Risk of colorectal cancer among fecal immunochemical test-positive individuals by timing of previous colonoscopy: A multicenter analysis.

BACKGROUND AND AIM: The risk of colorectal cancer among fecal immunochemistry test-positive individuals who had undergone previous colonoscopies remains unclear. Therefore, this study aimed to determine the differences in the risk of colorectal cancer among fecal immunochemistry test-positive individuals according to the timing of their previous colonoscopies. METHODS: This multicenter, retrospective, observational study was conducted in Japan as a subgroup analysis of the J-SCOUT study (UMIN000040690), which integrated and analyzed a database comprising all colonoscopies performed at participating Japanese institutions between 2010 and 2020. This study used colonoscopy data of fecal immunochemistry test-positive individuals aged ≥ 20 years from three facilities that entered the timing of previous colonoscopies into the endoscopy database. Histologically confirmed advanced neoplasia was the study's primary outcome. Multivariate logistic regression analysis was used to calculate the odds ratios for each variable. RESULTS: In total, 11,143 fecal immunochemistry test-positive patients underwent colonoscopy during the study period. Of these, 10,160 patients were included in the analysis after excluding those who met the exclusion criteria. The overall advanced neoplasia detection rate was 9.38% (953/10,160; 95% confidence interval: 8.82-9.96%). Compared with the first colonoscopy, the odds ratios for advanced neoplasia in individuals who underwent colonoscopies 1, 2, 3, 4, 5, > 5, and ≥ 10 years previously were 0.27, 0.15, 0.06, 0.10, 0.29, 0.31, and 0.31, respectively. CONCLUSIONS: The detection rates of advanced neoplasia were low among the fecal immunochemistry test-positive individuals who had undergone colonoscopy, particularly in the past 5 years.

Colorectal Neuroendocrine Neoplasm Detection Rate During Colonoscopy: Results From Large-Scale Data of Colonoscopies in Japan.

INTRODUCTION: This study investigated the detection rate of colorectal neuroendocrine neoplasms (NENs) using large-scale colonoscopy data. METHODS: This cross-sectional analysis used large-scale data from a Japanese multicenter observational study of colonoscopies performed from 2010 to 2020. RESULTS: Among 82,005 colonoscopy cases, colorectal NENs were identified in 71 (67 of which were neuroendocrine tumors), with a detection rate of 0.087% (95% confidence interval: 0.069-0.109). Most were small rectal lesions, with only 4 >10 mm in size and 3 located in the colon. DISCUSSION: The detection rate of colorectal NENs during colonoscopy is substantially higher than expected.

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.

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.

Expression of CA2 and CA9 carbonic anhydrases in ulcerative colitis and ulcerative colitis-associated colorectal cancer.

Ulcerative colitis (UC) is characterized by chronic inflammation in the colonic mucosa and submucosa with repeating relapse and remission, but the pathogenesis is unknown. Patients with long-standing UC are at high risk of neoplasm development. The aim of the present study was to identify molecules whose expression is associated with UC and UC-associated colorectal cancer (UCCA). Biopsy specimens from UC and normal colonic mucosae were analyzed using a proteomics approach, in which carbonic anhydrase 2 (CA2) was identified as a molecule downregulated in UC mucosae. Immunohistochemically, CA2 expression was detected in normal and diverticulitis mucosal epithelia, and its expression decreased as UC activity increased. CA2 expression was almost undetectable in UCCA. We also analyzed the expression of another carbonic anhydrase, CA9, and its upstream molecule, hypoxia-inducible factor-1α (HIF-1α), both of which are induced under hypoxic conditions. It was revealed that CA9 expression was relatively low in normal, diverticulitis and UC mucosae, and was upregulated in UCCA. HIF-1α expression was consistently low in all tissue types examined. In conclusion, these results suggest that CA2 and CA9 may be possible indicators of UC activity and UCCA development, respectively.

Predictors of invasive cancer of large laterally spreading colorectal tumors: A multicenter study in Japan.

