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.

Morbidity and Mortality of Total Pelvic Exenteration for Malignancy in the US.

BACKGROUND: Total pelvic exenterations (TPEs) for malignancies are complex operations often performed by multidisciplinary teams. The differences among primary cancer for TPE and multicentered results are not well described. We aimed to describe TPE outcomes for different malignant origins in a national multicentered sample. METHODS: Patients from the National Surgical Quality Improvement Program (NSQIP) database who underwent TPE between 2005 and 2016 for all malignant indications (colorectal, gynecologic, urologic, or other) were included. Chi square and Kruskal-Wallis tests were used to compare patient characteristics by primary malignancy. Multivariate logistic and linear regression models were used to determine factors associated with any 30-day Clavien-Dindo grade 3 or higher complication, length of hospital stay (LOS; days), 30-day wound infection, and 30-day mortality. RESULTS: Overall, 2305 patients underwent TPE. Indications for surgery included 33% (749) colorectal, 15% (335) gynecologic, 9% (196) other, and 45% (1025) urologic malignancies. Median LOS decreased from 10 to 8 days during the study period (p < 0.001), 36% were males, and 50% required blood transfusion. High-grade complications occurred in 15% of patients and were associated with bowel diversion [odds ratio (OR) 1.6, 95% confidence interval (CI) 1.1-2.4], disseminated cancer (OR 1.8, 95% CI 1.4-2.3), and gynecologic cancers (OR 2.9, 95% CI 1.8-4.7). Mortality was 2% and was associated with disseminated cancer (OR 2.2, 95% CI 1.1-4.3) and male sex (OR 2.4, 95% CI 1.3-4.4). CONCLUSIONS: TPE is associated with high rates of complications, however mortality rates remain low. Preoperative and perioperative outcomes differ depending on the origin of the primary malignancy.

Single-port robotic surgery: the next generation of minimally invasive urology.

INTRODUCTION: The da Vinci Single-Port (SP) platform (Intuitive Surgical Inc, Sunnyvale CA) is a recently approved robotic surgical platform which features several novel modifications from previously available single trocar models including a flexible camera, articulating instruments, and navigator guidance for real-time monitoring of instrument position. We sought to describe our clinical experience with this device as well as to review the current literature related to the use of the SP platform. METHODS: We provide a narrative review of clinical data related to single-port robotic surgery within the field of urology. In addition, we report our initial clinical experience for surgical procedures performed with the SP platform between December 2018 and April 2019 following installation of the system at our institution. RESULTS: Currently, the presently available literature for single-port robotic urological surgery consists of single-center case reports and series. Most major robotic urologic operations appear technically feasible using the da Vinci SP platform; however, additional multi-center studies and randomized trials are needed to determine what role the SP platform will play. CONCLUSIONS: Rather than an iterative step or a niche system, the SP platform provides for a new approach to single-site laparoscopic or robotic techniques and is demonstrated as a feasible approach for several major robotic urological operations. While comparative studies will be required to evaluate perioperative and long-term outcomes between SP and multi-port platforms, further technological advances will continue to push surgeons towards less morbid and more minimally invasive approaches for surgery.

Single port robotic radical prostatectomy with the da Vinci SP platform: a step by step approach.

The da Vinci single port (SP) robotic system (Intuitive Surgical, Sunnyvale, CA, USA) is a recently approved robotic platform designed with several modifications to the previously available multi-port robotic systems. This article describes the technique performed utilizing the SP robotic system for radical robotic-assisted laparoscopic prostatectomy (RALP) with or without bilateral pelvic lymph node dissection from a single institution. In this report we describe our step-by-step approach, technical modifications from the multi-port technique and initial results for performing single port robotic-assisted laparoscopic prostatectomy (SP-RALP). We describe our initial experience and technique with the SP robotic system consisting of 23 consecutive patients who underwent SP-RALP between December 2018 and May 2019. The median patient age was 62 years with approximately half of the patients undergoing pelvic lymphadenectomy. The median operative time was 236 minutes, median estimated blood loss was 50 mL and median length of hospital stay was 1 day. No unplanned port placements occurred and no conversions to open surgery occurred. We demonstrate the safety and feasibility of performing a transperitoneal prostatectomy with either a posterior or anterior approach.

Single-port robot-assisted laparoscopic radical prostatectomy: initial experience and technique with the da Vinci® SP platform.

