溃疡性结肠炎相关性结直肠癌研究进展

溃疡性结肠炎（UC）是一种病因未明、以结肠直肠黏膜弥漫性炎性损害为特征的慢性非特异性肠道炎性疾病。病程迁延不愈,复发率高,典型特征为反复发作的腹泻、腹痛及黏液脓血便,长期炎症可出现多种并发症。溃疡性结肠炎相关性结直肠癌（UC—CRC）是溃疡性结肠炎严重并发症之一。     

溃疡性结肠炎癌变相关机制研究进展

炎症性肠病(inflammatory bowel disease, IBD)包括溃疡性结肠炎(ulcerative colitis, UC)的发病率在我国呈逐渐升高的趋势。随着诊治水平的进展,长病程的UC患者逐渐增多,发生结直肠癌(colorectal cancer, CRC)的风险明显增加。UC癌变的危险因素主要包括长病程、广泛肠段受累、累积炎症负担(cumulative inflammatory burden, CIB)、合并原发性硬化性胆管炎(primary sclerosing cholangitis, PSC)、CRC家族史等,其中炎症的反复发作是癌变的独立危险因素。结肠炎相关结直肠癌(colitis-associated colorectal cancer, CAC)与散发性CRC在癌变模式、发生机制、分子特征等方面均存在差异。本文将结合近年来的研究进展,详细阐述遗传和表观遗传的改变、氧化应激、异常免疫反应以及肠道菌群失调在炎癌转化中发挥的作用。基于危险因素对UC患者进行CAC风险分层,高危患者应进行更频繁的结肠镜监测以便早发现、早干预、早治疗。     

溃疡性结肠炎相关性结直肠癌研究进展

首例溃疡性结肠炎（UC）并发肠癌报道于1925年。Goldgraber等 [1]总结1928年至1968年发表的50篇论文,UC相关的肠癌发病率在 0.6％～17％。Ekbom等[2]在3000例UC患者的研究中,结、直肠癌 (CRC)的相对危险性为5.7(95％CI4.6～7.0),UC患者具有较高的肠 癌发病率已是不争的事实。作者就近年来UC相关性CRC的有关研 究进展作一概述。 一、UC发生肠癌的危险因素UC形成CRC的两个最主要因素是疾病持续时间和病变范围。当 病程小于8～10年,很少发生肠癌,以后患癌的危险性每年上 升0.5％～1％[3],并有较高的累积癌变率,15年为2.5％,…     

反流性回肠炎与溃疡性结肠炎患者的结直肠癌密切相关

疾病波及范围和病程作为影响溃疡性结肠炎癌变的危险因素已被证实。本研究旨在验证反流性回肠炎 (ｂａｃｋｗａｓｈｉｌｅｉｔｉｓ,ＢＭＩ)是否为溃疡性结肠炎癌变的一个重要相关因素。方法　 1 982年～ 1 998年间 60 9例行结直肠切除术的溃疡性结肠炎病人 ,590例符合研究标准。ＢＭＩ为肉眼和组织学证实末端回肠粘膜炎症且病变长度不小于 5ｃｍ。病人根据炎症的范围分成 3组 :①有ＢＷＩ的全结肠炎 ,共1 0 7例 ;②没有ＢＷＩ的全结肠炎 ,共 3 69例 ;③左半结肠炎 ,共 1 1 4例。分别评估 3组病人与ＣＲＣ的关系。研究调查了性别、溃疡性结肠…     

溃疡性结肠炎癌变的回顾性分析

目的分析558例溃疡性结肠炎(UC)发生结直肠癌的风险以及危险因素,为溃疡性结肠炎相关癌(UC-CRC)的监测、筛查以及预防提供依据。方法 1997年1月至2007年12月南方医院共行结肠镜检查32926例,对其中558例UC患者以及UC-CRC患者的相关临床资料进行回顾性分析。结果在558例UC患者中,发现结直肠癌8例,均为进展期癌,总体风险为1.43%,2组病人在年龄、疾病病程、病变范围、诊断结直肠癌前活检是否有不典型增生、是否使用5-ASA类药物、激素治疗以及是否参加内镜随访等方面有显著性差别。危险因素分析提示,疾病病程、病变范围以及结肠镜检查发现不典型增生为UC-CRC的危险因素;定期内镜随访、5-ASA以及激素治疗可降低UC-RC发病的风险。结论 UC患者有较高癌变的风险,但总体风险较西方国家低;UC病程大于10年、全结肠炎以及活检发现有不典型增生是发生结肠癌的高危因素,定期内镜随访以及5-ASA和激素治疗是UC患者防止发生结直肠癌的保护因素。     

