Masao Ichinose

Cancer development based on chronic active gastritis and resulting gastric atrophy as assessed by serum levels of pepsinogen and Helicobacter pylori antibody titer

Our study investigated the relationship between gastric cancer development and activity of Helicobacter pylori‐associated chronic gastritis or the resulting chronic atrophic gastritis (CAG). A cohort of 4,655 healthy asymptomatic subjects, in whom serum pepsinogen (PG) and H. pylori antibody titer had been measured to assess the activity and stage of H. pylori‐associated chronic gastritis, was followed for up to 16 years, and cancer development was investigated. In subjects with a serologically diagnosed healthy stomach (H. pylori‐negative/CAG‐negative), cancer incidence rate was low, at 16/100,000 person‐years. With the establishment of H. pylori infection and progression of chronic gastritis, significant stepwise cancer risk elevations were seen from CAG‐free subjects (H. pylori‐positive/CAG‐negative) [hazard ratio (HR)u2009=u20098.9, 95% confidence interval (CI)u2009=u20092.7–54.7] to subjects with CAG (H. pylori‐positive/CAG‐positive) (HRu2009=u200917.7, 95% CIu2009=u20095.4–108.6) and finally to subjects with metaplastic gastritis (H. pylori‐negative/CAG‐positive) (HRu2009=u200969.7, 95% CIu2009=u200913.6–502.9). In H. pylori‐infected CAG‐free subjects, significantly elevated cancer risk was observed in the subgroup with active inflammation‐based high PG II level or potent immune response‐based high H. pylori antibody titer; the former was associated with a particularly high risk of diffuse‐type cancer, and both subgroups showed high cancer incidence rates of around 250/100,000 person‐years, comparable to that in subjects with CAG. No such risk elevation was observed in H. pylori‐infected subjects with CAG. These results clearly indicate that gastric cancer develops mainly from the gastritis‐atrophy‐metaplasia‐cancer sequence and partly from active inflammation‐based direct carcinogenesis, and that serum levels of PG and H. pylori antibody titer provide indices of cancer development in H. pylori‐infected subjects.

Usefulness of contrast-enhanced endoscopic sonography for discriminating mural nodules from mucous clots in intraductal papillary mucinous neoplasms: a single-center prospective study.

The aim of this study was to evaluate the ability of contrast‐enhanced endoscopic sonography for discrimination of mural nodules from mucous clots in intraductal papillary mucinous neoplasms of the pancreas.

Altered mucosal DNA methylation in parallel with highly active Helicobacter pylori-related gastritis

BackgroundChronic inflammation triggered by Helicobacter pylori causes altered DNA methylation in stomach mucosae, which is deeply involved in gastric carcinogenesis. This study aimed to elucidate the correlation between altered mucosal DNA methylation levels and activity of H. pylori-related gastritis, because inflammatory activity shows particular correlations with the development of diffuse-type cancer.MethodsMethylation levels in stomach mucosae of 78 healthy volunteers were determined by real-time methylation-specific PCR or bisulfite pyrosequencing. Examined loci were the promoter CpG islands of six genes (FLNc, HAND1, THBD, p41ARC, HRASLS, and LOX) and the CpG sites of non-coding repetitive elements (Alu and Satα) that are reportedly altered by H. pylori infection. Activity of H. pylori-related gastritis was evaluated using two serum markers: H. pylori antibody titer and pepsinogen II.ResultsMethylation levels of the six CpG islands were consistently increased, and those of the two repetitive elements were consistently decreased in a stepwise manner with the activity of gastric inflammation as represented by serum marker levels. Each serum marker level was well correlated with the overall DNA methylation status of stomach mucosa, and these two serologic markers were additive in the detection of the mucosa with severely altered DNA methylation.ConclusionsAlteration in mucosal DNA methylation level was closely correlated with activity of H. pylori-related gastritis as evaluated by serum markers. The observed correlation between altered DNA methylation levels and activity of H. pylori-related gastritis appears to be one of the relevant molecular mechanisms underlying the development of diffuse-type cancer.

Tumor vessel depiction with contrast-enhanced endoscopic ultrasonography predicts efficacy of chemotherapy in pancreatic cancer.

