Integrated environmental, lifestyle, and epigenetic risk prediction of primary gastric neoplasia using the longitudinally monitored cohorts.

BACKGROUND: DNA methylation accumulates in non-malignant gastric mucosa after exposure to pathogens. To elucidate how environmental, methylation, and lifestyle factors interplay to influence primary gastric neoplasia (GN) risk, we analyzed longitudinally monitored cohorts in Japan and Singapore. METHODS: Asymptomatic subjects who underwent a gastric mucosal biopsy on the health check-up were enrolled. We analyzed the association between clinical factors and GN development using Cox hazard models. We further conducted comprehensive methylation analysis on selected tissues, including (i) mucosae from subjects developing GN later, (ii) mucosae from subjects not developing GN later, and (iii) GN tissues and surrounding mucosae. We also use the methylation data of mucosa collected in Singapore. The association between methylation and GN risk, as well as lifestyle and methylation, were analyzed. FINDINGS: Among 4234 subjects, GN was developed in 77 subjects. GN incidence was correlated with age, drinking, smoking, and Helicobacter pylori (HP) status. Accumulation of methylation in biopsied gastric mucosae was predictive of higher future GN risk and shorter duration to GN incidence. Whereas methylation levels were associated with HP positivity, lifestyle, and morphological alterations, DNA methylation remained an independent GN risk factor through multivariable analyses. Pro-carcinogenic epigenetic alterations initiated by HP exposure were amplified by unfavorable but modifiable lifestyle choices. Adding DNA methylation to the model with clinical factors improved the predictive ability for the GN risk. INTERPRETATION: The integration of environmental, lifestyle, and epigenetic information can provide increased resolution in the stratification of primary GN risk. FUNDING: The funds are listed in Acknowledgements section.

Clinicopathologic Characteristics of Esophageal Ectopic Sebaceous Glands: Chronological Changes and Immunohistochemical Analysis.

Esophageal ectopic sebaceous glands are very rare lesions. A series of 5 cases in a single report has been the maximum number described in the English literature to date. We conducted a clinicopathologic study of 8 cases of esophageal ectopic sebaceous glands. The median patient age at the time of diagnosis was 60 years (range, 50-71 years), and 7 of the 8 patients were male. A focal lesion was observed in 7 cases, whereas 1 case exhibited multiple lesions throughout the esophagus. Four patients had previously undergone upper gastrointestinal endoscopy; in 3 patients, the focal lesion had not been detected. After diagnosis, 3 cases showed spontaneous regression at least once. Immunohistochemically, sebocytes of all 8 cases were negative for the estrogen receptor (ER) and the progesterone receptor (PgR), whereas sebocytes of 5 cases were positive for the androgen receptor (AR). Basal/parabasal cells were positive for AR, ER, and PgR in 5, 7, and 4 cases, respectively. GATA3 was expressed in the sebocytes and basal/parabasal cells of 6 out of 7 available cases, whereas all of 7 available cases were negative for mammaglobin and GCDFP15. Our report provides the basic clinicopathologic characteristics of esophageal ectopic sebaceous glands by the largest case series reported in English literature to date. Furthermore, the chronological changes, particularly spontaneous regression, and immunohistochemical expression of hormone receptors and GATA3 are compatible with lesions resulting from congenital misplacement under hormonal regulation. Therefore, they seem to be congenital misplacements detectable as a result of hormonal stimulated growth.

Relationship between time-varying status of reflux esophagitis and Helicobacter pylori and progression to long-segment Barrett's esophagus: time-dependent Cox proportional-hazards analysis.