溃疡性结肠炎相关腺瘤和结直肠癌回顾性临床病例分析

背景:研究表明溃疡性结肠炎(UC)患者发生结直肠癌的风险明显增加。目的:总结UC相关腺瘤和UC相关结直肠癌(UcCRC)的发病概况和临床病理特点。方法:选取2000年1月～2012年3月南京军区南京总医院住院确诊的UC患者603例,对其中UC相关腺瘤和UcCRC患者的性别、年龄、病程、临床症状、病理表现等临床资料进行回顾性分析经。结果:603例UC患者中,UC相关腺瘤28例,发病率为4.6%(28/603);UcCRC 4例,发病率为0.7%(4/603)。UC相关腺瘤患者的UC中位病程为3年,UcCRC患者的UC中位病程为29年。UC相关腺瘤好发部位依次为直肠/乙状结肠(16处)、降结肠(7处)、横结肠(6处)、升结肠以及回盲部(4处),UcCRC发病部位分别为升结肠(1例)、降结肠(2例)、乙状结肠(1例)。UC相关腺瘤和UcCRC的临床症状与一般UC相似。结论:UC相关腺瘤和UcCRC的发病率随UC病程的延长而增加。长期病程的UC患者应定期行结肠镜检查,对预防和早期检出结直肠癌具有积极意义。     

结直肠癌线粒体基因组的微卫星不稳定性

目的:探讨结直肠癌(colorectal cancer,CRC)线粒体DNA(mitochondrial DNA,mtDNA)非编码区及编码区的微卫星不稳定.方法:选取50例新鲜CRC及相应癌旁组织标本,提取基因组DNA.利用荧光标记聚合酶链反应及短重复序列位点扫描的方法,对线粒体DNA编码区及非编码区微卫星不稳定进行比较分析.结果:共检出19例线粒体微卫星不稳定(mitochondrial microsatellite instability,mtMSI),发生率为38%(19/50),线粒体非编码区微卫星与编码区微卫星不稳定有显著相关性(重要数据列出来P<0.05).结论:结直肠癌患者肠黏膜细胞mtDNA中存在较高频率的微卫星不稳定,在一些结直肠癌的发生中可能起一定作用.     

溃疡性结肠炎相关结直肠癌的基因组和表观遗传不稳定性

溃疡性结肠炎相关结直肠癌（UcCRC）是溃疡性结肠炎（UC）最严重的并发症。近年来,由遗传易感性与环境因素共同作用引起的、结直肠黏膜慢性炎症背景下的遗传学改变在UcCRC发生、发展中的作用备受关注。本文就UcCRC中的常见基因组和表观遗传不稳定性,包括染色体不稳定性（CIN）、微卫星不稳定性（MSI）、CpG岛甲基化表型（CIMP）作一综述。     

结直肠癌CpG岛甲基化表型的研究进展

结直肠癌(colorectal cancer,CRC)是常见的恶性肿瘤之一,是由遗传学和表观遗传学改变逐渐积累导致的.随着一类被称为CpG岛甲基化表型(CpG island methylator phenotype,CIMP)的CRC被发现,表观遗传学修饰在CRC发病中的作用就受到了越来越多的重视.CIMP是一类基因组中有高比例的基因启动子区发生了DNA高甲基化的CRC.目前研究显示CIMP具有多个分子水平的特征,而且CIMP与多个临床特征显著相关,但是还不清楚CIMP的具体致病原因和发病机制.CIMP在治疗上的预后和反应与其他CRC存在很大差异,但是目前没有被广泛认可的鉴定CIMP的生物标记,从而阻止了CIMP用于指导临床上CRC的个体化治疗.     

