Cancer risk and genotype-phenotype correlation in Japanese patients with Cowden syndrome.

BACKGROUND: Cowden syndrome (CS) is an autosomal-dominant hereditary disorder caused by a germline PTEN variant and characterized by multiple hamartomas and a high risk of cancers. However, no detailed data on CS in Asian patients nor genotype-phenotype correlation have been reported. METHODS: We performed the first Japanese nationwide questionnaire survey on CS and obtained questionnaire response data on 49 CS patients. RESULTS: Patients included 26 females (median age 48 years). The incidence of breast, thyroid, endometrium, and colorectal cancer was 32.7%, 12.2%, 19.2% (among females), and 6.1%, respectively. The incidence of any cancers was relatively high among all patients (46.9%, 23/49), and particularly female patients (73.1%, 19/26), compared with previous reports from Western countries. Gastrointestinal (GI) polyps were more frequently found throughout the GI tract compared with previous studies. PTEN variants were detected in 95.6% (22/23) of patients; 12 in the N-terminal region (11 in phosphatase domain) and 10 in the C-terminal (C2 domain) region. The incidence of cancer in the C2 domain group was significantly higher than in the N-terminal region (phosphatase) group. All female patients with C2 domain variant had breast cancer. CONCLUSION: Our data suggest that Japanese patients with CS, particularly female patients and patients with C2 domain variant may have a high risk of cancers.

Factors associated with complicated erosive esophagitis: A Japanese multicenter, prospective, cross-sectional study.

AIM: To assess the clinical characteristics of patients with complicated erosive esophagitis (EE) and their associated factors. METHODS: This prospective, cross-sectional study included patients diagnosed with EE by upper gastrointestinal endoscopy between October 2014 and March 2015 at 106 Japanese hospitals. Data on medical history, general condition, gastrointestinal symptoms, lifestyle habits, comorbidities, and endoscopic findings were collected using a standard form to create a dedicated database. Logistic regression analysis was used to calculate adjusted odds ratios (aOR) and 95%CI for the association with complicated EE. RESULTS: During the study period, 1749 patients diagnosed with EE, 38.3% of whom were prescribed proton pump inhibitors (PPIs) were included. Of them, 143 (8.2%) had EE complications. Esophageal bleeding occurred in 84 (4.8%) patients, esophageal strictures in 45 (2.6%) patients, and 14 (0.8%) patients experienced both. Multivariate analysis showed that increased age (aOR: 1.05; 95%CI: 1.03-1.08), concomitant use of psychotropic agents (aOR: 6.51; 95%CI: 3.01-13.61), and Los Angeles grades B (aOR: 2.69; 95%CI: 1.48-4.96), C (aOR: 15.38; 95%CI: 8.62-28.37), and D (aOR: 71.49; 95%CI: 37.47-142.01) were significantly associated with complications, whereas alcohol consumption 2-4 d/wk was negatively associated (aOR: 0.23; 95%CI: 0.06-0.61). Analyzing associated factors with each EE complication separately showed esophageal ulcer bleeding were associated with increased age (aOR: 1.05; 95%CI: 1.02-1.07) and Los Angeles grades B (aOR: 3.60; 95%CI: 1.52-8.50), C (aOR: 27.61; 95%CI: 12.34-61.80), and D (aOR: 119.09; 95%CI: 51.15-277.29), while esophageal strictures were associated with increased age (aOR: 1.07; 95%CI: 1.04-1.10), gastroesophageal reflux symptom (aOR: 2.51; 95%CI: 1.39-4.51), concomitant use of psychotropic agents (aOR: 11.79; 95%CI: 5.06-27.48), Los Angeles grades C (aOR: 7.35; 95%CI: 3.32-16.25), and D (aOR: 20.34; 95%CI: 8.36-49.53) and long-segment Barrett's esophagus (aOR: 4.63; 95%CI: 1.64-13.05). CONCLUSION: Aging and severe EE were common associated factors, although there were more associated factors in esophageal strictures than esophageal ulcer bleeding. Despite the availability and widespread use of PPIs, EE complications are likely to remain a problem in Japan owing to the aging population and high-stress society.

Influence of Helicobacter pylori status and eradication on the serum levels of trefoil factors and pepsinogen test: serum trefoil factor 3 is a stable biomarker.

