直肠异常隐窝病灶对结肠肿瘤的预警作用

目的 评判内镜下直肠异常隐窝病灶(ACF)与结肠病变及高癌变潜能肿瘤(AN)的关系.方法 接受全结肠镜检查的正常、息肉、腺瘤及癌的患者212例,在退镜时用0.4%靛胭脂对直肠进行染色,根据直肠ACF的数目对患者分级,无ACF者为0级,ACF数目为1～4,5～9,≥10者分别为Ⅰ、Ⅱ、Ⅲ级,统计分析ACF级别与结肠病变(息肉、腺瘤和癌),高癌变潜能肿瘤(≥1 cm,绒毛状、管状绒毛状,高度异型增生或浸润癌)的关系.结果 212例患者中,72例直肠ACF为0级,48例为Ⅰ级,41例为Ⅱ级,51例为Ⅲ级.直肠有ACF(包括Ⅰ、Ⅱ、Ⅲ级)的患者发生结肠病变及结肠高癌变潜能肿瘤的概率较无ACF者明显升高,其OR值(95%CI)分别为22.352(6.716～74.395),7.982(1.838～34.672).结论 直肠ACF对结肠病变及高癌变潜能肿瘤有预示作用.     

结肠癌患者直肠异型隐窝灶中脂肪酸合成酶的表达及其意义

背景：异型隐窝灶（ACF）是结直肠上皮性肿瘤最早期的形态学改变,可经腺瘤进展至结直肠癌。脂肪酸合成酶（FAS）在多数人恶性肿瘤组织中呈高表达。目的：检测结肠癌患者直肠ACF中的FAS表达情况,探讨ACF中FAS表达异常在结直肠癌形成中的意义。方法：30例确诊的散发性结肠癌患者纳入研究。以0.2%亚甲蓝溶液行直肠黏膜染色,通过放大结肠镜寻找、识别ACF,选取隐窝数目超过30个的较大的ACF为研究对象。以免疫组化染色检测直肠ACF以及配对结肠癌组织和正常结肠组织中的FAS表达。结果：30例结肠癌患者共确定116个目标ACF,不伴异型增生91个,伴异型增生25个。结肠癌组织中的FAS阳性表达率显著高于ACF和正常结肠组织（76.7%对32.8%和10.0%,P〈0.05）,ACF与正常结肠组织间差异亦有统计学意义（P〈0.05）。伴异型增生的ACF FAS阳性表达率与不伴异型增生者无明显差异（36.0%对31.9%,P〉0.05）。结论：F.AS在结直肠癌腺瘤-癌发生序列的最早期即已出现表达异常,在结直肠癌的形成中发挥重要作用。以FAS抑制剂抑制ACF进展可能成为结直肠癌化学预防的手段之一。     

二甲双胍对直肠异常隐窝病灶抑制作用的研究

[目的]探讨二甲双胍对直肠异常隐窝病灶(Aberrant Crypt Foci,ACF)的抑制作用及其可能机制。[方法]入选经消化内镜发现直肠ACF的非糖尿病患者86例,随机分成二甲双胍组、塞来昔布组及对照组。二甲双胍组口服二甲双胍500 mg 2次/d,塞来昔布组口服塞来昔布200 mg 2次/d,对照组不服用二甲双胍及塞来昔布。在治疗前及治疗后2个月行肠镜检查,予0.4%美兰染色直肠,用放大肠镜观察直肠中亨氏瓣到齿状线之间的ACF个数及形态,分析各组直肠ACF个数在治疗前、后的变化。同时用活检钳在直肠上亨氏瓣到中亨氏瓣之间随机取得直肠正常黏膜处的标本,应用PCNA(proliferating cell nuclear antigen)免疫组化染色及TUNEL(transferase deoxynucleotidyl uridine end labeling)染色法检测直肠正常黏膜的增殖及凋亡情况。[结果]3组治疗前ACF均数及临床特征比较均差异无统计学意义(P0.05)。二甲双胍组、塞来昔布组的ACF均数分别从治疗前的7.30±2.51、7.60±2.34减少至治疗后的4.77±1.57、5.83±1.46(P0.05),且相对于塞来昔布组,二甲双胍组对ACF的抑制作用更明显(P0.05)。对照组的ACF均数在治疗前后分别为7.40±2.11、7.43±2.13,差异无统计学意义(P0.05)。二甲双胍组、塞来昔布组的增殖指数分别从治疗前的48.87±1.78、49.93±2.59减少至治疗后的27.20±1.71、36.97±1.43(P0.05),且二甲双胍组显著低于塞来昔布组(P0.05)。对照组的增殖指数在治疗前后分别为49.17±2.35、49.23±2.42,差异无统计学意义(P0.05)。3组治疗后的凋亡指数分别为3.00±1.14、2.93±0.78、3.07±1.08,与本组治疗前相比均差异无统计学意义(P0.05)。[结论]二甲双胍及塞来昔布对非糖尿病患者的直肠ACF均具有抑制作用,且二甲双胍的作用优于塞来昔布,其机制可能是通过直接作用(非胰岛素依赖)来抑制组织细胞的增殖。     

