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Aim: Chronic, infected skin wounds, including VLU and DFU, are a major public health issue with limited treatment options. We have recently identified a class of small molecules, known as the epoxytiglianes, with the potential to treat these wound types. Method: Here, we assessed the ability of our current lead, EBC-1013, to treat non-healing veterinary wounds and a physiologically relevant preclinical mouse model (db/db) of chronic wounds that spontaneously develops a biofilm infection. The indirect antimicrobial and wound healing associated effects of EBC-1013 were also studied in vitro/in vivo (microarray, qPCR, respiratory burst, NETosis and cytokine bead assays) using human dermal fibroblasts (HDF), keratinocytes (HEK), blood-derived neutrophils (PMNL), peripheral blood mononuclear cells (PBMCs) and the aforementioned db/db model. Results / Discussion: EBC-1013 promoted wound closure in both veterinary cases and the db/db model detailed above. In terms of mechanism, EBC-1013 induced respiratory burst and NETosis in PMNL, and promoted the secretion of TNF, IL-1β and IL-8 from PBMCs. EBC-1013 treatment of HEKa/HDFa also led to the upregulation of innate immune defence genes encoding host defence peptides (DEFB4, DEFB103A, DEFB104A, RNASE7), various pro-inflammatory cytokines/chemokines (TNF, IL1B, IL6, IL8, CXCL12, CCL20), ECM components (LCE/KRT/SPRR genes, TNC, FN1, LAMC1) and pro-resolution molecules (IL1RN, IL1F5, SLPI) in these cell types. Consistent with the in vitro data, EBC-1013 also significantly upregulated several of these genes (Defb3, Defb14, Rnase6, Camp, Tnf, Il1b, Il6, Il1rn, Cxcl2, Sprr2e, Lce3d, Tnc) in db/db mouse wounds, together with promoting PMNL recruitment to these lesions in vivo. Conclusion: EBC-1013 can help resolve chronic, infected wounds through inducing an acute inflammatory response, which helps clear bacterial infection and resets the wound microenvironment. [ABSTRACT FROM AUTHOR]

Aim: Chronic, infected skin wounds, including VLU and DFU, are a major public health issue with limited treatment options. We have recently identified a class of small molecules, known as the epoxytiglianes, with the potential to treat these wound types. Method: Here, we assessed the ability of our current lead, EBC-1013, to treat non-healing veterinary wounds and a physiologically relevant preclinical mouse model (db/db) of chronic wounds that spontaneously develops a biofilm infection. The indirect antimicrobial and wound healing associated effects of EBC-1013 were also studied in vitro/in vivo (microarray, qPCR, respiratory burst, NETosis and cytokine bead assays) using human dermal fibroblasts (HDF), keratinocytes (HEK), blood-derived neutrophils (PMNL), peripheral blood mononuclear cells (PBMCs) and the aforementioned db/db model. Results / Discussion: EBC-1013 promoted wound closure in both veterinary cases and the db/db model detailed above. In terms of mechanism, EBC-1013 induced respiratory burst and NETosis in PMNL, and promoted the secretion of TNF, IL-1β and IL-8 from PBMCs. EBC-1013 treatment of HEKa/HDFa also led to the upregulation of innate immune defence genes encoding host defence peptides (DEFB4, DEFB103A, DEFB104A, RNASE7), various pro-inflammatory cytokines/chemokines (TNF, IL1B, IL6, IL8, CXCL12, CCL20), ECM components (LCE/KRT/SPRR genes, TNC, FN1, LAMC1) and pro-resolution molecules (IL1RN, IL1F5, SLPI) in these cell types. Consistent with the in vitro data, EBC-1013 also significantly upregulated several of these genes (Defb3, Defb14, Rnase6, Camp, Tnf, Il1b, Il6, Il1rn, Cxcl2, Sprr2e, Lce3d, Tnc) in db/db mouse wounds, together with promoting PMNL recruitment to these lesions in vivo. Conclusion: EBC-1013 can help resolve chronic, infected wounds through inducing an acute inflammatory response, which helps clear bacterial infection and resets the wound microenvironment. [ABSTRACT FROM AUTHOR]

