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Agalliu I.,Yeshiva University | San Luciano M.,University of California at San Francisco | MirelmanMD A.,Movement Disorders Unit | Giladi N.,Movement Disorders Unit | And 25 more authors.
JAMA Neurology | Year: 2015

IMPORTANCE: Patients with Parkinson disease (PD) who harbor LRRK2 G2019S mutations may have increased risks of nonskin cancers. However, the results have been inconsistent across studies. OBJECTIVES: To analyze pooled data from 5 centers to further examine the association between LRRK2 G2019S mutation and cancer among patients with PD and to explore factors that could explain discrepancies. DESIGN, SETTING, AND PARTICIPANTS: Clinical, demographic, and genotyping data aswell as cancer outcomes were pooled from 1549 patients with PD recruited across 5movement disorders clinics located in Europe, Israel, and the United States. Associations between LRRK2 G2019S mutation and the outcomes were examined using mixed-effects logistic regression models to estimate odds ratios (ORs) and 95%CIs. Models were adjusted for age and ethnicity (Ashkenazi Jewish vs others) as fixed effects and study center as a random effect. MAIN OUTCOMES AND MEASURES: All cancers combined, nonskin cancers, smoking-related cancers, hormone-related cancers, and other types of cancer. RESULTS: The overall prevalence of the LRRK2 G2019S mutation was 11.4%among all patients with PD. Mutation carriers were younger at PD diagnosis and more likely to be women (53.1%) and of Ashkenazi Jewish descent (76.8%) in comparison with individuals who were not mutation carriers. The LRRK2 G2019S mutation carriers had statistically significant increased risks for nonskin cancers (OR, 1.62; 95%CI, 1.04-2.52), hormone-related cancers (OR, 1.87; 95%CI, 1.07-3.26) and breast cancer (OR, 2.34; 95%CI, 1.05-5.22) in comparison with noncarriers. There were no associations with other cancers. There were no major statistically significant differences in the results when the data were stratified by Ashkenazi Jewish ethnicity; however, there was some evidence of heterogeneity across centers. CONCLUSIONS AND RELEVANCE: This multinational study from 5 centers demonstrates that LRRK2 G2019S mutation carriers have an overall increased risk of cancer, especially for hormone-related cancer and breast cancer in women. Larger prospective cohorts or family-based studies investigating associations between LRRK2 mutations and cancer among patients with PD are warranted to better understand the underlying genetic susceptibility between PD and hormone-related cancers. Copyright 2014 American Medical Association. All rights reserved.


Elad S.,University of Rochester | Jensen S.B.,Copenhagen University | Raber-Durlacher J.E.,University of Amsterdam | Raber-Durlacher J.E.,Academic Center for Dentistry Amsterdam | And 14 more authors.
Supportive Care in Cancer | Year: 2015

Background: The oral cavity is frequently affected in chronic graft-versus-host disease (cGVHD), with variable clinical presentations. The literature on the effective management of patients suffering from oral cGVHD is limited. Objective: The objective of this study was to assess the clinical approaches used in the diagnosis and treatment of cGVHD in a group of health-care providers specialized in the oral care of oncology patients. The secondary objective was to assess the level of implementation of the National Institutes of Health (NIH) guidelines for cGVHD patients. Methods: One hundred twenty questionnaires were sent to the members of the Oral Care Study Group (OCSG) of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). The questionnaire included 50 questions about the responder’s demographics, level of exposure to cGVHD patients, diagnostic and evaluation methods in their practice, preferred treatment strategies for mucosal and salivary gland involvement, and preventive measures. Results: Twelve responders, representing 12 sites, stated that they treat oral cGVHD patients on a regular basis. This fraction of responders was confirmed by another online survey. Eleven out of the 12 providers were dentists. Seventy-five percent of the providers did not use biopsy in order to diagnose oral cGVHD. The NIH scale for the clinical assessment was used sporadically. The first-line topical treatment for oral mucosal cGVHD was predominantly steroids (91.7 %), and the second preferred treatment was tacrolimus (41.7 %). The preferred treatment for hyposalivation was pilocarpine (41.7 %). The recommended frequency of oral cancer screening varied; half of the providers suggest a follow-up every 6 months. Conclusions: The responses described the common practices for oral cGVHD in several specialized centers across the world. The choice of topical treatments was influenced by the availability of medications in the provider’s country. © 2014, Springer-Verlag Berlin Heidelberg.