溃结康泰治疗溃疡性结肠炎的临床研究

目的：观察溃结康泰治疗溃疡性结肠炎的临床疗效。方法：对纤维结肠镜检查确诊的溃疡性结肠炎６４例应用溃结康泰治疗,５６ 例应用柳氮磺胺吡啶加甲硝唑治疗,并进行疗效对照观察。结果：溃结康泰组近期治愈率、总有效率分别为６４．０６％ 、９３．７４％ ;对照组分别为４１．０７％ 、８０．３５％ ,两组间近期治愈率、总有效率比较有极显著性差异（Ｐ＜ ０．０１）。随访２～４ 年,溃结康泰组复发率为１８．１８％ （６／３３）,对照组为５３．３０％ （１６／３０）,两组远期疗效比较有极显著性差异（Ｐ＜ ０．０１）。结论：溃结康泰治疗溃疡性结肠炎疗效可靠且副作用少。     

Tumor necrosis factor-alpha polymorphisms in ulcerative colitis-associated colorectal cancer

OBJECTIVES:  Ulcerative colitis (UC) is characterized by chronic recurrent mucosal inflammation. Genetic studies in UC have indicated linkage to chromosome 6 in the region of the tumor necrosis factor-alpha (TNF-α) gene, a potent proinflammatory cytokine. TNF-α production is influenced by multiple factors including the type of immune cell and its level of activation. However, several single nucleotide polymorphisms (SNP) in the promoter region of TNF-α have been correlated with either increased or decreased production, indicating that regulation of TNF-α is in part genetic. Because UC patients are at increased risk for developing colorectal cancer (CRC), we investigated if there was an association between SNPs in the promoter of the TNF-α gene and UC-CRC.
METHODS:  DNA was extracted from formalin-fixed, paraffin-embedded tissue from 114 UC-CRC cases and 114 UC-no CRC controls. Controls were frequency matched on duration and extent of colitis, age, ethnicity, and gender. All 228 tissue samples were analyzed for five TNF-α promoter polymorphisms (−238[G→A], −308[G→A], −857[C→T], −863[C→A], and −1031[T→C]) using PCR and sequencing.
RESULTS:  The −308(G→A) SNP was significantly associated with UC-CRC cases at both the allele and genotype level ( P < 0.0001). No other SNPs were significantly associated with UC-CRC.
CONCLUSION:  We report a novel finding of a strong association between the −308(G→A) SNP and UC-CRC. Complete elucidation of the mechanism of UC-CRC carcinogenesis will require investigation of other genes involved in modulating inflammation, but our results suggest that some UC patients may have additional genetic predispositions toward developing UC-CRC.     

Effect of adenovirus-mediated PTEN gene on ulcerative colitis-associated colorectal cancer

Purpose

This study investigated the expression pattern of PTEN and its effect on carcinogenesis of ulcerative colitis-associated colorectal cancer, leading to insights into the underlying molecular mechanism.

Methods

We established a mouse model of ulcerative colitis-associated colorectal cancer by treating the animals with azoxymethane (AOM) and dextran sulphate sodium (DSS), and investigated the inflammation–dysplasia–carcinoma sequence. Expression patterns of PTEN, p-Akt and Ki-67 were shown by immunohistochemistry; western blotting techniques were used to detect protein expression of PTEN, p-Akt and caspase 3; TUNEL assay was used to measure apoptosis in colon epithelial cells; and colorimetric analysis was able to determine MPO activity in colon tissues.

Results

During the inflammation–dysplasia–carcinoma sequence, PTEN expression gradually decreased, while p-Akt expression increased; PTEN and p-Akt levels were negatively correlated. Compared to the AOM-DSS and Ad-0 groups, Ad-PTEN mice had longer colons, fewer tumours (P?<?0.01) and smaller tumour sizes (P?<?0.05). After injecting Ad-PTEN, expression of p-Akt, Ki-67 and MPO activity decreased dramatically, whereas PTEN increased. The TUNEL assay showed increased apoptotic cells and caspase 3 expression in the Ad-PTEN group.

Conclusion

PTEN plays an important role in the inflammation–dysplasia–carcinoma sequence and may be a new molecular target in preventing and treating ulcerative colitis-associated colorectal cancer.     

