Revital Kariv

Colorectal cancer in inflammatory bowel disease: Results of the 3rd ECCO pathogenesis scientific workshop (I)

Epidemiological studies demonstrate an increased risk of colorectal cancer in patients with inflammatory bowel disease (IBD). A detailed literature review was conducted on epidemiology, risk factors, pathophysiology, chemoprevention and outcomes of colorectal cancer (CRC) in IBD as part of the 3rd ECCO scientific pathogenesis workshop.

Gastrointestinal Findings in the Largest Series of Patients With Hereditary Biallelic Mismatch Repair Deficiency Syndrome: Report from the International Consortium

Objectives:Hereditary biallelic mismatch repair deficiency (BMMRD) is caused by biallelic mutations in the mismatch repair (MMR) genes and manifests features of neurofibromatosis type 1, gastrointestinal (GI) polyposis, and GI, brain, and hematological cancers. This is the first study to characterize the GI phenotype in BMMRD using both retrospective and prospective surveillance data.Methods:The International BMMRD Consortium was created to collect information on BMMRD families referred from around the world. All patients had germline biallelic MMR mutations or lack of MMR protein staining in normal and tumor tissue. GI screening data were obtained through medical records with annual updates.Results:Thirty-five individuals from seven countries were identified with BMMRD. GI data were available on 24 of 33 individuals (73%) of screening age, totaling 53 person-years. The youngest age of colonic adenomas was 7, and small bowel adenoma was 11. Eight patients had 19 colorectal adenocarcinomas (CRC; median age 16.7 years, range 8–25), and 11 of 18 (61%) CRC were distal to the splenic flexure. Eleven patients had 15 colorectal surgeries (median 14 years, range 9–25). Four patients had five small bowel adenocarcinomas (SBC; median 18 years, range 11–33). Two CRC and two SBC were detected during surveillance within 6–11 months and 9–16 months, respectively, of last consecutive endoscopy. No patient undergoing surveillance died of a GI malignancy. Familial clustering of GI cancer was observed.Conclusions:The prevalence and penetrance of GI neoplasia in children with BMMRD is high, with rapid development of carcinoma. Colorectal and small bowel surveillance should commence at ages 3–5 and 8 years, respectively.

Determinants of adherence to screening by colonoscopy in individuals with a family history of colorectal cancer

OBJECTIVE Although first-degree relatives (FDRs) of colorectal cancer (CRC) patients, as a high-risk population, have the most to gain from colonoscopy screening, their adherence is suboptimal. Thus, an assessment of the determinants of adherence to screening is of potential importance. METHODS A cross-sectional study was conducted among 318 FDRs of 164 CRC patients treated at Tel-Aviv Sourasky Medical Center. Interviews were conducted with a questionnaire using I-Change Model. RESULTS Adherence to interval colonoscopy was low with only 73 FDRs (23.0%). Greater adherence was associated with socio-demographic variables (older age, siblings, having spouse, higher level of education and income) and behavioral variables (healthier lifestyle, utilization of preventive health services). Family physicians and kin were identified as the most influential figures on uptake. Intention, affective barriers, positive attitudes, social support, cues to action, age, and health maintenance were the strongest determinants of participation in CRC screening. CONCLUSION Adherence to colonoscopy is determined by multiple variables. Medical staff can play a key role in increasing adherence to colonoscopy. PRACTICE IMPLICATIONS Future interventions should focus on fostering positive attitudes, overcoming barriers, enhancing social support and providing a medical recommendation. Special efforts should be invested in young FDRs, those of low socio-economic status and those who underutilize preventive medicine.

Chimeric molecule IL-6/soluble IL-6 receptor is a potent mitogen for fetal hepatocytes

A novel recombinant molecule, termed IL‐6c and consisting of a chimera of interleukin 6 (IL‐6) and its soluble receptor is extremely potent in stimulating proliferation of hematopoietic progenitors. We investigated the effect of the IL‐6c on the proliferation and differentiation of E14 fetal hepatocytes. IL‐6c, in a dose‐dependent manner, stimulated proliferation of E14 fetal rat hepatocytes. Adult hepatocyte mitogens together with IL‐6c showed no further effect on proliferation. Hematopoietic stem cells mitogens SCF and flt3 ligand (FL) were also mitogenic for fetal hepatocytes, but did not further enhance the effect of IL‐6c on cell proliferation. IL‐6c decreased expression of fetal markers α‐fetoprotein (AFP) and gamma‐glutamyltranspeptidase, and induced expression of adult enzyme glucose‐6‐phosphatase (Gluc‐6‐P) in E14 hepatocytes. On the other hand, IL‐6c strongly reduced, in a dose‐dependant manner, expression of albumin and tyrosine aminotransferase (TAT). However, when the cells were grown for 3 days with IL‐6c, and IL‐6c was removed for the next 5 days, expression of albumin and TAT returned to levels found in control cultures. In conclusion, IL‐6c stimulated proliferation and affected gene expression in fetal hepatocytes in culture.

Large-scale population analysis reveals an extremely low threshold for “non-healthy” alanine aminotransferase that predicts diabetes mellitus

Background and Aims:  Serum alanine aminotransferase (ALT) is commonly used to detect liver damage. Recent studies indicate that ALT levels at the upper range of normal limits are predictors of adverse outcomes, especially diabetes mellitus (DM) and the metabolic syndrome. The aim of our study was to define the ALT threshold for both men and women that may predict the onset of DM.