OBJECTIVES: To assess the safety and feasibility of the da Vinci® SP (Intuitive Surgical, Sunnyvale, CA, USA) robotic platform for a consecutive series of patients who underwent single-port robot-assisted laparoscopic radical prostatectomy (SP-RALP). PATIENTS AND METHODS: In all, 10 consecutive patients with biopsy confirmed prostate cancer underwent SP-RALP at our institution. Pre-, peri-, and postoperative data were prospectively collected for key outcomes including: estimated blood loss (EBL), operative time, postoperative pain requirements, duration of hospital stay, and complications. RESULTS: The patients were aged 52-77 years with a body mass index of 24.4-36.7 kg/m2 . Prostate volumes ranged from 26 to 136 mL, with a mean (sd) PSA (prostate specific antigen) level of 11.0 (10.6) ng/mL. Lymph node dissection was performed in four patients and nerve sparing in five. No intraoperative complications occurred, and no patients required conversion to an open approach. Total EBL was 20-150 mL, with a median (interquartile range [IQR]) console time of 189 (171-207) min and operative time of 234 (216-247) min. No patients were readmitted or required intervention. Urethral catheters were removed at a median (IQR) of 10 (8-11) days after surgery. CONCLUSION: SP-RALP appears to be a safe and feasible approach to performing robotic radical prostatectomy. Long-term follow-up will be necessary to assess initial oncological and functional results.

The Capio Prostate Cancer Center Model for Prostate Cancer Diagnostics-Real-world Evidence from 2018 to 2022.

Background: The Capio Prostate Cancer Center (Capio PCC) in Stockholm, Sweden, adopts a comprehensive diagnostic approach, utilizing prostate-specific antigen (PSA), Stockholm3, and magnetic resonance imaging (MRI) for prostate cancer risk assessment, followed by targeted and systematic biopsies for high-risk cases. Objective: This study aims to elucidate the clinical process and real-world outcomes of the Capio PCC model for prostate cancer diagnosis at Capio S:t Göran Hospital. Design setting and participants: Between 2018 and 2022, a cohort of 12 406 men aged 45-75 yr underwent prostate cancer testing, adhering to Capio PCC's structured diagnostic protocol. Outcome measurements and statistical analysis: We provide a comprehensive description of the Capio PCC model and present results from its implementation, including assessments of PSA, Stockholm3, MRI scans, and biopsies. A comparative analysis is conducted between the diagnostic outcomes obtained at Capio PCC and those obtained at other regions in Sweden. Results and limitations: The median participant age was 61 yr (interquartile range [IQR]: 55-67), with PSA levels at 1.6 ng/ml (IQR: 0.8-3.3) and Stockholm3 scores at 4 (IQR: 3-11). Among 1064 men (8.6%) undergoing biopsies, 611 (57% of biopsied) were diagnosed with International Society of Urological Pathology grade ≥ 2 cancer. Notably, employing a Stockholm3 ≥ 15 cutoff for biopsy, in lieu of PSA ≥ 3 ng/ml, reduced biopsy recommendations by 43%. For men with PSA levels between 1.5 and 2.9 ng/ml, 360 (12%) exhibited Stockholm3 scores of ≥ 15, with 72 (56% of biopsied) diagnosed with clinically significant prostate cancer. A comparative analysis with national Swedish prostate cancer detection data indicated that the Capio PCC model (vs Sweden) revealed a distribution of 14% (vs 25%) low-risk, 59% (vs 42%) intermediate-risk, and 26% (vs 30%) high-risk and advanced cancers. Conclusions: This study underscores the effectiveness of the protocol-driven diagnostic process at Capio PCC, enabling earlier detection of intermediate-risk prostate cancer and reducing the need for MRI assessments compared with standard prostate cancer care in Sweden. Patient summary: At the Capio Prostate Cancer Center, a novel diagnostic approach incorporating prostate-specific antigen, Stockholm3, magnetic resonance imaging, and targeted biopsies has been implemented to enhance prostate cancer testing and diagnosis in Stockholm, Sweden.

Biomarker vs MRI-Enhanced Strategies for Prostate Cancer Screening: The STHLM3-MRI Randomized Clinical Trial.

