The Qidong Liver Cancer Institute (QDLCI) and the Qidong Cancer Registry were established in 1972 with input from doctors, other medical practitioners, and non-medical investigators arriving from urban centers such as Shanghai and Nanjing. Medical teams were established to quantify the extent of primary liver cancer in Qidong, a corn-growing peninsula on the north side of the Yangtze River. High rates of liver cancer were documented and linked to several etiologic agents, including aflatoxins. Local corn, the primary dietary staple, was found to be consistently contaminated with high levels of aflatoxins, and bioassays using this corn established its carcinogenicity in ducks and rats. Observational studies noted a positive association between levels of aflatoxin in corn and incidence of liver cancer across townships. Biomarker studies measuring aflatoxin B1 and its metabolite aflatoxin M1 in biofluids reflected the exposures. Approaches to decontamination of corn from aflatoxins were also studied. In 1993, investigators from Johns Hopkins University were invited to visit the QDLCI to discuss chemoprevention studies in some townships. A series of placebo-controlled clinical trials were conducted using oltipraz (a repurposed drug), chlorophyllin (an over-the-counter drug), and beverages prepared from 3-day-old broccoli sprouts (rich in the precursor phytochemical for sulforaphane). Modulation of biomarkers of aflatoxin DNA and albumin adducts established proof of principle for the efficacy of these agents in enhancing aflatoxin detoxication. Serendipitously, by 2012, aflatoxin exposures quantified using biomarker measurements documented a many hundred-fold reduction. In turn, the Cancer Registry documents that the age-standardized incidence rate of liver cancer is now 75% lower than that seen in the 1970s. This reduction is seen in Qidongese who have never received the hepatitis B vaccination. Aflatoxin mitigation driven by economic changes switched the dietary staple of contaminated corn to rice coupled with subsequent dietary diversity leading to lower aflatoxin exposures. This 50-year effort to understand the etiology of liver cancer in Qidong provides the strongest evidence for aflatoxin mitigation as a public health strategy for reducing liver cancer burden in exposed, high-risk populations. Also highlighted are the challenges and successes of international team science to solve pressing public health issues.

Liver cancer causes upwards of 1 million cancer deaths annually and is projected to rise by at least 55% over the next 15 years. Two of the major risk factors contributing to liver cancer have been well documented by multiple epidemiologic studies and the hepatitis B virus (HBV) and aflatoxin show a synergy that increases by more than 8-fold the risk of liver cancer relative to HBV alone. Using the population-based cancer registry established by the Qidong Liver Cancer Institute in 1972 and aflatoxin-specific biomarkers, we document that reduction of aflatoxin exposure has likely contributed to a nearly 70% decline in age-standardized liver cancer incidence over the past 30 years despite an unchanging prevalence of HBV infection in cases. A natural experiment of economic reform in the 1980s drove a rapid switch from consumption of heavily contaminated corn to minimally, if any, contaminated rice and subsequent dietary diversity. Aflatoxin consumption appears to accelerate the time to liver cancer diagnosis; lowering exposure to this carcinogen adds years of life before a cancer diagnosis. Thus, in 1990 the median age of diagnosis was 48 years, while increasing to 67 years by 2021. These findings have important translational public health implications since up to 5 billion people worldwide might be routinely exposed to dietary aflatoxin, especially in societies using corn as the staple food. Interventions against aflatoxin are an achievable outcome leading to a reduction in liver cancer incidence and years of delay of its nearly always fatal diagnosis.

