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).

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.

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.

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.

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.

Rectal granular-cell tumor difficult to distinguish from carcinoid tumor.

A 60-year-old man had a positive fecal occult-blood test on a medical check-up. Colonoscopy revealed a yellowish-white submucosal tumor 8 mm in diameter in the rectum. Endoscopic ultrasonography showed a well-demarcated mass with a homogeneous, low-level, internal echo in the second to third layers of the rectal wall. A carcinoid tumor was suspected, and the mass was resected endoscopically. Histopathological examination revealed a granular-cell tumor. Gastrointestinal granular-cell tumors rarely arise in the rectum, and the preoperative diagnosis of small lesions is often difficult. In our patient, granular-cell tumor was difficult to differentially diagnose because the endoscopic and endoscopic ultrasonographic findings closely resembled those of carcinoid tumor. Interestingly, the endoscopic characteristics of the rectal granular-cell tumor in our patient resembled those of a carcinoid tumor.

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.

Mucosal remodeling in long-standing ulcerative colitis with colorectal neoplasia: significant alterations of NCAM+ or alpha-SMA+ subepithelial myofibroblasts and interstitial cells.

Evidence has been provided in ulcerative colitis (UC) that early genomic instability of both epithelial and stromal cells is important for colorectal tumorigenesis, as well as remodeling and morphological alterations of mucosal crypts. To clarify roles of stromal cells in tumor development in UC, the present study focused on heterogeneous phenotypes of subepithelial myofibroblasts and interstitial cells, in association with mucosal remodeling. To clarify the relationship of alterations to tumorigenesis, mucosa of resected rectae from patients with UC (n= 49) and sporadic cancer (n= 10) were analyzed on immunohistochemistry and also on immunoelectron microscopy. Heterogeneous phenotypes of neural cell adhesion molecule (NCAM)+ and/or alpha-smooth muscle actin (alpha-SMA)+ subepithelial myofibroblasts and interstitial cells were demonstrated, corresponding to colonic stellate cells. Decrease of NCAM+ subepithelial myofibroblasts and interstitial cells, and increase of alpha-SMA+ interstitial cells were significant in UC with neoplasia as compared to without neoplasia. alpha-SMA+ muscularis mucosae was significantly more thickened in tumor cases. Deposits of Masson's trichrome+ and type III and I collagen in the muscularis mucosae and lamina propria appeared to increase in relation to the numbers of alpha-SMA+ interstitial cells. Mucosal remodeling with alterations of NCAM+ or alpha-SMA+ subepithelial and interstitial cells may play a critical role in UC-associated tumorigenesis.

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.

Endoscopic and chromoendoscopic atlas featuring dysplastic lesions in surveillance colonoscopy for patients with long-standing ulcerative colitis.

Clinical and epidemiological studies have revealed that the incidence of colorectal cancer associated with ulcerative colitis increases with long-term chronic inflammation. Careful endoscopic observation and histological studies to check for dysplasia in the colon are important in detecting neoplasia. Current surveillance protocols mainly involve frequent step biopsies to yield a reasonable rate of dysplasia detection. However, recent studies using chromoendoscopy or magnifying endoscopy have proposed that neoplastic changes may be detected efficiently. Therefore, it is very important to understand the typical endoscopic findings found in neoplastic changes in patients proven to have long-standing ulcerative colitis. In this review, we demonstrate the typical endoscopic findings by conventional endoscopy and chromoendoscopy.

[Single-balloon enteroscopy].

Double-balloon enteroscope (DBE) requires a long preparation time and scope insertion is often confused because balloons have to be attached to both the endoscope and the overtube. Single-balloon enteroscope (SBE) is a new model endoscope produced by Olympus Medical Systems, and SBE does not require a balloon to be attached to the scope and has only sliding tube. Therefore, examination, preparations and scope insertion are easier than with DBE. SBE provides high-quality 'Q' type endoscopic images, and narrow-band-imaging can be performed. A prototype ultrasonic probe for SBE is now available. We underwent enteroscopy with SBE in 40 patients, and the total number of sessions was 50. Total enteroscopy was possible in 3 of 5 patients, in whom SBE was inserted deeply through both mouth and anus. There were no serious complications. This newly developed enteroscopy is useful for the diagnosis and treatment of small intestinal bleeding, intestinal stricture and protruding lesions. We believe that the single-balloon enteroscope will be more widely used clinically in the near future.

P21WAF1/CIP1 expression in colorectal carcinomas is related to Kras mutations and prognosis.

