Hypermethylation of the CDKN2/p16 promoter during neoplastic progression in Barrett's esophagus

Background & Aims: Inactivation of the CDKN2/p16^INK4A tumor-suppressor gene is one of the most frequent genetic alterations in human malignancies. In esophageal adenocarcinomas, mutations of the p16 gene or homozygous deletions of the gene locus 9p21 are rare. This study investigated whether p16 promoter hypermethylation is an alternative mechanism for p16 gene inactivation during neoplastic progression in Barrett's esophagus. Methods: A methylation-specific polymerase chain reaction protocol was applied. A total of 95 specimens from 14 patients with Barrett's esophagus were analyzed longitudinally. The p16 promoter status was compared with histomorphological findings. Results: p16 promoter hypermethylation was detected in 9 of the 10 patients who had displayed dysplasia at some time during surveillance, whereas none of the patients who had not displayed dysplasia during surveillance had p16 promoter hypermethylation. p16 promoter hypermethylation was detected in 3% (2 of 67) of the samples without dysplasia, 60% (3 of 5) of the samples with lesions indefinite for dysplasia, 55.6% (10 of 18) of the specimens with low-grade dysplasia, and 75% (3 of 4) of the specimens with high-grade dysplasia. Conclusions: These data suggest that p16 promoter hypermethylation is a common mechanism of p16 gene inactivation during neoplastic progression in Barrett's esophagus.GASTROENTEROLOGY 1998;115:1381-1386     

Different expressions of sialyl Tn antigen between polypoid and flat-type early colorectal cancers

PURPOSE: Sialyl Tn (STn) antigen is a cancer-associated carbohydrate antigen expressed in cancers of the digestive tract. We compared the proportion of specimens of flat-type colorectal cancers expressing STn with that of polypoid cancers, by examining the immunohistochemical reactivity of STn in various morphologic types of early and advanced colorectal cancers. METHODS; A total of 111 biopsies from the colorectal area were examined for STn expression, including 11 adenomas, 58 early cancers, and 42 advanced cancers. Each section was stained immunohistochemically for STn antigen. In each section, we examined STn expression in the cancer area, adjacent mucosa, and normal epithelium. RESULTS: STn expression was detected in 90.9 percent of adenomas, 36.2 percent of early cancers (T1), 64.3 percent of advanced cancers (>T1), and 52 percent of mucosa adjacent to cancer. The morphology of cancer tissue did not influence the number of specimens exhibiting STn antigen expression in mucosa adjacent to cancer cells. STn antigen was rarely expressed in flat or depressed-type early cancers (T1; 7.1 percent), and the expression was higher in moderately than in well-differentiated adenocarcinomas. In advanced cancers (>T1), a similar proportion of protruding and small ulcerative cancers expressed STn. CONCLUSION: Our results suggest that the low expression of STn antigen in flat-type cancers may be the result of different mechanisms of cellular transformation during carcinogenesis from the usual adenoma-carcinoma sequence in colorectal neoplasms.     

Neoplasia in the ileoanal pouch following colectomy in patients with ulcerative colitis and primary sclerosing cholangitis

Background & AimsPrimary sclerosing cholangitis (PSC) is typically associated with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC). PSC–IBD patients are at an increased risk for colorectal neoplasia. The ileal pouch-anal anastomosis (IPAA) is a treatment option for patients with medically refractory UC or neoplasia. However, little is known about the development of pouch neoplasia in PSC–UC patients following an IPAA. We aim to describe the incidence of pouch neoplasia in PSC–UC patients after an IPAA.MethodsWe conducted a retrospective chart review of patients with a confirmed diagnosis of PSC and IBD who underwent colectomy with IPAA followed by pouch surveillance between 1995 and 2012.ResultsSixty-five patients were included in the cohort and were followed up from the time of colectomy/IPAA for a median of 6 years. The most common indications for surgery were low-grade dysplasia (LGD) and refractory colitis. Only 3 patients developed evidence of neoplasia (LGD n = 1, high-grade dysplasia n = 1, adenocarcinoma n = 1). The cumulative 5-year incidence of pouch neoplasia was 5.6% (95% confidence intervals [CI], 1.8%–16.1%).ConclusionBased on our short-term follow-up, surveying the pouch frequently appears to be an unnecessary practice in PSC–IBD patients. Longer follow-up will be needed to develop an optimal surveillance strategy for the development of dysplasia and cancer in such patients.     

