Takafumi Sugimoto

A Randomized Controlled Trial Evaluating the Usefulness of a Transparent Hood Attached to the Tip of the Colonoscope

OBJECTIVES:Considering the increasing demand for colonoscopy, auxiliary devices that could facilitate the examination would be useful. A hood attached to the tip of the colonoscope has been reported to be helpful in detecting and removing colorectal polyps. However, its usefulness in aiding scope intubation has not been fully evaluated.METHODS:Patients for colonoscopy between July 2004 and May 2005 in Tokyo University Hospital were enrolled to this randomized controlled trial, and assigned to colonoscopy with a transparent hood, a short hood, or no hood. Colonoscopies were conducted by trainees without sedation. The evaluated outcomes were cecal intubation rate, trainee intubation rate (cecal intubation within 15 min), cecal intubation time, and polyp detection rate.RESULTS:Enrolled 684 patients were randomly assigned to transparent hood (N = 221), short hood (N = 228), and no hood (N = 235) groups. The overall cecal intubation rate was 95.3% (652/684) and did not differ among the groups. The overall trainee intubation rate was 55.1% (377/684) and significantly higher in the transparent hood group than in the no hood group for female patients (60.7% vs 37.4%, P = 0.003). Cecal intubation time was 11.5, 13.5, and 14.0 min in the transparent, short, and no hood groups, respectively, and significantly shorter in the transparent hood group than in the no hood group among overall (P = 0.008), female (P = 0.001), and old (P = 0.04) patients. Polyp detection rate was higher in the transparent hood group than in the no hood group (49.3% vs 39.1%, P = 0.04).CONCLUSIONS:The transparent hood was useful in shortening the cecal intubation time especially in difficult cases.

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.

A male-killing Wolbachia carries a feminizing factor and is associated with degradation of the sex-determining system of its host.

Endosymbiotic bacteria of the genus Wolbachia induce diverse reproductive alterations in their insect hosts. Wolbachia (wSca) infecting the moth Ostrinia scapulalis causes unusual male killing, in which males (genotype: ZZ) selectively die during embryonic and larval development, whereas females (genotype: ZW), in turn, selectively die when cured of infection. To gain insight into the interaction between wSca and the host, we analysed phenotypic and genetic sexes of the embryos and larvae of normal, wSca-infected, and infected-and-cured O. scapulalis by diagnosing the sex-specifically spliced transcripts of Osdsx—a homologue of the sex-determining gene doublesex—and sex chromatin in interphase nuclei, respectively. It was observed that the female-type Osdsx was expressed in the infected male (ZZ) progenies destined to die, whereas the male-type Osdsx was expressed in the cured female (ZW) progenies destined to die. These findings suggest that (i) wSca, a male killer, carries a genetic factor that feminizes the male host, (ii) the sex-determining system of the host is degraded, and (iii) a mismatch between the genetic and phenotypic sexes underlies the sex-specific death.

Gastric cancer risk according to the distribution of intestinal metaplasia and neutrophil infiltration

Background and Aim:  Gastritis and intestinal metaplasia (IM) have long been known to be risk factors for and precursors of gastric cancer. We aimed to elucidate the association between gastric cancer risk and the distribution of precancerous lesions in the stomach by histological analyses.

Expression of a doublesex homologue is altered in sexual mosaics of Ostrinia scapulalis moths infected with Wolbachia.

A homologue of the sex-determining gene doublesex, Osdsx, was identified in the adzuki bean borer Ostrinia scapulalis. Three isoforms of the Osdsx transcript (Osdsx(M), Osdsx(FL) and Osdsx(FS)) differing in length were found. Osdsx(M) was specifically found in males, and contained an 852-bp ORF encoding a protein of 284 amino acids. Osdsx(FL) and Osdsx(FS) were found in females, and had the same 813-bp ORF encoding a protein of 271 amino acids. The Osdsx gene was inferred to have six exons and five introns. The variation in the transcript could be explained by the alternative splicing of Osdsx: Osdsx(M) was formed by the splicing of exons 1, 2, 5 and 6, Osdsx(FS) by the splicing of exons 1-4 and 6, and Osdsx(FL) by the splicing of exons 1-6. RT-PCR analysis indicated that Osdsx was transcribed in a sex-specific manner in all somatic tissues examined, regardless of developmental stage. In Wolbachia-induced sexual mosaics of O. scapulalis, which are genetically male, the female-specific isoform of Osdsx (Osdsx(FL)) was shown to be expressed in addition to the male-specific isoform (Osdsx(M)). This finding provides the first evidence that Wolbachia manipulates the sex of its host by interfering either with the sex-specific splicing of Osdsx itself or with another upstream sex determination process.

Sitafloxacin resistance in Helicobacter pylori isolates and sitafloxacin-based triple therapy as a third-line regimen in Japan

The third-line treatment regimen for Helicobacter pylori after failure of clarithromycin- and metronidazole-based therapies is not yet established. Sitafloxacin (STX) is a quinolone that possesses potent in vitro activity against H. pylori. In this study, the susceptibility of H. pylori isolates to STX was examined and the efficacy of STX-based triple therapy as a third-line regimen was evaluated. STX showed minimum inhibitory concentrations (MICs) of ≤1 μg/mL against all 100 H. pylori isolates, and the MIC(90) (MIC for 90% of the organisms) of STX was 5 log(2) dilutions lower than that of levofloxacin (LVX). The MIC(50) (MIC for 50% of the organisms) of STX against gyrA mutants was 0.12 μg/mL and was significantly lower than that of LVX (8 μg/mL). The activity of STX at pH 5.5 was significantly less than that at pH 7.0. In the clinical trial, 28 patients with two eradication failures were treated with STX-based triple therapy [rabeprazole 10 mg twice daily (b.i.d.), amoxicillin 750 mg b.i.d. and STX 100mg b.i.d. for 7 days]. The eradication rate was 75% using intention-to-treat analysis and 80% using per-protocol analysis. Two gyrA mutant strains were eradicated. Amongst participants, a low pepsinogen I/II ratio was associated with successful eradication. These results suggest that STX could be active against most clinical H. pylori isolates and that STX-based triple therapy is a promising and safe third-line therapy.

