Indication for Active Surveillance in the Era of MRI-Targeted Prostate Biopsies.

INTRODUCTION: Active surveillance (AS) strategies were established to avoid overtreatment of low-risk prostate cancer (PCa) patients. Low tumor volume represents one indication criteria; however, applying this criterion after MRI-targeted prostate biopsies may lead to overestimation of tumor volume; wherefore, patients suitable for AS would be exposed to the risk of overtreatment. METHODS: This retrospective analysis included 318 patients in which PCa was detected by MRI-TRUS fusion prostate biopsy. Classic and extended indication for AS included Gleason 6 and Gleason 3 + 4 cancer, respectively. We assessed the effect of targeted biopsies and temporary rating strategies on eligibility for AS and developed new "composite" algorithms to more accurately assess eligibility for AS. RESULTS: Forty-four (13.8%) and 60 (18.9%) of the 318 patients qualified for AS according to "classic" and "extended" criteria, respectively. Application of the "composite 1" definition led to AS eligibility of 52 of 248 patients (20.97%) in the classic and of 77 of 248 patients (31.05%) in the "extended" group. CONCLUSIONS: We could demonstrate that classic algorithms led to ineligibility of patients for AS. We propose a new rating algorithm to improve tumor assessment for a more accurate indication for AS.

Patterns of stemness-associated markers in the development of castration-resistant prostate cancer.

BACKGROUND: Putative castration-resistant (CR) stem-like cells (CRSC) have been identified based on their ability to initiate and drive prostate cancer (PCa) recurrence following castration in vivo. Yet the relevance of these CRSC in the course of the human disease and particularly for the transition from hormone-naive (HN) to castration-resistance is unclear. In this study, we aimed at deciphering the significance of CRSC markers in PCa progression. METHODS: We constructed a tissue microarray comprising 112 matched HN and CR tissue specimens derived from 55 PCa patients. Expression of eight stemness-associated markers (ALDH1A1, ALDH1A3, ALDH3A1, BMI1, NANOG, NKX3.1, OCT4, SOX2) was assessed by immunohistochemistry and scored as a percentage of positive tumor cells. For each marker, the resulting scores were statistically analyzed and compared to pathological and clinical data associated with the samples. Unsupervised clustering analysis was performed to stratify patients according to the expression of the eight CRSC markers. Publicly-available transcriptional datasets comprising HN and CR PCa samples were interrogated to assess the expression of the factors in silico. RESULTS: Immunohistochemical assessment of paired samples revealed atypical patterns of expression and intra- and intertumor heterogeneity for a subset of CRSC markers. While the expression of particular CRSC markers was dynamic over time in some patients, none of the markers showed significant changes in expression upon the development of castration resistance (CR vs HN). Using unsupervised clustering approaches, we identified phenotypic subtypes based on the expression of specific stem-associated markers. In particular, we found (a) patterns of mutual exclusivity for ALDH1A1 and ALDH1A3 expression, which was also observed at the transcriptomic level in publicly-available PCa datasets, and (b) a phenotypic cluster associated with more aggressive features. Finally, by comparing HN and CR matched samples, we identified phenotypic cluster switches (ie, change of phenotypic cluster between the HN and CR state), that may be associated with clinical and predictive relevance. CONCLUSIONS: Our findings indicate stemness-associated patterns that are associated with the development of castration-resistance. These results pave the way toward a deeper understanding of the relevance of CRSC markers in PCa progression and resistance to androgen-deprivation therapy.

Novices in MRI-targeted prostate biopsy benefit from structured reporting of MRI findings.

PURPOSE: The aim of this study was to investigate whether structured reports (SRs) of prostate MRI results are more suitable than non-structured reports (NSRs) for promoting the more accurate assessment of the location of a single prostate cancer lesion by novices in MRI-targeted biopsy. METHODS: 50 NSRs and 50 SRs describing a single prostatic lesion were presented to 5 novices in MRI-targeted biopsy. The participants were asked to plot the tumor location in a two-dimensional prostate diagram and to answer a questionnaire on the quality of the reports. The accuracy of the plotted tumor position was evaluated with a validated 30-point scoring system that distinguished between "major" and "minor" mistakes. RESULTS: The overall mean score for the accuracy of the tumor plotting was significantly higher for SRs than for NSRs (26.4 vs. 20.7, p < 0.01). The mean numbers of major (1.4 vs. 0.48, p < 0.01) and minor (3.05 vs. 1.15, p < 0.01) mistakes were significantly higher for NSRs than for SRs. Compared with NSRs, SRs received significantly higher ratings for the perceived quality of the summary (4.0 vs. 2.4, p < 0.01) as well as for the overall satisfaction with the report (4.1 vs. 2.1, p < 0.01). CONCLUSION: Novices in MRI-targeted biopsy prefer structured reporting of prostate MRI as an information tool. SRs allow for a more accurate assessment of the location of single prostate cancer lesions. Therefore, structured reporting of prostate MRI may help to foster the learning process of novices in MRI-targeted biopsy.

Delineation of human prostate cancer evolution identifies chromothripsis as a polyclonal event and FKBP4 as a potential driver of castration resistance.