Differences in colonic disease activity in patients with ulcerative colitis with and without primary sclerosing cholangitis

PURPOSE: A small group of patients with ulcerative colitis (UC) also suffer from primary sclerosing cholangitis (PSC). Genetic and immunologic differences exist between UC patients with and without concomitant PSC. Furthermore, UC patients with PSC are more prone to developing colonic dysplasia/aneuploidy compared with patients with UC only. Because colonic disease activity and treatment with sulfasalazine have been found to be of independent importance for development of colonic carcinoma in UC, this study aims to determine if differences exist concerning colonic disease activity in UC patients with and without PSC. METHODS: Twenty-nine PSC patients with total colitis were matched to two UC patients with total colitis but without liver disease. Case records and questionnaires were used to gain information on pharmacologic treatment and disease activity. RESULTS: Observation time was 20 (PSC group) and 23 years (UC only). Number of patients taking prophylactic treatment did not differ between groups. Patients with UC only had received treatment with systemic and local corticosteroids significantly more often than UC patients with PSC (P < 0.05 and P < 0.02). Patients with UC only were hospitalized because of colonic activity significantly more often (P < 0.02). Number of patients undergoing colectomy because of disease activity or number of patients with chronic continuous symptoms did not differ between the two groups. CONCLUSION: UC in patients with PSC runs a milder course than UC in patients without this complication, although the number of patients taking prophylactic treatment was the same. If lower disease activity reflects differences in pathogenesis of UC in patients with PSC or if it can explain increased risk to develop colonic malignancy in patients with both PSC and UC needs further elucidation.Supported by grants from Nanna Svartz Scholarship, Stockholm, Sweden.     

Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study

BACKGROUND & AIMS: Although inflammation is presumed to contribute to colonic neoplasia in ulcerative colitis (UC), few studies have directly examined this relationship. Our aim was to determine whether severity of microscopic inflammation over time is an independent risk factor for neoplastic progression in UC. METHODS: A cohort of patients with UC undergoing regular endoscopic surveillance for dysplasia was studied. Degree of inflammation at each biopsy site had been graded as part of routine clinical care using a highly reproducible histologic activity index. Progression to neoplasia was analyzed in proportional hazards models with inflammation summarized in 3 different ways and each included as a time-changing covariate: (1) mean inflammatory score (IS-mean), (2) binary inflammatory score (IS-bin), and (3) maximum inflammatory score (IS-max). Potential confounders were analyzed in univariate testing and, when significant, in a multivariable model. RESULTS: Of 418 patients who met inclusion criteria, 15 progressed to advanced neoplasia (high-grade dysplasia or colorectal cancer), and 65 progressed to any neoplasia (low-grade dysplasia, high-grade dysplasia, or colorectal cancer). Univariate analysis demonstrated significant relationships between histologic inflammation over time and progression to advanced neoplasia (hazard ration (HR), 3.0; 95% CI: 1.4-6.3 for IS-mean; HR, 3.4; 95% CI: 1.1-10.4 for IS-bin; and HR, 2.2; 95% CI: 1.2-4.2 for IS-max). This association was maintained in multivariable proportional hazards analysis. CONCLUSIONS: The severity of microscopic inflammation over time is an independent risk factor for developing advanced colorectal neoplasia among patients with long-standing UC.     

Neoplastic progression in ulcerative colitis: histology, DNA content, and loss of a p53 allele.

