Multi-Scale Digital Pathology Patch-Level Prostate Cancer Grading Using Deep Learning: Use Case Evaluation of DiagSet Dataset.

Prostate cancer remains a prevalent health concern, emphasizing the critical need for early diagnosis and precise treatment strategies to mitigate mortality rates. The accurate prediction of cancer grade is paramount for timely interventions. This paper introduces an approach to prostate cancer grading, framing it as a classification problem. Leveraging ResNet models on multi-scale patch-level digital pathology and the Diagset dataset, the proposed method demonstrates notable success, achieving an accuracy of 0.999 in identifying clinically significant prostate cancer. The study contributes to the evolving landscape of cancer diagnostics, offering a promising avenue for improved grading accuracy and, consequently, more effective treatment planning. By integrating innovative deep learning techniques with comprehensive datasets, our approach represents a step forward in the pursuit of personalized and targeted cancer care.

Ensemble Deep Learning-Based Image Classification for Breast Cancer Subtype and Invasiveness Diagnosis from Whole Slide Image Histopathology.

Cancer diagnosis and classification are pivotal for effective patient management and treatment planning. In this study, a comprehensive approach is presented utilizing ensemble deep learning techniques to analyze breast cancer histopathology images. Our datasets were based on two widely employed datasets from different centers for two different tasks: BACH and BreakHis. Within the BACH dataset, a proposed ensemble strategy was employed, incorporating VGG16 and ResNet50 architectures to achieve precise classification of breast cancer histopathology images. Introducing a novel image patching technique to preprocess a high-resolution image facilitated a focused analysis of localized regions of interest. The annotated BACH dataset encompassed 400 WSIs across four distinct classes: Normal, Benign, In Situ Carcinoma, and Invasive Carcinoma. In addition, the proposed ensemble was used on the BreakHis dataset, utilizing VGG16, ResNet34, and ResNet50 models to classify microscopic images into eight distinct categories (four benign and four malignant). For both datasets, a five-fold cross-validation approach was employed for rigorous training and testing. Preliminary experimental results indicated a patch classification accuracy of 95.31% (for the BACH dataset) and WSI image classification accuracy of 98.43% (BreakHis). This research significantly contributes to ongoing endeavors in harnessing artificial intelligence to advance breast cancer diagnosis, potentially fostering improved patient outcomes and alleviating healthcare burdens.

Distance to Treatment With Radical Cystectomy in a Rural State: Long Car Rides, Equivalent Outcomes.

INTRODUCTION: Radical cystectomy is a complex surgery with better outcomes reported when performed at high-volume centers. This may lead to patients traveling farther for care. We examined the impact of travel distance on clinical outcomes. METHODS: A total of 220 patients undergoing radical cystectomy from 2015-2021 were retrospectively reviewed. Distance traveled to the treatment center by patient zip codes was classified as <12.5 miles, 12.5-49.9 miles, and ≥50 miles. Multivariable logistic regression was used to assess complications, readmissions, 90-day mortality, and length of stay by distance traveled. Time to treatment based on distance traveled was compared. RESULTS: A total of 220 patients underwent radical cystectomy with complete 90-day follow-up. Of the patients 38.6% (85/220) were readmitted; 62.5% (53/85) presented to the treatment center or were transferred. All patients readmitted to an outside hospital traveled ≥12.5 miles (P < .001). Patients with high-grade complications were likely to be transferred to the treatment center with only 23.7% (9/38) definitively managed by outside hospital. Patients traveling >12.5 miles with low-grade complications were more likely to be managed at an outside hospital (57.5%, P = .01). There was no difference in time to initiation of neoadjuvant chemotherapy (P = .99) or time to radical cystectomy following neoadjuvant chemotherapy (P = .23) by distance traveled. For 49 muscle-invasive bladder cancer patients proceeding directly to surgery without neoadjuvant chemotherapy, time from diagnosis to radical cystectomy was increased if traveling >12.5 miles (P = .04). CONCLUSIONS: Increased travel distance did not impact early postoperative outcomes. Distance traveled may impact access to care, such as time to surgery or location of readmission to the treatment center postoperatively.

