Evaluation of trefoil factor 3 as a non-invasive biomarker of gastric intestinal metaplasia and gastric cancer in a high-risk population.

BACKGROUND: Adenocarcinoma is preceded by chronic atrophic gastritis, gastric intestinal metaplasia and dysplasia. Trefoil factor 3 (TFF3) is a peptide secreted by goblet cells, which is abundantly present in intestinal metaplasia. AIM: To evaluate the utility of serum TFF3 as a non-invasive biomarker for the diagnosis of intestinal metaplasia and gastric cancer. METHODS: Single-center, cross-sectional study of 274 patients who consecutively underwent upper gastrointestinal endoscopy with gastric biopsies (updated Sydney system). TFF3 levels were measured in serum by a commercial ELISA kit. Patients with normal histology or chronic atrophic gastritis without intestinal metaplasia comprised the control group. In addition, 14 patients with invasive gastric cancer were included as a reference group. The association between TFF3 levels and intestinal metaplasia was assessed by logistic regression. RESULTS: Patients with intestinal metaplasia (n=110) had a higher median TFF3 level as compared to controls (n=164), 13.1 vs. 11.9ng/mL, respectively (p=0.024). Multivariable logistic regression showed a no significant association between TFF3 levels and intestinal metaplasia (OR=1.20; 95%CI: 0.87-1.65; p-trend=0.273). The gastric cancer group had a median TFF3 level of 20.5ng/mL, and a significant association was found (OR=3.26; 95%CI: 1.29-8.27; p-trend=0.013). CONCLUSION: Serum levels of TFF3 do not discriminate intestinal metaplasia in this high-risk Latin American population. Nevertheless, we confirmed an association between TFF3 levels and invasive gastric cancer.

Colorectal cancer risk factors in asymptomatic Chilean population: a survey of international collaboration between Japan and Chile.

In Chile, the mortality from colorectal cancer has been on the rise. A national screening program based on a fecal immunochemical test was started in 2012 as an international collaboration with Japan. This case-control study was designed to identify the risk factors for colorectal cancer, with a goal of increasing the participation rate for colorectal cancer screening. In accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines, we conducted a case-control study from 2012 to 2017; 23 845 asymptomatic participants were enrolled in the study. Participants who were fecal immunochemical test-positive or had a family history of colorectal cancer underwent a colonoscopy. We analyzed the odds ratio of the risk factors for colorectal cancer, including sex, age, family history, BMI, hypertension, diabetes, regular use of nonsteroidal anti-inflammatory drugs, alcohol consumption, smoking, physical activity, and daily intake of certain food items. For the screening program, 202 cases of colorectal cancer were detected, and 195 of them were evaluated pathologically after resection. Of these, 173 cases (88.7%) had colorectal cancer stage 0/1, 151 (77.4%) of which were treated with endoscopic resection. In the multivariate analysis, male sex, family history of colorectal cancer, and low intake of cereals or fibers were closely related to a high colorectal cancer incidence. Moreover, participants in their 60s and 70s had a higher incidence of colorectal cancer than those in their 50s. These results suggest that intensive screening of the high-risk population can help in improving the detection of colorectal cancer, whereas higher consumption of cereals or fibers can be effective in preventing its onset.

Histopathologic study from a colorectal cancer screening in Chile: results from the first 2 years of an international collaboration between Chile and Japan.

A national colorectal cancer (CRC) screening program began in Chile in 2012, which is an international collaboration between Japan and Chile and is based on a standardized protocol supported by Tokyo Medical and Dental University. We describe the results from the first 2 years of screening at one public hospital in Punta Arenas, Chile. Of 4124 asymptomatic individuals aged between 50 and 75 years, 485 participants with immunological fecal occult blood test values of at least 100 ng/ml and/or those with family histories of CRC underwent colonoscopies. Lesions were found in 291 participants, and 642 histologic samples were obtained. Chilean pathologists made the initial histologic diagnoses, and a Japanese pathologist reviewed the histologic slides and analyzed the results. Of the 291 participants with lesions, 60 (20.6%) were diagnosed with adenocarcinomas, of which 50 (83.3%) were early-phase adenocarcinomas (pTis or pT1), and 163 (56.0%) were diagnosed with conventional adenomas, of which 96 (58.9%) were high-risk adenomas. The cancer prevalence within the screened population was 1.5% (60 of 4124). The colonoscopy cancer detection rate was 12.4% (60 of 485). Notably, we detected one flat-depressed (0-IIc) lesion that measured 5 mm and had invaded the submucosa. The findings from this screening program are the first to show the histopathologic distributions of consecutive lesions and the high incidence of CRC in Chile. The high detection rates for high-risk adenomas and cancer support the feasibility of early CRC screening and its potential to reduce the mortality associated with CRC.

