The relationship between diabetes mellitus and primary liver cancer was investigated in a case-control study conducted in Italy between 1984 and 1996 on 428 cases with incident, histologically confirmed hepatocellular carcinoma, 59 with gallbladder and bile duct cancer, and 1,502 control subjects in the hospital for acute non-neoplastic diseases. Sixty-four cases of hepatocellular carcinoma vs. 87 controls reported a history of diabetes, corresponding to an odds ratio (OR) of 2.3 after allowance for age, sex and area of residence, and of 2.1 [95% confidence interval (CI) = 1.4–3.2] after further allowance for alcohol and tobacco consumption, history of hepatitis and liver cirrhosis, body mass index and history of liver cancer in first-degree relatives. The ORs were similar both for subjects diagnosed with diabetes below age 45, who most likely had insulin-dependent diabetes, and for those diagnosed later, who were likelier to have non-insulin-dependent diabetes. The OR was 2.3 for subjects whose diabetes was diagnosed <5 years before diagnosis of liver cancer, 1.9 for those diagnosed 5–9 years in advance and 2.2 for those diagnosed since 10 years or more. Five cases of gallbladder and bile duct cancer reported a history of diabetes: the corresponding OR was 1.2 (95% CI 0.5–2.9). The OR of hepatocellular carcinoma was 2.4 for males and 2.0 for females, 3.0 for subjects diagnosed with liver cancer under age 60 and 1.8 for those diagnosed at age 60 or over. None of the other covariates considered, including education, history of hepatitis, liver cirrhosis and alcohol drinking showed any meaningful modifying effect or interaction. The potential pathogenic mechanisms include liver alteration—and consequent cell proliferation—in subjects with diabetes. Thus a history of diabetes mellitus could explain about 8% (95% CI 5–11) of cases of liver cancer in this population. Int. J. Cancer 73:204–207, 1997. © 1997 Wiley-Liss, Inc.

The relationship between intake of selected micronutrients and gastric cancer risk was investigated using data from a case-control study conducted in Italy between 1985 and 1992 on 723 cases of histologically confirmed, incident gastric cancer, and 2024 controls hospitalized for acute, nonneoplastic, nondigestive tract diseases. Relative risks of subsequent quintiles of intake were computed after allowance for sex, age, and other major identified potential confounding factors, including an estimate of total calorie intake. No trend in risk emerged for intake of retinol, vitamin D and vitamin E, whereas a protective pattern was observed for consumption of beta-carotene, ascorbic acid, folate, and nitrates, with risk estimates for the highest intake quintiles of 0.27, 0.40, 0.58, and 0.43, respectively. Significant direct trends in risk were found for methionine, calcium, and nitrites. When the effect of various micronutrients was taken into account, a residual protective effect was observed for beta-carotene and ascorbic acid, and a direct association with methionine remained, whereas the protective effect of folates and nitrates and the direct associations of nitrites were no longer evident. The risk estimates for the upper quintiles of beta-carotene, ascorbic acid, and methionine consumption were respectively 0.38, 0.53, and 2.40, and all the trends in risk were significant and consistent across strata of sex and age. Whether this reflects a specific effect of these micronutrients, rather than problems of collinearity or other limitations of the data, is open for discussion. Nonetheless, these data indicate that selected micronutrients may have an impact in the process of gastric carcinogenesis.

There is no adequate information on the carcinogenicity of coffee and, specifically, on a potential association of coffee drinking with non-Hodgkin's lymphoma. Consumption of coffee and other methylxanthine-containing beverages has been researched in a case-control study conducted in northern Italy. A total of 429 cases of incident histologically confirmed non-Hodgkin's lymphoma and 1,157 controls in hospital for acute, non-neoplastic, non-immunological, non-digestive tract diseases were interviewed during their hospital stay. Relative risk (RR) estimates and their 95% confidence intervals (CI), according to consumption of coffee and other methylxanthine-containing beverages, were derived from multiple logistic regression equations including terms for age, sex, study centre, body mass index, alcohol and smoking status. Compared with non-drinkers, the RR was 1.2 (95% CI, 0.8-1.7) for coffee drinkers. No trend in risk emerged with number of cups of coffee consumed/day (RR = 1.1 for one and three cups; RR = 1.2 for two; or RR = 0.9 for four cups/day), or duration of coffee intake (RR = 1.2 for less than 20 years; RR = 1.3 for 21-30 years; and RR = 1.1 for more than 30 years). Similarly, no significant association was observed with consumption of decaffeinated coffee (RR = 0.9) or tea (RR = 1.2). Consumption of cola was associated with a borderline risk (RR = 1.7; 95% CI 1.0-2.7). We found no association between non-Hodgkin's lymphoma and consumption of regular or decaffeinated coffee and tea.

