Early detection of gastric cancer after Helicobacter pylori eradication due to endoscopic surveillance.

BACKGROUND: Helicobacter pylori eradication therapy is commonly performed to reduce the incidence of gastric cancer. However, gastric cancer is occasionally discovered even after successful eradication therapy. Therefore, we examined the prognosis of gastric cancer patients, diagnosed after successful H. pylori eradication therapy. MATERIALS AND METHODS: All-cause death rates and gastric cancer-specific death rates in gastric cancer patients who received successful H. pylori eradication treatment was tracked and compared to rates in patients who did not receive successful eradication therapy. RESULTS: In total, 160 gastric cancer patients were followed-up for up to 11.7 years (mean 3.5 years). Among them, 53 gastric cancer patients received successful H. pylori eradication therapy prior to gastric cancer diagnosis. During the follow-up period, 11 all-cause deaths occurred. In the successful eradication group, the proportion of patients with cancer stage I was higher. The proportions of patients who received curative endoscopic therapy and endoscopic examination in the 2 years prior to gastric cancer diagnosis were also higher in the successful eradication group. Kaplan-Meier analysis of all-cause death and gastric cancer-specific death revealed a lower death rate in patients in the successful eradication group (P = .0139, and P = .0396, respectively, log-rank test). The multivariate analysis showed that endoscopy within 2 years before cancer diagnosis is associated with stage I cancer. CONCLUSIONS: Possible early discovery of gastric cancer after H. pylori eradication due to regular endoscopic surveillance may contribute to better prognosis of patients with gastric cancer.

Effects of patient age and choice of antisecretory agent on success of eradication therapy for Helicobacter pylori infection.

The effects of patient age on the efficacy of eradication treatment for Helicobacter pylori (H. pylori) remain unclear. The present study aimed to determine whether age affects eradication therapy involving vonoprazan, a novel potassium-competitive acid blocker (PCAB). We reviewed the cases of 3,261 patients who were administered first-line and second-line H. pylori eradication therapy at Toyoshima Endoscopy Clinic. The first-line treatment was clarithromycin and amoxicillin combined with a proton pump inhibitor (PPI) or a PCAB. The second-line treatment was metronidazole and amoxicillin combined with a PPI or PCAB. The patients were divided into a young to middle-aged group (age ≤50 years) and an older group (age >50 years) as well as into PPI and PCAB groups. The PPI-clarithromycin-amoxicillin regimen demonstrated a significantly lower H. pylori eradication rate than the PCAB-clarithromycin-amoxicillin regimen (p<0.001). With the PPI-clarithromycin-amoxicillin regimen, the eradication rate in the young to middle-aged group was significantly lower than that in the older group (p<0.001). Lastly, age had no impact on the eradication rate of PCAB-based therapy or metronidazole-based therapy. In conclusion, with clarithromycin-based triple therapy, PCAB is a better choice of antisecretory agent compared to PPIs, especially in young to middle-aged patients.

Irsogladine improves small-intestinal injuries in regular users of nonsteroidal anti-inflammatory drugs.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause a high frequency of mucosal injuries in the small intestine. However, no reliable intervention, other than cessation of NSAIDs, has been established. OBJECTIVE: To evaluate whether irsogladine maleate reduces these injuries while continuing NSAID therapy. DESIGN: Prospective, interventional, endoscopist-blinded, randomized, controlled trial (RCT). SETTING: University hospital. PATIENTS: Patients regularly taking conventional NSAIDs for more than 4 weeks. INTERVENTIONS: We initially examined small-intestinal mucosal injuries by capsule endoscopy (CE) and screened participants for the RCT. In the RCT, patients with any mucosal injury were randomly assigned to the irsogladine group (4 mg/day) or the control group. MAIN OUTCOME MEASUREMENTS: The primary endpoint was the rate of mucosal injury improvement after 4 weeks of treatment monitored with a second CE. RESULTS: Sixty-one patients were evaluated with the first CE. Small intestine mucosal injuries were found in 41 patients (67.2%) and erosive or ulcerative lesions in 21 patients (34.4%). The injury prevalence was not different with gastroprotective drug treatment. Of 41 patients enrolled, 39 (19 patients in the irsogladine group and 20 in the control group) completed the study. The improvement rate was significantly higher in the irsogladine group (16/19 patients; 84.2%) than in the control group (9/20 patients; 45.0%; P = .02). LIMITATIONS: Asymptomatic lesions, single-institution data, and single-blind setting. CONCLUSION: Irsogladine maleate was effective for reducing NSAID-induced small-intestinal mucosal injury. (University Hospital Medical Information Network Clinical Trials Registry number UMIN000001507.).