Importance: Prostate cancer guidelines often recommend obtaining magnetic resonance imaging (MRI) before a biopsy, yet MRI access is limited. To date, no randomized clinical trial has compared the use of novel biomarkers for risk estimation vs MRI-based diagnostic approaches for prostate cancer screening. Objective: To evaluate biomarker-based risk estimation (Stockholm3 risk scores or prostate-specific antigen [PSA] levels) with systematic biopsies vs an MRI-enhanced strategy (PSA levels and MRI with systematic and targeted biopsy) for the detection of clinically significant prostate cancer in a screening setting. Design, Setting, and Participants: This open-label randomized clinical trial conducted in Stockholm, Sweden, between April 4, 2018, and December 10, 2020, recruited men aged 50 to 74 years with no history of prostate cancer. Participants underwent blood sampling for PSA and Stockholm3 tests to estimate their risk of clinically significant prostate cancer (Gleason score ≥3 + 4). After the blood tests were performed, participants were randomly assigned in a 2:3 ratio to receive a Stockholm3 test with systematic biopsy (biomarker group) or a PSA test followed by MRI with systematic and targeted biopsy (MRI-enhanced group). Data were analyzed from September 1 to November 5, 2023. Interventions: In the biomarker group, men with a Stockholm3 risk score of 0.15 or higher underwent systematic biopsies. In the MRI-enhanced group, men with a PSA level of 3 ng/mL or higher had an MRI and those with a Prostate Imaging-Reporting and Data System (PI-RADS) score of 3 or higher (range: 1-5, with higher scores indicating a higher likelihood of clinically significant prostate cancer) underwent targeted and systematic biopsies. Main Outcomes and Measures: Primary outcome was detection of clinically significant prostate cancer (Gleason score ≥3 + 4). Secondary outcomes included detection of clinically insignificant cancer (Gleason score ≤6) and the number of biopsy procedures performed. Results: Of 12 743 male participants (median [IQR] age, 61 [55-67] years), 5134 were assigned to the biomarker group and 7609 to the MRI-enhanced group. In the biomarker group, 8.0% of men (413) had Stockholm3 risk scores of 0.15 or higher and were referred for systematic biopsies. In the MRI-enhanced group, 12.2% of men (929) had a PSA level of 3 ng/mL or higher and were referred for MRI with biopsies if they had a PI-RADS score of 3 or higher. Detection rates of clinically significant prostate cancer were comparable between the 2 groups: 2.3% in the biomarker group and 2.5% in the MRI-enhanced group (relative proportion, 0.92; 95% CI, 0.73-1.15). More biopsies were performed in the biomarker group than in the MRI-enhanced group (326 of 5134 [6.3%] vs 338 of 7609 [4.4%]; relative proportion, 1.43 [95% CI, 1.23-1.66]), and more indolent prostate cancers were detected (61 [1.2%] vs 41 [0.5%]; relative proportion, 2.21 [95% CI, 1.49-3.27]). Conclusions and Relevance: Findings of this randomized clinical trial indicate that combining a Stockholm3 test with systematic biopsies is comparable with MRI-based screening with PSA levels and systematic and targeted biopsies for detection of clinically significant prostate cancer, but this approach resulted in more biopsies as well as detection of a greater number of indolent cancers. In regions where access to MRI is lacking, the Stockholm3 test can aid in selecting patients for systematic prostate biopsy. Trial Registration: ClinicalTrials.gov Identifier: NCT03377881.

External Validation of the Rotterdam Prostate Cancer Risk Calculator and Comparison with Stockholm3 for Prostate Cancer Diagnosis in a Swedish Population-based Screening Cohort.

BACKGROUND: The Rotterdam Prostate Cancer Risk Calculator (RPCRC) and Stockholm3 can be used to aid urologists in their decision to refer men to magnetic resonance imaging (MRI) or biopsy for early detection of prostate cancer. OBJECTIVE: To assess the external validity of the RPCRC and compare it with using PSA and Stockholm3 to detect clinically significant prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Using data from the prospective, population-based, randomised STHLM3-MRI screening trial, we included participants with prostate-specific antigen (PSA) ≥3 ng/ml or Stockholm3 risk threshold ≥11% in the standard group who underwent systematic prostate biopsies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Probabilities for clinically significant prostate cancer (csPC, International Society of Urological Pathology grade ≥2) were calculated for each participant using the RPCRC and Stockholm3 with and without prostate volume. Performance of the risk calculators was assessed by discrimination, calibration, and clinical benefits. RESULTS AND LIMITATIONS: In total, 666 men with a median age of 67 yr (interquartile range [IQR]: 61-71) and PSA of 3.4 ng/ml (2.5-5.0) were included, of whom 154 (23%) had csPC. Risk distribution of the RPCRC was narrow: median risks of 2% (IQR 1-4%) compared with 14% (IQR: 9.5-23%) for Stockholm3. Using RPCRC's recommended risk threshold of ≥4% for finding csPC, 54% of all csPC cases would be detected versus 94% using Stockholm3 with a threshold of ≥11%. Calibration of Stockholm3 was adequate while RPCRC underestimated the risk of csPC. The Stockholm3 test showed positive net benefits at clinically relevant thresholds, while the RPCRC showed negative net benefits. Compared with PSA, the RPCRC was associated with lower detection of csPC (84 vs 103; 0.82 [0.71-0.93]), while Stockholm3 was associated with higher detection of csPC (143 vs 103; 1.40 [1.23-1.57]). The main limitation was that Stockholm3 was evaluated in a similar population to where it was developed. CONCLUSIONS: The performance of the RPCRC in a Swedish population-based cohort is suboptimal with a considerable underestimation of prostate cancer risk, while the Stockholm3 test showed superior performance and a positive clinical benefit. PATIENT SUMMARY: The use of the Rotterdam Prostate Cancer Risk Calculator available online to predict the risk of prostate cancer in a Swedish cohort was found to be clinically harmful as it underpredicted the risk of clinically significant prostate cancer, while the Stockholm3 test performed well showing clinical benefits.

