Endoscopic Removal of Premalignant Lesions Reduces Long-Term Colorectal Cancer Risk: Results From the Japan Polyp Study.

BACKGROUND & AIMS: To date, no regional evidence of long-term colorectal cancer (CRC) risk reduction after endoscopic premalignant lesion removal has been established. We aimed to analyze this over a long-term follow-up evaluation. METHODS: This was a prospective cohort study of participants from the Japan Polyp Study conducted at 11 Japanese institutions. Participants underwent scheduled follow-up colonoscopies after a 2-round baseline colonoscopy process. The primary outcome was CRC incidence after randomization. The observed/expected ratio of CRC was calculated using data from the population-based Osaka Cancer Registry. Secondary outcomes were the incidence and characteristics of advanced neoplasia (AN). RESULTS: A total of 1895 participants were analyzed. The mean number of follow-up colonoscopies and the median follow-up period were 2.8 years (range, 1-15 y) and 6.1 years (range, 0.8-11.9 y; 11,559.5 person-years), respectively. Overall, 4 patients (all males) developed CRCs during the study period. The observed/expected ratios for CRC in all participants, males, and females, were as follows: 0.14 (86% reduction), 0.18, and 0, respectively, and 77 ANs were detected in 71 patients (6.1 per 1000 person-years). Of the 77 ANs detected, 31 lesions (40.3%) were laterally spreading tumors, nongranular type. Nonpolypoid colorectal neoplasms (NP-CRNs), including flat (<10 mm), depressed, and laterally spreading, accounted for 59.7% of all detected ANs. Furthermore, 2 of the 4 CRCs corresponded to T1 NP-CRNs. CONCLUSIONS: Endoscopic removal of premalignant lesions, including NP-CRNs, effectively reduced CRC risk. More than half of metachronous ANs removed by surveillance colonoscopy were NP-CRNs. The Japan Polyp Study: University Hospital Medical Information Network Clinical Trial Registry: University Hospital Medical Information Network Clinical Trial Registry, C000000058; cohort study: UMIN000040731.

Endoscopist-related factors affecting adenoma detection during colonoscopy: Data from the J-SCOUT study.

OBJECTIVES: Colonoscopy withdrawal times are associated with the adenoma detection rate (ADR). However, the relationship between ADR and cecal insertion time has been inadequately characterized. We aimed to evaluate endoscopist-related factors involved in the ADR, including the average individual colonoscopy insertion and withdrawal times. METHODS: This observational study used a colonoscopy database with pathology data from routine clinical practice in Japanese institutions. The odds ratios (OR) of endoscopist-related factors related to ADRs were examined using a generalized linear mixed model. RESULTS: Of the 186,293 colonoscopies performed during the study period, 47,705 colonoscopies by 189 endoscopists in four hospitals were analyzed for ADR. The overall ADR was 38.3% (95% confidence interval [CI] 37.8, 38.7). Compared to endoscopists with mean cecal insertion times of <5 min, the OR of ADR for those with mean cecal insertion times of 5-9, 10-14, and ≥15 min were 0.84 (95% CI 0.71, 0.99), 0.68 (95% CI 0.52, 0.90), and 0.45 (95% CI 0.25, 0.78), respectively. Compared to endoscopists with mean withdrawal times of <6 min, the OR of ADR for those with mean withdrawal times of 6-9, 10-14, and ≥15 min were 1.38 (95% CI 1.03, 1.85), 1.48 (95% CI 1.09, 2.02), and 1.68 (95% CI 1.04, 2.61), respectively. There were no significant differences in ADRs by endoscopist specialty, gender, or the total number of examinations performed. CONCLUSION: Individual mean colonoscopy insertion time was associated with ADR and might be considered as a colonoscopy quality indicator as well as withdrawal time.

"Endoscopic" adenoma detection rate as a quality indicator of colonoscopy: First report from the J-SCOUT study.