There is a general agreement that fibroadenoma is associated with a certain increase in breast cancer risk, but the risk estimates appear heterogeneous according to various studies. To provide further quantitative and population-based estimates of breast cancer risk in women with histologically confirmed fibroadenomas, we linked data of 1,461 incident cases of fibroadenoma (median age, 37 years) to the Cancer Registry of the Swiss Canton of Vaud (about 600,000 inhabitants) over the period 1977-1991. After exclusion of 57 synchronous breast neoplasms, a total of 17 cases of breast cancer were observed vs. 10.9 expected (standardised incidence ratio, SIR, 1.6; 90% confidence interval: 1.1-2.1). The SIR was similar in the short term (3-5 years) and in the medium-long term (> 5 years) following diagnosis of fibroadenoma. The cumulative risk of invasive breast cancer was 0.7% after 5 years and 2.2% after 12 years following diagnosis of fibroadenoma. This is not negligible on account of the young age of our cohort.

The relationship between family history of selected neoplasms in first-degree relatives and the risk of pancreatic, liver, and gallbladder cancer was investigated using data from a case-control study conducted in northern Italy on 320 histologically confirmed incident cases of liver cancer, 58 of gallbladder cancer, 362 of pancreatic cancer, and 1408 controls admitted to the hospital for acute, nonneoplastic, nondigestive tract disorders. Significant associations were observed between family history of hepatocellular carcinoma and primary liver cancer [relative risk (RR) = 2.4; 95% confidence interval (CI), 1.3 to 4.4], between family history of pancreatic cancer and pancreatic cancer (RR = 3.0; 95% CI, 1.4 to 6.6), and between family history of gallbladder cancer and gallbladder cancer (RR = 13.9; 95% CI, 1.2 to 163.9). The elevated risk of liver cancer associated with family history was not materially modified by adjustment for tobacco, alcohol, and personal history of cirrhosis and hepatitis (RR = 2.9; 95% CI, 1.5 to 5.3). Similarly, the risk for pancreatic cancer did not appreciably change after allowance for tobacco, alcohol, dietary factors, and medical history of diabetes and pancreatitis (RR = 2.8; 95% CI, 1.3 to 6.3). This pattern of risk would support the existence of a genetic component in the familial aggregation of liver and pancreatic cancer. In terms of population attributable risk, approximately 3% of the newly diagnosed liver and pancreatic cancers would be related to this familial component.

In view of the persisting uncertainty concerning possible mechanisms by which high vegetable and fruit intake decreases cancer risk, foods with divergent values for potentially important micronutrients are a priority for investigation. Tomatoes are low in beta-carotene, but high in lycopene, an active antioxidative agent. In order to assess the effect of tomatoes on risk of cancers of the digestive tract, data were analyzed from an integrated series of case-control studies conducted between 1985 and 1991 in northern Italy, where tomato intake is high but, also, heterogeneous. The overall dataset included the following histologically confirmed cancer cases: oral cavity and pharynx, 314; esophagus, 85; stomach, 723; colon, 955; and rectum, 629; and a total of 2,879 controls admitted to hospital for acute non-neoplastic or non-digestive conditions, unrelated to long-term dietary modifications. Multivariate odds ratios (OR) and 95% confidence interval (CI) for subsequent quartiles of intake of raw tomatoes were derived, after allowance for age, sex, study center, education, smoking and drinking level, and tertile of total caloric intake. There was a consistent pattern of protection for all sites (OR in the upper quartile ranging between 0.4 and 0.7), most notably for gastrointestinal neoplasms. All trends in risk were highly significant. The beneficial effect of raw tomatoes in this population may be partly due to the fact that they constitute perhaps the most specific feature of the Mediterranean diet. However, if it is true that tomatoes protect against digestive-tract cancers, this is of interest from both a scientific and a public health viewpoint.

