African-specific molecular taxonomy of prostate cancer.

Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a significant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global averages1. The contributing genetic and non-genetic factors, and associated mutational processes, are unknown2,3. Here, through whole-genome sequencing of treatment-naive prostate cancer samples from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Significant African-ancestry-specific findings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes NCOA2, STK19, DDX11L1, PCAT1 and SETBP1. Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer differentiated by ancestry and defined as global mutational subtypes (GMS). By further including Chinese Asian data, we confirm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specific to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African-European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical benefit of including individuals of African ancestry, our GMS subtypes reveal different evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene-environment interaction-defined here as a different effect of an environmental surrounding in people with different ancestries or vice versa-we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.

Prostate-specific membrane antigen positron emission tomography in addition to multiparametric magnetic resonance imaging and biopsies to select prostate cancer patients for focal therapy.

OBJECTIVE: To evaluate the additional value of prostate-specific membrane antigen positron emission tomography (PSMA-PET) to conventional diagnostic tools to select patients for hemi-ablative focal therapy (FT). PATIENTS AND METHODS: We performed a retrospective analysis on a multicentre cohort (private and institutional) of 138 patients who underwent multiparametric magnetic resonance imaging (mpMRI), PSMA-PET, and systematic biopsies prior to radical prostatectomy between January 2011 and July 2021. Patients were eligible when they met the consensus criteria for FT: PSA <15 ng/mL, clinical/radiological T stage ≤T2b, and International Society of Urological Pathology (ISUP) grade 2-3. Clinically significant prostate cancer (csPCa) was defined as ISUP grade ≥2, extracapsular extension >0.5 mm or seminal vesicle involvement at final histopathology. The diagnostic accuracy of mpMRI, systematic biopsies and PSMA-PET for csPCa (separate and combined) was calculated within a four-quadrant prostate model by receiver-operating characteristic and 2 × 2 contingency analysis. Additionally, we assessed whether the diagnostic tools correctly identified patients suitable for hemi-ablative FT. RESULTS: In total 552 prostate quadrants were analysed and 272 (49%) contained csPCa on final histopathology. The area under the curve, sensitivity, specificity, positive predictive value and negative predictive value for csPCa were 0.79, 75%, 83%, 81% and 77%, respectively, for combined mpMRI and systematic biopsies, and improved after addition of PSMA-PET to 0.84, 87%, 80%, 81% and 86%, respectively (P < 0.001). On final histopathology 46/138 patients (33%) were not suitable for hemi-ablative FT. Addition of PSMA-PET correctly identified 26/46 (57%) non-suitable patients and resulted in 4/138 (3%) false-positive exclusions. CONCLUSIONS: Addition of PSMA-PET to the conventional work-up by mpMRI and systematic biopsies could improve selection for hemi-ablative FT and guide exclusion of patients for whom whole-gland treatments might be a more suitable treatment option.

Irreversible electroporation of localised prostate cancer downregulates immune suppression and induces systemic anti-tumour T-cell activation - IRE-IMMUNO study.

OBJECTIVES: To prospectively compare systemic anti-tumour immune responses induced by irreversible electroporation (IRE) and robot-assisted radical prostatectomy (RARP) in patients with localised intermediate-risk prostate cancer (PCa). PATIENTS AND METHODS: Between February 2021 and June 2022, before and after treatment (at 5, 14 and 30 days) peripheral blood samples of 30 patients with localised PCa were prospectively collected. Patient inclusion criteria were: International Society of Urological Pathologists Grade 2-3, clinical cancer stage ≤T2c, prostate-specific antigen level <20 ng/mL). Patients were treated with IRE (n = 20) or RARP (n = 10). Frequency and activation status of lymphocytic and myeloid immune cell subsets were determined using flow cytometry. PCa-specific T-cell responses to prostatic acid phosphatase (PSAP) and cancer testis antigen (New York oesophageal squamous cell carcinoma 1 [NY-ESO-1]) were determined by interferon-γ enzyme-linked immunospot assay (ELISpot). Repeated-measures analysis of variance and two-sided Student's t-tests were used to compare immune responses over time and between treatment cohorts. RESULTS: Patient and tumour characteristics were similar between the cohorts except for age (median 68 years [IRE] and 62 years [RARP], P = 0.01). IRE induced depletion of systemic regulatory T cells (P = 0.0001) and a simultaneous increase in activated cytotoxic T-lymphocyte antigen 4 (CTLA-4)+ cluster of differentiation (CD)4+ (P < 0.001) and CD8+ (P = 0.032) T cells, consistent with reduction of systemic immune suppression allowing for effector T-cell activation, peaking 14 days after IRE. Effects were positively correlated with tumour volume/ablation size. Accordingly, IRE induced expansion of PSAP and/or NY-ESO-1 specific T-cell responses in four of the eight immune competent patients. Temporarily increased activated myeloid derived suppressor cell frequencies (P = 0.047) were consistent with transient immunosuppression after RARP. CONCLUSIONS: Irreversible electroporation induces a PCa-specific systemic immune response in patients with localised PCa, aiding conversion of the tumour microenvironment into a more immune permissive state. Therapeutic efficacy might be further enhanced by combination with CTLA-4 checkpoint inhibition, potentially opening up a new synergistic treatment paradigm for high-risk localised or (oligo)metastatic disease.

