Maura Mezzetti

Biologic and clinicopathologic factors as indicators of specific relapse types in node-negative breast cancer.

PURPOSE AND METHODS We evaluated, in 1,800 patients with node-negative tumors treated with locoregional therapy until relapse, the competitive risks for different types of metastasis by cell proliferation (3H-thymidine labeling index [3H-dT LI]), estrogen receptors (ERs), and progesterone receptors (PgRs), and by the integration of biologic and clinicopathologic information. RESULTS Hormone receptor status and proliferative activity of the primary tumor were not indicative of contralateral failures. Hormone receptors failed to predict the 8-year incidence of locoregional recurrence, but they were significant indicators of distant metastasis and overall survival. The latter finding was confirmed even in multivariate analysis. Conversely, cell proliferation predicted both locoregional and distant metastases and survival, regardless of patient age, tumor size, and ER and PgR status. Recursive partitioning and amalgamation analysis ascribed to cell proliferation an important prognostic role for locoregional recurrence together with patient age and tumor size. CONCLUSION Biologic markers, in particular cell proliferation, provide information for the different types of relapse and could complement the predictive role of pathologic staging.

Inter‐observer variation in histopathological diagnosis and grading of vulvar intraepithelial neoplasia: results of an European collaborative study

Objective To evaluate the inter‐observer variability of vulvar intraepithelial neoplasia diagnosis and grading system.

Alcohol intake and risk of cancers of the colon and rectum

The relationship between alcohol drinking (mainly wine) and risk of colon and rectal cancer was considered in a case-control study conducted between 1991 and 1996 in six Italian centers. Cases were 1,225 patients < 75 years of age with histologically confirmed cancer of the colon and 728 patients with cancer of the rectum; controls were 4,154 patients admitted to hospital for a wide spectrum of acute, nonneoplastic diseases. Compared with never drinkers, the odds ratios (OR) for current drinkers in the higher quintile of total alcohol intake (> 51.82 g ethanol/day) were 1.01 for colon cancer and 0.90 for rectal cancer, and those for ex-drinkers were 1.20 and 1.07, respectively. The OR for wine drinkers in the highest quartile of intake were 1.07 for colon cancer and 0.97 for rectal cancer. No association was found with duration of the habit, time since starting, or age at starting. Among ex-drinkers, no association appeared with time since stopping. No significant heterogeneity was found across strata of age at diagnosis, sex, education, smoking status, physical activity, family history of colorectal cancer, beta-carotene, vitamin C, coffee, total fiber and folate intake, and number of meals per day. No significant association appeared for various intestinal subsites.

Attributable risks for colorectal cancer in northern Italy.

Using data from a case‐control study conducted between 1985 and 1992 in northern Italy on 828 cases of colon cancer, 498 cases of rectal cancer and 2,024 controls in hospital for acute, non‐neoplastic, non‐digestive tract disorders, we estimated the percent population attributable risk (PAR) for colorectal cancer in relation to β‐carotene, vitamin C (as markers of a diet rich in fruit and vegetables), red meat and seasoning fat intake, daily meal frequency and family history of the disease. On the basis of multivariate odds ratios, adjusted for total calorie intake, a low intake of β‐carotene accounted for 39% of all the cases and a low intake of vitamin C for 14%. These two micronutrients together explained 43% of all colorectal cancer cases in this population. A high frequency of intake of red meat consumption explained 17% of all cases, and a high score of seasoning fats 4%. A higher daily meal frequency was responsable for 13% of the cases, and these 5 dietary factors together explained 63% of colorectal cancer cases in this population. Family history of colorectal cancer accounted for 4% of all cases. These estimates were similar for colon and rectal cancers separately, in males and females, and in younger and elderly subjects, except for seasoning fats and family history, whose PARs were apparently greater for colon cancer and at younger age. Thus, even though available dietary data were limited in several aspects, and the PAR estimates were based on somewhat arbitrary assumptions regarding the exposure distribution, about two‐thirds of all colorectal cancers in this population could be explained in terms of a few risk factors or risk indicators considered. This would correspond to the avoidance of a large proportion of the over 18,000 deaths from colorectal cancer registered per year in the whole of Italy.

Fibers and breast cancer risk.

Data from a multicenter case-control study on breast cancer conducted in Italy were used to analyze the relationship between various types of fibers and breast cancer risk. Cases were 2,569 women with histologically confirmed, incident breast cancer; controls were 2,588 women admitted to the same network of hospitals for acute, nonneoplastic, non-hormone-related diseases. Cases and controls were interviewed between 1991 and 1994 using a validated food frequency questionnaire. The data were modeled through multiple logistic regression, controlling for demographic and reproductive breast cancer risk factors. The continuous odds ratios for the difference between the upper cut point of the fourth and the first quintile of intake were 0.90 [95% confidence interval = 0.82-0.98, p (for trend) < 0.05] for cellulose and 0.94 (95% confidence interval = 0.86-1.02) for soluble fibers. The protection tended to be stronger in premenopausal women. No material association was found for noncellulose polysaccharides and lignin. This study, based on a large data set from various Italian regions, suggests that fiber intake may confer some protection against breast cancer, particularly for cellulose and also for soluble fibers, i.e., those of vegetable origin. This possible protection has been related to an influence of fibers on levels and availability of estrogens and other steroid hormones in breast carcinogenesis.