Neoplastic progression in patients with chronic ulcerative colitis (UC) is characterized by the development of epithelial dysplasia, which is accompanied by genetic abnormalities that can be detected by flow cytometric and molecular biologic methods. Distribution of and correlation between histologic abnormalities, DNA content, and loss of heterozygosity for a p53 allele (p53 LOH) in the colons of nine UC patients were analyzed. Loss of a p53 allele was found in 85% (22/26) of biopsy specimens classified histologically as carcinoma, 63% (25/40) of biopsy specimens with high grade dysplasia, and 33% (7/21) of biopsy specimens with low grade dysplasia. Loss of heterozygosity for p53 was also found in 9% (5/57) of biopsy specimens indefinite for dysplasia and in 1/18 biopsy specimens negative for dysplasia, showing that this genetic change may occur early in the histological progression towards carcinoma. Aneuploid DNA contents were more common than p53 LOH in regions with negative, indefinite or low grade dysplastic histology; moreover, p53 LOH was detected only in aneuploid cells and not in diploid epithelium. Aneuploidy alone was not as specific a marker for the concomitant presence of dysplasia or carcinoma in a biopsy sample as aneuploidy combined with p53 LOH. These findings show that aneuploidy may precede both p53 LOH and epithelial dysplasia. Two UC patients' colons contained geographically separated clones of cells with different aneuploidies that also showed loss of different p53 alleles, suggesting that neoplasia may arise within different populations of cells in separate areas of the same colon.     

Cytomegalovirus infection in ulcerative colitis

Objective. Cytomegalovirus (CMV) infection has been reported as an exacerbating factor in inflammatory bowel disease but the relationship between CMV infection and ulcerative colitis (UC) remains unclear. There has been no detailed research to elucidate the clinicopathologic features of CMV infection in UC using surgical specimens. The aim of this study was to investigate the clinicopathologic features of CMV infection in UC patients who had undergone colectomy.

Material and methods. Surgical specimens taken from UC patients were examined for CMV infection. The patients were divided into three groups: severe, refractory, and UC-associated dysplasia or cancer according to the operative indications. CMV infection rates were evaluated and a comparison of clinical parameters was made between CMV-positive and CMV-negative patients, and the risk factors for CMV infection were analyzed using multivariate analyses.

Results. It was found that 25% of 32 patients were positive for CMV in the severe UC group; 8.3% of 72 patients were positive for CMV in the refractory UC group. None of the 22 patients was positive for CMV in the UC-associated dysplasia or cancer group. The CMV-positive rate in the severe UC group was significantly higher than that in the other groups (p<0.05). Patients’ age at the time of operation was higher in the CMV-positive group than in the CMV-negative group among the patients with severe UC (p<0.01), and age at operation was an independent risk factor for CMV infection.

Conclusions. CMV is found more frequently in severe UC than refractory UC and UC-associated cancer or dysplasia. Higher age can be a risk factor for CMV infection in patients with severe UC. However, a high steroid dose may not always be a risk factor for CMV infection.     

Chemoprevention of colorectal neoplasia in ulcerative colitis: the effect of 6-mercaptopurine.

BACKGROUND & AIMS: Evidence suggests that mesalamine-based anti-inflammatory medicines may prevent colorectal cancer (CRC) in ulcerative colitis (UC). If mesalamine exerts its chemopreventive effect by its anti-inflammatory activity, then other medications that reduce colitis activity also should possess chemopreventive properties. Our aim was to determine the effect of the immunomodulators 6-mercaptopurine (6MP) and azathioprine (AZA) in preventing the development of dysplasia or CRC in UC. METHODS: Patients with UC who underwent a surveillance colonoscopy in 1996-1997 were identified from a gastrointestinal pathology database. A proportional hazards analysis assessing 6MP/AZA use as a time-changing covariate was performed to evaluate the effect of 6MP/AZA on: (1) progression to any neoplasia (low-grade dysplasia, high-grade dysplasia, or CRC), and (2) progression to advanced neoplasia (high-grade dysplasia or CRC). RESULTS: A total of 315 subjects met inclusion criteria and were followed for an average of 8 years from their first surveillance examination. There were no significant differences in rates of progression to advanced neoplasia or to any neoplasia between 6MP/AZA users and never-users by log-rank testing. The proportional hazards analysis resulted in hazard ratios of 1.06 (95% confidence interval, .59-1.93) and 1.30 (95% confidence interval, .45-3.75) when considering the effect of exposure to 6MP/AZA on progression to any or to advanced neoplasia, respectively. The results were unaffected by known potential confounders. CONCLUSIONS: In UC patients with no initial history of dysplasia, 6MP/AZA use appears to have little or no effect on the rate of neoplastic transformation in the colon. Importantly, the use of 6MP/AZA did not increase malignant transformation in UC.     

