5-ASA在炎症性肠病相关结直肠癌中的化学预防作用

癌变是溃疡性结肠炎(ulcerative colitis,UC)最严重的并发症,其预防手段包括内镜监测、分子生物标志物、手术治疗及化学预防。5-氨基水杨酸盐(5-aminosalicylic acid,5-ASA)是轻-中度UC患者的一线用药,其对炎症性肠病(inflammatory bowel disease,IBD)相关结直肠癌的化学预防作用及机制尚不十分明确。本文较全面地阐述5-ASA的化学预防作用及机制研究进展,旨在为临床实践中预防IBD相关癌变用药方案提供更多依据。     

溃疡性结肠炎相关结直肠癌变机制研究进展

溃疡性结肠炎(ulcerative colitis,UC)是遗传易感因素和免疫系统异常所导致的一种肠道慢性炎症性疾病,长期病程可导致多种并发症的发生,其中以结直肠癌变后果最为严重.UC导致结直肠癌变的机制十分复杂,从遗传物质到信号转导等的一系列改变可能在UC相关的癌变进程中产生重要影响,同时在发病机制方面,UC相关结直肠癌(colorectal cancer,CRC)与散发性CRC仍存在一定差异性,本文重点就上述方面阐述UC相关结直肠癌变机制.     

PTEN和Cdx2在溃疡性结肠炎和结直肠癌中的表达

PTEN具有磷酸酶活性，能调控细胞的增殖、迁移和凋亡。Cdx2是一种肠道特异性转录因子，在调节肠上皮细胞分化、增殖中起关键作用。近年溃疡性结肠炎（UC）与结直肠癌之间的关系日益受到关注。目的：观察UC和结直肠癌组织中PTEN和Cdx2的表达，探讨两者在UC癌变进程中的作用。方法：在上海瑞金医院1997年1月-2007年10月诊断的UC患者中收集经病理检查确诊者的蜡块标本，其中UC组17例，UC相关结直肠癌组7例，另收集非UC相关结直肠癌标本35例和正常肠黏膜标本15例，以免疫组化方法检测PTEN和Cdx2表达。结果：PTEN和Cdx2在正常结直肠组织中基本呈阳性表达．阳性率分别为93.3％和100％，UC组织两者表达阳性率显著降低，均仅为6.7％。UC相关结直肠癌组PTEN和Cdx2表达阳性率显著低于非UC相关结直肠癌组（PTEN：28．6％对83．9％，Cdx2：42．9％对90．3％，P〈0．01）。结论：UC与结直肠癌之间可能存在相关性。PTEN和Cdx2在调控肠上皮分化、增殖的过程中可能有相似的调节点或具有协同作用，两者可能共同参与了对UC癌变进程的调控。     

溃疡性结肠炎癌变的中西医防治策略

溃疡性结肠炎是结直肠癌发生的重要危险因素，如何有效控制炎症、降低溃疡性结肠炎癌变发生率是临床重要问题。中医药多成分、多环节和多靶点的作用特点，在控制炎症、预防癌变、已变防复方面具有重要意义。本文对溃疡性结肠炎相关结直肠癌的发病机制、监测预防及中医药防治癌变的研究进展进行总结，重在探讨中医药防治溃疡性结肠炎癌变的策略，以期为临床提供参考。     

溃疡性结肠炎相关结直肠癌临床特点及癌变相关蛋白的表达

目的 探讨溃疡性结肠炎(UC)相关结直肠癌的临床特点及其癌变的可能机制.方法 收集北京协和医院1984年至2008年6例UC相关性结直肠癌,分析其发病情况、临床表现、病理类型、治疗及预后特点,免疫组化检测组织标本中结肠腺瘤性息肉蛋白(APC蛋白)、β-连环蛋白、p53蛋白和Wnt1蛋白表达的情况.结果 UC的癌变率为1.1%(6/534),女性多见(5/6),平均病程14.3年.临床均呈现典型的UC表现,病变常累及全结肠(5/6),均无原发性硬化性胆管炎.其中直肠癌4例、降结肠癌2例,病理类型以腺癌为主,预后较差.APC蛋白、β-连环蛋白、p53蛋白和wnt1蛋白表达的阳性率分别为6/6、6/6、5/6和6/6.结论 临床对病变累及全结肠、病程长的UC患者,应注意防止结直肠癌的发生,其癌变过程可能有多途径参与.     

