Carlo Zocchetti

Cancer Incidence in a Population Accidentally Exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin

In 1976, an accident in a plant near Seveso, Italy, exposed the local population to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Persons residing in three zones of decreasing TCDD contamination (A, B, and R) and a reference population were followed up for cancer occurrence in 1977–1986. The most exposed subgroup (A) was small, and only 14 cancer cases were observed. In zone B, hepatobiliary cancer was elevated, especially for those living in the area for >5 years [relative risk (RR) = 2.8; 95% confidence interval (CI) = 1.2–6.31. Men exhibited an increase in hematologic neoplasms, most notably lymphoreticulosarcoma (RR = 5.7; 95% CI = 1.7–19.0). Women experienced an increased incidence of multiple myeloma (RR = 5.3; 95% CI = 1.2–22.6) and myeloid leukemia (RR = 3.7; 95% CI = 0.9–15.7). In zone R, the incidence of soft tissue tumors and non-Hodgkins lymphomas was elevated, particularly among persons living in the area for >5 years (RR = 3.5; 95% CI = 1.2–10.4 for sarcomas, and RR = 2.0; 95% CI = 1.2–3.6 for non-Hodgkins lymphomas). Breast cancer among females was below expectations in the most contaminated zones, and a clear deficit for endometrial cancer was observed in zones B and R. (Epidemiology 1993;4:398–406)

Mortality in a Population Exposed to Dioxin after the Seveso, Italy, Accident in 1976: 25 Years of Follow-Up

The Seveso accident in 1976 caused a large, populated area north of Milan, Italy, to be contaminated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In this study, the authors followed up the exposed population for chronic effects; this paper reports the results of the mortality follow-up extension for 1997-2001. The study cohort includes 278,108 subjects resident at the time of the accident or immigrating/born in the 10 years thereafter in three contaminated zones with decreasing TCDD soil levels (zone A, very high; zone B, high; zone R, low) and in a reference territory comprising surrounding, noncontaminated municipalities. Vital status and cause-of-death ascertainment were 99% complete. Adjusted rate ratios and 95% confidence intervals were calculated by using Poisson regression. Results confirmed previous findings of excesses of lymphatic and hematopoietic tissue neoplasms in zones A (six deaths; rate ratio = 2.23, 95% confidence interval: 1.00, 4.97) and B (28 deaths; rate ratio = 1.59, 95% confidence interval: 1.09, 2.33). These zones also showed increased mortality from circulatory diseases in the first years after the accident, from chronic obstructive pulmonary disease, and from diabetes mellitus among females. A toxic and carcinogenic risk to humans after high TCDD exposure is supported by the results of this study.

Dioxin exposure and non-malignant health effects: a mortality study

OBJECTIVE: To investigate, in a population heavily exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the possible unusual occurrence of diseases other than cancer. METHODS: Five year extension of the follow up of the cohort involved in the Seveso accident. Soil measurements identified three exposure zones: (A) highest contamination, (B) substantial, and (R) low but higher than background contamination. Blood TCDD measurements, although limited in number, confirmed zone exposure ranking. The 15 year mortality in the exposed cohort was compared with that of a large population in the surrounding non-contaminated territory. Relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated with Poisson regression techniques. RESULTS: The already noted increased occurrence of cardiovascular deaths was confirmed, in particular in zone A, among males for chronic ischaemic heart disease (five deaths, RR 3.0, 95% CI 1.2 to 7.3), and among females for hypertensive disease (three deaths, RR 3.6, 95% CI 1.2 to 11.4) and chronic rheumatic heart disease. Novel findings were the increase of chronic obstructive pulmonary disease, most notably among males in zone A (four deaths, RR 3.7, 95% CI 1.4 to 9.9) and females in zone B (seven deaths, RR 2.4, 95% CI 1.1 to 5.1); and from diabetes, which was significantly increased in females in zone B (13 deaths, RR 1.9, 95% CI 1.1 to 3.2). In zone R, chronic ischaemic heart disease (males and females), hypertension (females), and diabetes (females) showed less pronounced, although significant excesses. CONCLUSIONS: As well as high TCDD exposure, the accident caused a severe burden of strain in the population. Both these factors might have contributed to the noted increased risks (in particular, circulatory and respiratory). The cardiovascular and immune toxicity of TCDD, as well as its complex interaction with the endocrine system, might be relevant to the explanations of these findings. These results, although not conclusive, concur with previous data in suggesting cardiopulmonary and endocrine effects in humans highly exposed to TCDD.