Rex D.K.,Indiana University | Adler S.N.,Digestive Diseases Institute | Aisenberg J.,Mount Sinai School of Medicine | Burch W.C.,Franklin Gastroenterology PLLC | And 18 more authors.
Gastroenterology | Year: 2015

Background & Aims Capsule colonoscopy is a minimally invasive imaging method. We measured the accuracy of this technology in detecting polyps 6 mm or larger in an average-risk screening population. Methods In a prospective study, asymptomatic subjects (n = 884) underwent capsule colonoscopy followed by conventional colonoscopy (the reference) several weeks later, with an endoscopist blinded to capsule results, at 10 centers in the United States and 6 centers in Israel from June 2011 through April 2012. An unblinded colonoscopy was performed on subjects found to have lesions 6 mm or larger by capsule but not conventional colonoscopy. Results Among the 884 subjects enrolled, 695 (79%) were included in the analysis of capsule performance for all polyps. There were 77 exclusions (9%) for inadequate cleansing and whole-colon capsule transit time fewer than 40 minutes, 45 exclusions (5%) before capsule ingestion, 15 exclusions (2%) after ingestion and before colonoscopy, and 15 exclusions (2%) for site termination. Capsule colonoscopy identified subjects with 1 or more polyps 6 mm or larger with 81% sensitivity (95% confidence interval [CI], 77%-84%) and 93% specificity (95% CI, 91%-95%), and polyps 10 mm or larger with 80% sensitivity (95% CI, 74%-86%) and 97% specificity (95% CI, 96%-98%). Capsule colonoscopy identified subjects with 1 or more conventional adenomas 6 mm or larger with 88% sensitivity (95% CI, 82%-93) and 82% specificity (95% CI, 80%-83%), and 10 mm or larger with 92% sensitivity (95% CI, 82%-97%) and 95% specificity (95% CI, 94%-95%). Sessile serrated polyps and hyperplastic polyps accounted for 26% and 37%, respectively, of false-negative findings from capsule analyses. Conclusions In an average-risk screening population, technically adequate capsule colonoscopy identified individuals with 1 or more conventional adenomas 6 mm or larger with 88% sensitivity and 82% specificity. Capsule performance seems adequate for patients who cannot undergo colonoscopy or who had incomplete colonoscopies. Additional studies are needed to improve capsule detection of serrated lesions. Clinicaltrials.gov number: NCT01372878. © 2015 AGA Institute.


Ben-Ari Z.,Liver Disease Center | Ben-Ari Z.,Liver Research Laboratory Tel Hashomer | Ben-Ari Z.,Tel Aviv University | Issan Y.,Research Laboratory | And 9 more authors.
Apoptosis | Year: 2013

Ischemia/reperfusion (I/R) injury is the main cause of primary graft dysfunction of liver allografts. Cobalt-protoporphyrin (CoPP)-dependent induction of heme oxygenase (HO)-1 has been shown to protect the liver from I/R injury. This study analyzes the apoptotic mechanisms of HO-1-mediated cytoprotection in mouse liver exposed to I/R injury. HO-1 induction was achieved by the administration of CoPP (1.5 mg/kg body weight i.p.). Mice were studied in in vivo model of hepatic segmental (70 %) ischemia for 60 min and reperfusion injury. Mice were randomly allocated to four main experimental groups (n = 10 each): (1) A control group undergoing sham operation. (2) Similar to group 1 but with the administration of CoPP 72 h before the operation. (3) Mice undergoing in vivo hepatic I/R. (4) Similar to group 3 but with the administration of CoPP 72 h before ischemia induction. When compared with the I/R mice group, in the I/R+CoPP mice group, the increased hepatic expression of HO-1 was associated with a significant reduction in liver enzyme levels, fewer apoptotic hepatocytes cells were identified by morphological criteria and by immunohistochemistry for caspase-3, there was a decreased mean number of proliferating cells (positively stained for Ki67), and a reduced hepatic expression of: C/EBP homologous protein (an index of endoplasmic reticulum stress), the NF-κB's regulated genes (CIAP2, MCP-1 and IL-6), and increased hepatic expression of IκBa (the inhibitory protein of NF-κB). HO-1 over-expression plays a pivotal role in reducing the hepatic apoptotic IR injury. HO-1 may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation. © 2013 Springer Science+Business Media New York.