CAROTID-ARTERY STENTING (CAS) HAS EVOLVED SIGNIFICANTLY over recent years to become a reasonable alternative to carotid endarterectomy (CEA) for selected patients with carotid-artery disease. An important procedural aspect of CAS is embolic protection, to prevent embolic debris from causing ischemic stroke during the procedure itself. Distal protection devices must, by necessity, cross the lesion before there is protection in place and, therefore, carry some risk of embolization when they cross the lesion. Proximal occlusion of the carotid artery causes cessation of antegrade flow, thereby preventing this embolization of debris from the lesion during equipment crossing. After the procedure, debris is suctioned out of the vessel before balloon deflation and restoration of blood flow. Thus, proximal protection using PEO (proximal endovascular occlusion) has the potential to lower the rate of ipsilateral stroke during CAS. To test this, Stabile et al examined their single-center registry of patients undergoing CAS using PEO. All patients undergoing CAS at their hospital in Italy were prospectively included in the registry. From 2004 to 2009, 1,300 patients had undergone CAS with PEO. Inclusion criteria were asymptomatic stenosis ≥80% or symptomatic stenosis ≥50%. Exclusion criteria were critical stenosis of the ipsilateral-common carotid artery, occlusion of the ipsilateral- external carotid artery (ECA), INR > 1.3, prior debilitating stroke, and contraindication to dual anti-platelet therapy. All patients received aspirin and thienopyridine prior to the procedure, then aspirin for life and thienopyridine for three months. All patients were reviewed by an independent neurologist after the procedure. Results: The majority (72%) of patients were male, mean age was 70 years (9% were over 80 years old), and 28% were symptomatic. Significant coronary artery disease was present in 66%, and 25% were diabetic. Contralateral internal carotid artery (ICA) stenosis > 70%, or occlusion, was present in 12.5%; ipsilateral ECA stenosis > 70% was present in 7% of patients. Average procedural time was 17 ±_8 minutes. Occlusion time was 198 ± 59 seconds. Transient neurological symptoms with full resolution were encountered by 20% of patients, but only 0.3% of patients were unable to tolerate the carotid-artery occlusion. The 30-day mortality rate was 0.61%, and the combined rate of death or stroke was 1.38%. The five in-hospital deaths were attributed to: one acute coronary syndrome, one acute pulmonary edema, one hemorrhagic stroke, one subarachnoid hemorrhage, and one acute renal failure precipitating multi-organ failure. The incidence of death or stroke was higher in symptomatic patients than in asymptomatic patients (3.0% vs. 0.8%, p < 0.01), but no difference was seen between patients with or without contralateral ICA occlusion. Multivariable analysis revealed that symptomatic status (odds ratio [OR] 4.25, p < 0.05) and hypertension (OR 3.7, p < 0.05) were independent predictors of stroke. Institutional experience increased over the time of the study, and death and stroke rate declined by approximately 70% (p < 0.01). High surgical risk features increased the total event rate, but this was not an independent predictor of death or stroke. The authors conclude that using PEO for CAS is safe and effective in an unselected population, and that anatomical and/or clinical conditions of high surgical risk were not associated with an increased rate of adverse events. [ABSTRACT FROM AUTHOR]

The article discusses research on the effect of cardiac surgery on nonagenarians over a period of 10 years in Italy. It references a study by G. Speziale and colleagues published in a 2010 issue of "Circulation." Results show overall 30-day surgical mortality was 13.4% in 127 patients who underwent coronary artery bypass grafting (CABG), valve surgery, or both. The researchers believe cardiac surgery can achieve functional improvement despite high complication rate.

Mentions a synthesis meeting on osteoporosis to be held in Milan, Italy in October 2000. How women are affected by osteoporosis; Clinical synthesis meetings being different from consensus meetings; Publication of papers from a joint clinical synthesis meeting on hormone replacement therapy in the `Journal of Epidemiology and Biostatistics.'

Background: Initial findings of the Italian Randomized Tamoxifen Prevention Trial found no reduction in risk of breast cancer with tamoxifen use, whereas the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial showed that tamoxifen treatment reduces risk of estrogen receptor-positive breast cancer. Here we present an extended follow-up of the Italian trial., Methods: From October 1, 1992, to December 31, 1997, 5408 otherwise healthy women who had undergone hysterectomy were randomly assigned in a double-blind manner to tamoxifen (20 mg daily) or placebo for 5 years. Rates of breast cancer and other events in the two groups were compared by the use of risk ratios (RRs) and 95% confidence intervals (CIs)., Results: After 11 years of follow-up, 136 women (74 placebo, 62 tamoxifen) developed breast cancer (RR = 0.84, 95% CI = 0.60 to 1.17; annual rates were 2.48 and 2.07 per 1000 women-years, respectively). The rates of breast cancer in the two study groups were similar among women who had had bilateral oophorectomy and among women at low risk for hormone receptor-positive (HR+) disease but were much lower in the tamoxifen group among women at high risk (placebo, 6.26 per 1000 women-years, tamoxifen, 1.50 per 1000 women-years; RR = 0.24, 95% CI = 0.10 to 0.59). During the treatment period, women in the tamoxifen group reported more hot flashes (RR = 1.78, 95% CI = 1.57 to 2.00), vaginal discharge (RR = 3.44, 95% CI = 2.90 to 4.09), and urinary disturbances (RR = 1.52, 95% CI = 1.23 to 1.89) but fewer headaches (RR = 0.68, 95% CI = 0.50 to 0.94) than women in the placebo group. Hypertriglyceridemia (RR = 4.33, 95% CI = 1.96 to 9.53), thromboembolic events (RR = 1.63, 95% CI = 1.02 to 2.62), and cardiac arrhythmia or atrial fibrillation (RR = 1.73, 95% CI = 1.01 to 2.98) were also more frequent in the tamoxifen group than in the placebo group., Conclusions: Appropriate selection of women at high risk for HR+ disease may improve the risk-benefit ratio of tamoxifen intervention.

We used data from a multicentre case-control study conducted in Italy between 1991 and 1994 on over 2500 cases of breast cancer and a comparable number of controls, and estimates of breast cancer incidence in Italy to compute individual breast cancer risk for Italian women. The estimated probabilities between age 50 and 80 ranged from approximately 5% (for a woman with no family history and low modifiable risk profile) to about 30% (for a woman with young family history and high modifiable risk) on the basis of various women's baseline characteristics. Expected numbers of breast cancer cases using the present model were compared with those based on the USA Gail model, and with the observed ones in the comparison group of the Italian Tamoxifen Trial. These show a closer agreement between the observed and the expected total numbers of breast cancers than the USA Gail model. Thus, the Gail model can be improved for use in other populations by using estimates of incidence and risk which are more appropriate to the target population.

