Risk factors for prostate cancer : analysis of primary data, pooling, and related methodological aspects

Prostate cancer is the second most common cancer among men worldwide, yet its etiology remains poorly understood. Obesity, on the other hand, is a prevalent but preventable medical condition that is associated with hormonal and metabolic changes. Since prostate cancer is a hormone-related cancer, the hypothesis of a link between body fatness and prostate cancer risk has been formulated. Furthermore, the considerable biologic heterogeneity of prostate cancer warrants analyses to be carried out separately by aggressiveness of the disease, differentiating indolent from potentially lethal tumors. This thesis has two aims. First, to elucidate the association between obesity, as measured by body mass index (BMI), and the risk of localized, advanced, and fatal prostate cancer. This is done using both primary data (Paper I) and aggregated data extracted from published epidemiological studies (Paper IV). Second, to deal with some methodological aspects related to the analysis of primary and aggregated data (Paper II; Paper III; Paper V). In Paper I, we used primary data from the Cohort of Swedish Men to examine the association of BMI during early adulthood (30 years of age) and middle-late adulthood (45–79 years of age) with the incidence of localized and advanced prostate cancer and with prostate cancer mortality. BMI during middle-late adulthood was observed to be inversely associated with the incidence of localized prostate cancer, while it was directly associated with the incidence of advanced prostate cancer and with prostate cancer mortality. At the same time, we observed limited evidence of an inverse association between BMI during early-adulthood and the risk of advanced and fatal prostate cancer. In Paper II, we extended the use of quantile regression for censored data to those situations where the time scale of interest is attained age at the event instead of follow-up time. In particular, we described how to use Laplace regression to model percentiles of age at the event in the presence of delayed entries, by conditioning on age at entry. In Paper III, we identified three major misinterpretations of risk and rate advancement periods (RAP): first, equating RAP with the difference in mean survival times; second, interpreting RAP as the time by which the survival curve for the exposed individuals is shifted compared with that for the unexposed; third, equating the RAP to a simple ratio of two log–relative risks. Furthermore, we showed how RAP estimation is sensitive to the specification of the age-disease association. In Paper IV, we carried out a dose–response meta-analysis to summarize the available evidence on the association between BMI during middle-late adulthood and the incidence of localized and advanced prostate cancer. Based on aggregated data extracted from 13 prospective studies, we observed that BMI was inversely associated with the incidence of localized prostate cancer, while it was directly associated with the incidence of advanced prostate cancer. In Paper V, we stressed the importance of assessing the goodness of fit of dose–response metaanalysis models. We presented and discussed three tools (deviance, coefficient of determination, and decorrelated-residuals–versus–exposure plot) that are useful to test, quantify, and visually display the fit of dose–response meta-analysis models, while taking into account the correlation structure of the study-specific log–relative risks. In conclusion, Paper I and Paper IV supported the hypothesis of etiological heterogeneity of prostate cancer in relation to obesity during middle-late adulthood. In particular, BMI was observed to be directly associated with advanced prostate cancer and with prostate cancer mortality. Paper II extended the use of quantile regression for censored data to those situations where attained age is the time scale of interest, Paper III clarified the appropriate use and interpretation of RAP, and Paper V proposed useful and relevant methods for assessing the goodness of fit of dose–response models in research synthesis

Low TLR7 gene expression in atherosclerotic plaques is associated with major adverse cardio- and cerebrovascular events

