy in the antepartum period.",
"affiliations": "Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.;Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.;Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.;Department of Pathology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.;Diagnostic Imaging, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.;Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.;Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.",
"authors": "Sipe|Bradley H|BH|;Običan|Sarah G|SG|;Henderson-Jackson|Evita|E|;Riddle|Nicole D|ND|https://orcid.org/0000-0001-5315-2874;Makanji|Rikesh|R|;Gonzalez|Ricardo J|RJ|;Brohl|Andrew S|AS|https://orcid.org/0000-0002-0071-0534",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/9982171",
"fulltext": "\n==== Front\nCase Rep Oncol Med\nCase Rep Oncol Med\nCRIONM\nCase Reports in Oncological Medicine\n2090-6706\n2090-6714\nHindawi\n\n10.1155/2021/9982171\nCase Report\nA Case of Retroperitoneal Synovial Sarcoma in Pregnancy Treated with Antepartum Doxorubicin plus Ifosfamide Chemotherapy\nSipe Bradley H. 1\nObičan Sarah G. 1\nHenderson-Jackson Evita 2\nhttps://orcid.org/0000-0001-5315-2874\nRiddle Nicole D. 3 4\nMakanji Rikesh 5\nGonzalez Ricardo J. 6\nhttps://orcid.org/0000-0002-0071-0534\nBrohl Andrew S. andrew.brohl@moffitt.org\n6\n1Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA\n2Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA\n3Department of Pathology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA\n4Ruffolo, Hooper, and AssociatesTampa, Florida, USA\n5Diagnostic Imaging, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA\n6Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA\nAcademic Editor: Ossama W. Tawfik\n\n2021\n16 7 2021\n2021 99821711 4 2021\n18 6 2021\nCopyright © 2021 Bradley H. Sipe et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nWe report a case of a 25-year-old pregnant woman diagnosed with a large, unresectable retroperitoneal synovial sarcoma. Successful neoadjuvant treatment with doxorubicin plus ifosfamide prepartum and continuing postpartum resulted in significant disease response allowing for later tumor resection. Following the first prepartum chemotherapy cycle, a decreased amniotic fluid index was noted, representing a potential complication of chemotherapy. Induction of labor was performed at 33 weeks gestation with excellent outcome in the newborn. This case highlights the complex medical decision-making process in the setting of cancer diagnosed during pregnancy, balancing oncologic and obstetric concerns, and to our knowledge is only the second reported case of synovial sarcoma treated with neoadjuvant cytotoxic chemotherapy in the antepartum period.\n==== Body\n1. Case Presentation\n\nA 25-year-old G3P0202 presented at 22w3d gestation for evaluation of a newly discovered retroperitoneal mass found during workup for abdominal pain. The patient had experienced one year of ongoing, worsening abdominal pain. She had a history of two prior preterm deliveries at 36 weeks gestation but otherwise was healthy with no chronic medical conditions.\n\nMagnetic resonance imaging (MRI) evaluation revealed a 13 cm transverse by 8 cm anterior-posterior by 9 cm craniocaudal smoothly marginated mass inferior to the pancreas which encased the left renal vessels, displaced the inferior vena cava (IVC) anteriorly, and partially encased the abdominal aorta (Figure 1). A computerized tomography (CT) guided biopsy was unable to be performed due to the surrounding anatomy and gravid uterus; therefore, a laparoscopic biopsy was planned. CT of the chest was performed showing no evidence of metastatic disease. The patient was readmitted for planned laparoscopic biopsy at 27w2d gestation. She was given corticosteroids for fetal lung maturity prior to the procedure due to the increased risk of preterm birth. Continuous fetal monitoring was performed throughout the surgery and was noted to be reassuring for the gestational age.\n\nHistopathology from the retroperitoneal biopsy demonstrated high-grade spindle cells with areas of herringbone pattern and small round blue cells (Figure 2). Frequent mitoses were noted (8/HPF). Immunohistochemistry (IHC) revealed tumor cells to be CD56+, bcl-2+, weakly TLE1+, partially CD34+, and focally S100+. Cells were negative for pankeratin, CAM 5.2, EMA, CD99, SOX10, SMA, desmin, synaptophysin, SALL4, CD10, CD31, CD117, WT1, and estrogen receptor. Fluorescence in situ hybridization (FISH) was positive for SYT (SS18) gene rearrangement. While the IHC profile was not specific, the morphologic features and positive SYT rearrangement result were consistent with a diagnosis of poorly differentiated synovial sarcoma, clinically staged IIIB (T3N0M0).\n\nThe case was discussed at a multidisciplinary sarcoma tumor board in consultation with Surgical Oncology, Medical Oncology, Radiology, Pathology, Teratology, and Maternal-Fetal Medicine with decision for neoadjuvant chemotherapy with doxorubicin and ifosfamide with modified dosing during the prepartum period as described in Mir et al [1]. The patient was admitted at 29w6d for cycle 1 of chemotherapy and at that time had a repeat baseline MRI which redemonstrated the now 15.5 × 10.2 × 10.6 cm mass encasing right renal pelvis and aorta, displacing left renal vessels posteriorly and IVC anterolateral (Figure 1). She received doxorubicin (50 mg/m2 day 1) and ifosfamide (2.5 g/m2/day, days 1-2) with standard mesna rescue without notable maternal side effects or fetal complications. She continued to follow closely for prenatal care and serial fetal growth ultrasounds. The timing for delivery was determined through multidisciplinary discussion with neonatology, maternal-fetal medicine, and oncology. Fetal antenatal testing was overall reassuring with normal fetal growth; however, the amniotic fluid index (AFI) was found to be borderline low (5.9 cm, with maximum vertical pocket (MVP) of 2.3 cm) and decreased from an AFI of 15.3 cm with an MVP of 5.7 cm prior to cycle 1 of neoadjuvant chemotherapy. Further, the patient had a prior history of two spontaneous preterm deliveries at approximately 36 wks. There was therefore a concern that delaying delivery for a second cycle of chemotherapy could result in a spontaneous delivery close to the administration of the chemotherapeutic agents which theoretically would increase the risk of neonatal adverse effects. Given the above considerations, the decision was made to proceed with a scheduled induction of labor (IOL) 3 wks after cycle 1 of neoadjuvant chemotherapy and to proceed with the remaining cycles postpartum. She was given a second course of corticosteroids for fetal lung maturity prior to her IOL, and she then underwent an uncomplicated IOL resulting in a vaginal delivery of a 1870 g (32nd percentile) male neonate with APGAR scores of 8 and 9 at 1 and 5 minutes, respectively. The patient had an uncomplicated postpartum course and was discharged home. The neonate's NICU course was complicated by mild respiratory distress syndrome requiring continuous positive airway pressure (CPAP) on admission which was weaned to room air by day of life (DOL) 7 as well as hyperbilirubinemia requiring 2 days of phototherapy. Otherwise, he had an uncomplicated NICU stay, was advanced to full PO feeds, monitored for temperature stability and adequate weight growth, and was discharged home on DOL 20 (corrected gestational age 36w0d).\n\nThe patient continued with neoadjuvant chemotherapy with cycle 2 beginning 1 week postpartum. She received doxorubicin (25 mg/m2/day, day 1-3) and ifosfamide (2.5 g/m2/day, day 1-4) with standard mesna rescue for the postpartum cycles. Restaging CT was performed following cycle 3 demonstrating marked decrease in the size of the retroperitoneal mass (Figure 1). She went on to complete three additional neoadjuvant chemotherapy cycles (6 total) without significant complication with restaging imaging again demonstrating substantial reduction in tumor size, then measuring 3.7 cm × 6.3 cm in greatest dimension (Figure 1).\n\nFollowing completion of neoadjuvant chemotherapy, she received neoadjuvant external beam radiation therapy consisting of 5750 cGy in 25 fractions, which was completed without significant complication. She then went on to undergo radical resection of the retroperitoneal tumor including en bloc resection of infrarenal IVC and aorta and portion of omentum with 10 cm × 14 mm aortic reconstruction with tube graft and omental flap coverage of aortic prosthetic reconstruction. Her surgical recovery was unremarkable except for requirement of packed red blood cell transfusion twice for asymptomatic anemia with hemoglobin < 7 gm/dL on postoperative day numbers 3 and 7 with adequate response. She was discharged on postoperative day number 7 in good condition.