Long-Term Oncological Outcomes after Nerve-Sparing Robot-Assisted Radical Prostatectomy for High-Risk Localized Prostate Cancer: A Single-Center, Two-Arm Prospective Study.

AIMS: To compare the oncological outcomes of patients with high-risk localized prostate cancer undergoing nerve-sparing and non-nerve-sparing robot-assisted radical prostatectomy (RARP). METHODS: Between November 2002 and December 2018, we prospectively recorded the data of patients undergoing RARP for high-risk localized prostate cancer (PCa) at our tertiary referral center. NSS (nerve-sparing surgery) was carefully offered on the basis of the preoperative clinical characteristics of the patients and an intraoperative assessment. The patients were stratified into two groups: nerve-sparing and non-nerve-sparing groups (yes/no). Radical prostatectomies were performed by 10 surgeons with a robot-assisted technique using a daVinci® surgical system. The primary oncological outcome evaluated was biochemical recurrence (BCR). The secondary oncological outcomes assessed were positive surgical margins (PSMs) and cancer-specific survival (CSS). RESULTS: A total of 779 patients were included in the study: 429 (55.1%) underwent NSS while 350 (44.9%) underwent non-NSS. After a mean (±SD) follow-up of 192 (±14) months, 328 (42.1%) patients developed BCR; no significant difference was found between the NSS and non-NSS groups (156 vs. 172; p = 0.09). Both our univariable and multivariable analyses found that the nerve-sparing approach was not a predictor of BCR (p > 0.05). Kaplan-Mayer survival curves for BCR showed no significant difference among the non-NSS, unilateral NSS, and bilateral NSS groups (log rank test = 0.6). PSMs were reported after RARPs for 254 (32.6%) patients, with no significant difference between the NSS and non-NSS group (143 vs. 111; p = 0.5). In the subgroup of 15 patients who died during the follow-up period, mean (±SD) CSS was 70.5 (±26.1) months, with no significant difference between the NSS and non-NSS groups (mean CSS: 70.3 vs. 70.7 months). CONCLUSIONS: NSS does not appear to negatively impact the oncological outcomes of patients with high-risk PCa. Randomized clinical trials are needed to confirm our promising findings.

Prediagnostic Prostate-specific Antigen Testing and Clinical Characteristics in Men with Lethal Prostate Cancer.

Background and objective: Prostate cancer (PC) is the fifth leading cause of cancer-related mortality in men worldwide. Opportunistic testing with prostate-specific antigen (PSA) has limited impact on PC mortality. Our objective was to assess prediagnostic PSA testing patterns and clinical characteristics at diagnosis in men with lethal PC. Methods: We conducted a population-based observational study of all men dying from PC in Stockholm County, Sweden, from 2015 to 2019. Data were retrieved from the National Prostate Cancer Register and the Stockholm PSA and Biopsy Register. If the first PSA was registered within 1 yr before diagnosis, men were categorised as PSA naïve. If an elevated PSA level was registered >1 yr before diagnosis without leading to prostate biopsy or repeating PSA within 1 yr, men were categorised as having delayed diagnosis. If a normal PSA level was registered within 5 yr before diagnosis, followed by an elevated PSA level that resulted in PC diagnosis within 1 yr, men were categorised as PSA tested. Clinical characteristics at diagnosis were stratified with D'Amico risk group classification. Key findings and limitations: Among 1473 men dying from PC, PSA test history was available for 995. Of these men, 60% (n = 592) were PSA naïve, 25% (n = 250) received delayed diagnosis, and 15% (n = 153) were PSA tested. After examining all 1473 men, 25% (n = 350) were diagnosed with low- or intermediate-risk cancer, 48% (n = 687) with high-risk cancer, and 27% (n = 385) with metastatic disease. Limitations include the retrospective design. Conclusions and clinical implications: Many men with lethal PC lacked PSA testing before diagnosis or had been tested without subsequent follow-up. Nearly half of the study population was diagnosed with high-risk cancer and almost one-third with metastatic disease. These findings suggest further evaluation of the current opportunistic PSA testing approach. Patient summary: Data from a population-based observational study of men dying from prostate cancer showed that many of them did not undergo either prostate-specific antigen (PSA) testing before diagnosis or subsequent follow-up if tested. These findings implicate deficiencies in the current opportunistic PSA testing approach.

Risk of Venous Thromboembolic Events After Surgery for Cancer.

