Viktor Berge

Focal Therapy: Patients, Interventions, and Outcomes—A Report from a Consensus Meeting

Background Focal therapy as a treatment option for localized prostate cancer (PCa) is an increasingly popular and rapidly evolving field. Objective To gather expert opinion on patient selection, interventions, and meaningful outcome measures for focal therapy in clinical practice and trial design. Design, setting, and participants Fifteen experts in focal therapy followed a modified two-stage RAND/University of California, Los Angeles (UCLA) Appropriateness Methodology process. All participants independently scored 246 statements prior to rescoring at a face-to-face meeting. The meeting occurred in June 2013 at the Royal Society of Medicine, London, supported by the Wellcome Trust and the UK Department of Health. Outcome measurements and statistical analysis Agreement, disagreement, or uncertainty were calculated as the median panel score. Consensus was derived from the interpercentile range adjusted for symmetry level. Results and limitations Of 246 statements, 154 (63%) reached consensus. Items of agreement included the following: patients with intermediate risk and patients with unifocal and multifocal PCa are eligible for focal treatment; magnetic resonance imaging–targeted or template-mapping biopsy should be used to plan treatment; planned treatment margins should be 5 mm from the known tumor; prostate volume or age should not be a primary determinant of eligibility; foci of indolent cancer can be left untreated when treating the dominant index lesion; histologic outcomes should be defined by targeted biopsy at 1 yr; residual disease in the treated area of ≤3 mm of Gleason 3 + 3 did not need further treatment; and focal retreatment rates of ≤20% should be considered clinically acceptable but subsequent whole-gland therapy deemed a failure of focal therapy. All statements are expert opinion and therefore constitute level 5 evidence and may not reflect wider clinical consensus. Conclusions The landscape of PCa treatment is rapidly evolving with new treatment technologies. This consensus meeting provides guidance to clinicians on current expert thinking in the field of focal therapy. Patient summary In this report we present expert opinion on patient selection, interventions, and meaningful outcomes for clinicians working in focal therapy for prostate cancer.

O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells.

Metabolic disruptions that occur widely in cancers offer an attractive focus for generalized treatment strategies. The hexosamine biosynthetic pathway (HBP) senses metabolic status and produces an essential substrate for O-linked β-N-acetylglucosamine transferase (OGT), which glycosylates and thereby modulates the function of its target proteins. Here, we report that the HBP is activated in prostate cancer cells and that OGT is a central regulator of c-Myc stability in this setting. HBP genes were overexpressed in human prostate cancers and androgen regulated in cultured human cancer cell lines. Immunohistochemical analysis of human specimens (n = 1987) established that OGT is upregulated at the protein level and that its expression correlates with high Gleason score, pT and pN stages, and biochemical recurrence. RNA interference-mediated siliencing or pharmacologic inhibition of OGT was sufficient to decrease prostate cancer cell growth. Microarray profiling showed that the principal effects of OGT inhibition in prostate cancer cells were related to cell-cycle progression and DNA replication. In particular, c-MYC was identified as a candidate upstream regulator of OGT target genes and OGT inhibition elicited a dose-dependent decrease in the levels of c-MYC protein but not c-MYC mRNA in cell lines. Supporting this relationship, expression of c-MYC and OGT was tightly correlated in human prostate cancer samples (n = 1306). Our findings identify HBP as a modulator of prostate cancer growth and c-MYC as a key target of OGT function in prostate cancer cells.

Detection of the index tumour and tumour volume in prostate cancer using T2-weighted and diffusion-weighted magnetic resonance imaging (MRI) alone

To examine the performance of T2‐weighted (T2W) and diffusion‐weighted (DW) magnetic resonance imaging (MRI) for detecting the index tumour in patients with prostate cancer and to examine the agreement between MRI and histology when assessing tumour volume (TV) and overall tumour burden.

Identification of prostate cancer biomarkers in urinary exosomes

Exosomes have recently appeared as a novel source of non-invasive cancer biomarkers since tumour-specific molecules can be found in exosomes isolated from biological fluids. We have here investigated the proteome of urinary exosomes by using mass spectrometry to identify proteins differentially expressed in prostate cancer patients compared to healthy male controls. In total, 15 control and 16 prostate cancer samples of urinary exosomes were analyzed. Importantly, 246 proteins were differentially expressed in the two groups. The majority of these proteins (221) were up-regulated in exosomes from prostate cancer patients. These proteins were analyzed according to specific criteria to create a focus list that contained 37 proteins. At 100% specificity, 17 of these proteins displayed individual sensitivities above 60%. Even though several of these proteins showed high sensitivity and specificity for prostate cancer as individual biomarkers, combining them in a multi-panel test has the potential for full differentiation of prostate cancer from non-disease controls. The highest sensitivity, 94%, was observed for transmembrane protein 256 (TM256; chromosome 17 open reading frame 61). LAMTOR proteins were also distinctly enriched with very high specificity for patient samples. TM256 and LAMTOR1 could be used to augment the sensitivity to 100%. Other prominent proteins were V-type proton ATPase 16 kDa proteolipid subunit (VATL), adipogenesis regulatory factor (ADIRF), and several Rab-class members and proteasomal proteins. In conclusion, this study clearly shows the potential of using urinary exosomes in the diagnosis and clinical management of prostate cancer.