溃疡性结直肠炎与结直肠癌的相关性

溃疡性结直肠炎(Ulcerative Colitis,UC)是一种病因不明的慢性非特异性炎症性疾病,主要侵犯大肠黏膜和黏膜下层,多数累及直肠和远端结肠,可向近端结肠发展,少数遍及全结肠.UC在西方国家常见,尤在英美及北欧的发病率较高,最新资料显示,大约3%的UC患者可能最后发生结直肠癌,较一般人群高3～5倍;10年以上病程的广泛性结肠炎及慢性持续型患者其危险性增加10～20倍,有报道[1,2]UC癌变危险性逐年递增1%～2%.     

结直肠息肉高危因素的研究进展

腺瘤性结直肠息肉是结直肠癌重要的癌前病变,早期对结直肠息肉进行筛查和预防可有效降低结直肠癌的发病率。结直肠息肉癌变的危险因素包括肠黏膜细胞APC、KRAS、TP53及SMAD4基因突变,年龄50岁,男性等。保护因素包括美国癌症协会(ACS)指导饮食、低蛋白饮食等。目前对结直肠息肉缺乏针对性的预防措施,部分研究认为阿司匹林等化学性药物、微生物制剂或激素替代疗法等可能有助于结直肠息肉的预防。该文从基因遗传、年龄、性别、生活饮食、药物、肠道微生物以及胆囊疾病等方面阐述其对结直肠息肉生长及癌变的影响,为结直肠息肉的筛查和预防提供依据。     

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。     

炎症性肠病患者结直肠癌化学预防研究进展

炎症性肠病（IBD）主要包括溃疡性结肠炎（UC）和克罗恩病（CD）两种疾病。近年我国IBD的发病率不断上升，如未及时治疗，长期炎症将最终导致结直肠癌的发生风险增高。在各种结直肠癌预防措施中，化学预防日益受到关注。本文主要对IBD合并结直肠癌的现状和发病机制作一综述，重点介绍几种用于化学预防的药物。     

溃疡性结直肠炎癌变的分子生物学机制研究进展

溃疡性结直肠炎（Ulcerative Colitis，UC）是一种病因不明的慢性非特异性炎症性疾病，随着UC的发病率不断上升，其癌变率也在逐年增加，有资料显示，UC患者终身发生结直肠癌（colorectal cancer，CRC）的概率为3．7％，每人每年的发病率为0．3％；UC癌变发生率以美国和英国为最高，每人每年发病率分别为5％和4％，也是UC患者的主要死因之一。目前认为，UC是CRC的一种癌前病变，其并发CRC的危险性较正常人群高20倍。     

Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis

BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) has shown effectiveness as a colon cancer chemopreventive agent in preclinical studies. In addition, a recent report suggests that it also may decrease the risk for developing colorectal dysplasia in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We sought to evaluate the effect of UDCA on colorectal neoplasia in a group of patients with UC and PSC enrolled in a randomized, placebo-controlled trial. METHODS: From a prior, randomized, placebo-controlled trial of UDCA therapy in PSC at our center, we followed-up patients with concomitant UC to assess the effect of UDCA on the development of colorectal dysplasia and cancer as compared with placebo. ReESULTS: Fifty-two subjects were followed-up for a total of 355 person-years. Those originally assigned to receive UDCA had a relative risk of 0.26 for developing colorectal dysplasia or cancer (95% confidence interval, 0.06-0.92; P = 0.034). Many of the patients originally assigned to the placebo group eventually received open-label UDCA. Assigning these patients to the UDCA group from the time they began active therapy did not change the magnitude of the protective effect (relative risk, 0.26; 95% confidence interval, 0.07-0.99; P = 0.049). CONCLUSIONS: UDCA significantly decreases the risk for developing colorectal dysplasia or cancer in patients with UC and PSC.     

