The connection between the consumption of dairy products and the risk of developing primary liver cancer (PLC) remains unclear. The present study performed a comprehensive meta-analysis with the aim of providing evidence for any connection between the risk of developing PLC and the consumption of dairy products. For this purpose, eligible studies were screened from the PubMed, Cochrane Library and Embase databases before December 2022. A total of 10 cohort studies and 8 case-control studies were included, making a total of 18 studies with 6,562,714 participants and 7,970 PLC cases. The relative risks (RRs) for milk and yogurt were 1.38 [95% confidence interval (CI), 1.07-1.77] and 0.49 (95% CI, 0.27-0.91), which revealed a positive and negative association, respectively, with the risk of developing PLC. There was no association between total dairy (RR, 1.04; 95% CI, 0.84-1.30) or cheese and curd (RR, 1.05; 95% CI, 0.87-1.27) consumption and the risk of developing PLC. On the whole, the findings of the present study demonstrated that high milk consumption was associated with a higher risk of developing PLC, while by contrast, yogurt consumption was associated with a lower risk of developing PLC. Consequently, further studies are required to further examine this association.

Diet is emerging as a modifiable component of lifestyle for influencing the incidence of liver cancer.

To investigate and quantify the potential relationship between food groups and liver cancer.

PubMed and Web of Science were searched for eligible observational studies until 31st March, 2023.

The meta-analysis was conducted by pooling relative risk (RR), odds ratio (OR) or hazards ratio (HR) with 95% confidence intervals (CIs). Potential sources of heterogeneity were detected by subgroup analysis. Sensitivity analysis and publication bias test were also carried out.

Through stepwise screening, a total of 27 studies were included. The pooled estimates of liver cancer for whole grains and legumes intake were 0.66 (95% CI: 0.54-0.82; I² = 25.3%) and 0.86 (95% CI: 0.75-0.99; I² = 14.3%), respectively. However, there were null associations of nuts, poultry, egg and sweetened beverages consumption with liver cancer and the association between refined grains and liver cancer was inconclusive. In dose-response meta-analysis, the pooled estimates of liver cancer were 0.77 (95% CI: 0.65-0.91) for every 50 g/day increment in whole grains intake. Non-linear dose-response relationship (P = 0.031) was observed in the association between the intake of legumes and liver cancer, and the protective effect occurred with the dose ranging from 8 g/day to 40 g/day.

This meta-analysis shows that whole grains and legumes were inversely associated with liver cancer, whereas intake of nuts, poultry, egg and sweetened beverages may not be associated with liver cancer. Further quantitative research needs to be undertaken within a range of populations to investigate the relationship between food groups and liver cancer.

PROSPERO registration no. CRD42021246142.

The relationship of dairy consumption and liver cancer risk is still controversial. We conducted a meta-analysis of published cohort and case-control studies to summarize the epidemiologic evidence on the relationship between dairy products consumption and the risk of liver cancer. The literatures were screened from PubMed, EMBASE, and Cochrane Library before May 2020. A total of seven cohort studies and eight case-control studies (5,121 cases) were included. The summary relative risks (RRs) were 1.17 (95% CI: 0.87‒1.57) and 1.08 (95% CI: 0.78‒1.51) for milk and total dairy, respectively. 0.50 (95% CI: 0.27-0.91) and 1.16 (95% CI: 0.83-1.52) were yogurt, cheese, and curd. Subgroup analysis revealed that study duration, alcohol, and design were associated the RRs. Dose-response analysis showed that the liver cancer risk was decreased by 5.4% (P for linear trend = 0.002) with a 40 g/day increment of yogurt intake. These results suggested that total dairy, milk, cheese, and curd were positive associations with the liver cancer risk although they were not statistically significant, however higher yogurt intake would reduce the risk. Further studies are necessary to verify the relationship of dairy foods with cancer.

The aim of this study was to compare the impact of fermented and unfermented soy intake, based on the following soy-derived products: tofu, soymilk, natto, and miso, on the risk of liver cancer among Japanese adults.

75,089 Participants of the Japan Public Health Center-based Prospective Study (JPHC Study) were followed from the time of the 5-year follow-up questionnaire until the end of 2012-2013. Subjects with available data on hepatitis B virus (HBV) and hepatitis C virus (HCV) infection status from blood samples (n = 14,016) and those who were anti-HCV antibody (anti-HCV) or hepatitis B virus antigen (HBsAg) positive (n = 1033) were also analyzed separately. Cox proportional hazard models were employed to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs).

During 1,145,453 person-years, 534 newly diagnosed cases of liver cancer were identified in the JPHC Study. For miso intake among men, the multivariate-adjusted highest versus lowest quartile HR was 0.65 (95% CI, 0.48-0.89); p for trend = 0.006. Results were similar in those who were anti-HCV or HBsAg positive, 0.24 (0.08-0.70); p for trend = 0.004 highest versus lowest tertile. For the sub-analysis among only participants with known hepatitis infection status and HCV and HBsAg adjustment, a similar association was observed. In the multivariate complete cohort analysis, among women, the highest intake of fried tofu was inversely associated with the risk of liver cancer, HR = 0.45 (0.26-0.80); p for trend = 0.014.