BACKGROUND: Reflux esophagitis (RE) and absence of Helicobacter pylori (non-H. pylori) are considered to be associated with the progression to long-segment Barrett's esophagus (LSBE). However, it is difficult to assess this association because RE and H. pylori status can change during follow-up. Additionally, the association between H. pylori eradication and LSBE remains unclear. METHODS: A total of 11,493 asymptomatic Japanese subjects who underwent medical check-ups and were endoscopically diagnosed with short-segment Barrett's esophagus (SSBE) between May 2006 and December 2015 were enrolled. The hazards of progression to LSBE were compared between time-varying RE and H. pylori infection/eradication by time-dependent multivariable Cox proportional hazards models. RESULTS: A total of 7637 subjects who underwent additional medical check-ups after being diagnosed with endoscopic SSBE were analyzed. Subjects with RE and without current/past H. pylori infection were strongly associated with a higher rate of progression to LSBE (adjusted hazard ratio [HR]: 7.17, 95% confidence interval [CI]: 2.48-20.73, p < 0.001 for RE and non-H. pylori vs. non-RE and H. pylori groups). Subjects with H. pylori had a lower rate of progression to LSBE (adjusted HR: 0.48, 95% CI: 0.22-1.07, p = 0.07 for H. pylori vs. non-H. pylori). Hazards of progression to LSBE were still lower in the H. pylori eradication group than that of the non-H. pylori group (adjusted HR: 0.51, 95% CI: 0.18-1.46, p = 0.21). CONCLUSIONS: RE and non-H. pylori were associated with the progression to LSBE, considering the changes in exposures. H. pylori infection was associated with the prevention of the development of LSBE irrespective of RE. The environment preventive of the development of LSBE persists for at least a few years after H. pylori eradication.

Association Between Helicobacter pylori Infection and Short-segment/Long-segment Barrett's Esophagus in a Japanese Population: A Large Cross-Sectional Study.

GOAL: The goal of this study was to investigate the relationship between Helicobacter pylori (H. pylori) infection and short-segment and long-segment Barrett's esophagus (SSBE and LSBE). BACKGROUND: H. pylori infection is reported to be inversely associated with Barrett's esophagus (BE) in western countries. However, the impact of BE segment length on the association between BE and H. pylori infection has scarcely been investigated. MATERIALS AND METHODS: The study subjects were 41,065 asymptomatic Japanese individuals who took medical surveys between October 2010 and September 2017. Using this large database of healthy Japanese subjects, we investigated the association between H. pylori infection and SSBE/LSBE. We used multivariable logistic regression analysis to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among the study subjects, 36,615 were eligible for the analysis. H. pylori seropositivity was significantly associated with a lower rate of LSBE (OR: 0.42; 95% CI: 0.16-0.91) and a higher rate of SSBE (OR: 1.66; 95% CI: 1.56-1.78) after multivariate adjustment. In the subgroup analysis, H. pylori seropositivity was significantly associated with a high rate of SSBE in subjects without reflux esophagitis (RE) (OR: 1.73; 95% CI: 1.61-1.85). However, H. pylori seropositivity was not associated with SSBE in subjects with RE (OR: 1.07; 95% CI: 0.84-1.37). CONCLUSION: In a Japanese population, H. pylori infection was inversely associated with LSBE but significantly associated with SSBE only in subjects without RE. H. pylori may be a risk factor for SSBE, especially in individuals without RE.

Association between visceral abdominal obesity and long-segment Barrett's esophagus in a Japanese population.

BACKGROUND: Visceral abdominal obesity is associated with Barrett's esophagus (BE), especially long-segment BE (≥ 3 cm) (LSBE), in white individuals. However, the association between central obesity and LSBE has not been well investigated in Asia. The aim of this study was to investigate the association between central obesity and LSBE in the Japanese population. METHODS: A total of 38,298 healthy subjects who took medical surveys between April 2006 and November 2018 were enrolled. We investigated the association between LSBE and central obesity indices [visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and the VAT to SAT ratio (VAT/SAT)] using a multivariable logistic regression model. RESULTS: A total of 37,686 subjects were eligible for the analysis. LSBE rates in the middle and high VAT/SAT groups were higher than those in the low VAT/SAT group [odds ratio (OR) 1.70, 95% confidence interval (CI) 1.07-2.69 for middle vs low; OR 2.02, 95% CI 1.17-3.49 for high vs low). These associational trends between VAT/SAT and LSBE remained in subgroups with and without reflux esophagitis. From subgroup analyses by SAT, we found that the OR between VAT and LSBE is higher in the low SAT subgroup (OR 2.43, 95% CI 1.34-4.40 for middle vs low; OR 2.55, 95% CI 1.01-6.40 for high vs low); but not large or imprecise due to limited event numbers in the middle and high SAT subgroups. CONCLUSIONS: VAT was associated with LSBE, especially among subjects with low SAT accumulation, who are seemingly not obese. VAT/SAT was associated with LSBE regardless of the presence of reflux esophagitis in a Japanese population.

Prevalence Rate and Predictive Factors of Pancreatic Diseases in Cases with Pancreatic Duct Dilatation: A Cross-sectional Study of a Large, Healthy Japanese Population.

