Aharon Hallak

Rofecoxib reduces polyp recurrence in familial polyposis

The long-term (mean of 16.4±4.2 months) efficacy and safety of rofecoxib (a specific COX-2 inhibitor) in maintaining the colon free of polyps in familial polyposis patients was assessed. Eight patients were treated with rofecoxib 25 mg every day. Sigmoidoscopy/colonoscopy was performed at study entry and every six months. At each endoscopy the number, size, and histological grade of all polyps were assessed, and the polyps were removed. The drug was well tolerated with no significant adverse events throughout the study. A highly significant reduction in the rate of polyp formation (70–100%) was observed in all patients from a mean number of 15.1±11.7 at baseline to 6.0±5.8 at one year and 1.6±1.6 at the end of follow-up (P =0.016 and 0.008, respectively). No patient developed cancer or high-grade adenoma. In conclusion, Long-term use of rofecoxib is well tolerated and effective in inhibiting polyp formation in polyposis patients.

Proton pump inhibitors reduce cell cycle abnormalities in Barrett's esophagus.

Neoplastic progression in Barretts esophagus is a multi-step process in which the metaplastic columnar epithelium sequentially evolves through a metaplasia-dysplasia-carcinoma sequence. The expression and DNA copy number of key cell cycle regulatory genes in paired normal and Barretts esophagus samples was evaluated. Protein levels were evaluated in 60 formalin-fixed, paraffin-embedded human tissues by immunohistochemistry. DNA copy number from 20 fresh tissue pairs was analysed by Southern blot analysis. All normal mucosal samples expressed the p27kip1 protein, but did not display appreciable nuclear staining for p16kip4, p21cip1 or cyclins D1 and E. Barretts metaplastic specimens displayed increased expression levels of p16kip4 (74%), p21cip1 (89%) and cyclins D1 (43%) and E (37%). p27 protein was absent in three cases. There was a significant correlation between the expression of p16kip4 and cyclin E, and p21cip1 and p27kip4 with cyclin D1. DNA analysis did not reveal any amplification or deletion of these genes. Acid suppression, however, was associated with significantly lower expression levels of key cell cycle proteins. Increased expression of key cell cycle regulatory genes appears to occur early in the neoplastic progression associated with Barretts esophagus. Treatment with proton pump inhibitors appears to alter this increased expression.

Low-dose low-molecular weight heparin (enoxaparin) is effective as adjuvant treatment in active ulcerative colitis an open trial

Ulcerative colitis is a chronic inflammatory bowel disorder of unknown etiology. Treatment of flare-ups is based on mesalamine and steroids. Treatment of moderate to severe ulcerative colitis with high-dose heparin and low-molecular-weight heparin was reported. The mechanism was assumed to be a combination of anti-coagulant and anti-inflammatory effects. Low-molecular-weight heparin is better and safer than unfractionated heparin. Studies of low-dose low-molecular-weight heparin in experimental models of inflammation and in inflammatory diseases demonstrated a beneficial effect. Our aim in this study was to evaluate the effect of low-dose, low-molecular-weight heparin in active ulcerative colitis. Twelve patients with flare-ups of colitis were prospectively enrolled. Subcutaneous injections of 5-mg enoxaparin were administered at weekly intervals for 12 weeks. Mesalamine doses remained unchanged. Clinical, laboratory, endoscopic, histologic, and quality-of-life scores were evaluated at the beginning and end of the study. Ten patients completed the study. Mean age was 40.1; the female–male ratio was 7:3. Mean Mayo scores were 9.0 ± 0.94 at baseline and 3.4 ± 2.0 at the end of the study (P = 0.0001). Endoscopic scores decreased from 2.2 ± 0.4 to 1.2 ± 1.0 (P = 0.049) and in 7 of 10 patients extent of disease shortened. A significant increase in IBDQL scores from 135.7 ± 37.17 to 179.6 ± 45.15 points was demonstrated (P = 0.0117). Adverse events were one hospitalization due to abdominal pain, arthralgia (1), transient peripheral edema (1), and elevation of alkaline phosphatase (1). During follow-up, one patient required colectomy and another experienced an exacerbation. In conclusion, low-dose low-molecular-weight heparin once a week, combined with mesalamine, may be an effective therapy for active ulcerative colitis. It may delay or preclude the need for steroid treatment. Controlled studies to evaluate efficacy are needed.

Elevated serum iron predicts poor response to interferon treatment in patients with chronic HCV infection

To date, there are no firm clinical, demographic, biochemical, serologic, or histologic features predicting which patients with chronic hepatitis C are more likely to respond to therapy with interferon-α. Serum iron, total iron-binding capacity, transferrin saturation, and ferritin were measured in the fasting state. The amount of stainable iron in liver biopsy specimens was evaluated histochemically as well. All patients received subcutaneous recombinant human IFN-α2a three million units thrice weekly by self-administration. Eleven of 13 (84%) responders had low to normal serum iron levels as compared to one of 26 (4%) nonresponders (P<0.001). The serum transferrin was similar in both groups, but iron saturation was significantly lower in responders (30±10%) than in nonresponders (53±12%) (P<0.001). Serum ferritin and hepatic iron content were higher in nonresponders (NS). It is suggested that increased serum iron and transferrin saturation blunt the action of interferon, as they have opposite effects on the immune system. Iron overload can thus lead to a poor response to interferon. It remains to be seen whether reducing iron overload will improve the response to interferon therapy.

