Primary liver cancer incidence-rates related to hepatitis-C virus infection: a correlational study in Osaka,Japan

Osaka, Japan, has one of the highest, primary liver cancer (PLC) incidence-rates in the world, although hepatitis-B virus (HBV) is not endemic. This paper addresses the question of whether the PLC-incidence variation within Osaka Prefecture is due to differences in the prevalence of hepatitis-C virus (HCV) infection. The screening data of antibody to HCV (anti-HCV) and of hepatitis-B virus antigen (HBsAg) in 111,069 male blood-donors, and the incidence data of male PLC obtained from the Osaka Cancer Registry were examined. In a multiple-weighted regression analysis, the age-standardized incidence rate of PLC in the 61 counties within Osaka was correlated significantly with the age-standardized prevalence of anti-HCV with adjustment for that of HBsAg (regression coefficient [RC]=7.26,P<0.0001). This finding was consistent with the relationship between the PLC incidence rate and the prevalence of high-titer (2¹²) anti-HCV (RC=11.18,P<0.0001). There was significant association between the prevalence of HBsAg and the PLC incidence rate with adjustment for that of anti-HCV (RC=7.08,P=0.018). These findings suggest that the PLC-incidence variation within Osaka is correlated with the geographic pattern of HCV infection as well as that of HBV infection among the residents.     

Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case–control study in Italy

Objective: Intrahepatic cholangiocarcinoma (ICC) is a rare type of primary liver cancer (PLC) arising from intrahepatic bile ducts. We carried out a case–control study to assess the association between ICC and hepatitis B and C virus (HBV and HCV) infections, alcohol intake, and hepatolithiasis in Brescia, North Italy. Methods: Among 370 subjects with histology-based diagnosis of PLC who were resident in the area and hospitalized in 1995–2000, 26 (7%) ICC cases were identified. A total of 824 subjects unaffected by hepatic diseases and frequency-matched with PLC cases by age, sex, date, and hospital of admission were recruited as controls. Results: Among ICC cases the mean age was 65 years, 80.8% were males, and 38.5% had cirrhosis. Seropositivity for anti-HCV, HBsAg, alcohol intake > 80 g/day and history of hepatolithiasis were found in 25%, 13%, 23.1%, and 26.9% of ICC cases and in 5.8%, 6.7%, 32.9%, and 10.6% of controls, respectively. The odds ratios adjusted for demographic factors by logistic regression (95% confidence interval; 95% CI) were 9.7 (1.6–58.9) for anti-HCV, 2.7 (0.4–18.4) for HBsAg, and 6.7 (1.3–33.4) for hepatolithiasis, whereas no association was found with alcohol drinking. Conclusions: HCV and hepatolithiasis may be risk factors for ICC in Western countries.     

Prospective study on the risk of hepatocellular carcinoma among hepatitis C virus-positive blood donors focusing on demographic factors, alanine aminotransferase level at donation and interaction with hepatitis B virus

The risk for hepatocellular carcinoma (HCC) among asymptomatic hepatitis C virus (HCV) carriers is not well understood. A community-based prospective study was conducted for over 8 years by record linkage to the Osaka Cancer Registry. The subjects were 1,927 individuals who were positive for anti-HCV through screening for second-generation HCV antibody (passive hemagglutination assay: >or= 2(12)) in voluntary blood donation. The risk factors for HCC and interaction between HCV and hepatitis B virus (HBV) infection were evaluated by including additional blood donors: 2,519 individuals positive for hepatitis B virus surface antigen (HBsAg) alone, 25 positive for both anti-HCV and HBsAg, 150,379 negative for both anti-HCV and HBsAg. The incidence of HCC (/10(5) person-years) among the HCV-positive individuals increased with age in both genders, ranging from 68 to 1,306 among those aged 45-74 years. In the HCV-positive individuals, the cumulative risk of developing HCC between the ages of 40 and 74 year was 21.6% among males and 8.7% among females. A stepwise increase in risk was noted as the serum alanine aminotransferase level increased or serum cholesterol level at baseline decreased in multivariate Cox proportional hazard analysis. The 9-year cumulative incidence of HCC among individuals positive for HCV alone, those positive for HBsAg alone and those positive for both was 3.0%, 2.0% and 12.0%, respectively. The age-and-sex-adjusted rate ratio was 126, 102 and 572, respectively, when those negative for both were used as a reference. The results demonstrate an increased risk for HCC among asymptomatic HCV-positive individuals in Japan. Coinfection with HBV and HCV carried a superadditive risk for HCC.     

