Publications by authors named "Revital Kariv"

78 Publications

A CRISPR knockout screen reveals new regulators of canonical Wnt signaling.

Authors:
Tamar Evron Michal Caspi Michal Kazelnik Yarden Shor-Nareznoy Shir Armoza-Eilat Revital Kariv Zohar Manber Ran Elkon Ella H Sklan Rina Rosin-Arbesfeld

Oncogenesis 2021 Sep 22;10(9):63. Epub 2021 Sep 22.

Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

The Wnt signaling pathways play fundamental roles during both development and adult homeostasis. Aberrant activation of the canonical Wnt signal transduction pathway is involved in many diseases including cancer, and is especially implicated in the development and progression of colorectal cancer. Although extensively studied, new genes, mechanisms and regulatory modulators involved in Wnt signaling activation or silencing are still being discovered. Here we applied a genome-scale CRISPR-Cas9 knockout (KO) screen based on Wnt signaling induced cell survival to reveal new inhibitors of the oncogenic, canonical Wnt pathway. We have identified several potential Wnt signaling inhibitors and have characterized the effects of the initiation factor DExH-box protein 29 (DHX29) on the Wnt cascade. We show that KO of DHX29 activates the Wnt pathway leading to upregulation of the Wnt target gene cyclin-D1, while overexpression of DHX29 inhibits the pathway. Together, our data indicate that DHX29 may function as a new canonical Wnt signaling tumor suppressor and demonstrates that this screening approach can be used as a strategy for rapid identification of novel Wnt signaling modulators.
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http://dx.doi.org/10.1038/s41389-021-00354-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458386PMC
September 2021

Proton pump inhibitors long term use-trends and patterns over 15 years of a large health maintenance organization.

Authors:
Vered Rosenberg Roie Tzadok Gabriel Chodick Revital Kariv

Pharmacoepidemiol Drug Saf 2021 Nov 6;30(11):1576-1587. Epub 2021 Sep 6.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Proton pump inhibitors (PPI) are used for a variety of indications. Despite reported associations with undesirable effects, their long-term use is on the rise, while appropriate indications, dose, and treatment duration may deviate from guideline recommendations.

Objectives: Primary to examine the annual patterns of PPI use. Secondary- to assess indications for initiating PPI treatment, long-term use, and factors associated with long-term use in a large Israeli health maintenance organization.

Methods: A historical cohort study of 528 420 eligible PPI users during 2000-2015, analyzed PPI use using defined daily doses and the proportion of patients covered method. Data on indications for treatment initiation, clinical and socio-demographic parameters were captured as well. A multivariable logistic-regression model was used to identify factors associated with long-term use of PPI.

Results: The annual incidence rates of patients initiating PPI treatment were relatively constant, ranging between 2.4% and 3.1% of the adult population, with a monotonic increase in annual consumption and prevalence (reaching 12.7% in 2015). Reflux, functional symptoms, and Helicobacter pylori eradication were the most common indications for initiating PPI therapy. However, 27% of patients had no recorded indication for treatment. Fifteen percent of patients used PPI for over 6 months, especially in older age groups.

Conclusions: Utilization of PPI increases steadily, mainly due to chronic use. Prolonged consumption is associated with specific clinical indications and older age. Health organizations should encourage awareness of appropriate use among physicians, specifically in the elderly, patients with reflux, and those with functional disorders.
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http://dx.doi.org/10.1002/pds.5352DOI Listing
November 2021

Diagnosis and classification of ileal pouch disorders: consensus guidelines from the International Ileal Pouch Consortium.

Authors:
Bo Shen Gursimran S Kochhar Revital Kariv Xiuli Liu Udayakumar Navaneethan David T Rubin Raymond K Cross Akira Sugita André D'Hoore Jason Schairer Francis A Farraye Ravi P Kiran Philip Fleshner Joel Rosh Samir A Shah Shannon Chang Ellen Scherl Darrell S Pardi David A Schwartz Paulo G Kotze David H Bruining Sunanda V Kane Jessica Philpott Bincy Abraham Jonathan Segal Rocio Sedano Maia Kayal Stuart Bentley-Hibbert Dino Tarabar Sandra El-Hachem

Lancet Gastroenterol Hepatol 2021 10 18;6(10):826-849. Epub 2021 Aug 18.

Division of Gastroenterology, Hepatology, and Nutrition, Allegheny Health Network, Pittsburgh, PA, USA.

Restorative proctocolectomy with ileal pouch-anal anastomosis is an option for most patients with ulcerative colitis or familial adenomatous polyposis who require colectomy. Although the construction of an ileal pouch substantially improves patients' health-related quality of life, the surgery is, directly or indirectly, associated with various structural, inflammatory, and functional adverse sequelae. Furthermore, the surgical procedure does not completely abolish the risk for neoplasia. Patients with ileal pouches often present with extraintestinal, systemic inflammatory conditions. The International Ileal Pouch Consortium was established to create this consensus document on the diagnosis and classification of ileal pouch disorders using available evidence and the panellists' expertise. In a given individual, the condition of the pouch can change over time. Therefore, close monitoring of the activity and progression of the disease is essential to make accurate modifications in the diagnosis and classification in a timely manner.
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http://dx.doi.org/10.1016/S2468-1253(21)00101-1DOI Listing
October 2021

Abdominal Desmoid: Course, Severe Outcomes, and Unique Genetic Background in a Large Local Series.

Authors:
Gilad Ophir Shamai Sivan Strul Hana Rosner Guy Gluck Nathan Fliss Isakov Naomi Klausner Joseph Wolf Ido Merimsky Ofer Goldberg Yael Levi Zohar Zer Alona Kariv Revital

Cancers (Basel) 2021 Jul 22;13(15). Epub 2021 Jul 22.

Tel-Aviv Medical Center, Department of Gastroenterology and Hepatology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 6997801, Israel.

Introduction: Abdominal desmoid tumors are locally aggressive tumors that develop in familial adenomatous polyposis (FAP) patients, within the mesentery or abdominal wall. The understanding and implications of the treatment regimens are evolving.

Aim: To assess the course, treatment, and outcomes of FAP and non-FAP abdominal desmoids and their related genetic alterations.

Methods: Retrospective cohort study. Demographics, tumor characteristics, oncological and surgical history, complications, genetic-testing, and mortality data were retrieved from two tertiary referral centers.

Results: Sixty-two patients were identified (46 FAP and 16 non-FAP). Thirty-eight patients (61.3%) underwent surgical procedures (12 urgent and 26 elective). Out of 33 tumor resections, 39.4% recurred. Hormonal therapy, COX-inhibitors, chemotherapy, imatinib, and sorafenib were used in 35 (56.4%), 30 (48.4%), 18 (29.1%), 7 (11.3%), and 8 (12.9%) of patients, respectively, with a 2 year progression-free survival of 67.8%, 57.7%, 38.4%, and 28.5%, respectively. Forty-one patients (66.1%) suffered complications: bowel obstruction (30.6%), hyperalimentation (14.5%), ureteral obstruction (12.9%), perforation (11.3%), abscess formation (3.2%), and spinal cord compression (3.2%). Non-FAP patients carried pathogenic mutations in and .