Importance: The risks and benefits of thromboprophylaxis therapy after cancer surgery are debated. Studies that determine thrombosis risk after cancer surgery with high accuracy are needed. Objectives: To evaluate 1-year risk of venous thromboembolic events after major cancer surgery and how these events vary over time. Design, Setting, and Participants: This register-based retrospective observational matched cohort study included data on the full population of Sweden between 1998 and 2016. All patients who underwent major surgery for cancer of the bladder, breast, colon or rectum, gynecologic organs, kidney and upper urothelial tract, lung, prostate, or gastroesophageal tract were matched in a 1:10 ratio with cancer-free members of the general population on year of birth, sex, and county of residence. Data were analyzed from February 13 to December 5, 2023. Exposure: Major surgery for cancer. Main Outcomes and Measures: The main outcome was incidence of venous thromboembolic events within 1 year after the surgery. Crude absolute risks and risk differences of events within 1 year and adjusted time-dependent cause-specific hazard ratios (HRs) of postdischarge events were calculated. Results: A total of 432 218 patients with cancer (median age, 67 years [IQR, 58-75 years]; 68.7% women) and 4 009 343 cancer-free comparators (median age, 66 years [IQR, 57-74 years]; 69.3% women) were included in the study. The crude 1-year cumulative risk of pulmonary embolism was higher among the cancer surgery population for all cancers, with the following absolute risk differences: for bladder cancer, 2.69 percentage points (95% CI, 2.33-3.05 percentage points); for breast cancer, 0.59 percentage points (95% CI 0.55-0.63 percentage points); for colorectal cancer, 1.57 percentage points (95% CI, 1.50-1.65 percentage points); for gynecologic organ cancer, 1.32 percentage points (95% CI, 1.22-1.41 percentage points); for kidney and upper urinary tract cancer, 1.38 percentage points (95% CI, 1.21-1.55 percentage points); for lung cancer, 2.61 percentage points (95% CI, 2.34-2.89 percentage points); for gastroesophageal cancer, 2.13 percentage points (95% CI, 1.89-2.38 percentage points); and for prostate cancer, 0.57 percentage points (95% CI, 0.49-0.66 percentage points). The cause-specific HR of pulmonary embolism comparing patients who underwent cancer surgery with matched comparators peaked just after discharge and generally plateaued 60 to 90 days later. At 30 days after surgery, the HR was 10 to 30 times higher than in the comparison cohort for all cancers except breast cancer (colorectal cancer: HR, 9.18 [95% CI, 8.03-10.50]; lung cancer: HR, 25.66 [95% CI, 17.41-37.84]; breast cancer: HR, 5.18 [95% CI, 4.45-6.05]). The hazards subsided but never reached the level of the comparison cohort except for prostate cancer. Similar results were observed for deep vein thrombosis. Conclusions and Relevance: This cohort study found an increased rate of venous thromboembolism associated with cancer surgery. The risk persisted for about 2 to 4 months postoperatively but varied between cancer types. The increased rate is likely explained by the underlying cancer disease and adjuvant treatments. The results highlight the need for individualized venous thromboembolism risk evaluation and prophylaxis regimens for patients undergoing different surgery for different cancers.

Risk of Postoperative Ischemic Stroke and Myocardial Infarction in Patients Operated for Cancer.

BACKGROUND: Risk assessment for ischemic stroke (IS) and myocardial infarction (MI) is done routinely before surgery, but the increase in risks associated with surgery is not known. The aim of this study is to assess the risk of arterial ischemic events during the first year after oncological surgery. METHODS: We used Swedish healthcare databases to identify 443,300 patients who underwent cancer surgery between 1987 and 2016 and 4,127,761 matched comparison subjects. We estimated odds ratios (ORs) for myocardial infarction and ischemic stroke during the hospitalization with logistic regression and calculated 1-year cumulative incidences and hazard ratios (HRs) with 95% confidence intervals (CIs) for the outcomes after discharge. RESULTS: The cumulative incidences of myocardial infarction and ischemic stroke during the first postoperative year were 1.33% and 1.25%, respectively. In the comparison cohort, the corresponding 1-year cumulative incidences were 1.04% and 1.00%. During the hospitalization, the OR for myocardial infarction was 8.81 (95% CI 8.24-9.42) and the OR for ischemic stroke was 6.71 (95% CI 6.22-7.23). After discharge, the average HR during follow-up for 365 days was 0.90 (95% CI 0.87-0.93) for myocardial infarction and 1.02 (95% CI 0.99-1.05) for ischemic stroke. CONCLUSIONS: We found an overall increased risk of IS and MI during the first year after cancer surgery that was attributable to events occurring during the hospitalization period. After discharge from the hospital, the overall risk of myocardial infarction was lower among the cancer surgery patients than among matched comparison subjects.

Population-based Organised Prostate Cancer Testing: Results from the First Invitation of 50-year-old Men.