Hepatitis B and C viruses in the etiology of hepatocellular carcinoma; a study in Greece using third-generation assays

Objectives: The purpose of this study was to describe the role of hepatitis B virus (HBV) and hepatitis C virus (HCV) in the etiology of hepatocellular carcinoma (HCC). Methods: During a 4-year period from January 1995 to December 1998, blood samples and questionnaire data were obtained from 333 incident cases of HCC from Athens, Greece, as well as from patients in two control groups, also from Athens. Controls were 272 metastatic liver cancer (MLC) patients and 360 patients hospitalized for injuries or eye, ear, nose or throat conditions. Coded sera were tested for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV) by third-generation enzyme immunoassays. Results: The odds ratios (with 95% confidence intervals) in logistic regression modeling comparing the HCC cases to the combined control series were 48.8 (30.5–78.3) for the presence of HBsAg and 23.2 (11.4–47.3) for the presence of anti-HCV. The odds ratio for concurrent infection with HBV and HCV was 46.2 (9.9–216.6) compared to infection with neither virus. Conclusions: Although HBV and HCV are both important causes of HCC in this study population the data do not suggest, neither do they conclusively refute, a super-additive interaction between the two infections in the development of this malignancy. In this population, 58% of HCC cases can be attributed to HBV, 12% to HCV, and 3% to dual infection with these viruses.     

Cumulative Risk of Hepatocellular Carcinoma in Hepatitis C Virus Carriers: Statistical Estimations from Cross-sectional Data

The probability of developing hepatocellular carcinoma (HCC) among hepatitis C virus (HCV) carriers during their life-time is unknown. This paper addresses the estimation of the cumulative risk of HCC among HCV carriers using cross-sectional data. Age-specific prevalences of HCV carriers among the general population were estimated according to 5-year age group, based on the data of 2nd-generation anti-HCV assay in blood donors resident in Osaka (33,226 males and 29,054 females). Seropositivity of anti-HCV among 422 HCC cases, and the Osaka Cancer Registry data on HCC were used in the estimations of 5-year age-specific incidence rates of HCV-linked HCC. Using these data, the cumulative risk, i.e., the probability of contracting HCC within the following 15 years in 50-year-old HCV carriers, was estimated as 28% for males and 6% for females.     

Higher lung cancer rates in young women than young men: Tasmania, 1983 to 1992

In a background of changing lung cancer rates in the past decade, mean incidence and mortality rates for persons aged 25–44 in Tasmania for the decade 1983 through 1992 were examined using Tasmanian Cancer Registry data. The smoking behavior of Tasmanian adults and schoolchildren was also investigated, using data from a social survey conducted by the Australian Bureau of Statistics and from five secondary school smoking surveys. The Tasmanian age-standardized lung cancer incidence rates in 25–44 year olds for the 10-year period were 6.2 per 100,000 females and 3.3 per 100,000 males. Mean rates of incidence were higher for females than for males (P=0.02). The corresponding mortality rates were 4.2 in females and 2.4 in males (P=0.08). The prevalence of smoking by adult Tasmanian women is higher than that for other Australian women (P<0.05), and their duration of smoking is longer (P<0.01). Tasmanian schoolgirls have a higher smoking prevalence than Australian mainland schoolgirls (P=0.01) and higher prevalence than Tasmanian schoolboys (P=0.01). The data suggest that smoking prevalence among teenagers passed that for males only a decade before the observed excess of female incident cases among 25–44 year olds in Tasmania.This project is funded partially by the Tasmanian Department of Community and Health Services in the form of an annual grant for the operation of the Tasmanian Cancer Registry.     