Can we deliver randomized trials of focal therapy in prostate cancer

Tissue-preserving focal therapies, such as brachytherapy, cryotherapy, high-intensity focused ultrasound and photodynamic therapy, aim to target individual cancer lesions rather than the whole prostate. These treatments have emerged as potential interventions for localized prostate cancer to reduce treatment-related adverse-effects associated with whole-gland treatments, such as radical prostatectomy and radiotherapy. In this article, the Prostate Cancer RCT Consensus Group propose that a novel cohort-embedded randomized controlled trial (RCT) would provide a means to study men with clinically significant localized disease, which we defined on the basis of PSA level (≤15 ng/ml or ≤20 ng/ml), Gleason grade (Gleason pattern ≤4 + 4 or ≤4 + 3) and stage (≤cT2cN0M0). This RCT should recruit men who stand to benefit from treatment, with the control arm being whole-gland surgery or radiotherapy. Composite outcomes measuring rates of local and systemic salvage therapies at 3–5 years might best constitute the basis of the primary outcome on which to change practice.

A prospective study of salvage high-intensity focused ultrasound for locally radiorecurrent prostate cancer: Early results

Abstract Objective. After radical external beam radiation therapy (EBRT), local recurrence may benefit from definitive local therapy. The objective of this study was to evaluate the safety and short-term biochemical results and morbidity after salvage high-intensity focused ultrasound (HIFU) treatment in patients with biopsy-proven local prostate cancer recurrence after EBRT. Material and methods. From October 2006 46 patients were treated with HIFU. Bone scan and abdominal CT/MRI scan were negative. Median follow-up was 9 months (range 3–24 months). Results. The median prostate-specific antigen (PSA) nadir was 0.3 ng/ml (range 0–24 ng/ml). Eighteen patients (39.1%) were classified as failures. In addition, there were four patients (8.7%) with post-HIFU PSA nadir > 0.5 ng/ml. No patients died during follow-up. One patient developed urethrorectal fistulae and was successfully treated conservatively. Two patients developed urethrocutaneous fistulae. Seven patients (15.2%) and one patient (2.1%) developed grade 2 and grade 3 incontinence, respectively. Seven men (15.2%) had erectile function sufficient for intercourse pre-HIFU and only two men (4.3%) post-HIFU. Conclusions. Early results of salvage HIFU in patients with local recurrence of prostate cancer after radical EBRT indicate the procedure to be a reasonable treatment option, but better patient selection criteria are needed. The side-effects are not negligible.

Hemi salvage high-intensity focused ultrasound (HIFU) in unilateral radiorecurrent prostate cancer: a prospective two-centre study

To report the oncological and functional outcomes of hemi salvage high‐intensity focused ultrasound (HSH) in patients with unilateral radiorecurrent prostate cancer.

Regulation of PBX3 expression by androgen and Let-7d in prostate cancer.

BackgroundThe pre-leukemia transcription factor 3 (PBX) is part of the PBX family of transcription factors, which is known to regulate genes involved in differentiation of urogenital organs and steroidogenesis. This is of interest with regard to prostate cancer progression as regulation of steroidogenesis is one of the mechanisms involved in the development of castration-resistant prostate cancer. In light of this we wanted to investigate the possible involvement of androgen regulation of PBX3 expression in prostate cancer.ResultsIn this study, we show that PBX3 is post-transcriptionally regulated by androgen in prostate cancer cells and that the effect might be independent of the androgen receptor. Furthermore, PBX3 was identified as a target of Let-7d, an androgen regulated microRNA. Let-7d was down-regulated in malignant compared to benign prostate tissue, whereas up-regulation of PBX3 expression was observed.ConclusionsWe demonstrate that PBX3 is up-regulated in prostate cancer and post- transcriptionally regulated by androgen through Let-7d.

A prospective study of transition from laparoscopic to robot-assisted radical prostatectomy: Quality of life outcomes after 36-month follow-up

OBJECTIVE To compare quality of life (QOL) outcomes after conversion from laparoscopic radical prostatectomy (LRP) to robot-assisted radical prostatectomy (RALP) as the routine procedure for surgical treatment of localized cancer of the prostate (CaP). METHODS In November 2007, we changed the routine operative technique for localized CaP from LRP to RALP. The last 210 consecutive patients operated with LRP were compared with the first 210 consecutive patients operated with RALP. The patients were mailed University of California Los Angeles-Prostate Cancer Index (UCLA-PCI) and Short Form Health Survey (SF)-12 questionnaires at baseline and at 3, 12, and 36-month follow-up. RESULTS In the LRP group, 89.0%, 93.8%, 93.8%, and 88.1% of patients answered questionnaires at baseline and at 3, 12, and 36-month follow-up. The corresponding numbers in the RALP group were 92.4%, 94.3%, 85.7%, and 76.4%. At 36-month follow-up, 87.9% and 82.6% of LRP and RALP patients, respectively, had regained baseline urinary function score (ns). At 36-month follow-up, 57.3% and 61.3% of LRP and RALP patients, respectively, had regained baseline sexual function score (ns). Nerve-sparing surgical procedures mitigated the adverse effects on sexual function in both groups. Surgical method was not associated with urinary function and sexual function at 36 months. Better urinary function was associated with better general mental health. CONCLUSION Introduction of RALP did not result in improvement of functional outcome. There was no difference regarding urologic function/bother score or sexual function/bother score at 36-month follow-up in patients treated with LRP or RALP.

Complications after prostate biopsies in men on active surveillance and its effects on receiving further biopsies in the Prostate cancer Research International: Active Surveillance (PRIAS) study

To study the risk of serial prostate biopsies on complications in men on active surveillance (AS) and determine the effect of complications on receiving further biopsies.