We observed no association between total soy intake, fermented and unfermented, and risk of liver cancer, and only an inverse association between miso intake and liver cancer among men.

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and its incidence has increased during the past decade. While hepatitis B and C virus infections and alcohol were established risk factors, the impact of smoking on the incidence and mortality of HCC was needed to be confirmed.

We reviewed cohort and case-control studies evaluating the association between cigarette smoking and incidence and mortality of HCC from MEDLINE and Google Scholar. We also checked reference lists of original studies and review articles manually for cross-references up to February 2016. We extracted the relevant information on participant characteristics and study outcomes, as well as information on the methodology of the studies. We also assessed the quality of the included trials using critical appraisal skills program checklists. Meta-analysis was performed by using RevMan 5.3 software.

A total of 81 studies were included in the systematic review. Pooled OR for HCC development with current smokers was 1.55 (95% CI: 1.46 to 1.65; P < 0.00001). Pooled OR for HCC development with former smokers was 1.39 (95% CI: 1.26 to 1.52; P < 0.00001) and pooled OR for HCC development with heavy smokers was 1.90 (95% CI: 1.68 to 2.14; P < 0.00001). Pooled OR for the mortality of current smokers with HCC was 1.29 (95% CI: 1.23 to 1.34; P < 0.00001); and for former smokers with HCC, it was 1.20 (95% CI: 1.00 to 1.42; P = 0.04).

Cigarette smoking increases the incidence and mortality of HCC. Further studies are needed to evaluate possible impact of quitting smoking on decreasing this risk.

Acrolein is a highly reactive unsaturated aldehyde widely present in the environment, particularly as a product of tobacco smoke. Our previous studies indicated the adverse consequences of even short-term acrolein exposure and proposed a molecular mechanism of its potential harmful effect on oral cavity keratinocytic cells. In this paper we chose to review the broad spectrum of acrolein sources such as pollution, food, and smoking. Consequently, in this paper we consider a high level of oral exposure to acrolein through these sources and discuss the noxious effects it has on the oral cavity including on salivary quality and contents, oral resistance to oxidative stress, and stress mechanism activation in a variety of oral cells.

Intake of dairy products has been associated with risk of some cancers, but findings are often inconsistent and information on hepatocellular carcinoma (HCC) risk is limited, particularly from prospective settings. The aim of our study was to investigate the association between consumption of total and specific dairy products (milk/cheese/yogurt) and their components (calcium/vitamin D/fats/protein), with first incident HCC (N(cases) = 191) in the European Prospective Investigation into Cancer and Nutrition cohort, including a nested case-control subset (N(cases) = 122) with the assessment of hepatitis B virus/hepatitis C virus infections status, liver damage and circulating insulin-like growth factor (IGF)-I levels. For cohort analyses, multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI). For nested case-control analyses, conditional logistic regression was used to calculate odds ratios and 95% CI. A total of 477,206 participants were followed-up for an average of 11 years (person-years follow-up = 5,415,385). In the cohort study, a significant positive HCC risk association was observed for total dairy products (highest vs. lowest tertile, HR = 1.66, 95% CI: 1.13-2.43; p(trend) = 0.012), milk (HR = 1.51, 95% CI: 1.02-2.24; p(trend) = 0.049), and cheese (HR = 1.56, 95% CI: 1.02-2.38; p(trend) = 0.101), but not yogurt (HR = 0.94, 95% CI: 0.65-1.35). Dietary calcium, vitamin D, fat and protein from dairy sources were associated with increased HCC risk, whereas the same nutrients from nondairy sources showed inverse or null associations. In the nested case-control study, similar results were observed among hepatitis-free individuals. Results from this large prospective cohort study suggest that higher consumption of dairy products, particularly milk and cheese, may be associated with increased HCC risk. Validation of these findings in other populations is necessary. Potential biologic mechanisms require further exploration.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. There is growing evidence for a chemopreventive role of nutrition in the development of HCC in at risk populations. Bibliographical searches were performed in PubMed for the terms 'nutrition and hepatocellular carcinoma', 'nutrition and liver cancer', 'nutrition and hepatic cancer', 'diet and hepatocellular carcinoma', 'diet and liver cancer'. High dietary sugar intake should be discouraged in at risk populations. Coffee, polyphenols, vanadium, dietary fibre, fruits and vegetables show encouraging results in terms of chemoprevention. Red meat intake may be associated with increased risk of HCC. The evidence for fatty acids is inconclusive, but they might exert anti-cancer effects. Inconclusive results are available on vitamins, selenium probiotics and prebiotics. There is increasing evidence that diet may play an important role in the development of HCC, and may also have a chemopreventive role in at risk populations.

While higher intake of fish and lower consumption of red/processed meats have been suggested to play a protective role in the etiology of several cancers, prospective evidence for hepatocellular carcinoma (HCC) is limited, particularly in Western European populations.

The associations of fish and meats with HCC risk were analyzed in the EPIC cohort. Between 1992 and 2010, 191 incident HCC were identified among 477 206 participants. Baseline diet was assessed using validated dietary questionnaires. A single 24-h diet recall from a cohort subsample was used for calibration. Multivariable proportional hazard regression was utilized to estimate hazard ratios (HR) and 95% confidence intervals (CI). In a nested case-control subset (HCC = 122), HBV/HCV status and liver function biomarkers were measured.

