Sherri O. Stuver

Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma

During a 4‐year period from January 1995 to December 1998, blood samples and questionnaire data were obtained from 333 incident cases of hepatocellular carcinoma (HCC), as well as from 360 controls who were hospitalized for eye, ear, nose, throat or orthopedic conditions in Athens, Greece. Coded sera were tested for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti‐HCV) by third‐generation enzyme immunoassays, and information on smoking habits and beverage consumption was obtained. We found a significant dose‐response, positive association between smoking and HCC risk [≥ 2 packs per day, odds ratio (OR)=2.5].This association was stronger in individuals without chronic infection with either HBV or HCV (≥ 2 packs per day, OR=2.8). Consumption of alcoholic beverages above a threshold of 40 glasses per week increased the risk of HCC (OR=1.9). We also found evidence of a strong, statistically significant and apparently super‐multiplicative effect of heavy smoking and heavy drinking in the development of HCC (OR for both exposures=9.6). This interaction was particularly evident among individuals without either HBsAg or anti‐HCV (OR for both exposures=10.9). Coffee intake was not positively associated with HCC risk, but the reverse could not be excluded for the subgroup of chronically infected individuals. In conclusion, tobacco smoking and heavy alcohol consumption are associated with increased risk of HCC, especially when these 2 exposures occur together. Int. J. Cancer 85:498–502, 2000.

Noninvasive Markers of Liver Fibrosis Are Highly Predictive of Liver-Related Death in a Cohort of HCV-Infected Individuals With and Without HIV Infection

OBJECTIVES:Noninvasive markers of liver fibrosis correlate with the stage of liver fibrosis, but have not been widely applied to predict liver-related mortality.METHODS:We assessed the ability of two indices of liver fibrosis, aspartate aminotransferase (AST)-to-platelet ratio index (APRI) and Fib-4, and two markers of extracellular matrix metabolism, hyaluronic acid (HA) and YKL40, to predict liver mortality in a prospective cohort of hepatitis C virus (HCV)-infected individuals with and without HIV coinfection. These were compared with two established prognostic scores, the Child–Pugh–Turcotte (CPT) and model of end-stage liver disease (MELD) scores.RESULTS:A total of 303 subjects, of whom 207 were HIV positive at study entry, were followed up for a mean period of 3.1 years. There were 33 deaths due to liver disease. The ability of each test and score to predict 3-year liver mortality was expressed as the area under the receiver operator curve. The area under the receiver operator curve 95% confidence intervals were: HA 0.92 (0.86–0.96), CPT 0.91 (0.79–0.96), APRI 0.88 (0.80–0.93), Fib-4 0.87 (0.77–0.92), MELD 0.84 (71–0.91). In multivariate analyses HA, APRI, and fib-4 were independent predictors of mortality when included in models with MELD or CPT.CONCLUSION:Noninvasive markers of liver fibrosis are highly predictive of liver outcome in HCV-infected individuals with and without HIV coinfection. These markers seem to have a prognostic value independent of CPT and MELD.

Findings from the Miyazaki cohort study

The purpose of the Miyazaki Cohort Study is to describe and analyze the natural history of human T-cell lymphotropic virus type I (HTLV-I) in a highly endemic population in southwestern Japan. As of August 1995, 1,960 individuals have been enrolled, of whom 27% were HTLV-I antibody positive at baseline. Our achievements over the past decade of following this cohort include the identification of several viral markers that characterize high-risk carriers and the documentation that carriers have subclinical evidence of impaired cellular immunity. We have begun to estimate the impact of the infection on the health of carriers and have found that men are at greater risk of HTLV-I-associated diseases than women. We have been able to identify prospectively risk factors associated with sexual transmission. Most important, by identifying subclinical markers of pathogenesis, we hope to provide the foundation for developing interventions to prevent HTLV-I-associated disease.

Intrauterine exposure to preeclampsia and adolescent blood pressure, body size, and age at menarche in female offspring.

OBJECTIVE To investigate whether female offspring of preeclamptic pregnancies have higher blood pressure, lower height, higher body mass index (BMI), and later age at menarche compared with offspring of normotensive pregnancies. METHODS Questionnaire information on age at menarche and measurements of blood pressure, height, and weight were collected among 4096 Norwegian girls 13–19 years old. Individual linkage to perinatal data registered at the national Medical Birth Registry allowed us to study the relationship of preeclampsia in the mother with adolescent blood pressure, body size, and age at menarche of daughters. RESULTS Maternal preeclampsia was associated in the female offspring with higher systolic (2.9 mm Hg difference, P < .001) and diastolic (1.7 mm Hg difference, P = .001) blood pressure during adolescence and higher weight (3.4 kg difference, P < .001) and BMI (22.6 versus 21.5, P < .001). After adjustment for adolescent BMI, the difference in systolic blood pressure was attenuated from 2.9 to 1.7 mm Hg (P = .017), and from 1.7 to 0.9 mm Hg (P = .08) for diastolic blood pressure. CONCLUSION Intrauterine exposure to preeclampsia was associated with increased adolescent blood pressure. The association may be causally related to adult hypertension but could also be confounded by higher BMI during adolescence.

