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ObjectiveTo study short-term (<90 days) morbidity and mortality following radical cystectomy (RC) for bladder cancer and identify modifiable risk factors associated with these.DesignSystematic review.MethodsThe systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed and EMBASE were searched for relevant papers on 11 June 2019 and rerun on 27 May 2020. Studies reporting complications, reoperations, length of stay and mortality within 90 days were included. Studies were reviewed according to criteria from the Oxford Centre for Evidence-Based Medicine and the quality of evidence was assessed using the Newcastle–Ottawa Scale.ResultsThe search retrieved 1957 articles. Sixty-six articles were included. The quality of evidence was poor to good. Most studies were retrospective, and no randomised clinical trials were identified. Of included studies a median of 6 Martin criteria for reporting complications after surgery were fulfilled. The Clavien-Dindo classification for grading complications was most frequently used. The weighted overall complication rate after RC was 34.9% (range 28.8–68.8) for in-house complications, 39.0% (range 27.3–80.0) for 30-day complications and 58.5% (range 36.1–80.5) for 90-day complications. The most common types of complications reported were gastrointestinal (29.0%) and infectious (26.4%). The weighted mortality rate was 2.4% (range 0.9–4.7) for in-house mortality, 2.1% (0.0–3.7) for 30-day mortality and 4.7% (range 0.0–7.0) for 90-day mortality. Age and comorbidity were identified as the best predictors for complications following RC.ConclusionShort-term morbidity and mortality are high following RC. Reporting of complications is heterogeneous and the quality of evidence is generally low. There is a continuous need for randomised studies to address any intervention that can reduce morbidity and mortality following RC.PROSPERO registration number104937.

Physical exercise has been shown to be effective in relation to fatigue, aerobic fitness, and lower body strength in men with prostate cancer. However, research into the clinically relevant effects of interventions conducted in heterogeneous patient populations and in real-life clinical practice settings is warranted. We conducted a pragmatic, multicentre, parallel randomised controlled trial in 5 Danish urological departments. Recruitment began in May 2015, the first participant was randomised in June 2015, and the last participant was included in February 2017. In total, 214 men with prostate cancer were randomly assigned to either 6 months of free-of-charge football training twice weekly at a local club (football group [FG]) (n = 109) or usual care (usual care group [UG]) (n = 105), including brief information on physical activity recommendations at randomisation. Participants were on average 68.4 (SD 6.2) years old, 157 (73%) were retired, 87 (41%) were on castration-based treatment, 19 (9%) had received chemotherapy, and 41 (19%) had skeletal metastases at baseline. In this 1-year follow-up study, we evaluated the effects of community-based football training on the following outcomes: primary outcome, quality of life; secondary outcomes: continuation of football after 6 months, hip and lumbar spine bone mineral density (BMD), mental health score, fat and lean body mass, and safety outcomes, i.e., fractures, falls, and hospital admissions. Intention to treat (ITT) and per protocol (PP) analyses were conducted. No statistically significant between-group difference was observed in change in prostate-cancer-specific quality of life (ITT: 1.9 points [95% CI -1.9 to 5.8], p = 0.325; PP: 3.6 points [95% CI -0.9 to 8.2], p = 0.119). A statistically significant between-group difference was observed in change in total hip BMD, in favour of FG (0.007 g/cm2 [95% CI 0.004 to 0.013], p = 0.037). No differences were observed in change in lumbar spine BMD or lean body mass. Among patients allocated to football, 59% chose to continue playing football after the end of the 6-month intervention period. At 1-year follow-up in the PP population, FG participants had more improvement on the Mental Component Summary (2.9 [95% CI 0.0 to 5.7], p = 0.048 points higher) than UG participants, as well as a greater loss of fat mass (-0.9 kg [95% CI -1.7 to -0.1], p = 0.029). There were no differences between groups in relation to fractures or falls. Hospital admissions were more frequent in UG compared to FG (33 versus 20; the odds ratio based on PP analysis was 0.34 for FG compared to UG). There were 3 deaths in FG and 4 in UG. Main limitations of the study were the physically active control group and assessment of physical activity by means of self-report. In this trial, participants allocated to football appeared to have improved hip BMD and fewer hospital admissions. Men who played football more than once a week for 1 year lost fat mass and reported improved mental health. Community-based football proved to be acceptable, even when club membership was not subsidised. ClinicalTrials.gov NCT02430792.