Median 4-year outcomes of salvage irreversible electroporation for localized radio-recurrent prostate cancer.

OBJECTIVES: To evaluate the safety, and short to mid-term oncological and quality-of-life (QoL) outcomes of focal irreversible electroporation (IRE) for radio-recurrent prostate cancer (PCa) at a median follow-up of 4 years. PATIENTS AND METHODS: This was a single-centre series of men with biopsy-proven radio-recurrent PCa treated with IRE between December 2013 and February 2022, with a minimum follow-up of 6 months. Follow-up included magnetic resonance imaging at 6 months, and standard transperineal saturation template biopsies at 12 months. Further biopsies were guided by suspicion on serial imaging or prostate-specific antigen (PSA) levels. Validated questionnaires were used to measure functional outcomes. Significant local recurrence was defined as any International Society of Urological Pathology (ISUP) score ≥ 2 on biopsies. Progression-free survival was defined as no signs of local or systemic disease on either imaging or template biopsies, or according to the Phoenix criteria for biochemical recurrence. RESULTS: Final analysis was performed on 74 men with radio-recurrent PCa (median age 69 years, median PSA level 5.4 ng/mL, 76% ISUP score 2/3). The median (range) follow-up was 48 (27-68) months. One rectal fistula occurred, and eight patients developed urethral sloughing that resolved with transurethral resection. Among patients who returned questionnaires (30/74, 41%), 93% (28/30) had preserved urinary continence and 23% (7/30) had sustained erectile function at 12-month follow-up. Local control was achieved in 57 patients (77%), who needed no further treatment. Biopsy diagnosed 41(55%) patients received follow up template biopsies, in-field recurrences occurred in 7% (3/41), and out-field recurrences occurred in 15% of patients (6/41). The metastasis-free survival rate was 91% (67/74), with a median (interquartile range) time to metastases of 8 (5-27) months. The Kaplan-Meier estimated 5-year progression-free survival rate was 60%. CONCLUSIONS: These short- to mid-term safety, oncological and QoL outcome data endorse results from smaller series and show the ability of salvage focal IRE to safely achieve oncological control in patients with radio-recurrent PCa.

Salvage irreversible electroporation for radio-recurrent prostate cancer - the prospective FIRE trial.

OBJECTIVES: To prospectively assess the safety, functional- and oncological-outcomes of irreversible electroporation (IRE) as salvage therapy for radio-recurrent focal prostate cancer in a multicenter setting. PATIENTS AND METHODS: Men with focal recurrent PCa after external beam radiation or brachytherapy without metastatic disease on staging imaging and co-registration between mpMRI and biopsies were prospectively included in this multicenter trial. Adverse events were reported following the Clavien-Dindo classification. Validated questionnaires were used for patient-reported functional outcomes. Follow-up consisted of 3 monthly prostate specific antigen (PSA) levels, a 6-month mpMRI and standardised transperineal template mapping biopsies at 12-months. Thereafter follow-up was guided by MRI and/or PSMA-PET/CT and PSA. Local recurrence was defined as any ISUP score ≥2 on biopsies. RESULTS: 37 patients were analysed with a median (interquartile range (IQR)) follow up of 29 (22-43) months. Median age was 71 (53-83), median PSA was 3.5 ng/mL (2.7-6.1). 28 (75.5%) patients harboured intermediate risk and 9 patients (24.5%) high risk PCa. Seven patients (19%) reported self-limiting urgency, frequency, or hematuria (grade 1-2). Seven patients (19%) developed a grade 3 AE; urethral sludge requiring transurethral resection. At 12 months post treatment 93% of patients remained continent and erectile function sufficient for intercourse deteriorated from 35% to 15% (4/27). Local control was achieved in 29 patients (78%) and 27 patients (73%) were clear of local and systemic disease. Four (11%) patients had local recurrence only. Six (16%) patients developed metastatic disease with a median time to metastasis of 8 months. CONCLUSION: The FIRE trial shows that salvage IRE after failed radiation therapy for localised PCa is safe with minimal toxicity, and promising functional and oncological outcomes. Salvage IRE can offer a possible solution for notoriously difficult to manage radio recurrent prostate tumours.