OBJECTIVES: To examine whether reasonable detection rate of endoscopically diagnosed lesions as adenoma ("endoscopic" adenoma detection rate [ADR]) could be calculated with a database generated from colonoscopy reports and whether it could be used as a surrogate colonoscopy quality indicator of "pathological" ADR. METHODS: A lesion-by-lesion database of colonoscopies performed between 2010 and 2020 at eight Japanese endoscopy centers and corresponding pathology database were integrated. Differences in numbers of detected polyps, "endoscopic" and "pathological" adenomas, and what these differences could be attributed to were examined. Polyp detection rate (PDR), "endoscopic" and "pathological" ADRs, and correlation coefficients between "pathological" ADR and PDR or "endoscopic" ADR by each endoscopist were calculated. RESULTS: Overall, 129,065 colonoscopy reports were analyzed. Among a total of 146,854 polyps, more "endoscopic" adenomas (n = 117,359) were observed than "pathological" adenomas (n = 70,076), primarily because adenomas were not resected on site, rather than because of a misdiagnosis. In all patients analyzed, PDR, "endoscopic" and "pathological" ADRs were 56.4% (95% confidence interval [CI] 56.2-56.7), 48.0% (95% CI 47.7-48.3), and 32.7% (95% CI 32.5-33.0), respectively. "Endoscopic" and "pathological" ADRs from each endoscopist showed a high correlation in hospitals where adenomas were usually resected at the time of examination. CONCLUSIONS: By appropriately describing endoscopically diagnosed lesions as "adenomas" in endoscopy reports, "endoscopic" ADR might be used as a surrogate colonoscopy quality indicator of "pathological" ADR (UMIN000040690).

Characteristics of colorectal neuroendocrine tumors in patients prospectively enrolled in a Japanese multicenter study: a first report from the C-NET STUDY.

BACKGROUND: This is the first report from a multicenter prospective cohort study of colorectal neuroendocrine tumor (NET), the C-NET STUDY, conducted to assess the long-term outcomes of the enrolled patients. This report aimed to elucidate the clinicopathological features of the enrolled patients and lesions. METHODS: Colorectal NET patients aged 20-74 years were consecutively enrolled and followed up at 50 institutions. The baseline characteristics and clinicopathological findings at enrollment and treatment were assessed. RESULTS: A total of 495 patients with 500 colorectal NETs were included. The median patient age was 54 years, and 85.3% were asymptomatic. The most frequent lesion location was the lower rectum (88.0%); 99.4% of the lesions were clinically diagnosed to be devoid of metastatic findings, and 95.4% were treated with endoscopic resection. Lesions < 10 mm comprised 87.0% of the total, 96.6% had not invaded the muscularis propria, and 92.6% were classified as WHO NET grade 1. Positive lymphovascular involvement was found in 29.2% of the lesions. Its prevalence was high even in small NETs with immunohistochemical/special staining for pathological assessment (26.4% and 40.9% in lesions sized < 5 mm and 5-9 mm, respectively). Among 70 patients who underwent radical surgery primarily or secondarily, 18 showed positive lymph node metastasis. CONCLUSIONS: The characteristics of real-world colorectal NET patients and lesions are elucidated. The high positivity of lymphovascular involvement in small NETs highlights the necessity of assessing the clinical significance of positive lymphovascular involvement based on long-term outcomes, which will be examined in later stages of the C-NET STUDY. TRIAL REGISTRATION NUMBER: UMIN000025215.

Risk stratification for advanced colorectal neoplasia based on the findings of the index and first surveillance colonoscopies.