Prostate Specific Antigen Testing Behaviors for Prostate Cancer Screening Among U.S. Immigrants: A Cross-sectional Analysis Using the National Health Interview Survey.

PURPOSE: Immigrants constitute 14% of the U.S. population, and this group is especially vulnerable to poor health care access. Prior research demonstrates U.S. immigrants have low rates of guideline-concordant breast and colorectal screening, but prostate cancer screening has not previously been evaluated. We sought to characterize screening behaviors among U.S. immigrants and to consider possible mechanisms to enhance PSA-based screening for this population. MATERIALS AND METHODS: Data were obtained from the 2010, 2013, 2015, and 2018 National Health Interview Survey reports, which were the recent survey years that included questions about PSA testing. Complex samples logistic regression was performed to assess the relationship between immigrant-specific characteristics including region of birth, citizenship status, length of residence within the U.S., English language proficiency, and history of PSA testing. RESULTS: There were 22,997 survey respondents; 3,257 were foreign-born and 19,740 were U.S.-born. Rates of PSA testing were much lower among the foreign-born population compared to the U.S.-born population (43% vs 60%). Citizenship status, length of residence in the U.S. for more than 15 years, and English proficiency were directly linked to increased rates of PSA testing. There was significant variability in PSA testing among immigrant subgroups and Asian immigrants had the lowest rate of PSA testing. Annual physician visits and English language proficiency were associated with increased PSA testing among the U.S. immigrant population. CONCLUSIONS: Immigrants have relatively low rates of PSA testing. Improving health care utilization and language services may help to narrow the gap in guideline-concordant prostate cancer screening between immigrants and nonimmigrants.

PRState: Incorporating genetic ancestry in prostate cancer risk scores for men of African ancestry.

BACKGROUND: Prostate cancer (PrCa) is one of the most genetically driven solid cancers with heritability estimates as high as 57%. Men of African ancestry are at an increased risk of PrCa; however, current polygenic risk score (PRS) models are based on European ancestry groups and may not be broadly applicable. The objective of this study was to construct an African ancestry-specific PrCa PRS (PRState) and evaluate its performance. METHODS: African ancestry group of 4,533 individuals in ELLIPSE consortium was used for discovery of African ancestry-specific PrCa SNPs. PRState was constructed as weighted sum of genotypes and effect sizes from genome-wide association study (GWAS) of PrCa in African ancestry group. Performance was evaluated using ROC-AUC analysis. RESULTS: We identified African ancestry-specific PrCa risk loci on chromosomes 3, 8, and 11 and constructed a polygenic risk score (PRS) from 10 African ancestry-specific PrCa risk SNPs, achieving an AUC of 0.61 [0.60-0.63] and 0.65 [0.64-0.67], when combined with age and family history. Performance dropped significantly when using ancestry-mismatched PRS models but remained comparable when using trans-ancestry models. Importantly, we validated the PRState score in the Million Veteran Program (MVP), demonstrating improved prediction of PrCa and metastatic PrCa in individuals of African ancestry. CONCLUSIONS: African ancestry-specific PRState improves PrCa prediction in African ancestry groups in ELLIPSE consortium and MVP. This study underscores the need for inclusion of individuals of African ancestry in gene variant discovery to optimize PRSs and identifies African ancestry-specific variants for use in future studies.

On-Clamp vs. Off-Clamp Robot-Assisted Partial Nephrectomy for cT2 Renal Tumors: Retrospective Propensity-Score-Matched Multicenter Outcome Analysis.