The relationship between biochemical recurrence and number of lymph nodes removed during surgery for localized prostate cancer.

PURPOSE: To assess whether completeness of pelvic lymph node dissection (PLND) as measured by lymph node yield reduces biochemical recurrence (BCR) in men undergoing radical prostatectomy (RP) for prostate cancer (PCa), stratified according to Briganti nomogram-derived risk (≥5% vs. < 5%) of lymph node invasion (LNI). METHODS: Retrospective study of 3724 men who underwent RP between January 1995 and January 2015 from our prospectively collected institutional database. All men included had minimum five years follow-up and were not given androgen deprivation therapy or radiotherapy prior to BCR. Primary endpoint was time to BCR as defined by PSA > 0.2ng/ml. Patients were analysed according to Briganti Nomogram derived risk of 'low-risk' (< 5%) vs. 'high-risk' (≥ 5%). Extent of PLND was analysed using number of nodes yielded at dissection as a continuous variable as well as a categorical variable: Group 1 (limited, 1-4 nodes), Group 2 (intermediate, 5-8 nodes) and Group 3(extensive, ≥9 nodes). RESULTS: Median follow-up in the overall cohort was 79.7 months and 65% of the total cohort underwent PLND. There were 2402 patients with Briganti risk of LNI < 5% and 1322 with a Briganti risk of LNI ≥5%. At multivariate analysis, only PSA (HR1.01, p < 0.001), extracapsular extension at RP (HR 1.86, p < 0.001), positive surgical margin (HR 1.61, p < 0.001) and positive lymph node on pathology (HR 1.52, p = 0.02) were independently associated with BCR. In the high-risk group, increased nodal yield at PLND was associated with reduction in risk of BCR (HR 0.97, 95%CI 0.95-1.00 p = 0.05, Cochran Mantel Haenszel test, p < 0.05: respectively). In the low-risk group increased number of nodes at PLND did not reduce risk of BCR. CONCLUSIONS: In this study of extent of PLND at RP, higher nodal yield did not reduce risk of BCR in low-risk men (Briganti risk < 5%), however there was a weak benefit in terms of reduced long-term risk of BCR in high-risk men (Briganti risk ≥5%).

How Does Age Affect Urinary Continence following Robot-Assisted Radical Prostatectomy? A Prospective Multi-Institutional Study Using Independently Collected, Validated Questionnaires.

PURPOSE: Robot-assisted radical prostatectomy (RARP) is associated with poorer postoperative urinary continence in older men. However, published studies reporting conflicting results have design limitations with insufficient data at the extremes of age. The purpose of this study was to assess the effect of age on post-RARP urinary continence. MATERIALS AND METHODS: This study included 5,648 patients from 2 prospective Australian databases who underwent a primary RARP for prostate cancer between 2008 and 2019. Significant urinary bother and pad-usage were evaluated 12 months post-RARP by EPIC-26 (Expanded Prostate Cancer Index Composite) questionnaires, independently collected by third parties. Multivariable logistic regression was used to investigate the relationship between continence and age. RESULTS: Percentages of significant bother increased with age: 4.2%, 6.8% 9.1% and 12.9% at age groups <55, 55-64, 65-74 and ≥75 years, respectively. Compared with men aged 65-69 years, the odds of significant bother in patients <55 years was significantly lower (odds ratio [OR] 0.49, 95% confidence interval [CI] 0.32-0.75, p=0.001). Corresponding OR found no significant difference in bother in patients ≥70 (OR 1.24, 95% CI 0.94-1.63, p=0.13) or ≥75 years (OR 1.41, 95% CI 0.88-2.25, p=0.16). Pad-free rates markedly decreased with age: 86%, 79%, 68% and 50% at ages, <55, 55-64, 65-74 and ≥75 years, respectively. Corresponding social continence (0-1 pads/day) rates also decreased with age: 98%, 96%, 92% and 85%. CONCLUSIONS: Urinary bother and pad-usage post-RARP are excellent in young men but worsen with age. Older patients were only slightly more likely to be "significantly bothered" by incontinence despite higher pad-usage.