BACKGROUND: The European Union recently recommended evaluation of the feasibility of organised prostate cancer screening. In Sweden, regional population-based organised prostate cancer testing (OPT) programmes were introduced in 2020. OBJECTIVE: To describe initial participation rates and diagnostic outcomes. DESIGN, SETTING, AND PARTICIPANTS: The three most populated Swedish regions invited all men aged 50 yr to OPT by a letter in 2020-2022. Men with prostate-specific antigen (PSA) ≥3 ng/ml were referred for prostate magnetic resonance imaging (MRI). PSA assays differed across regions. Men with Prostate Imaging Reporting and Data System (PI-RADS) 1-3 and PSA density ≥0.15 ng/ml/cm3 or PI-RADS 4-5 were referred for a biopsy. Data were obtained from the Swedish Register for Organised Prostate Cancer Testing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall and regional participation rates, PSA distributions, PI-RADS score distributions, cancer detection, and treatment were evaluated. RESULTS AND LIMITATIONS: A total of 23 855 (35%) of 68 060 invited men participated; 696 (2.9%) had PSA ≥3 ng/ml, and of them, 306 (44%) had a biopsy indication and 221 (32%) had a biopsy. On biopsy, 93 (42%) had Gleason grade group ≥2 (0.39% of PSA-tested men) and 44 (20%) Gleason grade group 1 cancer. Most men with cancer had treatment with curative intent (70%) or were under active surveillance (28%). Across regions, proportions of men with PSA ≥3 ng/ml ranged from 2.3% to 4.0%, and those with PI-RADS score 4-5 ranged from 12% to 21%. A limitation is that results are applicable only to first testing of men in their early 50s. CONCLUSIONS: The OPT programmes are feasible with good compliance to the diagnostic pathway. The use of MRI and PSA density avoided a biopsy for over half of the men with PSA ≥3 ng/ml. Inter-regional differences in diagnostic outcomes show a need for standardisation of the diagnostic pathway's components. PATIENT SUMMARY: We report the diagnostic outcomes of inviting 68 000 50-yr-old men to organised prostate cancer testing.

Assessing the Impact of Positive Surgical Margins on Mortality in Patients Who Underwent Robotic Radical Prostatectomy: 20 Years' Report from the EAU Robotic Urology Section Scientific Working Group.

BACKGROUND: Positive surgical margins (PSMs) are frequent in patients undergoing radical prostatectomy (RP). The impact of PSMs on cancer-specific (CSM) and overall (OM) mortality has not yet been proved definitively. OBJECTIVE: To evaluate whether the presence and the features of PSMs were associated with CSM and OM in patients who underwent robotic-assisted RP. DESIGN, SETTING, AND PARTICIPANTS: A cohort of 8141 patients underwent robotic-assisted RP with >10 yr of follow-up. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox multivariable analyses assessed the impact of margin status (positive vs negative) and PSM features (negative vs <3 mm vs >3 mm vs multifocal) on the risk of CSM, OM, and biochemical recurrence (BCR) after adjusting for potential confounders. We repeated our analyses after stratifying patients according to clinical (Cancer of the Prostate Risk Assessment [CAPRA] categories) and pathological characteristics (adverse: pT 3-4 and/or grade group [GG] 4-5 and/or pN1 and/or prostate-specific antigen [PSA] persistence). RESULTS AND LIMITATIONS: PSMs were found in 1348 patients (16%). Among these, 48 (3.6%) patients had multifocal PSMs. Overall, 1550 men experienced BCR and 898 men died, including 130 for prostate cancer. At Cox multivariable analyses, PSMs were associated with CSM in patients with adverse clinical (Intermediate risk: hazard ratio [HR]: 1.71, p = 0.048; high risk: HR: 2.20, p = 0.009) and pathological (HR: 1.79, p = 0.005) characteristics. Only multifocal PSMs were associated with CSM and OM in the whole population (HR for CSM: 4.68, p < 0.001; HR for OM: 1.82, p = 0.037) and in patients with adverse clinical (intermediate risk: HR for CSM: 7.26, p = 0.006; high risk: HR for CSM: 9.26, p < 0.001; HR for OM: 2.97, p = 0.006) and pathological (HR for CSM: 9.50, p < 0.001; HR for OM: 2.59, p = 0.001) characteristics. Potential limitations include a selection bias and a lack of information on the Gleason score at PSM location. CONCLUSIONS: We did not find an association between unifocal PSMs and mortality. Conversely, our results underscore the importance of avoiding multifocal PSMs in patients with adverse clinical (intermediate- and high-risk CAPRA score) and pathological (GG ≥4, pT ≥3, pN1, or PSA persistence) characteristics, to enhance overall survival and reduce CSM. PATIENT SUMMARY: In this study, we evaluated whether the presence and the characteristics of positive surgical margins were associated with mortality in patients who underwent robotic-assisted radical prostatectomy. We found that the presence of positive surgical margins, particularly multifocal margins, was associated with mortality only in patients with adverse clinical and pathological characteristics.