Biparametric Quantitative MRI for Prostate Cancer Detection.

OBJECTIVES: This study sought to prospectively investigate a novel quantitative biparametric prostate magnetic resonance imaging (MRI) protocol to detect prostate cancer (PCa) in biopsy-naïve men. Secondarily, this study reports the accuracy of fractional order calculus (FROC) diffusion and quantitative T2 compared with the Prostate Imaging Reporting & Data System (PI-RADS). METHODS: This prospective pilot study (NCT04175730) enrolled 50 prostate biopsy-naïve men who met eligibility criteria. All men received 3T MRI with T2 and diffusion-weighted imaging (DWI) (b-values: 50-4,000 s/mm2). Men with PI-RADS lesions ≥3 underwent targeted and systematic prostate biopsy, omitting systematic biopsy cores in peripheral zone lesions. DWI series images were fit to signal decay to calculate ADC (mm2/s) and the FROC model for coefficient DF (mm2/s). The primary end point was detection of Gleason grade group ≥2 (GG≥2) PCa. Receiver operating characteristic regression and area under the curve (AUC) were reported. RESULTS: Forty-eight men underwent MRI and biopsy. Mean age was 61.5 years (56-68), 29% were White, 52% were African American, mean PSA was 6.0 ng/mL (4.9-8.0), and mean PSA density was 0.14 ng/mL2. In total, 61 PI-RADS ≥3 lesions were targeted for biopsy. GG≥2 PC was found in 7% (1/14) of PI-RADS 3 lesions, 28% (10/36) of PI-RADS 4 lesions, and 36% (4/11) of PI-RADS 5 lesions. The AUC for detection of GG≥2 PC was 0.63 (0.5-0.76) for PI-RADS, 0.82 (0.68-0.96) for ADC, and 0.87 (0.77-0.97) for the FROC model. CONCLUSION: This small prospective pilot study demonstrates the feasibility of a novel quantitative biparametic MRI protocol to detect prostate cancer in biopsy-naïve men.

Perioperative outcomes in male patients undergoing cystectomy, radical colorectal procedure or total pelvic exenteration.

Background: Total pelvic exenteration (TPE) in men is a surgical procedure to treat genitourinary and colorectal malignancies. Despite improvement in multimodal strategies and technology, mortality is still high and literature is limited about perioperative outcomes comparison to other radical procedures. Methods: We analyzed National Surgical Quality Improvement Program (NSQIP) baseline database of all male patients undergoing cystectomy, low anterior resection/abdominoperineal resection (LAR/APR) or TPE from January 1, 2005 to December 31, 2016. Postoperative complications within 30 days after surgery were measured including: Wound infection, septic complications, deep vein thrombosis, cardiovascular events, and return to the operating room or mortality, etc. Differences between groups were analyzed using analysis of variance (ANOVA) tests. Results: A total of 7,375 patients underwent radical cystectomy, 49,762 underwent LAR/APR and 792 underwent TPE. Cystectomy patients were on average older compared to TPE or LAR/APR patients (P<0.001). In univariable and multivariable analysis, patients undergoing TPE had greater infectious and septic complications compared to cystectomy (odds ratio =1.09; 95% confidence interval (CI): 1.06-1.12) and LAR/APR (odds ratio =1.08; 95% CI: 1.05-1.11). Moreover, TPE had a slightly higher mortality within the 30-day postoperatively than those who underwent LAR/APR (odds ratio =1.01; 95% CI: 1.00-1.02) and cystectomy (odds ratio =1.01; 95% CI: 1.00-1.01). Conclusions: Men undergoing TPE had greater rates of infections and postoperative complications compared to those undergoing radical cystectomy and LAR/APR. From a clinical standpoint, TPE has high morbidity that could provide opportunity for quality improvement projects with the goal of mitigating high complication rates.

Progression on active surveillance for prostate cancer in Black men: a systematic review and meta-analysis.

