A phase II trial of apalutamide for intermediate-risk prostate cancer and molecular correlates.

OBJECTIVES: To determine whether 6 months of preoperative apalutamide for intermediate-risk prostate cancer (IRPCa) reduces the aggregate postoperative radiotherapy risk and to evaluate associations of molecular perturbations with clinical outcomes in this study cohort. PATIENTS AND METHODS: Between May 2018 and February 2020, eligible patients with IRPCa (Gleason 3 + 4 or 4 + 3 and clinical T2b-c or prostate-specific antigen level of 10-20 ng/mL) were treated with apalutamide 240 mg/day for 6 months followed by radical prostatectomy (RP) in this single-arm, phase II trial. The primary endpoint was presence of any adverse pathological feature at risk of pelvic radiation (pathological T stage after neoadjuvant therapy [yp]T3 or ypN1 or positive surgical margins). Translational studies, including germline and somatic DNA alterations and RNA and protein expression, were performed on post-apalutamide RP specimens, and assessed for associations with clinical outcomes. RESULTS: A total of 40 patients underwent a RP, and only one patient discontinued apalutamide prior to 6 months. In all, 40% had adverse pathological features at time of RP, and the 3-year biochemical recurrence (BCR) rate was 15%, with 27.5% being not evaluable. Genomic alterations frequently seen in metastatic PCas, such as androgen receptor (AR), tumour protein p53 (TP53), phosphatase and tensin homologue (PTEN), or BReast CAncer associated gene (BRCA1/2) were underrepresented in this localised cohort. Adverse pathological features and BCR at 3-years were associated with increased expression of select cell cycle (e.g., E2F targets: adjusted P value [Padj] < 0.001, normalised enrichment score [NES] 2.47) and oxidative phosphorylation (Padj < 0.001, NES 1.62) pathways. CONCLUSIONS: Preoperative apalutamide did not reduce the aggregate postoperative radiation risk to the pre-specified threshold in unselected men with IRPCa. However, transcriptomic analysis identified key dysregulated pathways in tumours associated with adverse pathological outcomes and BCR, which warrant future study. Further investigation of preoperative therapy is underway for men with high-risk PCa.

Capturing relationships between suturing sub-skills to improve automatic suturing assessment.

Suturing skill scores have demonstrated strong predictive capabilities for patient functional recovery. The suturing can be broken down into several substep components, including needle repositioning, needle entry angle, etc. Artificial intelligence (AI) systems have been explored to automate suturing skill scoring. Traditional approaches to skill assessment typically focus on evaluating individual sub-skills required for particular substeps in isolation. However, surgical procedures require the integration and coordination of multiple sub-skills to achieve successful outcomes. Significant associations among the technical sub-skill have been established by existing studies. In this paper, we propose a framework for joint skill assessment that takes into account the interconnected nature of sub-skills required in surgery. The prior known relationships among sub-skills are firstly identified. Our proposed AI system is then empowered by the prior known relationships to perform the suturing skill scoring for each sub-skill domain simultaneously. Our approach can effectively improve skill assessment performance through the prior known relationships among sub-skills. Through the proposed approach to joint skill assessment, we aspire to enhance the evaluation of surgical proficiency and ultimately improve patient outcomes in surgery.

Expert Perspectives on Controversies in Castration-Sensitive Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 1.

Purpose: Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC. Materials and Methods: The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy. Results: The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC. Conclusions: CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.

Expert Perspectives on Controversies in Metastatic Castration-Resistant Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 2.

Background: Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature. Materials and Methods: The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators. Results: This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1/2 mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)-positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non-BRCA1/2 mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies. Conclusions: The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.

Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series.

