Background & Aims The diagnosis of drug-induced liver injury relies on exclusion of other causes, including viral hepatitis A, B, and C. Hepatitis E virus (HEV) infection has been proposed as another cause of suspected drug-induced liver disease. We assessed the frequency of HEV infection among patients with drug-induced liver injury in the United States. Methods The Drug-Induced Liver Injury Network (DILIN) is a prospective study of patients with suspected drug-induced liver injury; clinical information and biological samples are collected to investigate pathogenesis and disease progression. We analyzed serum samples, collected from patients enrolled in DILIN, for immunoglobulin (Ig) G and IgM against HEV; selected samples were tested for HEV RNA. Results Among 318 patients with suspected drug-induced liver injury, 50 (16%) tested positive for anti-HEV IgG and 9 (3%) for anti-HEV IgM. The samples that contained anti-HEV IgM (collected 2 to 24 weeks after onset of symptoms) included 4 that tested positive for HEV RNA genotype 3. Samples from the 6-month follow-up visit were available from 4 patients; they were negative for anti-HEV IgM, but levels of anti-HEV IgG increased with time. Patients who had anti-HEV IgM were mostly older men (89%; mean age, 67 years), and 2 were human immunodeficiency virus positive. Clinical reassessment of the 9 patients with anti-HEV IgM indicated that acute hepatitis E was the most likely diagnosis for 7 and might be the primary diagnosis for 2. Conclusions HEV infection contributes to a small but important proportion of cases of acute liver injury that are suspected to be drug induced. Serologic testing for HEV infection should be performed, particularly if clinical features are compatible with acute viral hepatitis.

Low folate status increases colorectal cancer risk. Paradoxically, overly abundant folate supplementation, which is not uncommon in the United States, may increase risk. The mechanisms of these effects are unknown. We conducted two translational studies to define molecular pathways in the human colon altered either by folate supplementation or by dietary folate depletion (followed by repletion). In the first study, 10 healthy, at-risk volunteers (with documented stable/normal folate intake) received supplemental folic acid (1 mg/d) for 8 weeks. In the second study, 10 similar subjects were admitted to a hospital as inpatients for 12 weeks to study folate depletion induced by a low folate diet. A repletion regimen of folic acid (1 mg/d) was provided for the last 4 of these weeks. Both studies included an 8-week run-in period to ensure stabilized folate levels prior to intervention. We obtained 12 rectosigmoid biopsies (from 4 quadrants of normal-appearing mucosa 10–15 cm from the anal verge) at baseline and at measured intervals in both studies for assessing the primary endpoints: genome-wide gene expression, genomic DNA methylation, promoter methylation (depletion/repletion study only), and p53 DNA strand breaks. Serum and rectosigmoid folate concentrations accurately tracked all changes in folate delivery (P < 0.05). In the first study, gene array analysis revealed that supplementation upregulated multiple inflammation- and immune-related pathways in addition to altering several 1-carbon–related enzymes (P < 0.001). In the second study, folate depletion downregulated genes involved in immune response, inflammation, the cell cycle, and mitochondrial/energy pathways; repletion reversed most of these changes. However, changes in gene expression after repletion in the second study (involving immune response and inflammation) did not reach the levels seen after supplementation in the first study. Neither genomic nor promoter-specific DNA methylation changed during the course of the depletion/repletion protocol, and genomic methylation did not change with supplementation in the first study. p53 DNA strand breaks increased with depletion after 12 weeks. In sum, depletion downregulates, whereas repletion or supplementation upregulates pathways related to inflammation and immune response. These findings provide novel support to the concept that excessive folate supplementation might promote colorectal carcinogenesis by enhancing proinflammatory and immune response pathways. These results indicate that modest changes in folate delivery create substantial changes in the molecular milieu of the human colon. Cancer Prev Res; 4(4); 530–43. ©2011 AACR.