\n\nPathology from the resection specimen demonstrated a 6 cm mass that on histologic evaluation exhibited marked treatment effect with only microscopic foci of residual synovial sarcoma in a background of necrosis, pigment deposition, histiocytic infiltrate, and inflammatory cells (Figure 2). The tumor focally invaded the soft tissue surrounding the proximal aortic resection margin with all other margins uninvolved by tumor.\n\nFollowing resection of her sarcoma, the patient was followed with routine surveillance CT imaging including the chest, abdomen, and pelvis at 3-month intervals. Unfortunately, she developed an isolated pelvic recurrence 13-month postresection. As of this writing, she is undergoing salvage chemotherapy with neoadjuvant intent. Her 23-month-old son is healthy and has achieved appropriate developmental milestones.\n\n2. Discussion\n\nSynovial sarcomas (SS) are mesenchymal neoplasms that can occur throughout the body and account for 5-10% of all soft tissue sarcomas [2]. SS occur most common in the adolescent and young adult (AYA) age range with peak incidence in the third decade and hence can affect women of childbearing age. Presenting symptoms, particularly for retroperitoneal primary site locations, can often be vague and predate the diagnosis by years [2].\n\nFor nonmetastatic synovial sarcoma, surgery is the mainstay of therapy and only curative treatment. For higher risk tumors, traditionally defined by size ≥ 5 cm and high histologic grade, adjuvant or neoadjuvant therapy with radiation and/or systemic therapy is often considered for risk reduction of recurrence. Neoadjuvant treatment is increasingly utilized over adjuvant owing to the advantages of improved chance of conservative surgery as well as the ability to assess treatment response [3]. Regarding systemic therapy, synovial sarcoma is considered one of the most chemosensitive sarcoma subtypes and has among the strongest evidence for adjuvant/neoadjuvant chemotherapy use [4]. In the case described, even outside of the pregnancy considerations, there were strong indications for neoadjuvant chemotherapy given the high-risk features of the tumor and extensive visceral involvement complicating an initial surgical approach.\n\nIn review of the literature, there have been 13 previous cases on synovial sarcoma associated with pregnancy reported [5–18]. These patients, their treatment, and outcomes are summarized in Table 1. These cases occurred in various anatomical locations with two noted originating from soft tissue of the lower extremities, two from the oral cavity, three from the kidneys, one from the abdominal wall, and five from the chest. To our knowledge, ours is the first case reporting a synovial sarcoma originating in the retroperitoneum distinct from the renal structures during pregnancy. In only one of the previous reports was neoadjuvant chemotherapy administered antepartum.\n\nFor women diagnosed with malignancy during pregnancy, treatment decisions must balance optimal oncologic management with the interventional risks to both the mother and fetus. Regarding systemic chemotherapy, best available data suggests that the majority of agents evaluated do not appear to increase the risk of maternal or fetal complications when administered after the first trimester, nor appear to have long-term effects on children that were exposed in utero [19, 20]. Anthracycline-based chemotherapy combinations in particular have been fairly widely studied owing to their common use in the management of breast cancer and are considered relatively low risk for maternal and fetal complications [21]. Specific to sarcoma, prior literature regarding the use of neoadjuvant anthracycline plus ifosfamide chemotherapy is limited to one small series, suggesting this approach to be feasible and safe [1].\n\nSystemic chemotherapy is often considered for treatment of malignancy in pregnancy, especially during the second and third trimesters after organogenesis is completed [22]. However, there are still risks of obstetric complications despite the completion of the majority of organogenesis including preterm delivery, fetal growth restriction, and intrauterine fetal demise [22]. While fetal growth restriction has been demonstrated in cases of malignancy in pregnancy, data are limited in suggesting whether the cause is related to toxicity of the systemic cytotoxic treatment or simply the pathophysiology of the disease itself. Van Calsteren et al. demonstrated higher rates of small for gestational age neonates in patients receiving cytotoxic treatment compared to those without (20.4 vs. 9.2%) [23]; however, Cardonick did not show increased rates of fetal growth restriction with cytotoxic treatment in their cohorts (7.6 vs. 7.1%) [24]. Data regarding ifosfamide use in pregnancy is particularly limited; however, Mir et al.'s review of ifosfamide use in pregnancy noted oligohydramnios in 5 of the 11 patients given this drug at various doses [1], suggesting this as a potential fetal toxicity and is notable in light of the borderline low AFI observed in our case that developed post-ifosfamide therapy. Among the cases of synovial sarcoma in pregnancy, two experienced fetal growth restriction [6, 9], and one was delivered for oligohydramnios with nonreassuring fetal monitoring [11]. These constellations of findings emphasize the importance of frequent fetal monitoring during treatment in order to detect potential obstetrical complications and modify delivery planning as indicated.\n\nIn summary, we report a unique case of a large, borderline resectable retroperitoneal synovial sarcoma presenting in a pregnant woman in the second trimester. This case highlights the need for multidisciplinary management in this high-risk scenario and argues for an aggressive treatment approach including administration of systemic chemotherapy in the antepartum setting to achieve optimal oncologic and maternal-fetal outcomes. This case, along with previous small series, suggests the potential for decreased amniotic fluid volumes associated with the use of ifosfamide, and therefore, frequent fetal monitoring in this scenario is recommended.\n\nConsent\n\nConsent for publication of the case was provided by the patient.\n\nConflicts of Interest\n\nAll authors declare no competing interests related to this report.\n\nFigure 1 Radiology of synovial sarcoma case. Magnetic resonance imaging prior to treatment (a, b) demonstrating the large retroperitoneal mass. (a) Fluid sensitive axial image shows the mass partially encasing the abdominal aorta and compressing and displacing the inferior vena cava. Mild right hydronephrosis is evident. (b) T2 coronal image showing extensive encasement of the aorta and right renal artery by the large retroperitoneal mass. Computed tomography imaging post 3 cycles (c, d) and 6 cycles (e, f) of neoadjuvant chemotherapy demonstrating treatment response as evidenced by marked decrease in tumor size, decreased mass effect on the vena cava, resolution of right hydronephrosis, and deceased tumor density (suggestive of necrosis).\n\nFigure 2 Histology of synovial sarcoma case. Diagnostic biopsy (a) demonstrated proliferation of spindle to epithelioid cells of monomorphic appearance with elongated nuclei and scant cytoplasm arranged in a whorled “herringbone” architecture (Hematoxylin and Eosin, 100x). Fli-1 immunohistochemistry (b) demonstrated strong, diffuse nuclear staining, confirming the diagnosis (200x). The posttreatment resection specimen demonstrated substantial treatment effected with the majority of residual tumor mass now comprised of areas of histiocytic infiltration (c) fibrosis, pigment deposition, and chronic inflammation (d) (Hematoxylin and Eosin, 20x).\n\nTable 1 Synovial sarcoma cases in pregnancy.\n\nAuthor/year\tPatient presentation\tPathology\tOncologic treatment/outcome\tPregnancy treatment/outcome\t\nAdamesteanu, 2015 [5]\t19 yo presented to provider at 15 wks gestation for painful thigh lesion, clinically diagnosed as lipoma. Lesion grew throughout second and third trimesters. Referred for further evaluation postpartum.\tLarge biphasic synovial sarcoma invading surrounding fatty tissue, fascia, and tendons. IHC: vimentin+, B-cell lymphoma (bcl)+, epithelial membrane antigen (EMA) +; MIC occasionally +; Ki67 20%+. t (X; 18) (p11; q11) translocation unable to be tested.\tImaging evaluation for distant metastases was negative. Proceeded with left lower limb amputation with negative resection margins. Staged pT2bNx G3. Adjuvant chemotherapy with ifosfamide 5 g/m2 and doxorubicin 50 mg/m2 weekly x6 weeks. External radiotherapy 10 Gy/week for total dose of 50 Gy. Patient currently undergoing radiation, no evidence of local recurrence.