Risk stratification by index colonoscopy is well established for first surveillance endoscopy, but whether the previous two colonoscopies affect the subsequent advanced neoplasias has not been established. Therefore, the subsequent risk based on the findings of the index and first surveillance colonoscopies were investigated. This retrospective, cohort study was conducted in two clinics and included participants who had undergone two or more colonoscopies after index colonoscopy. High-risk was defined as advanced adenoma (≥ 1 cm, or tubulovillous or villous histology, or high-grade dysplasia). Based on the findings of the index and first surveillance colonoscopies, patients were classified into four categories: category A (both colonoscopy findings were normal), category B (no high-risk findings both times), category C (one time high-risk finding), and category D (high-risk findings both times). The incidence of subsequent advanced neoplasia was examined in each category. A total of 13,426 subjects were included and surveyed during the study periods. The subjects in category D had the highest risk of advanced neoplasia (27.4%, n = 32/117). The subjects in category A had the lowest risk (4.0%, n = 225/5,583). The hazard ratio for advanced neoplasia of category D compared to category A was 9.90 (95% Confidence interval 6.82-14.35, P<0.001). Classification based on the findings of index and first surveillance colonoscopies more effectively stratifies the risk of subsequent advanced neoplasia, resulting in more proper allocation of colonoscopy resources after two consecutive colonoscopies.

Randomised comparison of postpolypectomy surveillance intervals following a two-round baseline colonoscopy: the Japan Polyp Study Workgroup.

OBJECTIVE: To assess whether follow-up colonoscopy after polypectomy at 3 years only, or at 1 and 3 years would effectively detect advanced neoplasia (AN), including nonpolypoid colorectal neoplasms (NP-CRNs). DESIGN: A prospective multicentre randomised controlled trial was conducted in 11 Japanese institutions. The enrolled participants underwent a two-round baseline colonoscopy (interval: 1 year) to remove all neoplastic lesions. Subsequently, they were randomly assigned to undergo follow-up colonoscopy at 1 and 3 years (2-examination group) or at 3 years only (1-examination group). The incidence of AN, defined as lesions with low-grade dysplasia ≥10 mm, high-grade dysplasia or invasive cancer, at follow-up colonoscopy was evaluated. RESULTS: A total of 3926 patients were enrolled in this study. The mean age was 57.3 (range: 40-69) years, and 2440 (62%) were male. Of these, 2166 patients were assigned to two groups (2-examination: 1087, 1-examination: 1079). Overall, we detected 29 AN in 28 patients at follow-up colonoscopy in both groups. On per-protocol analysis (701 in 2-examination vs 763 in 1-examination group), the incidence of AN was similar between the two groups (1.7% vs 2.1%, p=0.599). The results of the non-inferiority test were significant (p=0.017 in per-protocol, p=0.001 in intention-to-treat analysis). NP-CRNs composed of dominantly of the detected AN (62%, 18/29), and most of them were classified into laterally spreading tumour non-granular type (83%, 15/18). CONCLUSION: After a two-round baseline colonoscopy, follow-up colonoscopy at 3 years detected AN, including NP-CRNs, as effectively as follow-up colonoscopies performed after 1 and 3 years.

Risk stratification of advanced colorectal neoplasia after baseline colonoscopy: Cohort study of 17 Japanese community practices.

BACKGROUND AND AIM: In Japan, risk stratification after baseline colonoscopy is not widely accepted. We investigated the findings of baseline colonoscopies at 17 community practices and evaluated the risk of the incidence of advanced neoplasia over a 5-year period. METHODS: This retrospective cohort study enrolled 3115 subjects over 40 years of age who underwent baseline colonoscopies and had at least one repeated colonoscopy within 5 years. Each group was classified based on the endoscopic findings of the baseline colonoscopy: no neoplasia/diminutive polyp <5 mm (N/D); small adenoma <10 mm; advanced adenoma; invasive cancer, respectively. We examined the incidence of advanced neoplasia during these 5 years and investigated the relationship between the surveillance colonoscopy and newly detected advanced neoplasia. RESULTS: The small adenoma group did not show any significant increased risk as compared to the N/D group (hazard ratio [HR]: 0.799. 95% CI 0.442-1.443). There was a significantly increased risk in the advanced adenoma and invasive cancer groups (HR: 4.996, 95% CI 2.940-8.491, HR: 3.737, 95% CI 1.309-10.666). Cancer incidences during the study period were 0.18% in the N/D group, and 1.9% in the invasive cancer group, respectively. Undergoing surveillance colonoscopies twice within 5 years decreased the risk of advanced neoplasia. CONCLUSIONS: There was a close relationship between the endoscopic findings of baseline colonoscopies and subsequent advanced neoplasia development. Risk stratification for advanced neoplasia based on the baseline findings can serve as a useful index for determining the optimal interval and frequency of colonoscopies over a 5-year period.