直肠异常隐窝病灶对大肠癌和进展型腺瘤的预警作用及其危险因素分析

目的 探讨直肠异常隐窝病灶（ACF）对大肠癌及进展型腺瘤的预警作用,并分析其危险因素.方法 应用独立样本t检验、单向方差分析及卡方检验分析比较直肠ACF的均数及发病率,应用Logistic回归分析直肠ACF与大肠癌及进展型腺瘤的关系,观察是否有预警作用,并筛选对ACF有显著意义的危险因素.结果 5个以上ACF显著增加大肠癌及进展型腺瘤的风险（P＜0.05）;高龄和吸烟为ACF的危险因素,而阿司匹林的应用为其保护因素.结论 5个以上ACF对大肠癌及进展型腺瘤有显著预警作用.在大肠癌的早期预防中,我们应该重视对ACF的形成有意义的影响因素.     

异常隐窝病灶研究进展

近20多年来，世界上多数国家大肠癌的发病率呈上升趋势，我国大肠癌发病率上升趋势亦十分显著。一般认为绝大多数大肠癌的发生归咎于腺瘤的癌变，部分直接起源于大肠黏膜生发中心的干细胞，少数可由增生性息肉经锯齿状腺瘤癌变等。但是随着1987年Bird对变异隐窝病灶（aberrant crypt foci，ACF）的首次报道及近年来对ACF的深入研究，ACF被认为是结直肠癌发生过程中可在光镜下观察到的最小和最早期的大肠黏膜病变。     

Ki-67在直肠类癌中的表达及其意义

背景:直肠类癌属于神经内分泌肿瘤,临床上较少见。目前对直径1~2 cm的直肠类癌的治疗方式尚存在争议。目的:检测Ki-67在直肠类癌中的表达水平,探讨直肠类癌内镜切除治疗的疗效和安全性。方法:回顾性收集重庆三峡中心医院和武汉同济医院2008年1月至2013年12月期间确诊为直肠类癌,肿瘤直径1.5 cm、行内镜黏膜切除术的患者83例,分析其病例资料,并以免疫组化方法检测肿瘤组织Ki-67表达。结果:术前内镜超声检查显示83例患者肿瘤均位于黏膜层或黏膜下层,无固有肌层浸润或转移,术后平均随访38个月,无一例患者复发或转移。所有患者肿瘤组织Ki-67均呈低表达(0.84%±0.67%),肿瘤直径1.0 cm与1.0~1.5 cm组间性别、年龄、肿瘤部位、Ki-67表达水平差异无统计学意义(P0.05)。以Ki-67指数均值0.84%为临界值分组,两组间各项临床病理参数差异亦无统计学意义(P0.05)。结论:本组直径1.5 cm的直肠类癌Ki-67均呈低表达,提示肿瘤细胞增殖不活跃。对于直径1.5 cm、无固有肌层浸润或转移、Ki-67低表达的直肠类癌,内镜局部切除治疗安全、有效。     

环氧合酶-2在结肠异常腺窝病灶组织中的表达及临床意义

Bird在1987年首次报道,在接受结肠致癌剂处理的鼠模型结肠黏膜表面可观察到异常腺窝病灶(ACF).ACF多数位于结肠的远端[1],为结肠癌的最早癌前病变,但发生机制尚不明了.我们对异常腺窝病灶组织中环氧合酶(COX)-2蛋白的表达进行检测,以探讨其可能的发生机制.     

