Objective
To review and quantify the association between endogenous and exogenous testosterone and prostate‐specific antigen (PSA) and prostate cancer.
Methods
Literature searches were performed ...according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. Prospective cohort studies that reported data on the associations between endogenous testosterone and prostate cancer, and placebo‐controlled randomized trials of testosterone replacement therapy (TRT) that reported data on PSA and/or prostate cancer cases were retained. Meta‐analyses were performed using random‐effects models, with tests for publication bias and heterogeneity.
Results
Twenty estimates were included in a meta‐analysis, which produced a summary relative risk (SRR) of prostate cancer for an increase of 5 nmol/L of testosterone of 0.99 (95% confidence interval CI 0.96, 1.02) without heterogeneity (I² = 0%). Based on 26 trials, the overall difference in PSA levels after onset of use of TRT was 0.10 ng/mL (−0.28, 0.48). Results were similar when conducting heterogeneity analyses by mode of administration, region, age at baseline, baseline testosterone, trial duration, type of patients and type of TRT. The SRR of prostate cancer as an adverse effect from 11 TRT trials was 0.87 (95% CI 0.30; 2.50). Results were consistent across studies.
Conclusions
Prostate cancer appears to be unrelated to endogenous testosterone levels. TRT for symptomatic hypogonadism does not appear to increase PSA levels nor the risk of prostate cancer development. The current data are reassuring, although some caution is essential until multiple studies with longer follow‐up are available.
Summary Background Russian adults have extraordinarily high rates of premature death. Retrospective enquiries to the families of about 50 000 deceased Russians had found excess vodka use among those ...dying from external causes (accident, suicide, violence) and eight particular disease groupings. We now seek prospective evidence of these associations. Methods In three Russian cities (Barnaul, Byisk, and Tomsk), we interviewed 200 000 adults during 1999–2008 (with 12 000 re-interviewed some years later) and followed them until 2010 for cause-specific mortality. In 151 000 with no previous disease and some follow-up at ages 35–74 years, Poisson regression (adjusted for age at risk, amount smoked, education, and city) was used to calculate the relative risks associating vodka consumption with mortality. We have combined these relative risks with age-specific death rates to get 20-year absolute risks. Findings Among 57 361 male smokers with no previous disease, the estimated 20-year risks of death at ages 35–54 years were 16% (95% CI 15–17) for those who reported consuming less than a bottle of vodka per week at baseline, 20% (18–22) for those consuming 1–2·9 bottles per week, and 35% (31–39) for those consuming three or more bottles per week; trend p<0·0001. The corresponding risks of death at ages 55–74 years were 50% (48–52) for those who reported consuming less than a bottle of vodka per week at baseline, 54% (51–57) for those consuming 1–2·9 bottles per week, and 64% (59–69) for those consuming three or more bottles per week; trend p<0·0001. In both age ranges most of the excess mortality in heavier drinkers was from external causes or the eight disease groupings strongly associated with alcohol in the retrospective enquiries. Self-reported drinking fluctuated; of the men who reported drinking three or more bottles of vodka per week who were reinterviewed a few years later, about half (185 of 321) then reported drinking less than one bottle per week. Such fluctuations must have substantially attenuated the apparent hazards of heavy drinking in this study, yet self-reported vodka use at baseline still strongly predicted risk. Among male non-smokers and among females, self-reported heavy drinking was uncommon, but seemed to involve similar absolute excess risks. Interpretation This large prospective study strongly reinforces other evidence that vodka is a major cause of the high risk of premature death in Russian adults. Funding UK Medical Research Council, British Heart Foundation, Cancer Research UK, European Union, WHO International Agency for Research on Cancer.
