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Men receiving androgen-deprivation therapy for nonmetastatic prostate cancer are at high risk for bone loss and fractures. This placebo-controlled study investigated the effects of denosumab, a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand, on bone mineral density and fractures in such men. Use of denosumab was associated with increased bone mineral density at all sites and reduction in the incidence of new vertebral fractures. This study investigated the effects of denosumab on bone mineral density and fractures in men receiving androgen-deprivation therapy for prostate cancer. Use of denosumab was associated with increased bone mineral density at all sites and reduction in the incidence of new vertebral fractures. Prostate cancer is the most common newly diagnosed cancer in men worldwide. 1 In the United States, prostate cancer accounts for approximately 25% of all new cancer diagnoses and 10% of all deaths from cancer. 2 Androgen-deprivation therapy, through bilateral orchiectomy or treatment with gonadotropin-releasing hormone (GnRH) agonists, is the standard first-line therapy for metastatic prostate cancer. 3 , 4 GnRH agonists are also frequently used to treat men with nonmetastatic prostate cancer. 5 Androgen-deprivation therapy improves disease-free and overall survival in various clinical settings, such as when used as adjuvant treatment in men with locally advanced prostate cancer who are undergoing radiation therapy 6 , . . .

Renal cancer (RC) presents a challenge with increasing incidence and mortality. This study compares RC cancer-specific survival (CSS) and overall survival (OS) based on histological type. This population-based retrospective cohort study covers 1995-2017, utilizing cases from the Finnish Cancer Registry. Comorbidity, procedure and treatment information from 1995-2018 were obtained from the national health care registry, while death data originated from the national death certificate registry. RC cases were categorized by histology to analyze CSS and OS via Fine and Gray's proportional sub-hazards model and Cox regression (adjusting for age, tumor extent, Charlson comorbidity index and treatment). The final cohort included 14,413 patients, predominantly ccRCC (75.5%), followed by papillary RCC (pRCC),5.8% and chromophobe RCC (chRCC) 2.1%. Univariate analysis showed better OS for non-ccRCC patients, with 5-year survival (5ySR) of 72.6% (95% CI 70.3-74.7%), compared to ccRCC (62.7%, 95%CI 61.8-63.5). Among non-ccRCC, the 5ySRs were as follows: pRCC 74.3% (95%CI 71.2-77.2), chRCC 82.2% (95% CI 77.2-86.1), sarcomatoid variants (sarcRC) 29.2% (95% CI 20.6-38.3), and collecting duct carcinoma (CDC) 23.5% (95%CI 7.3-44.9). Non-ccRCC showed improved CSS compared to ccRCC (sHR 0.69, 95% CI 0.60-0.78). Favorable CSS for chRCC (sHR 0.28, 95% CI 0.18-0.43) and pRCC (sHR 0.66, 95% CI 0.56-0.78), while sarcRC (sHR 1.83, 95% CI 1.36-2.46) and CDC (sHR 3.19, 95% CI 2.01-5.08) showed poorer CSS. Overall, non-ccRCC had a better prognosis, driven by pRCC and chRCC, whereas sarcRC and CDC had poor prognoses. CSS has improved over time, with a 62% reduction in death risk since 1995. Our results demonstrate that the histological subtype is a powerful predictor of survival. Histology should be used more in clinical decision-making. Having a histological confirmation would tailor the selection of treatment: surgical management for aggressive and ccRCC and conservative management for less aggressive histological types.

Standard therapy for metastatic, hormone-sensitive prostate cancer is androgen-deprivation therapy, usually with docetaxel. A large, multinational, phase 3 trial assessed the addition of the androgen-receptor blocker darolutamide to standard therapy. At 4 years, survival was higher with darolutamide than with placebo (62.7% vs. 50.4%), with no major differences in the frequency of adverse events.