We compared perioperative outcomes after on-clamp versus off-clamp robot-assisted partial nephrectomy (RAPN) for >7 cm renal masses. A multicenter dataset was queried for patients who had undergone RAPN for a cT2cN0cM0 kidney tumor from July 2007 to February 2022. The Trifecta achievement (negative surgical margins, no severe complications, and ≤ 30% postoperative estimated glomerular filtration rate (eGFR) reduction) was considered a surrogate of surgical quality. Overall, 316 cases were included in the analysis, and 58% achieved the Trifecta. A propensity-score-matched analysis generated two cohorts of 89 patients homogeneous for age, ASA score, preoperative eGFR, and RENAL score (all p > 0.21). Compared to the on-clamp approach, OT was significantly shorter in the off-clamp group (80 vs. 190 min; p < 0.001), the incidence of sRFD was lower (22% vs. 40%; p = 0.01), and the Trifecta rate higher (66% vs. 46%; p = 0.01). In a crude analysis, >20 min of hilar clamping was associated with a significantly higher risk of sRFD (OR: 2.30; 95%CI: 1.13−4.64; p = 0.02) and with reduced probabilities of achieving the Trifecta (OR: 0.46; 95%CI: 0.27−0.79; p = 0.004). Purely off-clamp RAPN seems to be a safe and viable option to treat cT2 renal masses and may outperform the on-clamp approach regarding perioperative surgical outcomes.

Clarifying the Trade-Offs of Risk-Stratified Screening for Prostate Cancer: A Cost-Effectiveness Study.

Cancer risk prediction is necessary for precision early detection, which matches screening intensity to risk. However, practical steps for translating risk predictions to risk-stratified screening policies are not well established. We used a validated population prostate-cancer model to simulate the outcomes of strategies that increase intensity for men at high risk and reduce intensity for men at low risk. We defined risk by the Prompt Prostate Genetic Score (PGS) (Stratify Genomics, San Diego, California), a germline genetic test. We first recalibrated the model to reflect the disease incidence observed within risk strata using data from a large prevention trial where some participants were tested with Prompt PGS. We then simulated risk-stratified strategies in a population with the same risk distribution as the trial and evaluated the cost-effectiveness of risk-stratified screening versus universal (risk-agnostic) screening. Prompt PGS risk-adapted screening was more cost-effective when universal screening was conservative. Risk-stratified strategies improved outcomes at a cost of less than $100,000 per quality-adjusted life year compared with biennial screening starting at age 55 years, but risk stratification was not cost-effective compared with biennial screening starting at age 45. Heterogeneity of risk and fraction of the population within each stratum were also important determinants of cost-effectiveness.

National Recommendations against Prostate Specific Antigen Screening versus Statewide Medicaid Expansion Initiatives: A Battle of the Titans.

PURPOSE: Medicaid expansion under the Patient Protection and Affordable Care Act occurred almost concurrently with 2012 U.S. Preventive Services Task Force recommendations against prostate specific antigen screening. Here the relative influence on prostate specific antigen screening rates by 2 concurrent and opposing system-level policy initiatives is investigated: improved access to care and change in clinical practice guidelines. MATERIALS AND METHODS: Behavioral Risk Factor Surveillance System data from years 2012 to 2018 were analyzed for trends in self-reported prostate specific antigen screening and insurance coverage. Subanalyses included state Medicaid expansion status and respondent federal poverty level. Multivariable logistic regression was performed to evaluate factors associated with prostate specific antigen screening. RESULTS: From 2012 to 2018 prostate specific antigen screening predominantly declined with a notable exception of an increase of 7.3% for men at <138% federal poverty level between 2011 and 2013 in early expansion states. Initial increases did not continue, and screening trends mirrored those of nonexpansion states by 2018. Notably, 2014 planned expansions states did not follow this trend with minimal change between 2015 and 2017 compared to declines in early expansion states and nonexpansion states (-0.4% vs -6.7% and -8.6%, respectively). CONCLUSIONS: Medicaid expansion was associated with increased rates of insured men at <138% federal poverty level from 2012 to 2018 in early expansion states. In this group, initial increases in prostate specific antigen screening were not durable and followed the trend of reduced screening seen across the United States. In planned expansions states the global drop in prostate specific antigen screening from 2016 to 2018 was offset in men at <138% federal poverty level by expanding access to care. Nonexpansion states showed a steady decline in prostate specific antigen screening rates. This suggests that policy such as U.S. Preventive Services Task Force recommendations against screening competes with and often outmatches access to care.

Meditative and mind-body practice among patients with genitourinary malignancy.