PURPOSE: Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer models. This initiative builds on the rich MD Anderson (MDA) prostate cancer (PCa) patient-derived xenograft (PDX) resource to complement existing publicly available databases by addressing gaps in clinically annotated models reflecting the heterogeneity of potentially lethal and lethal prostate cancer. EXPERIMENTAL DESIGN: We performed whole-genome, targeted, and RNA sequencing in representative samples of the same tumor from 44 PDXs derived from 38 patients linked to donor tumor metadata and corresponding organoids. The cohort includes models derived from different morphologic groups, disease states, and involved organ sites (including circulating tumor cells), as well as paired samples representing heterogeneity or stages before and after therapy. RESULTS: The cohort recapitulates clinically reported alterations in prostate cancer genes, providing a data resource for clinical and molecular interrogation of suitable experimental models. Paired samples displayed conserved molecular alteration profiles, suggesting the relevance of other regulatory mechanisms (e.g., epigenomic) influenced by the microenvironment and/or treatment. Transcriptomically, models were grouped on the basis of morphologic classification. DNA damage response-associated mechanisms emerged as differentially regulated between adenocarcinoma and neuroendocrine prostate cancer in a cross-interrogation of PDX/patient datasets. CONCLUSIONS: We addressed the gap in clinically relevant prostate cancer models through comprehensive molecular characterization of MDA PCa PDXs, providing a discovery platform that integrates with patient data and benchmarked to therapeutically relevant consensus clinical groupings. This unique resource supports robust hypothesis generation and testing from basic, translational, and clinical perspectives.

Does hormone therapy exacerbate other venous thromboembolism risk factors?

OBJECTIVE: Postmenopausal symptoms in women at higher risk for venous thromboembolism (VTE) due to comorbidities are often undertreated because of concerns that hormone therapy (HT) may increase VTE risk; however, it is unclear how much HT impacts risk of VTE when compared with other risk factors. METHODS: This is a case-control study in a commercial claims database from 2007 to 2019. Women aged 50 to 64 years (n = 223,949) were classified as cases if they had an International Classification of Diseases code indicating an acute VTE plus a filled prescription for an anticoagulant, placement of intravascular vena cava filter, or death within 30 days of diagnosis. Controls were matched 10:1 to each case by index date and age. Risk factors and comorbidities present within the year before index were examined. Exposure was defined as a HT prescription within 60 days before index. RESULTS: There were 20,359 VTE cases and 203,590 matched controls. A conditional logistic regression indicated that the greatest risks for VTE were from metastatic cancer (odds ratio [OR], 13.66; 95% CI, 12.64-14.75), hospitalization/surgery (OR, 8.51; 95% CI, 8.09-8.96), trauma (OR, 3.52; 95% CI, 3.32-3.73), comorbidity burden (OR, 3.51; 95% CI, 3.34-3.69), history of hypercoagulable condition (OR, 3.10; 95% CI, 2.87-3.36), and varicose veins (OR, 2.87; 95% CI, 2.56-3.22). Regarding hormone exposure, we observed ORs of 1.51 (95% CI, 1.43-1.60) for any recent hormone exposure; 1.13 (95% CI, 1.04-1.23; number needed to harm, 4,274) for unopposed estrogen menopausal HT; 1.23 (95% CI, 1.10-1.38; number needed to harm, 2,440) for combined menopausal HT; and 5.22 (95% CI, 4.67-5.84) for combined hormonal contraceptives compared with no recent HT exposure. CONCLUSIONS: Hormone therapy exposure did not appear to adversely influence other risk factors, and exposure generally played a minor role in VTE risk. Contraceptives, however, were a strong risk factor.

The association of body mass index with tumor aggression among men undergoing radical prostatectomy.

OBJECTIVES: To evaluate the association of preoperative body mass index (BMI) on adverse pathology in peripheral (PZ) and transition zone (TZ) tumors at time of prostatectomy for localized prostate cancer. METHODS: Clinical and pathologic characteristics were obtained from up to 100 consecutive prostatectomy patients from 10 prostate surgeons. BMI groups included normal (18.5-24.9), overweight (25-29.9) and obese (> 29.9). "Aggressive" pathology was defined as the presence of Grade Group (GG) 3 or higher and/or pT3a or higher. Pathologic characteristics were evaluated for association with BMI using univariate analyses. Our primary outcome was the association of BMI with adverse pathology, which was assessed using logistic regression accounting for patient age. We hypothesized that obese BMI would be associated with aggressive TZ tumor. RESULTS: Among 923 patients, 140 (15%) were classified as "normal" BMI, 413 (45%) were "overweight", and 370 (40%) were "obese." 474 patients (51%) had aggressive PZ tumors while 102 (11%) had aggressive TZ tumors. "Obese" BMI was not associated with aggressive TZ tumor compared to normal weight. Increasing BMI group was associated with overall increased risk of aggressive PZ tumor (HR 1.56 [95CI 1.04-2.34]; P = 0.03). Among patients with GG1 or GG2, increasing BMI was associated with presence of pT3a or higher TZ tumor (P = 0.03). CONCLUSIONS: Increased BMI is associated with adverse pathology in PZ tumors. TZ adverse pathology risk may be increased among obese men with GG1 or GG2 disease, which has implications for future studies assessing behavioral change among men whose tumors are actively monitored.