High serum concentrations of sialyl Tn antigen in carcinomas of the biliary tract and pancreas

Sialyl-Tn (STn) antigen is a cancer-associated carbohydrate antigen expressed in cancers of the digestive tract. In the present study, we compared the serum level of STn antigen in 14 patients with benign diseases of the biliary tract and pancreas, 15 patients with bile duct cancers, and 9 patients with cancer of the pancreas. High levels of serum STn (>45 U/ml) were frequently detected in patients with carcinoma of the biliary tract (53.3%) or pancreas (55.6%), compared with the detection of high levels in those with benign diseases (14.3%;P < 0.05). Serum levels of STn did not correlate with the presence of jaundice, cholangitis, or pancreatitis, or with the level of carcinoembryonic antigen (CEA) or carbohydrate antigen (CA) 19–9. In cancer tissues, the expression of STn antigen detected by immunostaining correlated significantly with serum STn (P < 0.05). Our results indicate that measurement of serum STn level may be potentially useful for the diagnosis of carcinomas of the biliary tract and pancreas, particularly when combined with other tumor markers such as CEA or CA19-9.     

Dysplasie und Adenokarzinome im Ileum-Pouch nach restaurativer Proktokolektomie wegen Colitis ulcerosa

Purpose

Restorative proctocolectomy (RPC) is the standard surgical treatment for ulcerative colitis (UC). Restorative proctocolectomy is indicated for UC that is refractory to medical treatment, for emergency conditions, and in cases of neoplastic transformation. The procedure substantially reduces the risk of UC-associated dysplasia/neoplasia. However, after RPC surgery, even with mucosectomy, cancers of the pouch and/or the anal transitional zone (ATZ) have been reported with increasing frequency since the first report in 1984. This review highlights pouch-related dysplastic and neoplastic transformation, prevalence and adverse events, risk factors and surveillance following surgery for UC.

Patients and methods

Reports in the literature on patients undergoing pouch surgery at different institutions up to May 2010 were reviewed to identify patients who developed these complications, and an attempt was made to develop a rational follow-up policy based on the available data.

Results

To date, there have been 43 reported cancers of the pouch or inlet after RPC for UC: 16 from retrospective series, one from a prospective study, and 26 in case reports. A total of 30 patients underwent mucosectomy and 13 had stapled anastomoses. To date, 28 patients have been diagnosed with dysplasia after RPC for UC. Mucosectomy was performed in 27 of these and in one a stapled anastomosis was constructed without mucosectomy. In all cases reviewed, the time interval from the onset of UC to dysplasia/neoplasia was over 10 years.

Conclusions

Neoplastic lesions occurring in UC patients after RPC have been shown to be absolutely inevitable. Even mucosectomy does not completely eliminate the risk. There is little evidence to support routine biopsy of the ileal mucosa or the ATZ except in patients with histological type C changes, sclerosing cholangitis, and unremitting pouchitis in the ileal mucosa. Such patients should be selected for endoscopic surveillance to detect dysplasia preceding pouch adenocarcinoma.     

DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis.