A Pilot Trial to Quantify Plasma Exosomes in Colorectal Cancer Screening from the International Collaborative Study between Chile and Japan.

BACKGROUND: In Chile, a national colorectal cancer (CRC) screening program using immunochemical fecal occult blood tests and colonoscopy was started in 2012 as an international collaboration between Chile and Japan. In the present study, we quantified exosomes in the peripheral blood and evaluated the implication of the results for CRC screening. METHODS: A total of 25 peripheral plasma samples from the participants of CRC screening in Punta Arenas, Chile, were analyzed for exosomes. RESULTS: Plasma exosomes were obtained from 5 participants with adenocarcinoma (4 pTis and 1 pT1), 8 with high-grade adenoma, 4 with low-grade adenoma, 4 with hyperplastic polyps, and 4 with normal findings. Participants with adenocarcinoma had significantly higher amounts of plasma exosomes (2.1-3.2 fold) than participants with normal findings, hyperplastic polyps, or low-grade adenoma (p = 0.016, p = 0.0034, and p = 0.0042 respectively; Tukey's multiple comparisons test). The size of the representative lesion, the number of lesions, and the sum of those 2 factors in each participant correlated significantly with the exosome amounts (r = 0.56, r = 0.58, and r = 0.72, respectively; p < 0.01; Spearman's correlation coefficient test). CONCLUSIONS: This pilot study demonstrated that quantification of plasma exosomes is a potential alternative screening method for detecting individuals with a high risk of colorectal malignancy.

Risk factors for intraoperative perforation during endoscopic submucosal dissection of superficial esophageal squamous cell carcinoma.

AIM: To identify the risk factors and clarify the subsequent clinical courses. METHODS: This study retrospectively analyzed consecutive patients with esophageal squamous cell carcinoma (ESCC) treated using endoscopic submucosal dissection (ESD) between April 2008 and October 2012. We divided the ESCC lesions into perforation cases and non-perforation cases, and compared characteristics and endoscopic findings between the two groups. "Intraoperative perforation" was defined as the detection of a perforation site during ESD and the presence of mediastinal emphysema. RESULTS: In total, 147 patients with 156 ESCC lesions were treated by ESD. Intraoperative perforation was recorded for nine lesions (5.8%) from nine patients. Multivariate analysis identified mucosal deficiency larger than 75% of the circumference of the esophagus as an independent risk factor for intraoperative perforation (OR = 7.37, 95%CI: 1.45-37.4, P = 0.016). The predominant site of perforation was the left wall [6/9 (67%)]. Six of nine perforation sites were successfully closed by clips during the procedures. Two of nine cases required drainage for pleural effusions; however, all nine cases recovered with conservative treatment and without surgical intervention. At the median follow up of 42 mo after ESD, no cases of local recurrence or distant organ metastasis had been observed. CONCLUSION: This study suggests that mucosal deficiency larger than 75% of the luminal circumference is a risk factor for intraoperative perforation during ESD for ESCC.

International collaboration between Japan and Chile to improve detection rates in colorectal cancer screening.