Endoscopic submucosal dissection is an effective and safe therapy for early gastric neoplasms: a multicenter feasible study.

BACKGROUND AND AIM: The technique of endoscopic submucosal dissection (ESD) was introduced to obtain en bloc specimens of large early gastrointestinal neoplasms. The drawback of ESD is its technical difficulty and, consequently, its higher rate of complication. In this multicenter study, we investigated the therapeutic outcomes of ESD in consecutive patients. METHODS: From January 2002 to December 2008, 485 early gastric neoplasms in 418 patients were consecutively treated by using ESD procedure performed by 6 endoscopists in 4 institutions in Tokyo. Demorgraphics, tumor location, therapeutic outcomes, and complication rates were analyzed. RESULTS: The rates of en bloc resection, complete en bloc resection, submucosal invasion, and piecemeal resection were 93.6%, 85.4%, 10.9%, and 5.4%, respectively. In multivariate analysis, the en bloc resection rate was independently lower in lesions in upper portion than in lower portion (P<0.01), lower in larger lesions (>30 mm, P<0.05; 20 to 30 mm, P<0.05), and lower in lesions with a scar (P<0.01). Delayed bleeding occurrence was independently high in larger lesions (>30 mm, P<0.01; 20 to 29 mm, P<0.01) than in small lesions (<20 mm). Institution and endoscopists were not risk factors of en bloc resection and complications CONCLUSIONS: ESD is an effective and safe therapy in the management of early gastric neoplasms when performed by well-trained endoscopists. Endoscopists should recognize the difficulty to perform ESD for en bloc resection of upper lesion, and the risk of delayed bleeding in cases of lesions >2 cm in size.

Altered composition of fatty acids exacerbates hepatotumorigenesis during activation of the phosphatidylinositol 3-kinase pathway.

BACKGROUND & AIMS: Some clinical findings have suggested that systemic metabolic disorders accelerate in vivo tumor progression. Deregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is implicated in both metabolic dysfunction and carcinogenesis in humans; however, it remains unknown whether the altered metabolic status caused by abnormal activation of the pathway is linked to the protumorigenic effect. METHODS: We established hepatocyte-specific Pik3ca transgenic (Tg) mice harboring N1068fs*4 mutation. RESULTS: The Tg mice exhibited hepatic steatosis and tumor development. PPARγ-dependent lipogenesis was accelerated in the Tg liver, and the abnormal profile of accumulated fatty acid (FA) composition was observed in the tumors of Tg livers. In addition, the Akt/mTOR pathway was highly activated in the tumors, and in turn, the expression of tumor suppressor genes including Pten, Xpo4, and Dlc1 decreased. Interestingly, we found that the suppression of those genes and the enhanced in vitro colony formation were induced in the immortalized hepatocytes by the treatment with oleic acid (OA), which is one of the FAs that accumulated in tumors. CONCLUSIONS: Our data suggest that the unusual FA accumulation has a possible role in promoting in vivo hepato-tumorigenesis under constitutive activation of the PI3K pathway. The Pik3ca Tg mice might help to elucidate molecular mechanisms by which metabolic dysfunction contributes to in vivo tumor progression.

Simple feedback of colonoscopy performance improved the number of adenomas per colonoscopy and serrated polyp detection rate.

Background and study aims High-quality endoscopy requires improvement of not only the adenoma detection rate (ADR) but also the serrated polyp (SP) detection rate and the mean number of adenomas per positive procedure (MAP +). We evaluated whether a simple feedback of colonoscopy performance improves those quality indicators using propensity-score matching. Patients and methods Eleven endoscopists were evaluated regarding colonoscopy performance including ADRs, SP detection rates, mean numbers of adenomas per procedure (MAPs), and MAPs + with their ranking in the clinic. Endoscopic performance was compared before and after the feedback. Results Colonoscopies were performed for 874 patients before the feedback and 1,272 patients after the feedback. Using propensity-score matching, 803 patients before the feedback and 803 patients after the feedback were matched. ADR after the feedback was significantly higher than that before the feedback (50.8 % and 40.8 %, respectively). MAP after feedback was significantly larger than that before the feedback (0.92 and 0.69, respectively), as well as MAP + (1.96 and 1.69, respectively). Clinically significant SP detection rate was also improved from 10.0 % to 14.9 %. Conclusions Feedback including ADR, MAP, MAP +, and clinically significant SR detection rate could improve on those quality indicators. Further studies are needed to effectively prevent colorectal cancer in colonoscopy practice.

Gastric cancer cell line Hs746T harbors a splice site mutation of c-Met causing juxtamembrane domain deletion.