Understanding the evolutionary mechanisms and genomic events leading to castration-resistant (CR) prostate cancer (PC) is key to improve the outcome of this otherwise deadly disease. Here, we delineated the tumour history of seven patients progressing to castration resistance by analysing matched prostate cancer tissues before and after castration. We performed genomic profiling of DNA content-based flow-sorted populations in order to define the different evolutionary patterns. In one patient, we discovered that a catastrophic genomic event, known as chromothripsis, resulted in multiple CRPC tumour populations with distinct, potentially advantageous copy number aberrations, including an amplification of FK506 binding protein 4 (FKBP4, also known as FKBP52), a protein enhancing the transcriptional activity of androgen receptor signalling. Analysis of FKBP4 protein expression in more than 500 prostate cancer samples revealed increased expression in CRPC in comparison to hormone-naïve (HN) PC. Moreover, elevated FKBP4 expression was associated with poor survival of patients with HNPC. We propose FKBP4 amplification and overexpression as a selective advantage in the process of tumour evolution and as a potential mechanism associated with the development of CRPC. Furthermore, FKBP4 interaction with androgen receptor may provide a potential therapeutic target in PC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Feasibility of freehand MRI/US cognitive fusion transperineal biopsy of the prostate in local anaesthesia as in-office procedure-experience with 400 patients.

BACKGROUND: Transrectal (TR) ultrasound-guided prostate biopsy is one of the most commonly performed urologic procedures worldwide. The major drawback of this approach is the associated risk for infectious complications. Sepsis rates are increasing due to rising antibiotic resistance, representing a global issue. The transperineal (TP) approach for prostate biopsy has recently been adopted at many centres as an alternative to the TR biopsy, and it was shown to be associated with a lower risk for sepsis. The aim of this study was to assess safety and tolerability of TP prostate biopsy performed in local anaesthesia. METHODS: We retrospectively analysed data of patients who had undergone office-based TP prostate biopsy in local anaesthesia, performed by a single surgeon between January 2015 and May 2019. We evaluated the patients' acceptance of the procedure by a pain score, as well as its safety and diagnostic performance. RESULTS: Four hundred patients were included. Median age was 66 years [range, 49-86]. Median prostate-specific antigen (PSA) concentration was 6.4 ng/ml [range, 0.3-1400], median PSA density was 0.15 ng/ml2 [range, 0-31.1] and median prostate volume was 40 ml [range, 6-150]. A total of 118 (29.5%) and 105 (26.2%) patients had orally received two and one doses of 500 mg fluoroquinolone, respectively, and 177 (44.3%) patients did not receive any antibiotic prophylaxis. No infectious complications occurred. Median pain score was 2.0 (range, 0-8). Overall cancer detection rate was 64.5% (258/400). CONCLUSIONS: Freehand TP prostate biopsy in local anaesthesia is a safe, effective and well-tolerated outpatient procedure with a high cancer detection rate. The elimination of infectious complications and its high accuracy make this technique a feasible alternative to the TR approach for the urological office. We assume that the single puncture and our trocar-like access sheath introduction technique diminish tissue trauma and bacterial exposition, and thus contribute to these promising results.

Building on a Solid Foundation: Enhancing Bacillus Calmette-Guérin Therapy.

CONTEXT: More than 40 yr ago, bacillus Calmette-Guérin (BCG) was introduced as an adjuvant therapy following transurethral resection of papillary tumours and as a treatment for carcinoma in situ of the bladder. Some 30 yr after its introduction, BCG maintenance therapy was found to be superior to induction therapy alone, representing the most relevant clinical improvement to BCG therapy since its inception. OBJECTIVE: To review current efforts and future opportunities to improve BCG immunotherapy. EVIDENCE ACQUISITION: English online databases (eg, PubMed and clinicaltrials.gov) were searched for clinical trials and meta-analyses of BCG therapy for bladder cancer. The information retrieved was reviewed and sel ected by all the authors and, while representative of the field, is not necessarily exhaustive. EVIDENCE SYNTHESIS: Current knowledge supports the notion that careful patient management from diagnosis to therapy may contribute positively to outcome following BCG immunotherapy. In the future, patient evaluation using predictive immunological or molecular biomarkers will help in identifying those most likely to benefit from BCG therapy. Trials assessing immune modulators in combination with BCG or the use of recombinant BCG are ongoing and results will be forthcoming in the near future. CONCLUSIONS: Enhancing BCG to improve patient outcomes is the responsibility of treating physicians and researchers. Future efforts will continue to improve how non-muscle-invasive urothelial carcinoma is evaluated, treated, and ultimately cured. PATIENT SUMMARY: Bacillus Calmette-Guérin (BCG) immunotherapy to prevent the recurrence and progression of urothelial carcinoma is invasive and demanding for patients. Meticulous diagnostics, correct application of BCG, and selection of patients likely to respond to therapy will ensure that the highest benefit can be attained from this therapy. Current research is focused on discovering biomarkers to identify patients most likely to benefit from BCG immunotherapy. Biomarker identification, new immune modulators, and genetically modified BCG strains are undergoing clinical trial testing to improve outcomes for bladder cancer patients.