Risk of hepatocellular carcinoma and habits of alcohol drinking,betel quid chewing and cigarette smoking: a cohort of 2416 HBsAg-seropositive and 9421 HBsAg-seronegative male residents in Taiwan

Objectives: Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC) in the world. The specific aim of this study is to assess the associations between the risk of HCC and habits of alcohol drinking, betel quid chewing and cigarette smoking among subjects with and without chronic HBV infection. Methods: A total of 11,837 male residents in Taiwan were recruited in this community-based cohort study. Hepatitis B surface antigen (HBsAg) and antibody against hepatitis C virus (anti-HCV) in serum were determined by enzyme immunoassay, and the habits of alcohol drinking, betel quid chewing and cigarette smoking were collected through standardized personal interview according to a structured questionnaire. During the follow-up period of 91,885 person-years, 115 incident HCC cases were identified through data linkage with national cancer registry profile. The relative risk (RR) of developing HCC for habits of various substance use and chronic HBV infection were estimated by Cox's proportional hazards regression analyses. Results: Significantly increased HCC risk was observed for seropositives of HBsAg or anti-HCV, alcohol drinkers, betel quid chewers and cigarette smokers. There was a significant dose–response relationship between the risk of HCC and the number of habits of substance use. The highest multivariate-adjusted HCC risk was observed among HBsAg-seropositive substance users (RRs: 17.9–26.9), followed by HBsAg-seropositive non-users (RRs: 13.1–19.2), HBsAg-seronegative substance users (RRs: 1.6–2.7) and HBsAg-seronegative non-users (referent with RR = 1). The multivariate-adjusted relative HCC risks for habits of use of various substances were more profound among HBsAg-seronegatives than HBsAg-seropositive ones. Conclusion: Habitual alcohol drinking, betel quid chewing and cigarette smoking are associated with an increased risk of HCC. Abstinence from substance use is important for the prevention of HCC in areas where chronic HBV infection is endemic.     

A case–control study on family history of liver cancer as a risk factor for hepatocellular carcinoma in North Italy

Objectives: We carried out a case–control study to investigate the role of history of liver cancer in a first-degree relative as a risk factor for hepatocellular carcinoma (HCC).Methods: Two hundred eighty-seven HCC incident cases and 450 subjects unaffected by liver disease (controls) were enrolled in the study. Family history of liver cancer and other malignancies and history of alcohol intake were collected by face-to-face interview. Blood samples were analyzed for HBsAg, anti-HCV and HCV RNA positivity.Results: Family history of liver cancer was associated with HCC (odds ratio [OR] = 2.4; 95% confidence interval [CI] = 1.2–4.7), whereas family history of other malignancies was not (OR = 1.0; 95% CI = 0.6–1.5). An increased OR for family history of liver cancer was found among subjects negative for the other risk factors (OR = 2.0; 95% CI = 0.6–6.9). A synergism of family history of liver cancer was also evident with hepatitis B and hepatitis C virus infection and with heavy alcohol intake.Conclusions: This study suggests a role of family history independent from and interacting with known risk factors for hepatocellular carcinoma.     

肝外胆管癌病人中的丙型肝炎病毒和乙型肝炎病毒感染

Objective:In China, the incidence of extrahepatic bile duct carcinoma (EBDC) tends to increase over the past decades. The etiology of the noted increase in EBDC is not identified. Approximately, in a half of the overall Chinese patients with EBDC, the causative factors in the development of EBDC have not been demonstrated. There is a high prevalence of hepatitis C virus (HCV) or hepatitis B virus (HBV)in China, both of which can induce malignant transformation of infected cells and strongly associated with hepatocellular carcinoma (HCC).In this study,EBDC tissues from Chinese patients were examined for the presence of HCV and HBV infection to investigate further the potential causes of EBDC. Methods:HCV NS5 protein and HBsAg were detected by labeled streptavidin biotin (LSAB) method; HCV RNA and HBV DNA were detected by in situ polymerase chain reaction (IS-PCR) in formalin fixed, paraffin embedded specimens from 51 Chinese patients with EBDC. HCV RNA and HBV DNA were detected by IS-PCR in 34 Chinese patients with specimens of benign lesions of hepatobiliary tract(control group). Results:In 51 case tissue sections of EBDC, NS5 protein was detected in 14 (27.5%), and HBsAg in 5 (9.8%), HCV RNA in 18(35.4%) and HBV DNA in 8 (15.9%), respectively, of which HCV and HBV co-infection was detected in 2 (3.9%). In 34 case tissue sections of the control group, HCV RNA was detected in 2 (5.9%), and HBV DNA in 3 (8.8%).Conclusion:In this study using standard histochemical and PCR techniques,HCV and HBV and HBV presence in EBDC tissues than would be expected on serologic grounds.The detectable rate of HCV RNA in EBDC tissues was significantly higher than in control group(x^2=9.808,P=0.002).As a result ,this study indicates that there is a correlation between the presence of HCV infection and EBDC,and HCV infection has possible ctiologic significance in the development of EBDCin China.While HBV DNA was detecled in EBDC tissues with the difference in the detectable rate of HBV.DNA being not significance betwwen EBDC tissues and the control group(x^2=0.853,P=0.356).Further research is necessary to determine the presence of a causal relationship between HCV/HBV infection and the development of EBDC.     

