Lior Galazan

Impact of genetic polymorphisms on adenoma recurrence and toxicity in a COX2 inhibitor (celecoxib) trial: results from a pilot study.

Objective Chemoprevention trials have shown that celecoxib reduces adenoma recurrence but can cause cardiovascular toxicity. In this pilot study, we evaluated associations between genetic variation in several candidate pathways (e.g. prostaglandin synthesis) and adenoma recurrence and cardiovascular and gastrointestinal toxicities. Methods Genotyping analysis was carried out on 117 Israeli colorectal adenoma patients who participated in the Prevention of Colorectal Sporadic Adenomatous Polyps trial. Reassessment followed after 3 years on celecoxib and after 2 years from termination of treatment with celecoxib. Efficacy (absence of colorectal adenomas) was measured by colonoscopy at years 1, 3, and 5. Toxicities were assessed by investigators during celecoxib treatment and by self-report post-treatment. A linkage disequilibrium-based selection algorithm (r2≥0.90, MAF≥4%) identified 255 tagSNPs in 25 analyzed candidate genes. Genotyping was performed by using Illumina GoldenGate technology. Results Multiple genetic variants were associated with adenoma recurrence and toxicity. Genetic variability in COX1, COX2, and ALOX12/15 genes played a role in adenoma recurrence, particularly among patients on placebo. More gene variants (especially variants in PGES, CRP, SRC, and GPX3) were associated with increased risk for cardiovascular toxicity and symptoms, compared with gastrointestinal toxicity and symptoms. The increased risk for cardiovascular toxicity/symptoms associated with the SRC gene variants (rs6017996, rs6018256, rs6018257) ranged from 6.61 (95% confidence interval 1.66–26.36, P<0.01) to 10.71 (95% confidence interval 1.96–58.60, P<0.01). Conclusion Genetic polymorphisms in multiple inflammation-related genes appear to interact with celecoxib on adenoma recurrence and its attendant toxicity, particularly cardiovascular toxicity/symptoms. Larger studies validating these pharmacogenetic relationships are needed.

Prevalence of colorectal neoplasms in young, average risk individuals: A turning tide between East and West

AIM To determine the prevalence of colorectal neoplasia in average risk persons 40-59 years of age in Israel and to compare the results with other populations. METHODS We reviewed the results of asymptomatic average-risk subjects, aged 40 to 59 years, undergoing their first screening colonoscopy between April 1994 and January 2014. The detection rates of adenoma, advanced adenoma (AA) and colorectal cancer (CRC) were determined in the 40s and 50s age groups by gender. The prevalence of lesions was compared between age groups. After meticulous review of the literature, these results were compared to published studies addressing the prevalence of colorectal neoplasia in similar patient groups, in a variety of geographical locations. RESULTS We included first screening colonoscopy results of 1750 individuals. The prevalence of adenomas, AA and CRC was 8.3%, 1.0% and 0.2% in the 40-49 age group and 13.7%, 2.4% and 0.2% in the 50-59 age group, respectively. Age-dependent differences in adenoma and AA rates were significant only among men (P < 0.005). Literature review disclosed 17 relevant studies. As expected, in both Asian and Western populations, the risks for overall adenoma and advanced adenoma was significantly higher in the 50s age group as compared to the 40s age group in a similar fashion. The result of the current study were similar to previous studies on Western populations. A substantially higher rate of adenoma, was observed in studies conducted among Asian populations in both age groups. CONCLUSION The higher rate of colorectal neoplasia in Asian populations requires further investigation and reconsideration as to the starting age of screening in that population.

Predictive Levels of CD24 in Peripheral Blood Leukocytes for the Early Detection of Colorectal Adenomas and Adenocarcinomas.

CD24 is expressed in 90% of colorectal adenomas and adenocarcinomas. Colorectal cancer (CRC) can be mostly prevented but average risk population screening by stool testing or colonoscopy faces many hurdles. Blood testing is clinically needed. We aimed to evaluate the utility of CD24 expression in peripheral blood leukocytes (PBLs). Two independent case studies were conducted in eligible individuals undergoing colonoscopy. Protein extracted from PBLs was subjected to immunoblotting using anti-CD24 monoclonal antibodies. CD24 sensitivity and specificity were determined using receiver operating characteristic (ROC) analysis. Initially, 150 subjects were examined: 63 had CRC, 19 had adenomas, and 68 had normal colonoscopies. The sensitivity and specificity of CD24 for distinguishing CRC from normal subjects were 70.5% (95% CI, 54.8–83.2%) and 83.8% (95% CI, 74.6–92.7%) and for adenomas 84.2% (95% CI, 60.4–96.4%) and 73.5% (95% CI, 61.4–83.5%), respectively. In the second trial (n = 149), a similar specificity but higher sensitivity was achieved: 80.0% (95% CI, 63.1–91.6%) for CRC and 89.2% (95% CI, 74.6–97%) for adenomas. A simple noninvasive blood test evaluating CD24 levels has high sensitivity and specificity for detecting colorectal adenomas and cancer in patients undergoing colonoscopy at an urban medical center. Larger multicenter studies are warranted to establish the potential of this promising test.

Incidence of colorectal neoplasms among male pilots.

