溃疡性结肠炎相关性结直肠癌的危险因素及预防

溃疡性结肠炎是一种直肠及结肠的慢性非特异性炎症性疾病,临床以反复发作的腹泻、腹痛和黏液脓血便为特征。溃疡性结肠炎相关性结直肠癌是溃疡性结肠炎严重的并发症及重要死亡原因,其危险因素包括病程、病变范围、原发性硬化性胆管炎、结直肠癌家族史、发病年龄及炎症严重程度等。不典型增生是溃疡性结肠炎相关性结直肠癌发生的重要环节,早期发现不典型增生,积极化学预防是预防溃疡性结肠炎癌变的关键。     

p53基因与溃疡性结肠炎

野生型ｐ５３蛋白具有抗细胞增殖功能，它可使ＤＮＡ有损伤的细胞生长停止于Ｇ１／Ｇ０期。散发性结直肠癌ｐ５３基因中常见点突变发生，发生于溃疡性结肠炎基础上的结直肠癌（ＵＣＡＣＲＣ）亦有很高的ｐ５３基因突变率。另一等位基因的杂合性缺失（ｐ５３ＬＯＨ）的发生也增高，加强溃疡性结肠炎病人ｐ５３基因点突变和ｐ５３ＬＯＨ的研究，可为监测ＵＣＡＣＲＣ的形成提供新方法。     

溃疡性结肠炎相关癌的回顾性探讨

目的 通过对565例溃疡性结肠炎患者进行癌变风险分析,为溃疡性结肠炎相关癌（UC-CRC）的早期筛查及预防提供依据.方法 对收治的565例溃疡性结肠炎患者进行分组,其中15例UC-CRC组患者,随机抽取28例溃疡性结肠炎组患者,对两组临床相关资料进行回顾性分析.结果 在565例溃疡性结肠炎患者中,UC-CRC组患者有15例,总体风险为3.77％.两组患者在年龄、病变内镜活检、疾病病程、血清CRP水平等方面差异有统计学意义（P ＜0.05,P＜0.01）.高危风险因素显示：疾病病程、病变范围、血清CRP水平、病理诊断为UC-CRC的高危因素.结论 溃疡性结肠炎患者中有较高的UC-CRC癌变风险,溃疡性结肠炎的疾病病程、血清CRP水平、内镜活检为不典型增生及程度与UC-CRC的发生呈正相关.     

microRNA在肠道伤口愈合中的作用

<正>据Chivukula RR 2014年5月27日[Cell,2014,157(5):1104-1116.]报道,美国德州大学癌症研究人员发现,在抑制结肠癌中的一个重要microRNA簇,也在肠道伤口愈合中发挥关键作用。研究结果首先在小鼠中获得,其后在人类细胞中得到再现。研究确定了microRNA在调节肠道伤口愈合中的一种新作用。这一发现对疾病如溃疡性结肠炎和克罗恩病有重要影响,并可能与其他组织中创面愈合机制相关。溃疡性结肠炎和克罗恩病是两种最常见的炎性肠疾病,源于一个异常的免疫反应。结肠慢性损伤被认为是结直肠癌的危险因素,了解所涉及的细胞通路,最终可能导致潜在的治疗方法。研究人员研究这些微小的"监管机构"(microRNA)如何正常工作,以及     

溃疡性结肠炎相关性结直肠癌发生过程中有关的基因改变

溃疡性结肠炎相关性结直肠癌与散发性大肠癌不仅在形态上有所不同 ,而且两者在分子发病学上也有差异。本文就两种癌的发生过程中 p5 3、K- RAS、APC、DCC等基因突变及微卫星不稳定性、异倍体的发生率及发生时间进行了综述 ,重点讨论了它们存在的差异和可能的原因     

抗人原肌球蛋白亚型5免疫与溃疡性结肠炎的研究进展

溃疡性结肠炎(ulcerative colitis,UC)是一种病因和发病机制尚未完全明确的直肠和结肠慢性非特异性炎症性疾病,其中,肠道黏膜免疫系统在炎症发生、发展、转归过程中始终发挥重要作用.国外初步研究发现,人类原肌球蛋白亚型5(hTM5)可能是溃疡性结肠炎患者结肠上皮细胞的一种抗原,可诱导溃疡性结肠炎患者产生相应...     