BACKGROUND: In Chile, mortality from colorectal cancer (CRC) has increased rapidly. To help address this issue, the Prevention Project for Neoplasia of the Colon and Rectum (PRENEC) program was initiated in 2012 with intensive support from Tokyo Medical and Dental University (TMDU) in Tokyo, Japan, as part of an international collaboration. METHODS: From June 2012 to July 2014, a total of 10,575 asymptomatic participants were enrolled in PRENEC. Participants with positive immunochemical fecal occult blood test (iFOBT) results or a family history of CRC underwent colonoscopy. The colonoscopy results from a similar, previous project in Chile (PREVICOLON) were compared with those from PRENEC. Furthermore, the initial colonoscopies of 1562 participants in PRENEC were analyzed according to whether the colonoscopists were from TMDU or Chile. RESULTS: The complete colonoscopy, adenoma detection, and cancer detection rates were 88.0%, 26.7%, and 1.1%, respectively, in PREVICOLON, while the corresponding values were 94.4%, 41.8%, and 6.0%, respectively, in PRENEC. In PRENEC, 107 cases of CRC were detected, amounting for 1.0% of all participants. Considering initial colonoscopies in PRENEC, the complete colonoscopy, adenoma detection, and cancer detection rates were 97.4%, 45.3%, and 9.3%, respectively, for physicians at TMDU and 93.3%, 41.5%, and 5.1%, respectively for Chilean physicians. The detection rates of intramucosal cancer were 7.3% and 3.7%, respectively, for TMDU and Chilean physicians. CONCLUSIONS: Quality indicators of colonoscopy substantially improved from PREVICOLON to PRENEC. The assessments made by Chilean physicians alone were improved in PRENEC, but remained better in the TMDU group. Moreover, physicians from TMDU detected more CRCs than Chilean physicians, especially at earlier stages.

Peritonitis related to percutaneous endoscopic gastrostomy using the direct method for cancer patients.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) using the direct method is generally indicated for cancer patients. However, there are little available data about peritonitis related to this method. The aim of this retrospective analysis was to assess peritonitis related to PEG using the direct method in patients with cancer. METHODS: We assessed the prevalence of peritonitis and the relationship between peritonitis and patients' backgrounds, as well as the clinical course after peritonitis. RESULTS: Between December 2008 and December 2011, peritonitis was found in 9 (2.1 %) of 421 patients. Of the 9 patients with peritonitis, 4 had received PEG prior to chemoradiotherapy. Emergency surgical drainage was required in 1 patient, and the remaining 8 recovered with conservative treatment. Peritonitis occurred within 8 days of PEG for 8 of the 9 patients and occurred within 2 days of suture removal for 4 of the 9 patients. CONCLUSION: Peritonitis related to PEG using the direct method was less frequent for cancer patients. Peritonitis tended to occur within a few days after removal of securing suture and in patients with palliative stage.

Clinicopathological differences of laterally spreading tumors arising in the colon and rectum.

PURPOSE: Laterally spreading tumors (LST) have been recognized worldwide. The aim of our retrospective study was to evaluate the clinicopathological differences of LST arising in the colon and rectum. METHODS: We investigated the clinical records of consecutive patients with LST that were endoscopically or surgically resected at our hospital between February 2006 and March 2011. LST were classified into three types: granular-homogenous (LST-GH), granular-nodular mixed (LST-GM), and nongranular (LST-NG) types. We also defined the hardly elevated flat lesion with a dilated pit pattern that occurs at the margins of LST as the "skirt." The clinicopathological characteristics of the LST arising in the colon and rectum, including the presence of the skirt, were compared. RESULTS: A total of 496 colorectal LST in 435 patients were examined. LST-GM was predominant in the rectum, whereas LST-NG was predominant in the colon (p < 0.001). The mean tumor size was larger in the rectum (39.3 ± 17.9 mm) than the colon (25.8 ± 13.6 mm) (p < 0.001). Low-grade dysplasia frequency was lower in the rectum than the colon (4 vs. 37%, p < 0.001). The skirt was identified in 15 lesions (3.0%), with a higher incidence in the rectum than the colon (17 vs. 0.5%, p < 0.001). The skirt was found only in LST-GM. CONCLUSIONS: A greater proportion of LST-GM, greater mean size, and lower incidence of low-grade dysplasia were found in rectal LST. The skirt was a novel and unique finding, primarily observed in rectal LST-GM cases.

Effect of novel bright image enhanced endoscopy using blue laser imaging (BLI).