HCC risk was inversely associated with intake of total fish (per 20 g/day increase, HR = 0.83, 95% CI 0.74-0.95 and HR = 0.80, 95% CI 0.69-0.97 before and after calibration, respectively). This inverse association was also suggested after adjusting for HBV/HCV status and liver function score (per 20-g/day increase, RR = 0.86, 95% CI 0.66-1.11 and RR = 0.74, 95% CI 0.50-1.09, respectively) in a nested case-control subset. Intakes of total meats or subgroups of red/processed meats, and poultry were not associated with HCC risk.

In this large European cohort, total fish intake is associated with lower HCC risk.

Given the close correlation between smoking and alcohol intake in most epidemiologic studies, it is difficult to exclude the residual confounding effect of alcohol in the association between smoking and hepatocellular carcinoma (HCC).

We evaluated the association between smoking and risk of HCC in the Singapore Chinese Health Study, a prospective cohort with a low prevalence of alcohol intake. Information on cigarette smoking and alcohol consumption was obtained through in-person interviews conducted at enrolment.

After a mean of 11.5 years of follow-up, there were 394 incident cases of HCC. Participants who consumed more than two alcoholic drinks per day showed an increased risk for HCC (hazard ratio (HR)=2.24; 95% confidence interval (CI)=1.46-3.41). After adjusting for alcohol consumption and other potential confounders, current vs never smokers had a statistically significant, increased risk of HCC (HR=1.63; 95% CI=1.27-2.10) that was dose-dependent (number of cigarettes per day, P for trend<0.001). The observed tobacco-HCC association also was duration-dependent (years of smoking in ever smokers, P for trend=0.002). When we excluded daily drinkers from the analysis, all risk estimates remained essentially the same and statistically significant.

Our findings strongly implicate tobacco smoke as a causal factor of HCC development.

The global risk of hepatocellular carcinoma (HCC) has been largely driven by hepatitis B virus (HBV) infection for the past century, along with hepatitis C virus (HCV), aflatoxin, excessive alcohol consumption, and obesity/diabetes. The dominant effect of HBV on global HCC risk should decline as the population vaccinated against HBV grows older. Infection with HCV is also expected to decline. Projections of HCV-related HCC rates remaining high for another 30 years may be overly pessimistic. Alcohol may be less of a factor in HCC in coming years. However, obesity and diabetes may become even more important risk factors for HCC.

Whereas the International Agency for Research on Cancer (IARC) Monograph concluded that the evidence for the relationship between cigarette smoking and liver cancer is sufficient, the US Surgeon General's report summarized the data as suggestive but not sufficient.

A meta-analysis of previous epidemiologic studies may help to clarify the potential association. We identified 38 cohort studies and 58 case-control studies in a systematic literature search for studies on liver cancer and cigarette smoking. The meta-relative risk (mRR) of liver cancer and dose-response trends were calculated. Tests for heterogeneity, publication bias assessment and influence analyses were performed.

Compared with never smokers, the adjusted mRR was 1.51 [95% confidence interval (CI) 1.37-1.67] for current smokers and 1.12 (95% CI 0.78-1.60) for former smokers. The increased liver cancer risk among current smokers appeared to be consistent in strata of different regions, study designs, study sample sizes and publication periods.

The results of our meta-analysis show that tobacco smoking is associated with liver cancer development, which supports the conclusion by the IARC Monograph. This conclusion has an important public health message for areas with high smoking prevalence and high liver cancer incidence such as China.

The incidence of hepatocellular carcinoma (HCC) is much higher in men than in women. Several experiment and epidemiological studies have suggested that estrogen might play an inhibitory role in the development of HCC. Because isoflavones have a similar structure as 17beta-estradiol and appear to have an anti-estrogenic effect in women and estrogenic effect in men, we hypothesized that the effect of isoflavones on HCC differs by sex. We investigated the association between isoflavones (genistein and daidzein) and soy products and HCC in Japan in a population-based prospective study in 19,998 Japanese (7,215 men and 12,783 women) aged 40-69 years. During 11.8 years of follow-up, 101 subjects (69 men and 32 women) were newly diagnosed with HCC. Case patients were grouped according to consumption of isoflavones and soy products and stratified by hepatitis virus infection. Hazard ratios (HRs) and 95% confidence intervals (CIs) for HCC were calculated by Cox proportional-hazards modeling. In women, genistein and daidzein were dose-dependently associated with an increased risk of HCC, with multivariable HRs for the highest versus lowest tertile of 3.19 (95%CI = 1.13-9.00, p(trend) = 0.03) and 3.90 (95% CI = 1.30-11.69, p(trend) = 0.01), respectively. No association between isoflavones and HCC was observed in men. These results persisted when analysis was restricted to subjects positive for either or both hepatitis C and B virus. In conclusion, isoflavone consumption may be associated with an increased risk of HCC in women. Women with hepatitis virus infection may be advised to abstain from isoflavone consumption. Further studies are warranted to confirm these findings.

