Prostatic diseases in the senescence: structural and proliferative features

Senescence is one of the main aetiological factors which are responsible for natural androgen ablation in men and occurrence of prostatic diseases. However, it is unclear how the prostatic lesions are signallised in the prostate. Thus, the aim of this study is to characterise the structural, the ultrastructural and the proliferative aspects of the peripheral prostatic zone in the elderly men with and without diagnoses of prostatic lesions and with potential precursors of prostate cancer. Sixty samples of prostatic tissue, from 60 to 90-year-old patients with and without lesions obtained from autopsied or prostatectomised patients were divided into four groups (15 samples per group): standard group (no lesions), benign prostatic hyper-plasia group, high-grade prostatic intra-epithelial neoplasia group and prostatic carcinoma group. The samples were submitted to morphometrical, structural and ultrastructural analyses in addition to cellular apoptosis and proliferative analyses. The results showed morphological damages in the stroma and cellular organelles involved in the secretory process of the prostate. Moreover, the prostatic lesions in elderly men demonstrated disturbance in the proliferation/apoptosis rate, indicating a prevalence of the proliferative process. Finally, the imbalance in prostatic stroma-epithelium interaction was a harmful feature in the elderly men as a result of structural changes, which are crucial factors for the development and progression of carcinogenesis.     

Environmental Tobacco Smoke Revisited: The Reliability of the Data Used for Risk Assessment

Several epidemiological studies have found a weak, but consistent association between lung cancer in nonsmokers and exposure to environmental tobacco smoke (ETS). In addition, a purported link between such exposure and coronary heart disease (CHD) has been of major concern. Although it is biologically plausible that ETS has a contributory role in the induction of lung cancer in nonsmoking individuals, dose-response extrapolation-supported by the more solid database for active smokers-gives an additional risk for lung cancer risk that is more than one order of magnitude lower than that indicated by major positive epidemiological studies. The discrepancy between available epidemiological data and dosimetric estimates seems, to a major part, to reflect certain systematic biases in the former that are difficult to control by statistical analysis when dealing with risks of such low magnitudes. These include, most importantly, misclassification of smoking status, followed by inappropriate selection of controls, as well as certain confounding factors mainly related to lifestyle, and possibly also hereditary disposition. A significant part of an association between lung cancer and exposure to ETS would disappear, if, on the average, 1 patient out of 20 nonsmoking cases had failed to tell the interviewer that he had, in fact, recently stopped smoking. In the large International Agency for Research on Cancer (IARC) multicenter study even lower misclassification rates would abolish the weak, statistically nonsignificant associations that were found. In the former study an apparent significant protective effect from exposure to ETS in childhood with respect to lung cancer later in life was reported, a most surprising finding. The fact that the mutation spectrum of the p53 tumor suppressor gene in lung tumors of ETS-exposed nonsmokers generally differs from that found in tumors of active smokers lends additional support to the notion that the majority of tumors found in ETS-exposed nonsmokers have nothing to do with tobacco smoke. The one-sided preoccupation with ETS as a causative factor of lung cancer in nonsmokers may seriously hinder the elucidation of the multifactorial etiology of these tumors. Due to the high prevalence of cardiovascular disease in the population, even a modest causal association with ETS would, if valid, constitute a serious public health problem. By pooling data from 20 published studies on ETS and heart disease, some of which reported higher risks than is known to be caused by active smoking, a statistically significant association with spousal smoking is obtained. However, in most of these studies, many of the most common confounding risk factors were ignored and there appears to be insufficient evidence to support an association between exposure to ETS and CHD. Further, it seems highly improbable that exposure to a concentration of tobacco smoke at a level that is generally much less than 1% of that inhaled by a smoker could result in an excess risk for CHD that-as has been claimed-is some 30% to 50% of that found in active smokers. There are certainly valid reasons to limit exposure to ETS as well as to other air pollutants in places such as offices and homes in order to improve indoor air quality. This goal can be achieved, however, without the introduction of an extremist legislation based on a negligible risk of lung cancer as well as an unsupported and highly hypothetical risk for CHD.     

