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1.
目的 探讨粪便硫酸类肝素蛋白多糖2(SDC2)基因甲基化检测在结直肠癌(CRC)筛查中的临床应用价值。方法 通过荧光聚合酶链反应(PCR)法检测在该院胃肠外科或消化内科就诊的96例患者粪便中SDC2基因甲基化情况,并收集其6种血清肿瘤标志物[血清癌胚抗原(CEA)、糖类抗原(CA)19-9、CA125、铁蛋白(SF)、细胞角蛋白19片段(CYFRA-21)、胃泌素释放肽前体(ProGRP)]的联合检测结果及肠镜、病理检查结果,以肠镜及病理检查结果为“金标准”分析比较粪便SDC2基因甲基化与6种血清肿瘤标志物检测对CRC的诊断效能。同时分析粪便SDC2基因甲基化与TNM分期及癌变部位等临床病理特征的关系。结果 根据肠镜或病理检查结果,将96例就诊者分为CRC组(32例)和对照组(64例),CRC组中粪便SDC2基因甲基化检测阳性率为84%(27/32),6种血清肿瘤标志物联合检测阳性率为44%(14/32);对照组中粪便SDC2基因甲基化检测阳性率为3%(2/64),6种血清肿瘤标志物联合检测阳性率为20%(13/64)。粪便SDC2基因甲基化诊断CRC的特异度(97%)、灵敏度(84%...  相似文献   

2.
外周血SEPT9基因甲基化检测在结直肠癌(CRC)诊断和筛查中敏感性及特异性较高,目前有关外周血SEPT9基因甲基化检测的四种算法中,Septin9(1/3)算法灵敏性最高,Septin9(2/3)算法特异性最高.可根据研究的目的进行外周血SEPT9基因甲基化检测的算法选择,满足实际检测需求.SEPT9基因甲基化检测在...  相似文献   

3.
目的 探讨粪便SEPT9(Septin9)基因甲基化检测在结直肠癌诊断中的价值.方法 从126例结直肠癌手术切除癌组织、癌旁组织及其术前粪便中提取DNA,应用多重置换扩增(MDA)结合巢式甲基化特异性PCR(nMSP)检测结直肠癌粪便SEPT9基因甲基化水平;以手术后病理诊断为标准,比较结直肠癌组织和粪便中SEPT9甲基化检测在结直肠癌诊断中的敏感性和特异性.结果 在126例结直肠癌中,癌组织SEPT9检出率为84.1%,癌旁组织检出率为7.9%,二者比较有统计学差异(P<0.01),特异性为92.1%;结直肠癌粪便SEPT9基因甲基化检测结果与组织检测结果一致;在各临床分期之间,SEPT9甲基化检出率无统计学差异(P>0.05).结论 结直肠癌组织SEPT9基因甲基化异常发生率高;粪便SEPT9甲基化异常可作为结直肠癌早期诊断的肿瘤标志物.  相似文献   

4.
目的探讨血清代替血浆检测SEPT9基因甲基化在结直肠癌(CRC)诊断中的价值。方法收集70例CRC患者、38例腺瘤或息肉患者及15例其他肠道疾病患者血清样本。用Epi pro Colon 2.0试剂盒进行SEPT9基因甲基化检测,依据肠镜病理诊断进行验证,比较SEPT9、癌胚抗原(CEA)和粪便潜血试验(FOBT)的敏感性和特异性,并进行统计学分析。结果 CRC患者血清SEPT9的阳性率(81.4%)明显高于对照组(13.2%),差异有统计学意义(χ2=92.814,P0.01)。CRC患者血清SEPT9的敏感性为81.4%(95%CI:72.4%~90.4%)、特异性为86.7%(95%CI:72.4%~100%)。临床分期为Ⅰ期的CRC患者SEPT9阳性率为42.9%,Ⅱ期为88.9%,Ⅲ期为82.4%,Ⅳ期为100%,差异有统计学意义(χ2=16.572,P0.01)。SEPT9的ROC曲线下面积(AUCROC)为0.841,明显高于CEA(0.716)和FOBT(0.792)。3者联合检测AUCROC可达0.935。结论血清SEPT9基因甲基化的检测是早期诊断CRC的有效方法,联合检测CEA及FOBT可以提高诊断效能。  相似文献   