异常隐窝病灶与大肠肿瘤关系及发生途径的初步研究

目的 实体镜下连续观察Wistar鼠大肠癌模型中异常隐窝病灶(ACF)的发生情况,探讨ACF与大肠肿瘤的相关性及其发生途径.方法 60只Wismr鼠给予二甲肼皮下注射,每周1次,连续18周,分组处死.将美蓝染色后的大肠组织在实体镜下观察.结果 发现2种不同镜下表现的ACF,即cACF和dACF.dACF与大肠肿瘤形成早期有相似的镜下形态及病理特点,而cACF则无类似特征.cACF与dACF在β-catenin中的表达异常率分别为4.8%和100.0%(P=0.000),在MMP-7中的阳性表达率分别为7.9%和81.8%(P=0.000),dACF与肿瘤在β-catenin的表达异常率以及在MMP-7的阳性表达率上的差异均无统计学意义(P>0.05).结论 cACF与肿瘤发生无明显相关,dACF与肿瘤发生关系密切,其发生遵循Wnt途径.     

放大色素内镜在结直肠肿瘤内镜黏膜切除治疗中的应用

目的 评估内镜黏膜切除术(EMR)结合放大色素内镜诊治结直肠肿瘤的有效性和安全性.方法 收集结肠镜检查患者中符合EMR指征的无蒂型或平坦、凹陷型病灶.观察病灶形态学与EMR术后组织学结果 的相关性,评估放大色素内镜判断病灶浸润深度的准确性.结果 81例患者经EMR切除病灶90个(无蒂型25个,平坦、凹陷型65个).组织学显示低级别上皮内瘤变(LGD)58个,高级别上皮内瘤变(HGD)20个,腺癌12个.其中HGD和癌变病灶直径大于LGD病灶[(1.4±0.5)cm和(1.6±0.5)cm比(1.05:0.4)cm],但组间差异无统计学意义(P>0.05).平坦、凹陷型病灶较无蒂型病灶更易出现HGD或癌,但差异亦无统计学意义[41.5%(27/65)比20.0%(5/25),P=0.084].病灶表面有凹陷者出现HGD或癌的比例显著高于无凹陷者[51.0%(25/49)比17.1%(7/41),P<0.01)].放大色素内镜判断病灶浸润深度的准确性为97.8%(88/90).完整的组织学切除占所有病灶的95.6%(86/90).结论 凹陷型和平坦型伴中央凹陷的结直肠病变的恶性倾向高.应用放大色素内镜能准确判断病灶浸润深度,从而使EMR治疗更安全有效.     

二甲双胍、塞来昔布对化学诱导小鼠结直肠异常隐窝病灶预防作用的比较

[目的]探讨二甲双胍对氧化偶氮甲烷(AOM)诱导的小鼠结直肠异常隐窝病灶(ACF)的预防作用,并与塞来昔布进行比较。[方法]45只6周龄BALB/c雌性小鼠随机分为对照组、二甲双胍组、塞来昔布组,每组15只;均腹腔注射AOM(10mg/kg),每周1次,连续2周以建立ACF模型;同时对照组、二甲双胍组、塞来昔布组小鼠分别予0.9%氯化钠溶液0.5ml·只~(-1)·d~(-1)、二甲双胍250mg·kg~(-1)·d~(-1)、塞来昔布20mg·kg~(-1)·d~(-1)灌胃处理,每周监测小鼠体质量变化。6周后处死小鼠并分离结直肠组织,美蓝染色后计数每只小鼠结直肠ACF个数和每个ACF中畸变隐窝(AC)个数。[结果]各组小鼠体质量随周龄增加均呈现增长趋势,干预后体质量比较均差异无统计学意义(P0.05)。对照组小鼠结直肠ACF及AC数量分别为(8.80±0.84)个、(26.75±2.63)个,二甲双胍组分别为(3.67±0.58)个、(8.33±0.58)个,塞来昔布组分别为(5.60±0.89)个、(13.40±1.67)个;与对照组相比,二甲双胍组、塞来昔布组小鼠ACF及AC均显著减少(P0.05);二甲双胍组小鼠ACF及AC均比塞来昔布组显著减少(P0.05)。[结论]二甲双胍、塞来昔布均能显著抑制ACF形成,对结直肠癌起到预防的作用,且二甲双胍的作用明显优于塞来昔布。     