Background: Low-dose spiral CT of the chest effectively detects early-stage lung cancer in high-risk individuals. The high rate of benign nodules and issues of making a differential diagnosis are critical factors that currently hamper introduction of large-scale screening programmes. We investigated the efficacy of repeated yearly spiral CT and selective use of positron emission tomography (PET) in a large cohort of high-risk volunteers., Methods: We enrolled 1035 individuals aged 50 years or older who had smoked for 20 pack-years or more. All patients underwent annual low-dose CT, with or without PET, for 5 years. Lesions up to 5 mm were deemed non-suspicious and low-dose CT was repeated after 12 months (year 2)., Findings: By year 2, 22 cases of lung cancer had been diagnosed (11 at baseline, 11 at year 2). 440 lung lesions were identified in 298 (29%) participants, and 95 were recalled for high-resolution contrast CT. PET scans were positive in 18 of 20 of the identified cancer cases. Six patients underwent surgical biopsy for benign disease because of false-positive results (6% of recalls, 22% of invasive procedures). Complete resection was achieved in 21 (95%) lung cancers, 17 (77%) were pathological stage I (100% at year 2), and the mean tumour size was 18 mm. There were no interval lung cancers in the 2.5 years of follow-up (average time on study from randomisation to last contact), although 19 individuals were diagnosed with another form of cancer (two deaths and 17 non-fatal admissions)., Interpretation: Combined use of low-dose spiral CT and selective PET effectively detects early lung cancer. Lesions up to 5 mm can be checked again at 12 months without major risks of progression.

Tamoxifen improves outcome in women with breast cancer and reduces the incidence of estrogen receptor-positive (ER+) breast tumors in prevention trials. Tamoxifen use is associated with an increased risk of potentially serious adverse events, principally endometrial cancer and venous thromboembolic events and, therefore, detailed knowledge of the effects of tamoxifen is important. With more cases of breast cancer being found as the follow-up time increases, it is now possible to perform more detailed analysis of the Italian Randomized Trial of Tamoxifen. Women with hysterectomy (N = 5408) were randomly assigned to receive 20 mg tamoxifen per day (N = 2700) or placebo (N = 2708). After a median of 81.2 months of follow-up, 79 case subjects (34 in the tamoxifen arm and 45 in the placebo arm) were diagnosed with breast cancer. We were able to identify a group of women at increased risk of ER+ breast cancers (high-risk group) on the basis of baseline as well as reproductive and hormonal characteristics (height, age at menarche, parity, age at first birth, and oophorectomy). Tamoxifen administered to women in the high-risk group showed statistically significantly reduced incidence of breast cancer (tamoxifen, 3 and placebo, 15; P =.003), but no such effect was seen in the low-risk group (tamoxifen, 31 and placebo, 30; P =.89). The positive effect of tamoxifen on breast cancer among high-risk women is most marked for ER+ tumors (tamoxifen, 1 and placebo, 11; P =.002). Chemoprevention of breast cancer with tamoxifen appears to be effective in women at high risk of ER+ tumors but not among women at low risk, who may well be protected naturally by late age at menarche or early first pregnancy, or artificially by removal of the ovaries. Tamoxifen could be offered as a preventive agent to women identified at high-risk of breast cancer because of hormone-related risk factors. Such a strategy would greatly reduce the numbers of women who would need to take tamoxifen to obtain the same absolute reduction in breast cancer. These findings are exploratory and need to be confirmed in other randomized trials.

Estimates of the total number of men with a previous diagnosis of prostate cancer in Italy range from 55,000 to 135,000. This wide range of variation is largely due to uncertainties on the number of protein-specific antigen-detected, asymptomatic cases. The number of clinically detected cases, including cases with advanced disease, is less subject to uncertainty, with reasonable estimates ranging from 45,000 to 60,000.

Background: Tamoxifen is a candidate chemopreventive agent in breast cancer, although the drug may be associated with the development of endometrial cancer. Therefore we did a trial in hysterectomised women of tamoxifen as a chemopreventive., Methods: In October, 1992, we started a double-blind placebo-controlled, randomised trial of tamoxifen in women (mainly in Italy) who did not have breast cancer and who had had a hysterectomy. Women were randomised to receive tamoxifen 20 mg per day or placebo, both orally for 5 years. The original plan was to follow the intervention phase by 5 years' follow-up. In June, 1997, the trialists and the data-monitoring committee decided to end recruitment primarily because of the number of women dropping out of the study. Recruitment ended on July 11, 1997, and the study will continue as planned. The primary endpoints are the occurrence of and deaths from breast cancer. This preliminary interim analysis is based on intention-to-treat., Findings: 5408 women were randomised; participating women have a median follow-up of 46 months for major endpoints. 41 cases of breast cancer occurred so far; there have been no deaths from breast cancer. There is no difference in breast-cancer frequency between the placebo (22 cases) and tamoxifen (19) arms. There is a statistically significant reduction of breast cancer among women receiving tamoxifen who also used hormone-replacement therapy during the trial: among 390 women on such therapy and allocated to placebo, we found eight cases of breast cancer compared with one case among 362 women allocated to tamoxifen. Compared with the placebo group, there was a significantly increased risk of vascular events and hypertriglyceridaemia among women on tamoxifen., Interpretation: Although this preliminary analysis has low power, in this cohort of women at low-to-normal risk of breast cancer, the postulated protective effects of tamoxifen are not yet apparent. Women using hormone-replacement therapy appear to have benefited from use of tamoxifen. There were no deaths from breast cancer recorded in women in the study. It is essential to continue follow-up to quantify the long-term risks and benefits of tamoxifen therapy.

