Roberto Zanetti

Once-Only Sigmoidoscopy in Colorectal Cancer Screening: Follow-up Findings of the Italian Randomized Controlled Trial—SCORE

BACKGROUND A single flexible sigmoidoscopy at around the age of 60 years has been proposed as an effective strategy for colorectal cancer (CRC) screening. METHODS We conducted a randomized controlled trial to evaluate the effect of flexible sigmoidoscopy screening on CRC incidence and mortality. A questionnaire to assess the eligibility and interest in screening was mailed to 236,568 men and women, aged 55-64 years, who were randomly selected from six trial centers in Italy. Of the 56,532 respondents, interested and eligible subjects were randomly assigned to the intervention group (invitation for flexible sigmoidoscopy; n = 17,148) or the control group (no further contact; n = 17,144), between June 14, 1995, and May 10, 1999. Flexible sigmoidoscopy was performed on 9911 subjects. Intention-to-treat and per-protocol analyses were performed to compare the CRC incidence and mortality rates in the intervention and control groups. Per-protocol analysis was adjusted for noncompliance. RESULTS A total of 34,272 subjects (17,136 in each group) were included in the follow-up analysis. The median follow-up period was 10.5 years for incidence and 11.4 years for mortality; 251 subjects were diagnosed with CRC in the intervention group and 306 in the control group. Overall incidence rates in the intervention and control groups were 144.11 and 176.43, respectively, per 100,000 person-years. CRC-related death was noted in 65 subjects in the intervention group and 83 subjects in the control group. Mortality rates in the intervention and control groups were 34.66 and 44.45, respectively, per 100,000 person-years. In the intention-to-treat analysis, the rate of CRC incidence was statistically significantly reduced in the intervention group by 18% (rate ratio [RR] = 0.82, 95% confidence interval [CI] = 0.69 to 0.96), and the mortality rate was non-statistically significantly reduced by 22% (RR = 0.78; 95% CI = 0.56 to 1.08) compared with the control group. In the per-protocol analysis, both CRC incidence and mortality rates were statistically significantly reduced among the screened subjects; CRC incidence was reduced by 31% (RR = 0.69; 95% CI = 0.56 to 0.86) and mortality was reduced by 38% (RR = 0.62; 95% CI = 0.40 to 0.96) compared with the control group. CONCLUSION A single flexible sigmoidoscopy screening between ages 55 and 64 years was associated with a substantial reduction of CRC incidence and mortality.

The multicentre south European study 'Helios'. II: Different sun exposure patterns in the aetiology of basal cell and squamous cell carcinomas of the skin.

The role of sun exposure in development of basal cell and squamous cell carcinomas among different populations from south Europe was investigated. Between 1989 and 1993 we interviewed incident cases and a random population sample of controls from five centres where a cancer registry was operating, whereas we selected a sample of hospital-based cases and controls from the other three centres. We gathered information on life-long exposure to sunlight during different activities. Results are analysed for 1549 basal cell carcinoma (BCC) cases and 228 squamous cell carcinoma (SCC) cases compared with 1795 controls. We observed a statistically significant increase of risk of SCC with increasing sun exposure beyond a threshold of 70,000 cumulated hours of exposure in a lifetime. Sun exposures during work and holidays were, however, inversely correlated. Odds ratios (ORs) of SCC were up to eight or nine times the reference for the highest exposures (200,000 cumulated hours or more). BCC exhibited a 2-fold increase of risk for lower exposure (8000-10,000 cumulated hours in a lifetime) with a plateau and a slight decrease of risk for the highest exposures (100,000 cumulated hours or more). Outdoor work showed a significantly increased risk of SCC (OR 1.6 for more than 54,000 cumulated hours of exposure in a lifetime), whereas recreational activities such as sun exposure during holidays at the beach (OR 1.6 for more than 2600 cumulated hours of exposure in a lifetime) or during water sports (OR 1.6 for more than 2600 cumulated hours of exposure in a lifetime) were associated with an increased risk of BCC. Risk patterns were different in poor or good tanners with a significant risk trend for good tanners, whereas poor tanners were on a plateau of increased risk at any level of exposure. Solar radiation is associated with a risk of BCC even for relatively short periods of exposure such as during holidays and sports, whereas SCC develops later if exposure continues. The skins ability to tan modulates the risk of BCC; subjects who tan poorly have a steady risk increase, whereas people who tan easily develop cancer only after prolonged exposures.