Final Analysis of the Magnetic Resonance Imaging in Active Surveillance Trial.

PURPOSE: This study aimed to assess the medium-term oncologic outcomes of an active surveillance protocol, replacing confirmatory biopsy with serial multiparametric magnetic resonance imaging. MATERIALS AND METHODS: A total of 172 men were enrolled in this single-arm prospective trial. Men with prostate cancer (Gleason 3+3=6 or Gleason 3+4=7 with ≤10% Gleason pattern 4 overall and <2 cores Gleason pattern 4) eligible for surveillance were included in the study. Men underwent baseline multiparametric magnetic resonance imaging and template ± targeted biopsy, then multiparametric magnetic resonance imaging at years 1 and 2 with a 3-year end-of-protocol biopsy. Biopsies during the 3-year protocol period were triggered by abnormalities on multiparametric magnetic resonance imaging and/or increases in prostate specific antigen density (>0.2 ng/ml/cc). RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value of multiparametric magnetic resonance imaging to detect progression to clinically significant prostate cancer were 57% (95% CI 39%-74%), 82% (95% CI 74%-89%), 50% (95% CI 38%-62%), and 86% (95% CI 81%-90%), respectively. Both multiparametric magnetic resonance imaging and prostate specific antigen density were significant predictors for progression (multiparametric magnetic resonance imaging OR 6.20, 95% CI 2.72-14.16, P < .001; prostate specific antigen density OR 6.19, 95% CI 2.14-17.92, P = .001). Only 2.3% (4/172) of patients had false-negative multiparametric magnetic resonance imaging and high-risk pathological features (pT3 or high-volume International Society of Urological Pathology >2). After a median 69 months (Q1-Q3 56-79) follow-up of all patients in the cohort, freedom from biochemical recurrence, metastasis, and prostate cancer-related death were 99.3%, 100%, and 100%, respectively. CONCLUSIONS: Final analysis of the Magnetic Resonance Imaging in Active Surveillance trial indicates that there is minimal risk to omitting 1-year confirmatory biopsy during active surveillance if baseline magnetic resonance-targeted + saturation template biopsy was performed; however, standardized 3-year systematic biopsy should be performed due to occasional magnetic resonance imaging-invisible tumors.

Salvage robot-assisted radical prostatectomy following focal ablation with irreversible electroporation: feasibility, oncological and functional outcomes.

BACKGROUND: To report the feasibility, oncological and functional outcomes of salvage robot-assisted radical prostatectomy (sRARP) for recurrent prostate cancer (PCa) after irreversible electroporation (IRE). METHODS: This was a retrospective analysis of patients who underwent sRARP by a single high-volume surgeon after IRE treatment in our institution. Surgical complications, oncological and functional outcomes were assessed. RESULTS: 15 patients with at least 12 months follow up were identified out of the 234 men who underwent primary IRE between 2013 and 2019. The median [IQR] age was 68 (62-70) years. The median [IQR] time from focal IRE to sRARP was 42 (21-57) months. There were no rectal, bladder or ureteric injuries. The T-stage was pT2 in 9 (60%) patients and pT3a in 6 (40%) patients. Only one (7%) patient had a positive surgical margin. At a median [IQR] follow up of 22 (16-32) months no patient had a biochemical recurrence (PSA > 0.2). All 15 patients were continent (pad-free) by 6 months and 9 (60%) patients had erections sufficient for intercourse with or without PDE5 inhibitors. No predisposing factors were identified for predicting erectile dysfunction after sRARP. CONCLUSIONS: In patients with recurrent or residual significant PCa after focal IRE ablation it is feasible to obtain good functional and oncological outcomes with sRARP. Our results demonstrate that good outcomes can be achieved with sRARP, when respecting close monitoring post-IRE, good patient selection and surgical experience. The limitations of this study are that it is a small series, with short follow up and a lack of standardised quality of life instruments.

Focal ablation of apical prostate cancer lesions with irreversible electroporation (IRE).