Conclusions: Abdominal desmoids are mostly FAP-related and are associated with severe outcomes. We also report a group of non-FAP abdominal desmoids, which includes patients with additional cancer-related gene alterations. This interesting group should be further explored.
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http://dx.doi.org/10.3390/cancers13153673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345061PMC
July 2021

Antibiotic use differentially affects the risk of anti-drug antibody formation during anti-TNFα therapy in inflammatory bowel disease patients: a report from the epi-IIRN.

Authors:
Yuri Gorelik Shay Freilich Shiran Gerassy-Vainberg Sigal Pressman Chagit Friss Alexandera Blatt Gili Focht Yiska Loewenberg Weisband Shira Greenfeld Revital Kariv Nathan Lederman Iris Dotan Naama Geva-Zatorsky Shai Shlomo Shen-Orr Yechezkel Kashi Yehuda Chowers

Gut 2021 Aug 3. Epub 2021 Aug 3.

Gastroenterology, Rambam Health Care Campus, Haifa, Israel

Objective: Anti-drug antibodies (ADA) to anti-tumour necrosis factor (anti-TNF) therapy drive treatment loss of response. An association between intestinal microbial composition and response to anti-TNF therapy was noted. We therefore aimed to assess the implications of antibiotic treatments on ADA formation in patients with inflammatory bowel disease (IBD).

Design: We analysed data from the epi-IIRN (epidemiology group of the Israeli IBD research nucleus), a nationwide registry of all patients with IBD in Israel. We included all patients treated with anti-TNF who had available ADA levels. Survival analysis with drug use as time varying covariates were used to assess the association between antibiotic use and ADA development. Next, specific pathogen and germ-free C57BL mice were treated with respective antibiotics and challenged with infliximab. ADA were assessed after 14 days.

Results: Among 1946 eligible patients, with a median follow-up of 651 days from initiation of therapy, 363 had positive ADA. Cox proportional hazard model demonstrated an increased risk of ADA development in patients who used cephalosporins (HR=1.97, 95% CI 1.58 to 2.44), or penicillins with β-lactamase inhibitors (penicillin-BLI, HR=1.4, 95% CI 1.13 to 1.74), whereas a reduced risk was noted in patients treated with macrolides (HR=0.38, 95% CI 0.16 to 0.86) or fluoroquinolones (HR=0.20, 95% CI 0.12 to 0.35). In mice exposed to infliximab, significantly increased ADA production was observed in cephalosporin as compared with macrolide pretreated mice. Germ-free mice produced no ADA.

Conclusion: ADA production is associated with the microbial composition. The risk of ADA development during anti-TNF therapy can possibly be reduced by avoidance of cephalosporins and penicillin-BLIs, or by treatment with fluoroquinolones or macrolides.
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http://dx.doi.org/10.1136/gutjnl-2021-325185DOI Listing
August 2021

BNT162b2 Messenger RNA COVID-19 Vaccine Effectiveness in Patients With Inflammatory Bowel Disease: Preliminary Real-World Data During Mass Vaccination Campaign.

Authors:
Amir Ben-Tov Tamar Banon Gabriel Chodick Revital Kariv Amit Assa Sivan Gazit

Gastroenterology 2021 Nov 2;161(5):1715-1717.e1. Epub 2021 Jul 2.

Maccabi Institute for Research & Innovation, Maccabi Healthcare Services, Tel Aviv, Israel.

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http://dx.doi.org/10.1053/j.gastro.2021.06.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252826PMC
November 2021

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in and : A Prospective Lynch Syndrome Database Study.

Authors:
Mev Dominguez-Valentin John-Paul Plazzer Julian R Sampson Christoph Engel Stefan Aretz Mark A Jenkins Lone Sunde Inge Bernstein Gabriel Capella Francesc Balaguer Finlay Macrae Ingrid M Winship Huw Thomas Dafydd Gareth Evans John Burn Marc Greenblatt Wouter H de Vos Tot Nederveen Cappel Rolf H Sijmons Maartje Nielsen Lucio Bertario Bernardo Bonanni Maria Grazia Tibiletti Giulia Martina Cavestro Annika Lindblom Adriana Della Valle Francisco Lopez-Kostner Karin Alvarez Nathan Gluck Lior Katz Karl Heinimann

J Clin Med 2021 Jun 28;10(13). Epub 2021 Jun 28.

Medical Genetics, Institute for Medical Genetics and Pathology, University Hospital Basel, 4031 Basel, Switzerland.

Background: Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown.

Objective: To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the and genes.

Methods: Carriers of pathogenic variants of () and () genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity.

Results: Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately.

Conclusion: Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of and .
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http://dx.doi.org/10.3390/jcm10132856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269121PMC
June 2021

Ultra-processed food is associated with features of metabolic syndrome and non-alcoholic fatty liver disease.

Authors:
Dana Ivancovsky-Wajcman Naomi Fliss-Isakov Muriel Webb Itay Bentov Oren Shibolet Revital Kariv Shira Zelber-Sagi

Liver Int 2021 Nov 14;41(11):2635-2645. Epub 2021 Jul 14.

School of Public Health, University of Haifa, Haifa, Israel.

Background & Aims: High consumption of ultra-processed food (UPF) is associated with mortality and chronic morbidity but has not been studied concerning to non-alcoholic fatty liver disease (NAFLD). We aimed to test the association of UPF consumption with metabolic syndrome, NAFLD and related-liver damage.

Methods: A cross-sectional study among volunteers who underwent abdominal ultrasound (AUS), anthropometrics, blood pressure measurements, and fasting blood tests including FibroMax for non-invasive assessment of NASH and significant fibrosis. A food-frequency questionnaire was used to evaluate UPF consumption using the NOVA classification.

Results: A total of 789 subjects were included in the total sample (mean age 58.83 ± 6.58 years, 52.60% men), a reliable FibroMax test was obtained from 714 subjects, 305 subjects were diagnosed with NAFLD. High consumption of UPF was associated with higher odds for metabolic syndrome (OR = 1.88, 95% CI 1.31-2.71, P = .001) and its components; hypertension, hypertriglyceridemia, and low HDL, among the entire sample (OR = 1.53, 1.07-2.19, P = .026; OR = 1.51, 1.08-2.11, P = .017; OR = 1.55, 1.05-2.29, P = .028). In addition, it was associated with higher odds for NASH and hypertension (OR = 1.89, 1.07-3.38, P = .030; OR = 2.26, 1.20-4.26, P = .012 respectively) among subjects with NAFLD. Stratification by smoking status revealed an association between high UPF consumption and significant fibrosis among ever smokers in the entire sample and among subjects with NAFLD (OR = 1.89, 95% CI 1.03-3.45, P = .039; OR = 2.85, 1.14-7.14, P = .026 respectively).