Summary Background Alcohol is an important determinant of the high and fluctuating adult mortality rates in Russia, but cause-specific detail is lacking. Our case–control study investigated the ...effects of alcohol consumption on male and female cause-specific mortality. Methods In three Russian industrial cities with typical 1990s mortality patterns (Tomsk, Barnaul, Biysk), the addresses of 60 416 residents who had died at ages 15–74 years in 1990–2001 were visited in 2001–05. Family members were present for 50 066 decedents; for 48 557 (97%), the family gave proxy information on the decedents' past alcohol use and on potentially confounding factors. Cases (n=43 082) were those certified as dying from causes we judged beforehand might be substantially affected by alcohol or tobacco; controls were the other 5475 decedents. Case versus control relative risks (RRs; calculated as odds ratios by confounder-adjusted logistic regression) were calculated in ever-drinkers, defining the reference category by two criteria: usual weekly consumption always less than 0·5 half-litre bottles of vodka (or equivalent in total alcohol content) and maximum consumption of spirits in 1 day always less than 0·5 half-litre bottles. Other ever-drinkers were classified by usual weekly consumption into three categories: less than one, one to less than three, and three or more (mean 5·4 SD 1·4) bottles of vodka or equivalent. Findings In men, the three causes accounting for the most alcohol-associated deaths were accidents and violence (RR 5·94, 95% CI 5·35–6·59, in the highest consumption category), alcohol poisoning (21·68, 17·94–26·20), and acute ischaemic heart disease other than myocardial infarction (3·04, 2·73–3·39), which includes some misclassified alcohol poisoning. There were significant excesses of upper aerodigestive tract cancer (3·48, 2·84–4·27) and liver cancer (2·11, 1·64–2·70). Another five disease groups had RRs of more than 3·00 in the highest alcohol category: tuberculosis (4·14, 3·44–4·98), pneumonia (3·29, 2·83–3·83), liver disease (6·21, 5·16–7·47), pancreatic disease (6·69, 4·98–9·00), and ill-specified conditions (7·74, 6·48–9·25). Although drinking was less common in women, the RRs associated with it were generally more extreme. After correction for reporting errors, alcohol-associated excesses accounted for 52% of all study deaths at ages 15–54 years (men 8182 59% of 13968, women 1565 33% of 4751) and 18% of those at 55–74 years (men 3944 22% of 17 536, women 1493 12% of 12 302). Allowance for under-representation of extreme drinkers would further increase alcohol-associated proportions. Large fluctuations in mortality from these ten strongly alcohol-associated causes were the main determinants of recent fluctuations in overall mortality in the study region and in Russia as a whole. Interpretation Alcohol-attributable mortality varies by year; in several recent years, alcohol was a cause of more than half of all Russian deaths at ages 15–54 years. Alcohol accounts for most of the large fluctuations in Russian mortality, and alcohol and tobacco account for the large difference in adult mortality between Russia and western Europe. Funding UK Medical Research Council, Cancer Research UK, British Heart Foundation, International Agency for Research on Cancer, and European Commission Directorate-General for Research.
Detection of lung cancer at an early stage by sensitive screening tests could be an important strategy to improving prognosis. Our objective was to identify a panel of circulating microRNAs in plasma ...that will contribute to early detection of lung cancer.
Plasma samples from 100 early stage (I to IIIA) non-small-cell lung cancer (NSCLC) patients and 100 non-cancer controls were screened for 754 circulating microRNAs via qRT-PCR, using TaqMan MicroRNA Arrays. Logistic regression with a lasso penalty was used to select a panel of microRNAs that discriminate between cases and controls. Internal validation of model discrimination was conducted by calculating the bootstrap optimism-corrected AUC for the selected model.
We identified a panel of 24 microRNAs with optimum classification performance. The combination of these 24 microRNAs alone could discriminate lung cancer cases from non-cancer controls with an AUC of 0.92 (95% CI: 0.87-0.95). This classification improved to an AUC of 0.94 (95% CI: 0.90-0.97) following addition of sex, age and smoking status to the model. Internal validation of the model suggests that the discriminatory power of the panel will be high when applied to independent samples with a corrected AUC of 0.78 for the 24-miRNA panel alone.