Non-occupational risk factors for adult soft-tissue sarcoma in northern Italy

The role of socioeconomic and anthropometric indicators, tobacco, alcohol consumption, dietary habits, and medical history in the etiology of soft-tissue sarcoma (STS) was examined in a hospital-based case-control study, conducted in the Friuli-Venezia Giulia region of northeast Italy, between 1985 and 1990. A total of 88 STS cases (53 males and 35 females; median age: 52 years) and of 610 controls (306 males and 304 females; median age: 54 years) were interviewed. There were significant excess risks associated with a history of herpes zoster infection (odds ratio [OR]=2.4,95 percent confidence interval [CI]=1.1–5.3), chicken pox (OR=2.2, CI=1.2–4.3) and mumps in childhood (OR=2.0, CI=1.1–3.9). History of diabetes was also linked to a nonsignificant increase in STS risk (OR=1.8, CI=0.6–5.4), whereas exposure to radiation for diagnostic or therapeutic purposes was not related to the probability of developing STS. None of the investigated socioeconomic and anthropometric indicators seemed to affect STS risk; neither did tobacco smoking, nor consumption of alcohol, coffee, and tea beverages. Conversely, among the dietary habits investigated, a significant positive association emerged with an increasing frequency of consumption of dairy products (% MathType!MTEF!2!1!+-% feaafeart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXafv3ySLgzGmvETj2BSbqefm0B1jxALjhiov2D% aebbfv3ySLgzGueE0jxyaibaiiYdd9qrFfea0dXdf9vqai-hEir8Ve% ea0de9qq-hbrpepeea0db9q8as0-LqLs-Jirpepeea0-as0Fb9pgea% 0lrP0xe9Fve9Fve9qapdbaqaaeGacaGaaiaabeqaamaabaabcaGcba% Gaae4XdmaaCaaaleqabaGaaGOmaaaaaaa!3DA2!\[{\rm{\chi }}^2\]for trend=6.8, P<0.01) and oil (% MathType!MTEF!2!1!+-% feaafeart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXafv3ySLgzGmvETj2BSbqefm0B1jxALjhiov2D% aebbfv3ySLgzGueE0jxyaibaiiYdd9qrFfea0dXdf9vqai-hEir8Ve% ea0de9qq-hbrpepeea0db9q8as0-LqLs-Jirpepeea0-as0Fb9pgea% 0lrP0xe9Fve9Fve9qapdbaqaaeGacaGaaiaabeqaamaabaabcaGcba% Gaae4XdmaaCaaaleqabaGaaGOmaaaaaaa!3DA2!\[{\rm{\chi }}^2\]for trend=4.3, P<0.05), while a negative association was seen for intake of whole grain bread and pasta (OR for highest cf lowest tertile=0.4, CI=0.2–0.9).Support for this project was contributed by the Italian Association for Cancer Research, Milan, and the Italian National Research Council (CNR Applied Project Oncology, Contract 87.01544.44).     

Clinical-guide risk prediction of hepatocellular carcinoma development in chronic hepatitis C patients after interferon-based therapy

Background:

Interferon (IFN)-based therapies could eradicate hepatitis C (HCV) and reduce the risk of hepatocellular carcinoma (HCC). However, HCC could still happen after sustained virological response (SVR). We aimed to develop a simple scoring system to predict the risk of HCC development among HCV patients after antiviral therapies.