5.
摘要:目的:评价血浆 Septin9 基因甲基化检测试剂盒对结直肠癌(CRC)的诊断价值,并进行性能验证。 方法:收集2016年10月至2017年5月CRC手术患者的术前血浆标本32例及健康成人血浆标本10例。采用血浆 Septin9 基因甲基化检测试剂盒检测两组血浆 Septin9 基因甲基化水平,对该试剂盒诊断CRC的符合率、最低检出限和精密度进行评价,并与癌胚抗原(CEA)和粪便隐血试验(FIT)进行方法学比较。 结果:血浆 Septin9 基因甲基化试剂盒检测CRC患者的阴、阳性符合率为100%;检测限参考品阳性;精密度变异系数<5%,符合基本性能要求。 Septin9 基因甲基化检测用于诊断CRC的敏感性为62.50%,特异性为90.00%,阳性预测值为95.20%,阴性预测值为42.90%。血浆 Septin9 基因甲基化检测对于CRC的检出率为62.50%,明显高FIT(28.13%)及CEA(28.13%)的检出率,差异均具有统计学意义(P均<0.05)。 Septin9 基因甲基化检测的曲线下面积(AUCROC)为0.762。 Septin9 基因甲基化检测对于Ⅰ期CRC的检出率为50.00%。 结论:该血浆 Septin9 基因甲基化试剂盒的性能指标满足预期临床用途要求,可以作为CRC血清学辅助诊断标志物。  相似文献   

6.
目的探讨粪便O6-甲基鸟嘌呤-DNA甲基转移酶基因(MGMT)甲基化和粪便隐血试验(FOBT)联合检测在结直肠癌(CRC)诊断中的价值。方法用甲基化特异性PCR(MSP)及FOBT对56例CRC患者和34例体检健康者进行粪便MGMT基因启动子甲基化联合检测,分析MGMT基因启动子甲基化和FOBT与CRC临床病理特征的关系。结果 CRC患者粪便MGMT基因启动子甲基化率为33.9%,体检健康者为2.9%;联合FOBT检测诊断CRC敏感性为55.4%,明显高于单独MGMT基因甲基化的33.9%(χ2=14.674,P<0.01)和单独FOBT的33.4%(χ2=14.322,P<0.01)。MGMT基因甲基化与CRC患者的肿瘤部位、肿瘤大小、分化程度、Dukes分期均无相关性(P>0.05)。结论联合检测粪便MGMT基因启动子甲基化及隐血可提高CRC的诊断效率,有望成为CRC的非侵入性筛查方法。  相似文献   

7.
结直肠癌(colorectal cancer,CRC)发病率高,致死性强,严重威胁人类健康。Septin9基因与CRC发生密切相关,其在癌组织中呈高度甲基化,是CRC的重要分子特征。检测Septin9基因在患者血浆中的甲基化水平对CRC筛查具有较为理想的效果。该法取样安全、方便,结果准确、稳定,有望取代传统的粪便潜血试验法与结肠镜检法。该文就近年来Septin9基因甲基化在CRC诊断中的研究进展作一综述。  相似文献   

8.
目的 探讨外周血Septin9基因甲基化和血清糖类抗原199(CA199)联合检测在结直肠癌(CRC)筛查中的诊断价值。方法 选取2018年8月至2020年8月云南新昆华医院收治的202例结直肠病变患者为研究对象,其中CRC患者93例(CRC组),结直肠息肉患者109例(结直肠息肉组);同时选择同期体检健康者50例作为对照组。采用实时荧光PCR测定Septin9基因甲基化的情况,化学发光法测定CA199的水平,采用受试者工作特征(ROC)曲线分析Septin9基因甲基化和CA199对结直肠癌的诊断价值。结果 CRC组外周血Septin9基因甲基化和CA199阳性率显著高于结直肠息肉组和对照组(P<0.05),结直肠息肉组Septin9基因甲基化和CA199阳性率亦高于对照组(P<0.05)。Septin9基因甲基化诊断CRC的灵敏度为89.32%,约登指数为0.681 1,AUC为0.793,均高于CA199检测的结果,但CA199诊断CRC的特异度较外周血Septin9基因甲基化高;二者联合检测的灵敏度、约登指数和AUC均较单项检测高(P<0.05)。治疗后,CRC...  相似文献   

