ObjectiveEarly-onset colorectal cancer (CRC) represents a clinically distinct form of CRC that is often associated with a poor prognosis. Methylation levels of genomic repeats such as LINE-1 elements have been recognized as independent factors for increased cancer-related mortality. The methylation status of LINE-1 elements in early-onset CRC has not been analyzed previously.DesignWe analyzed 343 CRC tissues and 32 normal colonic mucosa samples, including 2 independent cohorts of CRC diagnosed ≤50 years old (n = 188), a group of sporadic CRC >50 years (MSS n = 89; MSI n = 46), and a group of Lynch syndrome CRCs (n = 20). Tumor mismatch repair protein expression, microsatellite instability status, LINE-1 and MLH1 methylation, somatic BRAF V600E mutation, and germline MUTYH mutations were evaluated.ResultsMean LINE-1 methylation levels (±SD) in the five study groups were early-onset CRC, 56.6% (8.6); sporadic MSI, 67.1% (5.5); sporadic MSS, 65.1% (6.3); Lynch syndrome, 66.3% (4.5) and normal mucosa, 76.5% (1.5). Early-onset CRC had significantly lower LINE-1 methylation than any other group (p<0.0001). Compared to patients with <65% LINE-1 methylation in tumors, those with ≥65% LINE-1 methylation had significantly better overall survival (p = 0.026, log rank test).ConclusionsLINE-1 hypomethylation constitutes a potentially important feature of early-onset CRC, and suggests a distinct molecular subtype. Further studies are needed to assess the potential of LINE-1 methylation status as a prognostic biomarker for young people with CRC.

Chagas disease frequently causes megacolon. We investigated the enteric nervous systems in patients with chagasic megacolon compared to idiopathic megacolon and controls. Surgical specimens were obtained from 12 patients with chagasic megacolon (1 woman, 11 men, age range 41 to 72 y) and 9 patients with idiopathic megacolon (3 women, 6 men, age range 39 to 68 y), undergoing surgery for intractable constipation. A control group of 10 patients (9 women, 1 man, age range 43 to 75 y) undergoing left hemicolectomy for nonobstructing colorectal cancer was also studied. Colonic sections were investigated by conventional and immunohistochemical methods, also taking into consideration the presence of lymphocytes. Compared to controls, the 2 megacolon groups showed a decrease of enteric neurons (not due to increased apoptosis) and of enteric glial cells (all more important in chagasic patients). The interstitial cells of Cajal subtypes were decreased but not absent in megacolons, although an increase of the intramuscular subtype was found, suggesting a possible compensative mechanism. An increased amount of fibrosis was found in the smooth muscle and the myenteric plexus of chagasic patients compared to the idiopathic megacolon and the control group. A mild lymphocytic infiltration of the enteric plexuses (more evident in Chagas disease) was also found in megacolons but not in controls. Patients with chagasic megacolon display important abnormalities of several components of the enteric nervous system. Similar alterations, although of lesser severity, may be found in patients with idiopathic megacolon.

Background: Pouchitis has been suggested to be a recurrence of ulcerative colitis in a colon‐like mucosa. Topical steroids are a valid therapeutic alternative for distal forms of ulcerative colitis. Aim: To investigate the efficacy and tolerability of budesonide enema in the treatment of pouchitis compared with oral metronidazole. Materials and methods: Twenty‐six patients with an active episode of pouchitis (defined as a pouchitis disease activity index score ≥ 7) and no treatment during the previous month were randomized to receive either budesonide enema (2 mg/100 mL at bedtime) plus placebo tablets or oral metronidazole (0.5 g b.d.) plus placebo enema in a prospective, double‐blind, double‐dummy, 6‐week, controlled trial. Results: Based on the intention‐to‐treat principle, we detected a significant improvement in disease activity at the end of the first week with both drugs (P < 0.01). After that, improvement was moderated until stabilization at 4 weeks in both treatments. The per protocol analysis showed that both drugs had similar efficacy in terms of disease activity, clinical and endoscopic findings. Fifty‐eight per cent and 50% of patients improved (decrease in pouchitis disease activity index ≥ 3) with budesonide enema and metronidazole, respectively (odds ratio, 1.4; confidence interval, 0.2–8.9). Adverse effects were observed in 57% of patients given metronidazole and in 25% of patients given budesonide. Conclusions: Budesonide enemas are an alternative treatment for active pouchitis, with similar efficacy but better tolerability than oral metronidazole.

Purpose: No biomarker to personalize treatment in locally advanced rectal cancer (LARC) is currently available. We assessed in LARC whether a diagnostic biopsy-adapted immunoscore (IS B) could predict response to neoadjuvant treatment (nT) and better define patients eligible to an organ preservation strategy ("Watchand-Wait"). Experimental Design: Biopsies from two independent cohorts (n 1 ¼ 131, n 2 ¼ 118) of patients with LARC treated with nT followed by radical surgery were immunostained for CD3 þ and CD8 þ T cells and quantified by digital pathology to determine IS B. The expression of immune-related genes post-nT was investigated (n ¼ 64 patients). Results were correlated with response to nT and disease-free survival (DFS). The IS B prognostic performance was further assessed in a multicentric cohort (n ¼ 73 patients) treated by Watch-and-Wait. Results: IS B positively correlated with the degree of histologic response (P < 0.001) and gene expression levels for Th1 orientation and cytotoxic immune response, post-nT (P ¼ 0.006). IS B high identified patients at lower risk of relapse or death compared with IS B low [HR, 0.21; 95% confidence interval (CI), 0.06-0.78; P ¼ 0.009]. Prognostic performance of IS B for DFS was confirmed in a validation cohort. IS B was an independent parameter, more informative than pre-(P < 0.001) and post-nT (P < 0.05) imaging to predict DFS. IS B combined with imaging post-nT discriminated very good responders that could benefit from organ preservation strategy. In the "Watch-and-Wait" cohort (n ¼ 73), no relapse was observed in patients with IS B high (23.3%). Conclusions: IS B predicts response to nT and survival in patients with LARC treated by surgery. Its usefulness in the selection of patients eligible for a Watch-and-Wait strategy is strongly suggested.

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