Background and aims: Liver cancer is one of the most dominant malignant tumors in the world. The trends of liver cancer mortality over the past six decades have been tracked in the epidemic region of Qidong, China. Using epidemiological tools, we explore the dynamic changes in age-standardized rates to characterize important aspects of liver cancer etiology and prevention. Methods Mortality data of liver cancer in Qidong from 1958 to 1971 (death retrospective survey) and from 1972 to 2017 (cancer registration) were tabulated for the crude rate (CR), and age-standardized rate and age-birth cohorts. The average annual percentage change was calculated by the Joinpoint Regression Program. Results The natural death rate during 1958–2017 decreased from 9‰ to 5.4‰ and then increased to 8‰ as the population aged; cancer mortality rates rose continuously from 57/105 to 240/105. Liver cancer mortality increased from 20/105 to 80/105, and then dropped to less than 52/105 in 2017. Liver cancer deaths in 1972–2017 accounted for 30.53% of all cancers, with a CR of 60.48/105, age-standardized rate China (ASRC) of 34.78/105, and ASRW (world) of 45.71/105. Other key features were the CR for males and females of 91.86/105 and 29.92/105, respectively, with a sex ratio of 3.07:1. Period analysis showed that the ASRs for mortality of the age groups under 54 years old had a significant decreasing trend. Importantly, birth cohort analysis showed that the mortality rate of liver cancer in 40–44, 35–39, 30–34, 25–29, 20–24, 15–19 years cohort decreased considerably, but the rates in 70–74, and 75+ increased. Conclusions The crude mortality rate of liver cancer in Qidong has experienced trends from lower to higher levels, and from continued increase at a high plateau to most recently a gradual decline, and a change greatest in younger people. Many years of comprehensive prevention and intervention measures have influenced the decline of the liver cancer epidemic in this area. The reduction of intake levels of aflatoxin might be one of the most significant factors as evidenced by the dramatic decline of exposure biomarkers in this population during the past three decades.

该文简要介绍中国肿瘤防治高发现场之一的江苏启东,在党和政府的领导下,在医疗队专家们的支持和帮助下,开展肝癌防治工作所经历的创业与发展的几个侧面;回忆了部分代表性管理者和专家们对启东肝癌防治事业的贡献,介绍了部分代表性研究工作的成就,并就现场肿瘤防治所获得的启示作了回顾,对于今后的发展提出思考与展望.

Background: There was rare data to describe decades’ long natural history or changes of a cancer. We describe and explore the characteristics and trend of liver cancer mortality in Qidong, China over the past 60 years. Methods: Mortality data of liver cancer in Qidong from 1958 to 1971 (death retrospective survey) and from 1972 to 2017 (cancer registration) were tabulated for the crude rate (CR), age-standardized rate (by China’s population, ASRC and by Worlld population, ASRW) and age-birth cohorts. The average annual percentage change (AAPC) was calculated by the Joinpoint Regression Program. Findings: The natural death rate during 1958-2017 decreased from 9‰ to 5.4‰ and then increased to 8‰; Cancer mortality rate rose continuously from 57/10 5 to 240/10 5 . Liver cancer mortality increased from 20/10 5 to 80/105, and then dropped to less than 52/105 in 2017. Liver cancer deaths in 1972-2017 accounted for 30.53% of all cancers, with CR of 60.48/105, ASRC of 34.78/105, and ASRW of 45.71/105. The truncated rate of 35-64 was 104.06/105, cumulative mortality rate of 0-74 years, and cumulative risk rate were 4.79% and 4.68%, respectively. The CR for males and females were 91.86/105 and 29.92/105, respectively, with a sex ratio of 3.07:1. From 1972 to 2017, the AAPC of the ASRW derived by the Joinpoint analysis was -1.3%, in which -1.5% for men and -1.0% for women. The AAPC of joinpoints was -1.8% for both sexes, and -1.8% for males, -1.4% for females, respectively. Period analysis shows that the age-specific mortality rates of the age groups under 54 years old had a significant decreasing trend. Birth cohort analysis showed that the mortality rate of liver cancer in 40-44, 35-39, 30-34, 25-29, 20-24, 15-19 years cohort decreased, but the rates in 70-74, and 75+ were increased. Interpretation: The crude mortality rate of liver cancer in Qidong has experienced trends from lower to higher levels, and from continued increase at a high plateau to most recently a gradual decline, and change greatest in younger people. Many years of comprehensive prevention and intervention measures may have influenced the decrease of the liver cancer epidemic in this area. The reduction of intake levels of aflatoxin might be one of the most significant factors as evidenced by the decline of exposure biomarkers in this population. Funding Statement: The US National Institutes of Health through grants R01 CA196610 and R35 CA197222, the Chinese National Key Projects (2008ZX10002-015, 2008ZX10002-017, 2012ZX10002009), the Scientifc Research Projet of “333 Project” in Jiangsu (BRA2019030), and the Nantong Science and Techonology Project (MS22019008). Declaration of Interests: The authors declare no competing interests related to this study.

