农村现场肝癌早筛早诊队列建设与应用

1、启东农村现场肝癌早筛早诊队列建设与应用I. 背 景2历史沿革1972年12月8日发文建立启东县肝癌防治研究领导小组启东县肿瘤防治组3历史沿革1976年4月1日发文 挂牌启东肝癌防治研究所N JG4历史沿革1998年3月28日 成立启东市肿瘤诊疗中心2006年9月21日 增挂牌子 启东市肿瘤医院2011年5月与 启东市人民医院 合并QDLCI CHEN JG5第一批上海市 派遣赴启东县肿瘤科研小分队 1971年11月 X 5 年 队长为上海市肿瘤医院原副院长俞鲁谊，指导员为上海市肿瘤医院的许维珍。 队员合计13人，来自上海市肿瘤医院、上海中山医院、上海市肿瘤研究所、上海第一医学院等内外科、妇科、

2、护理、检验及卫生统计专业。QDLCI CHEN JG6第一批江苏省 启东科研医疗队X 5 年 1972年10月 队长为江苏省人民医院副院长(当时称副主任)薛集安，指导员是江苏新医学院（现南京医科大学及南京中医药大学）的尹力。 队员合计30人，来自省人民医院、省中医研究所、南京大学、南通医学院（现南通大学）及附院、省地理研究所、中科院南京土壤研究所、江苏新医学院、江苏农学院（现扬州大学）、省农药研究所（扬州）、省地质水文大队等单位。QDLCI CHEN JG7Mortality from Liver Cancer by Township:Jiangsu Province 50 per 105/y

3、rin HCC ratein 200 kmMedian age of liver cancerdeath is 45-50 yearsQidongShanghaiChen JG, Zhang SW. Seminar Cancer Biol. 2011; 21(1): 59-69.9主要病因Factors Attributed toLiver CancerKensler TW, et al. Nature Rev Cancer, 2003主要危险因素乙肝病毒黄曲霉毒素发病水平Crude Rate, ASR, Truncated Rate and Cummurative Ratefor Incid

4、ence of Leading Cancer Sites in Qidong, 1972-2011截缩率Trunc. Rate累积率Cum.Rate累积危险Cum. Risk0-74部位Site位次例数CRCASR(1/105)WASR(1/105)ICD-10%Rank No.Cases (1/105)35-64(1/105)0-640-74(%)(%)(%)肝 Liver胃 Stomach肺 LungC22C16C33-34123456789283981540115340603544143452327919301785161963.1734.2634.1213.439.8239.3216.

5、2515.746.204.184.653.293.472.671.5250.7125.5925.419.807.086.135.363.923.342.5530.6116.6016.536.504.763.723.532.081.921.74119.0640.0336.9614.369.034.001.411.320.510.320.490.260.250.230.125.285.153.103.221.150.880.640.660.360.360.293.153.271.160.880.640.670.360.360.29结直肠Colonrectum C18-21食管 Esophagus乳

6、腺 Breast胰腺 Pancreas白血病 Leukemia脑（CNS) Brain膀胱 BladderC15C50C25C91-95C70-72C677.6815.317.447.294.294.813.971.92103.603.30NHLC82-85/961114723.271.962.651.594.270.170.300.30宫颈鼻咽C53C11121312118292.691.841.501.102.101.471.310.894.393.130.150.110.230.160.230.16多发性骨髓瘤C90147151.590.841.240.771.960.070.160.1

7、6皮肤其它骨C441516177015945311.561.321.180.610.820.391.061.080.760.760.640.571.121.570.350.040.070.010.100.120.080.100.120.08C40-41C61前列腺胆囊胆管C23-24185301.180.540.850.571.310.040.100.10卵巢小肠C56C1719204724101.050.910.650.420.860.660.510.441.890.920.070.030.090.070.090.07全部All92780206.39110.80159.11100.00288

8、.4410.1018.1916.63粗发病率标化发病率Crude Incidence of leading cancer sitesCASR of leading cancer sites, Qidong100101100101LiverStomachLungLiverColon-rectumStomachLungEsophagusBreastColon-rectumPancreasLeukemiaEsophagusBreastPancreasLeukemia1972 1977 1982 1987 1992 1997 2002 2007 20121972 1977 1982 1987 1992

