Jonathan P. Terdiman

Effect of 5-Aminosalicylate Use on Colorectal Cancer and Dysplasia Risk: A Systematic Review and Metaanalysis of Observational Studies

OBJECTIVES:We performed a systematic review with metaanalysis of observational studies evaluating the association between 5-ASA use and colorectal cancer (CRC) or dysplasia among patients with ulcerative colitis.METHODS:We conducted a search of Medline Embase Biosis, Web of Science, Cochrane Collaboration, manually reviewed the literature, and consulted with experts. Studies were included if they 1) evaluated and clearly defined exposure to 5-aminosalicylates in patients with ulcerative colitis, 2) reported CRC or dysplasia outcomes, 3) reported relative risks or odds ratio or provided data for their calculations. Quantitative analysis using a random-effects model is presented.RESULTS:Nine studies (3 cohort, 6 case–control) containing 334 cases of CRC, 140 cases of dysplasia, and a total of 1,932 subjects satisfied all inclusion criteria. Five studies reported CRC outcomes alone, two studies reported separate cancer and dysplasia outcomes, and two studies reported a combined outcome of CRC or dysplasia. All primary estimates are homogenous. Pooled analysis showed a protective association between use of 5-aminosalicylates and CRC (OR = 0.51; 95% confidence interval (CI): 0.37–0.69) or a combined endpoint of CRC/dysplasia (OR 0.51; 95% CI: 0.38–0.69). 5-ASA use was not associated with a lower risk of dysplasia, although only two studies evaluated this outcome (OR = 1.18; 95% CI: 0.41–3.43).CONCLUSION:Pooled results of observational studies support a protective association between 5-aminosalicylates and CRC or a combined endpoint of CRC/dysplasia in patients with ulcerative colitis. Additional studies analyzing the effect of 5-ASA on risk of dysplasia are needed.

BRAF Mutation Is Frequently Present in Sporadic Colorectal Cancer with Methylated hMLH1, But Not in Hereditary Nonpolyposis Colorectal Cancer

Purpose: The BRAF gene encodes a serine/threonine kinase and plays an important role in the mitogen-activated protein kinase signaling pathway. BRAF mutations in sporadic colorectal cancer with microsatellite instability (MSI) are more frequently detected than those in microsatellite stable cancer. In this study, we sought to compare the frequencies of BRAF mutations in sporadic colorectal cancer with MSI with those in hereditary nonpolyposis colorectal cancer (HNPCC). Experimental Design: We analyzed BRAF mutations in 26 colorectal cancer cell lines, 80 sporadic colorectal cancers, and 20 tumors from HNPCC patients by DNA sequencing and sequence-specific PCR. The methylation status of the hMLH1 gene was measured by either sequencing or restriction enzyme digestion after NaHSO3 treatment. Results: We observed a strong correlation of BRAF mutation with hMLH1 promoter methylation. BRAF mutations were present in 13 of 15 (87%) of the colorectal cell lines and cancers with methylated hMLH1, whereas only 4 of 91 (4%) of the cell lines and cancers with unmethylated hMLH1 carried the mutations (P < 0.00001). Sixteen of 17 mutations were at residue 599 (V599E). A BRAF mutation was also identified at residue 463 (G463V) in one cell line. In addition, BRAF mutations were not found in any cancers or cell lines with K-ras mutations. In 20 MSI+ cancers from HNPCC patients, however, BRAF mutations were not detectable, including a subset of 9 tumors with negative hMLH1 immunostaining and methylated hMLH1. Conclusions: BRAF mutations are frequently present in sporadic colorectal cancer with methylated hMLH1, but not in HNPCC-related cancers. This discrepancy of BRAF mutations between sporadic MSI+ cancer and HNPCC might be used in a strategy for the detection of HNPCC families.

Intentional infliximab use during pregnancy for induction or maintenance of remission in Crohn's disease

Aim:  To study the effects of infliximab on pregnancy and foetal outcome.

Gynecologic cancer as a sentinel cancer for women with hereditary nonpolyposis colorectal cancer syndrome