BACKGROUND AND AIM: Although colorectal laterally spreading tumors (LSTs) can be classified into four subtypes, the histopathological characteristics are known to differ among these subtypes. We therefore performed a logistic regression analysis to determine whether the risk of pathological T1 cancer of large colorectal LSTs can be predicted based on factors such as endoscopic findings in a large group of patients enrolled in a multicenter study in Japan. METHODS: In the main study, we assessed 1236 colorectal adenomas or early cancers that were classified as LSTs measuring 20 mm or more in diameter and treated endoscopically. Logistic regression analysis was performed to determine whether factors such as the subtype of LST could be used to predict the risk of pathological T1 cancer. A validation study of 356 large colorectal LSTs was conducted to confirm the validity of the results obtained in the main study. RESULTS: The locations and tumor diameter of the LSTs in the main study were found to differ significantly according to the LST subclassification (P < 0.001). The frequency of pathological T1 cancers was the highest at 36% of LST nongranular pseudodepressed type, followed by 14% of LST nongranular flat-elevated type, 11% of LST granular nodular mixed type, and 3% of LST granular homogenous type lesions. The risk of pathological T1 cancer was significantly associated with LST subclassification and tumor diameter. The area under the curve (AUC) was high (0.743). In the validation study, the AUC was 0.573. CONCLUSIONS: In patients with large colorectal LSTs resected endoscopically, the risk of pathological T1 cancer can be predicted on the basis of the LST subclassification and tumor diameter.

Comparison of the histopathological characteristics of large colorectal laterally spreading tumors according to growth pattern.

OBJECTIVES: Colorectal laterally spreading tumors (LSTs) are widely recognized owing to their structural characteristics. This study aims to clarify the histopathological characteristics of large colorectal LSTs according to growth pattern. METHODS: We studied 297 colorectal LSTs measuring ≥20 mm in diameter. The LSTs were classified into four types: granular homogenous type (LST-G-H), granular nodular mixed type (LST-G-M), non-granular flat elevated type (LST-NG-F), and non-granular pseudo-depressed type (LST-NG-PD). Retrospectively collected data were examined to compare the histopathological characteristics of LSTs according to the growth pattern. RESULTS: LST-G-M lesions (142 lesions) were most common, followed by LST-NG-F (74 lesions), LST-G-H (61 lesions), and LST-NG-PD (20 lesions). The mean tumor diameter of LST-G lesions (38.5 ± 17.2 mm) was significantly greater than that of LST-NG lesions (26.3 ± 7.0 mm, P < 0.001). In particular, 45% of LST-G-M lesions were ≥40 mm in diameter. Adenomas accounted for 54% of LST-G-H lesions compared with only 10% of LST-NG-PD lesions. Pathological T1 carcinomas accounted for 55% of LST-NG-PD lesions and were not found among LST-G-H lesions. CONCLUSIONS: The biological malignancy of colorectal LSTs differs considerably depending on the growth pattern even among large lesions and therefore should be considered when selecting treatment regimens.

Roles of Capsule Endoscopy and Single-Balloon Enteroscopy in Diagnosing Unexplained Gastrointestinal Bleeding.

BACKGROUND/AIMS: The diagnostic algorithms used for selecting patients with obscure gastrointestinal bleeding (OGIB) for capsule endoscopy (CE) or balloon-assisted enteroscopy (BE) vary among facilities. We aimed to demonstrate the appropriate selection criteria of CE and single balloon-assisted enteroscopy (SBE) for patients with OGIB according to their conditions, by retrospectively comparing the diagnostic performances of CE and BE for detecting the source of the OGIB. METHODS: We investigated 194 patients who underwent CE and/or BE. The rate of positive findings, details of the findings, accidental symptoms, and hemostasis methods were examined and analyzed. RESULTS: CE and SBE were performed in 103 and 91 patients, respectively, and 26 patients underwent both examinations. The rate of positive findings was significantly higher with SBE (73.6%) than with CE (47.5%, p<0.01). The rate of positive findings was higher in overt bleeding cases than in occult bleeding cases for both BE and SBE. Among the overt bleeding cases, the rate was significantly higher in ongoing bleeding cases than in previous bleeding cases. CONCLUSIONS: Both CE and SBE are useful to diagnose OGIB. For overt bleeding cases and ongoing bleeding cases, SBE may be more appropriate than CE because endoscopic diagnosis and treatment can be completed simultaneously.