9、 1997 2002 2007 2012YearYearII. 早诊早治13启东肝癌筛查工作的历程第1阶段：1970s 采用甲胎蛋白（AFP）检测方法，在启东自然人群中检测 AFP 200多万人次，其中普查近180万人次，检出肝癌1000多例，其中早期(期)病例达到35%。这个阶段解决了肝癌早期诊断的问题，证实AFP 应用于现场的普查，其简便、易行、敏感、特异。QDLCI CHEN JG14启东肝癌筛查工作的历程第2阶段：1980s 启东重新估价了AFP 普查的作用，认为 AFP 普查的关键取决于普查对象、范围的择优选择；因此提出了选择特定的高危人群进行肝癌筛检的概念。在这个阶段，明确提出乙型

10、肝炎表面抗原（HBsAg）阳性的3059岁的男性为启东肝癌的高危险人群。QDLCI CHEN JG15高风险人群MaleHigh risk pop. 30-59 YrsHBsAg (+)Sex性别FemaleMale03060Age 年龄（+）（-）GeneralpopulationHBsAg乙型肝炎表面抗原启东肝癌筛查工作的历程第3阶段：1990s 选定启东40万人群范围中的肝癌高危险人群进行了周期性的筛查实践，确立了肝癌高危险人群筛检模式和可行方案。于“八五”期间对肝癌高危险人群模式、现场实施方案以及周期性筛检的亚临床平均滞溜时间、灵敏度和预测值及普查的超前时及最佳筛检间隔等进行了评价分析

11、 。QDLCI CHEN JG17启东肝癌筛查工作的历程第4阶段：2005 卫生部疾病控制局和中国癌症基金会根据中国癌症预防与控制规划纲要（2004-2010年）的部署，会同部分省卫生厅共同建立了癌症早诊早治示范基地，启动了癌症早诊早治项目。 江苏启东与广西扶绥作为全国肝癌早诊早治示范基地，自2007年开展了以肝癌的早诊早治筛查工作。“肝癌早诊早治示范基地”挂牌仪式建立市癌症早诊早治领导小组超 前 时计算出高年龄段 (4459岁)与低年龄段(3044岁)的平均滞留时间(MST)值分别为0.47年和 0.55 年，总的超前时为 0.49 年。用AFP和超作为筛查手段，筛查相对于未筛查的死亡危险度

12、显著下降 （OR0.631），筛查可以降低肝癌死亡的危险。筛 检 间 隔用Logistic 模型分析连续阴性筛查次数及最后一次阴性筛查至病例诊断的持续时间(TSLT)：阴性筛查对肝癌死亡的保护效应随时间的推移而逐步下降, 至阴性筛检后1.5年左右消失，说明两次筛查的间隔不能超过一年半。 AFP一次阴性筛查后，OR下降至基准的1020%左右; 连续次阴性筛查后, OR值下降至基准的12%。因此, 连续2次阴性筛查后可适当延长下次筛检时间。可检测的临床前期（DPP）经对前瞻资料统计进行再抽样组成病例对照,对最后一次阴性筛查至肝癌死亡的持续时间的分析来确定DPP。结果当DPP为 14 个月时, 最大

13、对数拟然值达极大, 因此用FP筛查肝癌的DPP为14 个月, 即应在病例诊断前一年半内进行筛检,效益最佳；也说明筛查可以提前诊断肝癌。Survival of liver cancer cases in screened(n = 240) and control (n = 108) groups(2 month prevalent cases excluded)1.0CTRLSCREENED0.80.60.40.20.001224364860MONTHS24国 家 卫 计 委癌 症 基 金 会QDLCI CHEN JG25Early Diagnosis and Treatment for the

14、 Liver CancerCases Screened from a Recent Program QidongEarly Diag.Cases inEarly TreatmentCases inDetectionRate inGroup A%PersonTimesScreenedNo. Cases *YearGroup AGroup AGroup A Group BNo.%No.%2007200820092010201120122013201420151 6162 5763 5673 6384 4814 4654 2254 3614 27015253227202019111713611141