BACKGROUND: Several studies evaluated prostate cancer (PCa) outcomes in Black men on active surveillance (AS); most studies contained few Black men and results were conflicting. We performed a systematic review and meta-analyze of race and outcomes on AS. METHODS: A systematic search was performed for articles of men with Grade Group 1 or 2 (GG1 or GG2) PCa on AS. All studies required race-specific comparative progression data. Progression to treatment, PSA, or biopsy progression were considered and relative risk (RR) estimates of Black men progressing were extracted and pooled using random-effects models. Differences by study-level characteristics were evaluated using subgroup and a cumulative meta-analysis by time. RESULTS: In total, 12 studies were included (3137 Black and 12,206 non-Black men); eight prospective (27%, n = 4210) and four retrospectives (73%, n = 11,133) cohorts. The overall RR of progression for Black men was 1.62 (95%CI, 1.21-2.17), I2 = 64% (95% CI, 32-80%), (χ2 = 30.23; P = 0.001; τ2 = 0.16). Black men with GG1 PCa alone had a higher pooled progression: RR = 1.81 (95% CI, 1.23-2.68). Including only studies with clinical progression (excluding progression to treatment), potentiated results: RR = 1.82 (95%CI, 1.27-2.60). However, a cumulative meta-analysis demonstrated decreasing pooled effect over time, with contemporary studies after 2019 showing a tempered effect (RR: 1.29, 95% CI: 1.20-1.39). CONCLUSIONS: Many studies attribute racial disparity in PCa to delayed presentation of disease, however, AS is unique since all AS eligible men have a low grade and stage PCa. Our findings suggest Black men may have an increased risk of progression during AS, but the association is not so strong that Black men should be discouraged from undergoing AS. Indeed, contemporary evidence suggests stricter inclusion, better confirmatory testing or better access to care may temper these findings. Importantly, these results utilize self-reported race, a social construct that has many limitations.

Radical prostatectomy technique in the robotic evolution: from da Vinci standard to single port-a single surgeon pathway.

To describe perioperative outcomes following robot-assisted prostatectomy performed by a single surgeon during transitions between da Vinci standard/Si/Xi and the single port. Perioperative data were retrospectively evaluated of the first 40 consecutive robot-assisted radical prostatectomies performed by a single surgeon using the da Vinci standard, Si, Xi and single port. A total of 160 patients were included. We matched standard vs Si (Match 1), Si vs Xi (Match 2) and Xi vs single port (Match 3) cohort. Mann-Whitney and Fisher's tests were used to test the difference among the groups. Univariate and multivariate logistic regression analyses were adopted to evaluate the predictors of overall and major complications. Single-port procedures in Match 3 showed significant shorter median operative time than Xi. Both Si and single-port groups showed significantly less median blood loss, a shorter median length of stay, respectively, than standard group in Match 1 and than Xi group in Match 3. 1 standard group patient required conversion to open surgery for an unsolvable conflict of the robotic arms. No other intraoperative complications were noted. On univariate and multivariate analyses, the da Vinci platform model was not a predicting factor of major complications (Clavien-Dindo ≥ 3). We described how technological progress impacted peri and postoperative outcomes during transitions between robotic surgical platforms for radical prostatectomy. In particular, the technological improvements associated to the increased surgeon's expertise made the transition to the single port safe and effective when compared with previous platforms.

Single-Port robot assisted partial nephrectomy: initial experience and technique with the da Vinci Single-Port platform (IDEAL Phase 1).

BACKGROUND: The aim of this paper was to evaluate the safety and feasibility of robotic-assisted laparoscopic partial nephrectomy (RAPN) performed using the da Vinci Single-Port (SP) platform. METHODS: A retrospective review was conducted from December 2018 to December 2019 of 14 consecutive patients with localized renal cancer who underwent SP robot-assisted partial nephrectomy at a single institution. The procedures were performed by 2 experienced robotic surgeons, reproducing the steps of the standard multiport robotic approach to partial nephrectomy. A transperitoneal approach was utilized with a 2.5 cm para-rectus incision with one assistant 12 mm laparoscopic port. RESULTS: No conversions to open or laparoscopic surgery occurred and no additional laparoscopic assistant ports were required. The median total operative time was 202 (162-231) minutes and the median total room time was 258 (215-295) minutes. The warm ischemia time averaged 20±8 minutes. 2 patients required angioembolization due to postoperative acute bleeding (Clavien-Dindo Grade 3a complication). Trifecta outcome (<25 min warm ischemia, no perioperative complications and negative margins) was achieved in 79% of patients. In one case, a positive margin was present. The median length of stay was of 1 day (Interquartile Range 1-2) with a median pain score on post-operative day 1 of 3.5 (Interquartile Range 2.4-5); 1/14 (7%) patient needed narcotic use at one week from discharge. At a median follow up of 5.0 (4.0-8.0) months, no patients have had evidence of disease recurrence. CONCLUSIONS: In this initial cohort, considering the introduction of a new technology, we observed satisfactory outcomes for several key perioperative variables including operative time, warm ischemia time, surgical margins, hospital stay, pain requirements in patients undergoing RAPN with the SP platform. For experienced robotic surgeons, RAPN with the SP platform is a safe and feasible approach for single site partial nephrectomy.