Role of HTLV‐1 proviral DNA load and clonality in the development of adult T‐cell leukemia/lymphoma in asymptomatic carriers

Akihiko OKAYAMA*, Sherri STUVER, Masao MATSUOKA, Junzo ISHIZAKI, Gen-ichi TANAKA, Yoko KUBUKI, Nancy MUELLER, Chung-cheng HSIEH, Nobuyoshi TACHIBANA and Hirohito TSUBOUCHI Department of Internal Medicine II, Miyazaki Medical College, Miyazaki, Japan Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Kyoto, Japan Division of Biostatistics and Epidemiology, University of Massachusetts Medical School Cancer Center, Boston, MA, USA Department of Nursing Science, Miyazaki Prefectural Nursing College, Miyazaki, Japan

Birth weight as a predictor of breast cancer: a case–control study in Norway

The hypothesis that birth weight is positively associated with adult risk of breast cancer implies that factors related to intrauterine growth may be important for the development of this malignancy. Using stored birth records from the two main hospitals in Trondheim and Bergen, Norway, we collected information on birth weight, birth length and placenta weight among 373 women who developed breast cancer. From the same archives, we selected as controls 1150 women of identical age as the cases without a history of breast cancer. Information on age at first birth and parity were collected from the Central Person Registry in Norway. Based on conditional logistic regression analysis, breast cancer risk was positively associated with birth weight and with birth length (P for trend=0.02). Birth weights in the highest quartile (3730 g or more) were associated with 40% higher risk (odds ratio, 1.4, 95% confidence interval, 1.1–1.9) of breast cancer compared to birth weights in the lowest quartile (less than 3090 g). For birth length, the odds ratio for women who were 51.5 cm or more (highest quartile) was 1.3 (95% confidence interval, 1.0–1.8) compared to being less than 50 cm (lowest quartile) at birth. Adjustment for age at first birth and parity did not change these estimates. Placenta weight was not associated with breast cancer risk. This study provides strong evidence that intrauterine factors may influence future risk of breast cancer. A common feature of such factors would be their ability to stimulate foetal growth and, simultaneously, to influence intrauterine development of the mammary gland.

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

AbstractObjectives: 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.

A Follow-Up Study of Morbidity and Mortality Associated with Hepatitis C Virus Infection and Its Interaction with Human T Lymphotropic Virus Type I in Miyazaki, Japan

A follow-up study was performed to analyze the effects of hepatitis C virus (HCV) infection on morbidity and mortality in the adult population from a village in Japan found to have endemic levels of both HCV and human T lymphotropic virus type I (HTLV-I). By use of the Cox proportional hazards model, rate ratios (RRs) and 95% confidence intervals (CIs) were estimated. Strong, significant effects of seropositivity for antibodies to HCV on self-reported incident liver disease (RR, 3.5; 95% CI, 1.9-6.4) and on death due to liver cancer (RR, 8.2; 95% CI, 1.6-41.4) were observed. Dual infection with HCV and HTLV-I seemed to have a synergistic effect on incident liver disease (RR, 5.9) as well as on death from liver cancer (RR, 21.9). HCV infection also was positively, although not significantly, associated with reported incident diabetes. Our findings suggest that coinfection with HTLV-I may affect the course of HCV-associated disease.

Insulin-like growth factor 1 in hepatocellular carcinoma and metastatic liver cancer in men.

The insulin‐like growth factor (IGF) axis has important autocrine, paracrine, and endocrine roles in the promotion of growth. Alterations of the IGF system have recently been implicated in the pathogenesis of several malignancies, but the relation to hepatocellular carcinoma (HCC) risk is unclear. To address this issue, we used an immunoradiometric assay to quantify IGF‐1 levels in serum samples in a hospital‐based, case‐control study in Greece. The study subjects were all men and included 53 patients with HCC positive for hepatitis B and/or hepatitis C virus infections, 20 virus‐negative HCC patients, 25 virus‐negative patients with metastatic liver cancer (MLC), and 111 virus‐negative control subjects. Data were analyzed by multiple linear regression, using IGF‐1 as the dependent variable. The mean value of IGF‐1 was 65.9 ng/ml among virus‐positive HCC patients, 79.5 ng/ml among virus‐negative HCC patients, 110.8 ng/ml among patients with MLC, and 174.7 ng/ml among hospital controls. After controlling for the degree of liver damage, as assessed by prothrombin time and serum albumin level, the reduction in IGF‐1 level among HCC patients was found to be more than could be attributed to liver damage alone. This finding may have both diagnostic and pathophysiological implications. Int. J. Cancer 87:118–121, 2000.

The Clonal Expansion of Human T Lymphotropic Virus Type 1–Infected T Cells: A Comparison between Seroconverters and Long-Term Carriers

BACKGROUND The clonal expansion of human T lymphotropic virus type 1 (HTLV-1)-infected T cells is considered to be important for the maintenance of infection. However, the process by which the clonality of HTLV-1-infected T cells is established is not understood. METHODS HTLV-1 clonality in 4 adult seroconverters was analyzed by inverse long polymerase chain reaction (PCR) followed by cloning of the PCR products and evaluation of restriction fragment-length polymorphism. The results were compared with those for 8 long-term HTLV-1 carriers. RESULTS The clonality of HTLV-1-infected T cells in the seroconverters arose stochastically and was variable 3-5 years after seroconversion. On the basis of the frequency with which clones of cells infected with unique HTLV-1 provirus integration sites appeared, it was clear that the seroconverters had a greater number of unique clones with fewer infected cells than did the long-term carriers. CONCLUSIONS The clonality of the HTLV-1-infected T cells in the adult seroconverters, who had been newly infected via HTLV-1-carrier spouses, was more heterogeneous and less stable than that of the HTLV-1-infected T cells in long-term carriers, who were more likely to have been infected during infancy. The mechanism for the selective maintenance of certain clones in asymptomatic HTLV-1 carriers likely plays a role in the initiation of leukemogenesis.