溃疡性结肠炎中西医结合治疗研究

溃疡性结肠炎是由多种病因引起的、发病机制尚不明确的、国际公认的难治病之一,成为近年研究的热点。目前西医、中医治疗该病均取得了较大的进步,但还没得出一个公认、统一、有效的根治方案。黄连素具有抗炎、抗癌、抑菌、降脂、降糖等多种作用,为研究治疗溃疡性结肠炎开展了新局面,现就西医、中医及中西医结合治疗溃疡性结肠炎作一综述。     

溃疡性结肠炎发病机制中免疫因素的研究进展

溃疡性结肠炎是一种常见的慢性肠道疾病,近年来发病呈上升趋势,而其发病机制目前尚不明确.目前认为与多种因素有关.环境因素作用于遗传易感者,在肠道菌丛的参与下,启动肠道免疫和非免疫系统,发生免疫反应和炎症,从而出现临床症状.其中免疫异常被认为是溃疡性结肠炎发病的重要因素,主要包括自身抗体、细胞免疫、细胞因子、环氧合酶与基质金属蛋白酶、氧自由基和一氧化氮等.本文综述了溃疡性结肠炎免疫发病机制中的各种影响因素.     

铁死亡在结直肠癌中的研究进展

结直肠癌是全球第3大癌症死亡原因, 具有基因频繁突变的特点。目前的化疗、放疗和手术治疗方案面临着癌症复发和耐药性等挑战。结直肠癌的治疗往往通过促进各种形式的程序性细胞死亡。铁死亡被发现是一种铁依赖性和脂质过氧化物驱动的程序性细胞死亡形式。研究表明, 铁死亡是结直肠癌的一种有效治疗策略。然而, 需要对结直肠癌中铁死亡的发生、传播和耐药机制有更深入的了解。主要对结直肠癌形成、代谢、治疗中的铁死亡机制及其耐药途径进行综述, 并对其未来研究方向进行展望, 为改善结直肠癌的治疗方案提供依据。     

大麻素受体激动剂HU210对实验性溃疡性结肠炎的治疗作用及可能的机制

<正>目的:探索大麻素受体激动剂HU210在改善溃疡性结肠炎中作用及可能机制。方法:选用TLR4基因敲除型(TLR4-/-)和野生型小鼠(WT),采用4%葡聚糖酸钠(dextran sulfate sodium salt,DSS)诱导溃疡性结肠炎。检测指标包括AP/PAS和HE染色观察组织结构病理变化并评分,细菌培养检测肠道黏膜菌群数量,流式细胞术检测肠道Peyer’s结中T细胞亚群比例,     

Diagnostic problems and advances in inflammatory bowel disease.