INTRODUCTION AND OBJECTIVE: To assess the safety, oncological and quality-of-life (QoL) outcomes of focal ablation of apical prostate cancer (PCa) lesions with irreversible electroporation (IRE). METHODS: Patients were included in the study if they had a PCa lesion within 3 mm of the apical capsule treated with IRE. The IRE procedure was performed in our institution by a single urologist. The QoL and functional data was collected prospectively from patients who provided consent using the Expanded Prostate Cancer Index Composite (EPIC). Oncological follow up included 3-month PSA levels, mpMRI at 6 months and transperineal biopsy at 1-year post treatment. RESULTS: A total of 50 patients had apical PCa lesions treated between February 2013 and September 2018. Median follow-up was 44 months. There were no Clavien-Dindo grade 3 events or higher. No perioperative complications were recorded. No significant difference was observed in the EPIC urinary or bowel QoL domain between baseline and 12-month post-treatment. One patient (2%) required one pad per day for urinary incontinence 12-month post-treatment. There was a small but significant decline in EPIC sexual QoL (65 at baseline and 59 at 12-month post-IRE). Of patient's potent pre-treatment, 94% remained potent after treatment. The median PSA nadir decreased by 71% (6.25-1.7 ng/mL). Only one patient (2.5%) had in-field residual disease on repeat biopsy. CONCLUSION: Focal ablation using IRE for PCa in the distal apex appears safe and feasible with acceptable early QoL and oncologic outcomes.

The Magnetic Resonance Imaging in Active Surveillance (MRIAS) Trial: Use of Baseline Multiparametric Magnetic Resonance Imaging and Saturation Biopsy to Reduce the Frequency of Surveillance Prostate Biopsies.

PURPOSE: Prospective studies are lacking in assessing the diagnostic utility of serial multiparametric magnetic resonance imaging to predict biopsy proven progression to clinically significant prostate cancer in men on active surveillance, as well as the oncologic safety of baseline magnetic resonance imaging and saturation diagnostic biopsy in replacing early confirmatory biopsy during active surveillance. MATERIALS AND METHODS: A total of 172 men were enrolled in this single arm prospective trial. Men with cT2 or lower histologically proven prostate cancer (Gleason 3+3=6 or Gleason 3+4=7 with 10% or less Gleason pattern 4 overall and less than 2 cores Gleason pattern 4) eligible for surveillance were included in the study. Men underwent baseline multiparametric magnetic resonance imaging and saturation biopsy followed by serial annual multiparametric magnetic resonance imaging until a 3-year end point per protocol saturation biopsy. The standardized 1-year confirmatory biopsy was omitted and biopsies during the protocol were triggered based on new abnormalities on multiparametric magnetic resonance imaging and prostate specific antigen density. RESULTS: We report the prespecified interim analysis of the first 100 men at 3 years. At baseline the median age was 64.5 (IQR 57.25-69) years, prostate specific antigen was 4.7 ng/ml (IQR 3.4-6.6), 91% had Gleason 3+3=6 prostate cancer and multiparametric magnetic resonance imaging was negative (Prostate Imaging Reporting and Data System 1/2/3) in 87% of men. Within 3 years 21% experienced pathological progression. The positive predictive value, negative predictive value, sensitivity and specificity for detection of clinically significant prostate cancer by surveillance multiparametric magnetic resonance imaging was 45%, 89%, 61% and 80%, respectively. Positive surveillance magnetic resonance imaging (p=0.002) and prostate specific antigen density greater than 0.2 ng/ml (p=0.042) had significant predictive value for clinically significant prostate cancer. CONCLUSIONS: Our novel active surveillance protocol incorporating multiparametric magnetic resonance imaging detected most cases of disease progression and may enable confirmatory biopsy to be deferred, but should not replace 3-year surveillance biopsy altogether due to occasional magnetic resonance imaging invisible tumors.

Metagenomic analysis reveals a rich bacterial content in high-risk prostate tumors from African men.

BACKGROUND: Inflammation is a hallmark of prostate cancer (PCa), yet no pathogenic agent has been identified. Men from Africa are at increased risk for both aggressive prostate disease and infection. We hypothesize that pathogenic microbes may be contributing, at least in part, to high-risk PCa presentation within Africa and in turn the observed ethnic disparity. METHODS: Here we reveal through metagenomic analysis of host-derived whole-genome sequencing data, the microbial content within prostate tumor tissue from 22 men. What is unique about this study is that patients were separated by ethnicity, African vs European, and environments, Africa vs Australia. RESULTS: We identified 23 common bacterial genera between the African, Australian, and Chinese prostate tumor samples, while nonbacterial microbes were notably absent. While the most abundant genera across all samples included: Escherichia, Propionibacterium, and Pseudomonas, the core prostate tumor microbiota was enriched for Proteobacteria. We observed a significant increase in the richness of the bacterial communities within the African vs Australian samples (t = 4.6-5.5; P = .0004-.001), largely driven by eight predominant genera. Considering core human gut microbiota, African prostate tissue samples appear enriched for Escherichia and Acidovorax, with an abundance of Eubacterium associated with host tumor hypermutation. CONCLUSIONS: Our study provides suggestive evidence for the presence of a core, bacteria-rich, prostate microbiome. While unable to exclude for fecal contamination, the observed increased bacterial content and richness within the African vs non-African samples, together with elevated tumor mutational burden, suggests the possibility that bacterially-driven oncogenic transformation within the prostate microenvironment may be contributing to aggressive disease presentation in Africa.

p53 nuclear accumulation as an early indicator of lethal prostate cancer.