15、21371.861.941.791.480.890.900.900.500.8011 73.33 1216 64.00 1927 84.38 3025 92.59 2515 75.00 1917 85.00 1715 78.95 1780.0076.0093.7592.5995.0085.0089.47100.00100.00763.64 111516 94.12 17合计33 199186821.12149 80.11 16789.78* Group A: Detected by screening; Group B: Found between the screening points.2

16、6III. 队列应用271. 前瞻研究队列在筛查的基础上，开展肝癌的前瞻研究2829HBsAg Cohort and Person YearsFollowed up (1977-2007)HBsAg CarrierHBsAg Non-carrierAll.AgeMFM+FMFM+FMFM+F15-20-25-30-35-40-45-50-55-60-65-70+338.0920.0562.01363.02222.42982.23472.43943.63897.33232.22580.21896.01474.52387.8900.02283.03680.64799.55590.86308.661

17、48.65017.83978.53033.22332.13777.31557.04375.92782.07259.64339.011635.519024.524447.428794.633593.335680.932393.028089.324473.421422.343561.81895.05295.93344.08622.65239.013918.522705.129246.934385.439902.041829.537410.732067.827506.623754.447339.11458.21817.32118.42365.02251.31785.61398.31137.2857.

18、67044.211980.315460.618306.221387.022661.820650.617816.015363.513342.327026.18502.414202.718442.821778.625330.726559.123882.720396.217259.514816.829413.98986.810804.112606.814571.315270.413528.011671.610247.18937.610488.412206.313019.111742.410273.39109.98080.01389.516535.717925.2合计 17836.4 30013.6

19、47850.0 113419.0 194036.0 307455.0 131255.4 224049.6 355305.0HBsAg Carrier State and Liver Cancerby Period, Qidong, ChinaHBsAg (+)HBsAg (-)PeriodSexRR95% CIP-YrsNo.RateP-YrsNo.Rate11030127974118371.71476546659816833.5811.0711.7111.7911.9817.0613.6912.3010.4611.706.08-21.134.84-31.127.22-19.818.09-18

20、.009.27-33.139.88-19.218.96-17.046.70-16.549.06-15.19MF1977-1986140.66247.62619.30193.96356.58661.57183.25361.5512.0121.0151.7011.3726.0453.7817.5230.90238275911425275428.824391554613495T13402.221653.535055.717836.430013.647850.083MF1977-19981977-200742131982.7207411.5113419.0194036.0307455.01251185

21、5TMF173THBVAge Specific Rates of Liver Cancerin HBsAg Carriers and Non-Carriers10000Chen JG, et al. Chin J Epidemiol,2010, 31(7): 721-726.100010010M 37.76F 10.46M 3.07HBs Ag(+) 男HBs Ag(+) 女HBs Ag(-) 男HBs Ag(-) 女 F 1.00125-30-35-40-45-50-55-60- 65- 70+32Age2. 免疫预防队列建立新生儿出生免疫队列开展随访研究33HB Vaccination S

22、tudy, 1984-1990, Qidong1400012000581456377376575672531000080006000400020000Control40,828518965315863520656394707Vaccinated40,6056930191876141984 1985 1986 1987 1988 1989 1990YearsImmunizationAimed to observe the final result of incidence rateof liver cancer by HBV vaccination in childrenCumulative m

23、ortality probability of liver diseasesin the vaccination and control groups.363. 基因突变研究利用筛查队列开展嵌式病例对照研究37Screening (A) and control (B) cohortsStudy design: size and the times of screening examinations (X)36,000+ men screened5581 HBsAg(+)SubjectsX+1158 X X37121869A2554 XB 1346 XXXXXXX+523Blood sample

24、s were collected and storedYe ar (1989)199019911992199319941995X = Screening38Qidong Liver Cancer Cohort (1989-2003)667 Cases of Liver Cancer from the cohort536 Samples with sufficient serum volume ( 100 l)515 Cases deceased prior to 12-31-2003355 (69%) DNA recovered from serum295 (83%) Mutation at

25、1762T/1764A83% of analyzable serum samples containeddouble mutation HBV DNAChen JG, et al. Acceleration to death from liver cancer in people with hepatitis B viralmutations detected in plasma by mass spectrometry. CEBP, 2007, 16(6):1213-1218.ENHANCED RISK OF LIVER CANCER FROMHBV DOUBLE MUTATION (% P