Role of protein kinase C ß and vascular endothelial growth factor receptor in malignant pleural mesothelioma: Therapeutic implications and the usefulness of Caenorhabditis elegans model organism.

PURPOSE: To examine the role of both protein kinase C (PKC)-ß and vascular endothelial growth factor receptor (VEGFR)-2 in malignant pleural mesothelioma (MPM) using respective inhibitors, enzastaurin and KRN633. MATERIALS AND METHODS: MPM cell lines, control cells, and a variety of archived MPM tumor samples were used to determine the protein expression levels of PKC-ß, VEGFR-2, VEGF, and p-AKT. Effects of enzastaurin and KRN633 on phosphorylation status of key signaling molecules and viability of the mesothelioma cells were determined. The common soil nematode, Caenorhabditis elegans, was treated with enzastaurin to determine its suitability to screen for highly potent kinase inhibitors. RESULTS: PKC-ß1, PKC-ß2 and VEGFR-2/KDR were overexpressed in MPM cell lines and MPM tumor tissues. Enzastaurin treatment resulted in significant loss in viability of VEGF induced cell proliferation; however, the effect of KRN633 was much less. Enzastaurin also dramatically decreased the phosphorylation of PKC-ß, its downstream target p-AKT, and surprisingly, the upstream VEGFR-2. The combination of the two drugs at best was additive and similar results were obtained with respect to cell viability. Treatment of C. elegans with enzastaurin resulted in clear phenotypic changes and the worms were hypermotile with abnormal pattern and shape of eggs, suggesting altered fecundity. CONCLUSIONS: PKC-ß1 and VEGFR-2 are both excellent therapeutic targets in MPM. Enzastaurin was better at killing MPM cells than KRN633 and the combination lacked synergy. In addition, we show here that C. elegans can be used to screen for the next generation inhibitors as treatment with enzastaurin resulted in clear phenotypic changes that could be assayed.

Ethnic variation in prostate cancer detection: a feasibility study for use of the Stockholm3 test in a multiethnic U.S. cohort.

BACKGROUND: The Stockholm3 test improves Gleason Grade Group ≥2 (GG ≥ 2) prostate cancer (PC) detection, however it has not been evaluated in an American cohort where clinical practice patterns and ethnicity differ. We aimed to identify subgroups within a Stockholm population with PC risk profiles matching American ethnicity-specific subgroups and compare the detection of PC and describe Stockholm3 performance within these subgroups. METHODS: All men age 49-70 years presenting for prostate biopsies were evaluated at UIC from 2016 to 2019, as well as men in Stockholm from 2012 to 2014 in the STHLM3 study. Propensity scores (PS) were estimated for each person using logistic regression for age, PSA, prostate volume, family history of PC, 5-alpha reductase inhibitor use, and prior biopsy. 3:1 PS matching was performed for Stockholm to Chicago ethnicity-specific cohorts and odds ratios (OR) were computed to compare detection of GG ≥ 2 PC between groups. RESULTS: 504 Chicago men and 6980 Stockholm men were included. In African American (AA) men, 51% had GG ≥ 2 PC detected, while in risk-matched Stockholm men, 34% had GG ≥ 2 PC detected (OR: 2.1, p < 0.001). There was no statistical difference in GG ≥ 2 PC detected when matching Stockholm men to non-Hispanic Caucasian men (31% vs. 24%, OR: 0.7, p = 0.30) or Hispanic Caucasian men (31% vs. 27%, OR: 1.2, p = 0.42). The AUC for the Stockholm3 test of the matched Stockholm cohorts for AA, non-Hispanic Caucasian, and Hispanic Caucasian men was 0.85, 0.89, and 0.90, respectively. CONCLUSIONS: Using statistical techniques to simulate a multi-ethnic Chicago cohort within the STHLM3 population, we found an excess risk of GG ≥ 2 PC among AA men. Our hypothesis that the Stockholm3 may have good predictive value in a multiethnic cohort is strengthened, and that recalibration to at least AA men seems likely to be needed to obtain well-calibrated predictions.

Incorporating Magnetic Resonance Imaging and Biomarkers in Active Surveillance Protocols - Results From the Prospective Stockholm3 Active Surveillance Trial (STHLM3AS).