AIMS: Processes in the development of atherosclerotic lesions can lead to plaque rupture or erosion, which can in turn elicit myocardial infarction or ischaemic stroke. The aims of this study were to determine whether Toll-like receptor 7 (TLR7) gene expression levels influence patient outcome and to explore the mechanisms linked to TLR7 expression in atherosclerosis. METHODS AND RESULTS: Atherosclerotic plaques were removed by carotid endarterectomy (CEA) and subjected to gene array expression analysis (n = 123). Increased levels of TLR7 transcript in the plaques were associated with better outcome in a follow-up study over a maximum of 8 years. Patients with higher TLR7 transcript levels had a lower risk of experiencing major cardiovascular and cerebrovascular events (MACCE) during the follow-up period after CEA (hazard ratio: 2.38, P = 0.012, 95% CI 1.21–4.67). TLR7 was expressed in all plaques by T cells, macrophages and endothelial cells in capillaries, as shown by immunohistochemistry. In short-term tissue cultures, ex vivo treatment of plaques with the TLR7 ligand imiquimod elicited dose-dependent secretion of IL-10, TNF-α, GM-CSF, and IL-12/IL-23p40. This secretion was blocked with a TLR7 inhibitor. Immunofluorescent tissue analysis after TLR7 stimulation showed IL-10 expression in T cells, macrophages and vascular smooth muscle cells. TLR7 mRNA levels in the plaques were correlated with IL-10 receptor (r = 0.4031, P < 0.0001) and GM-CSF receptor A (r = 0.4354, P < 0.0001) transcripts. CONCLUSION: These findings demonstrate that TLR7 is abundantly expressed in human atherosclerotic plaques. TLR7 ligation elicits the secretion of pro-inflammatory and anti-inflammatory cytokines, and high TLR7 expression in plaques is associated with better patient outcome, suggesting that TLR7 is a potential therapeutic target for prevention of complications of atherosclerosis

Prostate Cancer IRE Study (PRIS): A Randomized Controlled Trial Comparing Focal Therapy to Radical Treatment in Localized Prostate Cancer

The aim of focal treatments (FTs) in prostate cancer (PCa) is to treat lesions while preserving surrounding benign tissue and anatomic structures. Irreversible electroporation (IRE) is a nonthermal technique that uses high-voltage electric pulses to increase membrane permeability and induce membrane disruption in cells, which potentially causes less damage to the surrounding tissue in comparison to other ablative techniques. We summarize the study protocol for the Prostate Cancer IRE Study (PRIS), which involves two parallel randomized controlled trials comparing IRE with (1) robot-assisted radical prostatectomy (RARP) or (2) radiotherapy in men with newly diagnosed intermediate-risk PCa (NCT05513443). To reduce the number of patients for inclusion and the study duration, the primary outcomes are functional outcomes: urinary incontinence in study 1 and irritative urinary symptoms in study 2. Providing evidence of the lower impact of IRE on functional outcomes will lay a foundation for the design of future multicenter studies with an oncological outcome as the primary endpoint. Erectile function, quality of life, treatment failure, adverse events, and cost effectiveness will be evaluated as secondary objectives. Patients diagnosed with Gleason score 3 + 4 or 4 + 3 PCa from a single lesion visible on magnetic resonance imaging (MRI) without any Gleason grade 4 or higher in systematic biopsies outside of the target (unifocal significant disease), aged ≥40 yr, with no established extraprostatic extension on multiparametric MRI, a lesion volume of <1.5 cm3, prostate-specific antigen <20 ng/ml, and stage ≤T2b are eligible for inclusion. The study plan is to recruit 184 men

Instantaneous geometric rates via generalized linear models

The instantaneous geometric rate represents the instantaneous probability of an event of interest per unit of time. In this article, we propose a method to model the effect of covariates on the instantaneous geometric rate with two models: the proportional instantaneous geometric rate model and the proportional instantaneous geometric odds model. We show that these models can be fit within the generalized linear model framework by using two nonstandard link functions that we implement in the user-defined link programs log igr and logit igr. We illustrate how to fit these models and how to interpret the results with an example from a randomized clinical trial on survival in patients with metastatic renal carcinoma

Approximate Bayesian logistic regression via penalized likelihood by data augmentation

We present a command, penlogit, for approximate Bayesian logistic regression using penalized likelihood estimation via data augmentation. This command automatically adds specific prior-data records to a dataset. These records are computed so that they generate a penalty function for the log likelihood of a logistic model, which equals (up to an additive constant) a set of independent log prior distributions on the model parameters. This command overcomes the necessity of relying on specialized software and statistical tools (such as Markov chain Monte Carlo) for fitting Bayesian models, and allows one to assess the information content of a prior in terms of the data that would be required to generate the prior as a likelihood function. The command produces data equivalent to normal and generalized log-F priors for the model parameters, providing flexible translation of background information into prior data, which allows calculation of approximate posterior medians and intervals from ordinary maximum likelihood programs. We illustrate the command through an example using data from an observational study of neonatal mortality

