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Purpose Active surveillance represents a strategy to address the overtreatment of prostate cancer, yet uncertainty regarding individual patient outcomes remains a concern. We evaluated outcomes in a prospective multicenter study of active surveillance. Materials and Methods We studied 905 men in the prospective Canary PASS enrolled between 2008 and 2013. We collected clinical data at study entry and at prespecified intervals, and determined associations with adverse reclassification, defined as increased Gleason grade or greater cancer volume on followup biopsy. We also evaluated the relationships of clinical parameters with pathology findings in participants who underwent surgery after a period of active surveillance. Results At a median followup of 28 months 24% of participants experienced adverse reclassification, of whom 53% underwent treatment while 31% continued on active surveillance. Overall 19% of participants received treatment, 68% with adverse reclassification, while 32% opted for treatment without disease reclassification. In multivariate Cox proportional hazards modeling the percent of biopsy cores with cancer, body mass index and prostate specific antigen density were associated with adverse reclassification (p=0.01, 0.04, 0.04, respectively). Of 103 participants subsequently treated with radical prostatectomy 34% had adverse pathology, defined as primary pattern 4-5 or nonorgan confined disease, including 2 with positive lymph nodes, with no significant relationship between risk category at diagnosis and findings at surgery (p=0.76). Conclusions Most men remain on active surveillance at 5 years without adverse reclassification or adverse pathology at surgery. However, clinical factors had only a modest association with disease reclassification, supporting the need for approaches that improve the prediction of this outcome.

Objectives: To assess the value of dynamic contrast-enhanced (DCE) combined with T2-weighted (T2W) endorectal coil (ERC) magnetic resonance imaging (MRI) at 3 T for determining extracapsular extension (ECE) of prostate cancer.Methods: In this IRB-approved study, ERC 3-T MRI of the prostate was performed in 108 patients before radical prostatectomy. T2W fast spin-echo and DCE 3D gradient echo images were acquired. The interpretations of readers with varied experience were analysed. MRI-based staging results were compared with radical prostatectomy histology. Descriptive statistics were generated for prediction of ECE and staging accuracies were determined by the area under the receiver-operating characteristic curve.Results: The overall sensitivity, specificity, positive predictive value and negative predictive value for ECE were 75 %, 92 %, 79 % and 91 %, respectively. Diagnostic accuracy for staging was 86 %, 80 % and 91 % for all readers, experienced and less experienced readers, respectively.Conclusions: ERC 3-T MRI of the prostate combining DCE and T2W imaging is an accurate pretherapeutic staging tool for assessment of ECE in clinical practice across varying levels of reader experience.Key Points: • Endorectal coil (ERC) magnetic resonance imaging is widely used for imaging prostatic disease. • ERC 3-T MRI is reasonably accurate for local prostate cancer staging. • High diagnostic accuracy is achievable across different levels of reader experience. • MRI facilitates therapeutic decisions in patients with prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Limited survival benefit and excess treatment because of prostate-specific antigen (PSA) screening in randomized trials suggests a need for more restricted selection of prostate biopsy candidates by discerning risk of histologically aggressive versus indolent cancer before biopsy.Methods: Subjects undergoing first prostate biopsy enrolled in a multicenter, prospective cohort of the National Cancer Institute Early Detection Research Network (N = 635) were analyzed to develop a model for predicting histologically aggressive prostate cancers. The control arm of the Prostate Cancer Prevention Trial (N = 3833) was used to validate the generalization of the predictive model.Results: The Early Detection Research Network cohort was comprised of men among whom 57% had no cancer, 14% had indolent cancer, and 29% had aggressive cancer. Age, body mass index, family history of prostate cancer, abnormal digital rectal examination (DRE), and PSA density (PSAD) were associated with aggressive cancer (all P < .001). The Early Detection Research Network model outperformed PSA alone in predicting aggressive cancer (area under the curve [AUC] = 0.81 vs 0.71, P < .01). Model validation in the Prostate Cancer Prevention Trial cohort accurately identified men at low (<10%) risk of aggressive cancer for whom biopsy could be averted (AUC = 0.78; 95% confidence interval, 0.75-0.80). Under criteria from the Early Detection Research Network model, prostate biopsy can be restricted to men with PSAD >0.1 ng/mL/cc or abnormal DRE. When PSAD is <0.1 ng/mL/cc, family history or obesity can identify biopsy candidates.Conclusions: A predictive model incorporating age, family history, obesity, PSAD, and DRE elucidates criteria whereby ¼ of prostate biopsies can be averted while retaining high sensitivity in detecting aggressive prostate cancer. [ABSTRACT FROM AUTHOR]

Earlier detection of prostate cancer in the past decade has been accompanied by greater reduction in US prostate cancer mortality than that seen with any other cancer. Prostate cancer is usually diagnosed at early stages and is most commonly treated by prostatectomy, radiotherapy, or brachytherapy. For intermediate- and high-risk prostate cancers, randomized clinical trials have shown survival benefit subsequent to prostatectomy or to combined radiation with androgen-suppressive therapy. However, prostatectomy, radiotherapy, and brachytherapy each can lead to distinct adverse effects. Moreover, for the lowest-risk categories of early stage prostate cancer, evidence supporting an intervention is only indirect. New approaches to surveillance of prostate cancer have consequently emerged that do not eschew treatment altogether. Instead "active" surveillance aims to implement definitive intervention effectively for those low-risk cancers that show a propensity for progression as evidenced by histopathological or serological change during the surveillance interval. [ABSTRACT FROM AUTHOR]

Background: Although prostate-specific antigen (PSA) is a prototypic biomarker for prostate cancer, it has poor specificity. Expression of alpha-methylacyl-CoA racemase (AMACR), which is involved in the conversion of R-stereoisomers of branched-chain fatty acids to S-stereoisomers, has been shown to be specifically increased in prostate cancer epithelia. However, attempts to detect AMACR in circulation have not been successful. Hence, we determined whether an immune response to AMACR could be used as a serum biomarker for prostate cancer.Methods: Sera from patients with biopsy-proven prostate cancer and from control subjects were screened for a humoral immune response to selected tumor antigens, including AMACR, by using protein microarrays (46 patients, 28 control subjects). Humoral immune response to AMACR was then validated using high-throughput immunoblot analysis (151 patients, 259 control subjects) and enzyme-linked immunosorbent assay (ELISA) (54 patients, 55 control subjects). Receiver operating characteristic curves were used to determine the sensitivity and specificity of the immune response to AMACR to detect prostate cancer.Results: Immunoreactivity against AMACR was statistically significantly higher in sera from patients with prostate cancer than in control subjects by all three techniques (P(protein microarray) =.009, P(immunoblot)<.001, P(ELISA) =.011). High-throughput immunoblot analysis revealed that, in subjects with intermediate PSA levels (4-10 ng/mL), the immune response against AMACR was more sensitive and specific than was PSA in distinguishing sera from prostate cancer patients relative to control subjects (sensitivity and specificity of 77.8% and 80.6% versus 45.6% and 50%, respectively; area under the curve of 0.789 versus 0.492; P<.001).Conclusion: Assays to detect a humoral immune response against AMACR may have the potential to supplement PSA screening in identifying patients with clinically significant prostate cancer, especially those with intermediate PSA levels. [ABSTRACT FROM AUTHOR]