Background: Airborne pollutants have collectively been classified as a known human carcinogen and, more broadly, affect the health of hundreds of millions of people worldwide. Benzene is a frequent component of air pollution, and strategies to protect individuals against unavoidable exposure to this and other airborne carcinogens could improve the public's health. Earlier clinical trials in Qidong, China, demonstrated efficacy in enhancing the detoxication of benzene using a broccoli sprout beverage. Objectives: A randomized, placebo-controlled, multidose trial of a broccoli sprout beverage was designed to determine the lowest effective concentration that enhances benzene detoxication adjudged by enhanced excretion of the urinary biomarker, S-phenylmercapturic acid (SPMA). Methods: Following informed consent, 170 subjects were randomly assigned in 5 blocks of 34 each to drink either a placebo beverage (n = 55) or 1 of 3 graded concentrations of a broccoli sprout beverage [full (n = 25), one-half (n = 35), and one-fifth (n = 55)] for 10 consecutive days. Concentrations of SPMA arising through induced benzene conjugation with glutathione were quantified by MS in sequential 12-h overnight urine collections during the intervention. Results: MS was also used to quantify urinary sulforaphane metabolites in each dosing regimen that resulted in a median 24-h urinary output of 24.6, 10.3, and 4.3 mu mol, respectively, confirming a dose-dependent de-escalation of the inducing principle within the beverage. A statistically significant increase in benzene mercapturic acids in urine was found for the high-dose group (+63.2%) during the 10-d period. The one-half dose (+11.3%) and one-fifth dose groups (-6.4%) were not significantly different from placebo controls. Conclusions: An intervention with a broccoli sprout beverage enhanced the detoxication of benzene, an important airborne pollutant, when dosed at a concentration evoking a urinary elimination of similar to 25 mu mol sulforaphane metabolites per day, and it portends a practical and frugal population-based strategy to attenuate associated long-term health risks of air pollution.

Screening for liver cancer (hepatocellular carcinoma) in China started in early 1970s with the application of alpha-fetoprotein (AFP) in high-incidence regions. It has been extended to nationwide areas, emerging from the concepts of conducting screening in populations at-risk with positive hepatitis B surface antigen to the practice programs in rural and urban areas, and finally to the development of recommendations to guide medical practice for health care providers. The implementation of screening for liver cancer has resulted in earlier detection and hence the early curable treatment for patients who have gained short- or long-term survival, and even reduction in mortality rates, although these outcomes are more anecdotal than rigorously evidence-based. AFP or ultrasound examination has been considered as sensitive and specific methods for early detection but are with limitations. The combined use of these two modalities for screening populations at-risk every six months seems to have been reached consensus. The feasibility of screening for liver cancer is still debated because of differing opinions and even opposition to the choice of targeted sub-populations, the intrinsic necessity, and the contributions of the main risk factors among Western countries and China/Asian areas. Yet, the over 51％ of global burden of liver cancer is in China, the solution to the early detection and treatment of liver cancer should fully consider the actual situation in China. The effectiveness of screening for liver cancer is worthy of anticipation.

Population-based cancer survival is an improved index for evaluating the overall efficiency of cancer health services in a given region. The current study analysed the observed survival and relative survival of leading cancer sites from a population-based cancer registry between 1972 and 2011 in Qidong, China. A total of 92,780 incident cases with cancer were registered and followed-up for survival status. The main sites of the cancer types, based on the rank order of incidence, were the liver, stomach, lung, colon and rectum, oesophagus, breast, pancreas, leukaemia, brain and central nervous system (B and CNS), bladder, blood [non-Hodgkin's lymphoma (NHL)] and cervix. For all malignancies combined, the 5-year observed survival was 13.18% and the relative survival was 15.80%. Females had higher observed survival and relative survival (19.32 and 22.71%, respectively) compared with males (9.63 and 11.68%, respectively). The cancer sites with the highest five-year relative survival rates were the female breast, bladder, cervix and colon and rectum; followed by NHL, stomach, B and CNS cancer and leukaemia. The poorest survival rates were cancers of oesophagus, lung, pancreas and liver. Higher survival rates were observed in younger patients compared with older patients. Cancers of the oesophagus, female breast and bladder were associated with higher survival in middle-aged groups. Improved survival rates in the most recent two 5-year calendar periods were identified for stomach, lung, colon and rectum, oesophagus, female breast and bladder cancer, as well as leukaemia and NHL. The observations of the current study provide the opportunity for evaluation of the survival outcomes of frequent cancer sites that reflects the changes and improvement in a rural area in China.