BACKGROUND: Active surveillance (AS) for men with low-risk prostate cancer (PC) can lead to patient morbidity and healthcare overutilization. The aim of this study was to evaluate an AS protocol using the Stockholm3 test and magnetic resonance imaging (MRI) to reduce biopsy intensity. METHODS: We conducted a prospective multicenter study of 280 invited men from a contemporary screening study (STHLM3), with Gleason Score (GS) 3 + 3 PC on a current AS protocol. Patients underwent prostate-MRI and blood sampling for analysis of the Stockholm3 test including protein biomarkers, genetic variants, and clinical variables to predict risk of GS ≥3 + 4 PC followed by systematic biopsies and targeted biopsies (for Prostate Imaging Reporting and Data System version 2 ≥3 lesions) in all men. Primary outcomes were reclassification to GS ≥3 + 4 PC and clinically significant PC (csPCa), including unfavorable intermediate risk PC or higher based on National Comprehensive Cancer Network guidelines. RESULTS: Adding MRI-targeted biopsies to systematic biopsies increased sensitivity of GS ≥3 + 4 PC compared with systematic biopsies alone (relative sensitivity [RS] = 1.52, 95% confidence interval [CI] = 1.28 to 1.85). Performing biopsies in only MRI positive increased sensitivity of GS ≥3 + 4 PC (RS = 1.30, 95% CI = 1.04 to 1.67) and reduced number of biopsy procedures by 49.3% while missing 7.2% GS ≥3 + 4 PC and 1.4% csPCa. Excluding men with negative Stockholm3 test reduced the number of MRI investigations at follow-up by 22.5% and biopsies by 56.8% while missing 6.9% GS ≥3 + 4 PC and 1.3% csPCa. CONCLUSION: Including MRI and targeted/systematic biopsies in the follow-up for men on AS increased sensitivity of PC reclassification. Incorporation of risk prediction models including biomarkers may reduce the need for MRI use in men with low-risk PC.

Biomarker discrimination and calibration with MRI-targeted biopsies: an analysis with the Stockholm3 test.

BACKGROUND: The validated Stockholm3 test is used to improve PC detection. Stockholm3, however, was developed using systematic biopsies. We aimed to assess Stockholm3 operating performance when using MRI-targeted biopsies for PC detection. METHODS: A prospective cohort of 532 men was considered for prostate biopsy during 2016-2017. All men underwent Stockholm3 testing and MRI before biopsy. All PIRADs ≥3 lesion underwent targeted biopsy; all men underwent systematic biopsy. The primary outcome was ISUP Grade Group ≥2 (GG ≥ 2) PC. Detection strategies included: (1) systematic biopsies alone, (2) targeted biopsies alone, (3) targeted with associated systematic biopsies for MRI+, and (4) all biopsies in all men. For each strategy, the Stockholm3 operating characteristics were assessed with discrimination, calibration, and decision curve analysis (DCA). RESULTS: Median age was 65 years, median PSA was 6.2 ng/mL, median Stockholm3 score was 16.5%, and overall detection of GG ≥ 2 PC was 36% (193/532). Stockholm3 showed accurate discrimination for separating GG ≥ 2 cancer from benign and GG1, with an area under the curve of 0.84-0.86 depending on the biopsy strategy. Calibration analysis showed that Stockholm3 underestimated risks for GG ≥ 2 PC risk using MRI-targeted biopsies: there was a net benefit over biopsies in all men for Stockholm3 at risk thresholds varying from >3% in systematic biopsies to >15% in targeted with systematic biopsies in MRI+ men. When using a Stockholm3 score of >10% cutoff, a range of 32-38% of biopsies could be avoided while missing 5-11% of GG ≥ 2 PC and 0-3% of GG ≥ 3 PC. CONCLUSIONS: Stockholm3 shows high discriminatory performance in an MRI-targeted biopsy setting, however risks are underpredicted due to MRI-targeted biopsies being more sensitive than the systematic biopsies for which Stockholm3 was developed. Stockholm3, along with any risk prediction model developed for systematic prostate biopsy decisions, will need recalibration for optimal use in an MRI-driven biopsy setting.

Real world treatment utilization patterns in patients with castration-resistant prostate cancer.

