Benedikt Kranzbühler

Prospective evaluation of irrigation fluid absorption during pure transurethral bipolar plasma vaporisation of the prostate using expired‐breath ethanol measurements

To investigate if absorption of irrigation fluid occurs during bipolar plasma vaporisation (BPV) of the prostate. To examine the clinical predictors of increased risk of fluid absorption and to assess if changes in serum electrolytes, venous pH, haemoglobin or haematocrit are able to detect intra‐operative fluid absorption.

Long-term Adverse Effects of Extracorporeal Shock-wave Lithotripsy for Nephrolithiasis and Ureterolithiasis: A Systematic Review

This study presents a systematic review of the published literature on possible long-term adverse effects after extracorporeal shock wave lithotripsy (ESWL). Although published disagreement exists, this review finds that previous evidence supporting an association between ESWL and long-term adverse effects is weak and that the majority of studies show no evidence for any increase in post-ESWL incidence of arterial hypertension (24 of 30 studies), diabetes mellitus (4 of 6 studies), kidney dysfunction (14 of 14 studies), or infertility (2 of 2 studies). Currently, no strong evidence exists to support the hypothesis that ESWL causes long-term adverse effects.

Pure bipolar plasma vaporization of the prostate: the Zürich experience.

INTRODUCTION AND OBJECTIVES Bipolar plasma vaporization (BPV) has been introduced as an alternative to transurethral resection of the prostate (TURP). Promising short-term results, but inferior mid-term results compared to TURP have been reported following first-generation bipolar electrovaporization. Outcome data following second-generation BPV are still scarce. The aim of this investigation was to evaluate the intra- and postoperative outcomes of contemporary BPV in a center with long-standing expertise on laser vaporization of the prostate. METHODS A consecutive series of 83 patients undergoing BPV in a tertiary referral center was prospectively evaluated. The investigated outcome parameters included the maximum flow rate (Qmax), postvoid residual volume, International Prostate Symptom Score (IPSS)/quality of life (Qol), and prostate-specific antigen (PSA) tests. Follow-up investigations took place after 6 weeks, 6 months, and 12 months. The Wilcoxon signed-rank test was used to compare pre- and post-treatment parameters. RESULTS The median (range) preoperative prostate volume was 41 mL (17-111 mL). The preoperative IPSS, Qol, Qmax, and residual volume were 16 (2-35), 4 (0-6), 10.1 mL/s (3-29.3 mL/s), and 87 mL (0-1000 mL), respectively. One third of the patients were undergoing platelet aggregation inhibition (PAI). No intraoperative complications occurred. Postoperatively, 13 patients (15.7%) had to be recatheterized. Three patients (3.6%) had clot retention and 28 patients (34%) reported any grade of dysuria. After 6 weeks, all outcome parameters improved significantly and remained improved over the 12-month observation period [IPSS: 3 (0-2); Qol: 1 (0-4); Qmax: 17.2 mL/s (3.2-56 mL/s); residual volume 11 mL (0-190 mL)]. The PSA reduction was 60% at study conclusion. Three patients (3.6%) developed a urethral stricture and four patients (4.8%) bladder neck sclerosis. Re-resections were not necessary. CONCLUSIONS Contemporary BPV is a safe and efficacious treatment option even for patients undergoing PAI. Early urinary retention and temporary dysuria seem to be specific side effects of the treatment. Bleeding complications are rare. Long-term follow-up is needed to confirm these promising short-term results.

Pharmacological upregulation of prostate-specific membrane antigen (PSMA) expression in prostate cancer cells

Prostate‐specific membrane antigen (PSMA)‐based imaging and therapy are increasingly used for prostate cancer management. However, limitations are a low PSMA expression in certain patients. Androgen receptor axis inhibition can induce PSMA expression in vitro. We hypothesized that different approved compounds upregulate PSMA expression and tested their effect in vitro.

The central zone has increased 68Ga-PSMA-11 uptake: “Mickey Mouse ears” can be hot on 68Ga-PSMA-11 PET

PurposeGiven the good correlation between PSMA expression and intraglandular tumour aggressiveness based on immunohistochemistry, there is increasing interest in 68Ga-PSMA-11 PET/MRI for staging prostate cancer (PCA). Therefore, accurate knowledge of prostate anatomy as well as normal distribution of PSMA within the prostate gland is becoming essential. The aim of this study was to investigate the physiological intraprostatic distribution of 68Ga-PSMA-11.MethodsWe retrospectively analysed all patients who underwent a staging 68Ga-PSMA-11 PET/MRI scan between June 2016 and January 2018 for high-risk PCA, underwent radical prostatectomy in our institution, and gave written consent for further data analysis. In each patient, standardized volumes of interest (VOIs) were placed bilaterally in the central, transition and peripheral zones within the zonal anatomy according to T2 weighted sequences in the axial and coronal planes. VOIs were only placed if they were safely within healthy tissue without spillover from the PCA. SUVmax and SUVmean were determined and their differences among the regions were assessed using the Wilcoxon signed-ranks test.ResultsOf 283 consecutive patients scanned with 68Ga-PSMA-11 PET/MR, 31 were analysed. A total of 133 VOIs were placed, 46 in the central zone, 41 in the transition zone and 46 in the peripheral zone. Differences in SUVmax between the central zone (mean 3.9 ± 0.58) and transition zone (mean 3.2 ± 0.59) and between the central zone and peripheral zone (mean 2.7 ± 0.54) were statistically significant (both p < 0.001).ConclusionOur results suggest that higher 68Ga-PSMA-11 accumulation in the central zone than in the transition and peripheral zones is normal, and leads to a pattern resembling “Mickey Mouse ears” on 68Ga-PSMA-11 PET. This pattern could be helpful in avoiding false-positive interpretations of PET scans.