26、OSITIVE)Chen JG, et al. CEBP, 2005P = 0.083P = 0.01282938674P = 0.0688878928370908065887685A higher prevalenceof HBV mutations wasobserved in thosewho had shortersurvival times afterthe determination ofmutation Mutations are more common in younger people40Diamond Graph modeling from Li & Muoz, Am St

27、atistician (2003)Muoz A, Chen JG, Egner PA,et al. Carcinogenesis. 2011, 32(6): 860-865OR = 6.72图示病例组的HBV突变水平在50%百分位时是对照组的16倍病例对照The level of the HBV mutation was 15-fold greater at 50th percentile incases than in controls (P 40-fold)10080604020黄曲霉毒素白蛋白加合物过去28年中，黄曲霉毒素的暴露已经大大下降001989 1995 1999 2003 20

28、09 2012检不出样本的百分比204060801006. 早诊早治队列53High Risk PopulationMaleHigh risk pop. 30-59 YrsHBsAg (+)Sex性别FemaleMale03060Age年龄（+）（-）GeneralpopulationHBsAg乙型肝炎表面抗原15581 HBsAg+ve screendfrom 50 000+ residents.Survival of liver cancer cases in screened(A: n = 240) and control (B: n = 108) groups(2 month prev

29、alent cases excluded)1.0Group B:Group A:CTRLStage I: 6.0%Stage I: 29.6%SCREENED0.80.60.40.20.001224364860MONTHS56Chen JG, Parkin DM, Chen QG, et al. J Med Screen. 2003,10(4):204-209Early Diagnosis and Treatment for the Liver CancerCases Screened from a Recent Program QidongEarly Diag.Cases inEarly T

30、reatmentDetectionRate inGroup A%PersonTimesScreenedNo. Cases *Cases inGroup AYearGroup AGroup A Group BNo.%No.%2007200820092010201120122013201420151616257635673638448144654225436142701525322720201911171361114121371.861.941.791.480.890.900.900.500.8011 73.33 1216 64.00 1927 84.38 3025 92.59 2515 75.0

31、0 1917 85.00 1715 78.95 1780.0076.0093.7592.5995.0085.0089.47100.00100.00763.64 111516 94.12 17合计33199186821.12149 80.11 16789.78* Group A: Detected by screening; Group B: Found between the screening points.57反复筛查发现肝癌病例与自助就诊发现病例生存率比较（2007-2015）陈建国, 等. 中华肿瘤杂志, 发表中58IV. 效果评价59Analysis of HBV Mutations

32、 in PlasmaSamples of Liver Cancer Cases Plasma samples of adequate volume were available for 512 ofthe 667 liver cancer cases. HBV DNA was found in 371 (72.5%) of 512 samples. Using mass spectrometry, mutations in HBV weredetermined and 294 (79.2%) of these samplescontained a two nucleotide 1762T/17

33、64A mutation. 37 of the 294 samples had an additional doublemutation in the HBV X-gene coding sequence. 16 samples had novel mutations in the 1761 to 1767 region ofthe HBV genome. All detectable mutations were in the X-gene region.Most of the decline in liver cancer has occurredin young and middle a

34、ge birth cohorts60- 64 years old大部分肝55- 5950- 5445- 4940- 44100101likely vaccinatedin 2002 as 5 -10year olds癌的下降出现在中青年出生队列中35-393perhaps 25%vaccinatedno vaccinationvaccination0.11938-421948-52 1958-62 1968-72 1978-82 1988-92 1998-20021953-57 1963-67 1973-77 1983-87 1993-971943-47启东癌症登记处资料Data from Q

35、idong Cancer RegistryFive Year Birth CohortsEnvironmental Exposures are Associated withDeclining Liver Cancer Mortality in Qidong环境暴露物与启东肝癌死亡率的下降有关DifferentcohortsChen JG, Egner PA et al. CAPR 2013The difference (effectiveness) of early detection andtreatment in the field secondary prevention practice.ScreeningcohortGeneralpopulationIs that