Objectives To clarify the significance of ultrasonographically recorded pancreatic duct dilatation. Methods Various parameters predicting pancreatic disease were evaluated in relation to pancreatic duct dilatation using data from medical checkups of healthy examinees. Results Records of 281,384 subjects were analyzed. Pancreatic duct dilatation (≥3 mm) was determined ultrasonographically in 524 patients (0.19%). Subsequent detailed examinations revealed the presence of pancreatic disease in 24.8% of these patients, including pancreatic cysts (15.6%) and chronic pancreatitis (4.9%). Pancreatic cancer was found in 6 cases (1.3%). Predictive factors of pancreatic diseases in examinees with pancreatic duct dilatation were investigated, and the diameter of the pancreatic duct (p<0.001) and HbA1c (p=0.003) were identified by a multivariate analysis. The diameter of the pancreatic duct (p<0.013), HbA1c (p=0.009), and body mass index (p=0.032) were identified as predictive factors in pancreatic cancer. The diameter of the pancreatic duct (p<0.001), age (p=0.006), and bilirubin (p=0.020) in pancreatic cyst as well as the diameter of the pancreatic duct (p<0.001), white blood cells (p=0.022), HbA1c (p=0.033), and alkaline phosphatase (p=0.043) in chronic pancreatitis were also identified. In patients with pancreatic duct dilatation, the optimal cut-off values were 3.5 mm and 6.1% for the pancreatic duct diameter and age, respectively, based on a receiver operating characteristic analysis. Conclusion In cases with ultrasonography-determined pancreatic duct dilatation, subsequent detailed examinations of the pancreas were necessary because of the high-prevalence rate of 24.8%. In particular, marked pancreatic duct dilatation (≥3.5 mm) and elevated HbA1c (≥6.1%) strongly suggest the presence of pancreatic diseases.

Prediction of future gastric cancer risk using a machine learning algorithm and comprehensive medical check-up data: A case-control study.

A comprehensive screening method using machine learning and many factors (biological characteristics, Helicobacter pylori infection status, endoscopic findings and blood test results), accumulated daily as data in hospitals, could improve the accuracy of screening to classify patients at high or low risk of developing gastric cancer. We used XGBoost, a classification method known for achieving numerous winning solutions in data analysis competitions, to capture nonlinear relations among many input variables and outcomes using the boosting approach to machine learning. Longitudinal and comprehensive medical check-up data were collected from 25,942 participants who underwent multiple endoscopies from 2006 to 2017 at a single facility in Japan. The participants were classified into a case group (y = 1) or a control group (y = 0) if gastric cancer was or was not detected, respectively, during a 122-month period. Among 1,431 total participants (89 cases and 1,342 controls), 1,144 (80%) were randomly selected for use in training 10 classification models; the remaining 287 (20%) were used to evaluate the models. The results showed that XGBoost outperformed logistic regression and showed the highest area under the curve value (0.899). Accumulating more data in the facility and performing further analyses including other input variables may help expand the clinical utility.

Serum TFF1 and TFF3 but not TFF2 are higher in women with breast cancer than in women without breast cancer.

Breast cancer remains a common malignancy in women, but the take-up for breast cancer screening programs in Japan is still low, possibly due to its perceived inconvenience. TFF1 and TFF3 are expressed in both breast cancer tissue and normal breast. Serum trefoil proteins were reported as cancer screening markers for gastric, prostate, lung, pancreatic cancer and cholangio carcinoma. The purpose of this study was to examine whether serum trefoil proteins could be screening biomarkers for breast cancer. Serum trefoil proteins in 94 breast cancer patients and 84 health check females were measured by ELISA. Serum TFF1 and TFF3 were significantly higher and serum TFF2 was significantly lower in breast cancer patients. Area under the curve of receiver operating characteristic of TFF1, TFF2, and TFF3 was 0.69, 0.83, and. 0.72, respectively. AUC of the combination of TFF1, TFF2, and TFF3 was 0.96. Immunohistochemically, TFF1 expression was positive in 56.5% and TFF3 was positive in 73.9% of breast cancers, while TFF2 was negative in all tumors. Serum TFF1 had positive correlation with expression of TFF1 in breast cancer tissue. Serum concentrations of TFF1 and TFF3 but not TFF2 are higher in women with breast cancer than in women without breast cancer.