Although alcohol consumption has been recognized as a risk factor for primary liver cancer, it will be informative to summarize relevant epidemiologic data in the Japanese who have characteristic environmental determinants (e.g. hepatitis C virus infection) and genetic traits (e.g. presence of poor acetaldehyde metabolizers).

We systematically reviewed epidemiologic studies on alcohol drinking and liver cancer among Japanese populations. Original data were obtained through searches of the MEDLINE (PubMed) and Ichushi databases, complemented with manual searches. The evaluation was performed in terms of the magnitude of association ('strong', 'moderate', 'weak' or 'no association') in each study and the strength of evidence ('convincing', 'probable', 'possible' or 'insufficient'), together with biological plausibility as previously assessed by the International Agency for Research on Cancer.

Among 22 cohort studies identified, 14 (64%) reported weak to strong positive associations between alcohol and liver cancer risk, 3 (14%) reported no association and five (23%) reported weak to moderate inverse associations; such inverse associations were found mostly in follow-up studies of patients with chronic liver disease (particularly, cirrhotic patients), yet recent studies on patients with chronic hepatitis C presented fairly consistent positive associations. Of 24 case-control studies identified, 19 (79%) showed weak to strong positive associations, whereas the remainder demonstrated no association (n = 4) or a moderate inverse association (n = 1).

We conclude that there is 'convincing' evidence that alcohol drinking increases the risk of primary liver cancer among the Japanese population.

Emerging epidemiologic data suggest that cigarette smoking may increase the risk of hepatocellular carcinoma (HCC), yet considerable controversies (e.g. inconsistent dose-response relationships) still exist with this association. We examined whether smoking was associated with HCC risk in a case-control study including 209 incident HCC cases and two different control groups (256 hospital controls and 381 patients with chronic liver disease [CLD] without HCC). Comparison of HCC cases with CLD patients, but not with hospital controls, demonstrated a significantly increased risk of HCC for current smokers. After adjustment for sex, age, heavy drinking history and hepatitis virus markers, odds ratios (and 95% confidence intervals) for former and current smokers relative to never smokers were 1.0 (0.6-1.7) and 2.5 (1.4-4.6), respectively, against CLD patients, as compared with 0.8 (0.3-2.3) and 1.8 (0.6-5.1), respectively, against hospital controls. In terms of pack-years during lifetime, dose-response relationship was not evident against either control group (P trend = 0.43), but it became clearer for more recent cigarette use among CLD patients. For example, regarding cumulative cigarette consumption during the last 5 years, adjusted odds ratios (and 95% confidence intervals) for 1-4 and 5+ pack-years relative to no use were 1.9 (1.1-3.6) and 2.8 (1.5-5.2) (P trend = 0.003), respectively. These results suggest that cigarette smoking may play a crucial role in the late stage of HCC development and that CLD patients may benefit from their earliest smoking cessation.

Using the case-control data from the Selected Cancers Study, the authors assessed whether cigarette smoking increases the risk of primary liver cancer in the US.

Cases were men who were pathologically diagnosed with primary liver cancer during 1984-1988, were 31-59 years old, and lived in the areas covered by eight US cancer registries (n=168). Controls were men without a history of primary liver cancer who were selected by random-digit telephone dialing (n=1910).

Relative to non-smokers, the risks of liver cancer were 1.85 (95% confidence interval (CI), 1.05-3.25) and 1.49 (95% CI, 0.83-2.68) for former and current smokers, respectively. The adjusted odds ratio (OR) estimates were 0.96, 1.43, 1.80, and 1.87 for smoking for less than 15, 15-24, 25-34 and 35 or more years, respectively (p for trend=0.039). The OR estimates were 1.41 (95% CI, 0.74-2.68), 1.67 (95% CI, 0.93-2.98), and 1.83 (95% CI, 0.89-3.76) for less than 1, 1-2, and 2 or more packs smoked per day (p for trend=0.068).

Cigarette smoking may be a factor that contributes somewhat to the occurrence of primary liver cancer among men in the United States, a country with low risk of liver cancer.

Morbidity and mortality are classically used to measure disease burden. However, the allocation of limited health-care resources demands an agreed rational allocation principle and, consequently, the setting of priorities is of considerable importance. We collected data from the national death certificate database, and the national health insurance claim database and life tables. Using this data, we calculated disability adjusted life year (DALY) and health life year (HeaLY) values for smoking-related cancer. The burden of cancer due to smoking was estimated by multiplying the population attributable risk due to smoking by the DALY and HeaLY results for cancers. The burden of cancer due to smoking for Korean men was 1930.1 person-years by DALY and 1681.3 person-years by HeaLY per 100 000 people. Similarly, the burden of cancer due to smoking for Korean women was 352.6 person-years for DALY and 313.6 person-years for HeaLY per 100 000 people. Priority rankings for cancer burden due to smoking was somewhat different by DALY and HeaLY. The largest health gap for men was stomach cancer by DALY and lung cancer by HeaLY, whereas for women it was lung cancer by both methods. This study provides a rational basis for national cancer policy planning by presenting the priority burden of cancers caused by smoking.