9.
粪便DNA甲基化分析在结直肠癌诊断中的应用价值   总被引:4,自引:0,他引:4  
目的研究人粪便中分泌型卷曲相关蛋白2(SFRP2)、增生性息肉蛋白(HPPI)和O^6.甲基鸟嘌呤-DNA甲基转移酶(MGMT)基因甲基化状态及其用于结直肠癌(CRC)筛查的可行性。方法从52例CRC患者、35例结直肠良性疾病患者和24名正常对照者粪便标本中提取DNA,采用甲基化特异性PCR(MSP)技术分析粪便DNA中SFRP2、HPPI和MGMT基因甲基化状态。结果CRC患者粪便SFRF2、HPP1和MGMT基因甲基化阳性率分别为94.2%、71.2%和48.1%;96.2%的CRC和81.8%的癌前病变患者中至少存在1个基因的过甲基化。1例正常粪便标本SFRP2甲基化阳性。联合3个基因诊断CRC和癌前病变的敏感度、特异度、阳性预测值和阴性预测值分别为93.7%、77.1%、84.3%和90.2%。结论联合分析SFRP2、HPP1和MGMT基因甲基化是检测CRC及癌前病变的高敏感性方法。检测粪便基因甲基化有望成为CRC无创诊断或高风险人群筛查的一个新途径。  相似文献   

10.
目的 探讨粪便黏结蛋白聚糖2(SDC2)基因甲基化检测在结直肠癌辅助诊断中的价值。方法选取结直肠癌患者51例(结直肠癌组)、结直肠腺瘤患者22例(腺瘤组)、健康体检者39名(正常对照组),同时收集所有对象的粪便和血清样本,检测粪便SDC2基因甲基化和血清癌胚抗原(CEA)、糖类抗原19-9(CA19-9)水平;其中有26份粪便样本采用P12全自动样本预处理仪和手工法同时进行样本预处理,比较2种方法预处理后检测结果的相关性。采用Peason相关分析评估2种方法之间的相关性,采用kappa检验分析2种方法的一致性。结果 结直肠癌组粪便SDC2基因甲基化阳性率显著高于腺瘤组和正常对照组(P<0.01)。结直肠癌组粪便SDC2基因甲基化阳性率显著高于血清CEA和CA19-9的阳性率(P<0.01)。结直肠癌Ⅰ~Ⅳ期患者之间粪便SDC2基因甲基化阳性率差异均无统计学意义(P>0.05)。结直肠癌Ⅰ~Ⅲ期患者的粪便SDC2基因甲基化阳性率显著高于血清CEA和CA19-9的阳性率(P<0.01)。ROC曲线分析结果显示,粪便SDC2基因甲基化、血清CEA、CA19-9单项检测...  相似文献   

11.
目的 评估检测大肠肿瘤患者粪便中SEPT-9和微RNA(miRNA)-34b/c基因甲基化对大肠肿瘤筛查的临床性能。方法 采用病例对照研究方法,使用甲基化敏感性高分辨率熔解曲线法检测大肠肿瘤患者(大肠癌组35例、大肠腺瘤组47例)和正常对照人群(正常对照组52名)粪便中SEPT-9和miRNA-34b/c基因是否存在甲基化,来评估其筛查大肠肿瘤的性能。结果 大肠癌组SEPT-9和miRNA-34b/c基因的甲基化阳性率分别为68.6%、71.4%,大肠腺瘤组分别为57.4%、63.8%,正常对照组分别为9.6%、11.5%。3组的SEPT-9、miRNA-34b/c基因甲基化阳性率比较差异均有统计学意义(2SEPT-9 = 37.185,2miRNA-34b/c = 40.040,P均< 0.001),利用Bonferroni法进行两两比较,大肠癌组和大肠腺瘤组的甲基化阳性率比较差异无统计学意义,两者与正常对照组比较差异均有统计学意义(P均< 0.001)。3组联合检测SEPT-9和miRNA-34b/c基因的甲基化阳性率为88.6%、76.6%、13.5%,大肠癌组和大肠腺瘤组联合检测的甲基化阳性率均高于SEPT-9单基因检测和miRNA-34b/c单基因检测(P均< 0.05)。结论 检测粪便中SEPT-9和miRNA-34b/c基因甲基化具有效好的大肠肿瘤筛查性能,或许可作为大规模人群筛查大肠肿瘤新的生物标志物组合;多基因甲基化联合检测筛查的性能优于单基因。  相似文献   