Cohort profile: the Turin prostate cancer prognostication (TPCP) cohort.

Introduction: Prostate cancer (PCa) is the most frequent tumor among men in Europe and has both indolent and aggressive forms. There are several treatment options, the choice of which depends on multiple factors. To further improve current prognostication models, we established the Turin Prostate Cancer Prognostication (TPCP) cohort, an Italian retrospective biopsy cohort of patients with PCa and long-term follow-up. This work presents this new cohort with its main characteristics and the distributions of some of its core variables, along with its potential contributions to PCa research. Methods: The TPCP cohort includes consecutive non-metastatic patients with first positive biopsy for PCa performed between 2008 and 2013 at the main hospital in Turin, Italy. The follow-up ended on December 31st 2021. The primary outcome is the occurrence of metastasis; death from PCa and overall mortality are the secondary outcomes. In addition to numerous clinical variables, the study's prognostic variables include histopathologic information assigned by a centralized uropathology review using a digital pathology software system specialized for the study of PCa, tumor DNA methylation in candidate genes, and features extracted from digitized slide images via Deep Neural Networks. Results: The cohort includes 891 patients followed-up for a median time of 10 years. During this period, 97 patients had progression to metastatic disease and 301 died; of these, 56 died from PCa. In total, 65.3% of the cohort has a Gleason score less than or equal to 3 + 4, and 44.5% has a clinical stage cT1. Consistent with previous studies, age and clinical stage at diagnosis are important prognostic factors: the crude cumulative incidence of metastatic disease during the 14-years of follow-up increases from 9.1% among patients younger than 64 to 16.2% for patients in the age group of 75-84, and from 6.1% for cT1 stage to 27.9% in cT3 stage. Discussion: This study stands to be an important resource for updating existing prognostic models for PCa on an Italian cohort. In addition, the integrated collection of multi-modal data will allow development and/or validation of new models including new histopathological, digital, and molecular markers, with the goal of better directing clinical decisions to manage patients with PCa.

Prostate Cancer-specific and All-cause Mortality After Robot-assisted Radical Prostatectomy: 20 Years' Report from the European Association of Urology Robotic Urology Section Scientific Working Group.

BACKGROUND: Evidence on long-term oncological efficacy is available only for open radical prostatectomy but remains scarce for robot-assisted radical prostatectomy (RARP). OBJECTIVE: To validate the long-term survival rates after RARP and provide stratified outcomes based on contemporary prostate cancer (PCa) risk-stratification tools. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis of the European Association of Urology (EAU) Robotic Urology Section Scientific Working Group international multicenter database for RARP was performed. Patients who underwent RARP at seven pioneer robotic urology programs in Europe and the USA between 2002 and 2012 were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcomes were PCa-specific mortality and all-cause mortality. The probability of cancer-specific survival (CSS) was estimated with the competing risks method, and the probability of overall survival (OS) was estimated with the Kaplan-Meier method. RESULTS AND LIMITATIONS: A total of 9876 patients who underwent RARP between 2002 and 2012 were included. Within follow-up, 1071 deaths occurred and 159 were due to PCa. At 15 yr of follow-up, CSS and OS were 97.6% (97.2%, 98.0%) and 85.5% (84.6%, 86.4%), respectively. Stratified analyses based on EAU risk groups at diagnosis and pT stage showed favorable survival rates, with low-risk (n = 4601, 46.6%), intermediate-risk (n = 4056, 41.1%), and high-risk (n = 1219, 12.3%) patients demonstrating CSS rates of 99%, 98%, and 90% at 15 yr, respectively. Notably, patients with pT3a disease had similar survival outcomes to those with pT2 disease, with worse CSS in patients with pT3b PCa (98.9% vs 97.4% vs 86.5%). Multivariable analyses identified age, prostate-specific antigen, biopsy Gleason grade group, clinical T stage, and treatment year as independent predictors of worse oncological outcomes. CONCLUSIONS: Our multicenter study with long-term follow-up confirms favorable survival outcomes after RARP for localized PCa. Patients with low- and intermediate-risk disease face a higher risk of mortality from causes other than PCa. On the contrary, high-risk patients have a significantly higher risk of PCa-specific mortality. PATIENT SUMMARY: In the present study, we reported the outcomes of patients with prostate cancer (PCa) who underwent robot-assisted radical prostatectomy between 10 and 20 yr ago, and we found a very low probability of dying from PCa in patients with low- and intermediate-risk PCa.

Biochemical Recurrence and Risk of Mortality Following Radiotherapy or Radical Prostatectomy.