This paper reviews previously published models of the effect of parity and age at any birth on breast cancer risk. It is shown that these models are conceptually similar and can be written within a general model. Various restrictions on the parameters of the general model yield the specific models. The models are applicable in case control studies and are illustrated using data from a case control study of breast cancer in Italy.

Longer and better survival of End-Stage Renal Disease (ESRD) patients undergoing renal replacement therapy (RRT) is now associated with a higher prevalence of new elderly patients receiving renal replacement therapy (dialysis). In order to help clarify the association of cancer risk with RRT, the incidence of cancer in a population-based cohort of uraemic patients in the Region of Lombardy, northern Italy, was undertaken using data from the Lombardy Regional Dialysis and Renal Transplant Registry. A total of 479 cases of cancer of all sites was recorded in this population. There were statistically significantly elevated risks of primary liver cancer, kidney cancer, thyroid cancer, lymphoma and multiple myeloma. When the data were examined according to primary renal diseases, there did not appear to be any particular association between excess cancer risk and the underlying pathology. While some caution must be expressed in interpreting these data, due to the relatively small numbers of cases expected in many of the disease entities, the results indicate an excess of renal-cell and liver carcinomas and lymphomas in patients receiving RRT and highlight the necessity of careful follow-up and awareness of these associations, together with the need for early detection of such tumours.

To offer quantitative evidence on the association between pancreatitis and pancreatic cancer, we analyzed data from a hospital-based case-control study conducted in northern Italy between 1983 and 1992, including a total of 362 incident cases of histologically confirmed pancreatic cancer and 1,408 controls admitted to hospital for acute, nonneoplastic, nondigestive tract disorders. Information was obtained using a structured questionnaire on sociodemographic characteristics and lifestyle habits (including tobacco and alcohol consumption) and a problem-oriented medical history, which included history of pancreatitis and age at its first diagnosis. Pancreatitis was reported by 24 (6.6%) cases and 18 (1.3%) controls, yielding an age- and sex-adjusted relative risk (RR) of 5.7 (95% confidence interval, 2.9-11.4). The risk of pancreatic cancer was appreciably higher 5 or more years after diagnosis of pancreatitis (RR = 6.9) than in the first 4 years (RR = 2.1), and in subjects below age 60 (RR = 8.3) than in elderly ones (RR = 2.6), but similar in males and females. The time-risk relationship is strongly indicative of a real relationship between pancreatitis and pancreatic cancer. After allowing for tobacco and alcohol, besides area of residence and education, the association between pancreatitis and pancreatic cancer appeared to be partly explained by such covariates (RR = 3.9); however, this may represent some degree of overadjustment if, for instance, alcohol is causally linked to pancreatitis, which, in turn, is causally related to pancreatic cancer. In terms of population attributable risk, pancreatitis would explain approximately 5% of pancreatic cancer cases.

This combined analysis of data from three large case-control studies of oral cancer confirms the important effect of tobacco in the aetiology of the disease. The studies have been conducted in the United States, Italy and China and results for risks associated with tobacco smoking were generally consistent across centres, while those for alcohol were not; increased risks amongst alcohol drinkers were evident in two centres but not in the study conducted in Turin, Italy. In addition, the combined analysis had large enough numbers to analyse the risk of tobacco consumption in non-drinkers. In females these showed increased risks while in males the effect of tobacco alone was weaker. Given the popularity of tobacco smoking, and its consequent high attributable risk in terms of oral cancer it is reassuring, in terms of public health, that cessation will result in a substantial reduction in risk; a 30% reduction in risk for those stopping smoking between 1 and 9 years, and a 50% reduction for those stopping more than 9 years. Although encouraging smokers to stop should be the principal aim, decreases in risk for everyone could be achieved by encouraging high fruit and vegetable consumption.

There is currently a large breast cancer chemoprevention trial in Italy. The trial is based on the use of the antioestrogen tamoxifen, which is one of the most successful and most studied anticancer drugs. There is a strong evidence that this drug can prevent the growing of controlateral cancer in women previously operated for breast cancer. The chemoprevention trial using tamoxifen includes healthy women, aged 35 to 70 and hysterectomised. The participants are taking either 20 mg/day of tamoxifen or placebo for 5 years, in double blind; then they are followed-up clinically and instrumentally every 6 months for the further 5 years. The main end-point of the study is to verify the reduction of incidence and mortality from breast cancer. It was decided to recruit only hysterectomised women on the consideration that, according to some studies, tamoxifen could give an additional risk of endometrial cancer: the Italian study was especially designed with the intention of avoiding this unjustified risk.