256例大肠异常隐窝灶的内镜与病理特征分析

目的了解大肠异常隐窝灶的内镜和病理特点,探讨ACF与结直肠肿瘤的关系。方法随机选择2011年8月-2012年3月就诊于江西省萍乡市人民医院准备接受结肠镜检查的患者370例,在距肛门25～30 cm以下给予0.4%靛胭脂染色后观察、记录发现远端大肠ACF病例数及ACF数目,并且行病理检查。结果 370例患者共发现256例ACF病例(69.19%)。正常黏膜组、增生性息肉组、腺瘤组、结肠癌组ACF患病率分别为58.21%、78.18%、82.05%、88.89%。256例ACF患者Ⅰ级106例(41.41%)、Ⅱ级82例(32.03%)、Ⅲ级68例(26.56%)。病理有异型增生病例数39例(10.54%),均为轻度异型增生;病理无异型增生217例(58.65%)。有ACF组增生性息肉的发生率为16.8%,腺瘤的发生率25.0%,结直肠癌的发生率12.5%;而无ACF组分别为10.53%、12.58%、3.51%。结论异常隐窝灶是常见结肠镜下病变,异型增生ACF病变并不少见。ACF可能是结肠腺瘤和大肠癌的独立预测因素。     

Role of aberrant crypt foci detected using high-magnification-chromoscopic colonoscopy in human colorectal carcinogenesis

Abstract Liaison between gastrointestinal endoscopists and histopathologists is essential to provide the highest standards of diagnostic accuracy and patient management. The histopathologist needs to be aware of the endoscopic findings when interpreting endoscopic biopsies. High-magnification-chromoscopic-colonoscopy (HMCC) is a new technology that provides the endoscopists with much greater resolution and functional staining of the gastrointestinal tract. Using HMCC, the endoscopist is now able to identify subtle changes in the colorectal luminal openings or crypts. Changes in crypt appearances now allow detection of aberrant crypt foci (ACF) in the colon, which might themselves be precancerous lesions but additionally might serve as a valid biomarker of subsequent adenoma and colorectal cancer formation. This article describes the role of the aberrant crypt focus in colorectal carcinogenesis and discusses the clinical impact of HMCC techniques as applicable to ACF.     

Aberrant crypt foci: endoscopic assessment and cell kinetics characterization

Background and aims  Aberrant crypt foci (ACF) are preneoplastic lesions in animal models of colorectal cancer. The aim of the study is to investigate if ACF are involved in human colorectal carcinogenic process and if they can be helpful in predicting the presence of a colorectal neoplasia. Methods  The study included, between 2003 and 2005, 182 patients, 62 with adenoma, 55 with colorectal carcinoma, 53 without colorectal lesions, and 12 with nonneoplastic mucosal polyps. The number of rectal ACF was determined by colonoscopy. Proliferation and apoptosis indexes were evaluated by immunohistochemistry in rectal ACF, in normal rectal mucosa, and in carcinomatous tissue. Results  The mean number of rectal ACF in patients with rectal neoplasia was 12.64, significantly higher than in patients with neoplastic lesions elsewhere in the colon (p = 0.01). The apoptosis index in ACF of patients with colorectal carcinoma or adenoma aged 50 years or older was significantly lower than in younger patients (1.3% vs 2.7%, p = 0.01) and, in patients with carcinoma, lower than in normal mucosa (1.1% vs 2.1%, p = 0.002). The proliferation index was significantly higher in ACF of patients with colorectal neoplasia aged less than 50 years than in normal mucosa (10.9% vs 7.7%, p = 0.02). The apoptosis index in ACF foci of patients with carcinoma (1.1%) was significantly lower than in patients without lesions (2.2%) and than in normal mucosa (2%). The mean number of ACF is significantly higher in patients with polyps larger than 1 cm (11.28 vs 6.27, p = 0.02). Conclusion  Aberrant crypt foci probably precede the appearance of neoplasia and may be helpful in predicting the presence of a colorectal neoplastic lesion.     