BACKGROUND AND AIM: Emerging data indicate that serum trefoil factors (TFFs), especially TFF3, could be potential biomarkers for gastric cancer risk. We aimed to evaluate the influence of Helicobacter pylori (H. pylori) status and eradication on serum TFFs and the pepsinogen test. METHODS: Healthy individuals who underwent a thorough medical checkup were enrolled in study 1, and gastric ulcer patients who undertook H. pylori eradication therapy were enrolled in studies 2 and 3. Serum levels of the TFFs (TFF1, TFF2 and TFF3), H. pylori antibody and pepsinogen test were examined in all studies. In study 3, TFF expressions in biopsy samples of the gastric mucosa were additionally examined before and 2 months after eradication. RESULTS: In 1,260 healthy individuals enrolled in study 1, serum TFF1 and TFF2 levels were markedly different between H. pylori antibody-positive and -negative participants (P < 0.0001). Differences in serum TFF3 levels between H. pylori antibody-positive (5.85 ± 3.93 ng/ml) and -negative subjects (5.27 ± 2.38 ng/ml) were statistically significant (P = 0.002) but small in absolute value. In 178 gastric ulcer patients enrolled in study 2, serum TFF1, TFF2 and positive rates of the pepsinogen test significantly decreased 2 months after H. pylori eradication therapy (P < 0.001). In contrast, serum TFF3 levels and positive rates of high TFF3 levels (≥7 ng/ml) did not significantly change with H. pylori-eradication until 5 years after eradication. In 18 gastric ulcer patients (study 3), TFF1 and TFF2 were mainly expressed in the foveolar epithelium, and TFF2 was additionally expressed in the pyloric glands. These expressions significantly decreased with H. pylori eradication. TFF3s were scarcely expressed in the gastric mucosa except in goblet cells of intestinal metaplasia, which did not change with H. pylori eradication. CONCLUSION: In serum TFFs and pepsinogen tests, only serum TFF3s were not significantly affected by H. pylori eradication, suggesting that serum TFF3 could be a stable biomarker of gastric cancer risk even after H.pylori eradication in contrast with the pepsinogen test.

A case of chemical peritonitis and pleuritis caused by spontaneous rupture of a benign cystic ovarian teratoma that improved without surgical intervention.

Rupture of a benign cystic ovarian teratoma may result in severe chemical granulomatous peritonitis, a condition mimicking peritonitis carcinomatosa, with patients complaining of common abdominal symptoms. As the precipitating cause of rupture is often indeterminate and the rupture itself is hard to recognize, it is difficult to differentiate from peritonitis of other etiologies, such as gastrointestinal malignancy. We report the case of a 72-year-old female who presented with recurrent pyrexia and abdominal distension. Laboratory data showed signs of inflammation and a high level of carbohydrate antigen 125. Imaging examinations showed left-side-dominant pleural effusion, ascites with peritoneal adhesions, and a left cystic ovarian teratoma. Repeat paracentesis of both the pleural effusion and ascites demonstrated exudative characteristics, but there was no indication of malignancy or signs of infection, including those of tuberculosis. Although exploratory laparotomy was then recommended for conclusive diagnosis and ruling out such gynecological malignancy, the patient declined. Fortunately, laboratory data, radiological images, and other clinical findings gradually improved over the following 12 months. Moreover, a retrospective review of the computed tomography images revealed lipid particles in the ascites, indicative of teratoma rupture. The final diagnosis was chemical peritonitis and pleuritis caused by spontaneous rupture of the benign cystic teratoma. The present case was extremely rare with regard to its diagnosis and clinical progression. Our experience suggests that chemical peritonitis should be included in the differential diagnosis of peritonitis.

The combination of serum trefoil factor 3 and pepsinogen testing is a valid non-endoscopic biomarker for predicting the presence of gastric cancer: a new marker for gastric cancer risk.

BACKGROUND: A valid biomarker for predicting the presence of gastric cancer may contribute to reducing deaths from this disease. Although pepsinogen (PG) testing has been introduced as a predictor, its predictive power is not satisfactory. We examined whether serum trefoil factor (TFF) could be a non-endoscopic predictor of the presence of gastric cancer. METHODS: Gastric cancer patients who underwent preoperative endoscopy were sequentially recruited. Individuals who underwent a thorough medical checkup were enrolled as non-cancer controls. Serum levels of TFF1, TFF2, TFF3, Helicobacter pylori antibody, PG I, and PG II were examined. RESULTS: We studied 192 gastric cancer patients aged 64.3 ± 9.7 years and 1254 non-cancer controls aged 52.3 ± 12.4 years. In the age/gender-matched analysis (187 cases and 561 controls), significant relationships were demonstrated between gastric cancer presence and TFF3 (P < 0.0001), the PGI/II ratio (P < 0.0001), H. pylori antibody (P = 0.001), TFF1 (P = 0.012), and TFF2 (P = 0.020). The area under the receiver-operating characteristic curve for predicting gastric cancer presence was comparably high for all factors (0.893) and for the combination of TFF3 and the PG test (0.883), but was significantly (P < 0.0001) lower for the PG test alone (0.823). A positive PG test showed a sensitivity of 67% and specificity of 82%, whereas a combination of TFF3 and PG testing showed a sensitivity of 80% and specificity of 80% in predicting the presence of gastric cancer. CONCLUSION: The combination of serum TFF3 and PG testing might be a valid non-endoscopic biomarker for predicting the presence of gastric cancer.