The objective of the present study was to determine whether abnormal epithelial DNA content (aneuploidy) in colonic biopsy specimens from ulcerative colitis (UC) patients correlated with and predicted histological progression to dysplasia. Aneuploidy was absent in 20 low-cancer risk patients. In 81 high-cancer risk patients aneuploidy correlated significantly with the severity of histological abnormality (negative, indefinite, dysplasia, or cancer). Statistically our data suggest that many more biopsy specimens than are usually taken are needed to detect focal dysplastic lesions. Prospective study of 25 high risk patients without dysplasia revealed 5 with aneuploidy, all of whom progressed to dysplasia in 1-2.5 years, whereas 19 patients without aneuploidy did not progress to either aneuploidy or dysplasia within 2-9 years. Our data indicate that aneuploidy in mucosal biopsy specimens correlates with histological grade and identifies a subset of patients without dysplasia who are more likely to develop it. It was concluded that more frequent and extensive colonoscopic surveillance of this minority subset of high risk patients and less frequent surveillance in the remaining majority may reduce cost and detect more curable lesions.     

High-grade dysplastic adenoma-like mass lesions are not an indication for colectomy in patients with ulcerative colitis

Objective. The management of high-grade dysplasia (HGD) in polypoid lesions in patients with ulcerative colitis (UC) is not well characterized. The purpose of this study was to characterize the clinical course of patients with HGD in adenoma-like dysplasia-associated lesion or masses (DALMs) in the absence of any synchronous flat dysplasia. We hypothesize that colectomy is not warranted in patients who undergo complete excision of adenoma-like DALMs with HGD in UC. Material and methods. Pathology and clinical databases were systematically searched for the presence of dysplastic lesions in inflammatory bowel disease from 1997 to 2004. Patients with UC who had adenoma-like DALMs were identified, and a subset with HGD lesions was defined as our study cohort. Results. A total of 102 patients with UC were identified. Thirty of them (29%) had adenoma-like DALMs without synchronous flat dysplasia; 9 of these patients (30%) had HGD in these lesions. Thirty-two surveillance colonoscopies were performed in this cohort (mean 3.6 colonoscopies/patient). The patients were followed for a mean of 76.5 months (52–99 months). Three out of 9 patients (33%) had colectomy. None of the patients in this cohort was detected to have carcinoma in surveillance biopsies and/or in the resection specimens. Conclusions. Our data suggest that the presence of HGD in DALMs does not warrant colectomy. Continued close observation is suggested in this patient cohort after complete excision of polyps. Further prospective evaluation of this patient population is merited.     

Temporal trends in colon neoplasms in patients with primary sclerosing cholangitis and ulcerative colitis

Background and aimSurveillance for colon cancer is recommended in patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC). It is unclear whether characteristics of colon neoplasia have changed over time. The aim of the study was to examine the temporal trends in colon neoplasia in patients with PSC and UC.MethodsA total of 167 patients followed up at our institution between 1985 and 2011, 55 of these with neoplasia detected on colonoscopic biopsy were identified. Characteristics of patients with colon neoplasia in PSC–UC were studied for two different time periods: 1985–1998 (early cohort) compared to 1999–2011 (recent cohort).ResultsThe median age at diagnosis of colon neoplasms was 53 years (median IQR, 43–63). The baseline characteristics were similar in both cohorts. The colonic neoplasms that developed in PSC–UC patients were spread throughout the colon on colonoscopy, while there was predominant right sided distribution on colectomy in both cohorts. (81.7% vs. 18.3%, p < 0.001) Compared to the recent cohort, both the PSC (17 vs. 11 years, p = 0.02) and UC duration (20 vs. 12 years, p = 0.02) were longer in the early cohort. There were no differences in the grades and stages of cancer diagnosis. In addition, no differences in transplant-free survival or UC characteristics were revealed.ConclusionsWith annual colonoscopic surveillance, dysplasia and cancer in patients with a combined diagnosis of PSC//UC is being diagnosed in patients with a shorter duration of these conditions. The nature and the location of neoplasia have, however, not changed.     