Reduced susceptibility to azoxymethane-induced aberrant crypt foci formation and colon cancer in growth hormone deficient rats

ObjectivesTo evaluate the role of GH in colon carcinogenesis, we examined the formation of aberrant crypt foci (ACFs) and tumor development in wild type (WT) and GH-deficient, spontaneous dwarf rats (SDRs) exposed to the carcinogen azoxymethane (AOM).DesignACF were quantified by stereomicroscopy and tumor number and weights were recorded for each animal. Cell proliferation was measured by vincristine metaphase arrest, flow cytometry, and bromodeoxyuridine (BrdU) incorporation. Apoptosis was measured by TUNEL staining and cleaved caspase-3 immunohistochemistry. IGF-I was measured by radioimmunoassay (RIA). Hexokinase activity was measured by spectrophotometric assay. PARP cleavage, and IGF-IR, and p27^kip/cip expression were measured by Western blotting.ResultsACFs detected by stereomicroscopy were markedly reduced (～85%) in SDRs vs. WT rats at 10, 25, and 28 weeks after AOM. Tumor incidence, number, and weight also were reduced in SDR vs. WT animals. AOM treatment increased cell proliferation in the distal colon (where tumors occur) of WT rats but not SDRs, and these changes corresponded to increased ACF and tumor formation. Apoptosis rates were similar in AOM-treated WT and SDRs. Alterations in serum IGF-I levels may contribute to differences in the proliferative response to AOM and decreased ACF formation in SDR vs. WT rats.ConclusionsWe conclude that early neoplastic lesions (ACFs) were reduced in GH-deficient animals. This effect corresponds with differences in AOM-induced proliferation, but not apoptosis. These data indicate that GH is required for the full effect of AOM on colon ACF and tumor development, and that the SDR rat is a promising model for studies regarding the role ofGH/IGF system in the initiation and promotion of colon cancer.     

Ursolic acid inhibits the formation of aberrant crypt foci and affects colonic sphingomyelin hydrolyzing enzymes in azoxymethane-treated rats

Ursolic acid (UA) is a pentacyclic triterpenoid, with anti-cancer and anti-inflammatory properties. Sphingomyelin (SM) hydrolysis generates lipid messengers regulating cell survival. Earlier studies showed that UA has anti-proliferative and apoptotic effects on HT29 cells, accompanied by a rapid increase in alkaline sphingomyelinase (Alk-SMase) activity. This study examines the effect of orally administered UA on the formation of aberrant crypt foci (ACF) and intestinal SMase activity in azoxymethane (AOM)-treated rats. Sprague-Dawley rats were divided into eight groups, receiving AOM or vehicle, and fed normal diet or pellets containing 0.11% UA in the initiation or promotion/progression phase. The formation of ACF in the colon and the activities of three types of mucosal SMase were examined. UA significantly reduced the incidence of ACF containing three or more crypts in the initiation group, but had no significant effect in the promotion/progression group. AOM reduced mucosal Alk-SMase activity, and the inhibitory effects could not be prevented by UA. However, in both AOM-treated and normal rats, UA increased the activity of colonic neutral SMase markedly and that of acid SMase activity mildly. These results indicate that UA has chemopreventive effects in the initiation phase of colon cancer associated with changes in SM metabolism.     