INTRODUCTION AND OBJECTIVE: Research on the utility of meditative and mind-body (MB) practices has increased dramatically in the last two decades and both have been suggested as useful adjuncts in coping with stressors associated with cancer survivorship. There exists little data on use among genitourinary (GU) cancer survivors. This study seeks to describe meditative and MB utilization among GU cancer survivors. METHODS: Analysis of data from the 2012 and 2017 National Health Interview Survey was conducted. Patients aged 40 and older reporting a history of any cancer diagnosis (including 3 GU cancers) were included in the analysis. We explored questions about meditative and MB practices in the past 12 months. Complex Samples Logistic regression was performed to compare the relationship between cancer status and use of these practices. RESULTS: Self-reported meditative practices were more prevalent in 2017 (17%) than in 2012 (5%). Patients who self-reported a cancer diagnosis of any kind were significantly more likely to utilize meditative practices. Patients with kidney cancer were significantly more likely to meditate and trended towards higher MB utilization. In contrast, bladder cancer patients were less likely to meditate and use MB practices. Increases in meditation were greater than those seen for MB in all groups. CONCLUSIONS: Meditative and MB practices increased in prevalence between 2012 and 2017 with notable heterogeneity between cancer types. Given the potential benefit, more broad incorporation into survivorship programs may be warranted. Future work should explore the significance of this heterogeneity and the utility of these practices to patients with urologic malignancy.

Pathologic nodal downstaging in men with clinically involved lymph nodes undergoing radical prostatectomy: Implications for definitive locoregional therapy.

A prostate cancer (CaP) patient with nonmetastatic but clinical positive lymph nodes (cN+) represents a difficult clinical scenario. We compare overall survival (OS) between cN+ men that underwent radical prostatectomy (RP) and were found to have negative node status (pN) with those found to have positive nodal status (pN+), and assess predictors of discordant nodal status. We queried the National Cancer Data Base between 2004 and 2015 for patients that were cT1-3 cN+ cM0 CaP treated with RP. Patients with 0 nodes, cT4, or cM1 disease were excluded. We compared groups based on pathologic nodal status: Discordant (cN+ -> pN) & Concordant (cN+ -> pN+). Kaplan Meier estimations were used to compare OS. Logistic regression was used to determine possible predictors of nodal status. We find that of 6470 cN+ patients, 1,367 (21.1%) underwent RP, 866 (13.4%) had confirmed nodal status. Discordant status was found in 159 (18.4%) and concordant staging in 707 (81.6%). Differences exist in PSA at diagnosis (7.3 vs. 11.2), biopsy group, # of nodes examined (7 vs. 10), race, and Charlson index. Discordant staging had longer OS compared to Concordant staging (P = 0.007) and similar OS to a 3:1 matched cohort of high risk localized CaP patients used as reference (P = 0.46). Lower Gleason Score (GG1-3) was associated with an increased likelihood of discordant staging. Clinical nodal staging is associated with a substantial false positive rate. Discordant status had better OS than Concordant status and similar OS to matched patients with localized CaP. Clinical nodal staging may inappropriately lead to noncurative therapy in a substantial number of men with potentially curable disease.

Impact of positive surgical margins on survival after partial nephrectomy in localized kidney cancer: analysis of the National Cancer Database.

BACKGROUND: The impact of positive surgical margins (PSM) on outcomes in partial nephrectomy (PN) is controversial. We investigated impact of PSM for patients undergoing PN on overall survival (OS) in different stages of renal cell carcinoma (RCC). METHODS: Retrospective analysis of patients from the US National Cancer Database who underwent PN for cT1a-cT2b N0M0 RCC between 2004-13. Patients were stratified by pathological stage (pT1a, pT1b, pT2a, pT2b, and pT3a [upstaged]) and analyzed by margin status. Cox Regression multivariable analysis (MVA) was performed to investigate associations of PSM and covariates on all-cause mortality (ACM). Kaplan-Meier analysis (KMA) of OS was performed for PSM versus negative margin (NSM) by pathological stage. Sub-analysis of Charlson Comorbidity Index 0 (CCI=0) subgroup was conducted to reduce bias from comorbidities. RESULTS: We analyzed 42,113 PN (pT1a: 33,341 [79.2%]; pT1a, pT1b: 6689 [15.9%]; pT2a: 757 [1.8%]; pT2b: 165 [0.4%]; and pT3a: upstaged 1161 [2.8%]). PSM occurred in 6.7% (2823) (pT1a: 6.5%, pT1b: 6.3%, pT2a: 5.9%, pT2b: 6.1%, pT3a: 14.1%, P<0.001). On MVA, PSM was associated with 31% increase in ACM (HR 1.31, P<0.001), which persisted in CCI=0 sub-analysis (HR: 1.25, P<0.001). KMA revealed negative impact of PSM vs. NSM on 5-year OS: pT1 (87.3% vs. 90.9%, P<0.001), pT2 (86.7% vs. 82.5%, P=0.48), and upstaged pT3a (69% vs. 84.2%, P<0.001). CONCLUSIONS: PSM after PN was independently associated with across-the-board decrement in OS, which worsened in pT3a disease and persisted in sub-analysis of patients with CCI=0. PSM should prompt more aggressive surveillance or definitive resection strategies.