Circulating AIM as an indicator of liver damage and hepatocellular carcinoma in humans.

BACKGROUND: Hepatocellular carcinoma (HCC), the fifth most common cancer type and the third highest cause of cancer death worldwide, develops in different types of liver injuries, and is mostly associated with cirrhosis. However, non-alcoholic fatty liver disease often causes HCC with less fibrosis, and the number of patients with this disease is rapidly increasing. The high mortality rate and the pathological complexity of liver diseases and HCC require blood biomarkers that accurately reflect the state of liver damage and presence of HCC. METHODS AND FINDINGS: Here we demonstrate that a circulating protein, apoptosis inhibitor of macrophage (AIM) may meet this requirement. A large-scale analysis of healthy individuals across a wide age range revealed a mean blood AIM of 4.99 ± 1.8 µg/ml in men and 6.06 ± 2.1 µg/ml in women. AIM levels were significantly augmented in the younger generation (20s-40s), particularly in women. Interestingly, AIM levels were markedly higher in patients with advanced liver damage, regardless of disease type, and correlated significantly with multiple parameters representing liver function. In mice, AIM levels increased in response to carbon tetrachloride, confirming that the high AIM observed in humans is the result of liver damage. In addition, carbon tetrachloride caused comparable states of liver damage in AIM-deficient and wild-type mice, indicating no influence of AIM levels on liver injury progression. Intriguingly, certain combinations of AIM indexes normalized to liver marker score significantly distinguished HCC patients from non-HCC patients and thus could be applicable for HCC diagnosis. CONCLUSION: AIM potently reveals both liver damage and HCC. Thus, our results may provide the basis for novel diagnostic strategies for this widespread and fatal disease.

Circulating exosomal microRNAs as biomarkers of colon cancer.

PURPOSE: Exosomal microRNAs (miRNAs) have been attracting major interest as potential diagnostic biomarkers of cancer. The aim of this study was to characterize the miRNA profiles of serum exosomes and to identify those that are altered in colorectal cancer (CRC). To evaluate their use as diagnostic biomarkers, the relationship between specific exosomal miRNA levels and pathological changes of patients, including disease stage and tumor resection, was examined. EXPERIMENTAL DESIGN: Microarray analyses of miRNAs in exosome-enriched fractions of serum samples from 88 primary CRC patients and 11 healthy controls were performed. The expression levels of miRNAs in the culture medium of five colon cancer cell lines were also compared with those in the culture medium of a normal colon-derived cell line. The expression profiles of miRNAs that were differentially expressed between CRC and control sample sets were verified using 29 paired samples from post-tumor resection patients. The sensitivities of selected miRNAs as biomarkers of CRC were evaluated and compared with those of known tumor markers (CA19-9 and CEA) using a receiver operating characteristic analysis. The expression levels of selected miRNAs were also validated by quantitative real-time RT-PCR analyses of an independent set of 13 CRC patients. RESULTS: The serum exosomal levels of seven miRNAs (let-7a, miR-1229, miR-1246, miR-150, miR-21, miR-223, and miR-23a) were significantly higher in primary CRC patients, even those with early stage disease, than in healthy controls, and were significantly down-regulated after surgical resection of tumors. These miRNAs were also secreted at significantly higher levels by colon cancer cell lines than by a normal colon-derived cell line. The high sensitivities of the seven selected exosomal miRNAs were confirmed by a receiver operating characteristic analysis. CONCLUSION: Exosomal miRNA signatures appear to mirror pathological changes of CRC patients and several miRNAs are promising biomarkers for non-invasive diagnosis of the disease.

Antithrombotic drug does not affect the positive predictive value of an immunochemical fecal occult blood test.