\tFull-term cesarean delivery. No treatment/evaluation during pregnancy.\t\nAkhanoba, 2019 [6]\t28 yo pregnant HIV+ female noted to have a mass on her left thigh. Ultrasound of thigh suspicious for sarcoma. MRI demonstrated large mass within left medial thigh (14 cm × 10 cm × 8 cm) replacing distal fibers of left adductor longus muscle belly, encasing femoral vessels, and infiltrating into left sartorius muscle.\tBiopsy confirmed synovial sarcoma.\tCT scan no evidence of distant metastases. Stage pT2bN0M0 G2. Initial surgery (hip disarticulation) at 30 wk gestation. 4 wks postoperative represented with sepsis and infected wound stump. Required three wound debridements and long-term IV antibiotics. Surveillance plan: clinical review and chest X-ray every 3 months x2 years then every 6 months x3 years, then annually x5 years.\tAntenatal steroids given prior to initial surgery at 30 wk gestation. Presented at 34 wks with sepsis arising from infected leg stump. Fetal growth restriction suspected (EFW < 10% ile). Emergent cesarean and wound exploration and debridement at 34 wks. Delivered a female neonate weighing 1756 g.\t\nBettendorf, 2006 [7, 8]\t32 yo G1P0 presented for evaluation of large left kidney mass after experiencing gross hematuria starting 3 weeks earlier. Renal ultrasound demonstrated abnormal mass concerning for neoplasm. MRI confirmed findings of a large tumor in the left lower renal pole. No lymphadenopathy, adrenal involvement, or distant metastases were noted.\tMonomorphic cellular pattern with large cells and dark nucleoli. IHC vimentin+, bcl-2+, low growth ratio (MIB − 1 < 5%). CD 99-, estrogen receptor-, progesterone receptor-, AFP-, HCG-. RT-PCR confirmed t (X; 18) translocation with SYT-SSX2 fusion transcript confirming monophasic variant of synovial sarcoma.\tNephrectomy at time of cesarean delivery. Adjuvant chemotherapy with ifosfamide (5 g/m2) and doxorubicin (75 mg/m2) for two cycles followed by 54 Gy radiation to region. After radiation therapy, 2 additional cycles of ifosfamide/doxorubicin were given. Eight-month follow-up shows no recurrence.\t34-week cesarean delivery with left nephrectomy after administration of antenatal corticosteroids.\t\nBunch, 2012 [9]\t38 yo presented at 26 wk gestation with dyspnea, upper right back pain, and orthopnea. Chest X-ray and CT angiogram revealed large 12 cm mass in the right chest. CT-guided needle biopsy demonstrated high-grade neoplasm.\tHigh-grade, poorly differentiated pulmonary synovial sarcoma\tRight pneumonectomy and lymph node dissection performed at 28 wk gestation. Negative margins not obtained due to tumor burden. Patient presented 8 wks later with worsening dyspnea and new pulmonary embolism. Repeat CT revealed tumor growth and near complete occlusion of SVC. Radiation therapy administered. Unable to undergo chemotherapy due to liver dysfunction. Patient expired 2 weeks after readmission.\tAntenatal steroids prior to 28 wk pneumonectomy. Fetal growth restriction noted at 30 wks with subsequent poor interval growth leading to repeat cesarean section at 32 wks. Newborn required pulmonary artery banding but was discharged home on day of life 50.\t\nEsaka, 2008 [10]\tG2P1 presented at 34 wks gestation with worsening dyspnea and left-sided cheat pain for 1 month. Chest X-ray revealed a left apical pneumothorax treated with pigtail chest tube. Repeat chest X-ray concerning for mass in this area. CT revealed left pneumothorax with significant complex mass in the left lung. Cardiothoracic surgery proceeded with video-assisted thoracoscopy.\tPoorly differentiated synovial sarcoma within left pleural debris. IHC vimentin+, AW1/3+, CK7+, CK56+, K903+, S-100-, calretinin-.\tPostpartum left pneumonectomy followed by adjuvant chemotherapy. Patient expired 13 months after resection.\tInduction of labor after pathology findings confirmed neoplasm leading to a vacuum-assisted vaginal delivery of a 2125 g male neonate.\t\nHarris, 2014 [11]\t26 yo G2P1 at 21 wk gestation presented with dry cough and right sided pleuritic chest pain. CT revealed smooth, lobulated 6.5 cm mass in the right hilum. Bronchoscopy with multiple biopsies performed.\tMalignant spindle cells infiltrating endobronchial tissue. IHC CD99+, bcl-2+, CD34-, AE1/3-, Cam5.2-, desmin-, smooth muscle actin-, S-100-, HMB45-. FISH revealed predominant population of polypoid cells with multiple copies of SYT probe. Findings consistent with monophasic spindle cell synovial sarcoma.\tPrimary surgical management deferred given pregnancy. Patient given 2 cycles of neoadjuvant chemotherapy: ifosfamide 2 g/m2 IV bolus over 4 h followed by 2 g/m2/day continuous IV for 6 days (total dose 14 g/m2/cycle) given with mesna. Cycles given at 26 and 29 wk gestation. CT scan postdelivery showed a 30% decrease in size of primary mass. Two additional neoadjuvant cycles with doxorubicin, ifosfamide, and mesna were given. Right total pneumonectomy and mediastinal lymphadenectomy performed 8 wk postpartum. Lymph nodes and margins negative. Patient declined adjuvant chemotherapy. 5 months later, recurrence occurred. Patient given palliative radiation. Patient expired 13 months after diagnosis.\tPatient experienced decreased fetal movement at 31 wks and was diagnosed with oligohydramnios. She had a nonreassuring fetal heart tracing and was delivered via emergent cesarean delivery.\t\nKanade, 2013 [12]\t21 yo G1 presented with slow growing mass in anterior abdominal wall. MRI revealed soft tissue mass attached to anterior abdominal wall without metastasis. FNA cytology revealed spindle cell tumor. Total excision of mass was then completed.\tCrowded spindle cells in wavy, short fascicular pattern. IHC cytokeratin+, EMA+, Mic-2+, bcl-2+, calponin-. Pathological diagnosis of biphasic synovial sarcoma.\tPatient declined local radiation therapy and chemotherapy. She presented 6 months later with local recurrence. She declined further treatment and was lost to follow-up.\tNo information available.\t\nKhoja, 2013 [13]\t23 yo at 28 wk gestation presenting with fever, cough, and dyspnea. Ultrasound revealed a large mass in left hemi-thorax. Initial biopsy inconclusive, repeat CT-guided biopsy revealed synovial sarcoma.\tInformation not available.\tAdvised for surgical resection and chemo-radiation therapy but further information not available.\t32 wk cesarean delivery.\t\nNebhnani, 2014 [14]\t25 yo at 8 wk gestation presented with abdominal distension, left flank pain, and hematuria x10 months. 10 cm flank mass palpated. CT/MRI consistent with renal cell carcinoma without evidence of metastases.\tMalignant spindle cells arranged in sheets, fascicles, and whorls. IHC bcl2+, Mic2+, vimentin+. RT-PCR for fusion transcript SYT-SSX1 negative. Final diagnosis monophasic primary synovial sarcoma of the kidney.\tLeft radical nephrectomy referred to oncology for adjuvant chemotherapy.\tTermination of pregnancy at 8 wks.\t\nOrlandi, 2007 [15]\t23 yo at 22 wk gestation presented with palpable lesion in the left cheek. She underwent surgical resection at 23 wks gestation with rupture of capsule intra-op.\tBiphasic synovial sarcoma. IHC keratins+, EMA+, bcl-2+, CD99+. RT-PCR confirmed SYT-SSX1 fusion translocation.\tPost-op MRI revealed possible residual disease and concern for high rate of recurrence given capsule rupture. Decision made to proceed with radiation therapy at 30 wk gestation with shielding of the abdomen/uterus. Patient received 48 Gy (24 of 25 fractions planned) prior to delivery with remainder after delivery. Eight months posttreatment without evidence of recurrent disease.\tPlanned cesarean delivery at 36 wks. 2800 g newborn male. Newborn healthy at 8 months of age.\t\nOrtiz M, 2012 [16]\t23 yo pregnant patient presenting with acute airway obstruction due to large hypopharynx lesion.\tSynovial sarcoma.\tEmergent tracheotomy and tumor debulking, partial pharyngectomy 6 weeks postpartum; no recurrence at 30-month post-op.\t29-week preterm delivery.\t\nPathrose, 2017 [17]\t25 yo G2P1 at 10 wk 4 d gestation was incidentally noted to have a left maternal renal mass on perinatal ultrasound. MRI revealed a 13 × 11 × 10 cm mass arising from the left kidney suggestive of renal cell carcinoma.\tTumor completely replaced the left kidney. Well circumscribed neoplasm of round to oval to spindle cells in sheets, fascicles, and perivascular arrangement. IHC TLE-1+, CD56+, CD99+, vimentin+, desmin-, myogenin-, EMA-, CK-, WT1-. Molecular analysis confirmed presence of SYT-SSX2 translocation.\tOpen left radical nephrectomy. Adjuvant chemotherapy: ifosfamide (1800 mg/m2) and doxorubicin (25 mg/m2) for 3 cycles. Disease free at 3-year follow-up.