This study estimated the burden of premature death due to smoking in Korea between 1990 and 1999 using the years of life lost (YLL) due to premature death method. To implement this study, age-group-specific YLL due to premature death were calculated by employing the standard expected years of life lost method. YLL due to smoking were calculated based on assumptions and methods developed by the Global Burden of Disease Study Group. The burden of premature death due to smoking was estimated by multiplying the population attributable risk by the YLL of smoking-related diseases. In 1999, the burden of premature death due to smoking was 57.7% in males and 11.4% in females in Korea. The burden of premature death due to smoking increased from 1643 person years per 100,000 in 1990 to 1888 person years in 1999 for males, and increased from 151 person years in 1990 to 225 person years in 1999 for females in Korea. Our results suggest that the method employed in this study, generated in quantified terms, enabled the burden of premature death due to smoking to be obtained comparably with methods used by other international studies in this field, and thus can provide a rational basis for national health policy planning regarding premature death from smoking and the related risk factors in Korea.

Smoking has not been confirmed as a risk factor for cancers of the liver and stomach. The authors examined prospectively the relationship between smoking and these cancers in an endemic region.

The data used were a cohort study on the relationship between lifestyle and health in the region having the highest liver cancer mortality in Japan. Of the cohort members, 4050 males aged > or =40 years were included in the present analysis with a 9-year mean follow-up. Cox proportional hazards regression was used to estimate relative risks (RR) for cancer of the liver, stomach, smoking-related sites and others, while adjusting for age, residence, and alcohol intake.

By the end of the study period, 59 cases of liver cancer and 53 cases of stomach cancer were identified. Current smokers, compared to subjects who had never smoked, had a threefold risk of liver cancer (RR = 3.3; 95% CI: 1.2-9.5) and a twofold risk of stomach cancer (RR = 2.2; 95% CI: 0.8-5.7). Sub-cohort analysis showed that adjustment for history of chronic liver disease did not attenuate the risk of liver cancer. Light/medium smokers had almost the same risk of these cancers as heavy smokers, while they showed a relatively low risk of smoke-related cancers.

The present results indicate that smoking is a risk factor of liver and stomach cancer in a population with a high background risk for these cancers. However, causal inferences should be made cautiously due to a lack of information on known risk factors.

Hepatocellular carcinoma (HCC) is one of the major cancers in the world. There is a striking variation in HCC incidence rates between various countries, with a highest-to-lowest ratio of 112.5 for males and 54.7 for females. The high-risk populations are clustered in sub-Saharan Africa and eastern Asia. The male-to-female ratio for HCC ranges from < 1 to 6.4 and mostly from 2 to 4. There exist significant variations in the incidence of HCC among different ethnic groups living in the same area and among migrants of the same ethnic groups living in different areas. The age curves of HCC are significantly different in various countries, suggesting variability in exposure to risk factors. Chronic carriers of hepatitis B and C viruses (HBV and HCV, respectively) have an increased risk of HCC. The relative and attributable HCC risk of HBV and HCV carrier status varies in different countries. There exists a synergistic interaction on HCC between the two viruses. Aflatoxin exposure, cigarette smoking, heavy alcohol consumption, low vegetable intake, inorganic arsenic ingestion, radioactive thorium dioxide exposure, iron overload and the use of oral contraceptives and anabolic steroids have been documented as HCC risk factors. Recent molecular epidemiological studies have shown that low serum retinol levels as well as elevated serum levels of testosterone, neu oncoprotein and aflatoxin B1-albumin adduct are associated with an increased HCC risk. There is a synergistic interaction on HCC between chronic HBV infection and aflatoxin exposure. Familial aggregation of HCC exists and a major susceptibility gene of HCC has been hypothesized. Patients of some genetic diseases are at an increased risk of HCC. The genetic polymorphisms of cytochrome P450 2E1 and 2D6 and arylamine N-acetyltransferase 2 are associated with the development of HCC. A dose-response relationship between aflatoxin exposure and HCC has been observed among chronic HBV carriers who have null genotypes of glutathione S-transferase M1 or T1, but not among those who have non-null genotypes. Human hepatocarcinogenesis is a multistage process with the involvement of a multifactorial aetiology. Gene-environment interactions are involved in the development of HCC in humans.

Recent epidemiologic data confirm the results of earlier studies in supporting that alcoholic beverage consumption is a cause of cancer of the mouth, pharynx, larynx, esophagus, and liver. The effect of a specified level of alcohol intake on absolute risk of cancers of the head, neck, and esophagus depends on the presence of other risk factors, especially smoking. Whether alcoholic beverage consumption is a cause of cancer of the breast or large bowel is unclear. Alcohol intake appears not to increase risk of cancer of the lung, bladder, prostate, stomach, ovary, endometrium, or of melanoma. Indirect epidemiologic evidence suggests that alcohol may be a weak causal factor for pancreatic cancer. Although heavy alcohol consumption increases risk of cancer of the head, neck, esophagus, and liver, whether moderate alcohol consumption increases risk at these sites is unclear.

The aims of alpha-interferon treatment for chronic viral liver infections are clearance of the virus and healing of the disease. Hepatocellular carcinoma is a complication of viral cirrhosis; but it is not yet known whether treatment of viral cirrhosis with alpha-interferon prevents this complication.