Neoadjuvant rituximab modulates the tumor immune environment in patients with high risk prostate cancer.

BACKGROUND: Immunotherapeutic regulation of the tumor microenvironment in prostate cancer patients is not understood. Most antibody immunotherapies have not succeeded in prostate cancer. We showed previously that high-risk PCa patients have a higher density of tumor infiltrating B-cells in prostatectomy specimens. In mouse models, anti-CD20 antibody ablation of B-cells delayed PCa regrowth post-treatment. We sought to determine whether neoadjuvant anti-CD20 immunotherapy with rituximab could reduce CD20+ B cell infiltration of prostate tumors in patients. METHODS: An open label, single arm clinical trial enrolled eight high-risk PCa patients to receive one cycle of neoadjuvant rituximab prior to prostatectomy. Eleven clinical specimens with similar characteristics were selected as controls. Treated and control samples were concurrently stained for CD20 and digitally scanned in a blinded fashion. A new method of digital image quantification of lymphocytes was applied to prostatectomy sections of treated and control cases. CD20 density was quantified by a deconvolution algorithm in pathologist-marked tumor and adjacent regions. Statistical significance was assessed by one sided Welch's t-test, at 0.05 level using a gatekeeper strategy. Secondary outcomes included CD3+ T-cell and PD-L1 densities. RESULTS: Mean CD20 density in the tumor regions of the treated group was significantly lower than the control group (p = 0.02). Mean CD3 density in the tumors was significantly decreased in the treated group (p = 0.01). CD20, CD3 and PD-L1 staining primarily occurred in tertiary lymphoid structures (TLS). Neoadjuvant rituximab was well-tolerated and decreased B-cell and T-cell density within high-risk PCa tumors compared to controls. CONCLUSIONS: This is the first study to treat patients prior to surgical prostate removal with an immunotherapy that targets B-cells. Rituximab treatment reduced tumor infiltrating B and T-cell density especially in TLSs, thus, demonstrating inter-dependence between B- and T-cells in prostate cancer and that Rituximab can modify the immune environment in prostate tumors. Future studies will determine who may benefit from using rituximab to improve their immune response against prostate cancer. Trial registration NCT01804712, March 5th, 2013 https://clinicaltrials.gov/ct2/show/NCT01804712?cond=NCT01804712&draw=2&rank=1.

Receipt of Survivorship Care Plans and Self-Reported Health Status among Patients with Genitourinary Malignancy.