CpG island hypermethylation of tumor-suppressor genes in H. pylori-infected non-neoplastic gastric mucosa is linked with gastric cancer risk.

BACKGROUND AND AIM: Gastric carcinogenesis involves CpG island hypermethylation (CIHM) of tumor-suppressor genes. Although the CIHM of these genes occurs in non-neoplastic gastric cells, it is unclear whether this epigenetic alteration is linked with aging and/or gastric cancer risk. We investigated this linkage in noncancerous gastric mucosa infected with H. pylori. SUBJECTS AND METHODS: Noncancerous corpus mucosa was endoscopically obtained from H. pylori-positive gastric cancer patients (n = 34), and age-matched H. pylori-positive noncancerous controls (n = 68). Genomic DNA retrieved from the mucosa was subjected to methylation-specific polymerase chain reaction for p16, Ecad, and DAPK genes. Linkage between CIHM and clinicopathologic factors was evaluated. RESULTS: CIHM rates of DAPK, Ecad, and p16 promoters were significantly higher in noncancerous gastric mucosa of gastric cancer patients (91, 88, and 68%, respectively) than in noncancerous controls (71, 53, and 25%, respectively). Multivariate regression analysis showed a significant linkage between CIHM in noncancerous mucosa and coexistence of gastric cancer. Significant linkage between polymorphoneutrophil infiltration and CIHM was observed except for CIHM of p16. No linkage was observed between CIHM and other parameters, including age. High CIHM status (all three tested genes methylated) was associated with an increased risk of gastric cancer, with an odds ratio of 9.8 (95% confidence interval, 3.8-25.3). CONCLUSIONS: In a subset of the H. pylori-infected population, CIHM of tumor-suppressor genes in noncancerous gastric mucosa is linked with the risk of gastric cancer and polymorphoneutrophil infiltration, but not aging. CIHM is a potential marker of gastric cancer risk.

Inducible nitric oxide synthase gene promoter polymorphism is associated with increased gastric mRNA expression of inducible nitric oxide synthase and increased risk of gastric carcinoma.

BACKGROUND AND AIMS: Stimulation of inducible nitric oxide synthase gene expression by Helicobacter pylori, with subsequent overproduction of nitric oxide, has been implicated in gastric carcinogenesis. We investigated whether inducible nitric oxide synthase promoter gene polymorphisms are associated with (a) inducible nitric oxide synthase mRNA expression in the gastric mucosa, and (b) the risk of gastric carcinoma. MATERIALS AND METHODS: The relationship between gastric inducible nitric oxide synthase mRNA expression and inducible nitric oxide synthase promoter polymorphisms (CCTTT repeat polymorphism and -2445 C-->G SNP) was examined in 74 H. pylori-infected patients with gastric cancer, peptic ulcer, or functional dyspepsia. In a case-control study the prevalence of the polymorphisms was examined in H. pylori-infected gastric carcinomas (n=77) and noncancerous controls (n=154). RESULTS: Inducible nitric oxide synthase mRNA levels were significantly higher in long CCTTT repeat (either allele>11) carriers than in short ones (P=0.015). Multivariate regression analysis showed that inducible nitric oxide synthase mRNA expression was significantly linked to long CCTTT repeat and gastric cancer (P=0.026), but not to -2445 C-->G SNP and other parameters. The case-control study showed that long CCTTT repeat carriers had an increased risk of gastric cancer with an odds ratio of 2.0 (P=0.021). -2445 C-->G SNP was not associated with the risk. CONCLUSIONS: Helicobacter pylori induces higher inducible nitric oxide synthase mRNA expression in carriers of long CCTTT repeats of inducible nitric oxide synthase promoter, and this polymorphism is associated with an increased risk of gastric carcinoma.

Helicobacter pylori stimulates inducible nitric oxide synthase in diverse topographical patterns in various gastroduodenal disorders.

Overproduction of nitric oxide by inducible nitric oxide synthase (iNOS) acts cytotoxically and contributes to inflammation. We explored the roles of iNOS in the pathogenesis of Helicobacter pylori-associated diseases. Using reverse-transcribed PCR, we examined topographical patterns of iNOS mRNA expression in the gastroduodenal mucosa in H. pylori-negative controls and H. pylori-positive patients with duodenal ulcer (DU), gastric ulcer (GU), and ulcer-free gastritis. iNOS expression showed topographical variations among the tested disorders. As compared to controls, DU had a significantly higher expression of iNOS mRNA in the duodenum, GU in the antrum and duodenum, and gastritis in the antrum and corpus. H. pylori eradication yielded a significant reduction of iNOS mRNA in the duodenum of DU and in the antrum of GU. Diverse topographical patterns of H. pylori-induced iNOS expression may contribute to mechanisms by which H. pylori elicits different clinical disorders.