Exercise training reduces tumour growth by increasing tumour‐infiltrating T‐cell density in preclinical models. However, it remains unknown whether exercise training can modify intratumoural T cells in humans.The aim of this study was to compare the effects of an exercise training intervention versus control on human prostate intratumoural T‐cell density.This study is a secondary analysis of a randomized controlled trial. We randomly allocated men (age > 18 years) with treatment‐naive localized prostate cancer scheduled for radical prostatectomy 2:1 to exercise training intervention or control. The exercise intervention consisted of supervised, high‐intensity interval bicycling four times per week from the time of randomization until prostatectomy. Intratumoural CD3+ and CD8+ T‐cell densities in diagnostic biopsies and postsurgical prostatectomy specimens were quantified using immunohistochemistry. Between‐group differences in changes from baseline to follow‐up were estimated using constrained baseline linear mixed‐effect models.A total of 30 participants were included (exercise intervention, n = 20; control, n = 10). We found no between‐group differences in changes in CD3+ T cells [mean difference (95% confidence interval): −17 (−185; 150) cells/mm2] or CD8+ T cells [mean difference (95% confidence interval): −16 (−206; 172) cells/mm2]. Additionally, we found no statistically significant correlations between changes in T‐cell density and the number of exercise training sessions attended or changes in maximal oxygen consumption.In this secondary analysis of a randomized controlled trial, we found no impact of the exercise regimen on tumour‐infiltrating CD3+ and CD8+ T‐cell density in human prostate cancer. What is the central question of this study? Does exercise training increase human prostate intratumoural T‐cell density? What is the main finding and its importance? In this randomized controlled trial, we found no impact of the exercise training regimen on CD3+ and CD8+ T‐cell density. Although this suggests that exercise training might not modify intratumoural T‐cell composition in prostate cancer, important methodological challenges might limit the interpretation of our data. More studies are needed to evaluate the capacity of exercise training to modify human intratumoural immune cell composition.

The risk of missing prostate cancer in the transrectal ultrasound-guided systematic biopsies of the prostate in men with suspected prostate cancer is a key problem in urological oncology. Repeat biopsy or MRI-guided biopsies have been suggested to increase sensitivity for diagnosis of prostate cancer, but the risk of disease-specific mortality in men who present with raised prostate-specific antigen (PSA) concentration and a benign initial biopsy result remains unknown. We investigated the risk of overall and prostate cancer-specific mortality in men with a benign initial biopsy set. Data were extracted from the Danish Prostate Cancer Registry—a population-based registry including all men undergoing histopathological assessment of prostate tissue. All men who were referred for transrectal ultrasound-guided biopsy for assessment of suspected prostate cancer between Jan 1, 1995, and Dec 31, 2011, in Denmark were eligible for inclusion. Follow-up data were obtained on April 28, 2015. The primary endpoint was the cumulative incidence of prostate cancer-specific mortality, analysed in a competing risk setting, with death from other causes as the competing event. Between Jan 1, 1995, and Dec 31, 2011, 64 430 men were referred for transrectal ultrasound-guided biopsy, of whom 63 454 were eligible for inclusion. Median follow-up was 5·9 years (IQR 3·8–8·5) and the total follow-up time, from the enrolment of the first patient on Jan 1, 1995, until the extraction of causes of death on April 28, 2015, was 20 years. 10 407 (30%) of 35 159 men with malignant initial biopsy sets died from prostate cancer, compared with 541 (2%) of 27 181 men with benign initial biopsy sets. Estimated overall 20-year mortality was 76·1% (95% CI 73·0–79·2). In all men referred for transrectal ultrasound-guided biopsy, the cumulative incidence of prostate cancer-specific mortality after 20 years was 25·6% (24·7–26·5) versus 50·5% (47·5–53·5) for mortality from other causes. In men with benign initial biopsy sets, the cumulative incidence of prostate cancer-specific mortality was 5·2% (3·9–6·5) versus 59·9% (55·2–64·6) for mortality from other causes. In men with PSA concentrations 10 μg/L or lower and benign initial biopsy sets (2779 men), the cumulative incidence of prostate cancer-specific mortality was 0·7% (0·2–1·3). Cumulative incidence of prostate cancer specific mortality in men with benign initial biopsy sets was 3·6% (95% CI 0·1–7·2) for men with a PSA higher than 10 ng/mL but 20 ng/mL or less (855 men) and 17·6% (12·7–22·4) and for men with a PSA higher than 20 ng/mL (454 men). The first systematic transrectal ultrasound-guided biopsy set holds important prognostic information. The 20-year risk of prostate cancer-specific mortality in men with benign initial results is low. Our findings question whether men with low PSA concentration and a benign initial biopsy set should undergo further diagnostic assessment in view of the high risk of mortality from other causes. Capital Region of Denmark's Fund for Health Research, Danish Cancer Society, Danish Association for Cancer Research, and Krista and Viggo Petersen's Foundation.