PURPOSE: Implementation of survivorship care plans has been emphasized as a key component to improving care for cancer survivors. Our objective was to determine the prevalence of survivorship care plan receipt for survivors of genitourinary malignancy including kidney, prostate and bladder cancer, and evaluate whether receipt was associated with a measurable health benefit. MATERIALS AND METHODS: Data from the Behavioral Risk Factor Surveillance System Cancer Survivorship modules in 2012, 2014, 2016 and 2017 were analyzed. The proportion of patients with bladder, kidney or prostate cancer receiving a survivorship care plan was calculated. Complex samples multivariable logistic regressions were performed to determine the association of survivorship care plan receipt with sociodemographic variables, and assess the relationship between survivorship care plan receipt and self-reported health status (general, physical and mental). RESULTS: Survivorship care plan distribution increased from 27.5% in 2012 to 39.5% in 2017. Patients with low income, less formal education and extremes of age were less likely to receive a survivorship care plan. Those receiving a survivorship care plan were less likely to report poor physical health (OR 0.70, CI 0.52-0.96, p=0.026). Subanalysis showed a similar result for physical health of patients with prostate cancer (OR 0.68, CI 0.48-0.96, p=0.030) and general health of patients with kidney cancer (OR 0.37, CI 0.19-0.75, p=0.006). CONCLUSIONS: Distribution of survivorship care plans to genitourinary malignancy survivors has increased since 2012 in response to advocacy from national organizations. Nonetheless, utilization is low and there is heterogeneity in the populations likely to receive a survivorship care plan. There is a measurable association between survivorship care plans and improved health status but further study is needed to determine causality.

Neoadjuvant Approaches Prior To Radical Prostatectomy.

Patients with high-risk localized prostate cancer benefit from multimodality therapy of curative intent. Androgen-deprivation therapy (ADT) combined with radiation improves survival in this population. However, prior clinical trials of neoadjuvant ADT and surgery failed to consistently demonstrate a survival advantage. The development of novel, more potent hormonal agents presents an opportunity to revisit the potential for neoadjuvant therapy to improve long-term outcomes for patients with localized prostate cancer. We review recent advances in neoadjuvant approaches for prostate cancer and emerging clinical trials data supporting the use of neoadjuvant therapy prior to radical prostatectomy.

Association between Radical Prostatectomy and Survival in Men with Clinically Node-positive Prostate Cancer.

Evidence supporting radical prostatectomy (RP) for men with clinically node-positive (cN+) prostate cancer (PC) is limited. In a US national database, we identified 741 men with cN+ nonmetastatic PC diagnosed during 2000-2015 who underwent definitive local therapy with RP (n=78), radiotherapy (RT) with neoadjuvant androgen deprivation therapy (ADT) (n=193), or nondefinitive therapy with ADT alone (n=445) or observation (n=25). We compared PC-specific mortality (PCSM) and all-cause mortality (ACM) using multivariable Fine-Gray competing risk regression and Cox regression, respectively. Compared to nondefinitive therapy, RP was associated with significantly better PCSM (subdistribution hazard ratio [SHR] 0.32, 95% confidence interval [CI] 0.16-0.66; p=0.002) and ACM (HR 0.36, 95% CI 0.21-0.61; p<0.001). Compared to RT, RP was not associated with a significant difference in PCSM (SHR 0.47, 95% CI 0.19-1.17; p=0.1) or ACM (HR 0.88, 95% CI 0.46-1.70; p=0.71). These data suggest that RP is associated with favorable survival outcomes that appear to be superior to those for patients who did not receive definitive therapy and comparable to those for patients receiving definitive ADT/RT. Randomized trials of surgery with multimodal therapy are needed. PATIENT SUMMARY: We found that in clinically node-positive prostate cancer, radical prostatectomy was associated with a cancer-specific and overall survival benefit compared to nondefinitive therapy. Randomized clinical trials are required to determine the best treatment approach in this patient population.

Germline genetics in localized prostate cancer.

PURPOSE OF REVIEW: To provide the reader an understanding of the importance and limitations of prostate cancer (PCa) screening, the heritable component of PCa and the role that germline genetic markers can play in risk-adapted screening and treatment. RECENT FINDINGS: Despite strong science supporting the association of germline genetic change with PCa risk and outcome, there has been a reluctance to pursue practical application of these technologies. Recent findings suggest that actionable information may now be garnered from this form of testing, which can help men at risk for and with PCa. SUMMARY: This is an exciting time whereby germline genetic markers can help overcome some of the shortcomings of current PCa screening and treatment paradigms. Understanding their benefit and limitations while keeping the patient's best interest in mind will be the key for the responsible application of these exciting technologies.

Association of Treatment With 5α-Reductase Inhibitors With Time to Diagnosis and Mortality in Prostate Cancer.