AIM To assess the prevalence of colorectal neoplasms (adenomas, advanced adenomas and colorectal cancers) among Israeli military and commercial airline pilots. METHODS Initial screening colonoscopy was performed on average-risk (no symptoms and no family history) airline pilots at the Integrated Cancer Prevention Center (ICPC) in the Tel-Aviv Medical Center. Visualized polyps were excised and sent for pathological examination. Advanced adenoma was defined as a lesion >10 mm in diameter, with high-grade dysplasia or villous histology. The results were compared with those of an age- and gender-matched random sample of healthy adults undergoing routine screening at the ICPC. RESULTS There were 270 pilots (mean age 55.2 ± 7.4 years) and 1150 controls (mean age 55.7 ± 7.8 years). The prevalence of colorectal neoplasms was 15.9% among the pilots and 20.6% among the controls (P = 0.097, χ (2) test). There were significantly more hyperplastic polyps among pilots (15.5% vs 9.4%, P = 0.004) and a trend towards fewer adenomas (14.8% vs 20.3% P = 0.06). The prevalence of advanced lesions among pilots and control groups was 5.9% and 4.7%, respectively (P = 0.49), and the prevalence of cancer was 0.7% and 0.69%, respectively (P = 0.93). CONCLUSION There tends to be a lower colorectal adenoma, advanced adenoma and cancer prevalence but a higher hyperplastic polyp prevalence among pilots than the general population.

Abstract 2902: A simple blood test, evaluating the level of CD24 protein, can detect subjects with colorectal adenomas and adenocarcinomas

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: CD24 is a cell surface protein involved in cell adhesion and metastasis. Using gene expression array we have shown that CD24 expression is associated with colorectal cancer (CRC) [1,2]. The data was confirmed by IHC staining showing expression of CD24 in ∼90% of CR adenomas and adenocarcinomas. Two genetic variants of CD24, a C to T single nucleotide polymorphism (SNP), leading to an Ala/Val exchange (A57V) and a TG deletion in the 3’-UTR have been described, may have functional relevance, and affect CD24 protein level and stability. Objectives: To evaluate CD24 protein expression in peripheral blood leukocytes (PBLs) from normal, adenoma and CRC subjects, and score the associations of CD24 genetic variants and CRC risk. Methods: The calibration trial included 150 consented subjects (CRC=63, Adenomas=19, Normal=68) attending Tel Aviv Medical Center that underwent colonoscopy. PBLs were isolated and analyzed by Western blotting using anti-CD24. The samples were externally evaluated at the Technion, Haifa. The validation trial included 73 subjects. Additional 83 subjects were recently examined. Band intensities were scanned and tested for statistical significance. Sensitivity and specificity for CD24 was determined using receiver operating characteristic (ROC) curves. The study was approved by the Israel Ministry of Health. Results: The sensitivity and specificity of the CD24 test for distinguishing CRC from normal subjects was 70.5% (95% CI, 54.8-83.2%) and 83.8% (95% CI, 74.6-92.7%), respectively, and for advanced adenomas 84.2% (95% CI, 60.4-96.4%) and 73.5% (95% CI, 61.4-83.5%), respectively. The external evaluation study varied slightly. Improved values were achieved in the validation trial. Thus, the sensitivity for the detection of CRC was 92.3% (95% CI, 63.9-98.7%), with similar specificity, whereas the specificity for detecting adenomas was higher, 89.2% (95% CI, 74.6-96.9%). No significant correlations were found between the expression of CD24 and the two SNPs examined. However, preliminary data shows that the P170 C/T variant may increase susceptibility to CR adenomas (p=0.048) while the TG/del CD24 SNP may have a protective role (NS). Conclusions: The CD24 blood test is the first of its kind to be able to detect adenomas. It can also successfully distinguish CRC from healthy subjects. CD24 may serve as a potential and promising biomarker for the early detection of CRC. Larger studies are warranted to establish the future potential of this promising test. References: 1. Sagiv E., Gastroenterology 2006 2. Sagiv E., Can Res, 2008 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2902.

S1956 A Dinucleotide Deletion in CD24 Confers Protection Against CRC

controls. IL-6 gene polymorphism was analyzed by PCR-based restriction fragment length polymorphism and confirmed by genomic sequencing. The effects of IL-6 genotypes on the risk of gastric cancer were represented as odds ratios (OR) with 95% confidence interval (CI) by logistic regression. Relationships between IL-6 polymorphism and clinicopathologic characteristics of gastric cancer patients were compared using contingency tables and Pearsons χ2 test. Kaplan-Meier survival curves and the log-rank test for trend were used to evaluate the relationship between IL-6 polymorphism and the prognosis. The multivariate Cox regression analysis was performed to assess the prognostic value of IL-6 polymorphism with adjustment for confounding factors. Results: After adjustment for the potential confounding effects of gender and age, IL-6-6331TC genotype was associated with a decreased risk of gastric cancer compared with the CC genotype [adjusted Odds ratio (OR)=0.37, 95% confidence interval (CI)=0.15-0.94]. Further stratification analyses indicated that the protective effect of TC genotype was also observed in poorly differentiated gastric cancer (adjusted OR=0.36, 95% CI: 0.13-0.97), non-cardia gastric cancer (adjusted OR=0.38, 95% CI: 0.14-1.02) and intestinal type gastric cancer (adjusted OR=0.39, 95% CI: 0.15-1.02). TC genotype also resulted in decreased risk of lymph node metastasis (adjusted OR = 0.30, 95% CI: 0.12-0.79) through reduced risk of advanced tumor staging (adjusted OR=0.34, 95% CI: 0.13-0.88). Moreover, a trend towards a decreased risk of tumor development was also observed in patients at age 40 to 60 years after adjustment for gender. No significant relationship was observed between the IL-6-6331 polymorphism, gender difference and survival of gastric cancer patients. Conclusion: These results suggest that the IL-6-6331 polymorphism is involved in susceptibility to developing gastric cancer.