Aging and the Change in Fatigue and Sleep – A Longitudinal Study Across 8 Years in Three Age Groups

Fatigue is prevalent in the population and usually linked to sleep problems, and both are related to age. However, previous studies have been cross-sectional. The purpose of the present study was to investigate the trajectories of sleep and fatigue across 8 years of aging in a large group (N &gt; 8.000) of individuals. A second purpose was to investigate whether fatigue trajectories would differ between age groups, and whether different trajectories of fatigue would be reflected in a corresponding difference in trajectories for sleep variables. Results from mixed model analyses showed that fatigue decreased across 8 years in all age groups, while sleep problems increased, non-restorative sleep decreased, weekend sleep duration decreased, and weekday sleep duration showed different patterns depending on age. Furthermore, the larger the decrease in fatigue, the larger was the increase in sleep duration across years, the lower was the increase of sleep problems, and the larger was the decrease of non-restorative sleep. The results suggest that aging has positive effects on fatigue and sleep and that these changes are linked

Red and processed meat consumption and risk of bladder cancer : a dose-response meta-analysis of epidemiological studies.

BACKGROUND/OBJECTIVES: Several epidemiological studies have analyzed the associations between red and processed meat and bladder cancer risk but the shape and strength of the associations are still unclear. Therefore, we conducted a dose-response meta-analysis to quantify the potential association between red and processed meat and bladder cancer risk. METHODS: Relevant studies were identified by searching the PubMed database through January 2016 and reviewing the reference lists of the retrieved articles. Results were combined using random-effects models. RESULTS: Five cohort studies with 3262 cases and 1,038,787 participants and 8 cases-control studies with 7009 cases and 27,240 participants met the inclusion criteria. Red meat was linearly associated with bladder cancer risk in case-control studies, with a pooled RR of 1.51 (95% confidence interval (CI) 1.13, 2.02) for every 100 g increase per day, while no association was observed among cohort studies (P heterogeneity across study design = 0.02). Based on both case-control and cohort studies, the pooled relative risk (RR) for every 50 g increase of processed meat per day was 1.20 (95% CI 1.06, 1.37) (P heterogeneity across study design = 0.22). CONCLUSIONS: This meta-analysis suggests that processed meat may be positively associated with bladder cancer risk. A positive association between red meat and risk of bladder cancer was observed only in case-control studies, while no association was observe in prospective studies

Overall diet quality and risk of recurrence and progression of non-gallstone-related acute pancreatitis : a prospective cohort study.

PURPOSE: An incident episode of acute pancreatitis is often followed by recurrent attacks and/or progression to chronic pancreatitis, especially if the etiology is non-gallstone-related. We examined whether overall diet quality influences the natural history of non-gallstone-related acute pancreatitis. METHODS: Three hundred and eighty-six individuals (born 1914-1952) were included in a prospective study, all of whom had an incident diagnosis of non-gallstone-related acute pancreatitis in the Swedish National Patient Register between 1998 and 2013. Participants were already enrolled in two population-based cohorts and had completed a food frequency questionnaire in 1997. Overall diet quality was calculated using a recommended food score (RFS), which was based on 25 food items. Post-diagnosis follow-up was conducted throughout 2014 for recurrence of acute pancreatitis and/or progression to chronic pancreatic disease (including cancer). Hazard ratios were estimated using Cox models. RESULTS: During 1859 person-years of follow-up, 23.3% of the study population (n = 90) developed recurrent or progressive pancreatic disease. An inverse association was observed between the RFS and risk of recurrent and progressive pancreatic disease after adjustment for age and sex (hazard ratio for each 2-unit increase 0.90, 95% confidence interval 0.81-1.01) (P overall association = 0.06). However, the association became weaker and was not statistically significant after adjustment for other potential confounders, including alcohol drinking and cigarette smoking (P overall association = 0.27). CONCLUSIONS: In this prospective study of individuals with non-gallstone-related acute pancreatitis, there was no clear association between overall diet quality and risk of recurrent and progressive pancreatic disease