Neonatal hepatitis B vaccination has been implemented worldwide to prevent hepatitis B virus (HBV) infections. Its long-term protective efficacy on primary liver cancer (PLC) and other liver diseases has not been fully examined.The Qidong Hepatitis B Intervention Study, a population-based, cluster randomized, controlled trial between 1985 and 1990 in Qidong, China, included 39,292 newborns who were randomly assigned to the vaccination group in which 38,366 participants completed the HBV vaccination series and 34,441 newborns who were randomly assigned to the control group in which the participants received neither a vaccine nor a placebo. However, 23,368 (67.8%) participants in the control group received catch-up vaccination at age 10-14 years. By December 2013, a total of 3,895 (10.2%) in the vaccination group and 3,898 (11.3%) in the control group were lost to follow-up. Information on PLC incidence and liver disease mortality were collected through linkage of all remaining cohort members to a well-established population-based tumor registry until December 31, 2013. Two cross-sectional surveys on HBV surface antigen (HBsAg) seroprevalence were conducted in 1996-2000 and 2008-2012. The participation rates of the two surveys were 57.5% (21,770) and 50.7% (17,204) in the vaccination group and 36.3% (12,184) and 58.6% (17,395) in the control group, respectively. Using intention-to-treat analysis, we found that the incidence rate of PLC and the mortality rates of severe end-stage liver diseases and infant fulminant hepatitis were significantly lower in the vaccination group than the control group with efficacies of 84% (95% CI 23%-97%), 70% (95% CI 15%-89%), and 69% (95% CI 34%-85%), respectively. The estimated efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was 21% (95% CI 10%-30%), substantially weaker than that of the neonatal vaccination (72%, 95% CI 68%-75%). Receiving a booster at age 10-14 years decreased HBsAg seroprevalence if participants were born to HBsAg-positive mothers (hazard ratio [HR] = 0.68, 95% CI 0.47-0.97). Limitations to consider in interpreting the study results include the small number of individuals with PLC, participants lost to follow-up, and the large proportion of participants who did not provide serum samples at follow-up.Neonatal HBV vaccination was found to significantly decrease HBsAg seroprevalence in childhood through young adulthood and subsequently reduce the risk of PLC and other liver diseases in young adults in rural China. The findings underscore the importance of neonatal HBV vaccination. Our results also suggest that an adolescence booster should be considered in individuals born to HBsAg-positive mothers and who have completed the HBV neonatal vaccination series. Please see later in the article for the Editors' Summary.

This paper reports the strategies for prevention and control of liver cancer formed in the practice in Qidong field for liver cancer research, and the comprehensive measures aiming at the major risk factors in the past decades. The efficacy of these interventions is reflected in the substantial decrease in the rates of incidence and mortality of liver cancer in Qidong: the age-standardized rate of incidence rate is decreased by 44.35%, and the age-standardized rate of mortality is decreased by 44.20%, especially in younger population. These data are evidenced from the points of views in epidemiology, ecology, and biomarkers monitoring. The long-run profitability in the first prevention and secondary prevention can be benifited from the comprehensive control and intervention strategies in Qidong. DOI:10.3781/j.issn.1000-7431.2014.19.596