Statin Use and the Risk of Venous Thromboembolism in Women Taking Hormone Therapy.

Importance: Although hormone therapy (HT) in perimenopausal women is associated with increased risk for venous thromboembolism (VTE), it is unclear to what extent statins may mitigate this HT-associated risk. Objective: To estimate VTE risk in women aged 50 to 64 years taking HT with or without statins. Design, Setting, and Participants: This nested case-control study analyzed data from a commercially insured claims database in the US. Eligible participants included women aged 50 to 64 years with at least 1 year of continuous enrollment between 2008 and 2019. Data analysis occurred from January 2022 to August 2023. Exposure: Filled prescriptions for estrogens, progestogens, and statins were recorded in the 12 months prior to index. Recent HT was defined as any estrogen or progestogen exposure within 60 days before the index date. Current statin exposure was defined as 90 or more days of continuous exposure prior to and including the index date. Statin intensity was defined by the statin exposure 30 days prior to index. Main Outcomes and Measures: Cases were identified with VTE diagnoses (diagnostic codes) preceded by at least 12 months without VTE and followed within 30 days by anticoagulation, an inferior vena cava filter placement, or death. Controls were matched to cases (10:1) on date and age. Conditional logistic regression models estimated risk for HT and statin exposures with odds ratios (OR), adjusted for comorbidities. Conditional logistic regression models were used to estimate VTE risk for HT and statin exposures with odds ratios (ORs), adjusted for comorbidities. Intensity of statin therapy was measured as a subgroup analysis. Results: The total sample of 223 949 individuals (mean [SD] age, 57.5 [4.4] years) included 20 359 cases and 203 590 matched controls. Of the entire sample, 19 558 individuals (8.73%) had recent HT exposure and 36 238 individuals (16.18%) had current statin exposure. In adjusted models, individuals with any recent HT exposure had greater odds of VTE compared with those with no recent HT exposure (OR, 1.51; 95% CI, 1.43-1.60). Individuals receiving current statin therapy had lower odds of VTE compared with those with no current statin exposure (OR, 0.88; 95% CI, 0.84-0.93). When compared with those not recently taking HT or statins, the odds of VTE were greater for those taking HT without statins (OR, 1.53; 95% CI, 1.44-1.63) and for those taking HT with statins (OR, 1.25; 95% CI, 1.10-1.43), but were lower for those taking statins without HT (OR, 0.89; 95% CI, 0.85-0.94). Individuals taking HT with statin therapy had 18% lower odds of VTE than those taking HT without statins (OR, 0.82; 95% CI, 0.71-0.94) and there was greater risk reduction with higher intensity statins. Conclusions and Relevance: In this case-control study, statin therapy was associated with reduced risk of VTE in women taking HT, with greater risk reduction with high-intensity statins. These findings suggest that statins may reduce risk of VTE in women exposed to HT and that HT may not be contraindicated in women taking statins.

A Multi-institution Study on the Association of Virtual Reality Skills with Continence Recovery after Robot-assisted Radical Prostatectomy.