The sharp decline of beta estrogen receptors expression in long-lasting ulcerative-associated carcinoma

Abstract

Objective. Colorectal carcinoma is an important cause of death in inflammatory bowel diseases, thus requiring surveillance for dysplasia in long-standing ulcerative colitis (UC). Females show a lower incidence probably related to hormonal factors; therefore, a role of estrogen receptors (ERs) has been supposed in carcinoma-associated colitis (CAC) development. Our aim was to identify ER beta/alpha expression in long-lasting pancolitis through each grade of dysplasia to carcinoma and, furthermore, to investigate the simultaneous epithelial apoptosis/proliferation. Materials and methods. Forty-eight patients affected by long-lasting pancolitis were retrospectively investigated. Samples were divided into four groups: UC, low-grade dysplasia/high-grade dysplasia (UC-HGD), and CAC. Normal colon samples were used as controls. ER-beta, ER-alpha, Ki-67, and TUNEL expression (labeling/H index) were evaluated by immunohistochemistry. Results. ER-beta expression revealed an impressive reduction in CAC (10.4 ± 5.1; p < 0.001) compared to controls and UC (34.3 ± 3.1 and 26.8 ± 7.8, respectively), meanwhile ER-beta level in LGD (29.4 ± 3.7) was comparable to UC. As far ER-beta/ER-alpha mean value ratio revealed a progressive reduction. Ki67 demonstrated a progressive significant increase from UC until CAC (37.9 ± 6.4 < 45.7 ± 6.2 < 60.6 ± 5.2 < 71.1 ± 5.1; p < 0.001). Apoptotic index (TUNEL) revealed a strong fall in UC-HGD and CAC. Conclusions. ER-beta fall could be considered as a biomarker of UC-dysplasia progression. It occurs in HGD and overt neoplasia, while in LGD shows a normal expression. At the moment, we are unable to use this tool in the clinical practice to predict tumor progression, but it would be appropriate to encourage ER expression investigations in large samples for the interesting perspectives of application.     

Deregulated expression of Nucleophosmin 1 in gastric cancer and its clinicopathological implications

Background

Ulcerative colitis (UC) is a chronic, inflammatory bowel disease which may lead to dysplasia and adenocarcinoma in patients when long-lasting. Short telomeres have been reported in mucosal cells of UC patients. Telomeres are repetitive base sequences capping the ends of linear chromosomes, and protect them from erosion and subsequent wrongful recombination and end-to-end joining during cell division. Short telomeres are associated with the development of chromosomal instability and aneuploidy, the latter being risk factors for development of dysplasia and cancer. Specifically, the abrupt shortening of one or more telomeres to a critical length, rather than bulk shortening of telomeres, seems to be associated with chromosomal instability.

Methods

We investigated possible associations between dysplasia, aneuploidy and telomere status in a total of eight lesions from each of ten progressors and four nonprogressors suffering from longstanding UC. We have analyzed mean telomere length by qPCR, as well as the amount of ultra-short telomeres by the Universal STELA method.

Results

An increased amount of ultra-short telomeres, as well as general shortening of mean telomere length are significantly associated with dysplasia in longstanding UC. Furthermore, levels of ultra-short telomeres are also significantly increased in progressors (colons harbouring cancer/dysplasia and/or aneuploidy) compared to nonprogressors (without cancer/dysplasia/aneuploidy), whereas general shortening of telomeres did not show such associations.

Conclusions

Our data suggest that ultra-short telomeres may be more tightly linked to colorectal carcinogenesis through development of dysplasia in UC than general telomere shortening. Telomere status was not seen to associate with DNA aneuploidy.     

Hypermethylation of p14 (ARF) may be predictive of colitic cancer in patients with ulcerative colitis