BACKGROUND AND STUDY AIMS: The novel method of image-enhanced endoscopy (IEE) named blue laser imaging (BLI) can enhance the contrast of surface vessels using lasers for light illumination. BLI has two IEE modes: high contrast mode (BLI-contrast) for use with magnification, and bright mode (BLI-bright), which achieves a brighter image than BLI-contrast and yet maintains the enhanced visualization of vascular contrast that is expected for the detection of tumors from a far field of view. The aim of this study is to clarify the effect of BLI-bright with a far field of view compared to BLI-contrast and commonly available narrow-band imaging (NBI). PATIENTS AND METHODS: Patients with neoplasia, including early cancer in the pharynx, esophagus, stomach, or colorectum, were recruited and underwent tandem endoscopy with BLI and NBI systems. Six sets of images of the lesions were captured with a changing observable distance from 3 to 40 mm. Individual sets of images taken from various observable distances were assessed for visibility among BLI-bright, BLI-contrast, and NBI modes. The brightness and contrast of these images were also analyzed quantitatively. RESULTS: Of 51 patients, 39 were assessed. Image analysis indicated that only BLI-bright maintained adequate brightness and contrast up to 40 mm and had significantly longer observable distances compared to the other methods. Furthermore, BLI-bright enhanced the visualization of serious lesions infiltrating into deeper layers, such as esophageal lamina propria or gastric submucosal cancers. CONCLUSIONS: BLI-bright will be a helpful tool for the far-field view with IEE in organs with wider internal spaces such as the stomach.

Short- and long-term outcomes of endoscopic submucosal dissection for undifferentiated early gastric cancer.

BACKGROUND AND STUDY AIMS: Intramucosal undifferentiated early gastric cancer (EGC) up to 2 cm in size without ulceration has been treated by endoscopic submucosal dissection (ESD) because the incidence of lymph node metastasis is negligible. The aim of this retrospective study was to clarify the short-term and long-term outcomes of ESD carried out to treat undifferentiated EGC. PATIENTS AND METHODS: Between January 1999 and September 2011, 113 patients with poorly differentiated adenocarcinoma or signet ring cell carcinoma on preoperative biopsy underwent ESD. In 16 patients differentiated EGC had been diagnosed after the ESD and these patients were excluded from the study. Short-term outcomes were evaluated in the remaining 97 patients with undifferentiated EGC, and long-term outcomes analyzed in the 79 patients with undifferentiated EGC who had undergone ESD between 1999 and 2008. RESULTS: En bloc and R0 resection were achieved in 99.0 % and 90.7 % of patients, respectively. Median procedure time was 45 minutes. Postoperative bleeding, perforation during the procedure, and delayed perforation were noted in 4.1 %, 3.1 %, and 1.0 % respectively. Curative resection was achieved in 63.9 %. Additional surgery was performed in 21 of 35 patients in whom resection was noncurative: one (4.8 %) had local residual tumor and two (9.5 %) had lymph node metastases. Of the 46 /79 patients in the long-term outcome group who had curative resection, none had local recurrence or lymph node or distant metastasis during a median follow-up of 76.4 months. The 5-year overall mortality rate after curative resection was 7.0 %, and no patient died of gastric cancer. CONCLUSIONS: ESD for undifferentiated EGC can achieve curative resection with an excellent 5-year mortality rate.

What is the accuracy of autofluorescence imaging in identifying non-polypoid colorectal neoplastic lesions when reviewed by trainees? A pilot study.

BACKGROUND AND AIM: Non-polypoid colorectal neoplasms are difficult to identify using conventional white light (WL) colonoscopy. The aim of the present pilot study was to compare an autofluorescence imaging (AFI) system with conventional WL colonoscopy for the identification of non-polypoid neoplasms by trainees in a colonoscopic observational situation. METHODS: We selected clear images with both AFI and WL in the same field taken by experts at the National Cancer Center Hospital, Tokyo, from December 2009 to November 2010. One hundred and eighty sets of images (137 non-polypoid neoplasms and 43 without neoplasm) were selected. The images were reviewed by two trainees without AFI experience. After attending a short educational lecture on the AFI system, the reviewers determined the presence of lesions in the randomly arranged images. The accuracy of AFI and WL for identifying non-polypoid neoplasms by trainees was assessed. RESULTS: The sensitivity and specificity for identifying non-polypoid neoplasms by trainees was not significantly different between AFI and WL. However, the specificity tended to be lower in AFI images than in WL images. CONCLUSIONS: False-positive results tended to be more frequent for the AFI images than for the WL images. Further improvements in the technology and resolution are necessary for the AFI system to be useful for the detection of colorectal neoplasms. At present, clinical application of the AFI system may require more extensive structured training to improve its accuracy in the identification of non-polypoid colorectal neoplasms.