The relationship between diabetes mellitus and cancer risk was investigated using data from an integrated series of case-control studies conducted in Northern Italy between 1983 and 1992. Cases were 9,991 patients with incident, histologically confirmed neoplasms below age 75, including 181 cancers of the oral cavity and pharynx, 316 of the oesophagus, 723 of the stomach, 828 of the colon, 498 of the rectum, 320 of the liver, 58 of the gall bladder, 362 of the pancreas, 242 of the larynx, 3,415 of the breast, 726 of the endometrium, 971 of the ovary, 125 of the prostate, 431 of the bladder, 187 of the kidney, 208 of the thyroid, 80 Hodgkin's lymphomas, 200 non-Hodgkin's lymphomas and 120 multiple myelomas. Controls were 7,834 subjects in hospital for acute, non-neoplastic, non-metabolic, non-hormone-related disorders. A history of diabetes was reported by 5.1% of male and 5.4% of female controls. Significantly elevated relative risks (RRs) among subjects with diabetes were observed for cancers of the liver [RR = 2.8, 95% confidence interval (CI) 2.0-3.9], pancreas (RR = 2.1, 95% CI 1.5-2.9) and endometrium (RR 3.4, 95% CI 2.7-4.3). After allowance for obesity and education as well as age and sex, the RRs were 3.0 for liver, 2.3 for pancreas, and 2.8 for endometrium. Diabetic subjects had no elevated risk for any of the other cancer sites considered. For liver and endometrial cancer the RRs remained elevated up to 10 years after diagnosis of diabetes (RR 2.6 and 2.0 respectively), while the RR for pancreatic cancer declined from 3.2 in the first 5 years after diagnosis of diabetes to 2.3 from 5 to 9 years and to 1.3 (95% CI 0.7-2.3) 10 or more years since diagnosis. This suggests that the relationship between diabetes mellitus and liver and endometrial cancer is probably real, while that with pancreatic cancer is compatible with diabetes being an early symptom of the disease, or at least of preneoplastic lesions.

As part of a collaborative study of risk factors for childhood brain tumours, the effects of the mother's smoking and her potential for passive smoking exposure during the pregnancy were assessed in a case-control study. Parents of 91 cases and 321 population controls from Northern Italy, matched for age, sex and residence, were interviewed about their lifetime smoking habits. Mother's smoking during pregnancy was associated with an odds ratio (OR) of 1.7 (95% CI 0.8, 3.8) of brain tumour in her child although this was not statistically significant. Among non-smoking mothers, the risk for light and heavy exposure to passive smoking was 1.7 (0.8, 3.6) and 2.2 (1.1, 4.5) respectively, and a statistically significant dose-response relationship was found (p trend = 0.02). These results must be interpreted within the constraints of the relatively small sample size and the likely misclassification produced by the difference between the potential for exposure to passive smoke and the true exposure. However, they add another piece of information to the growing body of evidence available about the health consequences both of active and of passive smoking and highlight the need for more information about this putative association.

Benign Prostatic Hyperplasia (BPH) has undoubtedly been an important cause of the urinary difficulties observed in elderly men for many centuries although the condition was only recognised as such during the last century. Benign Prostatic Hyperplasia is a very common condition (88 per cent of autopsy specimens in men aged over 80 have histological BPH) and the cause of the commonest surgical procedure in elderly men (three men in ten ultimately may require surgery for this condition). A common cause of death in elderly men just 20-30 years ago, improved medical care has seen dramatic declines in this aspect of BPH and today treatment choices in BPH are largely determined by considerations of quality-of-life. Despite such a common occurrence, little is known with any certainty about the epidemiology of BPH. The incidence, even the population prevalence, is difficult to determine for a variety of reasons associated with difficulties surrounding the diagnosis of BPH and the identification of a source population to provide a denominator to calculate rates. Knowledge of risk factors is sparse: analytical epidemiologic studies of BPH are difficult to conduct. Case-control studies, the most commonly employed design in epidemiology, are problematic in that a control group may be difficult to define in view of the likelihood that a large proportion of these may have undiagnosed BPH. Against this background, knowledge of the prostate in the general population was sought in an international survey and found to be poor: although most men are aware of its existence, very few could correctly identify the function of the gland. Men tended to discuss urination problems with their doctors not when a symptom develops but when that symptom becomes bothersome. A 10-fold variation in frequency of rectal examination was identified between men in Germany and Italy which could not be explained by potential confounding variables. Given the large increases in the number of males reaching older ages, it is clear that BPH will continue to have substantial and increasing influence in terms of morbidity, mortality and health costs. Before the end of the present century, the life expectancy of a male at birth will exceed 80 years in many of the developed countries. Put put another way, one man in every two born can expect to reach an at which he has an 88 per cent chance of having a prostate with morphological BPH. Clearly, the need for high quality epidemiological information and consequent increased prospects for prevention is obvious.

The relationship between frequency of consumption of a selected number of indicator foods and oral and oropharyngeal cancer risk was analysed in a case-control study conducted in Northern Italy on 105 cases of oral and pharyngeal cancer and 1169 controls in hospital for acute, non-neoplastic or digestive diseases. Besides significant and strong direct associations with tobacco (relative risk, RR = 11.0 for current versus never smokers) and alcohol (RR = 5.8 for upper versus lower consumption tertile), consumption of six food items (milk, meat, cheese, carrots, green vegetables and fruit) were inversely and significantly related to oral and pharyngeal cancer risk. The strongest protection was apparently related to frequent fruit consumption, with RRs of 0.8 and 0.2 in the two highest tertiles. Allowance for major potential confounding factors, including tobacco, alcohol and social class indicators explained only part of the dietary correlates observed. The two items remaining significant after multivariate analysis were fruit (RR = 0.3 for the upper tertile) and alcohol (RR = 3.8 for the upper tertile). The associations observed may simply reflect a generally poorer nutritional status in the cases, although the observation that fruit consumption appears to be a particularly important protective factor against oropharyngeal cancer is of potential interest, in terms of aetiological clues and preventive implications.