Importance: Stratifying patients with biochemical recurrence (BCR) after primary treatment for prostate cancer based on the risk of prostate cancer-specific mortality (PCSM) is essential for determining the need for further testing and treatments. Objective: To evaluate the association of BCR after radical prostatectomy or radiotherapy and its current risk stratification with PCSM. Design, Setting, and Participants: This population-based cohort study included a total of 16 311 male patients with 10 364 (64%) undergoing radical prostatectomy and 5947 (36%) undergoing radiotherapy with curative intent (cT1-3, cM0) and PSA follow-up in Stockholm, Sweden, between 2003 and 2019. Follow-up for all patients was until death, emigration, or end of the study (ie, December 31, 2018). Data were analyzed between September 2022 and March 2023. Main Outcomes and Measures: Primary outcomes of the study were the cumulative incidence of BCR and PCSM. Patients with BCR were stratified in low- and high-risk according to European Association of Urology (EAU) criteria. Exposures: Radical prostatectomy or radiotherapy. Results: A total of 16 311 patients were included. Median (IQR) age was 64 (59-68) years in the radical prostatectomy cohort (10 364 patients) and 69 (64-73) years in the radiotherapy cohort (5947 patients). Median (IQR) follow-up for survivors was 88 (55-138) months and 89 (53-134) months, respectively. Following radical prostatectomy, the 15-year cumulative incidences of BCR were 16% (95% CI, 15%-18%) for the 4024 patients in the low D'Amico risk group, 30% (95% CI, 27%-32%) for the 5239 patients in the intermediate D'Amico risk group, and 46% (95% CI, 42%-51%) for 1101 patients in the high D'Amico risk group. Following radiotherapy, the 15-year cumulative incidences of BCR were 18% (95% CI, 15%-21%) for the 1230 patients in the low-risk group, 24% (95% CI, 21%-26%) for the 2355 patients in the intermediate-risk group, and 36% (95% CI, 33%-39%) for the 2362 patients in the high-risk group. The 10-year cumulative incidences of PCSM after radical prostatectomy were 4% (95% CI, 2%-6%) for the 1101 patients who developed low-risk EAU-BCR and 9% (95% CI, 5%-13%) for 649 patients who developed high-risk EAU-BCR. After radiotherapy, the 10-year PCSM cumulative incidences were 24% (95% CI, 19%-29%) for the 591 patients in the low-risk EAU-BCR category and 46% (95% CI, 40%-51%) for the 600 patients in the high-risk EAU-BCR category. Conclusions and Relevance: These findings suggest the validity of EAU-BCR stratification system. However, while the risk of dying from prostate cancer in low-risk EAU-BCR after radical prostatectomy was very low, patients who developed low-risk EAU-BCR after radiotherapy had a nonnegligible risk of prostate cancer mortality. Improving risk stratification of patients with BCR is pivotal to guide salvage treatment decisions, reduce overtreatment, and limit the number of staging tests in the event of PSA elevations after primary treatment.

Cardiovascular, bone, and metabolic health in men with castrate-resistant prostate cancer treated with androgen deprivation: a matched cohort study.

BACKGROUND: Descriptive data on late effects associated with castrate-resistant prostate cancer (CRPC) are sparse. We aimed to define the timing and incidence of cardiovascular disease (CVD), fractures, and diabetes in a patient population with CRPC. METHODS: In the population-based STHLM0 cohort 1464 men with CRPC were identified and matched with three men free from prostate cancer (PC) in the Stockholm region of Sweden. Kaplan-Meier estimates of net survival were used to describe time to CVD, fracture, and diabetes. Cox regression was used to compare incidence rates (IRRs) for the respective late effects. Cumulative incidence analyses of late effects in the presence of the competing risk of death were performed to estimate absolute risks. RESULTS: The Kaplan Meier estimates demonstrated a higher net probability for CVD, fracture, and diabetes among men diagnosed with CRPC compared to the matched comparators. The IRRs were 1.94 (95% CI: 1.79-2.12) for CVD, 2.08 (95% CI: 1.70-2.53) for fracture, and 2.00 (95% CI: 1.31-3.05) for diabetes, respectively, comparing men diagnosed with CRPC to men free from PC. The cumulative incidence of CVD at 12 months of follow-up was higher in men diagnosed with CRPC compared to healthy controls regardless of age with a difference in cumulative incidence being 0.20 for men aged <65 and 0.11 for men aged >84. CONCLUSIONS: In this cohort, the incidence of CVD was significantly higher among men with CRPC compared to healthy controls. Despite having this end-stage disease this finding proves that clinicians must recognize this late effect in men diagnosed with CRPC to improve preventive actions. These men did not have a higher absolute risk of fractures and diabetes after accounting for deaths due to any cause compared to healthy controls.

Effect of digital-enabled multidisciplinary therapy conferences on efficiency and quality of the decision making in prostate cancer care.