In this trial, investigators tested the effect of prostate-specific–antigen testing on the death rate from prostate cancer in more than 162,000 men between the ages of 55 and 69 years in seven European countries. A significant reduction in prostate-cancer mortality was found after a median follow-up of 9 years. Overdiagnosis and overtreatment were important limitations of the screening program. Measurement of serum prostate-specific antigen (PSA), a biomarker for prostate cancer, 1 is useful for the detection of early prostate cancer. 2 Nevertheless, the effect of PSA-based screening on prostate-cancer mortality remains unclear. 3 The European Randomized Study of Screening for Prostate Cancer (ERSPC) was initiated in the early 1990s to determine whether a reduction of 25% in prostate-cancer mortality could be achieved by PSA-based screening. 4 Preliminary data from this study have been published and can be accessed at www.erspc.org. Another randomized screening trial in the United States, the Prostate, Lung, Colon, and Ovarian (PLCO) Cancer Screening Trial, was initiated around the same . . .

The aim of this study was to investigate pre- and post-diagnostic use of antihypertensive drugs on prostate cancer (PCa)-specific survival and the initiation of androgen deprivation therapy (ADT). The cohort investigated 8,253 PCa patients with 837 PCa-specific deaths during the median follow-up of 7.6 years after diagnosis. Information on drug use, cancer incidence, clinical features of PCa, and causes of death was collected from Finnish registries. Hazard ratios with 95% confidence intervals were calculated using Cox regression with antihypertensive drug use as a time-dependent variable. Separate analyses were performed on PCa survival related to pre- and post-diagnostic use of drugs and on the initiation of ADT. Antihypertensive drug use overall was associated with an increased risk of PCa-specific death (Pre-PCa: 1.21 (1.04-1.4), Post-PCa: 1.2 (1.02-1.41)). With respect to the separate drug groups, angiotensin II type 1 receptor (ATr) blockers, were associated with improved survival (Post-PCa: 0.81 (0.67-0.99)) and diuretics with an increased risk (Post-PCa: 1.25 (1.05-1.49)). The risk of ADT initiation was slightly higher among antihypertensive drug users as compared to non-users. In conclusion, this study supports anti-cancer effect of ATr blockers on PCa prognosis and this should be investigated further in controlled clinical trials.

Androgen deprivation therapy is the cornerstone treatment of advanced prostate cancer. Eventually prostate cancer cells overcome androgen deprivation therapy, giving rise to castration resistant prostate cancer (CRPC) characterized by increased androgen receptor (AR) activity. Understanding the cellular mechanisms leading to CRPC is needed for development of novel treatments. We used long-term cell cultures to model CRPC; a testosterone-dependent cell line (VCaP-T) and cell line adapted to grow in low testosterone (VCaP-CT). These were used to uncover persistent and adaptive responses to testosterone level. RNA was sequenced to study AR-regulated genes. Expression level changed due to testosterone depletion in 418 genes in VCaP-T (AR-associated genes). To evaluate significance for CRPC growth, we compared which of them were adaptive i.e., restored expression level in VCaP-CT. Adaptive genes were enriched to steroid metabolism, immune response and lipid metabolism. The Cancer Genome Atlas Prostate Adenocarcinoma data were used to assess the association with cancer aggressiveness and progression-free survival. Expressions of 47 AR-associated or association gaining genes were statistically significant markers for progression-free survival. These included genes related to immune response, adhesion and transport. Taken together, we identified and clinically validated multiple genes being linked with progression of prostate cancer and propose several novel risk genes. Possible use as biomarkers or therapeutic targets should be studied further.