Risk factors for cholelithiasis were investigated in a case-control study conducted in northern Italy on 195 incident cases of gallstone disease requiring surgery (119 females, 76 males) and 1122 controls in hospital for acute, non-digestive tract, non-neoplastic conditions. There was no consistent association with socio-demographic indicators, such as marital status, education and social class nor with smoking and coffee consumption. The relative risk of cholelithiasis decreased with increasing alcohol consumption: compared with non-drinkers, the odds ratio (OR) was 0.8 for one to three drinks per day and 0.5 for over three. A direct association was observed with measures of body weight: relative to leaner individuals, the multivariate ORs were 1.2, 2.1 and 2.4 for subsequent levels of body mass. These trends in risk were statistically significant, consistent in the two sexes, and not apparently modified by adjustment for major identified potential confounding factors. History of hepatitis and liver cirrhosis were reported more frequently by cases, but it is difficult to assess the role of recall bias on these risk factors. No association was found with diabetes, thyroid disease and several digestive tract disorders. For females, no consistent pattern of risk was observed up to four births, but women with five or more births had an OR of 2.9 (95% confidence interval (Cl) = 1.1-7.3). The risk decreased with increasing age at first and last birth, both trends being statistically significant. Overweight and alcohol consumption were the most important risk and protective factors respectively for cholelithiasis requiring surgical intervention in this population.

The relationship between consumption of fat in seasoning and risk of breast cancer was considered in a case-control study conducted in northern Italy of 2663 cases of breast cancer and 2344 controls admitted in the same network of hospitals with acute, non-neoplastic and non-gynaecological conditions. Subjective scores corresponding to three levels (low, intermediate and high) of intake of butter, margarine and oil, together with a combined variable of these three items ("total fat"), were used to evaluate the personal use of fat in seasoning. Compared to low use, a slight but significant increase in risk was observed for intermediate and high intake of butter, oil and total fat with relative risks of 1.5 (95% confidence interval [CI], 1.1-1.9) for high intake of butter, 1.3 (95% CI, 1.0-1.6) for high intake of oil and 1.4 (95% CI, 1.2-1.7) for high intake of total seasoning fat. These results were not materially modified after allowance for a number of identified potentially distorting factors. The results of this study suggest that there is a positive association, although moderate, between breast cancer risk and intake of fat added in seasoning, which may represent an indirect indicator of the subject's attitude towards fat.

We used an age-period-cohort model with arbitrary constraints on the parameters, fitted to the mortality data for the period 1955-84, to project rates in mortality from all cancers and 11 major cancer sites in Italy for the period 1985-1999. For all neoplasms considered, using estimated age and cohort values, two models were fitted, one based on constant period effects, and one on a linear regression on the logarithm of the six calendar periods. Furthermore, "a priori" defined coefficients based on epidemiologic inferences were given to period values for tobacco-related neoplasms (below unity for males, above unity for females, on the basis of recent trends in tobacco prevalence in the two sexes), for breast and ovarian cancer (in relation to the potentially different effect of oral contraceptives, other female hormones, reproductive factors and treatment on these neoplasms), and for total cancer mortality. This produced a range of potential estimates, which were reasonably similar for neoplasms (such as stomach, intestines, breast, ovary or prostate) for which no major change in slope of the cohort effects was evident, but wider (i.e., between 188 and 264/100,000 males aged 40 to 79 in 1995-99) for lung or other tobacco-related cancers. Although this range of variation is far from negligible, the estimated values indicate that lung cancer among Italian males aged 40 to 79, even under the more optimistic assumption, will probably be higher at the end of the century than in the early 1980's, and that lung cancer alone will account for 35 to 42% of all cancer deaths in males between 40 and 79 years. Though any prediction has, by definition, inherent difficulties and uncertainties, cancer mortality in the near future will be strongly influenced by age and cohort effects already known, and hence its projections may offer some indication of public health relevance.

The relationship between frequency of intake of a selected number of indicator foods and the risk of laryngeal cancer was investigated in a case-control study conducted in northern Italy on 110 males with histologically confirmed cancer of the larynx and 843 controls in the hospital for acute, nonneoplastic or respiratory diseases. Significant direct associations were observed with tobacco [relative risk (RR) = 5.8 for current versus never smokers] and alcohol (RR = 2.3 for the upper versus lower tertile of consumption), while the frequency of consumption of three food items was inversely related with laryngeal cancer risk. These were fish (RR = 0.6 for the upper tertile), green vegetables (RR = 0.4), and fresh fruit (RR = 0.3). Multiple logistic regression analysis, including simultaneously major nondietary covariates and various food items, suggested that the strongest and most consistent protective effect was given by fruit. These findings can be generally interpreted as an indication that a "poorer" diet is related to a raised risk of laryngeal cancer, although the confirmed observation that fruit appears to be the main protective dietary factor against cancers of the upper respiratory and digestive tract is of potential interest and may suggest useful etiological clues. Dietary findings were similar in different strata of alcohol and tobacco consumption.

