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Bodo S.,French Institute of Health and Medical Research | Bodo S.,University ParisParis | Colas C.,French Institute of Health and Medical Research | Colas C.,University ParisParis | And 61 more authors.
Gastroenterology | Year: 2015

Background & Aims Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD. Methods We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD. Results In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features. Conclusion The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients. © 2015 AGA Institute. Source

Robert C.,University Paris - Sud | Robert C.,University of Sydney | Schachter J.,Ella Lemelbaum Institute for Melanoma | Schachter J.,University of Sydney | And 25 more authors.
New England Journal of Medicine | Year: 2015

Background The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. Methods In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival. Results The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P = 0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P = 0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%). Conclusions The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. © 2015 Massachusetts Medical Society. Source

Assayag M.,Hadassah Hebrew University Medical CenterJerusalem | Goldstein S.,Hebrew University of Jerusalem | Samuni A.,Hebrew University of Jerusalem | Berkman N.,Hadassah Hebrew University Medical CenterJerusalem
Free Radical Biology and Medicine | Year: 2015

The effects of stable cyclic nitroxide radicals have been extensively investigated both in vivo and in vitro demonstrating anti-inflammatory, radioprotective, anti-mutagenic, age-retardtogenic activities. Yet, these stable radicaant, hypotensive, anti-cancer and anti-terals have not been evaluated in asthma and other airway inflammatory disorders. The present study investigated the effect of 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (TPL) and 3-carbamoyl-proxyl (3-CP) in a mouse model of ovalbumin (OVA)-induced allergic asthma. Both 3-CP and TPL were non-toxic when administered either orally (1% w/w nitroxide-containing chow) or via intraperitoneal (IP) injection (∼300 mg/kg). Feeding the mice orally demonstrated that 3-CP was more effective than TPL in reducing inflammatory cell recruitment into the airway and in suppressing airway hyper-responsiveness (AHR) in OVA-challenged mice. To characterize the optimal time-window of intervention and mode of drug administration, 3-CP was given orally during allergen sensitization, during allergen challenge or during both sensitization and challenge stages, and via IP injection or intranasal instillation for 3 days during the challenge period. 3-CP given via all modes of delivery markedly inhibited OVA-induced airway inflammation, expression of cytokines, AHR and protein nitration of the lung tissue. Oral administration during the entire experiment was the most efficient delivery of 3-CP and was more effective than dexamethasone a potent corticosteroid used for asthma treatment. Under a similar administration regimen (IP injection before the OVA challenge), the effect of 3-CP was similar to that of dexamethasone and even greater on AHR and protein nitration. The protective effect of the nitroxides, which preferentially react with free radicals, in suppressing the increase of main asthmatic inflammatory markers substantiate the key role played by reactive oxygen and nitrogen species in the molecular mechanism of asthma. The present results demonstrate the therapeutic potential of nitroxides for the treatment of asthma. © 2015 Published by Elsevier Inc. Source

Langer D.,Hadassah and Hebrew University | Luria S.,Hadassah Hebrew University Medical CenterJerusalem | Bar-Haim Erez A.,Ono Academic College | Michailevich M.,Sherutay Briut ClalitJerusalem | And 2 more authors.
Journal of Hand Therapy | Year: 2015

Study design Cross-sectional. Introduction Stenosing flexor tenosynovitis (SFT) is a common hand disease, yet there is a lack of valid standard assessments for this population. Purpose of the study Validation of assessment for the evaluation of disability and quality of life related to SFT clinical severity. Methods Sixty five participants with SFT were matched to 71 controls. Participant's symptoms were graded using the Quinnell classification. Disability and quality of life were evaluated using the DASH and WHOQOL-BREF questionnaires. Results Small to moderate correlations were found between SFT grade and the DASH and WHOQOL-BREF. Both questionnaires differentiated between the first and third clinical grades and between SFT and healthy groups. Discussion Both questionnaires are useful tools to distinguish between participants with SFT and controls and between mild and severe clinical grades. Conclusion The DASH and WHOQOL-BREF may be implemented in the clinical management and research of SFT. Level of evidence Diagnostic III © 2015 Hanley & Belfus. Source

Mansura A.,Hadassah Hebrew University Medical CenterJerusalem | Maly A.,Hadassah Hebrew University Medical CenterJerusalem | Ramot Y.,Hadassah Hebrew University Medical CenterJerusalem | Zlotogorski A.,Hadassah Hebrew University Medical CenterJerusalem
Dermatology Online Journal | Year: 2015

Acantholytic dermatosis of the vulva is a rare condition, presenting with papular eruption in the genital area without history of Darier disease or Hailey-Hailey disease. We report a case with a papular pruritic eruption in the region of the vulva, coalescing into plaques. Biopsy specimen showed irregular acanthosis with an area of split-like bullous formation in the deeper part of the epidermis, as well as acantholytic cells, marked hypergranulosis and hyperkeratosis, compatible with the rare diagnosis of acantholytic dermatosis of the vulva. We review the clinical and histological characteristics of this uncommon disease. © 2015 by the article author(s). Source

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