Methods:

From 1999 to 2009, 1879 patients with biopsy-proven HCV infection treated with IFN-based therapies were analyzed.

Results:

Multivariable analysis showed old age (adjusted HR (aHR)=1.73, 95% CI=1.13–2.65 for aged 60–69 and aHR=2.20, 95% CI=1.43–3.37 for aged ⩾70), Male gender (aHR=1.74, 95% CI=1.26–2.41), platelet count <150 × 10⁹/l (HR=1.91, 95% CI=1.27–2.86), α-fetoprotein ⩾20 ng ml⁻¹ (HR=2.23, 95% CI=1.58–3.14), high fibrotic stage (HR=3.32, 95% CI=2.10–5.22), HCV genotype 1b (HR=1.53, 95% CI=1.10–2.14), and non SVR (HR=2.40, 95% CI=1.70–3.38) were independent risk factors for HCC. Regression coefficients were used to build up a risk score and the accuracy was evaluated by using the area under the receiver operating characteristic curve (AUC). Three groups as low-, intermediate-, and high-risk are classified based on the risk scores. One hundred sixty patients (12.78%) in the derivation and 82 patients (13.08%) in the validation cohort developed HCC with AUC of 79.4%, sensitivity of 84.38%, and specificity of 60.66%. In the validation cohort, the 5-year HCC incidence was 1.81%, 12.92%, and 29.95% in low-, intermediate-, and high-risk groups, with hazard ratios 4.49 in intermediate- and 16.14 in high-risk group respectively. The risk reduction of HCC is greatest in patients with SVR, with a 5-year and 10-year risk reduction of 28.91% and 27.99% respectively.

Conclusion:

The risk scoring system is accurate in predicting HCC development for HCV patients after antiviral therapies.     

A meta-analysis of case-control studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma in China

We investigated whether concurrent infection by hepatitis B virus (HBV) and hepatitis C virus (HCV) in China, a hyperepidemic area for these infections, was associated with a higher risk of causing hepatocellular carcinoma (HCC) than each infection alone in a meta-analysis in China, 32 case-control studies involving 3201 cases and 4005 controls, identified from a computer-based literature search from 1966 to 2004. The pooled odds ratio and 95% confidence interval (CI) for HBsAg positivity was 14.1 (95% CI: 10.6-18.8); for anti-HCV/HCV RNA positivity was 4.6 (95% CI: 3.6-5.9); for HBsAg positivity and anti-HCV/HCV RNA negativity were 15.6 (95% CI: 11.5-21.3); for HBsAg negativity and anti-HCV/HCV RNA positivity were 8.1 (95% CI: 5.0-13.0); and positivity for both HBsAg and anti-HCV/HCV RNA was 35.7 (95% CI: 26.2-48.5). We conclude that HBV and HCV infections are important independent risk factors for HCC in China, and that dual infection by HBV and HCV is associated with a higher risk of causing HCC than each infection alone, suggesting a synergism between HBV and HCV.     

Cancer incidence patterns among adolescents and young adults in the United States

Objective The purpose of this study was to examine age-specific cancer incidence patterns among adolescents and young adults (ages 15–49).Method Cancer incidence data for 1995–1999 from 22 population-based central cancer registries, covering about 47% of the US population, were used. Relative frequencies and average annual age-specific incidence rates per 100,000 person-year were computed for the five-year age groups from age 15–19 years through 45–49 years. Tests of significance for comparison were at a level of p<0.05.Results The age at crossover from a predominance of non-epithelial cancers to a predominance of epithelial cancers during adolescence and young adulthood varied by gender and race. Epithelial cancer became the predominant type of tumor after age 40 years among males while it was the predominant type after age 25 years among females. There was also a shift in the top five cancer types with increasing age, which varied by race and gender. Epithelial cancers of the thyroid, breast, ovary, and cervix uteri started to increase sharply among young women in their 20s while among males epithelial cancers rarely occurred untill the early 30s (ages 30–34). Cancers of the female breast, colon and rectum, and lung began to occur at an earlier age and increased more sharply among blacks than among whites. However, the incidence rates of epithelial thyroid and ovarian cancers rose more quickly among whites than blacks. Non-Hodgkin lymphoma and soft tissue sarcoma (excluded Kaposis sarcoma) increased with age among both whites and blacks but the rates were significantly higher among blacks than among whites. Both Kaposis sarcoma and testicular cancer incidence increased with age and peaked in the early 30s (ages 30–34). The former was significantly higher among blacks than whites while the latter was significantly higher among whites than blacks. Cervical cancer incidence leveled offf when white women reached their 30s, but for black women the rate continued to rise with advancing age. Cutaneous melanoma rates were significantly higher among females than among males between the ages of 15 and 39.Conclusion Cancer incidence patterns among adolescents and young adults are distinctive. Specific cancer prevention and control strategies should be targeted accordingly and tailored to their specific needs.     