The multicentre south European study 'Helios'. I: Skin characteristics and sunburns in basal cell and squamous cell carcinomas of the skin.

The aim of this study was to investigate constitutional and environmental determinants of non-melanocytic skin cancer among different populations from south Europe. Between 1989 and 1993 we interviewed incident cases and a random population sample of controls from five centres where a cancer registry was operating, whereas we selected a sample of hospital-based cases and controls from three other centres. Controls were stratified according to the age and sex distribution of cases. In all, 1549 cases of basal cell carcinoma (BCC), 228 of squamous cell carcinoma (SCC) and 1795 controls were interviewed. Both cancers affected primarily sun-exposed sites such as face, head and neck, but the prevalence of BCC on the trunk was higher than for SCC. Pigmentary traits such as hair and eye colour as well as tendency to sunburn were strong and independent indicators of risk for both BCC and SCC. In SCC, adjusted odds ratios (ORs) ranged from 1.6 for fair hair colour to 12.5 for red hair. Light-blonde hair entailed a risk of about 2 for BCC. Pale eye colour was associated with a risk of 1.8 for SCC and 1.4 for BCC. Subjects who always burn and never tan showed an adjusted OR of 2.7 for BCC and 2.0 for SCC. A history of sunburns and a young age at first sunburn were associated with an increased risk for BCC only (OR 1.7). Pigmentary traits and sun sensitivity of the skin confirmed their role as risk indicators. The effect of sunburns, as an indicator of both exposure and sun sensitivity of the skin, is less clear. Nevertheless, its association with BCC suggests, by analogy with melanoma, a relationship with intense sun exposure. Conversely, SCC would require prolonged exposure to sunlight.

Cutaneous Melanoma and Sunburns in Childhood in a Southern European Population

A population-based case-control study of 260 patients (74 males and 186 females, mean age = 56) with cutaneous malignant melanoma and 416 controls (211 males and 205 females, mean age = 55) was conducted in Turin, north-west Italy, to examine the relation between timing of sunburns and sun exposure and melanoma risk within a southern European population, which is still relatively little investigated. Particularly elevated risk was associated with history of sunburns in childhood [odds ratio 5.9; 95% confidence interval (CI) 3.6-9.5], and such risk elevation persisted after allowance for other major melanoma risk covariates. Conversely, risk increase from history of severe sunburns lifelong was lower (odds ratio = 1.7; 95% CI: 1.1-2.4) and was eliminated by allowance for type of skin reaction to sun exposure and history of sunburns in childhood. A significant increase in the risk of cutaneous malignant melanoma was also associated with number of weeks spent on holiday at the beach not only as an adult, but also as a child.

Risk of cancer in persons with AIDS in Italy, 1985-1998

A record linkage was carried out between the Italian Registry of AIDS and 19 Cancer Registries (CRs), which covered 23% of the Italian population, to estimate the overall cancer burden among persons with HIV or AIDS (PWHA) in Italy, according to various characteristics. Observed and expected numbers of cancer and standardised incidence ratios (SIRs) were assessed until 1998 in 12 104 PWHA aged 15–69 years, for a total of 60 421 person-years. Significantly increased SIRs were observed for Kaposis sarcoma (KS, 1749-fold higher than the general population), non-Hodgkins lymphomas (NHL, 352), and invasive cervical cancer (22). SIR was significantly elevated also for cancer of the anus (34), lung cancer (2.4), brain tumours (4.4), Hodgkins disease (16), and leukaemias (5.3). The majority of lung and brain cancers were not histologically confirmed, and the possibility of misclassification with KS or NHL cannot be ruled out. The SIR for all non-AIDS-defining cancers was 2.2 in men and 2.5 in women. Intravenous drug users showed significantly more elevated SIRs for lung cancer (9.4), and brain tumours (6.7) than other transmission categories (SIR=1.4 and 2.3, respectively). This study confirmed increased SIRs for haemolymphopoietic neoplasms other than NHL in PWHA, although many-fold smaller than for NHL. An association with human papillomavirus-related cancers was also confirmed.