Qidong City, China, has had high liver cancer incidence from endemic hepatitis B virus (HBV) infection and dietary exposure to aflatoxin. Based on etiologic studies, we began interventions in 1980 to reduce dietary aflatoxin and initiate neonatal HBV vaccination. We studied trends in liver cancer incidence rates in the 1.1 million inhabitants of Qidong and examined trends in aflatoxin exposure, staple food consumption, HBV infection markers and annual income. Aflatoxin exposure declined greatly in association with economic reform, increased earnings and educational programs to shift staple food consumption in the total population from moldy corn to fresh rice. A controlled neonatal HBV vaccination trial began in 1983 and ended in November, 1990, when vaccination was expanded to all newborns. Liver cancer incidence fell dramatically in young adults. Compared with 1980-83, the age-specific liver cancer incidence rates in 2005-08 significantly decreased 14-fold at ages 20-24, 9-fold at ages 25-29, 4-fold at ages 30-34, 1.5-fold at ages 35-39, 1.2-fold at ages 40-44 and 1.4-fold at ages 45-49, but increased at older ages. The 14-fold reduction at ages 20-24 might reflect the combined effects of reduced aflatoxin exposure and partial neonatal HBV vaccination. Decrease incidence in age groups >25 years could mainly be attributable to rapid aflatoxin reduction. Compared with 1980-83, liver cancer incidence in 1990-93 significantly decreased 3.4-fold at ages 20-24, and 1.9-fold at ages 25-29 when the first vaccinees were <11 years old.

Primary liver cancer (PLC) is the third leading cause of cancer mortality globally. In endemic areas of sub-Saharan Africa and Asia, PLC largely arises from chronic infection with hepatitis B virus (HBV) and ingestion of aflatoxins. Although synergistic interactions between these two risk factors have been observed in cohort studies in China, here we determined the impact of agricultural reforms in the 1980s leading to diminished maize consumption and implementation of subsidized universal vaccination against HBV in the 2000s on PLC primary prevention. A population-based cancer registry was used to track PLC mortality in Qidong, China and was compared with the timeline of HBV immunization. Randomly selected serum samples from archived cohort collections from the 1980s to present were analyzed for aflatoxin biomarkers. More than 50% reductions in PLC mortality rates occurred across birth cohorts from the 1960s to the 1980s for Qidongese less than 35 years of age although all were born before universal vaccination of newborns. Median levels of the aflatoxin biomarker decreased from 19.3 pg/mg albumin in 1989 to undetectable (<0.5 pg/mg) by 2009. A population attributable benefit of 65% for reduced PLC mortality was estimated from a government-facilitated switch of dietary staple from maize to rice; 83% of this benefit was in those infected with HBV. Food policy reforms in China resulted in a dramatic decrease in aflatoxin exposure, which, independent of HBV vaccination, reduced liver cancer risk. The extensive HBV vaccine coverage now in place augurs even greater risk reductions in the future.

OBJECTIVE:To observe the dynamic levels of serum Golgi protein 73(GP73) in patients prior to and after the onset of liver cancer, and to explore the related factors.METHODS:From 2007 to 2012, a periodical screening program was carried out in a group of high risk population with positive Hepatitis B surface antigens (HBsAg) , twice a year. Their serum specimens from every screening time point were kept in Qidong Biobank until liver cancer was diagnosed. Thirty-nine patients with liver cancer were recruited for the study, each of them at least had three times of specimens collected as well as B ultrasound scan (BUS) exam results at onset of disease and within 30 months before diagnosed, amongst 6 time points. In total, there were 162 specimens collected to test GP73 by double-antibody sandwich enzyme-linked immuno-sorbent assay (ELISA). Statistical analyses of time series and differences among groups were performed by stata software 10.RESULTS:The average value of 39 patient's GP73 at the time point of liver cancer onset was (126.77 ± 73.73) µg/L, while the values at the other five time points prior to the onset were (128.32 ± 81.18) , (129.97 ± 83.62) , (127.38 ± 80.10) , (135.52 ± 97.88) and (138.24 ± 93.58) µg/L, respectively, with no significant difference (F = 0.07, P = 0.997). No obvious changing trends of GP73 were observed among the 39 liver cancer cases at the 6 time points. All 162 samples were divided into two groups: without hepatic cirrhosis (63 samples) and with cirrhosis (99 samples) according to findings of B-ultrasonic wave; whose average GP73 values were separately (97.16 ± 51.39) and (151.20 ± 91.68) µg/L. The difference showed statistical significance (F = 18.22, P < 0.01). Furthermore, if we grouped the samples by the average value of GP73 at 130.19 µg/L, then there were only 1/14 of the subjects without hepatic cirrhosis having higher GP73 values, but 12 of the 25 subjects with hepatic cirrhosis having higher GP73 values. The difference showed statistical significance (P = 0.013). The results of Linear regression model also showed that there was no correlation between GP73 and time series (t = 0.75, P = 0.455), but significant correlation between GP73 and hepatic cirrhosis (t = 4.30, P < 0.01).CONCLUSION:No significant changes of the dynamic levels of GP73 could be found among the liver cancer patients within 30 months prior to the onset of disease. GP73 values of the patients with liver cancer may depend on their background of hepatic diseases; and hepatic cirrhosis might be one of the main influencing factors or confounding factors.