Conclusions: High UPF consumption is associated with metabolic syndrome in the general population, and among those with NAFLD it is associated with NASH marker. Ever-smoking may act synergistically with UPF to amplify the risk for fibrosis.
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http://dx.doi.org/10.1111/liv.14996DOI Listing
November 2021

Post-polypectomy surveillance colonoscopy: Comparison of the updated guidelines.

Authors:
Naim Abu-Freha Lior H Katz Revital Kariv Elez Vainer Ido Laish Nathan Gluck Elizabeth E Half Zohar Levi

United European Gastroenterol J 2021 Jul 2;9(6):681-687. Epub 2021 Jun 2.

Department of Gastroenterology, Beilinson Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Recently, three updated guidelines for post-polypectomy colonoscopy surveillance (PPCS) have been published. These guidelines are based on a comprehensive summary of the literature, while some recommendations are similar, different surveillance intervals are recommended after detection of specific types of polyps.

Aim: In this review, we aimed to compare and contrast these recommendations.

Methods: The updated guidelines for PPCS were reviewed and the recommendations were compared.

Results: For patients with 1-4 adenomas <10 mm with low-grade dysplasia, irrespective of villous components, or 1-4 serrated polyps <10 mm without dysplasia, the European Society of Gastrointestinal Endoscopy (ESGE) and British Society of Gastroenterology (BSG), the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and Public Health England (PHE) (BSG/ACPGBI/PHE) guidelines do not recommend colonoscopic surveillance and instead recommend that the participate in routine CRC screening program (typically based on the fecal immunochemical test), while the USMSTF recommends surveillance colonoscopies 7-10 years after diagnosis of 1-2 tubular adenomas <10 mm and 3-5 years for 3-4 tubular adenomas of the same size. The USMSTF define adenomas with tubulovillous or villous histology as high-risk adenomas; thus, surveillance colonoscopy is recommended after 3 years. However, the ESGE and BSG do not consider such histology as a criterion for repeating colonoscopy at this short interval. For patients with 1-2 sessile serrated polyps (SSPs) <10 mm and those with 3-4 SSPs <10 mm, the USMSTF recommends surveillance colonosocopy after 5-10 and 3-5 years, respectively.
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http://dx.doi.org/10.1002/ueg2.12106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280808PMC
July 2021

Perianal Crohn's Disease Is Associated With Poor Disease Outcome: A Nationwide Study From the epiIIRN Cohort.

Authors:
Ohad Atia Noa Asayag Gili Focht Rona Lujan Oren Ledder Shira Greenfeld Revital Kariv Iris Dotan Hagit Gabay Ran Balicer Ziona Haklai Daniel Nevo Dan Turner

Clin Gastroenterol Hepatol 2021 Apr 9. Epub 2021 Apr 9.

Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel. Electronic address:

Background & Aims: Limited population-based data have explored perianal involvement in Crohn's disease (CD) and compared the disease course between severe and non-severe perianal CD (PCD). We aimed to explore the disease course of these phenotypes in a population-based study of CD.

Methods: Cases were identified from the epi-IIRN cohort and included 2 Israeli health maintenance organizations covering 78% of the population. We validated specific algorithms to identify fistulizing PCD and to differentiate severe from non-severe disease by medication utilization, International Classification of Disease, 9th Revision codes, and perianal procedures.

Results: A total of 12,904 CD patients were included in an inception cohort from 2005 (2186 pediatric-onset, 17%) providing 86,119 person-years of follow-up. Fistulizing PCD was diagnosed in 1530 patients (12%) (574 with severe PCD, 4%). The prevalence of PCD was 7.9%, 9.4%, 10.3%, and 11.6% at 1, 3, 5, and 10 years from CD diagnosis, respectively. At 5 years, PCD patients were more likely to be hospitalized (36% in non-PCD vs 64% in PCD; P < .001), undergo inflammatory bowel disease-related surgeries (9% vs 38%, respectively; P < .001), and develop anorectal cancer (1.2/10,000 person-years for non-PCD vs 4.2/10,000 for PCD; P = .01). Severe PCD was associated with poorer outcomes compared with non-severe PCD, as shown for hospitalizations (61% in non-severe PCD vs 73% in severe; P = .004) and surgeries (35% vs 43%; P = .001).

Conclusions: Despite higher utilization of immunomodulators and biologics, PCD is associated with poor disease outcomes, especially in severe PCD.
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http://dx.doi.org/10.1016/j.cgh.2021.04.007DOI Listing
April 2021

Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

Authors:
Toni T Seppälä Mev Dominguez-Valentin Emma J Crosbie Christoph Engel Stefan Aretz Finlay Macrae Ingrid Winship Gabriel Capella Huw Thomas Eivind Hovig Maartje Nielsen Rolf H Sijmons Lucio Bertario Bernardo Bonanni Maria G Tibiletti Giulia M Cavestro Miriam Mints Nathan Gluck Lior Katz Karl Heinimann Carlos A Vaccaro Kate Green Fiona Lalloo James Hill Wolff Schmiegel Deepak Vangala Claudia Perne Hans-Georg Strauß Johanna Tecklenburg Elke Holinski-Feder

Eur J Cancer 2021 05 17;148:124-133. Epub 2021 Mar 17.

Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany; MGZ- Medical Genetics Center, Munich, Germany; The International Society for Gastrointestinal Hereditary Tumours (InSiGHT), The Polyposis Registry, St Mark's Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, UK; European Hereditary Tumour Group (EHTG), C/o Lindsays, Caledonian Exchange, 19A Canning Street, Edinburgh, EH3 8HE, United Kingdom.

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.

Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.

Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.

Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes.
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http://dx.doi.org/10.1016/j.ejca.2021.02.022DOI Listing
May 2021

Heterozygous APC germline mutations impart predisposition to colorectal cancer.

Authors:
Livia Preisler Aline Habib Guy Shapira Liron Kuznitsov-Yanovsky Yoav Mayshar Ilana Carmel-Gross Mira Malcov Foad Azem Noam Shomron Revital Kariv Dov Hershkovitz Dalit Ben-Yosef

Sci Rep 2021 Mar 4;11(1):5113. Epub 2021 Mar 4.

Wolfe PGD-Stem Cell Laboratory, Racine IVF Unit, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, 64239, Tel-Aviv, Israel.

