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In their paper on gender effects in familial cancer, Hemminki and Li1 reported that, among 15 cancer sites considered, only thyroid cancer showed a significant difference in the relative risk (RR) for concordant cancer by gender. Based on the nation-wide Swedish Family-Cancer Database, which included 10.2 million individuals and over 1 million cancers, the RR of thyroid cancer was 16.4 (95% confidence interval [CI] = 11.3–23.8) in the male but 6.6 (95% CI = 4.9–9.0) in the female offspring of thyroid cancer cases. Thus, the ratio observed for male compared to female offspring was 2.48 (95% CI = 1.5–4.0). Notably, women had a 2–3-fold higher thyroid cancer incidence rate compared to men in the general population of Sweden and most other countries.2 Because thyroid cancer is rare among men, the majority of our knowledge on thyroid cancer comes from data on women. In a pooled analysis of 12 case-control studies on thyroid cancer, which includes all ten published studies that have males, there were 2,094 female cases, but only 425 male cases (3,248 female and 928 male controls, respectively3). The only risk factor that appeared to be stronger in males than in females was a personal history of benign thyroid diseases (RR for goitre = 38.3, 95% CI = 5.0–291.2 in men and 5.9; 95% CI = 4.2–8.1 in women; RR for history of benign nodules/adenomas = infinity, 95% CI = 9.2-infinity in men and 29.9, 95% CI = 14.5–62.0 in women). The gender difference in the RRs resulted mainly from the rarity of goiter (1/836) and benign nodules/adenomas (0/531) among male controls. A history of goiter or benign nodules/adenomas was reported, respectively, by 1.8% and 0.3% of female controls.3 The similarity in the gender effect for family history of thyroid cancer and personal history of benign thyroid disease suggests that both factors can be considered markers of increased individual susceptibility to thyroid cancer. Lower RR for markers of individual susceptibility among women than men supports the suggestion4 that the greater risk of cancers of the thyroid in the general female population is chiefly attributable to female-specific environmental risk factors (e.g., female hormones, greater functional demand of iodine and thyroid hormones during reproductive years, etc.2). Conversely, in men, a greater proportion of thyroid cancer may be the result of genetic factors. The genetic bases for the commonest types of thyroid cancer (i.e., non-medullary forms) are not well understood.5 Linkage studies have identified a few genes (MNG1,6 TCO,7 PTC8), but single genes seem to explain only a minority of cases. Non-medullary thyroid cancer is thus likely to be a polygenic disease.9 Although surveillance bias may explain some of the findings related to benign thyroid disease,3 because women tend to undergo general medical examinations more frequently than men, it is unlikely to account for the gender-related difference in the influence of family history of thyroid cancer.1 Also in another cancer site, the breast, where the female excess is even greater than for the thyroid, a marker of individual susceptibility (history of contralateral breast cancer) showed a clear difference between the gender-specific RRs.10 The RR of contralateral breast cancer among men was 29.6 (95% CI = 15.5–52.4) compared to 1.8 (95% CI = 1.7–1.8) among women. In conclusion, the findings from Hemminki and Li1 and our own3 illustrate well the strong influence of non-genetic risk factors on the apparent strength of the RRs for genetic markers. As a consequence of a weaker “dilution effect” from non-genetic risk factors, family history of thyroid cancer and previous occurrence of goitre and benign nodules/adenomas can, however, distinguish high-risk men more accurately than high-risk women. The contribution of the Italian Association for Cancer Research, Milan, Italy is gratefully acknowledged. Yours sincerely, Silvia Franceschi*, Eva Negri , Carlo La Vecchia , * International Agency for Research on Cancer, Lyon, France, Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy, Istituto di Statistica Medica e Biometria, Università degli Studi di Milano, Milan, Italy

Several toxicological and epidemiological studies were published during the last five decades on non-sugar sweeteners (NSS) and cancer. Despite the large amount of research, the issue still continues to be of interest. In this review, we provided a comprehensive quantitative review of the toxicological and epidemiological evidence on the possible relation between NSS and cancer. The toxicological section includes the evaluation of genotoxicity and carcinogenicity data for acesulfame K, advantame, aspartame, cyclamates, saccharin, steviol glycosides and sucralose. The epidemiological section includes the results of a systematic search of cohort and case-control studies. The majority of the 22 cohort studies and 46 case-control studies showed no associations. Some risks for bladder, pancreas and hematopoietic cancers found in a few studies were not confirmed in other studies. Based on the review of both the experimental data on genotoxicity or carcinogenicity of the specific NSS evaluated, and the epidemiological studies it can be concluded that there is no evidence of cancer risk associated to NSS consumption.