BACKGROUND: Studies describing treatment utilization for castration-resistant prostate cancer (CRPC) are limited. We aimed to describe the treatment utilization of a contemporary population-based CRPC cohort between 2006 and 2016. METHODS: We identified 1699 men with a PC diagnosis between 2005 and 2015, who developed CRPC between 2006 and 2015 in the Stockholm region of Sweden. Demographic information, stage and grade at PC diagnosis, stage at CRPC, prostate-specific antigen (PSA) nadir, PSA doubling time, treatment utilization rate within 1 year of CRPC diagnosis, reason for stopping therapy, treatment sequence trajectory, overall and PC specific survival was described. RESULTS: Treatment for men with de novo metastatic disease (n = 463) was 32%, treatment for men with progressive metastatic disease after PC diagnosis (n = 66) was 44%, treatment for men with nonmetastatic CRPC (n = 113) was 34% and treatment for those with an unknown stage at time of CRPC diagnosis (n = 857) was 12%. Docetaxel was used in 39%, abiraterone acetate plus prednisone in 15%, enzalutamide in 13%, cabazitaxel in 11% and radium-223 in 5% of treatments. Treatment increased from 22% in 2006-2009 for metastatic cancer to 50% in 2013-2015 (p < .001). Factors associated with treatment were an unknown stage at diagnosis (OR: 0.3, 95% CI: 0.2-0.4), age ≥75 years (OR: 0.2, 95% CI: 0.1 - 0.3), PSA doubling time >3 months (OR: 0.4, 95% CI: 0.3 - 0.6) and a diagnosis between 2013 and 2015 (OR: 3.4, 95% CI: 2.0 - 5.8). CONCLUSIONS: Despite treatment availability, in this large real-world cohort we found treatment utilization to remain low.

Association between environmental quality and prostate cancer stage at diagnosis.

BACKGROUND: Prostate cancer (PC) etiology is up to 57% heritable, with the remainder attributed to environmental exposures. There are limited studies regarding national level environmental exposures and PC aggressiveness, which was the focus of this study METHODS: SEER was queried to identify PC cases between 2010 and 2014. The environmental quality index (EQI) is a county-level metric for 2000-2005 combining data from 18 sources and reports an overall ambient environmental quality index, as well as 5 environmental quality sub-domains (air, water, land, built, and sociodemographic) with higher values representing lower environmental quality. PC stage at diagnosis was determined and, multivariable logistic regression models which adjusted for age at diagnosis (years) and self-reported race (White, Black, Other, Unknown) were used to test associations between quintiles of EQI scores and advanced PC stage at diagnosis. RESULTS: The study cohort included 252,164 PC cases, of which 92% were localized and 8% metastatic at diagnosis. In the adjusted regression models, overall environmental quality EQI (OR 1.20, CI 1.15-1.26), water EQI (OR: 1.34, CI: 1.27-1.40), land EQI (OR: 1.35, CI: 1.29-1.42) and sociodemographic EQI (OR: 1.29, CI: 1.23-1.35) were associated with metastatic PC at diagnosis. For these domains there was a dose response increase in the OR from the lowest to the highest quintiles of EQI. Black race was found to be an independent predictor of metastatic PC at diagnosis (OR: 1.36, CI: 1.30-1.42) and in stratified analysis by race; overall EQI was more strongly associated with metastatic PC in Black men (OR: 1.53, CI: 1.35-1.72) compared to White men (OR: 1.18, CI: 1.12-1.24). CONCLUSION(S): Lower environmental quality was associated with advanced stage PC at diagnosis. The water, land and sociodemographic domains showed the strongest associations. More work should be done to elucidate specific modifiable environmental factors associated with aggressive PC.

A Comparison of Perioperative Outcomes Between Single-port and Multiport Robot-assisted Laparoscopic Prostatectomy.

Single-port (SP) robot-assisted laparoscopic prostatectomy (RALP) appears to be a safe and feasible approach for radical prostatectomy, but no prior studies have compared SP-RALP to a multiport (MP) platform. Using retrospective data from a single-center tertiary institution we compare 50 consecutive SP-RALP patients (da Vinci SP) to a contemporary cohort of 113 patients who underwent MP-RALP (da Vinci Xi). We found no significant differences in surgical or total operating room time. Pain scores were measured on a scale from 0 to 10. There were more pain-free patients on postoperative day 1 (18% difference, 95% confidence interval [CI] 9.9-27%) and there were shorter hospital stays (-1 d, 95% CI -1.0 to 0) in favor of SP. There were no significant differences in inpatient total morphine equivalents used, complication rates, or stress incontinence determined at a minimum of 90 d. These findings show that the learning curve for SP-RALP is relatively short for an experienced robotic surgeon and may favor better pain control and shorter hospitalization. PATIENT SUMMARY: We analyzed the differences in robotic surgery for localized prostate cancer using a single-port robotic platform compared to the traditional multiport robotic platform. We did not find significant differences in operative times, but significantly more patients were pain-free on the first postoperative day and had shorter hospital stays.