Familial adenomatous polyposis (FAP) is an inherited syndrome caused by a heterozygous adenomatous polyposis coli (APC) germline mutation, associated with a profound lifetime risk for colorectal cancer. While it is well accepted that tumorigenic transformation is initiated following acquisition of a second mutation and loss of function of the APC gene, the role of heterozygous APC mutation in this process is yet to be discovered. This work aimed to explore whether a heterozygous APC mutation induces molecular defects underlying tumorigenic transformation and how different APC germline mutations predict disease severity. Three FAP-human embryonic stem cell lines (FAP1/2/3-hESC lines) carrying germline mutations at different locations of the APC gene, and two control hESC lines free of the APC mutation, were differentiated into colon organoids and analyzed by immunohistochemistry and RNA sequencing. In addition, data regarding the genotype and clinical phenotype of the embryo donor parents were collected from medical records. FAP-hESCs carrying a complete loss-of-function of a single APC allele (FAP3) generated complex and molecularly mature colon organoids, which were similar to controls. In contrast, FAP-hESCs carrying APC truncation mutations (FAP1 and FAP2) generated only few cyst-like structures and cell aggregates of various shape, occasionally with luminal parts, which aligned with their failure to upregulate critical differentiation genes early in the process, as shown by RNA sequencing. Abnormal disease phenotype was shown also in non-pathological colon of FAP patients by the randomly distribution of proliferating cells throughout the crypts, compared to their focused localization in the lower part of the crypt in healthy/non-FAP patients. Genotype/phenotype analysis revealed correlations between the colon organoid maturation potential and FAP severity in the carrier parents. In conclusion, this study suggest that a single truncated APC allele is sufficient to initiate early molecular tumorigenic activity. In addition, the results hint that patient-specific hESC-derived colon organoids can probably predict disease severity among FAP patients.
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http://dx.doi.org/10.1038/s41598-021-84564-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933349PMC
March 2021

Pediatric-onset Inflammatory Bowel Disease Has Only a Modest Effect on Final Growth: A Report From the epi-IIRN.

Authors:
Amit Assa Noa Assayag Ran D Balicer Hagit Gabay Shira Greenfeld Revital Kariv Natan Ledderman Eran Matz Iris Dotan Oren Ledder Anat Yerushalmy-Feler Dan Turner Shlomi Cohen

J Pediatr Gastroenterol Nutr 2021 08;73(2):223-230

Pediatric Gastroenterology Unit, "Dana-Dwek" Children's Hospital, Tel-Aviv Sourasky Medical Center.

Objectives: The impact of pediatric-onset inflammatory bowel disease (IBD) on growth is debated. We aimed to investigate the effect of IBD on anthropometric measures at young adulthood.

Methods: Children diagnosed with Crohn disease (CD) or ulcerative colitis (UC) (2005-2019) were identified in a national database along with matched non-IBD controls.

Results: Overall, 2229 IBD cases (68% CD) were matched to 4338 controls. Only females with CD differed in final height from controls (z scores: -0.37 ± 1.09 vs -0.25 ± 1.06, respectively; P = 0.01), corresponding to a mean difference of 0.7 ± 0.2 cm (all females) and 1.2 ± 0.3 cm in females diagnosed <14 years (P = 0.02). Final height was reduced in both sexes according to adjusted mean height difference analysis (-0.43 cm, 95% confidence interval -0.85 to -0.02; P = 0.04). This difference increased in patients with CD who underwent abdominal surgery (-0.91 cm, 95% confidence interval -1.39 to -0.42; P = 0.01). The proportion of patients with CD achieving final height z scores of -1 and zero differed significantly from controls for both males (71.1% and 34.8% vs 79.1% and 43.0%, respectively; P < 0.001) and females (67.7% and 30.4% vs 79.6%, and 43.3%, respectively; P < 0.001). Patients treated with anti-tumor necrosis factor agents during growth potential had similar height improvement to other regimens. Predominantly, patients with CD were leaner, with a greater proportion of subjects with underweight, compared with controls.

Conclusions: In pediatric-onset IBD, absolute final height was modestly affected by females with CD. Nevertheless, greater proportions of both sexes with early diagnosis of CD failed to achieve normal final height, compared with controls.
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http://dx.doi.org/10.1097/MPG.0000000000003072DOI Listing
August 2021

Barriers to completing colonoscopy after a positive fecal occult blood test.

Authors:
Revital Azulay Liora Valinsky Fabienne Hershkowitz Einat Elran Natan Lederman Revital Kariv Benjamin Braunstein Anthony Heymann

Isr J Health Policy Res 2021 02 11;10(1):11. Epub 2021 Feb 11.

Meuhedet Health Care, 5 Pesach Lev, Lod, Israel.

Background: Colorectal cancer leads to significant morbidity and mortality. Early detection and treatment are essential. Screening using fecal occult blood tests has increased significantly, but adherence to colonoscopy follow-up is suboptimal, increasing CRC mortality risk. The aim of this study was to identify barriers to colonoscopy following a positive FOBT at the level of the patient, physician, organization and policymakers.

Methods: This mixed methods study was conducted at two health care organizations in Israel. The study included retrospective analyses of 45,281 50-74 year-old members with positive fecal immunochemical tests from 2010 to 2014, and a survey of 772 patients with a positive test during 2015, with and without follow-up. The qualitative part of the study included focus groups with primary physicians and gastroenterologists and in-depth interviews with opinion leaders in healthcare.

Results: Patient lack of comprehension regarding the test was the strongest predictor of non-adherence to follow-up. Older age, Arab ethnicity, and lower socio economic status significantly reduced adherence. We found no correlation with gender, marital status, patient activation, waiting time for appointments or distance from gastroenterology clinics. Primary care physicians underestimate non-adherence rates. They feel responsible for patient follow-up, but express lack of time and skills that will allow them to ensure adherence among their patients. Gastroenterologists do not consider fecal occult blood an effective tool for CRC detection, and believe that all patients should undergo colonoscopy. Opinion leaders in the healthcare field do not prioritize the issue of follow-up after a positive screening test for colorectal cancer, although they understand the importance.

Conclusions: We identified important barriers that need to be addressed to improve the effectiveness of the screening program. Targeted interventions for populations at risk for non-adherence, specifically for those with low literacy levels, and better explanation of the need for follow-up as a routine need to be set in place. Lack of agreement between screening recommendations and gastroenterologist opinion, and lack of awareness among healthcare authority figures negatively impact the screening program need to be addressed at the organizational and national level.

Trial Registration: This study was approved by the IRB in both participating organizations (Meuhedet Health Care Institutional Review Board #02-2-5-15, Maccabi Healthcare Institutional Review Board BBI-0025-16). Participant consent was waived by both IRB's.
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http://dx.doi.org/10.1186/s13584-021-00444-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879608PMC
February 2021

Increased incidence of coeliac disease autoimmunity rate in Israel: a 9-year analysis of population-based data.

Authors:
Niva Lechtman Raanan Shamir Shlomi Cohen Gabriel Chodick Revital Kariv Lia Supino-Rosin Yael Weintraub Anat Yerushalmy-Feler Amir Ben Tov

Aliment Pharmacol Ther 2021 03 5;53(6):696-703. Epub 2021 Feb 5.

Maccabi Institute for Research & Innovation, Maccabi Healthcare Services, Tel Aviv, Israel.

Background: Incidence rate and temporal trends in coeliac disease and coeliac disease autoimmunity incidence vary worldwide with most data available from North American and European countries.

Aims: To explore temporal trends in incidence of coeliac disease autoimmunity and their relation to increase in screening tests in Israel.

Methods: A large retrospective population-based study was conducted in Maccabi Healthcare Services, a 2.3-million-member health maintenance organisation operating in Israel. The cohort included all patients with newly diagnosed coeliac disease autoimmunity based on first positive anti-tissue transglutaminase type 2 IgA antibodies. Data were analysed for the years 2007-2015.