Our 24-microRNA predictor improves lung cancer prediction beyond that of known risk factors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Cervical cancer incidence remains high in several Baltic, central, and eastern European (BCEE) countries, mainly as a result of a historical absence of effective screening ...programmes. As a catalyst for action, we aimed to estimate the number of women who could be spared from cervical cancer across six countries in the region during the next 25 years, if effective screening interventions were introduced. Methods In this population-based study, we applied age–period–cohort models with spline functions within a Bayesian framework to incidence data from six BCEE countries (Estonia, Latvia, Lithuania, Belarus, Bulgaria, and Russia) to develop projections of the future number of new cases of cervical cancer from 2017 to 2040 based on two future scenarios: continued absence of screening (scenario A) versus the introduction of effective screening from 2017 onwards (scenario B). The timespan of available data varied from 16 years in Bulgaria to 40 years in Estonia. Projected rates up to 2040 were obtained in scenario A by extrapolating cohort-specific trends, a marker of changing risk of human papillomavirus (HPV) infection, assuming a continued absence of effective screening in future years. Scenario B added the effect of gradual introduction of screening in each country, under the assumption period effects would be equivalent to the decreasing trend by calendar year seen in Denmark (our comparator country) since the progressive regional introduction of screening from the late 1960s. Findings According to scenario A, projected incidence rates will continue to increase substantially in many BCEE countries. Very high age-standardised rates of cervical cancer are predicted in Lithuania, Latvia, Belarus, and Estonia (up to 88 cases per 100 000). According to scenario B, the beneficial effects of effective screening will increase progressively over time, leading to a 50–60% reduction of the projected incidence rates by around 2040, resulting in the prevention of cervical cancer in 1500 women in Estonia and more than 150 000 women in Russia. The immediate launch of effective screening programmes could prevent almost 180 000 new cervical cancer diagnoses in a 25-year period in the six BCEE countries studied. Interpretation Based on our findings, there is a clear need to begin cervical screening in these six countries as soon as possible to reduce the high and increasing incidence of cervical cancer over the next decades. Funding None.
TP53 mutations are common in lung cancers of smokers, with high prevalence of G:C-to-T:A transversions generally interpreted as mutagen fingerprints of tobacco smoke. In this study, TP53 (exons 5-9) ...and KRAS (codon 12) were analyzed in primary lung tumors of never (n = 40), former (n = 27), and current smokers (n = 64; mainly heavy smokers). Expression of p53, cyclooxygenase-2 (Cox-2), and nitrotyrosine (N-Tyr), a marker of protein damage by nitric oxide, were analyzed by immunohistochemistry. TP53 mutations were detected in 47.5% never, 55.6% former, and 77.4% current smokers. The relative risk for mutation increased with tobacco consumption (P(linear trend) < 0.0001). G:C-to-T:A transversions (P = 0.06, current versus never smokers) and A:T-to-G:C transitions (P = 0.03, former versus never smokers) were consistently associated with smoking. In contrast, G:C-to-A:T transitions were associated with never smoking (P = 0.02). About half of mutations in current smokers fell within a particular domain of p53 protein, suggesting a common structural effect. KRAS mutations, detected in 20 of 131 (15.3%) cases, were rare in squamous cell carcinoma compared with adenocarcinoma relative risk (RR), 0.2; 95% confidence interval (95% CI), 0.07-1 and were more frequent in former smokers than in other categories. No significant differences in Cox-2 expression were found between ever and never smokers. However, high levels of N-Tyr were more common in never than ever smokers (RR, 10; 95% CI, 1.6-50). These results support the notion that lung tumorigenesis proceeds through different molecular mechanisms according to smoking status. In never smokers, accumulation of N-Tyr suggests an etiology involving severe inflammation.
Purpose: To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau ( VHL ) gene in the cancer genome, unique to clear cell renal cancer ...(ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics.
Experimental Design: As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination
of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter.
Results: We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs
exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed
that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and
self-reported family history of RCC.
Conclusion: Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically
confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic,
prognostic, and translational studies.
Although physical activity (PA) has been recognized as a favourable factor in the prevention of various diseases, including certain forms of cancer, the relationship between PA and gastric cancer ...(GC) is not yet fully understood. This study aims to provide data from a pooled analysis of case-control studies within the Stomach cancer Pooling (StoP) Project to estimate the association between leisure-time PA and the occurrence of GC.
Six case-control studies from StoP project collected data on leisure-time PA, for a total of 2,343 cases and 8,614 controls. Subjects were classified into three leisure-time PA categories, either none/low, intermediate or high, based on study-specific tertiles. We used a two-stage approach. Firstly, we applied multivariable logistic regression models to obtain study-specific odds ratios (ORs) and corresponding 95% confidence intervals (CIs) then, we used a random-effect models to obtain pooled effect estimates. We performed stratified analyses according to demographic, lifestyle and clinical covariates.