BACKGROUND: After radical prostatectomy (RP) for prostate cancer (PC), p53 alterations predict biochemical relapse (BCR), however, recent evidence suggests that metastatic relapse (MR) not BCR is a surrogate for PC specific mortality (PCSM). This updated analysis of a previously published study investigated the association between p53 aberrations, MR and PCSM in men with localised PC. METHODS: Two hundred and seventy-one men with localised PC treated with RP were included. RP specimens stained for p53 by immunohistochemistry were scored as (a) percentage of p53-positive tumour nuclei; and (b) clustering, where ≥12 p53-positive cells within a ×200 power field was deemed 'cluster positive'. Associations between p53 status and clinical outcomes (BCR, MR and PCSM) were evaluated. RESULTS: Increasing percentage of p53-positive nuclei was significantly associated with shorter time to BCR, MR and PCSM (All p < 0.001). Half of the patients were p53 cluster positive. p53 cluster positivity was significantly associated with poorer outcomes at all clinical endpoints (BCR: HR 2.0, 95% CI 1.51-2.65, p < 0.001; MR: HR 4.1, 95% CI 2.02-8.14, p < 0.001; PCSM: HR 12.2, 95% CI 1.6-93; p = 0.016). These associations were independent of other established prognostic variables. CONCLUSIONS: p53 aberrations in radical prostatectomy tissue predict clinically relevant endpoints of MR and PCSM.

Altered mitochondrial genome content signals worse pathology and prognosis in prostate cancer.

BACKGROUND: Mitochondrial genome (mtDNA) content is depleted in many cancers. In prostate cancer, there is intra-glandular as well as inter-patient mtDNA copy number variation. In this study, we determine if mtDNA content can be used as a predictor for prostate cancer staging and outcomes. METHODS: Fresh prostate cancer biopsies from 115 patients were obtained at time of surgery. All cores underwent pathological review, followed by isolation of cancer and normal tissue. DNA was extracted and qPCR performed to quantify the total amount of mtDNA as a ratio to genomic DNA. Differences in mtDNA content were compared for prostate cancer pathology features and disease outcomes. RESULTS: We showed a significantly reduced mtDNA content in prostate cancer compared with normal adjacent prostate tissue (mean difference 1.73-fold, P-value <0.001). Prostate cancer with increased mtDNA content showed unfavorable pathologic characteristics including, higher disease stage (PT2 vs PT3 P-value = 0.018), extracapsular extension (P-value = 0.02) and a trend toward an increased Gleason score (P-value = 0.064). No significant association was observed between changes in mtDNA content and biochemical recurrence (median follow up of 107 months). CONCLUSIONS: Contrary to other cancer types, prostate cancer tissue shows no universally depleted mtDNA content. Rather, the change in mtDNA content is highly variable, mirroring known prostate cancer genome heterogeneity. Patients with high mtDNA content have an unfavorable pathology, while a high mtDNA content in normal adjacent prostate tissue is associated with worse prognosis.

Effect of FAK inhibitor VS-6063 (defactinib) on docetaxel efficacy in prostate cancer.

BACKGROUND: Docetaxel, the standard chemotherapy for metastatic castration-resistant prostate cancer (CRPC) also enhances the survival of patients with metastatic castration-sensitive prostate cancer (CSPC) when combined with androgen-deprivation therapy. Focal Adhesion Kinase (FAK) activation is a mediator of docetaxel resistance in prostate cancer cells. The aim of this study was to investigate the effect of the second generation FAK inhibitor VS-6063 on docetaxel efficacy in pre-clinical CRPC and CSPC models. METHODS: Docetaxel-resistant CRPC cells, mice with PC3 xenografts, and ex vivo cultures of patient-derived primary prostate tumors were treated with VS-6063 and/or docetaxel, or vehicle control. Cell counting, immunoblotting, and immunohistochemistry techniques were used to evaluate the treatment effects. RESULTS: Docetaxel and VS-6063 co-treatment caused a greater decrease in the viability of docetaxel-resistant CRPC cells, and a greater inhibition in PC3 xenograft growth compared to either monotherapy. FAK expression in human primary prostate cancer was positively associated with advanced tumor stage. Patient-derived prostate tumor explants cultured with both docetaxel and VS-6063 displayed a higher percentage of apoptosis in cancer cells, than monotherapy treatment. CONCLUSIONS: Our findings suggest that co-administration of the FAK inhibitor, VS-6063, with docetaxel represents a potential therapeutic strategy to overcome docetaxel resistance in prostate cancer.