脱氧胆酸诱导大肠癌发生的研究

胆汁酸中的脱氧胆酸可以促进肿瘤的形成,脱氧胆酸诱发的细胞凋亡在大肠癌的发生中起着重要作用。提高粪便中胆汁酸含量可增加患大肠癌的风险,表明脱氧胆酸可以促进大肠癌的发生、发展。脱氧胆酸作为一种促癌因子在大肠癌的发生中起很大作用,同时通过多种机制诱发大肠癌的发生。     

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。     

Up-regulation of mitochondrial chaperone TRAP1 in ulcerative colitis associated colorectal cancer

AIM:To characterize tumor necrosis factor receptorassociated protein 1(TRAP1)expression in the progression of ulcerative colitis(UC)-associated colorectal cancer.METHODS:Chronic UC is an inflammatory bowel disease that predisposes to colorectal cancer.Immunohistochemical analysis was used to evaluate TRAP1expression on tissue microarrays containing colonic tissues from 42 UC progressors(patients with cancer or dysplasia)and 38 non-progressors(dysplasia/cancer free patients).Statistical analyses of the TRAP1immunohistochemistry staining were performed using Graph Pad Prism.Differences in the TRAP1 level between non-progressors and progressors were tested for statistical significance using the Mann-Whitney test.Receiver operating characteristic curve method was used to quantify marker performance in distinguishing diseased cases from controls.RESULTS:TRAP1 was up-regulated in the colon tissues from UC progressors,but not in the colon tissues from UC non-progressors.Moreover,up-regulation of TRAP1 preceded the neoplastic changes:it was present in both the dysplastic and non-dysplastic tissues of UC progressors.When TRAP1 staining in rectal tissue was used as a diagnostic marker,it could distinguish progressors from non-progressors with 59%sensitivity and 80%specificity.Our study further showed that the increase of TRAP1 expression positively correlated with the degree of inflammation in the colorectal cancer tissues,which could be related to the increased oxidation present in the colonic mucosa from UC progressors.We then investigated the cellular proteome changes underlying oxidative stress,and found that oxidative stress could induce up-regulation of TRAP1 along with several other negative modulators of apoptosis.CONCLUSION:These results suggest that oxidative stress in long standing UC could lead to the increase of cytoprotective protein TRAP1,which in turn could promote cancer progression by preventing or protecting the oxidative damaged epithelial cells from undergoing apoptosis.TRAP1 could be a potential diagnostic marker for UC associated colorectal cancer.     

Will a 5-ASA a day keep the cancer (and dysplasia) away?

Prevention strategies for colorectal cancer in chronic ulcerative colitis (UC) are currently based on the identification of neoplasia by surveillance colonoscopy, but there is a great interest in the possibility of primary chemoprevention. 5-aminosalicylic acid (5-ASA) therapy is an attractive option for chemoprevention in UC due to the fact that it is a derivative of aspirin and has been shown to have a variety of other molecular and genetic targets of cancer prevention, but human studies in UC have been limited by observational design and limited data collection or follow-up. The recently performed metaanalysis of 5-ASA chemoprevention trials shows a favorable role of 5-ASA in the prevention of cancer and dysplasia in patients with UC, and adds to the available evidence favoring its use. This editorial discusses the substantial logistical and ethical challenges in designing a randomized double-blind trial to measure the effect of 5-ASA on cancer risk in UC. The authors conclude that the safety and current maintenance use of 5-ASA warrant its acceptance as a probable chemopreventive agent at this time.     