Results: During the study period (17.3 million person-years), a total of 403 283 patients were tested for coeliac disease autoimmunity, of whom 6444 were positive, representing an average incidence rate of 36.64 per 100 000 person-years (95% CI: 35.74-37.55). Incidence of coeliac disease autoimmunity increased from 25.4 per 100 000 in 2007 to 52.3 per 100 000 person-years in 2015 (Incidence rate ratio of 2.06, 95% CI 1.81-2.26). Coeliac disease autoimmunity incidence was highest in the paediatric age groups, especially in children aged 0-5, and was 4 times higher than the incidence in adults aged 26-55 (Incidence rate ratio of 0.24, 95% CI (0.22-0.26). The increase in incidence surpassed the increase in testing for new patients. Positive trends in incidence were highest in small children, whereas the incidence in adults was stable over the years.

Conclusions: There was a steady increase in coeliac disease autoimmunity incidence in our cohort between the years 2007-2015. The paediatric population was the only contributor to this trend.
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http://dx.doi.org/10.1111/apt.16282DOI Listing
March 2021

Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

Authors:
Mev Dominguez-Valentin Emma J Crosbie Christoph Engel Stefan Aretz Finlay Macrae Ingrid Winship Gabriel Capella Huw Thomas Sigve Nakken Eivind Hovig Maartje Nielsen Rolf H Sijmons Lucio Bertario Bernardo Bonanni Maria Grazia Tibiletti Giulia Martina Cavestro Miriam Mints Nathan Gluck Lior Katz Karl Heinimann Carlos A Vaccaro Kate Green Fiona Lalloo James Hill Wolff Schmiegel Deepak Vangala Claudia Perne Hans-Georg Strauß Johanna Tecklenburg Elke Holinski-Feder

Genet Med 2021 04 1;23(4):705-712. Epub 2020 Dec 1.

Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.

Purpose: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants.

Methods: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages.

Results: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively.

Conclusion: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.
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http://dx.doi.org/10.1038/s41436-020-01029-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026395PMC
April 2021

Ultra-Processed Food Intake and Smoking Interact in Relation with Colorectal Adenomas.

Authors:
Naomi Fliss-Isakov Shira Zelber-Sagi Dana Ivancovsky-Wajcman Oren Shibolet Revital Kariv

Nutrients 2020 Nov 14;12(11). Epub 2020 Nov 14.

Department of Gastroenterology, Tel Aviv Medical Center, Tel Aviv 6423906, Israel.

Smoking and ultra-processed foods (UPFs), a substantial part of the western diet, have been suggested to have a potential carcinogenic effect, though epidemiologic data are lacking. We aimed to examine the association between high UPF intake and colorectal adenomas, and to test the interaction with smoking. In a case-control study among consecutive subjects undergoing colonoscopy in a tertiary center during 2010-2015, UPF intake and smoking were compared between cases with colorectal adenomas and controls. Within 652 participants (cases, = 294 and controls, = 358), high UPF intake (defined as percent of kcal from UPF above the study sample upper tertile) was positively associated with adenomas (Odds ratio (OR) = 1.75, 95% Confidence interval (CI) 1.14-2.68), advanced and proximal adenomas (OR = 2.17, 1.29-3.65 and OR = 2.38, 1.37-4.11) among the whole study sample; and with adenomas (OR = 3.54, 1.90-6.61), non-advanced adenomas (OR = 2.60, 1.20-5.63), advanced adenomas (OR = 4.76, 2.20-10.30), proximal adenomas (OR = 6.23, 2.67-14.52), and distal adenomas (OR = 2.49, 1.21-5.13) among smokers. Additionally, a dose-dependent association was observed between tertiles of UPF intake and adenomas only among smokers ( for trend < 0.001). A significant interaction between smoking and high UPF intake was detected ( for interaction = 0.004). High intake of UPFs is strongly and independently associated with colorectal adenomas, especially advanced and proximal adenoma, and interacts with smoking. Results highlight smokers as more susceptible to the negative health effects of UPF consumption on colorectal neoplasia.
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http://dx.doi.org/10.3390/nu12113507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698317PMC
November 2020

Risk-Reducing Gynecological Surgery in Lynch Syndrome: Results of an International Survey from the Prospective Lynch Syndrome Database.

Authors:
Mev Dominguez-Valentin Toni T Seppälä Christoph Engel Stefan Aretz Finlay Macrae Ingrid Winship Gabriel Capella Huw Thomas Eivind Hovig Maartje Nielsen Rolf H Sijmons Lucio Bertario Bernardo Bonanni Maria Grazia Tibiletti Giulia Martina Cavestro Miriam Mints Nathan Gluck Lior Katz Karl Heinimann Carlos A Vaccaro Kate Green Fiona Lalloo James Hill Wolff Schmiegel Deepak Vangala Claudia Perne Hans-Georg Strauß Johanna Tecklenburg Elke Holinski-Feder Verena Steinke-Lange

J Clin Med 2020 Jul 18;9(7). Epub 2020 Jul 18.

Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, 80336 Munich, Germany.

Purpose: To survey risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) practice and advice regarding hormone replacement therapy (HRT) in women with Lynch syndrome.

Methods: We conducted a survey in 31 contributing centers from the Prospective Lynch Syndrome Database (PLSD), which incorporates 18 countries worldwide. The survey covered local policies for risk-reducing hysterectomy and BSO in Lynch syndrome, the timing when these measures are offered, the involvement of stakeholders and advice regarding HRT.

Results: Risk-reducing hysterectomy and BSO are offered to _ and carriers in 20/21 (95%) contributing centers, to carriers in 19/21 (91%) and to carriers in 14/21 (67%). Regarding the involvement of stakeholders, there is global agreement (~90%) that risk-reducing surgery should be offered to women, and that this discussion may involve gynecologists, genetic counselors and/or medical geneticists. Prescription of estrogen-only HRT is offered by 15/21 (71%) centers to women of variable age range (35-55 years).

Conclusions: Most centers offer risk-reducing gynecological surgery to carriers of , and variants but less so for carriers. There is wide variation in how, when and to whom this is offered. The Manchester International Consensus Group developed recommendations to harmonize clinical practice across centers, but there is a clear need for more research.
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http://dx.doi.org/10.3390/jcm9072290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408942PMC
July 2020

Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

Authors:
Mev Dominguez-Valentin Julian R Sampson Toni T Seppälä Sanne W Ten Broeke John-Paul Plazzer Sigve Nakken Christoph Engel Stefan Aretz Mark A Jenkins Lone Sunde Inge Bernstein Gabriel Capella Francesc Balaguer Huw Thomas D Gareth Evans John Burn Marc Greenblatt Eivind Hovig Wouter H de Vos Tot Nederveen Cappel Rolf H Sijmons Lucio Bertario Maria Grazia Tibiletti Giulia Martina Cavestro Annika Lindblom Adriana Della Valle Francisco Lopez-Köstner Nathan Gluck Lior H Katz Karl Heinimann Carlos A Vaccaro

Genet Med 2020 Sep;22(9):1569

Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41436-020-0892-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462742PMC
September 2020

Serum Malondialdehyde is Associated with Non-Alcoholic Fatty Liver and Related Liver Damage Differentially in Men and Women.