OBJECTIVES: To investigate the impact on efficiency and quality of preprostatectomy multidisciplinary therapy conferences (MDT) at Karolinska University Hospital related to the use of a digital solution compared with standard of care. Further, to explore whether gains in MDT efficiency and quality impact oncological or functional patient outcomes. METHODS: We conducted a prospective, observational study of preoperative prostate cancer MDT at Karolinska between February 2017 and March 2021, including 1329 patients. We compared efficiency and quality of the standard MDT and the MDT using the digital solution IntelliSpace Precision Medicine Multidisciplinary Team Orchestrator (ISPM) based on the previously used MDT-MODe approach. Clinical and patient-reported functional outcomes were derived from the medical records and the Swedish National Prostate Cancer Register. RESULTS: While ISPM was used during the MDT meeting, the time spent per patient was reduced by 24% (p<0.001) and most of the MDT-MODe items were scored significantly higher. There was a reduction in pelvic lymph-node dissection procedures in the ISPM cohort (p=0.001) and an increased proportion of unilateral nerve-sparing procedures (p=0.005), while all other outcome-related measures were not significantly different between the two patient groups. DISCUSSION AND CONCLUSION: To increase the value of the MDT, all data relevant for treatment decision need to be purposefully presented and compiled, which also enables secondary use of the data.The use of a digital solution during preoperative MDTs for prostate cancer decision making at Karolinska University Hospital improved the efficiency and quality of this multidisciplinary team meeting without impacting patient outcomes.

Characteristics of Patients in SPCG-15-A Randomized Trial Comparing Radical Prostatectomy with Primary Radiotherapy plus Androgen Deprivation Therapy in Men with Locally Advanced Prostate Cancer.

Background: There is no high-grade evidence for surgery as primary treatment for locally advanced prostate cancer. The SPCG-15 study is the first randomized trial comparing surgical treatment with radiotherapy. Objective: To describe the baseline characteristics of the first 600 randomized men in the SPCG-15 study. The study will compare mortality and functional outcomes. Design setting and participants: This study is a Scandinavian prospective, open, multicenter phase III randomized clinical trial aiming to randomize 1200 men. Intervention: Radical prostatectomy with or without consecutive radiotherapy (experimental) and radiotherapy with neoadjuvant androgen deprivation therapy (standard of care). Outcome measurements and statistical analysis: Cause-specific survival, metastasis-free survival, overall survival, and patient-reported bowel function, sexual health, and lower urinary tract symptoms were measured. Results and limitations: The distribution of characteristics was similar in the two study arms. The median age was 67 yr (range 45-75 yr). Among the operated men, 36% had pT3a stage of disease and 39% had pT3b stage. International Society of Urological Pathology grades 2, 3, 4, and 5 were prevalent in 21%, 35%, 7%, and 27%, respectively. Half of the men (51%) in the surgery arm had no positive lymph nodes. The main limitation is the pragmatic design comparing the best available practice at each study site leading to heterogeneity of treatment regimens within the study arms. Conclusions: We have proved that randomization between surgery and radiotherapy for locally advanced prostate cancer is feasible. The characteristics of the study population demonstrate a high prevalence of advanced disease, well-balanced comparison groups, and a demography mirroring the Scandinavian population of men with prostate cancer at large. Patient summary: This study, which has recruited >600 men, compares radiotherapy with surgery for prostate cancer, and an analysis at the time of randomization indicates that the study will be informative and generalizable to most men with locally advanced but not metastasized prostate cancer.

Travel vaccines are strongly associated to reduced mortality in prostate cancer patients - a real effect or residual confounding?

Repurposing of existing drugs and vaccines for diseases that they were not originally intended for is a promising research field. Recently there has been evidence that oral cholera vaccine might be used in the treatment of inflammatory disease and some common cancers. Specifically, Ji et al showed that the administration of cholera vaccine after a prostate cancer diagnosis reduced prostate cancer specific mortality rates by almost 50%. In a cohort of men from Stockholm, Sweden, with more detailed cancer data and a higher coverage of exposure to vaccine, we replicated these findings using a marginal structural Cox model. We showed that administration of cholera vaccine after prostate cancer diagnosis is associated with a significant reduction in mortality (HR 0.46, 95% CI 0.31-0.69, p-value 0.0001) even after adjusting for all known confounders. However, the same effect (or even stronger) could be seen for several other traveling vaccines and malaria prophylaxis. Therefore, we conclude that this effect is most likely due to a healthy traveler bias and is an example of residual confounding.

Mortality in men with castration-resistant prostate cancer-A long-term follow-up of a population-based real-world cohort.

