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.

Supplementary Tables from Bioavailability of Sulforaphane from Two Broccoli Sprout Beverages: Results of a Short-term, Cross-over Clinical Trial in Qidong, China

Qidong hepatitis B virus (HBV) infection cohort (QBC) is a prospective community-based study designed to investigate causative factors of primary liver cancer (PLC) in Qidong, China, where both PLC and HBV infection are highly endemic. Residents aged 20-65 years, living in seven townships of Qidong, were surveyed using hepatitis B surface antigen (HBsAg) serum test and invited to participate in QBC from June 1991 to December 1991. A total of 852 and 786 participants were enrolled in HBsAg-positive and HBsAg-negative sub-cohorts in May 1992, respectively. All participants were actively followed up in person, received HBsAg, alanine aminotransferase (ALT), alpha-fetoprotein (AFP) tests and upper abdominal ultrasonic examination, and donated blood and urine samples once or twice a year. The total response rate was 99.6%, and the number of incident PLC was 201 till the end of February 2017. The ratio of incidence rates was 12.32 (95% confidence interval[CI]=7.16-21.21, P < 0.0001) in HBsAg-positive arm compared with HBsAg-negative arm. The relative risk of PLC was 13.25 (95% CI=6.67-26.33, P < 0.0001) and 28.05 (95% CI=13.87-56.73, P < 0.0001) in the HBsAg+/HBeAg- group and the HBsAg+/HBeAg+ group, respectively, as compared to the HBsAg-/HBeAg- group. A series of novel PLC-related mutations including A2159G, A2189C and G2203W at the C gene, A799G, A987G and T1055A at the P gene of HBV genome were identified by using samples from the cohort. The mutation in hepatitis B virus (HBV) basal core promoter region of HBV genome has an accumulative effect on the occurrence of PLC. In addition, the tripartite relationship of aflatoxin exposure, P53 mutation and PLC was also investigated. Dynamic prediction model for PLC risk by using its long-term follow-up information and serial blood samples for QBC was developed. This model is expected to improve the efficiency of PLC screening in HBV infection individuals.

We read with great interest the recent publication by Kim et al 1 showing that patients with untreated immune tolerant (IT) chronic hepatitis B with normal alanine aminotransferase (ALT) levels had significantly higher risks of hepatocellular carcinoma (HCC) and death/transplantation than treated immune active (IA) patients who had elevated ALT levels. These results indicate that ALT is not a sensitive surrogate marker for liver cell damage, and the IT phase of HBV infection cannot be considered fully benign.2 Chu and Liaw3 have challenged this view because they speculated that the IT group in that study might include IA patients who were in remission state after experiencing unrecognised minimal ALT elevations. Apparently, the highly dynamic nature of ALT perturbation makes it inadequate to act as a predictor for HCC. We have developed and validated an easy-to-use scoring system for primary liver cancer (PLC) risk prediction. The development data set was set up in 1996 based on a community-based prospective cohort (qidong hepatitis B infection cohort (QBC)) established in Qidong, China.4 It contained …