BACKGROUND AND AIM: Antithrombotic drugs may affect the diagnostic performance of immunochemical fecal occult blood test (iFOBT) for colorectal cancer (CRC) screening. The aim of the present study was to assess the effect of antithrombotic drugs on the diagnostic performance of iFOBT. METHODS: We analyzed 1016 patients who underwent colonoscopy for positive iFOBT. Patients were classified as follows: patients who had advanced neoplasms detected and those who did not; patients who had cancers detected and those who did not; patients who had any neoplasms detected and those who did not. We compared the following factors between two paired groups: sex, age, endoscopists' experience, and antithrombotic drug usage. RESULTS: A total of 139 patients were taking antithrombotic drugs (13.7%). Advanced neoplasms, cancers, and any neoplasms were detected in 196 (19.3%), 59 (5.8%), and 490 (48.2%)patients, respectively. There were no higher detection rates in the antithrombotic drug (-) group than in the (+) group (advanced neoplasms: 19.3% vs 19.4%, P=1.000; cancers: 5.8% vs 5.8%, P=1.000; any neoplasms: 48.4% vs 47.5%, P=0.856). Multivariate logistic regression analysis revealed that none of aspirin, warfarin, or other antithrombotic drugs was a significant factor for advanced neoplasms (95% CI 0.350-1.216, P=0.179; 95% CI 0.421-1.899, P=0.772; 95% CI 0.323-1.810, P=0.764, respectively). As to cancers and any neoplasms, no antithrombotic drug also proved to be a significant factor. CONCLUSION: The present study demonstrated that the positive predictive value of iFOBT was not affected by ongoing antithrombotic therapy.

Endoscopic tissue shielding method with polyglycolic acid sheets and fibrin glue to cover wounds after colorectal endoscopic submucosal dissection (with video).

BACKGROUND: Colorectal endoscopic submucosal dissection (ESD) has made it possible to resect large specimens in an en bloc fashion. However, this can lead to postoperative adverse events, such as perforation and bleeding. Prevention of adverse events after colorectal ESD is therefore an important goal. OBJECTIVE: To evaluate the utility of a shielding method using polyglycolic acid (PGA) sheets and fibrin glue to manage ulcers after colorectal ESD. DESIGN: Prospective, single-arm, pilot study. SETTING: Single tertiary care center for colorectal ESD in Japan. PATIENTS: Ten patients with 10 colorectal tumors scheduled for ESD were enrolled between September and November 2012. INTERVENTIONS: Just after ESD, we placed PGA sheets on the mucosal defect with biopsy forceps. After the whole defect was covered, we sprayed fibrin glue through a special double-lumen spraying tube. We sprayed fibrinogen through 1 lumen and then thrombin through the other lumen. MAIN OUTCOME MEASUREMENTS: Success rate, mean procedure time, and adverse events associated with the covering technique and the persistence of PGA sheets at follow-up colonoscopy. RESULTS: All 10 tumors were successfully resected. Mean tumor size was 39.7 ± 15.2 mm. All mucosal defects were successfully covered with PGA sheets. Mean procedure time was 18.7 ± 15.9 minutes. No procedure-related adverse events occurred. Upon colonoscopy 9 to 12 days after ESD, the PGA sheets were still fixed on the whole defect in 8 patients. LIMITATIONS: Small sample size. CONCLUSIONS: Our technique, which uses PGA sheets and fibrin glue, appears to shield mucosal defects, and it may be effective in reducing postoperative adverse events.

Associations between healthy lifestyle behaviors and proteinuria and the estimated glomerular filtration rate (eGFR).

AIM: The aim was to investigate the respective associations between lifestyle and proteinuria and the estimated glomerular filtration rate (eGFR). METHODS: The lifestyle habits of 25,493 middle-aged participants were investigated in a cross-sectional study to find habits that are associated with a low eGFR (<60 mL/min/1.73 m(2)) and/or the presence of proteinuria. The lifestyle habits of the participants were evaluated using a questionnaire. Unhealthy lifestyle habits were defined as follows: 1. obesity, 2. being a current/former smoker, 3. eating irregular meals, 4. having less than 5 hours sleep, 5. exercising less than once a week, and 6. drinking more than once a week. The associations among unhealthy habits, eGFR, and proteinuria were evaluated using multivariate analysis. RESULTS: The following lifestyle factors were significantly and independently associated with proteinuria: obesity (odds ratio (OR): 1.18, 95%C.I: 1.04-1.34), being a current/former smoker (OR: 1.26, 95%C.I: 1.11-1.42), eating irregular meals (OR: 1.40, 95%C.I: 1.22-1.61), sleeping less than 5 hours (OR: 1.38, 95%C.I: 1.15-1.65), and exercising less than once a week (OR: 1.18, 95%C.I: 1.05-1.33). In contrast, the following unhealthy lifestyle factors were not clearly associated with a low eGFR: obesity (OR: 1.05, 95%C.I: 0.95-1.17), being a current/former smoker (OR: 0.76, 95%C.I: 0.69-0.84), eating irregular meals (OR: 0.91, 95%C.I: 0.79-1.04), sleeping less than 5 hours (OR: 1.02, 95%C.I: 0.85-1.22), and exercising less than once a week (OR: 0.91, 95%C.I: 0.83-0.99). CONCLUSION: Associations between proteinuria and unhealthy lifestyle habits were observed in our cross-sectional study. Unhealthy lifestyles should be monitored during the management of CKD patients with proteinuria.