Authors:
Shira Zelber-Sagi Dana Ivancovsky-Wajcman Naomi Fliss-Isakov Michal Hahn Muriel Webb Oren Shibolet Revital Kariv Oren Tirosh

Antioxidants (Basel) 2020 Jul 2;9(7). Epub 2020 Jul 2.

Institute of Biochemistry, Food Science and Nutrition, The RH Smit Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rechovot 76100001, Israel.

Background: Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are associated with increased oxidative stress and lipid peroxidation, but large studies are lacking. The aim was to test the association of malondialdehyde (MDA), as a marker of oxidative damage of lipids, with NAFLD and liver damage markers, and to test the association between dietary vitamins E and C intake and MDA levels.

Methods: A cross-sectional study was carried out among subjects who underwent blood tests including FibroMax for non-invasive assessment of NASH and fibrosis. MDA was evaluated by reaction with Thiobarbituric acid and HPLC-fluorescence detection method. NAFLD was diagnosed by abdominal ultrasound.

Findings: MDA measurements were available for 394 subjects. In multivariate analysis, the odds for NAFLD were higher with the rise of MDA levels in a dose-response manner, adjusting for age, gender, BMI, and lifestyle factors. Only among men, higher serum MDA was associated of higher odds for NAFLD and NASH and/or fibrosis (OR = 2.59, 95% CI 1.33-5.07, = 0.005; OR = 2.04, 1.02-4.06, = 0.043, respectively). Higher vitamin E intake was associated with lower odds of high serum MDA level (OR = 0.28 95% CI 0.13-0.62, = 0.002). In conclusion, serum MDA is associated with NAFLD and markers of NASH or fibrosis among men. Dietary vitamin E may be protective among women.
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http://dx.doi.org/10.3390/antiox9070578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401879PMC
July 2020

Higher phenolic acid intake independently associates with lower prevalence of insulin resistance and non-alcoholic fatty liver disease.

Authors:
Federico Salomone Dana Ivancovsky-Wajcman Naomi Fliss-Isakov Muriel Webb Giuseppe Grosso Justyna Godos Fabio Galvano Oren Shibolet Revital Kariv Shira Zelber-Sagi

JHEP Rep 2020 Apr 28;2(2):100069. Epub 2020 Jan 28.

School of Public Health, University of Haifa, Haifa, Israel.

Background & Aims: The inverse association between non-alcoholic fatty liver disease (NAFLD) and diets rich in fruit and vegetables has been demonstrated, but the specific compounds that may be responsible for this association need to be elucidated. The aim of this study was to test the association between phenolic acid consumption, NAFLD, and insulin resistance (IR).

Methods: A cross-sectional cohort of individuals included in a metabolic screening program was studied. Liver steatosis was evaluated by ultrasonography and quantified by the hepatorenal index (HRI); fibrosis was assessed by FibroTest; IR by the sample upper quartile of the homeostatic model assessment score. Dietary intake was measured by a food frequency questionnaire. The phenolic acid content of food was calculated according to Phenol-Explorer.

Results: A total of 789 individuals were included (52.6% men, age 58.83 ± 6.58 years). Higher (above the upper median) phenolic acid intake was inversely associated with the presence of NAFLD (odds ratio [OR] 0.69; 95% CI 0.49-0.98; 0.036), higher HRI (OR 0.64; 95% CI 0.45-0.91; 0.013) and higher IR (OR 0.61; 95% CI 0.42-0.87; 0.007), when adjusted for age, gender, body mass index, and lifestyle factors. Considering specific classes of phenolic acids, higher hydroxybenzoic acid intake was independently associated with lower odds of NAFLD, higher HRI and fibrosis. Higher hydroxycinnamic acid intake was independently associated with lower odds of IR.

Conclusion: A higher intake of phenolic acids is associated with a lower prevalence of liver steatosis and IR in a cross-sectional study, suggesting a possible protective effect that requires confirmation in prospective studies.

Lay Summary: High dietary intake of total phenolic acids is associated with a lower prevalence of non-alcoholic fatty liver disease and insulin resistance. A high intake of hydroxybenzoic acids, a class of phenolic acids, is associated with a lower prevalence of steatosis and clinically significant fibrosis, while a high intake of hydroxycinnamic acids, another class of phenolic acids, is associated with a lower prevalence of insulin resistance.
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http://dx.doi.org/10.1016/j.jhepr.2020.100069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078532PMC
April 2020

Geographic Heterogeneity for Mismatch Repair Proteins Is Associated with Defects in DNA Repair.

Authors:
Ariel Greenberg Revital Kariv Irit Solar Dov Hershkovitz

Isr Med Assoc J 2020 Jan;22(1):32-36

Department of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Background: Evaluation of mismatch repair (MMR) deficiency is conducted via immunohistochemistry or by microsatellite instability (MSI) analysis. Heterogeneous immunohistochemistry staining for MMR proteins may show different patterns; however, according to current guidelines, all of those patterns should be interpreted as MMR proficient. This conclusion might lead to false negative results because although most cases of heterogeneity stem from technical factors and biological variability, other types of heterogeneity represent true MMR deficiency.

Objectives: To identify a unique heterogeneity pattern that is associated with true MMR loss.

Methods: We analyzed 145 cases of colorectal carcinoma. Immunohistochemistry staining for MLH1, PMS2, MSH2, and MSH6 were performed. We defined geographic heterogeneity as areas of tumor nuclear staining adjacent to areas of loss of tumor nuclear staining with intact staining in the surrounding stroma. All cases were evaluated for the presence of geographic heterogeneity. In addition, 24 cases were also evaluated by MSI testing.

Results: Of the 145 cases, 24 (16.5%) were MMR deficient. Of the 24 cases for which MSI analysis was also available, 10 cases (41.7%) demonstrated biological heterogeneity, 5 (20.8%) demonstrated technical heterogeneity, and 2 (8.3%) demonstrated geographic heterogeneity. Only the two cases with geographic heterogeneity were MSI-high via MSI analysis. In addition, a germline mutation in MSH-6 was identified in one of these cases.

Conclusions: Geographic heterogeneity may raise a suspicion for a MMR-deficient case, which should be further analyzed using additional methodologies such as MSI analysis.
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January 2020

Genome analysis and knowledge-driven variant interpretation with TGex.

Authors:
Dvir Dahary Yaron Golan Yaron Mazor Ofer Zelig Ruth Barshir Michal Twik Tsippi Iny Stein Guy Rosner Revital Kariv Fei Chen Qiang Zhang Yiping Shen Marilyn Safran Doron Lancet Simon Fishilevich

BMC Med Genomics 2019 12 30;12(1):200. Epub 2019 Dec 30.