Radiomic features on MRI enable risk categorization of prostate cancer patients on active surveillance: Preliminary findings.

BACKGROUND: Radiomic analysis is defined as computationally extracting features from radiographic images for quantitatively characterizing disease patterns. There has been recent interest in examining the use of MRI for identifying prostate cancer (PCa) aggressiveness in patients on active surveillance (AS). PURPOSE: To evaluate the performance of MRI-based radiomic features in identifying the presence or absence of clinically significant PCa in AS patients. STUDY TYPE: Retrospective. SUBJECTS MODEL: MRI/TRUS (transperineal grid ultrasound) fusion-guided biopsy was performed for 56 PCa patients on AS who had undergone prebiopsy. FIELD STRENGTH/SEQUENCE: 3T, T2 -weighted (T2 w) and diffusion-weighted (DW) MRI. ASSESSMENT: A pathologist histopathologically defined the presence of clinically significant disease. A radiologist manually delineated lesions on T2 w-MRs. Then three radiologists assessed MRIs using PIRADS v2.0 guidelines. Tumors were categorized into four groups: MRI-negative-biopsy-negative (Group 1, N = 15), MRI-positive-biopsy-positive (Group 2, N = 16), MRI-negative-biopsy-positive (Group 3, N = 10), and MRI-positive-biopsy-negative (Group 4, N = 15). In all, 308 radiomic features (First-order statistics, Gabor, Laws Energy, and Haralick) were extracted from within the annotated lesions on T2 w images and apparent diffusion coefficient (ADC) maps. The top 10 features associated with clinically significant tumors were identified using minimum-redundancy-maximum-relevance and used to construct three machine-learning models that were independently evaluated for their ability to identify the presence and absence of clinically significant disease. STATISTICAL TESTS: Wilcoxon rank-sum tests with P < 0.05 considered statistically significant. RESULTS: Seven T2 w-based (First-order Statistics, Haralick, Laws, and Gabor) and three ADC-based radiomic features (Laws, Gradient and Sobel) exhibited statistically significant differences (P < 0.001) between malignant and normal regions in the training groups. The three constructed models yielded overall accuracy improvement of 33, 60, 80% and 30, 40, 60% for patients in testing groups, when compared to PIRADS v2.0 alone. DATA CONCLUSION: Radiomic features could help in identifying the presence and absence of clinically significant disease in AS patients when PIRADS v2.0 assessment on MRI contradicted pathology findings of MRI-TRUS prostate biopsies. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.

Prostate cancer in 432 men aged <50 years in the prostate-specific antigen era: a new outlook.

OBJECTIVE: To evaluate the clinical presentation and treatment outcomes of prostate cancer (PCa) in 432 consecutive patients aged < 50 years in the prostate-specific antigen (PSA) era. METHODS: Retrospective analysis was performed on all patients with PCa (14 570) from the years 1994 to 2017. A total of 432 consecutive patients aged < 50 years were identified. The patients were stratified by D'Amico risk groups, and their clinical presentation and treatment outcomes were analysed. The rates of biochemical recurrence after surgery were compared with the D'Amico prediction model as well as with older propensity-score-matched patients. The surgical pathology results in patients undergoing active surveillance (AS) were compared with those of low-risk patients who underwent immediate surgery. RESULTS: A total of 44%, 42% and 13% of patients harboured low-risk, intermediate-risk and high-risk PCa, respectively. Their median age was 47 years and a positive family history of PCa was reported in 39.1%. Clinical stage was T1 in 65.5% and T2 in 30.0% of patients, and 2.0% of patients had metastatic disease at presentation. Radical prostatectomy (RP) was performed in 78.4% of patients (n = 339) and the biochemical recurrence rates were 7.8% (low-risk), 15.3% (intermediate-risk) and 23.3% (high-risk) at 5 years post-surgery. These rates were lower than expected according to the D'Amico prediction model or when compared with older matched patients. A total of 74 patients with low-risk PCa underwent AS and only 17.6% (n = 13) required radical treatment after a median follow-up of 46 months. The surgical pathology results in patients undergoing ASdid not differ significantly from patients with low-risk PCa who underwent immediate surgery (positive surgical margins [P = 0.145], tumour volume [P = 0.257] or seminal vesicle involvement [P = 0.100]). Of the present cohort, only 0.4% died from PCa during a median follow-up of 65 months. CONCLUSIONS: The clinical presentation and prognosis of young patients has changed dramatically during the PSA era. Patients nowadays present with lower-risk disease that can be treated adequately, with reassuring biochemical recurrence rates at 5 years post-surgery. AS appears to be safe in patients with low-risk. PCa.