It has been suggested that the risk of stomach cancer is increased when there is a history of gastric ulcer, but decreased in those with a history of duodenal ulcer. To provide further information on the issue, data from a case-control study of gastric cancer conducted in greater Milan, northern Italy, between 1985 and 1993, were examined. There were 746 cases of gastric cancer below the age of 75 and 2,053 controls admitted to hospital for acute, non-neoplastic, non-hormone-related diseases. A total of 76 (10.2%) cases and 84 (4.1%) controls reported a history of gastric ulcer, corresponding to a multivariate odds ratio (OR) of 2.6 (95% confidence interval, CI = 1.8-3.6). Fifty nine cases (7.9%) and 111 (5.4%) controls reported a history of duodenal ulcer, corresponding to an OR of 1.3 (95% CI = 0.9-1.8). The OR of gastric cancer was significantly above unity for the first five years after diagnosis of gastric ulcer (OR = 7.4, 95% CI 3.7-14.8), and declined thereafter. No consistent pattern of risks was observed after duodenal ulcer. The present data therefore confirm that the risk of gastric cancer is increased after gastric ulcer. They do not support, however, a reduced risk after duodenal ulcer. This may be due to variable baseline characteristics of the populations studied, or to the different role and impact of Helicobacter pylori and other determinants of duodenal ulcer and gastric cancer in various countries.

We analysed determinants of hysterectomy and oophorectomy using data from hospital control subjects, interviewed in a large case-control study on risk factors for breast cancer, conducted since 1983 in the Greater Milan area, Italy. Out of the 2916 women interviewed 355 (12.2%) were hysterectomized. Mean age at hysterectomy was 52. The cumulative probability of hysterectomy was similar in women born during the periods from 1900 to 1909 and 1910 to 1919. It rose steadily in each subsequent cohort for all ages till the cohort born between 1930 and 1939, then decreased in the cohort born between 1940 and 1949. The cumulative probability of hysterectomy by 60 years of age was 12.8% in women born between 1900 and 1909, and of 9.8%, 16.7% and 22.0% respectively in subsequent cohorts. Concerning determinants of hysterectomy, we found no relation with education and parity. Among the 355 hysterectomized women, 178 (50.1%) underwent unilateral (40 women) or bilateral (138 women) oophorectomy. The probability of oophorectomy was higher in more educated women. Compared with women who had had hysterectomy before the age of 45, those aged between 45 and 54 reported more frequently oophorectomy (odds ratio (OR): 1.5, 95% confidence interval (CI) from 0.9 to 2.3), but the OR was only 0.8 in those aged 55 or more (95% CI from 0.3 to 2.2). We found no relation between menopausal status or cohort of birth and oophorectomy.

Aims and background Substantial upward trends for skin cancer mortality have been observed in most European countries in the last two decades. The distinction, however, between cutaneous malignant melanoma (CMM) and non-melanomatous skin cancers on the basis of death certification is unreliable Methods In order to assess the trends of CMM, analysis of the specific code for CMM (International Classification of Disease VIII and IX:172) was coupled with analysis of total skin cancer mortality rates, standardized on the 1981 Italian Census population, at all ages and in selected age groups (15-44, 45-64 and 65-84 years). The analyses were carried out for the whole of Italy and for Friuli-Venezia Giulia (FVG), a region in North-East Italy with a high proportion of fair-complexioned individuals, elevated frequency of sunbathing, and especially good diagnostic standards. Results In 1985-89 skin cancer mortality rates in men at all ages, as compared to 1970-74, were 33% higher in Italy and 46% higher in FVG. In women, there was a rise of 22% in Italy and 94% in FVG. More marked upward trends were observed in young and middle aged adults, especially among women in FVG (over 300% increase). In absolute terms, approximately 3000 more Italians died from skin cancers in 1985-89 as compared to 1970-74, about half of them prematurely (i.e., &lt; 65 years). CMM was mentioned in death certifications for skin cancer increasingly often in all age groups, particularly in FVG. Conclusions The analysis of mortality trends from skin cancer is consistent with a substantial rise of CMM-related deaths. The sensitivity of death certification with respect to CMM diagnosis is also increasing, especially in FVG. A public health strategy with the aim of reducing intermittent intense exposure to ultraviolet light, especially in children, is urgent in Italy as CMM represents one of the few causes of premature death with unfavorable trends.