\tTermination of pregnancy.\t\nSarkurai, 2006 [18]\t33 yo female 5 months pregnant presented with acute onset back pain and was diagnosed with pleural effusion. Thoracentesis revealed frank blood. She deteriorated and required video-thoracoscopic evaluation with evacuation of 2000 cc of blood and multiple tumors attached to the parietal and visceral pleura including one that was bleeding and was resected for hemostasis and diagnosis.\tMonophasic cells in plump, spindle-shaped appearance arranged in fascicles and herringbone pattern. Chromosomal translocation t (X; 18) (p11; q11) confirmed by FISH. Final diagnosis monophasic fibrous synovial sarcoma.\tPatient refused further treatment after initial emergent surgery.\tAbortion, not further specified.\n==== Refs\n1 Mir O. Berrada N. Domont J. Doxorubicin and ifosfamide for high-grade sarcoma during pregnancy Cancer Chemotherapy and Pharmacology 2012 69 2 357 367 10.1007/s00280-011-1707-8 2-s2.0-84856762008 21769666\n2 Thway K. Fisher C. Synovial sarcoma: defining features and diagnostic evolution Annals of Diagnostic Pathology 2014 18 6 369 380 10.1016/j.anndiagpath.2014.09.002 2-s2.0-84923617290 25438927\n3 Pasquali S. Gronchi A. Neoadjuvant chemotherapy in soft tissue sarcomas: latest evidence and clinical implications Therapeutic advances in medical oncology 2017 9 6 415 429 10.1177/1758834017705588 2-s2.0-85020205653 28607580\n4 Ferrari A. Gronchi A. Casanova M. Synovial sarcoma: a retrospective analysis of 271 patients of all ages treated at a single institution Cancer 2004 101 3 627 634 15274077\n5 Adamesteanu M. O. Scurtu R. Lascar I. Valcu M. Popescu S. A. Sebe I. T. Biphasic synovial sarcoma in a 19-year-old pregnant woman: a case report Romanian Journal of Morphology and Embryology 2015 56 1 289 294 25826519\n6 Akhanoba F. Huma E. Zill R. Pollock R. Edwards S. J. E. Synovial sarcoma in an HIV-positive pregnant woman and review of literature BMJ Case Reports 2019 12 1 p. e227646 10.1136/bcr-2018-227646 2-s2.0-85060949900 30700464\n7 Bettendorf O. Bierer S. Kohler G. Piechota H. J. Mesters R. M. Klockenbusch W. Neoplasia of the kidney--a rare event during pregnancy European Urology 2006 50 1 148 150 16519992\n8 Bettendorf O. Bierer S. Köhler G. Piechota H.-J. Mesters R. M. Klockenbusch W. Neoplasia of the kidney--a rare event during pregnancy: part 2 European Urology 2006 50 2 375 376 10.1016/j.eururo.2006.02.029 2-s2.0-39549111721 18217223\n9 Bunch K. Deering S. H. Primary pulmonary synovial sarcoma in pregnancy Case Reports in Obstetrics and Gynecology 2012 2012 3 326031\n10 Esaka E. J. Celebrezze J. U. Golde S. H. Chiossi G. Thomas R. L. Pulmonary synovial sarcoma presenting as a pneumothorax during pregnancy Obstetrics & Gynecology 2008 111, 2 Part 2 555 558 18239021\n11 Harris E. M. Allan R. W. Riggs C. E. Jr. Primary pulmonary synovial sarcoma during pregnancy: a diagnostic and therapeutic dilemma Case reports in oncology 2014 7 1 139 143 24707262\n12 Kanade U. S. Gadgil P. A. Birare S. D. Chaware S. A. Kamra H. Abdominal wall synovial sarcoma during pregnancy-a case report Indian Journal of Surgery 2013 75 Suppl 1 463 464\n13 Khoja A. Patel C. Jain D. Large synovial sarcoma complicating pregnancy European Respiratory Journal 2013 42 Suppl 57 p. P4538\n14 Nebhnani D. Fernandes G. Menon S. Naik L. Primary renal synovial sarcoma presenting in the first trimester of pregnancy Journal of obstetrics and gynaecology of India 2014 64 Suppl 1 22 23 25404798\n15 Orlandi E. Zonca G. Pignoli E. Postoperative radiotherapy for synovial sarcoma of the head and neck during pregnancy: clinical and technical management and fetal dose estimates Tumori 2007 93 1 45 52 10.1177/030089160709300109 17455871\n16 Ortiz M. Giraldez L. A. Riera-March A. Synovial sarcoma of the hypopharynx in pregnancy Boletin de la Asociacion Medica de Puerto Rico 2012 104 3 55 56\n17 Pathrose G. John N. T. Hariharan P. Renal synovial sarcoma in a young pregnant lady: a case report and clinico-pathological profile Journal of clinical and diagnostic research: JCDR 2017 11 7 Pd13 pd14\n18 Sakurai H. Hosokawa H. Hada M. Miyashita Y. Oyama T. Ashizawa I. Spontaneous hemothorax caused by intrathoracic synovial sarcoma General Thoracic and Cardiovascular Surgery 2006 54 5 217 220\n19 Amant F. Vandenbroucke T. Verheecke M. Pediatric outcome after maternal cancer diagnosed during pregnancy New England Journal of Medicine 2015 373 19 1824 1834\n20 Maggen C. Wolters V. E. Cardonick E. Pregnancy and cancer: the INCIP Project Current oncology reports 2020 22 2 1 10 31960161\n21 Ring A. E. Smith I. E. Jones A. Shannon C. Galani E. Ellis P. A. Chemotherapy for breast cancer during pregnancy: an 18-year experience from five London teaching hospitals Journal of clinical oncology 2005 23 18 4192 4197 15961766\n22 Albright C. M. Wenstrom K. D. Malignancies in pregnancy Best Practice & Research: Clinical Obstetrics & Gynaecology 2016 33 2 18 26542928\n23 Calsteren K. V. Heyns L. Smet F. D. Cancer during pregnancy: an analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes Journal of clinical oncology 2010 28 4 683 689 19841323\n24 Cardonick E. Usmani A. Ghaffar S. Perinatal outcomes of a pregnancy complicated by cancer, including neonatal follow-up after in utero exposure to chemotherapy: results of an international registry American journal of clinical oncology 2010 33 3 221 228 19745695\n\n",
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"journal": "Case reports in oncological medicine",
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"title": "A Case of Retroperitoneal Synovial Sarcoma in Pregnancy Treated with Antepartum Doxorubicin plus Ifosfamide Chemotherapy.",
"title_normalized": "a case of retroperitoneal synovial sarcoma in pregnancy treated with antepartum doxorubicin plus ifosfamide chemotherapy"
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"abstract": "•We present two cases of advanced uterine cancer that were treated with the combination of metronomic cyclophosphamide and bevacizumab.•Targeting angiogenesis can provide disease control in patients with advanced uterine cancer.•Randomized controlled trials comparing metronomic and conventional regimens in advanced uterine cancer are required.",
"affiliations": "Department of Gynecologic Oncology, SUNY-Downstate Medical Center, Brooklyn, NY, USA.;Department of Gynecologic Oncology, SUNY-Downstate Medical Center, Brooklyn, NY, USA.;Department of Gynecologic Oncology, SUNY-Downstate Medical Center, Brooklyn, NY, USA.;Department of Gynecologic Oncology, SUNY-Downstate Medical Center, Brooklyn, NY, USA.;Department of Gynecologic Oncology, SUNY-Downstate Medical Center, Brooklyn, NY, USA.",
"authors": "Alagkiozidis|Ioannis|I|;Lozano|Melissa|M|;Devraj|Mithun|M|;Lee|Yi-Chun|YC|;Abulafia|Ovadia|O|",
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"doi": "10.1016/j.gore.2014.12.004",
"fulltext": "\n==== Front\nGynecol Oncol RepGynecol Oncol RepGynecologic Oncology Reports2352-5789Elsevier S2352-5789(14)00048-410.1016/j.gore.2014.12.004Case SeriesMetronomic cyclophosphamide with bevacizumab provides disease stabilization in patients with advanced uterine cancer Alagkiozidis Ioannis alagkiozidis@gmail.com⁎Lozano Melissa Devraj Mithun Lee Yi-Chun Abulafia Ovadia Department of Gynecologic Oncology, SUNY-Downstate Medical Center, Brooklyn, NY, USA⁎ Corresponding author at: 450 Clarkson Avenue, Brooklyn, NY 11203, Box 25, USA. Fax: + 1 7182704173. alagkiozidis@gmail.com04 2 2015 4 2015 04 2 2015 12 23 26 3 10 2014 24 12 2014 © 2015 The Authors2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• We present two cases of advanced uterine cancer that were treated with the combination of metronomic cyclophosphamide and bevacizumab.\n\n• Targeting angiogenesis can provide disease control in patients with advanced uterine cancer.\n\n• Randomized controlled trials comparing metronomic and conventional regimens in advanced uterine cancer are required.\n\n\n\nKeywords\nMetronomicBevacizumabCyclophosphamideEndometrioid\n==== Body\nIntroduction\nTargeting angiogenesis in order to achieve tumor control was introduced by Folkman in 1971 (Folkman, 1971). Inhibition of angiogenesis can be achieved with the use of targeted therapies that affect critical steps in tumor vascularization or with the administration of cytotoxic agents in a metronomic regimen. Conventional chemotherapy is typically administered in 3–4 week cycles at the maximal tolerated dose. Metronomic chemotherapy is achieved by frequently administering doses that are significantly lower than the maximal tolerated dose. In the time interval between consecutive cycles the host can recover from adverse effects and the vascular damage can be rapidly repaired. Although the cancer cells have less chance of recovering, regrowth of part of the tumor can occur, especially if the drug-free period is too long. It has been shown that shortening the drug-free period increases the anti-angiogenic effects of cytotoxic drugs. An additional advantage in continuous low-dose chemotherapy is the minimization of toxic side-effects, while allowing combination with selective inhibitors of angiogenesis (Mross and Steinbild, 2012).