Diagnostic yield of routine push enteroscopy with a graded-stiffness enteroscope without overtube

BACKGROUND Push enteroscopy has become a standard procedure for evaluation of small intestinal disorders. Its diagnostic yield and acceptability, however, has been hampered by the use of an overtube, which is both inconvenient and potentially hazardous. This study assessed the clinical value of enteroscopy with a graded-stiffness videoenteroscope without an overtube. METHODS A total of 121 consecutive patients (mean age 59 years, range 12-89 years) underwent diagnostic enteroscopy. All procedures (n = 126) were performed with a push-type graded-stiffness videoenteroscope without an overtube. Indications were the following: unexplained iron deficiency anemia (45%), GI bleeding (29%), abdominal pain (6%), malabsorption (5.5%), imaging abnormality (5.5%), diarrhea (4%), intestinal obstruction (3%), and vomiting (2%). RESULTS The mean depth of instrument insertion distal to the pylorus was 121 cm. A diagnosis was made in 40% of all procedures. The findings included ulcerations or erosions in 43%, angioectasia in 35%, inflammation in 14%, tumors in 6%, and varices in 2%. In all cases of a positive enteroscopic diagnosis, therapeutic maneuvers were performed, and no patient needed a further diagnostic procedure. Patient comfort was good. No complications were observed. CONCLUSIONS Routine enteroscopy with a graded-stiffness enteroscope without an overtube is safe and comfortable for the patient and the endoscopist, and has a clinical efficacy comparable with that reported for enteroscopy with use of an overtube. A prospective, randomized study is warranted to assess the exact role of this form of enteroscopy in patient care.

Risk of colorectal neoplasia associated with the adenomatous polyposis coli E1317Q variant

BACKGROUND Reports of the risk of colorectal neoplasia associated with a variant of the adenomatous polyposis coli (APC E1317Q) gene are conflicting. Using a case-control design, we investigated this relationship within a clinic-based cohort followed through the Integrated Cancer Prevention Center and the Tel-Aviv Sourasky Medical Center. MATERIALS AND METHODS All study subjects were tested for the APC E1317Q variant at enrollment. Subjects underwent colonoscopic evaluation (+/-biopsy and/or polypectomy) and had cancer history and colorectal neoplasia risk factors assessed. The crude and adjusted risks of neoplasia associated with the E1317Q variant were calculated. RESULTS The prevalence of the E1317Q variant was 1.4% in the entire study sample and 3.2% in Sephardic Jews. E1317Q was more prevalent among cases: 15 of 458 (3.3%) cases were carriers compared with 11 of 1431 (0.8%) controls [odds ratio (OR) 4.4, 95% CI 2.0-9.6]. When stratified by neoplasia type, adenoma risk was significantly elevated in carriers (OR 4.1, 95% CI 1.8-9.4) but colorectal cancer risk was not (OR 2.1, 95% CI 0.8-5.3). After adjustment, the E1317Q variant remained a significant predictor of colorectal adenoma (OR 4.6, 95% CI 2.0-10.8). CONCLUSIONS The APC E1317Q variant is associated with colorectal neoplasia, particularly colorectal adenomas, but further studies are still needed. Variant prevalence is elevated in Sephardic Jews.

Chemopreventive effects of Coltect, a novel dietary supplement, alone and in combination with 5-aminosalicylic acid in 1,2-dimethylhydrazine-induced colon cancer in rats

Objectives: Coltect is a novel dietary supplement containing curcumin, green tea and selenomethionine. Previous reports have suggested that these agents can prevent colorectal cancer (CRC). The present study examined the chemopreventive effect of Coltect alone or combined with 5-aminosalicylic acid (5-ASA) using the 1,2-dimethylhydrazine (DMH) model in rats. Methods: The effect of Coltect was examined on HT-29 CRC cells by growth inhibition assay. Apoptosis was determined by annexin V-FITC/PI staining. Male rats were injected with DMH in vivo and treated with Coltect 150 mg/kg, 5-ASA 50 mg/kg or their combination, by oral gavage. Aberrant crypt foci (ACF) were identified by methylene blue staining. Results: HT-29 cells exhibited a dose-dependent response to Coltect. Part of the growth inhibition can be explained by the induction of mild-moderate apoptosis in cancer cells (28%) compared with the untreated cells (10%). In the in vivo model, the average number of ACF was divided into small (1-3 crypts) or large (≥4 crypts). The Coltect compound reduced the number of small and large ACF similarly to 5-ASA (40% reduction). This reduction was amplified by combining the two agents (70% reduction). Conclusion: Coltect inhibits the growth of colon cancer cells, induces apoptosis and inhibits ACF development. Furthermore, it augments the growth inhibitory effect of 5-ASA in vivo. This may be clinically important since this safe dietary supplement-drug combination can be administered as a chemopreventive regimen for the treatment of CRC.

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.

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.