Objectives Contrast-enhanced endoscopic ultrasonography (CE-EUS) is a new imaging modality for pancreatic lesions. The aim of this study was to evaluate if CE-EUS is useful for predicting treatment efficacy before pancreatic cancer chemotherapy by assessing intratumoral vessel flow. Methods Thirty-nine patients with unresectable advanced pancreatic cancer underwent CE-EUS before chemotherapy. The patients were divided into 2 groups according to the intratumoral vessel flow observed with CE-EUS: vessel sign–positive and vessel sign–negative groups. Patient prognosis was investigated according to presence or absence of the vessel sign. Results Two patients were excluded due to poor visualization of CE-EUS images; therefore, 37 patients were analyzed. Contrast-enhanced EUS revealed positive vessel sign in 20 patients, whereas it revealed negative vessel sign in 17 patients. Both progression-free survival and overall survival were significantly longer in the positive- versus negative vessel sign groups (P = 0.037 and P = 0.027, respectively). Multivariate analysis demonstrated that the positive vessel sign was an independent factor associated with longer overall survival (hazard ratio, 0.22; 95% confidence interval, 0.08–0.53). Conclusions Evaluation of intratumoral vessel flow by CE-EUS could be useful for predicting efficacy of chemotherapy in patients with pancreatic cancer. Contrast-enhanced EUS could be used before chemotherapy for inoperable pancreatic cancer.

Helicobacter pylori-related chronic gastritis as a risk factor for colonic neoplasms

To summarize the current views and insights on associations between Helicobacter pylori (H. pylori)-related chronic gastritis and colorectal neoplasm, we reviewed recent studies to clarify whether H. pylori infection/H. pylori-related chronic gastritis is associated with an elevated risk of colorectal neoplasm. Recent studies based on large databases with careful control for confounding variables have clearly demonstrated an increased risk of colorectal neoplasm associated with H. pylori infection. The correlation between H. pylori-related chronic atrophic gastritis (CAG) and colorectal neoplasm has only been examined in a limited number of studies. A recent large study using a national histopathological database, and our study based on the stage of H. pylori-related chronic gastritis as determined by serum levels of H. pylori antibody titer and pepsinogen, indicated that H. pylori-related CAG confers an increased risk of colorectal neoplasm, and more extensive atrophic gastritis will probably be associated with even higher risk of neoplasm. In addition, our study suggested that the activity of H. pylori-related chronic gastritis is correlated with colorectal neoplasm risk. H. pylori-related chronic gastritis could be involved in an increased risk of colorectal neoplasm that appears to be enhanced by the progression of gastric atrophy and the presence of active inflammation.

Associated Factors of Atrophic Gastritis Diagnosed by Double-Contrast Upper Gastrointestinal Barium X-Ray Radiography: A Cross-Sectional Study Analyzing 6,901 Healthy Subjects in Japan

Background Double-contrast upper gastrointestinal barium X-ray radiography (UGI-XR) is one of the most widely conducted gastric cancer screening methods. It has been executed to find gastric cancer, but has not been usually executed to detect premalignant atrophic mucosa of stomach. To understand the meaning of UGI-XR-based atrophic gastritis, we analyzed its association with several causative factors including Helicobacter pylori (HP) infection. Methods We evaluated 6,901 healthy adults in Japan. UGI-XR-based atrophic gastritis was diagnosed based on the irregular shape of areae gastricae and its expansion in the stomach. Results Of the 6,433 subjects with no history of HP eradication and free from gastric acid suppressants, 1,936 were diagnosed as UGI-XR-based atrophic gastritis (mild: 234, moderate: 822, severe: 880). These were univariately associated with serum HP IgG and serum pepsinogen I/II ratio with statistical significance. The multiple logistic analysis calculating standardized coefficients (β) and odds ratio (OR) demonstrated that serum HP IgG (βu200a=u200a1.499, ORu200a=u200a4.48), current smoking (βu200a=u200a0.526, ORu200a=u200a1.69), age (βu200a=u200a0.401, ORu200a=u200a1.49), low serum pepsinogen I/II ratio (βu200a=u200a0.339, ORu200a=u200a1.40), and male gender (βu200a=u200a0.306, ORu200a=u200a1.36) showed significant positive association with UGI-XR-based atrophic gastritis whereas drinking and body mass index did not. Among the age/sex/smoking/drinking-matched 227 pairs derived from chronically HP-infected and successfully HP-eradicated subjects, UGI-XR-based atrophic gastritis was detected in 99.1% of the former but in only 59.5% of the latter subjects (p<0.0001). Contrastively, UGI-XR-based atrophic gastritis was detected in 13 of 14 HP-positive proton pump inhibitor users (92.9%) and 33 of 34 HP-positive histamine H2-receptor antagonist users (97.1%), which are not significantly different from gastric acid suppressant-free subjects. Conclusions The presence of UGI-XR-based atrophic gastritis is positively associated with Helicobacter pylori infection, current smoking, age, decreased serum pepsinogen I/II ratio, and male gender. Eradication of Helicobacter pylori seems to superficially improve UGI-XR-based atrophic gastritis whereas intake of gastric acid suppressants does not.