Incidence of childhood cancer in twins

The incidence of childhood cancer in twins was evaluated by linking a roster of 30,925 twins born in Connecticut (United States) between 1930 and 1969 with the Connecticut Tumor Registry. Cancer, exclusive of nonmelanoma skin cancer, was identified in 19 females and 12 males under 15 years of age. The incidence rate among twins was 7.9 cancers per 100,000 person-years (PY) overall, and 9.7 and 6.1 per 100,000 PYs for females and males, respectively. Four of 13 leukemias occurred in two female twin pairs, representing concordance rates of 18 percent overall and 29 percent for like-sex pairs, which are somewhat higher than values reported previously. The number of cancers expected was computed on the assumption that twins experienced the same sex-, age-, and calendar time-specific cancer rates as recorded for all Connecticut-born children. Because active follow-up of individuals was not conducted, an adjustment to person-years of observation was made to account for childhood mortality, including the high perinatal mortality characteristie of twins. Childhood cancer was 30 percent less frequent than expected (standardized incidence ratio [SIR]=0.7; 95 percent confidence interval [CI]=0.5–0.9), a deficit that is marginally greater than those found in previous studies. Both leukemia (SIR=0.8; CI=0.4–1.4), and all other cancers combined (SIR=0.6; CI=0.3–0.9) occurred less often than expected. The deficit was greater among males (SIR=0.5; CI=0.2–0.8) than among females (SIR=0.9; CI=0.5–1.4) and was especially pronounced among males younger than five years (SIR=0.2; CI=0.0–0.7). The data support the view that twins, particularly male twins, have a lower risk of childhood cancer than single-born children. Any added risk for twins associated with their greater frequency of exposure to prenatal X-rays appears to have been insufficient to offset an effect of twinning per se. Possible explanations for this finding include (i) the low birthweight distribution of twins, or (ii) selective early mortality of twin fetuses or neonates who would otherwise have developed a clinical cancer.Drs Inskip, Boice, Stone, and Fraumeni are with the Epidemiology and Biostatistics Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Dr Harvey was in the Epidemiology and Biostatistics Program at the time of this research and is now with Sterling Drug, Malvern, PA, USA. Dr Matanoski is in the Department of Epidemiology, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD, USA. Dr Flannery is with the Connecticut Tumor Registry, Hartford, CT, USA. Address correspondence to Dr Inskip, Radiation Epidemiology Branch, National Cancer Institute, Executive Plaza North, Room 408, Rockville, MD 20852, USA. This study was supported in part by Contract N01-CPO-1047 with the National Cancer Institute, US Public Health Service.     

A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma

The aim of the study was to assess whether co-infection by hepatitis-B virus (HBV) and hepatitis-C virus (HCV) is associated with a higher risk of developing hepatocellular carcinoma (HCC) than each infection alone. A meta-analysis of data published up to June 1997 was performed. HBsAg and anti-HCV antibodies or HCV RNA (anti-HCV/HCV RNA) were considered as serological markers of current HBV and HCV infection respectively. A total of 32 case-control studies were suitable for a quantitative overview. The summary odds ratios (OR) were 13.7 for HBsAg positivity and 11.5 for anti-HCV/HCV RNA positivity. The OR for anti-HCV was lower among studies using second- or third-generation anti-HCV or HCV RNA (OR, 8.2) with respect to studies with first-generation anti-HCV test (OR, 19.1). When combining data from the studies with second- or third-generation anti-HCV or HCV RNA, the OR for HBsAg positivity and anti-HCV/HCV RNA negativity was 22.5 (95% confidence interval (CI), 19.5–26.0), the OR for anti-HCV/HCV RNA positivity and HBsAg negativity was 17.3 (95% CI, 13.9–21.6), and the OR for both markers positivity was 165 (95% CI: 81.2–374, based on 191 cases and 8 controls exposed). A synergism was found between HBV and HCV infections, the OR for co-infection being greater than the sum and lower than the product of those for each infection alone. The interaction was therefore negative according to the multiplicative model, providing epidemiological evidence both of an independent effect and of interference between the 2 viruses in the carcinogenic process. Int. J. Cancer 75:347–354, 1998. © 1998 Wiley-Liss, Inc.     

