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The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression. We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7–10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047. Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60–68). Median follow-up was 4·9 years (IQR 3·0–6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81–1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58–1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3–4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020). These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy. Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society.

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.

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 Kidney transplantation is the ultimate treatment for end-stage kidney disease. Function of the kidney graft is not only dependent on medical factors but also on a complication-free surgical procedure. In the event of major surgical complications, the kidney graft is potentially lost and the patient will return to the waiting list which may be long. To optimise peri-operative care and reduce complications, robot-assisted kidney transplantation (RAKT) has been introduced as an alternative to open kidney transplantation (OKT), but to our knowledge, no randomised clinical trials (RCT) have compared RAKT to OKT. In this study, we will explore whether robot-assisted surgery can reduce 30-day surgical complications compared to open surgery in kidney transplantation. Methods This is a single-site, open-label, randomised clinical trial comparing RAKT to OKT. Participants are adult recipients of kidney transplantation recruited from Copenhagen University Hospital – Rigshospitalet, Denmark. The study plans to include 106 participants who will be randomised in a 1:1 manner between OKT and RAKT. Primary outcomes are vascular- and major surgical complications at 30 days post-operatively. Participants will be followed for 2 years to evaluate secondary outcomes including recovery, late complications and kidney graft function. This is designed as a superiority trial and planned analyses will follow intention-to-treat principles. Discussion Studies indicate RAKT can reduce several surgical complications, but the lack of RCTs limits the extrapolation of these results to justify replacing an open approach with a robot-assisted one. Ultimately, the introduction of new surgical techniques should be as vigorously tested as any other new treatments. However, reducing surgical complications that compromise graft viability could lead to improved patient care and survival. Trial registration The trial was prospectively registered with ClinicalTrials.gov on February 15th, 2023, with the identifier NCT05730257.

Background One-fourth of men older than 70 years have lower urinary tract symptoms (LUTS) that impair their quality of life. Transurethral resection of the prostate (TURP) is considered the gold standard for surgical treatment of LUTS caused by benign prostatic hyperplasia (BPH) that cannot be managed conservatively or pharmacologically. However, TURP is only an option for patients fit for surgery and can result in complications. Transurethral microwave thermotherapy (TUMT) and prostatic artery embolisation (PAE) are alternative minimally invasive surgical therapies (MISTs) performed in an outpatient setting. Both treatments have shown to reduce LUTS with a similar post-procedure outcome in mean International Prostate Symptom Score (IPSS). It is however still unknown if TUMT and PAE perform equally well as they have never been directly compared in a randomised clinical trial. The objective of this clinical trial is to assess if PAE is non-inferior to TUMT in reducing LUTS secondary to BPH. Methods This study is designed as a multicentre, non-inferiority, open-label randomised clinical trial. Patients will be randomised with a 1:1 allocation ratio between treatments. The primary outcome is the IPSS of the two arms after 6 months. The primary outcome will be evaluated using a 95% confidence interval against the predefined non-inferiority margin of + 3 points in IPSS. Secondary objectives include the comparison of patient-reported and functional outcomes at short- and long-term follow-up. We will follow the patients for 5 years to track long-term effect. Assuming a difference in mean IPSS after treatment of 1 point with an SD of 5 and a non-inferiority margin set at the threshold for a clinically non-meaningful difference of + 3 points, the calculated sample size was 100 patients per arm. To compensate for 10% dropout, the study will include 223 patients. Discussion In this first randomised clinical trial to compare two MISTs, we expect non-inferiority of PAE to TUMT. The most prominent problems with MIST BPH treatments are the unknown long-term effect and the lack of proper selection of candidates for a specific procedure. With analysis of the secondary outcomes, we aspire to contribute to a better understanding of durability and provide knowledge to guide treatment decisions. Trial registration ClinicalTrials.gov NCT05686525. Registered on January 17, 2023, https://clinicaltrials.gov/study/NCT05686525 .

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/mm 2 ] or CD8 + T cells [mean difference (95% confidence interval): −16 (−206; 172) cells/mm 2 ]. 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.

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.

Prostate artery embolization (PAE) is an emerging therapy for benign prostatic hyperplasia (BPH). Optimal patient selection is an important step when introducing new treatments and several characteristics associated with a good clinical outcome has previously been proposed. However, no prognostic tool is yet available for PAE. Computed tomography perfusion is an imaging technique that provides hemodynamic parameters making it possible to estimate the prostatic blood flow (PBF). This study investigated the relationship between PBF and the response to PAE. A post hoc analysis including prostate-specific antigen (PSA) measurements before and 24-h after embolization from two prospective studies on sixteen patients undergoing PAE with BPH or prostate cancer were performed. The primary outcome was the correlation between baseline PBF and the change in PSA as a surrogate measure of treatment response. Prostate volume strongly correlated with treatment response and the response was greater with incremental amounts of injected embolic material. PBF was not associated with elevation in PSA and added no information that could guide patient selection.

AimsWe evaluated the consistency in ERG protein expression from diagnostic specimens through rebiopsies to radical prostatectomies in patients with clinically localised prostate cancer to investigate the validity of ERG status in biopsies.MethodsERG expression was assessed by immunohistochemistry (IHC) in 625 biopsy sets and 86 radical prostatectomy specimens from 265 patients with prostate cancer managed on active surveillance. For IHC, a rabbit monoclonal primary antibody was used (clone: EPR3864). TMPRSS2-ERG fluorescence in situ hybridisation (FISH) analyses were performed in 74 biopsies using the FISH ZytoLight TriCheck Probe (SPEC ERG/TMPRSS2). FISH results were correlated with IHC findings.ResultsThe concordance between FISH and IHC was 97.3% and IHC demonstrated a sensitivity and specificity for ERG rearrangement of 100% and 95.5%, respectively. Applying IHC, 38.1% of patients were ERG-positive, 53.6% were ERG-negative and 8.3% showed both ERG-positive and negative tumour foci (ERG heterogeneous) at diagnosis. When ERG status was dichotomised (ERG-positive or heterogeneous vs ERG-negative), 95.6%–97.1% of patients did not experience ERG reclassification during the first two rounds of rebiopsies. The concordance in ERG status between biopsies and surgical specimen was 89.5%–94.2% depending on the number of rebiopsies included. Sampling bias was assumed to explain most (81.3%) of the mismatches in ERG status.ConclusionsConsistency in ERG status ranged from 90% to 95% for patients undergoing serial biopsies and radical prostatectomy. This indicates that biopsies can be used reliably to investigate ERG's prognostic and predictive value.