BACKGROUND: Virtual reality (VR) simulators are increasingly being used for surgical skills training. It is unclear what skills are best improved via VR, translate to live surgical skills, and influence patient outcomes. OBJECTIVE: To assess surgeons in VR and live surgery using a suturing assessment tool and evaluate the association between technical skills and a clinical outcome. DESIGN, SETTING, AND PARTICIPANTS: This prospective five-center study enrolled participants who completed VR suturing exercises and provided live surgical video. Graders provided skill assessments using the validated End-To-End Assessment of Suturing Expertise (EASE) suturing evaluation tool. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A hierarchical Poisson model was used to compare skill scores among cohorts and evaluate the association of scores with clinical outcomes. Spearman's method was used to assess correlation between VR and live skills. RESULTS AND LIMITATIONS: Ten novices, ten surgeons with intermediate expertise (median 64 cases, interquartile range [IQR] 6-80), and 26 expert surgeons (median 850 cases, IQR 375-3000) participated in this study. Intermediate and expert surgeons were significantly more likely to have ideal scores in comparison to novices for the subskills needle hold angle, wrist rotation, and wrist rotation needle withdrawal (p < 0.01). For both intermediate and expert surgeons, there was positive correlation between VR and live skills for needle hold angle (p < 0.05). For expert surgeons, there was a positive association between ideal scores for VR needle hold angle and driving smoothness subskills and 3-mo continence recovery (p < 0.05). Limitations include the size of the intermediate surgeon sample and clinical data limited to expert surgeons. CONCLUSIONS: EASE can be used in VR to identify skills to improve for trainee surgeons. Technical skills that influence postoperative outcomes may be assessable in VR. PATIENT SUMMARY: This study provides insights into surgical skills that translate from virtual simulation to live surgery and that have an impact on urinary continence after robot-assisted removal of the prostate. We also highlight the usefulness of virtual reality in surgical education.

Hormone exposure and venous thromboembolism in commercially insured women aged 50 to 64 years.

Background: Menopausal hormone therapy (MHT) can elevate venous thromboembolism (VTE) risk, but less is known about formulations and routes of exposures. Objective: To estimate hormone-associated VTE risk by route and formulation in exposed and unexposed women aged 50 to 64 years in the US. Methods: In a nested case-control study of US commercially insured women aged 50 to 64 years (2007-2019), cases were defined as incident VTE diagnoses and matched to 10 controls by date of VTE and age, excluding prior VTE, inferior vena cava filter placement, or anticoagulants. Filled prescriptions in the prior year defined hormone exposures. International Classification of Diseases and Current Procedural Terminology codes identified risk factors and comorbidities. Results: Odds ratios (ORs) were estimated with conditional logistic regression controlling for differences between cases (n = 20,359) and controls (n = 203,590) in comorbidities and VTE risk factors. For exposures within 60 days, oral MHT risk was almost twice as high as transdermal MHT (OR = 1.92; 95% CI, 1.43-2.60); transdermal MHT did not elevate risk compared with no exposure (unopposed OR = 0.70; 95% CI, 0.59-0.83; combined OR = 0.73; 95% CI, 0.56-0.96). Risk was highest for MHT combinations with ethinyl estradiol, followed by conjugated equine estrogen (CEE) (ethinyl estradiol-CEE: OR = 1.55; 95% CI, 1.07-2.25), and lowest for estradiol (CEE-estradiol: OR = 1.33; 95% CI, 1.02-1.72). Combined hormonal contraceptives elevated risk 5 times higher than no exposure (OR = 5.22; 95% CI, 4.67-5.84) and 3 times higher than oral MHT (OR = 3.65; 95% CI, 3.09-4.31). Conclusion: The risk of VTE is much lower with MHT than combined hormone contraceptives and varies by hormone formulation and route of exposure. Transdermal MHT did not elevate risk. Oral MHT combinations with estradiol were lower risk than other forms of estrogen. Oral combined hormone contraceptives had much higher risk than oral combined hormonal MHT.

NCCN Guidelines® Insights: Prostate Cancer Early Detection, Version 1.2023.

The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for individuals with a prostate who opt to participate in an early detection program after receiving the appropriate counseling on the pros and cons. These NCCN Guidelines Insights provide a summary of recent updates to the NCCN Guidelines with regard to the testing protocol, use of multiparametric MRI, and management of negative biopsy results to optimize the detection of clinically significant prostate cancer and minimize the detection of indolent disease.