Objectives: The objective of this study is to find clinical variables that predict the prognosis for men with castration-resistant prostate cancer (CRPC) in a Swedish real-life CRPC cohort, including a risk group classification to clarify the risk of succumbing to prostate cancer. This is a natural history cohort representing the premodern drug era before the introduction of novel hormonal drug therapies. Methods: PSA tests from the clinical chemistry laboratories serving health care in six regions of Sweden were retrieved and cross-linked to the National Prostate Cancer Registry (NPCR) to identify men with a prostate cancer diagnosis. Through further cross-linking with data sources at the Swedish Board of Health and Welfare, we retrieved other relevant information such as prescribed drugs, hospitalizations, and cause of death. Men entered the CRPC cohort at the first date of doubling of their PSA nadir value with the last value being >2 ng/ml, or an absolute increase of >5 ng/ml or more, whilst on 3 months of medical castration or if they had been surgically castrated (n = 4098). By combining the two variables with the largest C-statistics, "PSA at time of CRPC" and "PSA doubling time," a risk group classification was created. Results: PSA-DT and PSA at date of CRPC are the strongest variables associated with PC specific survival. At the end of follow-up, the proportion of men who died due to PC was 57%, 71%, 81%, 86%, and 89% for risk categories one through five, respectively. The median overall survival in our cohort of men with CRPC was 1.86 years (95% CI: 1.79-1.97). Conclusion: For a man with castration-resistant prostate cancer, there is a high probability that this will be the main cause contributing to his death. However, there is a significant difference in mortality that varies in relation to tumor burden assessed as PSA doubling time and PSA at time of CRCP. This information could be used in a clinical setting when deciding when to treat more or less aggressively once entering the CRPC phase of the disease.

Association of Open vs Robot-Assisted Radical Cystectomy With Mortality and Perioperative Outcomes Among Patients With Bladder Cancer in Sweden.

Importance: Mortality rates resulting from bladder cancer have remained unchanged for more than 30 years. The surgical community has put hope in robot-assisted radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) in an effort to improve surgical outcomes and bladder cancer survival without strong supporting evidence. Objective: To evaluate perioperative, safety, and survival outcome differences between RARC with ICUD and open radical cystectomy (ORC). Design, Setting, and Participants: This nationwide population-based cohort study used data from the Swedish National Register of Urinary Bladder Cancer and population-based Cause of Death Register, which includes clinical information on tumor characteristics, treatment, and survival and covers approximately 97% of patients with urinary bladder cancer in Sweden. All patients who underwent radical cystectomy for bladder cancer in any hospital between January 2011 and December 2018 were included. Follow-up data were collected until December 2019. Data analysis was conducted from June to December 2020. Exposures: RARC or ORC. Main Outcomes and Measures: The main outcomes were all-cause and cancer-specific mortality between RARC and ORC, compared using propensity score matching. Secondary outcomes were differences in perioperative outcomes after the different surgical approaches. Results: Throughout the observation period, 889 patients underwent RARC and 2280 patients underwent ORC at 24 Swedish hospitals. The median (IQR) age was 71 (66-76) years and 2386 patients (75.3%) were men. After a median (IQR) follow-up of 47 (28-71) months, the 5-year cancer-specific mortality rates were 30.2% (variance, 1.59) for ORC and 27.6% (variance, 3.12) for RARC, and the overall survival rates were 57.7% (variance, 2.46) for ORC and 61.4% (variance, 5.11) for RARC. In the propensity score-matched analysis, RARC was associated with a lower all-cause mortality (hazard ratio, 0.71; 95% CI, 0.56-0.89; P = .004). Compared with ORC, RARC was associated with a lower estimated blood loss (median [IQR] 150 [100-300] mL vs 700 [400-1300] mL; P < .001), intraoperative transfusion rate (odds ratio [OR], 0.05; 95% CI, 0.03-0.08; P < .001), and shorter length of stay (median [IQR], 9 [6-13] days vs 13 [10-17] days; P < .001), and with a higher lymph node yield (median [IQR], 20 [15-27] lymph nodes vs 14 [8-24] lymph nodes; P < .001) and 90-day rehospitalization rate (OR, 1.28; 95% CI, 1.02-1.60; P = .03). The RARC group, compared with the ORC group had lower risk of Clavien-Dindo grade III or higher complications (OR, 0.62; 95% CI, 0.43-0.87; P = .009). Conclusions and Relevance: These findings suggest that compared with ORC, RARC with ICUD was associated with a lower overall mortality rate, fewer high-grade complications, and more favorable perioperative outcomes.

Prognostic Utility of the Gleason Grading System Revisions and Histopathological Factors Beyond Gleason Grade.