A cross-sectional study on the risk factors for erosive esophagitis in young adults.

OBJECTIVE: To investigate the impact of metabolic and lifestyle factors on erosive esophagitis in young adults. METHODS: A total of 5,069 people under the age of 40 years old were enrolled in a medical survey at our institute. People with a previous history of upper gastrointestinal tract surgery were excluded, as were individuals taking medication for reflux symptoms, peptic ulcers, or malignancies. Independent and significant predictors affecting the presence of erosive esophagitis were determined by multivariate analysis. RESULTS: A total of 4,990 participants (male/female; 3,871/1,119, age; 33.9±3.9 years) were eligible. A total of 728 participants (14.6%) had erosive esophagitis. Male gender and increasing age were independent predictors for increased prevalence of erosive esophagitis (odds ratio=2.242 and 1.045. 95% confidence interval=1.613-3.117 and 1.019-1.072; p<0.001 and 0.001, respectively). Moderate-to-heavy alcohol consumption, light-to-moderate-to-heavy smoking, hypertension, hyperglycemia, and hiatal hernia each significantly and independently increased the risk for erosive esophagitis (odds ratio=1.499, 1.398, 1.353, 1.570, 1.884, 1.297, 1.562, and 3.213. 95% confidence interval=1.181-1.903, 1.040-1.880, 1.094-1.675, 1.250-1.971, 1.307-2.716, 1.074-1.566, 1.063-2.295, and 2.712-3.807; p=0.001, 0.027, 0.005, <0.001, 0.001, <0.001, 0.007, 0.023, and <0.001 respectively). Helicobacter pylori infection decreased the risk for erosive esophagitis (odds ratio=0.575, 95% confidence interval =0.436-0.759 p<0.001). Neither body mass index nor waist girth conferred increased risk of erosive esophagitis after adjusting for potential confounding factors. CONCLUSION: Risk of erosive esophagitis in Japanese young adults was not increased by obesity, but it was increased by hiatal hernia and metabolic and lifestyle profiles including hypertension, hyperglycemia, alcohol consumption and smoking.

Magnifying endoscopy with narrow-band imaging helps determine the management of gastric adenomas.

BACKGROUND: There are no clear clinical criteria for the management of gastric lesions diagnosed as adenomas (Vienna classification category 3) by pre-treatment biopsy. In the present study, we examined the feasibility of magnifying endoscopy with narrow-band imaging (ME-NBI) in discriminating early gastric cancers (Vienna classification category 4 or 5) from adenomas in lesions diagnosed as adenomas by pre-treatment biopsy. METHODS: This was a single-center cross-sectional retrospective study at a tertiary referral center. One hundred thirty-seven consecutive cases of gastric lesions diagnosed as adenomas in pre-treatment forceps biopsy were examined with conventional non-magnifying endoscopy under white light, non-magnifying chromoendoscopy, and ME-NBI. We investigated the association between the final pathological diagnoses (carcinoma or adenoma) and the following factors: lesion size (mm), color (red or white), macroscopic type (depressed or others), presence of ulceration, and positive ME-NBI finding. The presence of an irregular microvascular pattern or an irregular microsurface pattern with a demarcation line between the lesion and the surrounding area was regarded as a positive ME-NBI finding. RESULTS: Lesion size was significantly larger in carcinomas than adenomas (P = 0.005). Depressed lesion (P = 0.011), red color (P < 0.001), and positive ME-NBI finding (P < 0.001) were significant predictive factors for carcinoma. Multivariate logistic regression confirmed that red color (odds ratio [OR] 3.04, 95% confidence interval [CI] 1.26-7.34, P = 0.14) and a positive ME-NBI finding (OR 13.68, 95% CI 5.69-32.88, P < 0.001) were independent predictive factors for carcinomas. A positive ME-NBI finding was the strongest predictive factor. CONCLUSIONS: ME-NBI is useful in planning the management of lesions diagnosed as adenomas by pre-treatment forceps biopsy.