Context: Molecular profiling of prostate cancer has led to the identification of candidate biomarkers and regulatory genes. Discoveries from these genome-scale approaches may have applicability in the analysis of diagnostic prostate specimens.Objectives: To determine the expression and clinical utility of alpha-methylacyl coenzyme A racemase (AMACR), a gene identified as being overexpressed in prostate cancer by global profiling strategies.Design: Four gene expression data sets from independent DNA microarray analyses were examined to identify genes expressed in prostate cancer (n = 128 specimens). A lead candidate gene, AMACR, was validated at the transcript level by reverse transcriptase polymerase chain reaction (RT-PCR) and at the protein level by immunoblot and immunohistochemical analysis. AMACR levels were examined using prostate cancer tissue microarrays in 342 samples representing different stages of prostate cancer progression. Protein expression was characterized as negative (score = 1), weak (2), moderate (3), or strong (4). Clinical utility of AMACR was evaluated using 94 prostate needle biopsy specimens.Main Outcome Measures: Messenger RNA transcript and protein levels of AMACR; sensitivity and specificity of AMACR as a tissue biomarker for prostate cancer in needle biopsy specimens.Results: Three of 4 independent DNA microarray analyses (n = 128 specimens) revealed significant overexpression of AMACR in prostate cancer (P<.001). AMACR up-regulation in prostate cancer was confirmed by both RT-PCR and immunoblot analysis. Immunohistochemical analysis demonstrated an increased expression of AMACR in malignant prostate epithelia relative to benign epithelia. Tissue microarrays to assess AMACR expression in specimens consisting of benign prostate (n = 108 samples), atrophic prostate (n = 26), prostatic intraepithelial neoplasia (n = 75), localized prostate cancer (n = 116), and metastatic prostate cancer (n = 17) demonstrated mean AMACR protein staining intensity of 1.31 (95% confidence interval, 1.23-1.40), 2.33 (95% CI, 2.13-2.52), 2.67 (95% CI, 2.52-2.81), 3.20 (95% CI, 3.10-3.28), and 2.50 (95% CI, 2.20-2.80), respectively (P<.001). Pairwise comparisons demonstrated significant differences in staining intensity between clinically localized prostate cancer compared with benign prostate tissue, with mean expression scores of 3.2 and 1.3, respectively (mean difference, 1.9; 95% CI, 1.7-2.1; P<.001). Using moderate or strong staining intensity as positive (score = 3 or 4), evaluation of AMACR protein expression in 94 prostate needle biopsy specimens demonstrated 97% sensitivity and 100% specificity for detecting prostate cancer.Conclusions: AMACR was shown to be overexpressed in prostate cancer using independent experimental methods and prostate cancer specimens. AMACR may be useful in the interpretation of prostate needle biopsy specimens that are diagnostically challenging. [ABSTRACT FROM AUTHOR]

Gene therapy holds great potential for urologic malignancies. However, further progress in vector development is needed before gene therapy becomes a standard component of urologic practice. [ABSTRACT FROM AUTHOR]

Background: New biomarkers, such as autoantibody signatures, may improve the early detection of prostate cancer.Methods: With a phage-display library derived from prostate-cancer tissue, we developed and used phage protein microarrays to analyze serum samples from 119 patients with prostate cancer and 138 controls, with the samples equally divided into training and validation sets. A phage-peptide detector that was constructed from the training set was evaluated on an independent validation set of 128 serum samples (60 from patients with prostate cancer and 68 from controls).Results: A 22-phage-peptide detector had 88.2 percent specificity (95 percent confidence interval, 0.78 to 0.95) and 81.6 percent sensitivity (95 percent confidence interval, 0.70 to 0.90) in discriminating between the group with prostate cancer and the control group. This panel of peptides performed better than did prostate-specific antigen (PSA) in distinguishing between the group with prostate cancer and the control group (area under the curve for the autoantibody signature, 0.93; 95 percent confidence interval, 0.88 to 0.97; area under the curve for PSA, 0.80; 95 percent confidence interval, 0.71 to 0.88). Logistic-regression analysis revealed that the phage-peptide panel provided additional discriminative power over PSA (P<0.001). Among the 22 phage peptides used as a detector, 4 were derived from in-frame, named coding sequences. The remaining phage peptides were generated from untranslated sequences.Conclusions: Autoantibodies against peptides derived from prostate-cancer tissue could be used as the basis for a screening test for prostate cancer. [ABSTRACT FROM AUTHOR]

Prostate specific antigen (PSA) screening has heralded stage migration in prostate cancer toward cancers that may be readily eliminated by primary intervention. We sought to identify contemporary, preprostatectomy measures of cancer severity useful and significant for predicting postprostatectomy, recurrence-free survival. The association of baseline variables clinical variables (age, clinical stage, serum PSA, and race) and prostate biopsy parameters (Gleason score, presence of perineural invasion, number of biopsy cores with cancer, and the greatest percentage of a biopsy core occupied by cancer--GPC) with recurrence-free survival was evaluated by multivariate Cox proportional hazards regression among consecutive patients that underwent radical prostatectomy as primary therapy between 1994 and 2002. Tables were generated depicting expected 5-year recurrence-free survival after prostatectomy. From 1414 patients, 183 developed biochemical recurrence, 8 died from prostate cancer, and 31 died of all causes. Multivariable Cox regression found that clinical stage, PSA, Gleason score, and the greatest percentage of a biopsy core involved by cancer (GPC), were each significant determinants of post-prostatectomy, PSA recurrence-free survival (P < 0.05 for each). Gleason score and GPC were also significantly associated with clinical recurrence-free survival and cancer death, whereas other biopsy parameters and PSA were not. The amount of cancer in a biopsy core is a significant predictor of recurrence-free survival after prostatectomy, and is a simple clinical measure that complements baseline PSA, and Gleason score in predicting outcome. Tabulated 5-year PSA-free survival outcomes, stratified by these preoperative parameters, provide a basis for preoperative counseling of patients regarding postprostatectomy cancer control expectations. [ABSTRACT FROM AUTHOR]

Background: Localized prostate tumors show significant spatial heterogeneity, with regions of high-grade disease adjacent to lower grade disease. Consequently, prostate cancer biopsies are prone to sampling bias, potentially leading to underestimation of tumor grade. To study the clinical, epidemiologic, and molecular hallmarks of this phenomenon, we conducted a prospective study of grade upgrading: differences in detected prostate cancer grade between biopsy and surgery., Methods: We established a prospective, multi-institutional cohort of men with grade group 1 (GG1) prostate cancer on biopsy who underwent radical prostatectomy. Upgrading was defined as detection of GG2+ in the resected tumor. Germline DNA from 192 subjects was subjected to whole-genome sequencing to quantify ancestry, pathogenic variants in DNA damage response genes, and polygenic risk., Results: Of 285 men, 67% upgraded at surgery. PSA density and percent of cancer in pre-prostatectomy positive biopsy cores were significantly associated with upgrading. No assessed genetic risk factor was predictive of upgrading, including polygenic risk scores for prostate cancer diagnosis., Conclusions: In a cohort of patients with low-grade prostate cancer, a majority upgraded at radical prostatectomy. PSA density and percent of cancer in pre-prostatectomy positive biopsy cores portended the presence of higher-grade disease, while germline genetics was not informative in this setting. Patients with low-risk prostate cancer, but elevated PSA density or percent cancer in positive biopsy cores, may benefit from repeat biopsy, additional imaging or other approaches to complement active surveillance., Impact: Further risk stratification of patients with low-risk prostate cancer may provide useful context for active surveillance decision-making., (©2024 The Authors; Published by the American Association for Cancer Research.)

Extramammary Paget disease (EMPD) is a rare dermatologic malignancy with a high rate of recurrence and increased risk for developing secondary malignancies. We present a 74-year-old male with previously resected primary EMPD who presented with widespread PSMA-avid lesions without prostatic uptake, an elevated PSA >100, and a negative prostate biopsy. Based on this and immunohistological staining, recurrent EMPD was suspected. However, after additional staining and reexamining their clinical presentation, metastatic prostate cancer without a detected primary lesion is more probable. This case highlights the diagnostic challenge variable expression of shared biomarkers found in EMPD and prostate cancer present to clinicians., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Viraj Master reports financial support was provided by Crotts Initiative. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Inc.)