The relationship between total alcohol consumption and intake of beer, wine and spirits and the risk of cancer of the pancreas was re-assessed in a pooled analysis of 3 case-control studies of pancreatic cancer from Italy, France and Switzerland, providing a total data-set of 494 cases and 1,704 controls. Logistic regression was used to obtain relative risks adjusted for study, age, sex, smoking and socio-economic status. Relative to non-drinkers, the risk estimates for subsequent levels of alcohol consumption were close to unity, and there was no evidence of a trend in risk with dose: the point estimate for more than 8 drinks per day was 0.8 (95% Confidence Interval, CI = 0.5-1.3). Likewise, no consistent association was observed for consumption of wine, beer or spirits: the relative risks for the highest consumption levels were 1.0 for wine, 0.9 for beer and 0.9 for spirits. No significant interaction was observed with study centre, sex or smoking habits. Given the large size of the data-set, of the consistency and the replication of findings across the 3 different studies, and of the elevated alcohol consumption of these populations, the present analysis gives reassuring evidence on the alcohol and pancreatic cancer issue in relation to total consumption of alcohol, of beer and of other alcoholic beverages.

The role of anthropometric variables in the risk of breast cancer has been investigated using pooled data from 2 hospital-based case-control studies conducted in Italy for a total data-set of 3,247 cases and 3,263 controls. No association was observed in pre-menopausal women between breast cancer risk and height, weight, indices of body mass (W/H2; W/H1.5) and surface area. In post-menopausal women, the risk of breast cancer was inversely related to height, being 0.8 in taller women (greater than 165 cm) compared with women 155 cm tall or less; the trend in risk, although not constantly decreasing, was statistically significant (p trend = 0.03). A direct, statistically significant association emerged with weight and indices of body mass and post-menopausal breast cancer risk. Considering 2 indices of body weight (W/H2 and W/H1.5) and relative to thinner women, the respective estimated risks of post-menopausal breast cancer increased to 1.4 and 1.3 for grossly obese women, and the corresponding p values for trend were respectively 0.002 and 0.02. The role of overweight was more evident in women with early age at menopause, thus suggesting a duration-risk effect.

The relationship between self-reported height and cancer risk was investigated in an integrated series of case-control studies including 273 cases of cancer of the oesophagus, 474 of the stomach, 558 of the colon, 352 of the rectum, 227 of the liver, 267 of the pancreas, 110 of the larynx, 2,388 of the breast, 545 of the cervix uteri, 563 of the endometrium, 688 of the ovary, 80 of the prostate, 263 of the bladder, 105 of the kidney, 43 Hodgkin's disease, 152 non-Hodgkin's lymphomas, 109 multiple myelomas, and a total of 5,574 controls admitted to hospital for acute, non-neoplastic conditions. No significant positive trend in risk was observed for any of the cancer sites considered, and some suggestion of elevated risks for the upper quintile of height was observed only for prostate (relative risk, RR = 1.4), kidney (RR = 2.7) and colon (RR = 1.2) in males (but not in females). For breast cancer, all the RRs for subsequent quintiles of height were close to unity. Four neoplasms showed significant inverse trends with height: oesophagus (RR = 0.7 for highest vs. lowest quintile), cervix (RR = 0.4), endometrium (RR = 0.7) and ovary (RR = 0.6). For oesophagus and cervix the trends could be explained, at least in part, in terms of social class correlates (multivariate RR 0.8 and 0.5, respectively), while for endometrium they could possibly be related to an inverse correlation between height and body mass (multivariate RR 0.9). Thus, our study did not support the hypothesis that nutrition in childhood and adolescence (which in this population is a determinant of adult height) is directly related to the subsequent risk of cancer at several major cancer sites. A number of inverse associations emerged, which may be either spurious and incidental, or suggest that poorer nutrition early in life may be an unfavourable indicator of the subsequent risk of selected neoplasms.

The relation between various aspects of medical history, selected indicator foods and the risk of pancreatic cancer was analyzed in a hospital-based case-control study conducted in Northern Italy on 247 patients with cancer of the pancreas, and 1,089 controls in hospitals for acute, nonneoplastic or digestive conditions. There was a significant association with history of pancreatitis (relative risk, RR 3.2, 95% confidence interval = 1.3-7.9), which was however reduced when the condition was first diagnosed at least 5 years previously. The point estimates were slightly, but not significantly, above unity for diabetes (RR = 1.5), gastrectomy (RR = 1.1) and cholelithiasis (RR = 1.3), and no association was found with liver disease or drug allergy. In relation to diet, there was some tendency for the risk to decrease with more frequent fruit consumption, but the results were largely inconsistent in relation to various indicators of meat, animal protein or fat intake. Although no important associations were found in this study with various aspects of medical history or diet indicators and pancreatic cancer risk, on account of the size of the dataset and the statistical power, this study contributes usefully to the debate on a common cancer whose causes are still largely undefined.

The relationship between the consumption of salt and the risk of gastrointestinal cancer was examined using data from a case-control study conducted in northern Italy. The study was conducted on 526 incident cases of gastric cancer, 621 of colon cancers, 382 of rectal cancers, and 1,223 controls admitted to hospital for acute, nonneoplastic, nondigestive tract disorders. Compared with those for people with low salt intakes, the relative risks (and 95% confidence intervals) for those with intermediate and high salt intakes were 1.3 (1.0-1.8) and 1.2 (0.8-1.7) for stomach, 1.0 (0.8-1.3) and 1.1 (0.8-1.5) for colon, and 1.2 (0.9-1.6) and 0.9 (0.6-1.3) for rectum. None of the trends in risk were statistically significant, and the risk estimates were not materially modified by allowance for major identified potential confounding factors. Thus, this study gives little support to the existence of any strong association between salt intake and gastrointestinal cancers. However, in view of the results obtained and of the uncertainties of salt intake measurement, the possibility exists of a real, although moderate, association of salt intake with gastric cancer.