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

Background: The clinical genetics revolution ushers in great opportunities, accompanied by significant challenges. The fundamental mission in clinical genetics is to analyze genomes, and to identify the most relevant genetic variations underlying a patient's phenotypes and symptoms. The adoption of Whole Genome Sequencing requires novel capacities for interpretation of non-coding variants.

Results: We present TGex, the Translational Genomics expert, a novel genome variation analysis and interpretation platform, with remarkable exome analysis capacities and a pioneering approach of non-coding variants interpretation. TGex's main strength is combining state-of-the-art variant filtering with knowledge-driven analysis made possible by VarElect, our highly effective gene-phenotype interpretation tool. VarElect leverages the widely used GeneCards knowledgebase, which integrates information from > 150 automatically-mined data sources. Access to such a comprehensive data compendium also facilitates TGex's broad variant annotation, supporting evidence exploration, and decision making. TGex has an interactive, user-friendly, and easy adaptive interface, ACMG compliance, and an automated reporting system. Beyond comprehensive whole exome sequence capabilities, TGex encompasses innovative non-coding variants interpretation, towards the goal of maximal exploitation of whole genome sequence analyses in the clinical genetics practice. This is enabled by GeneCards' recently developed GeneHancer, a novel integrative and fully annotated database of human enhancers and promoters. Examining use-cases from a variety of TGex users world-wide, we demonstrate its high diagnostic yields (42% for single exome and 50% for trios in 1500 rare genetic disease cases) and critical actionable genetic findings. The platform's support for integration with EHR and LIMS through dedicated APIs facilitates automated retrieval of patient data for TGex's customizable reporting engine, establishing a rapid and cost-effective workflow for an entire range of clinical genetic testing, including rare disorders, cancer predisposition, tumor biopsies and health screening.

Conclusions: TGex is an innovative tool for the annotation, analysis and prioritization of coding and non-coding genomic variants. It provides access to an extensive knowledgebase of genomic annotations, with intuitive and flexible configuration options, allows quick adaptation, and addresses various workflow requirements. It thus simplifies and accelerates variant interpretation in clinical genetics workflows, with remarkable diagnostic yield, as exemplified in the described use cases. TGex is available at http://tgex.genecards.org/.
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http://dx.doi.org/10.1186/s12920-019-0647-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937949PMC
December 2019

High Intake of Phenolic Acids Is Associated With Reduced Risk of Colorectal Adenomas Among Smokers.

Authors:
Naomi Fliss-Isakov Giuseppe Grosso Federico Salomone Justyna Godos Fabio Galvano Dana Ivancovsky-Wajcman Oren Shibolet Revital Kariv Shira Zelber-Sagi

Clin Gastroenterol Hepatol 2020 07 29;18(8):1893-1895.e3. Epub 2019 Aug 29.

Department of Gastroenterology, Tel Aviv Medical Center, Tel Aviv, Israel; School of Public Health, University of Haifa, Haifa, Israel.

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http://dx.doi.org/10.1016/j.cgh.2019.08.038DOI Listing
July 2020

A healthy lifestyle pattern has a protective association with colorectal polyps.

Authors:
Naomi Fliss-Isakov Revital Kariv Muriel Webb Dana Ivancovsky-Wajcman Oleg Zaslavsky Dana Margalit Oren Shibolet Shira Zelber-Sagi

Eur J Clin Nutr 2020 02 30;74(2):328-337. Epub 2019 Jul 30.

Department of Gastroenterology Tel Aviv Medical Center, Tel Aviv, Israel.

Background: Colorectal cancer is associated with lifestyle characteristics such as diet, physical inactivity, obesity, and smoking, but these are not incorporated in screening recommendations. Moreover, the joint association of these factors with various colorectal polyps is not established.

Methods: A case-control study, among consecutive subjects aged 40-70 years, undergoing colonoscopy. Cases with colorectal polyps were compared with controls. Detailed information was gathered regarding polyp histology and anatomic location, demographics, medical history, anthropometrics, and lifestyle. The healthy lifestyle index was estimated as the sum of: non-smoking, maintaining a healthy weight, healthy diet, and physical activity.

Results: A total of 788 participants were included (cases n = 403, controls n = 385). The healthy lifestyle index had a negative association with colorectal polyps (OR = 0.72, 95% CI 0.62-0.85, P < 0.001), both adenomas and serrated polyps (OR = 0.75, 0.64-0.89, and OR = 0.59, 0.44-0.79, respectively), and both proximal and distal adenomas (OR = 0.77, 0.62-0.95, and OR = 0.73, 0.59-0.90, respectively). Adherence to ≥ 2 healthy lifestyle components was strongly related with colorectal polyps (OR = 0.50, 0.34-0.75, P = 0.001). Abstinence from smoking, and a healthy diet were the factors most strongly associated with lower odds of colorectal polyps (OR = 0.58, 0.42-0.79, and OR = 0.61, 0.44-0.85, respectively).

Conclusions: Adherence to a healthy lifestyle (≥2 healthy lifestyle components) is inversely associated with colorectal polyps, especially serrated and distal polyps, with no dose-response association. Components most strongly associated with lower odds of colorectal polyps were maintaining a healthy diet and abstinence from smoking. Lifestyle-related characteristics may assist in risk stratification and are potential goals for colorectal neoplasia prevention.
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http://dx.doi.org/10.1038/s41430-019-0481-2DOI Listing
February 2020

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

Authors:
Mev Dominguez-Valentin Julian R Sampson Toni T Seppälä Sanne W Ten Broeke John-Paul Plazzer Sigve Nakken Christoph Engel Stefan Aretz Mark A Jenkins Lone Sunde Inge Bernstein Gabriel Capella Francesc Balaguer Huw Thomas D Gareth Evans John Burn Marc Greenblatt Eivind Hovig Wouter H de Vos Tot Nederveen Cappel Rolf H Sijmons Lucio Bertario Maria Grazia Tibiletti Giulia Martina Cavestro Annika Lindblom Adriana Della Valle Francisco Lopez-Köstner Nathan Gluck Lior H Katz Karl Heinimann Carlos A Vaccaro

Genet Med 2020 01 24;22(1):15-25. Epub 2019 Jul 24.

Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.

Purpose: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer.

Methods: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years.

Results: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer.

Conclusion: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.
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http://dx.doi.org/10.1038/s41436-019-0596-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371626PMC
January 2020

Resorting the function of the colorectal cancer gatekeeper adenomatous polyposis coli.

Authors:
Revital Kariv Michal Caspi Naomi Fliss-Isakov Yamit Shorer Yarden Shor Guy Rosner Eli Brazowski Gil Beer Shlomi Cohen Rina Rosin-Arbesfeld

Int J Cancer 2020 02 14;146(4):1064-1074. Epub 2019 Aug 14.

Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

As a large number of cancers are caused by nonsense mutations in key genes, read-through of these mutations to restore full-length protein expression is a potential therapeutic strategy. Mutations in the adenomatous polyposis coli (APC) gene initiate the majority of both sporadic and hereditary colorectal cancers (CRC) and around 30% of these mutations are nonsense mutations. Our goal was to test the feasibility and effectiveness of APC nonsense mutation read-through as a potential chemo-preventive therapy in Familial Adenomatous Polyposis (FAP), an inherited CRC syndrome patients. Ten FAP patients harboring APC nonsense mutations were treated with the read-through inducing antibiotic erythromycin for 4 months. Endoscopic assessment of the adenomas was performed at baseline, after 4 and after 12 months. Adenoma burden was documented in terms of adenoma number, maximal polyp size and cumulative polyp size per procedure. Tissue samples were collected and subjected to molecular and genetic analyses. Our results show that in the majority of patients the treatment led to a decrease in cumulative adenoma burden, median reduction in cumulative adenoma size and median reduction in adenoma number. Molecular and genetic analyses of the adenomas revealed that the treatment led to a reduced number of somatic APC mutations, reduced cellular proliferation and restoration of APC tumor-suppressing activity. Together, our findings show that induced read-through of APC nonsense mutations leads to promising clinical results and should be further investigated to establish its therapeutic potential in FAP and sporadic CRCs harboring nonsense APC mutations.
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http://dx.doi.org/10.1002/ijc.32557DOI Listing
February 2020

Dietary vitamin E and C intake is inversely associated with the severity of nonalcoholic fatty liver disease.

Authors:
Dana Ivancovsky-Wajcman Naomi Fliss-Isakov Federico Salomone Muriel Webb Oren Shibolet Revital Kariv Shira Zelber-Sagi

Dig Liver Dis 2019 12 4;51(12):1698-1705. Epub 2019 Jul 4.

School of Public Health, University of Haifa, Haifa, Israel; Department of Gastroenterology, Tel-Aviv Medical Center, Tel-Aviv, Israel. Electronic address:

Background & Aims: Although antioxidants have a protective potential in nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), there is limited evidence regarding the role of dietary intake of antioxidants. The aim was to test the association between dietary vitamins E and C intake and NAFLD, NASH and fibrosis markers.

Methods: Cross-sectional study of a large cohort of subjects undergoing colonoscopy. The presence of NAFLD was evaluated by ultrasonography. The level of steatosis was defined using SteatoTest, moderate-severe NASH using new quantitative NashTest and borderline-significant fibrosis ≥ F1-F2 using FibroTest. Nutritional intake was measured by food frequency questionnaire (FFQ).

Results: Overall, 789 subjects were included (52.6% men, age 58.83 ± 6.58 years), 714 had reliable FibroMax. Adjusting for BMI, dietary and lifestyle factors, the upper tertile of vitamin E intake/1000 Kcal was associated with lower odds of NASH (OR = 0.64, 0.43-0.94, P = 0.024). There was an inverse association between reaching the recommended vitamin E intake and NASH (OR = 0.48, 0.30-0.77, P = 0.002). The upper tertile of vitamin C intake/1000 Kcal was associated with lower odds of NAFLD and NASH (OR = 0.68, 0.47-0.99, P = 0.045; OR = 0.57, 0.38-0.84, P = 0.004, respectively). Both vitamins were related with the level of steatosis according to SteatoTest.

Conclusion: Vitamin E and C intake may be protective from NAFLD-related liver damage.
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http://dx.doi.org/10.1016/j.dld.2019.06.005DOI Listing
December 2019

5-Hydroxymethylcytosine as a clinical biomarker: Fluorescence-based assay for high-throughput epigenetic quantification in human tissues.

Authors:
Sapir Margalit Sigal Avraham Tamar Shahal Yael Michaeli Noa Gilat Prerna Magod Michal Caspi Shelly Loewenstein Guy Lahat Dinorah Friedmann-Morvinski Revital Kariv Rina Rosin-Arbesfeld Shahar Zirkin Yuval Ebenstein

Int J Cancer 2020 01 2;146(1):115-122. Epub 2019 Jul 2.

School of Chemistry, Center for Nanoscience and Nanotechnology, Center for Light-Matter Interaction, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel.

Epigenetic transformations may provide early indicators for cancer and other disease. Specifically, the amount of genomic 5-hydroxymethylcytosine (5-hmC) was shown to be globally reduced in a wide range of cancers. The integration of this global biomarker into diagnostic workflows is hampered by the limitations of current 5-hmC quantification methods. Here we present and validate a fluorescence-based platform for high-throughput and cost-effective quantification of global genomic 5-hmC levels. We utilized the assay to characterize cancerous tissues based on their 5-hmC content, and observed a pronounced reduction in 5-hmC level in various cancer types. We present data for glioblastoma, colorectal cancer, multiple myeloma, chronic lymphocytic leukemia and pancreatic cancer, compared to corresponding controls. Potentially, the technique could also be used to follow response to treatment for personalized treatment selection. We present initial proof-of-concept data for treatment of familial adenomatous polyposis.
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http://dx.doi.org/10.1002/ijc.32519DOI Listing
January 2020

Clinical and Histologic Overlap and Distinction Among Various Hamartomatous Polyposis Syndromes.

Authors:
Ophir Gilad Guy Rosner Naomi Fliss-Isakov Sivan Aharon-Kaspi Hana Strul Nathan Gluck Revital Kariv

Clin Transl Gastroenterol 2019 05;10(5):1-9

Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Introduction: Hamartomatous polyposis syndromes (HPS) are rare autosomal-dominant inherited disorders associated with gastrointestinal (GI) tract and other cancers. HPS include Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), and phosphatase and tensin homolog hamartomatous tumor syndromes (PHTS). Diagnosis, management, and outcome prediction of HPS pose a clinical challenge. To characterize genotype, phenotype, histology and outcomes of individuals with HPS.

Methods: A retrospective cohort study (2004-2017) of consecutive patients that were clinically diagnosed with HPS that visited a specialized GI oncology clinic. Demographic, clinicopathological, and genetic data were obtained from medical records.

Results: Fifty-two individuals from 34 families were included. Common clinical manifestations were GI bleeding (40% JPS, 23% PJS, and 25% PHTS) and bowel obstruction (46.15% PJS and 11.4% JPS). Twenty patients (38.4%) underwent surgery, 5 of whom required multiple procedures. Higher polyp burden was associated with the need for surgery (P = 0.007). Polyp histology varied widely with 69.2% of patients exhibiting histology different from the syndrome hallmark. GI cancer history was positive in 65%, 40%, and 50% of JPS, PJS, and PHTS families, respectively. Five (9.6%) patients developed cancers (one patient each had small bowel-1, colon-1, and thyroid-1, one patient had both small bowel adenocarcinoma and breast cancer, and one had both breast cancer and liposarcoma). Twenty (38.4%) patients tested positive for STK11, PTEN, SMAD4, BMPR1A, or AKT1 mutations: Sanger sequencing and multi-gene next generation sequencing panels detected mutations in 40.9% and 100% of tested cases, respectively.

Discussion: HPS patients present versatile phenotypes with overlapping clinical and histological characteristics. Polyp burden is associated with the need for surgery. Next-generation sequencing increases mutation detection.
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http://dx.doi.org/10.14309/ctg.0000000000000035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602765PMC
May 2019
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