A temporal shift of the evolutionary principle shaping intratumor heterogeneity in colorectal cancer.

Advanced colorectal cancer harbors extensive intratumor heterogeneity shaped by neutral evolution; however, intratumor heterogeneity in colorectal precancerous lesions has been poorly studied. We perform multiregion whole-exome sequencing on ten early colorectal tumors, which contained adenoma and carcinoma in situ. By comparing with sequencing data from advanced colorectal tumors, we show that the early tumors accumulate a higher proportion of subclonal driver mutations than the advanced tumors, which is highlighted by subclonal mutations in KRAS and APC. We also demonstrate that variant allele frequencies of subclonal mutations tend to be higher in early tumors, suggesting that the subclonal mutations are subject to selective sweep in early tumorigenesis while neutral evolution is dominant in advanced ones. This study establishes that the evolutionary principle underlying intratumor heterogeneity shifts from Darwinian to neutral evolution during colorectal tumor progression.

Endoscopic and Immunohistochemical Characteristics of Gastric Cancer with versus without Helicobacter Pylori Eradication.

BACKGROUND/AIMS: The rate of gastric cancer (GC) after Helicobacter pylori eradication has gradually increased; therefore, we investigate the clinicopathological features of GC following eradication in comparison with those of GC with H. pylori infection. METHODS: This study included 50 subjects with GC after eradication (GCE) and 151 patients with GC with H. pylori infection (GCI). Clinicopathological factors were assessed. The manifestation of GC was further evaluated using immunohistochemical analysis and in situ hybridization. RESULTS: Macroscopic analysis revealed a significantly higher ratio of depressed type /elevated type in the GCE compared with the GCI (30/19 vs. 61/77, p = 0.041). The gastric phenotype was more common in the GCE compared with the GCI, and the proportion of CDX2-positive cases was lower in the GCE (8 out of 18; 44.4%) compared with the GCI (18 out of 19; 94.7%; p = 0.00082). Ki-67 labeling index was significantly lower in the GCE (32.03 ± 22.15) compared with the GCI (79.20 ± 14.87, p < 0.0001). No patient in the GCE showed evidence of Epstein-Barr virus infection. CONCLUSION: The clinicopathological characteristics of GC following H. pylori eradication differ from those of GC in patients with H. pylori infection in terms of morphology, mucin phenotype, and proliferation rate.

Objective Endoscopic Analysis with Linked Color Imaging regarding Gastric Mucosal Atrophy: A Pilot Study.

OBJECTIVES: We aimed to determine whether linked color imaging (LCI), a new image-enhanced endoscopy that enhances subtle differences in mucosal colors, can distinguish the border of endoscopic mucosal atrophy. METHODS: This study included 30 patients with atrophic gastritis. In endoscopy, we continuously took images in the same composition with both LCI and white light imaging (WLI). In each image, the color values of atrophic and nonatrophic mucosae were quantified using the International Commission on Illumination 1976 (L∗, a∗, b∗) color space. Color differences at the atrophic border, defined as Euclidean distances of color values between the atrophic and nonatrophic mucosae, were compared between WLI and LCI for the overall cohort and separately for patients with Helicobacter pylori infection status. RESULTS: We found that the color difference became significantly higher with LCI than with WLI in the overall samples of 90 points in 30 patients. LCI was 14.79 ± 6.68, and WLI was 11.06 ± 5.44 (P < 0.00001). LCI was also more effective in both of the Helicobacter pylori-infected group (P = 0.00003) and the Helicobacter pylori-eradicated group (P = 0.00002). CONCLUSIONS: LCI allows clear endoscopic visualization of the atrophic border under various conditions of gastritis, regardless of Helicobacter pylori infection status.

Deep Ulcers in the Ileum Associated with Mycophenolate Mofetil.

A 54-year-old man was treated with mycophenolate mofetil (MMF) after undergoing living donor renal transplantation. Two years later, he experienced repeated episodes of diarrhea, and his C-reactive protein (CRP) level was found to be 12.63 mg/dL. Ileocolonoscopy showed multiple deep, punched-out ulcers that were similar to Behçet's disease (BD) and cytomegalovirus (CMV) in the ileum. CMV infection was suspected. However, anti-cytomegalovirus agents were ineffective. The patient was subsequently diagnosed with gastrointestinal toxicity of MMF and MMF was switched to mizoribine. His symptoms improved immediately, and his CRP level normalized. Six months later, the patient's mucosa was healed.

Marked improvement in gastric involvement in Behçet's disease with adalimumab treatment.

Gastric involvement is the least frequent manifestation of Behçet's disease, and effective treatment for it unknown. Here the case of a patient with gastric involvement in Behçet's disease that was markedly improved with adalimumab therapy is presented. A 68-year-old man developed an oral ulcer, erythema, folliculitis, and arthralgia. Behçet's disease was suspected; then, prednisolone and colchicine were administered. Esophagogastroduodenoscopy showed a punched-out ulcer in the posterior wall of the gastric antrum. Ileocolonoscopy showed multiple punched-out ulcers in the terminal ileum. Capsule endoscopy showed multiple circular ulcers throughout the entire small intestine. A diagnosis of non-steroidal, anti-inflammatory, drug-induced enteritis was made. Withdrawal from diclofenac and initiation of lansoprazole healed the circular ulcers in the small intestine, but were ineffective for the gastric ulcer and punched-out ulcers in the terminal ileum. Eradication of Helicobacter pylori was also ineffective. A diagnosis of gastric involvement of Behçet's disease was then made, and the gastric ulcer became steroid-dependent. Mesalazine powder was ineffective, and the patient was intolerant to azathioprine. Adalimumab healed the gastric ulcer, and prednisolone was withdrawn. The outcome of the present patient suggests that adalimumab is effective in the treatment of gastric involvement in Behçet's disease.