Azoxymethane-induced rat aberrant crypt foci： Relevance in studying chemoprevention of colon cancer

The pathogenesis of colon cancer involves sequential and multistep progression of epithelial cells initiated to a cancerous state with defined precancerous intermediaries. Aberrant crypt foci （ACF） represent the earliest identifiable intermediate precancerous lesions during colon carcinogenesis in both laboratory animals and humans. ACF are easily induced by colon-specific carcinogens in rodents and can be used to learn more about the process of colon carcinogenesis. For over two decades, since its first discovery, azoxymethane （AOM）-induced rodent ACF have served as surrogate biomarkers in the screening of various anticarcinogens and carcinogens. Several dietary constituents and phytochemicals have been tested for their colon cancer chemopreventive efficacy using the ACF system. There has been substantial effort in defining and refining ACF in terms of understanding their molecular make-up, and extensive research in this field is currently in progress. In chemoprevention studies, AOM-induced rat ACF have been very successful as biomarkers, and have provided several standardized analyses of data. There have been several studies that have reported that ACF data do not correlate to actual colon tumor outcome, however, and hence there has been an ambiguity about their role as biomarkers. The scope of this mini-review is to provide valuable insights and limitations of AOM-induced rat ACF as biomarkers in colon cancer chemoprevention studies. The role of the dynamics and biological heterogeneity of ACF is critical in understanding them as biomarkers in chemoprevention studies.     

塞来昔布对二甲基肼诱导的大鼠畸变隐窝灶的预防作用

目的　明确塞来昔布 (选择性COX 2抑制剂 )对二甲基肼 (DMH)诱导的大鼠畸变隐窝灶(ACF)的化学预防作用 ,并与舒林酸 (一种非甾体类抗炎药 )进行比较。方法　 32只 8周龄雌性SD大鼠 ,随机分为 4组 ,每组 8只。第 1组单次腹腔注射DMH(每千克体重 12 0mg) ;第 2组单次腹腔注射生理盐水 (1ml/只 ) ;第 3组先舒林酸 (每千克饲料 32 0mg)喂养 7d ,然后注射DMH ;第 4组先塞来昔布(每千克饲料 15 0 0mg)喂养 7d ,然后注射DMH。注射DMH 5周后处死大鼠 ,美蓝染色后计数每只大鼠大肠中ACF和畸变隐窝 (AC)个数。结果　第 1组平均每只大鼠结肠中ACF和AC分别为 (182 .4 0± 93.4 3)和 (2 6 2 .80± 197.80 )个。第 2组没有发现ACF。第 3组ACF和AC分别为 (91.2 5± 4 8.98)和(139.6 0± 6 8.5 2 )个 ,与第 1组相比差异有显著性 (P <0 .0 5 )。第 4组ACF和AC分别为 (6 5 .83± 38.5 4 )和 (10 6 .0 0± 6 1.0 3)个 ,与第 1组相比差异有显著性 (P <0 .0 1)。第 3组与第 4组相比 ,ACF及AC个数差异无显著性。结论　选择性COX 2抑制剂塞来昔布对实验诱导的大鼠ACF具有预防作用 ,其作用与舒林酸相当。     

Relationship of human rectal aberrant crypt foci and formation of colorectal polyp:One-year following up after polypectomy

AIM:To clarify the relationship of human rectal aberrant crypt foci and formation of colorectal polyp.METHODS:Eighty-nine subjects were recruited from the population of Japanese individuals who underwent polypectomy at Yokohama City University Hospital.All patients had baseline adenomas removed at year 0 colonoscopy.Aberrant crypt foci(ACF) were defined as lesions in which the crypts were more darkly stained with methylene blue than normal crypts and had larger diameters,often with oval or slit-like lumens and a thicker epithelial lining.RESULTS:A total of 366 ACFs were identified in 89 patients;all had baseline adenomas removed at the first examination(year 0) colonoscopy and returned for the second(year 1).ACF in the lower rectum were assessed at year 0 and study group were divided into two groups depend on ACF numbers,0-3 or over 3.All participants were examined in the number and maximum size of adenoma.There was no statistical difference in number and maximum size of ACF at year 0,however,maximum size of adenoma was larger in over 3 group than 0-3 group at year 1.CONCLUSION:The number of ACF may be a predictive factor of relatively large adenoma incidence in the pilot phase study.