Background and purpose: Radical prostatectomy can cause erectile dysfunction; however, subsequent treatment with, e.g., phosphodiesterase-5 inhibitors may improve sexual function in the patients. We aim to examine prescriptions for erectile dysfunction after radical prostatectomy and to identify factors that may affect the prescription rate. Patients and methods: A study based on men included in the Danish Prostate Registry (DanProst) in 1995-2021, and information on prescriptions for erectile dysfunction (ATC: GO4BE) from the Danish Prescription Registry. We calculated the proportion of prescriptions per month from 1 year before to 2 years after the initial biopsy and odds ratios (ORs) with 95% confidence intervals (Cls) for the risk of having a prescription. Results: We included 9,286 men with radical prostatectomy, 4,221 men managed on active surveillance, and 47,572 men with nonmalignant biopsies for comparison. The proportion of prescriptions increased significantly after biopsy among men with radical prostatectomy compared to men with nonmalignant biopsies and active surveillance. Patients with prior prescriptions for erectile dysfunction had an OR of 3.49 (95% Cl, 2.98-4.08) of new prescriptions 6 months after the initial biopsy. Compared to patients treated With bilateral nerve-sparing surgery, patients with unilateral nerve-sparing surgery had an OR of 1.23 (95% Cl, 1.06-1.43), whereas patients without nerve-sparing surgery had an OR of 0.40 (95% CI, 0.34-0.46). Interpretation: The observed patterns of prescriptions demonstrate a high demand for the treatment of erectile dysfunction following radical prostatectomy. The group of prostate cancer survivors is large, and, thus, a strong clinical focus on managing erectile dysfunction is needed.

Purpose To investigate differences in prescription rates of commonly used drugs among prostate cancer patients and cancer-free comparisons and between patients diagnosed with localized and non-localized disease. Methods We conducted a register-based study including all men aged 50–85 years diagnosed with prostate cancer in Denmark from 1998 to 2015 and an age-matched cancer-free comparison cohort. We calculated the number of new and total prescriptions from three years before to three years after the date of diagnosis of the case for selected drug classes divided by the number of person-months and stratified by stage at diagnosis. Results We included 54,286 prostate cancer patients and 249,645 matched comparisons. 30,712 patients were diagnosed with localized disease and 12,884 with non-localized disease. The rates of new prescriptions increased considerably among patients within the year before the diagnosis. Hereafter the rates varied between drug classes. For most drug classes, total prescription rates for patients and comparisons increased similarly in the study period. Total prescription rates varied between men with localized and non-localized disease for all drug classes apart from statins. Conclusion Our findings indicate that a large proportion of prostate cancer cases are likely diagnosed during medical work-up for other reasons than prostate cancer. Increased rates occur within the last year before diagnosis and future studies on the interaction between drug use and prostate cancer should at least include a one year pre-diagnostic lag-time. Post-diagnostic prescription rates demonstrated an increased use of drugs most likely associated with the consequences of the disease.

Background: A previous phase I/II study demonstrated potent and long-term immune responses in men with prostate cancer following vaccination with a 20mer synthetic peptide (RV001) derived from the Ras homolog gene family member C protein (RhoC). Moreover, a fraction of patients experienced prostate-specific antigen (PSA) responses, which prompted the initiation of a phase II double-blind randomized trial (NCT04114825). The primary endpoint was to study whether vaccination could postpone PSA progression. Furthermore, the study included an evaluation of vaccination-induced immune responses, and in-depth in vitro studies of RhoC-specific CD4+ T cell responses. Methods: Men with non-metastatic biochemical recurrence after either radical prostatectomy or radiation therapy were eligible for the study. Participants were randomized 1:1 to either subcutaneous injections of 0.1 mg/mL RV001 emulsified in Montanide ISA 51, or a placebo. Vaccinations were administered every 2 weeks for the first six times, then five times every 4 weeks for a total treatment time of 30 weeks. Blood samples were collected from a subset of patients (n = 38) over the course of vaccination, and peripheral blood mononuclear cells (PBMCs) isolated for immunological assessment of vaccine-induced immune responses. Experiments using PBMCs from a healthy donor and a patient were performed to study the phenotype and function of RV001-specific CD4+ T cells. Results: A total of 192 men entered the study. There was no difference in time to PSA doubling, with 7.5 versus 9.3 months, or in time to initiating further therapies, 11.2 versus 17.6 months for treatment and control groups, respectively. At long-term follow-up, 12.9% of the patients in the vaccination arm had developed metastasis compared to 12% in the placebo arm. No serious treatment-related side effects were observed, and treatment-related adverse events did not differ between groups. Immunological examinations in a subset of patients demonstrated that the vaccination induced potent, long-lasting CD4+ T cell responses capable of proliferation and cytokine production. RV001-specific CD4+ T cells were shown to mediate cytotoxicity against a RhoC-expressing cancer cell line in an HLA-class II-dependent manner. Conclusions: Men randomized to active treatment with RV001V demonstrated the induction of potent, functionally capable, anti RhoC-CD4+ T cell responses. However, there was no benefit in time to biochemical progression, and no difference in time to the initiation of second-line therapies.