The relation between cigarette smoking and risk of bladder cancer was analysed in a case-control study in Northern Italy of 337 cases of histologically confirmed invasive bladder cancer and 392 controls admitted to the same network of hospitals with acute, non-neoplastic, non-urological conditions. Compared with never-smokers, the multivariate relative risk (RR) was 1.9 (95% confidence interval, CI 1.2-3.1) for ex-smokers and 3.3 (95% CI 2.2-5.0) for current smokers. The risk was directly and significantly related to duration of smoking (RR 3.5 for 30 years or more) and dose (RR 3.9 for 20 cigarettes per day or more), and consistent among strata of sex and age (though the RRs were systematically higher at older ages). Smokers of black tobacco only had a RR of 3.7, compared with 2.6 for smokers of blond cigarettes or mixed types. The interaction between tobacco and several occupations associated with bladder cancer risk fitted an additive rather than a multiplicative model: compared with non-exposed never-smokers, RR was 2.5 for exposed non-smokers, 2.8 for non-exposed smokers and 3.7 for occupationally exposed smokers.

Death certification data on Hodgkin's disease in Italy over the period 1955-84 were studied in terms of age-standardized and age-specific national trends, and of geographical variation in mortality. There were substantial declines in death rates from the early 1970's onward, which can be largely attributed to therapeutic improvements. These led to avoidance of about 350 deaths, with a total 950 reported, which is probably the major absolute therapeutic advance identified for any cancer site. The declines started earlier in childhood and young adult age, and were restricted to population below age 60. The age distribution of the disease was different in the two sexes, since the age curve for males showed steady rises up to age 75, whereas that for females was clearly bimodal, with a peak around age 30, and another at oldest age. This divergent pattern is consistent with different exposure to (infectious) agent(s) in children of the two sexes, but also to occupational exposures potentially related to the risk of the disease. Examination of rates in various geographical areas showed generally higher rates in the North, and a few provinces with exceedingly high mortality in the central part of Northern Italy, particularly in a chiefly rural province (Mantua). This excess mortality (and, more in general, the observation that rates for Northern Italy are higher than in any other area of the EEC) could not be explained by obvious diagnostic or classification problems, were evident in both sexes, appeared to be consistent over the last decade and are reflected in available Italian cancer registration data.

The risk of breast cancer in relation to use of oral contraceptives was evaluated using data from a hospital-based case-control study from Northern Italy on 1517 cases below age 60 and 1351 controls admitted for acute diseases unrelated to any of the known or potential risk factors for breast cancer. The multivariate relative risk for ever vs. never users was 1.3 (95% confidence interval = 1.0-1.7). However, the risk was not related to duration of use: indeed the highest risk was observed among short-term users (less than 2 years), and the point estimate was 0.9 among users for 5 years or more. The elevated risk among short-term users, if not due to residual confounding or selection mechanisms, is probably explainable in terms of recall bias (i.e. more careful report of short or very short use by cases). No definite pattern was observed in relation to latency or recency of use, and the point estimates were 0.8 for women who had ever used the pill before age 25 and 0.8 for those who had ever used the pill before first full-term pregnancy. Thus, the study presents further reassuring information on the oral contraceptive/breast cancer debate. Its major limitation lies in the low prevalence of oral contraceptive users in Italy, with a consequently reduced statistical power, although, with the number of cases involved, it was possible to exclude a relative risk of 1.4 for long-term use or for ever use before first birth.

The analysis of alcohol and breast cancer risk from an Italian case-control study of breast cancer has been updated to include a total of 2402 women with histologically confirmed breast cancer and 2220 controls with acute conditions unrelated to any of the established or potential risk factors for breast cancer, admitted to a network of teaching and general hospitals in the greater Milan area. Compared with non-drinkers, the estimated relative risk for ever drinkers was 1.4 (95% CI = 1.2-1.6). The multivariate risks were 1.3 for less than 1 drink (e.g. 10 g of ethanol) per day, 1.3 for 1 less than 2 drinks, 1.4 for 2-3 and 2.2 for over 3 drinks per day. The positive association between alcohol and breast cancer was consistent across strata of age, socio-demographic variables, smoking, menstrual, reproductive, and hormonal factors, family history of breast cancer, nutrition and diet indicators. In particular, this study indicated that the alcohol-breast cancer relationship is probably not materially different in younger and older women, that alcohol drinking at an early age is not a particularly clear indicator of subsequent risk, nor that the effect of alcohol is enhanced in thin women. Thus, the findings of this study are both internally consistent and in agreement with most previous evidence, since the relative risks of 1.3-1.4 for a consumption of 10-30 g of alcohol per day compare well with the corresponding highest intake levels in most American studies. This study is of particular interest, since it provides data on higher levels of alcohol consumption, on which very little information is available. There are nontheless at least three elements which leave open the question of causality: the absence of duration-risk relationship, the inconsistency with evidence from descriptive epidemiology, and the lack of plausible biological mechanisms.