Yoshihiro Isomura

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.

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.

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.

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

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.

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.).

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.

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

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.

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.

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

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.

Mo1077 Randomized Controlled Trial of Efficacy of Mosapride Plus Omeprazole Versus Omeprazole Alone in Therapy of Gastroesophageal Reflux Disease

R10TD (0.98 ± 0.31, P = 0.037) and R20TD (1.03 ± 0.10, P = 0.018) were significantly higher than R10OD (0.64 ± 0.34). However, significant differences were not observed with L30TD (0.91 ± 0.20) and O20TD (0.91 ± 0.19) compared with R10OD. NAB was observed in seven subjects given R10OD, five given R20OD, four given R10TD, one given R20TD, three given L30TD, and three given O20TD. CONCLUSIONS: R10TD has more potent efficacy on night-time acid suppression compared with R20OD. R10TD has a potent efficacy similar to R20TD, L30TD and O20TD. Concerning night-time acid suppression, R10TD and R20TD have higher efficacies than R10OD. However, there are no significant differences in L30TD and O20TD compared with R10OD. Night-time acid-suppressive efficacies of twice daily administration may vary in different PPIs.