The T cell response to cancer controls disease progression and response to immunotherapy 1-3 . Despite extensive knowledge regarding CD8 T cells, how CD4 T cells contribute to this process is less well understood. Here we identified a population of PD1 + TCF1 + CD4 T cells with stem-like properties that are capable of self-renewal and differentiation into canonical CD4 effector cells. Primarily residing in tumour-draining lymph nodes (TDLNs), these tumour-specific CD4 T cells are restricted by T regulatory (T reg ) cells to a stem-like fate that predominantly generated induced T reg (iT reg ) cells, limiting effector CD8 T cell responses to the tumour. By contrast, upon T reg depletion, stem-like CD4 T cells differentiated into T helper 1 (T H 1) cells, and via IFNγ production induced robust effector differentiation from TCF1 + CD8 T cells in TDLNs, a state we defined as 'active'. Notably, enforcing TBET expression in transferred stem-like CD4 T cells was sufficient to overcome the established restricted T cell state. Despite the presence of T reg cells, endogenous stem-like CD4 T cells actively generated T H 1 cells, which were required to restore TDLN effector CD8 T cell differentiation, enhance tumour control and rescue response to immunotherapy. In agreement, T H 1 differentiation in patients with kidney cancer predicted successful immunotherapy responses and improved progression-free survival. Together, these findings identify a stem-like CD4 T cell population that through alternative differentiation fates controls the switch between restricted and active T cell states with implications for cancer immunotherapies., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Importance: The association between radiotherapy (RT) timing after radical prostatectomy and long-term patient-reported health-related quality of life (HRQOL) in men with prostate cancer is unknown., Objective: To measure long-term HRQOL in men with prostate cancer up to 15 years after prostatectomy with or without RT and examine whether early vs late postprostatectomy RT is associated with differences in sexual, urinary, and bowel HRQOL., Design, Setting, and Participants: A prospective, multicenter, longitudinal cohort analysis using HRQOL data from the PROST-QA (2003-2006) and RP2 consortium (2010-2013) studies was conducted. Men with localized prostate cancer undergoing radical prostatectomy were included. Data were analyzed between May 8, 2023, and March 1, 2024. The study was conducted in 12 high-volume academic medical centers in the US., Exposures: Men were stratified based on receipt and timing of postprostatectomy RT: prostatectomy only, early RT (<12 months), and late RT (≥12 months)., Main Outcomes and Measures: Longitudinal sexual, incontinence, urinary irritation, bowel, and hormonal/vitality HRQOL were measured via the Expanded Prostate Cancer Index Composite at baseline; months 2, 6, and 12; and annually thereafter. Treatment groups were compared using multivariable linear mixed-effects models of change in longitudinal domain scores. Pad use for incontinence was measured longitudinally among men receiving postprostatectomy RT., Results: A total of 1203 men were included in the study: prostatectomy only (n = 1082), early RT (n = 57), and late RT (n = 64). Median age for the entire cohort was 60.5 (range, 38.8-79.7) years, and 1075 men (92.0%) were White. Median follow-up was 85.6 (IQR, 35.8-117.2) months. Compared with men receiving prostatectomy alone, those receiving postprostatectomy RT had significantly greater decreases in sexual, incontinence, and urinary irritation HRQOL. However, timing of postprostatectomy RT, specifically early vs late, was not associated with a long-term decrease in any HRQOL domain. There was evidence of improved recovery of sexual, continence, and urinary irritation scores among men receiving early RT compared with those receiving late RT after prostatectomy. Before the start of postprostatectomy RT, 39.3% of men in the early RT cohort and 73.4% of men in the late RT cohort were pad-free. By the sixth visit post-RT, 67.4% in the early RT cohort and 47.6% in the late RT cohort were pad-free., Conclusions and Relevance: In this multicenter, prospective analysis, postprostatectomy RT appeared to be negatively associated with long-term HRQOL across all domains. However, receipt of early vs late postprostatectomy RT may result in similar long-term HRQOL outcomes.

Importance: Benefits of prostate cancer (PCa) screening with prostate-specific antigen (PSA) alone are largely offset by excess negative biopsies and overdetection of indolent cancers resulting from the poor specificity of PSA for high-grade PCa (ie, grade group [GG] 2 or greater)., Objective: To develop a multiplex urinary panel for high-grade PCa and validate its external performance relative to current guideline-endorsed biomarkers., Design, Setting, and Participants: RNA sequencing analysis of 58 724 genes identified 54 markers of PCa, including 17 markers uniquely overexpressed by high-grade cancers. Gene expression and clinical factors were modeled in a new urinary test for high-grade PCa (MyProstateScore 2.0 [MPS2]). Optimal models were developed in parallel without prostate volume (MPS2) and with prostate volume (MPS2+). The locked models underwent blinded external validation in a prospective National Cancer Institute trial cohort. Data were collected from January 2008 to December 2020, and data were analyzed from November 2022 to November 2023., Exposure: Protocolized blood and urine collection and transrectal ultrasound-guided systematic prostate biopsy., Main Outcomes and Measures: Multiple biomarker tests were assessed in the validation cohort, including serum PSA alone, the Prostate Cancer Prevention Trial risk calculator, and the Prostate Health Index (PHI) as well as derived multiplex 2-gene and 3-gene models, the original 2-gene MPS test, and the 18-gene MPS2 models. Under a testing approach with 95% sensitivity for PCa of GG 2 or greater, measures of diagnostic accuracy and clinical consequences of testing were calculated. Cancers of GG 3 or greater were assessed secondarily., Results: Of 761 men included in the development cohort, the median (IQR) age was 63 (58-68) years, and the median (IQR) PSA level was 5.6 (4.6-7.2) ng/mL; of 743 men included in the validation cohort, the median (IQR) age was 62 (57-68) years, and the median (IQR) PSA level was 5.6 (4.1-8.0) ng/mL. In the validation cohort, 151 (20.3%) had high-grade PCa on biopsy. Area under the receiver operating characteristic curve values were 0.60 using PSA alone, 0.66 using the risk calculator, 0.77 using PHI, 0.76 using the derived multiplex 2-gene model, 0.72 using the derived multiplex 3-gene model, and 0.74 using the original MPS model compared with 0.81 using the MPS2 model and 0.82 using the MPS2+ model. At 95% sensitivity, the MPS2 model would have reduced unnecessary biopsies performed in the initial biopsy population (range for other tests, 15% to 30%; range for MPS2, 35% to 42%) and repeat biopsy population (range for other tests, 9% to 21%; range for MPS2, 46% to 51%). Across pertinent subgroups, the MPS2 models had negative predictive values of 95% to 99% for cancers of GG 2 or greater and of 99% for cancers of GG 3 or greater., Conclusions and Relevance: In this study, a new 18-gene PCa test had higher diagnostic accuracy for high-grade PCa relative to existing biomarker tests. Clinically, use of this test would have meaningfully reduced unnecessary biopsies performed while maintaining highly sensitive detection of high-grade cancers. These data support use of this new PCa biomarker test in patients with elevated PSA levels to reduce the potential harms of PCa screening while preserving its long-term benefits.

Prostate cancer is a highly heterogeneous disease and mortality is mainly due to metastases but the initial steps of metastasis have not been well characterized. We have performed integrative whole exome sequencing and transcriptome analysis of primary prostate tumor foci and corresponding lymph node metastases (LNM) from 43 patients enrolled in clinical trial. We present evidence that, while there are some cases of clonally independent primary tumor foci, 87% of primary tumor foci and metastases are descended from a common ancestor. We demonstrate that genes related to oxidative phosphorylation are upregulated in LNM and in African-American patients relative to White patients. We further show that mutations in TP53 , FLT4 , EYA1 , NCOR2 , CSMD3 , and PCDH15 are enriched in prostate cancer metastases. These findings were validated in a meta-analysis of 3929 primary tumors and 2721 metastases and reveal a pattern of molecular alterations underlying the pathology of metastatic prostate cancer. We show that LNM contain multiple subclones that are already present in primary tumor foci. We observed enrichment of mutations in several genes including understudied genes such as EYA1 , CSMD3 , FLT4 , NCOR2 , and PCDH15 and found that mutations in EYA1 and CSMD3 are associated with a poor outcome in prostate cancer.