\n\nVascular endothelial growth factor (VEGF) is recognized as a major element in regulating angiogenesis. In animal models, VEGF plays a major role in mediating tumor growth while the VEGF monoclonal antibody has an inhibitory effect. Bevacizumab, the recombinant humanized version of this antibody, significantly improves outcome in various human tumors when combined with cytotoxic chemotherapy. In a phase II study, the combination of metronomic cyclophosphamide with bevacizumab has shown promising activity in recurrent ovarian cancer (Garcia et al., 2008). Although, metronomic chemotherapeutic regimens have been used in a variety of solid tumors, the data on patients with endometrial cancer is limited. Here, we present two patients with advanced uterine cancer that were treated with the combination of metronomic cyclophosphamide and bevacizumab. Pathology type for the first and second was endometrioid and uterine papillary serous (UPSC), respectively. With this regimen the patients achieved prolonged disease stabilization and improved quality of life.\n\nCase 1\nA 56 year-old nulliparous black female initially presented with complaints of irregular vaginal bleeding for the past 4 years and a 30 lb weight loss over the course of 3 months. Physical exam showed an obese woman with fullness of the right adnexa, 16-week uterus, midline, enlarged cervix and gross tumor exiting the os. Family history was unremarkable. An endometrial biopsy was obtained and revealed moderately differentiated endometrial carcinoma of the endometrioid type. CT abdomen and pelvis showed a left adnexal cystic/soft tissue mass (9 × 9.6 cm), a left lower quadrant cystic mass (4.6 × 7.2 cm) with a mural nodule and multiple hypodense hepatic lesions, the largest measuring 2.2 × 2.5 cm, suggestive of metastatic disease. Tumor markers were as follows: CA-125 1553 U/ml, CA 19-9 1491 U/ml and CEA < 0 .5 mcg/L. Given the multiple liver metastases, a primary optimal cytoreduction was not considered feasible and the patient was offered neoadjuvant chemotherapy with 3 cycles of carboplatin/paclitaxel and plan for interval debulking. Imaging after the completion of the chemotherapy course showed no interval change.\n\nIn addition, the patient had worsening bleeding requiring a blood transfusion and the decision was made to proceed with surgical management. The patient underwent an exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oopherectomy (BSO), resection of peritoneal metastatic implant and a liver biopsy. The findings were as follows: 15 week uterus, 20 × 20 cm solid left adnexal mass, along with a 5 × 8 cm peritoneal implant adjacent to the left paracolic gutter and multiple lesions on the surface of the liver consistent with metastases. The patient was suboptimally debulked with residual disease at the liver. Final pathology was FIGO Grade II endometrioid adenocarcinoma with depth of invasion 2.8 out of 3 cm and lymphovascular space invasion. Tumor size was 7.5 cm with involvement of both the anterior and posterior aspect of the endometrial cavity, cervical stroma, bilateral tubes and ovaries, left paracolic gutter and the liver. The patient was assigned a FIGO (2009) stage IVB endometrioid adenocarcinoma. Chemosensitivity studies (Precision Therapeutics) demonstrated resistance to all cytotoxic chemotherapeutics. The patient was started on a metronomic regimen consisting of cyclophosphamide 50 mg daily and bevacizumab 15 mg/kg every 3 weeks. This regimen was in place for 16 months while disease stabilization was achieved as evidenced by interval imaging (Fig. 1A). The sum of longest dimensions of target lesions was 65 mm on baseline CT before the initiation of the metronomic regimen, 55 mm after 6 months of treatment and 61 mm after one year of treatment. Serial measurements of CA-125 are consistent with biochemical response to therapy (Fig. 1B). During this time, the patient reported a good quality of life. The metronomic therapy was interrupted due to a Stage IV non-healing decubitus ulcer. Of note, the patient has been wheelchair bound for 10 years secondary to a spine injury. Subsequently, her disease progressed rapidly and she expired 2 months later.\n\nCase 2\nA 73 year-old black female Para 3 initially presented with complaints of abdominal pain, increased abdominal girth, nausea and vomiting for one week. Physical exam showed an obese woman with a distended abdomen that was tender to palpation. Bowel sounds were hyperactive. Pelvic exam revealed a 20-week size pelvic mass. Family history was unremarkable. CT abdomen and pelvis showed small bowel obstruction with transition point in the distal jejunum. There was a heterogeneous mass measuring 7.3 × 6.5 cm extending from the uterus to the left adnexa and causing small bowel obstruction. There was paraaortic, retroperitoneal and mesenteric lymphadenopathy. Multiple hypodensities consistent with metastases were seen in both lobes of the liver, the largest measuring 2 × 4 cm. CA-125 level was 135 U/ml. Given the clinical picture of small bowel obstruction, the patient was taken to the operating room and underwent an exploratory laparotomy, radical hysterectomy, BSO, tumor debulking, small bowel resection in 3 segments and anastomosis, partial cystectomy, cystotomy repair and ureteral stent placement, omentectomy, appendectomy, pelvic lymphadenectomy. The operative findings were as follows: 10 × 20 × 20 cm mass involving the uterus, bilateral tubes and ovaries, small bowel, sigmoid colon and appendix. Two tumor nodules measuring 2 cm each in the omentum.\n\nInnumerable subcentimeter tumor nodules in the surface of the liver. Three cm tumor plaque on the dome of the bladder. Gross adenopathy in left pelvic sidewall. At the completion of surgery, there was gross residual disease in the liver.\n\nHistology was consistent with UPSC involving the small bowel, omentum, appendix and bladder. Right tube and ovary, cervix, parametria and lymph nodes were positive. Final pathology was Stage IVB uterine papillary serous carcinoma. The treatment plan was adjuvant chemotherapy with carboplatin and paclitaxel. One week after the administration of the first cycle the patient presented to the emergency room with neutropenic urosepsis. She was treated with parenteral antibiotics (cefepime) and G-CSF (filgrastim). After she recovered, she declined any further cytotoxic chemotherapy. At that time, the option of metronomic chemotherapy with cyclophosphamide and bevacizumab was discussed and the patient agreed to pursue the latter treatment option. With the metronomic regimen, her disease remained stable for 16 months as evidenced by CA-125 monitoring (Fig. 2) and CT imaging. During that period of time the patient was asymptomatic. Eventually, her disease progressed in the pelvis causing bilateral obstructive nephropathy and the patient expired shortly thereafter. Total survival time status-post surgery was 18 months.\n\nDiscussion\nThe combination chemotherapy with carboplatin and paclitaxel has emerged as the treatment of choice for patients with advanced uterine cancer (Miller et al., 2012). For patients with poor response to the standard first line treatment, the options are limited and there is no standard of care regarding salvage treatment. Therapy typically employs either second line cytotoxic chemotherapy or hormonal agents. Based on data from GOG studies, cytotoxic chemotherapy for advanced or recurrent disease provides a median progression free survival of 8 months and the goal of care is usually palliation (Fleming et al., 2004). Moreover, the conventional chemotherapeutic regimens use the maximum tolerated doses and are often associated with severe, sometimes life threatening, side-effects.