OBJECTIVE To evaluate whether first-degree family history of liver cancer plays a role in liver cancer incidence by prospective evaluation of a patient cohort in Qidong, China over a 20-year period. METHODS In May 1992, 708 hepatitis B surface antigen (HBsAg) carriers and 730 HBsAg-negadve controls from Qidong city were enrolled for participation in a prospective cohort study ending in November 2012.Follow-up was carried out every 6 to 12 months, and evaluations included serum assays to measure concentrations of alpha fetoprotein (AFP), HBsAg and alanine aminotransferase (ALT), as well as abdominal ultrasound to assess liver disease.The relationship between baseline (study entry) information of patients with first-degree family history of liver cancer and liver cancer incidence during the two decades of study was statistically assessed. RESULTS There were 172 newly diagnosed liver cancer cases in the cohort during 25 753 person-years (py) of follow-up, representing an incidence of 667.88/100 000 py.The incidence rates of liver cancer among participants with or without liver cancer family history were 1 244.36/100 000 py and 509.70/100 000 py respectively, and the between-group difference reached the threshold for statistical significance (P less than 0.01, Relative Risk (RR):2.44, 95% Confidence Interval (CI):1.80-3.31).The incidence rates of liver cancer among participants who had a sibling with liver cancer and participants who had a parent with liver cancer were not significantly different (P > 0.05), but the liver cancer incidence among participants who had a mother with liver cancer was significantly higher than that of participants who had a father with liver cancer (P < 0.05, RR:1.86, 95% CI:1.03-3.36). Among the participants with liver cancer family history, 56.52% (39/69) were diagnosed before 50 years old, and this rate was significantly higher than that of participants without a family history of liver cancer (40.78%, 42/103, P less than 0.05).The incidence rate of liver cancer among the participants who were family history-positive and HBsAg-positive was significantly higher than that of participants who were family history-negative but HBsAg-positive (P < 0.01, RR:1.75, 95% CI:1.29-2.38), and was 59.59 times higher than for participants who were family history-negative and HBsAgnegative.Subgroup analysis of liver cancer incidence among participants who were family history-positive but HBsAg-negative and participants who were family history-negative and HBsAg-negative produced anRR of 2.60, but there was no statistically significant difference between the two subgroups (P > 0.05).At the study's end, the incidence rates of liver cancer for the different subgroups were 32.21% for the family history-positive and HBsAgpositive participants, 19.80% for the family history-negative and HBsAg-positive participants, 1.71% for the family history-positive and HBsAg-negative participants, and 0.65% for the family history-negative and HBsAg-negative participants. CONCLUSION First-degree family history of liver cancer is a risk factor of liver cancer in Chinese patients from Qidong, and exhibits synergism with HBsAg-positivity for incidence of liver cancer.

Broccoli sprouts are a convenient and rich source of the glucosinolate, glucoraphanin, which can generate the chemopreventive agent, sulforaphane, an inducer of glutathione S-transferases (GST) and other cytoprotective enzymes. A broccoli sprout-derived beverage providing daily doses of 600 μmol glucoraphanin and 40 μmol sulforaphane was evaluated for magnitude and duration of pharmacodynamic action in a 12-week randomized clinical trial. Two hundred and ninety-one study participants were recruited from the rural He-He Township, Qidong, in the Yangtze River delta region of China, an area characterized by exposures to substantial levels of airborne pollutants. Exposure to air pollution has been associated with lung cancer and cardiopulmonary diseases. Urinary excretion of the mercapturic acids of the pollutants, benzene, acrolein, and crotonaldehyde, were measured before and during the intervention using liquid chromatography tandem mass spectrometry. Rapid and sustained, statistically significant (P ≤ 0.01) increases in the levels of excretion of the glutathione-derived conjugates of benzene (61%), acrolein (23%), but not crotonaldehyde, were found in those receiving broccoli sprout beverage compared with placebo. Excretion of the benzene-derived mercapturic acid was higher in participants who were GSTT1-positive than in the null genotype, irrespective of study arm assignment. Measures of sulforaphane metabolites in urine indicated that bioavailability did not decline over the 12-week daily dosing period. Thus, intervention with broccoli sprouts enhances the detoxication of some airborne pollutants and may provide a frugal means to attenuate their associated long-term health risks.

Background/Aim: Hepatitis B Virus (HBV) mutations play a role in the development of hepatocellular carcinoma (HCC). However, the association between HBV polymerase gene mutations and HCC has not been reported. In this study, we conducted a multi-stage study to identify HCC-related mutations in the reverse transcriptase (RT) domain of the HBV polymerase gene.Methods: A total of 231 HCCs and 237 non-HCC controls from Qidong, China, were included in this study. The entire sequence of HBV RT was first compared between 29 HCC and 35 non-HCC cases, and candidate mutations were then evaluated in two independent validation sets.Results: There were 15 candidate mutations identified from the discovery set, with A799G and T1055A being consistently associated with HCC across all studies. A pooled analysis of samples revealed that A799G, A987G, and T1055A were independent risk factors for HCC, with adjusted odds ratios of 5.53 [95% confidence interval (CI), 1.69-18.10], 4.20 (95% CI, 1.15-15.35), and 3.78 (95% CI, 1.45-9.86), respectively. A longitudinal study showed that these mutations were detectable 45 years prior to HCC diagnosis.Conclusions: Our study provides evidence the first that HBV RT contains naturally occurring mutations that can be used as predictive markers for HCC.