Purpose: To determine whether addition of external beam radiation therapy (EBRT) to brachytherapy (BT) (COMBO) compared with BT alone would improve 5-year freedom from progression (FFP) in intermediate-risk prostate cancer., Methods: Men with prostate cancer stage cT1c-T2bN0M0, Gleason Score (GS) 2-6 and prostate-specific antigen (PSA) 10-20 or GS 7, and PSA < 10 were eligible. The COMBO arm was EBRT (45 Gy in 25 fractions) to prostate and seminal vesicles followed by BT prostate boost (110 Gy if 125-Iodine, 100 Gy if 103-Pd). BT arm was delivered to prostate only (145 Gy if 125-Iodine, 125 Gy if 103-Pd). The primary end point was FFP: PSA failure (American Society for Therapeutic Radiology and Oncology [ASTRO] or Phoenix definitions), local failure, distant failure, or death., Results: Five hundred eighty-eight men were randomly assigned; 579 were eligible: 287 and 292 in COMBO and BT arms, respectively. The median age was 67 years; 89.1% had PSA < 10 ng/mL, 89.1% had GS 7, and 66.7% had T1 disease. There were no differences in FFP. The 5-year FFP-ASTRO was 85.6% (95% CI, 81.4 to 89.7) with COMBO compared with 82.7% (95% CI, 78.3 to 87.1) with BT (odds ratio [OR], 0.80; 95% CI, 0.51 to 1.26; Greenwood T P = .18). The 5-year FFP-Phoenix was 88.0% (95% CI, 84.2 to 91.9) with COMBO compared with 85.5% (95% CI, 81.3 to 89.6) with BT (OR, 0.80; 95% CI, 0.49 to 1.30; Greenwood T P = .19). There were no differences in the rates of genitourinary (GU) or GI acute toxicities. The 5-year cumulative incidence for late GU/GI grade 2+ toxicity is 42.8% (95% CI, 37.0 to 48.6) for COMBO compared with 25.8% (95% CI, 20.9 to 31.0) for BT ( P < .0001). The 5-year cumulative incidence for late GU/GI grade 3+ toxicity is 8.2% (95% CI, 5.4 to 11.8) compared with 3.8% (95% CI, 2.0 to 6.5; P = .006)., Conclusion: Compared with BT, COMBO did not improve FFP for prostate cancer but caused greater toxicity. BT alone can be considered as a standard treatment for men with intermediate-risk prostate cancer.

Diagnostic tests usually need to operate at a high sensitivity or specificity level in practice. Accordingly, specificity at the controlled sensitivity, or vice versa, is a clinically sensible performance metric for evaluating continuous biomarkers. Meanwhile, the performance of a biomarker may vary across sub-populations as defined by covariates, and covariate-specific evaluation can be informative. In this article, we develop a novel modeling and estimation method for covariate-specific specificity at a controlled sensitivity level. Unlike existing methods which typically adopt elaborate models of covariate effects over the entire biomarker distribution, our approach models covariate effects locally at a specific sensitivity level of interest. We also extend our proposed model to handle the whole continuum of sensitivities via dynamic regression and derive covariate-specific ROC curves. We provide the variance estimation through bootstrapping. The asymptotic properties are established. We conduct extensive simulation studies to evaluate the performance of our proposed methods in comparison with existing methods, and further illustrate the applications in two clinical studies for aggressive prostate cancer., (© 2023 John Wiley & Sons Ltd.)

Continuous biomarkers are common for disease screening and diagnosis. To reach a dichotomous clinical decision, a threshold would be imposed to distinguish subjects with disease from nondiseased individuals. Among various performance metrics, specificity at a controlled sensitivity level (or vice versa) is often desirable because it directly targets the clinical utility of the intended clinical test. Meanwhile, covariates, such as age, race, as well as sample collection conditions, could impact the biomarker distribution and may also confound the association between biomarker and disease status. Therefore, covariate adjustment is important in such biomarker evaluation. Most existing covariate adjustment methods do not specifically target the desired sensitivity/specificity level, but rather do so for the entire biomarker distribution. As such, they might be more prone to model misspecification. In this paper, we suggest a parsimonious quantile regression model for the diseased population, only locally at the controlled sensitivity level, and assess specificity with covariate-specific control of the sensitivity. Variance estimates are obtained from a sample-based approach and bootstrap. Furthermore, our proposed local model extends readily to a global one for covariate adjustment for the receiver operating characteristic (ROC) curve over the sensitivity continuum. We demonstrate computational efficiency of this proposed method and restore the inherent monotonicity in the estimated covariate-adjusted ROC curve. The asymptotic properties of the proposed estimators are established. Simulation studies show favorable performance of the proposal. Finally, we illustrate our method in biomarker evaluation for aggressive prostate cancer., (© 2021 The International Biometric Society.)

The receiver operating characteristic (ROC) curve provides a comprehensive performance assessment of a continuous biomarker over the full threshold spectrum. Nevertheless, a medical test often dictates to operate at a certain high level of sensitivity or specificity. A diagnostic accuracy metric directly targeting the clinical utility is specificity at the controlled sensitivity level, or vice versa. While the empirical point estimation is readily adopted in practice, the nonparametric interval estimation is challenged by the fact that the variance involves density functions due to estimated threshold. In addition, even with a fixed threshold, many standard confidence intervals including the Wald interval for binomial proportion could have erratic behaviors. In this article, we are motivated by the superior performance of the score interval for binomial proportion and propose a novel extension for the biomarker problem. Meanwhile, we develop exact bootstrap and establish consistency of the bootstrap variance estimator. Both single-biomarker evaluation and two-biomarker comparison are investigated. Extensive simulation studies were conducted, demonstrating competitive performance of our proposals. An illustration with aggressive prostate cancer diagnosis is provided.

Invariant natural killer T cells (iNKT cells) express a semi-invariant T cell receptor that recognizes certain glycolipids (including α-galactosylceramide, αGC) bound to CD1d, and can induce potent antitumor responses. Here, we assessed whether αGC could enhance the efficacy of a GM-CSF-producing tumor cell vaccine in the transgenic SV40 T antigen-driven TRAMP prostate cancer model. In healthy mice, we initially found that optimal T cell responses were obtained with αGC-pulsed TRAMP-C2 cells secreting GM-CSF and milk fat globule epidermal growth factor protein-8 (MFG-E8) with an RGD to RGE mutation (GM-CSF/RGE TRAMP-C2), combined with systemic low dose IL-12. In a therapeutic model, transgenic TRAMP mice were then castrated at ~ 20 weeks, followed by treatment with the combination vaccine. Untreated mice succumbed to tumor by ~ 40 weeks, but survival was markedly prolonged by vaccine treatment, with most mice surviving past 80 weeks. Prostates in the treated mice were heavily infiltrated with T cells and iNKT cells, which both secreted IFNγ in response to tumor cells. The vaccine was not effective if the αGC, IL-12, or GM-CSF secretion was eliminated. Finally, immunized mice were fully resistant to challenge with TRAMP-C2 cells. Together these findings support further development of therapeutic vaccines that exploit iNKT cell activation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: We assessed whether Prostate Health Index results improve prediction of grade reclassification for men on active surveillance., Methods and Materials: We identified men in Canary Prostate Active Surveillance Study with Grade Group 1 cancer. Outcome was grade reclassification to Grade Group 2+ cancer. We considered decision rules to maximize specificity with sensitivity set at 95%. We derived rules based on clinical data (R 1 ) vs clinical data+Prostate Health Index (R 3 ). We considered an "or"-logic rule combining clinical score and Prostate Health Index (R 4 ), and a "2-step" rule using clinical data followed by risk stratification based on Prostate Health Index (R 2 ). Rules were applied to a validation set, where values of R 2 -R 4 vs R 1 for specificity and sensitivity were evaluated., Results: We included 1,532 biopsies (n = 610 discovery; n = 922 validation) among 1,142 men. Grade reclassification was seen in 27% of biopsies (23% discovery, 29% validation). Among the discovery set, at 95% sensitivity, R 2 yielded highest specificity at 27% vs 17% for R 1 . In the validation set, R 3 had best performance vs R 1 with Δsensitivity = -4% and Δspecificity = +6%. There was slight improvement for R 3 vs R 1 for confirmatory biopsy (AUC 0.745 vs R 1 0.724, ΔAUC 0.021, 95% CI 0.002-0.041) but not for subsequent biopsies (ΔAUC -0.012, 95% CI -0.031-0.006). R 3 did not have better discrimination vs R 1 among the biopsy cohort overall (ΔAUC 0.007, 95% CI -0.007-0.020)., Conclusions: Among active surveillance patients, using Prostate Health Index with clinical data modestly improved prediction of grade reclassification on confirmatory biopsy and did not improve prediction on subsequent biopsies.