Comparison of risk patterns in carcinoma and melanoma of the skin in men: a multi-centre case–case–control study

We directly compared risk factors between 214 histologically confirmed melanomas (CMM), 215 basal-cell carcinomas (BCC) and 139 squamous-cell carcinomas (SCC) in a multiple case–case–control study with 349 controls from patients without dermatological disease admitted to the same hospitals. Subjects with fair hair had a significant risk increase for all types of tumours at a comparable level (ORadj for blonde hair: CMM 2.3; SCC 2.4; BCC 2.3). The effect of pale eyes was significant and similar for CMM and BCC (ORadj 2.6). Intermittent sun exposure measured in hours spent at beach during holidays was significant for both CMM (ORadj 2.6 for more than 7000 lifelong hours) and BCC (ORadj 2.1 for more than 7000 lifelong hours), while SCC exhibited a significant risk increase for chronic exposure to sunlight measured in hours of outdoor work (ORadj 2.2 for more than 6000 lifelong hours). In the case–case comparison using a multinomial logistic regression model, we found a statistically significant risk difference for pale eyes, and number of naevi in the CMM group, compared to other skin cancers. For intermittent sun exposure, there was a significant risk difference of BCC when compared to the risk of SCC. Factors influencing risk of SCC are different, with chronic exposure to sun playing a major role in causing this type of carcinoma.

Ambient UV, personal sun exposure and risk of multiple primary melanomas

ObjectiveSun exposure is the main cause of melanoma in populations of European origin. No previous study has examined the effect of sun exposure on risk of multiple primary melanomas compared with people who have one melanoma.MethodsWe identified and enrolled 2,023 people with a first primary melanoma (controls) and 1,125 with multiple primary melanomas (cases) in seven centers in four countries, recorded their residential history to assign ambient UV and interviewed them about their sun exposure.ResultsRisk of multiple primary melanomas increased significantly (P < 0.05) to OR = 2.10 for the highest exposure quarter of ambient UV irradiance at birth and 10 years of age, to OR = 1.38 for lifetime recreational sun exposure, to OR = 1.85 for beach and waterside activities, to OR = 1.57 for vacations in a sunnier climate, to OR = 1.50 for sunburns. Occupational sun exposure did not increase risk (OR = 1.03 for highest exposure). Recreational exposure at any age increased risk and appeared to add to risk from ambient UV in early life.ConclusionsPeople who have had a melanoma can expect to reduce their risk of a further melanoma by reducing recreational sun exposure whatever their age. The same is probably true for a person who has never had a melanoma.

The Prevalence of CDKN2A Germ-Line Mutations and Relative Risk for Cutaneous Malignant Melanoma: An International Population-Based Study

Germ-line mutations of CDKN2A have been identified as strong risk factors for melanoma in studies of multiple-case families. However, an assessment of their relative risk for melanoma in the general population has been difficult because they occur infrequently. We addressed this issue using a novel population-based case-control study design in which “cases” have incident second- or higher-order melanomas [multiple primary melanoma (MPM)] and “controls” have incident first primary melanoma [single primary melanoma (SPM)]. Participants were ascertained from nine geographic regions in Australia, Canada, Italy, and United States. In the 1,189 MPM cases and 2,424 SPM controls who were eligible and available for analysis, the relative risk of a subsequent melanoma among patients with functional mutations who have an existing diagnosis of melanoma, after adjustments for age, sex, center, and known phenotypic risk factors, is estimated to be 4.3 (95% confidence interval, 2.3-7.7). The odds ratio varied significantly depending on the type of mutation involved. The results suggest that the relative risk of mutation carriers in the population may be lower than currently believed and that different mutations on the CDKN2A gene may confer substantially different risks of melanoma. (Cancer Epidemiol Biomarkers Prev 2006;15(8)1520–5)