Tests for serum levels of trefoil factor family proteins can improve gastric cancer screening.

BACKGROUND & AIMS: Improving methods for early detection of gastric cancer could reduce mortality. Measurements of serum pepsinogen levels have been used for screening in Japan without satisfactory levels of sensitivity or specificity. Trefoil factor family (TFF) proteins (TFF1, TFF2, and TFF3) are small and stable molecules secreted by the mammalian gastrointestinal tract. Foveolar hyperplasia, spasmolytic polypeptide (TFF2)-expressing metaplasia, and intestinal metaplasia are histologic changes observed in patients with atrophic gastritis; they express TFF1, TFF2, and TFF3, respectively. We investigated whether serum levels of TFF can be used as markers for gastric cancer screening. METHODS: Serum was collected from 183 patients with gastric cancer and 280 healthy individuals without cancer. Serum levels of anti-Helicobacter pylori immunoglobulin G, pepsinogen I, pepsinogen II, TFF1, TFF2, and TFF3 were measured by enzyme-linked immunosorbent assay and associated with gastric cancer. RESULTS: Using a cutoff of 3.6 ng/mL, the level of TFF3 was significantly increased in serum samples from patients with cancer (odds ratio, 18.1; 95% confidence interval, 11.2-29.2); using this test, patients with cancer were identified with 80.9% sensitivity and 81.0% specificity. The test for TFF3 had a significantly higher odds ratio than that for pepsinogen. A test for the combination of TFF3 and pepsinogen had better results than the test for only pepsinogen. CONCLUSIONS: Serum levels of TFF3 are a better marker of gastric cancer than pepsinogen; a test for the combined levels of serum pepsinogen and TFF3 could improve gastric cancer screening.

Risk factors for erosive esophagitis: a cross-sectional study of a large number of Japanese males.

BACKGROUND: The impact of obesity on gastroesophageal reflux disease remains controversial. We undertook this study, with a large sample size, to investigate risk factors for endoscopic erosive esophagitis by multivariate analysis, including visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) as covariates. METHODS: Japanese males who visited our institute for a comprehensive medical survey between 2007 and 2010 were enrolled. All subjects voluntarily participated in a self-paid health check-up program including blood test screening, physical examinations, and esophagogastroduodenoscopy. VAT and SAT were measured by computed tomography at the navel level. Independent and significant predictors of erosive esophagitis were determined by multivariate analysis. RESULTS: Of 9840 eligible subjects, 1831 (18.6%) were diagnosed with erosive esophagitis. Body mass index and triglyceride were predictors of an increased prevalence of erosive esophagitis (odds ratios [ORs] = 1.063 and 1.001; 95% confidence intervals [CIs] = 1.020-1.108 and 1.001-1.002; p = 0.004 and <0.001, respectively). Heavy alcohol consumption, heavy smoking, and hiatal hernia were also associated with an increased prevalence of erosive esophagitis (ORs = 1.276, 1.399, and 2.758; 95% CIs = 1.085-1.501, 1.220-1.605, and 2.474-3.075; p < 0.001 for all). Helicobacter pylori infection significantly and independently decreased the prevalence of erosive esophagitis (OR = 0.346, 95% CI = 0.299-0.401, p < 0.001). Central obesity, as determined by VAT and waist girth, did not confer an increased risk of erosive esophagitis after adjusting for confounders. CONCLUSIONS: Lifestyle factors including heavy alcohol consumption, heavy smoking, metabolic disorders, and hiatal hernia increased the risk of erosive esophagitis, but central obesity did not.

A prospective randomized trial of lafutidine vs rabeprazole on post-ESD gastric ulcers.