BACKGROUND: The International Society of Urological Pathology (ISUP) revised the Gleason system in 2005 and 2014. The impact of these changes on prostate cancer (PCa) prognostication remains unclear. OBJECTIVE: To evaluate if the ISUP 2014 Gleason score (GS) predicts PCa death better than the pre-2005 GS, and if additional histopathological information can further improve PCa death prediction. PATIENTS AND METHODS: We conducted a case-control study nested among men in the National Prostate Cancer Register of Sweden diagnosed with non-metastatic PCa 1998-2015. We included 369 men who died from PCa (cases) and 369 men who did not (controls). Two uro-pathologists centrally re-reviewed biopsy ISUP 2014 Gleason grading, poorly formed glands, cribriform pattern, comedonecrosis, perineural invasion, intraductal, ductal and mucinous carcinoma, percentage Gleason 4, inflammation, high-grade prostatic intraepithelial neoplasia (HGPIN) and post-atrophic hyperplasia. Pre-2005 GS was back-transformed using i) information on cribriform pattern and/or poorly formed glands and ii) the diagnostic GS from the registry. Models were developed using Firth logistic regression and compared in terms of discrimination (AUC). RESULTS: The ISUP 2014 GS (AUC = 0.808) performed better than the pre-2005 GS when back-transformed using only cribriform pattern (AUC = 0.785) or both cribriform and poorly formed glands (AUC = 0.792), but not when back-transformed using only poorly formed glands (AUC = 0.800). Similarly, the ISUP 2014 GS performed better than the diagnostic GS (AUC = 0.808 vs 0.781). Comedonecrosis (AUC = 0.811), HGPIN (AUC = 0.810) and number of cores with ≥50% cancer (AUC = 0.810) predicted PCa death independently of the ISUP 2014 GS. CONCLUSION: The Gleason Grading revisions have improved PCa death prediction, likely due to classifying cribriform patterns, rather than poorly formed glands, as Gleason 4. Comedonecrosis, HGPIN and number of cores with ≥50% cancer further improve PCa death discrimination slightly.

The 90-day cause-specific mortality after radical prostatectomy: a nationwide population-based study.

OBJECTIVE: To investigate the cause-specific mortality in the postoperative period after radical prostatectomy (RP) for prostate cancer (PCa). METHODS: In the National Prostate Cancer Register of Sweden (NPCR), we identified all men who died within 90 days after RP performed 1998-2018 and we assessed cause of death in a chart review. We compared the adjudications of death from our medical record review with those in in the Swedish Cause of Death Registry (CDR). RESULTS: Out of 44 635, 58 (0.13%) men who had undergone RP from 1998 through 2018 died within 90 days after RP. Per medical record review the most common causes of death were cardiac disease (30%) and venous thromboembolic events (VTE; 21%). No men died of metastatic PCa as was first indicated in the CDR. After robot-assisted RP (RARP) or open retropubic RP (RRP), the postoperative mortality was 0.09% (19/21 520) and 0.19% (37/19 635), respectively. The effect off modality was confounded mainly by year of surgery, age at surgery, Charlson Comorbidity Index score and the concomitant pelvic lymph node dissection. CONCLUSION: The validated absolute 90-day mortality after RP was 1.3/1000 during the 21-year study period. Cardiovascular diseases were the most common causes of death after RP. Our validation of the CDR refuted the occurrence of postoperative deaths from metastatic PCa. There were differences in rates and type of mortality between RRP and RARP, but the RARP cohort was more recent than the RRP cohort, which likely explain the differences.

Systematic review and meta-analysis: relationships between attention-deficit/hyperactivity disorder and urinary symptoms in children.

Lower urinary tract symptoms (LUTS), e.g., urinary frequency, pressure, urgency, and overactive bladder syndrome, are commonly reported in children with attention-deficit/hyperactivity disorder (ADHD). Understanding the co-occurrence of these conditions has implications regarding clinical approaches, treatments, and improved quality of life. We conducted a systematic review and meta-analysis to examine the relationships between LUTS and ADHD in children. We searched for articles published between January 1990 and July 2019, in PubMed, CENTRAL, and PsycNet. Two authors independently screened all articles and extracted data. We performed random-effect meta-analyses for ADHD with pooled outcomes for LUTS. We identified 119 relevant articles in the literature and 18 articles fulfilled the inclusion criteria for the systematic review, of which, 5 articles had sufficient data for meta-analysis. Examining ADHD among individuals with LUTS, the odds ratio was 2.99 (95% CI 1.13, 7.88, p < 0.001), compared to controls. In multiple studies, the mean overall score for LUTS, using a standardized measure, was significantly higher in patients with ADHD in comparison to controls, and the severity of ADHD was positively associated with the severity of LUTS. Younger age in children was correlated with a higher LUTS score. Different subtypes of urinary incontinence demonstrated differences in behavioral problems and psychiatric comorbidity. Sex differences in LUTS were not consistent across articles. Our results indicate clinically significant associations between ADHD and LUTS in children. Because LUTS and ADHD are common disorders in children, clinicians should be aware of these associations as they inform optimal assessment and treatment strategies.