Dioxin exposure and cancer risk : A 15-year mortality study after the Seveso accident

Dioxin (2,3,7,8‐tetrachlorodibenzo‐para‐dioxin, or TCDD) is a powerful carcinogen in experimental animals, whereas the evidence in humans is limited. We examined cancer mortality from 1976 to 1991 among residents of Seveso, Italy, which was highly contaminated after an industrial accident. The area was divided into zones with decreasing exposure to dioxin (A = highest, B = lower, R = lowest). The population of a surrounding noncontaminated area was used as a reference group. Zone A was small (11,516 person‐years); in that zone, we saw a moderate increase in mortality from digestive cancer among women [relative risk (RR) = 1.5; 95% confidence interval (CI) = 0.5–3.5]. In zone B, we also saw excesses at digestive sites (83,610 person‐years), 10 years after the accident. Women had an increased mortality from stomach cancer (RR = 2.4; 95% CI = 0.8–5.7), and men had increased mortality from rectal cancer (RR = 6.2; 95% CI = 1.7–15.9). Hematologic neoplasms were increased. The highest risks were seen in zone B for leukemia in men (RR = 3.1; 95% CI = 1.3–6.4), multiple myeloma in women (RR = 6.6; 95% CI = 1.8–16.8), and Hodgkins disease in both genders (RR = 3.3; 95% CI = 0.4–11.9 in men; and RR = 6.5; 95% CI = 0.7–23.5 in women). Soft tissue sarcoma was elevated only among zone R males (256,408 person‐years; RR = 2.1; 95% CI = 0.6–5.4). We found no increase for all‐cancer mortality or major specific sites (for example, respiratory among males, breast among females). The specific excesses that we observed were not explained by bias or confounding, and their association with dioxin exposure is plausible. The follow‐up is continuing.

Cancer mortality among man-made vitreous fiber production workers.

We have updated the follow‐up of cancer mortality for a cohort study of man‐made vitreous fiber production workers from Denmark, Finland, Norway, Sweden, United Kingdom, Germany, and Italy, from 1982 to 1990. In the mortality analysis, 22,002 production workers contributed 489,551 person‐years, during which there were 4,521 deaths. Workers with less than 1 year of employment had an increased mortality [standardized mortality ratio (SMR) = 1.45; 95% confidence interval (CI) = 1.37–1.53]. Workers with 1 year or more of employment, contributing 65% of person‐years, had an SMR of 1.05 (95% CI = 1.02–1.09). The SMR for lung cancer was 1.34 (95% CI = 1.08–1.63, 97 deaths) among rock/slag wool workers and 1.27 (95% CI = 1.07–1.50, 140 deaths) among glass wool workers. In the latter group, no increase was present when local mortality rates were used. Among rock/slag wool workers, the risk of lung cancer increased with time‐since‐first‐employment and duration of employment. The trend in lung cancer mortality according to technologic phase at first employment was less marked than in the previous follow‐up. We obtained similar results from a Poisson regression analysis limited to rock/slag wool workers. Five deaths from pleural mesothelioma were reported, which may not represent an excess. There was no apparent excess for other categories of neoplasm. Tobacco smoking and other factors linked to social class, as well as exposures in other industries, appear unlikely to explain the whole increase in lung cancer mortality among rock/slag wool workers. Limited data on other agents do not indicate an important role of asbestos, slag, or bitumen. These results are not sufficient to conclude that the increased lung cancer risk is the result of exposure to rock/slag wool; however, insofar as respirable fibers were an important component of the ambient pollution of the working environment, they may have contributed to the increased risk.

Mortality study of cancer risk among oil refinery workers

SummaryThe mortality experience of 1595 male workers employed in one of the largest Italian refineries in the period from 1949–1982 was examined. From the comparison with national and local death rates, increases in mortality owing to lung and kidney cancers, brain tumors, and leukemias emerged. No definite trends according to duration of exposure and years since first exposure were apparent. The increases regarding cancer of the lung, kidney and brain appeared to be associated with the early period of operations. Analysis by exposure category suggested an association of the increased mortality from leukemias with working in production (observed = 2; expected = 0.61). Kidney cancer mortality was elevated among maintenance workers (obs. = 2; exp. = 0.18). Small numbers prevented firmer conclusions. Workers in the moving department had a significantly increased mortality from all cancers (obs. = 22; exp. = 11.7), and lung cancer (obs. = 11; exp. = 3.6). Confounding by smoking could be excluded as sufficient explanation of the three-fold increase in lung cancer deaths. It was in moving that highest airborne levels of polynuclear aromatic hydrocarbons had been discovered in an independent environmental investigation.

Mortality study in an Italian oil refinery: Extension of the follow-up

This article present the results of the extension of the follow-up of a cohort of workers employed in an Italian oil refinery. 1,583 workers employed in 1949-1982 in a northern Italy oil refinery plant were followed-up for mortality as of May 31, 1991. Environmental measurements documented potential exposure to benzene. Standardized mortality ratios (SMR) and their 95% confidence intervals (95% CI) were calculated using as references national (1949-1968) and regional mortality rates (1969-1991). Elevated mortality from lymphoma (seven deaths, SMR 190, 95% CI 76-391) and leukemia (eight deaths, SMR 225, 95% CI 97-443) was observed. No consistent trends by length of employment or time since first exposure were apparent. Nonetheless, the excess risk was particularly and significantly increased among workers with 15 or more years of employment, and 30 or more years since first employment. The findings of elevated mortality from leukemia and lymphoma are in agreement with those of other oil refinery studies. Chance, confounding, or other biases might have played a marginal, if any, role in determining the results. Exposure to benzene is a biologically plausible explanation.