OBJECTIVE: Women with hereditary nonpolyposis colorectal cancer syndrome have a 40–60% lifetime risk for colon cancer, a 40–60% lifetime risk for endometrial cancer, and a 12% lifetime risk for ovarian cancer. A number of women with hereditary nonpolyposis colorectal cancer syndrome will have more than one cancer in their lifetime. The purpose of this study was to estimate whether women with hereditary nonpolyposis colorectal cancer syndrome who develop 2 primary cancers present with gynecologic or colon cancer as their “sentinel cancer.” METHODS: Women whose families fulfilled Amsterdam criteria for hereditary nonpolyposis colorectal cancer syndrome and who developed 2 primary colorectal/gynecologic cancers in their lifetime were identified from 5 large hereditary nonpolyposis colorectal cancer syndrome registries. Information on age at cancer diagnoses and which cancer (colon cancer or endometrial cancer/ovarian cancer) developed first was obtained. RESULTS: A total of 117 women with dual primary cancers from 223 Amsterdam families were identified. In 16 women, colon cancer and endometrial cancer/ovarian cancer were diagnosed simultaneously. Of the remaining 101 women, 52 (51%) women had an endometrial or ovarian cancer diagnosed first. Forty-nine (49%) women had a colon cancer diagnosed first. For women who developed endometrial cancer/ovarian cancer first, mean age at diagnosis of endometrial cancer/ovarian cancer was 44. For women who developed colon cancer first, the mean age at diagnosis of colon cancer was 40. CONCLUSION: In this large series of women with hereditary nonpolyposis colorectal cancer syndrome who developed 2 primary colorectal/gynecologic cancers, endometrial cancer/ovarian cancer was the “sentinel cancer,” preceding the development of colon cancer, in half of the cases. Therefore, gynecologists and gynecologic oncologists play a pivotal role in the identification of women with hereditary nonpolyposis colorectal cancer syndrome. LEVEL OF EVIDENCE: II-3

Strategies to Identify the Lynch Syndrome Among Patients With Colorectal Cancer: A Cost-Effectiveness Analysis

BACKGROUND Testing has been advocated for all persons with newly diagnosed colorectal cancer to identify families with the Lynch syndrome, an autosomal dominant cancer-predisposition syndrome that is a paradigm for personalized medicine. OBJECTIVE To estimate the effectiveness and cost-effectiveness of strategies to identify the Lynch syndrome, with attention to sex, age at screening, and differential effects for probands and relatives. DESIGN Markov model that incorporated risk for colorectal, endometrial, and ovarian cancers. DATA SOURCES Published literature. TARGET POPULATION All persons with newly diagnosed colorectal cancer and their relatives. TIME HORIZON Lifetime. PERSPECTIVE Third-party payer. INTERVENTION Strategies based on clinical criteria, prediction algorithms, tumor testing, or up-front germline mutation testing, followed by tailored screening and risk-reducing surgery. OUTCOME MEASURES Life-years, cancer cases and deaths, costs, and incremental cost-effectiveness ratios. RESULTS OF BASE-CASE ANALYSIS The benefit of all strategies accrued primarily to relatives with a mutation associated with the Lynch syndrome, particularly women, whose life expectancy could increase by approximately 4 years with hysterectomy and salpingo-oophorectomy and adherence to colorectal cancer screening recommendations. At current rates of germline testing, screening, and prophylactic surgery, the strategies reduced deaths from colorectal cancer by 7% to 42% and deaths from endometrial and ovarian cancer by 1% to 6%. Among tumor-testing strategies, immunohistochemistry followed by BRAF mutation testing was preferred, with an incremental cost-effectiveness ratio of

American Gastroenterological Association Institute Technical Review on the Use of Thiopurines, Methotrexate, and Anti–TNF-α Biologic Drugs for the Induction and Maintenance of Remission in Inflammatory Crohn's Disease

36,200 per life-year gained. RESULTS OF SENSITIVITY ANALYSIS The number of relatives tested per proband was a critical determinant of both effectiveness and cost-effectiveness, with testing of 3 to 4 relatives required for most strategies to meet a threshold of

Association of Large Serrated Polyps With Synchronous Advanced Colorectal Neoplasia

50,000 per life-year gained. Immunohistochemistry followed by BRAF mutation testing was preferred in 59% of iterations in probabilistic sensitivity analysis at a threshold of

Gender as a Risk Factor for Advanced Neoplasia and Colorectal Cancer: A Systematic Review and Meta-analysis

100,000 per life-year gained. Screening for the Lynch syndrome with immunohistochemistry followed by BRAF mutation testing only up to age 70 years cost

5-aminosalicylic acid therapy and the risk of colorectal cancer among patients with inflammatory bowel disease

44,000 per incremental life-year gained compared with screening only up to age 60 years, and screening without an upper age limit cost

Doubling the infliximab dose versus halving the infusion intervals in Crohn's disease patients with loss of response

88,700 per incremental life-year gained compared with screening only up to age 70 years. LIMITATION Other types of cancer, uncertain family pedigrees, and genetic variants of unknown significance were not considered. CONCLUSION Widespread colorectal tumor testing to identify families with the Lynch syndrome could yield substantial benefits at acceptable costs, particularly for women with a mutation associated with the Lynch syndrome who begin regular screening and have risk-reducing surgery. The cost-effectiveness of such testing depends on the participation rate among relatives at risk for the Lynch syndrome. PRIMARY FUNDING SOURCE National Institutes of Health.