Validation of prognostic indices using the frailty model

A major issue when proposing a new prognostic index is its generalisibility to daily clinical practice. Validation is therefore required. Most validation techniques assess whether “on average” the results obtained by the prognostic index in classifying patients in a new sample of patients are similar to the results obtained in the construction set. We introduce a new important aspect of the generalisibility of a prognostic index: the heterogeneity of the prognostic index risk group hazard ratios over different centers. If substantial variability between centers exists, the prognostic index may have no discriminatory capability in some of the centers. To model such heterogeneity, we use a frailty model including a random center effect and a random prognostic index by center interaction. Statistical inference is based on a Bayesian approach using a Laplacian approximation for the marginal posterior distribution of the variances of the random effects. We investigate different ways to summarize the information available from this marginal posterior distribution. Our approach is applied to a real bladder cancer database for which we demonstrate how to investigate and interpret heterogeneity in prognostic index effect over centers.     

Potency Factors for Risk Assessment at Libby,Montana

We reanalyzed the Libby vermiculite miners’ cohort assembled by Sullivan to estimate potency factors for lung cancer, mesothelioma, nonmalignant respiratory disease (NMRD), and all‐cause mortality associated with exposure to Libby fibers. Our principal statistical tool for analyses of lung cancer, NMRD, and total mortality in the cohort was the time‐dependent proportional hazards model. For mesothelioma, we used an extension of the Peto formula. For a cumulative exposure to Libby fiber of 100 f/mL‐yr, our estimates of relative risk (RR) are as follows: lung cancer, RR = 1.12, 95% confidence interval (CI) =[1.06, 1.17]; NMRD, RR = 1.14, 95% CI =[1.09, 1.18]; total mortality, RR = 1.06, 95% CI =[1.04, 1.08]. These estimates were virtually identical when analyses were restricted to the subcohort of workers who were employed for at least one year. For mesothelioma, our estimate of potency is K_M = 0.5 × 10^?8, 95% CI =[0.3 × 10^?8, 0.8 × 10^?8]. Finally, we estimated the mortality ratios standardized against the U.S. population for lung cancer, NMRD, and total mortality and obtained estimates that were in good agreement with those reported by Sullivan. The estimated potency factors form the basis for a quantitative risk assessment at Libby.     

The Use of Reality Orientation in Adult Foster Care Homes:

The emphasis in recent years on providing long-term care in community-based alternatives to the institutional setting can help to facilitate the development of new and exciting opportunities for enrichment in the lives of individuals whose educational needs often go unmet. Reality orientation has been demonstrated to be an effective approach to the treatment and prevention of loss of memory, confusion, and disorientation among institutionalized adults. However, certain problems can arise that may limit the potential benefits of reality orientation programs in institutions. This paper explores the rationale for considering the use of reality orientation in one alternative living arrangement, the adult foster care home. The personalized, family-like environment of the adult foster care setting might help to minimize or even eliminate many of the problems that detract from reality orientation programs in larger institutions.     

In life and in death: the story of people living with metastatic cancer

ABSTRACT

Advances in the treatment of metastatic cancers such as melanoma enable patients to live for many years. However, melanoma patients are under constant threat of a recurrence or a new growth, are under intensive follow-up, and must avoid exposure to the sun. These factors engender anxiety, a constant fear of recurrence, and a reduction in routine activity, thus requiring patients to develop mechanisms for coping simultaneously with the illness and the threat of death. This study uses content analysis of the documentation of a support group for metastatic melanoma patients to examine how they cope with both. The findings suggest that they are able to cope with both simultaneously. However, perhaps because they recognise their total lack of control over the illness, they exercise control in how they cope with death. The findings suggest that support groups like the one documented in this article could serve as sheltered and effective therapeutic spaces for coping with the threat of death.     