Risk factors for hepatocellular carcinoma among Japanese women

To elucidate the risk factors for hepatocellular carcinoma (HCC) among women, we made a combined analysis of the data from three case-control studies conducted in high-risk areas of Japan. A total of 120 cases and 257 controls were included in the analysis. After adjustment for the study category, age, and other potential confounders, significantly increased risks were associated with chronic hepatitis-B virus infection (odds ratio [OR]=42.4, 95 percent confidence interval [CI]=11.2–160.2), a past history of blood transfusion (OR=3.7, CI=1.8–7.5), and a history of smoking (OR=2.2, CI=12–4.1). In addition, women with a history of heavy drinking experienced an elevated risk of borderline significance (OR=4.2, CI=0.9–20.4, P=0.07). When these ORs were compared with the corresponding estimates among males from the same case-control studies, no significant differences were observed between the two genders. Among the factors examined in this analysis, drinking and smoking habits—which are more common among Japanese men than women—may partly account for a large male-predominance in the incidence of HCC. Further studies are needed to clarify the roles that sex-hormones and hepatitis-C virus infection might play in the large gender difference of HCC occurrence.     

Phase-I dose escalation and sequencing study of docetaxel and continuous infusion topotecan in patients with advanced malignancies

Purpose Anti-tumor activity can often be enhanced with combination therapy in managing patients with metastatic cancer. However, dose sequence and schedule of delivery can alter the pharmacokinetics, toxicity, and anti-tumor response. Therefore, attention to drug–drug interactions which may be sequence or schedule-dependent are necessary. Docetaxel and topotecan are non-cross-resistance cytotoxic agents with activity in a variety of malignancies. The goal of this study was to determine the maximum tolerated dose of docetaxel and continuous infusion topotecan using two sequences of administration.Experimental design Patients were randomized to schedule A or B and enrolled in four escalating-dose cohorts. On schedule A, docetaxel was administered over 1 h and followed by topotecan administered over 72 h. On schedule B, topotecan was given as a 72 h continuous infusion followed by a 1 h infusion of docetaxel. While the doses for the docetaxel and topotecan were the same for schedule A and schedule B, the toxicities, and thus the determination of maximum tolerated dose (MTD), were assessed independently. The plasma pharmacokinetic disposition of topotecan and docetaxel were evaluated during the first cycle of each sequence to assess drug interactions.Results Thirty patients, 20 males and 10 females were evaluable for toxicity and response. Four patients were chemonaive. Mean number cycles given were 3. Grade 3/4 thrombocytopenia and neutropenia were comparable on both schedules, as was the dose-limiting toxicity (DLT) for both schedules. There were no apparent differences in absolute neutrophil count or platelet nadirs between schedules A and B for three of the four cohorts. The principal non-hematologic toxicity was nausea and vomiting. The time of overlap of topotecan lactone or total concentrations and docetaxel concentrations were greater on schedule A as compared with schedule B and was associated with reduced clearance of docetaxel on schedule A as compared to schedule B. However, the mean clearance for docetaxel (1816 L h^–1 m^–2 and 2928 L h^–1 m^–2 on schedules A and B, respectively, and topotecan 1610 L h^–1 m^–2 and 76 L h^–1 m^–2 on schedules A and B, respectively) were not statistically different (P>0.05).Conclusions The observed toxicity was not sequence-dependent, despite the observed change in kinetics. Docetaxel and topotecan can be administered with acceptable toxicity at the recommended phase-II dose of docetaxel 60 mg m^–2 and topotecan 0.85 mg m^–2 day^–1×3 days.     