Purpose The microsatellite instability and CpG island hypermethylation of p14 ^ARF and p16 ^INK4a are related to the pathogenesis of neoplasia in ulcerative colitis. This study was designed to assess the significance of those genetic or epigenetic alterations for cancer surveillance in ulcerative colitis. Methods During surveillance colonoscopy in 39 patients with ulcerative colitis, biopsy specimens were obtained from the cecum and the rectum as well as from any other areas suspected of being neoplasia by chromoscopy. Using DNA extracts, the methylation status of p14 ^ARF and p16 ^INK4a and the microsatellite status were determined. Results Microsatellite instability was positive in one of five dysplasias, but it was negative in the cecum and the rectum. The incidence of hypermethylation of p14 ^ARF was 0 percent in the cecum, 26 percent in the rectum, and 100 percent in dysplasia, whereas that of p16 ^INK4a was 10, 10, and 0 percent, respectively. Patients who were positive for the hypermethylation of p14 ^ARF in the rectum had a longer duration of ulcerative colitis than those who were negative for such hypermethylation. Two of 10 patients who were positive for p14 ^ARF hypermethylation in the rectum and 1 of 29 patients who were negative for the hypermethylation had dysplasia. During the subsequent surveillance of 36 patients, dysplasia was detected in 2 of 8 patients with p14 ^ARF hypermethylation and in none of 28 patients without hypermethylation (P = 0.044). Conclusions In patients with ulcerative colitis, hypermethylation of p14 ^ARF seems to be associated with an early stage of dysplasia. The hypermethylation may be one of candidates for potential biomarker to identify patients at a high risk of dysplasia.     

肠上皮细胞DNA含量变化与炎症性肠病癌变相关性的研究

目的 探讨肠黏膜上皮细胞DNA含量和p53蛋白表达状态与炎症性肠病（IBD）癌变的关系.方法 选择83例炎症性肠病患者库存活检样本,其病理诊断分别为低度异常增生、高度异常增生的癌前病变（pre-CRC组）和结直肠腺癌（CRC组）,配对选取144例仅有炎症而无异常增生或癌变的样本（no-CRC组）作为对照,分别用流式细胞技术和免疫组化技术检测样本中的DNA倍体状态和肠上皮细胞p53蛋白的表达.DNA指数＞1.35为异倍体,p53阳性细胞＞15%为阳性.结果 DNA异倍体在pre-CRC的克罗恩病和溃疡性结肠炎组分别为52.6%和57.8%,肿瘤组为80%和100%,显著高于no-CRC的3.2%和7.3%（P＜0.001）;p53突变型在pre-CRC的克罗恩病和溃疡性结肠炎组分别为36.7%和42.1%,肿瘤组为80%和100%,明显高于no-CRC的8.1%和9.7%（P＜0.01）.结论 DNA异倍体和突变型p53的表达不仅在炎症性肠病相关的结直肠癌肠黏膜上皮细胞中,而且在炎症性肠病的癌前病变的异常增生阶段即有明显增加,提示此两个生物标志物与炎症性肠病癌变密切相关,有可能用于辅助内镜监测,预测癌症风险.     

The expression of matrix metalloproteinase matrilysin indicates the degree of inflammation in ulcerative colitis

Background: Any alteration in the synthesis and breakdown of the extracellular matrix is important in tissue remodeling during inflammation and wound healing. The degradation of the extracellular matrix components is regulated by a cascade of matrix metalloproteinases (MMPs). The present study attempted to assess the relationship between MMPs and the degree of inflammation in ulcerative colitis. Methods: The expression of MMPs, including MMP-1, -2, -3, -7 (matrilysin), and -9, and that of their inhibitors (tissue inhibitor of metalloproteinases [TIMP]-1 and -2) were analyzed immunohistochemically by using 52 formalin-fixed and paraffin-embedded specimens from patients with ulcerative colitis who had undergone a biopsy or surgery. Results: It was observed that MMP-1, -2, and -9, and the TIMPs were expressed in stromal cells, MMP-3 was expressed in both the epithelial cells and stromal components, and matrilysin was expressed only in the epithelial cells on the edge of ulcers. The expression of the MMPs was increased compared with that of the TIMPs. The frequency of matrilysin expression was increased corresponding to the severity of the inflammation. Matrilysin was also expressed in epithelial cells with dysplasia and cancer. Conclusions: Matrilysin expression could be an important marker of activity and could be used for the prediction of subsequent transformation in patients with ulcerative colitis. Received: May 7, 2002 / Accepted: September 6, 2002 Acknowledgments. This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (F.I. and K.I.) and from the Ministry of Health, Labour, and Welfare of Japan (F.I. and K.I.). Reprint requests to: Y. Adachi Editorial on page 412