Mezei G.,Exponent, Inc. | Sudan M.,University of California at Los Angeles | Izraeli S.,Sheba Medical Center Tel Hashomer | Izraeli S.,Tel Aviv University | Kheifets L.,University of California at Los Angeles
Cancer Epidemiology | Year: 2014

Down syndrome (DS) is a common congenital anomaly, and children with DS have a substantially higher risk of leukemia. Although understanding of genetic and epigenetic changes of childhood leukemia has improved, the causes of childhood leukemia and the potential role of environmental exposures in leukemogenesis remain largely unknown. Although many epidemiologic studies have examined a variety of environmental exposures, ionizing radiation remains the only generally accepted environmental risk factor for childhood leukemia. Among suspected risk factors, infections, exposure to pesticides, and extremely low frequency magnetic fields are notable. While there are well-defined differences between leukemia in children with and without DS, studies of risk factors for leukemia among DS children are generally consistent with trends seen among non-DS (NDS) children.We provide background on DS epidemiology and review the similarities and differences in biological and epidemiologic features of leukemia in children with and without DS. We propose that both acute lymphoblastic and acute myeloblastic leukemia among DS children can serve as an informative model for development of childhood leukemia. Further, the high rates of leukemia among DS children make it possible to study this disease using a cohort approach, a powerful method that is unfeasible in the general population due to the rarity of childhood leukemia. © 2014 Elsevier Ltd.


Keidan I.,Sheba Medical Center Tel Hashomer | Keidan I.,University of Florida | Ben-Menachem E.,Sheba Medical Center Tel Hashomer | Berger R.,Sheba Medical Center Tel Hashomer | And 2 more authors.
Journal of Vascular Access | Year: 2015

Purpose: To determine the feasibility and effectiveness of using a single injection of diluted sodium bicarbonate, while monitoring exhaled carbon dioxide changes, to reliably confirm correct placement of intravenous (IV) catheters. Methods: The study was conducted in the oncology day care clinic at a tertiary care center and included a selected group of patients with various oncological conditions who required IV chemotherapy. In each patient a newly inserted peripheral IV catheter or newly accessed central line was deemed positively intravascular if they had good blood return or most probably intravascular if there was no blood return but they flushed easily. This clinical diagnosis of correct positioning, was correlated with the results of a single injection of dilute sodium on the exhaled carbon dioxide, and with the ability of a blinded observer to report whether sodium bicarbonate or saline was injected. Results: A total of 67 patients were enrolled in the study; 56 had positively intravascular IV catheter while 11 had most probably intravascular IV catheter. A single injection of 20 mL 4.2% sodium bicarbonate had a positive and clinically detectable response that was diagnosed with high sensitivity and specificity. Conclusions: IV injection of 20 mL of 4.2% sodium bicarbonate with exhaled carbon dioxide monitoring can be used to reliably confirm correct intravascular placement of a catheter intended to be used for chemotherapy. © 2015 Wichtig Publishing.


De Castro H.,Sheba Medical Center Tel Hashomer | De Castro H.,Tel Aviv University | Haas J.,Sheba Medical Center Tel Hashomer | Haas J.,Tel Aviv University | And 8 more authors.
BJOG: An International Journal of Obstetrics and Gynaecology | Year: 2016