Objective: To explore the relationship between the mutations in the reverse transcriptase(RT) domain of hepatitis B virus polymerase(HBV-P) gene and the occurrence and development of hepatocellular carcinoma(HCC). Methods: In this case-control study, the serum samples from 202 HCC patients and 202 chronic hepatitis B virus(CHB) carriers matching for age and gender were collected. The sequence of the RT domain of HBV-P gene was determined by direct sequencing following PCR amplifi cation. The relationship between the mutations in the RT domain of HBV-P gene and the occurrence and development of HCC was analyzed. Results: The T895A, A904T and C955T mutations in the RT domain of HBV-P gene were all signif icantly associated with HCC compared to non-HCC controls(P = 0.034, 47.5% vs 37.1%; P = 0.011, 5.4% vs 1.0%; P = 0.030, 5.4% vs 1.5%). Furthermore, the Logistic multivariate analysis showed that T895A was an independent risk factor for HCC [odds ratio(OR) = 2.230, 95% confi dence interval(CI): 1.230-4.044, P = 0.008]. A904T or C955T increased the risk of HCC occurrence either(OR = 6.523, 95% CI: 0.838-50.733; OR = 2.904,95% CI: 0.599-14.093), but it did not reach statistical signifi cance. The mutation rate of combined mutation occurrence either in A904 or C955T was 9.4% in HCC group and 2.5% in non-HCC controls(P = 0.003). The adjusted OR was 4.145(95% CI: 1.170-14.681), demonstrating its signif icant association with HCC(P = 0.028). Conclusion: The mutations in the RT domain of HBV-P gene are associated with the tumorigenesis of HCC.

AIM:To develop a novel non-sequencing method for the detection of hepatitis B virus (HBV) pre-S deletion mutants in HBV carriers. METHODS:The entire region of HBV pre-S1 and pre-S2 was amplified by polymerase chain reaction (PCR). The size of PCR products was subsequently determined by capillary gel electrophoresis (CGE). CGE were carried out in a PACE-MDQ instrument equipped with a UV detector set at 254 nm. The samples were separated in 50 μm ID eCAP Neutral Coated Capillaries using a voltage of 6 kV for 30 min. Data acquisition and analysis were performed using the 32 Karat Software. A total of 114 DNA clones containing different sizes of the HBV pre-S gene were used to determine the accuracy of the CGE method. One hundred and fifty seven hepatocellular carcinoma (HCC) and 160 non-HCC patients were recruited into the study to assess the association between HBV pre-S deletion and HCC by using the newly-established CGE method. Nine HCC cases with HBV pre-S deletion at the diagnosis year were selected to conduct a longitudinal observation using serial serum samples collected 2-9 years prior to HCC diagnosis. RESULTS:CGE allowed the separation of PCR products differing in size > 3 bp and was able to identify 10% of the deleted DNA in a background of wild-type DNA. The accuracy rate of CGE-based analysis was 99.1% compared with the clone sequencing results. Using this assay, pre-S deletion was more frequently found in HCC patients than in non-HCC controls (47.1% vs 28.1%, P < 0.001). Interestingly, the increased risk of HCC was mainly contributed by the short deletion of pre-S. While the deletion ≤ 99 bp was associated with a 2.971-fold increased risk of HCC (95%CI: 1.723-5.122, P < 0.001), large deletion (> 99 bp) did not show any association with HCC (P = 0.918, OR = 0.966, 95%CI: 0.501-1.863). Of the 9 patients who carried pre-S deletions at the stage of HCC, 88.9% (8/9) had deletions 2-5 years prior to HCC, while only 44.4%4 (4/9) contained such deletions 6-9 years prior to HCC. CONCLUSION:CGE is a sensitive approach for HBV pre-S deletion analysis. Pre-S deletion, especially for short DNA fragment deletion, is a useful predictive marker for HCC.