Phlegmonous gastritis caused by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA)

Phlegmonous gastritis (PG) is a rare, often fatal, condition characterized by suppurative bacterial infection of the stomach. Mucosal damage of the stomach, alcoholism and an immunocompromised state are predisposing factors. Phlegmonous gastritis rarely develops after therapeutic endoscopy and only a few instances have been reported. We describe a patient with PG that arose as a complication after endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). A 70-year-old woman with a diagnosis of pancreatic tumor attended our hospital. A 50-mm, low echoic lesion at the pancreatic body was identified by EUS and EUS-FNA proceeded through the stomach using a 19-gauge needle (Echo Tip®Ultra;Wilson-Cook,Winston Salem, NC, USA). She was discharged on the following day. She returned to our hospital 1 week later due to persistent upper abdominal pain and low-grade fever. Her vital signs were: blood pressure, 105/ 66 mmHg; regular pulse, 96 b.p.m. and temperature of 38°C. The patient’s abdomen was soft, flat, and slightly distended with mild tenderness in the upper area. The laboratory findings were as follows: obvious inflammation with white blood cells (WBC) 13 500/mL and C-reactive protein (CRP) 28 mg/ dL. Multi-detector row computed tomography (MDCT) revealed diffuse thickening of the gastric wall and air trapped within it (Fig. 1). Upper gastrointestinal endoscopy revealed diffuse erythema, edema and erosions (Fig. 2). EUS also showed diffuse gastric wall thickening, predominantly in the submucosa (Fig. 3). The culture of several biopsy specimens from the mucosal surface revealed a-Streptococcus and PG caused by EUS-FNA was clinically diagnosed. The patient recovered after antibiotic therapy with peperacillin/ tazobactam and she was discharged on hospital day 15. EUS-FNA is a safe procedure with a complication rate of approximately 1% that does not normally require antibiotic prophylaxis. However, the risk of PG must be considered for immunocompromised patients with advanced cancer and preventative antibiotics may be necessary.

A case of chronic pancreatitis in which endoscopic ultrasonography was effective in the diagnosis of a pseudoaneurysm

Endoscopic ultrasonography (EUS) was performed on a patient being treated for chronic pancreatitis because a submucosal tumor was observed in the stomach during gastrointestinal endoscopy. As internal pulsatile blood flow on Doppler was present, the diagnosis of an aneurysm was made. The pseudoaneurysm of the left gastric artery was embolized with histoacryl and lipiodol and the splenic artery was embolized with coils at the location of the pseudoaneurysm to prevent hemorrhage. Follow up EUS confirmed the cessation of blood flow from the pseudoaneurysm. Clinicians encountering a gastric submucosal tumor-like protrusion in a patient with chronic pancreatitis should use EUS to investigate the possibility of a pseudoaneurysm, which must be treated as quickly as possible once identified.

Serum pepsinogen levels can quantify the risk of development of metachronous gastric cancer after endoscopic resection

We have previously reported that serum pepsinogen (PG) can quantify the level of gastric mucosal atrophy, and that H. pylori eradication reduces cancer development in subjects with mild atrophy identified by serum PG levels. The aim of this study was to elucidate the predictive ability of serum PG levels for the development of metachronous gastric cancer (MGC) after endoscopic resection (ER) of primary cancer in association with H. pylori eradication. A retrospective chart review was performed, and 330 patients who underwent ER for initial early gastric cancer were enrolled. Presence or absence of H. pylori, serum PG levels, and endoscopic atrophy at ER were evaluated. H. pylori eradication was performed at the patients request after ER. The incidence of MGC in these patients was analyzed. Of 330 patients, 47 developed MGC. Endoscopic extensive atrophy was observed more frequently in patients with MGC (pu2009=u20090.001). Although PG I or PG II alone did not significantly differ according to development of MGC, the proportion of PG I/IIu2009≤u20093.0, which is one of the criteria of PG test‐positive, was significantly higher in patients with MGC (83 vs. 69%, pu2009=u20090.04). H. pylori eradication after ER did not affect MGC development (pu2009=u20090.2). On multivariate analysis, serum PG I/II ratiou2009≤u20093.3 was significantly associated with the development of MGC (hazard ratio: 3.66, 95% confidence interval: 1.47–12.25, pu2009=u20090.004). The risk of MGC after ER could be quantitatively predicted by the PG I/II ratio regardless of H. pylori status.

Endoscopic features associated with development of metachronous gastric cancer in patients who underwent endoscopic resection followed by Helicobacter pylori eradication.

The preventive effect of Helicobacter pylori (HP) eradication on metachronous gastric cancer development after endoscopic resection remains controversial. The aim of the present study was to identify specific endoscopic features that correlated with the risk of metachronous gastric cancer development after endoscopic submucosal dissection (ESD) using both endoscopic findings before ESD and changes of findings after HP eradication.