SEE ARTICLE ON PAGE 492 Mass vaccination campaigns against HBV and treatment of chronic HBV carriers with oral nucleos(t)ide analogues (NUCs) represent the pillars of World Health Organization campaigns aiming to curb life‐threatening complications of chronic hepatitis B (CHB), including HCC.[1] Over 250 million people worldwide remain persistently infected with HBV, and <3% of them are currently covered by NUC treatment.[2] This notion, coupled with the evidence that even lifelong NUC regimens may not eliminate the risk of HCC,[2] has prompted the assessment of additional strategies for cancer prevention. Particular attention in recent years has been given to largely prescribed over‐the‐counter (OTC) drugs that may possess anti‐HCC potential. In this context, aspirin at low doses—having platelet‐specific effects with minimal anti‐inflammatory or analgesic/antipyretic properties[3] and long assumed to reduce the risk of developing different solid tumors in humans[4,5]—has been shown to prevent and/or delay the onset of HCC in animal models of chronic HBV infection.[6,7] Mechanistically, the sustained inhibition of platelet function by low‐dose aspirin reduces the intrahepatic accumulation of pathogenic HBV‐specific cluster of differentiation 8–positive T cells that would otherwise trigger immunopathological responses leading to fibrosis, cirrhosis, and HCC.[6,7] These preclinical studies have been supported by epidemiological evidence that evaluated the risk of HCC in patients suffering from liver diseases, particularly chronic HBV and HBV infections. Indeed, most of these studies reported that regular and long‐term use of low‐dose aspirin is associated with reduced HCC incidence and mortality, with little or no excess risk of gastrointestinal bleeding.[8–18] Along these lines, in this issue of hepatology, Jang et al. conducted a record‐linkage cohort study of low‐dose aspirin and HCC among >300,000 Korean patients with CHB over a 10‐year period (2007–2017).[19] By defining patients treated with aspirin as those individuals receiving aspirin prescriptions for 90 or more consecutive days, the authors derived a propensity score–matched cohort of 19,003 pairs.[19] With a median follow‐up of 6.7 years, 2697 patients developed HCC, 1232 in the treated and 1465 in the untreated group.[19] The 10‐year cumulative incidence of HCC was 9.5% in the treated versus 11.3% in the untreated group, corresponding to an adjusted HR of 0.85 (95% CI, 0.78–0.92).[19] Aspirin use for 90 or more consecutive days was therefore inversely related to HCC, but there was no evidence of a duration–risk relationship. When the analysis was restricted to the 14,689 patients with CHB who had used aspirin for >1 year (and 14,689 untreated), the HR was 0.86 (95% CI 0.78–0.94).[19] A stratified analysis was also provided for patients without cirrhosis versus those with cirrhosis treated or not with aspirin. Among the patients without cirrhosis, 900 cases of HCC were registered in individuals who received aspirin treatment, while there were 1059 HCC cases in untreated individuals, corresponding to an HR of 0.87 (95% CI 0.79–0.95).[19] By contrast, there was no association with aspirin use and reduced HCC risk among patients with cirrhosis: 323 and 333 HCCs were observed in aspirin‐treated versus aspirin‐untreated individuals with cirrhosis, corresponding to an adjusted HR of 1.00 (95% CI 0.85–1.15).[19] The latter finding may depend on cirrhosis‐linked thrombocytopenia, which could have weakened the capacity of aspirin to inhibit platelet function.[19] However, the divergence of results between those without cirrhosis and patients with cirrhosis was of borderline significance (p for interaction = 0.04) and was less evident in a sensitivity analysis using a 1:3 (instead of a 1:1) propensity score–matched cohort, where the HR was 0.81 among those without cirrhosis and 0.94 among patients with cirrhosis.