Faculty Bibliography

The role of dietary fiber in colon cancer prevention remains controversial. We investigated its impact on anti-tumor immunity and the gut microbiota in APCmin/+ mice infected with Enterotoxigenic Bacteroides fragilis. Mice were fed high-fiber, low-fiber, or chow diets, and tumor burden, survival, cytokines, microbiota, and metabolites were analyzed. Contrary to the belief that high fiber inhibits tumor progression, it had no significant impact compared to chow diet. However, the low-fiber diet significantly reduced tumor burden and improved survival. Mechanistically, high fiber increased pro-inflammatory cytokines and CD4+Foxp3+RORγt+IL-17A+ regulatory T cells, while low fiber enhanced anti-inflammatory cytokines and cytotoxic T-cells. High fiber enriched microbial taxa associated with IL-17A+RORγt+ Tregs and altered metabolites, including reduced tryptophan and increased short-chain fatty acids and bile acids. Low fiber produced opposite effects. These findings suggest that dietary fiber's effects on colon cancer depends on microbial infection and immune status, emphasizing the need for personalized dietary interventions in colon cancer management.

Objectives/UNASSIGNED:To assess bone marrow (BM) sampling in academic medical centers. Methods/UNASSIGNED:Data from 6,374 BM samples obtained in 32 centers in 2001 and 2011, including core length (CL), were analyzed. Results/UNASSIGNED:BM included a biopsy (BMB; 93%) specimen, aspirate (BMA; 92%) specimen, or both (83%). The median (SD) CL was 12 (8.5) mm, and evaluable marrow was 9 (7.6) mm. Tissue contraction due to processing was 15%. BMB specimens were longer in adults younger than 60 years, men, and bilateral, staging, and baseline samples. Only 4% of BMB and 2% of BMB/BMA samples were deemed inadequate for diagnosis. BM for plasma cell dyscrasias, nonphysician operators, and ancillary studies usage increased, while bilateral sampling decreased over the decade. BM-related quality assurance programs are infrequent. Conclusions/UNASSIGNED:CL is shorter than recommended and varies with patient age and sex, clinical circumstances, and center experience. While pathologists render diagnoses on most cases irrespective of CL, BMB yield improvement is desirable.

Colorectal medullary carcinoma, recognized by the World Health Organization as a distinct histologic subtype, is commonly regarded as a specific entity with an improved prognosis and unique molecular pathogenesis. A fundamental but as yet unaddressed question, however, is whether it can be diagnosed reproducibly. In this study, by analyzing 80 colorectal adenocarcinomas whose dominant growth pattern was solid (thus encompassing medullary carcinoma and its mimics), we provided a detailed description of the morphological spectrum from "classic medullary histology" to nonmedullary poorly differentiated histologies and demonstrated significant overlapping between categories. By assessing a selected subset (n=30) that represented the spectrum of histologies, we showed that the interobserver agreement for diagnosing medullary carcinoma by using 2010 World Health Organization criteria was poor; the κ value among 5 gastrointestinal pathologists was only 0.157 (95% confidence interval, 0.127-0.263; P=.001). When we arbitrarily classified the entire cohort into "classic" and "indeterminate" medullary tumors (group 1, n=19; group 2, n=26, respectively) and nonmedullary poorly differentiated tumors (group 3, n=35), groups 1 and 2 were more likely to exhibit mismatch repair protein deficiency than group 3 (P<.001); however, improved survival could not be detected in either group compared with group 3. Our findings suggest that the diagnosis of medullary carcinoma, as currently applied, may only serve as a morphological descriptor indicating an increased likelihood of mismatch-repair deficiency. Additional evidence including a more objective classification system is needed before medullary carcinoma can be regarded as a distinct entity with prognostic relevance. Until such evidence becomes available, caution should be exercised when making this diagnosis, as well as when comparing results across different studies.

ARID1A is a chromatin remodeling gene that is mutated in a number of cancers including colorectal carcinoma (CRC). Loss of ARID1A has been associated with an adverse outcome in some types of cancer. However, literature data have not been consistent. Major limitations of some outcome studies include small sample size and heterogeneous patient population. In this study, we evaluated the prognostic value of ARID1A in a homogeneous group of early stage CRC patients, a population where prognostic markers are particularly relevant. We collected a retrospective series of 578 stage I or II CRCs. All patients underwent surgery with curative intent and without neoadjuvant or adjuvant therapy. ARID1A expression was analyzed by immunohistochemistry using tissue microarray. We found ARID1A loss in 49 of 552 analyzable tumors (8.9%). Compared with the ARID1A-retained group, cases with ARID1A loss were associated with female sex (P<.001), mismatch-repair protein deficiency (P<.001), poor differentiation (P<.001), lymphovascular invasion (P=.001), and higher pT stage (P=.047). However, at a median follow-up of 49months, ARID1A loss did not correlate with overall, disease-specific, or recurrence-free survival. This is the first systematic analysis to evaluate the prognostic significance of ARID1A in stage I/II CRCs, and our data indicate that ARID1A loss lacks prognostic significance in this population despite its association with other adverse features. Such data are clinically relevant, as efforts are ongoing in identifying markers that can detect the small but significant subset of early stage CRCs that will have a poor outcome.