12.
DNA methylation biomarkers for blood-based colorectal cancer screening   总被引:4,自引:0,他引:4  
BACKGROUND: Sensitive, specific blood-based tests are difficult to develop unless steps are taken to maximize performance characteristics at every stage of marker discovery and development. We describe a sieving strategy for identifying high-performing marker assays that detect colorectal cancer (CRC)-specific methylated DNA in plasma. METHODS: We first used restriction enzyme-based discovery methods to identify marker candidates with obviously different methylation patterns in CRC tissue and nonpathologic tissue. We then used a selection process incorporating microarrays and/or real-time PCR analysis of tissue samples to further test marker candidates for maximum methylation in CRC tissue and minimum amplification in tissues from both healthy individuals and patients with other diseases. Real-time assays of 3 selected markers were validated with plasma samples from 133 CRC patients and 179 healthy control individuals in the same age range. RESULTS: Restriction enzyme-based testing identified 56 candidate markers. This group was reduced to 6 with microarray and real-time PCR testing. Three markers, TMEFF2, NGFR, and SEPT9, were tested with plasma samples. TMEFF2 methylation was detected in 65% [95% confidence interval, 56%-73%] of plasma samples from CRC patients and not detected in 69% (62%-76%) of the controls. The corresponding results for NGFR were 51% (42%-60%) and 84% (77%-89%); for SEPT9, the values were 69% (60%-77%) and 86% (80%-91%). CONCLUSIONS: The stringent criteria applied at all steps of the selection and validation process enabled successful identification and ranking of blood-based marker candidates.  相似文献   

13.
Review of: Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, Ahlquist DA, Berger BM. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med 2014;370(14):1287–97.

This Practice Pearl reviews the results of a prospective, multicenter, cross-sectional clinical study that evaluated the performance of a new multitarget stool DNA (or mt-sDNA) screening test for colorectal cancer (CRC) and compared it with a fecal immunochemical test (FIT) in individuals at average risk for CRC. The potential impact of this test on the future of CRC screening is also discussed in a brief commentary. mt-sDNA testing is a noninvasive screening test designed to detect DNA biomarkers associated with colorectal neoplasia and occult hemoglobin in the stool. The sensitivity of mt-sDNA testing for detection of CRC was 92.3%, compared with 73.8% for FIT (p = 0.002). Sensitivity for detecting advanced precancerous lesions was 42.4% for mt-sDNA testing and 23.8% for FIT (p < 0.001). The specificities of mt-sDNA testing and FIT were 86.6% and 94.9%, respectively (p < 0.001). mt-sDNA testing thus may be a first-line screening option for asymptomatic individuals at average risk for CRC who do not want to have a colonoscopy.  相似文献   


14.
  目的  评价结肠镜、免疫法粪便潜血检测(fecal immunochemical test,FIT)及风险分级筛查策略在人群结直肠癌筛查中的可行性和有效性。  方法  基于2018年5月—2021年5月全国6个中心开展的人群结直肠癌筛查随机对照试验(TARGET-C研究),将符合要求的受试者按照1∶2∶2的比例随机分配至结肠镜组、FIT组、分级筛查组(经风险评估,高风险人群接受结肠镜检查;低风险人群接受FIT检测,FIT阳性者接受结肠镜检查)。3组人群分别接受不同方案的结直肠癌筛查,其中结肠镜组仅接受基线筛查,FIT组与分级筛查组在基线筛查的基础上接受每年1次的随访筛查。主要研究结局为进展期肿瘤(包括结直肠癌和进展期腺瘤)检出率。比较3种筛查方案的人群参与率、进展期肿瘤检出率和结肠镜检查负荷。  结果  共入选符合纳入与排除标准的受试者19 373名,包括男性8082名(41.7%),女性11 291名(58.3%);平均年龄(60.5±6.5)岁。其中结肠镜组3883名、FIT组7793名、分级筛查组7697名。FIT组与分级筛查组已完成2轮次随访筛查。FIT组整体人群筛查参与率最高(99.3%),分级筛查组次之(89.2%),结肠镜组最低(42.3%)。意向性分析结果显示,结肠镜组进展期肿瘤检出率高于FIT组(2.76%比2.17%,OR结肠镜组比FIT组=1.30,95% CI:1.01~1.65,P=0.037),结肠镜组与分级筛查组进展期肿瘤检出率无统计学差异(2.76%比2.35%,OR结肠镜组比分级筛查组=1.19, 95% CI:0.93~1.51,P=0.156),分级筛查组与FIT组进展期肿瘤检出率亦无统计学差异(2.35%比2.17%,OR分级筛查组比FIT组=1.09,95% CI:0.88~1.34,P=0.440)。以每检出1例进展期肿瘤所需要的结肠镜检查次数作为评价人群筛查时结肠镜检查负荷的指标,结肠镜组的结肠镜检查负荷最高(15.4次),分级筛查组次之(10.2次),FIT组最低(7.8次)。  结论  基于结直肠癌风险评估的分级筛查策略对于人群结直肠癌的筛查具有可行性和有效性,可作为传统结肠镜检查和FIT筛查方案的有效补充。  相似文献   