Primary liver cancer has been the leading cause of cancer death in Qidong, China, with about 800 deaths annually in this region of 1.1 million residents. Epidemiological studies have highlighted the importance of infection with hepatitis B virus (HBV) and dietary exposure to hepatocarcinogenic aflatoxins as key, interactive determinants of risk in Qidong and other endemic areas. Identification of these risk factors was enabled through the development of biomarkers allowing for measures of their prevalence in case-control and other study cohorts. Vaccination against HBV began in pilot studies in the 1980s in Qidong but did not become universal for newborns until earlier this decade. Despite minimal impact on cancer mortality to date, vaccination programs are poised to blunt the development of liver diseases including cancer in this region over the next generations. Strategies for reducing aflatoxin exposure are also required, especially for those already infected with HBV. We have conducted a series of proof-of-principle clinical trials in which drugs, dietary supplements and foods have been used to alter the metabolism and elimination of aflatoxins following unavoidable exposures. Using aflatoxin biomarkers as intermediate endpoints, the efficacy of these agents (oltipraz, chlorophyllin, broccoli sprout beverages) has been demonstrated, highlighting roles for frugal approaches to chemoprevention against environmental carcinogenesis. Remarkably, recent evidence garnered from retrospective analysis of archived serum samples from the past quarter century demonstrates a 40-fold drop in aflatoxin exposure in Qidong, likely driven by changes in the primary dietary staple from maize to rice. Thus, primary prevention, evoked by changing economic and agricultural policies in the 1980s, heralds the unanticipated promise of elimination of liver cancer from this endemic region in a fore-shortened timeframe.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Primary liver cancer (PLC) causes nearly 700,000 annual deaths worldwide predominately in Asia and sub-Saharan Africa; >370,000 deaths occur in the People's Republic of China, alone. Two factors synergistically associated with PLC are chronic infection with hepatitis B (HBV) and repetitive ingestion of aflatoxin (AFB)-contaminated foods. Utilizing information collected over several decades by the Qidong Cancer Registry, mortality rates from PLC were compared to timelines for regional implementation of HBV vaccination and levels of AFB exposure. The concentration of the AFB-lysine adduct was quantified by isotope dilution mass spectrometry in randomized, age-matched subsets of archived serum samples collected from 1989-2012. Economic, social and public health changes occurring during this time period were examined including implementation of a universal vaccination program and the adaptation of an open policy of food provisionment which led to rice replacing maize as the major dietary staple in the Qidong region. Although the crude rates of PLC increased from 1972-1990s (50/100,000 to a steady-state rate of 75/100,000), much of the increase can be attributed to a proportionate aging population. Upon stratifying by birth cohort, no significant change in mortality rate from PLC was found for individuals over 40 years of age. However, 60-75% mortality declines in 20-24, 25-29, 30-34 year olds born 1973-177 compared to similar birth cohorts of 1958-1962 were observed. The prevalence of HBV surface antigen positivity was unchanged; moreover, all these birth cohorts were born before the universal HBV vaccination of newborns. Median levels of the aflatoxin biomarker dropped from 19.3 pg/mg albumin in 1989 to non-detectable by 2009. The estimated population attributable risk of AFB-related PLC decreased from 45% in 1989 to 11% in 2012. Significant reductions in PLC mortality occurred prior to the introduction of universal hepatitis vaccination in Qidongese newborns. Agricultural and economic reforms instituted in the 1980s leading to the establishment of rice as a dietary staple was associated with a 40-fold reduction in AFB exposure. Thus, by extrapolation, changes in food-based policies altering exposure to carcinogens in the diet can have a dramatic impact on PLC mortality worldwide. Supported by NIEHS P01 ES 006052, NST China No. 2008ZX10002-015, No. 2012ZX10002-008. Citation Format: Patricia A. Egner, Jian-Guo Chen, Derek Ng, Lisa P. Jacobson, Alvaro Munoz, Jian-Hua Lu, Yuan-Rong Zhu, Geng-Sun Qian, Tao-Yang Chen, Felicia Wu, Jian-Min Wang, John D. Groopman, Thomas W. Kensler. Reduction in aflatoxin exposure drives decrease in primary liver cancer in Qidong, China. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1381. doi:10.1158/1538-7445.AM2013-1381