[19] Likewise, when liver disease–related mortality was considered, the overall HR was 0.80 (95% CI 0.71–0.90); the HR was lower among individuals without cirrhosis (0.84) versus those with cirrhosis (0.91), but the heterogeneity was not significant. Hence, it is plausible that a favorable effect of aspirin on HCC may be greater in patients without cirrhosis, but a similar effect cannot be excluded in patients with cirrhosis. A multivariate analysis on all cohorts—in addition to the propensity score–derived data sets—could provide more precise quantifications. Major bleeding was reported in 1738 patients (908 treated with aspirin, 830 untreated), corresponding to an overall adjusted HR of 1.09 (95% CI 0.99–1.07). The HR was apparently greater in patients with cirrhosis (1.15) than in those without cirrhosis (1.05), but, again, the heterogeneity was not significant.[19] The findings of this Korean report are consistent with those of two studies from Taiwan and Sweden, both of which used a similar record‐linkage design.[14,18] The inverse association between aspirin use and HCC risk, however, appears less strong in the Korean study. The multivariate HRs of HCC for aspirin‐treated versus aspirin‐untreated patients were 0.68 in the Taiwanese study of patients with CHB[14] and 0.69 in the Swedish study, which included patients chronically infected with HBV or HCV and used a standard full‐cohort analysis rather than a propensity score design.[18] At variance with the Korean report, the Swedish study also documented a strong inverse duration–risk relationship, with an HR of 0.57 for the use of aspirin at 5 years or more compared to its short‐term use (3 months–1 year).[18] All of these studies share similar strengths (i.e., cohort designs with defined measures of exposure and outcome, large sample sizes, and allowance for a considerable number of covariates). Aspirin is a widely available and cheap drug, and exposure information based on prescription record linkage does not necessarily include OTC sales. The possible bias introduced by OTC sales is, however, probably unrelated to HCC outcome and, if anything, should lead to an underestimate of the association. In keeping with this, findings from five cohort and case–control studies that were pooled in a meta‐analysis and that were based on aspirin exposure (where the information about exposure was collected at direct interview and, therefore, was not affected by bias) revealed that the overall pooled relative risk was 0.71 for HCC and 0.62 (95% CI 0.44–0.86) for all hepatobiliary cancers.[15] The implications from this Korean report must be taken with caution due to the limited strength of the association between aspirin use and HCC risk and the rather surprising absence of a duration–risk relationship. This is particularly difficult to interpret for a disease like CHB‐associated HCC, which normally develops after several decades of persistent, immune‐mediated liver injury.[20] However, the overall evidence now available from three record‐linkage reports[14,18,19] and five additional studies[15] allows us to confidently conclude that the regular use of low‐dose aspirin has a favorable effect on HCC risk in patients with CHB. Because this Korean study reported a moderate excess in the risk of bleeding as documented in the previous Taiwanese and Swedish studies[14,18] (on the order of 10%, not significant in each single study but similar across various populations), it remains to be debated whether it is now time to recommend aspirin treatment initiation in selected patient populations or whether it is better to wait for improved biomarkers predicting HCC risk and/or dedicated and randomized clinical trials. To the least, this additional study by Jang et al.[19] should encourage a discussion on the future of antiplatelet therapies in patients with CHB. CONFLICT OF INTEREST Dr. Guidotti is a member of the board of directors and stockholder at Genenta Science, is a member of the Scientific Advisory Board at Antios Therapeutics and Ananda Immunotherapies, and participates in advisory boards/consultancies at Gilead Sciences, Roche, Arbutus Biopharma, and Chroma Medicine. Dr. Colombo participates in advisory boards for Galapagos, Exelixis, and Target HCC.