\n\nTherefore, the introduction of new strategies with at least equivalent efficacy and decreased toxicity is highly desirable. Metronomic chemotherapy is designed to maintain stable disease for advanced cancer patients with minimal toxicity. It has been suggested that frequent administering of low-dose chemotherapy targets the dividing endometrial cells and inhibits the formation of tumor-associated capillaries. This hypothesis is supported by in vitro data showing selective cytotoxicity of low-dose chemotherapy for human vascular endothelial cells. Other mechanisms which have been proposed include the induction of endogenous inhibitors of angiogenesis, the activation of apoptotic pathways and the inhibition of recruitment of progenitor endothelial cells. The daily low-dose cyclophosphamide has demonstrated remarkable efficacy and tolerability in various animal models. Metronomic regimens have been associated with favorable responses in patients with various advanced solid tumors. A phase II study showed that the combination of metronomic cyclophosphamide with bevacizumab can be effective and well tolerated in patients with recurrent ovarian cancer. The response rate in this study is favorably compared to other conventional or investigational treatment modalities for recurrent ovarian cancer (Garcia et al., 2008).\n\nThe use of metronomic regimens in the treatment of advanced uterine cancer is supported by in vitro data showing that angiogenesis plays an important role in the growth of uterine tumors. Furthermore, a higher expression of VEGF has been documented in malignant compared to benign or hyperplastic endometrium (Abulafia et al., 1995). Limited clinical data on the use of the combination of metronomic chemotherapy with bevacizumab in patients with advanced uterine cancer who failed multiple conventional chemotherapies suggest the potential for therapeutic benefit (Wright et al., 2007). In our cases, the progression free interval exceeds the previously reported median progression free survival for patients treated with conventional or investigational regimens.\n\nAdditionally, the patients continued to report a good quality of life during their progression-free survival interval. None of the common side effects of Bevacizumab such as hypertension and bowel perforation occurred in our cases. Bevacizumab might have contributed to the non healing decubitus ulcer in Case 1. Metronomic therapy is commonly regarded as the ‘last resort’ for patients with advanced malignancies when multiple cytotoxic regimens have failed and before withdrawal of anti-cancer treatment. One of the recognized benefits of anti-angiogenic therapies is control of ascites formation in patients with carcinomatosis through the inhibition of malignant vascularization and stabilization of tumor capillaries (Anon., 1995). In our case the tumors were purely solid and they were stabilized with the anti-angiogenic therapy. Frequently, concerns about the toxicity related to bevacizumab and cost considerations lead providers to attempt a number of cytotoxic agents before a metromonic regimen. This delay may have a negative impact on the main objectives of metronomic treatment, which are disease stabilization and maintenance of quality of life. The implementation of the metronomic regimen relatively early in the course of the disease while the patient is still in good performance status and before the tumor load becomes overwhelming, may be associated with a higher response rate.\n\nFurthermore, starting the metronomic therapy early may reduce the risk for life threatening toxicities of bevacizumab that are associated with a higher tumor load like thromboembolism and bowel perforation. The concept of early implementation of metronomic therapy is more applicable in tumors with inherent resistance to cytotoxic chemotherapy, like the endometrioid- type endometrial cancer.\n\nIn conclusion, the presented cases suggest that the combination of metronomic cyclophosphamide with bevacizumab can be an effective strategy against tumor progression in patients with advanced uterine cancer when first line chemotherapy fails. Controlled randomized trials comparing conventional versus metronomic regimens are required in order to define optimal drug combinations with maximal anti-tumor activity and minimal toxicity.\n\nConflict of interest statement\nThe authors declare that there are no conflicts of interest.\n\nFig. 1 A. CT Abdomen shows multiple metastatic lesions (left). Stable metastatic liver lesions after 12 months of treatment with metronomic cyclophosphamide and bevacizumab (right).\n\nB. Disease stabilization with metronomic cyclophosphamide and bevacizumab in patient with advanced endometrioid adenocarcinoma as evidenced by CA-125 levels.\n\nFig. 2 Disease stabilization with metronomic cyclophosphamide and bevacizumab in a patient with UPSC as evidenced by CA-125 levels.\n==== Refs\nReferences\nAbulafia O. Triest W.E. Angiogenesis in endometrial hyperplasia and stage I endometrial carcinoma Obstet. Gynecol. 86 4 Pt 1 1995 479 485 7545803 \nAnon. Pathogenesis of ascites tumor growth: angiogenesis, vascular remodeling and stroma formation in the peritoneal lining Cancer Res. 55 1995 376 385 7529135 \nFleming Phase II trial of doxorubicin plus cisplatin, with or without paclitaxel plus filgastrim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study J. Clin. Oncol. 22 11 2004 2159 2166 15169803 \nFolkman J. Tumor angiogenesis: therapeutic implications N. Engl. J. Med. 285 1971 1182 1186 4938153 \nGarcia Agustin A. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital Phase II Consortia J. Clin. Oncol. 26 2008 76 82 (Volume 28, number 1. January 1) 18165643 \nMiller D. Filiaci V. Fleming G. Mannel R. Cohn D. Matsumoto T. Tewari K. DiSilvestro P. Pearl M. Zaino R. Randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: a Gynecologic Oncology Group study Gynecol. Oncol. 125 2012 771 773 \nMross K. Steinbild S. Metronomic anti-cancer therapy—an ongoing treatment option for advanced cancer patients J. Cancer Ther. Res. 1 2012 32 \nWright Jason D. Powell Matthew A. Bevacizumab therapy in patients with recurrent uterine neoplasms Anticancer Res. 27 2007 3525 3528 17972512\n\n",
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"title": "Metronomic cyclophosphamide with bevacizumab provides disease stabilization in patients with advanced uterine cancer.",
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"abstract": "Anthracyclines, including doxorubicin, are an important class of chemotherapeutic agents. Their efficacy, however, is limited by cardiotoxicity. Risk factors for anthracycline-associated cardiotoxicity include dose, treatment-specific risk factors including adjunctive radiotherapy, patient-specific modifiable cardiac risk factors including hypertension, hyperlipidemia, diabetes mellitus, tobacco use and obesity, and patient-specific non-modifiable risk factors such as age. The reduction of treatment-specific factors is not always possible, but treatment and reduction of modifiable risk factors should always be an important aspect of the management plan and may reduce the risk of anthracycline-induced cardiotoxicity. We present the case of a 65-year-old male with multiple modifiable cardiovascular risk factors who developed cardiogenic shock shortly after the administration of combination therapy with anthracyclines for the treatment of Hodgkin's lymphoma.",
"affiliations": "Internal Medicine, University of Connecticut Health Center, Farmington, USA.;Internal Medicine, University of Connecticut Health Center, Farmington, USA.;Internal Medicine, University of Connecticut Health Center, Farmington, USA.;Internal Medicine, St. George's University School of Medicine, St. George's, GRD.",
"authors": "Gabriel|Andre|A|;Stringer|Bryan|B|;Hadfield|Matthew J|MJ|;Madady|Mona|M|",
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"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.4961CardiologyOncologyCase of Anthracycline-induced Cardiogenic Shock: A Call to Optimize Modifiable Cardiac Risk Factors Prior to Chemotherapy Muacevic Alexander Adler John R Gabriel Andre 1Stringer Bryan 1Hadfield Matthew J 1Madady Mona 2\n1 \nInternal Medicine, University of Connecticut Health Center, Farmington, USA \n2 \nInternal Medicine, St. George's University School of Medicine, St. George's, GRD \nAndre Gabriel agabriel@uchc.edu20 6 2019 6 2019 11 6 e49616 6 2019 20 6 2019 Copyright © 2019, Gabriel et al.2019Gabriel 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/20676-case-of-anthracycline-induced-cardiogenic-shock-a-call-to-optimize-modifiable-cardiac-risk-factors-prior-to-chemotherapyAnthracyclines, including doxorubicin, are an important class of chemotherapeutic agents. Their efficacy, however, is limited by cardiotoxicity. Risk factors for anthracycline-associated cardiotoxicity include dose, treatment-specific risk factors including adjunctive radiotherapy, patient-specific modifiable cardiac risk factors including hypertension, hyperlipidemia, diabetes mellitus, tobacco use and obesity, and patient-specific non-modifiable risk factors such as age. The reduction of treatment-specific factors is not always possible, but treatment and reduction of modifiable risk factors should always be an important aspect of the management plan and may reduce the risk of anthracycline-induced cardiotoxicity. We present the case of a 65-year-old male with multiple modifiable cardiovascular risk factors who developed cardiogenic shock shortly after the administration of combination therapy with anthracyclines for the treatment of Hodgkin’s lymphoma.