Trastuzumab-Related Cardiotoxicity in Early Breast Cancer: A Cohort Study

BACKGROUND Concerns have been raised about the cardiac safety profile of trastuzumab for the adjuvant treatment of early stage breast cancer in clinical practice. We assessed trastuzumab-related cardiotoxicity and its predictors in a large cohort of Italian women. METHODS Through a record linkage between four regional health care databases, we identified the rate of severe cardiac adverse events among women treated with trastuzumab for early breast cancer in Lombardy. The cumulative risk of cardiotoxicity was estimated using the Kaplan-Meier method, and independent predictors were assessed using the Cox model. RESULTS Of 2,046 trastuzumab users, 53 (2.6%) experienced at least one hospitalization for a cardiac event, and there were two cardiac deaths. The cumulative risk of cardiotoxicity increased up to 2 years after starting treatment, reaching a plateau at 2.8%. The risk was low (0.2%) among young women, whereas the incidence was approximately 10% in women aged ≥70 years, irrespective of cardiovascular risk factors. Age and history of cardiac disease were strong predictors of cardiotoxicity, with a hazard ratio of 11.3 (95% confidence interval [CI]: 3.5-36.6) for women aged ≥70 years as compared with those <50 years of age. Hazard ratio was 4.4 (95% CI: 2.1-9.5) for women with a history of cardiac disease compared with those without a history of cardiac disease. CONCLUSIONS Cardiotoxicity of trastuzumab varies considerably across subgroups of patients. The long-term safety profile was less favorable than in the largest clinical trial. Strategies to reduce cardiotoxicity in high-risk women should be investigated.

Perimenopausal risk factors and future health

BACKGROUND Lifestyle changes around the time of menopause have the potential to impact on morbidity and eventual mortality. Here we review this topic to identify how such changes may improve health at perimenopause and beyond. METHODS Searches were performed in Medline and other databases. Each subject summary was presented to the ESHRE Workshop Group, where omissions or disagreements were resolved by discussion. RESULTS Body weight increases because the decline in physical activity during the perimenopause is greater than the concomitant decline in energy intake. It is imperative to stop smoking before menopause because the risk of acute myocardial infarction rises sharply thereafter. Cardiovascular events can be reduced by managing risk factors, such as hypertension and increased lipids and body weight. Breast cancer risk is increased to a similar extent by hormone use, decreased physical activity, increased calorie intake and alcohol use, all reflecting lifestyle decisions. Smoking, alcohol and exercise may increase or decrease risk of aging brain disorders, especially dementia and Parkinsons disease, while stress is consistently associated with increased risk and a prudent diet is consistently associated with reduced risk. Osteoarthritis frequency increases after 50 years of age and risk is elevated 3-fold by obesity, while risk of osteoporosis can be minimized by smoking cessation, adequate vitamin D intake and regular weight-bearing exercise. CONCLUSIONS Lifestyle changes around the time of the perimenopause can reduce the likelihood and severity of heart disease and chronic illness in later years and the cost of care of elderly women.

Bevacizumab in Clinical Practice: Prescribing Appropriateness Relative to National Indications and Safety

The aim of this study was to describe the clinical use of bevacizumab in Lombardy (9.5 million inhabitants), Italy, during 2006-2007 in patients with metastatic colorectal cancer (mCRC) to evaluate compliance with the Italian Medicine Agency (AIFA) indications, the incidence of adverse events, and the survival rate. We performed computerized record linkage among three different Lombardy health care databases: File F registry, Regional discharge database, and Registry Office records. Patients were classified into approved and off-label uses according to the AIFA indications. Treatment with bevacizumab was administered to 780 patients, of whom 81.7% (n = 637) had mCRC. Among these, 37.8% (n = 241) of patients received the drug in observance of AIFA indications. Overall, ∼10% of patients had serious treatment-related toxicities (fistula, 3.5%; venous thromboembolism, 2.8%; hemorrhage, 1.9%; intestinal perforation and arterial thromboembolism, <1%). The 1-year survival rate was 74.3% and the 2-year survival rate was 39.2%. The median survival time was 20.5 months, and there were no meaningful differences between gender and age groups. There was a gap between the bevacizumab approved indication and clinical practice pattern: overall, less than one half of the patients received bevacizumab in observance with the regulatory indication. The main reason for nonadherence to the indication was use as a second-line or advanced line of therapy. The incidence of serious adverse events and the survival rates of mCRC patients were similar to those reported in clinical trials.