The incidence and the risk (Cox regression analysis) of developing hepatocellular carcinoma were calculated in 347 patients with hepatic cirrhosis; 227 (34 hepatitis B virus and 193 hepatitis C virus related) were treated with alpha-interferon and 120 (28 hepatitis B virus and 92 hepatitis C virus) did not receive this treatment, in order to evaluate the efficacy of alpha-interferon in the prevention of hepatocellular carcinoma. In all patients, the cirrhosis was well compensated (Child A).

Over mean follow-up periods of 49 months for hepatitis B virus and 32 months for hepatitis C virus, 20/347 patients (6/62 hepatitis B virus and 14/285 hepatitis C virus) developed hepatocellular carcinoma. The risk of developing this tumor was significantly greater in males (p < 0.007) and in patients not treated with alpha-interferon (p < 0.01). The Relative Risk of developing hepatocellular carcinoma increased significantly (p < 0.0002) with each passing year. In patients with hepatic cirrhosis secondary to hepatitis B virus infections, the risk did not seem to be modified by alpha-interferon treatment, even though a greater, but not significant risk (Relative Risk = 4.9; p = 0.3) was calculated for untreated patients; in contrast, in hepatitis C virus-related cirrhosis, this risk was reduced by a factor of 4.0 (p = 0.04). The tumor developed only in non-responder patients regardless of virus type. After adjustment for confounding factors (sex, age, alcohol consumption, cigarette smoking), a statistically significant (p < 0.025) effect of interferon treatment in preventing hepatocellular carcinoma was still demonstrated when responders were matched with controls, but not when responders were compared with non-responders.

These results show that, in addition to its ability to halt the progression of viral-induced liver disease, alpha-interferon is also of benefit in patients with hepatitis C virus cirrhosis who respond to this treatment by lowering their risk of developing hepatocellular carcinoma.

Recent epidemiologic data continue to support alcoholic beverage consumption as a cause of cancer of the mouth, pharynx, larynx, esophagus, and liver. The effect of a given alcohol intake on absolute risk of these cancers depends on the prevalence of other risk factors. Whether alcoholic beverage consumption is a cause of cancer of the breast or large bowel is unclear. Alcohol intake appears not to increase risk of cancer of the lung, bladder, prostate, stomach, ovary, endometrium, or of melanoma. Indirect epidemiologic evidence suggests that alcohol may be a weak causal factor for pancreatic cancer. Additional research is needed to determine whether middle-aged women who drink moderately may experience a slight increase in longevity if they decrease alcohol intake. A number of biologically plausible mechanisms exist by which alcohol may cause cancer.

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.

Most studies on the association between antibodies against hepatitis C virus (anti-HCV) and primary liver cancer (PLC) were limited to case-series, or cross-sectional case-control studies leaving a controversy on causal temporality. A nested case-control study on 38 newly-developed PLC patients and 152 matched controls selected from a cohort of 9,775 men in Taiwan recruited from September, 1984, to February, 1986, was carried out to examine the relation between HCV infection and PLC. Case-control pairs were matched on age (+/- 1 year), residence, and the date at recruitment. Serum samples collected from study subjects at the initial recruitment were examined for anti-HCV by enzyme immunoassay and hepatitis B surface antigen (HBsAg) by reverse passive hemagglutination assay combined with radioimmunoassay. History of cigarette smoking, alcohol consumption, vegetable consumption, vegetarian habit, and chronic liver diseases were also obtained through standardized interviews according to a structured questionnaire at the recruitment. After adjusting for HBsAg status and other risk factors, the anti-HCV was significantly associated with the development of PLC showing a multivariate-adjusted relative risk of 88.24. The results suggest that HCV infection may play an important role in the etiology of human PLC in Taiwan.

A case-control study investigating risk factors for hepatocellular carcinoma (HCC) was conducted in Hanoi, in the north of Vietnam, between 1989 and 1992. Male cases of HCC (152) diagnosed in 2 hospitals were included. Hospital controls (241) admitted mainly to abdominal surgery departments were frequency-matched to cases for sex, age, hospital and place of residence (Hanoi, province). Odds ratios adjusted for matching variables and other potential confounders were estimated using unconditional logistic regression, or exact non-parametric statistical inference when numbers were small. Positivity for hepatitis B surface antigen (HBsAg) was the main risk factor for HCC in this sample. Five subjects (3 cases, 2 controls) had been infected by hepatitis C virus (HCV), and none of them were carriers of HBsAg, giving an OR of 38 associated with HCV infection among HBsAG-negative subjects. Alcohol drinking was associated with HCC and interacted with HBsAg positivity. Agricultural use of organophosphorous pesticides (30 liters/year or more) and military service in the south of Vietnam for 10 years or more were also associated with an increased risk of HCC. This study confirms the major role played by HBV infection and its association with HCC in south-east Asia. It also suggests how other factors such as alcohol consumption or exposure to chemicals may interact with HBV infection.