Multiple biomarkers are often combined to improve disease diagnosis. The uniformly optimal combination, i.e., with respect to all reasonable performance metrics, unfortunately requires excessive distributional modeling, to which the estimation can be sensitive. An alternative strategy is rather to pursue local optimality with respect to a specific performance metric. Nevertheless, existing methods may not target clinical utility of the intended medical test, which usually needs to operate above a certain sensitivity or specificity level, or do not have their statistical properties well studied and understood. In this article, we develop and investigate a linear combination method to maximize the clinical utility empirically for such a constrained classification. The combination coefficient is shown to have cube root asymptotics. The convergence rate and limiting distribution of the predictive performance are subsequently established, exhibiting robustness of the method in comparison with others. An algorithm with sound statistical justification is devised for efficient and high-quality computation. Simulations corroborate the theoretical results, and demonstrate good statistical and computational performance. Illustration with a clinical study on aggressive prostate cancer detection is provided.

Extremely rare circulating tumor cell (CTC) clusters are both increasingly appreciated as highly metastatic precursors and virtually unexplored. Technologies are primarily designed to detect single CTCs and often fail to account for the fragility of clusters or to leverage cluster-specific markers for higher sensitivity. Meanwhile, the few technologies targeting CTC clusters lack scalability. Here, we introduce the Cluster-Wells, which combines the speed and practicality of membrane filtration with the sensitive and deterministic screening afforded by microfluidic chips. The >100,000 microwells in the Cluster-Wells physically arrest CTC clusters in unprocessed whole blood, gently isolating virtually all clusters at a throughput of >25 mL/h, and allow viable clusters to be retrieved from the device. Using the Cluster-Wells, we isolated CTC clusters ranging from 2 to 100+ cells from prostate and ovarian cancer patients and analyzed a subset using RNA sequencing. Routine isolation of CTC clusters will democratize research on their utility in managing cancer., (© 2022. The Author(s).)

Objectives: Black men are more likely to die of prostate cancer (PCa) than White men. Whether this difference is driven by biological versus sociodemographic and access to care differences is actively investigated. However, studies that have highlighted racial disparities in PCa outcomes have been poorly represented by elderly men, a notoriously undertreated group. Herein, we evaluated use of curative treatment between Black and White elderly men with aggressive PCa in a large US database., Methods: Men ≥80 years diagnosed with National Comprehensive Cancer Network-defined high risk PCa between 2004 and 2016 were analyzed from the National Cancer Database. Multivariable logistic regression was used to model the effect of race and sociodemographic factors on receipt of definitive therapy (surgery or radiation +/- androgen deprivation therapy [ADT]) versus non-definitive therapy (ADT alone or observation) in inverse probability weighted groups matched for stage, prostate-specific antigen, and Gleason score., Results: Between 2004 and 2016, utilization of definitive therapy with either surgery or radiation therapy increased in both White and Black men in the United States. However, we found that Black men compared with White men were significantly less likely to receive definitive therapy (OR 0.71, 95% CI 0.64-0.79, p < .001). Using multivariable modeling, effect size diminished after adjusting for sociodemographic variables. Notably, there is evidence of the racial disparity narrowing over time., Conclusions: These findings highlight striking but improving racial disparities in elderly men with high risk PCa in the US, an overall undertreated population., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

BACKGROUNDProstate cancer is multifocal with distinct molecular subtypes. The utility of genomic subtyping has been challenged due to inter- and intrafocal heterogeneity. We sought to characterize the subtype-defining molecular alterations of primary prostate cancer across all tumor foci within radical prostatectomy (RP) specimens and determine the prevalence of collision tumors.METHODSFrom the Early Detection Research Network cohort, we identified 333 prospectively collected RPs from 2010 to 2014 and assessed ETS-related gene (ERG), serine peptidase inhibitor Kazal type 1 (SPINK1), phosphatase and tensin homolog (PTEN), and speckle type BTB/POZ protein (SPOP) molecular status. We utilized dual ERG/SPINK1 immunohistochemistry and fluorescence in situ hybridization to confirm ERG rearrangements and characterize PTEN deletion, as well as high-resolution melting curve analysis and Sanger sequencing to determine SPOP mutation status.RESULTSBased on index focus alone, ERG, SPINK1, PTEN, and SPOP alterations were identified in 47.5%, 10.8%, 14.3%, and 5.1% of RP specimens, respectively. In 233 multifocal RPs with ERG/SPINK1 status in all foci, 139 (59.7%) had discordant molecular alterations between foci. Collision tumors, as defined by discrepant ERG/SPINK1 status within a single focus, were identified in 29 (9.4%) RP specimens.CONCLUSIONInterfocal molecular heterogeneity was identified in about 60% of multifocal RP specimens, and collision tumors were present in about 10%. We present this phenomenon as a model for the intrafocal heterogeneity observed in previous studies and propose that future genomic studies screen for collision tumors to better characterize molecular heterogeneity.FUNDINGEarly Detection Research Network US National Cancer Institute (NCI) 5U01 CA111275-09, Center for Translational Pathology at Weill Cornell Medicine (WCM) Department of Pathology and Laboratory Medicine, US NCI (WCM SPORE in Prostate Cancer, P50CA211024-01), R37CA215040, Damon Runyon Cancer Research Foundation, US MetLife Foundation Family Clinical Investigator Award, Norwegian Cancer Society (grant 208197), and South-Eastern Norway Regional Health Authority (grant 2019016 and 2020063).

Purpose: We characterized population-level cancer-specific outcomes for prostate cancer patients based on use of prebiopsy prostate MRI., Methods: Using SEER-Medicare claims, we identified men diagnosed with localized prostate cancer from 2010-2015 and prostate-specific antigen (PSA) < 20 ng/mL. Primary exposure was prebiopsy prostate MRI prior to diagnosis (i.e., CPT 72197 linked to urology-specific diagnosis). Outcomes included diagnosis of Grade Group 2+ disease on biopsy and proportion treated with prostatectomy. We assessed those treated with prostatectomy and evaluated association with prebiopsy MRI and grade concordance between biopsy and prostatectomy. We estimated adjusted odds ratios with multivariable regression after accounting for other factors (e.g., age, year, PSA, race/ethnicity)., Results: We identified 48,574 patients, where 915 (1.9%) underwent prebiopsy MRI. Patients with prebiopsy MRI had more GG>2 cancer on biopsy (70.0% MRI vs. 62.8% no MRI) but lost significance after adjustment (OR 1.12, 95% CI 0.96-1.30). Patients with prebiopsy MRI were more likely to have prostatectomy (39.2% vs. 28.5%, adjusted OR 1.51, 95%CI 1.31-1.76). Downgrading from biopsy GG 3-5 to final GG 1-2 was less common after prebiopsy MRI (21.3% vs. 28.2% no MRI, P = 0.05) but not significant after adjustment (OR 0.74, 95% CI 0.51 - 1.08). Among 14,027 men with prostatectomy, accurate risk classification was not more likely with a prebiopsy MRI (48.0% no MRI vs. 49.6% prebiopsy MRI, P = 0.56)., Conclusion: During initial adoption, men with prebiopsy prostate MRI had marginally increased detection of significant cancer on biopsy and were more likely to be treated with prostatectomy. For those treated with prostatectomy, use of prebiopsy MRI was not associated with a greater likelihood of accurate risk classification or grade concordance between biopsy and final pathology results., (Published by Elsevier Inc.)

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion ( MAST3 , p = 6.9×10 -7 and GAB2 , p = 2.0×10 -6 ). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS- versus treatment for the initial management of patients with low-risk PC., Competing Interests: Declaration of Interests The authors declare no competing interests.