Clinical usefulness of endoscopic ultrasonography for the evaluation of ulcerative colitis-associated tumors.

AIM: To evaluate the clinical usefulness of endoscopic ultrasonography (EUS) for the diagnosis of the invasion depth of ulcerative colitis-associated tumors. METHODS: The study group comprised 13 patients with 16 ulcerative colitis (UC)-associated tumors for which the depth of invasion was preoperatively estimated by EUS. The lesions were then resected endoscopically or by surgical colectomy and were examined histopathologically. The mean age of the subjects was 48.2 ± 17.1 years, and the mean duration of UC was 15.8 ± 8.3 years. Two lesions were treated by endoscopic resection and the other 14 lesions by surgical colectomy. The depth of invasion of UC-associated tumors was estimated by EUS using an ultrasonic probe and was evaluated on the basis of the deepest layer with narrowing or rupture of the colonic wall. RESULTS: The diagnosis of UC-associated tumors by EUS was carcinoma for 13 lesions and dysplasia for 3 lesions. The invasion depth of the carcinomas was intramucosal for 8 lesions, submucosal for 2, the muscularis propria for 2, and subserosal for 1. Eleven (69%) of the 16 lesions arose in the rectum. The macroscopic appearance was the laterally spreading tumor-non-granular type for 4 lesions, sessile type for 4, laterally spreading tumor-granular type for 3, semi-pedunculated type (Isp) for 2, type 1 for 2, and type 3 for 1. The depth of invasion was correctly estimated by EUS for 15 lesions (94%) but was misdiagnosed as intramucosal for 1 carcinoma with high-grade submucosal invasion. The 2 lesions treated by endoscopic resection were intramucosal carcinoma and dysplasia, and both were diagnosed as intramucosal lesions by EUS. CONCLUSION: EUS provides a good estimation of the invasion depth of UC-associated tumors and may thus facilitate the selection of treatment.

Diagnostic performance of EUS for evaluating the invasion depth of early colorectal cancers.

BACKGROUND: EUS is one technique used to estimate the invasion depth of early colorectal cancer (CRC), but its diagnostic accuracy remains a matter of debate. OBJECTIVE: To assess the accuracy of EUS for estimating the invasion depth of early CRC. DESIGN: Retrospective analysis. SETTING: Tertiary-care academic medical center. PATIENTS: The invasion depth of early CRC was estimated by EUS from 1989 through 2012. INTERVENTIONS EUS MAIN OUTCOME MEASUREMENTS: Accuracy of EUS diagnosis, risk factors for misdiagnosis, and characteristics of lesions that were difficult to image. RESULTS: We estimated the invasion depth of 714 cases of early CRC on EUS. Of the lesions able to be visualized on EUS, the overall diagnostic accuracy of EUS for differentiating between lesions that could be resected endoscopically (Tis and T1a cancers), and those that required colectomy (T1b cancers) was 89%. Submucosal cancer and a macroscopic classification of superficial type were independent risk factors for misdiagnosis. Ninety lesions (13%) were difficult to image. Risk factors for difficulty in imaging were protruding-type morphology and tumor location in the sigmoid colon or from the descending colon to the cecum. LIMITATIONS: Single center, retrospective. Experienced endoscopists performed EUS. CONCLUSIONS: Although some lesions that were protruding or located in the proximal colon were difficult to visualize, EUS is considered a useful technique for the diagnosis of invasion depth and the selection of treatment in patients with early CRC.

Clinical Study of the Relation between Mucosal Healing and Long-Term Outcomes in Ulcerative Colitis.