Reduced expression of RAS protein activator like-1 in gastric cancer

RAS signaling is frequently deregulated in human neoplasms. However, RAS mutations have been found in only a small proportion of human gastric cancers, implicating other mechanisms in the activation of RAS signaling in gastric tumorigenesis. We have previously reported that decreased expression of RAS protein activator like‐1 (RASAL1), a member of the RAS‐GTPase‐activating proteins that switch off RAS activity, contributes to colon tumor progression. In our study, we explored the involvement of decreased RASAL1 expression in gastric tumorigenesis. RASAL1 expression was reduced in 6 of 10 gastric cancer cell lines examined by immunoblotting. Knockdown of RASAL1 increased mitogen‐activated protein kinase signaling in response to growth factor stimulation, and the forced expression of RASAL1 reduced proliferation of gastric cancer cells. Immunohistochemical analyses in primary gastric tumors showed that RASAL1 expression was reduced in 23 of 48 (48%) of the gastric cancers but in none of the adenomas (0/10). Methylation of the RASAL1 promoter region and loss of heterozygosity (LOH) at the RASAL1 locus were examined to investigate the causes of RASAL1 silencing. All cell lines with reduced RASAL1 had RASAL1 methylation, and two had LOH. In primary gastric cancers, methylation or LOH was detected in 50% (6/12) of those with reduced RASAL1. Furthermore, RASAL1 expression was restored in some cell lines by histone deacetylase inhibitor treatment. Our findings demonstrate that reduced RASAL1 expression, partly due to genetic and epigenetic changes, contributes to gastric carcinogenesis, and also re‐emphasize the importance of RAS signaling in gastric cancer development.

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.

Macroscopic morphologic subtypes of laterally spreading colorectal tumors showing distinct molecular alterations.

Recent advances in colonoscopic techniques have resulted in more frequent detection of superficial‐type colorectal tumors, that is, laterally spreading tumors (LSTs), although little is known about the characteristic clinical features and genetic alterations of LSTs. To elucidate the molecular characteristics of LSTs, genetic alterations in the KRAS, BRAF and PIK3CA genes and abnormal expression of the p53, β‐catenin and MYC proteins were analyzed using direct DNA sequencing and immunohistochemistry for 50 protruded‐type tumors (Protruded), 35 granular‐type LSTs (LST‐G) and 19 nongranular‐type LSTs (LST‐NG). In addition, loss of heterozygosity (LOH) close to the adenomatous polyposis coli (APC) gene (5q21) was examined in these tumors. In univariate analyses, significant differences were noted in the percentages with KRAS mutations (Protruded, LST‐G, LST‐NG = 30.0%, 54.3%, 21.1%, respectively, p = 0.0156), nuclear accumulation of β‐catenin (Protruded, LST‐G, LST‐NG = 50.0%, 37.1%, 68.4%, respectively, p = 0.0267), expression of MYC (Protruded, LST‐G, LST‐NG = 26.0%, 17.1%, 42.1%, respectively, p = 0.0456) and LOH at the APC gene locus (Protruded, LST‐G, LST‐NG = 22.0%, 20.0%, 47.4%, respectively, p = 0.0302). Multivariate analysis demonstrated that the macroscopic subtype of LST was significantly associated with KRAS mutation (for LST‐NG: odds ratio [OR] 0.23, 95% CI 0.06–0.90) and nuclear accumulation of β‐catenin (for LST‐NG: OR 4.05, 95% CI 1.11–14.8). Our data revealed that the 2 subtypes of LST have different molecular characteristics, suggesting that 2 or more different molecular mechanisms result in colorectal tumors with a similar growth pattern.

Genetic alterations in colorectal cancers with demethylation of insulin-like growth factor II

Loss of genomic imprinting is an epigenetic alteration of some cancers involving the absence of parental origin-specific expression of imprinted genes. Loss of genomic imprinting of insulin-like growth factor II is often detected in colorectal cancer. However, the genetic alterations accompanied by colorectal cancer with insulin-like growth factor II loss of genomic imprinting have not been fully determined. Genomic DNA samples were collected from 52 colorectal cancer tissues and analyzed. The loss of insulin-like growth factor II genomic imprinting status was determined by assessing the demethylation of the insulin-like growth factor II differentially methylated region using bisulfite sequencing. The molecular signatures were also examined: genetic mutations of KRAS, BRAF, and PIK3CA; the expression of CTNNB1 and TP53; and microsatellite instability status. Several cases of colorectal cancer with normal insulin-like growth factor II imprinting were located in the distal colon; in contrast, colorectal cancer with loss of genomic imprinting tended to be found in the proximal colon (22.7 versus 56.6%). The PIK3CA gene mutation was highly detected in normal imprinting tumors compared to colorectal cancers with insulin-like growth factor II loss of genomic imprinting (27.3% versus 6.7%). In multivariate analysis of these clinicopathologic and molecular factors of tumors, statistically significant relationships were observed among the proximal location of the tumor (odds ratio, 12.9; 95% confidence interval, 1.52-110.13), PIK3CA genetic mutation (odds ratio, 0.082; 95% confidence interval, 0.01-0.73), and insulin-like growth factor II genomic imprinting status. Our findings indicate that colorectal cancers with demethylation of the insulin-like growth factor II gene are distinct from normal imprinting tumors, both in clinical and genetic features.