Cholesterol-lowering treatment has been suggested to delay progression of prostate cancer by decreasing serum LDL. We studied in vitro the effect of extracellular LDL-cholesterol on the number of prostate epithelial cells and on the expression of key regulators of cholesterol metabolism. Two normal prostatic epithelial cell lines (P96E, P97E), two in vitro immortalized epithelial cell lines (PWR-1E, RWPE-1) and two cancer cell lines (LNCaP and VCaP) were grown in cholesterol-deficient conditions. Cells were treated with 1-50 µg/ml LDL-cholesterol and/or 100 nM simvastatin for seven days. Cell number relative to control was measured with crystal violet staining. Changes in mRNA and protein expression of key effectors in cholesterol metabolism (HMGCR, LDLR, SREBP2 and ABCA1) were measured with RT-PCR and immunoblotting, respectively. LDL increased the relative cell number of prostate cancer cell lines, but reduced the number of normal epithelial cells at high concentrations. Treatment with cholesterol-lowering simvastatin induced up to 90% reduction in relative cell number of normal cell lines but a 15-20% reduction in relative number of cancer cells, an effect accompanied by sharp upregulation of HMGCR and LDLR. These effects were prevented by LDL. Compared to the normal cells, prostate cancer cells showed high expression of cholesterol-producing HMGCR but failed to express the major cholesterol exporter ABCA1. LDL increased relative cell number of cancer cell lines, and these cells were less vulnerable than normal cells to cholesterol-lowering simvastatin treatment. Our study supports the importance of LDL for prostate cancer cells, and suggests that cholesterol metabolism in prostate cancer has been reprogrammed to increased production in order to support rapid cell growth.

[This corrects the article DOI: 10.1371/journal.pone.0329000.].

Purpose We explored renal cell cancer (RCC) survival among users of antihypertensive medication as hypertension is proposed to be a risk factor for RCC and ACE-inhibitors and angiotensin receptor blockers (ARBs) have been associated with improved prognosis of RCC. Methods Finnish cohort of 13,873 participants with RCC diagnosed between 1995–2012 was formed from three national databases. RCC cases were identified from Finnish Cancer Registry, medication usage from national prescription database and co-morbidities from Care Registry of Healthcare. Logistic regression was used to calculate odds ratios for metastatic tumor extent at the time of diagnosis. Risk of RCC specific death after diagnosis was analyzed using Cox regression adjusted for tumor clinical characteristics. Results A total of 5,179 participants died of RCC during the follow-up. No risk association was found for metastatic tumor extent for any drug group. ACE-inhibitors, but no other drug group were associated with decreased risk of RCC specific death overall (HR 0.88, 95% CI 0.82–0.95) compared to non-users. In time-dependent analysis high-dose use of ACE-inhibitors (392 Defined Daily Dose (DDD)/year), HR 0.54, 95% CI 0.45–0.66) and ARBs (786.1 DDD/year, HR 0.66, 95% CI 0.50–0.87) associated with improved RCC survival. No information of TNM-classification or tobacco smoking was available. Conclusion ACE-inhibitors and ARBs in high dose associated with improved RCC specific survival. This may reflect overall benefit of treating hypertension with medication targeting renin-angiotensin system (RAS) system among RCC patients. Further studies are needed to explore the role of RAS in RCC.

PurposeWe assessed the risk of death from prostate cancer (PCa) in relation to men’s screening histories, i.e., screening attendance among men who were offered screening.MethodsMen in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) screening arm were invited to up to three screening rounds with the serum prostate-specific antigen (PSA) test at 4-year intervals during 1996–2007.Case subjects (n = 330) were men who died from PCa. Each case was matched to five controls (n = 1544) among the men who were free of PCa.Screening history was defined as (1) never/ever attended screening prior to the case diagnosis; (2) attended at the first screening round; and (3) recency of screening, calculated as the time from last screening attendance to the date of case diagnosis.The association between screening history and the risk of death from PCa was estimated by odds ratios (OR) with 95% confidence intervals (CI) using conditional logistic regression.ResultsHaving ever attended screening versus never attended was associated with a reduced risk of PCa death (OR 0.60, 95% CI 0.45–0.81) and a similar association was found for those attended (versus not attended) the first screening round (OR 0.67, 95% CI 0.51–0.87).The effect by time since last screen for the risk of PCa death was significantly lower 2–7 years since last screen.ConclusionAmong men invited to screening, subjects who attended any PSA screening during the previous 19 years had a 40% reduction in PCa mortality compared to non-screened men.