\n\nanthracyclinescardio-toxicityhypertensionhyperlipidemiachemotherapycarvedilolThe 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\nAnthracyclines are an important class of chemotherapeutic agents and a staple in many modern chemotherapy regimens. They are routinely used in the treatment of lymphomas and solid tumors. They exert their anti-cancer properties through a variety of mechanisms including the inhibition of DNA-topoisomerase II, the production of reactive oxygen species, and mitochondrial dysfunction [1]. The primary target of these agents are rapidly proliferating cells, as would be found in malignancy. Unfortunately, the deleterious effects are not limited to the cancer cells. Although anthracyclines’ primary mechanism of action is through DNA damage of targeted cancer cells, other cells such as cardiomyocytes are also negatively affected by free radical production and mitochondrial dysfunction [1]. Since cardiomyocytes have a high concentration of mitochondria, it is believed that they are highly sensitive to these agents and hence the increased frequency of cardiotoxicity [1].\n\nThe primary and greatest risk for doxorubicin cardiomyopathy is dose [2]. According to previous studies, incidence of cardiomyopathy is approximately 5% at 400 mg/m2 and increases to 48% at 700 mg/m2 [2]. Cardiotoxicity at doses less than 100 mg/m2 is exceedingly rare and carries an odds ratio of 1 [1]. Although acute toxicity does occur, the negative effects of anthracyclines are typically seen after many doses or the completion of treatment [1]. This can be explained by the cumulative dose effect. In the cases of acute toxicity, the role that additional risk factors play in increasing the risk of cardiotoxicity is unclear.\n\nPatient-specific non-modifiable risk factors for cardiotoxicity from doxorubicin include age (greater than 65 or less than 18), having multiple cardiac risk factors and pre-existing cardiac dysfunction [3]. Treatment-specific factors include adjunctive radiotherapy, radiotherapy of the mediastinum, and combination therapy with other cardiotoxic agents such as trastuzumab [3]. Reduction of treatment-specific factors is not always possible based on cancer-specific factors. For example, hyperleukocytosis as seen in acute leukemia is associated with elevated mortality due to its ability to induce leukostasis, disseminated intravascular coagulopathy and tumor lysis syndrome and requires prompt induction chemotherapy [4]. Additionally, the use of anthracyclines in high-risk age groups and in persons with pre-existing cardiac dysfunction is often necessary and cannot be avoided. This often leaves cardiac risk factors as the only modifiable part of a treatment regimen.\n\nCancer patients often have concurrent cardiac risk factors including hyperlipidemia, hypertension, tobacco use, and obesity. For example, breast cancer and cardiovascular disease (CVD) have many overlapping risk factors [5]. The exact mechanism or the cumulative effect these risk factors have on exacerbating anthracycline toxicity is not known; however, treatment and reduction of these associated risk factors should be an important aspect of these patients’ management plan. In this case report, we examine the case of a 65-year-old male with multiple modifiable cardiovascular risk factors, who developed cardiogenic shock shortly after administration of combination therapy with anthracyclines for the treatment of Hodgkin’s lymphoma.\n\nCase presentation\nA 65-year-old male with a past medical history of hypothyroidism, obesity, hyperlipidemia, hypertension, and type II diabetes presented to the emergency room with increasing weakness and decreased oral intake. He admitted to increasing lethargy, 40 lbs of unintentional weight loss, and had also been experiencing nausea and vomiting. At the time of admission, his vital signs were within normal limits with the exception of a low-grade temperature of 100.3F. His initial physical exam was significant for general pallor and abdominal distension, but was otherwise unremarkable. Laboratory work performed at that time showed pancytopenia with leukocytes of 3.4 g/dl, hemoglobin of 8.9 g/dl (baseline of 10.5 g/dl from three months prior), hematocrit of 27.8% and platelet count of 123 x 10*3/uL. He was also noted to have modest elevation in liver enzymes and lactate dehydrogenase level of 348 U/L. The patient underwent a computed tomography (CT) scan of the abdomen and pelvis, which revealed multiple enlarged pre-aortic, aorto-caval and retro-caval lymph nodes, with the largest node located in the retro-caval region, measuring 3.4 cm (Figure 1). The scan was also remarkable for moderate splenomegaly. Subsequent CT scan of the thorax revealed mediastinal and right hilar lymphadenopathy. Due to concern for underlying malignancy, the inpatient oncology team was consulted.\n\nFigure 1 CT of the abdomen and pelvis demonstrating extensive retroperitoneal lymphadenopathy. Outlined in green is the largest node in the retrocaval area measuring 3.4 cm\nThe patient underwent a positron emission tomography (PET) scan, which revealed widespread uptake including lesions in the bone, liver, spleen, as well as mediastinal and retroperitoneal lymph nodes with additional involvement of the right hilar lymph nodes (Figure 2). Tissue diagnosis was made after the patient underwent mediastinoscopy for lymph node sampling. Pathology was consistent with classic-type Hodgkin’s lymphoma, staged at IVB by Ann Arbor criteria. At this point, the patient’s condition started to deteriorate. He developed persistent fevers with hypotension and decreased urine output and required upgrade to ICU level of care for vasopressor support.\n\nFigure 2 PET study demonstrating widespread involvement of bone, liver, spleen, right hilum, mediastinum and retroperitoneum\n PET - positron emission tomography\n\nOnce he was successfully weaned off vasopressor support and his overall condition appeared to improve, the patient was then initiated on adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) for treatment of lymphoma. An echocardiogram was performed before the initiation of chemotherapy and demonstrated normal left ventricular ejection fraction estimated at 55%-65% (Video 1). There was trivial pericardial effusion; however, no other abnormalities were noted. Given his normal cardiac function the patient was deemed appropriate for chemotherapy treatment. Just prior to starting chemotherapy the patient had a precipitous drop in hemoglobin and hematocrit and overt melena that required blood transfusion before initiating chemotherapy.\n\nVideo 1 Initial echocardiogram demonstrating normal left ventricular systolic function with an estimated ejection fraction of 55%-65%\nThe patient received his first dose of ABVD (dose adjusted for elevated bilirubin) and tolerated the treatment without any issues. The day following the initiation of therapy, the patient was found to be obtunded, hypotensive, and tachycardic. He did not respond to fluid resuscitation and required intubation for worsening hypoxia and airway protection. A CT scan was performed due to concern for pulmonary embolism, which was subsequently found to be negative. The patient was profoundly fluid overloaded at this point and did not respond to aggressive diuresis with furosemide, metolazone or bumetanide. The patient was initiated on continuous venovenous hemofiltration (CVVH) with no improvement in overall condition. Due to profound hypotension, the patient required three vasopressors for hemodynamic support but remained hypotensive. An echocardiogram revealed severe decrease in left ventricular ejection fraction to 15%-25% with Simpson’s biplane ejection fraction of 26% (Video 2). The patient continued to decline and was unable to maintain oxygen saturations despite aggressive ventilator settings. The final cause of death was deemed to be cardiogenic shock secondary to receiving adriamycin in the setting of newly diagnosed IVB Hodgkin’s lymphoma.\n\nVideo 2 Echocardiogram after the initiation of chemotherapy demonstrating severe reduction in left ventricular function with estimated ejection fraction of 15%-25%\nDiscussion\nOur patient developed cardiogenic shock after receiving a single dose of ABVD with adriamycin for Hodgkin’s lymphoma and subsequently died as a result of dilated cardiomyopathy. Although he had an elevated risk profile that included advanced age, hypertension, hyperlipidemia, and type 2 diabetes, the occurrence of cardiotoxicity was unexpected.