This review summarizes current diagnostic problems and advances with regard to patterns of inflammation and dysplasia in ulcerative colitis and Crohn's disease. Ulcerative colitis and Crohn's disease have a variety of characteristic but non-specific pathologic features. In approximately 5% of inflammatory bowel disease cases, a definite diagnosis of ulcerative colitis or Crohn's disease cannot be established, in which case the term "indeterminate" colitis is used. Most cases of indeterminate colitis are related to fulminant colitis, a condition in which the classic features of ulcerative colitis or Crohn's disease may be obscured by severe ulceration with early superficial fissuring ulceration, transmural lymphoid aggregates, and relative rectal sparing. Approximately 20% of patients with indeterminate colitis develop severe pouch complications, which is intermediate in frequency between ulcerative colitis (8-10%) and Crohn's disease (30-40%). In order to establish a diagnosis of ulcerative colitis or Crohn's disease, it is important to evaluate pathologic material in conjunction with clinical, laboratory, radiologic, and endoscopic features and to recognize the variety of changes that may be seen in fulminant ulcerative colitis. There are a number of exceptions to the classic principles of inflammatory bowel disease pathology that may lead to diagnostic confusion. For instance, apparent skip lesions on biopsy analysis may occur in patients with ulcerative colitis in the following settings; long term oral or topical therapy, focal ascending colon, cecum and/or appendiceal involvement in patients with left sided ulcerative colitis, upper gastrointestinal involvement in patients with ulcerative colitis, and at initial presentation of ulcerative colitis in pediatric patients. In all of these circumstances, the finding of patchy disease and/or rectal sparing should not be misinterpreted as either evidence against a diagnosis of ulcerative colitis, or as representing skip areas characteristic of Crohn's disease. Patients with ulcerative colitis and Crohn's disease are at increased risk for the development of dysplasia and carcinoma. Recent studies suggest that given a similar duration and extent of disease, patients with Crohn's disease have a similar risk of dysplasia and cancer as patients with ulcerative colitis. Dysplasia in ulcerative colitis may be classified as flat or elevated (dysplasia associated lesion or mass [DALM]). Patients with flat high grade dysplasia are generally treated with colectomy. However, there is recent evidence to suggest that patients with flat low grade dysplasia, particularly if detected at the time of initial endoscopic exam, or if its multifocal or synchronous, should also be treated with colectomy. Elevated lesions in ulcerative colitis (DALM) are subdivided into "adenoma-like" and "non-adenoma-like" lesions based on their endoscopic appearance. Recent data suggests that adenoma-like lesions, regardless of the grade of dysplasia, or the location of the lesion (i.e., inside or outside areas of established colitis) may be treated adequately by polypectomy if there are no other areas of flat dysplasia in the patient. Although there are some histologic and molecular features that can help differentiate sporadic adenomas from adenoma-like polypoid dysplastic lesions related to ulcerative colitis, none of these adjunctive techniques can help distinguish these lesions definitively in any single patient. Patients with a non-adenoma-like DALM, (irregular, broad based, or strictured lesion) should be treated with colectomy because of the high probability of adenocarcinoma. The surveillance and treatment options for patients with flat and elevated dysplasia in ulcerative colitis are reviewed in detail.     

Overexpression of fatty acid synthase in ulcerative colitis

Fatty acid synthase is an enzyme that catalyzes the synthesis of long-chain fatty acids. The enzyme expression is minimal in adult tissues and very high in many cancers. Ulcerative colitis is a chronic inflammatory bowel disease that, when long-standing, is associated with an increased risk of colon cancer. The aim of the present study was to establish whether fatty acid synthase levels in the mucosa without dysplasia of patients with long-standing ulcerative colitis were higher than in control subjects. Three groups of patients were selected: 30 with active ulcerative colitis, 30 with ulcerative colitis in remission, and 30 undergoing colonoscopy for colorectal cancer screening, as healthy control subjects. Fatty acid synthase expression was evaluated with immunohistochemical procedures. The enzyme was detected in all patients with active colitis, in most patients with quiescent disease, in both pathologic and normal mucosa, but in only 3 healthy control subjects. Our results suggest that extension of ulcerative colitis is greater than that revealed by common diagnostic techniques.     

Circulating DNA and its methylation level in inflammatory bowel disease and related colon cancer

Both of chronic inflammation and abnormal immune in inflammatory bowel disease can induce colon cancer. Previous research showed that cell apoptosis and necrosis become the main source of circulating DNA in the peripheral blood during tumorigenesis that reduced along with methylation degree. However, its role in the process of colitis transforming to colon cancer is not clarified. Drinking 3% DSS was used to establish colitis model, while 3% dextran sodium sulfate (DSS) combined with azo oxidation methane (AOM) intraperitoneal injection was applied to establish colitis related colon cancer model. Circulating DNA and its methylation level in peripheral blood were tested. Morphology observation, HE staining, and p53 and β-catenin expression detection confirmed that drinking 3% DSS and 3% DSS combined with AOM intraperitoneal injection can successfully establish colitis and colitis associated colorectal cancer models. Circulating DNA level in colitis and colon cancer mice increased by gradient compared with control, while significant difference was observed between each other. Circulating DNA methylation level decreased obviously in colitis and colon cancer, and significant difference was observed between each other. Abnormal protein expression, circulating DNA and its methylation level in ulcerative colitis associated colorectal tissues change in gradient, suggesting that circulating DNA and its methylation level can be treated as new markers for colitis cancer transformation that has certain significance to explore the mechanism of human ulcerative colitis canceration.     

CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice

Inflammatory bowel diseases, including ulcerative colitis and Crohn's disease, increase the risk of colorectal cancer in humans. It has been recently shown in humans and animal models that intestinal microbiota and host immunity are integral in the progression of large bowel diseases. Lymphocytes are widely believed to prevent bacterially induced inflammation in the bowel, and lymphocytes are also critical in protecting against primary tumors of intestinal epithelia in mice. Taken together, this raises the possibility that lymphocytes may inhibit colon carcinogenesis by reducing bacterially driven inflammation. To examine the role of bacteria, lymphocytes, and inflammatory bowel disease in the development of colon cancer, 129/SvEv Rag-2-deficient and congenic wild-type mice were orally inoculated with a widespread enteric mouse bacterial pathogen, Helicobacter hepaticus, or sham-dosed with media only. H. hepaticus-infected Rag2-/-, but not sham-dosed Rag2-/- mice, rapidly developed colitis and large bowel carcinoma. This demonstrated a link between microbially driven inflammation and cancer in the lower bowel and suggested that innate immune dysregulation may have an important role in inflammatory bowel disease and progression to cancer. H. hepaticus-infected wild-type mice did not develop inflammation or carcinoma showing that lymphocytes were required to prevent bacterially induced cancer at this site. Adoptive transfer with CD4+ CD45RBlo CD25+ regulatory T cells into Rag-deficient hosts significantly inhibited H. hepaticus-induced inflammation and development of cancer. These results suggested that the ability of CD4+ T cells to protect against intestinal cancer was correlated with their ability to reduce bacterially induced inflammatory bowel disease. Further, regulatory T cells may act directly on the innate immune system to reduce or prevent disease. These roles for T cells in protection against colon carcinoma may have implications for new modes of prevention and treatment of cancer in humans.     

Morphology of colorectal lymphoid aggregates in cancer, diverticular and inflammatory bowel diseases.

The present study compares the characteristics of colorectal lymphoid aggregates in patients with carcinoma, diverticular disease, Crohn's disease, or ulcerative colitis of the large bowel. A total of 77 patients (41 colorectal cancer, 27 diverticular disease, six ulcerative colitis, three Crohn's disease) undergoing colorectal resection were included. Acetic acid staining, hematoxylin and eosin staining, CD3, CD20, and MIB1 immunostaining were employed in order to assess density, diameter, subepithelial or basal location, cellular profile, and proliferation of lymphoid aggregates in normal-appearing and actively inflamed large bowel. In normal-appearing tissue, mean density of lymphoid aggregates was lower in patients with ulcerative colitis and Crohn's disease than in those with colorectal cancer or diverticular disease. A larger mean diameter of aggregates was observed in patients with Crohn's disease. In inflammatory bowel diseases, a marked increase of the mean density of lymphoid aggregates was observed in actively affected specimens. In Crohn's disease more than in ulcerative colitis, the aggregates had a predominant basal or transmural distribution. In diverticular disease, active inflammation determined a less significant increase of subepithelial aggregates harboring a lower proportion of germinal centers. No significant variations of CD3, CD20, and MIB1 were recorded among the four disease groups. The lymphoid aggregate derangements observed not only in the actively affected mucosa but also in the unaffected colorectal lining of patients with Crohn's disease and ulcerative colitis support a relevant involvement of lymphoid aggregate system in the pathogenesis of inflammatory bowel diseases.     

Misplaced epithelium in ulcerative colitis and Crohns disease of the colon and its relationship to malignant mucosal changes

The presence of misplaced mucosal epithelium was studied in the colectomy specimens from 30 patients with Crohn's disease, 30 patients with ulcerative colitis, 15 patients with ulcerative colitis complicated by carcinoma and 30 patients with non-colitic colorectal carcinoma. Misplaced epithelium was present in 21 (70%) of the resection specimens with Crohn's disease, 20 (66.7%) with ulcerative colitis and 12 (80%) with ulcerative colitis complicated by carcinoma. None of the specimens with non-colitic colorectal adenocarcinoma showed misplaced foci of epithelium. Two pathogenetic mechanisms for epithelial misplacement are proposed: (1) the effects of mucosal inflammation and repair; and (2) muscular abnormalities in inflammatory bowel disease. The proposed mechanisms and patterns of epithelial misplacement are discussed and illustrated. The importance of its recognition is emphasized because, when associated with mucosal dysplasia, difficulties in interpretation arise in distinguishing it from 'early' invasive adenocarcinoma. Epithelial misplacement is common in patients with longstanding ulcerative colitis and may be a factor in increasing the significance of pre-existing mucosal dysplasia and promoting the development of adenocarcinoma. This may explain the unusual growth pattern encountered in ulcerative colitis, of submucosal cancer underlying a flat, non-dysplastic mucosa.     