OBJECTIVE:To survey the levels of Golgi glycoprotein (GP73), a hepatocellular carcinoma (HCC) marker, in residents of Qidong and determine the correlation of detected GP73 concentration ranges with outcome at two-year follow-up.METHODS:A total of 12,378 individuals (age range: 35-69 years old) from Qidong were enrolled in the study. All participants were tested for hepatitis B virus (HBV) by detecting hepatitis B surface antigen (HBsAg) in serum. One-tenth of the participants were assigned to a stratified-random sample group (those with identification numbers ending with "0") to represent a "subgroup of the natural population" (HBsAgPop, n = 1227). All HBsAg carriers were stratified as a "subgroup of positivity" (HBsAgPve, n = 1025). One-tenth of all HBsAg-negative individuals were assigned to a stratified-random sample group to represent a "subgroup of negativity" (HBsAgNve, n = 1132). Enzyme-linked immunoassay was used to measure the serum GP73 and alpha-fetoprotein (AFP) levels; the distribution, medians (50th percentile), and 95th percentiles of GP73 were determined for the three subgroups. A two-year follow-up was carried out to observe the differential incidence of HCC between the HBsAgPve and HBsAgNve subgroups.RESULTS:A positively skewed distribution of the GP73 values was observed for all three subgroups. The medians for HBsAgPve, HBsAgNve, and HBsAgPop were 67 mug/L, 54 mug/L, and 55 mug/L; the 95th percentiles were 174 mug/L, 108 mug/L, and 114 mug/L, respectively. The AFP positivity rates were 7.23% (37/512) for carriers whose GP73 values were above the median level and 0.78% (4/513) for carriers with GP73 values below the median level, with a highly significant difference between the two (P less than 0.01). A the two-year follow-up, 23 (4.49%) of the 512 carriers with GP73 more than or equal to 67 mug/L had developed HCC, while only one patient (0.19%) of the 513 carriers with GP73 less than 67 mug/L developed HCC, which yielded a relative risk value of 23.6. In the non-carriers, no HCC cases had occurred, regardless of serum GP73 level.CONCLUSION:Serum GP73 has a higher potential as a diagnostic/prognostic marker of HCC in individuals with HBsAg positivity. In follow-up of HBsAg carriers, GP73 may help in the early detection of liver cancer.