Association between Gastric Cancer Risk and Serum Helicobacter pylori Antibody Titers.

BACKGROUND/AIMS: It is difficult to confirm the accurate cutoff value to diagnose Helicobacter pylori (Hp) infection using commercial serology kits. It is reported that there were many cases with present/past infection that even the serum Hp-IgG antibody (HpAb) titers were below the cutoff value (e.g., 10 U/mL for E-Plate®), suggesting that we might overlook many gastric cancer (GC). We investigated an association between gastric cancer risk and serum Helicobacter pylori antibody titers. METHODS: We conducted a primary screening between 2014 and 2015. We performed gastroendoscopy if HpAb titers were ≥3.0 U/mL (i.e., more than measurable limit, E-Plate). These patients were divided into two groups: HpAb = 3.0-9.9 U/mL ("negative-high" group) and HpAb ≥ 10 U/mL; cutoff value ("over-10 U/mL" group). Hp infection status was investigated, and the number of GC patients was counted. RESULTS: Among the 3321 subjects in the primary screening, 56.9% (1891/3321) showed HpAb titers ≥3.0 U/mL; 1314 patients underwent gastroendoscopy. Ten were GC. 421 patients were "negative-high" group; two were GC. After evaluating 381 patients for Hp infection, 22.6%/60.6% was with present/past infection among the "negative-high" group. CONCLUSION: We also found a correlation between HpAb titers and Hp infection status. "Negative-high" group has a risk of GC.

Esomeprazole- or rabeprazole-based triple therapy eradicated Helicobacter pylori comparably regardless of clarithromycin susceptibility and CYP2C19 genotypes.

The aim of this study was to assess the efficacy of esomeprazole-based triple therapy compared with rabeprazole-based triple therapy according to CYP2C19 genotype and clarithromycin susceptibility status for first-line eradication therapy of Helicobacter pylori (H. pylori) in Japan. We enrolled 219 H. pylori-infected patients, and randomly allocated patients to the EAC group (esomeprazole 20 mg, clarithromycin 200 mg, amoxicillin 750 mg for one week, with all drugs given twice daily) or RAC group (rabeprazole 10 mg, clarithromycin 200 mg, amoxicillin 750 mg for one week, with all drugs given twice daily). The H. pylori eradication rate according to the PP analyses was 75.0% (95% CI: 65.2-82.8%) in the EAC group and 71.4% (95% CI: 61.4-79.1%) in the RAC group. There were no statistically significant differences. The eradication rates of the clarithromycin-resistant/-sensitive strains were, respectively, 45.0% (95% CI: 30.7-60.2%)/98.0% (95% CI: 88.7-100%) in the EAC group and 39.5% (95% CI: 25.6-55.3%)/93.5% (95% CI: 81.9-98.4%) in the RAC group. The eradication rate of the clarithromycin-sensitive strains was significantly higher than that of the resistant strains in both groups. In conclusion, EAC and RAC therapies show a comparable efficacy regardless of the CYP2C19 genotype and clarithromycin susceptibility status in Japan.

Comparison of the efficacy of irsogladine maleate and famotidine for the healing of gastric ulcers after Helicobacter pylori eradication therapy: a randomized, controlled, prospective study.

OBJECTIVE: Helicobacter pylori eradication therapy alone cannot heal gastric ulcers in Japanese patients. Irsogladine has previously been shown to accelerate the healing of gastric ulcers after H. pylori eradication therapy. And we previously reported that histamine H(2) receptor antagonists inhibit gastric ulcer relapse after H. pylori eradication therapy. We therefore compared the efficacy of irsogladine with famotidine as appropriate treatments for ulcers after eradication therapy. METHODS: Gastric ulcer patients with H. pylori infection (n = 119) were randomized to treatment with irsogladine 4 mg/day (n = 60) or famotidine 40 mg/day (n = 59) following 1-week H. pylori eradication therapy. After treatment, assessments of gastric ulcer healing were performed. RESULTS: The ulcer healing rates in patients receiving irsogladine and famotidine were 85.2% (46/54) and 79.6% (43/54), respectively, and were not significantly different (p = 0.4484). In the famotidine group, the healing rate was significantly lower in patients who drink alcohol than in those who do not (60.0% vs. 91.2%; p = 0.0119). However, in the irsogladine group the healing rate did not differ between patients who drink alcohol and those who do not. Furthermore, the healing rate in smokers was significantly higher in the irsogladine group (88.0%) than in the famotidine group (59.1%) (p = 0.0233). CONCLUSIONS: Irsogladine and famotidine are both acceptable in treatment after H. pylori eradication therapy in gastric ulcer patients. Findings also suggest that irsogladine is more beneficial than famotidine in patients who drink alcohol and smoke.

Computed tomography of the gastrointestinal manifestation of hereditary angioedema.

We report a case of gastrointestinal manifestation of hereditary angioedema. Computed tomography (CT) revealed wall thickening of the gastric antrum, duodenum, and jejunum. Dilatation of the third part of the duodenum, thickening of the small bowel mesentery and omentum, and retroperitoneal edema were present. The importance of considering this condition in patients presenting such CT findings correlated with the appropriate history is discussed.