Prostate cancer (PCa) cells become castrate-resistant after initial tumor regression following castration-based lowering of testosterone (T). De-novo intra-tumoral steroid synthesis is a suggested biological mechanism of castration resistant PCa, but the regulators are unknown. Testicular T production is controlled by the luteinizing hormone/choriogonadotropin receptor (LHCGR). To elucidate the influence of LHCGR on PCa development the presence and effects of LHCGR in PCa and whether LHCGR in serum holds prognostic information in PCa patients is investigated. LHCGR expression was investigated by RT-PCR, WB, IHC, qPCR in PCa cell lines and prostatic tissue. Steroid production was measured in media from cell lines with LC-MS/MS and expression of steroidogenic enzymes with qPCR. Serum LHCGR (sLHCGR) was measured with ELISA in PCa patients (N = 157). Presence of LHCGR was established in prostatic tissue and PCa cell lines. Cell proliferation increased by 1.29-fold in LNCaP (P = 0.007) and 1.33-fold in PC-3 cells (P = 0.0007), when stimulated by luteinizing hormone. Choriogonadotropin stimulation decreased proliferation 0.93-fold in DU145 cells (P = 0.05), but none of the treatments altered steroid metabolite secretion. Low sLHCGR concentration was associated with a higher risk of biochemical failure after radical prostatectomy (HR = 3.05, P = 0.06) and castration resistance (HR = 6.92, P = 0.004) compared to high sLHCGR concentration. LHCGR is expressed in PCa and may exert a growth regulatory role in PCa derived cell lines. A potential prognostic role of sLHCGR for determining recurrence risk in PCa patients is found in this pilot study but needs verification in larger cohorts.

Background The effect of lifestyle, anthropometry and cardiovascular risk factors on cardiovascular disease in men with prostate cancer (PCa) remains unclear. Methods Using a population-based cohort of 25,436 Danish, cancer-free men aged 50–64 years, we obtained information on self-reported pre-cancer lifestyle, objectively measured anthropometry and cardiovascular risk factors, and linked them to national health registers for information on major cardiovascular outcomes. We assessed hazard ratios (HRs) of incident acute myocardial infarction (MI), ischaemic stroke (IS) and heart failure (HF) among 1546 men diagnosed with PCa treated with first-line active surveillance, watchful waiting, intended curative or palliative treatment compared with PCa-free men during 18 years of follow-up. Results Men who received first-line palliative treatment had higher rates of IS and HF with adjusted HRs of 2.09 (95% CI 1.49–2.93) and 2.05 (95% CI 1.43–2.94), respectively, compared with PCa-free men. The risks were increased from start of treatment. We did not find the same relation for men in any other treatment group. No differences between men treated for PCa and cancer-free controls were observed for MI after adjustment for lifestyle, anthropometry, and cardiovascular risk factors. Conclusion Pre-diagnosis lifestyle, anthropometry or cardiovascular risk factors did not explain the risk of IS and HF in PCa patients receiving palliative treatment. The results emphasise the need for balancing disease management and monitoring of cardiovascular health in this patient group.

Docetaxel (DTX) was the first chemotherapeutic agent to demonstrate significant efficacy in the treatment of men with metastatic castration-resistant prostate cancer. However, response to DTX is generally short-lived, and relapse eventually occurs due to emergence of drug-resistance. We previously established two DTX-resistant prostate cancer cell lines, LNCaP R and C4-2B R , derived from the androgen‐dependent LNCaP cell line, and from the LNCaP lineage-derived androgen-independent C4-2B sub-line, respectively. Using an unbiased drug screen, we identify itraconazole (ITZ), an oral antifungal drug, as a compound that can efficiently re-sensitize drug-resistant LNCaP R and C4-2B R prostate cancer cells to DTX treatment. ITZ can re-sensitize multiple DTX-resistant cell models, not only in prostate cancer derived cells, such as PC-3 and DU145, but also in docetaxel-resistant breast cancer cells. This effect is dependent on expression of ATP-binding cassette (ABC) transporter protein ABCB1, also known as P-glycoprotein (P-gp). Molecular modeling of ITZ bound to ABCB1, indicates that ITZ binds tightly to the inward-facing form of ABCB1 thereby inhibiting the transport of DTX. Our results suggest that ITZ may provide a feasible approach to re-sensitization of DTX resistant cells, which would add to the life-prolonging effects of DTX in men with metastatic castration-resistant prostate cancer.