Serum selenium concentration in patients with ulcerative colitis

Selenium deficiency may be implicated in the pathogenesis of some human diseases, including colon cancer. The incidence of carcinoma of the colon is increased in patients with ulcerative colitis. We measured the serum concentration of selenium (S-Se) in 20 patients with ulcerative colitis and 20 sex-, age-, height- and weight-matched controls. Although no significant difference was found in mean S-Se between patients and controls (patients: S-Se = 0.93 mumol/l, controls: S-Se = 0.98 mumol/l), the S-Se level decreased with increasing extension of the disease (p less than 0.02). No correlation was found between S-Se and the sex, age, height, or weight of the person or between S-Se and the activity or duration of the disease. The inverse correlation between S-Se and the extension of the disease may be caused by a decreased absorption of selenium from the diseased colon in ulcerative colitis. The significance of the decreased S-Se in patients with extensive disease is unknown, but the possibility exists that this may further increase their risk of developing colonic cancer.     

Characterization of N-acetyltransferase 1 and 2 polymorphisms and haplotype analysis for inflammatory bowel disease and sporadic colorectal carcinoma

Background  

N-acetyltransferase 1 (NAT1) and 2 (NAT2) are polymorphic isoenzymes responsible for the metabolism of numerous drugs and carcinogens. Acetylation catalyzed by NAT1 and NAT2 are important in metabolic activation of arylamines to electrophilic intermediates that initiate carcinogenesis. Inflammatory bowel diseases (IBD) consist of Crohn's disease (CD) and ulcerative colitis (UC), both are associated with increased colorectal cancer (CRC) risk. We hypothesized that NAT1 and/or NAT2 polymorphisms contribute to the increased cancer evident in IBD.     

Ulcerative colitis and colorectal cancer. A population-based study

BACKGROUND. The risk of colorectal cancer is increased among patients with ulcerative colitis. The magnitude of this increase in risk and the effects of the length of follow-up, the extent of disease at diagnosis, and age at diagnosis vary substantially in different studies. METHODS. To provide accurate estimates of the risk of colorectal cancer among patients with ulcerative colitis, we studied a population-based cohort of 3117 patients given a diagnosis of ulcerative colitis from 1922 through 1983 who were followed up through 1984. RESULTS. Ninety-two cases of colorectal cancer occurred in 91 patients. As compared with the expected incidence, the incidence of colorectal cancer in the cohort was increased (standardized incidence ratio [ratio of observed to expected cases] = 5.7; 95 percent confidence interval, 4.6 to 7.0). Less extensive disease at diagnosis was associated with a lower risk; for patients with ulcerative proctitis, the standardized incidence ratio was 1.7 (95 percent confidence interval, 0.8 to 3.2); for those with left-sided colitis, 2.8 (95 percent confidence interval, 1.6 to 4.4); and for those with pancolitis (extensive colitis, or inflammation of the entire colon), 14.8 (95 percent confidence interval, 11.4 to 18.9). Age at diagnosis and the extent of disease at diagnosis were strong and independent risk factors for colorectal cancer. For each increase in age group at diagnosis (less than 15 years, 15 to 29 years, 30 to 39 years, 40 to 49 years, 50 to 59 years, and greater than or equal to 60 years), the relative risk of colorectal cancer, adjusted for the extent of disease at diagnosis, decreased by about half (adjusted standardized incidence ratio = 0.51; 95 percent confidence interval, 0.46 to 0.56). The absolute risk of colorectal cancer 35 years after diagnosis was 30 percent for patients with pancolitis at diagnosis and 40 percent for those given this diagnosis at less than 15 years of age. CONCLUSIONS. Close surveillance and perhaps even prophylactic proctocolectomy should be recommended for patients given a diagnosis of pancolitis, especially those who are less than 15 years of age at diagnosis.