Receptor tyrosine kinases (RTKs) are involved in oncogenesis and disease progression for many cancers. Inhibitors targeting them are vigorously developed and some of them are tested in the clinical setting. Amplifications of certain RTKs (c-Met, FGFR2 and ErbB2) have been associated with human gastric cancer progression. According to our genome-wide scans of genetic lesions in 34 gastric cancer cell lines using high-density single-nucleotide polymorphism genotyping microarrays, we confirmed that the c-met locus was amplified in four gastric cancer cell lines (Hs746T, MKN45, NUGC4 and SNU5). It was reported that somatic mutation is occasionally detected in tumor samples of a certain type of cancer with gene amplification. Previous reports showed gastric cancers harbored mutations of FGFR2 and ErbB2, but c-Met oncogenic mutation had not yet been reported. We performed mutational analysis of the cytoplasmic domains of c-Met using the genome DNA of the gastric cancer cell lines, and found that Hs746T cells had a splice site mutation of exon 14. By cDNA sequencing and Western blotting, we showed that the mutation caused juxtamembrane domain deletion. Previously, this mutation had been detected only in lung cancer specimens and this deletion resulted in the loss of Cbl E3-ligase binding causing decreased ubiquitination and delayed down-regulation. In conclusion, four gastric cancer cell lines harbored amplification of c-met locus, and among them, Hs746T had a putative oncogenic mutation with amplification. This information will be useful for screening of inhibitors targeting gastric cancer with c-Met aberration.

The efficacy and safety of lenvatinib for advanced hepatocellular carcinoma in a real-world setting.

BACKGROUND/PURPOSE: Lenvatinib (an inhibitor of vascular endothelial growth factor (GF) receptors 1-3, fibroblast GF receptors 1-4, platelet-derived GF receptor α, rearranged during transfection, and stem cell factor receptor) was non-inferior to sorafenib in a phase 3 (REFLECT) trial of advanced hepatocellular carcinoma. This study examined the efficacy and safety of lenvatinib in a real-world setting. METHODS: This was a retrospective, multicenter, observational study. Inclusion and exclusion criteria were based on the phase 3 trial, and participants were observed for at least 12 weeks. Therapeutic effect was determined using the modified Response Evaluation Criteria In Solid Tumors (m-RECIST) at the 8th week. Patients received oral lenvatinib 12 mg/day (body weight > 60 kg) or 8 mg/day (body weight < 60 kg). Dose interruptions followed by reductions for lenvatinib-related toxicities were permitted. Grades of adverse events (AEs) complied with the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: All 16 patients included in this study had prior treatment history, and a median 3.9 years had passed since the first treatment. Fatigue, hypertension, and proteinuria were the most frequent AEs, and were higher than Grade 2. AEs could be controlled by appropriate dose reduction, interruption, and symptomatic treatment according to the protocol. In the m-RECIST evaluation at the 8th week, 0, 6, 8, and 1 patients had achieved complete response, partial response, stable disease, and progressive disease, respectively. The objective response rate was 40%. CONCLUSION: Lenvatinib treatment could be accomplished with safety and good response in a real-world setting.

Vonoprazan versus conventional proton pump inhibitor-based triple therapy as first-line treatment against Helicobacter pylori: A multicenter retrospective study in clinical practice.

OBJECTIVE: Vonoprazan is a potassium-competitive acid blocker, a new type of acid-suppressing drug, and has recently become available for peptic ulcers, gastroesophageal reflux disease, and Helicobacter pylori (H. pylori) eradication. Its efficacy for H. pylori eradication has been reported. However, the evidence for its efficacy and feasibility remains limited. We aimed to compare the feasibility, effectiveness and safety of vonoprazan-based triple therapy with conventional proton pump inhibitor (PPI)-based triple therapy in multicenter clinical practice. METHODS: We performed a multicenter retrospective study on patients receiving first-line H. pylori eradication therapy between March 2013 and November 2015 with either vonoprazan-based triple therapy or conventional PPI-based triple therapy. RESULTS: A total of 2715 patients aged 63.0 ± 12.1 years (1412 [52.0%] males) were analyzed. Eradication rates were 87.2% (368/422) for vonoprazan-based therapy and 72.4% (1661/2293) for conventional PPI-based therapy (P < 0.01). Among the former group, there were 10 cases of diarrhea, six of nausea/vomiting, and five of rash, but the rates of these adverse events were similar to those in the conventional PPI group. CONCLUSION: Vonoprazan-based triple therapy is feasible, and has a higher rate for H. pylori eradication than conventional PPI as a first-line regimen.

Neutrophil infiltration and the distribution of intestinal metaplasia is associated with metachronous gastric cancer following endoscopic submucosal dissection.