Trends of ulcerative colitis-associated colorectal cancer in Korea: A KASID study

Background and Aim:  The number of patients with ulcerative colitis (UC) in Korea has increased. In addition, the number of patients with colorectal cancer (CRC) associated with UC has also increased. Therefore, this population-based nationwide study was conducted to investigate the incidence of CRC in patients with UC in Korea and compare these results to those of studies conducted in other countries.
Methods:  The Korean Association for the Study of Intestinal Diseases (KASID) reviewed 7061 cases of UC that occurred between 1970 and 2005 and found a total of 26 cases of CRC.
Results:  The overall prevalence of CRC in patients with UC was 0.37%. In addition, the estimated cumulative risk of UC-associated CRCs was 0.7% for patients that had UC for 10 years, 7.9% for patients that had UC for 20 years, and 33.2% for patients that had UC for 30 years. The mean age at the time of diagnosis with CRC was 49.6 years, and the mean duration of UC prior to the development of CRC was 11.5 years. Most UC-associated CRCs were diagnosed after they were already in advanced stages; however, the stage at diagnosis was lower in patients that had good compliance with medical treatment.
Conclusion:  The cumulative incidence of UC-associated CRCs in Korea was found to be comparable to that of western countries. The overall occurrence of UC-associated CRC in Korea may be growing, therefore, intensive surveillance colonoscopy and constructive chemoprevention should be encouraged to enable early detection and treatment of UC-associated CRCs in Korea.     

Clinical characteristics of 56 cases of ulcerative colitis-associated dysplasia and colorectal cancer

<正>Objective To analyze the clinical characteristics of patients with ulcerative colitis( UC)-associated neoplasia,including UC-associated dysplasia and ulcerative colitis-associated colorectal cancer( UC-CRC).Methods From January 2010 to July 2019,the clinical data of 56 patients with UC-associated neoplasia at Xijing Hospital of Digestive Diseases were retrospectively analyzed.     

Limits of diagnosis and molecular markers for early detection of ulcerative colitis-associated colorectal neoplasia

The incidence of colorectal neoplasia has been increasing among patients with long-standing and extensive ulcerative colitis (UC), and therefore surveillance colonoscopy has been widely recommended. However, because UC-associated neoplasia is often difficult to detect endoscopically and to discriminate from inflammatory regenerative epithelium histologically, the efficacy of current surveillance remains unsatisfactory. In order to overcome these difficulties, adjunctive modalities for diagnosing UC-associated neoplasia, chromo- and magnifying endoscopy for endoscopic diagnosis and analysis of p53 alteration for histological diagnosis have been introduced. Furthermore, if it were possible to differentiate UC patients with long-standing and extensive colitis into subgroups with a high and a low risk of neoplasia, it would enable physicians to conduct more intensive surveillance with these modalities for patients at higher risk. Several molecular alterations of nonneoplastic epithelium in UC patients with neoplasia may be promising as markers for identifying individuals with UC at increased risk of neoplasia. We evaluated estrogen receptor (ER) methylation of nonneoplastic colorectal epithelium to clarify whether this epigenetic alteration can contribute to the prediction of increased neoplasia risk in UC patients and demonstrated that the ER methylation level in nonneoplastic epithelium was higher throughout the colorectum in patients with neoplasia than in those without. These results suggest that analysis of ER gene methylation may be potentially useful for identifying individuals at increased risk of neoplasia among patients with long-standing and extensive UC.     

Ulcerative colitis-associated colorectal cancer

The association between ulcerative colitis(UC) and colorectal cancer(CRC) has been acknowledged. One of the most serious and life threatening consequences of UC is the development of CRC(UC-CRC). UC-CRC patients are younger, more frequently have multiple cancerous lesions, and histologically show mucinous or signet ring cell carcinomas. The risk of CRC begins to increase 8 or 10 years after the diagnosis of UC. Risk factors for CRC with UC patients include young age at diagnosis, longer duration, greater anatomical extent of colonic involvement, the degree of inflammation, family history of CRC, and presence of primary sclerosing cholangitis. CRC on the ground of UC develop from non-dysplastic mucosa to indefinite dysplasia, lowgrade dysplasia, high-grade dysplasia and finally to invasive adenocarcinoma. Colonoscopy surveillance programs are recommended to reduce the risk of CRC and mortality in UC. Genetic alterations might play a role in the development of UC-CRC. 5-aminosalicylates might represent a favorable therapeutic option for chemoprevention of CRC.