Naohisa Yahagi

Endoscopic submucosal dissection for early gastric cancer using the tip of an electrosurgical snare (thin type)

Background:  Although the strip biopsy method and aspiration method are popular endoscopic mucosal resection techniques for its convenience and reliability, they have limitations in resectable tumor size and location. Endoscopic submucosal dissection techniques using the diathermic needle knife or the insulated‐tip diathermic knife have been introduced to overcome this disadvantage, but they have high risks for bleeding and perforation. Therefore, we have developed a new endoscopic submucosal dissection technique using the tip of an electrosurgical snare (thin type) and assessed its efficacy.

Clinical Application of Serum Pepsinogen I and II Levels for Mass Screening to Detect Gastric Cancer

A considerable number of gastric cancers derive from stomach mucosa where chronic atrophic gastritis is severe and extensive. Based on the fact that the serum pepsinogen levels provide a precise measure of the extent of chronic atrophic gastritis, we have devised a mass screening method involving serum pepsinogen measurement to identify subjects at high risk of gastric cancer. In 1991, we screened 4,647 workers (male: 4,113, female: 534, mean age: 49.0 years) at a Japanese company using this method. Out of 875 subjects (18.8%) with a serum pepsinogen I level of less than 50 μg/liter and a pepsinogen I/II ratio of less than 3.0, 676 subjects (14.5%) were selected for further investigation by endoscopy. This led to the detection of four subjects (0.086%) with gastric cancer (three in an early stage) and four subjects with adenoma. The cancer detection rate of this new screening method was comparable, and in some respects superior, to that of the traditional barium X‐ray screening. Since the incidence of test‐positive subjects was as low as 10% amongst subjects aged less than 40, this screening method appears to be especially useful for screening of younger generations. The new method is less expensive than the traditional barium X‐ray and subjects experience little discomfort. Further, many serum samples can be quickly measured simultaneously. The results of this study have indicated that serum pepsinogen screening provides a valuable method for detecting gastric cancers.

JGES guidelines for colorectal endoscopic submucosal dissection/endoscopic mucosal resection

Colorectal endoscopic submucosal dissection (ESD) has become common in recent years. Suitable lesions for endoscopic treatment include not only early colorectal carcinomas but also many types of precarcinomatous adenomas. It is important to establish practical guidelines in which the preoperative diagnosis of colorectal neoplasia and the selection of endoscopic treatment procedures are properly outlined, and to ensure that the actual endoscopic treatment is useful and safe in general hospitals when carried out in accordance with the guidelines. In cooperation with the Japanese Society for Cancer of the Colon and Rectum, the Japanese Society of Coloproctology, and the Japanese Society of Gastroenterology, the Japan Gastroenterological Endoscopy Society has recently compiled a set of colorectal ESD/endoscopic mucosal resection (EMR) guidelines using evidence‐based methods. The guidelines focus on the diagnostic and therapeutic strategies and caveat before, during, and after ESD/EMR and, in this regard, exclude the specific procedures, types and proper use of instruments, devices, and drugs. Although eight areas, ranging from indication to pathology, were originally planned for inclusion in these guidelines, evidence was scarce in each area. Therefore, grades of recommendation were determined largely through expert consensus in these areas.

Local Recurrence After Endoscopic Resection for Large Colorectal Neoplasia: A Multicenter Prospective Study in Japan

OBJECTIVES:Conventional endoscopic resection (CER) is a widely accepted treatment for early colorectal neoplasia; however, large colorectal neoplasias remain problematic, as they necessitate piecemeal resection, increasing the risk of local recurrence. Endoscopic submucosal dissection (ESD) can improve the en bloc resection rate. This study aimed to evaluate local recurrence and its associated risk factors after endoscopic resection (ER) for colorectal neoplasias ≥20 mm.METHODS:A multicenter prospective study at 18 medium- and high-volume specialized institutions was conducted in Japan. Follow-up colonoscopy was performed after 12 months in cases of complete resection and after 3–6 months in cases of incomplete resection. Local recurrence was confirmed by endoscopic findings and/or pathological analysis.RESULTS:Follow-up colonoscopy was performed in 1,524 of 1,845 enrolled colorectal neoplasias (mean age, 65 years; 885 men; median tumor size, 32.8 mm). The local recurrence rates were 4.3% (65/1,524), 6.8% (55/808), and 1.4% (10/716) for the entire cohort, for CER, and for ESD, respectively. The relative risks of local recurrence were 0.21 (95% confidence interval, 0.11–0.39) with ESD compared with CER, 0.32 (95% confidence interval, 0.11–0.92) with en bloc ESD compared with en bloc CER, and 0.90 (95% confidence interval, 0.39–2.12) with piecemeal ESD compared with piecemeal CER. Significant factors associated with local recurrence were piecemeal resection, laterally spreading tumors of granular type, tumor size ≥40 mm, no pre-treatment magnification, and ≤10 years of experience in CER, and piecemeal resection only in ESD.CONCLUSIONS:En bloc ESD reduces the local recurrence rate for large colorectal neoplasias. Piecemeal resection is the most important risk factor for local recurrence regardless of the ER method used.