Impact of retroflexion in the right colon after repeated forward-view examinations.

BACKGROUND AND AIM: Right colon polyps can especially be overlooked when they are located on the backs of haustral folds. Previous studies have reported that repeated forward-view examinations in the right colon were effective in reducing adenoma miss rates. The aim of this study was to clarify the impact of retroflexion in the right colon after repeated forward-view examinations. METHODS: This multicenter, prospective, observational study was conducted at three institutions in Kumamoto, Japan, between February 2014 and December 2015. Subjects who were over 40 years old and scheduled for colonoscopy were recruited. For the forward view, after cecal intubation, the colonoscope was withdrawn to the hepatic flexure. The colonoscope was sequentially reinserted to the cecum and then withdrawn to the hepatic flexure. For the retroflexion view (RV), the colonoscope was reinserted to the cecum, retroflexed, and then withdrawn to the hepatic flexure. All polyps were resected at the time of detection. The primary outcome of this study was the adenoma miss rate for the repeated forward-view examinations. RESULTS: Of the 777 enrolled participants, retroflexion was successful in 730 (94.0%). The repeated forward-view withdrawal technique detected 291 adenomas, while the third withdrawal in the RV detected 53. The adenoma miss rate for the repeated forward-view withdrawal was 15.4%. No severe adverse events occurred during retroflexion. CONCLUSION: Because adenomas located on potential blind spots can be missed when only using forward-view examinations, retroflexion in the right colon after repeated forward-view examinations might improve colonoscopy detection rates.

Relationship between frequency of surveillance colonoscopy and colorectal cancer prevention.

BACKGROUND AND AIM: The impact of frequent colonoscopy on colorectal cancer (CRC) remains unclear. The present study aimed to determine the relationship between frequency of surveillance colonoscopy and CRC prevention. METHODS: From April 2010 to April 2011, patients who underwent surveillance colonoscopy after screening and polypectomy in four Japanese endoscopy centers were enrolled in this multicenter historical cohort study. Patients were classified into the following two groups according to the findings of past colonoscopy: a low-risk group (no neoplasia or 1-2 cumulative adenomas <10 mm) and an increased-risk group (advanced adenoma or ≥ 3 cumulative adenomas). The relationship between colonoscopy frequency within the previous 5 years and the prevalence of advanced neoplasia in each group was analyzed using multiple logistic regression. RESULTS: The final analysis included 2391 patients. In the low-risk group, the odds ratios for advanced adenoma in patients undergoing moderately frequent colonoscopy (2-3 times within the previous 5 years), and frequent colonoscopy (≥ 4 times within 5 years) were 0.33 (95% confidence interval [CI], 0.14-0.81) and 0.21 (95% CI, 0.02-1.60), respectively, compared with infrequent colonoscopy (once or not at all within 5 years). In the increased-risk group, the respective odds ratios were 0.48 (95% CI, 0.28-0.83) and 0.28 (95% CI, 0.12-0.64). CONCLUSIONS: Although frequent colonoscopy provides benefits against advanced adenoma, the optimal benefit was achieved at 2-3 times. With very frequent colonoscopy (i.e. ≥ 4 times within 5 years), the additional risk reduction for advanced adenoma was relatively small.

Differentiation between sessile serrated adenoma/polyp and non-sessile serrated adenoma/polyp in large hyper plastic polyp: A Japanese collaborative study.