Background and Objectives. Mucosal healing (MH) is considered an important therapeutic goal in ulcerative colitis (UC). We evaluate the severity of intestinal inflammation and clarify the relation between MH and long-term outcomes. Methods. The study group comprised 38 patients with UC in clinical remission on total colonoscopy who were followed up for at least 5 years. Clinical remission was defined as a Mayo score of 0 for both stool frequency and rectal bleeding. Colonoscopic findings were evaluated into 4 grades according to the Mayo endoscopic subscore (MES). Results. During clinical remission, the MES was 0 in only 24% of the patients, 1 in 40%, 2 in 26%, and 3 in 10%. Seventy-six percent of the patients thus had active disease on colonoscopy. After initial colonoscopy, the cumulative rate of remission maintenance was 100% in MES 0, 1 in 93%, 2 in 70%, and 3 in 50% at 6 months and 78%, 40%, 10%, and 0%, respectively, at 5 years (P < 0.001). Conclusion. Many patients with UC in clinical remission have active lesions. Patients with a higher MES have a higher rate of recurrence. To improve long-term outcomes, an MES of 0 should be the treatment goal.

Clinical usefulness of single-balloon endoscopy in patients with previously incomplete colonoscopy.

AIM: To evaluate the clinical usefulness of single-balloon endoscopy (SBE) in patients in whom a colonoscope was technically difficult to insert previously. METHODS: The study group comprised 15 patients (8 men and 7 women) who underwent SBE for colonoscopy (30 sessions). The number of SBE sessions was 1 in 7 patients, 2 in 5 patients, 3 in 1 patient, 4 in 1 patient, and 6 in 1 patient. In all patients, total colonoscopy was previously unsuccessful. The reasons for difficulty in scope passage were an elongated colon in 6 patients, severe intestinal adhesions after open surgery in 4, an elongated colon and severe intestinal adhesions in 2, a left inguinal hernia in 2, and multiple diverticulosis of the sigmoid colon in 1. Three endoscopists were responsible for SBE. The technique for inserting SBE in the colon was basically similar to that in the small intestine. The effectiveness of SBE was assessed on the basis of the success rate of total colonoscopy and the presence or absence of complications. We also evaluated the diagnostic and treatment outcomes of colonoscopic examinations with SBE. RESULTS: Total colonoscopy was successfully accomplished in all sessions. The mean insertion time to the cecum was 22.9 ± 8.9 min (range 9 to 40). Abnormalities were found during 21 sessions of SBE. The most common abnormality was colorectal polyps (20 sessions), followed by radiation colitis (3 sessions) and diverticular disease of the colon (3 sessions). Colorectal polyps were resected endoscopically in 15 sessions. A total of 42 polyps were resected endoscopically, using snare polypectomy in 32 lesions, hot biopsy in 7 lesions, and endoscopic mucosal resection in 3 lesions. Fifty-six colorectal polyps were newly diagnosed on colonoscopic examination with SBE. Histopathologically, these lesions included 2 intramucosal cancers, 42 tubular adenomas, and 2 tubulovillous adenomas. The mean examination time was 48.2 ± 20.0 min (range 25 to 90). Colonoscopic examination or endoscopic treatment with SBE was not associated with any serious complications. CONCLUSION: SBE is a useful and safe procedure in patients in whom a colonoscope is technically difficult to insert.

Comparison of diagnostic accuracies of various endoscopic examination techniques for evaluating the invasion depth of colorectal tumors.