Unexpected endoscopic full-thickness resection of a duodenal neuroendocrine tumor.

A 57-year-old man underwent endoscopy for investigation of a duodenal polyp. Endoscopy revealed a hemispheric submucosal tumor, about 5 mm in diameter, in the anterior wall of the duodenal bulb. Endoscopic biopsy disclosed a neuroendocrine tumor histologically, therefore endoscopic mucosal resection was conducted. The tumor was effectively and evenly elevated after injection of a mixture of 0.2% hyaluronic acid and glycerol at a ratio of 1:1 into the submucosal layer. A small amount of indigo-carmine dye was also added for coloration of injection fluid. The lesion was completely resected en bloc with a snare after submucosal fluid injection. Immediately, muscle-fiber-like tissues were identified in the marginal area of the resected defect above the blue-colored layer, which suggested perforation. The defect was completely closed with a total of 9 endoclips, and no symptoms associated with peritonitis appeared thereafter. Histologically, the horizontal and vertical margins of the resected specimen were free of tumor and muscularis propria was also seen in the resected specimen. Generally, endoscopic mucosal resection is considered to be theoretically successful if the mucosal defect is colored blue. The blue layer in this case, however, had been created by unplanned injection into the subserosal rather than the submucosal layer.

Small undifferentiated intramucosal gastric cancer with lymph-node metastasis: case report.

It has been reported recently that small undifferentiated intramucosal early gastric cancer (EGC) < 20 mm in size without any lymphovascular involvement or ulcerative findings had virtually no risk of lymph-node (LN) metastasis. Consequently, the indications for endoscopic resection were expanded to include such undifferentiated EGC lesions. We describe herein a case of a small undifferentiated intramucosal EGC < 20 mm in size without lymphovascular involvement or ulcerative findings that involved lymph-node metastasis. A 57-year-old female underwent pylorus preserving gastrectomy as standard treatment for an undifferentiated EGC 15 mm in size without any ulcerative finding. The surgical specimen revealed a signet-ring cell carcinoma with a moderately to poorly differentiated adenocarcinoma limited to the mucosa that was 15 mm in size with no lymphovascular involvement or ulcerative findings. This case involved LN metastasis, however, and the lesion was diagnosed as pathological stage IIA (T1N2M0) according to the Japanese Classification of Gastric Carcinoma.

Learning curve for endoscopic submucosal dissection of early gastric cancer based on trainee experience.

BACKGROUND AND AIM: There have been few previous reports on endoscopic submucosal dissection (ESD) learning curve for early gastric cancer (EGC) so we retrospectively assessed this subject based on experience of our trainees. METHODS: Trainees in our center start performing ESDs for lesions in lower third of stomach with hands-on support by experts during first 10 cases and then perform ESDs by themselves primarily with verbal guidance from experts. They are gradually assigned to perform ESDs in middle and upper thirds of stomach. From January 1999 to December 2008, 464 EGC patients, who underwent ESD performed by 13 trainees, were assessed by dividing ESD cases into five training periods (A, 1-10; B, 11-20; C, 21-30; D, 31-40; and E, 41-50). We compared data from B to C, D and E. RESULTS: Lesions in lower third were A/59%, B/57%, C/55%, D/36% and E/40% with B significantly higher than D (p<0.01) and E (p<0.05). Mean tumor sizes were A/13.9 ± 7.5mm, B/18.3 ± 11.4mm, C/19.0 ± 12.5mm, D/19.3 ± 11.7 mm and E/16.8 ± 10.3mm. En-bloc resection rate was 100% in every period. Delayed bleeding / perforation rates were A/0%/1.8%, B/2.8%/1.9%, C/1.9%/2.9%, D/1.1%/0% and E/2.1%/2.1%, respectively. Lower third procedure times were A/76 ± 39, B/90 ± 61, C/70 ± 48, D/60 ± 50 and E/55 ± 26 minutes with B significantly longer than D and E (p<0.05). Middle and upper third procedure times were A/104 ± 80, B/115 ± 68, C/106 ± 67, D/134 ± 86 and E/96 ± 55 minutes. CONCLUSION: Step-by-step training was highly effective with 100% en-bloc resection rate and few complications. Learning curve point for our trainees to acquire performing ESD in lower third of stomach was 30 cases.