15.
BACKGROUND: Testing for mutant K-ras in stool has been proposed for the detection of pancreatic and colorectal cancer (CRC). Different analytical techniques have been developed, but studies of this biomarker in the general population are lacking. We investigated the prevalence and potential determinants of mutant K-ras in stool in a large sample of unselected older adults and assessed the association with colonoscopic findings. METHODS: In stool samples from 875 older adults (age range 50-75 years) participating in a large-scale population-based cohort study, we used mutant-enriched PCR and allele-specific hybridization reaction to analyze mutations in codons 12 and 13 of the K-ras gene. We assessed the association between mutant K-ras in stool and risk factors for gastrointestinal cancer sites, exocrine pancreatic insufficiency determined by fecal pancreas elastase 1, and colonoscopic findings. RESULTS: The overall prevalence of mutant K-ras in stool was 8% (95% confidence interval 6%-10%). There was a tentative association between increased fecal pancreas elastase 1 and mutant K-ras in stool (P = 0.09). Patients with advanced colorectal neoplasia diagnosed within 2 years after stool collection (24 with advanced adenomas, 7 with CRC) all tested negative. CONCLUSION: The proposed assay identifies mutant K-ras in stool at a higher prevalence than has been reported for other analytical techniques. Our findings do not support the use of this assay for CRC screening, but its potential use for early detection of pancreatic cancer (in combination with other markers) requires further investigation.  相似文献   

16.
BackgroundColonoscopic examination is the common pathway for positive screening tests detecting colorectal lesions. We evaluated a specific, quantitative high-throughput automatic immunochemical fecal occult blood test (Auto iFOBT) method for colorectal cancer (CRC) screening and to determine its concordance with physician assessments informed by complete colonoscopy, the gold-standard technique for evaluation of the colonic mucosa.Methods1200 CRC symptomatic patients were recruited for a retrospective investigation. Colorectal neoplasia were localized by colonoscopy and cancer outcomes were enumerated according to severity. In addition, stool samples were collected and analyzed by Auto iFOBT to derive sensitivity, specificity, and positive predictive value. Qualitative colonoscopy and Auto iFOBT results were correlated, as were cancer severities and quantitative hemoglobin concentrations.ResultsNinety-one patients were found positive for CRC; 50 mucosal, 20 submucosal, and 21 advanced. At standard cutoff, sensitivity was 60%, 90%, and 95%, respectively. Specificity and positive predictive value for all neoplasia and cancers were 89.6% and 86.4%, and 60.9% and 33.7%, respectively. Cancer severities could be approximated roughly according to hemoglobin concentrations.ConclusionsSpecific qualitative 2-day Auto iFOBT is an accurate tool for the detection of colorectal cancer and therefore provides the basis for a large-scale screening program.  相似文献   