This study was designed to assess the clinical value of magnifying endoscopy combined with EUS for estimating the invasion depth of colorectal tumors. We studied 168 colorectal adenomas and carcinomas that were sequentially examined by conventional endoscopy followed by magnifying endoscopy and EUS in the same session to evaluate invasion depth. Endoscopic images obtained by each technique were reassessed by 3 endoscopists to determine whether endoscopic resection (adenoma, mucosal cancer, or submucosal cancer with slight invasion) or colectomy (submucosal cancer with massive invasion or advanced cancer) was indicated. The accuracy of differential diagnosis was compared among the examination techniques. The rate of correct differential diagnosis according to endoscopic examination technique was similar. The proportion of lesions that were difficult to diagnose was significantly higher for EUS (15.5%) than for conventional endoscopy and magnifying endoscopy. Among lesions that could be diagnosed, the rate of correct differential diagnosis was the highest for EUS (89.4%), but did not significantly differ among three endoscopic examination techniques. When it is difficult to evaluate the invasion depth of colorectal tumors on conventional endoscopy alone, the combined use of different examination techniques such as EUS may enhance diagnostic accuracy in some lesions.

Cytoglobin expression of rectal subepithelial myofibroblasts: significant alterations of cytoglobin+ stromal cells in long-standing ulcerative colitis.

Cytoglobin/stellate cell activation-associated protein (Cygb/STAP), a hemoprotein, functions as part of an O2 reservoir with protective effects against oxidative stress in hepatic stellate cells. Heterogeneous expression of the neural cell adhesion molecule (NCAM)+ and/or α-smooth muscle actin (αSMA)+ has been noted in subepithelial myofibroblasts and interstitial cells of the same lineage in the colorectum. We have demonstrated that early genomic instability of both epithelial and stromal cells in ulcerative colitis (UC) is important for colorectal tumorigenesis, as well as for mucosal remodeling. To further clarify possible roles of stromal cells in mucosal remodeling and tumor development in UC, we here focused on Cygb expression of subepithelial myofibroblasts and interstitial cells, as well as αSMA and HSP47. Noncancerous mucosa of resected rectae from UC patients with or without colorectal neoplasia (14 and 20 cases, respectively) and of sporadic rectal cancer cases (16) was analyzed immunohistochemically, as well as by immuno-fluorescence and electron microscopy. The results, heterogeneous phenotypes of Cygb+, αSMA+ and HSP47+ subepithelial myofibroblasts and interstitial cells, corresponding to rectal stellate cells, were demonstrated. A decrease of Cygb+ subepithelial myofibroblasts and an increase of αSMA+ interstitial cells were significant in UC, as compared to normal rectal mucosa. Furthermore, a decrease of Cygb+ subepithelial myofibroblasts, correlating with αSMA+ and HSP47+ cells, was significant in long-standing UC with neoplasia. In conclusion, there are heterogeneous phenotypes of Cygb+, αSMA+ and HSP47+ subepithelial myofibroblasts and interstitial cells in the rectal mucosa. Mucosal remodeling with alterations of Cygb+ and/or αSMA+/HSP47+ stromal cells might have some relation to UC-associated tumorigenesis.

Submucosal fibrosis and basic-fibroblast growth factor-positive neutrophils correlate with colonic stenosis in cases of ulcerative colitis.

BACKGROUND AND AIMS: The frequency of benign stenosis in ulcerative colitis (UC) is low, reported as being 3.2-11.2%, with fibrosis in the submucosa or deeper pointed out as one of the causes. The aim of the present study was to assess stenosis in UC cases using immunostaining and to analyze differences between stenotic and nonstenotic cases, focusing on basic-fibroblast growth factor (b-FGF) expression and myofibroblasts. METHODS: Totals of 9 stenotic and 17 nonstenotic UC cases were histopathologically examined and immunohistochemically stained for b-FGF, α-smooth muscle actin (α-SMA), CD34, CD68 and IL-6. To identify b-FGF-positive cells, double immunostaining for b-FGF and myeloperoxidase or CD68 was performed. RESULTS: In addition to submucosal fibrosis, a significant increase of b-FGF-positive inflammatory cells and myofibroblasts was observed in stenotic portions. Most b-FGF-positive cells were also positive for myeloperoxidase, and a correlation between b-FGF-positive and total neutrophil counts was found. CONCLUSIONS: One of the major causes of stenosis in long-standing UC is fibrosis in the bowel wall, possibly induced by infiltrating inflammatory neutrophils producing b-FGF.