Current and potential future role of PSMA-PET in patients with castration-resistant prostate cancer

PurposeTo review the current literature and discuss potential future roles of the novel positron emission tomography (PET) tracers targeting the prostate-specific membrane antigen (PSMA) in patients with castration-resistant prostate cancer (CRPC).MethodsA literature search on February 19th 2018 was conducted using the Medline database and www.clinicaltrials.gov. Additionally, illustrative cases of CRPC patients from our own institution who were restaged and treated based on PSMA-PET scan results are provided.Results11 Studies met the inclusion criteria. PSMA-PET detected more metastatic lesions compared to conventional bone scan. Several patients were up-staged from non-metastatic CRPC (nmCRPC) to metastatic CRPC (mCRPC). Currently, no clear consensus exists regarding treatment response assessment in PSMA-PET scans for mCRPC patients undergoing treatment. Also, the role of PSMA-PET as a gatekeeper for systemic therapy or radioligands is currently undefined. PSMA-guided metastasis-directed radiotherapy may not only alleviate local symptoms but has the potential to defer systemic treatment in patients with oligoprogressive CRPC.ConclusionCompared to bone scan, PSMA-PET is more sensitive and specific to detect metastases but the therapeutic consequences of PSMA-PET results in the setting of CRPC remain unclear. Until future studies define the role of PSMA-PET in patients with CRPC, the current standard for imaging remains bone scan and computerized tomography.

Inhibition of autophagy significantly increases the antitumor effect of Abiraterone in prostate cancer

PurposeAbiraterone acetate (AA) plus prednisone is an approved treatment of advanced prostate cancer (PCa). Autophagy is linked to drug resistance in numerous types of cancers. We hypothesized, that upregulation of autophagy is one of the mechanisms by which PCa cells survive AA anti-tumor treatment and therefore evaluated the potential effect of a combination with autophagy inhibition.MethodsHuman PCa LNCaP cell lines were cultured in steroid-free medium and treated with AA. Autophagy was inhibited by 3-methyladenine, chloroquine and ATG5 siRNA knock-down. Cell viability and apoptosis was assessed by flow cytometry and fluorescence microscopy, and autophagy was monitored by immunohistochemistry, AUTOdot and Western blotting.ResultsWestern blot revealed upregulation of ATG5 and LC3 II with a reduction of p62 protein expression in AA-treated cells, indicating upregulation of autophagy. These data were supported by results obtained with immunocytochemistry and AUTOdot assays. Using flow cytometry, we showed that combining AA with autophagy inhibition significantly impaired cell viability (1.3–1.6-fold, p < 0.001) and increased apoptosis (1.4–1.5-fold, p < 0.001) compared to AA treatment alone.ConclusionsAA activates autophagy as a cytoprotective mechanism in LNCaP prostate cancer cells and targeting of autophagy enhances the antitumor effect of the compound.

Combined N-terminal androgen receptor and autophagy inhibition increases the antitumor effect in enzalutamide sensitive and enzalutamide resistant prostate cancer cells

Multiple androgen receptor (AR)‐dependent and ‐independent resistance mechanisms limit the efficacy of current castration‐resistant prostate cancer (CRPC) treatment. Novel N‐terminal domain (NTD) binding AR‐targeting compounds, including EPI‐001 (EPI), have the promising ability to block constitutively active splice variants, which represent a major resistance mechanism in CRPC. Autophagy is a conserved lysosomal degradation pathway that acts as survival mechanism in cells exposed to anticancer treatments. We hypothesized, that promising NTD‐AR treatment may upregulate autophagy and that a combination of NTD‐AR and autophagy inhibition might therefore increase antitumor effects.