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.

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.

Background: Glypican-3 (GPO) is a novel histochemical marker of hepatocellular carcinoma (HCC). However, its utility as a serologic marker for HCC is not conclusive. Methods: A total of 1037 subjects, including 155 patients with HCC, 180 with chronic hepatitis, 124 with liver cirrhosis, 442 with non-HCC cancer and 136 healthy controls, were analyzed for serum GPO (sGPC3) by an ELISA constructed with 2 monoclonal antibodies. Results: The average level of sGPO in HCC patients was 99.94 2672 ng/ml, which was significantly higher than in patients with chronic hepatitis (10.45 46.02 ng/ml, P < 0.0001), liver cirrhosis (19.44 50.88 ng/ml, P = 0.0013), non-HCC cancer (20.50 9833 ng/ml, P < 0.0001) and healthy controls (4.14 31.65 ng/ml, P < 0.0001). The sensitivity of sGPO in HCC diagnosis was 40.0%, whereas the specificity was 98.5%, 94.4% and 87.1% in healthy controls, chronic hepatitis patients and liver cirrhosis patients, respectively. In addition, 13.5% (28/207) of lung cancer patients and 13.2% (9/68) of thyroid cancer patients had positive results with sGPC3. Conclusion: Serum GPO is a potential marker for HCC. However, the presence of 5GPC3 in patients with lung cancer and thyroid cancer might limit its application as a single marker in the diagnosis of HCC 0 2013 Elsevier B.V. All rights reserved.

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

Objectives: To characterize the mutation pattern of a hepatitis B virus (HBV) core protein (HBcAg) derived from hepatocellular carcinoma (HCC) and adjacent nontumor tissues. Methods: HBV core gene fragments (nt. 1901–2365) were amplified from 98 HBV-related HCC tissues and 33 adjacent nontumor tissues. The deduced amino acids (AAs) of the core gene were aligned with the prototype sequences of HBV genotypes B and C. Results: In total, there were 54 positions that showed polymorphism at the deduced AA level. The mutations were predominantly located in three major (codons 83–87, 95–104 and 130–135) and three minor (codons 21–38, 59–63 and 151–155) mutation-clustering regions (MCRs). The substitution rate in MCRs was significantly higher than in mutation-devoid regions (p < 0.001). The most frequently occurring mutations in rank were codon P130T (38.8%), I97L (37.8%) and S87G (23.5%). In addition, there were 7 patients that showed internal deletions in the middle of HBcAg with sizes ranging from 34 to 59 AAs. Unexpectedly, the core genes isolated from tumor tissues had fewer mutations compared with those isolated from adjacent nontumor tissues from the same patients (p < 0.05). Conclusions: Accumulation of naturally occurring mutations in certain restricted segments of HBcAg may be related to the development of HCC.

作者自1973年以江苏省赴启东医疗队队员的身份开始参加启东肝癌研究,围绕黄曲霉毒素这一肝癌的主要病因,与启东肝癌防治研究所以及国内外同仁一起共同奋斗,开展了长期的合作研究.