\n\nAs discussed previously, the greatest factor in anthracycline toxicity is the cumulative dose administered, with toxicity increasing in a stepwise manner. The deleterious effects of these agents typically manifest after treatment is completed and often become clinically significant only years after therapy [1]. Cases of acute onset of doxorubicin toxicity are extremely rare but have been reported in several case reports over the years. Hayek et al. described a case of acute doxorubicin-induced cardiotoxicity following the administration of 50 mg/m2 of doxorubicin while using hepatic artery chemoembolization treatment for carcinoid tumor [6]. Bristow et al. described a similar case of a patient suffering a myocardial infarction within 24 hours of receiving 60 mg/m2 of doxorubicin [7].\n\nGiven the established cardiotoxic effects of anthracyclines, strategies have been developed to reduce the risk of toxicity and to detect early signs of toxicity. Treatment-specific strategies include use of infusion therapy in place of bolus administration, use of liposomal encapsulation of anthracyclines, and the use of cardio-protective agents, such as dexrazoxane [8]. Additionally, the use of echocardiography with strain imaging and monitoring of cardiac biomarkers has allowed for the early detection of subclinical signs of myocardial injury [9]. Despite being effective, these strategies often do not take into consideration the treatment of modifiable cardiac risk factors such as hypertension. In a study by Szmit S et al. it was found that hypertension itself intensified the effects of doxorubicin toxicity and hence caused delay in treatment and subsequent worse outcomes [10].\n\nIn patients receiving chemotherapeutic agents, such as the patient presented here, we believe that pretreatment with and concurrent use of agents targeting pre-existing cardiac risk factors such as beta-blockers, ace inhibitors, and statins may play a significant role in decreasing risk of toxicity, although this was challenging and not feasible in our patient, given his overall clinical picture. Pretreatment with these agents as a means of decreasing cardiotoxicity from anthracyclines has shown to be promising in research, but remains underutilized in practice and not yet part of standard guideline therapy. Furthermore, how these agents would decrease the risk of acute doxorubicin toxicity is not known. A study by Kalay et al. showed that prophylactic beta-blocker use decreased the incidence of reduced ejection fraction [11]. Avila et al. also showed that prophylactic use of carvedilol was associated with lower incidence of early onset diastolic dysfunction and lower levels of cardiac biomarkers [12]. Additional studies also suggest that statin therapy decreases the incidence of heart failure in breast cancer patients treated with anthracyclines [13]. These studies were not robust, however, and were too small to formulate guidelines. Current randomized stage III trials by the National Cancer Institute (NCI) to investigate the efficacy of carvedilol in preventing cardiac toxicity in patients with metastatic Her-2 positive breast cancer are ongoing.\n\nConclusions\nThe use of prophylactic agents targeting pre-existing cardiac risk factors is not currently part of guideline therapy when using anthracyclines, but given their potential benefits, this may soon change. In our patient, it was not possible to implement these preventative strategies given hypotension and impaired liver function. Also, given the rarity of acute doxorubicin toxicity at such low doses, the use of agents may not have been justified. Nonetheless, when able to safely implement these medications, providers should strongly consider their use to prevent cardiotoxicity.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment Curr Cardiol Rev Volkova M Russell R 214 220 7 2011 22758622 \n2 Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials Cancer Swain SM Whaley FS Ewer MS 2869 2879 97 2003 12767102 \n3 Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline J Clin Oncol Armenian S Lacchetti C Barac A 893 911 35 2017 27918725 \n4 Hyperleukocytosis, leukostasis and leukapheresis: practice management Blood Rev Ganzel C Becker J Mintz PD 117 122 26 2012 22364832 \n5 Cardiovascular disease and breast cancer: where these entities intersect. A scientific statement from the American Heart Association Circulation Mehta LS Watson KE Barac A 30 130 2018 \n6 Acute doxorubicin cardiotoxicity N Engl J Med Hayek ER Speakman E Rehmus E 2456 2457 352 2005 15944435 \n7 Early anthracycline cardiotoxicity Am J Med Bristow M Thompson P Martin R 823 832 65 1978 707541 \n8 Potential therapeutic strategies for hypertension-exacerbated cardiotoxicity of anticancer drugs Oxid Med Cell Longev Kuriakose RK Kukreja RC Xi L 8139861 2016 2016 27829985 \n9 Early detection and prediction of cardiotoxicity in chemotherapy-treated patients Am J Cardiol Sawaya H Sebag IA Plana JC 1375 1380 107 2011 21371685 \n10 Pre-existing arterial hypertension as a risk factor for early left ventricular systolic dysfunction following (R)-CHOP chemotherapy in patients with lymphoma J Am Soc Hypertens Szmit S Jurczak W Zaucha JM 791 799 8 2014 25455004 \n11 Protective effects of carvedilol against anthracycline-induced cardiomyopathy J Am Coll Cardiol Kaley N Basar E Ozdogru I 2258 2262 48 2006 17161256 \n12 Carvedilol for prevention of chemotherapy-related cardiotoxicity: the CECCY Trial J Am Coll Cardiol Avila MS Ayub-Ferreira SM de Barros Wanderley MR Jr 2281 2290 71 2018 29540327 \n13 Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy J Am Coll Cardiol Seicean S Seicean A Plana JC Budd GT Marwick TH 2384 2390 60 2012 23141499\n\n",
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"title": "Case of Anthracycline-induced Cardiogenic Shock: A Call to Optimize Modifiable Cardiac Risk Factors Prior to Chemotherapy.",
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{
"abstract": "Aim: To compare the incidence of febrile neutropenia and related outcomes of prophylactic same-day versus next-day pegfilgrastim/pegfilgrastim-cbqv in patients with lymphoma receiving cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone (CHOP)-like chemotherapy. Methods: Retrospective, real-world, single-institution study. Results: 93 patients received 460 cycles of CHOP-like chemotherapy. The incidence of febrile neutropenia and grade 3/4 chemotherapy-induced neutropenia was 5 and 16.5%, respectively. In 401 cycles pegfilgrastim was administered same-day versus 12 cycles next-day. Febrile neutropenia occurred in 17 cycles versus 0 cycles (p = 1.00) and grade 3/4 chemotherapy-induced neutropenia in 65 cycles (16.2%) versus 1 cycle (16.7%; p = 1.00) with same-day versus next-day pegfilgrastim administration, respectively. Conclusion: Pegfilgrastim may be safely administered on the same day as chemotherapy in patients with lymphoma receiving CHOP-like chemotherapy.",
"affiliations": "Banner University Medical Center, Tucson, AZ 85719, USA.;Center for Health Outcomes & PharmacoEconomic Research, University of Arizona, Tucson, AZ 85721, USA.;Banner University Medical Center, Tucson, AZ 85719, USA.;Banner University Medical Center, Tucson, AZ 85719, USA.;Banner University Medical Center, Tucson, AZ 85719, USA.;Center for Health Outcomes & PharmacoEconomic Research, University of Arizona, Tucson, AZ 85721, USA.",
"authors": "McBride|Ali|A|https://orcid.org/0000-0002-9430-4675;Alrawashdh|Neda|N|https://orcid.org/0000-0002-4663-1831;Bartels|Trace|T|;Moore|Logan|L|;Persky|Daniel|D|;Abraham|Ivo|I|https://orcid.org/0000-0003-0490-4421",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.2217/fon-2021-0532",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1479-6694",
"issue": "17(26)",
"journal": "Future oncology (London, England)",
"keywords": "CHOP; R-CHOP; chemotherapy-induced neutropenia; febrile neutropenia; hospitalization; lymphoma; pegfilgrastim; pegfilgrastim-cbqv; same-day administration",
"medline_ta": "Future Oncol",
"mesh_terms": null,
"nlm_unique_id": "101256629",
"other_id": null,
"pages": "3485-3497",
"pmc": null,
"pmid": "34241542",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Same-day versus next-day pegfilgrastim or pegfilgrastim-cbqv in patients with lymphoma receiving CHOP-like chemotherapy.",
"title_normalized": "same day versus next day pegfilgrastim or pegfilgrastim cbqv in patients with lymphoma receiving chop like chemotherapy"
} | [
{
"companynumb": "US-AMGEN-USASP2021107796",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": "3",
... |
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