A hyperplastic polyp (HP) >10 mm is described as a large hyperplastic polyp (LHP). Previous studies have considered LHP and sessile serrated adenoma/polyp (SSA/P) as synonymous. Although HP and SSA/P have previously been morphologically distinguished, differences between LHP and SSA/P have not yet been reported. The present study aimed to define the differences between SSA/P and non-SSA/P in LHP using immunohistochemistry for Ki67. Colorectal serrated lesions (>10 mm) that were completely resected by endoscope and derived from 11 institutions in Japan [Dokkyo Medical University School of Medicine (Mibu), Takahiro Fujii Clinic (Tokyo), Sano Hospital (Kobe), Oda GI Clinic, Hattori GI Endoscopy and Oncology Clinic (Kumamoto), Ohta Clinic (Nagoya), Hiroshima University (Hiroshima), Iwate Medical University (Morioka), Juntendo and Kyorin Universities (Tokyo) as well as Toyama University (Toyama)] affiliated with the Japanese Society for Cancer of the Colon and Rectum (JSCCR) between January 2003 and December 2010 were selected. The histological criteria of the Japanese Society for Cancer of the Colon and Rectum (JSCCR, project meeting; editor-in chief, Takashi Yao) were used to distinguish SSA/P and non-SSA/P from LHP. Non-SSA/P comprises both incomplete SSA/P and HP. A total of 154 samples diagnosed as SSA/P or non-SSA/P from 148 patients were used. This study comprised 107 SSA/P and 47 non-SSA/P cases, whereby lesions were located on the right side of the colon (73.2 and 26.8%, respectively). Ki67-positivity in SSA/Ps was significantly higher compared to non-SSA/Ps. A greater number of SSA/Ps in LHP were located on the right side of the colon compared to the left side. SSA/Ps occurring on the right side of the colon may be precursor lesions of colorectal carcinoma in serrated neoplasia pathways. In conclusion, LHPs and SSA/Ps limited to the right side of the colon are suggested to be clinically treated as the same type of lesions.

Proportion of flat- and depressed-type and laterally spreading tumor among advanced colorectal neoplasia.

BACKGROUND & AIMS: Flat- and depressed-type neoplasias along with laterally spreading tumors (LSTs) have been reported in colorectal neoplasias. We estimated the prevalence of flat and depressed types and LSTs along with their proportion among advanced neoplasias in a large average-risk population undergoing screening colonoscopy. METHODS: This was a cross-sectional study performed at a single, general community institution, with subjects who were 40 to 79 years old, asymptomatic, and who had undergone their first colonoscopy for screening between 2003 and 2009 (n = 4910). Among the neoplasias detected, advanced neoplasias were morphologically classified as the polypoid type, flat and depressed type, or LST. We determined the prevalence and proportion for each type among the advanced neoplasias, with morphologies defined according to the Japanese endoscopic classification. RESULTS: Advanced neoplasias were detected in 7.9% of men, 4.7% of women, and 6.1% of overall subjects. The polypoid type, the flat and depressed types, and the LSTs accounted for 75.3%, 7.5%, and 17.2% of advanced neoplasia, respectively. There was a high proportion of T1 cancers among the depressed types (40%). Approximately 80% of LSTs were located on the right side of the colon and more than 30% of LSTs showed high-grade dysplasia or T1 cancer. CONCLUSIONS: Most advanced neoplasias detected were of the polypoid type. LSTs accounted for a considerable proportion among advanced neoplasia and tended to be located on the right side of the colon. The influences of any LSTs need to be taken into consideration for preventing colorectal cancer.

Five-year incidence of advanced neoplasia after initial colonoscopy in Japan: a multicenter retrospective cohort study.