Journal Article Changes in diagnostic procedure utilization in Italy, 1980–83 Get access ROMANO PAGANO, ROMANO PAGANO Central Institute of Statistics00100 Rome, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar CARLO LA VECCHIA CARLO LA VECCHIA Central Institute of Statistics00100 Rome, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar International Journal of Epidemiology, Volume 17, Issue 2, June 1988, Pages 473–474, https://doi.org/10.1093/ije/17.2.473 Published: 01 June 1988

The relationship between cigarette smoking and risk of cervical neoplasia was evaluated in a case-control study of 183 women with cervical intraepithelial neoplasia compared with 183 age-matched outpatient controls, and of 230 cases of invasive cervical cancer compared with 230 controls in hospital for acute conditions unrelated to any of the identified or suspected risk factors for cervical cancer. Current cigarette smoking was associated with an elevated risk of cervical intraepithelial neoplasia (relative risk = 1.76, 95 per cent confidence interval = 1.14-2.27) and of invasive cancer (relative risk = 1.69, 95 per cent confidence interval = 1.08-2.65). This association was only partially accounted for by a large number of identified potential confounding factors, including indicators of socioeconomic status and sexual habits. The risk increased with the number of cigarettes smoked and was apparently greater for women who started smoking at younger ages. The relative risk of intraepithelial neoplasia was elevated within 20 years after the start of smoking and showed little tendency to increase with increasing duration. On the other hand, the risk of invasive cervical cancer was apparently unaffected by smoking less than 20 years and increased steadily thereafter, reaching a point estimate of 3.63 after 40 years or more. If one assumes that intraepithelial neoplasia is an early stage of cervical cancer, this pattern of risk is consistent with the predictions from the multistage theory of carcinogenesis, if the effect of smoking is on one of the earlier stages. No obvious distorting factors, apart from the play of chance, is likely to produce such a risk pattern.

Limited data on smoking prevalence allowing valid between-country comparison are available in Europe. The aim of this study is to provide data on smoking prevalence and its determinants in 18 European countries. In 2010, within the Pricing Policies And Control of Tobacco in Europe (PPACTE) project, we conducted a face-to-face survey on smoking in 18 European countries (Albania, Austria, Bulgaria, Czech Republic, Croatia, England, Finland, France, Greece, Hungary, Ireland, Italy, Latvia, Poland, Portugal, Romania, Spain and Sweden) on a total of 18 056 participants, representative for each country of the population aged 15 years or older. Overall, 27.2% of the participants were current smokers (30.6% of men and 24.1% of women). Smoking prevalence was highest in Bulgaria (40.9%) and Greece (38.9%) and lowest in Italy (22.0%) and Sweden (16.3%). Smoking prevalence ranged between 15.7% (Sweden) and 44.3% (Bulgaria) for men and between 11.6% (Albania) and 38.1% (Ireland) for women. Multivariate analysis showed a significant inverse trend between smoking prevalence and the level of education in both sexes. Male-to-female smoking prevalence ratios ranged from 0.85 in Spain to 3.47 in Albania and current-to-ex prevalence ratios ranged from 0.68 in Sweden to 4.28 in Albania. There are considerable differences across Europe in smoking prevalence, and male-to-female and current-to-ex smoking prevalence ratios. Eastern European countries, lower income countries and those with less advanced tobacco control policies have less favourable smoking patterns and are at an earlier stage of the tobacco epidemic.

The relationship between pancreatic cancer and coffee, decaffeinated coffee and tea drinking habits was evaluated using data from a hospital-based case-control study conducted in Northern Italy on 150 histologically confirmed cases and 605 controls with acute, non-neoplastic, other than digestive tract diseases unrelated to coffee consumption or to any of the known or potential risk factors for cancer of the pancreas. Compared with subjects who did not drink coffee, the multivariate relative risks were 1.7 for those who drank less than 2 cups per day, but only 1.4, and 1.1 respectively for drinkers of 3 or 4 and 5 or more cups. Likewise, there was no association with duration of consumption of coffee, decaffeinated coffee or tea. These findings were reviewed together with published evidence from other case-control studies (or cohort studies analyzed as case-control) of coffee and pancreatic cancer. When appropriate statistical methods were used to pool information, and the data from the first study which was the basis of the hypothesis were omitted, the relative risk of pancreatic cancer based on 1,464 cases was 1.2 for moderate coffee drinkers and 1.4 for heavy drinkers, and we suspect that at least part of this moderate residual association is confounded by cigarette smoking. Thus, although the present investigation and a general overview of published epidemiological evidence are compatible with a small effect of coffee on pancreatic carcinogenesis, interpretation of these findings is not obvious on account of the possibility of residual confounding and other sources of bias.