Parallel risk assessment of melanoma and basal cell carcinoma: skin characteristics and sun exposure.

In this study we compared the strength of the association of constitutional factors and sun exposure with cutaneous malignant melanoma (CMM) and basal cell carcinoma (BCC). We analysed 260 incident cases of CMM, 425 incident cases of BCC and two sets of population controls from previous case-control studies conducted in Turin, Italy. Simultaneous comparison was accomplished by comparing separate simple logistic and polytomous logistic regressions. Tendency to sunburn was shown to be the most important risk indicator for both types of tumours, being associated with a two- to three-fold increase in risk for CMM and a two-fold increase in risk for BCC. Intermittent and intense sun exposure, as during beach holidays, increased the risk of both CMM and BCC, while prolonged exposure to sun, as during outdoor occupations, was not associated with CMM or BCC. The increase in risk during beach holidays occurred mainly during childhood for CMM cases, while for BCC cases it also continued during adulthood. Analysis of the independent effect of risk factors confirmed the role of skin phenotype (eye colour odds ratio [OR] = 1.6, tendency to sunburn OR = 2.1) and intermittent sun exposure (sunburns in childhood OR = 3.8, sun exposure during beach holidays OR = 1.2) in CMM. Risk of CMM showed a significant increase when sun exposure exceeded the threshold of about 3500 h during beach holidays cumulated in a lifetime. In contrast, the role of skin phenotype in BCC is less strong, but cumulated hours of sun exposure during beach holidays in a lifetime showed a constant risk rise with an early plateau at a low exposure level. 1998 Lippincott Williams & Wilkins

Tumor-Infiltrating Lymphocyte Grade in Primary Melanomas Is Independently Associated With Melanoma-Specific Survival in the Population-Based Genes, Environment and Melanoma Study

PURPOSE Although most hospital-based studies suggest more favorable survival with tumor-infiltrating lymphocytes (TILs) present in primary melanomas, it is uncertain whether TILs provide prognostic information beyond existing melanoma staging definitions. We addressed the issue in an international population-based study of patients with single and multiple primary melanomas. PATIENTS AND METHODS On the basis of the Genes, Environment and Melanoma (GEM) study, we conducted follow-up of 2,845 patients diagnosed from 1998 to 2003 with 3,330 invasive primary melanomas centrally reviewed for TIL grade (absent, nonbrisk, or brisk). The odds of TIL grades associated with clinicopathologic features and survival by TIL grade were examined. RESULTS Independent predictors (P < .05) for nonbrisk TIL grade were site, histologic subtype, and Breslow thickness, and for brisk TIL grade, they were age, site, Breslow thickness, and radial growth phase. Nonbrisk and brisk TIL grades were each associated with lower American Joint Committee on Cancer (AJCC) tumor stage compared with TIL absence (P(trend) < .001). Death as a result of melanoma was 30% less with nonbrisk TIL grade (hazard ratio [HR], 0.7; 95% CI, 0.5 to 1.0) and 50% less with brisk TIL grade (HR, 0.5; 95% CI, 0.3 to 0.9) relative to TIL absence, adjusted for age, sex, site, and AJCC tumor stage. CONCLUSION At the population level, higher TIL grade of primary melanoma is associated with a lower risk of death as a result of melanoma independently of tumor characteristics currently used for AJCC tumor stage. We conclude that TIL grade deserves further prospective investigation to determine whether it should be included in future AJCC staging revisions.