Background: A high dietary calcium intake with adequate vitamin D status has been linked to lower colorectal cancer risk, but the mechanisms of these

Despite recent population data, the influence of dietary folate supplementation on colon cancer risk remains controversial. This study examines the effects of folate deficiency, in combination with choline, methionine, and vitamin B12 depletion, on intestinal tumorigenesis in Apc^Min/+ mice. Methyl donor sufficient (MDS) and deficient (MDD) diets were started at five or 10 weeks of age and tumors evaluated at 16 weeks. MDD suppressed intestinal tumor formation in Apc^Min/+ mice (∼80%) when started at five weeks of age. The protective effect was lost when MDD was initiated at 10 weeks of age, indicating an important time dependency on cancer suppression. Concomitant with cancer protection, MDD restricted body weight gain. Therefore, a second study was conducted in which MDS was given ad libitum or pair-fed with MDD. Although small intestinal tumors were reduced 54% in pair-fed MDS mice, MDD caused a further reduction (96%). In colon, although MDD did not affect tumor numbers, tumor size was reduced. Gene expression profiling of normal-appearing colonic mucosa after 11 weeks on MDD identified a total of 493 significantly downregulated genes relative to the MDS group. Pathway analysis placed many of these genes within general categories of inflammatory signaling and cell-cycle regulation, consistent with recently published human data obtained during folate depletion. Further studies are warranted to investigate the complex interplay of methyl donor status and cancer protection in high-risk populations. Cancer Prev Res; 5(7); 911–20. ©2012 AACR.

Objective Although appendiceal cancer remains a rare gastrointestinal malignancy compared with colorectal cancer, incidence rates of appendiceal cancer have increased in the last two decades. Appendiceal and cecal adenocarcinomas have distinct genomic profiles, but chemotherapy protocols for these malignancies are the same and survival outcomes between them have not been compared extensively. To this end, we conducted a comparative survival analysis of appendiceal and cecal adenocarcinomas. Design Using the Surveillance, Epidemiology and End Results (SEER) database, we identified individuals ≥30 years of age with appendiceal or cecal adenocarcinoma from 1975 to 2016. Demographic, clinical and county-level socioeconomic data were extracted using SEER*Stat software. Survival was compared by Mantel-Haenszel log-rank test, and survival curves were generated using the Kaplan-Meier method. Relative HRs for death in the 5-year period following diagnosis were calculated using multivariable Cox regression analysis, adjusted for all other covariates. The significance level was set at p<0.05 for two-tailed tests. Data were analysed using SAS V.9.4 and R software. Results We identified 6491 patients with appendiceal adenocarcinoma and 99 387 patients with cecal adenocarcinoma. Multivariable Cox regression analysis demonstrated significantly higher cancer-specific and overall survival in appendiceal adenocarcinoma compared with cecal adenocarcinoma. Male sex, older age, earlier year of diagnosis, black race, single marital status, non-Hispanic ethnicity, and non-mucinous histology were associated with increased mortality rates. In addition, counties with lower percentage of individuals below the poverty line and higher colorectal cancer screening rates had better survival. Conclusion This is the first study to show greater survival in appendiceal adenocarcinoma compared with cecal adenocarcinoma. We also highlighted novel associations of county-level socioeconomic factors with increased mortality in appendiceal adenocarcinoma. Future efforts to develop targeted molecular therapies and reduce socioeconomic barriers to diagnosis and treatment are warranted to improve survival.

Introduction Anal adenocarcinoma is a rare malignancy with a poor prognosis. Methods We present a case of rare anal adenocarcinoma in a patient with normal screening colonoscopy. Using the Surveillance, Epidemiology and End Result database between 2000 and 2016, we performed survival analysis among individuals>20 years old comparing anal and rectal cancers. Results Survival analysis showed that anal adenocarcinoma is associated with worse outcomes compared with rectal adenocarcinoma and anal squamous cell carcinoma. Discussion This case and survival data illustrate the importance of prompt investigation of symptoms irrespective of colorectal cancer screening status with careful attention to examination of the anal area.