Three hundred and sixty-eight case-control sets (male 287 pairs; female 81 sets) were collected for a hospital-based case-control study of primary hepatocellular carcinoma (HCC) conducted in Northern Kyushu, Japan. All incident cases of HCC were collected weekly from the inpatients (aged 40-69) of the Second Department of Internal Medicine, Kurume University Hospital between April, 1986 and May, 1992. One control for a male case and 4 controls for a female case were sampled, being matched to a case on age (same 5-year age class), sex, residence (prefecture) and time of hospitalization (within 2 months after a case interview) from the inpatients of two general hospitals in Kurume. Information was collected by interview in person by a well-trained interviewer and from a review of hospital records by the authors. Multivariate analyses based on a conditional logistic regression model without an interaction term revealed that hepatitis B surface antigen (HBsAg) positive status (odds ratio (OR) = 8.67; 95% confidence interval (95%CI) = 2.54-29.57), history of blood transfusion over 10 years previously (2.40; 1.26-4.56), parental history of hepatic diseases (2.31; 1.11-4.80) and heavy alcohol drinking (60 < or = drink-years) by age 40 (3.23; 1.61-6.51) were statistically significant risk factors of male HCC. Univariate analysis for females also showed an elevated OR of HBsAg (7.58; 1.96-29.35). Although the sample size was limited, univariate analysis indicated that anti-hepatitis C virus antibody by c100-3 antigen positive status had a statistically significant OR for HCC in both sexes.

To detect potentially curable cases of hepatocellular carcinoma, outpatients with chronic hepatitis or compensated liver cirrhosis who were seen at the Center for Adult Diseases (Osaka, Japan) were examined periodically by means of ultrasonography and measurement of serum alpha-fetoprotein. Risk factors for hepatocellular carcinoma were identified with a Cox proportional-hazards model.

A total of 917 patients, 40 to 69 years old, were registered from May 1987 to March 1991. By the end of September 1991, liver cancer had developed in 54. The three-year cumulative risk of liver cancer was 12.5 percent for 240 patients with liver cirrhosis at enrollment and 3.8 percent for 677 patients with chronic hepatitis. Cox regression analysis showed that the risk of liver cancer was increased almost sevenfold in patients with hepatitis B surface antigen (rate ratio, 6.92; 95 percent confidence interval, 2.92 to 16.39) and fourfold in patients with hepatitis C antibody (rate ratio, 4.09; 95 percent confidence interval, 1.30 to 12.85). A high alpha-fetoprotein value at enrollment was also a risk marker for liver cancer.

Patients with hepatitis C virus infection have a greatly increased risk of liver cancer. Further studies are required to clarify the roles of other risk factors, including drinking and smoking habits.

The roles of the hepatitis B virus (HBV), cigarette smoking and alcohol consumption in the etiology of hepatocellular carcinoma (HCC) were examined in a case-control study involving 204 patients with HCC and 410 control subjects in Fukuoka prefecture, where HCC risk is among the highest in Japan. Information on smoking and drinking habits was obtained by a detailed interview survey, and the results were analyzed in conjunction with serum hepatitis B surface antigen (HBsAg) status after adjustment for sex, age and other possible confounding factors. Individuals positive for serum HBsAg showed a relative risk (RR) for HCC of 13.8 (95% confidence interval, Cl 5.9 to 32.5), whereas heavy drinkers experienced about a 2-fold risk increase compared with non-drinkers. Light or moderate drinkers, however, demonstrated RRs near the unity. Some risk excess was observed among ex-smokers (RR = 1.5, 95% CI 0.8 to 2.8) and current smokers (RR = 1.5, 0.8 to 2.7) compared with non-smokers, but without evidence for a dose-response relationship in terms of pack-years. Analysis among HBsAg-negative subjects revealed similar non-significant association with smoking, and there was no clear interaction between alcohol and cigarette consumption on HCC risk. Other significant risk factors included positive histories of blood transfusion (RR = 3.7, 2.2 to 6.3) and familiar liver disease (RR = 2.6, 1.6 to 4.2). Attributable risk calculations suggest that chronic HBV infection and heavy drinking may account for 17% and 13% of HCC occurrence, respectively, in this high risk area. The association of cigarette smoking with HCC was not evident in our study.

Smoking has now been identified as a definite cause of cancer at many sites (Table 2). Of all cancers in the United States, 30% could be prevented if cigarette smoking were eliminated. Organs in direct contact with smoke--the oral cavity, esophagus, lung, and bronchus--are at the greatest risk of malignancy among smokers. As many as 90% of these cancers are attributable to smoking. Organs and tissues distant from smoke are also at some increased risk. Among smokers, rates of cancer of the cervix, pancreas, bladder, kidney, stomach, and hematopoietic tissue are increased 50% to 200% over rates in nonsmokers. Risk of cancer at all sites increases with increasing exposure to cigarette smoke. Cigarette smoke contains potent carcinogens that influence carcinogenesis at both early and late stages. These carcinogens can interact with other exposures, such as alcohol, to synergistically increase the risk of cancer. The adverse carcinogenic effects of cigarette smoking, however, can be reduced for all smokers if tobacco use is stopped. The prevalence of smoking among the US population as a whole has declined from 40% in 1965 to 29% in 1987. This progress against the epidemic of tobacco use has already produced a decrease in the occurrence of the most common tumor among men, lung cancer. Unfortunately, the decline in smoking prevalence and cancer incidence has not occurred equally across US populations. Death rates of lung cancer in women continue to rise, and, based upon current smoking patterns, these rates will continue to increase into the next century. The challenge to physicians and public health workers is compelling and immediate: Abstaining from smoking is the single most effective way to reduce an individual's risk of cancer.