Purpose: Our goal was to evaluate the comparative effectiveness of robot-assisted laparoscopic prostatectomy (RALP) and open radical prostatectomy (ORP) in a multicenter study., Materials and Methods: We evaluated men with localized prostate cancer at 11 high-volume academic medical centers in the United States from the PROST-QA (2003-2006) and the PROST-QA/RP2 cohorts (2010-2013) with a pre-specified goal of comparing RALP (549) and ORP (545). We measured longitudinal patient-reported health-related quality of life (HRQOL) at pre-treatment and at 2, 6, 12, and 24 months, and pathological and perioperative outcomes/complications., Results: Demographics, cancer characteristics, and margin status were similar between surgical approaches. ORP subjects were more likely to undergo lymphadenectomy (89% vs 47%; p <0.01) and nerve sparing (94% vs 89%; p <0.01). RALP vs ORP subjects experienced less mean intraoperative blood loss (192 vs 805 mL; p <0.01), shorter mean hospital stay (1.6 vs 2.1 days; p <0.01), and fewer blood transfusions (1% vs 4%; p <0.01), wound infections (2% vs 4%; p=0.02), other infections (1% vs 4%; p <0.01), deep venous thromboses (0.5% vs 2%; p=0.04), and bladder neck contractures requiring dilation (1.6% vs 8.3%; p <0.01). RALP subjects reported less pain (p=0.04), less activity interference (p <0.01) and higher incision satisfaction (p <0.01). Surgical approach (RALP vs ORP) was not a significant predictor of longitudinal HRQOL change in any HRQOL domain., Conclusions: In high-volume academic centers, RALP and ORP patients may expect similar long-term HRQOL outcomes. Overall, RALP patients have less pain, shorter hospital stays, and fewer post-surgical complications such as blood transfusions, infections, deep venous thromboses, and bladder neck contractures.

Background: Prebiopsy magnetic resonance imaging (MRI) of the prostate improves detection of significant tumors, while decreasing detection of less-aggressive tumors. Therefore, its use has been increasing over time. In this study, the use of prebiopsy MRI among Medicare beneficiaries with prostate cancer was examined. It was hypothesized that patients of color and those in isolated areas would be less likely to undergo this approach for cancer detection., Methods: Using cancer registry data from the Surveillance, Epidemiology, and End Results (SEER) program linked to billing claims for fee-for-service Medicare beneficiaries, men with nonmetastatic prostate cancer were identified from 2010 through 2015 with prostate-specific antigen (PSA) <30 ng/mL. Outcome was prebiopsy MRI of the prostate performed within 6 months before diagnosis (ie, Current Procedural Terminology 72197). Exposures were patient race/ethnicity and rural/urban status. Multivariable regression estimated the odds of prebiopsy prostate MRI. Post hoc analyses examined associations with the registry-level proportion of non-Hispanic Black patients and MRI use, as well as disparities in MRI use in registries with data on more frequent use of prostate MRI., Results: There were 50,719 men identified with prostate cancer (mean age, 72.1 years). Overall, 964 men (1.9% of cohort) had a prebiopsy MRI. Eighty percent of patients with prebiopsy MRI lived in California, New Jersey, or Connecticut. Non-Hispanic Black men (0.6% vs 2.1% non-Hispanic White; odds ratio [OR], 0.28; 95% CI, 0.19-0.40) and men in less urban areas (1.1% vs 2.2% large metro; OR, 0.65; 95% CI, 0.44-0.97) were less likely to have prebiopsy MRI of the prostate., Conclusions: Non-Hispanic Black patients with prostate cancer and those in less urban areas were less likely to have prebiopsy MRI of the prostate during its initial adoption as a tool for improving prostate cancer detection., (© 2021 American Cancer Society.)

Introduction: Men diagnosed with localized prostate cancer must navigate a highly preference-sensitive decision between treatment options with varying adverse outcome profiles. We evaluated whether use of a decision support tool previously shown to decrease decisional conflict also impacted the secondary outcome of post-treatment decision regret., Methods: Participants were randomized to receive personalized decision support via the Personal Patient Profile-Prostate or usual care prior to a final treatment decision. Symptoms were measured just before randomization and 6 months later; decision regret was measured at 6 months along with records review to ascertain treatment choices. Regression modeling explored associations between baseline variables including race and D`Amico risk, study group, and 6-month variables regret, choice, and symptoms., Results: At 6 months, 287 of 392 (73%) men returned questionnaires of which 257 (89%) had made a treatment choice. Of that group, 201 of 257 (78%) completely answered the regret scale. Regret was not significantly different between participants randomized to the P3P intervention compared to the control group (P = 0.360). In univariate analyses, we found that Black men, men with hormonal symptoms, and men with bowel symptoms reported significantly higher decision regret (all P < 0.01). Significant interactions were detected between race and study group (intervention vs. usual care) in the multivariable model; use of the Personal Patient Profile-Prostate was associated with significantly decreased decisional regret among Black men (P = 0.037). Interactions between regret, symptoms and treatment revealed that (1) men choosing definitive treatment and reporting no hormonal symptoms reported lower regret compared to all others; and (2) men choosing active surveillance and reporting bowel symptoms had higher regret compared to all others., Conclusion: The Personal Patient Profile-Prostate decision support tool may be most beneficial in minimizing decisional regret for Black men considering treatment options for newly-diagnosed prostate cancer., Trial Registration: NCT01844999., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Current PSA-based tests used to detect prostate cancer (PCa) lack sufficient specificity, leading to significant overdetection and overtreatment. Our previous studies showed that serum fucosylated PSA (Fuc-PSA) and soluble TEK receptor tyrosine kinase (Tie-2) had the ability to predict aggressive (AG) PCa. Additional biomarkers are needed to address this significant clinical problem. Methods: A comprehensive Pubmed search followed by multiplex immunoassays identified candidate biomarkers associated with AG PCa. Subsequently, multiplex and lectin-based immunoassays were applied to a case-control set of sera from subjects with AG PCa, low risk PCa, and non-PCa (biopsy negative). These candidate biomarkers were further evaluated for their ability as panels to complement the prostate health index ( phi ) in detecting AG PCa. Results: When combined through logistic regression, two panel of biomarkers achieved the best performance: 1) phi, Fuc-PSA, SDC1, and GDF-15 for the detection of AG from low risk PCa and 2) phi , Fuc-PSA, SDC1, and Tie-2 for the detection of AG from low risk PCa and non-PCa, with noticeable improvements in ROC analysis over phi alone (AUCs: 0.942 vs 0.872, and 0.934 vs 0.898, respectively). At a fixed sensitivity of 95%, the panels improved specificity with statistical significance in detecting AG from low risk PCa (76.0% vs 56%, p =0.029), and from low risk PCa and non-PCa (78.2% vs 65.5%, p =0.010). Conclusions: Multivariate panels of serum biomarkers identified in this study demonstrated clinically meaningful improvement over the performance of phi , and warrant further clinical validation, which may contribute to the management of PCa., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Prostate cancer remains the most common non-skin cancer and second leading cause of death among men in the United States. Although progress has been made in diagnosis and risk assessment, many clinical questions remain regarding early identification of prostate cancer and management. The early detection of aggressive disease continues to provide high curative rates if diagnosed in a localized state. Unfortunately, prostate cancer displays significant heterogeneity within the prostate organ and between individual patients making detection and treatment strategies complex. Although prostate cancer is common among men, the majority will not die from prostate cancer, introducing the issue of overtreatment as a major concern in clinical management of the disease. The focus of the future is to identify those at highest risk for aggressive prostate cancer and to develop prevention and screening strategies, as well as discerning the difference in malignant potential of diagnosed tumors. The Prostate Cancer Research Group of the National Cancer Institute's Early Detection Research Network has contributed to the progress in addressing these concerns. This summary is an overview of the activities of the group. See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible.", (©2020 American Association for Cancer Research.)