N-nitroso compounds are carcinogens that can be ingested directly or synthesized from nitrites and nitrates. The possible role of N-nitroso compounds in the induction of upper aerodigestive tract tumours was considered in a case-control study conducted in the Valle d'Aosta, an Italian region with a high incidence of these neoplasms. Nitrate, nitrite, labile and stable N-nitroso compounds were analysed in the saliva of 36 patients with cancers of the upper aerodigestive tract and 23 healthy individuals. After allowing for tobacco, salivary nitrate, nitrite and N-nitroso compounds were not associated with an increased risk of upper aerodigestive tract cancers. The odds ratio for continuous units of total N-nitros compounds was 0.99 (95% confidence interval 0.9-1.1). Thus, salivary nitrate, nitrite and N-nitroso compounds might not be suitable markers for the assessment of the risk of cancer of the upper aerodigestive tract, although a role for N-nitroso compounds cannot be excluded.

The association between a family history of endometrial, breast and ovarian cancer and the risk of endometrial cancer was analyzed on the basis of data from a case-control study conducted in northern Italy between 1983 and 1993. A total of 726 histologically confirmed endometrial-cancer patients (median age 61) admitted to a network of general and teaching hospitals in the Greater Milan area were interviewed. The controls were 2,123 women (median age 59), admitted for acute, non-neoplastic, non-hormone-related diseases to the same network of hospitals where the cases had been identified, with admission diagnoses unrelated to any of the known or suspected risk factors for endometrial cancer. Among cases, 37 (5.1%) reported a history of endometrial cancer in first-degree relatives. The corresponding figure among controls was 77 (3.6%). In comparison with women with no family history of endometrial cancer, the odds ratio (OR) of endometrial cancer was 1.5 (95% CI [confidence interval], 1.0-2.3) in women with a history of endometrial cancer in first-degree relatives. No relation emerged between endometrial cancer and a family history of breast or ovarian cancer. These results suggest that a family history of endometrial cancer increases the risk of contracting the same disease. However, the proportion of cases attributable to this factor was small: less than 1% of endometrial cancers in this population were attributable to familial (and hence potentially genetic) factors.

The relationship between various types of fiber and colorectal cancer risk was investigated using data from a case-control study conducted between January 1992 and June 1996 in Italy. The study included 1953 cases of incident, histologically confirmed colorectal cancers (1225 colon cancers and 728 rectal cancers) admitted to the major teaching and general hospitals in the study areas and 4154 controls with no history of cancer admitted to hospitals in the same catchment areas for acute nonneoplastic diseases. Dietary habits were investigated using a validated food frequency questionnaire. Odds ratios (ORs) were computed after allowance for age, sex, and other potential confounding factors, including physical activity and protein, fat, and carbohydrate intake. Fiber was analyzed both as a continuous variable and in quintiles. For most types of fiber, the OR of colon and rectal cancers was significantly below 1, and no appreciable differences emerged between the two. When the unit was set at the difference between the upper cutpoints of the fourth and first quintile, i.e., the 80th and 20th percentiles, the ORs for colorectal cancer were 0.68 for total fiber (determined by the Englyst method as nonstarch polysaccharides), 0.67 for soluble noncellulose polysaccharides (NCPs), 0.71 for total insoluble fiber, 0.67 for cellulose, 0.82 for insoluble NCPs, and 0.88 for lignin. When fiber was classified according to the source, the OR was 0.75 for vegetable fiber, 0.85 for fruit fiber, and 1.09 for cereal fiber. The ORs were similar for the two sexes and the strata of age, education, physical activity, family history of colorectal cancer, and energy intake. Likewise, no appreciable differences emerged when subsites of the colon and rectum were investigated separately. This study provides additional support for a protective and independent effect of fiber on colorectal cancer, particularly for cellulose and soluble NCPs, and of fiber of vegetable or fruit origin.