Guidelines for endoscopic submucosal dissection and endoscopic mucosal resection for early gastric cancer

In response to the rapid and wide acceptance and use of endoscopic treatments for early gastric cancer, the Japan Gastroenterological Endoscopy Society (JGES), in collaboration with the Japanese Gastric Cancer Association (JGCA), has produced ‘Guidelines for ESD and EMR for Early Gastric Cancer’, as a set of basic guidelines in accordance with the principles of evidence‐based medicine. These Guidelines cover the present state of knowledge and are divided into the following seven categories: Indications, Preoperative diagnosis, Techniques, Evaluation of curability, Complications, Long‐term postoperative surveillance, and Histology. Twenty‐three statements were finally accepted as guidelines, and the majority of these were obtained from descriptive studies with lower evidence levels. A number of statements had to be created by consensus (the lowest evidence level), as evidence levels remain low for many specific areas in this field.

Frequent Loss of Brm Expression in Gastric Cancer Correlates with Histologic Features and Differentiation State

The mammalian SWI/SNF chromatin remodeling complex, an essential epigenetic regulator, contains either a single Brm or BRG1 molecule as its catalytic subunit. We observed frequent loss of Brm expression but not of BRG1 in human gastric cancer cell lines. Treatment with histone deacetylase inhibitor rescued Brm expression, indicating epigenetic regulation of this gene, and an RNA interference-based colony formation assay revealed antioncogenic properties of Brm. Brm immunostaining of 89 primary gastric cancers showed an obvious reduction in 60 cases (67%) and a severe decrease in 37 cases (42%). Loss of Brm is frequent in the major gastric cancer types (well- or moderately-differentiated tubular adenocarcinoma and poorly-differentiated adenocarcinoma) and positively correlates with the undifferentiated state. Among the minor gastric cancer types, Brm expression persists in signet-ring cell carcinoma and mucinous adenocarcinoma, but a marked decrease is observed in papillary adenocarcinoma. Intestinal metaplasia never shows decreased expression, indicating that Brm is a valid marker of gastric oncogenesis. In contrast, BRG1 is retained in most cases; a concomitant loss of BRG1 and Brm is rare in gastric cancer, contrary to other malignancies. We further show that Brm is required for villin expression, a definitive marker of intestinal metaplasia and differentiation. Via regulating such genes important for gut differentiation, Brm should play significant roles in determining the histologic features of gastric malignancy.

The Brm gene suppressed at the post-transcriptional level in various human cell lines is inducible by transient HDAC inhibitor treatment, which exhibits antioncogenic potential

The mammalian SWI/SNF chromatin remodeling complex is composed of more than 10 protein subunits, and plays important roles in epigenetic regulation. Each complex includes a single BRG1 or Brm molecule as the catalytic subunit. We previously reported that loss of Brm, but not BRG1, causes transcriptional gene silencing of murine leukemia virus-based retrovirus vectors. To understand the biological function and biogenesis of Brm protein, we examined seven cell lines derived from various human tumors that do not produce Brm protein. We show here that these Brm-deficient cell lines transcribe the Brm genes efficiently as detected by nuclear run-on transcription assay, whereas Brm mRNA and Brm hnRNA were undetectable by reverse transcription–polymerase chain reaction analysis. These results indicate that expression of Brm is strongly and promptly suppressed at the post-transcriptional level, through processing and transport of the primary transcript or through stability of mature Brm mRNA. This suppression was attenuated by transient treatment of these cell lines with HDAC inhibitors probably through indirect mechanism. Importantly, all of the treated cells showed prolonged induction of Brm expression after the removal of HDAC inhibitors, and acquired the ability to maintain retroviral gene expression. These results indicate that these Brm-deficient human tumor cell lines carry a functional Brm gene. Treatment with HDAC inhibitors or introduction of exogenous Brm into Brm-deficient cell lines significantly reduced the oncogenic potential as assessed by colony-forming activity in soft agar or invasion into collagen gel, indicating that, like BRG1, Brm is involved in tumor suppression.