17.
ObjectiveTo assess health care provider (HCP) preferences related to colorectal cancer (CRC) screening overall, and by HCP and patient characteristics.Participants and MethodsWe developed a survey based on the Theoretical Domains Framework to assess factors associated with CRC screening preferences in clinical practice. The survey was administered online November 6 through December 6, 2019, to a validated panel of HCPs drawn from US national databases and professional organizations. The final analysis sample included 779 primary care clinicians (PCCs) and 159 gastroenterologists (GIs).ResultsHCPs chose colonoscopy as their preferred screening method for average-risk patients (96.9% (154/159) for GIs, 75.7% (590/779) for PCCs). Among PCCs, 12.2% (95/779) preferred multi-target stool DNA (mt-sDNA), followed by fecal immunochemical test (FIT), (7.3%; 57/779) and guaiac-based fecal occult blood test (gFOBT) (4.8%; 37/779). Preference among PCCs and GIs generally shifted toward noninvasive screening options for patients who were unable to undergo invasive procedures; concerned about taking time from work; unconvinced about need for screening; and refusing other screening recommendations. Among PCCs, preference for mt-sDNA over FIT and gFOBT was less frequent in larger compared with smaller clinical practices. Additionally, preference for mt-sDNA over FIT was more likely among PCCs with more years of clinical experience, higher patient volumes (> 25/day), and practice locations in suburban and rural settings (compared to urban).ConclusionBoth PCCs and GIs preferred colonoscopy for CRC screening of average-risk patients, although PCCs did so less frequently and with approximately a quarter preferring stool-based tests (particularly mt-sDNA). PCCs’ preference varied by provider and patient characteristics. Our findings underscore the importance of informed choice and shared decision-making about CRC screening options.  相似文献   

18.
ObjectiveTo estimate the cost-effectiveness of multitarget stool DNA testing (MT-sDNA) compared with colonoscopy and fecal immunochemical testing (FIT) for Alaska Native adults.Patients and MethodsA Markov model was used to evaluate the 3 screening test effects over 40 years. Outcomes included colorectal cancer (CRC) incidence and mortality, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). The study incorporated updated evidence on screening test performance and adherence and was conducted from December 15, 2016, through November 6, 2019.ResultsWith perfect adherence, CRC incidence was reduced by 52% (95% CI, 46% to 56%) using colonoscopy, 61% (95% CI, 57% to 64%) using annual FIT, and 66% (95% CI, 63% to 68%) using MT-sDNA. Compared with no screening, perfect adherence screening extends life by 0.15, 0.17, and 0.19 QALYs per person with colonoscopy, FIT, and MT-sDNA, respectively. Colonoscopy is the most expensive strategy: approximately $110 million more than MT-sDNA and $127 million more than FIT. With imperfect adherence (best case), MT-sDNA resulted in 0.12 QALYs per person vs 0.05 and 0.06 QALYs per person by FIT and colonoscopy, respectively. Probabilistic sensitivity analyses supported the base-case analysis. Under varied adherence scenarios, MT-sDNA either dominates or is cost-effective (ICERs, $1740-$75,868 per QALY saved) compared with FIT and colonoscopy.ConclusionEach strategy reduced costs and increased QALYs compared with no screening. Screening by MT-sDNA results in the largest QALY savings. In Markov model analysis, screening by MT-sDNA in the Alaska Native population was cost-effective compared with screening by colonoscopy and FIT for a wide range of adherence scenarios.  相似文献   

19.
Background Magnetic resonance colonography (MRC) with fecal tagging has recently been investigated in clinical studies for the detection of polyps. We assessed fecal tagging MRC in a field trial. Methods Forty-two patients in a private gastroenterologic practice underwent MRC with barium-based fecal tagging (150 mL of 100% barium at each of 6 main meals before MRC) and conventional colonoscopy. Diagnostic accuracy of MRC and patient acceptance were assessed and compared with the respective results of conventional colonoscopy. Results Eighteen percent of all MRC examinations showed a remaining high stool signal in the colon that impeded a reliable inclusion or exclusion of polyps. On a lesion-by-lesion basis, sensitivities for polyp detection were 100% for polyps larger than 2 cm (n = 1), 40% for polyps between 10 and 19 mm, 16.7% for polyps between 6 and 9 mm, and 9.1% for polyps smaller than 6 mm. The main reason for the low acceptance of MRC was the barium preparation, which was rated worse than the bowel cleaning procedure with conventional colonoscopy. Conclusion MRC with fecal tagging must be further optimized. The large amount of barium resulted in poor patient acceptance, and barium according to this protocol did not provide sufficient stool darkening. Other strategies, such as increasing the hydration of stool, must be developed.  相似文献   

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