The RECOURSE Study: Long-term Oncologic Outcomes Associated With Robotically Assisted Minimally Invasive Procedures for Endometrial, Cervical, Colorectal, Lung, or Prostate Cancer: A Systematic Review and Meta-analysis.

OBJECTIVE: To assess long-term outcomes with robotic versus laparoscopic/thoracoscopic and open surgery for colorectal, urologic, endometrial, cervical, and thoracic cancers. BACKGROUND: Minimally invasive surgery provides perioperative benefits and similar oncological outcomes compared with open surgery. Recent robotic surgery data have questioned long-term benefits. METHODS: A systematic review and meta-analysis of cancer outcomes based on surgical approach was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines using Pubmed, Scopus, and Embase. Hazard ratios for recurrence, disease-free survival (DFS), and overall survival (OS) were extracted/estimated using a hierarchical decision tree and pooled in RevMan 5.4 using inverse-variance fixed-effect (heterogeneity nonsignificant) or random effect models. RESULTS: Of 31,204 references, 199 were included (7 randomized, 23 database, 15 prospective, 154 retrospective studies)-157,876 robotic, 68,007 laparoscopic/thoracoscopic, and 234,649 open cases. Cervical cancer: OS and DFS were similar between robotic and laparoscopic [1.01 (0.56, 1.80), P =0.98] or open [1.18 (0.99, 1.41), P =0.06] surgery; 2 papers reported less recurrence with open surgery [2.30 (1.32, 4.01), P =0.003]. Endometrial cancer: the only significant result favored robotic over open surgery [OS; 0.77 (0.71, 0.83), P <0.001]. Lobectomy: DFS favored robotic over thoracoscopic surgery [0.74 (0.59, 0.93), P =0.009]; OS favored robotic over open surgery [0.93 (0.87, 1.00), P =0.04]. Prostatectomy: recurrence was less with robotic versus laparoscopic surgery [0.77 (0.68, 0.87), P <0.0001]; OS favored robotic over open surgery [0.78 (0.72, 0.85), P <0.0001]. Low-anterior resection: OS significantly favored robotic over laparoscopic [0.76 (0.63, 0.91), P =0.004] and open surgery [0.83 (0.74, 0.93), P =0.001]. CONCLUSIONS: Long-term outcomes were similar for robotic versus laparoscopic/thoracoscopic and open surgery, with no safety signal or indication requiring further research (PROSPERO Reg#CRD42021240519).

Assessing associations between insecure income and US workers' health: An IPUMS-MEPS analysis.

Gig economy compensation policy initiatives, such as California Prop 22, are increasing the number of US workers receiving piece rate pay (PRP) and other forms of insecure income. However, there is limited evidence about how this trend affects people's health. Using data from the 2008-19 IPUMS Medical Expenditure Panel Survey (MEPS), we examined associations between insecure compensation and US adults' self-reported overall health as well as psychological distress. We report significant associations with three types of insecure income - PRP, hourly, and daily pay - on overall health and psychological distress. These effects were robust to adjustment for suspected confounders, but point estimates suggested that the effect of each type of non-salary compensation differed by sex, level of education, income level, and health insurance coverage. These findings warrant policy makers' consideration as they balance the purported benefits of gig economy non-salary compensated work with implications for workers' health.

Clinically Localized Prostate Cancer: AUA/ASTRO Guideline. Part III: Principles of Radiation and Future Directions.

PURPOSE: The summary presented herein represents Part III of the three-part series dedicated to Clinically Localized Prostate Cancer: AUA/ASTRO Guideline, discussing principles of radiation and offering several future directions of further relevant study in patients diagnosed with clinically localized prostate cancer. Please refer to Parts I and II for discussion of risk assessment, staging, and risk-based management (Part I), and principles of active surveillance and surgery and follow-up (Part II). MATERIALS AND METHODS: The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles. RESULTS: The Clinically Localized Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with clinically localized prostate cancer. Statements regarding management of patients using radiation therapy as well as important future directions of research are detailed herein. CONCLUSIONS: This guideline aims to inform clinicians treating patients with clinically localized prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to further improve care for these men.