Importance: 5α-Reductase inhibitors (5-ARIs), commonly used to treat benign prostatic hyperplasia, reduce serum prostate-specific antigen (PSA) concentrations by 50%. The association of 5-ARIs with detection of prostate cancer in a PSA-screened population remains unclear. Objective: To test the hypothesis that prediagnostic 5-ARI use is associated with a delayed diagnosis, more advanced disease at diagnosis, and higher risk of prostate cancer-specific mortality and all-cause mortality than use of other or no PSA-decreasing drugs. Design, Setting, and Participants: This population-based cohort study linked the Veterans Affairs Informatics and Computing Infrastructure with the National Death Index to obtain patient records for 80 875 men with American Joint Committee on Cancer stage I-IV prostate cancer diagnosed from January 1, 2001, to December 31, 2015. Patients were followed up until death or December 31, 2017. Data analysis was performed from March 2018 to May 2018. Exposures: Prediagnostic 5-ARI use. Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality (PCSM). Secondary outcomes included time from first elevated PSA (defined as PSA≥4 ng/mL) to diagnostic prostate biopsy, cancer grade and stage at time of diagnosis, and all-cause mortality (ACM). Prostate-specific antigen levels for 5-ARI users were adjusted by doubling the value, consistent with previous clinical trials. Results: Median (interquartile range [IQR]) age at diagnosis was 66 (61-72) years; median [IQR] follow-up was 5.90 (3.50-8.80) years. Median time from first adjusted elevated PSA to diagnosis was significantly greater for 5-ARI users than 5-ARI nonusers (3.60 [95% CI, 1.79-6.09] years vs 1.40 [95% CI, 0.38-3.27] years; P < .001) among patients with known prostate biopsy date. Median adjusted PSA at time of biopsy was significantly higher for 5-ARI users than 5-ARI non-users (13.5 ng/mL vs 6.4 ng/mL; P < .001). Patients treated with 5-ARI were more likely to have Gleason grade 8 or higher (25.2% vs 17.0%; P < .001), clinical stage T3 or higher (4.7% vs 2.9%; P < .001), node-positive (3.0% vs 1.7%; P < .001), and metastatic (6.7% vs 2.9%; P < .001) disease than 5-ARI nonusers. In a multivariable regression, patients who took 5-ARI had higher prostate cancer-specific (subdistribution hazard ratio [SHR], 1.39; 95% CI, 1.27-1.52; P < .001) and all-cause (HR, 1.10; 95% CI, 1.05-1.15; P < .001) mortality. Conclusions and Relevance: Results of this study demonstrate that prediagnostic use of 5-ARIs was associated with delayed diagnosis and worse cancer-specific outcomes in men with prostate cancer. These data highlight a continued need to raise awareness of 5-ARI-induced PSA suppression, establish clear guidelines for early prostate cancer detection, and motivate systems-based practices to facilitate optimal care for men who use 5-ARIs.

Systemic therapy in the management of localized and locally advanced renal cell carcinoma: Current state and future perspectives.

Systemic therapy strategies in the setting of localized and locally advanced renal cell carcinoma have continued to evolve in two directions: (i) as adjuvant therapy (to reduce the risk of recurrence or progression in high-risk localized groups); or (ii) as neoadjuvant therapy as a strategy to render primary renal tumors amenable to planned surgical resection in settings where radical resection or nephron-sparing surgery was not thought to be safe or feasible. In the realm of adjuvant therapy, the results of adjuvant therapy phase III randomized clinical trials have been mixed and contradictory; nevertheless, the findings of the landmark Sunitinib Treatment of Renal Adjuvant Cancer study have led to approval of sunitinib as an adjuvant agent in the USA. In the realm of neoadjuvant therapy, presurgical tumor reduction has been shown in a number of phase II studies utilizing targeted molecular agents and in a recently published small randomized double-blind placebo-controlled study, and an expanding body of literature suggests benefit in select patients. Thus, large randomized clinical trial data are not present to support this approach, and guidelines for use of presurgical therapy have not been promulgated. The advent of immunomodulation through checkpoint inhibition represents an exciting horizon for adjuvant and neoadjuvant strategies. The present article reviews the current status and future prospects of adjuvant and neoadjuvant therapy in localized and locally advanced renal cell carcinoma.