The meta-analysis showed ORs of GC with no significant differences between intermediate vs low and high vs low PA level (OR 1.05 95%CI 0.76-1.45; OR 1.23 95%CI 0.78-1.94, respectively). GC risk estimates did not strongly differ across strata of selected covariates except for age ≤ 55 years old (high vs low level: OR 0.72 95%CI 0.55-0.94) and for control population-based studies (high vs low level: OR 0.79 95%CI 0.68-0.93).
No association was found between leisure time PA and GC, apart from a slight suggestion of decreased risk below age 55 and in control population-based studies. These results may reflect specific characteristics of GC at a younger age, or the presence of a cohort effect mediating and interacting with socioeconomic determinants of GC The different distribution of PA levels among hospitalized controls could have led to an underestimated effect of PA on GC risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent studies support an important role for human papillomavirus (HPV) in a subgroup of head and neck squamous cell carcinomas (HNSCC). We have evaluated the HPV deoxyribonucleic acid (DNA) ...prevalence as well as the association between serological response to HPV infection and HNSCC in two distinct populations from Central Europe (CE) and Latin America (LA).
Cases (n = 2214) and controls (n = 3319) were recruited from 1998 to 2003, using a similar protocol including questionnaire and blood sample collection. Tumour DNA from 196 fresh tissue biopsies was analysed for multiple HPV types followed by an HPV type-specific polymerase chain reaction (PCR) protocol towards the E7 gene from HPV 16. Using multiplex serology, serum samples were analysed for antibodies to 17 HPV types. Statistical analysis included the estimation of adjusted odds ratios (ORs) and the respective 95% confidence intervals (CIs).
HPV16 E7 DNA prevalence among cases was 3.1% (6/196), including 4.4% in the oropharynx (3/68), 3.8% in the hypopharynx/larynx (3/78) and 0% among 50 cases of oral cavity carcinomas. Positivity for both HPV16 E6 and E7 antibodies was associated with a very high risk of oropharyngeal cancer (OR = 179, 95% CI 35.8-899) and hypopharyngeal/laryngeal cancer (OR = 14.9, 95% CI 2.92-76.1).
A very low prevalence of HPV DNA and serum antibodies was observed among cases in both CE and LA. The proportion of head and neck cancer caused by HPV may vary substantially between different geographical regions and studies that are designed to evaluate the impact of HPV vaccination on HNSCC need to consider this heterogeneity.
Renal tumor heterogeneity studies have utilized the von Hippel-Lindau VHL gene to classify disease into molecularly defined subtypes to examine associations with etiologic risk factors and prognosis. ...The aim of this study was to provide a comprehensive analysis of VHL inactivation in clear cell renal tumors (ccRCC) and to evaluate relationships between VHL inactivation subgroups with renal cancer risk factors and VHL germline single nucleotide polymorphisms (SNPs). VHL genetic and epigenetic inactivation was examined among 507 sporadic RCC/470 ccRCC cases using endonuclease scanning and using bisulfite treatment and Sanger sequencing across 11 CpG sites within the VHL promoter. Case-only multivariate analyses were conducted to identify associations between alteration subtypes and risk factors. VHL inactivation, either through sequence alterations or promoter methylation in tumor DNA, was observed among 86.6% of ccRCC cases. Germline VHL SNPs and a haplotype were associated with promoter hypermethylation in tumor tissue (OR = 6.10; 95% CI: 2.28-16.35, p = 3.76E-4, p-global = 8E-5). Risk of having genetic VHL inactivation was inversely associated with smoking due to a higher proportion of wild-type ccRCC tumors former: OR = 0.70 (0.20-1.31) and current: OR = 0.56 (0.32-0.99); P-trend = 0.04. Alteration prevalence did not differ by histopathologic characteristics or occupational exposure to trichloroethylene. ccRCC cases with particular VHL germline polymorphisms were more likely to have VHL inactivation through promoter hypermethylation than through sequence alterations in tumor DNA, suggesting that the presence of these SNPs may represent an example of facilitated epigenetic variation (an inherited propensity towards epigenetic variation) in renal tissue. A proportion of tumors from current smokers lacked VHL alterations and may represent a biologically distinct clinical entity from inactivated cases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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