Focal irreversible electroporation as primary treatment for localized prostate cancer.

OBJECTIVES: To determine the safety, quality of life (QoL) and short-term oncological outcomes of primary focal irreversible electroporation (IRE) for the treatment of localized prostate cancer (PCa), and to identify potential risk factors for oncological failure. PATIENTS AND METHODS: Patients who met the consensus guidelines on patient criteria and selection methods for primary focal therapy were eligible for analysis. Focal IRE was performed for organ-confined clinically significant PCa, defined as high-volume disease with Gleason sum score 6 (International Society of Urological Pathology [ISUP] grade 1) or any Gleason sum score of 7 (ISUP grades 2-3). Oncological, adverse event (AE) and QoL outcome data, with a minimum of 6 months' follow-up, were analysed. Patient characteristics and peri-operative treatment variables were compared between patients with and without oncological failure on follow-up biopsy. Wilcoxon's signed rank test, Wilcoxon's rank sum test and the chi-squared test were used to assess statistically significant differences in paired continuous, unpaired continuous and categorical variables respectively. RESULTS: A total of 63 patients met all eligibility criteria and were included in the final analysis. No high-grade AEs occurred. QoL questionnaire analysis demonstrated no significant change from baseline in physical (P = 0.81), mental (P = 0.48), bowel (P = 0.25) or urinary QoL domains (P = 0.41 and P = 0.25), but there was a mild decrease in the sexual QoL domain (median score 66 at baseline vs 54 at 6 months; P < 0.001). Compared with baseline, a decline of 70% in prostate-specific antigen level (1.8 ng/mL, interquartile range 0.96-4.8 ng/mL) was seen at 6-12 months. A narrow safety margin (P = 0.047) and system errors (P = 0.010) were identified as potential early risk factors for in-field oncological failure. In-field and whole-gland oncological control on follow-up biopsies was 84% (38/45 patients) and 76% (34/45 patients); this increased to 97% (38/39 patients) and 87% (34/39 patients) when patients treated with a narrow safety margin and system errors were excluded. CONCLUSION: Our data support the safety and feasibility of focal IRE as a primary treatment for localized PCa with effective short-term oncological control in carefully selected men.

Radiomic features for prostate cancer detection on MRI differ between the transition and peripheral zones: Preliminary findings from a multi-institutional study.

PURPOSE: To evaluate in a multi-institutional study whether radiomic features useful for prostate cancer (PCa) detection from 3 Tesla (T) multi-parametric MRI (mpMRI) in the transition zone (TZ) differ from those in the peripheral zone (PZ). MATERIALS AND METHODS: 3T mpMRI, including T2-weighted (T2w), apparent diffusion coefficient (ADC) maps, and dynamic contrast-enhanced MRI (DCE-MRI), were retrospectively obtained from 80 patients at three institutions. This study was approved by the institutional review board of each participating institution. First-order statistical, co-occurrence, and wavelet features were extracted from T2w MRI and ADC maps, and contrast kinetic features were extracted from DCE-MRI. Feature selection was performed to identify 10 features for PCa detection in the TZ and PZ, respectively. Two logistic regression classifiers used these features to detect PCa and were evaluated by area under the receiver-operating characteristic curve (AUC). Classifier performance was compared with a zone-ignorant classifier. RESULTS: Radiomic features that were identified as useful for PCa detection differed between TZ and PZ. When classification was performed on a per-voxel basis, a PZ-specific classifier detected PZ tumors on an independent test set with significantly higher accuracy (AUC = 0.61-0.71) than a zone-ignorant classifier trained to detect cancer throughout the entire prostate (P < 0.05). When classifiers were evaluated on MRI data from multiple institutions, statistically similar AUC values (P > 0.14) were obtained for all institutions. CONCLUSION: A zone-aware classifier significantly improves the accuracy of cancer detection in the PZ. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:184-193.