MP02-02 PURE BIPOLAR PLASMA VAPORIZATION OF THE PROSTATE: 5-YEAR FOLLOW-UP FROM A PROSPECTIVE 3D ULTRASOUND VOLUMETRY STUDY

INTRODUCTION AND OBJECTIVES: Pure bipolar plasma vaporization (BPV) has been established as low-morbidity alternative to conventional transurethral resection of the prostate (TURP). Low intraand postoperative morbidity as well as excellent functional short-term results have been reported. However, long-term outcome is still lacking. The extent of prostate tissue removal, which impacts the durability of postoperative functional improvements, is also unknown after BPV. The aim of the present study was to investigate the long-term functional outcome and associated prostate volume changes following pure BPV of the prostate. METHODS: A consecutive series of 75 patients treated by pure BPV in a tertiary care academic center was prospectively investigated. Prostate volume was assessed using planimetric volumetry following transrectal 3D-ultrasound of the prostate. Prostate volume and clinical parameters were recorded preoperatively and regularly after BPV (after catheter removal, 6W, 6M, 1, 3 and 5Y). RESULTS: Median (interquartile range; IQR) preoperative prostate volume was 41 ml (26.8ml), IPSS 16 (10), QoL 4 (2), Qmax 10.1ml/s (8ml/s), PVR 91ml (140ml) and PSA 2.57ng/ml (3.5ng/ml). A significant relative prostate volume reduction (RVR) of 33.3% (IQR: 22.3%; p<0.001) was already detectable at the time of catheter removal. Relative volume reduction increased significantly up to 12M (6W: 45.9% (17.4%; p<0.001), 6M: 50.5% (16.1%; p<0.001) and 12M 52.2% (17.4%; p1⁄40.014). After 12M the RVR remained stable with 50.6% (14.3%; p1⁄40.58) after 3Y and 52.6% (14.1%; p1⁄40.59) after 5Y. Postoperatively, all investigated clinical parameters improved significantly and remained stable during the 5Y follow-up [5Y results (IQR): IPSS: 3 (8), QoL: 1 (1), Qmax: 16.3ml/s (13.7ml/s), PVR 20ml (46.5ml)]. Median PSA reduction after 5Y was 55% (36.2%). During the observation period 9 urethral strictures (12%) were detected of which 7 were de novo strictures. Bladder neck incisions for postoperative bladder neck stenosis were performed in 6 patients (8%). Median prostate volume in these patients was 30.6ml (18.2ml). Re-resections for regrown adenoma were not necessary. CONCLUSIONS: Low intraand postoperative morbidity in combination with excellent functional outcome and durable prostate volume reduction confirm the role of contemporary BPV as a minimally invasive alternative to conventional TURP. However, postoperative bladder neck stenoses appeared rather frequent after BPV and might be a procedure-specific drawback.

MP83-07 N-TERMINAL TARGETING OF ANDROGEN RECEPTOR BY EPI-001 IN COMBINATION WITH AUTOPHAGY INHIBITORS ENHANCES THE ANTI-TUMOR EFFECT IN LNCAP PROSTATE CANCER CELLS

INTRODUCTION AND OBJECTIVES: Following the results of the TOPARP-A Phase II trial, Olaparib, an oral PARP inhibitor was recently recognized as a FDA breakthrough therapy for metastatic castration recurrent prostate cancer (mCRPC) patients who have germline mutations in DNA repair genes. Although these results are noteworthy, the problem remains of how to treat the remaining mCRPC patients who do not have detectable germline mutations of DNA repair genes. Androgen receptor (AR) signaling regulates DNA repair in prostate cancer and AR modulating drugs induce DNA damage. Thus a combination approach using AR modulating drugs with a PARP inhibitor could be a promising option for the treatment of mCRPC. All currently approved AR modulating drugs, such as enzalutamide and abiraterone, either directly or indirectly target the AR C-terminus ligand-binding domain (LBD). Such drugs are often unsuccessful due to the emergence of AR splice variants (ARV-7, ARv567es) that are constitutively active and lack a LBD. EPI-002 is a first-in-class AR antagonist that targets both full-length AR and AR splice variants. Here we present data to support that a combination of Olaparib, a PARP inhibitor, and EPI002 have beneficial effects in vitro. METHODS: Combination therapy using EPI-002 and Olaparib were evaluated in vitro using human prostate cancer cells, LNCaP (androgen sensitive and expresses full-length AR) and LNCaP95, an androgen-independent cell line that expresses full-length AR and ARV7 and is resistant to enzalutamide. The effects of monotherapy and combination therapy on cell cycle and DNA damage were analysed using FACS and Western blot. RESULTS: Unexpectedly, EPI-002 caused an enormous decrease of Checkpoint kinase 1 (Chk1) protein levels in LNCaP and LNCaP95 cells. Chk1 is one of the important mediators in cell cycle checkpoint during the DNA damage response. Whereas, enzalutamide also decreased the expression of Chk1 in LNCaP, it had no effect on Chk1 levels in LNCaP95 cells. Consistent with these data, AR knockdown in LNCaP cells also decreased Chk1 levels. The PARP inhibitor, Olaparib, induced phosphorylation of Chk1. EPI-002 induced G1 cell cycle arrest whereas Olaparib induced G2/M cell cycle arrest. FACS analysis of gH2AX showed increased DNA damage with combination therapy compared to monotherapies. CONCLUSIONS: EPI-002 decreased the expression of Chk1 in prostate cancer cells that expressed both full-length AR and AR-V7. Combination therapy of EPI-002 plus Olaparib may provide a therapeutic approach for prostate cancer that expresses AR-V7.