Alcohol and colorectal cancer: a case-control study from northern Italy

The role of alcohol consumption in the etiology of colorectal cancer has been investigated in a case-control study conducted from 1985 to 1990 in the northern part of Italy, on 889 cases of colon cancer, 581 cases of rectal cancer, and 2,475 controls admitted to hospital for acute, non-neoplastic, nodigestive disordes. After allowance for age, education, study center, body mass index, and approximate total energy intake, no significant associations between alcohol intake and the risk of cancer of the colon or rectum were found (odds ratios [OR] for 42 drinks/week cf none =1.0 (95 percent confidence interval [CI]=0.8–1.4) and 0.7 (CI=0.5–1.0) for cancer of the colon and rectum, respectively). A significant increase in the risk of colon cancer with increasing alcohol consumption was, however, observed in females (OR for 28 drinks/week cf none = 1.8 (CI=1.1–3.0)). While the results of the present case-control study do not suggest that alcohol plays a role in the etiology of colon or rectum cancer overall, they provide a hint for a weak association between alcohol consumption and colon cancer among females which, because of the similarities with breast cancer, should be evaluated in the context of the possible relationship between colon cancer, alcohol intake, and female hormones.Drs Barra, Franceschi, and Guarneri, are with the Epidemiology Unit, Aviano Cancer Center Aviano, Italy. Dr Franceschi is also with the European Cancer Prevention Organisation (ECP), Epidemiology and Cancer Working Group, Brussels, Belgium. Drs Negri and La Vecchia are with the Mario Negri Institute for Pharmacological Research, Milan, Italy. Dr La Vecchia is also with the Institute of Social and Preventive Medecine, University of Lausanne, Lausanne, Switzerland. Address correspondence to Dr Barra, Epidemiology Unit, Aviano Cancer Center, Via Pedemontana Occ., 33081 Aviano (PN) Italy. Support for this project was contributed by the Italian Association for Research on Cancer and the Italian League against Tumors, Milan and the Italian National Research Council (CNR Applied Project Clinical Applications of Oncological Research).     

Disposition of total and unbound etoposide following high-dose therapy

Total and unbound etoposide pharmacokinetics were studied in 16 adult patients (median age, 34 years; range, 18–61 years) undergoing autologous bone marrow transplantation for advanced lymphoma after receiving high-dose etoposide (35–60 mg/kg) as a single intravenous infusion. Pretreatment values for mean serum albumin and total bilirubin were 3.0±0.4 g/dl and 0.5±0.4 mg/dl, respectively. Etoposide plasma concentrations and protein binding (% unbound) were determined by high-performance liquid chromatography (HPLC) and equilibrium dialysis, respectively. Pharmacokinetic parameters for unbound and total etoposide were calculated by nonlinear regression analysis using a two-compartment model. Te mean (±SD) parameters for total etoposide included: clearance (CL), 31.8±17.7 ml min^–1 m^–2; volume of distribution (V_ss), 11.5±5.9 l/m², and terminal half-life (t _1/2 ), 7.2±3.7 h. Mean unbound CL was 209.6±62.7 ml min^–1 m^–2 and %unbound was 16%±5%. The mean etoposide %unbound was inversely related to serum albumin (r ²=0.45,P=0.0043). The mean %unbound at the end of the etoposide infusion was higher than that at the lowest measured concentration (21% vs 13%, respectively;P=0.017), suggesting that concentration-dependent binding may occur after high etoposide doses. The median total CL was higher in patients with serum albumin concentrations of 3.0 g/dl than in those with levels of >3.0 g/dl (34.6 vs 23.5 ml min^–1 m^–2,P=0.05). Total CL was directly related to %unbound (r ²=0.61,P=0.0004). Unbound CL was unrelated to either serum albumin or %unbound. These results demonstrate that hypoalbuminemia is independently associated with an increased etoposide %unbound and rapid total CL after the administration of high-dose etoposide. Unbound CL in hypoalbuminemic patients is unchanged in the presence of normal total bilirubin values.This study was supported in part by Bristol-Myers. Oncology Division