OBJECTIVE: The National Polyp Study is used as the basis of recommendations for colonoscopic surveillance after polypectomy, establishing an interval of 3 years after removal of newly diagnosed adenomas. The aim of this retrospective cohort study was to estimate the incidence of advanced neoplasia after initial colonoscopy and compare the differences among risk groups. METHODS: Patients over 40 years who were referred for initial colonoscopy at six institutes were selected. They were classified into four groups based on the initial colonoscopy: A, patients without any adenoma; B, with adenomas of <6 mm only; C, with adenomas of >or=6 mm; D, with any intramucosal cancer. The index lesion (IL) at follow-up colonoscopy was defined as large adenoma >or=10 mm, intramucosal/invasive cancer. RESULTS: A total of 5309 patients were enrolled in this study. Overall, median follow-up period was 5.1 years. The numbers of eligible patients in the various subgroups were A, 2006; B, 1655; C, 1123; D, 525. A total of 379 ILs were newly diagnosed during follow-up colonoscopy. The cumulative incidence of ILs in each group was A, 2.6%; B, 6.7%; C, 13.4%; and D, 12.6%. CONCLUSIONS: Patients with any adenomas >6 mm or intramucosal cancer at the initial colonoscopy have a higher risk of advanced neoplasia during follow-up colonoscopy.

Proportion of de novo cancers among colorectal cancers in Japan.

BACKGROUND & AIMS: Adenomatous polyps are main precursors of colorectal cancers (CRCs). In Japan, de novo cancers, which do not arise from preexisting adenomas, are considered to account for a substantial number of CRCs, but the relative importance of de novo carcinogenesis remains controversial. This study estimated the proportion of de novo cancers among CRCs in Japan. METHODS: The subjects were persons 40-79 years of age who were relatively similar to those in the general population. The subjects underwent colonoscopy between 1997 and 2001. Early cancers among CRCs detected in this study were classified as de novo cancers or polyp cancers derived from adenomas. The age-specific incidence of the early CRCs was calculated, and the proportion of de novo cancers was estimated. The lifetime risk of early CRCs was estimated. RESULTS: The study group comprised 14,817 persons. CRCs were diagnosed in 189 subjects, including 83 early cancers. There were no differences with regard to size and location between de novo cancers and polyp cancers, but morphology differed. Eighty-four percent (16/19) of de novo cancers were flat elevated or depressed. The expected lifetime risk of developing early CRCs was 5.27% for men and 3.21% for women. Among persons with early cancers, the expected probabilities of developing de novo cancer were 18.6% for men, 27.4% for women. CONCLUSIONS: De novo cancers account for a considerable proportion in Japan. This information suggests that the recommended interval for colonoscopic examination in Japan should be shorter than that in the United States.

Expression of somatostatin receptor and effects of somatostatin analog on pancreatic endocrine tumors.

PURPOSE: Somatostatin analogs have been administered to patients with pancreatic endocrine tumors in an attempt to inhibit hormone hypersecretion and prevent tumor growth. It is speculated that their efficacy is correlated with the expression of specific subtypes of somatostatin receptors. The aim of this study was to immunohistochemically evaluate the expression of somatostatin receptor subtypes in human pancreatic endocrine tumors, and to determine whether the expression of these subtypes is correlated with the effectiveness of the somatostatin analogs. METHODS: Somatostatin receptor subtypes 1, 2, and 3 (sst 1, 2, and 3) were immunohistochemically investigated in seven pancreatic endocrine tumors: four insulinomas, one VIPoma, and two nonfunctioning tumors associated with multiple endocrine neoplasia type I, using paraffin sections. Three of the four patients with insulinoma were given an octreotide injection. RESULTS: Cells were homogeneously stained in the tumor region. More than 85% of the specimens expressed sst 1, 2, and 3. There was no difference among the immunohistochemical stainings of somatostatin receptor subtypes according to most tumor characteristics; however, the expression of sst 2 was extremely positive, and the expression of sst 3 was moderately positive in the specimen from a patient in whom the octreotide injection had proven very effective. CONCLUSION: These findings indicate that the efficacy of octreotide may be correlated with the density of sst 2 and 3 in an immunohistological study using paraffin sections.