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Objectives The BRAF V600E mutation is associated with treatment resistance and is a poor prognostic indicator in colorectal adenocarcinomas (CRAs). Prior studies have shown that the BRAF V600E mutation confers resistance to apoptosis by Mcl-1 gene upregulation. We evaluated the clinical effect of Mcl-1 expression on BRAF-mutated (BM) MMR-deficient (dMMR) CRAs. Methods Thirty-one BM dMMR CRAs were included in a tissue microarray. The intensity and extent of Mcl-1 expression were evaluated by immunohistochemistry. Staining intensity (0-3+) and percentage of cells with positive staining (none, 50% = 3) were determined. Cases were considered positive when the intensity score multiplied by the percentage category score was >4. Mcl-1 expression was correlated with clinicopathologic features. Results Positive Mcl-1 staining was identified in 13 (42%), among which 9 (69.2%) were well to moderately differentiated with lymphovascular invasion present in 4 (30.8%), lymph nodes metastases in 3 (23.1%), and AJCC stage pT3 or greater in 8 (61.5%). In contrast, 18 (58%) were Mcl-1 negative, among which 10 (55.6%) were poorly differentiated with lymphovascular invasion present in 12 (66.7%), lymph node metastases in 9 (50%), and AJCC stage pT3 or greater in 14 (77.8%). Conclusion Among 31 examined BM dMMR CRAs, cases that demonstrated Mcl-1 expression were associated with a lower grade, lower rate of lymphovascular invasion and lymph node metastasis, and lower AJCC stage. While Mcl-1 expression confers resistance to apoptosis, this study suggests that Mcl-1–positive tumors demonstrate pathologic features associated with a favorable clinical outcome.

Background Approximately 15–20% of ulcerative colitis patients and 20–40% of those with Crohn’s disease experience extraintestinal manifestations (EIMs) of their inflammatory bowel disease (IBD). Clinicians who treat IBD must manage EIMs affecting multiple organs that variably correlate with intestinal disease activity. Vedolizumab is a monoclonal antibody for the treatment of IBD with a gut-selective mechanism of action. Aims This report evaluates whether vedolizumab is an effective treatment of EIMs, given its gut-specific mechanism of action. Methods We report 8 case studies of patients with various EIMs, including pyoderma gangrenosum, peripheral arthralgia/arthritis, axial arthropathies, erythema nodosum, and uveitis, who received vedolizumab therapy. Results Vedolizumab therapy was effective for pyoderma gangrenosum in ulcerative colitis, uveitis, erythema nodosum, polyarticular arthropathy, and ankylosing spondylitis/sacroiliitis but did not provide sustained benefit for the treatment of pyoderma gangrenosum in a patient with Crohn’s disease. Conclusions These cases demonstrate the potential of vedolizumab as a treatment of EIMs in patients with IBD.

BACKGROUND Approximately 10% of pancreatic ductal adenocarcinoma (PDAC) is due to a genetic predisposition, including the breast and ovarian cancer syndrome germline mutations BRCA1 and BRCA2. Knowledge of specific genetic mutations predisposing to PDAC may enable risk stratification, early detection, and the development of effective screening and surveillance programs. In the current study, the authors attempted to determine the diagnostic yield of testing for BRCA1/2 germline mutations in a PDAC screening cohort and a PDAC cohort referred for genetic testing. METHODS Patients in a high-risk PDAC prevention and genetics program or those with a personal history of PDAC who were referred for genetic evaluation underwent testing for BRCA1/2 germline mutations. Clinical BRCA1/2 genetic testing included testing for the 3 Ashkenazi Jewish founder mutations or BRCA1/2 comprehensive testing. RESULTS A total of 37 patients without PDAC underwent BRCA1/2 testing at the study institution. Genetic testing identified 7 patients who were BRCA1/2 carriers for a yield of 18.9%. Six patients carried Ashkenazi Jewish founder mutations (3 with BRCA1 and 3 with BRCA2), and 1 patient was found to have a BRCA2 mutation on comprehensive testing. Thirty-two patients with PDAC underwent BRCA1/2 genetic testing. Five patients had Ashkenazi Jewish founder mutations (2 with BRCA1 and 3 with BRCA2), and 2 patients were found to have BRCA2 mutations on comprehensive testing. The diagnostic yield was 7 of 32 patients (21.9%). CONCLUSIONS BRCA1/2 testing is useful in PDAC risk stratification and alters risk assignment and screening recommendations for mutation-positive patients and their families. Clinical BRCA1/2 testing should be considered in patients of Ashkenazi Jewish descent with a personal history or family history of PDAC, even in the absence of a family history of breast and ovarian cancer. Cancer 2014;120:1960–1967. © 2014 American Cancer Society.