AIM: To compare the effects of rabeprazole and lafutidine on post-endoscopic submucosal dissection (ESD) gastric ulcers. METHODS: Patients with gastric tumors indicated for ESD were prospectively studied. After ESD, all patients were treated with intravenous omeprazole for the first 3 d. Patients were then randomly assigned to oral lafutidine or rabeprazole. Ulcer size, ulcer size reduction rate, and ulcer stage were evaluated 4 wk later. Occurrence of complication was monitored throughout the 4-wk period. RESULTS: Sixty five patients were enrolled in the study, and 60 patients were subjected to the final analysis. In the lafutidine group (30 lesions in 29 patients), initial and 4-wk post-ESD ulcer sizes were 33.3 ± 9.2 and 10.5 ± 4.8 mm, respectively. In the rabeprazole group (34 lesions in 31 patients), the values were 34.7 ± 11.3 and 11.8 ± 6.7 mm, respectively. Ulcer size reduction rates in lafutidine and rabeprazole groups were 32.3% and 33.5%, respectively (P = 0.974). Ulcer stage 4 wk post-ESD did not differ significantly between the two groups (P = 0.868). Two cases in the rabeprazole group and no cases in the lafutidine group developed ulcer bleeding during the oral dose period, although the difference of bleeding rate between the two groups was not statistically significant (P = 0.157). CONCLUSION: Lafutidine and rabeprazole have equivalent therapeutic effects on post-ESD gastric ulcers.

Risk factors for bleeding after endoscopic submucosal dissection for gastric lesions.

AIM: To assess risk factors for bleeding after gastric endoscopic submucosal dissection (ESD) and to develop preventive measures. METHODS: This retrospective study was performed in a tertiary referral center. A total of 328 patients underwent ESD for 398 gastric neoplasms between July 2007 and June 2009. The main outcome was association between post-ESD bleeding and the following: age; sex; comorbidities; daily use of medicine potentially related to gastric injury/bleeding; location, size, and histological depth of lesions; ulceration; experience of operator coagulating the ulcer floor, and duration of operation. We also determined the relationship between the location of post-ESD bleeding and risk factors for hemorrhage. RESULTS: Univariate analysis revealed significant risk factors: tumor location [odds ratio (OR), 2.86; 95% CI: 1.21-6.79, P = 0.024], coagulator experience (OR, 4.29; 95% CI: 1.43-12.86, P = 0.009), and medicine potentially related to gastric injury/bleeding (OR, 2.80; 95% CI: 1.14-6.90, P = 0.039). Multivariate logistic regression analysis confirmed significant, independent risk factors: tumor in lower third of stomach (OR, 2.47; 95% CI: 1.02-5.96, P = 0.044), beginner coagulator (OR, 3.93; 95% CI: 1.29-11.9, P = 0.016), and medicine (OR, 2.76; 95% CI: 1.09-6.98, P = 0.032). We classified cases of post-ESD bleeding into two groups (bleeding at the ulcer margin vs bleeding at the center) and found that bleeding at the margin occurred more frequently with beginner coagulators compared with experts (OR, 16.00; 95% CI: 1.22-210.59, P = 0.040). CONCLUSION: Beginner coagulators, tumor in the antrum, and medicines were significant risk factors for post-ESD bleeding. Bleeding at the ulcer margin frequently occurred with beginner operators.

Adiponectin knockout mice on high fat diet develop fibrosing steatohepatitis.

BACKGROUND AND AIM: Low levels of serum adiponectin have been reported to be associated with obesity, diabetes, and non-alcoholic steatohepatitis (NASH), as well as several malignancies. Adiponectin knockout (KO) mice have been reported to cause insulin resistance and neointimal formation of the artery. We used adiponectin KO mice fed a high fat (HF) diet, and investigated the effect of adiponectin on the progression of steatohepatitis and carcinogenesis in vivo. METHODS: Adiponectin KO mice and wild type (WT) mice were fed a HF diet or normal chow for the periods of 24 and 48 weeks. The HF diet contained 60% of calories from fat. RESULTS: The adiponectin KO mice on the HF diet showed obesity, marked elevation of serum transaminase levels, and hyperlipidemia. At 24 weeks, hepatic expression of tumor necrosis factor-alpha and procollagen alpha (I) was higher in KO mice as compared with WT mice. At 48 weeks, liver triglyceride contents in KO mice on normal chow were significantly higher than those in WT mice. Hepatocyte ballooning, spotty necrosis, and pericellular fibrosis around central veins were observed in KO mice on the HF diet. The pericellular fibrosis was more severe in KO mice on the HF diet than that in WT mice (1.62% vs 1.16%, P = 0.033). Liver adenoma and hyperplastic nodules developed in a KO mouse on the HF diet at 48 weeks (12.5%, n = 1/8), whereas no tumor was detected in WT mice (n = 10). CONCLUSIONS: Adiponectin may play a protective role in the progression of NASH in the early stages by suppressing tumor necrosis factor-alpha expression and liver fibrosis.