A recently introduced enzyme immunoassay procedure for antibodies against the hepatitis-C virus (HCV) was used to test samples from 185 cases with hepatocellular carcinoma (HCC) and 432 hospital controls. The anti-HCV results were examined in conjunction with previously reported data from this study concerning hepatitis-B virus (HBV) serology, hepatitis-D virus (HDV) antibodies, presence of cirrhosis and tobacco smoking. There was evidence for interaction between HBV and HCV in the causation of HCC: as previously reported, the rate ratio (RR) linking the presence of anti-HCV to HCC among subjects positive for hepatitis-B surface antigen (HBsAg) was substantially higher than the corresponding RR among those negative for this marker; furthermore, among HCC patients positive for HBsAg, a high proportion (33/61) of those who were positive for hepatitis-Be antigen (HBeAg) or its antibody were positive for anti-HCV, whereas among HBsAg-positive controls who were also positive for HBeAg or its antibody, none was positive for anti-HCV (0/18; p less than 10(-4)). The anti-HCV-related RR for HCC was also higher among HCC patients with cirrhosis than among those without evidence of co-existing cirrhosis (RR 11.4 vs. 4.4; p = 0.06). In addition, there was some evidence of interaction between tobacco smoking and HCV in the origin of HCC; after controlling for age, sex and HBsAg status, the RR for subjects positive for anti-HCV was 6.8 among smokers but only 3.2 among non-smokers (p = 0.26). By contrast, there was no suggestion of an interaction between anti-HCV and anti-HDV, in agreement with the presumed minimal role, if any, of HDV in HCC etiology. These results support the notion that HCV is involved in the etiology of HCC by advancing, through a chronic liver disease process, carcinogenesis initiated by other factors.

Independent and interactive effects related to the development of hepatocellular carcinoma were assessed using a community-based case-control study for hepatitis B virus, habitual alcohol drinking, cigarette smoking, peanut consumption and history of hepatocellular carcinoma among the immediate family. All 200 male newly diagnosed hepatocellular carcinoma patients were recruited consecutively through the period of study as the case group from two teaching medical centers in northern and southern Taiwan. Healthy community residents matched one-to-one with cases on age, sex, ethnic group and residential area were selected as the control group. The carrier status of HBsAg and HBeAg was determined by blind radioimmunoassays, and other risk factors were obtained through standardized interviews according to a structured questionnaire. Conditional logistic regression analysis showed a significant association between hepatocellular carcinoma and the carrier status of HBsAg and HBeAg with an odds ratio of 16.7 and 56.5, respectively, for carriers of HBsAg alone and for carriers of both HBsAg and HBeAg. There was a dose-response relationship between cigarette smoking and hepatocellular carcinoma with an odds ratio of 1.1, 1.5 and 2.6, respectively, for those who smoked 1 to 10, 11 to 20 and more than 20 cigarettes a day. A significant association with hepatocellular carcinoma was also observed for the habitual alcohol consumer with an odds ratio of 3.4. Those whose immediate family had a history of hepatocellular carcinoma were more likely to have the disease develop, with an odds ratio of 4.6. However, the frequency of peanut consumption was not significantly associated with hepatocellular carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship of tobacco use with risk of primary liver cancer was investigated using data from a 26-year mortality follow-up of nearly 250,000 US veterans, mostly from World War I. Significantly increased risks for liver cancer (289 deaths) were associated with most forms of tobacco use, including pipe and cigar smoking. Elevated relative risks (RRs) were seen for current cigarette smokers (RR = 2.4; 95 percent confidence interval [CI] 1.6-3.5) and former cigarette smokers (RR = 1.9, 1.2-2.9). A strong dose-response relationship (P less than 0.001) was found for cigarette smoking, with smokers of 40 or more cigarettes per day having almost a fourfold risk (RR = 3.8, 1.9-8.0). Risks were also found to increase significantly with years of cigarette use and with earlier age at the start of cigarette smoking. These results are consistent with those of other cohort and case-control studies, suggesting that cigarette smoking may be related to the risk of liver cancer.

The influence of hepatitis B virus infection, alcohol consumption, tobacco smoking and use of oral contraceptives on the risk of hepatocellular carcinoma (HCC) was evaluated in a hospital-based case-control study in Catalonia, in the Mediterranean coastal area of north-eastern Spain. A total of 96 HCC cases (86.5% of them with associated liver cirrhosis) and 190 age- and sex-matched controls were studied. The odds ratio of HCC and 95% confidence interval among hepatitis B surface antigen (HBsAg) carriers was 4.9 (1.3-21.9). The OR was not significantly elevated in smokers, and a marginally significant increased risk was found among users of oral contraceptives based on 6 female cases. There was a significant dose-response relationship between alcohol consumption and risk of HCC (chi 2 for trend: 24.3, p less than 0.001). Although hepatitis B infection was strongly associated with HCC, alcohol abuse leading to cirrhosis appears to be one of the main causes of HCC in this region.