Objective To assess the success rate of vaginal delivery among women with twin pregnancies; the Twin Birth Study has shown that vaginal delivery and caesarean section are equally safe for twin delivery but >40% of the planned vaginal delivery group delivered by caesarean section. Design A retrospective cohort study. Setting A tertiary medical centre. Population A total of 2194 women with twin pregnancies not complicated with very low birthweight. Methods Planned mode of delivery was documented in the woman's electronic record upon entering the delivery room. Information regarding maternal age at delivery, parity, gestational age, presentation, previous history of caesarean delivery, birthweight and Apgar score was collected from the obstetric electronic charts. Main outcome measured Rate of vaginal twin delivery. Results Of the 2194 women included, 1311 twin pregnancies had planned caesarean delivery and 883 underwent a trial of labour. Of the 883 women who underwent a trial of labour, the rate of vaginal delivery was 86.9%, whereas the rates of caesarean delivery and combined vaginal-caesarean delivery were 11.1% and 2.0%, respectively. Presentation of second twin, gestational age and maternal age did affect the chances of success. Nulliparity [odds ratio (OR) 2.38, 95% confidence interval (95% CI) 1.4-4.05], Foley induction of labour (OR 2.33, 95% CI 1.38-3.91) and body mass index >30 kg/m2 (OR 1.76, 95% CI 1.03-3) were independent risk factors for caesarean delivery. Conclusions The rate of vaginal delivery among women with twin pregnancies who undergo labour can be high, especially in women who laboured spontaneously and have delivered before. Tweetable abstract The rate of vaginal delivery of twins can be high, especially in women who have delivered before. © 2015 Royal College of Obstetricians and Gynaecologists.


Weisshof R.,Rambam Health Care Campus | Weisshof R.,Technion - Israel Institute of Technology | Ungar B.,Sheba Medical Center Tel Hashomer | Blatt A.,Rambam Health Care Campus | And 9 more authors.
Inflammatory Bowel Diseases | Year: 2016

Background: About 60% of infliximab (IFX)-treated patients develop antidrug antibodies (ADA), although their clinical significance remains disputed. The aim of this study was to develop an assay for assessing ADA-neutralizing potential, and clinical significance. Methods: An immune assay was devised in which the inhibition of IFX binding to plated-tumor necrosis factor in the presence of patient sera or controls, was assessed and defined as IFX-tumor necrosis factor binding reduction ratio (ITBR). The assay was compared to a bioassay in which tumor necrosis factor-α-induced interleukin-8 secretion from HT-29 cells was assessed after addition of IFX to ADA-containing sera or control sera. Results: Both assays detected neutralizing antibodies in 39 of 44 ADA-positive sera. The median ITBR was 3.66 (mean 4.9 ± 3.2) in 29 ADA-positive patients with loss of response (LOR), and 1.3 (mean 1.9 ± 1.3) in 15 patients without LOR (P 0.001). ADA titers in both groups were similar (median 9.5 and 10.2 g/mL, respectively P 0.74). Using an ITBR of 1.65, the sensitivity for LOR detection was 86.2% and the specificity was 66.7%. (positive predictive value 83%; negative predictive value 71.4%; P 0.001). When early ADA-IFX-sera from IFX-treated patients with or without subsequent LOR were compared, the median ITBRs were 1.1 and 0.57, respectively (P 0.028). Conclusions: Detection of neutralizing antibody activity was superior to antibody quantization by enzyme-linked immunosorbent assay with respect to correlation with clinical LOR, and for prediction of subsequent LOR. These findings may assist in optimizing infliximab therapy in patients with inflammatory bowel disease. © Copyright 2016 Crohn's & Colitis Foundation of America, Inc.


PubMed | Sheba Medical Center Tel Hashomer
Type: Journal Article | Journal: Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology | Year: 2012

Patients with five or more unexplained recurrent pregnancy losses (RPL) have a poor prognosis for a subsequent delivery compared to patients with two to three RPL. Treatment guidelines are needed to address this select group of patients.


PubMed | Sheba Medical Center Tel Hashomer, Institute of Pathology, Institute of Human Genetics and Sheba Medical Center
Type: Journal Article | Journal: Ultrasound international open | Year: 2016

Walker-Warburg phenotype is a severe and lethal autosomal recessive disorder, belonging to a group of congenital malformations defined as abnormal pial basement membrane formation. So far, prenatal diagnosis was considered possible only during late pregnancy.First trimester assessment of a pregnancy suspected to be affected by Walker-Warburg phenotype, using a high-resolution transvaginal ultrasound probe (6-12MHz), T2 MR imaging (1.5T), molecular genetics and histopathology.Very early diagnosis of the Walker-Warburg phenotype at 11 weeks of gestation proved possible by depicting the classic signs of this entity, confirmed by molecular genetics, post-abortion MR imaging and histopathology.Advancements in ultrasound equipment and technology, molecular genetics and histopathology have made very early detection of this syndrome possible, thus shedding new light on the natural history of this malformation.

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