CURRENT STATUS IN THE OCCURRENCE OF POSTOPERATIVE BLEEDING, PERFORATION AND RESIDUAL/LOCAL RECURRENCE DURING COLONOSCOPIC TREATMENT IN JAPAN

Bleeding, perforation, and residual/local recurrence are the main complications associated with colonoscopic treatment of colorectal tumor. However, current status regarding the average incidence of these complications in Japan is not available. We conducted a questionnaire survey, prepared by the Colorectal Endoscopic Resection Standardization Implementation Working Group, Japanese Society for Cancer of the Colon and Rectum (JSCCR), to clarify the incidence of postoperative bleeding, perforation, and residual/local recurrence associated with colonoscopic treatment. The total incidence of postoperative bleeding was 1.2% and the incidence was 0.26% with hot biopsy, 1.3% with polypectomy, 1.4% with endoscopic mucosal resection (EMR), and 1.7% with endoscopic submucosal dissection (ESD). The total incidence of perforation was 0.74% (0.01% with the hot biopsy, 0.17% with polypectomy, 0.91% with EMR, and 3.3% with ESD). The total incidence of residual/local recurrence was 0.73% (0.007% with hot biopsy, 0.34% with polypectomy, 1.4% with EMR, and 2.3% with ESD). Colonoscopic examination was used as a surveillance method for detecting residual/local recurrence in all hospitals. The surveillance period differed among the hospitals; however, most of the hospitals reported a surveillance period of 3–6 months with mainly transabdominal ultrasonography and computed tomography in combination with the colonoscopic examination.

Effects of methylenetetrahydrofolate reductase and reduced folate carrier 1 polymorphisms on high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia or lymphoma

The authors investigated whether high-dose methotrexate-induced toxicity differed according to the presence of methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier 1 (RFC1) genetic polymorphism. The authors studied 15 children with acute lymphoblastic leukemia or lymphoblastic lymphoma who were treated using protocols that included high-dose methotrexate (3.0 g/m2), for an overall total of 43 courses. Methotrexate-induced toxicities and the plasma methotrexate concentrations were evaluated retrospectively. Hematologic toxicity was the most frequently observed toxicity, appearing in 87% of the patients. In a subset of patients (47%), elevation of liver transaminase levels showed a repeated tendency to develop. High plasma methotrexate concentrations at 48 hours after the methotrexate infusion were not significantly related to methotrexate-induced toxicities except for mucositis. A generalized estimating equation analysis revealed that vomiting during the high-dose methotrexate treatment was more pronounced in patients who had a larger number of G alleles at the RFC1 80G>A polymorphism. No significant differences in the development of other toxicities or in the plasma methotrexate concentrations were observed for the different MTHFR 677C>T or RFC1 80G>A polymorphisms. This study suggests but does not prove that the RFC1 80G>A polymorphism may contribute to interindividual variability in responses to high-dose methotrexate.

MULTICENTER QUESTIONNAIRE SURVEY ON THE CURRENT SITUATION OF COLORECTAL ENDOSCOPIC SUBMUCOSAL DISSECTION IN JAPAN

In order to understand the current use of endoscopic submucosal dissection (ESD) for the treatment of colorectal tumors in Japan, we administered a questionnaire survey to 1356 institutions all over the country. The subject of the survey was colorectal ESD performed from January 2000 to September 2008. Among the 1356 institutions, 391 (28.8%) responded to the questionnaire, and colorectal ESD was currently being performed in 194 institutions. The 194 institutions were almost equally distributed in Japan, that is, colorectal ESD has been performed all over the country. Among these 194 institutions, the procedure had been performed in 100 or more cases in 22 (11.3%) institutions and in 50–99 cases in 18 institutions (9.3%). The knives used in colorectal ESD were the Hook knife, Flush knife, and Flex knife. The average time required for colorectal ESD was 92.2 min, the rate of complete en bloc resection was 83.8%, the perforation rate was 4.8%, and no case of death from complications was reported.