OBJECTIVE To describe and analyze the charecteristics and trends of liver cancer mortality during the past fifty years in Qidong, China. METHODS Retrospective mortality survey was conducted to get the data on liver cancer death in the period of 1958-1971, and the data from 1972 to 2007 were obtained from the records of cancer registration in Qidong. The crude mortality rate (CR) of liver cancer, and age-standardized rate by Chinese population (CASR) and by world population (WASR) were calculated and analyzed. The total percent changes (PC) and annual percent changes (APC) were used for evaluating the increasing trends of the mortality. The sex-specific rate, age-specific rate, truncated rate of the age group 35 - 64, cumulative rate of the age group 0-74, cumulative risk, period-rate, and the rate for age-birth cohort were compared. RESULTS The natural death rate in Qidong residents for the past five-decade period experienced a wave interval of 8.62‰ in 1958 down to 5.37‰ in 1979, and up to 7.75‰ in 2007. The mortality rate for all-site cancers was increased from 56.69 per 100, 000 to 234.97 per 100, 000. The mortality rate of liver cancer, being 20.45 per 100, 100 in 1958 was increased to 49.04 per 100, 000 in 1972, and up to 69.29 per 100, 000 in 2007. According to the registration data of 1972 - 2007, the death from liver cancer was accounted for 34.88% of all deaths due to cancers, with a CR of 58.86 per 100, 000, CASR of 38.36 per 100, 000, and WASR, 49.37 Per 100, 000 in Qidong. The truncated rate for the age group 35 - 64 was 117.08 per 100, 000, and the cumulative rate for the age group 0-74 and the cumulative risk were 5.15% and 5.02%, respectively. The CRs for males was 90.52 per 100, 000 and for females was 27.93 per 100, 000, with a sex ratio of 3.24:1. For the period of 1972 - 2007, the PC for CR was 49.71%, and APC was +1.41%, showing an increasing variation tendency. The APCs for CASR and WASR, however, were decreasing, with a percentage of -1.11%, and -0.84%, respectively. The age-specific mortality rates by period showed a decreasing trend for those under age of 44. Moreover, age-birth cohort analysis showed a more rapid lowering mortality in the age groups 35-, 30-, 25-, and 15-, that is, those born after 1950's. CONCLUSIONS Liver cancer remains the leading death cause due to cancers in Qidong, with a continuing higher crude mortality rate. Yet the age-standardized mortality rate has presented a declining posture. The liver cancer mortality in young people in Qidong demonstrates a continuously falling trend. The campaign for the control of liver cancer in Qidong has achieved initial success.

启东肝癌防治现场经历40年的努力,通过坚持适合自身发展的举措,逐步打造成一个癌症防治研究的示范基地。继续巩固和发挥现场优势、利用和加强协作优势,是现场防治研究可持续发展的关键。

针对HBV感染、AFB1暴露、饮用水污染和微量元素硒缺乏等肝癌相关病因因素,启东当地持续多年采取了"防治肝炎、管粮防霉、改良饮水、适量补硒"的综合性预防措施,自20世纪90年代以来取得了一些新进展。全文就启东地区对肝癌主要病因的预防研究进展作一综述。

Abstract One of several challenges in design of clinical chemoprevention trials is the selection of the dose, formulation, and dose schedule of the intervention agent. Therefore, a cross-over clinical trial was undertaken to compare the bioavailability and tolerability of sulforaphane from two of broccoli sprout–derived beverages: one glucoraphanin-rich (GRR) and the other sulforaphane-rich (SFR). Sulforaphane was generated from glucoraphanin contained in GRR by gut microflora or formed by treatment of GRR with myrosinase from daikon (Raphanus sativus) sprouts to provide SFR. Fifty healthy, eligible participants were requested to refrain from crucifer consumption and randomized into two treatment arms. The study design was as follows: 5-day run-in period, 7-day administration of beverages, 5-day washout period, and 7-day administration of the opposite intervention. Isotope dilution mass spectrometry was used to measure levels of glucoraphanin, sulforaphane, and sulforaphane thiol conjugates in urine samples collected daily throughout the study. Bioavailability, as measured by urinary excretion of sulforaphane and its metabolites (in approximately 12-hour collections after dosing), was substantially greater with the SFR (mean = 70%) than with GRR (mean = 5%) beverages. Interindividual variability in excretion was considerably lower with SFR than with GRR beverage. Elimination rates were considerably slower with GRR, allowing for achievement of steady-state dosing as opposed to bolus dosing with SFR. Optimal dosing formulations in future studies should consider blends of sulforaphane and glucoraphanin as SFR and GRR mixtures to achieve peak concentrations for activation of some targets and prolonged inhibition of others implicated in the protective actions of sulforaphane. Cancer Prev Res; 4(3); 384–95. ©2011 AACR.