Erratum to: A flow cytometry-based reporter assay identifies macrolide antibiotics as nonsense mutation read-through agents

A large number of human diseases are caused by nonsense mutations. These mutations result in premature protein termination and the expression of truncated, usually nonfunctional products. A promising therapeutic strategy for patients suffering from premature termination codon (PTC)-mediated disorders is to suppress the nonsense mutation and restore the expression of the affected protein. Such a suppression approach using specific antibiotics and other read-through promoting agents has been shown to suppress PTCs and restore the production of several important proteins. Here, we report the establishment of a novel, rapid, and very efficient method for screening stop-codon read-through agents. We also show that, in both mammalian cells and in a transgenic mouse model, distinct members of the macrolide antibiotic family can induce read-through of disease-causing stop codons leading to reexpression of several key proteins and to reduced disease phenotypes. Taken together, our results may help in the identification and characterization of well-needed customized pharmaceutical PTC suppression agents. Key messages & Establishment of a flow cytometry-based reporter assay to identify nonsense mutation read-through agents. & Macrolide antibiotics can induce read-through of diseasecausing stop codons. & Macrolide-induced protein restoration can alleviate disease-like phenotypes.

Low-dose naltrexone for the treatment of irritable bowel syndrome

with functional constipation, ranging in age from six to eighteen years (M 9.9, SD 3.2), and their parents. Children completed self-report measures of defecation anxiety scale (Defecation Anxiety Scale–Self-Report) and general anxiety (Revised Children’s Manifest Anxiety Scale), and their parents rated their children’s defecation anxiety (Defecation Anxiety Scale—Parent Rating Scales). The information was collected prospectively. Results: By self-report and parent report, children with functional constipation were found to have more defecation anxiety than a normative group of well children. By parent report, children with constipation were also found to have more defecation anxiety than a normative group of children with asthma. As a whole, children with constipation did not manifest clinically significant general anxiety. Defecation anxiety and general anxiety were found to be positively correlated. Discussion: The results suggest that children with functional constipation have significantly more anxiety specific to toileting behavior than well children and, at least by parent report, children with asthma, without displaying significant general anxiety. Though causality cannot be inferred, the positive correlation between defecation anxiety and general anxiety underscores the importance of addressing anxiety when treating children with constipation.

Performance analysis of a machine learning flagging system used to identify a group of individuals at a high risk for colorectal cancer

Individuals with colorectal cancer (CRC) have a tendency to intestinal bleeding which may result in mild to severe iron deficiency anemia, but for many colon cancer patients hematological abnormalities are subtle. The fecal occult blood test (FOBT) is used as a pre-screening test whereby those with a positive FOBT are referred to colonscopy. We sought to determine if information contained in the complete blood count (CBC) report coud be processed automatically and used to predict the presence of occult colorectal cancer (CRC) in the setting of a large health services plan. Using the health records of the Maccabi Health Services (MHS) we reviewed CBC reports for 112,584 study subjects of whom 133 were diagnosed with CRC in 2008 and analysed these with the MeScore tool. The odds ratio for being diagnosed with CRC in 2008 was calculated with regards to the MeScore, using cutoff levels of 97% and 99% percentiles. For individuals in the highest one percentile, the odds ratio for CRC was 21.8 (95% CI 13.8 to 34.2). For the majority of the individuals with cancer, CRC was not suspected at the time of the blood draw. Frequent use of anticoagulants, the presence of other gastrointestinal pathologies and non-GI malignancies were assocaitged with false positive MeScores. The MeScore can help identify individuals in the population who would benefit most from CRC screening, including those with no clinical signs or symptoms of CRC.

Computer-Assisted Flagging of Individuals at High Risk of Colorectal Cancer in a Large Health Maintenance Organization Using the ColonFlag Test

PURPOSE To evaluate in a sample of adults who had been noncompliant with colorectal cancer (CRC) screening whether screening could be enhanced by an automated patient recall system based on identifying high-risk individuals using the ColonFlag test and an electronic medical record database. METHODS A total of 79,671 individuals who were determined to be noncompliant with current screening recommendations were identified in the Maccabi Health Services program in Israel. Their cancer risk was determined by ColonFlag using information on age, sex, and CBC results. Doctors of individuals who were flagged as high risk were notified and asked to follow up with their patients. RESULTS The ColonFlag identified 688 men and women who scored in the highest 0.87 percentile. Of these individuals, 254 had colonoscopies performed by Maccabi physicians, and 19 CRCs (7.5%) were found. An additional 15 cancers primarily identified outside of Maccabi were found through code matching. CONCLUSION The ColonFlag test is a rapid, efficient, and inexpensive test that can be applied to scan electronic medical records to identify individuals at high risk of CRC who would otherwise avoid screening.

Predicting the presence of colon cancer in members of a health maintenance organisation by evaluating analytes from standard laboratory records

Background:A valid risk prediction model for colorectal cancer (CRC) could be used to identify individuals in the population who would most benefit from CRC screening. We evaluated the potential for information derived from a panel of blood tests to predict a diagnosis of CRC from 1 month to 3 years in the future.Methods:We abstracted information on 1755 CRC cases and 54 730 matched cancer-free controls who had one or more blood tests recorded in the electronic records of Maccabi Health Services (MHS) during the period 30–180 days before diagnosis. A scoring model (CRC score) was constructed using the study subjects’ blood test results. We calculated the odds ratio for being diagnosed with CRC after the date of blood draw, according to CRC score and time from blood draw.Results:The odds ratio for having CRC detected within 6 months for those with a score of four or greater (vs three or less) was 7.3 (95% CI: 6.3–8.5) for men and was 7.8 (95% CI: 6.7–9.1) for women.Conclusions:Information taken from routine blood tests can be used to predict the risk of being diagnosed with CRC in the near future.