Appendix adenocarcinoma associated with ulcerative colitis: a case report and literature review

Ulcerative colitis (UC) represents a risk factor for colorectal cancer, but the association between UC and appendix cancer is uncommon. A 60–year–old woman with a 5–year history of UC initially received medical treatment with mesalazine and prednisone with no satisfactory response; therefore surgery was indicated. The procedure was a total intersphincteric proctocolectomy with ileostomy. Histopathological analysis indicated adenocarcinoma from the cecal appendix, and chronic–active ulcerative colitis of the colon. In conclusion, surgeons and pathologists should examine every surgical specimen from patients with UC because of the possibility, although remote, of a neoplasic pathology. The appendix adenocarcinoma and ulcerative colitis may or may not be associated, same as colon cancer in patients with UC.     

Hepatopancreatobiliary manifestations of inflammatory bowel disease

Inflammatory bowel disease (IBD) is frequently associated with extraintestinal manifestations such as hepatopancreatobiliary manifestations (HPBMs), which include primary sclerosing cholangitis (PSC), pancreatitis, and cholelithiasis. PSC is correlated with IBD, particularly ulcerative colitis (UC); 70–80% of PSC patients in Western countries and 20–30% in Japan have comorbid UC. Therefore, patients diagnosed with PSC should be screened for UC by total colonoscopy. While symptoms of PSC-associated UC are usually milder than PSC-negative UC, these patients have a higher risk of colorectal cancer, particularly in the proximal colon. Therefore, regular colonoscopy surveillance is required regardless of UC symptoms. Administration of 5-aminosalicylic acid or ursodeoxycholic acid may prevent colorectal cancer and cholangiocarcinoma. While PSC is diagnosed by diffuse multifocal strictures on cholangiography, it must be carefully differentiated from immunoglobulin G4 (IgG4)-associated cholangitis, which shows a similar cholangiogram but requires different treatment. When PSC is suspected despite a normal cholangiogram, the patient may have small-duct PSC, which requires a liver biopsy. IBD patients have a high incidence of acute and chronic pancreatitis. Most cases are induced by cholelithiasis or medication, although some patients may have autoimmune pancreatitis (AIP), most commonly type 2 without elevation of serum IgG4. AIP should be accurately identified based on characteristic image findings, because AIP responds well to corticosteroids. Crohn’s disease is frequently associated with gallstones, and several risk factors are indicated. HPBMs may influence the management of IBD, therefore, accurate diagnosis and an appropriate therapeutic strategy are important, as treatment depends upon the type of HPBM.     

Colorectal cancer in inflammatory bowel disease: Molecular and clinical considerations

Opinion statement Adenocarcinoma of the colon is an accepted and feared complication of chronic ulcerative colitis (UC) and colonic Crohn’s disease (CD). When cancer is identified, surgery is necessary, and unlike with sporadic colorectal cancer (CRC), in which partial colectomy is effective, proctocolectomy is required. As CRC is a rare complication of these diseases, studies of the pathogenesis are limited primarily to observational studies; thus, the mechanism and molecular events that lead to neoplastic change are not fully understood or well known. Precancerous dysplasia has been associated with concurrent or future CRC in UC and, although less studied, in CD, and is therefore considered a marker of cancer risk in inflammatory bowel disease (IBD). Risk factors for dysplasia and CRC in IBD include longer duration of disease, greater extent of disease, younger age at diagnosis, diagnosis with primary sclerosing cholangitis (PSC), family history of CRC, and possibly backwash ileitis and degree of inflammation of the bowel over time. Prevention of cancer in IBD has been focused on secondary measures of identifying dysplasia in flat mucosa or protruding lesions during surveillance colonoscopy with random biopsies and, when confirmed, performing proctocolectomy. Studies of primary prevention of dysplasia and CRC using chemopreventive agents have suggested a possible benefit with a number of agents. These include ursodeoxycholic acid (in patients with PSC and UC), aminosalicylates, and possibly statins.