BACKGROUND/AIM: P21WAF1/CIP1 is a cyclin-dependent kinase inhibitor activated by p53 to produce cell cycle arrest. A consensus has not been reached concerning the prognostic value of p21WAF1/CIP1 expression in colorectal cancers. PATIENTS/METHODS: P21WAF1/CIP1 expression was determined immunohistochemically in a series of 211 cases of colorectal carcinomas, together with its relation to p53, bcl-2, cell turnover (as assessed by Ki67 expression and apoptotic counts) and the Kras gene status. The expression of p21WAF1/CIP1 was also compared with reference to clinicopathological parameters and patient survival. RESULTS: The median value for nuclear p21WAF1/CIP1 expression was 31% (interquartile range, 13-47%) and the fraction of cases considered to be high expressers (>20%) was 66%. Expression of p21WAF1/CIP1 was not associated with immunoreactivity for p53 or bcl-2, or cell turnover. P21WAF1/CIP1 high-expressing tumors were more often well differentiated (P<0.001), node-negative (P=0.037), Dukes' B (P=0.027) and Kras gene-mutated cases (P=0.04). On univariate analysis, low p21WAF1/CIP1 expressers (

Contribution of TIA-1+ and granzyme B+ cytotoxic T lymphocytes to cryptal apoptosis and ulceration in active inflammatory bowel disease.

In spite of the clinicopathological differences between Crohn's disease (CD) and ulcerative colitis (UC), they share the fundamental feature of destructive inflammatory processes involving the intestinal wall. The aim of the present study was to investigate the contribution of cell-mediated cytotoxicity to mucosal damage in CD and UC. Colonic mucosal biopsy specimens from patients with active CD (n=25) and UC (n=26) and normal controls (n=12) were immunohistochemically analyzed for the expression of CD3, CD4, CD8, and T cell-restricted intracellular antigen (TIA)-1, which promotes apoptosis by alternative splicing of pre-messenger RNA of the Fas receptor, and granzyme B (GrB), which leads to apoptosis through induction of perforin. Histological scores for cryptal apoptosis and ulceration were assessed in hematoxylin- and eosin-stained sections. In patients with CD and UC, CD3+(P<0.001), CD4+(P<0.001), CD8+(P<0.01), TIA-1+(CD, P<0.01; UC, P<0.001), and GrB+(CD, P<0.01; UC, P<0.001) intraepithelial lymphocytes (IELs) were significantly increased as compared with controls. Positive relationships were found between the histological scores for apoptosis or ulceration and the numbers of CD8+or TIA-1+IELs. In conclusion, cytotoxic T lymphocytes are present in increased numbers in the mucosa of patients with active CD and UC, and local activation of IELs may contribute to mucosal damage with these diseases.

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.

Comparative histologic assessment of proctocolectomy specimens from Japanese and American patients with ulcerative colitis with or without dysplasia.

There have been no reports of histologic differences in ulcerative colitis (UC) between Japanese and American patients. We therefore compared histology in proctocolectomy resection specimens between Japanese patients with UC (19 cases with and 21 without dysplasia) at the Kitasato University East Hospital and American patients with UC (21 cases with and 24 without dysplasia) at the University of Washington Medical Center. In cases of UC with, but not without dysplasia, cryptitis (p = 0.010) and epithelial apoptosis (p < 0.001) in the nondysplastic mucosa were more frequently observed in Japanese than in American cases, whereas lamina propria fibrosis was more prominent in American counterparts (p = 0.008). In patients with UC with dysplasia, the duration of disease was significantly longer in American than in Japanese patients (median, 17 vs 14 years, respectively; p = 0.038). This might, in part, explain the histologic variation. Another possibility for the differences is that the preoperative medications may have differed in the populations.

Venous invasion and down-regulation of p21(WAF1/CIP1) are associated with metastasis in colorectal carcinomas.

BACKGROUND/AIMS: Liver and lymph node metastasis the major prognostic factor in patients with colorectal carcinoma. The aim of this work was to search for tumor parameters which can be employed to predict whether this has occurred. METHODOLOGY: A total of 211 patients with a colorectal carcinoma (Dukes' B group, 83; Dukes' C, 94; Dukes' D, 34) were investigated for 10 clinicopathological variables, as well as apoptotic activity, expression of Ki-67, p21(WAF1/CIP1), p53, bcl-2 and DCC proteins, and the c-Ki-ras mutations. Data were analyzed by univariate and multivariate statistics. RESULTS: Lymph node metastasis-predictive models were developed using the venous involvement index (the number of vascular involvements per elastica van Gieson-stained slide; Odds ratio [OR], 2.38; 95% confidence interval [CI], 1.52-3.71; p=0.0001), tumor size (OR, 0.82; 95% CI, 0.70-0.97; p=0.0179), and p21(WAF1/CIP1) immunolabeled index (the percentages of positive tumor cells; OR, 0.76; 95% CI, 0.64-0.90; p=0.0011). Liver metastasis-predictive models were developed using the venous involvement index (OR, 2.40; 95% CI, 1.71-3.37; p=0.0000) and tumor location (rectum vs. colon; OR, 9.31; 95% CI, 2.41-36.01; p=0.0012). CONCLUSIONS: Down-regulation of p21(WAF1/CIP1) as well as marked venous involvement, small tumor size and colonic tumor are associated with lymph node and/or liver metastasis. Criteria for assessment of metastasis risk provide a basis for additional treatment guidelines.