Purpose: To evaluate the role of confirmatory in-bore MRI-guided biopsy in patients with low- or intermediate-risk disease diagnosed at prior transrectal US-guided biopsy and to evaluate the rate and predictors for missed cancers., Materials and Methods: A retrospective evaluation of 50 consecutive men who had previously undergone transrectal US-guided biopsy with positive results and who underwent subsequent in-bore MRI-guided biopsy at our university hospital (average time interval, 11 months) between 2012 and 2016 was performed. Ten men were excluded because of a history of treatment after transrectal US-guided biopsy. A total of 40 men (mean age, 63 years; range, 47-84 years) were included in this study. Multiparametric 3-T MRI (T2-weighted, diffusion-weighted, and dynamic contrast material-enhanced) and transrectal in-bore MRI-guided biopsy were performed. Cancer detection, disease-grade changes, and cancers missed at in-bore MRI-guided biopsy were evaluated. Descriptive statistics were used to report different rates. The Fisher exact test was used for categoric variables. The Mann-Whitney U test and independent Student t test were used for nonparametric and parametric data, respectively. The McNemar test was used for paired data., Results: The overall cancer detection rate when using in-bore MRI-guided biopsy was 65% (26 of 40). In-bore MRI-guided biopsy detected 14 previously undiscovered cancerous lesions (clinically significant cancers [CSCs], 57.1% [eight of 14]). An overall disease upgrade by in-bore MRI-guided biopsy occurred in 40% (16 of 40) of cases (61.5% [16 of 26] of cases with positive results from in-bore MRI-guided biopsy). One case was downgraded from a Gleason score (GS) of 3 + 4 = 7 to a GS of 3 + 3 = 6. Out of 71 sextant biopsies with positive results detected by transrectal US-guided biopsy (from all 40 patients), 80% (57 of 71) were visible on MR images (in-bore MRI-guided biopsy results were positive in 52.6% [30 of 57]), and 20% (14 of 71) had no image correlates on MR images. In-bore MRI-guided biopsy upgraded 60% (18 of 30) and downgraded 3.3% (one of 30) of detected lesions. The false-negative rate was 35% (14.2% [two of 14] of patients had CSCs; GS ≥ 7), was higher in prostate volumes of greater than 40 mL, and was lower in the anterior gland location ( P = .04 and .01, respectively)., Conclusion: Performing confirmatory in-bore MRI-guided biopsy following positive transrectal US-guided biopsy resulted in a high disease-upgrade incidence with subsequently improved disease-risk stratification, particularly when considering patients for active surveillance or focal therapy. Supplemental material is available for this article. © RSNA, 2020See also the commentary by Weiss and Solomon in this issue., (2020 by the Radiological Society of North America, Inc.)

Purpose: Radical prostatectomy (RP) alone is often inadequate in curing men with clinically localized, high-risk prostate cancer (PC). We hypothesized that chemohormonal therapy (CHT) with androgen-deprivation therapy plus docetaxel before RP would improve biochemical progression-free survival (BPFS) over RP alone., Patients and Methods: Men with clinically localized, high-risk PC were assigned to RP alone or neoadjuvant CHT with androgen deprivation plus docetaxel (75 mg/m 2 body surface area every 3 weeks for 6 cycles) and RP. The primary end point was 3-year BPFS. Biochemical failure was defined as a serum prostate-specific antigen level > 0.2 ng/mL that increased on 2 consecutive occasions that were at least 3 months apart. Secondary end points included 5-year BPFS, overall BPFS, local recurrence, metastasis-free survival (MFS), PC-specific mortality, and overall survival (OS)., Results: In total, 788 men were randomly assigned. Median follow-up time was 6.1 years. The overall rates of grade 3 and 4 adverse events during chemotherapy were 26% and 19%, respectively. No difference was seen in 3-year BPFS between neoadjuvant CHT plus RP and RP alone (0.89 v 0.84, respectively; 95% CI for the difference, -0.01 to 0.11; P = .11). Neoadjuvant CHT was associated with improved overall BPFS (hazard ratio [HR], 0.69; 95% CI, 0.48 to 0.99), improved MFS (HR, 0.70; 95% CI, 0.51 to 0.95), and improved OS (HR, 0.61; 95% CI, 0.40 to 0.94) compared with RP alone., Conclusion: The primary study end point, 3-year BPFS, was not met. Although some improvement was seen in secondary end points, any potential benefit must be weighed against toxicity. Our data do not support the routine use of neoadjuvant CHT and RP in patients with clinically localized, high-risk PC at this time., Competing Interests: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Objective: To compare pre- and post-radical prostatectomy (RP) responses in the urinary incontinence domain of Expanded Prostate Cancer Index Composite-26 (EPIC-26) in cohorts from the USA, Norway and Spain., Methods: A prospective study of pre- and 1-year post-treatment responses in American ( n =537), Norwegian ( n =520) and Spanish ( n =111) patients, establishing the prevalence of urinary incontinence defined according to published dichotomization. Thereafter we focused on the response alternatives "occasional dribbling", pad use and problem experience. A multivariate logistic regression analysis (significance level ≤ 0.01) considered risk factors for "not retaining total control"., Results: Compared to the European men, the American patients were younger, healthier and more presented with lower risk tumors. Before RP no inter-country differences emerged the prevalence of urinary incontinence (6%). One-year post-treatment urinary incontinence was described by 30% of the American and 41% of the European patients, occasional dribbling being the most frequent type of urinary leakage. In the multivariate analysis the risk of "not retaining total control" increased almost 3-fold in European compared to American patients, with age and co-morbidity being additional independent risk factor., Conclusion: After RP patients from Spain and Norway reported more unfavorable outcomes by EPIC-26 than the American patients to most of the urinary incontinence items, the difference between the European and American patients remaining in the multivariate analysis. The most frequent post-RP response alternative "occasional dribbling" needs to be validated with pad weighing as "gold standard"., (© 2020 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V.)

Tumour-infiltrating lymphocytes are associated with a survival benefit in several tumour types and with the response to immunotherapy 1-8 . However, the reason some tumours have high CD8 T cell infiltration while others do not remains unclear. Here we investigate the requirements for maintaining a CD8 T cell response against human cancer. We find that CD8 T cells within tumours consist of distinct populations of terminally differentiated and stem-like cells. On proliferation, stem-like CD8 T cells give rise to more terminally differentiated, effector-molecule-expressing daughter cells. For many T cells to infiltrate the tumour, it is critical that this effector differentiation process occur. In addition, we show that these stem-like T cells reside in dense antigen-presenting-cell niches within the tumour, and that tumours that fail to form these structures are not extensively infiltrated by T cells. Patients with progressive disease lack these immune niches, suggesting that niche breakdown may be a key mechanism of immune escape.

Purpose: To investigate the pathologic outcomes of additional random biopsies from areas with no visible MR targets in the setting of targeted in-bore MRI-guided biopsy and to assess the negative predictive value (NPV) of areas with no visible MR targets stratified according to patients' different biopsy statuses., Materials and Methods: A retrospective analysis of patients who underwent in-bore MRI-guided biopsy with additional random biopsies in areas with no visible MR targets (Prostate Imaging-Reporting and Data System, version 2 category 1 or 2) was conducted in this study. Diagnostic scans and in-bore MRI-guided biopsy were performed with a 3-T MRI scanner. Areas with no visible MR targets were biopsied in a random fashion whenever a zone or side did not have a visible focal target. Clinically significant cancers (CSCs) were defined as a Gleason score of 7 or greater. NPVs were stratified based on patient's prior biopsy status. Descriptive analysis was performed., Results: A total of 59 consecutive patients were included, with a median age of 65 years (interquartile range [IQR], 59-71 years). The median prostate-specific antigen level was 7 ng/mL (IQR, 4.9-10.8 ng/mL). Of the 59 patients, 16 (27.1%) were biopsy naive, 24 (40.7%) had prior negative transrectal US-guided biopsy findings, and 19 (32.2%) had prior positive transrectal US-guided biopsy findings. Forty-two (71.2%) biopsies revealed prostate cancer. A total of 112 areas with no visible MR targets were biopsied, of which 20 (17.9%) were cancers and 11 (9.8%) were CSCs. The NPV of areas with no visible MR targets was approximately 78% for all cancers and was 88.1% for CSCs. NPVs in biopsy-naive patients, patients with prior negative transrectal US-guided biopsy findings, and patients with prior positive transrectal US-guided biopsy findings were 62.5%, 83.3%, and 84.2%, respectively, for all cancers and 75.0%, 91.7%, and 94.7%, respectively, for CSCs., Conclusion: Areas with no visible MR targets in patients with MR-suspicious foci may still harbor CSCs that may significantly affect management plans. Additional biopsies from areas with no visible MR targets are warranted in this population. Keywords: Biopsy/Needle Aspiration, Interventional-Body, MR-Imaging, Prostate, Urinary© RSNA, 2019., Competing Interests: Disclosures of Conflicts of Interest: K.K.E. disclosed no relevant relationships. C.P.F. disclosed no relevant relationships. M.G.S. disclosed no relevant relationships. A.O.O. disclosed no relevant relationships. S.G.N. disclosed no relevant relationships., (2019 by the Radiological Society of North America, Inc.)