Frequentist and Bayesian approaches for a joint model for prostate cancer risk and longitudinal prostate-specific antigen data

The paper describes the use of frequentist and Bayesian shared-parameter joint models of longitudinal measurements of prostate-specific antigen (PSA) and the risk of prostate cancer (PCa). The motivating dataset corresponds to the screening arm of the Spanish branch of the European Randomized Screening for Prostate Cancer study. The results show that PSA is highly associated with the risk of being diagnosed with PCa and that there is an age-varying effect of PSA on PCa risk. Both the frequentist and Bayesian paradigms produced very close parameter estimates and subsequent 95% confidence and credibility intervals. Dynamic estimations of disease-free probabilities obtained using Bayesian inference highlight the potential of joint models to guide personalized risk-based screening strategies.     

EPA Underestimates,Oversimplifies, Miscommunicates,and Mismanages Cancer Risks by Ignoring Human Susceptibility

If exposed to an identical concentration of a carcinogen, every human being would face a different level of risk, determined by his or her genetic, environmental, medical, and other uniquely individual characteristics. Various lines of evidence indicate that this susceptibility variable is distributed rather broadly in the human population, with perhaps a factor of 25‐ to 50‐fold between the center of this distribution and either of its tails, but cancer risk assessment at the EPA and elsewhere has always treated every (adult) human as identically susceptible. The National Academy of Sciences “Silver Book” concluded that EPA and the other agencies should fundamentally correct their mis‐computation of carcinogenic risk in two ways: (1) adjust individual risk estimates upward to provide information about the upper tail; and (2) adjust population risk estimates upward (by about sevenfold) to correct an underestimation due to a mathematical property of the interindividual distribution of human susceptibility, in which the susceptibility averaged over the entire (right‐skewed) population exceeds the median value for the typical human. In this issue of Risk Analysis, Kenneth Bogen disputes the second adjustment and endorses the first, though he also relegates the problem of underestimated individual risks to the realm of “equity concerns” that he says should have little if any bearing on risk management policy. In this article, I show why the basis for the population risk adjustment that the NAS recommended is correct—that current population cancer risk estimates, whether they are derived from animal bioassays or from human epidemiologic studies, likely provide estimates of the median with respect to human variation, which in turn must be an underestimate of the mean. If cancer risk estimates have larger “conservative” biases embedded in them, a premise I have disputed in many previous writings, such a defect would not excuse ignoring this additional bias in the direction of underestimation. I also demonstrate that sensible, legally appropriate, and ethical risk policy must not only inform the public when the tail of the individual risk distribution extends into the “high‐risk” range, but must alter benefit‐cost balancing to account for the need to try to reduce these tail risks preferentially.     

Prostate-specific antigen decline pattern in advanced prostate cancer receiving androgen deprivation therapy and relationship with prostate-specific antigen progression

Introduction: The aim of this study is to evaluate prostate-specific antigen decline pattern including prostate-specific antigen kinetics following androgen deprivation therapy on prostate-specific antigen progression in the patients with advanced prostate cancer.

Materials and methods: Ninety-seven advanced prostate cancer patients receiving maximum androgen deprivation therapy were enrolled in case–control study. Baseline prostate-specific antigen, Gleason Score, bone metastase, nadir prostate-specific antigen, time to nadir prostate-specific antigen, declining slope to nadir prostate-specific antigen, estimated baseline prostate-specific antigen half-time, current prostate-specific antigen, post-nadir prostate-specific antigen time, estimated prostate-specific antigen, estimated decline of baseline prostate-specific antigen as quantitative, and ratio were recorded and calculated.

Results: The ratio of prostate-specific antigen progression was significantly lower at the patients who had slower declining slope to prostate-specific antigen, longer time to nadir prostate-specific antigen, and lower estimated decline ratio of baseline prostate-specific antigen (p: .016, p: .020, and p: .026, respectively).

Conclusions: The shorter time to nadir prostate-specific antigen following androgen deprivation therapy, faster declining slope to nadir prostate-specific antigen and higher estimated decline ratio of baseline prostate-specific antigen are associated with higher risk of disease progression in patients with hormone-sensitive prostate cancer.