OBJECTIVETo explore the relationship between serum HBV DNA load and hepatocellular carcinogenesis in Qidong HBsAg carriers.METHODSIn 1997, 477 HBsAg carriers and 477 age, gender and residence matched HBsAg negative controls were enrolled as a prospective cohort in Qidong city. The entry serum samples were detected for the levels of HBeAg and HBV DNA. The relationship between baseline HBV DNA load and hepatocellular carcinoma (HCC) during the follow-up period from June 1997 to June 2011 were analyzed.RESULTSThe total observed person-years (PY) were 12 200. Eighty-seven patients developed HCC with an incidence of 1498/100 000 PY in the HBsAg positive group versus 6 with an incidence of 94/100 000 PY (P = 0.000) in the HBsAg negative group. The relative risk (RR) was 15.96. N o significant difference existed between the incidences of other tumors in two groups (P = 0.161). Compared with the HBsAg negative group, the RR of HCC was 11.38 (95%CI 4.87 - 26.62, P < 0.01)in the HBsAg+/HBeAg- group and 29.08 (95%CI 12.37 - 68.37, P < 0.01) in the HBsAg+/HBeAg+ group; 5.80 (95%CI 2.29 - 14.70, P < 0.01) in the HBsAg+/HBV DNA- group and 27.75 (95%CI 12.07 - 63.81, P < 0.01) in the HBsAg+/HBV DNA+ group. In HBsAg positive subjects, while the HBV DNA load was classified into 5 levels namely 250 - 10(4), 10(4)-, 10(5)-, 10(6)- and ≥ 10(7) copies/ml, the relative risks for HCC at each level were 2.84 (95%CI 1.44 - 5.61, P < 0.01), 5.75 (95%CI 2.77 - 11.95, P < 0.01), 9.05 (95%CI 4.71 - 17.41, P < 0.01), 6.39 (95%CI 2.79 - 14.64, P < 0.01) and 4.35 (95%CI 2.21 - 8.56, P < 0.01) respectively versus the < 250 copies/ml group.CONCLUSIONHBV DNA is an important risk predictor of hepatocellular carcinoma. The HBsAg carriers with the serum loads of HBV DNA between 10(5) - 10(6) copies/ml are most likely to present with HCC.

Epidemiological evidence has suggested that consumption of a diet rich in cruciferous vegetables reduces the risk of several types of cancers and chronic degenerative diseases. In particular, broccoli sprouts are a convenient and rich source of the glucosinolate, glucoraphanin, which can release the chemopreventive agent, sulforaphane, an inducer of glutathione S-transferases. Two broccoli sprout-derived beverages, one sulforaphane-rich (SFR) and the other glucoraphanin-rich (GRR), were evaluated for pharmacodynamic action in a crossover clinical trial design. Study participants were recruited from the farming community of He Zuo Township, Qidong, China, previously documented to have a high incidence of hepatocellular carcinoma with concomitant exposures to aflatoxin and more recently characterized with exposures to substantive levels of airborne pollutants. Fifty healthy participants were randomized into two treatment arms. The study protocol was as follows: a 5 days run-in period, a 7 days administration of beverage, a 5 days washout period and a 7 days administration of the opposite beverage. Urinary excretion of the mercapturic acids of acrolein, crotonaldehyde, ethylene oxide and benzene were measured both pre- and postinterventions using liquid chromatography tandem mass spectrometry. Statistically significant increases of 20-50% in the levels of excretion of glutathione-derived conjugates of acrolein, crotonaldehyde and benzene were seen in individuals receiving SFR, GRR or both compared with their preintervention baseline values. No significant differences were seen between the effects of SFR versus GRR. Intervention with broccoli sprouts may enhance detoxication of airborne pollutants and attenuate their associated health risks.

自2006年开展癌症早诊早治项目以来,已筛查1027 140例高危个体,检出6866例患者,早诊率为77.9％,治疗率为80.4％[1].如何评价这一结果,受到广泛关注.按照循证医学的原则,癌症早诊早治评价有明确的标准和方法[2],绩效评价的终点指标是死亡率下降,而卫生经济学评价,则要求详细计算癌症早诊早治的费用,以及相应的健康收益,分别以成本效果、成本效用和成本效益来表述,并与未干预的相应指标进行比较.我国的肿瘤登记和社会信息收集尚在完善之中,基于精确计算、符合循证医学标准的绩效评价和卫生经济学评价颇为困难,同时,由于观察时间较长,也难于满足目前工作的需要.

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.