Time course of fenretinide-induced modulation of circulating insulin-like growth factor (IGF)-I, IGF-II and IGFBP-3 in a bladder cancer chemoprevention trial

The insulin‐like growth factor (IGF) system is widely involved in human carcinogenesis. A significant association between high circulating IGF‐I concentrations and an increased risk of lung, colon, prostate and pre‐menopausal breast cancer has recently been reported. Lowering plasma IGF‐I may thus represent an attractive strategy to be pursued for chemopreventive purposes. We have previously shown that the synthetic retinoid fenretinide (4‐HPR) lowers plasma IGF‐I in pre‐menopausal breast cancer patients. We investigated the effect of fenretinide on circulating IGF‐I, IGF‐II and IGFBP‐3 measured at yearly intervals during the 2‐year treatment period and one year after treatment discontinuation in a predominantly male population of patients with superficial bladder cancer. Repeated measures analysis, after adjustment for age, body mass index (BMI) and year of study, showed a significant effect of fenretinide on IGF‐I levels, which were further lowered after the second year of treatment and only partially recovered after drug discontinuation. Differently from breast cancer patients, the effect of fenretinide was not modified by age. No significant effect was evident on IGFBP‐3, IGF‐II and the IGF‐I+IGF‐II/IGFBP‐3 molar ratio, expressing the tissue availability of the mitogenic peptides, although IGF‐II and the molar ratio were lowered by treatment by an overall mean of 16% and 15%, respectively. Given the increasingly recognized importance of circulating IGFs in the pathogenesis of different solid tumors, our findings strengthen the rationale for studying fenretinide as a chemopreventive agent. Int. J. Cancer 87:601–605, 2000.

Nonparametric estimation of survival functions by means of partial exchangeability structures

In the causal analysis of survival data a time-based response is related to a set of explanatory variables. However, selection and proper design of the latter may become a difficult task, particularly in the preliminary stage, when the information is limited. We propose an alternative nonparametric approach to estimate the survival function which allows one to evaluate the relative importance of each potential explanatory variable, in a simple and exploratory fashion. To achieve this aim, each of the explanatory variables is used to partition the observed survival times. The observations are assumed to be partially exchangeable according to such partition. We then consider, conditionally on each partition, a hierarchical nonparametric Bayesian model on the hazard functions. In order to measure the importance of each explanatory variable, we derive the posterior probability of the corresponding partition. Such probabilities are then employed to estimate the hazard functions by averaging the estimated conditional hazard over the set of all entertained partitions.

A hierarchical Bayesian approach to age‐specific back‐calculation of cancer incidence rates

We propose a Bayesian hierarchical model to estimate age-specific cancer incidence per year from age-specific cancer mortality. The model is based upon the empirical Bayesian approach of Liao and Brookmeyer (1995) and extends that model by consideration of the dependence on age. The incident cases per year are considered as observations from a discrete-time stochastic process following an autoregressive structure within a Poisson regression model. The model assumes that the survival probability among those with cancer is known. We have investigated the sensitivity of the model to the choice of this distribution and have found that this is the most sensitive part of the model. By comparison the predictions of the model are relatively robust to changes in other key areas, such as the number of years an incident case contributes before death, assumptions about parameter equality for identification and the initial prior distributions. The proposed methodology has been investigated using lung cancer mortality data from Scotland. Parameter estimates were obtained through Markov chain Monte Carlo methods, implemented using BUGS.

Estimating cancer incidence using a Bayesian back-calculation approach

We propose a Bayesian hierarchical model for the calculation of incidence counts from mortality data by a convolution equation that expresses mortality through its relationship with incidence and the survival probability density. The basic idea is to use mortality data together with an estimate of the survival distribution from cancer incidence to cancer mortality to reconstruct the numbers of individuals who constitute previously incident cases that give rise to the observed pattern of cancer mortality. This model is novel because it takes into account the uncertainty from the survival distribution; thus, a Bayesian-mixture cure model for survival is introduced. Furthermore, projections are obtained starting from a Bayesian age-period-cohort model. The main advantage of the proposed approach is its consideration of the three components of the model: the convolution equation, the survival mixture cure model and the age-period-cohort projection within a directed acyclic graph model. Furthermore, the estimation are obtained through the Gibbs sampler. We applied the model to cases of women with stomach cancer using six age classes [15-45], [45-55], [55-65], [65-75], [75-85] and [85-95] and validated it by using data from the Tuscany Cancer Registry. The model proposed and the program implemented are convenient because they allow different cancer disease to be analysed because the survival time is modelled by flexible distributions that are able to describe different trends.