BACKGROUND: Endoscopic submucosal dissection (ESD) of early gastric cancer is a minimally invasive procedure. However, the risk for metachronous cancers after successful cancer treatment remains high and the risk factors for metachronous cancers have not been elucidated. OBJECTIVE: To evaluate the risk factors for metachronous gastric cancers after ESD with a long-term follow-up. METHODS: A total of 155 consecutive patients (119 men, 36 women, mean age 68.9 years) were treated with ESD between September 2000 and September 2009. Biopsy specimens were obtained from the greater curvature of the antrum and middle corpus to evaluate gastric mucosal status, including Helicobacter pylori, intestinal metaplasia (IM) and neutrophil infiltration (NI) before ESD. Follow-up endoscopy after ESD was scheduled at two and six months, one year and annually thereafter. H pylori eradication was recommended when possible. RESULTS: The median follow-up period was 4.2 years. Metachronous gastric cancers were found in 23 of 155 patients (3.5% per year). No local recurrences were observed. The cumulative incidence of metachronous gastric cancer was significantly high in IM and NI in the corpus (P=0.0093 and P=0.0025, respectively [log-rank test]). The ORs for IM and NI in the corpus were 2.65 and 3.06, respectively, according to the Cox proportional hazards model (P=0.024 and P=0.0091, respectively). CONCLUSIONS: The presence of IM and NI in the corpus was closely related to the development of metachronous gastric cancer after ESD.

Randomized controlled trial comparing the efficacy of mosapride plus omeprazole combination therapy to omeprazole monotherapy in gastroesophageal reflux disease.

OBJECTIVE: We investigated whether the prokinetic activity of mosapride, a 5-hydroxytryptamine 4 receptor agonist, in combination with proton pump inhibitor (PPI) would ameliorate symptoms of gastroesophageal reflux disease (GERD) in Japanese patients. METHODS: Patients who experienced reflux symptoms more than twice weekly were eligible for this study. In all, 60 patients were randomized to receive mosapride 5 mg thrice daily combined with omeprazole 10 mg once daily (GO group), or omeprazole alone (O group) for 4 weeks. The patients completed the frequency scale for the symptoms of GERD (FSSG) at the beginning and the end of the study. The primary outcome compared changes in the FSSG reflux-related symptom (RS) score between treatment groups during the study period. RESULTS: The FSSG RS scores significantly decreased both in the GO group and the O group, with no differences in improvement between the groups (-5.86 for the GO group vs -4.89 for the O group, P = 0.49). In non-erosive reflux disease (NERD) patients the improvement was significantly lower than that in erosive GERD patients (-4.00 vs -7.67, P = 0.02). However, the addition of mosapride was effective in subgroup analyses of specific symptoms, such as burping. CONCLUSIONS: Combining mosapride with PPI provided no additional amelioration of reflux symptoms compared to PPI alone. Both regimens provided less relief from reflux symptoms in NERD than in erosive GERD patients. The addition of mosapride ameliorated reflux in patients with symptoms like burping.

A genetic polymorphism of CYP2C19 is associated with susceptibility to biliary tract cancer.

PURPOSE: Cytochrome P450 2C19 (CYP2C19) is clinically important for the metabolism of many therapeutic drugs. CYP2C19 has two main point mutation sites leading to low metabolic capacity. Several CYP enzymes are also important for the metabolism of chemical carcinogens, and several studies have reported associations between CYP polymorphism and cancer susceptibility. Speculating on a potential association between CYP2C19 polymorphism and cancer susceptibility, we conducted this study in two phases. Cell lines of various gastroenterological cancers were screened in the first phase. A clinical investigation was then conducted to confirm the association with the candidate cancer in the second phase. METHODS: Genetic polymorphism of CYP2C19 was investigated in a total of 114 cell lines of five gastroenterological cancers. Based on this screening investigation suggesting an association with biliary tract cancer, we conducted a related study by recruiting 65 patients with biliary tract cancer and 566 patients with benign diseases as controls. RESULTS: Among the 114 cell lines investigated, biliary tract cancer was suggested to be most strongly associated with poor metabolizers of CYP2C19. Among 65 patients with biliary tract cancer, 18 (28%) were poor metabolizers of CYP2C19, whereas 87 (15%) of 566 control patients were poor metabolizers. The age- and gender-adjusted odds ratios for intermediate and poor metabolizers regarding the risk of biliary tract cancer were 1.5 (95% CI: 0.8-3.0, P = 0.17) and 2.7 (1.3-5.9, P = 0.006) compared to extensive metabolizers. CONCLUSIONS: A genetic polymorphism of CYP2C19 is associated with susceptibility to biliary tract cancer.