Objectives: To develop a risk classifier using urine-derived extracellular vesicle (EV)-RNA capable of providing diagnostic information on disease status prior to biopsy, and prognostic information for men on active surveillance (AS)., Patients and Methods: Post-digital rectal examination urine-derived EV-RNA expression profiles (n = 535, multiple centres) were interrogated with a curated NanoString panel. A LASSO-based continuation ratio model was built to generate four prostate urine risk (PUR) signatures for predicting the probability of normal tissue (PUR-1), D'Amico low-risk (PUR-2), intermediate-risk (PUR-3), and high-risk (PUR-4) prostate cancer. This model was applied to a test cohort (n = 177) for diagnostic evaluation, and to an AS sub-cohort (n = 87) for prognostic evaluation., Results: Each PUR signature was significantly associated with its corresponding clinical category (P < 0.001). PUR-4 status predicted the presence of clinically significant intermediate- or high-risk disease (area under the curve = 0.77, 95% confidence interval [CI] 0.70-0.84). Application of PUR provided a net benefit over current clinical practice. In an AS sub-cohort (n = 87), groups defined by PUR status and proportion of PUR-4 had a significant association with time to progression (interquartile range hazard ratio [HR] 2.86, 95% CI 1.83-4.47; P < 0.001). PUR-4, when used continuously, dichotomized patient groups with differential progression rates of 10% and 60% 5 years after urine collection (HR 8.23, 95% CI 3.26-20.81; P < 0.001)., Conclusion: Urine-derived EV-RNA can provide diagnostic information on aggressive prostate cancer prior to biopsy, and prognostic information for men on AS. PUR represents a new and versatile biomarker that could result in substantial alterations to current treatment of patients with prostate cancer., (© 2019 The Authors BJU International Published by John Wiley & Sons Ltd on behalf of BJU International.)

Background: MicroRNAs (miRNAs or miR-) have been linked to factors associated with aggressive prostate cancer such as biochemical recurrence and metastasis. We investigated whether circulating miRNAs in plasma could be used as diagnostic biomarkers for more aggressive prostate cancer at prostate biopsy., Methods: Men, aged 40 years and above, newly diagnosed with prostate cancer were categorized into two risk groups, low-grade (Gleason score, 6 or 7 [3 + 4] and serum prostate-specific antigen [PSA], <20 ng/mL) and high-grade (Gleason score, ≥7 (4 + 3) and serum PSA, ≥20 ng/mL) prostate cancers. The limma R package was used to compare the expression of miRNAs in plasma between the two risk groups, adjusting for age., Results: There were 66 men, aged 46-86 years, included: 40 men with low-grade and 26 men with high-grade prostate cancers. There were lower expressions of miR-28, miR-100, miR-942, and miR-28-3p, and higher expressions of miR-708, miR-1298, miR-886-3p, miR-374, miR-376c, miR-202, miR-128a, and miR-185 in high-grade compared to low-grade prostate cancer cases at biopsy, after adjusting for age (P < 0.05). These differences were no longer statistically significant after adjusting the P values for multiple comparisons., Conclusion: There was no circulating miRNA associated with high-grade prostate cancer at biopsy after adjusting for age and multiple comparisons. Nevertheless, relationships between these circulating miRNAs and high-grade prostate cancer were observed, which suggest them as promising prostate cancer biomarkers. Further investigation in a larger cohort may provide insight into their diagnostic potential for aggressive prostate cancer., (© 2019 Wiley Periodicals, Inc.)

Background: The incidence of node-positive prostate cancer has risen and might be partially explained by evolving use of lymphadenectomy at a population level. We assessed trends of node-positive prostate cancer in context of extent of lymphadenectomy among men treated surgically for prostate cancer., Patients and Methods: This was a retrospective study using data from a population-based cancer registry to identify men older than 50 years of age diagnosed with prostate cancer from 2010 to 2015 without distant metastases. We considered extent of node dissection as ordinal (1-4, 5-9, 10-14, 15-19, ≥20) and dichotomous (1-14, ≥15) variables. We fit multivariable models to assess trends in receipt of extended lymphadenectomy and then estimated odds of node-positive cancer on the basis of extent of lymphadenectomy., Results: We identified 280,156 men diagnosed from 2010 to 2015; 5355 men (1.9%) had positive lymph nodes. Incidence of positive nodes increased from 6.4 to 8.4 cases per 100,000 men from 2010 to 2015 (standardized rate ratio, 1.31; 95% confidence interval [CI], 1.20-1.44). Compared with 2010, prostatectomy patients with high-risk (odds ratio [OR], 1.66; 95% CI, 1.42-1.95) and intermediate-risk tumors (OR, 1.66; 95% CI, 1.47-1.88) were more likely to undergo extended lymphadenectomy in 2015. Among high-risk patients, men with ≥20 nodes removed were 7 times more likely to have positive nodes, versus <5 removed (6.1% for 1-4 vs. 32.4% for ≥20; OR, 7.32; 95% CI, 6.16-8.71). After adjusting for extent of dissection, odds of node-positive disease did not increase between 2010 and 2015 (OR, 1.17; 95% CI, 0.98-1.39) among high-risk patients., Conclusion: Increased incidence of node-positive prostate cancer in the United States is partially explained by more frequent use of extended lymphadenectomy., (Published by Elsevier Inc.)

Objectives: To test the validity of an Internet-based version of Expanded Prostate Cancer Index Composite (EPIC-26) versus the phone-based version. Most men will survive for years after treatment for localized prostate cancer (PCa) and may experience lasting treatment-related toxicities affecting health-related quality of life. The EPIC-26 is a validated instrument that measures health-related quality of life across 5 PCa-specific domains. Previously, EPIC-26 was administered via phone in a large multicenter clinical trial., Methods: We developed an Internet-based version of EPIC-26. We recruited subjects from two prospective longitudinal study cohorts of PCa patients undergoing local therapy: PROST-QA, and PROSTQA-RP2. Subjects were randomized to either an "Internet-first" or "phone-first" group. Subjects were offered the alternate questionnaire modality 2 weeks after completing the initial modality., Results: 181 subjects were offered enrollment; 133 agreed to participate. 65 subjects were randomized to the "Internet- first" group and 68 subjects to the "phone-first" group. Of these, 37 and 26 subjects respectively completed both questionnaire versions (response rate: 44.4%). Test-retest analysis showed significant intraclass correlations in all 5 domains of EPIC-26: urinary incontinence (r = 0.96), urinary irritation (r = 0.85), bowel function (r = 0.61), sexual function (r = 0.94), and hormonal function (r = 0.89). There was no effect of order of questionnaire administration., Conclusion: This study demonstrates excellent correlation of responses between Internet-based and phone-based EPIC-26 administration. All domains demonstrated test-retest reliability between modalities, without ordering effect. This validates the use of internet-based EPIC-26 in international registries as part of the International Consortium for Health Outcomes Measurement effort, and may facilitate its use in clinical practice and quality improvement., (Copyright © 2019 Elsevier Inc. All rights reserved.)